Diagnosis and Therapy

THE MERCK MANUAL OF DIAGNOSIS AND THERAPY - 19th Ed.
(2011)
Front Matter
Title Page
The Merck Manual Of Diagnosis and Therapy, Nineteenth Edition
Robert S. Porter MD, Editor-in-Chief
Justin L. Kaplan MD, Senior Assistant Editor
Editorial Board
Richard K. Albert MD
Marjorie A. Bowman MD, MPA
Glenn D. Braunstein MD
Sidney Cohen MD
Linda Emanuel PhD
Jan Fawcett MD
Eugene P. Frenkel MD
Susan L. Hendrix DO
Michael Jacewicz MD
Matthew E. Levison MD
James Jeffrey Malatack MD
Brian F. Mandell MD, PhD
Gerald L. Mandell MD
Judith S. Palfrey MD
Albert A. Rundio Jr., PhD
David A. Spain MD
Paul H. Tanser MD
Michael R. Wasserman MD
Merck Sharp & Dohme Corp., A Subsidiary of Merck & Co., Inc.
Whi tehous e Sta ti on, NJ
2011
Copyright Page
Editorial and Production Staff
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ISBN (13 di gi t) 978-0-911910-19-3
ISBN (10 di gi t) 0-911910-19-0
ISSN 0076-6526
Copyri ght 2011 by Merck Sha rp & Dohme Corp., a s ubs i di a ry of Merck & Co, Inc.
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Other Merck Books
The MERCK Ma nua l
1s t Edi ti on - 1899
2nd Edi ti on - 1901
3rd Edi ti on - 1905
4th Edi ti on - 1911
THE MERCK INDEX
First Edition, 1889
THE MERCK VETERINARY MANUAL
First Edition, 1955
THE MERCK MANUAL OF GERIATRICS

First Edition, 1990
THE MERCK MANUAL OF MEDICAL INFORMATIONHOME EDITION
First Edition, 1997
THE MERCK MANUAL OF HEALTH & AGING
First Edition, 2004
THE MERCK/MERIAL MANUAL FOR PET HEALTH
First Edition, 2007
THE MERCK MANUAL OF PATIENT SYMPTOMS
First Edition, 2008
Merck books a re publ i s hed on a nonprofi t ba s i s a s a s ervi ce to the s ci enti fi c communi ty a nd the publ i c.
Preface
At the begi nni ng of the 2nd deca de of the 21s t century, the a mount of i nforma ti on a va i l a bl e to hea l th ca re pra cti ti oners i s i mmens e. Medi ca l
webs i tes a nd journa l s s end da i l y mes s a ges a nnounci ng res ul ts of the l a tes t s tudi es . Wi thi n mi nutes , s ubs peci a l ty da ta heretofore found onl y i n
uni vers i ty l i bra ri es ca n be unea rthed, a l ong wi th a va s t a rra y of i nforma ti on from a ca demi cs , commerci a l orga ni za ti ons , a dvoca cy groups , the
government, a nd s eemi ngl y a nyone wi th a computer a nd a n i nternet connecti on.
Wha t i s the rol e of a genera l reference work s uch a s The Merck Manual when s eemi ngl y the enti re body of medi ca l knowl edge i s a t one's fi ngerti ps
el ectroni ca l l y? Wi th s uch a va s t body of knowl edge a va i l a bl e, fi ndi ng a good s ta rti ng pl a ce ca n be di ffi cul t. The Manual ha s a l wa ys been i ntended
a s the fi rs t s top on the roa d to unders ta ndi ng for rea ders encounteri ng a topi c for the fi rs t ti me or for the fi rs t ti me i n a l ong ti me. After di ges ti ng a
Merck Manual topi c, rea ders wi l l be wel l prepa red to unders ta nd a nd eva l ua te the wea l th of more deta i l ed i nforma ti on a va i l a bl e el s ewhere.
As i t ha s for over 110 yea rs , The Merck Manual focus es on di s cus s i ons of s peci fi c di s orders , orga ni zed by orga n s ys tem or medi ca l s peci a l ty. In i ts
s tructured i ntroducti ons to medi ca l di s orders , The Manual provi des hea l th ca re pra cti ti oners a nd s tudents wi th s tra i ghtforwa rd, pra cti ca l
expl a na ti ons of "wha t to do" to di a gnos e a nd trea t thos e condi ti ons . We di s cus s when to s us pect a di s ea s e, the proper s equence of eva l ua ti on,
a nd the fi rs t-l i ne opti ons for trea tment a l ong wi th s el ected a l terna ti ves . In a ddi ti on, we provi de enough ba ckground i nforma ti on on eti ol ogy a nd
pa thophys i ol ogy to ens ure comprehens i on of the ma na gement recommenda ti ons .
The Manual conti nues to enha nce i ts a cces s i bi l i ty. In a ddi ti on to ha vi ng i ntroductory "nut-s hel l s " a t the begi nni ng of ea ch di s ea s e di s cus s i on, we
ha ve i ncl uded bul l eted l i s ts i n the text whenever pos s i bl e, i ncl udi ng a t the begi nni ng of di a gnos i s a nd trea tment di s cus s i ons .
In the i nteres t of brevi ty, The Merck Manual ha s never ci ted references to the medi ca l l i tera ture. Nonethel es s , rea ders ca n be a s s ured tha t our
hundreds of contri butors a nd dozens of peer revi ewers a re pres enti ng the bes t current recommenda ti ons , s oundl y ba s ed on a va i l a bl e evi dence.
Al though the pri nted Merck Manual ha s l ong s i nce grown too bi g to be ca rri ed i n a l a b coa t, i t ha s returned to the pocket a s content on ma ny
di fferent ha ndhel d el ectroni c devi ces . In a ddi ti on, The Merck Manual conti nues to be a va i l a bl e to a l l rea ders free of cha rge a t
www.merckma nua l s .com. Al though our el ectroni c vers i ons ha ve a currency tha t a pri nted product ca nnot, the book s ti l l provi des a better i n-depth
rea di ng experi ence a l ong wi th a ta cti l e s a ti s fa cti on a nd ea s e of perus a l not pos s es s ed by el ectroni c devi ces . Undoubtedl y thi s wi l l cha nge a s
technol ogy a dva nces , but wha tever the pl a tform, we wi l l conti nue to s tri ve to keep The Merck Manual a s us eful a s ever.
We tha nk the numerous contri butors who ha ve worked di l i gentl y wi th us to cra ft thi s edi ti on, a nd we hope you wi l l fi nd i t worthy of conti nued a nd
frequent us e. As a l wa ys , s ugges ti ons for i mprovements wi l l be wa rml y wel comed a nd ca reful l y cons i dered.
Robert S. Porter, MD
Editor-in-Chief
Committed to Providing Medical Information: Merck and The Merck Manuals
In 1899, the Ameri ca n drug ma nufa cturer Merck & Co. fi rs t publ i s hed a s ma l l book ti tl ed Merck's Manual of the Materia Medica. It wa s mea nt a s a n a i d
to phys i ci a ns a nd pha rma ci s ts , remi ndi ng doctors tha t "Memory i s trea cherous ." Compa ct i n s i ze, ea s y to us e, a nd comprehens i ve, The Merck
Manual (a s i t wa s l a ter known) beca me a fa vori te of thos e i nvol ved i n medi ca l ca re a nd others i n need of a medi ca l reference. Even Al bert
Schwei tzer ca rri ed a copy to Afri ca i n 1913, a nd Admi ra l Byrd ca rri ed a copy to the South Pol e i n 1929.
By the 1980s , the book ha d become the worl d's l a rges t s el l i ng medi ca l text a nd wa s tra ns l a ted i nto more tha n a dozen l a ngua ges . Whi l e the na me
of the pa rent compa ny ha s cha nged s omewha t over the yea rs , the book's na me ha s rema i ned cons ta nt, known offi ci a l l y a s The Merck Manual of
Diagnosis and Therapy but us ua l l y referred to a s The Merck Manual a nd s ometi mes "The Merck."
In 1990, the edi tors of The Merck Manual i ntroduced The Merck Manual of Geriatrics. Thi s new book qui ckl y beca me the bes t-s el l i ng textbook of
geri a tri c medi ci ne, provi di ng s peci fi c a nd comprehens i ve i nforma ti on on the ca re of ol der peopl e. The 3rd edi ti on wa s publ i s hed i n fi ve
l a ngua ges .
In 1997, The Merck Manual of Medical Information-Home Edition wa s publ i s hed. In thi s revol uti ona ry book, the edi tors tra ns l a ted the compl ex medi ca l
i nforma ti on i n The Merck Manual i nto pl a i n l a ngua ge, produci ng a book mea nt for a l l thos e peopl e i nteres ted i n medi ca l ca re who di d not ha ve a
medi ca l degree. The book recei ved cri ti ca l a ccl a i m a nd s ol d over 2 mi l l i on copi es . The Second Home Edition wa s rel ea s ed i n 2003. Merck's
commi tment to provi di ng comprehens i ve, unders ta nda bl e medi ca l i nforma ti on to a l l peopl e conti nued wi th The Merck Manual Home Health
Handbook, publ i s hed i n 2009.
The Merck Manual of Health & Aging, publ i s hed i n 2004, conti nued Merck's commi tment to educa ti on a nd geri a tri c ca re, provi di ng i nforma ti on on
a gi ng a nd the ca re of ol der peopl e i n words unders ta nda bl e by the l a y publ i c.
In 2008, The Merck Manual of Patient Symptoms wa s i ntroduced to compl ement The Merck Manual a nd wa s i ntended to hel p newcomers to cl i ni ca l
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Merck a l s o s upports the communi ty of chemi s ts a nd others wi th the need to know a bout chemi ca l compounds wi th The Merck Index. Fi rs t publ i s hed
i n 1889, thi s publ i ca ti on a ctua l l y preda tes The Merck Manual a nd i s the mos t wi del y us ed text of i ts ki nd. The Merck Veterinary Manual wa s fi rs t
publ i s hed i n 1955. It provi des i nforma ti on on the hea l th ca re of a ni ma l s a nd i s the preemi nent text i n i ts fi el d.
Merck & Co., Inc., i s one of the worl d's l a rges t pha rma ceuti ca l compa ni es . Merck i s commi tted to provi di ng excel l ent medi ca l i nforma ti on a nd, a s
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Contents
Gui de for Rea ders vi i i
Abbrevi a ti ons i x
Edi tors a nd Edi tori a l Boa rdxi
Cons ul ta nts xi i i
Contri butors xv
1 Nutri ti ona l Di s orders 1
2 Ga s troi ntes ti na l Di s orders 67
3 Hepa ti c a nd Bi l i a ry Di s orders 203
4 Mus cul os kel eta l a nd Connecti ve Ti s s ue Di s orders 281
5 Ea r, Nos e, Throa t, a nd Denta l Di s orders 411
6 Eye Di s orders 535
7 Derma tol ogi c Di s orders 629
8 Endocri ne a nd Meta bol i c Di s orders 755
9 Hema tol ogy a nd Oncol ogy 915
10 Immunol ogy; Al l ergi c Di s orders 1077
11 Infecti ous Di s ea s es 1143
12 Ps ychi a tri c Di s orders 1483
13 Neurol ogi c Di s orders 1583
14 Pul mona ry Di s orders 1823
15 Ca rdi ova s cul a r Di s orders 2015
16 Cri ti ca l Ca re Medi ci ne 2243
17 Geni touri na ry Di s orders 2303
18 Gynecol ogy a nd Obs tetri cs 2479
19 Pedi a tri cs 2691
20 Geri a tri cs 3069
21 Cl i ni ca l Pha rma col ogy 3165
22 Injuri es ; Poi s oni ng 3187
23 Speci a l Subjects 3371
Appendi xes 3489
Rea dy Reference Gui des 3489
Norma l La bora tory Va l ues 3491

Tra de Na mes of Some Commonl y Us ed Drugs 3505
Index3521
Guide For Readers
The Contents (p. vi i ) s hows the pa ges on whi ch rea ders ca n fi nd the Edi tors a nd Edi tori a l Boa rd members , cons ul ta nts , a ddi ti ona l revi ewers , a nd
contri butors , a s wel l a s ti tl es of s ecti ons , a ppendi xes , a nd the i ndex. Thumb ta bs wi th a ppropri a te a bbrevi a ti ons a nd s ecti on numbers ma rk ea ch
s ecti on a nd the i ndex.
Ea ch Section begi ns wi th i ts own ta bl e of contents , l i s ti ng cha pters a nd topi cs i n tha t s ecti on. Cha pters a re numbered s eri a l l y from the begi nni ng
to the end of the book.
The Index i s hi ghl y deta i l ed a nd conta i ns ma ny cros s -entri es . In a ddi ti on, rea ders wi l l fi nd ma ny cross-references throughout the text to s peci fi c
pa ges where a ddi ti ona l or rel a ted i nforma ti on ca n be found.
Running heads ca rry the s ecti on number a nd ti tl e on l eft-ha nd pa ges a nd the cha pter number a nd ti tl e on ri ght-ha nd pa ges .
Abbreviations and symbols, us ed throughout the text a s es s enti a l s pa ce s a vers , a re l i s ted on pa ges i x a nd x. Other a bbrevi a ti ons i n the text a re
expa nded a t fi rs t menti on i n the cha pter or topi c.
Tables and figures a re referenced i n the i ndex but a re not l i s ted i n a s epa ra te ta bl e of contents . An i ns ert of col or pl a tes conta i ns photogra phs of
ma ny eye, ea r, endocri ne, s ki n, a nd gynecol ogi c di s orders a s wel l a s i nfecti ous di s ea s es .
Laboratory values i n the book a re gi ven i n conventi ona l uni ts . In mos t ca s es , SI uni ts fol l ow i n pa renthes es . Appendi x II conta i ns s evera l ta bl es
l i s ti ng norma l l a bora tory va l ues for ma ny tes ts conducted on bl ood, pl a s ma , s erum, uri ne, CSF, a nd s tool .
Drugs a re des i gna ted i n the text by generi c (nonpropri eta ry) na mes . In Appendi x III, ma ny of the drugs menti oned i n the book a re l i s ted
a l pha beti ca l l y, wi th ea ch generi c na me fol l owed by one or more tra de na mes .
Secti on 23, Special Subjects, ha s di s cus s i ons on cl i ni ca l deci s i on ma ki ng, ra di ol ogi c i ma gi ng, compl ementa ry a nd a l terna ti ve medi ci ne, di eta ry
s uppl ements , geneti cs , s moki ng ces s a ti on, reha bi l i ta ti on, ca re of the s urgi ca l pa ti ent, fi na nci a l i s s ues i n hea l th ca re, a nd ca re of the dyi ng
pa ti ent, a mong others .
Important: The a uthors , revi ewers , a nd edi tors of thi s book ha ve ma de extens i ve efforts to ens ure tha t trea tments , drugs , a nd dos a ge regi mens a re
a ccura te a nd conform to the s ta nda rds a ccepted a t the ti me of publ i ca ti on. However, cons ta nt cha nges i n i nforma ti on res ul ti ng from conti nui ng
res ea rch a nd cl i ni ca l experi ence, rea s ona bl e di fferences i n opi ni ons a mong a uthori ti es , uni que a s pects of i ndi vi dua l cl i ni ca l s i tua ti ons , a nd the
pos s i bi l i ty of huma n error i n prepa ri ng s uch a n extens i ve text requi re tha t the rea der exerci s e i ndi vi dua l judgment when ma ki ng a cl i ni ca l
deci s i on a nd, i f neces s a ry, cons ul t a nd compa re i nforma ti on from other s ources . In pa rti cul a r, the rea der i s a dvi s ed to check the product
i nforma ti on provi ded by the ma nufa cturer of a drug product before pres cri bi ng or a dmi ni s teri ng i t, es peci a l l y i f the drug i s unfa mi l i a r or i s us ed
i nfrequentl y.
Note: Rea ders ca n fi nd up-to-da te i nforma ti on, a ddi ti ona l ta bl es a nd fi gures , a s wel l a s mul ti medi a enha ncements a t www.merckma nua l s .com.
Vi s i t the web s i te frequentl y for new enha ncements a nd the l a tes t i nforma ti on on cl i ni ca l devel opments .
Abbreviations
The fol l owi ng a bbrevi a ti ons a re us ed throughout the text; other a bbrevi a ti ons a re expa nded a t fi rs t menti on i n the cha pter or s ubcha pter.
ABG
ACE
ACTH
ADH
AIDS
ALT
AST
ATP
BCG
bid
BMR
BP
BSA
BUN
C
Ca
cAMP
a rteri a l bl ood ga s
a ngi otens i n converti ng enzyme
a drenocorti cotropi c hormone
a nti di ureti c hormone
a cqui red i mmunodefi ci ency s yndrome
a l a ni ne tra ns a mi na s e (formerl y SGPT)
a s pa rta te tra ns a mi na s e (formerl y SGOT)
a denos i ne tri phos pha te
ba ci l l e Ca l mette-Gueri n
2 ti mes a da y (onl y i n dos a ges )
ba s a l meta bol i c ra te
bl ood pres s ure
body s urfa ce a rea
bl ood urea ni trogen
Cel s i us ; centi gra de
ca l ci um
cycl i c a denos i ne monophos pha te
CBC
cGy
Ci
CK
CK-MB
Cl
cm
CNS
CO2
compl ete bl ood count

centi gra y
curi e
crea ti ne ki na s e
crea ti ne ki na s e of mus cl e ba nd
chl ori de; chl ori ne
centi meter
centra l nervous s ys tem
COPD
CPR
CSF
CT
cu
D &C
dL
DNA
DTP
D/W or D
ECF
ECG
EEG
ENT
ERCP
ESR
F
FDA
ft
FUO
g
GFR
GI
G6PD
GU
Gy
h
Hb
HCl
HCO3
chroni c obs tructi ve pul mona ry di s ea s e

ca rdi opul mona ry res us ci ta ti on
cerebros pi na l fl ui d
computed tomogra phy
cubi c
di l a ti on a nd curetta ge
deci l i ter (= 100 mL)
deoxyri bonucl ei c a ci d
di phtheri a -teta nus -pertus s i s (toxoi ds /va cci ne)
dextros e
extra cel l ul a r fl ui d
el ectroca rdi ogra m, el ectroca rdi ogra phy
el ectroencepha l ogra m, el ectroencepha l ogra phy
ea r, nos e, a nd throa t
endos copi c retrogra de chol a ngi opa ncrea togra phy
erythrocyte s edi menta ti on ra te
Fa hrenhei t
US Food a nd Drug Admi ni s tra ti on
foot; feet (mea s ure)
fever of unknown ori gi n
gra m
gl omerul a r fi l tra ti on ra te
ga s troi ntes ti na l
gl ucos e-6-phos pha te dehydrogena s e
geni touri na ry
gra y
hour
hemogl obi n
hydrochl ori c a ci d; hydrochl ori de
Hct
Hg
HIV
HLA
HMG-CoA
Hz
ICF
ICU
IgA, etc
IL-1, etc
IM
INR
IU
IV
IVU
K
kcal
kg
L
hema tocri t
mercury
huma n i mmunodefi ci ency vi rus
huma n l eukocyte a nti gen
hydroxymethyl gl uta ryl coenzyme A
hertz (cycl es /s econd)
i ntra cel l ul a r fl ui d
i ntens i ve ca re uni t
i mmunogl obul i n A, etc
i nterl euki n-1, etc
i ntra mus cul a r(l y)
i nterna ti ona l norma l i zed ra ti o
i nterna ti ona l uni t
i ntra venous (l y)
i ntra venous urogra phy
pota s s i um
ki l oca l ori e (food ca l ori e)
ki l ogra m
l i ter
ca rbon di oxi de
bi ca rbona te
lb
LDH
M
m
MAOI
MCH
MCHC
mCi
MCV
mEq
Mg
mg
MI
MIC
min
mIU
mL
mm
mmol
mo
mOsm
MRI
N
Na
NaCl
ng
NGT
nm
nmol
npo
NSAID
O2
pound
l a cti c dehydrogena s e
mol a r
meter
monoa mi ne oxi da s e i nhi bi tor
mea n corpus cul a r hemogl obi n
mea n corpus cul a r hemogl obi n concentra ti on
mi l l i curi e
mea n corpus cul a r vol ume
mi l l i equi va l ent
ma gnes i um
mi l l i gra m
myoca rdi a l i nfa rcti on
mi ni mum i nhi bi tory concentra ti on
mi nute
mi l l i -i nterna ti ona l uni t
mi l l i l i ter
mi l l i meter
mi l l i mol e
month
mi l l i os mol e
ma gneti c res ona nce i ma gi ng
ni trogen; norma l (s trength of s ol uti on)
s odi um
s odi um chl ori de
na nogra m (= mi l l i mi crogra m)
na s oga s tri c tube
na nometer (= mi l l i mi cron)
na nomol e
nothi ng by mouth
nons teroi da l a nti -i nfl a mma tory drug
OTC
oz
P
PACO2
over-the-counter (pha rma ceuti ca l s )

ounce
phos phorus
PaCO2
a rteri a l ca rbon di oxi de pa rti a l pres s ure
PAO2
a l veol a r oxygen pa rti a l pres s ure
PaO2
a rteri a l oxygen pa rti a l pres s ure
PCO2
ca rbon di oxi de pa rti a l pres s ure (or tens i on)
PCR
PET
pg
pH
PMN
po
PO2
pol ymera s e cha i n rea cti on

pos i tron emi s s i on tomogra phy
pi cogra m (= mi cromi crogra m)
hydrogen i on concentra ti on
pol ymorphonucl ea r l eukocyte
ora l l y
PPD
ppm
prn
PT
PTT
q
qid
RA
RBC
RNA
puri fi ed protei n deri va ti ve (tubercul l i n)

pa rts per mi l l i on
a s needed
prothrombi n ti me
pa rti a l thrombopl a s ti n ti me
every (onl y i n dos a ges )
rheuma toi d a rthri ti s
red bl ood cel l
ri bonucl ei c a ci d
oxygen
a l veol a r ca rbon di oxi de pa rti a l pres s ure
oxygen pa rti a l pres s ure (or tens i on)
SaO2
sc
sec
SI
SIDS
SLE
sp
spp
sp gr
sq
SSRI
TB
tid
TNF
TPN
TSH
URI
UTI
vs
WBC
WHO
wk
wt
yr
Ci
g
L
m
mol
Osm
m
a rteri a l oxygen s a tura ti on

s ubcuta neous
s econd
Interna ti ona l Sys tem of Uni ts
s udden i nfa nt dea th s yndrome
s ys temi c l upus erythema tos us
s peci es (when referri ng to the s i ngul a r) [eg, Clostridium s p]
s peci es (when referri ng to the pl ura l ) [eg, Nocardia a nd Myocardia s pp]
s peci fi c gra vi ty
s qua re
s el ecti ve s erotoni n reupta ke i nhi bi tor
tubercul os i s
tumor necros i s fa ctor
tota l pa rentera l nutri ti on
thyroi d-s ti mul a ti ng hormone
upper res pi ra tory i nfecti on
uri na ry tra ct i nfecti on
vers us
whi te bl ood cel l
Worl d Hea l th Orga ni za ti on
week
wei ght
yea r
mi cro-; mi cron
mi crocuri e
mi crogra m
mi crol i ter
mi crometer (= mi cron)
mi cromol e
mi cro-os mol e
mi l l i mi cron
Editors
Editor-in-Chief
ROBERT S. PORTER, MD
Merck & Co., Inc, a nd Cl i ni ca l As s i s ta nt Profes s or, Depa rtment of Emergency Medi ci ne, Jeffers on
Medi ca l Col l ege
Senior Assistant Editor
JUSTIN L. KAPLAN, MD
Merck & Co., Inc, a nd Cl i ni ca l As s oci a te Profes s or, Depa rtment of Emergency Medi ci ne, Jeffers on
Medi ca l Col l ege
Editorial Board
RICHARD K. ALBERT, MD
Profes s or, Depa rtment of Medi ci ne, Uni vers i ty
of Col ora do Hea l th Sci ences Center; Chi ef of
Medi ci ne, Denver Hea l th Medi ca l Center
MARJORIE A. BOWMAN, MD, MPA
Profes s or a nd Foundi ng Cha i r of Fa mi l y
Pra cti ce a nd Communi ty Hea l th, Uni vers i ty of
Penns yl va ni a School of Medi ci ne
GLENN D. BRAUNSTEIN, MD
Profes s or of Medi ci ne, Da vi d Geffen School
of Medi ci ne a t Uni vers i ty of Ca l i forni a , Los
Angel es ; Cha i rma n, Depa rtment of Medi ci ne,
Ceda rs -Si na i Medi ca l Center
SIDNEY COHEN, MD
Profes s or of Medi ci ne a nd Di rector, Res ea rch
Progra ms , Thoma s Jeffers on Uni vers i ty School
of Medi ci ne
LINDA EMANUEL, PhD
Profes s or of Medi ci ne, Northwes tern Uni vers i ty,
Fei nberg School of Medi ci ne, Buehl er Center
on Agi ng
JAN FAWCETT, MD
Profes s or of Ps ychi a try, Uni vers i ty of New
Mexi co School of Medi ci ne
EUGENE P. FRENKEL, MD
Profes s or of Interna l Medi ci ne a nd Ra di ol ogy,
Pa ts y R. a nd Ra ymond D. Na s her Di s ti ngui s hed
Cha i r i n Ca ncer Res ea rch, El a i ne Dewey
Sa mmons Di s ti ngui s hed Cha i r i n Ca ncer
Res ea rch i n honor of Eugene P. Frenkel , MD,
A. Kenneth Pye Profes s ors hi p i n Ca ncer
Res ea rch, Ha rol d C. Si mmons Comprehens i ve
Ca ncer Center, The Uni vers i ty of Texa s
Southwes tern Medi ca l Center a t Da l l a s
SUSAN L. HENDRIX, DO
Cl i ni ca l Profes s or, Depa rtment of Obs tetri cs
a nd Gynecol ogy, Mi chi ga n Sta te Uni vers i ty
School of Os teopa thi c Medi ci ne, a nd a pa rtner
i n Hutzel Women's Hos pi ta l a t the Detroi t
Medi ca l Center
MICHAEL JACEWICZ, MD
Profes s or of Neurol ogy, Uni vers i ty of
Tennes s ee Hea l th Sci ence Center; As s i s ta nt
Chi ef of Neurol ogy, VA Medi ca l Center,
Memphi s
MATTHEW E. LEVISON, MD
Adjunct Profes s or of Medi ci ne, Drexel
Uni vers i ty Col l ege of Medi ci ne; Profes s or,
School of Publ i c Hea l th, Drexel Uni vers i ty
JAMES JEFFREY MALATACK, MD
Profes s or of Pedi a tri cs , Thoma s Jeffers on
Uni vers i ty School of Medi ci ne; Di vi s i on Chi ef
of Di a gnos ti c Referra l Servi ce a nd Medi ca l
Li ver Tra ns pl a nta ti on, Al fred I. duPont
Hos pi ta l for Chi l dren
BRIAN F. MANDELL, MD, PhD
Profes s or a nd Vi ce Cha i rma n of Medi ci ne,
Depa rtment of Rheuma ti c a nd Immunol ogi c
Di s ea s es , Center for Va s cul i ti s Ca re a nd
Res ea rch, Cl evel a nd Cl i ni c Lerner Col l ege of
Medi ci ne a t Ca s e Wes tern Res erve Uni vers i ty
GERALD L. MANDELL, MD
Profes s or of Medi ci ne (Emeri tus ), Owen R.
Chea tha m Profes s or of the Sci ences
(Emeri tus ), Chi ef of Infecti ous Di s ea s es
(Emeri tus ), Uni vers i ty of Vi rgi ni a Hea l th
Sys tem
JUDITH S. PALFREY, MD
T. Berry Bra zel ton Profes s or of Pedi a tri cs ,
Ha rva rd Medi ca l School
ALBERT A. RUNDIO, Jr., PhD
As s oci a te Profes s or of Nurs i ng, The Ri cha rd
Stockton Col l ege of New Jers ey; Nurs e
Pra cti ti oner, Li ghthous e a t Ma ys La ndi ng
DAVID A. SPAIN, MD
Profes s or of Surgery a nd Chi ef of Tra uma /

Surgi ca l Cri ti ca l Ca re, Sta nford Uni vers i ty
PAUL H. TANSER, MD
Profes s or of Medi ci ne (Emeri tus ), McMa s ter
Uni vers i ty; Medi ca l Ca rdi ol ogi s t, North Shore
a nd Wa i ta kere Hos pi ta l s , Auckl a nd
MICHAEL R. WASSERMAN, MD
Co-founder, Seni or Ca re of Col ora do, PC
Consultants
NOEL A. ARMENAKAS, MD
Cl i ni ca l As s oci a te Profes s or, Depa rtment
of Urol ogy, Wei l l Cornel l Medi ca l School ;
Attendi ng Phys i ci a n, Lenox Hi l l Hos pi ta l
a nd New York Pres byteri a n Hos pi ta l
Genitourinary (Urologic) Disorders
INA CALLIGARO, PharmD
As s i s ta nt Dea n for Educa ti on a nd As s oci a te
Profes s or of Pha rma cy Pra cti ce, Templ e
Uni vers i ty School of Pha rma cy
Pediatric Pharmaceutical Preparations and
Dosages
MICHAEL F. CELLUCCI, MD
Attendi ng Phys i ci a n, Depa rtment of Pedi a tri cs ,
Di a gnos ti c Referra l Di vi s i on, Al fred I. duPont
Hos pi ta l for Chi l dren; Cl i ni ca l Ins tructor,
Jeffers on Medi ca l Col l ege
Pediatrics
ROBERT B. COHEN, DMD
Cl i ni ca l As s oci a te Profes s or of Denti s try
a nd Pra cti ce Coordi na tor, Tufts Uni vers i ty
School of Denta l Medi ci ne
Dental Disorders
DEBORAH M. CONSOLINI, MD
As s i s ta nt Profes s or of Pedi a tri cs , Jeffers on
Medi ca l Col l ege; Sta ff Phys i ci a n, Di a gnos ti c
Referra l Di vi s i on, Al fred I. duPont Hos pi ta l
for Chi l dren
Pediatrics
J. CARLTON GARTNER, Jr., MD
Profes s or of Pedi a tri cs , Jeffers on Medi ca l
Col l ege; Pedi a tri ci a n-i n-Chi ef, Al fred I. duPont
Pediatrics
SIDNEY N. KLAUS, MD
Profes s or of Medi ci ne, Secti on of Derma tol ogy,
Da rtmouth Medi ca l School ; Chi ef of
Derma tol ogy, Whi te Ri ver Juncti on, Vermont
VA Medi ca l Center
Dermatologic Disorders
CHRISTOPHER P. RAAB, MD
Cl i ni ca l Ins tructor, Thoma s Jeffers on Uni vers i ty;
Sta ff Phys i ci a n, Pedi a tri cs Depa rtment,
Di a gnos ti c Referra l Di vi s i on, Al fred I. duPont
Pediatrics
MELVIN I. ROAT, MD
Cl i ni ca l As s oci a te Profes s or, Wi l l s Eye Ins ti tute,
Depa rtment of Ophtha l mol ogy, Jeffers on
Medi ca l Col l ege, Thoma s Jeffers on Uni vers i ty
Eye Disorders
JAMES R. ROBERTS, MD
Profes s or a nd Vi ce Cha i rma n, Depa rtment

of Emergency Medi ci ne, Drexel Uni vers i ty
Col l ege of Medi ci ne; Cha i r, Depa rtment of
Emergency Medi ci ne a nd Di rector, Di vi s i on
of Toxi col ogy, Mercy Ca thol i c Medi ca l Center
Injuries and Poisoning
ROBERT J. RUBEN, MD
Di s ti ngui s hed Uni vers i ty Profes s or, Depa rtment
of Otorhi nol a ryngol ogy-Hea d & Neck Surgery,
Al bert Ei ns tei n Col l ege of Medi ci ne a nd
Montefi ore Medi ca l Center
Ear, Nose, and Throat Disorders
STEWART SHANKEL, MD
Cl i ni ca l Profes s or of Medi ci ne a nd Di rector of
Cl i ni ca l Ins tructi on, Uni vers i ty of Ca l i forni a ,
Ri vers i de
Genitourinary (Nephrotic) Disorders
EVA M. VIVIAN, PharmD
Cl i ni ca l As s oci a te Profes s or, Uni vers i ty of
Wi s cons i n School of Pha rma cy
Adult Pharmaceutical Preparations and
Dosages
Reviewers for Selected Chapters
Wi l l i a m E. Bra nt, MD
Arthur Coverda l e, MD
Al bert T. Deri va n, MD
Robert A. Dobi e, MD
Norton J. Greenberger, MD
John E. Greenl ee, MD
Ma ry L. Ha rdy, MD
Ra nda l l Hughes , MD
Di a ne Kra ft, MS, RD, LDN
Dougl a s La ns ka , MD, MS, MSPH
Edwi n M. Lei dhol dt, Jr., PhD
Mi cha el C. Levi n, MD
S. Gene McNeel ey, MD
Col onel Da vi d F. Murchi s on, DDS, MMS
Da vi d S. Rootma n, MD
Mi cha el B. Stei nberg, MD, MPH
Ja mes Wa yne Wa rni ca , MD
Acknowledgments
We tha nk Ba rba ra P. Homei er, MD, Noel l e Rotondo, DO, a nd Oren Tra ub, MD, PhD, for thei r edi tori a l a s s i s ta nce. We a l s o tha nk Pa ul Fennes s y a nd
the tea m a t Nes bi tt Gra phi cs for thei r a s s i s ta nce i n produci ng thi s book.
We tha nk the fol l owi ng peopl e a nd i ns ti tuti ons for a l l owi ng us to publ i s h thei r photogra phs i n the col or pl a tes : Pi et va n Ha s s el t, MD (Plate 1);
Becha ra Ghora yeb, MD (Plate 2); Robert Ma chemer vi a the Online Journal of Ophthalmology (ONJOPH) (Plates 3, 5, 10, 11 [bottom], 23, and 25 [bottom]);
Ophtha l mi c Cl i ni c of the Hea l th Center of the Uni vers i ty of Erl a ngen-Nurnberg vi a ONJOPH (Plates 4 and 17 [bottom]); A. Vi es tenz vi a ONJOPH (Plate 6);
Jona tha n J. Dutton vi a ONJOPH (Plate 7); Profes s or J. Wol l ens a k vi a ONJOPH (Plates 8, 9, 15, 16, 17 [top], and 18); Dr. Brooks McCuen vi a ONJOPH (Plate 11
[top]); Jona tha n J. Dutton vi a ONJOPH (Plate 12); Uni vers i ty of Ca l i forni a a t Sa n Di ego vi a ONJOPH (Plate 13); Profes s or H.J. Meyer vi a ONJOPH (Plate 14);
Dr. Ja mes Ga rri ty (Plate 19); Worl d Hea l th Orga ni za ti on vi a ONJOPH (Plate 20); C. Newma n (Plate 21) a nd B. Bi l l er (Plate 22) from Atlas of Clinical
Endocrinology: Neuroendocrinology and Pituitary Disease; Thoma s Ha bi f, MD (Plates 24, 26-30, 32-37, 38 [top], 39-47, 49, 51-55, and 60); Prof. Dr. K.W.
Ruprecht a nd Dr. Med. B. Ka es ma nn-Kel l ner vi a ONJOPH (Plate 25 [top]); Al l en W. Ma thi es , MD, vi a the Publ i c Hea l th Ima ge Li bra ry of the Centers for
Di s ea s e Control a nd Preventi on (CDC) (Plate 31); Denni s D. Jura nek, MD, vi a the Publ i c Hea l th Ima ge Li bra ry of the CDC (Plate 38 [bottom]) a nd vi a
www.doctorfungus .com (Plates 48 and 50); S. Dei tcher from Atlas of Clinical Hematology (Plate 56); E. Joe a nd N. Soter from Current Dermatologic Diagnosis
and Treatment (Plate 57); Publ i c Hea l th Ima ge Li bra ry of the CDC (Plates 58, 64-67, and 70); Drs . S.E. Thomps on a nd J. Pl edger vi a the Publ i c Hea l th
Ima ge Li bra ry of the CDC (Plate 59); Noel Armena ka s , MD (Plate 61); Dr. Sus a n Li nds l ey vi a the Publ i c Hea l th Ima ge Li bra ry of the CDC (Plate 62); Joe
Mi l l er a nd Dr. Cornel i o Areva l o vi a the Publ i c Hea l th Ima ge Li bra ry of the CDC (Plate 63); M.S. Kl empner from Atlas of Infectious Diseases: External
Manifestations of Systemic Infections (Plate 68); R. Ka ufma n a nd D. Brown from Atlas of Clinical Gynecology: Gynecologic Pathology (Plate 69); J.D. Sobel from
Atlas of Infectious Diseases: Fungal Infections (Plate 71); A. Os ter a nd R. Ros a from Atlas of Ophthalmology (Plate 72); I. Scott, R. Wa rma n, a nd T. Murra y
from Atlas of Ophthalmology (Plate 73); J. Burns a nd M. Gl ode from Atlas of Infectious Diseases: Pediatric Infectious Diseases (Plate 74); Steven E. Wol f, MD
(Plates 75 and 76).
Contributors
BOLA ADAMOLEKUN, MD
Di rector of Epi l eps y, Depa rtment of Neurol ogy,
Uni vers i ty of Tennes s ee Hea l th Sci ence Center
Seizure Disorders
NEIL B. ALEXANDER, MD
Profes s or, Depa rtment of Interna l Medi ci ne,
Di vi s i on of Geri a tri c Medi ci ne, Uni vers i ty of
Mi chi ga n; As s oci a te Profes s or for Res ea rch;
Di rector, VA Ann Arbor Hea l th Ca re Sys tem,
Geri a tri cs Res ea rch, Educa ti on a nd Cl i ni ca l
Center
Falls in the Elderly
ROY D. ALTMAN, MD
Profes s or of Medi ci ne, Di vi s i on of
Rheuma tol ogy a nd Immunol ogy, Uni vers i ty
of Ca l i forni a , Los Angel es
Joint Disorders; Paget's Disease of Bone
BRADLEY D. ANAWALT, MD
As s oci a te Profes s or of Medi ci ne, Uni vers i ty
of Wa s hi ngton; As s oci a te Chi ef of Medi ci ne,
VA Puget Sound
Male Reproductive Endocrinology
MARY ANN ANDERSON, PhD, RN
As s oci a te Profes s or, Uni vers i ty of Il l i noi s a t
Chi ca go, Col l ege of Nurs i ng, Qua d Ci ti es
Regi ona l Progra m
Provision of Care
GERALD L. ANDRIOLE, MD
Profes s or a nd Chi ef of Urol ogi c Surgery,
Ba rnes -Jewi s h Hos pi ta l , Wa s hi ngton
Uni vers i ty School of Medi ci ne
Benign Prostate Disease
PARSWA ANSARI, MD
As s i s ta nt Progra m Di rector, Depa rtment of
Surgery, Lenox Hi l l Hos pi ta l , New York
GI Bleeding; Acute Abdomen and Surgical
Gastroenterology; Anorectal Disorders
BRIAN R. APATOFF, MD, PhD
As s oci a te Profes s or of Neurol ogy a nd
Neuros ci ence, Wei l l Cornel l Medi ca l Col l ege;
Cl i ni ca l Attendi ng of Neurol ogy, New York
Pres byteri a n Hos pi ta l
Demyelinating Disorders
NOEL A. ARMENAKAS, MD
Cl i ni ca l As s oci a te Profes s or, Depa rtment of
Urol ogy, Wei l l Cornel l Medi ca l Col l ege;
Attendi ng Phys i ci a n, Lenox Hi l l Hos pi ta l a nd
New York Pres byteri a n Hos pi ta l
Genitourinary Tract Trauma
J. MALCOLM O. ARNOLD, MD
Profes s or of Medi ci ne, Phys i ol ogy a nd
Pha rma col ogy, Uni vers i ty of Wes tern Onta ri o;
Ca rdi ol ogi s t, Uni vers i ty Hos pi ta l , London
Hea l th Sci ences Center
Heart Failure; Cardiomyopathies
ALEXANDER AUCHUS, MD
Profes s or a nd McCa rty Cha i r of Neurol ogy,
Uni vers i ty of Mi s s i s s i ppi Medi ca l Center
Delirium and Dementia; Function and
Dysfunction of the Cerebral Lobes
GEORGE L. BAKRIS, MD
Profes s or of Medi ci ne a nd Di rector,
Hypertens i ve Di s ea s es Uni t, Uni vers i ty
of Chi ca go-Pri tzker School of Medi ci ne
Arterial Hypertension
DAVID H. BARAD, MD, MS

As s oci a te Cl i ni ca l Profes s or, Al bert Ei ns tei n
Col l ege of Medi ci ne
Approach to the Gynecologic Patient
PEGGY P. BARCO, MS, OTR/L
Progra m i n Occupa ti ona l Thera py,
Wa s hi ngton Uni vers i ty Medi ca l School ;
Dri vi ng Connecti ons , The Reha bi l i ta ti on
Ins ti tute of Sa i nt Loui s
The Older Driver
ROBERT A. BARISH, MD, MBA
Profes s or of Emergency Medi ci ne, Cha ncel l or,
Loui s i a na Sta te Uni vers i ty Hea l th Sci ences
Center a t Shreveport
Bites and Stings
JOHN G. BARTLETT, MD
Profes s or of Medi ci ne, Johns Hopki ns
Acute Bronchitis; Pneumonia; Lung Abscess
ROSEMARY BASSON, MD
Cl i ni ca l Profes s or, Depa rtment of Ps ychi a try,
Uni vers i ty of Bri ti s h Col umbi a a nd Va ncouver
Hos pi ta l
Sexual Dysfunction in Women
BYRON E. BATTEIGER, MD
Profes s or of Medi ci ne a nd Mi crobi ol ogy a nd
Immunol ogy, Di vi s i on of Infecti ous Di s ea s es ,
Indi a na Uni vers i ty School of Medi ci ne
Chlamydia and Mycoplasmas
LEE B. BEERMAN, MD
Profes s or of Pedi a tri cs , Di vi s i on of Pedi a tri c
Ca rdi ol ogy, Chi l dren's Hos pi ta l of Pi tts burgh
of UPMC, Uni vers i ty of Pi tts burgh School of
Medi ci ne
Congenital Cardiovascular Anomalies
J. BRAD BELLOTTE, MD
Di rector of Compl ex Spi ne Surgery a nd
Di rector of Neurotra uma , Depa rtment of
Neuros urgery, Al l egheny Genera l Hos pi ta l ,
Pi tts burgh
Spinal Trauma
JOSHUA O. BENDITT, MD
Profes s or of Medi ci ne, Di vi s i on of Pul mona ry
a nd Cri ti ca l Ca re, Uni vers i ty of Wa s hi ngton
School of Medi ci ne; Di rector of Res pi ra tory
Ca re Medi ci ne, Uni vers i ty of Wa s hi ngton
Medi ca l Center
Bronchiectasis
JAMES R. BERENSON, MD
Medi ca l a nd Sci enti fi c Di rector, Ins ti tute for
Myel oma a nd Bone Ca ncer Res ea rch, Wes t
Hol l ywood
Plasma Cell Disorders
BARBARA J. BERKMAN, DSW, PhD
Hel en Rehr/Ruth Fi tzda l e Profes s or, Col umbi a
Uni vers i ty School of Soci a l Work; Pri nci pa l
Inves ti ga tor a nd Na ti ona l Di rector, Ha rtford
Geri a tri c Soci a l Work Fa cul ty Schol a rs Progra m
Social Issues in the Elderly
CHESTON M. BERLIN, Jr., MD
Uni vers i ty Profes s or of Pedi a tri cs a nd
Profes s or of Pha rma col ogy, Penn Sta te
Uni vers i ty Col l ege of Medi ci ne
Principles of Drug Treatment in Children

JESSICA R. BERMAN, MD
As s i s ta nt Profes s or of Medi ci ne, Wei l l Cornel l
Medi ca l Col l ege; As s i s ta nt Attendi ng Phys i ci a n,
Hos pi ta l for Speci a l Surgery
Approach to the Patient With Joint Disease
RICHARD W. BESDINE, MD
Profes s or of Medi ci ne, Greer Profes s or of
Geri a tri c Medi ci ne, a nd Di rector, Di vi s i on of
Geri a tri cs (Medi ci ne) a nd of the Center for
Gerontol ogy a nd Hea l thca re Res ea rch, The
Wa rren Al pert Medi ca l School of Brown
Uni vers i ty
Approach to the Geriatric Patient; Quality of
Life and Therapeutic Objectives
ADIL E. BHARUCHA, MBBS, MD
Ga s troenterol ogy a nd Hepa tol ogy, Ma yo
Cl i ni c Col l ege of Medi ci ne
Approach to the Patient With Lower GI
Complaints; Irritable Bowel Syndrome
ALBERT W. BIGLAN, MD
Adjunct As s oci a te Profes s or of Ophtha l mol ogy,
Uni vers i ty of Pi tts burgh School of Medi ci ne;
Sta ff Phys i ci a n, Chi l dren's Hos pi ta l of Pi tts burgh
Eye Defects and Conditions in Children
JOSEPH J. BIUNDO, MD
Cl i ni ca l Profes s or of Medi ci ne, Tul a ne Medi ca l
Center
Bursa, Muscle, and Tendon Disorders
SEAN C. BLACKWELL, MD
As s i s ta nt Profes s or, Depa rtment of Obs tetri cs ,
Gynecol ogy, a nd Reproducti ve Sci ences , The
Uni vers i ty of Texa s Hea l th Sci ences Center a t
Hous ton
Pregnancy Complicated by Disease
RUSSELL BLAIR, MD
Fel l ow, Secti on of Pul mona ry, Cri ti ca l Ca re,
Al l ergy a nd Immunol ogi c Di s ea s es , Wa ke
Fores t Uni vers i ty Ba pti s t Medi ca l Center
Asthma
CHARLES D. BORTLE, EdD
Di rector of Logi s ti cs a nd Fi el d Opera ti ons ,
Depa rtment of Emergency Medi ci ne, Al bert
Ei ns tei n Medi ca l Center
Respiratory Arrest
ANN S. BOTASH, MD
Profes s or of Pedi a tri cs , Sta te Uni vers i ty of
New York, Ups ta te Medi ca l Uni vers i ty
Child Maltreatment
ALFRED A. BOVE, MD, PhD
Chi ef of Ca rdi ol ogy, Ca rdi ol ogy Secti on,
Templ e Uni vers i ty School of Medi ci ne
Injury During Diving or Work in Compressed
Air
THOMAS G. BOYCE, MD, MPH
As s oci a te Profes s or of Pedi a tri cs a nd Cons ul ta nt
i n Pedi a tri c Infecti ous Di s ea s es a nd Immunol ogy,
Ma yo Cl i ni c Col l ege of Medi ci ne
Gastroenteritis
PETER C. BRAZY, MD
Profes s or of Medi ci ne, Uni vers i ty of Wi s cons i n-
Ma di s on
Renal Transport Abnormalities; Congenital
Renal Transport Abnormalities
JEREMY S. BREIT, MD
Fel l ow, Secti on of Pul mona ry, Cri ti ca l Ca re,
Al l ergy a nd Immunol ogi c Di s ea s es , Wa ke Fores t
Uni vers i ty Ba pti s t Medi ca l Center
Asthma
CHRISTIAN M. BRIERY, MD
Di rector of Ma terna l -Feta l Medi ci ne, Wi l l i s Kni ghton Medi ca l Center, Shreveport
High-Risk Pregnancy
GEORGE R. BROWN, MD
Profes s or a nd As s oci a te Cha i rma n, Depa rtment
of Ps ychi a try, Ea s t Tennes s ee Sta te Uni vers i ty;
Chi ef of Ps ychi a try, Ja mes H. Qui l l en VA
Medi ca l Center
Sexuality and Sexual Disorders
HAYWOOD L. BROWN, MD
Roy T. Pa rker Profes s or a nd Cha i r, Depa rtment
of Obs tetri cs a nd Gynecol ogy, Duke
Uni vers i ty Medi ca l Center
Normal Pregnancy, Labor, and Delivery
ROBERT G. BRZYSKI, MD, PhD
As s oci a te Profes s or of Obs tetri cs a nd
Gynecol ogy, The Uni vers i ty of Texa s
Hea l th Sci ence Center a t Sa n Antoni o
Female Reproductive Endocrinology
REBECCA H. BUCKLEY, MD
J. Buren Si dbury Profes s or of Pedi a tri cs a nd
Profes s or of Immunol ogy, Duke Uni vers i ty
School of Medi ci ne
Immunodeficiency Disorders
LARRY M. BUSH, MD
As s oci a te Cl i ni ca l Profes s or of Medi ci ne,
Uni vers i ty of Mi a mi -Mi l l er School of Medi ci ne/
Fl ori da Atl a nti c Uni vers i ty; Chi ef, Di vi s i on of
Infecti ous Di s ea s es , JFK Medi ca l Center
Gram-Positive Bacilli; Gram-Positive Cocci
JERROLD T. BUSHBERG, PhD,
DABMP
Cl i ni ca l Profes s or of Ra di ol ogy a nd Ra di a ti on
Oncol ogy, School of Medi ci ne, Uni vers i ty of
Ca l i forni a , Da vi s
Radiation Exposure and Contamination
JUAN R. BUSTILLO, MD
As s oci a te Profes s or of Ps ychi a try a nd
Neuros ci ences , Uni vers i ty of New Mexi co
Schizophrenia and Related Disorders
DAVID B. CARR, MD
As s oci a te Profes s or of Interna l Medi ci ne a nd
Neurol ogy, Wa s hi ngton Uni vers i ty School of
Medi ci ne-Ol der Adul t Hea l th Center
The Older Driver
MARY T. CASERTA, MD
As s oci a te Profes s or of Pedi a tri cs , Di vi s i on of
Infecti ous Di s ea s es , Uni vers i ty of Roches ter
School of Medi ci ne; Attendi ng Phys i ci a n,
Gol i s a no Chi l dren's Hos pi ta l a t Strong,
Uni vers i ty of Roches ter Medi ca l Center
Enteroviruses; Other Viruses; Infections in
Neonates
BRUCE A. CHABNER, MD
Profes s or of Medi ci ne, Ha rva rd Medi ca l School ;
Cl i ni ca l Di rector, Ma s s a chus etts Genera l
Hos pi ta l Ca ncer Center
Overview of Cancer; Principles of Cancer
Therapy
FREDY CHAPARRO-ROJAS, MD
Interna l Medi ci ne Res i dent, Uni vers i ty of
Mi a mi -Mi l l er School of Medi ci ne/Fl ori da
Atl a nti c Uni vers i ty a t JFK Medi ca l Center
Gram-Positive Cocci
IAN M. CHAPMAN, MBBS, PhD
As s oci a te Profes s or of Endocri nol ogy,
Uni vers i ty of Adel a i de, Depa rtment of
Medi ci ne, Roya l Adel a i de Hos pi ta l
Pituitary Disorders
RACHEL L. CHAPMAN, MD
As s oci a te Profes s or of Pedi a tri cs , Di vi s i on of
Neona ta l -Peri na ta l Medi ci ne, Uni vers i ty of
Mi chi ga n, C.S. Mott Chi l dren's Hos pi ta l
Approach to the Care of Normal Infants and
Children; Perinatal Physiology; Caring for
Sick Children and Their Families
WILLIAM J. COCHRAN, MD
Vi ce Cha i rma n, Depa rtment of Pedi a tri cs ,
Gei s i nger Cl i ni c, Da nvi l l e, PA
Gastrointestinal Disorders in Neonates and
Infants; Congenital Gastrointestinal Anomalies
ALAN S. COHEN, MD
Di s ti ngui s hed Profes s or of Medi ci ne (Emeri tus ),
Conra d Wes s ol hoeft Profes s or of Medi ci ne,
Bos ton Uni vers i ty School of Medi ci ne; Edi tori n-Chi ef, Amyloid: The Journal of Protein
Folding Disorders
Amyloidosis
ROBERT B. COHEN, DMD
Cl i ni ca l As s oci a te Profes s or of Denti s try a nd
Pra cti ce Coordi na tor, Tufts Uni vers i ty School
of Denta l Medi ci ne
Approach to Dental and Oral Symptoms
SIDNEY COHEN, MD
Profes s or of Medi ci ne a nd Di rector, Res ea rch
Progra ms , Thoma s Jeffers on Uni vers i ty
Gastritis and Peptic Ulcer Disease; Bezoars
and Foreign Bodies; Hepatitis
KATHRYN COLBY, MD, PhD
As s i s ta nt Profes s or of Ophtha l mol ogy, Ha rva rd
Medi ca l School ; Di rector, Cl i ni ca l Res ea rch
Center, Ma s s a chus etts Eye a nd Ea r Infi rma ry
Approach to the Ophthalmologic Patient;
Cataract; Eye Injuries
DANIEL W. COLLISON, MD
As s oci a te Profes s or of Medi ci ne a nd Surgery,
Secti on of Derma tol ogy, Da rtmouth Medi ca l
School
Sweating Disorders; Benign Tumors; Pressure
Ulcers
EVE R. COLSON, MD
As s oci a te Profes s or of Pedi a tri cs , Ya l e
Uni vers i ty School of Medi ci ne; Di rector, Wel l
Newborn Nurs ery, Ya l e-New Ha ven Chi l dren's
Hos pi ta l
Children; Perinatal Physiology; Caring for

Sick Children and Their Families
MARY ANN COOPER, MD
Profes s or, Depa rtment of Emergency
Medi ci ne, Uni vers i ty of Il l i noi s a t Chi ca go
Electrical and Lightning Injuries
WILLIAM CORYELL, MD
George Wi nokur Profes s or of Ps ychi a try,
Uni vers i ty of Iowa
Mood Disorders
BRYAN D. COWAN, MD
Profes s or a nd Cha i rma n, Depa rtment of
Obs tetri cs a nd Gynecol ogy, Uni vers i ty of
Mi s s i s s i ppi Medi ca l Center
Uterine Fibroids
JILL P. CRANDALL, MD
As s oci a te Profes s or of Cl i ni ca l Medi ci ne,
Al bert Ei ns tei n Col l ege of Medi ci ne
Diabetes Mellitus and Disorders of
Carbohydrate Metabolism
RICARDO CRUCIANI, MD, PhD
Cl i ni ca l As s i s ta nt a nd Profes s or, Depa rtment
of Neurol ogy a nd Anes thes i ol ogy, Al bert
Ei ns tei n Col l ege of Medi ci ne; Di rector,
Res ea rch Di vi s i on, Depa rtment of Pa i n
Medi ci ne a nd Pa l l i a ti ve Ca re, Beth Is ra el
Medi ca l Center
Neurotransmission
BURKE A. CUNHA, MD
Profes s or of Medi ci ne, Sta te Uni vers i ty of
New York School of Medi ci ne, Stony Brook;
Chi ef, Infecti ous Di s ea s e Di vi s i on, Wi nthropUni vers i ty Hos pi ta l , Mi neol a
Gram-Negative Bacilli; Spirochetes
EMMETT T. CUNNINGHAM, Jr., MD,
PhD, MPH
Profes s or of Ophtha l mol ogy, Sta nford
Uni vers i ty; Di rector, The Uvei ti s Servi ce,
Ca l i forni a Pa ci fi c Medi ca l Center a nd Cl i ni c
Uveitis
DREW C. CUTLER, MD
As s oci a te Profes s or of Pedi a tri cs , Loma Li nda
Cystic Kidney Disease
RALPH E. CUTLER, MD (Decea s ed)
Profes s or of Medi ci ne (Emeri tus ), Loma Li nda
Uni vers i ty School of Medi ci ne; Cons ul ta nt i n
Nephrol ogy, Loma Li nda VA Medi ca l Center
Obstructive Uropathy; Urinary Tract Infections
PATRICIA A. DALY, MD
Vi s i ti ng As s i s ta nt Profes s or of Medi ci ne,
Uni vers i ty of Vi rgi ni a ; Cl i ni ca l Endocri nol ogi s t,
Front Roya l Interna l Medi ci ne, VA
Multiple Endocrine Neoplasia Syndromes
DANIEL F. DANZL, MD
Profes s or a nd Cha i r of Emergency Medi ci ne,
Uni vers i ty of Loui s vi l l e School of Medi ci ne
Cold Injury
NORMAN L. DEAN, MD
Fel l ow (Emeri tus ), Ameri ca n Col l ege of Ches t
Phys i ci a ns ; Li feti me Fel l ow, Ameri ca n Col l ege
of Phys i ci a ns
Drowning
ALAN H. DeCHERNEY, MD
Bra nch Chi ef, Reproducti ve Bi ol ogy a nd
Medi ci ne, Na ti ona l Ins ti tute of Chi l d Hea l th
a nd Huma n Devel opment, Na ti ona l Ins ti tutes
of Hea l th
Endometriosis
PETER J. DELVES, PhD
Rea der i n Immunol ogy, Depa rtment of
Immunol ogy a nd Mol ecul a r Pa thol ogy,
Di vi s i on of Infecti on a nd Immuni ty, Uni vers i ty
Col l ege London
Biology of the Immune System; Allergic and
Other Hypersensitivity Disorders
ARA DerMARDEROSIAN, PhD
Profes s or of Pha rma cognos y a nd Medi ci na l
Chemi s try, Roth Cha i r of Na tura l Products ,
Sci enti fi c Di rector, Compl ementa ry a nd
Al terna ti ve Medi ci ne Ins ti tute, Uni vers i ty of
the Sci ences i n Phi l a del phi a
Dietary Supplements
DEEPINDER K. DHALIWAL, MD
As s oci a te Profes s or, Depa rtment of
Ophtha l mol ogy, Uni vers i ty of Pi tts burgh
School of Medi ci ne; Di rector of Cornea /
Externa l Di s ea s e a nd Di rector of Refra cti ve
Surgery, Uni vers i ty of Pi tts burgh Medi ca l
Center Eye Center; Medi ca l Di rector,
Uni vers i ty of Pi tts burgh Medi ca l Center La s er
Center; Di rector a nd Founder, Center for
Integra ti ve Eye Ca re, Uni vers i ty of Pi tts burgh
Refractive Error
A. DAMIAN DHAR, MD, JD
Pri va te Pra cti ce, North Atl a nta Derma tol ogy
Bacterial Skin Infections; Fungal Skin Infections
MICHAEL C. DiMARINO, MD
Cl i ni ca l As s i s ta nt Profes s or of Medi ci ne,
Di vi s i on of Ga s troenterol ogy a nd Hepa tol ogy,
Depa rtment of Medi ci ne, Thoma s Jeffers on
Uni vers i ty
Esophageal and Swallowing Disorders;
Diverticular Disease
JAMES G.H. DINULOS, MD
As s i s ta nt Profes s or of Medi ci ne a nd Pedi a tri cs
(Medi ci ne), Da rtmouth Medi ca l School
Parasitic Skin Infections; Viral Skin Diseases;
Cornification Disorders
CAROLINE CARNEY DOEBBELING,
MD, MSc
Chi ef Executi ve Offi cer, Ceta n Hea l th
Cons ul ta nts LLC; As s oci a te Profes s or of
Interna l Medi ci ne a nd Ps ychi a try, Indi a na
Uni vers i ty School of Medi ci ne; Res ea rch
Sci enti s t, Regens tri ef Ins ti tute
Approach to the Patient With Mental Symptoms
KARL DOGHRAMJI, MD
Profes s or of Ps ychi a try a nd Huma n Beha vi or
a nd Medi ca l Di rector, Jeffers on Sl eep
Di s orders Center, Thoma s Jeffers on Uni vers i ty
Sleep and Wakefulness Disorders
DANIEL A. DOYLE, MD
As s oci a te Profes s or of Pedi a tri cs , Thoma s
Jeffers on Uni vers i ty; Di vi s i on of Endocri nol ogy,
A.I. duPont Chi l dren's Hos pi ta l
Physical Growth and Development

ANTONETTE T. DULAY, MD
As s i s ta nt Profes s or, Di vi s i on of Ma terna l Feta l Medi ci ne, Depa rtment of Obs tetri cs ,
Gynecol ogy, a nd Reproducti ve Sci ences ,
Ya l e Uni vers i ty School of Medi ci ne
Abnormalities of Pregnancy
JEFFREY S. DUNGAN, MD
As s oci a te Profes s or, Depa rtment of Obs tetri cs
a nd Gynecol ogy, Northwes tern Uni vers i ty,
Fei nberg School of Medi ci ne
Prenatal Genetic Counseling and Evaluation
SOUMITRA R. EACHEMPATI, MD
As s oci a te Profes s or of Surgery a nd Publ i c
Hea l th, Wei l l Cornel l Medi ca l Col l ege
Approach to the Critically Ill Patient
MEGAN A. ECONOMIDIS, MD
As s oci a te Di rector, Fel l ows hi p i n Fa mi l y
Pl a nni ng, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Keck School of Medi ci ne,
Uni vers i ty of Southern Ca l i forni a
Family Planning
DAVID EIDELBERG, MD
Sus a n a nd Leona rd Fei ns tei n Profes s or of
Neurol ogy a nd Neuros urgery, New York
Uni vers i ty School of Medi ci ne; Di rector,
Center for Neuros ci ences , The Fei ns tei n
Ins ti tute for Medi ca l Res ea rch, North ShoreLong Is l a nd Jewi s h Hea l th Sys tem
Movement and Cerebellar Disorders
SHERMAN ELIAS, MD
John J. Sci a rra Profes s or a nd Cha i r,
Depa rtment of Obs tetri cs a nd Gynecol ogy,
Northwes tern Uni vers i ty, Fei nberg School
of Medi ci ne; Cha i rma n, Obs tetri cs a nd
Gynecol ogy, Prenti ce Women's Hos pi ta l of
Northwes tern Memori a l Hos pi ta l
Prenatal Genetic Counseling and Evaluation
NORAH C. FEENY, PhD
As s oci a te Profes s or, Depa rtment of Ps ychol ogy,
Ca s e Wes tern Res erve Uni vers i ty
Medical Examination of the Rape Victim
MICHAEL C. FIORE, MD
Profes s or of Medi ci ne, Uni vers i ty of
Wi s cons i n School of Medi ci ne a nd Publ i c
Hea l th; Di rector, Uni vers i ty of Wi s cons i n
Center for Toba cco Res ea rch a nd Interventi on
Smoking Cessation
CHIN-TO FONG, MD
As s oci a te Profes s or of Pedi a tri cs a nd Medi ci ne,
Bi ochemi s try & Bi ophys i cs , Medi ca l Huma ni ti es
a nd Denti s try; Chi ef, Di vi s i on of Geneti cs ,
Depa rtment of Pedi a tri cs a nd Medi ci ne;
Uni vers i ty of Roches ter School of Medi ci ne
a nd Denti s try
Inherited Disorders of Metabolism
STEVEN D. FREEDMAN, MD, PhD
As s oci a te Profes s or of Medi ci ne, Ha rva rd
Medi ca l School ; Di rector, The Pa ncrea s
Center, Beth Is ra el Dea cones s Medi ca l Center
Pancreatitis
EMIL J FREIREICH, MD
Profes s or, Depa rtment of Leukemi a , a nd
Di rector, Adul t Leukemi a Res ea rch Progra ms ,

The Uni vers i ty of Texa s MD Anders on Ca ncer
Center
Leukemias
EUGENE P. FRENKEL, MD
Profes s or of Interna l Medi ci ne a nd Ra di ol ogy,
Pa ts y R. a nd Ra ymond D. Na s her Di s ti ngui s hed
Cha i r i n Ca ncer Res ea rch; El a i ne Dewey
Sa mmons Di s ti ngui s hed Cha i r i n Ca ncer
Res ea rch i n honor of Eugene P. Frenkel , MD;
a nd A. Kenneth Pye Profes s ors hi p i n Ca ncer
Res ea rch, Ha rol d C. Si mmons Comprehens i ve
Ca ncer Center, The Uni vers i ty of Texa s
Iron Overload
MARVIN P. FRIED, MD
Otorhi nol a ryngol ogy-Hea d & Neck Surgery,
Al bert Ei ns tei n Col l ege of Medi ci ne a nd
Approach to the Patient With Nasal and
Pharyngeal Symptoms; Nose and Paranasal
Sinus Disorders
MITCHELL H. FRIEDLAENDER, MD
Adjunct Profes s or, The Scri pps Res ea rch
Ins ti tute; Hea d, Di vi s i on of Ophtha l mol ogy,
Scri pps Cl i ni c
Conjunctival and Scleral Disorders
DMITRY GABRILOVICH, MD, PhD
Robert Rothma n Endowed Cha i r i n Ca ncer
Res ea rch, Hea d, Secti on of Dendri ti c Cel l
Bi ol ogy, H. Lee Moffi tt Ca ncer Center a nd
Res ea rch Ins ti tute; Profes s or of Oncol ogi c
Sci ences a nd Mol ecul a r Medi ci ne, Uni vers i ty
of South Fl ori da
Tumor Immunology
SUNIR J. GARG, MD
As s i s ta nt Profes s or of Ophtha l mol ogy, Thoma s
Jeffers on Uni vers i ty; As s i s ta nt Surgeon, The
Reti na Servi ce of Wi l l s Eye Ins ti tute
Retinal Disorders
JAMES GARRITY, MD
Whi tney a nd Betty Ma cMi l l a n Profes s or of
Ophtha l mol ogy, Ma yo Cl i ni c
Eyelid and Lacrimal Disorders; Optic Nerve
Disorders; Orbital Diseases
BRIAN K. GEHLBACH, MD
As s i s ta nt Profes s or of Medi ci ne, Secti on of
Pul mona ry a nd Cri ti ca l Medi ci ne, Uni vers i ty
of Chi ca go
Respiratory Failure and Mechanical Ventilation
JAMES N. GEORGE, MD
George Lynn Cros s Res ea rch Profes s or,
Depa rtment of Medi ci ne, Col l ege of Medi ci ne
a nd Depa rtment of Bi os ta ti s ti cs a nd
Epi demi ol ogy, Col l ege of Publ i c Hea l th,
The Uni vers i ty of Okl a homa Hea l th Sci ences
Center
Thrombocytopenia and Platelet Dysfunction;
Bleeding Due to Abnormal Blood Vessels
DAVID M. GERSHENSON, MD
Gynecol ogi c Oncol ogy a nd J. Ta yl or Wha rton,
MD, Di s ti ngui s hed Cha i r i n Gynecol ogi c
Oncol ogy, The Uni vers i ty of Texa s MD
Anders on Ca ncer Center

Gynecologic Tumors
ELIAS A. GIRALDO, MD
As s i s ta nt Profes s or a nd Seni or As s oci a te
Cons ul ta nt, Depa rtment of Neurol ogy, Ma yo
Cl i ni c
Stroke
ANNE CAROL GOLDBERG, MD
As s oci a te Profes s or of Medi ci ne, Wa s hi ngton
Lipid Disorders
STEPHEN E. GOLDFINGER, MD
Profes s or of Medi ci ne, Ha rva rd Medi ca l
School ; Phys i ci a n, Ma s s a chus etts Genera l
Hos pi ta l
Hereditary Periodic Fever Syndromes
M. JAY GOODKIND, MD
As s oci a te Profes s or (Emeri tus ) of Cl i ni ca l
Medi ci ne, Uni vers i ty of Penns yl va ni a School
of Medi ci ne; Chi ef of Ca rdi ol ogy (Reti red),
Mercer Medi ca l Center
Cardiac Tumors
CARMEN E. GOTA, MD
Sta ff Phys i ci a n, Depa rtment of Rheuma tol ogy,
Cl evel a nd Cl i ni c Founda ti on
Vasculitis
NORTON J. GREENBERGER, MD
Cl i ni ca l Profes s or of Medi ci ne, Ha rva rd
Medi ca l School ; Seni or Phys i ci a n, Bri gha m
a nd Women's Hos pi ta l
Approach to the Patient With Upper GI
Complaints; Diagnostic and Therapeutic GI
Procedures
JOHN H. GREIST, MD
Cl i ni ca l Profes s or of Ps ychi a try, Uni vers i ty
of Wi s cons i n; Di s ti ngui s hed Seni or Sci enti s t,
Ma di s on Ins ti tute of Medi ci ne
Anxiety Disorders
ASHLEY B. GROSSMAN, MD
Profes s or of Neuroendocri nol ogy, St.
Ba rthol omew's Hos pi ta l a nd The London
Adrenal Disorders
JOHN G. GUNDERSON, MD
Profes s or of Ps ychi a try, Ha rva rd Medi ca l
School ; Di rector, Ps ychos oci a l a nd Pers ona l i ty
Res ea rch, Borderl i ne Pers ona l i ty Di s order
Center, McLea n Hos pi ta l
Personality Disorders
RULA A. HAJJ-ALI, MD
Sta ff Phys i ci a n, Center of Va s cul i ti s Ca re
a nd Res ea rch, Depa rtment of Rheuma ti c a nd
Immunol ogi c Di s ea s e, Cl evel a nd Cl i ni c
Founda ti on
Autoimmune Rheumatic Disorders
JESSE B. HALL, MD
Profes s or of Medi ci ne, Depa rtment of
Anes thes i a a nd Cri ti ca l Ca re a nd Secti on
Chi ef, Pul mona ry a nd Cri ti ca l Ca re Medi ci ne,
Uni vers i ty of Chi ca go
Respiratory Failure and Mechanical Ventilation
JUDITH G. HALL, MD
Profes s or Emeri tus of Pedi a tri cs a nd Medi ca l

Geneti cs , Uni vers i ty of Bri ti s h Col umbi a
General Principles of Medical Genetics
JOHN W. HALLETT, Jr., MD
Cl i ni ca l Profes s or of Surgery, Medi ca l
Uni vers i ty of South Ca rol i na ; Medi ca l Di rector
a nd Va s cul a r Surgeon, Roper St. Fra nci s Hea rt
a nd Va s cul a r Center
Diseases of the Aorta and Its Branches;
Peripheral Arterial Disorders
KEVIN C. HAZEN, PhD
Profes s or of Pa thol ogy a nd Mi crobi ol ogy
a nd Di rector of Cl i ni ca l Mi crobi ol ogy a nd
Mol ecul a r Di a gnos ti cs -Infecti ous Di s ea s e,
Uni vers i ty of Vi rgi ni a Hea l th Sys tem
Laboratory Diagnosis of Infectious Disease
R. PHILLIPS HEINE, MD
As s oci a te Profes s or, Di vi s i on of Ma terna l Feta l Medi ci ne, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Duke Uni vers i ty Medi ca l Center
Approach to the Pregnant Woman and Prenatal
Care
MELISSA R. HELD, MD
As s i s ta nt Profes s or of Pedi a tri cs , Uni vers i ty of
Connecti cut School of Medi ci ne; Di rector,
Inpa ti ent Pedi a tri cs Cl erks hi p, Connecti cut
Chi l dren's Medi ca l Center
Children
SUSAN L. HENDRIX, DO
Cl i ni ca l Profes s or, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Mi chi ga n Sta te Uni vers i ty School
of Os teopa thi c Medi ci ne, a nd a pa rtner i n Hutzel
Women's Hos pi ta l a t the Detroi t Medi ca l Center
Menopause
STEVEN K. HERRINE, MD
Ga s troenterol ogy a nd Hepa tol ogy, Thoma s
Jeffers on Uni vers i ty; As s i s ta nt Dea n for
Aca demi c Affa i rs , Jeffers on Medi ca l Col l ege
Approach to the Patient With Liver Disease;
Drugs and the Liver; Liver Masses and
Granulomas
JEROME M. HERSHMAN, MD
Di s ti ngui s hed Profes s or of Medi ci ne, Da vi d
Geffen School of Medi ci ne, Uni vers i ty of
Ca l i forni a , Los Angel es ; As s oci a te Chi ef,
Endocri nol ogy a nd Di a betes Di vi s i on, Wes t
Los Angel es VA Medi ca l Center
Thyroid Disorders
MARTIN HERTL, MD, PhD
As s i s ta nt Profes s or of Surgery, Ha rva rd
Medi ca l School ; Surgi ca l Di rector, Li ver
Tra ns pl a nta ti on Progra m, Ma s s a chus etts
Genera l Hos pi ta l
Transplantation
ROBERT M. A. HIRSCHFELD, MD
Ha rry K. Da vi s Profes s or, Ti tus H. Ha rri s
Cha i r, Depa rtment of Ps ychi a try a nd
Beha vi ora l Sci ences , The Uni vers i ty of Texa s
Medi ca l Bra nch a t Ga l ves ton
Suicidal Behavior
BRIAN D. HOIT, MD
Profes s or of Medi ci ne a nd Phys i ol ogy a nd
Bi ophys i cs , Ca s e Wes tern Res erve Uni vers i ty;

Di rector of Echoca rdi ogra phy, Uni vers i ty
Hos pi ta l s of Cl evel a nd
Pericarditis
WAUN KI HONG, MD
Ameri ca n Ca ncer Soci ety Profes s or a nd
Sa ms ung Di s ti ngui s hed Uni vers i ty Cha i r i n
Ca ncer Medi ci ne; Profes s or of Medi ci ne,
Depa rtment of Thora ci c/Hea d a nd Neck
Medi ca l Oncol ogy, a nd Hea d, Di vi s i on of
Ca ncer Medi ci ne, The Uni vers i ty of Texa s
MD Anders on Ca ncer Center
Tumors of the Lungs
DANIEL A. HUSSAR, PhD
Remi ngton Profes s or of Pha rma cy, Phi l a del phi a
Col l ege of Pha rma cy, Uni vers i ty of the Sci ences
i n Phi l a del phi a
Concepts in Pharmacotherapy
MICHAEL JACEWICZ, MD
Profes s or of Neurol ogy, Uni vers i ty of
Tennes s ee Hea l th Sci ence Center; As s i s ta nt
Chi ef of Neurol ogy, VA Medi ca l Center,
Memphi s
Approach to the Neurologic Patient;
Neuro-Ophthalmologic and Cranial Nerve
Disorders; Meningitis; Brain Infections
HARRY S. JACOB, MD
Mi nnes ota Medi ca l School ; Edi tor-i n-Chi ef,
Hematology/Oncology Today
Spleen Disorders
JON A. JACOBSON, MD
As s oci a te Profes s or of Ra di ol ogy, Uni vers i ty
of Mi chi ga n
Principles of Radiologic Imaging
NAVIN JAIPAUL, MD, MHS
As s i s ta nt Profes s or of Medi ci ne, Loma Li nda
Uni vers i ty School of Medi ci ne; Sta ff
Nephrol ogi s t, VA Loma Li nda Hea l thca re
Sys tem
Tubulointerstitial Diseases
JAMES W. JEFFERSON, MD
Cl i ni ca l Profes s or of Ps ychi a try, Uni vers i ty of
Wi s cons i n; Di s ti ngui s hed Seni or Sci enti s t,
Ma di s on Ins ti tute of Medi ci ne
Anxiety Disorders
JANI R. JENSEN, MD
Fel l ow, Reproducti ve Endocri nol ogy a nd
Inferti l i ty, The Uni vers i ty of Texa s Hea l th
Sci ence Center a t Sa n Antoni o
Female Reproductive Endocrinology
LARRY E. JOHNSON, MD, PhD
As s oci a te Profes s or of Geri a tri cs a nd
Fa mi l y a nd Preventi ve Medi ci ne, Uni vers i ty
of Arka ns a s for Medi ca l Sci ences ; Attendi ng
Phys i ci a n, Centra l Arka ns a s Vetera ns
Hea l thca re Sys tem
Vitamin Deficiency, Dependency, and Toxicity;
Mineral Deficiency and Toxicity
ROBERT G. JOHNSON, MD
C. Rol l i ns Ha nl on Profes s or a nd Cha i r,
Depa rtment of Surgery, Sa i nt Loui s Uni vers i ty
Care of the Surgical Patient
BRIAN D. JOHNSTON
Fi tnes s Cl i ni ci a n a nd Educa tor wi th the
Interna ti ona l As s oci a ti on of Res i s ta nce
Tra i ners , Onta ri o
Exercise and Sports Injury
HUGH F. JOHNSTON, MD
Cl i ni ca l As s oci a te Profes s or, Depa rtment of
Ps ychi a try a nd Offi ce of Conti nui ng Medi ca l
Educa ti on, Uni vers i ty of Wi s cons i n Medi ca l
School ; Medi ca l Di rector, Burea u of Menta l
Hea l th a nd Subs ta nce Abus e
Mental Disorders in Children and Adolescents
THOMAS V. JONES, MD, MPH
Di rector, Infl a mma tory Di s ea s es , Speci a l ty
Ca re Bus i nes s Uni t, Pfi zer
Motion Sickness
NICHOLAS JOSPE, MD
Profes s or of Pedi a tri cs , Uni vers i ty of
Roches ter School of Medi ci ne a nd Denti s try
Metabolic, Electrolyte, and Toxic Disorders in
Neonates; Endocrine Disorders in Children
MICHAEL J. JOYCE, MD
As s oci a te Cl i ni ca l Profes s or, Orthopa edi c
Surgery, Ca s e Wes tern Res erve Uni vers i ty;
Orthopa edi c Surgeon, Cl evel a nd Cl i ni c
Tumors of Bones and Joints
JAMES O. JUDGE, MD
As s oci a te Cl i ni ca l Profes s or of Medi ci ne,
Uni vers i ty of Connecti cut School of Medi ci ne;
Medi ca l Di rector, Everca re Connecti cut
Gait Disorders in the Elderly
ANAND D. KANTAK, MD
Cl i ni ca l As s oci a te Profes s or of Pedi a tri cs ,
Northea s tern Ohi o Uni vers i ti es Col l eges of
Medi ci ne a nd Pha rma col ogy, Roots town;
Di rector, Di vi s i on of Neona tol ogy, Akron
Chi l dren's Hos pi ta l
Respiratory Disorders in Neonates, Infants,
and Young Children
DANIEL B. KAPLAN, MSW
Doctora l Student, Col umbi a Uni vers i ty School
of Soci a l Work; Progra m Eva l ua tor, Ha rtford
Fa cul ty Schol a rs Progra m
Social Issues in the Elderly
KENNETH M. KAYE, MD
As s i s ta nt Profes s or, Di vi s i on of Infecti ous
Di s ea s es , Depa rtment of Medi ci ne, Bri gha m a nd
Women's Hos pi ta l , Ha rva rd Medi ca l School
Viruses; Herpesviruses; Arboviridae,
Arenaviridae, and Filoviridae
JAMES W. KENDIG, MD (Decea s ed)
Profes s or of Pedi a tri cs , Penn Sta te Uni vers i ty
Perinatal Problems
TALMADGE E. KING, Jr., MD
Chi ef, Depa rtment of Medi ci ne; Jul i us R.
Kreva ns Di s ti ngui s hed Profes s ors hi p i n
Interna l Medi ci ne, Uni vers i ty of Ca l i forni a ,
Sa n Fra nci s co
Interstitial Lung Diseases
JAMES P. KNOCHEL, MD
Cl i ni ca l Profes s or of Interna l Medi ci ne, The
Uni vers i ty of Texa s Southwes tern Medi ca l

Center a t Da l l a s ; Pa s t Cha i rma n, Depa rtment
of Interna l Medi ci ne, Pres byteri a n Hos pi ta l of
Da l l a s
Heat Illness
KAREN BIRCKELBAW KOPACEK, RPh
Cl i ni ca l As s i s ta nt Profes s or a nd Cl i ni ca l
Pha rma ci s t, Di vi s i on of Pha rma cy Pra cti ce,
Uni vers i ty of Wi s cons i n School of Pha rma cy
Pharmacokinetics
DAVID N. KORONES, MD
As s oci a te Profes s or of Pedi a tri cs , Oncol ogy,
a nd Neurol ogy, Uni vers i ty of Roches ter
Medi ca l Center
Pediatric Cancers
JULES Y.T. LAM, MD
As s oci a te Profes s or of Medi ci ne, Uni vers i ty
of Montrea l ; Ca rdi ol ogi s t, Montrea l Hea rt
Ins ti tute
Arteriosclerosis
LEWIS LANDSBERG, MD
Irvi ng S. Cutter Profes s or of Medi ci ne a nd
Dea n (Emeri tus ), Northwes tern Uni vers i ty
Multiple Endocrine Neoplasia Syndromes
NOAH LECHTZIN, MD, MHS
As s i s ta nt Profes s or, Depa rtment of Medi ci ne,
Di vi s i on of Pul mona ry a nd Cri ti ca l Ca re
Medi ci ne, Johns Hopki ns Uni vers i ty School of
Medi ci ne
Approach to the Patient With Pulmonary
Symptoms; Diagnostic and Therapeutic
Pulmonary Procedures
MATHEW H.M. LEE, MD
Howa rd A. Rus k Profes s or of Reha bi l i ta ti on
Medi ci ne a nd Cha i rma n, Depa rtment of
Reha bi l i ta ti on Medi ci ne, New York Uni vers i ty
Rehabilitation
JOSEPH R. LENTINO, MD, PhD
Profes s or of Medi ci ne, Loyol a Uni vers i ty
Stri tch School of Medi ci ne; Chi ef, Infecti ous
Di s ea s es , Hi nes VA Hos pi ta l
Anaerobic Bacteria
WENDY S. LEVINBOOK, MD
As s i s ta nt Profes s or of Derma tol ogy,
Uni vers i ty of Connecti cut Hea l th Center
Hair Disorders
MATTHEW E. LEVISON, MD
Adjunct Profes s or of Medi ci ne, Drexel
Uni vers i ty Col l ege of Medi ci ne; Profes s or,
School of Publ i c Hea l th, Drexel Uni vers i ty
Bacteria and Antibacterial Drugs
RICHARD LEVITAN, MD
As s oci a te Profes s or of Emergency Medi ci ne,
Thoma s Jeffers on Uni vers i ty Hos pi ta l s ;
Pres i dent, Ai rwa y Ca m Tech, Inc.
Respiratory Arrest
SHARON LEVY, MD, MPH
As s i s ta nt Profes s or of Pedi a tri cs , Ha rva rd
Medi ca l School ; Center for Adol es cent
Subs ta nce Abus e Res ea rch, Chi l dren's
Hos pi ta l , Bos ton
Approach to the Care of Adolescents
JAMES L. LEWIS, III, MD

Nephrol ogy As s oci a tes , P.C. of Bi rmi ngha m
Fluid and Electrolyte Metabolism; Acid-Base
Regulation and Disorders
ALAN E. LICHTIN, MD
As s oci a te Profes s or, Depa rtment of Medi ci ne,
Cl evel a nd Cl i ni c Lerner Col l ege of Medi ci ne
of Ca s e Wes tern Res erve; Sta ff Phys i ci a n,
Hema tol ogi c Oncol ogy a nd Bl ood Di s orders ,
Cl evel a nd Cl i ni c
Approach to the Patient With Anemia; Anemias
Caused by Deficient Erythropoiesis; Anemias
Caused by Hemolysis
PAUL LAWRENCE LIEBERT, MD
Pri va te Pra cti ce, Toma h Memori a l Hos pi ta l ,
Toma h, WI
Exercise and Sports Injury
RICHARD W. LIGHT, MD
Profes s or of Medi ci ne, Di vi s i on of Al l ergy,
Pul mona ry, a nd Cri ti ca l Ca re Medi ci ne,
Va nderbi l t Uni vers i ty Medi ca l Center
Mediastinal and Pleural Disorders
GREGORY S. LIPTAK, MD, MPH
Profes s or of Pedi a tri cs , a nd Di rector, Center
for Devel opment, Beha vi or, a nd Geneti cs ,
Ups ta te Medi ca l Uni vers i ty
Congenital Craniofacial and Musculoskeletal
Abnormalities; Congenital Neurologic Anomalies;
Chromosomal Anomalies
JEFFREY M. LIPTON, MD, PhD
Chi ef, Hema tol ogy/Oncol ogy, Schnei der
Chi l dren's Hos pi ta l ; Profes s or of Pedi a tri cs ,
Al bert Ei ns tei n Col l ege of Medi ci ne
Histiocytic Syndromes
ELLIOT M. LIVSTONE, MD
Attendi ng Phys i ci a n, Sa ra s ota Memori a l
Hos pi ta l , Sa ra s ota , FL
Tumors of the GI Tract
PHILIP LOW, MD
Robert D. a nd Pa tri ci a E. Kern Profes s or of
Neurol ogy, Ma yo Cl i ni c Col l ege of Medi ci ne
Autonomic Nervous System
PAUL D. LUI, MD
As s oci a te Profes s or of Urol ogy, Loma Li nda
Voiding Disorders; Penile and Scrotal
Disorders
JOANNE LYNN, MD, MA, MS
Cl i ni ca l Improvement Expert, Col ora do
Founda ti on for Medi ca l Ca re
The Dying Patient
ROBERT J. MacNEAL, MD
As s i s ta nt Profes s or, Depa rtment of Genera l
Interna l Medi ci ne a nd Secti on of Derma tol ogy,
Da rtmouth Hi tchcock Medi ca l Center
Approach to the Dermatologic Patient;
Reactions to Sunlight
MARCELLA A. MADERA, MD
Ins tructor, Depa rtment of Neuros urgery, Johns
Hopki ns Uni vers i ty School of Medi ci ne
Traumatic Brain Injury
KENNETH MAIESE, MD
Profes s or a nd Cha i r, Depa rtment of Neurol ogy
a nd Neuros ci ences , Uni vers i ty of Denti s try a nd
Medi ci ne of New Jers ey
Coma and Impaired Consciousness
JAMES F. MARKMANN, MD, PhD
Profes s or of Surgery, Ha rva rd Medi ca l School ;
Cl i ni ca l Di rector, Di vi s i on of Tra ns pl a nta ti on,
Ma s s a chus etts Genera l Hos pi ta l
Transplantation
JOHN T. McBRIDE, MD
Profes s or of Pedi a tri cs , Northea s tern Ohi o
Uni vers i ti es Col l eges of Medi ci ne a nd
Pha rma col ogy, Roots town; Vi ce-Cha i r,
Depa rtment of Pedi a tri cs , Akron Chi l dren's
Hos pi ta l
Respiratory Disorders in Neonates, Infants,
and Young Children
MARGARET C. McBRIDE, MD
Profes s or of Pedi a tri cs (Neurol ogy),
Northea s tern Ohi o Uni vers i ti es Col l eges of
Medi ci ne a nd Pha rma col ogy, Roots town;
Di rector, Neurodevel opmenta l Center,
Akron Chi l dren's Hos pi ta l
Neurologic Disorders in Children;
Neurocutaneous Syndromes
DANIEL J. McCARTY, MD
Wi l l a nd Ca va Ros s Profes s or of Medi ci ne
(Emeri tus ), Medi ca l Col l ege of Wi s cons i n
Crystal-Induced Arthritides
J. ALLEN McCUTCHAN, MD, MSc
Profes s or of Medi ci ne, Di vi s i on of Infecti ous
Di s ea s es , School of Medi ci ne, Uni vers i ty of
Ca l i forni a a t Sa n Di ego
Human Immunodeficiency Virus; Sexually
Transmitted Diseases
DOUGLAS L. McGEE, DO
Di rector, Emergency Medi ci ne Res i dency
Progra m, Al bert Ei ns tei n Medi ca l Center;
Chi ef Aca demi c Offi cer, Al bert Ei ns tei n
Hea l thca re Network
Clinical Decision Making
DANIEL E. McGINLEY-SMITH, MD
Pri va te Pra cti ce, New Engl a nd Derma tol ogy,
Leba non, NH; Sta ff Derma tol ogi s t, New London
Hos pi ta l
Pigmentation Disorders
ROBERT S. McKELVIE, MD, PhD, MSc
Profes s or of Medi ci ne, McMa s ter Uni vers i ty;
Medi ca l Di rector, Ca rdi a c Hea l th a nd
Reha bi l i ta ti on Center
Sports and the Heart
KAREN McKOY, MD, MPH
As s i s ta nt Profes s or i n Cl i ni ca l Derma tol ogy,
Ha rva rd Medi ca l School ; Seni or Sta ff, Group
Pra cti ce, Depa rtment of Derma tol ogy, La hey
Cl i ni c Medi ca l Center
Acne and Related Disorders; Dermatitis;
Principles of Topical Dermatologic Therapy
JAMES I. McMILLAN, MD
As s oci a te Profes s or of Medi ci ne, Loma Li nda
Uni vers i ty; Chi ef of Nephrol ogy, VA Loma
Li nda Hea l thca re Sys tem
Renal Failure; Renal Replacement Therapy;
Glomerular Disorders
S. GENE McNEELEY, MD
Chi ef of Gynecol ogy, Hutzel Women's
Hos pi ta l ; Cl i ni ca l Profes s or, Mi chi ga n Sta te
Uni vers i ty, Col l ege of Os teopa thi c Medi ci ne,
Hutzel Women's Hea l th Speci a l i s ts
Benign Gynecologic Lesions; Pelvic Relaxation
Syndromes
NOSHIR R. MEHTA, DMD, MDS, MS
Profes s or a nd Cha i rma n of Genera l Denti s try;
As s i s ta nt Dea n, Interna ti ona l Rel a ti ons ; a nd
Di rector, Cra ni ofa ci a l Pa i n Center, Tufts
Uni vers i ty School of Denta l Medi ci ne
Temporomandibular Disorders
DANIEL R. MISHELL, Jr., MD
The Lyl e G. McNei l e Profes s or, Depa rtment
of Obs tetri cs a nd Gynecol ogy, Keck School of
Medi ci ne, Uni vers i ty of Southern Ca l i forni a ;
Chi ef Phys i ci a n, Women's a nd Chi l dren's
Hos pi ta l , Los Angel es County a nd Uni vers i ty
of Southern Ca l i forni a Medi ca l Center
Family Planning
L. BRENT MITCHELL, MD
Profes s or a nd Hea d, Depa rtment of Ca rdi a c
Sci ences , Uni vers i ty of Ca l ga ry; Di rector,
Li bi n Ca rdi ova s cul a r Ins ti tute of Al berta ,
Ca l ga ry Hea l th Regi on a nd Uni vers i ty of
Ca l ga ry
Arrhythmias and Conduction Disorders
RICHARD T. MIYAMOTO, MD
Ari l l a Spence DeVa ul t Profes s or a nd
Cha i rma n, Depa rtment of Otol a ryngol ogyHea d & Neck Surgery, Indi a na Uni vers i ty
Middle Ear and Tympanic Membrane Disorders
JOEL L. MOAKE, MD
Seni or Res ea rch Sci enti s t, Ri ce Uni vers i ty;
Profes s or of Medi ci ne (Emeri tus ), Ba yl or
Hemostasis; Coagulation Disorders;
Thrombotic Disorders
JULIE S. MOLDENHAUER, MD
Attendi ng Phys i ci a n, The Center for Feta l
Di a gnos i s a nd Trea tment, The Chi l dren's
Hos pi ta l of Phi l a del phi a
Abnormalities and Complications of Labor and
Delivery; Postpartum Care
JOHN E. MORLEY, MB, BCh
Da mmert Profes s or of Gerontol ogy a nd
Di rector, Di vi s i on of Geri a tri c Medi ci ne, Sa i nt
Loui s Uni vers i ty Medi ca l Center; Di rector,
Geri a tri c Res ea rch, Educa ti on a nd Cl i ni ca l
Center, St. Loui s VA Medi ca l Center
Undernutrition; Principles of Endocrinology
ANGELA CAFIERO MORONEY,
PharmD
Seni or Cl i ni ca l Sci ence Ma na ger a nd Gl oba l
Pha rma ceuti ca l Res ea rch a nd Devel opment,
Abbott La bora tori es
Pharmacodynamics
ALEX MOROZ, MD
As s i s ta nt Profes s or, Depa rtment of
Reha bi l i ta ti on Medi ci ne, New York
Uni vers i ty School of Medi ci ne; Di rector of
Mus cul os kel eta l Reha bi l i ta ti on Uni t a nd

Di rector of Res i dency Tra i ni ng a nd Medi ca l
Educa ti on, Rus k Ins ti tute of Reha bi l i ta ti on
Medi ci ne
Rehabilitation
JOHN MORRISON, MD
Profes s or of Obs tetri cs /Gynecol ogy a nd
Pedi a tri cs , Uni vers i ty of Mi s s i s s i ppi Medi ca l
Center
High-Risk Pregnancy
SAM P. MOST, MD
Chi ef, Di vi s i on of Fa ci a l Pl a s ti c a nd
Recons tructi ve Surgery, Sta nford Uni vers i ty
Facial Trauma
DAVID F. MURCHISON, DDS, MMS
Col onel , Uni ted Sta tes Ai r Force; Di rector, Ai r
Force Denta l Opera ti ons , Uni ted Sta tes Ai r Force
Denta l Servi ce, La ckl a nd-Kel l y Ai r Force Ba s e
Dental Emergencies
CARLENE A. MUTO, MD, MS
As s i s ta nt Profes s or, Epi demi ol ogy a nd
Medi ci ne, Di vi s i on of Infecti ous Di s ea s es ,
Uni vers i ty of Pi tts burgh School of Medi ci ne;
Medi ca l Di rector of Infecti on Control , Dona l d
D. Wol ff, Jr. Center for Qua l i ty Improvement
a nd Innova ti on, Uni vers i ty of Pi tts burgh
Medi ca l Center Hea l th Sys tem
Neisseriaceae
RAJ K. NARAYAN, MD
Fra nk H. Ma yfi el d Profes s or a nd Cha i rma n,
The Neuros ci ence Ins ti tute, Depa rtment of
Neuros urgery, Uni vers i ty of Ci nci nna ti
Col l ege of Medi ci ne a nd Ma yfi el d Cl i ni c
EDWARD A. NARDELL, MD
As s oci a te Profes s or, Ha rva rd Medi ca l School ,
Ha rva rd School of Publ i c Hea l th, Bri gha m a nd
Women's Hos pi ta l
Mycobacteria
VICTOR J. NAVARRO, MD
Profes s or of Medi ci ne, Pha rma col ogy a nd
Experi menta l Thera peuti cs a nd Medi ca l
Di rector, Hepa tol ogy a nd Li ver Tra ns pl a nta ti on
Progra m, Jeffers on Medi ca l Col l ege, Thoma s
Jeffers on Uni vers i ty
Drugs and the Liver
JOHN H. NEWMAN, MD
El s a S. Ha ni ga n Profes s or of Pul mona ry
Medi ci ne, Va nderbi l t Uni vers i ty School of
Medi ci ne
Pulmonary Embolism; Pulmonary Hypertension
LEE S. NEWMAN, MD, MA
Profes s or, Depa rtment of Envi ronmenta l a nd
Occupa ti ona l Hea l th, Col ora do School of
Publ i c Hea l th a nd Depa rtment of Medi ci ne,
Uni vers i ty of Col ora do a t Denver
Environmental Pulmonary Diseases;
Sarcoidosis
JENNIFER R. NIEBYL, MD
Profes s or, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Uni vers i ty of Iowa Ca rver
Conception and Prenatal Development
MARY LYNN R. NIERODZIK, MD

As s i s ta nt Profes s or, New York Uni vers i ty
School of Medi ci ne; Chi ef, Hema tol ogy/
Oncol ogy, Bel l evue Hos pi ta l Center
Eosinophilic Disorders
JAMES M. O'BRIEN, Jr., MD, MSc
As s oci a te Profes s or, Center for Cri ti ca l Ca re,
Di vi s i on of Pul mona ry, Al l ergy, Cri ti ca l Ca re
a nd Sl eep Medi ci ne, The Ohi o Sta te Uni vers i ty
Medi ca l Center
Tests of Pulmonary Function
PATRICK G. O'CONNOR, MD, MPH
Profes s or of Medi ci ne; Chi ef, Secti on of
Genera l Interna l Medi ci ne, Ya l e Uni vers i ty
Drug Use and Dependence
GERALD F. O'MALLEY, DO
Cl i ni ca l Res ea rch Di rector, Thoma s Jeffers on
Uni vers i ty
Poisoning
JOHN S. OGHALAI, MD
As s i s ta nt Profes s or of Otol ogy, Neurotol ogy,
a nd Skul l Ba s e Surgery, Ba yl or Col l ege of
Medi ci ne; Di rector, The Hea ri ng Center a t
Texa s Chi l dren's Hos pi ta l
Inner Ear Disorders
JAMES T. PACALA, MD, MS
As s oci a te Profes s or a nd Di s ti ngui s hed
Uni vers i ty Tea chi ng Profes s or, Fa mi l y
Pra cti ce a nd Communi ty Hea l th, Uni vers i ty
of Mi nnes ota Medi ca l School
Prevention of Disease and Disability in the
Elderly
STEVEN A. PAGET, MD
Profes s or of Medi ci ne a nd Phys i ci a n i n Chi ef,
Di vi s i on of Rheuma tol ogy, Hos pi ta l for
Speci a l Surgery a nd Wei l l Cornel l Medi ca l
Col l ege
Approach to the Patient With Joint Disease
ELIZABETH J. PALUMBO, MD
Pri va te Pra cti ce, The Pedi a tri c Group, Fa i rfa x,
VA
Miscellaneous Disorders in Infants and
Children
DAVID A. PAUL, MD
Profes s or of Pedi a tri cs , Jeffers on Medi ca l
Col l ege, Thoma s Jeffers on Uni vers i ty;
Attendi ng Neona tol ogi s t, Chri s ti a na Ca re
Hea l th Sys tem
Perinatal Hematologic Disorders
RICHARD D. PEARSON, MD
Profes s or of Medi ci ne a nd Pa thol ogy,
As s oci a te Dea n for Student Affa i rs , Uni vers i ty
of Vi rgi ni a School of Medi ci ne
Approach to Parasitic Infections; Nematodes;
Trematodes; Cestodes; Intestinal Protozoa;
Extraintestinal Protozoa
LAWRENCE L. PELLETIER, Jr., MD
Profes s or, Interna l Medi ci ne, Uni vers i ty of
Ka ns a s School of Medi ci ne; Sta ff Phys i ci a n,
Robert J. Dol e VA Medi ca l a nd Regi ona l
Offi ce Center, Wi chi ta
Endocarditis
MARIA T. PEREZ, MD
As s oci a te Pa thol ogi s t, Depa rtment of
Pa thol ogy a nd La bora tory Medi ci ne,
Wel l i ngton Regi ona l Medi ca l Center,
Wes t Pa l m Bea ch
Gram-Positive Bacilli; Gram-Positive Cocci
FRANK PESSLER, MD, PhD
Pedi a tri c Rheuma tol ogi s t, Kl i ni k und
Pol i kl i ni c fur Ki nder und Jugendmedi zi n,
Medi zi ni s che Fa kul ta t Ca rl -Gus ta v-Ca rus ,
Techni s che Uni vers i ta t Dres den, Germa ny
Rheumatic Fever; Bone and Connective
Tissue Disorders in Children
STEPHEN P. PETERS, MD, PhD
Profes s or of Medi ci ne a nd Pedi a tri cs a nd
As s oci a te Di rector, Center for Huma n
Genomi cs , Wa ke Fores t Uni vers i ty Hea l th
Sci ences
Asthma
WILLIAM A. PETRI, Jr., MD, PhD
Wa de Ha mpton Fros t Profes s or of
Epi demi ol ogy a nd Chi ef, Di vi s i on of
Infecti ous Di s ea s es a nd Interna ti ona l Hea l th,
Uni vers i ty of Vi rgi ni a School of Medi ci ne
Rickettsiae and Related Organisms
KATHARINE A. PHILLIPS, MD
Profes s or of Ps ychi a try a nd Huma n Beha vi or,
Butl er Hos pi ta l a nd The Wa rren Al pert
Medi ca l School of Brown Uni vers i ty
Somatoform and Factitious Disorders
JoANN V. PINKERTON, MD
Profes s or of Obs tetri cs a nd Gynecol ogy
a nd Di rector, Mi dl i fe Hea l th, Uni vers i ty of
Vi rgi ni a Hea l th Sys tem
Menstrual Abnormalities
RUSSELL K. PORTENOY, MD
Profes s or of Neurol ogy a nd Anes thes i ol ogy,
Al bert Ei ns tei n Col l ege of Medi ci ne;
Cha i rma n, Depa rtment of Pa i n Medi ci ne a nd
Pa l l i a ti ve Ca re, Beth Is ra el Medi ca l Center
Pain
CAROL S. PORTLOCK, MD
Profes s or of Cl i ni ca l Medi ci ne, Wei l l Cornel l
Medi ca l Col l ege; Attendi ng Phys i ci a n,
Lymphoma Servi ce, Memori a l Sl oa n-Ketteri ng
Ca ncer Center
Lymphomas
MICHAEL POURFAR, MD
As s i s ta nt Profes s or, Depa rtment of Medi ci ne,
New York Uni vers i ty School of Medi ci ne
Movement and Cerebellar Disorders
JOSEF T. PRCHAL, MD
Profes s or of Medi ci ne, Di vi s i on of Hema tol ogy,
Uni vers i ty of Uta h; George E. Wa hl en VA
Medi ca l Center
Myeloproliferative Disorders
GLENN M. PREMINGER, MD
Profes s or of Urol ogi c Surgery a nd Di rector,
Comprehens i ve Ki dney Stone Center, Duke
Urinary Calculi
SALLY PULLMAN-MOOAR, MD
Cl i ni ca l As s oci a te Profes s or, Depa rtment
of Medi ci ne, Di vi s i on of Rheuma tol ogy,

Uni vers i ty of Penns yl va ni a ; Chi ef, Depa rtment
of Rheuma tol ogy, Phi l a del phi a VA Medi ca l
Center
Neck and Back Pain
RONALD RABINOWITZ, MD
Profes s or of Urol ogy a nd Pedi a tri cs ,
Uni vers i ty of Roches ter School of Medi ci ne a nd
Denti s try; Chi ef of Pedi a tri c Urol ogy, Strong
Memori a l a nd Roches ter Genera l Hos pi ta l s
Congenital Renal and Genitourinary Anomalies
LAWRENCE G. RAISZ, MD (Decea s ed)
Boa rd of Trus tees Di s ti ngui s hed Profes s or
of Medi ci ne a nd Di rector, UConn Center for
Os teoporos i s , Uni vers i ty of Connecti cut
Hea l th Center
Osteoporosis
PEDRO T. RAMIREZ, MD
As s i s ta nt Profes s or, Gynecol ogi c Oncol ogy
Depa rtment, The Uni vers i ty of Texa s MD
Gynecologic Tumors
LEONARD RAPPAPORT, MD, MS
Ma ry Demi g Scott Profes s or of Pedi a tri cs ,
Ha rva rd Medi ca l School ; Chi ef, Di vi s i on of
Devel opmenta l Medi ci ne, Chi l dren's Hos pi ta l
Incontinence in Children
ROBERT W. REBAR, MD
Executi ve Di rector, Ameri ca n Soci ety for
Reproducti ve Medi ci ne; Vol unteer Cl i ni ca l
Profes s or, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Uni vers i ty of Al a ba ma
Infertility
WINGFIELD E. REHMUS, MD, MPH
Cl i ni ca l As s i s ta nt Profes s or, Uni vers i ty of
Bri ti s h Col umbi a
Hypersensitivity and Inflammatory Disorders;
Nail Disorders
DOUGLAS J. RHEE, MD
As s i s ta nt Profes s or, Ma s s a chus etts Eye a nd
Ea r Infi rma ry, Ha rva rd Medi ca l School
Glaucoma
MELVIN I. ROAT, MD
Cl i ni ca l As s oci a te Profes s or, Wi l l s Eye Ins ti tute,
Depa rtment of Ophtha l mol ogy, Jeffers on
Medi ca l Col l ege, Thoma s Jeffers on Uni vers i ty
Corneal Disorders
JAMES R. ROBERTS, MD
Profes s or a nd Vi ce Cha i rma n, Depa rtment
of Emergency Medi ci ne, Drexel Uni vers i ty
Col l ege of Medi ci ne; Cha i r, Depa rtment of
Emergency Medi ci ne a nd Di rector, Di vi s i on
of Toxi col ogy, Mercy Ca thol i c Medi ca l Center
Fractures, Dislocations, and Sprains; Heat
Illness
KENNETH B. ROBERTS, MD
Profes s or of Pedi a tri cs , Uni vers i ty of North
Ca rol i na School of Medi ci ne; Di rector,
Pedi a tri c Tea chi ng Progra m, Mos es Cone
Hea l th Sys tem, Greens boro
Dehydration and Fluid Therapy
BERYL J. ROSENSTEIN, MD
Profes s or of Pedi a tri cs , Johns Hopki ns

Cystic Fibrosis
STEVEN ROSENZWEIG, MD
Cl i ni ca l As s oci a te Profes s or, Drexel
Uni vers i ty Col l ege of Medi ci ne
Complementary and Alternative Medicine
NOELLE ROTONDO, DO
Cl i ni ca l As s i s ta nt Profes s or of Emergency
Medi ci ne, Penn Sta te Hers hey Medi ca l Center;
Adjunct Cl i ni ca l Profes s or of Emergency
Medi ci ne, Drexel Uni vers i ty Col l ege of
Medi ci ne
Approach to the Trauma Patient
ROBERT J. RUBEN, MD
Di s ti ngui s hed Uni vers i ty Profes s or,
Depa rtment of Otorhi nol a ryngol ogy-Hea d &
Neck Surgery, Al bert Ei ns tei n Col l ege of
Medi ci ne a nd Montefi ore Medi ca l Center
Hearing Loss
FRED H. RUBIN, MD
Pi tts burgh, School of Medi ci ne; Cha i r,
Depa rtment of Medi ci ne, Uni vers i ty of
Pi tts burgh Medi ca l Center Pres byteri a n
Sha dys i de Hos pi ta l , Sha dys i de Ca mpus
Immunization
MICHAEL RUBIN, MD
Profes s or of Cl i ni ca l Neurol ogy,
Wei l l Cornel l Medi ca l Col l ege; Di rector,
Neuromus cul a r Servi ce a nd EMG La bora tory,
New York Pres byteri a n Hos pi ta l -Cornel l
Medi ca l Center
Craniocervical Junction Abnormalities;
Inherited Muscular Disorders; Spinal Cord
Disorders; Peripheral Nervous System and
Motor Unit Disorders
ATENODORO R. RUIZ, Jr., MD
Seni or Attendi ng Phys i ci a n, Depa rtment of
Medi ci ne-Ga s troenterol ogy, Ka i s er Perma nente,
Sa nta Cl a ra
Malabsorption Syndromes
J. MARK RUSCIN, PharmD
Profes s or, Depa rtment of Pha rma cy Pra cti ce,
Southern Il l i noi s Uni vers i ty Edwa rds vi l l e School
of Pha rma cy
Drug Therapy in the Elderly
JULIE E. RUSSAK, MD
Mel a noma Fel l ow, Ri gel Derma tol ogy
(Pri va te Pra cti ce As s oci a ted Wi th New York
Uni vers i ty Medi ca l Center)
Bullous Diseases
PAUL S. RUSSELL, MD
John Homa ns Di s ti ngui s hed Profes s or of
Surgery, Ha rva rd Medi ca l School ; Seni or
Surgeon, Ma s s a chus etts Genera l Hos pi ta l
Transplantation
CHARLES SABATINO, JD
Adjunct Profes s or, Georgetown Uni vers i ty
La w Center; Di rector, Commi s s i on on La w
a nd Agi ng, Ameri ca n Ba r As s oci a ti on
Medicolegal Issues
DAVID B. SACHAR, MD
Cl i ni ca l Profes s or of Medi ci ne, Mount Si na i
School of Medi ci ne; Di rector (Emeri tus ),

Dr. Henry D. Ja nowi tz Di vi s i on of
Ga s troenterol ogy, The Mount Si na i Hos pi ta l
Inflammatory Bowel Disease
SEYED-ALI SADJADI, MD
As s oci a te Profes s or of Medi ci ne, Loma Li nda
Approach to the Genitourinary Patient;
Renovascular Disorders
SCOTT SAMUELSON, MD
Ins tructor of Medi ci ne, Hema tol ogy Di vi s i on,
Uni vers i ty of Uta h; Attendi ng Phys i ci a n, Uta h
Ca ncer Speci a l i s ts
Myeloproliferative Disorders
CHRISTOPHER SANFORD, MD, MPH,
DTM&H
Cl i ni ca l As s i s ta nt Profes s or, Depa rtment of
Fa mi l y Medi ci ne; Co-Di rector, Tra vel Cl i ni c,
Ha l l Hea l th Center, Uni vers i ty of Wa s hi ngton
Medical Aspects of Travel
RAVINDRA SARODE, MD
Profes s or of Pa thol ogy a nd Di rector,
Tra ns fus i on Medi ci ne a nd Hemos ta s i s
La bora tory, The Uni vers i ty of Texa s
Transfusion Medicine
CLARENCE T. SASAKI, MD
The Cha rl es W. Os he Profes s or of Surgery
a nd Chi ef of Otol a ryngol ogy, Ya l e School
of Medi ci ne; Di rector, Hea d a nd Neck
Tumor Boa rd, Ya l e Comprehens i ve Ca ncer
Center
Laryngeal Disorders, Oral and Pharyngeal
Disorders
PETER C. SCHALOCK, MD
Ins tructor i n Derma tol ogy, Ha rva rd Medi ca l
School ; As s i s ta nt i n Derma tol ogy,
Ma s s a chus etts Genera l Hos pi ta l
Psoriasis and Scaling Diseases
STEVEN SCHMITT, MD
Hea d, Secti on of Bone a nd Joi nt Infecti ons ,
Depa rtment of Infecti ous Di s ea s e, Cl evel a nd
Cl i ni c
Infections of Joints and Bones
MARVIN I. SCHWARZ, MD
The Ja mes C. Ca mpbel l Profes s or of
Pul mona ry Medi ci ne, Di vi s i on of Pul mona ry
Sci ences a nd Cri ti ca l Ca re Medi ci ne,
Uni vers i ty of Col ora do Denver
Diffuser Alveolar Hemorrhage and PulmonaryRenal Syndromes
ELDON A. SHAFFER, MD
Profes s or of Medi ci ne, Fa cul ty of Medi ci ne,
Uni vers i ty of Ca l ga ry
Testing for Hepatic and Biliary Disorders;
Alcoholic Liver Disease; Fibrosis and Cirrhosis;
Vascular Disorders of the Liver; Gallbladder
and Bile Duct Disorders
STEWART SHANKEL, MD
Cl i ni ca l Profes s or of Medi ci ne a nd Di rector
of Cl i ni ca l Ins tructi on, Uni vers i ty of Ca l i forni a ,
Ri vers i de
Urinary Tract Infections
WILLIAM R. SHAPIRO, MD
Profes s or of Cl i ni ca l Neurol ogy, Uni vers i ty
of Ari zona Col l ege of Medi ci ne, Tucs on;
Chi ef, Neuro-oncol ogy, Ba rrow Neurol ogi ca l
Ins ti tute
Intracranial and Spinal Tumors
MICHAEL J. SHEA, MD
Profes s or of Interna l Medi ci ne, Secti on Hea d,
Ca rdi ova s cul a r Medi ci ne Outpa ti ent Servi ces
a nd Cl i ni ca l Eva l ua ti on, Uni vers i ty of
Mi chi ga n Hea l th Sys tems
Cardiovascular Tests and Procedures
DAVID D. SHERRY, MD
Penns yl va ni a ; Di rector, Cl i ni ca l
Rheuma tol ogy, The Chi l dren's Hos pi ta l of
Phi l a del phi a
Rheumatic Fever; Bone and Connective Tissue
Disorders in Children
STEPHEN D. SILBERSTEIN, MD
Profes s or of Neurol ogy, Hea da che Center,
Thoma s Jeffers on Uni vers i ty
Headache
DAPHNE SIMEON, MD
Ps ychi a try, Mount Si na i School of Medi ci ne
Dissociative Disorders
ADAM J. SINGER, MD
Profes s or a nd Vi ce Cha i rma n for Res ea rch,
Depa rtment of Emergency Medi ci ne, Stony
Brook Uni vers i ty a nd Medi ca l Center
Lacerations
ASHISH C. SINHA, MD, PhD
As s i s ta nt Profes s or, Anes thes i ol ogy a nd
Cri ti ca l Ca re, Uni vers i ty of Penns yl va ni a
Obesity and the Metabolic Syndrome
(Bariatric Surgery portion)
RICHARD V. SMITH, MD
Vi ce Cha i r, Depa rtment of Otol a ryngol ogyHea d & Neck Surgery, Al bert Ei ns tei n Col l ege
of Medi ci ne; Di rector, Hea d & Neck Servi ce,
Tumors of the Head and Neck
NORMAN SOHN, MD
Cl i ni ca l As s i s ta nt Profes s or of Surgery, New
York Uni vers i ty School of Medi ci ne;
Attendi ng Surgeon, Lenox Hi l l Hos pi ta l
Anorectal Disorders
DAVID E. SOPER, MD
Profes s or a nd Vi ce Cha i rma n for Cl i ni ca l
Affa i rs , Depa rtment of Obs tetri cs a nd
Gynecol ogy, Medi ca l Uni vers i ty of South
Ca rol i na
Vaginitis and Pelvic Inflammatory Disease
DAVID R. STEINBERG, MD
Orthopa edi c Surgery a nd Di rector, Ha nd &
Upper Extremi ty Fel l ows hi p, Depa rtment
of Orthopa edi c Surgery, Uni vers i ty of
Penns yl va ni a
Hand Disorders
MARVIN E. STEINBERG, MD
Profes s or (Emeri tus ) of Orthopa edi c Surgery,

Uni vers i ty of Penns yl va ni a School of
Medi ci ne
Osteonecrosis
KINGMAN P. STROHL, MD
Profes s or of Medi ci ne a nd Oncol ogy,
Depa rtment of Medi ci ne, Di vi s i on of
Pul mona ry, Cri ti ca l Ca re a nd Sl eep Medi ci ne,
Ca s e Medi ca l Center; Di rector, Center for
Sl eep Di s orders Res ea rch, Ca s e Wes tern
Res erve Uni vers i ty
Sleep Apnea
ALBERT J. STUNKARD, MD
Profes s or of Ps ychi a try, Uni vers i ty of
Penns yl va ni a School of Medi ci ne
Eating Disorders
ALAN M. SUGAR, MD
Profes s or of Medi ci ne (Emeri tus ), Bos ton
Uni vers i ty School of Medi ci ne; Medi ca l
Di rector, Infecti ous Di s ea s e Cl i ni ca l Servi ces
a nd HIV/AIDS Progra m, Ca pe Cod Hea l thca re
Fungi
STEPHEN BRIAN SULKES, MD
Profes s or of Pedi a tri cs , Di vi s i on of
Neurodevel opmenta l a nd Beha vi ora l
Pedi a tri cs , Gol i s a no Chi l dren's Hos pi ta l a t
Strong, Uni vers i ty of Roches ter School of
Medi ci ne a nd Denti s try
Learning and Developmental Disorders;
Behavioral Concerns and Problems in Children
GEETA K. SWAMY, MD
As s oci a te Profes s or, Di vi s i on of Ma terna l Feta l Medi ci ne, Depa rtment of Obs tetri cs a nd
Gynecol ogy, Duke Uni vers i ty Medi ca l Center
Approach to the Pregnant Woman and Prenatal
Care
DAVID A. SWANSON, MD
Cl i ni ca l Profes s or, Depa rtment of Urol ogy,
The Uni vers i ty of Texa s MD Anders on Ca ncer
Center
Genitourinary Cancer
PAUL H. TANSER, MD
Profes s or of Medi ci ne (Emeri tus ), McMa s ter
Uni vers i ty; Medi ca l Ca rdi ol ogi s t, North Shore
a nd Wa i ta kere Hos pi ta l s , Auckl a nd
Approach to the Cardiac Patient; Valvular
Disorders
SYED H. TARIQ, MD
Fel l ow, Di vi s i on of Ga s troenterol ogy a nd
Hepa tol ogy, Sa i nt Loui s Uni vers i ty School
of Medi ci ne
Polyglandular Deficiency Syndromes
JOAN B. TARLOFF, PhD
Profes s or, Depa rtment of Pha rma ceuti ca l
Sci ences , Uni vers i ty of the Sci ences i n
Phi l a del phi a
Adverse Drug Reactions
MARY TERRITO, MD
Profes s or of Medi ci ne, Di rector of
Hema topoi eti c Stem Cel l Tra ns pl a nta ti on,
Uni vers i ty of Ca l i forni a , Los Angel es
Neutropenia and Lymphocytopenia
DAVID R. THOMAS, MD
Profes s or of Medi ci ne, Di vi s i on of Geri a tri c

Medi ci ne, Sa i nt Loui s Uni vers i ty Hea l th
Sci ences Center
Nutritional Support
ELIZABETH CHABNER THOMPSON,
MD, MPH
Pri va te Pra cti ce, New York Group for Pl a s ti c
Surgery
Overview of Cancer; Principles of Cancer
Therapy
STIG THUNELL, MD, PhD
Profes s or, Ka rol i ns ka Ins ti tute; Seni or
Cons ul ta nt, Porphyri a Center Sweden,
Ka rol i ns ka Uni vers i ty Hos pi ta l Huddi nge,
Stockhol m
Porphyrias
SHELLY D. TIMMONS, MD, PhD
As s i s ta nt Profes s or a nd Chi ef of Neurotra uma
Di vi s i on, Depa rtment of Neuros urgery,
Uni vers i ty of Tennes s ee; Pri va te Pra cti ce,
Semmes -Murphey Neurol ogi c & Spi ne Ins ti tute
COURTNEY M. TOWNSEND, Jr., MD
Profes s or a nd John Woods Ha rri s Di s ti ngui s hed
Cha i rma n, Depa rtment of Surgery, The
Uni vers i ty of Texa s Medi ca l Bra nch a t
Ga l ves ton
Carcinoid Tumors
AMAL TRIVEDI, MD, MPH
As s i s ta nt Profes s or of Communi ty Hea l th,
The Wa rren Al pert Medi ca l School of
Brown Uni vers i ty; Inves ti ga tor, REAP On
Outcomes a nd Qua l i ty i n Chroni c Di s ea s e
a nd Reha bi l i ta ti on, Provi dence VA Medi ca l
Center
Funding Health Care for the Elderly; Financial
Issues in Health Care
ANNE S. TSAO, MD
As s i s ta nt Profes s or, Depa rtment of Thora ci c/
Hea d & Neck Oncol ogy, Di vi s i on of Ca ncer
Medi ci ne, The Uni vers i ty of Texa s MD
Tumors of the Lungs
DEBARA L. TUCCI, MD
As s oci a te Profes s or of Surgery, Di vi s i on of
Otol a ryngol ogy-Hea d a nd Neck Surgery, Duke
Approach to the Patient With Ear Problems
ALLAN R. TUNKEL, MD, PhD
Cha i r, Depa rtment of Medi ci ne, Monmouth
Medi ca l Center; Profes s or of Medi ci ne,
Drexel Uni vers i ty Col l ege of Medi ci ne
Biology of Infectious Disease
RONALD B. TURNER, MD
Profes s or of Pedi a tri cs , Uni vers i ty of Vi rgi ni a
Respiratory Viruses
ALEXANDER G.G. TURPIE, MD
Profes s or of Medi ci ne, McMa s ter Uni vers i ty
a nd Ha mi l ton Hea l th Sci ences Genera l Hos pi ta l
Peripheral Venous and Lymphatic Disorders
JAMES T. UBERTALLI, DMD
As s i s ta nt Cl i ni ca l Profes s or, Tufts Uni vers i ty
School of Denta l Medi ci ne; Pri va te Pra cti ce,

Hi ngha m, MA
Common Dental Disorders
VICTOR G. VOGEL, MD, MHS
Na ti ona l Vi ce Pres i dent for Res ea rch, Ameri ca n
Ca ncer Soci ety
Breast Disorders
AARON E. WALFISH, MD
Cl i ni ca l As s i s ta nt Attendi ng, Di vi s i on of
Di ges ti ve Di s ea s es , Beth Is ra el Medi ca l
Center; Cl i ni ca l Ins tructor, Mount Si na i
Medi ca l Center
Inflammatory Bowel Disease
JAMES WAYNE WARNICA, MD
Profes s or of Medi ci ne, Depa rtment of Ca rdi a c
Sci ence, Uni vers i ty of Ca l ga ry; Di rector,
Ca rdi a c Intens i ve Ca re Uni t, Foothi l l s Medi ca l
Center
Coronary Artery Disease
MAX HARRY WEIL, MD, PhD, ScD
(Hon)
Di s ti ngui s hed Profes s or a nd Foundi ng
Pres i dent, Wei l Ins ti tute of Cri ti ca l Ca re
Medi ci ne; Res ea rch Profes s or of Surgery,
Keck School of Medi ci ne, The Uni vers i ty of
Southern Ca l i forni a , Los Angel es
Cardiac Arrest; Shock and Fluid Resuscitation;
Sepsis and Septic Shock
GEOFFREY A. WEINBERG, MD
Roches ter School of Medi ci ne a nd Denti s try;
Di rector, Pedi a tri c HIV Progra m, Gol i s a no
Chi l dren's Hos pi ta l a t Strong, Uni vers i ty of
Roches ter Medi ca l Center
Miscellaneous Infections in Infants and
Children; Human Immunodeficiency Virus
Infection in Infants and Children
LAURA WEISSMAN, MD
As s i s ta nt Profes s or i n Medi ci ne a nd Ins tructor
i n Pedi a tri cs , Ha rva rd Medi ca l School
Incontinence in Children
GREGORY L. WELLS, MD
Res i dent i n Derma tol ogy, Da rtmouth Medi ca l
School a nd Da rtmouth-Hi tchcock Medi ca l
Center
Cancers of the Skin
JOHN B. WEST, MD, PhD, DSc
Profes s or of Medi ci ne a nd Phys i ol ogy,
Uni vers i ty of Ca l i forni a , Sa n Di ego
Altitude Sickness
KENDRICK ALAN WHITNEY, DPM
As s i s ta nt Profes s or, Depa rtment of Medi ci ne
a nd Orthopedi cs , Templ e Uni vers i ty School of
Podi a tri c Medi ci ne
Foot and Ankle Disorders
FRANK H. WIANS, Jr., PhD
Profes s or of Pa thol ogy (Reti red), Depa rtment
of Pa thol ogy, The Uni vers i ty of Texa s
Normal Laboratory Values
JAMES E. WILBERGER, MD
Neuros urgery, Al l egheny Genera l Hos pi ta l ,
Pi tts burgh; Vi ce Dea n, Drexel Uni vers i ty

Spinal Trauma
MARGARET-MARY G. WILSON, MD
Medi ca l Di rector, Hea l th Servi ces , Uni ted
Hea l thca re, Ma ryl a nd Hei ghts
Nutrition: General Considerations; Syndromes
of Uncertain Origin
G. TERENCE WILSON, PhD
Os ca r K. Buros Profes s or of Ps ychol ogy,
Gra dua te School of Appl i ed a nd Profes s i ona l
Ps ychol ogy, Rutgers Uni vers i ty
Eating Disorders
ROBERT A. WISE, MD
Profes s or of Medi ci ne, Pul mona ry a nd
Cri ti ca l Ca re, Johns Hopki ns Uni vers i ty
Chronic Obstructive Pulmonary Disease
GARY WITTERT, MB, Bch, MD
Profes s or a nd Hea d, Depa rtment of Medi ci ne,
Roya l Adel a i de Hos pi ta l
Obesity and the Metabolic Syndrome
STEVEN E. WOLF, MD
Betty a nd Bob Kel s o Di s ti ngui s hed Cha i r i n
Burns a nd Tra uma , Vi ce Cha i r for Res ea rch,
a nd Profes s or, Depa rtment of Surgery, The
Uni vers i ty of Texa s Hea l th Sci ence Center a t
Sa n Antoni o; Chi ef, Cl i ni ca l Res ea rch, Uni ted
Sta tes Army Ins ti tute of Surgi ca l Res ea rch
Burns
EIJI YANAGISAWA, MD
Cl i ni ca l Profes s or of Otol a ryngol ogy, Ya l e
External Ear Disorders
HEIDI YEH, MD
Ins tructor i n Surgery, Ha rva rd Medi ca l
School ; As s i s ta nt i n Surgery, Ma s s a chus etts
Genera l Hos pi ta l
Transplantation
1 - Nutritional Disorders
Chapter 1. Nutrition: General Considerations
Introduction
Nutri ti on i s the s ci ence of food a nd i ts rel a ti ons hi p to hea l th. Nutri ents a re chemi ca l s i n foods tha t a re us ed by the body for growth, ma i ntena nce,
a nd energy. Nutri ents tha t ca nnot be s ynthes i zed by the body a nd thus mus t be deri ved from the di et a re cons i dered es s enti a l . They i ncl ude
vi ta mi ns , mi nera l s , s ome a mi no a ci ds , a nd s ome fa tty a ci ds . Nutri ents tha t the body ca n s ynthes i ze from other compounds , a l though they ma y
a l s o be deri ved from the di et, a re cons i dered nones s enti a l . Ma cronutri ents a re requi red by the body i n rel a ti vel y l a rge a mounts ; mi cronutri ents
a re needed i n mi nute a mounts .
La ck of nutri ents ca n res ul t i n defi ci ency s yndromes (eg, kwa s hi orkor, pel l a gra ) or other di s orders (s ee p. 9). Exces s i nta ke of ma cronutri ents ca n
l ea d to obes i ty (s ee p. 56) a nd rel a ted di s orders ; exces s i nta ke of mi cro-nutri ents ca n be toxi c. Al s o, the ba l a nce of va ri ous types of nutri ents , s uch
a s how much us a tura ted vs s a tura ted fa t i s cons umed, ca n i nfl uence the devel opment of di s orders .
Macronutrients
Ma cronutri ents cons ti tute the bul k of the di et a nd s uppl y energy a nd ma ny es s enti a l nutri ents . Ca rbohydra tes , protei ns (i ncl udi ng es s enti a l
a mi no a ci ds ), fa ts (i ncl udi ng es s enti a l fa tty a ci ds ), ma cromi nera l s , a nd wa ter a re ma cronutri ents . Ca rbohydra tes , fa ts , a nd protei ns a re
i ntercha ngea bl e a s s ources of energy; fa ts yi el d 9 kca l /g (37.8 kJ/g); protei ns a nd ca rbohydra tes yi el d 4 kca l /g (16.8 kJ/g).
Carbohydrates: Di eta ry ca rbohydra tes a re broken down i nto gl ucos e a nd other monos a ccha ri des . Ca rbohydra tes i ncrea s e bl ood gl ucos e l evel s ,
s uppl yi ng energy. Si mpl e ca rbohydra tes a re compos ed of s ma l l mol ecul es , genera l l y monos a ccha ri des or di s a ccha ri des , whi ch i ncrea s e bl ood
gl ucos e l evel s ra pi dl y. Compl ex ca rbohydra tes a re compos ed of l a rger mol ecul es , whi ch a re broken down i nto monos a ccha ri des . Compl ex
ca rbohydra tes i ncrea s e bl ood gl ucos e l evel s more s l owl y but for a l onger ti me. Gl ucos e a nd s ucros e a re s i mpl e ca rbohydra tes ; s ta rches a nd fi ber
a re compl ex ca rbohydra tes .
The gl ycemi c i ndex mea s ures how ra pi dl y cons umpti on of a ca rbohydra te i ncrea s es pl a s ma gl ucos e l evel s . Va l ues ra nge from 1 (the s l owes t
i ncrea s e) to 100 (the fa s tes t i ncrea s e, equi va l ent to pure gl ucos es ee
Ta bl e 1-1). However, the a ctua l ra te of i ncrea s e a l s o depends on wha t foods a re cons umed wi th the ca rbohydra te.
Ca rbohydra tes wi th a hi gh gl ycemi c i ndex ma y i ncrea s e pl a s ma gl ucos e to hi gh l evel s ra pi dl y. It i s hypothes i zed tha t, a s a res ul t, i ns ul i n l evel s
i ncrea s e, i nduci ng hypogl ycemi a a nd hunger, whi ch tends to l ea d to cons umpti on of exces s ca l ori es a nd wei ght ga i n. Ca rbohydra tes wi th a l ow
gl ycemi c i ndex i ncrea s e pl a s ma gl ucos e l evel s s l owl y, res ul ti ng i n l ower pos tpra ndi a l i ns ul i n l evel s a nd l es s hunger, whi ch proba bl y ma kes
cons umpti on of exces s ca l ori es l es s l i kel y. Thes e effects a re predi cted to res ul t i n a more fa vora bl e l i pi d profi l e a nd a decrea s ed ri s k of obes i ty,
di a betes mel l i tus , a nd compl i ca ti ons of di a betes i f pres ent.
Proteins: Di eta ry protei ns a re broken down i nto pepti des a nd a mi no a ci ds . Protei ns a re requi red for ti s s ue ma i ntena nce, repl a cement, functi on,
a nd growth. However, i f the body i s not getti ng enough ca l ori es from di eta ry s ources or ti s s ue s tores (pa rti cul a rl y of fa t), protei n ma y be us ed for
energy.
As the body us es di eta ry protei n for ti s s ue producti on, there i s a net ga i n of protei n (pos i ti ve ni trogen ba l a nce). Duri ng ca ta bol i c
[Table 1-1. Gl ycemi c Index of Some Foods ]
s ta tes (eg, s ta rva ti on, i nfecti ons , burns ), more protei n ma y be us ed (beca us e body ti s s ues a re broken down) tha n i s a bs orbed, res ul ti ng i n a net
l os s of protei n (nega ti ve ni trogen ba l a nce). Ni trogen ba l a nce i s bes t determi ned by s ubtra cti ng the a mount of ni trogen excreted i n uri ne a nd feces
from the a mount of ni trogen cons umed.
Of the 20 a mi no a ci ds , 9 a re es s enti a l a mi no a ci ds (EAAs ); they ca nnot be s ynthes i zed a nd mus t be obta i ned from the di et. Al l peopl e requi re 8
EAAs ; i nfa nts a l s o requi re hi s ti di ne.
The wei ght-a djus ted requi rement for di eta ry protei n correl a tes wi th growth ra te, whi ch decrea s es from i nfa ncy unti l a dul thood. The da i l y di eta ry
protei n requi rement decrea s es from 2.2 g/kg i n 3-mo-ol d i nfa nts to 1.2 g/kg i n 5-yr-ol d chi l dren a nd to 0.8 g/kg i n a dul ts . Protei n requi rements
corres pond to EAA requi rements (s ee
Ta bl e 1-2). Adul ts tryi ng to i ncrea s e mus cl e ma s s need very l i ttl e extra protei n beyond the requi rements i n the ta bl e.
The a mi no a ci d compos i ti on of protei n va ri es wi del y. Bi ol ogi ca l va l ue (BV) refl ects the s i mi l a ri ty i n a mi no a ci d compos i ti on of protei n to tha t of
a ni ma l ti s s ues ; thus , BV i ndi ca tes wha t percenta ge of a di eta ry protei n provi des EAAs for the body. A perfect ma tch i s egg protei n, wi th a va l ue of
100. Ani ma l protei ns i n mi l k a nd mea t ha ve a hi gh BV (~90); protei ns i n cerea l a nd vegeta bl es ha ve a l ower BV (~40), a nd s ome deri ved protei ns
(eg, gel a ti n) ha ve a BV of 0. The extent to whi ch di eta ry protei ns s uppl y ea ch other's mi s s i ng a mi no a ci ds (compl ementa ri ty) determi nes the
overa l l BV of the di et. The recommended da i l y a l l owa nces (RDA) for protei n a s s umes tha t the a vera ge mi xed di et ha s a BV of 70.
Fats: Fa ts a re broken down i nto fa tty a ci ds a nd gl ycerol . Fa ts a re requi red for ti s s ue growth a nd hormone producti on. Sa tura ted fa tty a ci ds ,
common i n a ni ma l fa ts , tend to be s ol i d a t room tempera ture. Except for pa l m a nd coconut oi l s , fa ts deri ved from pl a nts tend to be l i qui d a t room
tempera ture; thes e fa ts conta i n hi gh l evel s of monouns a tura ted fa tty a ci ds or pol yuns a tura ted fa tty a ci ds (PUFAs ).
Pa rti a l hydrogena ti on of uns a tura ted fa tty a ci ds (a s occurs duri ng food ma nufa cturi ng) produces tra ns fa tty a ci ds , whi ch a re s ol i d or s emi s ol i d a t
room tempera ture. In the US, the ma i n di eta ry s ource of tra ns fa tty a ci ds i s pa rti a l l y hydrogena ted vegeta bl e oi l s , us ed i n ma nufa cturi ng certa i n
foods (eg, cooki es , cra ckers , chi ps ) to prol ong s hel f-l i fe. Tra ns fa tty a ci ds ma y el eva te LDL chol es terol a nd l ower HDL; they ma y a l s o i ndependentl y
i ncrea s e the ri s k of corona ry a rtery di s ea s e.
Es s enti a l fa tty a ci ds (EFAs ) a re l i nol ei c a ci d, a n -6 (n-6) fa tty a ci d, a nd l i nol eni c a ci d, a n -3 (n-3) fa tty a ci d. Other -6 a ci ds (eg, a ra chi doni c a ci d)
a nd other -3 fa tty a ci ds (eg, ei cos a penta enoi c a ci d, docos a hexa enoi c a ci d) a re requi red by the body but ca n be s ynthes i zed from EFAs .
EFAs (s ee a l s o p. 19) a re needed for the forma ti on of va ri ous ei cos a noi ds (bi ol ogi ca l l y a cti ve l i pi ds ), i ncl udi ng pros ta gl a ndi ns , thromboxa nes ,
pros ta cycl i ns , a nd l eukotri enes . Cons umpti on of -3 fa tty a ci ds ma y decrea s e the ri s k of corona ry a rtery di s ea s e.
[Table 1-2. Es s enti a l Ami no Aci d Requi rements i n mg/kg Body Wei ght]
Requi rements for EFAs va ry by a ge. Adul ts requi re a mounts of l i nol ei c a ci d equa l to a t l ea s t 2% of tota l ca l ori c needs a nd l i nol eni c a ci d equa l to
a t l ea s t 0.5%. Vegeta bl e oi l s provi de l i nol ei c a ci d a nd l i nol eni c a ci d. Oi l s ma de from s a ffl ower, s unfl ower, corn, s oya , pri mros e, pumpki n, a nd
whea t germ provi de l a rge a mounts of l i nol ei c a ci d. Ma ri ne fi s h oi l s a nd oi l s ma de from fl a x-s eeds , pumpki n, s oy, a nd ca nol a provi de l a rge
a mounts of l i nol eni c a ci d. Ma ri ne fi s h oi l s a l s o provi de s ome other -3 fa tty a ci ds i n l a rge a mounts .
Macrominerals: Na , Cl , K, Ca , P, a nd Mg a re requi red i n rel a ti vel y l a rge a mounts per da y (s ee
Ta bl es 1-3,
1-4, a nd
5-2).
Water: Wa ter i s cons i dered a ma cronutri ent beca us e i t i s requi red i n a mounts of 1 mL/kca l (0.24 mL/kJ) of energy expended, or a bout 2500 mL/da y.
Needs va ry wi th fever, phys i ca l a cti vi ty, a nd cha nges i n cl i ma te a nd humi di ty.
[Table 1-3. Ma cromi nera l s ]
[Table 1-4. Recommended Di eta ry Reference Inta kes * for Some Ma cronutri ents , Food a nd Nutri ti on Boa rd, Ins ti tute of Medi ci ne of the Na ti ona l
Aca demi es ]
Micronutrients
Vi ta mi ns a nd mi nera l s requi red i n mi nute a mounts (tra ce mi nera l s ) a re mi cronutri ents (s ee Chs . 4 a nd 5).
Water-soluble vitamins a re vi ta mi n C (a s corbi c a ci d) a nd 8 members of the vi ta mi n B compl ex: bi oti n, fol a te, ni a ci n, pa ntotheni c a ci d, ri bofl a vi n
(vi ta mi n B 2 ), thi a mi n (vi ta mi n B 1 ), vi ta mi n B 6 (pyri doxi ne), a nd vi ta mi n B 12 (coba l a mi n).
Fat-soluble vitamins a re vi ta mi ns A (reti nol ), D (chol eca l ci ferol a nd ergoca l ci ferol ), E (-tocopherol ), a nd K (phyl l oqui none a nd mena qui none).
Onl y vi ta mi ns A, E, a nd B 12 a re s tored to a ny s i gni fi ca nt extent i n the body; the other vi ta mi ns mus t be cons umed regul a rl y to ma i nta i n ti s s ue
hea l th.
Essential trace minerals i ncl ude chromi um, copper, i odi ne, i ron, ma nga nes e, mol ybdenum, s el eni um, a nd zi nc. Except for chromi um, ea ch of thes e i s
i ncorpora ted i nto enzymes or hormones requi red i n meta bol i s m. Except for defi ci enci es of i ron a nd zi nc, mi cromi nera l defi ci enci es a re uncommon
i n devel oped countri es (s ee Ch. 5).
Other mi nera l s (eg, a l umi num, a rs eni c, boron, coba l t, fl uori de, ni ckel , s i l i con, va na di um) ha ve not been proved es s enti a l for peopl e. Fl uori de,
a l though not es s enti a l , hel ps prevent tooth deca y by formi ng a compound wi th Ca (Ca F 2 ), whi ch s ta bi l i zes the mi nera l ma tri x i n teeth.
Al l tra ce mi nera l s a re toxi c a t hi gh l evel s , a nd s ome (a rs eni c, ni ckel , a nd chromi um) ma y ca us e ca ncer.
Other Dietary Substances
The da i l y huma n di et typi ca l l y conta i ns a s ma ny a s 100,000 chemi ca l s (eg, coffee conta i ns 1000). Of thes e, onl y 300 a re nutri ents , onl y s ome of
whi ch a re es s enti a l . However, ma ny nonnutri ents i n foods a re us eful . For exa mpl e, food a ddi ti ves (eg, pres erva ti ves , emul s i fi ers , a nti oxi da nts ,
s ta bi l i zers ) i mprove the producti on a nd s ta bi l i ty of foods . Tra ce components (eg, s pi ces , fl a vors , odors , col ors , phytochemi ca l s , ma ny other na tura l
products ) i mprove a ppea ra nce a nd ta s te.
Fiber: Fi ber occurs i n va ri ous forms (eg, cel l ul os e, hemi cel l ul os e, pecti n, gums ). It i ncrea s es GI moti l i ty, prevents cons ti pa ti on, a nd hel ps control
di verti cul a r di s ea s e. Fi ber i s thought to a ccel era te the el i mi na ti on of ca ncer-ca us i ng s ubs ta nces produced by ba cteri a i n the l a rge i ntes ti ne.
Epi demi ol ogi c evi dence s ugges ts a n a s s oci a ti on between col on ca ncer a nd l ow fi ber i nta ke a nd a benefi ci a l effect of fi ber i n pa ti ents wi th
functi ona l bowel di s orders , Crohn's di s ea s e, obes i ty, a nd hemorrhoi ds . Sol ubl e fi ber (pres ent i n frui ts , vegeta bl es , oa ts , ba rl ey, a nd l egumes )
reduces the pos tpra ndi a l i ncrea s e i n bl ood gl ucos e a nd i ns ul i n a nd ca n reduce chol es terol l evel s .
The typi ca l Wes tern di et i s l ow i n fi ber (a bout 12 g/da y) beca us e of a hi gh i nta ke of hi ghl y refi ned whea t fl our a nd a l ow i nta ke of frui ts a nd
vegeta bl es . Increa s i ng fi ber i nta ke to a bout 30 g/da y by cons umi ng more vegeta bl es , frui ts , a nd hi gh-fi ber cerea l s a nd gra i ns i s genera l l y
recommended. However, very hi gh fi ber i nta ke ma y reduce a bs orpti on of certa i n mi nera l s .
Nutritional Requirements
Good nutri ti on a i ms to a chi eve a nd ma i nta i n a des i ra bl e body compos i ti on a nd hi gh potenti a l for phys i ca l a nd menta l work. Ba l a nci ng energy
i nta ke wi th energy expendi ture i s neces s a ry for a des i ra bl e body wei ght. Energy expendi ture depends on a ge, s ex, wei ght (s ee Ta bl e 1-4), a nd
meta bol i c a nd phys i ca l a cti vi ty. If energy i nta ke exceeds expendi ture, wei ght i s ga i ned. Ta ki ng i n a bout 100 ca l ori es /da y more tha n needed res ul ts
i n a wei ght ga i n of a bout 4 to 5 kg i n a yea r. If energy i nta ke i s l es s tha n expendi ture, wei ght i s l os t.
Da i l y di eta ry requi rements for es s enti a l nutri ents a l s o depend on a ge, s ex, wei ght, a nd meta bol i c a nd phys i ca l a cti vi ty. Every 5 yr, the Food a nd
Nutri ti on Boa rd of the Na ti ona l Aca demy of Sci ences /Na ti ona l Res ea rch Counci l a nd the US Depa rtment of Agri cul ture (USDA) i s s ues the di eta ry
reference i nta kes (DRIs ) for protei n, energy, a nd s ome vi ta mi ns a nd mi nera l s (s ee Ta bl es 1-4,
4-1, a nd 5-2). For vi ta mi ns a nd mi nera l s a bout whi ch l es s i s known, s a fe a nd a dequa te da i l y di eta ry i nta kes a re es ti ma ted.
Pregna nt women (s ee p. 2608) a nd i nfa nts (s ee p. 2703) ha ve s peci a l nutri ti ona l needs .
The USDA publ i s hes the Food Gui de Pyra mi d, whi ch s peci fi es the number of recommended da i l y s ervi ngs of va ri ous food groups . The
recommenda ti ons a re i ndi vi dua l i zed ba s ed on a ge, s ex, a nd phys i ca l a cti vi ty (s ee
Ta bl e 1-5). Genera l l y, the recommended i nta ke decrea s es wi th a gi ng beca us e phys i ca l a cti vi ty tends to decrea s e, res ul ti ng i n l es s energy
expended. The new Food Gui de Pyra mi d empha s i zes the fol l owi ng:
Increa s i ng cons umpti on of whol e gra i ns
Increa s i ng cons umpti on of vegeta bl es a nd frui ts
Subs ti tuti ng fa t-free or l ow-fa t mi l k products (or equi va l ents ) for whol e-fa t mi l k products
Reduci ng cons umpti on of s a tura ted fa ts a nd tra ns fa tty a ci ds
Exerci s i ng regul a rl y
Adequa te fl ui d i nta ke i s a l s o i mporta nt.
Fa ts s houl d cons ti tute 30% of tota l ca l ori es , a nd s a tura ted a nd tra ns fa tty a ci ds s houl d cons ti tute < 10%. Exces s i nta ke of s a tura ted fa ts
contri butes to a theros cl eros i s . Subs ti tuti ng pol yuns a tura ted fa tty a ci ds for s a tura ted fa ts ca n decrea s e the ri s k of a theros cl eros i s . Routi ne us e of
nutri ti ona l s uppl ements i s not neces s a ry or benefi ci a l ; s ome s uppl ements ca n be ha rmful . For exa mpl e, exces s vi ta mi n A ca n l ea d to
hypervi ta mi nos i s A, wi th hea da ches , os teoporos i s , a nd ra s h.
Nutrition in Clinical Medicine
Nutri ti ona l defi ci enci es ca n often wors en hea l th outcomes (whether a di s order i s pres ent or not), a nd s ome di s orders (eg, ma l a bs orpti on) ca n
ca us e nutri ti ona l defi ci enci es . Al s o, ma ny pa ti ents (eg, el derl y pa ti ents duri ng a cute hos pi ta l i za ti on) ha ve uns us pected nutri ti ona l defi ci enci es
tha t requi re trea tment. Ma ny medi ca l centers ha ve mul ti -di s ci pl i na ry nutri ti on s upport tea ms of phys i ci a ns , nurs es , di eti ti a ns , a nd pha rma ci s ts to
hel p the cl i ni ci a n prevent, di a gnos e, a nd trea t occul t nutri ti ona l defi ci enci es .
Overnutri ti on ma y contri bute to chroni c di s orders , s uch a s ca ncer, hypertens i on, obes i ty, di a betes mel l i tus , a nd corona ry a rtery di s ea s e. Di eta ry
res tri cti ons a re neces s a ry i n ma ny heredi ta ry meta bol i c di s orders (eg, ga l a ctos emi a , phenyl ketonuri a ).
Evaluation of Nutritional Status
Indi ca ti ons for nutri ti ona l eva l ua ti on i ncl ude undes i ra bl e body wei ght or body compos i ti on, s us pi ci on of s peci fi c defi ci enci es or toxi ci ti es
[Table 1-5. Recommended Di eta ry Inta ke for 40-yr-Ol ds wi th Modera te Phys i ca l Acti vi ty*]
of es s enti a l nutri ents , a nd, i n i nfa nts a nd chi l dren, i ns uffi ci ent growth or devel opment. Nutri ti ona l s ta tus s houl d be eva l ua ted routi nel y a s pa rt
of the cl i ni ca l exa mi na ti on for i nfa nts a nd chi l dren, the el derl y, peopl e ta ki ng s evera l drugs , peopl e wi th ps ychi a tri c di s orders , a nd peopl e wi th
s ys temi c di s orders tha t l a s t l onger tha n s evera l da ys .
Eva l ua ti ng genera l nutri ti ona l s ta tus i ncl udes hi s tory, phys i ca l exa mi na ti on, a nd s ometi mes tes ts . If undernutri ti on i s s us pected, l a bora tory tes ts
(eg, a l bumi n l evel s ) a nd s ki n tes ts for del a yed hypers ens i ti vi ty ma y be done (s ee p.
13). Body compos i ti on a na l ys i s (eg, s ki nfol d mea s urements , bi oel ectri ca l i mpeda nce a na l ys i s ) i s us ed to es ti ma te percenta ge of body fa t a nd to
eva l ua te obes i ty (s ee p. 58).
Hi s tory i ncl udes ques ti ons a bout di eta ry i nta ke, wei ght cha nge, a nd ri s k fa ctors for nutri ti ona l defi ci enci es a nd a focus ed revi ew of s ys tems (s ee
Ta bl e 2-1 on p. 11). A di eti ti a n ca n obta i n a more deta i l ed di eta ry hi s tory. It us ua l l y i ncl udes a l i s t of foods ea ten wi thi n the previ ous 24 h a nd a
food ques ti onna i re. A food di a ry ma y be us ed to record a l l foods ea ten. The wei ghed a d l i bi tum di et, i n whi ch the pa ti ent wei ghs a nd wri tes down
a l l foods cons umed, i s the mos t a ccura te record.
A compl ete phys i ca l exa mi na ti on, i ncl udi ng mea s urement of hei ght a nd wei ght a nd di s tri buti on of body fa t, s houl d be done. Body ma s s i ndex
(BMI)wei ght(kg)/hei ght(m) 2 , whi ch a djus ts wei ght for hei ght (s ee
Ta bl e 6-2 on p. 59), i s more a ccura te tha n hei ght a nd wei ght ta bl es . There a re s ta nda rds for growth a nd wei ght ga i n i n i nfa nts , chi l dren, a nd
a dol es cents (s ee p. 2756).
Di s tri buti on of body fa t i s i mporta nt. Di s proporti ona te trunca l obes i ty (i e, wa i s t/hi p ra ti o > 0.8) i s a s s oci a ted wi th ca rdi ova s cul a r a nd
cerebrova s cul a r di s orders , hypertens i on, a nd di a betes mel l i tus more often tha n fa t l oca ted el s ewhere. Mea s uri ng wa i s t ci rcumference i n pa ti ents
wi th a BMI of < 35 hel ps determi ne whether they ha ve trunca l obes i ty a nd hel ps predi ct ri s k of di a betes , hypertens i on, hyperchol es terol emi a , a nd
ca rdi ova s cul a r di s orders . Ri s k i s i ncrea s ed i f wa i s t ci rcumference i s > 102 cm (> 40 i n) i n men or > 88 cm (> 35 i n) i n women.
Nutrient-Drug Interactions
Nutri ti on ca n a ffect the body's res pons e to drugs ; convers el y, drugs ca n a ffect the body's nutri ti on.
Foods ca n enha nce, del a y, or decrea s e drug a bs orpti on. Foods i mpa i r a bs orpti on of ma ny a nti bi oti cs . They ca n a l ter meta bol i s m of drugs ; eg,
hi gh-protei n di ets ca n a ccel era te meta bol i s m of certa i n drugs by s ti mul a ti ng cytochrome P-450. Ea ti ng gra pefrui t ca n i nhi bi t cytochrome P-450 34A,
s l owi ng meta bol i s m of s ome drugs (eg, a mi oda rone, ca rba ma zepi ne, cycl os pori ne, certa i n Ca cha nnel bl ockers ). Di ets tha t a l ter the ba cteri a l fl ora
ma y ma rkedl y a ffect the overa l l meta bol i s m of certa i n drugs . Some foods a ffect the body's res pons e to drugs . For exa mpl e, tyra mi ne, a component
of chees e a nd a potent va s ocons tri ctor, ca n ca us e hypertens i ve cri s i s i n s ome pa ti ents who ta ke monoa mi ne oxi da s e i nhi bi tors a nd ea t chees e.
Nutri ti ona l defi ci enci es ca n a ffect drug a bs orpti on a nd meta bol i s m. Severe energy a nd protei n defi ci enci es reduce enzyme ti s s ue concentra ti ons
a nd ma y i mpa i r the res pons e to drugs by reduci ng a bs orpti on or protei n bi ndi ng a nd ca us i ng l i ver dys functi on. Cha nges i n the GI tra ct ca n i mpa i r
a bs orpti on a nd a ffect the res pons e to a drug. Defi ci ency of Ca , Mg, or zi nc ma y i mpa i r drug meta bol i s m. Vi ta mi n C defi ci ency decrea s es a cti vi ty of
drug-meta bol i zi ng enzymes , es peci a l l y i n the el derl y.
Ma ny drugs a ffect a ppeti te, food a bs orpti on, a nd ti s s ue meta bol i s m (s ee
Ta bl e 1-6). Some drugs (eg, metocl opra mi de) i ncrea s e GI moti l i ty, decrea s i ng food a bs orpti on. Other drugs (eg, opi oi ds , a nti chol i nergi cs ) decrea s e
GI moti l i ty. Some drugs a re better tol era ted i f ta ken wi th food.
Certa i n drugs a ffect mi nera l meta bol i s m. For exa mpl e, di ureti cs , es peci a l l y thi a zi des , a nd corti cos teroi ds ca n depl ete body K, i ncrea s i ng
s us cepti bi l i ty to di goxi n-i nduced ca rdi a c a rrhythmi a s . Repea ted us e of l a xa ti ves ma y depl ete K. Corti s ol , des oxycorti cos terone, a nd a l dos terone
ca us e ma rked Na a nd wa ter retenti on, a t l ea s t tempora ri l y; retenti on i s much l es s wi th predni s one, predni s ol one, a nd s ome other corti cos teroi d
a na l ogs . Sul fonyl urea s a nd l i thi um ca n i mpa i r the upta ke or rel ea s e of i odi ne by the thyroi d. Ora l contra cepti ves ca n l ower bl ood zi nc l evel s a nd
i ncrea s e copper l evel s . Certa i n a nti bi oti cs (eg, tetra cycl i nes ) reduce i ron a bs orpti on, a s ca n certa i n foods (eg, vegeta bl es , tea , bra n).
Certa i n drugs a ffect vi ta mi n a bs orpti on or meta bol i s m. Etha nol i mpa i rs thi a mi n uti l i za ti on, a nd i s oni a zi d i nterferes wi th ni a ci n a nd pyri doxi ne
meta bol i s m. Etha nol a nd ora l contra cepti ves i nhi bi t fol a te (fol i c a ci d) a bs orpti on. Mos t pa ti ents recei vi ng phenytoi n, phenoba rbi ta l , pri mi done,
or phenothi a zi nes devel op fol a te defi ci ency, proba bl y beca us e hepa ti c mi cros oma l drug-meta bol i zi ng enzymes a re a ffected. Fol a te s uppl ements
ma y
[Table 1-6. Effects of Some Drugs on Nutri ti on]
ma ke phenytoi n l es s effecti ve. Anti convul s a nts ca n ca us e vi ta mi n D defi ci ency. Ma l a bs orpti on of vi ta mi n B 12 ca n occur wi th us e of a mi nos a l i cyl i c
a ci d, s l ow-rel ea s e K i odi de, col chi ci ne, tri fl uopera zi ne, etha nol , a nd ora l contra cepti ves . Ora l contra cepti ves wi th a hi gh proges ti n dos e ca n ca us e
depres s i on, proba bl y beca us e of meta bol i ca l l y i nduced tryptopha n defi ci ency.
Food Additives and Contaminants
Additives: Chemi ca l s a re often combi ned wi th foods to fa ci l i ta te thei r proces s i ng a nd pres erva ti on or to enha nce thei r des i ra bi l i ty. Onl y a mounts
of a ddi ti ves s hown to be s a fe by l a bora tory tes ts a re permi tted i n commerci a l l y prepa red foods .
Wei ghi ng the benefi ts of a ddi ti ves (eg, reduced wa s te, i ncrea s ed va ri ety of a va i l a bl e foods , protecti on a ga i ns t food-borne i l l nes s ) a ga i ns t the
ri s ks i s often compl ex. For exa mpl e, ni tri te, whi ch i s us ed i n cured mea ts , i nhi bi ts the growth of Clostridium botulinum a nd i mproves fl a vor. However,
ni tri te converts to ni tros a mi nes , whi ch a re ca rci nogens i n a ni ma l s . On the other ha nd, the a mount of ni tri te a dded to cured mea t i s s ma l l
compa red wi th the a mount from na tura l l y occurri ng food ni tra tes converted to ni tri te by the s a l i va ry gl a nds . Di eta ry vi ta mi n C ca n reduce ni tri te
forma ti on i n the GI tra ct. Ra rel y, s ome a ddi ti ves (eg, s ul fi tes ) ca us e food hypers ens i ti vi ty (a l l ergy) rea cti ons . Mos t of thes e rea cti ons a re ca us ed by
ordi na ry foods (s ee p. 1118).
Contaminants: Someti mes l i mi ted a mounts of conta mi na nts a re a l l owed i n foods beca us e the conta mi na nts ca nnot be compl etel y el i mi na ted
wi thout da ma gi ng the foods . Common conta mi na nts a re pes ti ci des , hea vy meta l s (l ea d, ca dmi um, mercury), ni tra tes (i n green l ea fy vegeta bl es ),
a fl a toxi ns (i n nuts a nd mi l k), growth-promoti ng hormones (i n da i ry products a nd mea t), a ni ma l ha i rs a nd feces , a nd i ns ect pa rts .
FDA-es ti ma ted s a fe l evel s a re l evel s tha t ha ve not ca us ed i l l nes s or a dvers e effects i n peopl e. However, demons tra ti ng a ca us a l rel a ti ons hi p
between extremel y l ow l evel expos ures a nd a dvers e effects i s di ffi cul t; l ong-term a dvers e effects , a l though unl i kel y, a re s ti l l pos s i bl e. Sa fe l evel s
a re often determi ned by cons ens us ra ther tha n by ha rd evi dence.
Chapter 2. Undernutrition
Introduction
Undernutrition is a form of malnutrition. (Malnutrition also includes overnutritionsee Ch. 6). Undernutrition can result from inadequate ingestion of nutrients,
malabsorption, impaired metabolism, loss of nutrients due to diarrhea, or increased nutritional requirements (as occurs in cancer or infection). Undernutrition
progresses in stages; each stage usually takes considerable time to develop. First, nutrient levels in blood and tissues change, followed by intracellular changes in
biochemical functions and structure. Ultimately, symptoms and signs appear.
Risk Factors
Undernutri ti on i s a s s oci a ted wi th ma ny di s orders a nd ci rcums ta nces , i ncl udi ng poverty a nd s oci a l depri va ti on. Ri s k i s a l s o grea ter a t certa i n ti mes
(i e, duri ng i nfa ncy, ea rl y chi l dhood, a dol es cence, pregna ncy, brea s tfeedi ng, a nd ol d a ge).
Infancy and childhood: Infa nts a nd chi l dren a re pa rti cul a rl y s us cepti bl e to undernutri ti on beca us e of thei r hi gh dema nd for energy a nd es s enti a l
nutri ents . Beca us e vi ta mi n K does not rea di l y cros s the pl a centa , neona tes ma y be defi ci ent, s o a l l a re gi ven a s i ngl e i njecti on of vi ta mi n K wi thi n
1 h of bi rth to prevent hemorrha gi c di s ea s e of the newborn, a l i fe-threa teni ng di s order (s ee pp. 46 a nd
2783). Infa nts fed onl y brea s t mi l k, whi ch i s typi ca l l y l ow i n vi ta mi n D, a re gi ven s uppl ementa l vi ta mi n D; they ca n devel op vi ta mi n B 12 defi ci ency i f
the mother i s a vega n. Ina dequa tel y fed i nfa nts a nd chi l dren a re a t ri s k of protei n-energy undernutri ti on (PEUprevi ous l y ca l l ed protei n-energy
ma l nutri ti on) a nd defi ci enci es of i ron, fol a te (fol i c a ci d), vi ta mi ns A a nd C, copper, a nd zi nc. Duri ng a dol es cence, nutri ti ona l requi rements
i ncrea s e beca us e the growth ra te a ccel era tes . Anorexi a nervos a (s ee p. 1535) ma y a ffect a dol es cent gi rl s i n pa rti cul a r.
Pregnancy and breastfeeding: Requi rements for nutri ents i ncrea s e duri ng pregna ncy a nd brea s tfeedi ng. Aberra ti ons of di et, i ncl udi ng pi ca
(cons umpti on of nonnutri ti ve s ubs ta nces , s uch a s cl a y a nd cha rcoa l ), ma y occur duri ng pregna ncy. Anemi a due to i ron defi ci ency i s common, a s i s
a nemi a due to fol a te defi ci ency, es peci a l l y a mong women who ha ve ta ken ora l contra cepti ves . Vi ta mi n D defi ci ency i s common duri ng l a te
pregna ncy, predi s pos i ng the chi l d to decrea s ed bone ma s s .
Old age: Agi ngeven when di s ea s e or di eta ry defi ci ency i s a bs entl ea ds to s a rcopeni a (progres s i ve l os s of l ea n body ma s s ), s ta rti ng a fter a ge 40
a nd eventua l l y a mounti ng to a mus cl e l os s of a bout 10 kg (22 l b) i n men a nd 5 kg (11 l b) i n women. Undernutri ti on contri butes to s a rcopeni a , a nd
s a rcopeni a a ccounts for ma ny of the compl i ca ti ons of undernutri ti on (eg, decrea s ed ni trogen ba l a nce, i ncrea s ed s us cepti bi l i ty to i nfecti ons ).
Ca us es of s a rcopeni a i ncl ude the fol l owi ng:
Decrea s ed phys i ca l a cti vi ty
Decrea s ed food i nta ke
Increa s ed l evel s of cytoki nes (pa rti cul a rl y i nterl euki n-6)
Decrea s ed l evel s of growth hormone a nd mecha no growth fa ctor (i ns ul i n-l i ke growth fa ctor-3)
In men, decrea s i ng a ndrogen l evel s
Agi ng decrea s es ba s a l meta bol i c ra te (due ma i nl y to decrea s ed fa t-free ma s s ), tota l body wei ght, hei ght, a nd s kel eta l ma s s ; a gi ng i ncrea s es
mea n body fa t (a s a percenta ge of body wei ght) to a bout 30% (from 20%) i n men a nd to 40% (from 27%) i n women.
From a ge 20 to 80, food i nta ke decrea s es , es peci a l l y i n men. Anorexi a due to a gi ng i ts el f ha s ma ny ca us es , i ncl udi ng reduced a da pti ve rel a xa ti on
of the s toma ch's fundus , i ncrea s ed rel ea s e a nd a cti vi ty of chol ecys toki ni n (whi ch produces s a ti a ti on), a nd i ncrea s ed l epti n (a n a norecti c hormone
produced by fa t cel l s ). Di mi ni s hed ta s te a nd s mel l ca n decrea s e ea ti ng pl ea s ure but us ua l l y decrea s e food i nta ke onl y s l i ghtl y. Anorexi a ma y
ha ve other ca us es (eg, l onel i nes s , i na bi l i ty to s hop or prepa re mea l s , dementi a , s ome chroni c di s orders , us e of certa i n drugs ). Depres s i on i s a
common ca us e. Occa s i ona l l y, a norexi a nervos a (s ometi mes ca l l ed a norexi a ta rdi ve i n the el derl y), pa ra noi a , or ma ni a i nterferes wi th ea ti ng.
Denta l probl ems l i mi t the a bi l i ty to chew a nd s ubs equentl y to di ges t foods . Swa l l owi ng di ffi cul ti es (eg, due to s trokes , other neurol ogi c
di s orders , es opha gea l ca ndi di a s i s , or xeros tomi a ) a re common. Poverty or functi ona l i mpa i rment l i mi ts a cces s to nutri ents .
The i ns ti tuti ona l i zed el derl y a re a t pa rti cul a r ri s k of PEU. They a re often confus ed a nd ma y be una bl e to expres s hunger or preferences for foods .
They ma y be phys i ca l l y una bl e to feed thems el ves . Chewi ng or s wa l l owi ng ma y be very s l ow, ma ki ng i t tedi ous for a nother pers on to feed them
enough food.
In the el derl y, pa rti cul a rl y the i ns ti tuti ona l i zed el derl y, i na dequa te i nta ke a nd often decrea s ed a bs orpti on or s ynthes i s of vi ta mi n D, i ncrea s ed
dema nd for vi ta mi n D, a nd i na dequa te expos ure to s uns hi ne contri bute to os teoma l a ci a (s ee p. 41).
Disorders and medical procedures: Di a betes , s ome chroni c di s orders tha t a ffect the GI tra ct, i ntes ti na l res ecti on, a nd certa i n other GI s urgi ca l
procedures tend to i mpa i r a bs orpti on of fa t-s ol ubl e vi ta mi ns , vi ta mi n B 12 , Ca , a nd i ron. Gl uten enteropa thy, pa ncrea ti c i ns uffi ci ency, or other
di s orders ca n res ul t i n ma l a bs orpti on. Decrea s ed a bs orpti on pos s i bl y contri butes to i ron defi ci ency a nd os teoporos i s . Li ver di s orders i mpa i r
s tora ge of vi ta mi ns A a nd B 12 a nd i nterfere wi th meta bol i s m of protei n a nd energy s ources . Rena l i ns uffi ci ency predi s pos es to protei n, i ron, a nd
vi ta mi n D defi ci enci es . Anorexi a ca us es s ome pa ti ents wi th ca ncer or depres s i on a nd ma ny wi th AIDS to cons ume i na dequa te a mounts of food.
Infecti ons , tra uma , hyperthyroi di s m, extens i ve burns , a nd prol onged fever i ncrea s e meta bol i c dema nds . Any condi ti on tha t i ncrea s es cytoki nes
ma y be a ccompa ni ed by mus cl e l os s , l i pol ys i s , l ow a l bumi n l evel s , a nd a norexi a .
Vegetarian diets: Iron defi ci ency ca n occur i n ovo-l a cto vegeta ri a ns (a l though s uch a di et ca n be compa ti bl e wi th good hea l th). Vega ns ma y devel op
vi ta mi n B 12 defi ci ency unl es s they cons ume yea s t extra cts or As i a n-s tyl e fermented foods . Thei r i nta ke of Ca , i ron, a nd zi nc a l s o tends to be l ow. A
frui t-onl y di et i s not recommended beca us e i t i s defi ci ent i n protei n, Na , a nd ma ny mi cronutri ents .
Fad diets: Some fa d di ets res ul t i n vi ta mi n, mi nera l , a nd protei n defi ci enci es ; ca rdi a c, rena l , a nd meta bol i c di s orders ; a nd s ometi mes dea th. Very
l ow ca l ori e di ets (< 400 kca l /da y) ca nnot s us ta i n hea l th for l ong.
Drugs and nutritional supplements: Ma ny drugs (eg, a ppeti te s uppres s a nts , di goxi n) decrea s e a ppeti te; others i mpa i r nutri ent a bs orpti on or
meta bol i s m. Some drugs (eg, s ti mul a nts ) ha ve ca ta bol i c effects . Certa i n drugs ca n i mpa i r a bs orpti on of ma ny nutri ents ; eg, a nti convul s a nts ca n
i mpa i r a bs orpti on of vi ta mi ns .
Alcohol or drug dependency: Pa ti ents wi th a l cohol or drug dependency ma y negl ect thei r nutri ti ona l needs . Abs orpti on a nd meta bol i s m of nutri ents
ma y a l s o be i mpa i red. IV drug a ddi cts typi ca l l y become undernouri s hed, a s do
[
Table 2-1. Symptoms a nd Si gns of Nutri ti ona l Defi ci ency]
a l cohol i cs who cons ume 1 qua rt of ha rd l i quor/da y. Al cohol i s m ca n ca us e defi ci enci es of Mg, zi nc, a nd certa i n vi ta mi ns , i ncl udi ng thi a mi n.
Symptoms and Signs
Symptoms va ry dependi ng on the ca us e a nd type of undernutri ti on (s ee p. 15 a nd Chs . 4 a nd 5).
Evaluation
Di a gnos i s i s ba s ed on res ul ts of medi ca l a nd di et hi s tori es , phys i ca l exa mi na ti on, body compos i ti on a na l ys i s (s ee p. 58), a nd s el ected l a bora tory
tes ts .
History: Hi s tory s houl d i ncl ude ques ti ons a bout di eta ry i nta ke (s ee
Fi g. 2-1), recent cha nges i n wei ght, a nd ri s k fa ctors for undernutri ti on, i ncl udi ng drug a nd a l cohol us e. Uni ntenti ona l l os s of 10% of us ua l body
wei ght duri ng a 3-mo peri od i ndi ca tes a hi gh proba bi l i ty of undernutri ti on. Soci a l hi s tory s houl d i ncl ude ques ti ons a bout whether money i s
a va i l a bl e for food a nd whether the pa ti ent ca n s hop a nd cook.
Revi ew of s ys tems s houl d focus on s ymptoms of nutri ti ona l defi ci enci es (s ee Ta bl e 2-1). For exa mpl e, i mpa i red ni ght vi s i on ma y i ndi ca te vi ta mi n
A defi ci ency.
Physical examination: Phys i ca l exa mi na ti on s houl d i ncl ude mea s urement of hei ght a nd wei ght, i ns pecti on of body fa t di s tri buti on, a nd
a nthropometri c mea s urements of l ea n body ma s s . Body ma s s i ndex (BMI = wei ght(kg)/hei ght(m) 2 ) a djus ts wei ght for hei ght (s ee
Ta bl e 6-2 on p. 59). If wei ght i s < 80% of wha t i s predi cted for the pa ti ent's hei ght or i f BMI i s 18, undernutri ti on s houl d be s us pected. Al though
thes e fi ndi ngs a re us eful i n di a gnos i ng undernutri ti on a nd a re a ccepta bl y s ens i ti ve, they l a ck s peci fi ci ty.
[Fig. 2-1. Mi ni nutri ti ona l a s s es s ment.]
The mi d upper a rm mus cl e a rea es ti ma tes l ea n body ma s s . Thi s a rea i s deri ved from the tri ceps s ki nfol d thi cknes s (TSF) a nd mi d upper a rm
ci rcumference. Both a re mea s ured a t the s a me s i te, wi th the pa ti ent's ri ght a rm i n a rel a xed pos i ti on. The a vera ge mi d upper a rm ci rcumference i s
a bout 32 5 cm for men a nd 28 6 cm for women. The formul a for ca l cul a ti ng the mi d upper a rm mus cl e a rea i n cm 2 i s a s fol l ows :
Thi s formul a corrects the upper a rm a rea for fa t a nd bone. Avera ge va l ues for the mi d upper a rm mus cl e a rea a re 54 11 cm 2 for men a nd 30 7
cm 2 for women. A va l ue < 75% of thi s s ta nda rd (dependi ng on a ge) i ndi ca tes depl eti on of l ea n body ma s s (s ee
Ta bl e 2-2). Thi s mea s urement ma y be a ffected by phys i ca l a cti vi ty, geneti c fa ctors , a nd a ge-rel a ted mus cl e l os s .
Phys i ca l exa mi na ti on s houl d focus on s i gns of s peci fi c nutri ti ona l defi ci enci es . Si gns of PEU (eg, edema , mus cl e wa s ti ng, s ki n cha nges ) s houl d be
s ought. Exa mi na ti on s houl d a l s o focus on s i gns of condi ti ons tha t coul d predi s pos e to nutri ti ona l defi ci enci es , s uch a s denta l probl ems . Menta l
s ta tus s houl d be a s s es s ed, beca us e depres s i on a nd cogni ti ve i mpa i rment ca n l ea d to wei ght l os s .
The wi del y us ed Subjecti ve Gl oba l As s es s ment (SGA) us es i nforma ti on from the pa ti ent hi s tory (eg, wei ght l os s , cha nge i n i nta ke, GI s ymptoms ),
phys i ca l exa mi na ti on fi ndi ngs (eg, l os s of mus cl e a nd s ubcuta neous fa t, edema , a s ci tes ), a nd the cl i ni ci a n's judgment of the pa ti ent's nutri ti ona l
s ta tus . The Mi ni Nutri ti ona l As s es s ment (MNA) ha s been va l i da ted a nd i s wi del y us ed, es peci a l l y for el derl y pa ti ents (s ee Fi g. 2-1). The Si mpl i fi ed
Nutri ti on As s es s ment Ques ti onna i re (SNAQ), a s i mpl e, va l i da ted method of predi cti ng future wei ght l os s , ma y be us ed (s ee
Fi g. 2-2).
Testing: The extent of l a bora tory tes ti ng needed i s uncl ea r a nd ma y depend on the pa ti ent's ci rcums ta nces . If the ca us e i s obvi ous a nd correcta bl e
(eg, a wi l dernes s s urvi va l s i tua ti on), tes ti ng i s proba bl y of l i ttl e benefi t. Other pa ti ents ma y requi re more deta i l ed eva l ua ti on.
Serum a l bumi n mea s urement i s the l a bora tory tes t mos t often us ed. Decrea s es i n a l bumi n a nd other protei ns (eg, prea l bumi n [tra ns thyreti n],
tra ns ferri n, reti nol -bi ndi ng protei n) ma y i ndi ca te protei n defi ci ency or PEU. As undernutri ti on progres s es , a l bumi n decrea s es s l owl y; prea l bumi n,
tra ns ferri n, a nd reti nol -bi ndi ng protei n decrea s e ra pi dl y. Al bumi n mea s urement i s i nexpens i ve a nd predi cts morbi di ty a nd morta l i ty better tha n
mea s urement of the other protei ns . However, the correl a ti on of a l bumi n wi th morbi di ty a nd morta l i ty ma y be rel a ted to nonnutri ti ona l a s wel l a s
nutri ti ona l fa ctors . Infl a mma ti on produces cytoki nes tha t ca us e a l bumi n a nd other nutri ti ona l protei n ma rkers to extra va s a te, decrea s i ng s erum
l evel s . Beca us e prea l bumi n, tra ns ferri n, a nd reti nol -bi ndi ng protei n decrea s e more ra pi dl y duri ng s ta rva ti on tha n does a l bumi n, thei r
mea s urements a re s ometi mes us ed to di a gnos e or a s s es s the s everi ty of a cute s ta rva ti on. However, whether they a re more s ens i ti ve or s peci fi c
tha n a l bumi n i s uncl ea r.
Tota l l ymphocyte count, whi ch often decrea s es a s undernutri ti on progres s es , ma y be determi ned. Undernutri ti on ca us es a ma rked decl i ne i n CD4+
T l ymphocytes , s o thi s count ma y not be us eful i n pa ti ents who ha ve AIDS.
Ski n tes ts us i ng a nti gens ca n detect i mpa i red cel l -medi a ted i mmuni ty i n PEU a nd i n s ome other di s orders of undernutri ti on (s ee p.
1098).
Other l a bora tory tes ts , s uch a s mea s uri ng vi ta mi n a nd mi nera l l evel s , a re us ed s el ecti vel y to di a gnos e s peci fi c defi ci enci es .
[Table 2-2. Mi d Upper Arm Mus cl e Area i n Adul ts ]
[Figure 2-2. Si mpl i fi ed Nutri ti on As s es s ment Ques ti onna i re (SNAQ).]
Protein-Energy Undernutrition
Protein-energy undernutrition (PEU), previously called protein-energy malnutrition, is an energy deficit due to chronic deficiency of all macronutrients. It
commonly includes deficiencies of many micronutrients. PEU can be sudden and total (starvation) or gradual. Severity ranges from subclinical deficiencies to
obvious wasting (with edema, hair loss, and skin atrophy) to starvation. Multiple organ systems are often impaired. Diagnosis usually involves laboratory testing,
including serum albumin. Treatment consists of correcting fluid and electrolyte deficits with IV solutions, then gradually replenishing nutrients, orally if possible.
In devel oped countri es , PEU i s common a mong the i ns ti tuti ona l i zed el derl y (a l though often not s us pected) a nd a mong pa ti ents wi th di s orders
tha t decrea s e a ppeti te or i mpa i r nutri ent di ges ti on, a bs orpti on, or meta bol i s m. In devel opi ng countri es , PEU a ffects chi l dren who do not cons ume
enough ca l ori es or protei n.
Classification and Etiology
PEU i s gra ded a s mi l d, modera te, or s evere. Gra de i s determi ned by ca l cul a ti ng wei ght a s a percenta ge of expected wei ght for l ength or hei ght
us i ng i nterna ti ona l s ta nda rds (norma l , 90 to 110%; mi l d PEU, 85 to 90%; modera te, 75 to 85%; s evere, <75%).
PEU ma y be pri ma ry or s econda ry. Pri ma ry PEU i s ca us ed by i na dequa te nutri ent i nta ke. Seconda ry PEU res ul ts from di s orders or drugs tha t i nterfere
wi th nutri ent us e.
Primary PEU: Worl dwi de, pri ma ry PEU occurs mos tl y i n chi l dren a nd the el derl y who l a ck a cces s to nutri ents , a l though a common ca us e i n the
el derl y i s depres s i on. PEU ca n a l s o res ul t from fa s ti ng or a norexi a nervos a . Chi l d or el der a bus e ma y be a ca us e.
In chi l dren, chroni c pri ma ry PEU ha s 2 common forms : ma ra s mus a nd kwa s hi orkor. The form depends on the ba l a nce of nonprotei n a nd protei n
s ources of energy. Sta rva ti on i s a n a cute s evere form of pri ma ry PEU.
Ma ra s mus (a l s o ca l l ed the dry form of PEU) ca us es wei ght l os s a nd depl eti on of fa t a nd mus cl e. In devel opi ng countri es , ma ra s mus i s the mos t
common form of PEU i n chi l dren.
Kwa s hi orkor (a l s o ca l l ed the wet, s wol l en, or edema tous form) i s a s s oci a ted wi th prema ture a ba ndonment of brea s tfeedi ng, whi ch typi ca l l y
occurs when a younger s i bl i ng i s born, di s pl a ci ng the ol der chi l d from the brea s t. So chi l dren wi th kwa s hi orkor tend to be ol der tha n thos e wi th
ma ra s mus . Kwa s hi orkor ma y a l s o res ul t from a n a cute i l l nes s , often ga s troenteri ti s or a nother i nfecti on (proba bl y s econda ry to cytoki ne rel ea s e),
i n a chi l d who a l rea dy ha s PEU. A di et tha t i s more defi ci ent i n protei n tha n energy ma y be more l i kel y to ca us e kwa s hi orkor tha n ma ra s mus . Les s
common tha n ma ra s mus , kwa s hi orkor tends to be confi ned to s peci fi c pa rts of the worl d, s uch a s rura l Afri ca , the Ca ri bbea n, a nd the Pa ci fi c
i s l a nds . In thes e a rea s , s ta pl e foods (eg, ya ms , ca s s a va s , s weet pota toes , green ba na na s ) a re l ow i n protei n a nd hi gh i n ca rbohydra tes . In
kwa s hi orkor, cel l membra nes l ea k, ca us i ng extra va s a ti on of i ntra va s cul a r fl ui d a nd protei n, res ul ti ng i n peri phera l edema .
Sta rva ti on i s a compl ete l a ck of nutri ents . It occa s i ona l l y occurs when food i s a va i l a bl e (a s i n fa s ti ng or a norexi a nervos a ) but us ua l l y occurs
beca us e food i s una va i l a bl e (eg, duri ng fa mi ne or wi l dernes s expos ure).
Secondary PEU: Thi s type mos t commonl y res ul ts from the fol l owi ng:
Di s orders tha t a ffect GI functi on: Thes e di s orders ca n i nterfere wi th di ges ti on (eg, pa ncrea ti c i ns uffi ci ency), a bs orpti on (eg, enteri ti s ,
enteropa thy), or l ympha ti c tra ns port of nutri ents (eg, retroperi tonea l fi bros i s , Mi l roy's di s ea s e).
Wa s ti ng di s orders : In wa s ti ng di s orders (eg, AIDS, ca ncer) a nd rena l fa i l ure, ca ta bol i s m ca us es cytoki ne exces s , res ul ti ng i n undernutri ti on vi a
a norexi a a nd ca chexi a (wa s ti ng of mus cl e a nd fa t). End-s ta ge hea rt fa i l ure ca n ca us e ca rdi a c ca chexi a , a s evere form of undernutri ti on;
morta l i ty ra te i s pa rti cul a rl y hi gh. Fa ctors contri buti ng to ca rdi a c ca chexi a ma y i ncl ude pa s s i ve hepa ti c conges ti on (ca us i ng a norexi a ), edema of
the i ntes ti na l tra ct (i mpa i ri ng a bs orpti on), a nd, i n a dva nced di s ea s e, i ncrea s ed O2 requi rement due to a na erobi c meta bol i s m. Wa s ti ng
di s orders ca n decrea s e a ppeti te or i mpa i r meta bol i s m of nutri ents .
Condi ti ons tha t i ncrea s e meta bol i c dema nds : Thes e condi ti ons i ncl ude i nfecti ons , hyperthyroi di s m, pheochromocytoma , other endocri ne
di s orders , burns , tra uma , s urgery, a nd other cri ti ca l i l l nes s es .
Pathophysiology
The i ni ti a l meta bol i c res pons e i s decrea s ed meta bol i c ra te. To s uppl y energy, the body fi rs t brea ks down a di pos e ti s s ue. However, l a ter when
thes e ti s s ues a re depl eted, the body ma y us e protei n for energy, res ul ti ng i n a nega ti ve ni trogen ba l a nce. Vi s cera l orga ns a nd mus cl e a re broken
down a nd decrea s e i n wei ght. Los s of orga n wei ght i s grea tes t i n the l i ver a nd i ntes ti ne, i ntermedi a te i n the hea rt a nd ki dneys , a nd l ea s t i n the
nervous s ys tem.
Symptoms and Signs
Symptoms of modera te PEU ca n be cons ti tuti ona l or i nvol ve s peci fi c orga n s ys tems . Apa thy a nd i rri ta bi l i ty a re common. The pa ti ent i s wea k, a nd
work ca pa ci ty decrea s es . Cogni ti on a nd s ometi mes cons ci ous nes s a re i mpa i red. Tempora ry l a ctos e defi ci ency a nd a chl orhydri a devel op. Di a rrhea
i s common a nd ca n be a ggra va ted by defi ci ency of i ntes ti na l di s a ccha ri da s es , es peci a l l y l a cta s e (s ee p. 157). Gona da l ti s s ues a trophy. PEU ca n
ca us e a menorrhea i n women a nd l os s of l i bi do i n men a nd women.
Wa s ti ng of fa t a nd mus cl e i s common i n a l l forms of PEU. In a dul t vol unteers who fa s ted for 30 to 40 da ys , wei ght l os s wa s ma rked (25% of i ni ti a l
wei ght). If s ta rva ti on i s more prol onged, wei ght l os s ma y rea ch 50% i n a dul ts a nd pos s i bl y more i n chi l dren.
In a dul ts , ca chexi a i s mos t obvi ous i n a rea s where promi nent fa t depots norma l l y exi s t. Mus cl es s hri nk a nd bones protrude. The s ki n becomes
thi n, dry, i nel a s ti c, pa l e, a nd col d. The ha i r i s dry a nd fa l l s out ea s i l y, becomi ng s pa rs e. Wound hea l i ng i s i mpa i red. In el derl y pa ti ents , ri s k of hi p
fra ctures a nd pres s ure (decubi tus ) ul cers i ncrea s es .
Wi th a cute or chroni c s evere PEU, hea rt s i ze a nd ca rdi a c output decrea s e; pul s e s l ows
[
Table 2-3. Va l ues Commonl y Us ed to Gra de the Severi ty of Protei n-Energy Undernutri ti on]
a nd BP fa l l s . Res pi ra tory ra te a nd vi ta l ca pa ci ty decrea s e. Body tempera ture fa l l s , s ometi mes contri buti ng to dea th. Edema , a nemi a , ja undi ce, a nd
petechi a e ca n devel op. Li ver, ki dney, or hea rt fa i l ure ma y occur.
Cel l -medi a ted i mmuni ty i s i mpa i red, i ncrea s i ng s us cepti bi l i ty to i nfecti ons . Ba cteri a l i nfecti ons (eg, pneumoni a , ga s troenteri ti s , oti ti s medi a ,
UTIs , s eps i s ) a re common i n both forms of PEU. Infecti ons res ul t i n rel ea s e of cytoki nes , whi ch ca us e a norexi a , wors en mus cl e wa s ti ng, a nd ca us e
a ma rked decrea s e i n s erum a l bumi n l evel s .
Ma ra s mus i n i nfa nts ca us es hunger, wei ght l os s , growth reta rda ti on, a nd wa s ti ng of s ubcuta neous fa t a nd mus cl e. Ri bs a nd fa ci a l bones a ppea r
promi nent. Loos e, thi n s ki n ha ngs i n fol ds .
Kwa s hi orkor i s cha ra cteri zed by peri phera l a nd peri orbi ta l edema . The a bdomen protrudes beca us e a bdomi na l mus cl es a re wea kened, the
i ntes ti ne i s di s tended, the l i ver enl a rges , a nd a s ci tes i s pres ent. The s ki n i s dry, thi n, a nd wri nkl ed; i t ca n become hyperpi gmented a nd fi s s ured
a nd l a ter hypopi gmented, fri a bl e, a nd a trophi c. Ski n i n di fferent a rea s of the body ma y be a ffected a t di fferent ti mes . The ha i r ca n become thi n,
reddi s h brown, or gra y. Sca l p ha i r fa l l s out ea s i l y, eventua l l y becomi ng s pa rs e, but eyel a s h ha i r ma y grow exces s i vel y. Al terna ti ng epi s odes of
undernutri ti on a nd a dequa te nutri ti on ma y ca us e the ha i r to ha ve a dra ma ti c "s tri ped fl a g" a ppea ra nce. Affected chi l dren ma y be a pa theti c but
become i rri ta bl e when hel d.
Tota l s ta rva ti on i s fa ta l i n 8 to 12 wk. Thus , certa i n s ymptoms of PEU do not ha ve ti me to devel op.
Diagnosis
Di a gnos i s us ua l l y ba s ed on hi s tory
To determi ne s everi ty: BMI, s erum a l bumi n, tota l l ymphocyte count, CD4+ count, s erum tra ns ferri n
To di a gnos e compl i ca ti ons a nd cons equences : CBC, el ectrol ytes , BUN, gl ucos e, Ca , Mg, phos pha te
Di a gnos i s ca n be ba s ed on hi s tory when di eta ry i nta ke i s ma rkedl y i na dequa te. The ca us e of i na dequa te i nta ke, pa rti cul a rl y i n chi l dren, needs to
be i denti fi ed. In chi l dren a nd a dol es cents , chi l d a bus e a nd a norexi a nervos a s houl d be cons i dered.
Phys i ca l exa mi na ti on fi ndi ngs ca n us ua l l y confi rm the di a gnos i s . La bora tory tes ts a re requi red i f di eta ry hi s tory does not cl ea rl y i ndi ca te
i na dequa te ca l ori c i nta ke. Mea s urement of s erum a l bumi n, tota l l ymphocyte count, CD4+ T l ymphocytes , tra ns ferri n, a nd res pons e to s ki n a nti gens
ma y hel p determi ne the s everi ty of PEU (s ee Ta bl e 2-3) or confi rm the di a gnos i s i n borderl i ne ca s es . Ma ny other tes t res ul ts ma y be a bnorma l : eg,
decrea s ed l evel s of hormones , vi ta mi ns , l i pi ds , chol es terol , prea l bumi n, i ns ul i n growth fa ctor-1, fi bronecti n, a nd reti nol -bi ndi ng protei n. Uri na ry
crea ti ne a nd methyl hi s ti di ne l evel s ca n be us ed to ga uge the degree of mus cl e wa s ti ng. Beca us e protei n ca ta bol i s m s l ows , uri na ry urea l evel
a l s o decrea s es . Thes e fi ndi ngs ra rel y a ffect trea tment.
La bora tory tes ts a re requi red to i denti fy ca us es of s us pected s econda ry PEU. C-rea cti ve protei n or s ol ubl e i nterl euki n-2 receptor s houl d be
mea s ured when the ca us e of undernutri ti on i s uncl ea r; thes e mea s urements ca n hel p determi ne whether there i s cytoki ne exces s . Thyroi d
functi on tes ts ma y a l s o be done.
Other l a bora tory tes ts ca n detect a s s oci a ted a bnorma l i ti es tha t ma y requi re trea tment. Serum el ectrol ytes , BUN, gl ucos e, a nd pos s i bl y l evel s of
Ca , Mg, a nd phos pha te s houl d be mea s ured. Level s of s erum gl ucos e, el ectrol ytes (es peci a l l y K, occa s i ona l l y Na ), phos pha te, Ca , a nd Mg a re
us ua l l y l ow. BUN i s often l ow unl es s rena l fa i l ure i s pres ent. Meta bol i c a ci dos i s ma y be pres ent. CBC i s us ua l l y obta i ned; normocyti c a nemi a
(us ua l l y due to protei n defi ci ency) or mi crocyti c a nemi a (due to s i mul ta neous i ron defi ci ency) i s us ua l l y pres ent.
Stool cul tures s houl d be obta i ned a nd checked for ova a nd pa ra s i tes i f di a rrhea i s s evere or does not res ol ve wi th trea tment. Someti mes
uri na l ys i s , uri ne cul ture, bl ood cul tures , tubercul i n tes ti ng, a nd a ches t x-ra y a re us ed to di a gnos e occul t i nfecti ons beca us e peopl e wi th PEU ma y
ha ve a muted res pons e to i nfecti ons .
Prognosis
Children: In chi l dren, morta l i ty va ri es from 5 to 40%. Morta l i ty ra tes a re l ower i n chi l dren wi th mi l d PEU a nd thos e gi ven i ntens i ve ca re. Dea th i n the
fi rs t da ys of trea tment i s us ua l l y due to el ectrol yte defi ci ts , s eps i s , hypothermi a , or hea rt fa i l ure. Impa i red cons ci ous nes s , ja undi ce, petechi a e,
hypona tremi a , a nd pers i s tent di a rrhea a re omi nous s i gns . Res ol uti on of a pa thy, edema , a nd a norexi a i s a fa vora bl e s i gn. Recovery i s more ra pi d
i n kwa s hi orkor tha n i n ma ra s mus .
Long-term effects of PEU i n chi l dren a re not ful l y documented. Some chi l dren devel op chroni c ma l a bs orpti on a nd pa ncrea ti c i ns uffi ci ency. In very
young chi l dren, mi l d i ntel l ectua l di s a bi l i ty ma y devel op a nd pers i s t unti l a t l ea s t s chool a ge. Perma nent cogni ti ve i mpa i rment ma y occur,
dependi ng on the dura ti on, s everi ty, a nd a ge a t ons et of PEU.
Adults: In a dul ts , PEU ca n res ul t i n morbi di ty a nd morta l i ty (eg, progres s i ve wei ght l os s i ncrea s es morta l i ty ra te for el derl y pa ti ents i n nurs i ng
homes ). In el derl y pa ti ents , PEU i ncrea s es the ri s k of morbi di ty a nd morta l i ty due to s urgery, i nfecti ons , or other di s orders . Except when orga n
fa i l ure occurs , trea tment i s uni forml y s ucces s ful .
Treatment
Us ua l l y, ora l feedi ng
Pos s i bl y a voi da nce of l a ctos e (eg, i f pers i s tent di a rrhea s ugges ts l a ctos e i ntol era nce)
Supporti ve ca re (eg, envi ronmenta l cha nges , a s s i s ta nce wi th feedi ng, orexi geni c drugs )
For chi l dren, feedi ng del a yed 24 to 48 h
Worl dwi de, the mos t i mporta nt preventi ve s tra tegy i s to reduce poverty a nd i mprove nutri ti ona l educa ti on a nd publ i c hea l th mea s ures .
Mi l d or modera te PEU, i ncl udi ng bri ef s ta rva ti on, ca n be trea ted by provi di ng a ba l a nced di et, prefera bl y ora l l y. Li qui d ora l food s uppl ements
(us ua l l y l a ctos e-free) ca n be us ed when s ol i d food ca nnot be a dequa tel y i nges ted. Di a rrhea often compl i ca tes ora l feedi ng beca us e s ta rva ti on
ma kes the GI tra ct more l i kel y to move ba cteri a i nto Peyer's pa tches , fa ci l i ta ti ng i nfecti ous di a rrhea . If di a rrhea pers i s ts (s ugges ti ng l a ctos e
i ntol era nce), yogurt-ba s ed ra ther tha n mi l k-ba s ed formul a s a re gi ven beca us e peopl e wi th l a ctos e i ntol era nce ca n tol era te yogurt. Pa ti ents
s houl d a l s o be gi ven a mul ti vi ta mi n s uppl ement.
Severe PEU or prol onged s ta rva ti on requi res trea tment i n a hos pi ta l wi th a control l ed di et. The fi rs t pri ori ty i s to correct fl ui d a nd el ectrol yte
a bnorma l i ti es (s ee Ch. 97) a nd trea t i nfecti ons . Next i s to s uppl y ma cronutri ents ora l l y or, i f neces s a ry (eg, when s wa l l owi ng i s di ffi cul t), through a
feedi ng tube, a na s oga s tri c tube (us ua l l y), or a ga s tros tomy tube. Pa rentera l nutri ti on i s i ndi ca ted i f ma l a bs orpti on i s s evere (s ee p. 23).
Other trea tments ma y be needed to correct s peci fi c defi ci enci es , whi ch ma y become evi dent a s wei ght i ncrea s es . To a voi d defi ci enci es , pa ti ents
s houl d ta ke mi cronutri ents a t a bout twi ce the recommended da i l y a l l owa nce (RDA) unti l recovery i s compl ete.
Children: Underl yi ng di s orders s houl d be trea ted. For chi l dren wi th di a rrhea , feedi ng ma y be del a yed 24 to 48 h to a voi d ma ki ng the di a rrhea wors e;
duri ng thi s i nterva l , chi l dren requi re ora l or IV rehydra ti on. Feedi ngs a re gi ven often (6 to 12 ti mes /da y) but, to a voi d overwhel mi ng the l i mi ted
i ntes ti na l a bs orpti ve ca pa ci ty, a re l i mi ted to s ma l l a mounts (< 100 mL). Duri ng the fi rs t week, mi l k-ba s ed formul a s wi th s uppl ements a dded a re
us ua l l y gi ven i n progres s i vel y i ncrea s i ng a mounts ; a fter a week, the ful l a mounts of 175 kca l /kg a nd 4 g of protei n/kg ca n be gi ven. Twi ce the RDA
of mi cronutri ents s houl d be gi ven, us i ng commerci a l mul ti vi ta mi n s uppl ements . After 4 wk, the formul a ca n be repl a ced wi th whol e mi l k pl us cod
l i ver oi l a nd s ol i d foods , i ncl udi ng eggs , frui t, mea ts , a nd yea s t.
Energy di s tri buti on a mong ma cronutri ents s houl d be a bout 16% protei n, 50% fa t, a nd 34% ca rbohydra te. An exa mpl e i s a combi na ti on of powdered
cow's s ki mmed mi l k (110 g), s ucros e (100 g), vegeta bl e oi l (70 g), a nd wa ter (900 mL). Ma ny other formul a s (eg, whol e [ful l -fa t] fres h mi l k pl us corn
oi l a nd ma l todextri n) ca n be us ed. Mi l k powders us ed i n formul a s a re di l uted wi th wa ter.
Us ua l l y, s uppl ements s houl d be a dded to formul a s :
Mg 0.4 mEq/kg/da y IM i s gi ven for 7 da ys .
B-compl ex vi ta mi ns a t twi ce the RDA a re gi ven pa rentera l l y for the fi rs t 3 da ys , us ua l l y wi th vi ta mi n A, phos phorus , zi nc, ma nga nes e, copper,
i odi ne, fl uori de, mol ybdenum, a nd s el eni um.
Beca us e a bs orpti on of ora l i ron i s poor i n chi l dren wi th PEU, ora l or IM i ron s uppl ementa ti on ma y be neces s a ry.
Pa rents a re ta ught a bout nutri ti ona l requi rements .
Adults: Underl yi ng di s orders s houl d be trea ted. For exa mpl e, i f AIDS or ca ncer res ul ts i n exces s cytoki ne producti on, meges trol a ceta te or
medroxyproges terone ma y i mprove food i nta ke. However, beca us e thes e drugs dra ma ti ca l l y decrea s e tes tos terone i n men (pos s i bl y ca us i ng
mus cl e l os s ), tes tos terone s houl d be repl a ced. Beca us e thes e drugs ca n ca us e a drena l i ns uffi ci ency, they s houl d be us ed onl y s hort-term (< 3 mo).
In pa ti ents wi th functi ona l l i mi ta ti ons , home del i very of mea l s a nd feedi ng a s s i s ta nce a re key.
An orexi geni c drug, s uch a s the ca nna bi s extra ct drona bi nol , s houl d be gi ven to pa ti ents wi th a norexi a when no ca us e i s obvi ous or to pa ti ents a t
the end of l i fe when a norexi a i mpa i rs qua l i ty of l i fe. An a na bol i c s teroi d (eg, ena ntha te, na ndrol one, tes tos terone) or growth hormone ca n
benefi t pa ti ents wi th ca chexi a due to rena l fa i l ure a nd pos s i bl y el derl y pa ti ents (eg, by i ncrea s i ng l ea n body ma s s or pos s i bl y by i mprovi ng
functi on).
Correcti on of PEU i n a dul ts genera l l y res embl es tha t i n chi l dren; feedi ngs a re often l i mi ted to s ma l l a mounts . However, for mos t a dul ts , feedi ng
does not need to be del a yed. A commerci a l formul a for ora l feedi ng ca n be us ed. Da i l y nutri ent s uppl y s houl d be gi ven a t a ra te of 60 kca l /kg a nd
1.2 to 2 g of protei n/kg. If l i qui d ora l s uppl ements a re us ed wi th s ol i d food, they s houl d be gi ven a t l ea s t 1 h before mea l s s o tha t the a mount of
food ea ten a t the mea l i s not reduced.
Trea tment of i ns ti tuti ona l i zed el derl y pa ti ents wi th PEU requi res mul ti pl e i nterventi ons :
Envi ronmenta l mea s ures (eg, ma ki ng the di ni ng a rea more a ttra cti ve)
Feedi ng a s s i s ta nce
Cha nges i n di et (eg, us e of food enha ncers a nd ca l ori c s uppl ements between mea l s )
Trea tment of depres s i on a nd other underl yi ng di s orders

Us e of orexi geni cs , a na bol i c s teroi ds , or both
The l ong-term us e of ga s tros tomy tube feedi ng i s es s enti a l for pa ti ents wi th s evere dys pha gi a ; i ts us e i n pa ti ents wi th dementi a i s controvers i a l .
Increa s i ng evi dence s upports the a voi da nce of unpa l a ta bl e thera peuti c di ets (eg, l ow s a l t, di a beti c, l ow chol es terol ) i n i ns ti tuti ona l i zed pa ti ents
beca us e thes e di ets decrea s e food i nta ke a nd ma y ca us e s evere PEU.
Complications of treatment: Trea tment of PEU ca n ca us e compl i ca ti ons (refeedi ng s yndrome), i ncl udi ng fl ui d overl oa d, el ectrol yte defi ci ts ,
hypergl ycemi a , ca rdi a c a rrhythmi a s , a nd di a rrhea . Di a rrhea i s us ua l l y mi l d a nd res ol ves ; however, di a rrhea i n pa ti ents wi th s evere PEU
occa s i ona l l y ca us es s evere dehydra ti on or dea th. Ca us es of di a rrhea (eg, s orbi tol us ed i n el i xi r tube feedi ngs , Clostridium difficile i f the pa ti ent ha s
recei ved a n a nti bi oti c) ma y be correcta bl e. Os moti c di a rrhea due to exces s ca l ori es i s ra re i n a dul ts a nd s houl d be cons i dered onl y when other
ca us es ha ve been excl uded.
Beca us e PEU ca n i mpa i r ca rdi a c a nd rena l functi on, hydra ti on ca n ca us e i ntra va s cul a r vol ume overl oa d. Trea tment decrea s es extra -cel l ul a r K a nd
Mg. Depl eti on of K or Mg ma y ca us e a rrhythmi a s . Ca rbohydra te meta bol i s m tha t occurs duri ng trea tment s ti mul a tes i ns ul i n rel ea s e, whi ch dri ves
phos pha te i nto cel l s . Hypophos pha temi a ca n ca us e mus cl e wea knes s , pa res thes i a s , s ei zures , coma , a nd a rrhythmi a s . Beca us e phos pha te l evel s
ca n cha nge ra pi dl y duri ng pa rentera l feedi ng, l evel s s houl d be mea s ured regul a rl y.
Duri ng trea tment, endogenous i ns ul i n ma y become i neffecti ve, l ea di ng to hypergl ycemi a . Dehydra ti on a nd hyperos mol a ri ty ca n res ul t. Fa ta l
ventri cul a r a rrhythmi a s ca n devel op, pos s i bl y ca us ed by a prol onged QT i nterva l .
Carnitine Deficiency
Carnitine deficiency results from inadequate intake of or inability to metabolize the amino acid carnitine. It can cause a heterogeneous group of disorders. Muscle
metabolism is impaired, causing myopathy, hypoglycemia, or cardiomyopathy. Infants typically present with hypoglycemic, hypoketotic encephalopathy. Most
often, treatment consists of dietary L-carnitine.
The a mi no a ci d ca rni ti ne i s requi red for the tra ns port of l ong-cha i n fa tty a cyl coenzyme A (CoA) es ters i nto myocyte mi tochondri a , where they a re
oxi di zed for energy. Ca rni ti ne i s obta i ned from foods , pa rti cul a rl y a ni ma l -ba s ed foods , a nd vi a endogenous s ynthes i s .
Ca us es of ca rni ti ne defi ci ency i ncl ude the fol l owi ng:
Ina dequa te i nta ke (eg, due to fa d di ets , l a ck of a cces s , or l ong-term TPN)
Ina bi l i ty to meta bol i ze ca rni ti ne due to enzyme defi ci enci es (eg, ca rni ti ne pa l mi toyl tra ns fera s e defi ci ency, methyl ma l oni ca ci duri a ,
propi oni ca ci demi a , i s ova l eri ca ci demi a )
Decrea s ed endogenous s ynthes i s of ca rni ti ne due to a s evere l i ver di s order
Exces s l os s of ca rni ti ne due to di a rrhea , di ures i s , or hemodi a l ys i s
A heredi ta ry di s order i n whi ch ca rni ti ne l ea ks from rena l tubul es
Increa s ed requi rements for ca rni ti ne when ketos i s i s pres ent or dema nd for fa t oxi da ti on i s hi gh (eg, duri ng a cri ti ca l i l l nes s s uch a s s eps i s or
ma jor burns ; a fter ma jor s urgery of the GI tra ct)
Decrea s ed mus cl e ca rni ti ne l evel s due to mi tochondri a l i mpa i rment (eg, due to us e of zi dovudi ne)
Us e of va l proa te
The defi ci ency ma y be genera l i zed (s ys temi c) or ma y a ffect ma i nl y mus cl e (myopa thi c).
Symptoms and Signs
Symptoms a nd the a ge a t whi ch s ymptoms a ppea r depend on the ca us e. Ca rni ti ne defi ci ency ma y ca us e mus cl e necros i s , myogl obi nuri a , l i pi ds tora ge myopa thy, hypogl ycemi a , fa tty l i ver, a nd hypera mmonemi a wi th mus cl e a ches , fa ti gue, confus i on, a nd ca rdi omyopa thy.
Diagnosis
In neona tes , ca rni ti ne pa l mi toyl tra ns fera s e defi ci ency i s di a gnos ed us i ng ma s s s pectrometry to s creen bl ood. Prena ta l di a gnos i s ma y be pos s i bl e
us i ng a mni oti c vi l l ous cel l s . In a dul ts , the defi ni ti ve di a gnos i s i s ba s ed on a cyl ca rni ti ne l evel s i n s erum, uri ne, a nd ti s s ues (mus cl e a nd l i ver for
s ys temi c defi ci ency; mus cl e onl y for myopa thi c defi ci ency).
Treatment
Avoi da nce of fa s ti ng a nd s trenuous exerci s e
Di eta ry i nterventi ons , ba s ed on ca us e
Ca rni ti ne defi ci ency due to i na dequa te di eta ry i nta ke, i ncrea s ed requi rements , exces s l os s es , decrea s ed s ynthes i s , or (s ometi mes ) enzyme
defi ci enci es ca n be trea ted by gi vi ng L-ca rni ti ne 25 mg/kg po q 6 h.
Al l pa ti ents mus t a voi d fa s ti ng a nd s trenuous exerci s e. Cons umi ng uncooked corns ta rch a t bedti me prevents ea rl y morni ng hypogl ycemi a . Some
pa ti ents requi re s uppl ementa ti on wi th medi um-cha i n tri gl yceri des a nd es s enti a l fa tty a ci ds (eg, l i nol ei c a ci d, l i nol eni c a ci d). Pa ti ents wi th a fa tty
a ci d oxi da ti on di s order requi re a hi gh-ca rbohydra te, l ow-fa t di et.
Essential Fatty Acid Deficiency
Essential fatty acid (EFA) deficiency is rare, occurring most often in infants fed diets deficient in EFAs. Signs include scaly dermatitis, alopecia, thrombocytopenia,
and, in children, growth retardation. Diagnosis is clinical. Dietary replenishment of EFAs reverses the deficiency.
The EFAs l i nol ei c a nd l i nol eni c a ci d a re s ubs tra tes for the endogenous s ynthes i s of other fa tty a ci ds tha t a re needed for ma ny phys i ol ogi c
proces s es , i ncl udi ng ma i nta i ni ng the i ntegri ty of s ki n a nd cel l membra nes a nd s ynthes i zi ng pros ta gl a ndi ns a nd l eukotri enes . For exa mpl e,
ei cos a penta enoi c a ci d a nd docos a hexa enoi c a ci d, s ynthes i zed from EFAs , a re i mporta nt components of the bra i n a nd reti na .
For EFA defi ci ency to devel op, di eta ry i nta ke mus t be very l ow. Even s ma l l a mounts of EFAs ca n prevent EFA defi ci ency. Cow's mi l k ha s onl y a bout
25% of the l i nol ei c a ci d i n huma n mi l k, but when i nges ted i n norma l a mounts , i t ha s enough l i nol ei c a ci d to prevent EFA defi ci ency. Tota l fa t
i nta ke of peopl e i n ma ny devel opi ng countri es ma y be very l ow, but the fa t i s often vegeta bl e ba s ed, wi th l a rge a mounts of l i nol ei c a ci d a nd
enough l i nol eni c a ci d to prevent EFA defi ci ency.
Ba bi es fed a formul a l ow i n l i nol ei c a ci d, s uch a s a s ki m-mi l k formul a , ca n devel op EFA defi ci ency. EFA defi ci ency us ed to res ul t from l ong-term
TPN i f fa t wa s not i ncl uded. But now, mos t TPN s ol uti ons i ncl ude fa t emul s i ons to prevent EFA defi ci ency. In pa ti ents wi th fa t ma l a bs orpti on or
i ncrea s ed meta bol i c needs (eg, beca us e of s urgery, mul ti pl e tra uma , or burns ), l a bora tory evi dence of EFA defi ci ency ma y be pres ent wi thout
cl i ni ca l s i gns .
Derma ti ti s due to EFA defi ci ency i s genera l i zed a nd s ca l y; i n i nfa nts , i t ca n res embl e congeni ta l i chthyos i s . The derma ti ti s i ncrea s es wa ter l os s
from the s ki n.
Di a gnos i s i s us ua l l y cl i ni ca l ; however, l a bora tory a s s a ys a re now a va i l a bl e i n l a rge res ea rch centers .
Trea tment cons i s ts of di eta ry EFAs , revers i ng the defi ci ency.
Chapter 3. Nutritional Support

Introduction
Ma ny undernouri s hed pa ti ents need nutri ti ona l s upport, whi ch a i ms to i ncrea s e l ea n body ma s s . Ora l feedi ng ca n be di ffi cul t for s ome pa ti ents
wi th a norexi a or wi th ea ti ng or a bs orpti on probl ems . Beha vi ora l mea s ures tha t s ometi mes enha nce ora l i nta ke i ncl ude the fol l owi ng:
Encoura gi ng pa ti ents to ea t
Hea ti ng or s ea s oni ng foods
Provi di ng fa vori te or s trongl y fl a vored foods
Encoura gi ng pa ti ents to ea t s ma l l porti ons
Schedul i ng a round mea l s
As s i s ti ng pa ti ents wi th feedi ng
If beha vi ora l mea s ures a re i neffecti ve, nutri ti ona l s upportora l , entera l tube, or pa rentera l nutri ti oni s i ndi ca ted, except s ometi mes for dyi ng or
s everel y demented pa ti ents (s ee p. 25).
Predicting Nutritional Requirements
Nutri ti ona l requi rements a re predi cted s o tha t i nterventi ons ca n be pl a nned. Requi rements ca n be es ti ma ted by formul a s or mea s ured by i ndi rect
ca l ori metry. Indi rect ca l ori metry requi res us e of a meta bol i c ca rt (a cl os ed rebrea thi ng s ys tem tha t determi nes energy expendi ture ba s ed on tota l
CO2 producti on), whi ch requi res s peci a l experti s e a nd i s not a l wa ys a va i l a bl e. Thus , tota l energy expendi ture (TEE) a nd protei n requi rements
us ua l l y a re es ti ma ted.
Energy expenditure: TEE va ri es ba s ed on the pa ti ent's wei ght, a cti vi ty l evel , a nd degree of meta bol i c s tres s (meta bol i c dema nds ); TEE ra nges from 25
kca l /kg/da y for peopl e who a re s edenta ry a nd not under s tres s to a bout 40 kca l /kg/da y for peopl e who a re cri ti ca l l y i l l . TEE equa l s the s um of
Res ti ng meta bol i c ra te (RMR, or res ti ng energy expendi ture ra te), whi ch i s norma l l y a bout 70% of TEE
Energy di s s i pa ted by meta bol i s m of food (10% of TEE)
Energy expended duri ng phys i ca l a cti vi ty (20% of TEE)
Undernutri ti on ca n decrea s e RMR up to 20%. Condi ti ons tha t i ncrea s e meta bol i c s tres s (eg, cri ti ca l i l l nes s , i nfecti on, i nfl a mma ti on, tra uma ,
s urgery) ca n i ncrea s e RMR but ra rel y by > 50%.
The Mi ffl i n-St. Jeor equa ti on es ti ma tes RMR more preci s el y a nd wi th fewer errors tha n the commonl y us ed Ha rri s -Benedi ct equa ti on, us ua l l y
provi di ng res ul ts tha t a re wi thi n 20% of thos e mea s ured by i ndi rect ca l ori metry. The Mi ffl i n-St. Jeor equa ti on es ti ma tes RMR a s fol l ows :
Men: kca l / da y = 66 + (13.7 wt[kg]) + (5 hei ght[cm]) - (6.8 a ge)
Women: kca l / da y = 665 + (9.6 wt[kg]) + (1.8 hei ght[cm]) - (4.7 a ge)
TEE ca n be es ti ma ted by a ddi ng a bout 10% (for s edenta ry peopl e) to a bout 40% (for peopl e who a re cri ti ca l l y i l l ) to RMR.
Protein requirements: For hea l thy peopl e, protei n requi rements a re es ti ma ted a t 0.8 g/kg/da y. However, for pa ti ents wi th meta bol i c s tres s or ki dney
fa i l ure a nd for el derl y pa ti ents , requi rements ma y be hi gher (s ee
Ta bl e 3-1).
Assessing Response to Nutritional Support
There i s no gol d s ta nda rd to a s s es s res pons e. Cl i ni ci a ns commonl y us e i ndi ca tors of l ea n body ma s s s uch a s the fol l owi ng:
Body ma s s i ndex (BMI)
Body compos i ti on a na l ys i s
Body fa t di s tri buti on (s ee pp.
11 a nd 58)
Ni trogen ba l a nce, res pons e to s ki n a nti gens , mus cl e s trength mea s urement, a nd i ndi rect ca l ori metry ca n a l s o be us ed.
[Table 3-1. Es ti ma ted Adul t Da i l y Protei n Requi rement]
Nitrogen balance, whi ch refl ects the ba l a nce between protei n needs a nd s uppl i es , i s the di fference between a mount of ni trogen i nges ted a nd
a mount l os t. A pos i ti ve ba l a nce (i e, more i nges ted tha n l os t) i mpl i es a dequa te i nta ke. Preci s e mea s urement i s i mpra cti ca l , but es ti ma tes hel p
a s s es s res pons e to nutri ti ona l s upport. Ni trogen i nta ke i s es ti ma ted from protei n i nta ke: ni trogen (g) equa l s protei n (g)/6.25. Es ti ma ted ni trogen
l os s es cons i s t of uri na ry ni trogen l os s es (es ti ma ted by mea s uri ng urea ni trogen content of a n a ccura tel y obta i ned 24-h uri ne col l ecti on) pl us s tool
l os s es (es ti ma ted a t 1 g/da y i f s tool i s produced; negl i gi bl e i f s tool i s not produced) pl us i ns ens i bl e a nd other unmea s ured l os s es (es ti ma ted a t
3 g).
Response to skin antigens, a mea s ure of del a yed hypers ens i ti vi ty, often i ncrea s es to norma l a s undernouri s hed pa ti ents res pond to nutri ti ona l
s upport. However, other fa ctors ca n a ffect res pons e to s ki n a nti gens .
Muscle strength i ndi rectl y refl ects i ncrea s es i n l ea n body ma s s . It ca n be mea s ured qua nti ta ti vel y, by ha nd-gri p dyna mometry, or
el ectrophys i ol ogi ca l l y (typi ca l l y by s ti mul a ti ng the ul na r nerve wi th a n el ectrode).
Levels of acute-phase reactant s erum protei ns (pa rti cul a rl y s hort-l i ved protei ns s uch a s prea l bumi n [tra ns thyreti n], reti nol -bi ndi ng protei n, a nd
tra ns ferri n) s ometi mes correl a te wi th i mproved nutri ti ona l s ta tus , but thes e l evel s correl a te better wi th i nfl a mma tory condi ti ons .
Enteral Tube Nutrition
Entera l tube nutri ti on i s i ndi ca ted for pa ti ents who ha ve a functi oni ng GI tra ct but ca nnot i nges t enough nutri ents ora l l y beca us e they a re una bl e
or unwi l l i ng to ta ke ora l feedi ngs . Compa red wi th pa rentera l nutri ti on, entera l nutri ti on ha s the fol l owi ng a dva nta ges :
Better pres erva ti on of the s tructure a nd functi on of the GI tra ct
Lower cos t
Proba bl y fewer compl i ca ti ons , pa rti cul a rl y i nfecti ons
Specific indications for entera l nutri ti on i ncl ude the fol l owi ng:
Prol onged a norexi a
Severe protei n-energy undernutri ti on
Coma or depres s ed s ens ori um
Li ver fa i l ure
Ina bi l i ty to ta ke ora l feedi ngs due to hea d or neck tra uma or neurol ogi c di s orders
Cri ti ca l i l l nes s es (eg, burns ) ca us i ng meta bol i c s tres s
Other i ndi ca ti ons ma y i ncl ude bowel prepa ra ti on for s urgery i n s eri ous l y i l l or undernouri s hed pa ti ents , cl os ure of enterocuta neous fi s tul a s , a nd
s ma l l -bowel a da pta ti on a fter ma s s i ve i ntes ti na l res ecti on or i n di s orders tha t ma y ca us e ma l a bs orpti on (eg, Crohn's di s ea s e).
Procedure: If tube feedi ng i s needed for 4 to 6 wk, a s ma l l -ca l i ber, s oft na s oga s tri c or na s oenteri c (eg, na s oduodena l ) tube ma de of s i l i cone or
pol yuretha ne i s us ua l l y us ed. If a na s a l i njury or deformi ty ma kes na s a l pl a cement di ffi cul t, a n oroga s tri c or other oroenteri c tube ca n be pl a ced.
Tube feedi ng for > 4 to 6 wk us ua l l y requi res a ga s tros tomy or jejunos tomy tube, pl a ced endos copi ca l l y, s urgi ca l l y, or ra di ol ogi ca l l y. Choi ce
depends on phys i ci a n ca pa bi l i ti es a nd pa ti ent preference.
Jejunos tomy tubes a re us eful for pa ti ents wi th contra i ndi ca ti ons to ga s tros tomy (eg, ga s trectomy, bowel obs tructi on proxi ma l to the jejunum).
However, thes e tubes do not pos e l es s ri s k of tra cheobronchi a l a s pi ra ti on tha n ga s tros tomy tubes , a s i s often thought. Jejunos tomy tubes a re
ea s i l y di s l odged a nd a re us ua l l y us ed onl y for i npa ti ents .
Feedi ng tubes a re s urgi ca l l y pl a ced i f endos copi c a nd ra di ol ogi c pl a cement i s una va i l a bl e, techni ca l l y i mpos s i bl e, or uns a fe (eg, beca us e of
overl yi ng bowel ). Open or l a pa ros copi c techni ques ca n be us ed.
Formulas: Li qui d formul a s commonl y us ed i ncl ude feedi ng modul es a nd pol ymeri c or other s peci a l i zed formul a s .
Feeding modules a re commerci a l l y a va i l a bl e products tha t conta i n a s i ngl e nutri ent, s uch a s protei ns , fa ts , or ca rbohydra tes . Feedi ng modul es ma y
be us ed i ndi vi dua l l y to trea t a s peci fi c defi ci ency or combi ned wi th other formul a s to compl etel y s a ti s fy nutri ti ona l requi rements .
Polymeric formulas (i ncl udi ng bl enderi zed food a nd mi l k-ba s ed or l a ctos e-free commerci a l formul a s ) a re commerci a l l y a va i l a bl e a nd genera l l y
provi de a compl ete, ba l a nced di et. For ora l or tube feedi ngs , they a re us ua l l y preferred to feedi ng modul es . In hos pi ta l i zed pa ti ents , l a ctos e-free
formul a s a re the mos t commonl y us ed pol ymeri c formul a s . However, mi l k-ba s ed formul a s tend to ta s te better tha n l a ctos e-free formul a s . Pa ti ents
wi th l a ctos e i ntol era nce ma y be a bl e to tol era te mi l k-ba s ed formul a s gi ven s l owl y by conti nuous i nfus i on.
Specialized formulas i ncl ude hydrol yzed protei n or s ometi mes a mi no a ci d formul a s , whi ch a re us ed for pa ti ents who ha ve di ffi cul ty di ges ti ng
compl ex protei ns . However, thes e formul a s a re expens i ve a nd us ua l l y unneces s a ry. Mos t pa ti ents wi th pa ncrea ti c i ns uffi ci ency, i f gi ven enzymes ,
a nd mos t pa ti ents wi th ma l a bs orpti on ca n di ges t compl ex protei ns . Other s peci a l i zed formul a s (eg, ca l ori e- a nd protei n-dens e formul a s for
pa ti ents whos e fl ui ds a re res tri cted, fi ber-enri ched formul a s for cons ti pa ted pa ti ents ) ma y be hel pful .
Administration: Pa ti ents s houl d be s i tti ng upri ght a t 30 to 45 duri ng tube feedi ng a nd for 1 to 2 h a fterwa rd to mi ni mi ze i nci dence of nos ocomi a l
a s pi ra ti on pneumoni a a nd to a l l ow gra vi ty to hel p propel the food. Tube feedi ngs a re gi ven i n bol us es s evera l ti mes a da y or by conti nuous
i nfus i on. Bol us feedi ng i s more phys i ol ogi c a nd ma y be preferred for pa ti ents wi th di a betes . Conti nuous i nfus i on i s neces s a ry i f bol us es ca us e
na us ea .
[
Table 3-2. Compl i ca ti ons of Entera l Tube Nutri ti on]
For bol us feedi ng, tota l da i l y vol ume i s di vi ded i nto 4 to 6 s epa ra te feedi ngs , whi ch a re i njected through the tube wi th a s yri nge or i nfus ed by
gra vi ty from a n el eva ted ba g. After feedi ngs , the tube i s fl us hed wi th wa ter to prevent cl oggi ng.
Nasogastric or nasoduodenal tube feeding often ca us es di a rrhea i ni ti a l l y; thus , feedi ngs a re us ua l l y s ta rted wi th s ma l l a mounts of di l ute
prepa ra ti ons a nd i ncrea s ed a s tol era ted. Mos t formul a s conta i n 0.5, 1, or 2 kca l /mL. Formul a s wi th hi gher ca l ori c concentra ti on (l es s wa ter per
ca l ori e) ma y ca us e decrea s ed ga s tri c emptyi ng a nd thus hi gher ga s tri c res i dua l s tha n when more di l ute formul a s wi th the s a me number of
ca l ori es a re us ed. Ini ti a l l y, a 1-kca l /mL commerci a l l y prepa red s ol uti on ma y be gi ven undi l uted a t 50 mL/h or, i f pa ti ents ha ve not been fed for a
whi l e, a t 25 mL/h. Us ua l l y, thes e s ol uti ons do not s uppl y enough wa ter, pa rti cul a rl y i f vomi ti ng, di a rrhea , s wea ti ng, or fever ha s i ncrea s ed wa ter
l os s . Extra wa ter i s s uppl i ed a s bol us es vi a the feedi ng tube or IV. After a few da ys , the ra te or concentra ti on ca n be i ncrea s ed a s needed to meet
ca l ori c a nd wa ter needs .
Jejunostomy tube feeding requi res grea ter di l uti on a nd s ma l l er vol umes . Feedi ng us ua l l y begi ns a t a concentra ti on of 0.5 kca l /mL a nd a ra te of 25
mL/h. After a few da ys , concentra ti ons a nd vol umes ca n be i ncrea s ed to eventua l l y meet ca l ori c a nd wa ter needs . Us ua l l y, the ma xi mum tha t ca n
be tol era ted i s 0.8 kca l /mL a t 125 mL/h, provi di ng 2400 kca l /da y.
Complications: Compl i ca ti ons a re common a nd ca n be s eri ous (s ee Ta bl e 3-2).
Total Parenteral Nutrition
Pa rentera l nutri ti on i s by defi ni ti on gi ven IV.
Partial parenteral nutrition s uppl i es onl y pa rt of da i l y nutri ti ona l requi rements , s uppl ementi ng ora l i nta ke. Ma ny hos pi ta l i zed pa ti ents a re gi ven
dextros e or a mi no a ci d s ol uti ons by thi s method.
Total parenteral nutrition (TPN) s uppl i es a l l da i l y nutri ti ona l requi rements . TPN ca n be us ed i n the hos pi ta l or a t home. Beca us e TPN s ol uti ons a re
concentra ted a nd ca n ca us e thrombos i s of peri phera l vei ns , a centra l venous ca theter i s us ua l l y requi red.
Pa rentera l nutri ti on s houl d not be us ed routi nel y i n pa ti ents wi th a n i nta ct GI tra ct. Compa red wi th entera l nutri ti on, i t ca us es more
compl i ca ti ons , does not pres erve GI tra ct s tructure a nd functi on a s wel l , a nd i s more expens i ve.
Indications: TPN ma y be the onl y fea s i bl e opti on for pa ti ents who do not ha ve a functi oni ng GI tra ct or who ha ve di s orders requi ri ng compl ete
bowel res t, s uch a s the fol l owi ng:
Some s ta ges of Crohn's di s ea s e or ul cera ti ve col i ti s
Bowel obs tructi on
Certa i n pedi a tri c GI di s orders (eg, congeni ta l GI a noma l i es , prol onged di a rrhea rega rdl es s of i ts ca us e)
Short bowel s yndrome due to s urgery
Nutritional content: TPN requi res wa ter (30 to 40 mL/kg/da y), energy (30 to 60 kca l /kg/da y, dependi ng on energy expendi ture), a mi no a ci ds (1 to 2.0
g/kg/da y, dependi ng on the degree of ca ta bol i s m), es s enti a l fa tty a ci ds , vi ta mi ns , a nd mi nera l s (s ee
Ta bl e 3-3). Chi l dren who need TPN ma y ha ve di fferent fl ui d requi rements a nd need more energy (up to 120 kca l /kg/da y) a nd a mi no a ci ds (up to 2.5
or 3.5 g/kg/da y).
Ba s i c TPN s ol uti ons a re prepa red us i ng s teri l e techni ques , us ua l l y i n l i ter ba tches a ccordi ng to s ta nda rd formul a s . Norma l l y, 2 L/da y of the
s ta nda rd s ol uti on i s needed. Sol uti ons ma y be modi fi ed ba s ed on l a bora tory res ul ts , underl yi ng di s orders , hypermeta bol i s m, or other fa ctors .
Mos t ca l ori es a re s uppl i ed a s ca rbohydra te. Typi ca l l y, a bout 4 to 5 mg/kg/da y of dextros e i s gi ven. Sta nda rd s ol uti ons conta i n up to a bout 25%
dextros e, but the a mount a nd concentra ti on depend on other fa ctors , s uch a s meta bol i c needs a nd the proporti on of ca l ori c needs tha t a re
s uppl i ed by l i pi ds . Commerci a l l y a va i l a bl e l i pi d emul s i ons a re often a dded to s uppl y es s enti a l fa tty a ci ds a nd tri gl yceri des ; 20 to 30% of tota l
ca l ori es a re us ua l l y s uppl i ed a s l i pi ds . However, wi thhol di ng l i pi ds a nd thei r ca l ori es ma y hel p obes e pa ti ents mobi l i ze endogenous fa t s tores ,
i ncrea s i ng i ns ul i n s ens i ti vi ty.
Solutions: Ma ny s ol uti ons a re commonl y us ed. El ectrol ytes ca n be a dded to meet the pa ti ent's needs .
Sol uti ons va ry dependi ng on other di s orders pres ent a nd pa ti ent a ge, a s for the fol l owi ng:
For rena l i ns uffi ci ency not bei ng trea ted wi th di a l ys i s or for l i ver fa i l ure: Reduced protei n content a nd a hi gh percenta ge of es s enti a l a mi no
a ci ds
For hea rt or ki dney fa i l ure: Li mi ted vol ume (l i qui d) i nta ke
For res pi ra tory fa i l ure: A l i pi d emul s i on tha t provi des mos t of nonprotei n ca l ori es to mi ni mi ze CO2 producti on by ca rbohydra te meta bol i s m
For neona tes : Lower dextros e concentra ti ons (17 to 18%)
Beginning TPN administration: Beca us e the centra l venous ca theter needs to rema i n i n pl a ce for a l ong ti me, s tri ct s teri l e techni que mus t be us ed
duri ng i ns erti on a nd ma i ntena nce. The TPN l i ne s houl d not be us ed for a ny other purpos e. Externa l tubi ng s houl d be cha nged every 24 h wi th the
fi rs t ba g of the da y. In-l i ne fi l ters ha ve not been s hown to decrea s e compl i ca ti ons . Dres s i ngs s houl d be kept s teri l e a nd a re us ua l l y cha nged every
48 h us i ng s tri ct s teri l e techni ques . If TPN i s gi ven outs i de the hos pi ta l , pa ti ents mus t be ta ught to recogni ze s ymptoms of i nfecti on, a nd qua l i fi ed
home nurs i ng mus t be a rra nged.
The s ol uti on i s s ta rted s l owl y a t 50% of the ca l cul a ted requi rements , us i ng 5% dextros e to ma ke up the ba l a nce of fl ui d requi rements . Energy a nd
ni trogen s houl d be gi ven s i mul ta neous l y. The a mount of regul a r i ns ul i n gi ven (a dded di rectl y to the TPN s ol uti on) depends on the pl a s ma gl ucos e
l evel ; i f the l evel i s norma l a nd the fi na l s ol uti on conta i ns 25% dextros e, the us ua l s ta rti ng dos e i s 5 to 10 uni ts of regul a r i ns ul i n/L of TPN fl ui d.
Monitoring: Progres s s houl d be fol l owed on a fl owcha rt. An i nterdi s ci pl i na ry nutri ti on tea m, i f a va i l a bl e, s houl d moni tor pa ti ents . Wei ght, CBC,
el ectrol ytes , a nd BUN s houl d be moni tored often (eg, da i l y for i npa ti ents ). Pl a s ma gl ucos e s houl d be moni tored every 6 h unti l pa ti ents a nd
gl ucos e l evel s become s ta bl e. Fl ui d i nta ke a nd output s houl d be moni tored conti nuous l y. When pa ti ents become s ta bl e, bl ood tes ts ca n be done
much l es s often.
Li ver functi on tes ts s houl d be done. Pl a s ma protei ns (eg, s erum a l bumi n, pos s i bl y tra ns thyreti n or reti nol -bi ndi ng protei n), PT, pl a s ma a nd uri ne
os mol a l i ty, a nd Ca , Mg, a nd phos pha te s houl d be mea s ured twi ce/wk. Cha nges i n tra ns thyreti n a nd reti nol -bi ndi ng protei n refl ect overa l l cl i ni ca l
s ta tus ra ther tha n nutri ti ona l s ta tus a l one. If pos s i bl e, bl ood tes ts s houl d not be done duri ng gl ucos e i nfus i on. Ful l nutri ti ona l a s s es s ment
(i ncl udi ng BMI ca l cul a ti on a nd a nthropometri c mea s urements s ee pp. 11 a nd 58) s houl d be repea ted a t 2-wk i nterva l s .
Complications: About 5 to 10% of pa ti ents ha ve compl i ca ti ons rel a ted to centra l venous a cces s .
[Table 3-3. Ba s i c Adul t Da i l y Requi rements for Tota l Pa rentera l Nutri ti on]
Ca theter-rel a ted s eps i s occurs i n a bout 50% of pa ti ents . Gl ucos e a bnorma l i ti es (hypergl ycemi a or hypogl ycemi a ) or l i ver dys functi on occurs i n >
90% of pa ti ents .
Glucose abnormalities a re common. Hypergl ycemi a ca n be a voi ded by moni tori ng pl a s ma gl ucos e often, a djus ti ng the i ns ul i n dos e i n the TPN
s ol uti on a nd gi vi ng s ubcuta neous i ns ul i n a s needed. Hypogl ycemi a ca n be preci pi ta ted by s uddenl y s toppi ng cons ta nt concentra ted dextros e
i nfus i ons . Trea tment depends on the degree of hypogl ycemi a . Short-term hypogl ycemi a ma y be revers ed wi th 50% dextros e IV; more prol onged
hypogl ycemi a ma y requi re i nfus i on of 5 or 10% dextros e for 24 h before res umi ng TPN vi a the centra l venous ca theter.
Hepatic complications i ncl ude l i ver dys functi on, pa i nful hepa tomega l y, a nd hypera mmonemi a . They ca n devel op a t a ny a ge but a re mos t common
a mong i nfa nts , pa rti cul a rl y prema ture ones (whos e l i ver i s i mma ture).
Li ver dys functi on ma y be tra ns i ent, evi denced by i ncrea s ed tra ns a mi na s es , bi l i rubi n, a nd a l ka l i ne phos pha ta s e; i t commonl y occurs when TPN i s
s ta rted. Del a yed or pers i s tent el eva ti ons ma y res ul t from exces s a mi no a ci ds . Pa thogenes i s i s unknown, but chol es ta s i s a nd i nfl a mma ti on ma y
contri bute. Progres s i ve fi bros i s occa s i ona l l y devel ops . Reduci ng protei n del i very ma y hel p.
Pa i nful hepa tomega l y s ugges ts fa t a ccumul a ti on; ca rbohydra te del i very s houl d be reduced.
Hypera mmonemi a ca n devel op i n i nfa nts , ca us i ng l etha rgy, twi tchi ng, a nd genera l i zed s ei zures . Argi ni ne s uppl ementa ti on a t 0.5 to 1.0
mmol /kg/da y ca n correct i t.
If i nfa nts devel op a ny hepa ti c compl i ca ti on, l i mi ti ng a mi no a ci ds to 1.0 g/kg/da y ma y be neces s a ry.
Abnormalities of serum electrolytes and minerals s houl d be corrected by modi fyi ng s ubs equent i nfus i ons or, i f correcti on i s urgentl y requi red, by
begi nni ng a ppropri a te peri phera l vei n i nfus i ons . Vi ta mi n a nd mi nera l defi ci enci es a re ra re when s ol uti ons a re gi ven correctl y. El eva ted BUN ma y
refl ect dehydra ti on, whi ch ca n be corrected by gi vi ng free wa ter a s 5% dextros e vi a a peri phera l vei n.
Volume overload (s ugges ted by > 1 kg/da y wei ght ga i n) ma y occur when pa ti ents ha ve hi gh da i l y energy requi rements a nd thus requi re l a rge fl ui d
vol umes .
Metabolic bone disease, or bone demi nera l i za ti on (os teoporos i s or os teoma l a ci a ), devel ops i n s ome pa ti ents gi ven TPN for > 3 mo. The mecha ni s m
i s unknown. Adva nced di s ea s e ca n ca us e s evere peri a rti cul a r, l ower-extremi ty, a nd ba ck pa i n. Tempora ri l y or perma nentl y s toppi ng TPN i s the onl y
known trea tment.
Adverse reactions to lipid emulsions (eg, dys pnea , cuta neous a l l ergi c rea cti ons , na us ea , hea da che, ba ck pa i n, s wea ti ng, di zzi nes s ) a re uncommon but
ma y occur ea rl y, pa rti cul a rl y i f l i pi ds a re gi ven a t > 1.0 kca l /kg/h. Tempora ry hyperl i pi demi a ma y occur, pa rti cul a rl y i n pa ti ents wi th ki dney or l i ver
fa i l ure; trea tment i s us ua l l y not requi red. Del a yed a dvers e rea cti ons to l i pi d emul s i ons i ncl ude hepa tomega l y, mi l d el eva ti on of l i ver enzymes ,
s pl enomega l y, thrombocytopeni a , l eukopeni a , a nd, es peci a l l y i n prema ture i nfa nts wi th res pi ra tory di s tres s s yndrome, pul mona ry functi on
a bnorma l i ti es . Tempora ri l y or perma nentl y s l owi ng or s toppi ng l i pi d emul s i on i nfus i on ma y prevent or mi ni mi ze thes e a dvers e rea cti ons .
Gallbladder complications i ncl ude chol el i thi a s i s , ga l l bl a dder s l udge, a nd chol ecys ti ti s . Thes e compl i ca ti ons ca n be ca us ed or wors ened by
prol onged ga l l bl a dder s ta s i s . Sti mul a ti ng contra cti on by provi di ng a bout 20 to 30% of ca l ori es a s fa t a nd s toppi ng gl ucos e i nfus i on s evera l hours a
da y i s hel pful . Ora l or entera l i nta ke a l s o hel ps . Trea tment wi th metroni da zol e, urs odeoxychol i c a ci d, phenoba rbi ta l , or chol ecys toki ni n hel ps
s ome pa ti ents wi th chol es ta s i s .
Nutritional Support for Dying or Severely Demented Patients
Anorexi a or l os s of a ppeti te i s common a mong dyi ng pa ti ents (s ee p. 3485). Beha vi ora l mea s ures (eg, us i ng fl exi bl e feedi ng s chedul es , feedi ng
s l owl y, gi vi ng s ma l l porti ons or fa vori te or s trongl y fl a vored foods ) ca n often i ncrea s e ora l i nta ke. A s ma l l a mount of a fa vori te a l cohol i c dri nk,
gi ven 30 mi n before mea l s , ma y a l s o hel p. Certa i n a nti depres s a nts , meges trol a ceta te, a nd drona bi nol ma y s ti mul a te a ppeti te. Metocl opra mi de
enha nces ga s tri c emptyi ng, but i t ma y ta ke 1 to 2 wk to rea ch pea k effecti venes s .
Adva nced dementi a eventua l l y l ea ds to i na bi l i ty to ea t; s ometi mes a ffected pa ti ents a re gi ven tube feedi ngs . However, there i s no convi nci ng
evi dence tha t tube feedi ngs prol ong l i fe, provi de comfort, i mprove functi on, or prevent compl i ca ti ons (eg, a s pi ra ti on, pres s ure ul cers ).
Tube feedi ngs a nd pa rentera l nutri ti on ca us e di s comfort a nd a re us ua l l y not i ndi ca ted for pa ti ents who a re dyi ng or too demented to ea t.
Forgoi ng nutri ti ona l s upport ma y be di ffi cul t for fa mi l y members to a ccept, but they s houl d unders ta nd tha t pa ti ents a re us ua l l y more comforta bl e
ea ti ng a nd dri nki ng a s they choos e. Si ps of wa ter a nd ea s y-to-s wa l l ow foods ma y be us eful . Supporti ve ca re, i ncl udi ng good ora l hygi ene (eg,
brus hi ng the teeth, moi s teni ng the ora l ca vi ty wi th s wa bs a nd i ce chi ps a s needed, a ppl yi ng l i p s a l ve), ca n phys i ca l l y a nd ps ychol ogi ca l l y comfort
the pa ti ents a nd the fa mi l y members who provi de the ca re.
Couns el i ng ma y hel p fa mi l y members who a re dea l i ng wi th a nxi eti es a bout whether to us e i nva s i ve nutri ti ona l s upport.
Chapter 4. Vitamin Deficiency, Dependency, and Toxicity

Introduction
Vi ta mi ns ma y be fa t s ol ubl e (vi ta mi ns A, D, E, a nd K) or wa ter s ol ubl e (B vi ta mi ns a nd vi ta mi n C). The B vi ta mi ns i ncl ude bi oti n, fol a te, ni a ci n,
pa ntotheni c a ci d, ri bofl a vi n (B 2 ), thi a mi n (B 1 ), B 6 (eg, pyri doxi ne), a nd B 12 (coba l a mi ns ). For di eta ry requi rements , s ources , functi ons , effects of
defi ci enci es a nd toxi ci ti es , bl ood l evel s , a nd us ua l thera peuti c dos a ges for vi ta mi ns , s ee
Ta bl es 4-1 a nd
4-2.
Di eta ry requi rements for vi ta mi ns (a nd other nutri ents ) a re expres s ed a s da i l y recommended i nta ke (DRI). There a re 3 types of DRI:
Recommended daily allowance (RDA): RDAs a re s et to meet the needs of 97 to 98% of hea l thy peopl e.
Adequate intake (AI): When da ta to ca l cul a te a n RDA a re i ns uffi ci ent, AIs a re ba s ed on obs erved or experi menta l l y determi ned es ti ma tes of
nutri ent i nta ke by hea l thy peopl e.
Tolerable upper intake level (UL): ULs a re the l a rges t a mount of a nutri ent tha t mos t a dul ts ca n i nges t da i l y wi thout ri s k of a dvers e hea l th effects .
In devel oped countri es , vi ta mi n defi ci enci es res ul t ma i nl y from poverty, food fa ddi s m, drugs (s ee p. 7 a nd
Ta bl e 4-3), a l cohol i s m, or prol onged a nd i na dequa tel y s uppl emented pa rentera l feedi ng. Mi l d vi ta mi n defi ci ency i s common a mong fra i l a nd
i ns ti tuti ona l i zed el derl y peopl e who ha ve protei n-energy undernutri ti on. In devel opi ng countri es , defi ci enci es ca n res ul t from l a ck of a cces s to
nutri ents . Defi ci enci es of wa ter-s ol ubl e vi ta mi ns (except vi ta mi n B 12 ) ma y devel op a fter weeks to months of undernutri ti on. Defi ci enci es of fa ts ol ubl e vi ta mi ns a nd of vi ta mi n B 12 ta ke > 1 yr to devel op beca us e the body s tores them i n rel a ti vel y l a rge a mounts . Inta ke of vi ta mi ns s uffi ci ent
to prevent cl a s s i c vi ta mi n defi ci enci es (l i ke s curvy or beri beri ) ma y not be a dequa te for opti mum hea l th. Thi s a rea rema i ns one of controvers y a nd
a cti ve res ea rch.
Vi ta mi n dependency res ul ts from a geneti c defect i nvol vi ng meta bol i s m of a vi ta mi n. In s ome ca s es , vi ta mi n dos es a s hi gh a s 1000 ti mes the DRI
i mprove functi on of the a l tered meta bol i c pa thwa y. Vi ta mi n toxi ci ty (hypervi ta mi nos i s ) us ua l l y res ul ts from ta ki ng mega dos es of vi ta mi n A, D, C,
B 6 , or ni a ci n.
Beca us e ma ny peopl e ea t i rregul a rl y, foods a l one ma y provi de s ubopti ma l a mounts of s ome vi ta mi ns . In thes e ca s es , the ri s k of certa i n ca ncers or
other di s orders ma y be i ncrea s ed. Beca us e of thi s ri s k, routi ne da i l y mul ti vi ta mi n s uppl ements a re s ometi mes recommended.
Biotin and Pantothenic Acid
Bi oti n a cts a s a coenzyme for ca rboxyl a ti on rea cti ons es s enti a l to fa t a nd ca rbohydra te meta bol i s m. Adequa te i nta ke for a dul ts i s 30 g/da y.
Pa ntotheni c a ci d i s wi del y di s tri buted i n foods ; i t i s a n es s enti a l component of coenzyme A. Adul ts proba bl y requi re a bout 5 mg/da y. A benefi ci a l
rol e for pa ntotheni c a ci d s uppl ementa ti on i n l i pi d meta bol i s m, RA, or a thl eti c performa nce rema i ns unproved. Is ol a ted defi ci ency of bi oti n or
pa ntotheni c a ci d vi rtua l l y never occurs .
Folate
Fol a te (fol i c a ci d) i s now a dded to enri ched gra i n foods i n the US. Fol a te i s a l s o pl enti ful i n va ri ous pl a nt foods a nd mea ts , but i ts bi oa va i l a bi l i ty
i s grea ter when i t i s i n s uppl ements
[Table 4-1. Recommended Da i l y Inta kes for Vi ta mi ns ]
or enri ched foods tha n when i t occurs na tura l l y i n food.
Fol a tes a re i nvol ved i n RBC ma tura ti on a nd s ynthes i s of puri nes a nd pyri mi di nes . They a re requi red for devel opment of the feta l nervous s ys tem.
Abs orpti on occurs i n the duodenum a nd upper jejunum. Enterohepa ti c ci rcul a ti on of fol a te occurs . Fol a te s uppl ements
[Table 4-2. Sources , Functi ons , a nd Effects of Vi ta mi ns ]
do not protect a ga i ns t corona ry a rtery di s ea s e or s troke (by l oweri ng homocys tei ne l evel s ); thei r rol e i n reduci ng the ri s k of va ri ous ca ncers i s
uncl ea r. The upper l i mi t for fol a te i nta ke i s 1000 g; hi gher dos es (up to 5 mg) a re recommended for women who ha ve ha d a ba by wi th a neura l
tube defect. Fol a te i s es s enti a l l y nontoxi c.
Folate Deficiency
Fol a te defi ci ency i s common. It ma y res ul t from i na dequa te i nta ke, ma l a bs orpti on, or us e of va ri ous drugs . Defi ci ency ca us es mega l obl a s ti c
a nemi a (i ndi s ti ngui s ha bl e from tha t due to vi ta mi n B 12 defi ci ency). Ma terna l defi ci ency i ncrea s es the ri s k of neura l tube bi rth defects . Di a gnos i s
requi res l a bora tory tes ti ng to confi rm. Mea s urement of neutrophi l hypers egmenta ti on i s s ens i ti ve a nd rea di l y a va i l a bl e. Trea tment wi th ora l
fol a te i s us ua l l y s ucces s ful .
Etiology and Pathophysiology
The mos t common ca us es a re i na dequa te i nta ke (us ua l l y i n pa ti ents wi th undernutri ti on or a l cohol i s m), i ncrea s ed dema nd (eg, due to pregna ncy
or brea s tfeedi ng), a nd i mpa i red a bs orpti on (eg, i n tropi ca l s prue, due to certa i n drugs ). Defi ci ency ca n a l s o res ul t from i na dequa te bi oa va i l a bi l i ty
a nd i ncrea s ed excreti on (s ee
Ta bl e 4-4).
Prol onged cooki ng des troys fol a te, predi s pos i ng to i na dequa te i nta ke. Inta ke i s s ometi mes ba rel y a dequa te (eg, i n a l cohol i cs ). Li ver s tores
provi de onl y a s evera l -month s uppl y.

Al cohol i nterferes wi th fol a te a bs orpti on, meta bol i s m, rena l excreti on, a nd enterohepa ti c rea bs orpti on, a s wel l a s i nta ke. 5-Fl uoroura ci l ,
metformi n, methotrexa te, phenoba rbi ta l , phenytoi n, s ul fa s a l a zi ne, tri a mterene, a nd tri methopri m i mpa i r fol a te meta bol i s m.
In the US, ma ny di eta ry s ta pl es (eg, cerea l s , gra i n products ) a re routi nel y enri ched wi th fol a te, tendi ng to reduce ri s k of defi ci ency.
[Table 4-3. Potenti a l Vi ta mi n-Drug Intera cti ons ]
Symptoms and Signs
Fol a te defi ci ency ma y ca us e gl os s i ti s , di a rrhea , depres s i on, a nd confus i on. Anemi a ma y devel op i ns i di ous l y a nd, beca us e of compens a tory
mecha ni s ms , be more s evere tha n s ymptoms s ugges t.
Fol a te defi ci ency duri ng pregna ncy i ncrea s es the ri s k of feta l neura l tube defects a nd perha ps other bra i n defects (s ee p. 2992).
Diagnosis
CBC a nd s erum vi ta mi n B 12 a nd fol a te l evel s
CBC ma y i ndi ca te mega l obl a s ti c a nemi a i ndi s ti ngui s ha bl e from tha t of vi ta mi n B 12 defi ci ency. If s erum fol a te i s < 3 g/L or ng/mL (< 7 nmol /L),
defi ci ency i s l i kel y. Serum fol a te refl ects fol a te s ta tus unl es s i nta ke ha s recentl y i ncrea s ed or decrea s ed. If i nta ke ha s cha nged, erythrocyte (RBC)
fol a te l evel better refl ects ti s s ue s tores . A l evel of < 140 g/L or ng/mL (< 305 nmol /L) i ndi ca tes i na dequa te s ta tus . Al s o, a n i ncrea s e i n the
homocys tei ne l evel s ugges ts ti s s ue fol a te defi ci ency (but the l evel i s a l s o a ffected by vi ta mi n B 12 a nd vi ta mi n B 6 l evel s , rena l i ns uffi ci ency, a nd
geneti c fa ctors ). A norma l methyl ma l oni c a ci d (MMA) l evel ma y di fferenti a te fol a te defi ci ency from vi ta mi n B 12 defi ci ency beca us e MMA l evel s ri s e
i n vi ta mi n B 12 defi ci ency but not i n fol a te defi ci ency.
Treatment
Suppl ementa l ora l fol a te
Fol a te 400 to 1000 g po once/da y repl eni s hes ti s s ues a nd i s us ua l l y s ucces s ful even i f defi ci ency ha s res ul ted from ma l a bs orpti on. The norma l
requi rement i s 400 g/da y.
[Table 4-4. Ca us es of Fol a te Defi ci ency]
(CAUTION: In patients with megaloblastic anemia, vitamin B 12 deficiency must be ruled out before treating with folate. If vitamin B 12 deficiency is present, folate
supplementation can alleviate the anemia but does not reverse and may even worsen neurologic deficits.) For pregna nt women, the recommended da i l y
a l l owa nce (RDA) i s 600 g/da y. For women who ha ve ha d a fetus or i nfa nt wi th a neura l tube defect, the recommended dos e i s 1000 to 5000 g/da y.
Niacin
Ni a ci n (ni coti ni c a ci d, ni coti na mi de) deri va ti ves i ncl ude ni coti na mi de a deni ne di nucl eoti de (NAD) a nd ni coti na mi de a deni ne di nucl eoti de
phos pha te (NADP), whi ch a re coenzymes i n oxi da ti on-reducti on rea cti ons . They a re vi ta l i n cel l meta bol i s m. Beca us e di eta ry tryptopha n ca n be
meta bol i zed to ni a ci n, foods ri ch i n tryptopha n (eg, da i ry products ) ca n compens a te for i na dequa te di eta ry ni a ci n.
Niacin Deficiency
Dietary niacin deficiency (causing pellagra) is uncommon in developed countries. Clinical manifestations include the "three Ds": localized pigmented rash
(dermatitis); gastroenteritis (diarrhea); and widespread neurologic deficits, including cognitive decline (dementia). Diagnosis is usually clinical, and dietary
supplementation (oral or, if needed, IM) is usually successful.
Etiology
Pri ma ry defi ci ency res ul ts from extremel y i na dequa te i nta ke of both ni a ci n a nd tryptopha n, whi ch us ua l l y occurs i n a rea s where ma i ze (Indi a n
corn) cons ti tutes a s ubs ta nti a l pa rt of the di et. Bound ni a ci n, found i n ma i ze, i s not a s s i mi l a ted i n the GI tra ct unl es s i t ha s been previ ous l y
trea ted wi th a l ka l i , a s when torti l l a s a re prepa red. Corn protei n i s a l s o defi ci ent i n tryptopha n. The hi gh i nci dence of pel l a gra i n Indi a a mong
peopl e who ea t mi l l et wi th a hi gh l euci ne content ha s l ed to the hypothes i s tha t a mi no a ci d i mba l a nce ma y contri bute to defi ci ency. Defi ci enci es
of protei n a nd ma ny B vi ta mi ns commonl y a ccompa ny pri ma ry ni a ci n defi ci ency.
Seconda ry defi ci ency ma y be due to di a rrhea , ci rrhos i s , or a l cohol i s m. Pel l a gra a l s o ma y occur i n ca rci noi d s yndrome (tryptopha n i s di verted to
form 5-hydroxytryptopha n a nd s erotoni n) a nd i n Ha rtnup di s ea s e (a bs orpti on of tryptopha n by the i ntes ti ne a nd ki dneys i s defecti ve).
Symptoms and Signs
Pel l a gra i s cha ra cteri zed by s ki n, mucous membra ne, CNS, a nd GI s ymptoms . Adva nced pel l a gra ca n ca us e a s ymmetri c photos ens i ti ve ra s h,
s toma ti ti s , gl os s i ti s , di a rrhea , a nd menta l a berra ti ons . Symptoms ma y a ppea r a l one or i n combi na ti on.
Skin symptoms i ncl ude s evera l types of l es i ons , whi ch a re us ua l l y bi l a tera l l y s ymmetri c. The di s tri buti on of l es i ons a t pres s ure poi nts or s unexpos ed s ki ni s more pa thognomoni c tha n the form of the l es i ons . Les i ons ca n devel op i n a gl ovel i ke di s tri buti on on the ha nds (pel l a grous
gl ove) or i n a boot-s ha ped di s tri buti on on the feet a nd l egs (pel l a grous boot). Sunl i ght ca us es Ca s a l 's neckl a ce a nd butterfl y-s ha ped l es i ons on
the fa ce.
Mucous membrane symptoms a ffect pri ma ri l y the mouth but ma y a l s o a ffect the va gi na a nd urethra . Gl os s i ti s a nd s toma ti ti s cha ra cteri ze a cute
defi ci ency. As the defi ci ency progres s es , the tongue a nd ora l mucous membra nes become reddened, fol l owed by pa i n i n the mouth, i ncrea s ed
s a l i va ti on, a nd edema of the tongue. Ul cera ti ons ma y a ppea r, es peci a l l y under the tongue, on the mucos a of the l ower l i p, a nd oppos i te the
mol a r teeth.
GI symptoms ea rl y i n the defi ci ency i ncl ude burni ng i n the pha rynx a nd es opha gus a nd a bdomi na l di s comfort a nd di s tenti on. Cons ti pa ti on i s
common. La ter, na us ea , vomi ti ng, a nd di a rrhea ma y occur. Di a rrhea i s often bl oody beca us e of bowel hyperemi a a nd ul cera ti on.
CNS symptoms i ncl ude ps ychos i s , encepha l opa thy (cha ra cteri zed by i mpa i red cons ci ous nes s ), a nd cogni ti ve decl i ne (dementi a ). Ps ychos i s i s
cha ra cteri zed by memory i mpa i rment, di s ori enta ti on, confus i on, a nd confa bul a ti on; the predomi na nt s ymptom ma y be exci tement, depres s i on,
ma ni a , del i ri um, or pa ra noi a .
Diagnosis
Cl i ni ca l eva l ua ti on
Di a gnos i s i s cl i ni ca l a nd ma y be s tra i ghtforwa rd when s ki n a nd mouth l es i ons , di a rrhea , del i ri um, a nd dementi a occur s i mul ta neous l y. More
often, the pres enta ti on i s not s o s peci fi c. Di fferenti a ti ng the CNS cha nges from thos e i n thi a mi n defi ci ency i s di ffi cul t. A hi s tory of a di et l a cki ng
ni a ci n a nd tryptopha n ma y hel p es ta bl i s h the di a gnos i s . A fa vora bl e res pons e to trea tment wi th ni a ci n ca n us ua l l y confi rm i t. If a va i l a bl e,
l a bora tory tes ti ng ca n hel p confi rm the di a gnos i s , pa rti cul a rl y when the di a gnos i s i s otherwi s e uncl ea r. Uri na ry excreti on of N1 methyl ni coti na mi de (NMN) i s decrea s ed; < 0.8 mg/da y (< 5.8 mol /da y) s ugges ts a ni a ci n defi ci ency.
Treatment
Ni coti na mi de a nd other nutri ents
Beca us e mul ti pl e defi ci enci es a re common, a ba l a nced di et, i ncl udi ng other B vi ta mi ns (pa rti cul a rl y ri bofl a vi n a nd pyri doxi ne), i s needed.
Ni coti na mi de i s us ua l l y us ed to trea t defi ci ency, beca us e ni coti na mi de, unl i ke ni coti ni c a ci d (the mos t common form of ni a ci n), does not ca us e
fl us hi ng, i tchi ng, burni ng, or ti ngl i ng s ens a ti ons . Ni coti na mi de i s gi ven i n dos es ra ngi ng from 40 to 250 mg/da y po i n di vi ded dos es 3 to 4 ti mes a
da y.
Niacin Toxicity
Niacin (nicotinic acid) in large amounts is sometimes used to lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and to increase high-density
lipoprotein (HDL) cholesterol levels. Symptoms may include flushing and, rarely, hepatotoxicity.
Immedi a te- a nd s us ta i ned-rel ea s e prepa ra ti ons of ni a ci n (but not ni coti na mi de) ma y i mprove l i pi d l evel s . Fl us hi ng, whi ch i s pros ta gl a ndi nmedi a ted, i s more common wi th i mmedi a te-rel ea s e prepa ra ti ons . It ma y be more i ntens e a fter a l cohol i nges ti on, a erobi c a cti vi ty, s un expos ure,
a nd cons umpti on of s pi cy foods . Fl us hi ng i s mi ni mi zed i f ni a ci n i s ta ken a fter mea l s or i f a s pi ri n (325 mg) i s ta ken 30 to 45 mi n before ni a ci n. The
cha nce of s evere fl us hi ng ca n be reduced by s ta rti ng i mmedi a te-rel ea s e ni a ci n a t a l ow dos e (eg, 50 mg ti d) a nd i ncrea s i ng i t very s l owl y. At
i ntermedi a te dos es (1000 mg/da y), tri gl yceri de l evel s decrea s e 15 to 20%, a nd HDL chol es terol l evel s i ncrea s e 15 to 30%. Reducti ons i n LDL
chol es terol a re modes t (< 10%). Hi gher dos es of ni a ci n (3000 mg/da y) reduce LDL chol es terol 15 to 20% but ma y ca us e ja undi ce, a bdomi na l
di s comfort, bl urred vi s i on, wors eni ng of hypergl ycemi a , a nd preci pi ta ti on of preexi s ti ng gout. Peopl e wi th a l i ver di s order proba bl y s houl d not
ta ke hi gh-dos e ni a ci n.
Hepa totoxi ci ty ma y be more common wi th s ome s us ta i ned-rel ea s e prepa ra ti ons . Some a uthori ti es recommend checki ng l evel s of uri c a ci d, s erum
gl ucos e, a nd pl a s ma tra ns a mi na s es every 6 to 8 wk unti l the dos e of ni a ci n ha s been s ta bi l i zed.
Riboflavin
Ri bofl a vi n (vi ta mi n B 2 ) i s i nvol ved i n ca rbohydra te meta bol i s m a s a n es s enti a l coenzyme i n ma ny oxi da ti on-reducti on rea cti ons . Ri bofl a vi n i s
es s enti a l l y nontoxi c.
Riboflavin Deficiency
Riboflavin deficiency usually occurs with other B-vitamin deficiencies. Symptoms and signs include sore throat, lesions of the lips and mucosa of the mouth,
glossitis, conjunctivitis, seborrheic dermatitis, and normochromicnormocytic anemia. Diagnosis is usually clinical. Treatment consists of oral or, if needed, IM
riboflavin.
Pri ma ry ri bofl a vi n defi ci ency res ul ts from i na dequa te i nta ke of forti fi ed cerea l s , mi l k, a nd other a ni ma l products . The mos t common ca us es of
s econda ry defi ci ency a re chroni c di a rrhea , ma l a bs orpti on s yndromes , l i ver di s orders , hemodi a l ys i s , peri tonea l di a l ys i s , l ong-term us e of
ba rbi tura tes , a nd chroni c a l cohol i s m.
Symptoms and Signs
The mos t common s i gns a re pa l l or a nd ma cera ti on of the mucos a a t the a ngl es of the mouth (a ngul a r s toma ti ti s ) a nd vermi l i on s urfa ces of the
l i ps (chei l os i s ), eventua l l y repl a ced by s uperfi ci a l l i nea r fi s s ures . The fi s s ures ca n become i nfected wi th Candida albicans, ca us i ng gra yi s h whi te
l es i ons (perl eche). The tongue ma y a ppea r ma genta . Seborrhei c derma ti ti s devel ops , us ua l l y a ffecti ng the na s ol a bi a l fol ds , ea rs , eyel i ds , a nd
s crotum or l a bi a ma jora . Thes e a rea s become red, s ca l y, a nd grea s y.
Ra rel y, neova s cul a ri za ti on a nd kera ti ti s of the cornea occur, ca us i ng l a cri ma ti on a nd photophobi a .
Diagnosis
The l es i ons cha ra cteri s ti c of ri bofl a vi n defi ci ency a re nons peci fi c. Ri bofl a vi n defi ci ency s houl d be s us pected i f cha ra cteri s ti c s i gns devel op i n a
pa ti ent wi th other B vi ta mi n defi ci enci es . Di a gnos i s ca n be confi rmed by a thera peuti c tri a l or l a bora tory tes ti ng, us ua l l y by mea s uri ng uri na ry
excreti on of ri bofl a vi n.
Treatment
Ri bofl a vi n 5 to 10 mg/da y po i s gi ven unti l recovery. Other wa ter-s ol ubl e vi ta mi ns s houl d a l s o be gi ven.
Thiamin
Thi a mi n (vi ta mi n B 1 ) i s wi del y a va i l a bl e i n the di et. Thi a mi n i s i nvol ved i n ca rbohydra te, fa t, a mi no a ci d, gl ucos e, a nd a l cohol meta bol i s m.
Thi a mi n i s es s enti a l l y nontoxi c.
Thiamin Deficiency
Thiamin deficiency (causing beriberi) is most common among people subsisting on white rice or highly refined carbohydrates in developing countries and among
alcoholics. Symptoms include diffuse polyneuropathy, high-output heart failure, and Wernicke-Korsakoff syndrome. Thiamin is given to help diagnose and treat
the deficiency.
Etiology
Pri ma ry thi a mi n defi ci ency i s ca us ed by i na dequa te i nta ke of thi a mi n. It i s commonl y due to a di et of hi ghl y refi ned ca rbohydra tes (eg, pol i s hed
ri ce, whi te fl our, whi te s uga r). It a l s o devel ops when i nta ke of other nutri ents i s i na dequa te; i t often occurs wi th other B vi ta mi n defi ci enci es .
Seconda ry thi a mi n defi ci ency i s ca us ed by i ncrea s ed dema nd (eg, due to hyperthyroi di s m, pregna ncy, brea s tfeedi ng, s trenuous exerci s e, or fever),
i mpa i red a bs orpti on (eg, due to prol onged di a rrhea ), or i mpa i red meta bol i s m (eg, due to hepa ti c i ns uffi ci ency). In a l cohol i cs , ma ny mecha ni s ms
contri bute to thi a mi n defi ci ency; they i ncl ude decrea s ed i nta ke, i mpa i red a bs orpti on a nd us e, i ncrea s ed dema nd, a nd pos s i bl y a n a poenzyme
defect.
Pathophysiology
Defi ci ency ca us es degenera ti on of peri phera l nerves , tha l a mus , ma mmi l l a ry bodi es , a nd cerebel l um. Cerebra l bl ood fl ow i s ma rkedl y reduced,
a nd va s cul a r res i s ta nce i s i ncrea s ed.
The hea rt ma y become di l a ted; mus cl e fi bers become s wol l en, fra gmented, a nd va cuol i zed, wi th i nters ti ti a l s pa ces di l a ted by fl ui d. Va s odi l a ti on
occurs a nd ca n res ul t i n edema i n the feet a nd l egs . Arteri ovenous s hunti ng of bl ood i ncrea s es . Eventua l l y, hi gh-output hea rt fa i l ure ma y occur.
Symptoms and Signs
Ea rl y s ymptoms a re nons peci fi c: fa ti gue, i rri ta bi l i ty, poor memory, s l eep di s turba nces , precordi a l pa i n, a norexi a , a nd a bdomi na l di s comfort.
Dry beriberi refers to peri phera l neurol ogi c defi ci ts due to thi a mi n defi ci ency. Thes e defi ci ts a re bi l a tera l a nd roughl y s ymmetri c, occurri ng i n a
s tocki ng-gl ove di s tri buti on. They a ffect predomi na ntl y the l ower extremi ti es , begi nni ng wi th pa res thes i a s i n the toes , burni ng i n the feet
(pa rti cul a rl y s evere a t ni ght), mus cl e cra mps i n the ca l ves , pa i ns i n the l egs , a nd pl a nta r dys es thes i a s . Ca l f mus cl e tendernes s , di ffi cul ty ri s i ng
from a s qua tti ng pos i ti on, a nd decrea s ed vi bra tory s ens a ti on i n the toes a re ea rl y s i gns . Mus cl e wa s ti ng occurs . Conti nued defi ci ency wors ens
pol yneuropa thy, whi ch ca n eventua l l y a ffect the a rms .
Wernicke-Korsakoff syndrome, whi ch combi nes Werni cke's encepha l opa thy (s ee p. 1522) a nd Kors a koff's ps ychos i s (s ee p. 1523), occurs i n s ome
a l cohol i cs who do not cons ume foods forti fi ed wi th thi a mi n. Werni cke's encepha l opa thy cons i s ts of ps ychomotor s l owi ng or a pa thy, nys ta gmus ,
a ta xi a , ophtha l mopl egi a , i mpa i red cons ci ous nes s , a nd, i f untrea ted, coma a nd dea th. It proba bl y res ul ts from s evere a cute defi ci ency
s uperi mpos ed on chroni c defi ci ency. Kors a koff's ps ychos i s cons i s ts of menta l confus i on, dys phoni a , a nd confa bul a ti on wi th i mpa i red memory of
recent events . It proba bl y res ul ts from chroni c defi ci ency a nd ma y devel op a fter repea ted epi s odes of Werni cke's encepha l opa thy.
Cardiovascular (wet) beriberi i s myoca rdi a l di s ea s e due to thi a mi n defi ci ency. The fi rs t effects a re va s odi l a ti on, ta chyca rdi a , a wi de pul s e pres s ure,
s wea ti ng, wa rm s ki n, a nd l a cti c a ci dos i s . La ter, hea rt fa i l ure devel ops , ca us i ng orthopnea a nd pul mona ry a nd peri phera l edema . Va s odi l a ti on ca n
conti nue, s ometi mes res ul ti ng i n s hock.
Infantile beriberi occurs i n i nfa nts (us ua l l y by a ge 3 to 4 wk) who a re brea s tfed by thi a mi n-defi ci ent mothers . Hea rt fa i l ure (whi ch ma y occur
s uddenl y), a phoni a , a nd a bs ent deep tendon refl exes a re cha ra cteri s ti c.
Beca us e thi a mi n i s neces s a ry for gl ucos e meta bol i s m, gl ucos e i nfus i ons ma y preci pi ta te or wors en s ymptoms of defi ci ency i n thi a mi n-defi ci ent
peopl e.
Diagnosis
Fa vora bl e res pons e to thi a mi n
Di a gnos i s i s us ua l l y ba s ed on a fa vora bl e res pons e to trea tment wi th thi a mi n i n a pa ti ent wi th s ymptoms or s i gns of defi ci ency. Si mi l a r bi l a tera l
l ower-extremi ty pol yneuropa thi es due to other di s orders (eg, di a betes , a l cohol i s m, vi ta mi n B 12 defi ci ency, hea vy meta l poi s oni ng) do not res pond
to thi a mi n. Si ngl e-nerve neuri ti des (mononeuropa thi es eg, s ci a ti ca ) a nd mul ti pl e mononeuropa thi es (mononeuri ti s mul ti pl ex) a re unl i kel y to
res ul t from thi a mi n defi ci ency.
El ectrol ytes , i ncl udi ng Mg, s houl d be mea s ured to excl ude other ca us es . For confi rma ti on i n equi voca l ca s es , erythrocyte tra ns ketol a s e a cti vi ty a nd
24-h uri na ry thi a mi n excreti on ma y be mea s ured.
Di a gnos i s of ca rdi ova s cul a r beri beri ca n be di ffi cul t i f other di s orders tha t ca us e hea rt fa i l ure a re pres ent. A thera peuti c tri a l of thi a mi n ca n hel p.
Treatment
Suppl ementa l thi a mi n, wi th dos e ba s ed on cl i ni ca l ma ni fes ta ti ons
Ens uri ng tha t di eta ry s uppl i es of thi a mi n a re a dequa te i s i mporta nt rega rdl es s of s ymptoms . Beca us e IV gl ucos e ca n wors en thi a mi n defi ci ency,
a l cohol i cs a nd others a t ri s k of thi a mi n defi ci ency s houl d recei ve IV thi a mi n 100 mg before recei vi ng IV gl ucos e s ol uti ons .
For mi l d pol yneuropa thy, thi a mi n 10 to 20 mg po once/da y i s gi ven for 2 wk. For modera te or a dva nced neuropa thy, the dos e i s 20 to 30 mg/da y; i t
s houl d be conti nued for s evera l weeks a fter s ymptoms di s a ppea r. For edema a nd conges ti on due to ca rdi ova s cul a r beri beri , thi a mi n 100 mg IV
once/da y i s gi ven for s evera l da ys . Hea rt fa i l ure i s a l s o trea ted.
For Werni cke-Kors a koff s yndrome, thi a mi n 50 to 100 mg IM or IV bi d mus t us ua l l y be gi ven for s evera l da ys , fol l owed by 10 to 20 mg once/da y unti l
a thera peuti c res pons e i s obta i ned. Ana phyl a cti c rea cti ons to IV thi a mi n a re ra re. Symptoms of ophtha l mopl egi a ma y res ol ve i n a da y;
i mprovement i n pa ti ents wi th Kors a koff ps ychos i s ma y ta ke 1 to 3 mo. Recovery from neurol ogi c defi ci ts i s often i ncompl ete i n Werni cke-Kors a koff
s yndrome a nd i n other forms of thi a mi n defi ci ency.
Beca us e thi a mi n defi ci ency often occurs wi th other B vi ta mi n defi ci enci es , mul ti pl e wa ter-s ol ubl e vi ta mi ns a re us ua l l y gi ven for s evera l weeks .
Pa ti ents s houl d conti nue to cons ume a nutri ti ous di et, s uppl yi ng 1 to 2 ti mes the da i l y recommended i nta ke of vi ta mi ns ; a l l a l cohol i nta ke s houl d
s top.
Vitamin A
Vi ta mi n A (reti nol ) i s requi red for the forma ti on of rhodops i n, a photoreceptor pi gment i n the reti na . Vi ta mi n A hel ps ma i nta i n epi thel i a l ti s s ues .
Norma l l y, the l i ver s tores 80 to 90% of the body's vi ta mi n A. To us e vi ta mi n A, the body rel ea s es i t i nto the ci rcul a ti on bound to prea l bumi n
(tra ns thyreti n) a nd reti nol -bi ndi ng protei n. -Ca rotene a nd other provi ta mi n ca rotenoi ds , conta i ned i n green l ea fy a nd yel l ow vegeta bl es a nd
deep- or bri ght-col ored frui ts , a re converted to vi ta mi n A. Ca rotenoi ds a re a bs orbed better from vegeta bl es when they a re cooked or homogeni zed
a nd s erved wi th s ome fa ts or oi l s .
Reti nol a cti vi ty equi va l ents (RAE) were devel oped beca us e provi ta mi n A ca rotenoi ds ha ve l es s vi ta mi n A a cti vi ty tha n preformed vi ta mi n A; 1 g
reti nol = 3.33 IU.
Syntheti c vi ta mi n a na l ogs (reti noi ds ) a re bei ng us ed i ncrea s i ngl y i n derma tol ogy. The pos s i bl e protecti ve rol e of -ca rotene, reti nol , a nd reti noi ds
a ga i ns t s ome epi thel i a l ca ncers i s under s tudy. However, ri s k of certa i n ca ncers ma y be i ncrea s ed a fter -ca rotene s uppl ementa ti on.
Vitamin A Deficiency
Vitamin A deficiency can result from inadequate intake, fat malabsorption, or liver disorders. Deficiency impairs immunity and hematopoiesis and causes rashes
and typical ocular effects (eg, xerophthalmia, night blindness). Diagnosis is based on typical ocular findings and low vitamin A levels. Treatment consists of
vitamin A given orally or, if symptoms are severe or malabsorption is the cause, parenterally.
Etiology
Pri ma ry vi ta mi n A defi ci ency i s us ua l l y ca us ed by prol onged di eta ry depri va ti on. It i s endemi c i n a rea s s uch a s s outhern a nd ea s tern As i a , where
ri ce, devoi d of -ca rotene, i s the s ta pl e food. Xerophtha l mi a due to pri ma ry defi ci ency i s a common ca us e of bl i ndnes s a mong young chi l dren i n
devel opi ng countri es .
Seconda ry vi ta mi n A defi ci ency ma y be due to decrea s ed bi oa va i l a bi l i ty of provi ta mi n A ca rotenoi ds or to i nterference wi th a bs orpti on, s tora ge, or
tra ns port of vi ta mi n A. Interference wi th a bs orpti on or s tora ge i s l i kel y i n s prue, cys ti c fi bros i s , pa ncrea ti c i ns uffi ci ency, duodena l bypa s s , chroni c
di a rrhea , bi l e duct obs tructi on, gi a rdi a s i s , a nd ci rrhos i s . Vi ta mi n A defi ci ency i s common i n prol onged protei n-energy undernutri ti on not onl y
beca us e the di et i s defi ci ent but a l s o beca us e vi ta mi n A s tora ge a nd tra ns port i s defecti ve. In chi l dren wi th compl i ca ted mea s l es , vi ta mi n A ca n
s horten the dura ti on of the di s order a nd reduce the s everi ty of s ymptoms a nd ri s k of dea th.
Symptoms and Signs
Impa i red da rk a da pta ti on of the eyes , whi ch ca n l ea d to ni ght bl i ndnes s , i s a n ea rl y s ymptom. Xerophtha l mi a (whi ch i s nea rl y pa thognomoni c)
res ul ts from kera ti ni za ti on of the eyes . It i nvol ves dryi ng (xeros i s ) a nd thi ckeni ng of the conjuncti va e a nd cornea s . Superfi ci a l foa my pa tches
compos ed of epi thel i a l debri s a nd s ecreti ons on the expos ed bul ba r conjuncti va (Bi tot's s pots ) devel op. In a dva nced defi ci ency, the cornea
becomes ha zy a nd ca n devel op eros i ons , whi ch ca n l ea d to i ts des tructi on (kera toma l a ci a ).
Kera ti ni za ti on of the s ki n a nd of the mucous membra nes i n the res pi ra tory, GI, a nd uri na ry tra cts ca n occur. Dryi ng, s ca l i ng, a nd fol l i cul a r
thi ckeni ng of the s ki n a nd res pi ra tory i nfecti ons ca n res ul t. Immuni ty i s genera l l y i mpa i red.
The younger the pa ti ent, the more s evere a re the effects of vi ta mi n A defi ci ency. Growth reta rda ti on a nd i nfecti ons a re common a mong chi l dren.
Morta l i ty ra te ca n exceed 50% i n chi l dren wi th s evere vi ta mi n A defi ci ency.
Diagnosis
Serum reti nol l evel s , cl i ni ca l eva l ua ti on, a nd res pons e to vi ta mi n A
Ocul a r fi ndi ngs s ugges t the di a gnos i s . Da rk a da pta ti on ca n be i mpa i red i n other di s orders (eg, zi nc defi ci ency, reti ni ti s pi gmentos a , s evere
refra cti ve errors , ca ta ra cts , di a beti c reti nopa thy). If da rk a da pta ti on i s i mpa i red, rod s cotometry a nd el ectroreti nogra phy a re done to determi ne
whether vi ta mi n A defi ci ency i s the ca us e.

Serum l evel s of reti nol a re mea s ured. Norma l ra nge i s 28 to 86 g/dL (1 to 3 mol /L). However, l evel s decrea s e onl y a fter the defi ci ency i s
a dva nced beca us e the l i ver conta i ns l a rge s tores of vi ta mi n A. Al s o, decrea s ed l evel s ma y res ul t from a cute i nfecti on, whi ch ca us es reti nol bi ndi ng protei n a nd tra ns thyreti n (a l s o ca l l ed prea l bumi n) l evel s to decrea s e tra ns i entl y. A thera peuti c tri a l of vi ta mi n A ma y hel p confi rm the
di a gnos i s .
Prevention
The di et s houl d i ncl ude da rk green l ea fy vegeta bl es , deep- or bri ght-col ored frui ts (eg, pa pa ya s , ora nges ), ca rrots , a nd yel l ow vegeta bl es (eg,
s qua s h, pumpki n). Vi ta mi n A-forti fi ed mi l k a nd cerea l s , l i ver, egg yol ks , a nd fi s h l i ver oi l s a re hel pful . Ca rotenoi ds a re a bs orbed better when
cons umed wi th s ome di eta ry fa t. If mi l k a l l ergy i s s us pected i n i nfa nts , they s houl d be gi ven a dequa te vi ta mi n A i n formul a feedi ngs . In
devel opi ng countri es , prophyl a cti c s uppl ements of vi ta mi n A pa l mi ta te i n oi l 60,000 RAE (200,000 IU) po every 6 mo a re a dvi s ed for a l l chi l dren
between 1 a nd 5 yr of a ge; i nfa nts < 6 mo ca n be gi ven a one-ti me dos e of 15,000 RAE (50,000 IU), a nd thos e a ged 6 to 12 mo ca n be gi ven a oneti me dos e of 30,000 RAE (100,000 IU).
Treatment
Vi ta mi n A pa l mi ta te
Di eta ry defi ci ency i s tra di ti ona l l y trea ted wi th vi ta mi n A pa l mi ta te i n oi l 60,000 IU po once/da y for 2 da ys , fol l owed by 4500 IU po once/da y. If
vomi ti ng or ma l a bs orpti on i s pres ent or xerophtha l mi a i s proba bl e, a dos e of 50,000 IU for i nfa nts < 6 mo, 100,000 IU for i nfa nts 6 to 12 mo, or
200,000 IU for chi l dren > 12 mo a nd a dul ts s houl d be gi ven for 2 da ys , wi th a thi rd dos e a t l ea s t 2 wk l a ter. The s a me dos es a re recommended for
i nfa nts a nd chi l dren wi th compl i ca ted mea s l es . Infa nts born of HIV-pos i ti ve mothers s houl d recei ve 50,000 IU (15,000 RAE) wi thi n 48 h of bi rth.
Prol onged da i l y a dmi ni s tra ti on of l a rge dos es , es peci a l l y to i nfa nts , mus t be a voi ded beca us e toxi ci ty ma y res ul t.
For pregna nt or brea s tfeedi ng women, prophyl a cti c or thera peuti c dos es s houl d not exceed 10,000 IU (3000 RAE)/da y to a voi d pos s i bl e da ma ge to
the fetus or i nfa nt.
Vitamin A Toxicity
Vitamin A toxicity can be acute (usually due to accidental ingestion by children) or chronic. Both types usually cause headache and increased intracranial pressure.
Acute toxicity also causes nausea and vomiting. Chronic toxicity also causes changes in skin, hair, and nails; abnormal liver test results; and, in a fetus, birth
defects. Diagnosis is usually clinical. Unless birth defects are present, adjusting the dose almost always leads to complete recovery.
Acute vi ta mi n A toxi ci ty i n chi l dren ma y res ul t from ta ki ng l a rge dos es (> 100,000 RAE [> 300,000 IU]), us ua l l y a cci denta l l y. In a dul ts , a cute toxi ci ty
ha s occurred when a rcti c expl orers i nges ted pol a r bea r or s ea l l i vers , whi ch conta i n s evera l mi l l i on uni ts of vi ta mi n A.
Chroni c toxi ci ty i n ol der chi l dren a nd a dul ts us ua l l y devel ops a fter dos es of > 30,000 RAE (> 100,000 IU)/da y ha ve been ta ken for months .
Mega vi ta mi n thera py i s a pos s i bl e ca us e, a s a re ma s s i ve da i l y dos es (50,000 to 120,000 RAE [150,000 to 350,000 IU]) of vi ta mi n A or i ts meta bol i tes ,
whi ch a re s ometi mes gi ven for nodul a r a cne or other s ki n di s orders . Adul ts who cons ume > 1500 RAE (> 4500 IU)/da y of vi ta mi n A ma y devel op
os teoporos i s . Infa nts who a re gi ven exces s i ve dos es (6,000 to 20,000 RAE [18,000 to 60,000 IU]/da y) of wa ter-mi s ci bl e vi ta mi n A ma y devel op toxi ci ty
wi thi n a few weeks . Bi rth defects occur i n chi l dren of women recei vi ng i s otreti noi n (whi ch i s rel a ted to vi ta mi n A) for a cne trea tment duri ng
pregna ncy.
Al though ca rotene i s converted to vi ta mi n A i n the body, exces s i ve i nges ti on of ca rotene ca us es ca rotenemi a , not vi ta mi n A toxi ci ty. Ca rotenemi a i s
us ua l l y a s ymptoma ti c but ma y l ea d to ca rotenodermi a , i n whi ch the s ki n becomes yel l ow. When ta ken a s a s uppl ement, -ca rotene ha s been
a s s oci a ted wi th i ncrea s ed ca ncer ri s k; ri s k does not s eem to i ncrea s e when ca rotenoi ds a re cons umed i n frui ts a nd vegeta bl es .
Symptoms and Signs
Al though s ymptoms ma y va ry, hea da che a nd ra s h us ua l l y devel op duri ng a cute or chroni c toxi ci ty. Acute toxi ci ty ca us es i ncrea s ed i ntra cra ni a l
pres s ure. Drows i nes s , i rri ta bi l i ty, a bdomi na l pa i n, na us ea , a nd vomi ti ng a re common. Someti mes the s ki n s ubs equentl y peel s .
Ea rl y s ymptoms of chroni c toxi ci ty a re s pa rs el y di s tri buted, coa rs e ha i r; a l opeci a of the eyebrows ; dry, rough s ki n; dry eyes ; a nd cra cked l i ps . La ter,
s evere hea da che, ps eudotumor cerebri , a nd genera l i zed wea knes s devel op. Corti ca l hyperos tos i s of bone a nd a rthra l gi a ma y occur, es peci a l l y i n
chi l dren. Fra ctures ma y occur ea s i l y, es peci a l l y i n the el derl y. In chi l dren, toxi ci ty ca n ca us e pruri tus , a norexi a , a nd fa i l ure to thri ve. Hepa tomega l y
a nd s pl enomega l y ma y occur.
In ca rotenodermi a , the s ki n (but not the s cl era ) becomes deep yel l ow, es peci a l l y on the pa l ms a nd s ol es .
Diagnosis
Di a gnos i s i s cl i ni ca l . Bl ood vi ta mi n l evel s correl a te poorl y wi th toxi ci ty. However, i f cl i ni ca l di a gnos i s i s equi voca l , l a bora tory tes ti ng ma y hel p. In
vi ta mi n A toxi ci ty, fa s ti ng s erum reti nol l evel s ma y i ncrea s e from norma l (28 to 86 g/dL [1 to 3 mol /L]) to > 100 g/dL (> 3.49 mol /L), s ometi mes to
> 2000 g/dL (> 69.8 mol /L). Hyperca l cemi a i s common.
Di fferenti a ti ng vi ta mi n A toxi ci ty from other di s orders ma y be di ffi cul t. Ca rotenodermi a ma y a l s o occur i n s evere hypothyroi di s m a nd a norexi a
nervos a , pos s i bl y beca us e ca rotene i s converted to vi ta mi n A more s l owl y.
Prognosis
Compl ete recovery us ua l l y occurs i f vi ta mi n A i nges ti on s tops . Symptoms a nd s i gns of chroni c toxi ci ty us ua l l y di s a ppea r wi thi n 1 to 4 wk. However,
bi rth defects i n the fetus of a mother who ha s ta ken mega dos es of vi ta mi n A a re not revers i bl e.
Treatment
Vi ta mi n A i s s topped.
Vitamin B6
Vi ta mi n B 6 i ncl udes a group of cl os el y rel a ted compounds : pyri doxi ne, pyri doxa l , a nd pyri doxa mi ne. They a re meta bol i zed i n the body to pyri doxa l
phos pha te, whi ch a cts a s a coenzyme i n ma ny i mporta nt rea cti ons i n bl ood, CNS, a nd s ki n meta bol i s m. Vi ta mi n B 6 i s i mporta nt i n heme a nd
nucl ei c a ci d bi os ynthes i s a nd i n l i pi d, ca rbohydra te, a nd a mi no a ci d meta bol i s m.
Vitamin B6 Deficiency and Dependency
Because vitamin B6 is present in most foods, dietary deficiency is rare. Secondary deficiency may result from various conditions. Symptoms can include
peripheral neuropathy, a pellagra-like syndrome, anemia, and seizures, which, particularly in infants, may not resolve when treated with anticonvulsants.
Impaired metabolism (dependency) is rare; it causes various symptoms, including seizures, intellectual disability, and anemia. Diagnosis is usually clinical; no
laboratory test readily assesses vitamin B6 status. Treatment consists of giving oral vitamin B6 and, when possible, treating the cause.
Di eta ry defi ci ency, though ra re, ca n devel op beca us e extens i ve proces s i ng ca n depl ete foods of vi ta mi n B 6 . Seconda ry defi ci ency mos t often
res ul ts from protei n-energy undernutri ti on, ma l a bs orpti on, a l cohol i s m, us e of pyri doxi ne-i na cti va ti ng drugs (eg, a nti convul s a nts , i s oni a zi d,
cycl os eri ne, hydra l a zi ne, corti cos teroi ds , peni ci l l a mi ne), or exces s i ve l os s . Ra rel y, i t res ul ts from i ncrea s ed meta bol i c dema nd (eg, i n
hyperthyroi di s m).
Ra re i nborn errors of meta bol i s m ca n a ffect pyri doxi ne meta bol i s m.
The rol e of vi ta mi n B 6 defi ci ency i n i ncrea s i ng pl a s ma homocys tei ne l evel s a nd i n contri buti ng to va s cul a r di s orders i s under s tudy.
Symptoms and Signs
Defi ci ency ca us es a pel l a gra -l i ke s yndrome, wi th s eborrhei c derma ti ti s , gl os s i ti s , a nd chei l os i s , a nd, i n a dul ts , ca n ca us e depres s i on, confus i on,
EEG a bnorma l i ti es , a nd s ei zures . Ra rel y, defi ci ency or dependency ca us es s ei zures i n i nfa nts . Sei zures , pa rti cul a rl y i n i nfa nts , ma y be refra ctory to
trea tment wi th a nti convul s a nts . Normocyti c, mi crocyti c, or s i derobl a s ti c a nemi a ca n a l s o devel op.
Diagnosis
Vi ta mi n B 6 defi ci ency s houl d be cons i dered i n a ny i nfa nt who ha s s ei zures , a ny pa ti ent who ha s s ei zures refra ctory to trea tment wi th
a nti convul s a nts , a nd a ny pa ti ent wi th defi ci enci es of other B vi ta mi ns , pa rti cul a rl y i n pa ti ents wi th a l cohol i s m or protei n-energy undernutri ti on.
Di a gnos i s i s us ua l l y cl i ni ca l . There i s no s i ngl e a ccepted l a bora tory tes t of vi ta mi n B 6 s ta tus ; mea s urement of s erum pyri doxa l phos pha te i s mos t
common.
Treatment
Pyri doxi ne
El i mi na ti on of ri s k fa ctors when pos s i bl e
For s econda ry defi ci ency, ca us es (eg, us e of pyri doxi ne-i na cti va ti ng drugs , ma l a bs orpti on) s houl d be corrected i f pos s i bl e. Us ua l l y, pyri doxi ne 50
to 100 mg po once/da y corrects the defi ci ency i n a dul ts . Mos t peopl e ta ki ng i s oni a zi d s houl d a l s o be gi ven pyri doxi ne 30 to 50 mg/da y. For
defi ci ency due to i ncrea s ed meta bol i c dema nd, a mounts l a rger tha n the da i l y recommended i nta ke ma y be requi red. For mos t ca s es of i nborn
errors of meta bol i s m, hi gh dos es of pyri doxi ne ma y be effecti ve.
Vitamin B6 Toxicity
The i nges ti on of mega dos es (> 500 mg/da y) of pyri doxi ne (eg, ta ken to trea t ca rpa l tunnel s yndrome or premens trua l s yndrome a l though effi ca cy i s
unproved) ma y ca us e peri phera l neuropa thy wi th defi ci ts i n a s tocki ng-gl ove di s tri buti on, i ncl udi ng progres s i ve s ens ory a ta xi a a nd s evere
i mpa i rment of pos i ti on a nd vi bra ti on s ens es . Sens es of touch, tempera ture, a nd pa i n a re l es s a ffected. Motor a nd centra l nervous s ys tems a re
us ua l l y i nta ct.
Di a gnos i s i s cl i ni ca l . Trea tment i s to s top ta ki ng vi ta mi n B 6 . Recovery i s s l ow a nd, for s ome pa ti ents , i ncompl ete.
Vitamin B12
Coba l a mi n i s a genera l term for compounds wi th bi ol ogi c vi ta mi n B 12 a cti vi ty. Thes e compounds a re i nvol ved i n nucl ei c a ci d meta bol i s m, methyl
tra ns fer, a nd myel i n s ynthes i s a nd repa i r. They a re neces s a ry for the forma ti on of norma l RBCs .
Food-bound vi ta mi n B 12 i s rel ea s ed i n the s toma ch's a ci d envi ronment a nd i s bound to R protei n (ha ptocorri n). Pa ncrea ti c enzymes cl ea ve thi s B 12
compl ex (B 12 -R protei n) i n the s ma l l i ntes ti ne. After cl ea va ge, i ntri ns i c fa ctor, s ecreted by pa ri eta l cel l s i n the ga s tri c mucos a , bi nds wi th vi ta mi n
B 12 . Intri ns i c fa ctor i s requi red for a bs orpti on of vi ta mi n B 12 , whi ch ta kes pl a ce i n the termi na l i l eum.
Vi ta mi n B 12 i n pl a s ma i s bound to tra ns coba l a mi ns I a nd II. Tra ns coba l a mi n II i s res pons i bl e for del i veri ng vi ta mi n B 12 to ti s s ues . The l i ver s tores
l a rge a mounts of vi ta mi n B 12 . Enterohepa ti c rea bs orpti on hel ps reta i n vi ta mi n B 12 . Li ver vi ta mi n B 12 s tores ca n norma l l y s us ta i n phys i ol ogi c needs
for 3 to 5 yr i f B 12 i nta ke s tops (eg, i n peopl e who become vega ns ) a nd for months to 1 yr i f enterohepa ti c rea bs orpti on ca pa ci ty i s a bs ent.
La rge a mounts of vi ta mi n B 12 s eem to be nontoxi c but a re not recommended for regul a r us e (i e, a s a genera l toni c).
Vitamin B12 Deficiency
Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency
causes megaloblastic anemia, damage to the white matter of the spinal cord and brain, and peripheral neuropathy. Diagnosis is usually made by measuring
serum vitamin B12 levels. The Schilling test helps determine etiology. Treatment consists of oral or parenteral vitamin B12 . Folate (folic acid) should not be used
instead of vitamin B12 because folate may alleviate the anemia but allow neurologic deficits to progress.
Etiology
Ina dequa te vi ta mi n B 12 i nta ke i s pos s i bl e i n vega ns but i s otherwi s e unl i kel y. Brea s tfed ba bi es of vega n mothers ma y devel op vi ta mi n B 12
defi ci ency by a ge 4 to 6 mo beca us e thei r
[
Table 4-5. Ca us es of Vi ta mi n B 12 Defi ci ency]
l i ver s tores (whi ch a re norma l l y extens i ve) a re l i mi ted a nd thei r ra pi d growth ra te res ul ts i n hi gh dema nd.
Vi ta mi n B 12 defi ci ency us ua l l y res ul ts from i na dequa te a bs orpti on (s ee Ta bl e 4-5 a nd p. 153), whi ch, i n the el derl y, mos t commonl y res ul ts from
decrea s ed a ci d s ecreti on. In s uch ca s es , crys ta l l i ne vi ta mi n B 12 (s uch a s tha t a va i l a bl e i n vi ta mi n s uppl ements ) ca n be a bs orbed, but food-bound
vi ta mi n B 12 i s not l i bera ted a nd a bs orbed norma l l y. Ina dequa te a bs orpti on ma y occur i n bl i nd l oop s yndrome (wi th overgrowth of ba cteri a ) or fi s h
ta peworm i nfes ta ti on; i n thes e ca s es , ba cteri a or pa ra s i tes us e i nges ted vi ta mi n B 12 s o tha t l es s i s a va i l a bl e for a bs orpti on. Vi ta mi n B 12
a bs orpti on ma y be i na dequa te i f i l ea l a bs orpti ve s i tes a re des troyed by i nfl a mma tory bowel di s ea s e or a re s urgi ca l l y removed. Les s common
ca us es of i na dequa te vi ta mi n B 12 a bs orpti on i ncl ude chroni c pa ncrea ti ti s , ga s tri c s urgery, ma l a bs orpti on s yndromes , AIDS, us e of certa i n drugs
(eg, a nta ci ds , metformi n), repea ted expos ure to ni trous oxi de, a nd a geneti c di s order ca us i ng ma l a bs orpti on i n the i l eum (Imers l und-Gra es beck
s yndrome).
Pernicious anemia i s often us ed s ynonymous l y wi th vi ta mi n B 12 defi ci ency. However, perni ci ous a nemi a s peci fi ca l l y refers to a nemi a res ul ti ng from
vi ta mi n B 12 defi ci ency ca us ed by a n a utoi mmune meta pl a s ti c a trophi c ga s tri ti s wi th l os s of i ntri ns i c fa ctor (s ee p. 133). Pa ti ents wi th cl a s s i c
perni ci ous a nemi a , mos t commonl y younger a dul ts , a re a t i ncrea s ed ri s k of s toma ch a nd other GI ca ncers .
Subacute combined degeneration refers to degenera ti ve cha nges i n the nervous s ys tem due to vi ta mi n B 12 defi ci ency; they a ffect mos tl y bra i n a nd
s pi na l cord whi te ma tter. Demyel i na ti ng or a xona l peri phera l neuropa thi es ca n occur.
Symptoms and Signs
Anemi a us ua l l y devel ops i ns i di ous l y. It i s often more s evere tha n i ts s ymptoms i ndi ca te beca us e i ts s l ow evol uti on a l l ows phys i ol ogi c
a da pta ti on. Occa s i ona l l y, s pl enomega l y a nd hepa tomega l y occur. Va ri ous GI s ymptoms , i ncl udi ng wei ght l os s a nd poorl y l oca l i zed a bdomi na l
pa i n, ma y occur. Gl os s i ti s , us ua l l y des cri bed a s burni ng of the tongue, i s uncommon.
Neurol ogi c s ymptoms devel op i ndependentl y from a nd often wi thout hema tol ogi c a bnorma l i ti es . In ea rl y s ta ges , decrea s ed pos i ti on a nd vi bra tory
s ens a ti on i n the extremi ti es i s a ccompa ni ed by mi l d to modera te wea knes s a nd hyporefl exi a . In l a ter s ta ges , s pa s ti ci ty, extens or pl a nta r
res pons es , grea ter l os s of pos i ti on a nd vi bra tory s ens a ti on i n the l ower extremi ti es , a nd a ta xi a emerge. Thes e defi ci ts ma y devel op i n a s tocki nggl ove di s tri buti on. Ta cti l e, pa i n, a nd tempera ture s ens a ti ons a re us ua l l y s pa red but ma y be di ffi cul t to a s s es s i n the el derl y.
Some pa ti ents a re a l s o i rri ta bl e a nd mi l dl y depres s ed. Pa ra noi a (mega l obl a s ti c ma dnes s ), del i ri um, confus i on, s pa s ti c a ta xi a , a nd, a t ti mes ,
pos tura l hypotens i on ma y occur i n a dva nced ca s es . The confus i on ma y be di ffi cul t to di fferenti a te from a ge-rel a ted dementi a s , s uch a s
Al zhei mer's di s ea s e.
Diagnosis
CBC a nd vi ta mi n B 12 a nd fol a te l evel s
Someti mes methyl ma l oni c a ci d l evel s or Schi l l i ng tes t
Di a gnos i s i s ba s ed on CBC a nd vi ta mi n B 12 a nd fol a te l evel s . It i s i mporta nt to remember tha t s evere neurol ogi c di s ea s e ma y occur wi thout
a nemi a or ma crocytos i s .
CBC detects mega l obl a s ti c a nemi a . Ti s s ue defi ci ency a nd ma crocyti c i ndexes ma y precede the devel opment of a nemi a . A vi ta mi n B 12 l evel < 200
pg/mL (< 145 pmol /L) i ndi ca tes vi ta mi n B 12 defi ci ency. The fol a te l evel i s mea s ured beca us e vi ta mi n B 12 defi ci ency mus t be di fferenti a ted from
fol a te defi ci ency a s a ca us e of mega l obl a s ti c a nemi a ; fol a te s uppl ementa ti on ca n ma s k vi ta mi n B 12 defi ci ency a nd ma y a l l evi a te mega l obl a s ti c
a nemi a but a l l ow the neurol ogi c defi ci ts to progres s or even a ccel era te.
When cl i ni ca l judgment s ugges ts vi ta mi n B 12 defi ci ency but the vi ta mi n B 12 l evel i s l ow-norma l (200 to 350 pg/mL [145 to 260 pmol /L]) or
hema tol ogi c i ndexes a re norma l , other tes ts ca n be done. Mea s uri ng s erum methyl ma l oni c a ci d (MMA) l evel s ma y be us eful . An el eva ted MMA
l evel s upports vi ta mi n B 12 defi ci ency but ma y be due to rena l fa i l ure. MMA l evel s ca n a l s o be us ed to moni tor the res pons e to trea tment. MMA
l evel s rema i n norma l i n fol a te defi ci ency; homocys tei ne l evel s ma y be el eva ted wi th ei ther vi ta mi n B 12 or fol a te defi ci ency. Les s commonl y,
hol otra ns coba l a mi n II (tra ns coba l a mi n II-B 12 compl ex) content i s mea s ured; when hol otra ns coba l a mi n II i s < 40 pg/mL (< 30 pmol /L), vi ta mi n B 12
i s defi ci ent.
After defi ci ency i s di a gnos ed, a ddi ti ona l tes ts ma y be i ndi ca ted for younger a dul ts but us ua l l y not for the el derl y. Unl es s di eta ry vi ta mi n B 12 i s
obvi ous l y i na dequa te, mea s urement of s erum ga s tri n l evel s or a utoa nti bodi es to i ntri ns i c fa ctor ma y be done; s ens i ti vi ty a nd s peci fi ci ty of thes e
tes ts ma y be poor.
Schilling test: The Schi l l i ng tes t i s us eful onl y i f di a gnos i ng i ntri ns i c fa ctor defi ci ency i s i mporta nt, a s i n cl a s s i c perni ci ous a nemi a . Thi s tes t i s not
neces s a ry for mos t el derl y pa ti ents . The Schi l l i ng tes t mea s ures a bs orpti on of free ra di ol a bel ed vi ta mi n B 12 . Ra di ol a bel ed vi ta mi n B 12 i s gi ven
ora l l y, fol l owed i n 1 to 6 h by 1000 g (1 mg) of pa rentera l vi ta mi n B 12 , whi ch reduces upta ke of ra di ol a bel ed vi ta mi n B 12 by the l i ver. Abs orbed
ra di ol a bel ed vi ta mi n B 12 i s excreted i n uri ne, whi ch i s col l ected for 24 h. The a mount excreted i s mea s ured, a nd the percenta ge of tota l
ra di ol a bel ed vi ta mi n B 12 i s determi ned. If a bs orpti on i s norma l , 9% of the dos e gi ven a ppea rs i n the uri ne. Reduced uri na ry excreti on (< 5% i f
ki dney functi on i s norma l ) i ndi ca tes i na dequa te vi ta mi n B 12 a bs orpti on. Improved a bs orpti on wi th the s ubs equent a ddi ti on of i ntri ns i c fa ctor to
ra di ol a bel ed vi ta mi n B 12 confi rms the di a gnos i s of perni ci ous a nemi a . The tes t i s often di ffi cul t to do or i nterpret beca us e of i ncompl ete uri ne
col l ecti on or rena l i ns uffi ci ency. In a ddi ti on, beca us e the Schi l l i ng tes t does not mea s ure a bs orpti on of protei n-bound vi ta mi n B 12 , the tes t does
not detect defecti ve l i bera ti on of vi ta mi n B 12 from foods , whi ch i s common a mong the el derl y. The Schi l l i ng tes t repl etes vi ta mi n B 12 a nd ca n ma s k
defi ci ency, s o i t s houl d be done onl y a fter a l l other di a gnos ti c tes ts a nd thera peuti c tri a l s .
If ma l a bs orpti on i s i denti fi ed, the Schi l l i ng tes t ca n be repea ted a fter a 2-wk tri a l of a n ora l a nti bi oti c. If a nti bi oti c thera py corrects
ma l a bs orpti on, the l i kel y ca us e i s i ntes ti na l overgrowth of ba cteri a (eg, bl i nd-l oop s yndrome).
Treatment
Suppl ementa l vi ta mi n B 12
Vi ta mi n B 12 1000 to 2000 g po ca n be gi ven once/da y to pa ti ents who do not ha ve s evere defi ci ency or neurol ogi c s ymptoms or s i gns . A na s a l gel
prepa ra ti on of vi ta mi n B 12 i s a va i l a bl e a t a hi gher pri ce. La rge ora l dos es ca n be a bs orbed by ma s s a cti on, even when i ntri ns i c fa ctor i s a bs ent. If
the MMA l evel (s ometi mes us ed to moni tor trea tment) does not decrea s e, pa ti ents ma y not be ta ki ng vi ta mi n B 12 . For more s evere defi ci ency,
vi ta mi n B 12 1 mg IM i s us ua l l y gi ven 1 to 4 ti mes /wk for s evera l weeks unti l hema tol ogi c a bnorma l i ti es a re corrected; then i t i s gi ven once/mo.
Al though hema tol ogi c a bnorma l i ti es a re us ua l l y corrected wi thi n 6 wk (reti cul ocyte count s houl d i mprove wi thi n 1 wk), res ol uti on of neurol ogi c
s ymptoms ma y ta ke much l onger. Neurol ogi c s ymptoms tha t pers i s t for months or yea rs become i rrevers i bl e. In mos t el derl y peopl e wi th vi ta mi n
B 12 defi ci ency a nd dementi a , cogni ti on does not i mprove a fter trea tment. Vi ta mi n B 12 trea tment mus t be conti nued for l i fe unl es s the
pa thophys i ol ogi c mecha ni s m for the defi ci ency i s corrected.
Infa nts of vega n mothers s houl d recei ve s uppl ementa l vi ta mi n B 12 from bi rth.
Vitamin C
Vi ta mi n C (a s corbi c a ci d) pl a ys a rol e i n col l a gen, ca rni ti ne, hormone, a nd a mi no a ci d forma ti on. It i s es s enti a l for wound hea l i ng a nd fa ci l i ta tes
recovery from burns . Vi ta mi n C i s a l s o a n a nti oxi da nt, s upports i mmune functi on, a nd fa ci l i ta tes the a bs orpti on of i ron.
Vitamin C Deficiency
In developed countries, vitamin C deficiency can occur as part of general undernutrition, but severe deficiency (causing scurvy) is uncommon. Symptoms include
fatigue, depression, and connective tissue defects (eg, gingivitis, petechiae, rash, internal bleeding, impaired wound healing). In infants and children, bone growth
may be impaired. Diagnosis is usually clinical. Treatment consists of oral vitamin C.
Severe defi ci ency res ul ts i n s curvy, a di s order cha ra cteri zed by hemorrha gi c ma ni fes ta ti ons a nd a bnorma l os teoi d a nd denti n forma ti on.
Etiology
In a dul ts , pri ma ry defi ci ency i s us ua l l y due to i na dequa te di et. The need for di eta ry vi ta mi n C i s i ncrea s ed by febri l e i l l nes s es , i nfl a mma tory
di s orders (pa rti cul a rl y di a rrhea l di s orders ), a chl orhydri a , s moki ng, thyrotoxi cos i s , i ron defi ci ency, col d or hea t s tres s , s urgery, burns , a nd protei n
defi ci ency. Hea t (eg, s teri l i za ti on of formul a s , cooki ng) ca n des troy s ome of the vi ta mi n C i n food.
Pathophysiology
Forma ti on of i ntercel l ul a r cement s ubs ta nces i n connecti ve ti s s ues , bones , a nd denti n i s defecti ve, res ul ti ng i n wea kened ca pi l l a ri es wi th
s ubs equent hemorrha ge a nd defects i n bone a nd rel a ted s tructures .
Bone ti s s ue forma ti on becomes i mpa i red, whi ch, i n chi l dren, ca us es bone l es i ons a nd poor bone growth. Fi brous ti s s ue forms between the
di a phys i s a nd the epi phys i s , a nd cos tochondra l juncti ons enl a rge. Dens el y ca l ci fi ed fra gments of ca rti l a ge a re embedded i n the fi brous ti s s ue.
Subperi os tea l hemorrha ges , s ometi mes due to s ma l l fra ctures , ma y occur i n chi l dren or a dul ts .
Symptoms and Signs
In a dul ts , s ymptoms devel op a fter weeks to months of vi ta mi n C depl eti on. La s s i tude, wea knes s , i rri ta bi l i ty, wei ght l os s , a nd va gue mya l gi a s a nd
a rthra l gi a s ma y devel op ea rl y.
La ter, s ymptoms rel a ted to defects i n connecti ve ti s s ues devel op. Fol l i cul a r hyperkera tos i s , coi l ed ha i r, a nd peri fol l i cul a r hemorrha ges ma y
devel op. Gums ma y become s wol l en, purpl e, s pongy, a nd fri a bl e; they bl eed ea s i l y i n s evere defi ci ency. Eventua l l y, teeth become l oos e a nd
a vul s ed. Seconda ry i nfecti ons ma y devel op. Wounds hea l poorl y a nd tea r ea s i l y, a nd s ponta neous hemorrha ges ma y occur, es peci a l l y a s
ecchymos es i n the s ki n of the l ower l i mbs or a s bul ba r conjuncti va l hemorrha ge.
Other s ymptoms a nd s i gns i ncl ude femora l neuropa thy due to hemorrha ge i nto femora l s hea ths (whi ch ma y mi mi c deep venous thrombos i s ),
l ower-extremi ty edema , a nd pa i nful bl eedi ng or effus i ons wi thi n joi nts .
Diagnosis
Us ua l l y, s ki n or gi ngi va l fi ndi ngs a nd ri s k fa ctors
Di a gnos i s i s us ua l l y ma de cl i ni ca l l y i n a pa ti ent who ha s s ki n or gi ngi va l s i gns a nd i s a t ri s k of vi ta mi n C defi ci ency. La bora tory confi rma ti on ma y
be a va i l a bl e. Anemi a i s common. Bl eedi ng, coa gul a ti on, a nd PT a re norma l .
Skel eta l x-ra ys ca n hel p di a gnos e chi l dhood (but not a dul t) s curvy. Cha nges a re mos t evi dent a t the ends of l ong bones , pa rti cul a rl y a t the knee.
Ea rl y cha nges res embl e a trophy. Los s of tra becul a e res ul ts i n a ground-gl a s s a ppea ra nce. The cortex thi ns . A l i ne of ca l ci fi ed, i rregul a r ca rti l a ge
(whi te l i ne of Fra enkel ) ma y be vi s i bl e a t the meta phys i s . A zone of ra refa cti on or a l i nea r fra cture proxi ma l a nd pa ra l l el to the whi te l i ne ma y be
vi s i bl e a s onl y a tri a ngul a r defect a t the bone's l a tera l ma rgi n but i s s peci fi c. The epi phys i s ma y be compres s ed. Hea l i ng s ubperi os tea l
hemorrha ges ma y el eva te a nd ca l ci fy the peri os teum.
La bora tory di a gnos i s , whi ch requi res mea s uri ng bl ood a s corbi c a ci d, i s s ometi mes done a t a ca demi c centers . Level s of < 0.6 mg/dL (< 34 mol /L)
a re cons i dered ma rgi na l ; l evel s of < 0.2 mg/dL (< 11 mol /L) i ndi ca te vi ta mi n C defi ci ency. Mea s urement of a s corbi c a ci d l evel s i n the WBC-pl a tel et
l a yer of centri fuged bl ood i s not wi del y a va i l a bl e or s ta nda rdi zed.
In a dul ts , s curvy mus t be di fferenti a ted from a rthri ti s , hemorrha gi c di s orders , gi ngi vi ti s , a nd protei n-energy undernutri ti on. Hyperkera toti c ha i r
fol l i cl es wi th s urroundi ng hyperemi a or hemorrha ge a re a l mos t pa thognomoni c. Bl eedi ng gums , conjuncti va l hemorrha ges , mos t petechi a e, a nd
ecchymos es a re nons peci fi c.
Treatment
Nutri ti ous di et wi th s uppl ementa l a s corbi c a ci d
For s curvy i n a dul ts , a s corbi c a ci d 100 to 500 mg po ti d i s gi ven for 1 to 2 wk, unti l s i gns di s a ppea r, a nd fol l owed by a nutri ti ous di et s uppl yi ng 1 to
2 ti mes the da i l y recommended i nta ke. In s curvy, thera peuti c dos es of a s corbi c a ci d res tore the functi ons of vi ta mi n C i n a few da ys . The s ymptoms
a nd s i gns us ua l l y di s a ppea r over 1 to 2 wk. Chroni c gi ngi vi ti s wi th extens i ve s ubcuta neous hemorrha ge pers i s ts l onger.
Prevention
Vi ta mi n C 75 mg po once/da y for women a nd 90 mg po once/da y for men prevents defi ci ency. Smokers s houl d cons ume a n a ddi ti ona l 35 mg/da y.
Fi ve s ervi ngs of mos t frui ts a nd vegeta bl es (recommended da i l y) provi de > 200 mg of vi ta mi n C.
Vitamin C Toxicity
The upper l i mi t for vi ta mi n C i nta ke i s 2000 mg/da y. Up to 10 g/da y of vi ta mi n C a re s ometi mes ta ken for unproven hea l th benefi ts , s uch a s
preventi ng or s horteni ng the dura ti on of vi ra l i nfecti ons or s l owi ng or revers i ng the progres s i on of ca ncer or a theros cl eros i s . Such dos es ma y
a ci di fy the uri ne, ca us e na us ea a nd di a rrhea , i nterfere wi th the hea l thy a nti oxi da nt-prooxi da nt ba l a nce i n the body, a nd, i n pa ti ents wi th
tha l a s s emi a or hemochroma tos i s , promote i ron overl oa d. Inta ke bel ow the upper l i mi t does not ha ve toxi c effects i n hea l thy a dul ts .
Vitamin D
Vi ta mi n D ha s 2 ma i n forms : D 2 (ergoca l ci ferol ) a nd D 3 (chol eca l ci ferol ); the l a tter i s the na tura l l y occurri ng form a nd the form us ed for l ow-dos e
s uppl ementa ti on. Vi ta mi n D 3 i s s ynthes i zed i n s ki n by expos ure to di rect s unl i ght (ul tra vi ol et B ra di a ti on) a nd obta i ned i n the di et chi efl y i n fi s h
l i ver oi l s a nd s a l t wa ter fi s h. In s ome devel oped countri es , mi l k a nd other foods a re forti fi ed wi th vi ta mi n D. Huma n brea s t mi l k i s l ow i n vi ta mi n
D, conta i ni ng a n a vera ge of onl y 10% of the a mount i n forti fi ed cow's mi l k. Requi rements for vi ta mi n D i ncrea s e wi th a ge beca us e s ki n s ynthes i s
decl i nes . Suns creen us e a nd da rk s ki n pi gmenta ti on a l s o reduce s ki n s ynthes i s of vi ta mi n D.
Vi ta mi n D i s a prohormone wi th s evera l a cti ve meta bol i tes tha t a ct a s hormones . Vi ta mi n D i s meta bol i zed by the l i ver to 25(OH)D, whi ch i s then
converted by the ki dneys to 1,25(OH) 2 D (1,25-di hydroxychol eca l ci ferol , ca l ci tri ol , or a cti ve vi ta mi n D hormone). 25(OH)D, the ma jor ci rcul a ti ng form,
ha s s ome meta bol i c a cti vi ty, but 1,25(OH) 2 D i s the mos t meta bol i ca l l y a cti ve. The convers i on to 1,25(OH) 2 D i s regul a ted by i ts own concentra ti on,
pa ra thyroi d hormone (PTH), a nd s erum concentra ti ons of Ca a nd phos pha te.
[
Table 4-6. Acti ons of Vi ta mi n D a nd i ts Meta bol i tes ]
Vi ta mi n D a ffects ma ny orga n s ys tems (s ee Ta bl e 4-6), but ma i nl y i t i ncrea s es Ca a nd phos pha te a bs orpti on from the i ntes ti ne a nd promotes
norma l bone forma ti on a nd mi nera l i za ti on. Vi ta mi n D a nd rel a ted a na l ogs ma y be us ed to trea t ps ori a s i s , hypopa ra thyroi di s m, rena l
os teodys trophy, a nd pos s i bl y l eukemi a a nd brea s t, pros ta te, a nd col on ca ncers ; they ma y a l s o be us ed for i mmunos uppres s i on.
Vitamin D Deficiency and Dependency
Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in
adults and possibly contributing to osteoporosis. Treatment usually consists of oral vitamin D; Ca and phosphate are supplemented as needed. Prevention is often
possible. Rarely, hereditary disorders cause impaired metabolism of vitamin D (dependency).

Vi ta mi n D defi ci ency i s a common ca us e of ri ckets a nd os teoma l a ci a , but thes e di s orders ma y a l s o res ul t from other condi ti ons , s uch a s va ri ous
rena l tubul a r di s orders , fa mi l i a l hypophos pha temi c (vi ta mi n D-res i s ta nt) ri ckets (s ee p. 2991), chroni c meta bol i c a ci dos i s , hypopa ra thyroi di s m
(whi ch reduces vi ta mi n D a bs orpti on), i na dequa te di eta ry Ca , a nd di s orders or drugs tha t i mpa i r the mi nera l i za ti on of bone ma tri x.
Vi ta mi n D defi ci ency ca us es hypoca l cemi a , whi ch s ti mul a tes producti on of PTH, ca us i ng hyperpa ra thyroi di s m. Hyperpa ra thyroi di s m i ncrea s es
a bs orpti on, bone mobi l i za ti on, a nd rena l cons erva ti on of Ca but i ncrea s es excreti on of phos pha te. As a res ul t, the s erum l evel of Ca ma y be
norma l , but beca us e of hypophos pha temi a , bone mi nera l i za ti on i s i mpa i red.
Etiology
Vi ta mi n D defi ci ency ma y res ul t from the fol l owi ng.
Inadequate exposure or intake: Ina dequa te di rect s unl i ght expos ure (or s uns creen us e) a nd i na dequa te i nta ke us ua l l y occur s i mul ta neous l y to res ul t
i n cl i ni ca l defi ci ency. Sus cepti bl e peopl e i ncl ude the el derl y (who a re often undernouri s hed a nd a re not expos ed to enough s unl i ght), a nd certa i n
communi ti es (eg, women a nd chi l dren who a re confi ned to the home or who wea r cl othi ng tha t covers the enti re body a nd fa ce). Ina dequa te
vi ta mi n D s tores a re common a mong the el derl y, pa rti cul a rl y thos e who a re hous e-bound, i ns ti tuti ona l i zed, or hos pi ta l i zed or who ha ve ha d a hi p
fra cture. Recommended di rect s unl i ght expos ure i s 5 to 15 mi n (s uberythema l dos e) to a rms a nd l egs , or fa ce, a rms a nd ha nds , a t l ea s t 3 ti mes a
week.
Reduced absorption: Ma l a bs orpti on ca n depri ve the body of di eta ry vi ta mi n D; onl y a s ma l l a mount of 25(OH)D i s reci rcul a ted enterohepa ti ca l l y.
Abnormal metabolism: Vi ta mi n D defi ci ency ma y res ul t from defects i n the producti on of 25(OH)D or 1,25(OH) 2 D. Peopl e wi th a chroni c rena l di s order
commonl y devel op ri ckets or os teoma l a ci a beca us e rena l producti on of 1,25 (OH) 2 D i s decrea s ed a nd phos pha te l evel s a re el eva ted. Hepa ti c
dys functi on ca n a l s o i nterfere wi th producti on of a cti ve vi ta mi n D meta bol i tes .
Type I heredi ta ry vi ta mi n D-dependent ri ckets i s a n a utos oma l reces s i ve di s order cha ra cteri zed by a bs ent or defecti ve convers i on of 25(OH)D to
1,25(OH) 2 D i n the ki dneys . X-l i nked fa mi l i a l hypophos pha temi a reduces vi ta mi n D s ynthes i s i n the ki dneys . Ma ny a nti convul s a nts a nd
gl ucocorti coi d us e i ncrea s e the need for vi ta mi n D s uppl ementa ti on.
Resistance to effects of vitamin D: Type II heredi ta ry vi ta mi n D-dependent ri ckets ha s s evera l forms a nd i s due to muta ti ons i n the 1,25(OH) 2 D
receptor. Thi s receptor a ffects the meta bol i s m of gut, ki dney, bone, a nd other cel l s . In thi s di s order, 1,25(OH) 2 D i s a bunda nt but i neffecti ve
beca us e the receptor i s not functi ona l .
Symptoms and Signs
Vi ta mi n D defi ci ency ca n ca us e mus cl e a ches , mus cl e wea knes s , a nd bone pa i n a t a ny a ge.
Vi ta mi n D defi ci ency i n a pregna nt woma n ca us es defi ci ency i n the fetus . Occa s i ona l l y, defi ci ency s evere enough to ca us e ma terna l os teoma l a ci a
res ul ts i n ri ckets wi th meta phys ea l l es i ons i n neona tes . In young i nfa nts , ri ckets ca us es s ofteni ng of the enti re s kul l (cra ni ota bes ). When
pa l pa ted, the occi put a nd pos teri or pa ri eta l bones feel l i ke a pi ng pong ba l l . In ol der i nfa nts wi th ri ckets , s i tti ng a nd cra wl i ng a re del a yed, a s i s
fonta nel l e cl os ure; there i s bos s i ng of the s kul l a nd cos tochondra l thi ckeni ng. Cos tochondra l thi ckeni ng ca n l ook l i ke bea dl i ke promi nences
a l ong the l a tera l ches t wa l l (ra chi ti c ros a ry). In chi l dren 1 to 4 yr, epi phys ea l ca rti l a ge a t the l ower ends of the ra di us , ul na , ti bi a , a nd fi bul a
enl a rges ; kyphos col i os i s devel ops , a nd wa l ki ng i s del a yed. In ol der chi l dren a nd a dol es cents , wa l ki ng i s pa i nful ; i n extreme ca s es , deformi ti es
s uch a s bowl egs a nd knock-knees devel op.
Teta ny i s ca us ed by hypoca l cemi a a nd ma y a ccompa ny i nfa nti l e or a dul t vi ta mi n D defi ci ency. Teta ny ma y ca us e pa res thes i a s of the l i ps , tongue,
a nd fi ngers ; ca rpopeda l a nd fa ci a l s pa s m; a nd, i f very s evere, s ei zures . Ma terna l defi ci ency ca n ca us e teta ny i n neona tes .
Os teoma l a ci a predi s pos es to fra ctures . In the el derl y, hi p fra ctures ma y res ul t from onl y mi ni ma l tra uma .
Diagnosis
Level s of 25(OH)D (D 2 +D 3 )
Di a gnos i s ma y be s us pected ba s ed on a ny of the fol l owi ng:
A hi s tory of i na dequa te s unl i ght expos ure or di eta ry i nta ke
Symptoms a nd s i gns of ri ckets , os teoma l a ci a , or neona ta l teta ny
Cha ra cteri s ti c bone cha nges s een on x-ra y
X-ra ys of the ra di us a nd ul na pl us s erum l evel s of Ca , phos pha te, a l ka l i ne phos pha ta s e, PTH, a nd 25(OH)D a re needed to di fferenti a te vi ta mi n D
defi ci ency from other ca us es of bone demi nera l i za ti on.
As s es s ment of vi ta mi n D s ta tus a nd s erol ogi c tes ts for s yphi l i s ca n be cons i dered for i nfa nts wi th cra ni ota bes ba s ed on the hi s tory a nd phys i ca l ,
but mos t ca s es of cra ni ota bes res ol ve s ponta neous l y. Ri ckets ca n be di s ti ngui s hed from chondrodys trophy beca us e the l a tter i s cha ra cteri zed by a
l a rge hea d, s hort extremi ti es , thi ck bones , a nd norma l s erum Ca , phos pha te, a nd a l ka l i ne phos pha ta s e l evel s .
Teta ny due to i nfa nti l e ri ckets ma y be cl i ni ca l l y i ndi s ti ngui s ha bl e from s ei zures due to other ca us es . Bl ood tes ts a nd cl i ni ca l hi s tory ma y hel p
di s ti ngui s h them.
Bone cha nges , s een on x-ra ys , precede cl i ni ca l s i gns . In ri ckets , cha nges a re mos t evi dent a t the l ower ends of the ra di us a nd ul na . The
di a phys ea l ends l os e thei r s ha rp, cl ea r outl i ne; they a re cup-s ha ped a nd s how a s potty or fri ngy ra refa cti on. La ter, beca us e the ends of the ra di us
a nd ul na ha ve become nonca l ci fi ed a nd ra di ol ucent, the di s ta nce between them a nd the meta ca rpa l bones a ppea rs i ncrea s ed. The bone ma tri x
el s ewhere a l s o becomes more ra di ol ucent. Cha ra cteri s ti c deformi ti es res ul t from the bones bendi ng a t the ca rti l a ge-s ha ft juncti on beca us e the
s ha ft i s wea k. As hea l i ng begi ns , a thi n whi te l i ne of ca l ci fi ca ti on a ppea rs a t the epi phys i s , becomi ng dens er a nd thi cker a s ca l ci fi ca ti on
proceeds . La ter, the bone ma tri x becomes ca l ci fi ed a nd opa ci fi ed a t the s ubperi os tea l l evel .
In a dul ts , bone demi nera l i za ti on, pa rti cul a rl y i n the s pi ne, pel vi s , a nd l ower extremi ti es , ca n be s een on x-ra ys ; the fi brous l a mel l a e ca n a l s o be
s een, a nd i ncompl ete ri bbonl i ke a rea s of demi nera l i za ti on (ps eudofra ctures , Loos er's l i nes , Mi l kma n's s yndrome) a ppea r i n the cortex.
Beca us e l evel s of s erum 25(OH)D refl ect body s tores of vi ta mi n D a nd correl a te wi th s ymptoms a nd s i gns of vi ta mi n D defi ci ency better tha n l evel s
of other vi ta mi n D meta bol i tes , 25(OH)D (D 2 +D 3 ) mea s urement i s genera l l y cons i dered the bes t wa y to di a gnos e defi ci ency. Goa l 25(OH)D l evel s
a re 30 to 40 ng/mL (a bout 75 to 100 nmol /L); whether hi gher l evel s ma y be benefi ci a l rema i ns uncerta i n.
If the di a gnos i s i s uncl ea r, s erum l evel s of 1,25(OH) 2 D a nd uri na ry Ca concentra ti on ca n be mea s ured. In s evere defi ci ency, s erum 1,25(OH) 2 D i s
a bnorma l l y l ow, us ua l l y undetecta bl e. Uri na ry Ca i s l ow i n a l l forms of the defi ci ency except thos e a s s oci a ted wi th a ci dos i s .
In vi ta mi n D defi ci ency, s erum Ca ma y be l ow or, beca us e of s econda ry hyperpa ra thyroi di s m, ma y be norma l . Serum phos pha te us ua l l y decrea s es ,
a nd s erum a l ka l i ne phos pha ta s e us ua l l y i ncrea s es . Serum PTH i s el eva ted.
Type I heredi ta ry vi ta mi n D-dependent ri ckets res ul ts i n norma l s erum 25(OH)D, l ow s erum 1,25(OH) 2 D a nd Ca , a nd norma l or l ow s erum
phos pha te.
Treatment
Correcti on of Ca a nd phos pha te defi ci enci es
Suppl ementa l vi ta mi n D
Ca defi ci ency (whi ch i s common) a nd phos pha te defi ci ency s houl d be corrected. As l ong a s Ca a nd phos pha te i nta ke i s a dequa te, a dul ts wi th
os teoma l a ci a a nd chi l dren wi th uncompl i ca ted ri ckets ca n be cured by gi vi ng vi ta mi n D 40 g (1600 IU) po once/da y. Serum 25(OH)D a nd 1,25(OH) 2 D
begi n to i ncrea s e wi thi n 1 or 2 da ys . Serum Ca a nd phos pha te i ncrea s e a nd s erum a l ka l i ne phos pha ta s e decrea s es wi thi n a bout 10 da ys . Duri ng
the 3rd wk, enough Ca a nd phos pha te a re depos i ted i n bones to be vi s i bl e on x-ra ys . After a bout 1 mo, the dos e ca n us ua l l y be reduced gra dua l l y
to the us ua l ma i ntena nce l evel of 10 to 15 g (400 to 600 IU) once/da y. If teta ny i s pres ent, vi ta mi n D s houl d be s uppl emented wi th IV Ca s a l ts for
up to 1 wk (s ee p. 841). El derl y pa ti ents ma y need 25 to 50 g (1000 to 2000 IU) da i l y to ma i nta i n a 25(OH)D l evel > 30 ng/mL (> 75 nmol /L); thi s
dos e i s hi gher tha n the recommended da i l y a l l owa nce (RDA) for peopl e > 70 yr (600 IU) a nd ma y exceed the current upper l i mi t of 2000 IU/da y.
Beca us e ri ckets a nd os teoma l a ci a due to defecti ve producti on of vi ta mi n D meta bol i tes a re vi ta mi n D-res i s ta nt, they do not res pond to the dos es
us ua l l y effecti ve for ri ckets due to i na dequa te i nta ke. Endocri nol ogi c eva l ua ti on i s requi red beca us e trea tment depends on the s peci fi c defect.
When 25(OH)D producti on i s defecti ve, vi ta mi n D 50 g (2000 IU) once/da y i ncrea s es s erum l evel s a nd res ul ts i n cl i ni ca l i mprovement. Pa ti ents
wi th ki dney di s orders often need 1,25(OH) 2 D s uppl ementa ti on.
Type I heredi ta ry vi ta mi n D-dependent ri ckets res ponds to 1,25(OH) 2 D 1 to 2 g po once/da y. Some pa ti ents wi th type II heredi ta ry vi ta mi n Ddependent ri ckets res pond to very hi gh dos es (eg, 10 to 24 g/da y) of 1,25(OH) 2 D; others requi re l ong-term i nfus i ons of Ca .
Prevention
Di eta ry couns el i ng i s pa rti cul a rl y i mporta nt i n communi ti es whos e members a re a t ri s k of vi ta mi n D defi ci ency. Forti fyi ng unl ea vened cha pa ti
fl our wi th vi ta mi n D (125 g/kg) ha s been effecti ve a mong Indi a n i mmi gra nts i n Bri ta i n. The benefi ts of s unl i ght expos ure for vi ta mi n D s ta tus
mus t be wei ghed a ga i ns t the i ncrea s ed s ki n da ma ge a nd s ki n ca ncer ri s ks .
Al l brea s tfed i nfa nts s houl d be gi ven s uppl ementa l vi ta mi n D 5 g (200 IU) once/da y from bi rth to 6 mo; a t 6 mo, a more di vers i fi ed di et i s
a va i l a bl e. For a dol es cents a t ri s k, a s i ngl e IM dos e of ergoca l ci ferol 2.5 mg (100,000 IU) gi ven i n the fa l l ca n ma i nta i n a dequa te 25(OH)D l evel s
throughout the wi nter. The recommended da i l y a l l owa nce (RDA) for vi ta mi n D i s 400 IU for peopl e a ged 51 to 70 a nd 600 IU for thos e >70; ma ny
cons i der thi s i nta ke too l ow, a nd the 2005 Di eta ry Gui del i nes for Ameri ca ns recommends tha t hea l thy ol der a dul ts cons ume 1000 IU/da y.
Vitamin D Toxicity
Usually, vitamin D toxicity results from taking excessive amounts. Marked hypercalcemia commonly causes symptoms. Diagnosis is typically based on elevated
blood levels of 25(OH)D. Treatment consists of stopping vitamin D, restricting dietary Ca, restoring intravascular volume deficits, and, if toxicity is severe, giving
corticosteroids or bisphosphonates.
Beca us e s ynthes i s of 1,25(OH) 2 D (the mos t a cti ve meta bol i te of vi ta mi n D) i s ti ghtl y regul a ted, vi ta mi n D toxi ci ty us ua l l y occurs onl y i f exces s i ve
dos es (pres cri pti on or mega vi ta mi n) a re ta ken. Vi ta mi n D 1000 g (40,000 IU)/da y ca us es toxi ci ty wi thi n 1 to 4 mo i n i nfa nts . In a dul ts , ta ki ng 1250
g (50,000 IU)/da y for s evera l months ca n ca us e toxi ci ty. Vi ta mi n D toxi ci ty ca n occur i a trogeni ca l l y when hypopa ra thyroi di s m i s trea ted too
a ggres s i vel y (s ee p.
844).
Symptoms and Signs
The ma i n s ymptoms res ul t from hyperca l cemi a . Anorexi a , na us ea , a nd vomi ti ng ca n devel op, often fol l owed by pol yuri a , pol ydi ps i a , wea knes s ,
nervous nes s , pruri tus , a nd eventua l l y rena l fa i l ure. Protei nuri a , uri na ry ca s ts , a zotemi a , a nd meta s ta ti c ca l ci fi ca ti ons (pa rti cul a rl y i n the ki dneys )
ca n devel op.
Diagnosis
Hyperca l cemi a pl us ri s k fa ctors or el eva ted s erum 25(OH)D l evel s
A hi s tory of exces s i ve vi ta mi n D i nta ke ma y be the onl y cl ue di fferenti a ti ng vi ta mi n D toxi ci ty from other ca us es of hyperca l cemi a . El eva ted s erum
Ca l evel s of 12 to 16 mg/dL (3 to 4 mmol /L) a re a cons ta nt fi ndi ng when toxi c s ymptoms occur. Serum 25(OH)D l evel s a re us ua l l y el eva ted > 150
ng/mL (> 375 nmol /L). Level s of 1,25(OH) 2 D, whi ch need not be mea s ured to confi rm the di a gnos i s , ma y be norma l .
Serum Ca s houl d be mea s ured often (weekl y a t fi rs t, then monthl y) i n a l l pa ti ents recei vi ng l a rge dos es of vi ta mi n D, pa rti cul a rl y the potent
1,25(OH) 2 D.
Treatment
IV hydra ti on pl us corti cos teroi ds or bi s phos phona tes
After s toppi ng vi ta mi n D i nta ke, hydra ti on wi th IV norma l s a l i ne a nd corti cos teroi ds or bi s phos phona tes (whi ch i nhi bi t bone res orpti on) a re us ed
to reduce bl ood Ca l evel s .
Ki dney da ma ge or meta s ta ti c ca l ci fi ca ti ons , i f pres ent, ma y be i rrevers i bl e.
Vitamin E
Vi ta mi n E i s a group of compounds (i ncl udi ng tocopherol s a nd tocotri enol s ) tha t ha ve s i mi l a r bi ol ogi c a cti vi ti es . The mos t bi ol ogi ca l l y a cti ve i s tocopherol , but -, -, a nd -tocopherol s , 4 tocotri enol s , a nd s evera l s tereoi s omers ma y a l s o ha ve i mporta nt bi ol ogi c a cti vi ty. Thes e compounds a ct
a s a nti oxi da nts , whi ch prevent l i pi d peroxi da ti on of pol yuns a tura ted fa tty a ci ds i n cel l ul a r membra nes . Pl a s ma tocopherol l evel s va ry wi th tota l
pl a s ma l i pi d l evel s . Norma l l y, the pl a s ma -tocopherol l evel i s 5 to 20 g/mL (11.6 to 46.4 mol /L). Hi gh-dos e vi ta mi n E s uppl ements do not protect
a ga i ns t ca rdi ova s cul a r di s orders ;whether s uppl ements ca n protect a ga i ns t Al zhei mer's di s ea s e, ta rdi ve dys ki nes i a , a nd pros ta te ca ncer a mong
s mokers i s controvers i a l .
Al though the a mount of vi ta mi n E i n ma ny forti fi ed foods a nd s uppl ements i s gi ven i n IU, current recommenda ti ons a re to us e mg.
Vitamin E Deficiency
Dietary vitamin E deficiency is common in developing countries; deficiency among adults in developed countries is uncommon and usually due to fat
malabsorption. The main symptoms are hemolytic anemia and neurologic deficits. Diagnosis is based on measuring the ratio of plasma -tocopherol to total
plasma lipids; a low ratio suggests vitamin E deficiency. Treatment consists of oral vitamin E, given in high doses if there are neurologic deficits or if deficiency
results from malabsorption.
Vi ta mi n E defi ci ency ca us es fra gi l i ty of RBCs a nd degenera ti on of neurons , pa rti cul a rl y peri phera l a xons a nd pos teri or col umn neurons .
Etiology
In devel opi ng countri es , the mos t common ca us e i s i na dequa te i nta ke of vi ta mi n E. In devel oped countri es , the mos t common ca us es a re
di s orders tha t ca us e fa t ma l a bs orpti on, i ncl udi ng a beta l i poprotei nemi a (Ba s s en-Kornzwei g s yndrome, due to geneti c a bs ence of a pol i poprotei n
B), chroni c chol es ta ti c hepa tobi l i a ry di s ea s e, pa ncrea ti ti s , s hort bowel s yndrome, a nd cys ti c fi bros i s . A ra re geneti c form of vi ta mi n E defi ci ency
wi thout fa t ma l a bs orpti on res ul ts from defecti ve l i ver meta bol i s m.
Symptoms and Signs
The ma i n s ymptoms a re mi l d hemol yti c a nemi a a nd nons peci fi c neurol ogi c defi ci ts . Abeta l i poprotei nemi a res ul ts i n progres s i ve neuropa thy a nd
reti nopa thy i n the fi rs t 2 deca des of l i fe (s ee p. 904).
Vi ta mi n E defi ci ency ma y contri bute to reti nopa thy of prema turi ty (a l s o ca l l ed retrol enta l fi bropl a s i a ) i n prema ture i nfa nts a nd to s ome ca s es of
i ntra ventri cul a r a nd s ubependyma l hemorrha ge i n neona tes . Affected prema ture neona tes ha ve mus cl e wea knes s .
In chi l dren, chroni c chol es ta ti c hepa tobi l i a ry di s ea s e or cys ti c fi bros i s ca us es neurol ogi c defi ci ts , i ncl udi ng s pi nocerebel l a r a ta xi a wi th l os s of
deep tendon refl exes , trunca l a nd l i mb a ta xi a , l os s of vi bra ti on a nd pos i ti on s ens es , ophtha l mopl egi a , mus cl e wea knes s , ptos i s , a nd dys a rthri a .
In a dul ts wi th ma l a bs orpti on, vi ta mi n E defi ci ency very ra rel y ca us es s pi nocerebel l a r a ta xi a beca us e a dul ts ha ve l a rge vi ta mi n E s tores i n a di pos e
ti s s ue.
Diagnosis
Low -tocopherol l evel or l ow ra ti o of s erum -tocopherol to s erum l i pi ds
Wi thout a hi s tory of i na dequa te i nta ke or a predi s pos i ng condi ti on, vi ta mi n E defi ci ency i s unl i kel y. Confi rma ti on us ua l l y requi res mea s uri ng the
vi ta mi n l evel . Mea s uri ng RBC hemol ys i s i n res pons e to peroxi de ca n s ugges t the di a gnos i s but i s nons peci fi c. Hemol ys i s i ncrea s es a s vi ta mi n E
defi ci ency i mpa i rs RBC s ta bi l i ty.
Mea s uri ng the s erum -tocopherol l evel i s the mos t di rect method of di a gnos i s . In a dul ts , vi ta mi n E defi ci ency i s s ugges ted i f the -tocopherol
l evel i s < 5 g/mL (< 11.6 mol /L). Beca us e a bnorma l l i pi d l evel s ca n a ffect vi ta mi n E s ta tus , a l ow ra ti o of s erum -tocopherol to l i pi ds (< 0.8 mg/g
tota l l i pi d) i s the mos t a ccura te i ndi ca tor i n a dul ts wi th hyperl i pi demi a .
In chi l dren a nd a dul ts wi th a beta l i poprotei nemi a , s erum -tocopherol l evel s a re us ua l l y undetecta bl e.
Treatment
Suppl ementa l -tocopherol
If ma l a bs orpti on ca us es cl i ni ca l l y evi dent defi ci ency, -tocopherol 15 to 25 mg/kg po once/da y s houl d be gi ven. However, l a rger dos es gi ven by
i njecti on a re requi red to trea t neuropa thy duri ng i ts ea rl y s ta ges or to overcome the defect of a bs orpti on a nd tra ns port i n a beta l i poprotei nemi a .
Prevention
Al though prema ture neona tes ma y requi re s uppl ementa ti on, huma n mi l k a nd commerci a l formul a s ha ve enough vi ta mi n E for ful l -term neona tes .
Vitamin E Toxicity
Ma ny a dul ts ta ke rel a ti vel y l a rge a mounts of vi ta mi n E (-tocopherol 400 to 800 mg/da y) for months to yea rs wi thout a ny a ppa rent ha rm.
Occa s i ona l l y, mus cl e wea knes s , fa ti gue, na us ea , a nd di a rrhea occur. The mos t s i gni fi ca nt ri s k i s bl eedi ng. However, bl eedi ng i s uncommon
unl es s the dos e i s > 1000 mg/da y or the pa ti ent ta kes ora l couma ri n or wa rfa ri n. Thus , the upper l i mi t for a dul ts a ged 19 yr i s 1000 mg for a ny form
of -tocopherol . Recent a na l ys es of previ ous s tudi es report tha t hi gh vi ta mi n E i nta kes ma y i ncrea s e the ri s k of hemorrha gi c s troke a nd prema ture
dea th.
Vitamin K
Vi ta mi n K1 (phyl l oqui none) i s di eta ry vi ta mi n K. Di eta ry fa t enha nces i ts a bs orpti on. Infa nt formul a s conta i n s uppl ementa l vi ta mi n K. Vi ta mi n K2
refers to a group of compounds (mena qui nones ) s ynthes i zed by ba cteri a i n the i ntes ti na l tra ct; the a mount s ynthes i zed does not s a ti s fy the
vi ta mi n K requi rement.
Vi ta mi n K control s the forma ti on of coa gul a ti on fa ctors II (prothrombi n), VII, IX, a nd X i n the l i ver. Other coa gul a ti on fa ctors dependent on vi ta mi n
K a re protei n C, protei n S, a nd protei n Z; protei ns C a nd S a re a nti coa gul a nts . Meta bol i c pa thwa ys cons erve vi ta mi n K. Once vi ta mi n K ha s
pa rti ci pa ted i n forma ti on of coa gul a ti on fa ctors , the rea cti on product, vi ta mi n K epoxi de, i s enzyma ti ca l l y converted to the a cti ve form, vi ta mi n K
hydroqui none.
The a cti ons of vi ta mi n K-dependent protei ns requi re Ca . The vi ta mi n K-dependent protei ns , os teoca l ci n a nd ma tri x -ca rboxy-gl uta myl (Gl a )
protei n, ma y ha ve i mporta nt rol es i n bone a nd other ti s s ues . Forms of vi ta mi n K a re common thera py for os teoporos i s i n Ja pa n a nd other
countri es .
Vitamin K Deficiency
Vitamin K deficiency results from extremely inadequate intake, fat malabsorption, or use of coumarin anticoagulants. Deficiency is particularly common among
breastfed infants. It impairs clotting. Diagnosis is suspected based on routine coagulation study findings and confirmed by response to vitamin K. Treatment
consists of vitamin K given orally or, when fat malabsorption is the cause or risk of bleeding is high, parenterally.
Vi ta mi n K defi ci ency decrea s es l evel s of prothrombi n a nd other vi ta mi n K-dependent coa gul a ti on fa ctors , ca us i ng defecti ve coa gul a ti on a nd,
potenti a l l y, bl eedi ng.
Etiology
Worl dwi de, vi ta mi n K defi ci ency ca us es i nfa nt morbi di ty a nd morta l i ty. Vi ta mi n K defi ci ency ca us es hemorrha gi c di s ea s e of the newborn, whi ch
us ua l l y occurs 1 to 7 da ys pos tpa rtum. In a ffected neona tes , bi rth tra uma ca n ca us e i ntra cra ni a l hemorrha ge. Neona tes a re prone to vi ta mi n K
defi ci ency beca us e of the fol l owi ng:
The pl a centa tra ns mi ts l i pi ds a nd vi ta mi n K rel a ti vel y poorl y.
The neona ta l l i ver i s i mma ture wi th res pect to prothrombi n s ynthes i s .
Brea s t mi l k i s l ow i n vi ta mi n K, conta i ni ng a bout 2.5 g/L (cow's mi l k conta i ns 5000 g/L).
The neona ta l gut i s s teri l e duri ng the fi rs t few da ys of l i fe.
La te hemorrha gi c di s ea s e (occurri ng 3 to 8 wk pos tpa rtum) i s us ua l l y a s s oci a ted wi th brea s tfeedi ng, ma l a bs orpti on, or a l i ver di s order. If the
mother ha s ta ken phenytoi n a nti convul s a nts , couma ri n a nti coa gul a nts , or cepha l os pori n a nti bi oti cs , the ri s k of both types of hemorrha gi c di s ea s e
i s i ncrea s ed.
In hea l thy a dul ts , di eta ry vi ta mi n K defi ci ency i s uncommon beca us e vi ta mi n K i s wi del y di s tri buted i n green vegeta bl es a nd the ba cteri a of the
norma l gut s ynthes i ze mena qui nones . However, bi l i a ry obs tructi on, ma l a bs orpti on, cys ti c fi bros i s , a nd res ecti on of the s ma l l i ntes ti ne ca n
contri bute to vi ta mi n K defi ci ency.
Couma ri n a nti coa gul a nts i nterfere wi th the s ynthes i s of vi ta mi n K-dependent coa gul a ti on protei ns (fa ctors II, VII, IX, a nd X) i n the l i ver. Certa i n
a nti bi oti cs (pa rti cul a rl y s ome cepha l os pori ns a nd other broa d-s pectrum a nti bi oti cs ), s a l i cyl a tes , mega dos es of vi ta mi n E, a nd hepa ti c
i ns uffi ci ency i ncrea s e ri s k of bl eedi ng i n pa ti ents wi th vi ta mi n K defi ci ency.
Symptoms and Signs
Bl eedi ng i s the us ua l ma ni fes ta ti on. Ea s y brui s a bi l i ty a nd mucos a l bl eedi ng (es peci a l l y epi s ta xi s , GI hemorrha ge, menorrha gi a , a nd hema turi a )
ca n occur. Bl ood ma y ooze from puncture s i tes or i nci s i ons .
Hemorrha gi c di s ea s e of the newborn a nd l a te hemorrha gi c di s ea s e i n i nfa nts ma y ca us e cuta neous , GI, i ntra thora ci c, or, i n the wors t ca s es ,
i ntra cra ni a l bl eedi ng. If obs tructi ve ja undi ce devel ops , bl eedi ngi f i t occurs us ua l l y begi ns a fter the 4th or 5th da y. It ma y begi n a s a s l ow ooze
from a s urgi ca l i nci s i on, the gums , the nos e, or GI mucos a , or i t ma y begi n a s ma s s i ve bl eedi ng i nto the GI tra ct.
Diagnosis
Us ua l l y, prol onged PT tha t decrea s es a fter phytona di one
Vi ta mi n K defi ci ency or a nta goni s m (due to couma ri n a nti coa gul a nts ) i s s us pected when a bnorma l bl eedi ng occurs i n a pa ti ent a t ri s k. Bl ood
coa gul a ti on s tudi es ca n prel i mi na ri l y confi rm the di a gnos i s . PT, us ua l l y reported a s the INR, i s prol onged, but PTT, thrombi n ti me, pl a tel et count,
bl eedi ng ti me, a nd l evel s of fi bri nogen, fi bri n-s pl i t products , a nd D-di mer a re norma l . If phytona di one (USP generi c na me for vi ta mi n K1 ) 1 mg IV
s i gni fi ca ntl y decrea s es PT wi thi n 2 to 6 h, a l i ver di s order i s not the l i kel y ca us e, a nd the di a gnos i s of vi ta mi n K defi ci ency i s confi rmed. Some
centers ca n detect vi ta mi n K defi ci ency more di rectl y by mea s uri ng the s erum vi ta mi n l evel . The s erum l evel of vi ta mi n K1 ra nges from 0.2 to 1.0
ng/mL i n hea l thy peopl e cons umi ng a dequa te qua nti ti es of vi ta mi n K1 (50 to 150 g/da y). Knowi ng vi ta mi n K i nta ke ca n hel p i nterpret s erum
l evel s ; recent i nta ke a ffects l evel s i n s erum but not i n ti s s ues .
More s ens i ti ve i ndi ca tors of vi ta mi n K s ta tus , s uch a s PIVKA (Protei n Induced i n Vi ta mi n K Abs ence or Anta goni s m) a nd under-ca rboxyl a ted
os teoca l ci n, a re under s tudy.
Treatment
Phytona di one
Whenever pos s i bl e, phytona di one s houl d be gi ven po or s c. The us ua l a dul t dos e i s 5 to 20 mg. (Ra rel y, even when phytona di one i s correctl y
di l uted a nd gi ven s l owl y, IV repl a cement ca n res ul t i n a na phyl a xi s or a na phyl a ctoi d rea cti ons .) INR us ua l l y decrea s es wi thi n 6 to 12 h. The dos e
ma y be repea ted i n 6 to 8 h i f INR ha s not decrea s ed s a ti s fa ctori l y. Phytona di one 2.5 to 10 mg po i s i ndi ca ted for nonemergency correcti on of a
prol onged INR i n pa ti ents ta ki ng a nti coa gul a nts . Correcti on us ua l l y occurs wi thi n 6 to 8 h. When onl y pa rti a l correcti on of INR i s des i ra bl e (eg,
when INR s houl d rema i n s l i ghtl y el eva ted beca us e of a pros theti c hea rt va l ve), l ower dos es (eg, 1 to 2.5 mg) of phytona di one ca n be gi ven.
In i nfa nts , bl eedi ng due to defi ci ency ca n be corrected by gi vi ng phytona di one 1 mg s c or IM once. The dos e i s repea ted i f INR rema i ns el eva ted.
Hi gher dos es ma y be neces s a ry i f the mother ha s been ta ki ng ora l a nti coa gul a nts .
Prevention
Phytona di one 0.5 to 1 mg IM (or 0.3 mg/kg for preterm i nfa nts ) i s recommended for a l l neona tes wi thi n 6 h of bi rth to reduce the i nci dence of
i ntra cra ni a l hemorrha ge due to bi rth tra uma a nd of cl a s s i c hemorrha gi c di s ea s e of the newborn (i ncrea s ed bl eedi ng ri s ks 1 to 7 da ys a fter bi rth).
It i s a l s o us ed prophyl a cti ca l l y before s urgery. Some cl i ni ci a ns recommend tha t pregna nt women ta ki ng a nti convul s a nts recei ve phytona di one 10
mg po once/da y for the 1 mo or 20 mg po once/da y for the 2 wk before del i very. The l ow vi ta mi n K1 content i n brea s t mi l k ca n be i ncrea s ed by
i ncrea s i ng ma terna l di eta ry i nta ke of phyl l oqui none to 5 mg/da y.
Vitamin K Toxicity
Vi ta mi n K1 (phyl l oqui none) i s not toxi c when cons umed ora l l y, even i n l a rge a mounts . However, mena di one (a s yntheti c, wa ter-s ol ubl e vi ta mi n K
precurs or) ca n ca us e toxi ci ty a nd s houl d not be us ed to trea t vi ta mi n K defi ci ency.
Chapter 5. Mineral Deficiency and Toxicity

Introduction
Si x ma cromi nera l s a re requi red by peopl e i n gra m a mounts . Four (Na , K, Ca , a nd Mg) a re ca ti ons ; two (Cl a nd P) a re a ccompa nyi ng a ni ons (s ee p.
820). Da i l y requi rements ra nge from 0.3 to 2.0 g. Bone, mus cl e, hea rt, a nd bra i n functi on depend on thes e mi nera l s .
Ni ne tra ce mi nera l s (mi cromi nera l s ) a re requi red by peopl e i n mi nute a mounts : chromi um, copper, i odi ne, i ron, fl uori ne, ma nga nes e,
mol ybdenum, s el eni um, a nd zi nc. (For s ources , functi ons , effects of defi ci ency a nd toxi ci ty, a nd di eta ry requi rements , s ee
Ta bl es 5-1 a nd
5-2.) Al l tra ce mi nera l s a re toxi c a t hi gh l evel s ; s ome mi nera l s (a rs eni c, ni ckel , a nd chromi um) ma y be ca rci nogens .
Mi nera l defi ci enci es (except of i odi ne, i ron, a nd zi nc) do not often devel op s ponta neous l y i n a dul ts on ordi na ry di ets ; i nfa nts a re more vul nera bl e
beca us e thei r growth i s ra pi d a nd i nta ke va ri es . Tra ce mi nera l i mba l a nces ca n res ul t from heredi ta ry di s orders (eg, hemochroma tos i s , Wi l s on's
di s ea s e), ki dney di a l ys i s , pa rentera l nutri ti on, or res tri cti ve di ets pres cri bed for peopl e wi th i nborn errors of meta bol i s m.
Chromium
Onl y 1 to 3% of bi ol ogi ca l l y a cti ve tri va l ent chromi um (Cr) i s a bs orbed. Norma l pl a s ma l evel s a re 0.05 to 0.50 g/L (1.0 to 9.6 nmol /L). Chromi um
potenti a tes i ns ul i n a cti vi ty a nd i ncrea s es the growth ra te i n undernouri s hed chi l dren. Suppl ements do not enha nce mus cl e s i ze or s trength i n
men.
Deficiency: Four pa ti ents recei vi ng l ong-term TPN devel oped pos s i bl e chromi um defi ci ency, wi th gl ucos e i ntol era nce, wei ght l os s , a ta xi a , a nd
peri phera l neuropa thy. Symptoms res ol ved i n 3 who were gi ven tri va l ent chromi um 150 to 250 mg.
Toxicity: Hi gh dos es of tri va l ent chromi um gi ven pa rentera l l y ca us e s ki n i rri ta ti on, but l ower dos es gi ven ora l l y a re not toxi c. Expos ure to
hexa va l ent chromi um (CrO3 ) i n the workpl a ce ma y i rri ta te the s ki n, l ungs , a nd GI tra ct a nd ma y ca us e perfora ti on of the na s a l s eptum a nd l ung
ca rci noma .
Copper
Copper i s a component of ma ny body protei ns ; a l mos t a l l of the body's copper i s bound to copper protei ns . Unbound (free) copper i ons a re toxi c.
Geneti c mecha ni s ms control the i ncorpora ti on of copper i nto a poprotei ns a nd the proces s es tha t prevent toxi c a ccumul a ti on of copper i n the body.
Copper a bs orbed i n exces s of meta bol i c requi rements i s excreted through bi l e.
[Table 5-1. Tra ce Mi nera l s ]
Acquired Copper Deficiency
If the geneti c mecha ni s ms control l i ng copper meta bol i s m a re norma l , di eta ry defi ci ency ra rel y ca us es cl i ni ca l l y s i gni fi ca nt copper defi ci ency. The
onl y reported ca us es a re kwa s hi orkor, pers i s tent i nfa nti l e di a rrhea (us ua l l y a s s oci a ted wi th a di et l i mi ted to mi l k), s evere ma l a bs orpti on (a s i n
s prue), a nd exces s i ve zi nc i nta ke.
Defi ci ency ma y ca us e neutropeni a , i mpa i red bone ca l ci fi ca ti on, a nd hypochromi c a nemi a not res pons i ve to i ron s uppl ements .
Di a gnos i s i s ba s ed on l ow s erum l evel s of copper a nd cerul opl a s mi n, a l though thes e tes ts a re not a l wa ys rel i a bl e. Trea tment i s di rected a t the
ca us e, a nd copper 1.5 to 3 mg/da y po (us ua l l y a s copper s ul fa te) i s gi ven.
Inherited Copper Deficiency
(Menkes Syndrome)
Inheri ted copper defi ci ency occurs i n ma l e i nfa nts who i nheri t a muta nt X-l i nked gene. Inci dence i s a bout 1 i n 50,000 l i ve bi rths . Copper i s
defi ci ent i n the l i ver, s erum, a nd es s enti a l copper protei ns , i ncl udi ng cytochrome-c oxi da s e, cerul opl a s mi n, a nd l ys yl oxi da s e.
Symptoms a re s evere i ntel l ectua l di s a bi l i ty, vomi ti ng, di a rrhea , protei n-l os i ng enteropa thy, hypopi gmenta ti on, bone cha nges , a nd a rteri a l
rupture; the ha i r i s s pa rs e, s teel y, or ki nky.
Diagnosis
Serum copper a nd cerul opl a s mi n l evel s
Serum l evel s of dopa mi ne, norepi nephri ne, di hydroxyphenyl a ceti c a ci d, a nd di hydroxyphenyl gl ycol i n i nfa nts a t ri s k
Di a gnos i s i s ba s ed on l ow copper a nd cerul opl a s mi n l evel s i n s erum, a l though thes e tes ts a re not a l wa ys rel i a bl e. Beca us e ea rl y di a gnos i s a nd
trea tment s eem to res ul t i n a better prognos i s , the di s order i s i dea l l y detected before a ge 2 wk. However, di a gnos ti c a ccura cy of thes e tes ts i s
l i mi ted. Thus , i nfa nts a t ri s k (eg, thos e wi th a fa mi l y hi s tory) ca n be s creened by mea s uri ng dopa mi ne, norepi nephri ne, di hydroxyphenyl a ceti c
a ci d, a nd di hydroxyphenyl gl ycol i n s erum. A di hydroxyphenyl a ceti c a ci d:di hydroxyphenyl gl ycol ra ti o of > 4 s eems to i ndi ca te defi ci ency, a nd a
dopa mi ne:norepi nephri ne ra ti o of > 0.2 s eems to confi rm i t.
Treatment
Copper hi s ti di ne
Pa rentera l copper i s us ua l l y gi ven a s copper hi s ti di ne 250 g s c bi d to a ge 1 yr, then 250 g s c once/da y unti l a ge 3 yr; moni tori ng ki dney functi on i s
es s enti a l duri ng trea tment. Des pi te ea rl y trea tment, ma ny chi l dren ha ve a bnorma l neurodevel opment.
Acquired Copper Toxicity
Acqui red copper toxi ci ty ca n res ul t from i nges ti ng or a bs orbi ng exces s copper (eg, from i nges ti ng a n a ci di c food or bevera ge tha t ha s ha d
prol onged conta ct wi th a copper conta i ner). Sel f-l i mi ted ga s troenteri ti s wi th na us ea , vomi ti ng, a nd di a rrhea ma y occur.
[Table 5-2. Gui del i nes for Da i l y Inta ke of Mi nera l s ]
More s evere toxi ci ty res ul ts from i nges ti on (us ua l l y wi th s ui ci da l i ntent) of gra m qua nti ti es of a copper s a l t (eg, copper s ul fa te) or from a bs orpti on
of l a rge a mounts through the s ki n (eg, i f compres s es s a tura ted wi th a s ol uti on of a copper s a l t a re a ppl i ed to l a rge a rea s of burned s ki n).
Hemol yti c a nemi a a nd a nuri a ca n res ul t a nd ma y be fa ta l .
Indi a n chi l dhood ci rrhos i s , non-Indi a n chi l dhood ci rrhos i s , a nd i di opa thi c copper toxi ci ty a re proba bl y i denti ca l di s orders i n whi ch exces s copper
ca us es ci rrhos i s . Al l s eem to be ca us ed by i nges ti ng mi l k tha t ha s been boi l ed or s tored i n corroded copper or bra s s ves s el s . Recent s tudi es
s ugges t tha t i di opa thi c copper toxi ci ty ma y devel op onl y i n i nfa nts wi th a n unknown geneti c defect.
Di a gnos i s us ua l l y requi res l i ver bi ops y, whi ch s hows Ma l l ory hya l i n bodi es .
Treatment
Chel a ti on
Supporti ve mea s ures
For copper toxi ci ty due to i nges ti ng gra ms of copper, prompt ga s tri c l a va ge i s done. Copper toxi ci ty tha t ca us es compl i ca ti ons s uch a s hemol yti c
a nemi a , a nuri a , or hepa totoxi ci ty i s a l s o trea ted wi th ei ther ora l peni ci l l a mi ne 250 mg q 6 h to 750 mg q 12 h (1000 to 1500 mg/da y i n 2 to 4 dos es )
or di merca prol 3 to 5 mg/kg IM q 4 h for 2 da ys , then q 4 to 6 h (s ee a l s o
Ta bl e 340-4 a nd copper s a l ts i n
Ta bl e 340-8). If us ed ea rl y, hemodi a l ys i s ma y be effecti ve. Occa s i ona l l y, copper toxi ci ty i s fa ta l des pi te trea tment.
Inherited Copper Toxicity
(Wi l s on's Di s ea s e)
Inherited copper toxicity results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low
serum ceruloplasmin level, high urinary excretion of copper, and sometimes liver biopsy results. Treatment consists of a low-copper diet and chelation, usually
with penicillamine or dimercaprol.
Wi l s on's di s ea s e i s a progres s i ve di s order of copper meta bol i s m tha t a ffects 1 pers on i n 30,000. Affected peopl e a re homozygous for the muta nt
reces s i ve gene, l oca ted on chromos ome 13. Heterozygous ca rri ers , who cons ti tute a bout 1.1% of the popul a ti on, a re a s ymptoma ti c.
Pathophysiology
The geneti c defect i mpa i rs copper tra ns port. The i mpa i red tra ns port decrea s es copper s ecreti on i nto the bi l e, thus ca us i ng the copper overl oa d
a nd res ul ta nt a ccumul a ti on i n the l i ver, whi ch begi ns a t bi rth. The i mpa i red tra ns port a l s o i nterferes wi th i ncorpora ti on of copper i nto the copper
protei n cerul opl a s mi n, thus decrea s i ng s erum l evel s of cerul opl a s mi n.
Hepa ti c fi bros i s devel ops , ul ti ma tel y ca us i ng ci rrhos i s . Copper di ffus es out of the l i ver i nto the bl ood, then i nto other ti s s ues . It i s mos t
des tructi ve to the bra i n but a l s o da ma ges the ki dneys a nd reproducti ve orga ns a nd ca us es hemol yti c a nemi a . Some copper i s depos i ted i n
Des cemet's membra ne of the cornea , ca us i ng Ka ys er-Fl ei s cher ri ngs .
Symptoms and Signs
Symptoms us ua l l y devel op between a ges 5 a nd 40. In a l mos t ha l f of pa ti ents , pa rti cul a rl y a dol es cents , the fi rs t s ymptom i s hepa ti ti s a cute,
chroni c a cti ve, or ful mi na nt. But hepa ti ti s ma y devel op a t a ny ti me. In a bout 40% of pa ti ents , pa rti cul a rl y young a dul ts , the fi rs t s ymptoms refl ect
CNS i nvol vement. Motor defi ci ts a re common, i ncl udi ng a ny combi na ti on of tremors , dys toni a , dys a rthri a , dys pha gi a , chorea , drool i ng, a nd
i ncoordi na ti on. Someti mes the fi rs t s ymptoms a re cogni ti ve or ps ychi a tri c a bnorma l i ti es . In 5 to 10% of pa ti ents , the fi rs t s ymptom i s i nci denta l l y
noted gol d or greeni s h gol d Ka ys er-Fl ei s cher ri ngs or cres cents (due to copper depos i ts i n the cornea ), a menorrhea or repea ted mi s ca rri a ges , or
hema turi a .
Diagnosis
Sl i t-l a mp exa mi na ti on for Ka ys er-Fl ei s cher ri ngs
Serum cerul opl a s mi n a nd 24-h uri na ry copper excreti on
Someti mes confi rma ti on by peni ci l l a mi ne provoca ti on tes t or l i ver bi ops y
Wi l s on's di s ea s e s houl d be s us pected i n peopl e < 40 wi th a ny of the fol l owi ng:
An unexpl a i ned hepa ti c, neurol ogi c, or ps ychi a tri c di s order
An unexpl a i ned pers i s tent el eva ti on i n hepa ti c tra ns a mi na s es
A s i bl i ng, pa rent, or cous i n wi th Wi l s on's di s ea s e

Ful mi na nt hepa ti ti s
If Wi l s on's di s ea s e i s s us pected, s l i t-l a mp exa mi na ti on for Ka ys er-Fl ei s cher ri ngs i s requi red, a nd s erum cerul opl a s mi n a nd copper l evel s a nd 24h uri na ry copper excreti on a re mea s ured. Tra ns a mi na s e l evel s a re a l s o often mea s ured; hi gh l evel s a re cons i s tent wi th the di a gnos i s .
Kayser-Fleischer rings: Thes e ri ngs pl us typi ca l motor neurol ogi c a bnorma l i ti es or a decrea s e i n cerul opl a s mi n a re nea rl y pa thognomoni c for
Wi l s on's di s ea s e. Ra rel y, thes e ri ngs occur i n other l i ver di s orders (eg, bi l i a ry a tres i a , pri ma ry bi l i a ry ci rrhos i s ), but cerul opl a s mi n l evel s s houl d
be una ffected.
Ceruloplasmin: Serum cerul opl a s mi n (norma l l y 20 to 35 mg/dL) i s us ua l l y l ow i n Wi l s on's di s ea s e but ca n be norma l . It ca n a l s o be l ow i n
heterozygous ca rri ers a nd thos e wi th other l i ver di s orders (eg, vi ra l hepa ti ti s , drug- or a l cohol -i nduced l i ver di s ea s e). A l ow cerul opl a s mi n l evel i n
a pa ti ent wi th a Ka ys er-Fl ei s cher ri ng i s di a gnos ti c. Al s o, a l evel of < 5 mg/dL i s hi ghl y s ugges ti ve rega rdl es s of cl i ni ca l fi ndi ngs .
Serum copper: Des pi te the copper a ccumul a ti on i n the body, s erum copper l evel s a re decrea s ed beca us e of the decrea s ed cerul opl a s mi n l evel s .
Urinary copper excretion: In Wi l s on's di s ea s e, 24-h uri na ry copper excreti on (norma l l y, 30 g/da y) i s us ua l l y > 100 g/da y. If s erum cerul opl a s mi n i s
l ow a nd uri na ry copper excreti on i s hi gh, di a gnos i s i s cl ea r. If l evel s a re equi voca l , mea s uri ng uri na ry copper excreti on a fter peni ci l l a mi ne i s gi ven
(peni ci l l a mi ne provoca ti on tes t) ma y confi rm the di a gnos i s ; thi s tes t i s not us ua l l y done i n a dul ts beca us e cutoff va l ues a re not wel l -es ta bl i s hed.
Liver biopsy: In uncl ea r ca s es (eg, el eva ted tra ns a mi na s es , no Ka ys er-Fl ei s cher ri ngs , i ndetermi na te va l ues for cerul opl a s mi n a nd uri na ry copper),
the di a gnos i s i s ma de by doi ng a l i ver bi ops y to mea s ure hepa ti c copper concentra ti on. However, fa l s e-nega ti ve res ul ts ma y occur beca us e of a
s a mpl i ng error (due to l a rge va ri a ti ons i n copper concentra ti ons i n the l i ver) or ful mi na nt hepa ti ti s (ca us i ng necros i s tha t rel ea s es l a rge a mounts
of copper).
Screening: Beca us e ea rl y trea tment i s mos t effecti ve, s creeni ng i s i ndi ca ted for a nyone who ha s a s i bl i ng, cous i n, or pa rent wi th Wi l s on's di s ea s e.
Screeni ng cons i s ts of a s l i t-l a mp exa mi na ti on a nd mea s urement of tra ns a mi na s e l evel s , s erum copper a nd cerul opl a s mi n, a nd 24-h uri ne copper
excreti on. If a ny res ul ts a re a bnorma l , l i ver bi ops y i s done to mea s ure hepa ti c copper concentra ti on. Infa nts s houl d not be tes ted unti l a fter a ge 1
yr beca us e cerul opl a s mi n l evel s a re l ow duri ng the fi rs t few months of l i fe. Chi l dren < 6 yr wi th norma l tes t res ul ts s houl d be retes ted 5 to 10 yr
l a ter.
Geneti c tes ti ng i s under i nves ti ga ti on.
Prognosis
Prognos i s i s us ua l l y good, unl es s di s ea s e i s a dva nced before trea tment begi ns . Untrea ted Wi l s on's di s ea s e i s fa ta l , us ua l l y by a ge 30.
Treatment
Peni ci l l a mi ne or a nother chel a ti ng drug i f needed to remove a ccumul a ted copper
Low-copper di et
For ma i ntena nce, l i fel ong l ow-dos e chel a ti on thera py or ora l zi nc
Conti nua l , l i fel ong trea tment i s ma nda tory rega rdl es s of whether s ymptoms a re pres ent. Accumul a ted copper s houl d be removed wi th chel a ti ng
drugs . A l ow-copper di et (eg, a voi di ng beef l i ver, ca s hews , bl a ck-eyed pea s , vegeta bl e jui ce, s hel l fi s h, mus hrooms , a nd cocoa ) a nd us e of ei ther
l ow-dos e chel a ti on thera py or ora l zi nc ca n prevent copper from a ccumul a ti ng.
Peni ci l l a mi ne i s the mos t commonl y us ed chel a ti ng drug but ha s cons i dera bl e toxi ci ty (eg, fever, ra s h, neutropeni a , thrombocytopeni a ,
protei nuri a ). Cros s -rea cti vi ty ma y occur i n peopl e wi th peni ci l l i n a l l ergy. Pa ti ents > 5 yr a re gi ven ora l dos es of 62.5 mg q 6 h to 250 mg q 12 h (250 to
500 mg/da y i n 2 to 4 dos es ) a nd s l owl y i ncrea s ed to a ma xi mum of 250 mg q 6 h to 750 mg q 12 h (1000 to 1500 mg/da y i n 2 to 4 dos es ). Younger
chi l dren a re gi ven 10 mg/kg bi d or 6.7 mg/kg ti d (20 mg/kg/d) po. Pyri doxi ne 25 mg po once/da y i s gi ven wi th peni ci l l a mi ne. Occa s i ona l l y, us e of
peni ci l l a mi ne i s a s s oci a ted wi th wors eni ng neurol ogi c s ymptoms .
Tri enti ne hydrochl ori de i s a n a l terna ti ve trea tment to peni ci l l a mi ne. Dos es a re 375 to 750 mg po bi d or 250 to 500 mg po ti d (750 to 1500 mg/da y).
Zi nc a ceta te 50 mg po ti d ca n prevent rea ccumul a ti on of copper i n pa ti ents who ca nnot tol era te peni ci l l a mi ne or tri enti ne or who ha ve neurol ogi c
s ymptoms tha t do not res pond to the other drugs . (CAUTION: Penicillamine or trientine must not be given with zinc because either drug can bind zinc,
forming a compound with no therapeutic effect.)
Poor l ong-term a dherence to drug thera py i s common. After 1 to 5 yr of thera py, l ower dos e ma i ntena nce drug thera py ca n be cons i dered. Regul a r
fol l ow-up ca re wi th a n expert i n l i ver di s ea s e i s recommended.
Li ver tra ns pl a nta ti on ma y be l i fes a vi ng for pa ti ents who ha ve Wi l s on's di s ea s e a nd ful mi na nt hepa ti c fa i l ure or s evere hepa ti c i ns uffi ci ency
refra ctory to drugs .
Fluorine
Mos t of the body's fl uori ne (F) i s conta i ned i n bones a nd teeth. Fl uori de (the i oni c form of fl uori ne) i s wi del y di s tri buted i n na ture. The ma i n
s ource of fl uori de i s fl uori da ted dri nki ng wa ter.
Deficiency: Fl uori ne defi ci ency ca n l ea d to denta l ca ri es a nd pos s i bl y os teoporos i s . Fl uori da ti on of wa ter tha t conta i ns < 1 ppm (the i dea l ) reduces
the i nci dence of denta l ca ri es . If a chi l d's dri nki ng wa ter i s not fl uori da ted, ora l fl uori de s uppl ements ca n be pres cri bed.
Toxicity: Exces s fl uori ne ca n a ccumul a te i n teeth a nd bones , ca us i ng fl uoros i s . Dri nki ng wa ter conta i ni ng > 10 ppm i s a common ca us e. Perma nent
teeth tha t devel op duri ng hi gh fl uori de i nta ke a re mos t l i kel y to be a ffected. Expos ure mus t be much grea ter to a ffect deci duous teeth.
The ea rl i es t s i gns a re cha l ky whi te, i rregul a rl y di s tri buted pa tches on the s urfa ce of the ena mel ; thes e pa tches become s ta i ned yel l ow or brown,
produci ng a cha ra cteri s ti c mottl ed a ppea ra nce. Severe toxi ci ty wea kens the ena mel , pi tti ng i ts s urfa ce. Bony cha nges , i ncl udi ng os teos cl eros i s ,
exos tos es of the s pi ne, a nd genu va l gum, ca n devel op but onl y i n a dul ts a fter prol onged hi gh i nta ke of fl uori de.
No tes ts to di a gnos e toxi ci ty a re a va i l a bl e.
Trea tment i nvol ves reduci ng fl uori de i nta ke; eg, i n a rea s wi th hi gh fl uori de wa ter l evel s , pa ti ents s houl d not dri nk fl uori da ted wa ter or ta ke
fl uori de s uppl ements . Chi l dren s houl d a l wa ys be tol d not to s wa l l ow fl uori da ted toothpa s tes .
Iodine
In the body, i odi ne (I) i s i nvol ved pri ma ri l y i n the s ynthes i s of 2 thyroi d hormones , thyroxi ne (T4 ) a nd tri i odothyroni ne (T3 ). Iodi ne occurs i n the
envi ronment a nd i n the di et pri ma ri l y a s i odi de. In a dul ts , a bout 80% of the i odi de a bs orbed i s tra pped by the thyroi d gl a nd. Mos t envi ronmenta l
i odi ne occurs i n s ea wa ter a s i odi de; a s ma l l a mount enters the a tmos phere a nd, through ra i n, enters ground wa ter a nd s oi l nea r the s ea . Thus ,
peopl e l i vi ng fa r from the s ea a nd a t hi gher a l ti tudes a re a t pa rti cul a r ri s k of defi ci ency. Forti fyi ng ta bl e s a l t wi th i odi de (typi ca l l y 70 g/g) hel ps
ens ure a dequa te i nta ke (150 g/da y). Requi rements a re hi gher for pregna nt (220 g/da y) a nd brea s tfeedi ng (290 g/da y) women.
Iodine Deficiency
Defi ci ency i s ra re i n a rea s where i odi zed s a l t i s us ed but common worl dwi de. Iodi ne defi ci ency devel ops when i odi de i nta ke i s < 20 g/da y. In
mi l d or modera te defi ci ency, the thyroi d gl a nd, i nfl uenced by thyroi d-s ti mul a ti ng hormone (TSH), hypertrophi es to concentra te i odi de i n i ts el f,
res ul ti ng i n col l oi d goi ter. Us ua l l y, pa ti ents rema i n euthyroi d; however, s evere i odi ne defi ci ency i n a dul ts ma y ca us e hypothyroi di s m (endemi c
myxedema ). It ca n decrea s e ferti l i ty a nd i ncrea s e ri s k of s ti l l bi rth, s ponta neous a borti on, a nd prena ta l a nd i nfa nt morta l i ty. Severe ma terna l
i odi ne defi ci ency reta rds feta l growth a nd bra i n devel opment, s ometi mes res ul ti ng i n bi rth defects , a nd, i n i nfa nts , ca us es creti ni s m, whi ch ma y
i ncl ude i ntel l ectua l di s a bi l i ty, dea f-muti s m, di ffi cul ty wa l ki ng, s hort s ta ture, a nd s ometi mes hypothyroi di s m.
Diagnosis
As s es s ment of thyroi d s tructure a nd functi on
Di a gnos i s i n a dul ts a nd chi l dren i s us ua l l y ba s ed on thyroi d functi on, exa mi na ti on for goi ter, a nd i ma gi ng tes ts i denti fyi ng a bnorma l i ti es i n
thyroi d functi on a nd s tructure (s ee p.
776). Al l neona tes s houl d be s creened by mea s uri ng the TSH l evel .
Treatment
Iodi de wi th or wi thout l evothyroxi ne
Infa nts wi th i odi ne defi ci ency a re gi ven L-thyroxi ne 3 g/kg po once/da y for a week pl us i odi de 50 to 90 g po once/da y for s evera l weeks to qui ckl y
res tore a euthyroi d s ta te. Chi l dren a re trea ted wi th i odi de 90 to 120 g once/da y. Adul ts a re gi ven i odi de 150 g once/da y. Iodi ne defi ci ency ca n
a l s o be trea ted by gi vi ng l evothyroxi ne. Serum TSH l evel s a re moni tored i n a l l pa ti ents unti l the l evel s a re norma l (i e, < 5 IU/mL).
Iodine Toxicity
Chroni c toxi ci ty ma y devel op when i nta ke i s > 1.1 mg/da y. Mos t peopl e who i nges t exces s a mounts of i odi ne rema i n euthyroi d. Some peopl e who
i nges t exces s a mounts of i odi ne, pa rti cul a rl y thos e who were previ ous l y defi ci ent, devel op hyperthyroi di s m (Jod-Ba s edow phenomenon).
Pa ra doxi ca l l y, exces s upta ke of i odi ne by the thyroi d ma y i nhi bi t thyroi d hormone s ynthes i s (ca l l ed Wol ff-Cha i koff effect). Thus , i odi ne toxi ci ty ca n
eventua l l y ca us e i odi de goi ter, hypothyroi di s m, or myxedema . Very l a rge a mounts of i odi de ma y ca us e a bra s s y ta s te i n the mouth, i ncrea s ed
s a l i va ti on, GI i rri ta ti on, a nd a cnei form s ki n l es i ons . Pa ti ents expos ed to frequent l a rge a mounts of ra di ogra phi c contra s t dyes or the drug
a mi oda rone a l s o need to ha ve thei r thyroi d functi on moni tored.
Di a gnos i s i s us ua l l y ba s ed on thyroi d functi on a nd i ma gi ng tes t fi ndi ngs (s ee p. 776), whi ch a re correl a ted wi th cl i ni ca l da ta . Iodi ne excreti on ma y
be more s peci fi c but i s not us ua l l y mea s ured. Trea tment cons i s ts of correcti ng thyroi d a bnorma l i ti es a nd, i f i nta ke i s exces s i ve, di eta ry
modi fi ca ti on.
Iron
Iron (Fe) i s a component of hemogl obi n, myogl obi n, a nd ma ny enzymes i n the body. Heme i ron, conta i ned ma i nl y i n a ni ma l products , i s a bs orbed
much better tha n nonheme i ron (eg, i n pl a nts a nd gra i ns ), whi ch a ccounts for > 85% of i ron i n the a vera ge di et. However, a bs orpti on of nonheme
i ron i s i ncrea s ed when i t i s cons umed wi th a ni ma l protei n a nd vi ta mi n C.
Deficiency: Iron defi ci ency i s one of the mos t common mi nera l defi ci enci es i n the worl d. It ma y res ul t from the fol l owi ng:
Ina dequa te i ron i nta ke, common i n i nfa nts , a dol es cent gi rl s , a nd pregna nt women
Ma l a bs orpti on (eg, cel i a c s prue)
Chroni c bl eedi ng
Chroni c bl eedi ng due to col on ca ncer i s a s eri ous ca us e i n mi ddl e-a ged peopl e a nd the el derl y.
When defi ci ency i s a dva nced, mi crocyti c a nemi a devel ops (s ee p. 924).
In a ddi ti on to a nemi a , i ron defi ci ency ma y ca us e pi ca (a cra vi ng for nonfoods ) a nd s poon na i l s a nd i s a s s oci a ted wi th res tl es s l eg s yndrome.
Ra rel y, i ron defi ci ency ca us es dys pha gi a due to pos tcri coi d es opha gea l web.
Di a gnos i s i nvol ves CBC, s erum ferri ti n, a nd pos s i bl y mea s urement of tra ns ferri n s a tura ti on (i ron ca pa ci ty).
Al l peopl e wi th modera te or s evere i ron defi ci ency a nd s ome peopl e wi th mi l d defi ci ency requi re i ron s uppl ementa ti on.
Toxicity: Iron ma y a ccumul a te i n the body beca us e of
Iron thera py gi ven i n exces s i ve a mounts or for too l ong
Repea ted bl ood tra ns fus i ons
Chroni c a l cohol i s m
Overdos e of i ron
Iron overl oa d ca n a l s o res ul t from a n i nheri ted i ron overl oa d di s ea s e (hemochroma tos i s s ee p. 1032), a potenti a l l y fa ta l but ea s i l y trea ta bl e
geneti c di s order i n whi ch too much i ron i s a bs orbed. Hemochroma tos i s a ffects > 1 mi l l i on Ameri ca ns .
An overdos e of i ron i s toxi c (s ee p. 3341), ca us i ng vomi ti ng, di a rrhea , a nd da ma ge to the i ntes ti ne a nd other orga ns .
Di a gnos i s i s s i mi l a r to tha t for i ron defi ci ency.
Trea tment often i nvol ves deferoxa mi ne, whi ch bi nds wi th i ron a nd i s excreted i n uri ne.
Manganese
Ma nga nes e (Mn), neces s a ry for hea l thy bone s tructure, i s a component of s evera l enzyme s ys tems , i ncl udi ng ma nga nes e-s peci fi c
gl ycos yl tra ns fera s es a nd phos phoenol pyruva te ca rboxyki na s e. Medi a n i nta ke i s between 1.6 a nd 2.3 mg/da y; a bs orpti on i s 5 to 10%.
Defi ci ency ha s not been concl us i vel y documented, a l though one experi menta l ca s e i n a vol unteer res ul ted i n tra ns i ent derma ti ti s ,
hypochol es terol emi a , a nd i ncrea s ed a l ka l i ne phos pha ta s e l evel s .
Toxi ci ty i s us ua l l y l i mi ted to peopl e who mi ne a nd refi ne ore; prol onged expos ure ca us es neurol ogi c s ymptoms res embl i ng thos e of pa rki ns oni s m
or Wi l s on's di s ea s e.
Molybdenum
Mol ybdenum (Mo) i s a component of coenzymes neces s a ry for the a cti vi ty of xa nthi ne oxi da s e, s ul fi te oxi da s e, a nd a l dehyde oxi da s e.
Geneti c a nd nutri ti ona l defi ci enci es of mol ybdenum ha ve been reported but a re ra re. Geneti c s ul fi te oxi da s e defi ci ency wa s des cri bed i n 1967 i n
a chi l d. It res ul ted from the i na bi l i ty to form the mol ybdenum coenzyme des pi te the pres ence of a dequa te mol ybdenum. The defi ci ency ca us ed
i ntel l ectua l di s a bi l i ty, s ei zures , opi s thotonus , a nd l ens di s l oca ti on.
Mol ybdenum defi ci ency res ul ti ng i n s ul fi te toxi ci ty occurred i n a pa ti ent recei vi ng l ong-term TPN. Symptoms were ta chyca rdi a , ta chypnea ,
hea da che, na us ea , vomi ti ng, a nd coma . La bora tory tes ts s howed hi gh l evel s of s ul fi te a nd xa nthi ne a nd l ow l evel s of s ul fa te a nd uri c a ci d i n the
bl ood a nd uri ne. Ammoni um mol ybda te 300 g/da y IV ca us ed dra ma ti c recovery.
A ca s e of mol ybdenum toxi ci ty ma y ha ve occurred i n 1961; i t ca us ed goutl i ke s ymptoms a nd a bnorma l i ti es of the GI tra ct, l i ver, a nd ki dneys .
Selenium
Sel eni um (Se) i s a pa rt of the enzyme gl uta thi one peroxi da s e, whi ch meta bol i zes hydro-peroxi des formed from pol yuns a tura ted fa tty a ci ds .
Sel eni um i s a l s o a pa rt of the enzymes tha t dei odi na te thyroi d hormones . Genera l l y, s el eni um a cts a s a n a nti oxi da nt tha t works wi th vi ta mi n E.
Some epi demi ol ogi c s tudi es a s s oci a te l ow s el eni um l evel s wi th ca ncer. In chi l dren wi th Down s yndrome, s el eni um s uppl ements ma y hel p
prevent ba cteri a l i nfecti ons . Pl a s ma l evel s va ry from 8 to 25 g/dL, dependi ng on s el eni um i nta ke. Di a gnos i s i s us ua l l y cl i ni ca l ; s ometi mes bl ood
gl uta thi one peroxi da s e i s mea s ured.
Deficiency: Defi ci ency i s ra re, even i n New Zea l a nd a nd Fi nl a nd, where s el eni um i nta ke i s 30 to 50 g/da y, compa red wi th 100 to 250 g/da y i n the
US a nd Ca na da . In certa i n a rea s of Chi na , where i nta ke a vera ges 10 to 15 g/da y, s el eni um defi ci ency predi s pos es pa ti ents to Kes ha n di s ea s e, a n
endemi c vi ra l ca rdi omyopa thy a ffecti ng pri ma ri l y chi l dren a nd young women. Thi s ca rdi omyopa thy ca n be prevented but not cured by s odi um
s el eni te s uppl ements of 50 g/da y po. Pa ti ents recei vi ng l ong-term TPN ha ve devel oped s el eni um defi ci ency wi th mus cl e pa i n a nd tendernes s
tha t res ponded to a s el enomethi oni ne s uppl ement. In Si beri a n Rus s i a a nd Chi na , growi ng chi l dren wi th s el eni um defi ci ency ma y devel op chroni c
os teoa rthropa thy (Ka s hi n-Beck di s ea s e). Sel eni um defi ci ency ma y contri bute s ynergi s ti ca l l y wi th i odi ne defi ci ency to the devel opment of goi ter
a nd hypothyroi di s m.
Di a gnos i s i s ma de cl i ni ca l l y or s ometi mes by mea s uri ng gl uta thi one peroxi da s e a cti vi ty or pl a s ma s el eni um, but nei ther of thes e tes ts i s rea di l y
a va i l a bl e. Trea tment cons i s ts of s odi um s el eni te 100 g/da y po.
Toxicity: At hi gh dos es (> 900 g/da y), s el eni um ca us es toxi ci ty. Ma ni fes ta ti ons i ncl ude ha i r l os s , a bnorma l na i l s , derma ti ti s , peri phera l
neuropa thy, na us ea , di a rrhea , fa ti gue, i rri ta bi l i ty, a nd a ga rl i c odor of the brea th. Toxi c l evel s of pl a s ma s el eni um a re not wel l defi ned.
Zinc
Zi nc (Zn) i s conta i ned ma i nl y i n bones , teeth, ha i r, s ki n, l i ver, mus cl e, l eukocytes , a nd tes tes . Zi nc i s a component of s evera l hundred enzymes ,
i ncl udi ng ma ny ni coti na mi de a deni ne di nucl eoti de (NADH) dehydrogena s es , RNA a nd DNA pol ymera s es , a nd DNA tra ns cri pti on fa ctors a s wel l a s
a l ka l i ne phos pha ta s e, s uperoxi de di s muta s e, a nd ca rboni c a nhydra s e. A di et hi gh i n fi ber a nd phyta te (eg, i n whol e-gra i n brea d) reduces zi nc
a bs orpti on.
Deficiency: Di eta ry defi ci ency i s unl i kel y i n hea l thy peopl e. Seconda ry zi nc defi ci ency ca n devel op i n the fol l owi ng:
Some pa ti ents wi th hepa ti c i ns uffi ci ency (beca us e the a bi l i ty to reta i n zi nc i s l os t)
Pa ti ents ta ki ng di ureti cs
Pa ti ents wi th di a betes mel l i tus , s i ckl e cel l di s ea s e, chroni c rena l fa i l ure, or ma l a bs orpti on
Pa ti ents wi th s tres s ful condi ti ons (eg, s eps i s , burns , hea d i njury)
El derl y i ns ti tuti ona l i zed a nd homebound pa ti ents (common)
Ma terna l zi nc defi ci ency ma y ca us e feta l ma l forma ti ons a nd l ow bi rth wei ght.
Zi nc defi ci ency i n chi l dren ca us es i mpa i red growth a nd i mpa i red ta s te (hypogeus i a ). Other s ymptoms a nd s i gns i n chi l dren i ncl ude del a yed s exua l
ma tura ti on a nd hypogona di s m. In chi l dren or a dul ts , s ymptoms i ncl ude hypogona di s m, a l opeci a , i mpa i red i mmuni ty, a norexi a , derma ti ti s , ni ght
bl i ndnes s , a nemi a , l etha rgy, a nd i mpa i red wound hea l i ng.
Zi nc defi ci ency s houl d be s us pected i n undernouri s hed pa ti ents wi th typi ca l s ymptoms or s i gns . However, beca us e ma ny of the s ymptoms a nd
s i gns a re nons peci fi c, cl i ni ca l di a gnos i s of mi l d zi nc defi ci ency i s di ffi cul t. La bora tory di a gnos i s i s a l s o di ffi cul t. Low a l bumi n l evel s , common i n
zi nc defi ci ency, ma ke s erum zi nc l evel s di ffi cul t to i nterpret; di a gnos i s us ua l l y requi res the combi na ti on of l ow l evel s of zi nc i n s erum a nd
i ncrea s ed uri na ry zi nc excreti on. If a va i l a bl e, i s otope s tudi es ca n mea s ure zi nc s ta tus more a ccura tel y.
Trea tment cons i s ts of el ementa l zi nc 15 to 120 mg/da y po unti l s ymptoms a nd s i gns res ol ve.
Acrodermatitis enteropathica (a ra re, once fa ta l a utos oma l reces s i ve di s order) ca us es ma l a bs orpti on of zi nc. Ps ori a s i form derma ti ti s devel ops
a round the eyes , nos e, a nd mouth; on the buttocks ; a nd i n a n a cra l di s tri buti on. The di s order a l s o ca us es ha i r l os s , pa ronychi a , i mpa i red
i mmuni ty, recurrent i nfecti on, i mpa i red growth, a nd di a rrhea . Symptoms a nd s i gns us ua l l y devel op a fter i nfa nts a re wea ned from brea s t mi l k. In
s uch ca s es , doctors s us pect the di a gnos i s . If defi ci ency i s di a gnos ed, zi nc s ul fa te 30 to 150 mg/da y po us ua l l y res ul ts i n compl ete remi s s i on.
Toxicity: The recommended upper l i mi t for zi nc i nta ke i s 40 mg/da y. Toxi ci ty i s ra re. Inges ti ng dos es of el ementa l zi nc ra ngi ng from 100 to 150
mg/da y for prol onged peri ods i nterferes wi th copper meta bol i s m a nd ca us es l ow bl ood copper l evel s , RBC mi crocytos i s , neutropeni a , a nd
i mpa i red i mmuni ty; hi gher dos es s houl d be gi ven onl y for s hort peri ods of ti me a nd the pa ti ent s houl d be fol l owed cl os el y. Inges ti ng l a rger
a mounts (200 to 800 mg/da y), us ua l l y by cons umi ng a ci di c food or dri nk from a ga l va ni zed (zi nc-coa ted) conta i ner, ca n ca us e a norexi a , vomi ti ng,
a nd di a rrhea . Meta l fume fever, a l s o ca l l ed bra s s -founders ' a gue or zi nc s ha kes , i s ca us ed by i nha l i ng i ndus tri a l zi nc oxi de fumes ; i t res ul ts i n
neurol ogi c da ma ge. Symptoms us ua l l y res ol ve a fter 12 to 24 h i n a zi nc-free envi ronment.
Chapter 6. Obesity and the Metabolic Syndrome

Obesity
Obesity is excess body fat; consequences depend not only on the absolute amount but also on the distribution of the fat. Complications include cardiovascular
disorders, diabetes mellitus, many cancers, cholelithiasis, fatty liver and cirrhosis, osteoarthritis, reproductive disorders in men and women, psychologic disorders,
and premature death. Diagnosis is based on body mass index (BMIcalculated from height and weight) and waist circumference. BP, fasting plasma glucose, and
lipid levels should be measured. Treatment includes physical activity, dietary and behavioral modification, and sometimes drugs or surgery.
Preva l ence of obes i ty i n the US i s hi gh a nd i s i ncrea s i ng, pa rti cul a rl y a mong chi l dren a nd a dol es cents (s ee
Ta bl e 6-1).
Preva l ence i s more tha n twi ce a s hi gh a t a ge 55 a s a t a ge 20. Obes i ty i s twi ce a s common a mong women i n a l ower s oci oeconomi c group a s a mong
thos e i n a hi gher group. Preva l ence a mong bl a ck a nd whi te men does not di ffer s i gni fi ca ntl y, but i t i s hi gher a mong bl a ck women tha n whi te
women. More tha n 50% of bl a ck women 40 yr a re obes e; > 80% a re overwei ght.
In the US, obes i ty a nd i ts compl i ca ti ons ca us e a s ma ny a s 300,000 prema ture dea ths ea ch yea r, ma ki ng i t s econd onl y to ci ga rette s moki ng a s a
preventa bl e ca us e of dea th.
[Table 6-1. Cha nges i n Preva l ence of Obes i ty Accordi ng to Nha nes ]
Etiology
Al mos t a l l ca s es of obes i ty res ul t from a combi na ti on of geneti c predi s pos i ti on a nd a chroni c i mba l a nce between energy i nta ke, energy uti l i za ti on
for ba s i c meta bol i c proces s es , a nd energy expendi ture from phys i ca l a cti vi ty.
Genetic factors: Heri ta bi l i ty of BMI i s a bout 66%. Geneti c fa ctors ma y a ffect the ma ny s i gna l i ng mol ecul es a nd receptors us ed by pa rts of the
hypotha l a mus a nd GI tra ct to regul a te food i nta ke (s ee Si deba r 6-1). Ra rel y, obes i ty res ul ts from a bnorma l l evel s of pepti des tha t regul a te food
i nta ke (eg, l epti n) or a bnorma l i ti es i n thei r receptors (eg, mel a nocorti n-4 receptor).
Geneti c fa ctors a l s o regul a te energy expendi ture, i ncl udi ng BMR, di et-i nduced thermogenes i s , a nd nonvol unta ry a cti vi ty-a s s oci a ted
thermogenes i s . Geneti c fa ctors ma y ha ve a grea ter effect on the di s tri buti on of body fa t, pa rti cul a rl y a bdomi na l fa t (s ee Meta bol i c Syndrome on p.
64), tha n on the a mount of body fa t.
Environmental factors: Wei ght i s ga i ned when ca l ori c i nta ke exceeds energy needs . Importa nt determi na nts of energy i nta ke i ncl ude porti on s i zes
a nd the energy dens i ty of the food. Hi gh-fa t foods , proces s ed foods , a nd di ets hi gh i n refi ned ca rbohydra tes , s oft dri nks , frui t jui ces , a nd a l cohol
promote wei ght ga i n. Di ets hi gh i n fres h frui t a nd vegeta bl es , fi ber, a nd compl ex ca rbohydra tes , wi th wa ter a s the ma i n fl ui d cons umed, mi ni mi ze
wei ght ga i n. A s edenta ry l i fes tyl e promotes wei ght ga i n.
Regulatory factors: Prena ta l ma terna l obes i ty, prena ta l ma terna l s moki ng, i ntra uteri ne growth res tri cti on, a nd i ns uffi ci ent s l eep ca n di s turb wei ght
regul a ti on. About 15% of women perma nentl y ga i n 20 l b wi th ea ch pregna ncy. Obes i ty tha t pers i s ts beyond ea rl y chi l dhood ma kes wei ght l os s i n
l a ter l i fe more di ffi cul t.
Drugs , i ncl udi ng corti cos teroi ds , l i thi um, tra di ti ona l a nti depres s a nts (tri cycl i cs , tetra cycl i cs , a nd monoa mi ne oxi da s e i nhi bi tors [MAOIs ]),
benzodi a zepi nes , a nd a nti ps ychoti c drugs , often ca us e wei ght ga i n.
Uncommonl y, wei ght ga i n i s ca us ed by one of the fol l owi ng di s orders :
Bra i n da ma ge ca us ed by a tumor (es peci a l l y a cra ni opha ryngi oma ) or a n i nfecti on (pa rti cul a rl y thos e a ffecti ng the hypotha l a mus ), whi ch ca n
s ti mul a te cons umpti on of exces s ca l ori es
Hyperi ns ul i ni s m due to pa ncrea ti c tumors
Hypercorti s ol i s m due to Cus hi ng's s yndrome, whi ch ca us es predomi na ntl y a bdomi na l obes i ty
Hypothyroi di s m (ra rel y a ca us e of s ubs ta nti a l wei ght ga i n)
Sidebar 6-1 Pathways Regulating Food Intake

Prea bs orpti ve a nd pos ta bs orpti ve s i gna l s from the GI tra ct a nd cha nges i n pl a s ma nutri ent l evel s provi de s hort-term feedba ck to regul a te food
i nta ke:
GI hormones (eg, gl uca gon-l i ke pepti de 1 [GLP-1], chol ecys toki ni n [CCK]) reduce food i nta ke.
Ghrel i n, s ecreted pri ma ri l y by the s toma ch, i ncrea s es food i nta ke.
Lepti n, s ecreted from a di pos e ti s s ue, i nforms the bra i n a s to how much fa t i s s tored; hi gh l epti n l evel s correl a te wi th i ncrea s ed body fa t.
The hypotha l a mus i ntegra tes va ri ous s i gna l s i nvol ved i n the regul a ti on of energy ba l a nce a nd then a cti va tes pa thwa ys tha t i ncrea s e or decrea s e
food i nta ke:
Neuropepti de Y (NPY), a gouti -rel a ted pepti de (ARP), -mel a nocyte-s ti mul a ti ng hormone (-MSH), coca i ne- a nd a mpheta mi ne-rel a ted
tra ns cri pt (CART), orexi n, a nd mel a ni n-concentra ti ng hormone (MCH) i ncrea s e food i nta ke.
Corti cotropi c hormone (CRH) a nd urocorti n decrea s e i t.
Eating disorders: At l ea s t 2 pa thol ogi c ea ti ng pa tterns ma y be a s s oci a ted wi th obes i ty:

Binge eating disorder i s cons umpti on of l a rge a mounts of food qui ckl y wi th a s ubjecti ve s ens e of l os s of control duri ng the bi nge a nd di s tres s a fter
i t (s ee p. 1537). Thi s di s order does not i ncl ude compens a tory beha vi ors , s uch a s vomi ti ng. Preva l ence i s 1 to 3% a mong both s exes a nd 10 to 20%
a mong peopl e enteri ng wei ght reducti on progra ms . Obes i ty i s us ua l l y s evere, l a rge a mounts of wei ght a re frequentl y ga i ned or l os t, a nd
pronounced ps ychol ogi c di s turba nces a re pres ent.
Night-eating syndrome cons i s ts of morni ng a norexi a , eveni ng hyperpha gi a , a nd i ns omni a . At l ea s t 25 to 50% of da i l y i nta ke occurs a fter the
eveni ng mea l . About 10% of peopl e s eeki ng trea tment for s evere obes i ty ma y ha ve thi s di s order. Ra rel y, a s i mi l a r di s order i s i nduced by us e of
a hypnoti c s uch a s zol pi dem.
Si mi l a r but l es s extreme pa tterns , cl a s s i fi ed a s ea ti ng di s orders not otherwi s e s peci fi ed (EDNOS), proba bl y contri bute to exces s wei ght ga i n i n
more peopl e. For exa mpl e, nocturna l ea ti ng contri butes to exces s wei ght ga i n i n ma ny peopl e who do not ha ve ni ght-ea ti ng s yndrome.
Complications
Compl i ca ti ons of obes i ty i ncl ude the fol l owi ng:
Meta bol i c s yndrome
Di a betes mel l i tus
Ca rdi ova s cul a r di s ea s e
Nona l cohol i c s tea tohepa ti ti s (fa tty l i ver)
Ga l l bl a dder di s ea s e
Ga s troes opha gea l refl ux
Obs tructi ve s l eep a pnea
Reproducti ve s ys tem di s orders
Ma ny ca ncers
Os teoa rthri ti s
Soci a l a nd ps ychol ogi c probl ems
Ins ul i n res i s ta nce, dys l i pi demi a s , a nd hypertens i on (the meta bol i c s yndrome) devel op, often l ea di ng to di a betes mel l i tus a nd corona ry a rtery
di s ea s e (s ee p. 64). Thes e compl i ca ti ons a re more l i kel y i n pa ti ents wi th fa t tha t i s concentra ted a bdomi na l l y, a hi gh s erum tri gl yceri de l evel , a
fa mi l y hi s tory of type 2 di a betes mel l i tus or prema ture ca rdi ova s cul a r di s ea s e, or a combi na ti on of thes e ri s k fa ctors .
Obes i ty i s a l s o a ri s k fa ctor for nona l cohol i c s tea tohepa ti ti s (whi ch ma y l ea d to ci rrhos i s ) a nd for reproducti ve s ys tem di s orders , s uch a s a l ow
s erum tes tos terone l evel i n men a nd pol ycys ti c ova ry s yndrome i n women.
Obs tructi ve s l eep a pnea ca n res ul t i f exces s fa t i n the neck compres s es the a i rwa y duri ng s l eep. Brea thi ng s tops for moments , a s often a s
hundreds of ti mes a ni ght (s ee p. 1903). Thi s di s order, often undi a gnos ed, ca n ca us e l oud s nori ng a nd exces s i ve da yti me s l eepi nes s a nd
i ncrea s es the ri s k of hypertens i on, ca rdi a c a rrhythmi a s , a nd meta bol i c s yndrome.
Obes i ty ma y ca us e the obes i ty-hypoventi l a ti on s yndrome (Pi ckwi cki a n s yndrome). Impa i red brea thi ng l ea ds to hyperca pni a , reduced s ens i ti vi ty to
CO2 i n s ti mul a ti ng res pi ra ti on, hypoxi a , cor pul mona l e, a nd ri s k of prema ture dea th. Thi s s yndrome ma y occur a l one or s econda ry to obs tructi ve
s l eep a pnea .
Os teoa rthri ti s a nd tendon a nd fa s ci a l di s orders ma y res ul t from obes i ty. Ski n di s orders a re common; i ncrea s ed s wea t a nd s ki n s ecreti ons ,
tra pped i n thi ck fol ds of s ki n, a re conduci ve to funga l a nd ba cteri a l growth, ma ki ng i ntertri gi nous i nfecti ons es peci a l l y common. Bei ng overwei ght
proba bl y predi s pos es to chol el i thi a s i s , gout, deep venous thrombos i s a nd pul mona ry embol i s m, a nd ma ny ca ncers (es peci a l l y col on a nd brea s t
ca ncers ).
Obes i ty l ea ds to s oci a l , economi c, a nd ps ychol ogi c probl ems a s a res ul t of prejudi ce, di s cri mi na ti on, poor body i ma ge, a nd l ow s el f-es teem. For
exa mpl e, peopl e ma y be underempl oyed or unempl oyed.
Diagnosis
BMI
Wa i s t ci rcumference
Someti mes body compos i ti on a na l ys i s
In a dul ts , BMI, defi ned a s wei ght (kg) di vi ded by the s qua re of the hei ght (m 2 ), i s us ed to s creen for overwei ght or obes i ty. BMI of 25 to 29.9 kg/m 2
i ndi ca tes overwei ght; BMI 30 kg/m 2 i ndi ca tes obes i ty (s ee
Ta bl e 6-2). However, BMI i s a crude s creeni ng tool a nd ha s l i mi ta ti ons i n ma ny s ubpopul a ti ons . BMI i s a ge- a nd ra ce-s peci fi c; i ts us e i s l i mi ted i n
chi l dren a nd the el derl y. In chi l dren a nd a dol es cents , overwei ght i s BMI a t the 95th percenti l e ba s ed on a ge- a nd s ex-s peci fi c Centers for
Di s ea s e Control a nd Preventi on (CDC) growth cha rts a t the CDC web s i te.
As i a ns , Ja pa nes e, a nd ma ny a bori gi na l popul a ti ons ha ve a l ower cut-off (23 kg/m 2 ) for overwei ght. In a ddi ti on, BMI ma y be hi gh i n mus cul a r
a thl etes who l a ck exces s body fa t, a nd norma l or l ow i n formerl y overwei ght peopl e who ha ve l os t mus cl e ma s s .
The ri s k of meta bol i c a nd ca rdi ova s cul a r compl i ca ti ons due to obes i ty i s determi ned more a ccura tel y by the fol l owi ng:
Other ri s k fa ctors , pa rti cul a rl y a fa mi l y hi s tory of type 2 di a betes or prema ture ca rdi ova s cul a r di s ea s e
Wa i s t ci rcumference
Serum tri gl yceri des
The wa i s t ci rcumference tha t i ncrea s es ri s k of compl i ca ti ons due to obes i ty va ri es by ethni c group a nd s ex:
Whi te men: > 93 cm (> 36.6 i n), pa rti cul a rl y > 101 cm (> 39.8 i n)
Whi te women: > 79 cm (> 31.1 i n), pa rti cul a rl y > 87 cm (> 34.2 i n)
As i a n Indi a n men: > 78 cm (> 30.7 i n), pa rti cul a rl y > 90 cm (> 35.4 i n)
As i a n Indi a n women: > 72 cm (> 28.3 i n), pa rti cul a rl y > 80 cm (> 31.5 i n)
Body composition analysis: Body compos i ti onthe percenta ge of body fa t a nd mus cl ei s a l s o cons i dered when obes i ty i s di a gnos ed. Al though
proba bl y unneces s a ry i n routi ne cl i ni ca l pra cti ce, body compos i ti on a na l ys i s ca n be hel pful i f cl i ni ci a ns ques ti on whether el eva ted BMI i s due to
mus cl e or exces s i ve fa t.
The percenta ge of body fa t ca n be es ti ma ted by mea s uri ng s ki nfol d thi cknes s (us ua l l y over the tri ceps ) or determi ni ng mi d upper a rm a rea (s ee p.
13).
Bi oel ectri ca l i mpeda nce a na l ys i s (BIA) ca n es ti ma te percenta ge of body fa t s i mpl y a nd noni nva s i vel y. BIA es ti ma tes percenta ge of tota l body
wa ter di rectl y; percenta ge of body fa t i s deri ved i ndi rectl y. BIA i s mos t rel i a bl e i n hea l thy peopl e a nd i n peopl e wi th onl y a few chroni c di s orders
tha t do not cha nge the percenta ge of tota l body wa ter (eg, modera te obes i ty, di a betes mel l i tus ). Whether mea s uri ng BIA pos es ri s ks i n peopl e
wi th i mpl a nted defi bri l l a tors i s uncl ea r.
Underwa ter (hydros ta ti c) wei ghi ng i s the mos t a ccura te method for mea s uri ng percenta ge of body fa t. Cos tl y a nd ti me-cons umi ng, i t i s us ed more
often i n res ea rch tha n i n cl i ni ca l ca re. To be wei ghed a ccura tel y whi l e s ubmerged, peopl e mus t ful l y exha l e beforeha nd.
Ima gi ng procedures , i ncl udi ng CT, MRI, a nd dua l -energy x-ra y a bs orpti ometry (DEXA), ca n a l s o es ti ma te the percenta ge a nd di s tri buti on of body fa t
but a re us ua l l y us ed onl y for res ea rch.
Other testing: Obes e pa ti ents s houl d be s creened for obs tructi ve s l eep a pnea wi th a n i ns trument s uch a s the Epworth Sl eepi nes s Sca l e a nd often
the a pnea -hypopnea i ndex (tota l number of a pnea or hypopnea epi s odes occurri ng per hour of s l eeps ee p. 1904). Thi s di s order i s often
underdi a gnos ed, a nd obes i ty i ncrea s es the ri s k.
Fa s ti ng gl ucos e a nd l i pi d l evel s s houl d be mea s ured routi nel y i n pa ti ents wi th a l a rge wa i s t ci rcumference or a fa mi l y hi s tory of type 2 di a betes
mel l i tus or prema ture ca rdi ova s cul a r di s ea s e.
Prognosis
Untrea ted, obes i ty tends to progres s . The proba bi l i ty a nd s everi ty of compl i ca ti ons a re proporti ona l to the a bs ol ute a mount of fa t, the di s tri buti on
of the fa t, a nd a bs ol ute mus cl e ma s s . After wei ght l os s , mos t peopl e return to thei r pretrea tment wei ght wi thi n 5 yr, a nd
[Table 6-2. Body Ma s s Index (BMI)]
a ccordi ngl y, obes i ty requi res a l i fel ong ma na gement progra m s i mi l a r to tha t for a ny other chroni c di s order.
Treatment
Nutri ti on ma na gement
Phys i ca l a cti vi ty
Beha vi ora l thera py
Drugs (eg, s i butra mi ne, orl i s ta t)
Ba ri a tri c s urgery
Wei ght l os s of even 5 to 10% i mproves overa l l hea l th a nd wel l -bei ng a nd i n pa rti cul a r hel ps reduce ri s k of ca rdi ova s cul a r di s orders a nd type 2
di a betes . Wei ght l os s ca n l ea d to i mprovement i n pa ti ents wi th obs tructi ve s l eep a pnea , but s ometi mes a l ot of wei ght mus t be l os t for the
di s order to res ol ve.
Support from hea l th ca re pra cti ti oners , peers , a nd fa mi l y members a nd va ri ous s tructured progra ms ca n hel p wi th wei ght l os s a nd wei ght
ma i ntena nce.
Nutrition: A norma l ea ti ng pa ttern i s i mporta nt. Peopl e who mi s s brea kfa s t tend to pa s s i vel y cons ume too ma ny ca l ori es l a ter i n the da y. Pa ti ents
s houl d ea t s ma l l mea l s a nd a voi d or ca reful l y choos e s na cks . Low-fa t (pa rti cul a rl y very l ow s a tura ted fa t), hi gh-fi ber di ets wi th modes t ca l ori e
res tri cti on (by 600 kca l /da y) a nd s ubs ti tuti on of s ome protei n for ca rbohydra te s eem to ha ve the bes t l ong-term outcome. Fres h frui ts a nd
vegeta bl es a nd s a l a ds s houl d be s ubs ti tuted for refi ned ca rbohydra tes a nd proces s ed food, a nd wa ter for s oft dri nks or jui ces . Al cohol
cons umpti on s houl d be l i mi ted to modera te l evel s . Foods wi th a l ow gl ycemi c i ndex (s ee
Ta bl e 1-1 on p. 3) a nd ma ri ne fi s h oi l s or monouns a tura ted fa ts deri ved from pl a nts (eg, ol i ve oi l ) reduce the ri s k of ca rdi ova s cul a r di s orders a nd
di a betes . Low-fa t da i ry products a re a l s o pa rt of a hea l thy di et. Pa ti ents need a n a dequa te a mount of vi ta mi n D, prefera bl y obta i ned by exerci s i ng
outdoors i n the s uns hi ne.
Us e of mea l repl a cements ha s proven effi ca cy; us e ca n be ongoi ng or i ntermi ttent. Di ets tha t requi re unus ua l ea ti ng ha bi ts s houl d be a voi ded.
They a re unl i kel y to be ma i nta i ned, a nd wei ght i ncrea s es when pa ti ents res ume previ ous poor ea ti ng ha bi ts . Di ets of < 1200 kca l /da y ca nnot be
s us ta i ned, but s uch di ets a re s ometi mes needed to a chi eve ra pi d s hort-term wei ght l os s (eg, to prepa re for s urgery, to l es s en obs tructi ve s l eep
a pnea ). Di ets of < 800 kca l /da y do not produce grea ter wei ght l os s a nd a re l es s wel l tol era ted.
Physical activity: Exerci s e i ncrea s es energy expendi ture, BMR, a nd di et-i nduced thermogenes i s . Exerci s e a l s o s eems to regul a te a ppeti te to more
cl os el y ma tch ca l ori c needs . Other benefi ts i ncl ude
Increa s ed i ns ul i n s ens i ti vi ty
Improved l i pi d profi l e
Lower BP
Better a erobi c fi tnes s
Improved ps ychol ogi c wel l -bei ng
Strengtheni ng (res i s ta nce) exerci s es i ncrea s e mus cl e ma s s . Beca us e mus cl e ti s s ue burns more ca l ori es a t res t tha n does fa t ti s s ue, i ncrea s i ng
mus cl e ma s s produces l a s ti ng i ncrea s es i n BMR. Exerci s e tha t i s i nteres ti ng a nd enjoya bl e i s more l i kel y to be s us ta i ned. A combi na ti on of
a erobi c a nd res i s ta nce exerci s e i s better tha n ei ther a l one.
Behavioral therapy: Beha vi ora l thera py a i ms to i mprove ea ti ng ha bi ts a nd phys i ca l a cti vi ty l evel . Ri gi d di eti ng i s di s coura ged i n fa vor of hea l thy
ea ti ng. Common-s ens e mea s ures i ncl ude the fol l owi ng:
Avoi di ng hi gh-ca l ori e s na cks
Choos i ng hea l thful foods when di ni ng out
Ea ti ng s l owl y
Subs ti tuti ng a phys i ca l l y a cti ve hobby for a pa s s i ve one
Soci a l s upport, cogni ti ve thera py, a nd s tres s ma na gement ma y hel p, pa rti cul a rl y duri ng the l a ps es us ua l l y experi enced duri ng a ny l ong-term
wei ght l os s progra m. Sel f-moni tori ng i s us eful , a nd ma i ntena nce of a di et di a ry i s pa rti cul a rl y effecti ve.
Drugs: Drugs ma y be us ed i f BMI i s > 30 or i f BMI i s > 27 a nd pa ti ents ha ve compl i ca ti ons (eg, hypertens i on, i ns ul i n res i s ta nce). Mos t wei ght l os s
due to drug trea tment i s modes t (5 to 10%) a t bes t a nd occurs duri ng the fi rs t 6 mo; not a l l pa ti ents benefi t. Drugs a re more us eful for ma i nta i ni ng
wei ght l os s but mus t be conti nued i ndefi ni tel y for wei ght l os s to be ma i nta i ned. Premenopa us a l women ta ki ng s ys temi ca l l y a cti ng drugs for
wei ght control s houl d us e contra cepti on.
Si butra mi ne i s a centra l l y a cti ng a ppeti te s uppres s a nt tha t produces dos e-rel a ted wei ght l os s . The us ua l s ta rti ng dos e i s 10 mg po once/da y; the
dos e ca n be decrea s ed to 5 mg or i ncrea s ed to 15 mg. Common a dvers e effects a re hea da che, dry mouth, i ns omni a , a nd cons ti pa ti on; the mos t
common s eri ous one i s hypertens i on. Ca rdi ova s cul a r di s orders , pa rti cul a rl y poorl y control l ed hypertens i on, a re contra i ndi ca ti ons .
Orl i s ta t i nhi bi ts i ntes ti na l l i pa s e, decrea s i ng fa t a bs orpti on a nd i mprovi ng s erum gl ucos e a nd l i pi ds . Beca us e orl i s ta t i s not a bs orbed, s ys temi c
effects a re ra re. Fl a tus , oi l y s tool s , a nd di a rrhea a re common but tend to res ol ve duri ng the 2nd yr of trea tment. A dos e of 120 mg po ti d s houl d be
ta ken wi th mea l s tha t i ncl ude fa t. A vi ta mi n s uppl ement s houl d be ta ken a t l ea s t 2 h before or a fter ta ki ng orl i s ta t. Ma l a bs orpti on a nd
chol es ta s i s a re contra i ndi ca ti ons ; i rri ta bl e bowel s yndrome a nd other GI di s orders ma y ma ke orl i s ta t di ffi cul t to tol era te. Orl i s ta t i s a va i l a bl e
OTC.
Other OTC wei ght-l os s drugs a re not recommended. Some (eg, ca ffei ne, ephedri ne, gua ra na , phenyl propa nol a mi ne) ma y be ma rgi na l l y effecti ve,
but thei r a dvers e effects outwei gh thei r a dva nta ges . Others (eg, bri ndl eberry, L-ca rni ti ne, chi tos a n, pecti n, gra pes eed extra ct, hors e ches tnut,
chromi um pi col i na te, fucus ves i cul os us , gi nkgo bi l oba ) ha ve not been s hown to be effecti ve a nd ma y ha ve a dvers e effects .
Surgery: Surgery i s the mos t effecti ve trea tment for extremel y obes e pa ti ents (s ee p. 61).
Special Populations
Obes i ty i s a pa rti cul a r concern i n chi l dren a nd the el derl y.

Children: Chi l dhood obes i ty i s even more worri s ome tha n a dul t obes i ty. For obes e chi l dren, compl i ca ti ons a re more l i kel y beca us e chi l dren a re
obes e l onger. About 20 to 25% of chi l dren a nd a dol es cents a re overwei ght or obes e. Ri s k fa ctors for obes i ty i n i nfa nts a re l ow bi rth wei ght a nd
ma terna l obes i ty, di a betes , a nd s moki ng. After puberty, food i nta ke i ncrea s es ; i n boys , the extra ca l ori es a re us ed to i ncrea s e protei n depos i ti on,
but i n gi rl s , fa t s tora ge i s i ncrea s ed.
For obes e chi l dren, ps ychol ogi c compl i ca ti ons (eg, poor s el f-es teem, s oci a l di ffi cul ti es , depres s i on) a nd mus cul os kel eta l compl i ca ti ons ca n
devel op ea rl y. Some mus cul os kel eta l compl i ca ti ons , s uch a s s l i pped ca pi ta l femora l epi phys es , occur onl y i n chi l dren. Other ea rl y compl i ca ti ons
ma y i ncl ude obs tructi ve s l eep a pnea , i ns ul i n res i s ta nce, hyperl i pi demi a , a nd nona l cohol i c s tea tohepa ti ti s . Ri s k of ca rdi ova s cul a r, res pi ra tory,
meta bol i c, hepa ti c, a nd other obes i ty-rel a ted compl i ca ti ons i ncrea s es when thes e chi l dren become a dul ts .
Ri s k of obes i ty pers i s ti ng i nto a dul thood depends pa rtl y on when obes i ty fi rs t devel ops :
Duri ng i nfa ncy: Low ri s k
Between 6 mo a nd 5 yr: 25%
After 6 yr: > 50%
Duri ng a dol es cence i f a pa rent i s obes e: > 80%
In chi l dren, preventi ng further wei ght ga i n, ra ther tha n l os i ng wei ght, i s a rea s ona bl e goa l . Di et s houl d be modi fi ed, a nd phys i ca l a cti vi ty
i ncrea s ed. Increa s i ng genera l a cti vi ti es a nd pl a y i s more l i kel y to be effecti ve tha n a s tructured exerci s e progra m. Pa rti ci pa ti ng i n phys i ca l
a cti vi ti es duri ng chi l dhood ma y promote a l i fel ong phys i ca l l y a cti ve l i fes tyl e. Drugs a nd s urgery a re a voi ded but, i f compl i ca ti ons of obes i ty a re
l i fe threa teni ng, ma y be wa rra nted.
Mea s ures tha t control wei ght a nd prevent obes i ty i n chi l dren ma y benefi t publ i c hea l th the mos t. Such mea s ures s houl d be i mpl emented i n the
fa mi l y, s chool s , a nd pri ma ry ca re progra ms .
The elderly: In the US, the percenta ge of obes e el derl y peopl e ha s been i ncrea s i ng.
Wi th a gi ng, body fa t i ncrea s es a nd i s redi s tri buted to the a bdomen, a nd mus cl e ma s s i s l os t, l a rgel y beca us e of phys i ca l i na cti vi ty, but decrea s ed
a ndrogens a nd growth hormone (whi ch a re a na bol i c) a nd i nfl a mma tory cytoki nes produced i n obes i ty ma y a l s o pl a y a rol e.
Ri s k of compl i ca ti ons depends on
Body fa t di s tri buti on (i ncrea s i ng wi th a predomi na ntl y a bdomi na l di s tri buti on)
Dura ti on a nd s everi ty of obes i ty
As s oci a ted s a rcopeni a
Increa s ed wa i s t ci rcumference, s ugges ti ng a bdomi na l fa t di s tri buti on, predi cts morbi di ty (eg, hypertens i on, di a betes mel l i tus , corona ry a rtery
di s ea s e) a nd morta l i ty ri s k better i n the el derl y tha n does BMI.
For the el derl y, i ncrea s ed phys i ca l a cti vi ty i s us ua l l y prefera bl e to di eta ry res tri cti on unl es s res tri cted mobi l i ty prohi bi ts a cti vi ty; i n s uch ca s es ,
ca l ori c res tri cti on ma y be needed to reduce wei ght enough to res tore mobi l i ty. Phys i ca l a cti vi ty a l s o i mproves mus cl e s trength, endura nce, a nd
overa l l wel l -bei ng. Acti vi ty s houl d i ncl ude s trengtheni ng a nd endura nce exerci s es .
Rega rdl es s of whether ca l ori c res tri cti on i s cons i dered neces s a ry, nutri ti on s houl d be opti mi zed.
Wei ght-l os s drugs s uch a s s i butra mi ne or fl uoxeti ne a re not recommended for the el derl y beca us e the pos s i bl e benefi ts do not outwei gh the
a dvers e effects . However, orl i s ta t ma y be us eful for obes e el derl y pa ti ents , pa rti cul a rl y thos e wi th di a betes mel l i tus or hypertens i on. Surgery i s
us ua l l y bes t a voi ded, a l though i t ha s proven effi ca cy a nd benefi ts outwei gh ri s ks i n ca reful l y s el ected pa ti ents .
Prevention
Regul a r phys i ca l a cti vi ty a nd hea l thy ea ti ng i mprove genera l fi tnes s , ca n control wei ght, a nd hel p prevent obes i ty a nd di a betes mel l i tus . Even
wi thout wei ght l os s , exerci s e decrea s es the ri s k of ca rdi ova s cul a r di s orders . Di eta ry fi ber decrea s es the ri s k of col on ca ncer a nd ca rdi ova s cul a r
di s orders . Suffi ci ent a nd good-qua l i ty s l eep, ma na gement of s tres s , a nd modera ti on of a l cohol i nta ke a re a l s o i mporta nt.
Bariatric Surgery
Bariatric surgery is the surgical alteration of the stomach, intestine, or both to cause weight loss.
In the US, ba ri a tri c s urgery i s done over 200,000 ti mes a nnua l l y, a ccounti ng for a l mos t two thi rds of a l l ba ri a tri c opera ti ons done worl dwi de.
Devel opment of s a fer l a pa ros copi c a pproa ches ha s ma de thi s s urgery more popul a r.
Indications
To qua l i fy for ba ri a tri c s urgery, pa ti ents s houl d
Ha ve a ccepta bl e opera ti ve ri s k
Be wel l -i nformed a nd moti va ted
Ha ve uns ucces s ful l y tri ed a l l rea s ona bl e nons urgi ca l methods to l os e wei ght a nd ma na ge obes i ty-a s s oci a ted compl i ca ti ons
Ha ve a BMI of > 40 kg/m 2 or a BMI > 35 kg/m 2 pl us a s eri ous compl i ca ti on (eg, di a betes , hypertens i on, obs tructi ve s l eep a pnea , hi gh-ri s k l i pi d
profi l e) tha t coul d be expected to be mea ni ngful l y reduced wi th a wei ght l os s of 5 to 10%
Contra i ndi ca ti ons i ncl ude uncontrol l ed ma jor depres s i on or ps ychos i s , bi nge ea ti ng di s orders , current drug or a l cohol a bus e, s evere coa gul opa thy,
a nd i na bi l i ty to compl y wi th nutri ti ona l requi rements , i ncl udi ng l i fel ong vi ta mi n repl a cement (when i ndi ca ted). Whether ba ri a tri c s urgery i s
a ppropri a te for pa ti ents < 18 or > 65 yr i s controvers i a l .
Procedures
Res tri cti ve procedures (a djus ta bl e ga s tri c ba ndi ng, verti ca l ba nded ga s tropl a s ty)
Ma l a bs orpti ve procedures (Roux-en-Y ga s tri c bypa s s )
Mos t procedures ca n be done l a pa ros copi ca l l y, but the a pproa ch depends on the type of procedure a s wel l a s pa ti ent wei ght. Morbi di ty a nd
morta l i ty tend to be l ower wi th l a pa ros copi c tha n wi th open s urgery. However, i f pa ti ents wei gh 180 kg, open s urgery i s more l i kel y to be
s ucces s ful . In a bout 8% of ca s es overa l l (fewer wi th experi enced s urgeons ), s urgery begun l a pa ros copi ca l l y mus t be fi ni s hed a s open s urgery.
Procedures ca n be res tri cti ve, ma l a bs orpti ve, or both.
Restrictive procedures: Res tri cti ve procedures l i mi t the vol ume of the s toma ch a va i l a bl e for i nges ted food. Thi s l i mi ted vol ume hel ps res tri ct food
i nta ke, proba bl y beca us e of ea rl i er s a ti ety. The effects ca n be pa rti a l l y defea ted by pa ti ents who cons ume more hi gh-ca l ori e l i qui d foods (eg,
mi l k s ha kes , a l cohol ), whi ch pa s s through the res tri cted porti on qui cker.
Purel y res tri cti ve procedures i ncl ude a djus ta bl e ga s tri c ba ndi ng a nd verti ca l ba nded ga s tropl a s ty.
[
Fig. 6-1. Adjus ta bl e ga s tri c ba ndi ng.]
Adjus ta bl e ga s tri c ba ndi ng a ccounts for a bout 15% of ba ri a tri c procedures done i n the US; i t i s much more common i n Europe a nd i s growi ng i n
popul a ri ty i n the US. It i s the 2nd mos t common ba ri a tri c procedure. A ba nd i s pl a ced a round the upper pa rt of the s toma ch to di vi de the s toma ch
i nto a s ma l l upper pouch a nd a l a rger l ower pouch. Sa l i ne ca n be i njected i nto the ba nd vi a a s ubcuta neous a cces s port. When s a l i ne i s i njected,
the ba nd expa nds , decrea s i ng the s i ze of the pa s s a gewa y through the s toma ch. As a res ul t, the upper pouch fi l l s more qui ckl y, s endi ng a mes s a ge
to the bra i n tha t the s toma ch i s ful l ; pa ti ents ea t s ma l l er mea l s a nd l os e s ubs ta nti a l a mounts of wei ght over ti me. Thi s procedure i s us ua l l y done
l a pa ros copi ca l l y. Sa l i ne ca n be removed to ma ke the pa s s a gewa y l a rger. Even though wei ght l os s from ga s tri c ba ndi ng i s s l i ghtl y l es s tha n tha t
from Roux-en-Y, morbi di ty a nd morta l i ty a re much l es s a nd ga s tri c ba ndi ng ca n be revers ed i f neces s a ry.
Vertical banded gastroplasty i s no l onger commonl y done. A s ta pl er i s us ed to di vi de the s toma ch i nto a s ma l l upper pouch a nd a l a rger l ower pouch.
A nonexpa nda bl e pl a s ti c ba nd i s pl a ced a round the openi ng where the upper pouch empti es i nto the l ower pouch.
Malabsorptive procedures: Ma l a bs orpti ve procedures , s uch a s bi l i opa ncrea ti c di vers i on wi th a duodena l s wi tch a nd Roux-en-Y ga s tri c bypa s s , res ul t
i n i nges ted food bypa s s i ng pa rts of the s toma ch a nd s ma l l i ntes ti ne, crea ti ng ma l a bs orpti on, whi ch l ea ds to wei ght l os s . Thes e procedures a re
a l s o res tri cti ve.
Roux-en-Y gastric bypass surgery a ccounts for a bout 80% of ba ri a tri c procedures i n the US. It ca n often be done l a pa ros copi ca l l y. A s ma l l pa rt of the
proxi ma l s toma ch i s deta ched from the res t, crea ti ng a s toma ch pouch of < 30 mL. Beca us e s toma ch vol ume i s s ma l l er, s a ti ety occurs ea rl i er. Al s o,
food bypa s s es pa rt of the s toma ch a nd s ma l l i ntes ti ne, where i t i s norma l l y a bs orbed, reduci ng the a mount of food a nd ca l ori es a bs orbed. The
pouch i s connected to the proxi ma l jejunum wi th a na rrow openi ng, produci ng even more res tri cti on. The s egment of bypa s s ed proxi ma l s ma l l
i ntes ti ne (a nd thus the bypa s s ed s toma ch) i s a tta ched to the di s ta l s ma l l i ntes ti ne, ena bl i ng bi l e a ci ds a nd pa ncrea ti c enzymes to mi x wi th GI
contents ; thi s mi xi ng l i mi ts ma l a bs orpti on a nd nutri ti ona l defi ci enci es . Beca us e a ga s trojejunos tomy i s crea ted, s ymptoms s i mi l a r to the
dumpi ng-s yndrome ma y occur a fter hi gh gl ycemi c l oa ds ; s ymptoms (l i ght-hea dednes s , di a phores i s , na us ea , a bdomi na l pa i n, di a rrhea ) ma y i nhi bi t
the cons umpti on of s uch foods by a dvers e condi ti oni ng.
Biliopancreatic diversion with a duodenal switch a ccounts for < 5% of ba ri a tri c procedures done i n the US. Pa rt of the s toma ch i s removed, ca us i ng
res tri cti on. The rema i ni ng pa rt empti es i nto the duodenum. The duodenum i s cut
[
Fig. 6-2. Roux-en-Y ga s tri c bypa s s s urgery.]
a nd a tta ched to the i l eum, bypa s s i ng much of the s ma l l i ntes ti ne, i ncl udi ng the s phi ncter of Oddi (where bi l e a ci ds a nd pa ncrea ti c enzymes
enter); ma l a bs orpti on res ul ts . Thi s procedure i s techni ca l l y dema ndi ng but ca n s ometi mes be done l a pa ros copi ca l l y. Ma l a bs orpti on a nd
nutri ti ona l defi ci enci es often devel op.
Preoperative Evaluation
Eva l ua ti on s houl d determi ne whether pa ti ents ha ve a ps ychol ogi c commi tment to the l i fes tyl e cha nges a nd whether opera ti ve ri s ks a re
a ccepta bl e. Sl eep a pnea tes ti ng i s done.
Extens i ve preopera ti ve eva l ua ti on i s proba bl y unneces s a ry. However, for certa i n morbi dl y obes e pa ti ents (BMI > 50 kg/m 2 ), exa mi ni ng the ca rdi a c,
pul mona ry, GI, meta bol i c, a nd ps ychol ogi c s ys tems hel ps i denti fy pa ti ents wi th a ccepta bl e opera ti ve ri s k a nd hel ps s el ect the a ppropri a te
procedure. For thes e pa ti ents , routi ne preopera ti ve tes ts ma y i ncl ude
Liver function tests: Increa s ed l i ver enzymes , es peci a l l y ALT, a re common but do not contra i ndi ca te s urgery.
Kidney function tests: If rena l bl ood fl ow a nd gl omerul a r fi l tra ti on ra te a re i ncrea s ed, protei nuri a i s more l i kel y a nd rena l cl ea ra nce of drugs ma y
be i ncrea s ed. Thus , drug dos a ges ma y need to be a djus ted.
ECG and echocardiography: Thes e tes ts a re needed beca us e i denti fyi ng hea rt fa i l ure a nd pul mona ry hypertens i on cl i ni ca l l y i n morbi dl y obes e
pa ti ents i s di ffi cul t. Si gns of hea rt fa i l ure (eg, i ncrea s ed jugul a r venous pres s ure, hepa tomega l y, pul mona ry cra ckl es ) a re ha rd to i denti fy when
body fa t i s exces s i ve. Pul mona ry hypertens i on i s a l s o di ffi cul t to i denti fy beca us e ma ny pa ti ents ca nnot exerci s e to the poi nt where exerti ona l
dys pnea , fa ti gue, or s yncope woul d res ul t. Pul mona ry hypertens i on i s di a gnos ed i f echoca rdi ogra phy s hows tri cus pi d regurgi ta ti on a nd ECG
s hows ta l l R wa ves , ri ght a xi s devi a ti on, a nd ri ght ventri cul a r s tra i n.
Sleep study: Pol ys omnogra phy (s ee p.
1706) ca n confi rm obs tructi ve s l eep a pnea , whi ch i s common, a nd determi ne i ts s everi ty. An a pnea -hypopnea i ndex of > 30 s i gna l s hi gh ri s k of
morbi di ty a nd prema ture dea th. Obs tructi ve s l eep a pnea does not contra i ndi ca te s urgery but i s done to hel p pl a n for us e of conti nuous
pos i ti ve a i rwa y pres s ure (CPAP) pos topera ti vel y.
Risks
The mos t common peri opera ti ve compl i ca ti on i s wound i nfecti on (i n a bout 3%); the mos t common l a te compl i ca ti on i s a na s tomoti c s toma ch
s tenos i s (i n a bout 5%).
Other ea rl y compl i ca ti ons i ncl ude wound i nfecti on, i nci s i ona l herni a , s ma l l -bowel obs tructi on, GI bl eedi ng, ventra l herni a , deep venous
thrombos i s , a nd pneumoni a . Thes e compl i ca ti ons ca n ca us e s i gni fi ca nt morbi di ty, prol ong hos pi ta l i za ti on, a nd i ncrea s e cos ts .
The mos t common ca us e of ea rl y (wi thi n a bout 6 wk) pos topera ti ve dea th (i n up to 0.5%) i s pul mona ry embol i s m, fol l owed by a na s tomoti c l ea k.
Ta chyca rdi a ma y be the onl y ea rl y s i gn of a na s tomoti c l ea k. Les s common ca us es of ea rl y pos topera ti ve dea th a re MI, pneumoni a , a nd bowel
obs tructi on.
La ter probl ems ma y i ncl ude prol onged na us ea a nd vomi ti ng s econda ry to s ma l l -bowel obs tructi on, a nd a na s tomoti c s tenos i s . Nutri ti ona l
defi ci enci es (eg, protei n-energy undernutri ti on, vi ta mi n B 12 defi ci ency) ma y res ul t from i na dequa te i nta ke, i na dequa te s uppl ementa ti on, or
ma l a bs orpti on. Ma l odorous fl a tul ence, di a rrhea , or both ma y devel op, pa rti cul a rl y a fter ma l a bs orpti ve procedures . Ca a nd vi ta mi n D a bs orpti on
ma y be i mpa i red, ca us i ng defi ci enci es a nd s ometi mes hypoca l cemi a a nd s econda ry hyperpa ra thyroi di s m. Wi th prol onged vomi ti ng, thi a mi n
defi ci ency ma y occur. After Roux-en-Y ga s tri c bypa s s , i ron defi ci ency ma y res ul t. Pa ti ents ma y ha ve s ymptoms of refl ux, es peci a l l y a fter
bi l i opa ncrea ti c di vers i on wi th a duodena l s wi tch. After ra pi d wei ght l os s , chol el i thi a s i s ma y devel op.
Ea ti ng ha bi ts ma y be di s ordered. Adjus ti ng to new ea ti ng ha bi ts ca n be di ffi cul t.
Prognosis
Overa l l , 30-da y pos topera ti ve ri s k of dea th i s 0.2 to 1%. Ri s k i s hi gher i n el derl y pa ti ents a nd i n pa ti ents who ha ve ha d a n open procedure, who a re
extremel y morbi dl y obes e (> 50 kg), or who ha ve es ta bl i s hed orga n fa i l ure. Ri s k of dea th ma y be l owes t wi th l a pa ros copi c a djus ta bl e ga s tri c
ba ndi ng. Ri s k of dea th i s a l mos t 3 ti mes hi gher i n hos pi ta l s tha t do < 50 of thes e procedures /yr tha n i n thos e tha t do >150 procedures /yr. The
Ameri ca n Soci ety of Ba ri a tri c Surgery ma y des i gna te hos pi ta l s wi th better res ul ts a s a Center of Excel l ence, ba s ed on res ources a nd excel l ent
s hort- a nd l ong-term outcomes .
In mos t pa ti ents , comorbi di ti es (eg, i ns ul i n i ns ens i ti vi ty, dys l i pi demi a s , hypertens i on, obs tructi ve s l eep a pnea , pol ycys ti c ova ry s yndrome,
nona l cohol i c s tea tohepa ti ti s ) tend to res ol ve.
Avera ge l os s of exces s wei ght (rea l wei ght mi nus i dea l wei ght) i s a bout 60%, or a bout 40 to 60 kg i n mos t pa ti ents . Dependi ng on the procedure,
exces s wei ght l os s ca n va ry between 50% a nd 70%; l os s tends to be l ower wi th ga s tri c ba ndi ng a nd s omewha t hi gher wi th Roux-en-Y ga s tri c
bypa s s . In ma ny pa ti ents , wei ght l os s , a l though i ni ti a l l y ra pi d, pl a tea us a fter a bout 2 yr; then pa ti ents ma y s l owl y rega i n wei ght.
Mood a nd work a nd pers ona l rel a ti ons hi ps us ua l l y i mprove.
Long-term fol l ow-up da ta a re not yet a va i l a bl e beca us e thes e procedures a re rel a ti vel y new.
Follow-up
Pa ti ents s houl d be moni tored every 4 to 6 wk whi l e wei ght l os s i s ra pi d (us ua l l y a bout the fi rs t 6 mo a fter s urgery), then every 6 to 12 mo. Wei ght
a nd BP a re checked, a nd ea ti ng ha bi ts a re revi ewed. Bl ood tes ts (us ua l l y CBC, el ectrol ytes , gl ucos e, BUN, crea ti ni ne, a l bumi n, a nd protei n) a nd
l i ver functi on tes ts a re done a t ea ch vi s i t. If a l ka l i ne phos pha ta s e i s i ncrea s ed, pa ra thyroi d hormone l evel i s mea s ured; i f pa ra thyroi d hormone
l evel i s a bnorma l , bone dens i ty i s moni tored. If wei ght l os s exceeds a bout 9 kg (20 l b)/mo, vi s i ts s houl d be s chedul ed a t l ea s t monthl y, a nd bl ood
tes ts s houl d i ncl ude Mg, phos phorus , vi ta mi n B 12 , a nd i ron l evel s . Nutri ti ona l s uppl ementa ti on i s s ometi mes neces s a ry.
Metabolic Syndrome
Metabolic syndrome (syndrome X, insulin resistance syndrome) is characterized by a clustering of risk factors for cardiovascular disease and type 2 diabetes
mellitus. They commonly include excess intra-abdominal fat, insulin resistance, and 1 of the following: elevated serum triglyceride levels, decreased highdensity lipoprotein (HDL) cholesterol level, and hypertension. Causes, complications, diagnosis, and treatment are similar to those of obesity.
In devel oped countri es , meta bol i c s yndrome i s a s eri ous probl em. It i s very common; i n the US, > 40% of peopl e > 50 yr ma y ha ve i t. Chi l dren a nd
a dol es cents ca n devel op

[
Table 6-3. Cri teri a Often Us ed for Di a gnos i s of Meta bol i c Syndrome*]
meta bol i c s yndrome, but i n thes e a ge groups , no defi ni ti on i s es ta bl i s hed.
Devel opment of meta bol i c s yndrome depends on di s tri buti on a s wel l a s a mount of fa t. Exces s fa t i n the a bdomen (ca l l ed a ppl e s ha pe),
pa rti cul a rl y when i t res ul ts i n a hi gh wa i s t-to-hi p ra ti o (refl ecti ng a rel a ti vel y l ow mus cl e-to-fa t ma s s ra ti o), i ncrea s es ri s k. The s yndrome i s l es s
common a mong peopl e who ha ve exces s s ubcuta neous fa t a round the hi ps (ca l l ed pea r s ha pe) a nd a l ow wa i s t-to-hi p ra ti o (refl ecti ng a hi gher
mus cl e-to-fa t ma s s ra ti o).
Exces s a bdomi na l fa t l ea ds to exces s free fa tty a ci ds i n the porta l vei n, i ncrea s i ng fa t a ccumul a ti on i n the l i ver. Fa t a l s o a ccumul a tes i n mus cl e
cel l s . Ins ul i n res i s ta nce devel ops , wi th hyperi ns ul i nemi a . Gl ucos e meta bol i s m i s i mpa i red, a nd dys l i pi demi a s a nd hypertens i on devel op. Serum
uri c a ci d l evel s a re typi ca l l y el eva ted, a nd a prothromboti c s ta te (wi th i ncrea s ed l evel s of fi bri nogen a nd pl a s mi nogen a cti va tor i nhi bi tor I) a nd a n
i nfl a mma tory s ta te devel op. Pa ti ents ha ve a n i ncrea s ed ri s k of obs tructi ve s l eep a pnea . Other ri s ks i ncl ude nona l cohol i c s tea tohepa ti ti s , chroni c
ki dney di s ea s e, pol ycys ti c ova ry s yndrome (for women), a nd l ow s erum tes tos terone, erecti l e dys functi on, or both (for men).
Diagnosis
Wa i s t ci rcumference a nd BP
Fa s ti ng pl a s ma gl ucos e a nd a l i pi d profi l e
Screeni ng i s i mporta nt. A fa mi l y hi s tory pl us mea s urement of wa i s t ci rcumference a nd BP a re pa rt of routi ne ca re. If pa ti ents wi th a fa mi l y hi s tory
of type 2 di a betes mel l i tus , pa rti cul a rl y thos e 40 yr, ha ve a wa i s t ci rcumference grea ter tha n tha t recommended for ra ce a nd s ex, fa s ti ng pl a s ma
gl ucos e a nd a l i pi d profi l e mus t be determi ned.
Meta bol i c s yndrome ha s ma ny di fferent defi ni ti ons , but i t i s mos t often di a gnos ed when 3 of the fol l owi ng a re pres ent: exces s a bdomi na l fa t, a
hi gh fa s ti ng pl a s ma gl ucos e l evel , hypertens i on, a hi gh tri gl yceri de l evel , a nd a l ow HDL chol es terol l evel (s ee Ta bl e 6-3).
Treatment
Hea l thy di et a nd exerci s e
Someti mes metformi n
Ma na gement of ca rdi ova s cul a r ri s k fa ctors
Opti ma l l y, the ma na gement a pproa ch res ul ts i n wei ght l os s ba s ed on a hea l thy di et a nd regul a r phys i ca l a cti vi ty, whi ch i ncl udes a combi na ti on of
a erobi c a cti vi ty a nd res i s ta nce tra i ni ng, rei nforced wi th beha vi ora l thera py. Metformi n, a n i ns ul i n s ens i ti zer, ma y be us eful . Wei ght l os s of 7%
ma y be s uffi ci ent to revers e the s yndrome, but i f not, ea ch fea ture of the s yndrome s houl d be ma na ged to a chi eve recommended ta rgets ;
a va i l a bl e drug trea tment i s very effecti ve.
Other ca rdi ova s cul a r ri s k fa ctors (eg, s moki ng ces s a ti on) a l s o need to be ma na ged. Increa s ed phys i ca l a cti vi ty ha s ca rdi ova s cul a r benefi ts even i f
wei ght i s not l os t.
2 - Gastrointestinal Disorders
Chapter 7. Approach to the Patient With Upper GI Complaints
Introduction
Upper GI compl a i nts i ncl ude ches t pa i n (s ee p. 2025), chroni c a nd recurrent a bdomi na l pa i n, dys peps i a , l ump i n the throa t, ha l i tos i s (s ee p. 506),
hi ccups , na us ea a nd vomi ti ng, a nd rumi na ti on. Some upper GI compl a i nts repres ent functi ona l i l l nes s (i e, no phys i ol ogi c ca us e found a fter
extens i ve eva l ua ti on).
History: Us i ng open-ended, i ntervi ew-s tyl e ques ti ons , the phys i ci a n i denti fi es the l oca ti on a nd qua l i ty of s ymptoms a nd a ny a ggra va ti ng a nd
a l l evi a ti ng fa ctors . Ps ychol ogi c s tres s fa ctors mus t be s peci fi ca l l y s ought. Beca us e a ps ychi a tri c di s order does not precl ude phys i ol ogi c di s ea s e,
the s i gni fi ca nce of va gue, dra ma ti c, or bi za rre compl a i nts s houl d not be mi ni mi zed.
Pa ti ents report s ymptoms di fferentl y dependi ng on thei r pers ona l i ty, the i mpa ct of the i l l nes s on thei r l i fe, a nd s oci ocul tura l i nfl uences . For
exa mpl e, na us ea a nd vomi ti ng ma y be mi ni mi zed or reported i ndi rectl y by a s everel y depres s ed pa ti ent but pres ented wi th dra ma ti c urgency by a
hi s tri oni c one.
Physical examination: Ins pecti on of the a bdomen wi th the pa ti ent s upi ne ma y s how a convex a ppea ra nce when bowel obs tructi on, a s ci tes , or,
ra rel y, a l a rge ma s s i s pres ent. Aus cul ta ti on to a s s es s bowel s ounds a nd determi ne pres ence of brui ts s houl d fol l ow. Percus s i on el i ci ts
hyperres ona nce (tympa ny) i n the pres ence of bowel obs tructi on a nd dul l nes s wi th a s ci tes a nd ca n determi ne the s pa n of the l i ver. Pa l pa ti on
proceeds s ys tema ti ca l l y, begi nni ng gentl y to i denti fy a rea s of tendernes s a nd, i f tol era ted, pa l pa ti ng deeper to l oca te ma s s es or orga nomega l y.
Di gi ta l recta l exa mi na ti on wi th tes ti ng for occul t bl ood a nd (i n women) pel vi c exa mi na ti on compl ete the eva l ua ti on of the a bdomen.
Testing: Pa ti ents wi th a cute, nons peci fi c s ymptoms (eg, dys peps i a , na us ea ) a nd a n unrema rka bl e phys i ca l exa mi na ti on ra rel y requi re tes ti ng.
Fi ndi ngs s ugges ti ng s i gni fi ca nt di s ea s e (a l a rm s ymptoms ) s houl d prompt further eva l ua ti on:
Anorexi a
Anemi a
Bl ood i n s tool (gros s or occul t)
Dys pha gi a
Fever
Hepa tomega l y
Pa i n tha t a wa kens pa ti ent
Pers i s tent na us ea a nd vomi ti ng
Wei ght l os s
Chroni c or recurrent s ymptoms , even wi th a n unrema rka bl e exa mi na ti on, a l s o wa rra nt eva l ua ti on. Speci fi c GI tes ts a re di s cus s ed i n Ch. 9.
Chronic and Recurrent Abdominal Pain
Chroni c a bdomi na l pa i n (CAP) pers i s ts for more tha n 3 mo ei ther conti nuous l y or i ntermi ttentl y. Intermi ttent pa i n ma y be referred to a s recurrent
a bdomi na l pa i n (RAP). Acute a bdomi na l pa i n i s di s cus s ed on p. 105. CAP occurs a ny ti me a fter 5 yr of a ge. Up to 10% of chi l dren requi re eva l ua ti on
for RAP. About 2% of a dul ts , predomi na ntl y women, ha ve CAP (a much hi gher percenta ge of a dul ts ha ve s ome type of chroni c GI s ymptoms ,
i ncl udi ng nonul cer dys peps i a a nd va ri ous bowel di s turba nces ).
Nea rl y a l l pa ti ents wi th CAP ha ve ha d pri or medi ca l eva l ua ti on tha t di d not yi el d a di a gnos i s a fter hi s tory, phys i ca l , a nd ba s i c tes ti ng.
Pathophysiology
Functi ona l a bdomi na l pa i n s yndrome (FAPS) i s pa i n tha t pers i s ts > 6 mo wi thout evi dence of phys i ol ogi c di s ea s e, s hows no rel a ti ons hi p to
phys i ol ogi c events (eg, mea l s , defeca ti on, mens es ), a nd i nterferes wi th da i l y functi oni ng. FAPS i s poorl y unders tood but s eems to i nvol ve a l tered
noci cepti on. Sens ory neurons i n the dors a l horn of the s pi na l cord ma y become a bnorma l l y exci ta bl e a nd hypera l ges i c due to a combi na ti on of
fa ctors . Cogni ti ve a nd ps ychol ogi c fa ctors (eg, depres s i on, s tres s , cul ture, s econda ry ga i n, copi ng a nd s upport mecha ni s ms ) ma y ca us e efferent
s ti mul a ti on tha t a mpl i fi es pa i n s i gna l s , res ul ti ng i n percepti on of pa i n wi th l ow l evel i nputs a nd pers i s tence of pa i n l ong a fter the s ti mul us ha s
cea s ed. Addi ti ona l l y, the pa i n i ts el f ma y functi on a s a s tres s or, perpetua ti ng a pos i ti ve feedba ck l oop.
In a ddi ti on, menopa us e i ncrea s es GI s ymptoms i n s evera l di s orders i ncl udi ng i rri ta bl e bowel s yndrome, i nfl a mma tory bowel di s ea s e,
endometri os i s , a nd nonul cer dys peps i a .
Etiology
Perha ps 10% of pa ti ents ha ve a n occul t phys i ol ogi c i l l nes s (s ee
Ta bl e 7-1); the rema i nder ha ve a functi ona l proces s . However, determi ni ng whether a pa rti cul a r a bnorma l i ty (eg, a dhes i ons , ova ri a n cys t,
endometri os i s ) i s the ca us e of CAP s ymptoms or a n i nci denta l fi ndi ng ca n be di ffi cul t.
Evaluation
History: History of present illness s houl d el i ci t pa i n l oca ti on, qua l i ty, dura ti on, ti mi ng a nd frequency of recurrence, a nd fa ctors tha t wors en or rel i eve
pa i n (pa rti cul a rl y ea ti ng or movi ng bowel s ). A s peci fi c i nqui ry a s to whether mi l k a nd mi l k products ca us e a bdomi na l cra mps , bl oa ti ng, or
di s tenti on i s needed, beca us e l a ctos e i ntol era nce i s common, es peci a l l y a mong bl a cks .
Review of systems s eeks concomi ta nt GI s ymptoms s uch a s ga s troes opha gea l refl ux, a norexi a , bl oa ti ng or "ga s ," na us ea , vomi ti ng, ja undi ce,
mel ena , hema turi a , hema temes i s , wei ght l os s , a nd mucus or bl ood i n the s tool . Bowel s ymptoms , s uch a s di a rrhea , cons ti pa ti on, a nd cha nges i n
s tool cons i s tency, col or, or el i mi na ti on pa ttern, a re pa rti cul a rl y i mporta nt.
In a dol es cents , a di et hi s tory i s i mporta nt beca us e i nges ti on of l a rge a mounts of col a bevera ges a nd frui t jui ces (whi ch ma y conta i n s i gni fi ca nt
qua nti ti es of fructos e a nd s orbi tol ) ca n a ccount for otherwi s e puzzl i ng a bdomi na l pa i n.
Past medical history s houl d i ncl ude na ture a nd ti mi ng of a ny a bdomi na l s urgery a nd the res ul ts of previ ous tes ts tha t ha ve been done a nd
trea tments tha t ha ve been tri ed. A drug hi s tory s houl d i ncl ude deta i l s concerni ng pres cri pti on a nd i l l i ci t drug us e a s wel l a s a l cohol .
Fa mi l y hi s tory of RAP, fevers , or both s houl d be a s certa i ned, a s wel l a s known di a gnos es of s i ckl e cel l tra i t or di s ea s e, fa mi l i a l Medi terra nea n
fever, a nd porphyri a .
Physical examination: Revi ew of vi ta l s i gns s houl d pa rti cul a rl y note pres ence of fever or ta chyca rdi a .
Genera l exa mi na ti on s houl d s eek pres ence of ja undi ce, s ki n ra s h, a nd peri phera l edema . Abdomi na l exa mi na ti on s houl d note a rea s of
tendernes s , pres ence of peri tonea l fi ndi ngs (eg, gua rdi ng, ri gi di ty, rebound), a nd a ny ma s s es or orga nomega l y. Recta l exa mi na ti on a nd (i n
women) pel vi c exa mi na ti on to l oca te tendernes s , ma s s es , a nd bl ood a re es s enti a l .
Red flags: The fol l owi ng fi ndi ngs a re of pa rti cul a r concern:
Fever
Anorexi a , wei ght l os s
Pa i n tha t a wa kens pa ti ent
Bl ood i n s tool or uri ne
Ja undi ce
Edema
Abdomi na l ma s s or orga nomega l y
Interpretation of findings: Cl i ni ca l exa mi na ti on a l one i nfrequentl y provi des a fi rm di a gnos i s .
Determi ni ng whether CAP i s phys i ol ogi c or functi ona l ca n be di ffi cul t. Al though the pres ence of red fl a g fi ndi ngs i ndi ca tes a hi gh l i kel i hood of a
phys i ol ogi c ca us e, thei r a bs ence does not rul e i t out. Other hi nts a re tha t phys i ol ogi c ca us es us ua l l y ca us e pa i n tha t i s wel l l oca l i zed, es peci a l l y
to a rea s other tha n the peri umbi l i ca l regi on. Pa i n tha t wa kes the pa ti ent i s us ua l l y phys i ol ogi c. Some fi ndi ngs s ugges ti ve of s peci fi c di s orders a re
l i s ted i n Ta bl e 7-1.
Functi ona l CAP ma y res ul t i n pa i n s i mi l a r to tha t of phys i ol ogi c ori gi n. However, there a re no a s s oci a ted red fl a g fi ndi ngs , a nd ps ychos oci a l
fea tures a re often promi nent. A hi s tory of phys i ca l or s exua l a bus e or a n unres ol ved l os s (eg, di vorce, mi s ca rri a ge, or dea th of a fa mi l y member)
ma y be a cl ue.
The Rome cri teri a for di a gnos i s of i rri ta bl e bowel s yndrome a re the pres ence of a bdomi na l pa i n or di s comfort for a t l ea s t 3 da ys /mo i n the l a s t 3
mo a l ong wi th a t l ea s t 2 of the fol l owi ng: (1) i mprovement wi th defeca ti on; (2) ons et (of ea ch epi s ode of di s comfort) a s s oci a ted wi th a cha nge i n
frequency of defeca ti on; a nd (3) cha nge i n cons i s tency of s tool .
Testing: In genera l , s i mpl e tes ts (i ncl udi ng uri na l ys i s , CBC, l i ver tes ts , ESR, a myl a s e, a nd l i pa s e) s houl d be done. Abnorma l i ti es i n thes e tes ts , the
pres ence of red fl a g fi ndi ngs , or s peci fi c cl i ni ca l fi ndi ngs ma nda te further tes ti ng, even i f previ ous a s s es s ments ha ve been nega ti ve. Speci fi c tes ts
depend on the fi ndi ngs (s ee Ta bl e 7-1) but typi ca l l y i ncl ude CT of the a bdomen a nd pel vi s wi th contra s t, upper GI endos copy or col onos copy, a nd
perha ps s ma l l -bowel x-ra ys or s tool tes ti ng.
The benefi ts of tes ti ng pa ti ents wi th no red fl a g fi ndi ngs a re uncl ea r. Thos e > 50 s houl d proba bl y ha ve a col onos copy; thos e 50 ca n be obs erved
or ha ve CT of the a bdomen a nd pel vi s wi th contra s t i f a n i ma gi ng s tudy i s des i red. Ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP), ERCP,
a nd l a pa ros copy a re ra rel y hel pful i n the a bs ence of s peci fi c i ndi ca ti ons .
Between the i ni ti a l eva l ua ti on a nd the fol l ow-up vi s i t, the pa ti ent (or fa mi l y, i f the pa ti ent i s a chi l d) s houl d record a ny pa i n, i ncl udi ng
[Table 7-1. Phys i ol ogi c Ca us es of Chroni c Abdomi na l Pa i n]
i ts na ture, i ntens i ty, dura ti on, a nd preci pi ta ti ng fa ctors . Di et, defeca ti on pa ttern, a nd a ny remedi es tri ed (a nd the res ul ts obta i ned) s houl d a l s o
be recorded. Thi s record ma y revea l i na ppropri a te beha vi or pa tterns a nd exa ggera ted res pons es to pa i n or otherwi s e s ugges t a di a gnos i s .
Treatment
Phys i ol ogi c condi ti ons a re trea ted.
If the di a gnos i s of functi ona l CAP i s ma de, frequent exa mi na ti ons a nd tes ts s houl d be a voi ded beca us e they ma y focus on or ma gni fy the phys i ca l
compl a i nts or i mpl y tha t the phys i ci a n l a cks confi dence i n the di a gnos i s .
There a re no moda l i ti es to cure functi ona l CAP; however, ma ny hel pful mea s ures a re a va i l a bl e. Thes e mea s ures res t on a founda ti on of a trus ti ng,
empa thi c rel a ti ons hi p a mong the phys i ci a n, pa ti ent, a nd fa mi l y. Pa ti ents s houl d be rea s s ured tha t they a re not i n da nger; s peci fi c concerns
s houl d be s ought a nd a ddres s ed. The phys i ci a n s houl d expl a i n the l a bora tory fi ndi ngs a nd the na ture of the probl em a nd des cri be how the pa i n
i s genera ted a nd how the pa ti ent percei ves i t (i e, tha t there i s a cons ti tuti ona l tendency to feel pa i n a t ti mes of s tres s ). It i s i mporta nt to a voi d
perpetua ti ng the nega ti ve ps ychos oci a l cons equences of chroni c pa i n (eg, prol onged a bs ences from s chool or work, wi thdra wa l from s oci a l
a cti vi ti es ) a nd to promote i ndependence, s oci a l pa rti ci pa ti on, a nd s el f-rel i a nce. Thes e s tra tegi es hel p the pa ti ent control or tol era te the
s ymptoms whi l e pa rti ci pa ti ng ful l y i n everyda y a cti vi ti es .
Drugs s uch a s a s pi ri n, NSAIDs , H 2 receptor bl ockers , proton pump i nhi bi tors , a nd tri cycl i c a nti depres s a nts ca n be effecti ve. Opi oi ds s houl d be
a voi ded beca us e they i nva ri a bl y l ea d to dependency.
Cogni ti ve methods (eg, rel a xa ti on tra i ni ng, bi ofeedba ck, hypnos i s ) ma y hel p by contri buti ng to the pa ti ent's s ens e of wel l -bei ng a nd control .
Regul a r fol l ow-up vi s i ts s houl d be s chedul ed weekl y, monthl y, or bi monthl y, dependi ng on the pa ti ent's needs , a nd s houl d conti nue unti l wel l
a fter the probl em ha s res ol ved. Ps ychi a tri c referra l ma y be requi red i f s ymptoms pers i s t, es peci a l l y i f the pa ti ent i s depres s ed or there a re
s i gni fi ca nt ps ychol ogi c di ffi cul ti es i n the fa mi l y.
School pers onnel s houl d become i nvol ved for chi l dren who ha ve CAP. Chi l dren ca n res t bri efl y i n the nurs e's offi ce duri ng the s chool da y, wi th the
expecta ti on tha t they return to cl a s s a fter 15 to 30 mi n. The s chool nurs e ca n be a uthori zed to di s pens e a mi l d a na l ges i c (eg, a ceta mi nophen). The
nurs e ca n s ometi mes a l l ow the chi l d to ca l l a pa rent, who s houl d encoura ge the chi l d to s ta y i n s chool . However, once pa rents s top trea ti ng thei r
chi l d a s s peci a l or i l l , the s ymptoms ma y wors en before they a ba te.
Key Points
Mos t ca s es repres ent a functi ona l proces s .
Red fl a g fi ndi ngs i ndi ca te a phys i ol ogi c ca us e a nd need for further a s s es s ment.
Tes ti ng i s gui ded by cl i ni ca l fea tures .
Repea ted tes ti ng a fter phys i ol ogi c ca us es a re rul ed out i s us ua l l y counterproducti ve.
Dyspepsia
Dys peps i a i s a s ens a ti on of pa i n or di s comfort i n the upper a bdomen; i t often i s recurrent. It ma y be des cri bed a s i ndi ges ti on, ga s s i nes s , ea rl y
s a ti ety, pos tpra ndi a l ful l nes s , gna wi ng, or burni ng.
Etiology
There a re s evera l common ca us es of dys peps i a (s ee
Ta bl e 7-2).
Ma ny pa ti ents ha ve fi ndi ngs on tes ti ng (eg, duodeni ti s , pyl ori c dys functi on, moti l i ty di s turba nce, Helicobacter pylori ga s tri ti s , l a ctos e defi ci ency,
chol el i thi a s i s ) tha t correl a te poorl y wi th s ymptoms (i e, correcti on of the condi ti on does not a l l evi a te dys peps i a ).
Nonulcer (functional) dyspepsia i s defi ned a s dys pepti c s ymptoms i n a pa ti ent who ha s no a bnorma l i ti es on phys i ca l exa mi na ti on a nd upper GI
endos copy.
Evaluation
History: History of present illness s houl d el i ci t a cl ea r des cri pti on of the s ymptoms , i ncl udi ng whether they a re a cute or chroni c a nd recurrent. Other
el ements i ncl ude ti mi ng a nd frequency of recurrence, a ny di ffi cul ty s wa l l owi ng, a nd rel a ti ons hi p of s ymptoms to ea ti ng or ta ki ng drugs . Fa ctors
tha t wors en s ymptoms (pa rti cul a rl y exerti on, certa i n foods or a l cohol ) or rel i eve them (pa rti cul a rl y ea ti ng or ta ki ng a nta ci ds ) a re noted.
Review of systems s eeks concomi ta nt GI s ymptoms s uch a s a norexi a , na us ea , vomi ti ng, hema temes i s , wei ght l os s , a nd bl oody or bl a ck (mel a noti c)
s tool s . Other s ymptoms i ncl ude dys pnea a nd di a phores i s .
Past medical history s houl d i ncl ude known GI a nd ca rdi a c di a gnos es , ca rdi a c ri s k fa ctors (eg, hypertens i on, hyperchol es terol emi a ), a nd the res ul ts
of previ ous tes ts tha t ha ve been done a nd trea tments tha t ha ve been tri ed. Drug hi s tory s houl d i ncl ude pres cri pti on a nd i l l i ci t drug us e a s wel l a s
a l cohol .
Physical examination: Revi ew of vi ta l s i gns s houl d note pres ence of ta chyca rdi a or i rregul a r pul s e.
Genera l exa mi na ti on s houl d note pres ence of pa l l or or di a phores i s , ca chexi a , or ja undi ce. Abdomen i s pa l pa ted for tendernes s , ma s s es , a nd
orga nomega l y. Recta l exa mi na ti on i s done to detect gros s or occul t bl ood.
[Table 7-2. Some Ca us es of Dys peps i a ]
Acute epi s ode wi th dys pnea , di a phores i s , or ta chyca rdi a
Anorexi a
Na us ea or vomi ti ng
Wei ght l os s
Bl ood i n the s tool
Dys pha gi a or odynopha gi a
Fa i l ure to res pond to thera py wi th H 2 bl ockers or proton pump i nhi bi tors (PPIs )
Interpretation of findings: Some fi ndi ngs a re hel pful (s ee Ta bl e 7-2).
A pa ti ent pres enti ng wi th a s i ngl e, a cute epi s ode of dys peps i a i s of concern, pa rti cul a rl y i f s ymptoms a re a ccompa ni ed by dys pnea , di a phores i s ,
or ta chyca rdi a ; s uch pa ti ents ma y ha ve a cute corona ry i s chemi a . Chroni c s ymptoms tha t occur wi th exerti on a nd a re rel i eved by res t ma y repres ent
a ngi na .
GI ca us es a re mos t l i kel y to ma ni fes t a s chroni c compl a i nts . Symptoms a re s ometi mes cl a s s i fi ed a s ul cer-l i ke, dys moti l i ty-l i ke, or refl ux-l i ke;
thes e cl a s s i fi ca ti ons s ugges t but do not confi rm a n eti ol ogy. Ul cer-l i ke s ymptoms cons i s t of pa i n tha t i s l oca l i zed i n the epi ga s tri um, frequentl y
occurs before mea l s , a nd i s pa rti a l l y rel i eved by food, a nta ci ds , or H 2 bl ockers . Dys moti l i ty-l i ke s ymptoms cons i s t of di s comfort ra ther tha n pa i n,
a l ong wi th ea rl y s a ti ety, pos tpra ndi a l ful l nes s , na us ea , vomi ti ng, bl oa ti ng, a nd s ymptoms tha t a re wors ened by food. Refl ux-l i ke s ymptoms
cons i s t of hea rtburn or a ci d regurgi ta ti on. However, s ymptoms often overl a p.
Al terna ti ng cons ti pa ti on a nd di a rrhea wi th dys peps i a s ugges ts i rri ta bl e bowel s yndrome or exces s i ve us e of OTC l a xa ti ves or a nti di a rrhea l s .
[
Table 7-3. Some Ora l Drugs for Dys peps i a ]
Testing: Pa ti ents i n whom s ymptoms s ugges t a cute corona ry i s chemi a , pa rti cul a rl y thos e wi th ri s k fa ctors , s houl d be s ent to the emergency
depa rtment for urgent eva l ua ti on, i ncl udi ng ECG a nd s erum ca rdi a c ma rkers .
For pa ti ents wi th chroni c, nons peci fi c s ymptoms , routi ne tes ts i ncl ude CBC (to excl ude a nemi a ca us ed by GI bl ood l os s ) a nd routi ne bl ood
chemi s tri es . If res ul ts a re a bnorma l , a ddi ti ona l tes ts (eg, i ma gi ng s tudi es , endos copy) s houl d be cons i dered. Beca us e of the ri s k of ca ncer,
pa ti ents > 45 a nd thos e wi th new-ons et red fl a g fi ndi ngs s houl d undergo upper GI endos copy. For pa ti ents < 45 wi th no red fl a g fi ndi ngs , s ome
a uthori ti es recommend empi ri c thera py for 2 to 4 wk wi th a nti s ecretory a gents fol l owed by endos copy i n trea tment fa i l ures . Others recommend
s creeni ng for H. pylori i nfecti on wi th a C14 -urea brea th tes t or s tool a s s a y (s ee p. 129). However, ca uti on i s requi red i n us i ng H. pylori or a ny other
nons peci fi c fi ndi ngs to expl a i n s ymptoms .
Es opha gea l ma nometry a nd pH s tudi es a re i ndi ca ted i f refl ux s ymptoms pers i s t a fter upper GI endos copy a nd a 2- to 4-wk tri a l wi th a PPI.
Treatment
Speci fi c condi ti ons a re trea ted. Pa ti ents wi thout i denti fi a bl e condi ti ons a re obs erved over ti me a nd rea s s ured. Symptoms a re trea ted wi th PPIs , H 2
bl ockers , or a cytoprotecti ve a gent (s ee Ta bl e 7-3). Proki neti c drugs (eg, metocl opra mi de, erythromyci n) gi ven a s a l i qui d s us pens i on a l s o ma y be
tri ed i n pa ti ents wi th dys moti l i ty-l i ke dys peps i a . However, there i s no cl ea r evi dence tha t ma tchi ng the drug cl a s s to the s peci fi c s ymptoms (eg,
refl ux vs dys moti l i ty) ma kes a di fference. Mi s opros tol a nd a nti chol i nergi cs a re not effecti ve i n functi ona l dys peps i a . Drugs tha t a l ter s ens ory
percepti on (eg, tri cycl i c a nti depres s a nts ) ma y be hel pful .
Key Points
Corona ry i s chemi a i s pos s i bl e i n a pa ti ent wi th a cute "ga s ."
Endos copy i s i ndi ca ted for thos e > 45 or wi th red fl a g fi ndi ngs .
Empi ri c trea tment wi th a n a ci d bl ocker i s rea s ona bl e for thos e < 45 wi thout red fl a g fi ndi ngs . Thos e who do not res pond i n 2 to 4 wk requi re
further eva l ua ti on.
Hiccups
Hi ccups (hi ccough, s i ngul tus ) a re repea ted i nvol unta ry s pa s ms of the di a phra gm fol l owed by s udden cl os ure of the gl otti s , whi ch checks the
i nfl ow of a i r a nd ca us es the cha ra cteri s ti c s ound. Tra ns i ent epi s odes a re very common. Pers i s tent (> 2 da ys ) a nd i ntra cta bl e (> 1 mo) hi ccups a re
uncommon but qui te di s tres s i ng.
Etiology
Hi ccups fol l ow i rri ta ti on of a fferent or efferent di a phra gma ti c nerves or of medul l a ry centers tha t control the res pi ra tory mus cl es , pa rti cul a rl y the
di a phra gm. Hi ccups a re more common a mong men.
Ca us e i s genera l l y unknown, but tra ns i ent hi ccups a re often ca us ed by the fol l owi ng:
Ga s tri c di s tenti on
Al cohol cons umpti on

Swa l l owi ng hot or i rri ta ti ng s ubs ta nces
Pers i s tent a nd i ntra cta bl e hi ccups ha ve myri a d ca us es (s ee
Ta bl e 7-4).
Evaluation
History: History of present illness s houl d note dura ti on of hi ccups , remedi es tri ed, a nd rel a ti ons hi p of ons et to recent i l l nes s or s urgery.
Review of systems s eeks concomi ta nt GI s ymptoms s uch a s ga s troes opha gea l refl ux a nd s wa l l owi ng di ffi cul ti es ; thora ci c s ymptoms s uch a s cough,
fever, or ches t pa i n; a nd a ny neurol ogi c s ymptoms .
Past medical history s houl d query known GI a nd neurol ogi c di s orders . A drug hi s tory s houl d i ncl ude deta i l s concerni ng a l cohol us e.
Physical examination: Exa mi na ti on i s us ua l l y unrewa rdi ng but s houl d s eek s i gns of chroni c di s ea s e (eg, ca chexi a ). A ful l neurol ogi c exa mi na ti on i s
i mporta nt.
Red flags: The fol l owi ng i s of pa rti cul a r concern:
Neurol ogi c s ymptoms or s i gns
Interpretation of findings: Few fi ndi ngs a re s peci fi c. Hi ccups a fter a l cohol cons umpti on or s urgery ma y wel l be rel a ted to thos e events . Other
pos s i bl e ca us es (s ee Ta bl e 7-4) a re both numerous a nd ra rel y a ca us e of hi ccups .
Testing: No s peci fi c eva l ua ti on i s requi red for a cute hi ccups i f routi ne hi s tory a nd phys i ca l exa mi na ti on a re unrema rka bl e; a bnorma l i ti es a re
purs ued wi th a ppropri a te tes ti ng.
Pa ti ents wi th hi ccups of l onger dura ti on a nd no obvi ous ca us e s houl d ha ve tes ti ng, proba bl y i ncl udi ng s erum el ectrol ytes , BUN a nd crea ti ni ne,
ches t x-ra y, a nd ECG. Upper GI endos copy a nd perha ps es opha gea l pH moni tori ng s houl d be cons i dered. If thes e a re unrema rka bl e, bra i n MRI a nd
ches t CT ma y be done.
[Table 7-4. Some Ca us es of Intra cta bl e Hi ccups ]
Treatment
Identi fi ed probl ems a re trea ted (eg, proton pump i nhi bi tors for ga s troes opha gea l refl ux di s ea s e, di l a ti on for es opha gea l s tri cture).
For s ymptom rel i ef, ma ny s i mpl e mea s ures ca n be tri ed, a l though none a re more tha n s l i ghtl y effecti ve: Pa CO2 ca n be i ncrea s ed a nd
di a phra gma ti c a cti vi ty ca n be i nhi bi ted by a s eri es of deep brea th-hol ds or by brea thi ng deepl y i n to a nd out of a pa per ba g. (CAUTION: Plastic bags
can cling to the nostrils and should not be used.) Va ga l s ti mul a ti on by pha ryngea l i rri ta ti on (eg, s wa l l owi ng dry brea d, gra nul a ted s uga r, or crus hed i ce;
a ppl yi ng tra cti on on the tongue; s ti mul a ti ng ga ggi ng) ma y work. Numerous other fol k remedi es exi s t.
Pers i s tent hi ccups a re often reca l ci tra nt to trea tment. Ma ny drugs ha ve been us ed i n a necdota l s eri es . Ba cl ofen, a -a mi nobutyri c a ci d a goni s t (5
mg po q 6 h i ncrea s i ng to 20 mg/dos e), ma y be effecti ve. Other drugs i ncl ude chl orproma zi ne 10 to 50 mg po ti d a s needed, metocl opra mi de 10 mg
po bi d to qi d, a nd va ri ous a nti convul s a nts (eg, ga ba penti n). Addi ti ona l l y, a n empi ri c tri a l of proton pump i nhi bi tors ma y be gi ven. For s evere
s ymptoms , chl orproma zi ne 25 to 50 mg IM or IV ca n be gi ven. In i ntra cta bl e ca s es , the phreni c nerve ma y be bl ocked by s ma l l a mounts of 0.5%
proca i ne s ol uti on, wi th ca uti on bei ng ta ken to a voi d res pi ra tory depres s i on a nd pneumothora x. Even bi l a tera l phreni cotomy does not cure a l l
ca s es .
Key Points
The ca us e i s us ua l l y unknown.
Ra rel y, a s eri ous di s order i s pres ent.
Eva l ua ti on i s typi ca l l y unrewa rdi ng but s houl d be purs ued for hi ccups of l ong dura ti on.
Numerous remedi es exi s t, none wi th cl ea r s uperi ori ty (or perha ps even effecti venes s ).
Lump in Throat
Lump i n the throa t (gl obus s ens a ti on, gl obus hys teri cus ) i s the s ens a ti on of a l ump or ma s s i n the throa t, unrel a ted to s wa l l owi ng, when no ma s s
i s pres ent. (If a ma s s i s pres ent, s ee p.
461.)
Etiology
No s peci fi c eti ol ogy or phys i ol ogi c mecha ni s m ha s been es ta bl i s hed. Some s tudi es s ugges t tha t el eva ted cri copha ryngea l (upper es opha gea l
s phi ncter) pres s ure or a bnorma l hypopha ryngea l moti l i ty occur duri ng the ti me of s ymptoms . The s ens a ti on ma y a l s o res ul t from
ga s troes opha gea l refl ux di s ea s e (GERD) or from frequent s wa l l owi ng a nd dryi ng of the throa t a s s oci a ted wi th a nxi ety or a nother emoti ona l s ta te.
Al though not a s s oci a ted wi th s tres s fa ctors or a s peci fi c ps ychi a tri c di s order, gl obus s ens a ti on ma y be a s ymptom of certa i n mood s ta tes (eg, gri ef,
pri de); s ome pa ti ents ma y ha ve a predi s pos i ti on to thi s res pons e.
Di s orders tha t ca n be confus ed wi th gl obus s ens a ti on i ncl ude cri copha ryngea l (upper es opha gea l ) webs , s ymptoma ti c di ffus e es opha gea l s pa s m,
GERD, s kel eta l mus cl e di s orders (eg, mya s theni a gra vi s , myotoni a dys trophi ca , pol ymyos i ti s ), a nd ma s s l es i ons i n the neck or medi a s ti num tha t
ca us e es opha gea l compres s i on.
Evaluation
The ma i n goa l i s to di s ti ngui s h gl obus s ens a ti on from true dys pha gi a (s ee p. 120), whi ch s ugges ts a s tructura l or motor di s order of the pha rynx or
es opha gus .
History: History of present illness s houl d el i ci t a cl ea r des cri pti on of the s ymptom, pa rti cul a rl y a s to whether there i s a ny pa i n wi th s wa l l owi ng,
di ffi cul ty s wa l l owi ng (i ncl udi ng s ens a ti on of food s ti cki ng). Ti mi ng of s ymptoms i s i mporta nt, pa rti cul a rl y whether i t occurs wi th ea ti ng or dri nki ng
or i s i ndependent of thos e a cti vi ti es ; a s s oci a ti on wi th emoti ona l events s houl d be queri ed s peci fi ca l l y.
Review of systems s eeks wei ght l os s (a s evi dence of a s wa l l owi ng di s order) a nd s ymptoms of mus cl e wea knes s .
Past medical history s houl d i ncl ude known neurol ogi c di a gnos es , pa rti cul a rl y thos e ca us i ng wea knes s .
Physical examination: The neck a nd fl oor of the mouth a re pa l pa ted for ma s s es . The oropha rynx i s i ns pected (i ncl udi ng by di rect l a ryngos copy).
Swa l l owi ng (of wa ter a nd a s ol i d food s uch a s cra ckers ) s houl d be obs erved. Neurol ogi c exa mi na ti on wi th pa rti cul a r a ttenti on to motor functi on i s
i mporta nt.
Neck or throa t pa i n
Wei ght l os s
Abrupt ons et a fter a ge 50
Pa i n, choki ng, or di ffi cul ty wi th s wa l l owi ng
Regurgi ta ti on of food
Mus cl e wea knes s
Pa l pa bl e or vi s i bl e ma s s
Progres s i ve wors eni ng of s ymptoms
Interpretation of findings: Symptoms unrel a ted to s wa l l owi ng, wi th no pa i n or di ffi cul ty wi th s wa l l owi ng, or s ens a ti on of food s ti cki ng i n the throa t
i n a pa ti ent wi th a norma l exa mi na ti on i mpl y gl obus s ens a ti on. Any red fl a g fi ndi ngs or a bnorma l fi ndi ngs on exa mi na ti on s ugges t a mecha ni ca l
or motor di s order of s wa l l owi ng. Chroni c s ymptoms tha t occur duri ng unres ol ved or pa thol ogi c gri ef a nd tha t ma y be rel i eved by cryi ng s ugges t
gl obus s ens a ti on.
Testing: Thos e wi th fi ndi ngs typi ca l of gl obus s ens a ti on need no tes ti ng. If the di a gnos i s i s uncl ea r or the cl i ni ci a n ca nnot a dequa tel y vi s ua l i ze
the pha rynx, tes ti ng a s for dys pha gi a i s done. Typi ca l tes ts i ncl ude pl a i n or vi deo es opha gogra phy, mea s urement of s wa l l owi ng ti me, ches t x-ra y,
a nd es opha gea l ma nometry.
Treatment
Trea tment i nvol ves rea s s ura nce a nd s ympa theti c concern. No drug i s of proven benefi t. Underl yi ng depres s i on, a nxi ety, or other beha vi ora l
di s turba nces s houl d be ma na ged s upporti vel y, wi th ps ychi a tri c referra l i f neces s a ry. At ti mes , communi ca ti ng to the pa ti ent the a s s oci a ti on
between s ymptoms a nd mood s ta te ca n be benefi ci a l .
Key Points
Gl obus s ymptoms a re unrel a ted to s wa l l owi ng.
Tes ts a re not needed unl es s s ymptoms a re rel a ted to s wa l l owi ng, exa mi na ti on i s a bnorma l , or there a re red fl a g fi ndi ngs .
Nausea and Vomiting
(For na us ea a nd vomi ti ng i n i nfa nts a nd chi l dren, s ee p. 2746.)
Na us ea , the unpl ea s a nt feel i ng of needi ng to vomi t, repres ents a wa renes s of a fferent s ti mul i (i ncl udi ng i ncrea s ed pa ra s ympa theti c tone) to the
medul l a ry vomi ti ng center. Vomi ti ng i s the forceful expul s i on of ga s tri c contents ca us ed by i nvol unta ry contra cti on of the a bdomi na l mus cul a ture
when the ga s tri c fundus a nd l ower es opha gea l s phi ncter a re rel a xed.
Vomi ti ng s houl d be di s ti ngui s hed from regurgi ta ti on, the s pi tti ng up of ga s tri c contents wi thout a s s oci a ted na us ea or forceful a bdomi na l
mus cul a r contra cti ons . Pa ti ents wi th a cha l a s i a or a Zenker's di verti cul um ma y regurgi ta te undi ges ted food wi thout na us ea .
Complications: Severe vomi ti ng ca n l ea d to s ymptoma ti c dehydra ti on a nd el ectrol yte a bnorma l i ti es (typi ca l l y a meta bol i c a l ka l os i s wi th
hypoka l emi a ) or ra rel y to a n es opha gea l tea r, ei ther pa rti a l (Ma l l ory-Wei s s ) or compl ete (Boerha a ve's s yndrome). Chroni c vomi ti ng ca n res ul t i n
undernutri ti on, wei ght l os s , a nd meta bol i c a bnorma l i ti es .

Etiology
Na us ea a nd vomi ti ng occur i n res pons e to condi ti ons tha t a ffect the vomi ti ng center. Ca us es ma y ori gi na te i n the GI tra ct or CNS or ma y res ul t from
a number of s ys temi c condi ti ons (s ee
Ta bl e 7-5).
The mos t common ca us es a re the fol l owi ng:
Ga s troenteri ti s
Drugs
Toxi ns
Cycl i c vomi ti ng s yndrome i s a n uncommon di s order cha ra cteri zed by s evere, di s crete a tta cks of vomi ti ng or s ometi mes onl y na us ea tha t occur a t
va ryi ng i nterva l s , wi th norma l hea l th between epi s odes . It i s mos t common i n chi l dhood (mea n a ge of ons et 5 yr) a nd tends to remi t wi th
a dul thood. The condi ti on ma y be a s s oci a ted wi th mi gra i ne hea da ches , pos s i bl y repres enti ng a mi gra i ne va ri a nt.
Evaluation
History: History of present illness s houl d el i ci t frequency a nd dura ti on of vomi ti ng; i ts rel a ti on to pos s i bl e preci pi ta nts s uch a s drug or toxi n
i nges ti on, hea d i njury, a nd moti on (eg, ca r, pl a ne, boa t, a mus ement ri des ); a nd whether vomi tus conta i ned bi l e (bi tter, yel l ow-green) or bl ood
(red or "coffee ground" ma teri a l ). Importa nt a s s oci a ted s ymptoms i ncl ude pres ence of a bdomi na l pa i n a nd di a rrhea ; the l a s t pa s s a ge of s tool
a nd fl a tus ; a nd pres ence of hea da che, verti go, or both.
Review of systems s eeks s ymptoms of ca us a ti ve di s orders s uch a s a menorrhea , brea s t s wel l i ng (pregna ncy); pol yuri a , pol ydi ps i a (di a betes ); a nd
hema turi a , fl a nk pa i n (ki dney s tones ).
Past medical history s houl d a s certa i n known ca us es s uch a s pregna ncy, di a betes , mi gra i ne, hepa ti c or rena l di s ea s e, ca ncer (i ncl udi ng ti mi ng of a ny
chemothera py or ra di a ti on thera py), a nd previ ous a bdomi na l s urgery (whi ch ma y ca us e bowel obs tructi on due to a dhes i ons ). Al l drugs a nd
s ubs ta nces i nges ted recentl y s houl d be a s certa i ned; certa i n s ubs ta nces ma y not ma ni fes t toxi ci ty unti l s evera l da ys a fter i nges ti on (eg,
a ceta mi nophen, s ome mus hrooms ).
Fa mi l y hi s tory of recurrent vomi ti ng s houl d be noted.
Physical examination: Vi ta l s i gns s houl d pa rti cul a rl y note pres ence of fever a nd s i gns of hypovol emi a (eg, ta chyca rdi a , hypotens i on, or both).
Genera l exa mi na ti on s houl d s eek pres ence of ja undi ce a nd s ki n ra s h.
On a bdomi na l exa mi na ti on, the cl i ni ci a n s houl d l ook for di s tenti on a nd s urgi ca l s ca rs ; l i s ten for pres ence a nd qua l i ty of bowel s ounds (eg,
norma l , hi gh-pi tched); percus s for tympa ny; a nd pa l pa te for tendernes s , peri tonea l fi ndi ngs (eg, gua rdi ng, ri gi di ty, rebound), a nd a ny ma s s es ,
orga nomega l y, or herni a s . Recta l exa mi na ti on a nd (i n women) pel vi c exa mi na ti on to l oca te tendernes s , ma s s es , a nd bl ood a re es s enti a l .
Neurol ogi c exa mi na ti on s houl d pa rti cul a rl y note menta l s ta tus , nys ta gmus , meni ngi s mus (eg, s ti ff neck, Kerni g's or Brudzi ns ki 's s i gns ), a nd ocul a r
s i gns of i ncrea s ed i ntra cra ni a l pres s ure (eg, pa pi l l edema , a bs ence of venous pul s a ti ons , 3rd cra ni a l nerve pa l s y) or s uba ra chnoi d hemorrha ge
(reti na l hemorrha ge).
Si gns of hypovol emi a
Hea da che, s ti ff neck, or menta l s ta tus cha nge
Peri tonea l s i gns
Di s tended, tympa ni ti c a bdomen
Interpretation of findings: Ma ny fi ndi ngs a re s ugges ti ve of a ca us e or group of ca us es (s ee Ta bl e 7-5). Vomi ti ng occurri ng s hortl y a fter drug or toxi n
i nges ti on or expos ure to moti on i n a pa ti ent wi th a n unrema rka bl e neurol ogi c a nd a bdomi na l exa mi na ti on ca n confi dentl y be a s cri bed to thos e
ca us es , a s ma y vomi ti ng i n a woma n wi th a known pregna ncy a nd a beni gn exa mi na ti on. Acute vomi ti ng a ccompa ni ed by di a rrhea i n a n otherwi s e
[Table 7-5. Some Ca us es of Na us ea a nd Vomi ti ng]
hea l thy pa ti ent wi th a beni gn exa mi na ti on i s hi ghl y l i kel y to be i nfecti ous ga s troenteri ti s ; further a s s es s ment ma y be deferred.
Vomi ti ng tha t occurs a t the thought of food or tha t i s not tempora l l y rel a ted to ea ti ng s ugges ts a ps ychogeni c ca us e, a s does pers ona l or fa mi l y
hi s tory of functi ona l na us ea a nd vomi ti ng. Pa ti ents s houl d be ques ti oned a bout the rel a ti ons hi p between vomi ti ng a nd s tres s ful events beca us e
they ma y not recogni ze the a s s oci a ti on or even a dmi t to feel i ng di s tres s a t thos e ti mes .
Testing: Al l fema l es of chi l dbea ri ng a ge s houl d ha ve a uri ne pregna ncy tes t. Pa ti ents wi th s evere vomi ti ng, vomi ti ng l a s ti ng over 1 da y, or s i gns of
dehydra ti on on exa mi na ti on s houl d ha ve other l a bora tory tes ts (eg, el ectrol ytes , BUN, crea ti ni ne, gl ucos e, uri na l ys i s , a nd s ometi mes l i ver tes ts ).
Pa ti ents wi th red fl a g fi ndi ngs s houl d ha ve tes ti ng a ppropri a te to the s ymptoms (s ee Ta bl e 7-5).
The a s s es s ment of chroni c vomi ti ng us ua l l y i ncl udes the previ ous l y l i s ted l a bora tory tes ts pl us upper GI endos copy, s ma l l -bowel x-ra ys , a nd tes ts
to a s s es s ga s tri c emptyi ng a nd a ntra l -duodena l moti l i ty.
Treatment
Speci fi c condi ti ons , i ncl udi ng dehydra ti on, a re trea ted. Even wi thout s i gni fi ca nt dehydra ti on, IV fl ui d thera py (0.9% s a l i ne 1 L, or 20 mL/kg i n
chi l dren) often l ea ds to reducti on of s ymptoms . In a dul ts , va ri ous a nti emeti cs a re effecti ve (s ee
Ta bl e 7-6). Choi ce of a gent va ri es s omewha t wi th the ca us e a nd s everi ty of s ymptoms . Typi ca l us e i s the fol l owi ng:
Moti on s i cknes s : Anti hi s ta mi nes , s copol a mi ne pa tches , or both
Mi l d to modera te s ymptoms : Prochl orpera zi ne or metocl opra mi de
Severe or refra ctory vomi ti ng a nd vomi ti ng ca us ed by chemothera py: 5-HT3 a nta goni s ts
Obvi ous l y, onl y pa rentera l a gents s houl d be us ed i n a cti vel y vomi ti ng pa ti ents .
For ps ychogeni c vomi ti ng, rea s s ura nce i ndi ca tes a wa renes s of the pa ti ent's di s comfort a nd a des i re to work towa rd rel i ef of s ymptoms , rega rdl es s
of ca us e. Comments s uch a s "nothi ng i s wrong" or "the probl em i s emoti ona l " s houl d be a voi ded. Bri ef s ymptoma ti c trea tment wi th a nti emeti cs
ca n be tri ed. If l ong-term ma na gement i s neces s a ry, s upporti ve, regul a r offi ce vi s i ts ma y hel p res ol ve the underl yi ng probl em.
Key Points
Ma ny epi s odes ha ve a n obvi ous ca us e a nd beni gn exa mi na ti on a nd requi re onl y s ymptoma ti c trea tment.
Phys i ci a ns s houl d be a l ert for s i gns of a n a cute a bdomen or s i gni fi ca nt i ntra cra ni a l di s order.
Pregna ncy s houl d a l wa ys be cons i dered i n fema l es of chi l dbea ri ng a ge.
Rumination
Rumi na ti on i s the (us ua l l y i nvol unta ry) regurgi ta ti on of s ma l l a mounts of food from the s toma ch (mos t often 15 to 30 mi n a fter ea ti ng) tha t a re
rechewed a nd, i n mos t ca s es , a ga i n s wa l l owed. Pa ti ents do not compl a i n of na us ea or a bdomi na l pa i n.
[Table 7-6. Some Drugs for Vomi ti ng]
Rumi na ti on i s commonl y obs erved i n i nfa nts . The i nci dence i n a dul ts i s unknown, beca us e i t i s ra rel y reported by pa ti ents thems el ves .
Etiology
Pa ti ents wi th a cha l a s i a or a Zenker's di verti cul um ma y regurgi ta te undi ges ted food wi thout na us ea . In the ma jori ty of pa ti ents who do not ha ve
thes e obs tructi ve es opha gea l condi ti ons , the pa thophys i ol ogy i s poorl y unders tood. The revers e peri s ta l s i s i n rumi na nts ha s not been reported i n
huma ns . The di s order i s proba bl y a l ea rned, ma l a da pti ve ha bi t a nd ma y be pa rt of a n ea ti ng di s order. The pers on l ea rns to open the l ower
es opha gea l s phi ncter a nd propel ga s tri c contents i nto the es opha gus a nd throa t by i ncrea s i ng ga s tri c pres s ure vi a rhythmi c contra cti on a nd
rel a xa ti on of the di a phra gm.
Symptoms
Na us ea , pa i n, a nd dys pha gi a do not occur. Duri ng peri ods of s tres s , the pa ti ent ma y be l es s ca reful a bout concea l i ng rumi na ti on. Seei ng the a ct
for the fi rs t ti me, others ma y refer the pa ti ent to a phys i ci a n. Ra rel y, pa ti ents regurgi ta te a nd expel enough food to l os e wei ght.
Diagnosis
Someti mes endos copy, es opha gea l moti l i ty s tudi es , or both
Rumi na ti on i s us ua l l y di a gnos ed through obs erva ti on. A ps ychos oci a l hi s tory ma y di s cl os e underl yi ng emoti ona l s tres s . Endos copy or a n upper GI
s eri es i s neces s a ry to excl ude di s orders ca us i ng mecha ni ca l obs tructi on or Zenker's di verti cul um. Es opha gea l ma nometry a nd tes ts to a s s es s
ga s tri c emptyi ng a nd a ntra l -duodena l moti l i ty ma y be us ed to i denti fy a moti l i ty di s turba nce.
Treatment
Beha vi ora l techni ques
Trea tment i s s upporti ve. Drug thera py genera l l y does not hel p. Moti va ted pa ti ents ma y res pond to beha vi ora l techni ques (eg, rel a xa ti on,
bi ofeedba ck, tra i ni ng i n di a phra gma ti c brea thi ng [us i ng the di a phra gm i ns tea d of ches t mus cl es to brea the]). Ps ychi a tri c cons ul ta ti on ma y be
hel pful .
Functional GI Illness
Often, no phys i ol ogi c ca us e for GI compl a i nts i s found, even a fter extens i ve eva l ua ti on. Such pa ti ents a re s a i d to ha ve functi ona l i l l nes s , whi ch
a ccounts for 30 to 50% of referra l s to ga s troenterol ogi s ts . Functi ona l i l l nes s ma y ma ni fes t wi th upper a nd/or l ower GI s ymptoms .
The rea s ons for functi ona l s ymptoms a re not cl ea r. Some evi dence s ugges ts tha t s uch pa ti ents ha ve vi s cera l hypers ens i ti vi ty, a di s turba nce of
noci cepti on i n whi ch they experi ence di s comfort ca us ed by s ens a ti ons (eg, l umi na l di s tenti on, peri s ta l s i s ) tha t other peopl e do not fi nd
di s tres s i ng. In s ome pa ti ents , ps ychol ogi c condi ti ons s uch a s a nxi ety (wi th or wi thout a eropha gi a ), convers i on di s order, s oma ti za ti on i n
depres s i on, or hypochondri a s i s a re a s s oci a ted wi th GI s ymptoms . Ps ychol ogi c theori es hol d tha t functi ona l s ymptoms ma y s a ti s fy certa i n
ps ychol ogi c needs . For exa mpl e, s ome pa ti ents wi th chroni c i l l nes s deri ve s econda ry benefi ts from bei ng s i ck. For s uch pa ti ents , s ucces s ful
trea tment of s ymptoms ma y l ea d to devel opment of other s ymptoms .
Ma ny referri ng phys i ci a ns a nd GI s peci a l i s ts fi nd functi ona l GI compl a i nts di ffi cul t to unders ta nd a nd trea t, a nd uncerta i nty ma y l ea d to
frus tra ti on a nd judgmenta l a tti tudes . Phys i ci a ns s houl d a voi d orderi ng repea ted s tudi es or mul ti pl e drug tri a l s for the i ns i s tent pa ti ent wi th
i nexpl i ca bl e compl a i nts . When s ymptoms a re not s ugges ti ve of s eri ous i l l nes s , the phys i ci a n s houl d wa i t ra ther tha n emba rk on a nother
di a gnos ti c or thera peuti c pl a n. In ti me, new i nforma ti on ma y di rect eva l ua ti on a nd ma na gement. Functi ona l compl a i nts a re s ometi mes pres ent i n
pa ti ents wi th phys i ol ogi c di s ea s e (eg, pepti c ul cer, es opha gi ti s ); s uch s ymptoms ma y not remi t even when a phys i ol ogi c i l l nes s i s a ddres s ed.
Chapter 8. Approach to the Patient With Lower GI Complaints

Introduction
Lower GI compl a i nts i ncl ude cons ti pa ti on, di a rrhea , ga s a nd bl oa ti ng, a bdomi na l pa i n (s ee a l s o p. 105), a nd recta l pa i n or bl eedi ng (s ee Ch. 21).
As wi th upper GI compl a i nts , l ower GI compl a i nts res ul t from phys i ol ogi c i l l nes s or repres ent a functi ona l di s order (i e, no ra di ol ogi c, bi ochemi ca l ,
or pa thol ogi c a bnorma l i ti es found even a fter extens i ve eva l ua ti on). The rea s ons for functi ona l s ymptoms a re not cl ea r. Evi dence s ugges ts tha t
pa ti ents wi th functi ona l s ymptoms ma y ha ve di s turba nces of moti l i ty, noci cepti on, or both; i e, they percei ve a s uncomforta bl e certa i n s ens a ti ons
(eg, l umi na l di s tenti on, peri s ta l s i s ) tha t other peopl e do not fi nd di s tres s i ng.
No bodi l y functi on i s more va ri a bl e a nd s ubject to externa l i nfl uences tha n defeca ti on. Bowel ha bi ts va ry cons i dera bl y from pers on to pers on a nd
a re a ffected by a ge, phys i ol ogy, di et, a nd s oci a l a nd cul tura l i nfl uences . Some peopl e ha ve unwa rra nted preoccupa ti on wi th bowel ha bi ts . In
Wes tern s oci ety, norma l s tool frequency ra nges from 2 to 3/da y to 2 to 3/wk. Cha nges i n s tool frequency, cons i s tency, vol ume, or compos i ti on (i e,
pres ence of bl ood, mucus , pus , or exces s fa tty ma teri a l ) ma y i ndi ca te di s ea s e.
Constipation
Cons ti pa ti on i s di ffi cul t or i nfrequent pa s s a ge of s tool , ha rdnes s of s tool , or a feel i ng of i ncompl ete eva cua ti on.
Ma ny peopl e i ncorrectl y bel i eve tha t da i l y defeca ti on i s neces s a ry a nd compl a i n of cons ti pa ti on i f s tool s occur l es s frequentl y. Others a re
concerned wi th the a ppea ra nce (s i ze, s ha pe, col or) or cons i s tency of s tool s . Someti mes the ma jor compl a i nt i s di s s a ti s fa cti on wi th the a ct of
defeca ti on or the s ens e of i ncompl ete eva cua ti on a fter defeca ti on. Cons ti pa ti on i s bl a med for ma ny compl a i nts (a bdomi na l pa i n, na us ea ,
fa ti gue, a norexi a ) tha t a re a ctua l l y s ymptoms of a n underl yi ng probl em (eg, i rri ta bl e bowel s yndrome [IBS], depres s i on). Pa ti ents s houl d not
expect a l l s ymptoms to be rel i eved by a da i l y bowel movement, a nd mea s ures to a i d bowel ha bi ts s houl d be us ed judi ci ous l y.
Obs es s i ve-compul s i ve pa ti ents often feel the need to ri d the body da i l y of "uncl ea n" wa s tes . Such pa ti ents often s pend exces s i ve ti me on the
toi l et or become chroni c us ers of ca tha rti cs .
Etiology
Acute cons ti pa ti on s ugges ts a n orga ni c ca us e, wherea s chroni c cons ti pa ti on ma y be orga ni c or functi ona l (s ee
Ta bl e 8-1).
In ma ny pa ti ents , cons ti pa ti on i s a s s oci a ted wi th s l uggi s h movement of s tool through the col on. Thi s del a y ma y be due to drugs , orga ni c
condi ti ons , or a di s order of defeca tory functi on (i e, pel vi c fl oor dys functi on). Pa ti ents wi th di s ordered defeca ti on do not genera te a dequa te recta l
propul s i ve forces , do not rel a x the puborecta l i s a nd the externa l a na l s phi ncter duri ng defeca ti on, or both. In IBS, pa ti ents ha ve s ymptoms (eg,
a bdomi na l di s comfort a nd a l tered bowel ha bi ts ) but genera l l y norma l col oni c tra ns i t a nd a norecta l functi ons . However, IBS-di s ordered defeca ti on
ma y coexi s t.
Exces s i ve s tra i ni ng, perha ps s econda ry to pel vi c fl oor dys functi ons , ma y contri bute to a norecta l pa thol ogy (eg, hemorrhoi ds , a na l fi s s ures , a nd
recta l prol a ps e) a nd pos s i bl y even to s yncope. Feca l i mpa cti on, whi ch ma y ca us e or devel op from cons ti pa ti on, i s a l s o common a mong el derl y
pa ti ents , pa rti cul a rl y wi th prol onged bed res t or decrea s ed phys i ca l a cti vi ty. It i s a l s o common a fter ba ri um ha s been gi ven by mouth or enema .
Changes with aging: Cons ti pa ti on i s common a mong el derl y peopl e beca us e of l ow-fi ber di ets , l a ck of exerci s e, coexi s ti ng medi ca l condi ti ons , a nd
us e of cons ti pa ti ng drugs . Ma ny el derl y peopl e ha ve mi s concepti ons a bout norma l bowel ha bi ts a nd us e l a xa ti ves regul a rl y. Other cha nges tha t
predi s pos e the el derl y to cons ti pa ti on i ncl ude i ncrea s ed recta l compl i a nce a nd i mpa i red recta l s ens a ti on (s uch tha t l a rger recta l vol umes a re
needed to el i ci t the des i re to defeca te).
Evaluation
History: A l i feti me hi s tory of the pa ti ent's s tool frequency, cons i s tency, need to s tra i n or us e peri nea l ma neuvers (eg, pus hi ng on the peri neum,
gl utea l regi on, or recto-va gi na l wa l l ) duri ng defeca ti on, a nd s a ti s fa cti on a fter defeca ti on s houl d be obta i ned, i ncl udi ng frequency a nd dura ti on of
l a xa ti ve or enema us e. Some pa ti ents deny previ ous cons ti pa ti on
[Table 8-1. Ca us es of Cons ti pa ti on]
but, when ques ti oned s peci fi ca l l y, a dmi t to s pendi ng 15 to 20 mi n per bowel movement. The pres ence, a mount, a nd dura ti on of bl ood i n the s tool
s houl d a l s o be el i ci ted.
Symptoms of meta bol i c (eg, hypothyroi di s m, di a betes mel l i tus ) a nd neurol ogi c (eg, s pi na l cord i njury) di s orders a nd s ys temi c s ymptoms (eg,
wei ght l os s ) s houl d a l s o be s ought. Pres cri pti on a nd nonpres cri pti on drug us e s houl d be a s s es s ed, wi th s peci fi c ques ti oni ng a bout
a nti chol i nergi c a nd opi oi d drugs .
Physical examination: A genera l exa mi na ti on i s done to l ook for s i gns of s ys temi c di s ea s e, i ncl udi ng fever a nd ca chexi a . Abdomi na l ma s s es s houl d
be s ought by pa l pa ti on. A recta l exa mi na ti on s houl d be done not onl y for fi s s ures , s tri ctures , bl ood, or ma s s es (i ncl udi ng feca l i mpa cti on) but
a l s o to eva l ua te a na l res ti ng tone (the puborecta l i s "l i ft" when pa ti ents s queeze the a na l s phi ncter), peri nea l des cent duri ng s i mul a ted
eva cua ti on, a nd recta l s ens a ti on. Pa ti ents wi th defeca tory di s orders ma y ha ve i ncrea s ed a na l res ti ng tone (or a ni s mus ), reduced (i e, < 2 cm) or
i ncrea s ed (i e, > 4 cm) peri nea l des cent, a nd/or pa ra doxi ca l contra cti on of the puborecta l i s duri ng s i mul a ted eva cua ti on.
Red flags: Certa i n fi ndi ngs ra i s e s us pi ci on of a more s eri ous eti ol ogy of chroni c cons ti pa ti on:
Di s tended, tympa ni ti c a bdomen
Vomi ti ng
Bl ood i n s tool
Wei ght l os s
Severe cons ti pa ti on of recent ons et/wors eni ng i n el derl y pa ti ents
Interpretation of findings: Certa i n s ymptoms (eg, a s ens e of a norecta l bl ocka ge, prol onged or di ffi cul t defeca ti on), pa rti cul a rl y when a s s oci a ted wi th
a bnorma l (i e, i ncrea s ed or reduced) peri nea l moti on duri ng s i mul a ted eva cua ti on, s ugges t a defeca tory di s order. A tens e, di s tended, tympa ni ti c
a bdomen, pa rti cul a rl y when there i s na us ea a nd vomi ti ng, s ugges ts mecha ni ca l obs tructi on.
Pa ti ents wi th IBS typi ca l l y ha ve a bdomi na l pa i n wi th di s ordered bowel ha bi ts (s ee p. 162). Chroni c cons ti pa ti on wi th modes t a bdomi na l
di s comfort i n a pa ti ent who ha s us ed l a xa ti ves for a l ong ti me s ugges ts s l ow-tra ns i t cons ti pa ti on. Acute cons ti pa ti on coi nci dent wi th the s ta rt of a
cons ti pa ti ng drug i n pa ti ents wi thout red fl a g fi ndi ngs s ugges ts the drug i s the ca us e. New-ons et cons ti pa ti on tha t pers i s ts for weeks or occurs
i ntermi ttentl y wi th i ncrea s i ng frequency or s everi ty, i n the a bs ence of a known ca us e, s ugges ts col oni c tumor or other ca us es of pa rti a l
obs tructi on. Exces s i ve s tra i ni ng or prol onged or uns a ti s fa ctory defeca ti on, wi th or wi thout a na l di gi ta ti on, s ugges ts a defeca tory di s order. Pa ti ents
wi th feca l i mpa cti on ma y ha ve cra mps a nd ma y pa s s wa tery mucus or feca l ma teri a l a round the i mpa cted ma s s , mi mi cki ng di a rrhea (pa ra doxi c
di a rrhea ).
Testing: Tes ti ng i s gui ded by cl i ni ca l pres enta ti on.
Cons ti pa ti on wi th a cl ea r eti ol ogy (drugs , tra uma , bed res t) ma y be trea ted s ymptoma ti ca l l y wi thout further s tudy. Pa ti ents wi th s ymptoms of
bowel obs tructi on requi re fl a t a nd upri ght a bdomi na l x-ra ys , pos s i bl y a wa ter-s ol ubl e contra s t enema to eva l ua te for col oni c obs tructi on, a nd
pos s i bl y a CT s ca n or ba ri um x-ra y of the s ma l l i ntes ti ne (s ee a l s o p.
116). Mos t pa ti ents wi thout a cl ea r eti ol ogy s houl d ha ve s i gmoi dos copy or col onos copy a nd a l a bora tory eva l ua ti on (CBC, thyroi d-s ti mul a ti ng
hormone, fa s ti ng gl ucos e, el ectrol ytes , a nd Ca ).
Further tes ts a re us ua l l y res erved for pa ti ents wi th a bnorma l fi ndi ngs on the previ ous l y menti oned tes ts or who do not res pond to s ymptoma ti c
trea tment. If the pri ma ry compl a i nt i s i nfrequent defeca ti on, col oni c tra ns i t ti mes s houl d be mea s ured wi th ra di opa que ma rkers or s ci nti gra phy. If
the pri ma ry compl a i nt i s di ffi cul ty wi th defeca ti on, a norecta l ma nometry a nd recta l ba l l oon expul s i on s houl d be a s s es s ed.
Treatment
Pos s i bl y di s conti nua ti on of ca us a ti ve drugs (s ome ma y be neces s a ry)
Increa s e i n di eta ry fi ber
Pos s i bl y tri a l wi th a bri ef cours e of os moti c l a xa ti ves
Any i denti fi ed condi ti ons s houl d be trea ted.
Agents us ed to trea t cons ti pa ti on a re s umma ri zed i n
Ta bl e 8-2. La xa ti ves s houl d be us ed judi ci ous l y. Some (eg, phos pha te, bra n, cel l ul os e) bi nd drugs a nd i nterfere wi th a bs orpti on. Ra pi d feca l
tra ns i t ma y rus h s ome drugs a nd nutri ents beyond thei r opti ma l a bs orpti ve l ocus . Contra i ndi ca ti ons to l a xa ti ve a nd ca tha rti c us e i ncl ude a cute
a bdomi na l pa i n of unknown ori gi n, i nfl a mma tory bowel di s orders , i ntes ti na l obs tructi on, GI bl eedi ng, a nd feca l i mpa cti on.
Diet and behavior: The di et s houl d conta i n enough fi ber (typi ca l l y 15 to 20 g/da y) to ens ure a dequa te s tool bul k. Vegeta bl e fi ber, whi ch i s l a rgel y
i ndi ges ti bl e a nd una bs orba bl e, i ncrea s es s tool bul k. Certa i n components of fi ber a l s o a bs orb fl ui d, ma ki ng s tool s s ofter a nd fa ci l i ta ti ng thei r
pa s s a ge. Frui ts a nd vegeta bl es a re recommended s ources , a s a re cerea l s conta i ni ng bra n. Fi ber s uppl ementa ti on i s pa rti cul a rl y effecti ve i n
trea ti ng norma l -tra ns i t cons ti pa ti on but i s not very effecti ve for s l ow-tra ns i t cons ti pa ti on or defeca tory di s orders .
[Table 8-2. Agents Us ed to Trea t Cons ti pa ti on]
Beha vi ora l cha nges ma y hel p. Pa ti ents s houl d try to move thei r bowel s a t the s a me ti me da i l y, prefera bl y 15 to 45 mi n a fter brea kfa s t, beca us e
food i nges ti on s ti mul a tes col oni c moti l i ty. Ini ti a l efforts a t regul a r, unhurri ed bowel movements ma y be a i ded by gl yceri n s uppos i tori es .
Expl a na ti on i s i mporta nt, but i t i s di ffi cul t to convi nce obs es s i ve-compul s i ve pa ti ents tha t thei r a tti tude towa rd defeca ti on i s a bnorma l .
Phys i ci a ns mus t expl a i n tha t da i l y bowel movements a re not es s enti a l , tha t the bowel mus t be gi ven a cha nce to functi on, a nd tha t frequent us e
of l a xa ti ves or enema s (> once/3 da ys ) deni es the bowel tha t cha nce.
Types of laxatives: Bul ki ng a gents (eg, ps yl l i um, Ca pol yca rbophi l , methyl cel l ul os e) a ct s l owl y a nd gentl y a nd a re the s a fes t a gents for promoti ng
el i mi na ti on. Proper us e i nvol ves gra dua l l y i ncrea s i ng the dos ei dea l l y ta ken ti d or qi d wi th s uffi ci ent l i qui d (eg, 500 mL/da y of extra fl ui d) to
prevent i mpa cti onunti l a s ofter, bul ki er s tool res ul ts . Bl oa ti ng ma y be reduced by gra dua l l y ti tra ti ng the dos e of di eta ry fi ber to the
recommended dos e, or by s wi tchi ng to a s yntheti c fi ber prepa ra ti on s uch a s methyl cel l ul os e.
Os moti c a gents conta i n poorl y a bs orbed pol yva l ent i ons (eg, Mg, phos pha te, s ul fa te), pol ymers (eg, pol yethyl ene gl ycol ), or ca rbohydra tes (eg,
l a ctul os e, s orbi tol ) tha t rema i n i n the bowel , i ncrea s i ng i ntra l umi na l os moti c pres s ure a nd thereby dra wi ng wa ter i nto the i ntes ti ne. The
i ncrea s ed vol ume s ti mul a tes peri s ta l s i s . Thes e a gents us ua l l y work wi thi n 3 h.
In genera l , os moti c l a xa ti ves a re rea s ona bl y s a fe even when us ed regul a rl y. However, Na phos pha te s houl d not be us ed for bowel cl ea ns i ng
beca us e i t ma y ra rel y ca us e a cute rena l fa i l ure even a fter a s i ngl e us e for bowel prepa ra ti on. Thes e events occurred pri ma ri l y i n el derl y pa ti ents ,
thos e wi th preexi s ti ng rena l di s ea s e, a nd thos e who were ta ki ng drugs tha t a ffect rena l perfus i on or functi on (eg, di ureti cs , ACE i nhi bi tors ,
a ngi otens i n II receptor bl ockers ). Al s o, Mg a nd phos pha te a re pa rti a l l y a bs orbed a nd ma y be detri menta l i n s ome condi ti ons (eg, rena l
i ns uffi ci ency). Na (i n s ome prepa ra ti ons ) ma y exa cerba te hea rt fa i l ure. In l a rge or frequent dos es , thes e drugs ma y ups et fl ui d a nd el ectrol yte
ba l a nce. Another a pproa ch to cl ea ns i ng the bowel for di a gnos ti c tes ts or s urgery or s ometi mes for chroni c cons ti pa ti on us es l a rge vol umes of a
ba l a nced os moti c a gent (eg, pol yethyl ene gl ycol -el ectrol yte s ol uti on) gi ven ora l l y or vi a NGT.
Secretory or s ti mul a nt ca tha rti cs (eg, phenol phtha l ei n, bi s a codyl , a nthra qui nones , ca s tor oi l , a nthra qui nones ) a ct by i rri ta ti ng the i ntes ti na l
mucos a or by di rectl y s ti mul a ti ng the s ubmucos a l a nd myenteri c pl exus . Al though phenol phtha l ei n wa s wi thdra wn from the US ma rket a fter
a ni ma l s tudi es s ugges ted the compound wa s ca rci nogeni c, there i s no epi demi ol ogi c evi dence of thi s i n huma ns . Bi s a codyl i s a n effecti ve res cue
drug for chroni c cons ti pa ti on. The a nthra qui nones s enna , ca s ca ra s a gra da , a l oe, a nd rhuba rb a re common cons ti tuents of herba l a nd OTC
l a xa ti ves . They pa s s uncha nged to the col on where ba cteri a l meta bol i s m converts them to a cti ve forms . Advers e effects i ncl ude a l l ergi c rea cti ons ,
el ectrol yte depl eti on, mel a nos i s col i , a nd ca tha rti c col on. Mel a nos i s col i i s a browni s h bl a ck col orecta l pi gmenta ti on of unknown compos i ti on.
Ca tha rti c col on refers to a l tera ti ons i n col oni c a na tomy obs erved on ba ri um enema i n pa ti ents wi th chroni c s ti mul a nt l a xa ti ve us e. It i s uncl ea r
whether ca tha rti c col on, whi ch ha s been a ttri buted to des tructi on of myenteri c pl exus neurons by a nthra qui nones , i s ca us ed by currentl y a va i l a bl e
a gents or other neurotoxi c a gents (eg, podophyl l i n), whi ch a re no l onger a va i l a bl e. There does not s eem to be a n i ncrea s ed ri s k of col on ca ncer
wi th l ong-term a nthra qui none us e.
Enema s ca n be us ed, i ncl udi ng ta p wa ter a nd commerci a l l y prepa red hypertoni c s ol uti ons .
Emol l i ent a gents (eg, docus a te, mi nera l oi l ) a ct s l owl y to s often s tool s , ma ki ng them ea s i er to pa s s . However, they a re not potent s ti mul a tors of
defeca ti on. Docus a te i s a s urfa cta nt, whi ch a l l ows wa ter to enter the feca l ma s s to s often a nd i ncrea s e i ts bul k.
Fecal impaction: Feca l i mpa cti on i s trea ted i ni ti a l l y wi th enema s of ta p wa ter fol l owed by s ma l l enema s (100 mL) of commerci a l l y prepa red
hypertoni c s ol uti ons (eg, Na phos pha te). If thes e do not work, ma nua l fra gmenta ti on a nd di s i mpa cti on of the ma s s i s neces s a ry. Thi s procedure i s
pa i nful , s o peri recta l a nd i ntra recta l a ppl i ca ti on of l oca l a nes theti cs (eg, l i doca i ne 5% oi ntment or di buca i ne 1% oi ntment) i s recommended.
Some pa ti ents requi re s eda ti on.
Key Points
Drug ca us es a re common (eg, chroni c l a xa ti ve a bus e, us e of a nti chol i nergi c or opi oi d drugs ).
Cl i ni ci a ns s houl d be wa ry of bowel obs tructi on when cons ti pa ti on i s a cute a nd s evere.
Symptoma ti c trea tment i s rea s ona bl e i n the a bs ence of red fl a g fi ndi ngs a nd a fter excl udi ng pel vi c fl oor dys functi on.
Dyschezia
(Di s ordered Eva cua ti on; Dys functi on of Pel vi c Fl oor or Ana l Sphi ncters ; Functi ona l Defeca tory Di s orders ; Dys s ynergi a )
Dyschezia is difficulty defecating. Patients sense the presence of stool and the need to defecate but are unable. It results from a lack of coordination of pelvic
floor muscles and anal sphincters. Diagnosis requires anorectal testing. Treatment is difficult, but biofeedback may be of benefit.
Etiology
Norma l l y, when a pers on tri es to defeca te, recta l pres s ure ri s es i n coordi na ti on wi th rel a xa ti on of the externa l a na l s phi ncter. Thi s proces s ma y
be a ffected by one or more dys functi ons (eg, i mpa i red recta l contra cti on, exces s i ve contra cti on of the a bdomi na l wa l l , pa ra doxi c a na l contra cti on,
fa i l ure of a na l rel a xa ti on) of uncl ea r eti ol ogy. Functi ona l defeca tory di s orders ma y ma ni fes t a t a ny a ge. In contra s t, Hi rs chs prung's di s ea s e, whi ch
i s due to a n a bs ent recto-a na l i nhi bi tory refl ex, i s a l mos t a l wa ys di a gnos ed i n i nfa ncy or chi l dhood.
Symptoms and Signs
The pa ti ent ma y or ma y not s ens e tha t s tool i s pres ent i n the rectum. Des pi te prol onged s tra i ni ng, eva cua ti on i s tedi ous or i mpos s i bl e, frequentl y
even for s oft s tool or enema s . Pa ti ents ma y compl a i n of a na l bl ocka ge a nd ma y di gi ta l l y remove s tool from thei r rectum or ma nua l l y s upport thei r
peri neum or s pl i nt the va gi na to eva cua te. Actua l s tool frequency ma y or ma y not be decrea s ed.
Diagnosis
Recta l a nd pel vi c exa mi na ti ons ma y revea l hypertoni a of the pel vi c fl oor mus cl es a nd a na l s phi ncters . Wi th bea ri ng down, pa ti ents ma y not
demons tra te the expected a na l rel a xa ti on a nd peri nea l des cent. Wi th exces s i ve s tra i ni ng, the a nteri or recta l wa l l prol a ps es i nto the va gi na i n
pa ti ents wi th i mpa i red a na l rel a xa ti on; thus rectocel es a re us ua l l y a s econda ry ra ther tha n a pri ma ry di s turba nce. Long-s ta ndi ng dys chezi a wi th
chroni c s tra i ni ng ma y ca us e a s ol i ta ry recta l ul cer or va ryi ng degrees of recta l prol a ps e or exces s i ve peri nea l des cent or a n enterocoel e. Anorecta l
ma nometry a nd recta l ba l l oon expul s i on, occa s i ona l l y s uppl emented by defeca tory or ma gneti c res ona nce proctogra phy, a re neces s a ry to
di a gnos e the condi ti on.
Treatment
Beca us e trea tment wi th l a xa ti ves i s uns a ti s fa ctory, i t i s i mporta nt to a s s es s a norecta l functi ons i n pa ti ents wi th refra ctory cons ti pa ti on.
Bi ofeedba ck thera py ca n i mprove coordi na ti on between a bdomi na l contra cti on a nd pel vi c fl oor rel a xa ti on duri ng defeca ti on, thereby a l l evi a ti ng
s ymptoms . However, pel vi c fl oor retra i ni ng for defeca tory di s orders i s hi ghl y s peci a l i zed a nd a va i l a bl e a t s el ect centers onl y. A col l a bora ti ve
a pproa ch (phys i othera pi s ts , di eti ti a ns , beha vi or thera pi s ts , ga s troenterol ogi s ts ) i s neces s a ry.
Diarrhea
(See a l s o Chs . 17 a nd 19. For di a rrhea i n chi l dren, s ee p. 2737.)
Stool i s 60 to 90% wa ter. In Wes tern s oci ety, s tool a mount i s 100 to 200 g/da y i n hea l thy a dul ts a nd 10 g/kg/da y i n i nfa nts , dependi ng on the
a mount of una bs orba bl e di eta ry ma teri a l (ma i nl y ca rbohydra tes ). Di a rrhea i s defi ned a s s tool wei ght > 200 g/da y. However, ma ny peopl e cons i der
a ny i ncrea s ed s tool fl ui di ty to be di a rrhea . Al terna ti vel y, ma ny peopl e who i nges t fi ber ha ve bul ki er but formed s tool s but do not cons i der
thems el ves to ha ve di a rrhea .

Complications: Compl i ca ti ons ma y res ul t from di a rrhea of a ny eti ol ogy. Fl ui d l os s wi th cons equent dehydra ti on, el ectrol yte l os s (Na , K, Mg, Cl ), a nd
even va s cul a r col l a ps e s ometi mes occur. Col l a ps e ca n devel op ra pi dl y i n pa ti ents who ha ve s evere di a rrhea (eg, pa ti ents wi th chol era ) or a re very
young, very ol d, or debi l i ta ted. HCO3 l os s ca n ca us e meta bol i c a ci dos i s . Hypoka l emi a ca n occur when pa ti ents ha ve s evere or chroni c di a rrhea or i f
the s tool conta i ns exces s mucus . Hypoma gnes emi a a fter prol onged di a rrhea ca n ca us e teta ny.
Etiology
Norma l l y, the s ma l l i ntes ti ne a nd col on a bs orb 99% of fl ui d res ul ti ng from ora l i nta ke a nd GI tra ct s ecreti ons a tota l fl ui d l oa d of a bout 9 of 10 L
da i l y. Thus , even s ma l l reducti ons (i e, 1%) i n i ntes ti na l wa ter a bs orpti on or i ncrea s es i n s ecreti on ca n i ncrea s e wa ter content enough to ca us e
di a rrhea .
There a re a number of ca us es of di a rrhea (s ee
Ta bl e 8-3). Severa l ba s i c mecha ni s ms a re res pons i bl e for mos t cl i ni ca l l y s i gni fi ca nt di a rrhea s : i ncrea s ed os moti c l oa d, i ncrea s ed s ecreti ons , a nd
decrea s ed conta ct ti me/s urfa ce a rea . In ma ny di s orders , more tha n one mecha ni s m i s a cti ve. For exa mpl e, di a rrhea i n i nfl a mma tory bowel
di s ea s e res ul ts from mucos a l des tructi on, exuda ti on i nto the l umen, a nd from mul ti pl e s ecreta gogues a nd ba cteri a l toxi ns tha t a ffect enterocyte
functi on.
[Table 8-3. Some Ca us es of Di a rrhea *]
Osmotic load: Di a rrhea occurs when una bs orba bl e, wa ter-s ol ubl e s ol utes rema i n i n the bowel a nd reta i n wa ter. Such s ol utes i ncl ude pol yethyl ene
gl ycol , Mg s a l ts (hydroxi de a nd s ul fa te), a nd Na phos pha te, whi ch a re us ed a s l a xa ti ves . Os moti c di a rrhea occurs wi th s uga r i ntol era nce (eg,
l a ctos e i ntol era nce ca us ed by l a cta s e defi ci ency). Inges ti ng l a rge a mounts of hexi tol s (eg, s orbi tol , ma nni tol , xyl i tol ) or hi gh fructos e corn s yrups ,
whi ch a re us ed a s s uga r s ubs ti tutes i n ca ndy, gum, a nd frui t jui ces , ca us es os moti c di a rrhea beca us e hexi tol s a re poorl y a bs orbed. La ctul os e,
whi ch i s us ed a s a l a xa ti ve, ca us es di a rrhea by a s i mi l a r mecha ni s m. Overi nges ti ng certa i n foods tuffs (s ee
Ta bl e 8-4) ca n ca us e os moti c di a rrhea .
Increased secretions: Di a rrhea occurs when the bowel s s ecrete more el ectrol ytes a nd wa ter tha n they a bs orb. Ca us es of i ncrea s ed s ecreti ons
i ncl ude i nfecti ons , una bs orbed fa ts , certa i n drugs , a nd va ri ous i ntri ns i c a nd extri ns i c s ecreta gogues .
Infecti ons (eg, ga s troenteri ti s ; di s cus s ed i n Ch. 16) a re the mos t common ca us es of s ecretory di a rrhea . Infecti ons combi ned wi th food poi s oni ng
a re the mos t common ca us es of a cute di a rrhea (< 4 da ys i n dura ti on). Mos t enterotoxi ns bl ock Na +-H + excha nge, whi ch i s a n i mporta nt dri vi ng force
for fl ui d a bs orpti on i n the s ma l l bowel a nd col on.
Una bs orbed di eta ry fa t a nd bi l e a ci ds (a s i n ma l a bs orpti on s yndromes a nd a fter i l ea l res ecti on) ca n s ti mul a te col oni c s ecreti on a nd ca us e
di a rrhea .
Drugs ma y s ti mul a te i ntes ti na l s ecreti ons di rectl y (eg, qui ni di ne, qui ni ne, col chi ci ne, a nthra qui none ca tha rti cs , ca s tor oi l , pros ta gl a ndi ns ) or
i ndi rectl y by i mpa i ri ng fa t a bs orpti on (eg, orl i s ta t).
Va ri ous endocri ne tumors produce s ecreta gogues , i ncl udi ng vi poma s (va s oa cti ve i ntes ti na l pepti de), ga s tri noma s (ga s tri n), ma s tocytos i s
(hi s ta mi ne), medul l a ry ca rci noma of the thyroi d (ca l ci toni n a nd pros ta gl a ndi ns ), a nd ca rci noi d tumors (hi s ta mi ne, s erotoni n, a nd pol ypepti des ).
Some of thes e medi a tors (eg, pros ta gl a ndi ns , s erotoni n, rel a ted compounds ) a l s o a ccel era te i ntes ti na l tra ns i t, col oni c tra ns i t, or both.
Reduced contact time/surface area: Ra pi d i ntes ti na l tra ns i t a nd di mi ni s hed s urfa ce a rea i mpa i r fl ui d a bs orpti on a nd ca us e di a rrhea . Common
ca us es i ncl ude s ma l l -bowel or l a rge-bowel res ecti on or bypa s s , ga s tri c res ecti on,
[Table 8-4. Di eta ry Fa ctors tha t Ma y Wors en Di a rrhea ]
a nd i nfl a mma tory bowel di s ea s e. Other ca us es i ncl ude mi cros copi c col i ti s (col l a genous or l ymphocyti c col i ti s ) a nd cel i a c s prue.
Sti mul a ti on of i ntes ti na l s mooth mus cl e by drugs (eg, Mg-conta i ni ng a nta ci ds , l a xa ti ves , chol i nes tera s e i nhi bi tors , SSRIs ) or humora l a gents (eg,
pros ta gl a ndi ns , s erotoni n) a l s o ca n s peed tra ns i t.
Evaluation
History: Dura ti on a nd s everi ty of di a rrhea , ci rcums ta nces of ons et (i ncl udi ng recent tra vel , food i nges ted, s ource of wa ter), drug us e (i ncl udi ng a ny
a nti bi oti cs wi thi n the previ ous 3 mo), a bdomi na l pa i n or vomi ti ng, frequency a nd ti mi ng of bowel movements , cha nges i n s tool cha ra cteri s ti cs (eg,
pres ence of bl ood, pus , or mucus ; cha nges i n col or or cons i s tency; evi dence of s tea torrhea ), a s s oci a ted cha nges i n wei ght or a ppeti te, a nd recta l
urgency or tenes mus s houl d be noted. Si mul ta neous occurrence of di a rrhea i n cl os e conta cts s houl d be a s certa i ned.
Physical examination: Fl ui d a nd hydra ti on s ta tus s houl d be eva l ua ted. A ful l exa mi na ti on wi th a ttenti on to the a bdomen a nd a di gi ta l recta l
exa mi na ti on for s phi ncter competence a nd occul t bl ood tes ti ng a re i mporta nt.
Red flags: Certa i n fi ndi ngs ra i s e s us pi ci on of a n orga ni c or more s eri ous eti ol ogy of di a rrhea :
Bl ood or pus
Fever
Si gns of dehydra ti on
Chroni c di a rrhea
Wei ght l os s
Interpretation of findings: Acute, wa tery di a rrhea i n a n otherwi s e hea l thy pers on i s l i kel y to be of i nfecti ous eti ol ogy, pa rti cul a rl y when tra vel ,
pos s i bl y ta i nted food, or a n outbrea k wi th a poi nt-s ource i s i nvol ved. Acute bl oody di a rrhea wi th or wi thout hemodyna mi c i ns ta bi l i ty i n a n
otherwi s e hea l thy pers on s ugges ts a n enteroi nva s i ve i nfecti on. Di verti cul a r bl eedi ng a nd i s chemi c col i ti s a l s o ma ni fes t wi th a cute bl oody
di a rrhea . Recurrent bouts of bl oody di a rrhea i n a younger pers on s ugges t i nfl a mma tory bowel di s ea s e. In the a bs ence of l a xa ti ve us e, l a rgevol ume di a rrhea (eg, da i l y s tool vol ume > 1 L/da y) s trongl y s ugges ts a n endocri ne ca us e i n pa ti ents wi th norma l GI a na tomy. A hi s tory of oi l
dropl ets i n s tool , pa rti cul a rl y i f a s s oci a ted wi th wei ght l os s , s ugges ts ma l a bs orpti on.
Di a rrhea tha t cons i s tentl y fol l ows i nges ti on of certa i n foods (eg, fa ts ) s ugges ts food i ntol era nce. Recent a nti bi oti c us e s houl d ra i s e s us pi ci on for
a nti bi oti c-a s s oci a ted di a rrhea , i ncl udi ng Clostridium difficile col i ti s .
The s ymptoms ca n hel p i denti fy the a ffected pa rt of the bowel . Genera l l y, i n s ma l l -bowel di s ea s es , s tool s a re vol umi nous a nd wa tery or fa tty. In
col oni c di s ea s es , s tool s a re frequent, s ometi mes s ma l l i n vol ume, a nd pos s i bl y a ccompa ni ed by bl ood, mucus , pus , a nd a bdomi na l di s comfort. In
i rri ta bl e bowel s yndrome (IBS), a bdomi na l di s comfort i s rel i eved by defeca ti on, a s s oci a ted wi th more l oos e or frequent s tool s , or both. However,
thes e s ymptoms a l one do not di s cri mi na te IBS from other di s ea s es (eg, i nfl a mma tory bowel di s ea s e). Pa ti ents wi th IBS or recta l mucos a l
i nvol vement often ha ve ma rked urgency, tenes mus , a nd s ma l l , frequent s tool s (s ee p. 163).
Extra -a bdomi na l fi ndi ngs tha t s ugges t a n eti ol ogy i ncl ude s ki n l es i ons or fl us hi ng (ma s tocytos i s ), thyroi d nodul es (medul l a ry ca rci noma of the
thyroi d), ri ght-s i ded hea rt murmur (ca rci noi d), l ympha denopa thy (l ymphoma , AIDS), a nd a rthri ti s (i nfl a mma tory bowel di s ea s e, cel i a c di s ea s e).
Testing: Acute di a rrhea (< 4 da ys ) typi ca l l y does not requi re tes ti ng. Excepti ons a re pa ti ents wi th s i gns of dehydra ti on, bl oody s tool , fever, s evere
pa i n, hypotens i on, or toxi c fea tures pa rti cul a rl y thos e who a re very young or very ol d. Thes e pa ti ents s houl d ha ve a CBC a nd mea s urement of
el ectrol ytes , BUN, a nd crea ti ni ne. Stool s a mpl es s houl d be col l ected for mi cros copy, cul ture, feca l l eukocyte tes ti ng, a nd, i f a nti bi oti cs ha ve been
ta ken recentl y, C. difficile toxi n a s s a y.
Chroni c di a rrhea (> 4 wk) requi res eva l ua ti on, a s does a s horter (1 to 3 wk) bout of di a rrhea i n i mmunocompromi s ed pa ti ents or thos e who a ppea r
s i gni fi ca ntl y i l l . Ini ti a l s tool tes ti ng s houl d i ncl ude cul ture, feca l l eukocytes (detected by s mea r or mea s urement of feca l l a ctoferri n), mi cros copi c
exa mi na ti on for ova a nd pa ra s i tes , pH (ba cteri a l fermenta ti on of una bs orbed ca rbohydra te l owers s tool pH < 6.0), fa t (by Suda n s ta i n), a nd
el ectrol ytes (Na a nd K). If no s ta nda rd pa thogens a re found, s peci fi c tes ts for Giardia a nti gen a nd Aeromonas, Plesiomonas, cocci di a , a nd
mi cros pori di a s houl d be reques ted. Si gmoi dos copy or col onos copy wi th bi ops i es s houl d fol l ow to l ook for i nfl a mma tory ca us es .
If no di a gnos i s i s a ppa rent a nd Suda n s ta i n i s pos i ti ve for fa t, feca l fa t excreti on s houl d be mea s ured, fol l owed by s ma l l -bowel enterocl ys i s or CT
enterogra phy (s tructura l di s ea s e) a nd endos copi c s ma l l -bowel bi ops y (mucos a l di s ea s e). If eva l ua ti on s ti l l yi el ds nega ti ve fi ndi ngs , a s s es s ment
of pa ncrea ti c s tructure a nd functi on (s ee p. 142) s houl d be cons i dered for pa ti ents who ha ve unexpl a i ned s tea torrhea . Infrequentl y, ca ps ul e
endos copy ma y uncover l es i ons , predomi na ntl y Crohn's di s ea s e or NSAID enteropa thy, not i denti fi ed by other moda l i ti es .
The s tool os moti c ga p, whi ch i s ca l cul a ted 290 - 2 (s tool Na + s tool K), i ndi ca tes whether di a rrhea i s s ecretory or os moti c. An os moti c ga p < 50
mEq/L i ndi ca tes s ecretory di a rrhea ; a l a rger ga p s ugges ts os moti c di a rrhea . Pa ti ents wi th os moti c di a rrhea ma y ha ve covert Mg l a xa ti ve i nges ti on
(detecta bl e by s tool Mg l evel s ) or ca rbohydra te ma l a bs orpti on (di a gnos ed by hydrogen brea th tes t, l a cta s e a s s a y, a nd di eta ry revi ew).
Undi a gnos ed s ecretory di a rrhea requi res tes ti ng (eg, pl a s ma ga s tri n, ca l ci toni n, va s oa cti ve i ntes ti na l pepti de l evel s , hi s ta mi ne, uri na ry 5hydroxyi ndol e a ceti c a ci d [5-HIAA]) for endocri ne-rel a ted ca us es . A revi ew for s ymptoms a nd s i gns of thyroi d di s ea s e a nd a drena l i ns uffi ci ency
s houl d be done. Surrepti ti ous l a xa ti ve a bus e mus t be cons i dered; i t ca n be rul ed out by a feca l l a xa ti ve a s s a y.
Treatment
Fl ui d a nd el ectrol ytes for dehydra ti on
Pos s i bl y a nti di a rrhea l s for nonbl oody di a rrhea i n pa ti ents wi thout s ys temi c toxi ci ty
Severe di a rrhea requi res fl ui d a nd el ectrol yte repl a cement to correct dehydra ti on, el ectrol yte i mba l a nce, a nd a ci dos i s . Pa rentera l fl ui ds
conta i ni ng Na Cl , KCl , a nd gl ucos e a re genera l l y requi red. Sa l ts to countera ct a ci dos i s (Na l a cta te, a ceta te, HCO3 ) ma y be i ndi ca ted i f s erum HCO3 i s
< 15 mEq/L. An ora l gl ucos e-el ectrol yte s ol uti on ca n be gi ven i f di a rrhea i s not s evere a nd na us ea a nd vomi ti ng a re mi ni ma l (s ee p.
2809). Ora l a nd pa rentera l fl ui ds a re s ometi mes gi ven s i mul ta neous l y when wa ter a nd el ectrol ytes mus t be repl a ced i n ma s s i ve a mounts (eg, i n
chol era ).
Di a rrhea i s a s ymptom. When pos s i bl e, the underl yi ng di s order s houl d be trea ted, but s ymptoma ti c trea tment i s often neces s a ry. Di a rrhea ma y be
decrea s ed by ora l l opera mi de 2 to 4 mg ti d or qi d (prefera bl y gi ven 30 mi n before mea l s ), di phenoxyl a te 2.5 to 5 mg (ta bl ets or l i qui d) ti d or qi d,
codei ne phos pha te 15 to 30 mg bi d or ti d, or pa regori c (ca mphora ted opi um ti ncture) 5 to 10 mL once/da y to qi d.
Beca us e a nti di a rrhea l s ma y exa cerba te C. difficile col i ti s or i ncrea s e the l i kel i hood of hemol yti c-uremi c s yndrome i n Shiga toxi n-produci ng
Escherichia coli i nfecti on, they s houl d not be us ed i n bl oody di a rrhea of unknown ca us e. Thei r us e s houl d be res tri cted to pa ti ents wi th wa tery
di a rrhea a nd no s i gns of s ys temi c toxi ci ty. However, there i s l i ttl e evi dence to jus ti fy previ ous concerns a bout prol ongi ng excreti on of pos s i bl e
ba cteri a l pa thogens wi th a nti di a rrhea l s .
Ps yl l i um or methyl cel l ul os e compounds provi de bul k. Al though us ua l l y pres cri bed for cons ti pa ti on, bul ki ng a gents gi ven i n s ma l l dos es decrea s e
the fl ui di ty of l i qui d s tool s . Ka ol i n, pecti n, a nd a cti va ted a tta pul gi te a ds orb fl ui d. Os moti ca l l y a cti ve di eta ry s ubs ta nces (s ee Ta bl e 8-4) a nd
s ti mul a tory drugs s houl d be a voi ded.
Key Points
In pa ti ents wi th a cute di a rrhea , s tool exa mi na ti on (cul tures , ova a nd pa ra s i tes , C. difficile cytotoxi n) i s onl y neces s a ry for thos e who ha ve
prol onged s ymptoms (i e, > 1 wk) or red fl a g fi ndi ngs .

Anti di a rrhea l s s houl d be us ed ca uti ous l y i f there i s a pos s i bi l i ty of C. difficile, Salmonella, or s hi gel l os i s .
Gas-Related Complaints
The gut conta i ns < 200 mL of ga s , wherea s da i l y ga s expul s i on a vera ges 600 to 700 mL a fter cons umi ng a s ta nda rd di et pl us 200 g of ba ked bea ns .
About 75% of fl a tus i s deri ved from col oni c ba cteri a l fermenta ti on of i nges ted nutri ents a nd endogenous gl ycoprotei ns . Ga s es i ncl ude hydrogen
(H 2 ), metha ne (CH 4 ), a nd ca rbon di oxi de (CO2 ). Fl a tus odor correl a tes wi th H 2 s ul phi de concentra ti ons . Swa l l owed a i r (a eropha gi a ) a nd di ffus i on
from the bl ood i nto the l umen a l s o contri bute to i ntes ti na l ga s . Ga s di ffus es between the l umen a nd the bl ood i n a di recti on tha t depends on the
di fference i n pa rti a l pres s ures . Thus , mos t ni trogen (N2 ) i n the l umen ori gi na tes from the bl oods trea m, a nd mos t H 2 i n the bl oods trea m ori gi na tes
from the l umen.
Etiology
There a re 3 ma i n ga s -rel a ted compl a i nts : exces s i ve bel chi ng, di s tenti on (bl oa ti ng), a nd exces s i ve fl a tus , ea ch wi th a number of ca us es (s ee
Ta bl e 8-5). Infa nts 2 to 4 mo of a ge wi th recurrent cryi ng s pel l s often a ppea r to obs ervers to be i n pa i n, whi ch i n the pa s t ha s been a ttri buted to
a bdomi na l cra mpi ng or ga s a nd termed col i c. However, s tudi es s how no i ncrea s e i n H 2 producti on or i n mouth-to-cecum tra ns i t ti mes i n col i cky
i nfa nts . Hence, the ca us e of i nfa nti l e col i c rema i ns uncl ea r (s ee p. 2725).
Excessive belching: Bel chi ng (eructa ti on) res ul ts from s wa l l owed a i r or from ga s genera ted by ca rbona ted bevera ges . Aeropha gi a occurs norma l l y i n
s ma l l a mounts duri ng ea ti ng a nd dri nki ng, but s ome peopl e uncons ci ous l y s wa l l ow a i r repea tedl y whi l e ea ti ng or s moki ng a nd a t other ti mes ,
es peci a l l y when a nxi ous or i n a n a ttempt to i nduce bel chi ng. Exces s i ve s a l i va ti on i ncrea s es a eropha gi a a nd ma y be a s s oci a ted wi th va ri ous GI
di s orders (eg, ga s troes opha gea l refl ux di s ea s e), i l l -fi tti ng dentures , certa i n drugs , gum chewi ng, or na us ea of a ny ca us e.
Mos t s wa l l owed a i r i s eructa ted. Onl y a s ma l l a mount of s wa l l owed a i r pa s s es i nto the s ma l l bowel ; the a mount i s a ppa rentl y i nfl uenced by
pos i ti on. In a n upri ght pers on, a i r i s rea di l y bel ched; i n a s upi ne pers on, a i r tra pped a bove the s toma ch fl ui d tends to be propel l ed i nto the
duodenum. Exces s i ve eructa ti on ma y a l s o be vol unta ry; pa ti ents who bel ch a fter ta ki ng a nta ci ds ma y a ttri bute the rel i ef of s ymptoms to bel chi ng
ra ther tha n to a nta ci ds a nd ma y i ntenti ona l l y bel ch to rel i eve di s tres s .
Distention (bloating): Abdomi na l bl oa ti ng ma y occur i n i s ol a ti on or a l ong wi th other GI s ymptoms i n pa ti ents wi th functi ona l di s orders (eg,
a eropha gi a , nonul cer dys peps i a , ga s tropa res i s , i rri ta bl e bowel s yndrome) or orga ni c di s orders (eg, ova ri a n ca ncer, col on ca ncer). However,
exces s i ve i ntes ti na l ga s i s not cl ea rl y l i nked to thes e compl a i nts . In mos t hea l thy peopl e, 1 L/h of ga s ca n be i nfus ed i nto the gut wi th mi ni ma l
s ymptoms . It i s l i kel y tha t ma ny s ymptoms a re i ncorrectl y a ttri buted to "too much ga s ."
On the other ha nd, s ome pa ti ents wi th recurrent GI s ymptoms often ca nnot tol era te s ma l l qua nti ti es of ga s : Retrogra de col oni c di s tenti on by
ba l l oon i nfl a ti on or a i r i ns ti l l a ti on duri ng col onos copy often el i ci ts s evere di s comfort i n s ome pa ti ents (eg, thos e wi th i rri ta bl e bowel s yndrome)
but mi ni ma l s ymptoms i n others . Si mi l a rl y, pa ti ents wi th ea ti ng di s orders (eg, a norexi a nervos a , bul i mi a ) often mi s percei ve a nd a re pa rti cul a rl y
s tres s ed by s ymptoms s uch a s bl oa ti ng. Thus , the ba s i c a bnorma l i ty i n pa ti ents wi th ga s -rel a ted s ymptoms ma y be a hypers ens i ti ve i ntes ti ne.
Al tered moti l i ty ma y contri bute further to s ymptoms .
Excessive flatus: There i s grea t va ri a bi l i ty i n the qua nti ty a nd frequency of recta l ga s pa s s a ge. As wi th s tool frequency, peopl e who compl a i n of
fl a tul ence often ha ve a mi s concepti on of wha t i s norma l . The a vera ge number of ga s pa s s a ges i s a bout 13 to 21/da y. Objecti vel y recordi ng fl a tus
frequency (us i ng a di a ry kept by the pa ti ent) i s a fi rs t s tep i n eva l ua ti on.
Fl a tus i s a meta bol i c byproduct of i ntes ti na l ba cteri a ; a l mos t none ori gi na tes from s wa l l owed a i r or ba ck-di ffus i on of ga s es (pri ma ri l y N2 ) from
the bl oods trea m. Ba cteri a l meta bol i s m yi el ds s i gni fi ca nt vol umes of H 2 , CH 4 , a nd CO2 .
H 2 i s produced i n l a rge qua nti ti es i n pa ti ents wi th ma l a bs orpti on s yndromes a nd a fter i nges ti on of certa i n frui ts a nd vegeta bl es conta i ni ng
i ndi ges ti bl e ca rbohydra tes (eg, ba ked bea ns ), s uga rs (eg, fructos e), or s uga r a l cohol s (eg, s orbi tol ). In pa ti ents wi th di s a ccha ri da s e defi ci enci es
(mos t commonl y l a cta s e defi ci ency), l a rge a mounts of di s a ccha ri des pa s s i nto the col on a nd a re fermented to H 2 . Cel i a c di s ea s e, tropi ca l s prue,
pa ncrea ti c i ns uffi ci ency, a nd other ca us es of ca rbohydra te ma l a bs orpti on s houl d a l s o be cons i dered i n ca s es of exces s col oni c ga s .
CH 4 i s a l s o produced by col oni c ba cteri a l meta bol i s m of the s a me foods (eg, di eta ry fi ber). However, a bout 10% of peopl e ha ve ba cteri a tha t
produce CH 4 but not H 2 .
CO2 i s a l s o produced by ba cteri a l meta bol i s m a nd genera ted i n the rea cti on of HCO3 - a nd H +. H + ma y come from ga s tri c HCl or from fa tty a ci ds
rel ea s ed duri ng di ges ti on of fa ts the l a tter s ometi mes produces s evera l hundred mEq of H +. The a ci d products rel ea s ed by ba cteri a l
fermenta ti on of una bs orbed ca rbohydra tes i n the col on ma y a l s o rea ct wi th HCO3 - to produce CO2 . Al though bl oa ti ng ma y occa s i ona l l y occur, the
ra pi d di ffus i on of CO2 i nto the bl ood genera l l y prevents di s tenti on.
[Table 8-5. Some Ca us es of Ga s -Rel a ted Compl a i nts ]
Di et a ccounts for much of the va ri a ti on i n fl a tus producti on a mong i ndi vi dua l s , but poorl y unders tood fa ctors (eg, di fferences i n col oni c fl ora a nd
moti l i ty) ma y a l s o pl a y a rol e.
Des pi te the fl a mma bl e na ture of the H 2 a nd CH 4 i n fl a tul ence, worki ng nea r open fl a mes i s not ha za rdous . However, ga s expl os i on, even wi th
fa ta l outcome, ha s been reported duri ng jejuna l a nd col oni c s urgery a nd col onos copy, when di a thermy wa s us ed duri ng procedures i n pa ti ents
wi th i ncompl ete bowel cl ea ni ng.
Evaluation
History: Pa ti ents wi th bel chi ng s houl d ha ve the hi s tory di rected a t fi ndi ng the ca us e of a eropha gi a , es peci a l l y di eta ry ca us es .
In pa ti ents compl a i ni ng of ga s , bl oa ti ng, or fl a tus , the rel a ti ons hi p between s ymptoms a nd mea l s (both ti mi ng a nd type a nd a mount of food),
bowel movements , a nd exerti on s houl d be expl ored. Certa i n pa ti ents , pa rti cul a rl y i n the a cute s etti ng, ma y us e the term "ga s " to des cri be thei r
s ymptoms of corona ry i s chemi a . Cha nges i n frequency a nd col or a nd cons i s tency of s tool a re s ought. Hi s tory of wei ght l os s i s noted.
Physical examination: The exa mi na ti on i s genera l l y norma l , but i n pa ti ents wi th bl oa ti ng or fl a tus , s i gns of a n underl yi ng orga ni c di s order s houl d
be s ought on a bdomi na l , recta l , a nd (for women) pel vi c exa mi na ti on.
Red flags: The fol l owi ng fi ndi ngs a re of concern:
Wei ght l os s
Bl ood i n s tool (occul t or gros s )
Interpretation of findings: Chroni c, recurrent bl oa ti ng or di s tenti on rel i eved by defeca ti on a nd a s s oci a ted wi th cha nge i n frequency or cons i s tency of
s tool but wi thout red fl a g fi ndi ngs s ugges ts i rri ta bl e bowel s yndrome.
Long-s ta ndi ng s ymptoms i n a n otherwi s e wel l young pers on who ha s not l os t wei ght a re unl i kel y to be ca us ed by s eri ous phys i ol ogi c di s ea s e,
a l though a n ea ti ng di s order s houl d be cons i dered, pa rti cul a rl y i n young women. Bl oa ti ng a ccompa ni ed by di a rrhea , wei ght l os s , or both (or onl y
a fter i nges ti on of certa i n foods ) s ugges ts a ma l a bs orpti on s yndrome.
Testing: Tes ti ng i s not i ndi ca ted for bel chi ng unl es s other s ymptoms s ugges t a pa rti cul a r di s order. Tes ti ng for ca rbohydra te i ntol era nce (eg,
l a ctos e, fructos e) wi th brea th tes ts s houl d be cons i dered pa rti cul a rl y when the hi s tory s ugges ts s i gni fi ca nt cons umpti on of thes e s uga rs . Tes ti ng
for s ma l l -bowel ba cteri a l overgrowth s houl d a l s o be cons i dered, pa rti cul a rl y i n pa ti ents who a l s o ha ve di a rrhea , wei ght l os s , or both, prefera bl y
by a erobi c a nd a na erobi c cul ture of s ma l l -bowel a s pi ra tes obta i ned duri ng upper GI endos copy. Tes ti ng for ba cteri a l overgrowth wi th H 2 brea th
tes ts , genera l l y gl ucos e-H 2 brea th tes ts , i s prone to fa l s e-pos i ti ve (i e, wi th ra pi d tra ns i t) a nd fa l s e-nega ti ve (i e, when there a re no H 2 -produci ng
ba cteri a ) res ul ts . New, pers i s tent bl oa ti ng i n mi ddl e-a ged or ol der women (or thos e wi th a n a bnorma l pel vi c exa mi na ti on) s houl d prompt pel vi c
ul tra s onogra phy to rul e out ova ri a n ca ncer.
Treatment
Bel chi ng a nd bl oa ti ng a re di ffi cul t to rel i eve beca us e they a re us ua l l y ca us ed by uncons ci ous a eropha gi a or i ncrea s ed s ens i ti vi ty to norma l
a mounts of ga s . Aeropha gi a ma y be reduced by el i mi na ti ng gum a nd ca rbona ted bevera ges , cogni ti ve beha vi ora l techni ques to prevent a i r
s wa l l owi ng, a nd ma na gement of a s s oci a ted upper GI di s ea s es (eg, pepti c ul cer). Foods conta i ni ng una bs orba bl e ca rbohydra tes s houl d be
a voi ded. Even l a ctos e-i ntol era nt pa ti ents genera l l y tol era te up to 1 gl a s s of mi l k drunk i n s ma l l a mounts throughout the da y. The mecha ni s m of
repea ted bel chi ng s houl d be expl a i ned a nd demons tra ted. When a eropha gi a i s troubl es ome, beha vi ora l thera py to encoura ge open-mouth,
di a phra gma ti c brea thi ng a nd mi ni mi ze s wa l l owi ng ma y be effecti ve.
Sidebar 8-1 Essay on Flatulence

(Fi rs t pri nted i n the 14th Edi ti on of The Merck Manual)
Fl a tul ence, whi ch ca n ca us e grea t ps ychos oci a l di s tres s , i s unoffi ci a l l y des cri bed a ccordi ng to i ts s a l i ent cha ra cteri s ti cs : (1) the "s l i der" (crowded
el eva tor type), whi ch i s rel ea s ed s l owl y a nd noi s el es s l y, s ometi mes wi th deva s ta ti ng effect; (2) the open s phi ncter, or "pooh" type, whi ch i s s a i d
to be of hi gher tempera ture a nd more a roma ti c; (3) the s ta cca to or drumbea t type, pl ea s a ntl y pa s s ed i n pri va cy; a nd (4) the "ba rk" type (des cri bed
i n a pers ona l communi ca ti on) i s cha ra cteri zed by a s ha rp excl a ma tory erupti on tha t effecti vel y i nterrupts (a nd often concl udes ) convers a ti on.
Aroma ti ci ty i s not a promi nent fea ture. Ra rel y, thi s us ua l l y di s tres s i ng s ymptom ha s been turned to a dva nta ge, a s wi th a Frenchma n referred to a s
"Le Petoma ne," who beca me a ffl uent a s a n effl uent performer who pl a yed tunes wi th the ga s from hi s rectum on the Moul i n Rouge s ta ge.
Drugs provi de l i ttl e benefi t. Res ul ts wi th s i methi cone, a n a gent tha t brea ks up s ma l l ga s bubbl es , a nd va ri ous a nti chol i nergi cs a re poor. Some
pa ti ents wi th dys peps i a a nd pos tpra ndi a l upper a bdomi na l ful l nes s benefi t from a nta ci ds , a l ow dos e of tri cycl i c a nti depres s a nts (eg,
nortri ptyl i ne 10 to 50 mg po once/da y), or both to reduce vi s cera l hypers ens i ti vi ty.
Compl a i nts of exces s fl a tus a re trea ted wi th a voi da nce of tri ggeri ng s ubs ta nces (s ee Ta bl e 8-5). Rougha ge (eg, bra n, ps yl l i um s eed) ma y be a dded
to the di et to try to i ncrea s e col oni c tra ns i t; however, i n s ome pa ti ents , wors eni ng of s ymptoms ma y res ul t. Acti va ted cha rcoa l ca n s ometi mes hel p
reduce ga s a nd unpl ea s a nt odor; however, i t s ta i ns cl othi ng a nd the ora l mucos a . Cha rcoa l -l i ned underga rments a re a va i l a bl e. Probi oti cs (eg,
VSL#3) ma y a l s o reduce bl oa ti ng a nd fl a tul ence by modul a ti ng i ntes ti na l ba cteri a l fl ora . Anti bi oti cs a re us eful i n pa ti ents wi th documented
ba cteri a l overgrowth.
Functi ona l bl oa ti ng, di s tenti on, a nd fl a tus ma y run a n i ntermi ttent, chroni c cours e tha t i s onl y pa rti a l l y rel i eved by thera py. When a ppropri a te,
rea s s ura nce tha t thes e probl ems a re not detri menta l to hea l th i s i mporta nt.
Key Points
Tes ti ng s houl d be gui ded by the cl i ni ca l fea tures .
Cl i ni ci a ns s houl d be wa ry of new-ons et, pers i s tent s ymptoms i n ol der pa ti ents .
Chapter 9. Diagnostic and Therapeutic GI Procedures

Introduction
Di a gnos ti c tes ts a nd thera peuti c procedures a va i l a bl e for pa ti ents wi th GI di s orders i ncl ude a ci d-rel a ted tes ts , endos copy, l a pa ros copy,
ma nometry, nucl ea r s ca ns , x-ra y contra s t s tudi es , na s oga s tri c or i ntes ti na l i ntuba ti on, a nos copy a nd s i gmoi dos copy, a bdomi na l pa ra centes i s ,
el ectroga s trogra phy, a nd el ectri ca l i mpeda nce tes ti ng. CT, MRI, a nd ul tra s onogra phy a re a l s o commonl y done for GI di s orders , a nd s ometi mes
a ngi ogra phy i s us ed. The s el ecti on of procedures i s di s cus s ed i n s ubs equent cha pters . ERCP, percuta neous tra ns hepa ti c chol a ngi ogra phy, a nd
l i ver bi ops y a re di s cus s ed i n Ch. 24.
Acid-Related Tests
Aci d-rel a ted tes ts a re us ed to a s certa i n the effecti venes s of a ci d-bl ocki ng drugs . Al l requi re na s oga s tri c or na s oes opha gea l i ntuba ti on.
Compl i ca ti ons a re very ra re. Pa ti ents mus t ha ve nothi ng by mouth (npo) a fter mi dni ght.
Ambulatory pH Monitoring
Ambul a tory 24-h es opha gea l pH moni tori ng i s currentl y the bes t a va i l a bl e tes t for qua nti fyi ng es opha gea l a ci d expos ure. The pri nci pa l i ndi ca ti ons
a re
To document exces s i ve a ci d expos ure i n pa ti ents wi thout endos copi c evi dence of es opha gi ti s
To eva l ua te the effecti venes s of medi ca l or s urgi ca l trea tments
A thi n tube conta i ni ng a pH probe i s pos i ti oned 5 cm a bove the l ower es opha gea l s phi ncter. The pa ti ent records s ymptoms , mea l s , a nd s l eep for
24 h. Es opha gea l a ci d expos ure i s defi ned by the percenta ge of the 24-h recordi ng ti me tha t the pH i s < 4.0. Va l ues > 3.5% a re cons i dered
a bnorma l . However, s ymptoms ma y not correl a te wi th a ci d expos ure or the pres ence of es opha gi ti s . Thi s ma y be beca us e s ymptoms ma y res ul t
from nona ci di c a s wel l a s a ci di c refl uxa te. Mul ti cha nnel i ntra l umi na l i mpeda nce tes ti ng a l l ows for recogni ti on of ma jor a ci d, mi nor a ci d, nona ci d,
a nd ga s refl ux, a l l of whi ch ca n ca us e refl ux s ymptoms .
Gastric Analysis
Sa mpl es of s toma ch contents obta i ned vi a NGT a re us ed to mea s ure ga s tri c a ci d output i n a ba s a l a nd s ti mul a ted s ta te. Thi s i nforma ti on ma y be
us eful i n a pa ti ent who devel ops a recurrent ul cer a fter s urgi ca l va gotomy for pepti c ul cer di s ea s e. In thi s ca s e, a pos i ti ve a ci d res pons e to
s ti mul a ti on (s ha m feedi ng) i ndi ca tes a n i ncompl ete va gotomy. The tes t a l s o i s us ed to eva l ua te a pa ti ent wi th el eva ted s erum ga s tri n l evel s .
Hyperchl orhydri a i n the pres ence of el eva ted ga s tri n us ua l l y i ndi ca tes Zol l i nger-El l i s on s yndrome. Hypochl orhydri a i n the pres ence of el eva ted
ga s tri n i ndi ca tes i mpa i rment of a ci d output, s uch a s occurs i n perni ci ous a nemi a , a trophi c ga s tri ti s , a nd Menetri er's di s ea s e a nd a fter i nhi bi ti on
of ga s tri c a ci d s ecreti on by potent a nti s ecretory drugs .
To do ga s tri c a na l ys i s , a n NGT i s i ns erted a nd the ga s tri c contents a re a s pi ra ted a nd di s ca rded. Ga s tri c jui ce i s then col l ected for 1 h, di vi ded i nto
four 15-mi n s a mpl es . Thes e s a mpl es repres ent ba s a l a ci d output.
Endoscopy
Fl exi bl e endos copes equi pped wi th vi deo ca mera s ca n be us ed to vi ew the upper GI tra ct from pha rynx to upper duodenum a nd the l ower GI tra ct
from a nus to cecum (a nd, s ometi mes , termi na l i l eum). Severa l other di a gnos ti c a nd thera peuti c i nterventi ons a l s o ca n be done endos copi ca l l y.
The potenti a l to combi ne di a gnos i s a nd thera py i n one procedure gi ves endos copy a s i gni fi ca nt a dva nta ge over procedures tha t provi de onl y
i ma gi ng (eg, x-ra y contra s t s tudi es , CT, MRI) a nd often outwei ghs endos copy's hi gher cos t a nd need for s eda ti on.
Di a gnos ti c procedures i ncl ude the us e of ul tra s ound-equi pped endos copes to eva l ua te bl ood fl ow or provi de i ma gi ng of l es i ons . Endos copi c
ul tra s ound ca n provi de i nforma ti on (eg, the depth a nd extent of l es i ons ) tha t i s not a va i l a bl e vi a conventi ona l endos copy. Other di a gnos ti c
procedures i ncl ude cel l a nd ti s s ue s a mpl e col l ecti on by brus h or bi ops y forceps .
Screeni ng col onos copy i s recommended for pa ti ents a t hi gh ri s k of col on ca ncer a nd for everyone 50. Col onos copy s houl d be done every 10 yr for
pa ti ents wi th no ri s k fa ctors a nd wi th a norma l i ni ti a l col onos copy. CT col onogra phy (s ee p. 98) i s a n a l terna ti ve to col onos copy for s creeni ng for
col oni c tumors .
Thera peuti c endos copi c procedures i ncl ude remova l of forei gn bodi es ; hemos ta s i s by therma l coa gul a ti on, l a s er photocoa gul a ti on, va ri cea l
ba ndi ng, or s cl erothera py; debul ki ng of tumors by l a s er or bi pol a r el ectrocoa gul a ti on; di l a ti on of webs or s tri ctures ; s tent pl a cement; reducti on of
vol vul us or i ntus s us cepti on; a nd decompres s i on of a cute or s uba cute col oni c di l a ta ti on.
Absolute contraindications to endos copy i ncl ude
Shock
Acute MI
Peri toni ti s
Acute perfora ti on
Ful mi na nt col i ti s
Rel a ti ve contra i ndi ca ti ons i ncl ude poor pa ti ent coopera ti on, coma (unl es s the pa ti ent i s i ntuba ted), a nd ca rdi a c a rrhythmi a s or recent myoca rdi a l
i s chemi a .
Pa ti ents ta ki ng a nti coa gul a nts or chroni c NSAID thera py ca n s a fel y undergo di a gnos ti c endos copy. However, i f there i s a pos s i bi l i ty tha t bi ops y or
photocoa gul a ti on wi l l be done, thes e drugs s houl d be s topped for a n a ppropri a te i nterva l before the procedure. Ora l i ron-conta i ni ng drugs
s houl d be s topped 4 to 5 da ys before col onos copy, beca us e certa i n green vegeta bl es i ntera ct wi th i ron to form a s ti cky res i due tha t i s di ffi cul t to
remove wi th a bowel prepa ra ti on a nd i nterferes wi th vi s ua l i za ti on. The Ameri ca n Hea rt As s oci a ti on no l onger recommends endoca rdi ti s
prophyl a xi s for pa ti ents ha vi ng GI endos copy.
Routi ne prepa ra ti ons for endos copy i ncl ude no s ol i ds for 6 to 8 h a nd no l i qui ds for 4 h before the procedure. Addi ti ona l l y, col onos copy requi res
cl ea ns i ng of the col on. A va ri ety of regi mens ma y be us ed, but a l l typi ca l l y i ncl ude a ful l or cl ea r l i qui d di et for 24 to 48 h a nd s ome type of
l a xa ti ve, wi th or wi thout a n enema . A common l a xa ti ve prepa ra ti on i nvol ves ha vi ng the pa ti ent dri nk a hi gh-vol ume (4 L) ba l a nced el ectrol yte
s ol uti on over a peri od of 3 to 4 h before the procedure. Pa ti ents who ca nnot tol era te thi s s ol uti on ma y be gi ven Mg ci tra te, Na phos pha te,
l a ctul os e, or other l a xa ti ves . Enema s ca n be done wi th ei ther Na phos pha te or ta p wa ter. Phos pha te prepa ra ti ons s houl d not be us ed i n pa ti ents
wi th rena l i ns uffi ci ency.
Endos copy genera l l y requi res IV s eda ti on a nd, for upper endos copy, topi ca l a nes thes i a of the throa t. Excepti ons a re a nos copy a nd s i gmoi dos copy
(s ee p. 98), whi ch genera l l y requi re nothi ng. The overa l l compl i ca ti on ra te of endos copy i s 0.1 to 0.2%; morta l i ty i s a bout 0.03%. Compl i ca ti ons a re
us ua l l y drug rel a ted (eg, res pi ra tory depres s i on); procedura l compl i ca ti ons (eg, a s pi ra ti on, perfora ti on, s i gni fi ca nt bl eedi ng) a re l es s common.
Video capsule endoscopy: In vi deo ca ps ul e endos copy (wi rel es s vi deo endos copy), pa ti ents s wa l l ow a ca ps ul e conta i ni ng a ca mera tha t tra ns mi ts
i ma ges to a n externa l recorder. Thi s noni nva s i ve technol ogy provi des di a gnos ti c i ma gi ng of the s ma l l bowel tha t i s otherwi s e di ffi cul t to obta i n.
Thi s procedure i s pa rti cul a rl y us eful i n pa ti ents wi th occul t GI bl eedi ng. Ca ps ul e endos copy i s more di ffi cul t i n the col on; products a nd procedures
a re under devel opment.
Laparoscopy
Di a gnos ti c l a pa ros copy i s a s urgi ca l procedure us ed to eva l ua te i ntra -a bdomi na l or pel vi c pa thol ogy (eg, tumor, endometri os i s ) i n pa ti ents wi th
a cute or chroni c a bdomi na l pa i n a nd opera bi l i ty i n pa ti ents wi th ca ncer. It a l s o i s us ed for l ymphoma s ta gi ng a nd l i ver bi ops y.
Absolute contraindications i ncl ude
A coa gul a ti on or bl eedi ng di s order
Poor pa ti ent coopera ti on
Peri toni ti s
Intes ti na l obs tructi on
Infecti on of the a bdomi na l wa l l
Rel a ti ve contra i ndi ca ti ons i ncl ude s evere ca rdi a c or pul mona ry di s ea s e, l a rge a bdomi na l herni a s , mul ti pl e a bdomi na l opera ti ons , a nd tens e
a s ci tes .
CBC, coa gul a ti on s tudi es , a nd type a nd Rh tes ti ng a re done before l a pa ros copy. X-ra ys of the ches t a nd a bdomen (ki dneys , ureters , a nd bl a dder)
a re a l s o ta ken. La pa ros copy i s done wi th s teri l e techni que i n a n opera ti ng room or a wel l -equi pped endos copy s ui te. The pa ti ent i s gi ven l oca l
a nes thes i a pl us IV s eda ti on a nd a na l ges i a wi th a n opi oi d a nd s hort-a cti ng s eda ti ve (eg, mi da zol a m, propofol ).
The procedure i nvol ves i ns erti on of a pneumoperi toneum needl e i nto the peri tonea l ca vi ty a nd i nfus i on of ni trous oxi de to di s tend the a bdomen.
After the openi ng i s enl a rged, a peri toneos cope i s i ns erted i nto the a bdomen a nd the a bdomi na l contents a re exa mi ned. Surgi ca l i ns truments for
bi ops y a nd other procedures a re i ns erted through s epa ra te openi ngs . When the procedure i s compl eted, the ni trous oxi de i s expel l ed by the
pa ti ent wi th a Va l s a l va ma neuver a nd the ca nnul a i s removed. Compl i ca ti ons ca n i ncl ude bl eedi ng, ba cteri a l peri toni ti s , a nd perfora ti on of a
vi s cus .
Manometry
Ma nometry i s mea s urement of pres s ure wi thi n va ri ous pa rts of the GI tra ct. It i s done by pa s s i ng a ca theter conta i ni ng s ol i d-s ta te or l i qui d-fi l l ed
pres s ure tra ns ducers through the mouth or a nus i nto the l umen of the orga n to be s tudi ed. Ma nometry typi ca l l y i s done to eva l ua te moti l i ty
di s orders i n pa ti ents i n whom s tructura l l es i ons ha ve been rul ed out by other s tudi es . Ma nometry i s us ed i n the es opha gus , s toma ch a nd
duodenum, s phi ncter of Oddi , a nd rectum. As i de from mi nor di s comfort, compl i ca ti ons a re very ra re. Pa ti ents mus t ha ve nothi ng by mouth (npo)
a fter mi dni ght.
Esophageal manometry: Thi s tes t i s us ed to eva l ua te pa ti ents wi th dys pha gi a , hea rtburn, or ches t pa i n. It mea s ures the pres s ure i n the upper a nd
l ower es opha gea l s phi ncters , determi nes the effecti venes s a nd coordi na ti on of propul s i ve movements , a nd detects a bnorma l contra cti ons .
Ma nometry i s us ed to di a gnos e a cha l a s i a , di ffus e s pa s m, s ys temi c s cl eros i s , a nd l ower es opha gea l s phi ncter hypotens i on a nd hypertens i on. It
a l s o i s us ed to eva l ua te es opha gea l functi on before certa i n thera peuti c procedures (eg, a nti refl ux s urgery, pneuma ti c di l a ti on for a cha l a s i a ).
Gastroduodenal manometry: In thi s tes t, tra ns ducers a re pl a ced i n the ga s tri c a ntrum, duodenum, a nd proxi ma l jejunum. Pres s ure i s moni tored for 5
to 24 h i n both fa s ti ng a nd fed s ta tes . Thi s tes t i s us ed ma i nl y i n pa ti ents who ha ve s ymptoms s ugges ti ve of dys moti l i ty but norma l ga s tri c
emptyi ng s tudi es .
Barostat: Thi s i s a pres s ure-s ens i ng devi ce tha t i s pl a ced i n the s toma ch to mea s ure ga s tri c a ccommoda ti on. The devi ce cons i s ts of a pl a s ti c
ba l l oon a nd a n el ectroni c control l er tha t va ri es the a mount of a i r i n the ba l l oon to ma i nta i n cons ta nt pres s ure. Thi s devi ce i s us ed ma i nl y i n
res ea rch s tudi es a s s es s i ng s ens ory thres hol d a nd a l tered vi s cera l percepti on, pa rti cul a rl y i n functi ona l GI di s orders .
Anorectal manometry: Thi s tes t eva l ua tes the a norecta l s phi ncter mecha ni s m a nd recta l s ens a ti on i n pa ti ents wi th i nconti nence (a nd s ometi mes
cons ti pa ti on) by mea ns of a pres s ure tra ns ducer i n the a nus . It ca n hel p di a gnos e Hi rs chs prung's di s ea s e a nd provi de bi ofeedba ck tra i ni ng for
feca l i nconti nence.
Nuclear Scans
Gastric emptying ca n be mea s ured by ha vi ng the pa ti ent i nges t a ra di ol a bel ed mea l (s ol i d or l i qui d) a nd obs ervi ng i ts pa s s a ge out of the s toma ch
wi th a ga mma ca mera . Beca us e thi s tes t ca nnot di fferenti a te phys i ca l obs tructi on from ga s tropa res i s , further di a gnos ti c s tudi es typi ca l l y a re done
i f emptyi ng i s del a yed. The tes t a l s o i s us eful i n moni tori ng res pons e to promoti l i ty drugs (eg, metocl opra mi de, erythromyci n).
Bleeding scans us e 99mTc-l a bel ed RBCs , or occa s i ona l l y 99mTc-l a bel ed col l oi d, to determi ne the ori gi n of l ower GI hemorrha ge before s urgery or
a ngi ogra phy. Acti ve bl eedi ng s i tes a re i denti fi ed by foca l a rea s of tra cer tha t conform to bowel a na tomy, i ncrea s e wi th ti me, a nd move wi th
peri s ta l s i s . Bl eedi ng s ca ns a re us eful ma i nl y for col oni c bl eedi ng i n pa ti ents wi th s i gni fi ca nt hemorrha ge a nd a n unprepa red bowel , i n whom
endos copi c vi s ua l i za ti on i s di ffi cul t.
A Meckel scan i denti fi es ectopi c ga s tri c mucos a (a s i n a Meckel 's di verti cul um) by us i ng a n i njecti on of 99mTc pertechneta te, whi ch i s ta ken up by
mucus -s ecreti ng cel l s of the ga s tri c mucos a . Foca l upta ke outs i de of the s toma ch a nd i n the s ma l l bowel i ndi ca tes a Meckel 's di verti cul um.
X-Ray and Other Imaging Contrast Studies
X-ra y a nd other i ma gi ng contra s t s tudi es vi s ua l i ze the enti re GI tra ct from pha rynx to rectum a nd a re mos t us eful for detecti ng ma s s l es i ons a nd
s tructura l a bnorma l i ti es (eg, tumors , s tri ctures ). Si ngl e-contra s t s tudi es fi l l the l umen wi th ra di opa que ma teri a l , outl i ni ng the s tructure. Better,
more deta i l ed i ma ges a re obta i ned from doubl e-contra s t s tudi es , i n whi ch a s ma l l a mount of hi gh-dens i ty ba ri um coa ts the mucos a l s urfa ce a nd
ga s di s tends the orga n a nd enha nces contra s t. The ga s i s i njected by the opera tor i n doubl e-contra s t ba ri um enema , wherea s i n other s tudi es ,
i ntri ns i c GI tra ct ga s i s a dequa te. In a l l ca s es , pa ti ents turn thems el ves to properl y di s tri bute the ga s a nd ba ri um. Fl uoros copy ca n moni tor the
progres s of the contra s t ma teri a l . Ei ther vi deo or pl a i n fi l ms ca n be ta ken for documenta ti on, but vi deo i s pa rti cul a rl y us eful when a s s es s i ng
motor di s orders (eg, cri copha ryngea l s pa s m, a cha l a s i a ).
The ma i n contra i ndi ca ti on to x-ra y contra s t s tudi es i s s us pected perfora ti on, beca us e free ba ri um i s hi ghl y i rri ta ti ng to the medi a s ti num a nd
peri toneum; wa ter-s ol ubl e contra s t i s l es s i rri ta ti ng a nd ma y be us ed i f perfora ti on i s pos s i bl e. Ol der pa ti ents ma y ha ve di ffi cul ty turni ng
thems el ves to properl y di s tri bute the ba ri um a nd i ntra l umi na l ga s .
Pa ti ents ha vi ng upper GI x-ra y contra s t s tudi es mus t ha ve nothi ng by mouth (npo) a fter mi dni ght. Pa ti ents ha vi ng ba ri um enema fol l ow a cl ea r
l i qui d di et the da y before, ta ke a n ora l Na phos pha te l a xa ti ve i n the a fternoon, a nd ta ke a bi s a codyl s uppos i tory i n the eveni ng. Other l a xa ti ve
regi mens a re effecti ve.
Compl i ca ti ons a re ra re. Perfora ti on ca n occur i f ba ri um enema i s done i n a pa ti ent wi th toxi c mega col on. Ba ri um i mpa cti on ma y be prevented by
pos tprocedure ora l fl ui ds a nd s ometi mes l a xa ti ves .
An upper GI examination i s bes t done a s a bi pha s i c s tudy begi nni ng wi th a doubl e-contra s t exa mi na ti on of the es opha gus , s toma ch, a nd
duodenum, fol l owed by a s i ngl e-contra s t s tudy us i ng l ow-dens i ty ba ri um. Gl uca gon 0.5 mg IV ca n fa ci l i ta te the exa mi na ti on by ca us i ng ga s tri c
hypotoni a .
A small-bowel meal i s done by us i ng fl uoros copy a nd provi des a more deta i l ed eva l ua ti on of the s ma l l bowel . Shortl y before the exa mi na ti on, the
pa ti ent i s gi ven metocl opra mi de 20 mg po to ha s ten tra ns i t of the contra s t ma teri a l .
Enteroclysis (s ma l l -bowel enema ) provi des s ti l l better vi s ua l i za ti on of the s ma l l bowel but requi res i ntuba ti on of the duodenum wi th a fl exi bl e,
ba l l oon-ti pped ca theter. A ba ri um s us pens i on i s i njected, fol l owed by a s ol uti on of methyl cel l ul os e, whi ch functi ons a s a doubl e-contra s t a gent
tha t enha nces vi s ua l i za ti on of the s ma l l -bowel mucos a .
A barium enema ca n be done a s a s i ngl e-or doubl e-contra s t s tudy. Si ngl e-contra s t ba ri um enema s a re us ed for potenti a l obs tructi on, di verti cul i ti s ,
fi s tul a s , a nd mega col on. Doubl e-contra s t s tudi es a re preferred for detecti on of tumors .
CT scanning of the abdomen: CT s ca nni ng us i ng ora l a nd IV contra s t a l l ows excel l ent vi s ua l i za ti on of both the s ma l l bowel a nd col on a s wel l a s of
other i ntra -a bdomi na l s tructures .
CT enterography provi des opti ma l vi s ua l i za ti on of the s ma l l -bowel mucos a ; i t i s prefera bl y done by us i ng a mul ti detector CT (MDCT) s ca nner.
Pa ti ents a re gi ven a l a rge vol ume (1350 mL) of 0.1% ba ri um s ul fa te before i ma gi ng. For certa i n i ndi ca ti ons (eg, obs cure GI bl eedi ng, s ma l l -bowel
tumors , chroni c i s chemi a ), a bi pha s i c contra s t-enha nced MDCT s tudy i s done.
CT colonography (vi rtua l col onos copy) genera tes 3D a nd 2D i ma ges of the col on by us i ng MDCT a nd a combi na ti on of ora l contra s t a nd ga s
di s tenti on of the col on. Vi ewi ng the hi gh-res ol uti on 3D i ma ges s omewha t s i mul a tes the a ppea ra nce of opti ca l endos copy, hence the na me.
Opti ma l CT col onogra phy techni que requi res ca reful cl ea ns i ng a nd di s tenti on of the col on. Res i dua l s tool ca us es probl ems s i mi l a r to thos e
encountered wi th ba ri um enema beca us e i t s i mul a tes pol yps or ma s s es . Three-di mens i ona l endol umi na l i ma ges a re us eful to confi rm the
pres ence of a l es i on a nd to i mprove di a gnos ti c confi dence.
CT enterogra phy a nd CT col onos copy ha ve l a rgel y s uppl a nted s ta nda rd s ma l l -bowel s eri es a nd ba ri um enema exa mi na ti ons .
GI Procedures for the Generalist
Nasogastric or Intestinal Intubation
Na s oga s tri c or i ntes ti na l i ntuba ti on i s us ed to decompres s the s toma ch. It i s us ed to trea t ga s tri c a tony, i l eus , or obs tructi on; remove i nges ted
toxi ns , gi ve a nti dotes (eg, a cti va ted cha rcoa l ), or both; obta i n a s a mpl e of ga s tri c contents for a na l ys i s (vol ume, a ci d content, bl ood); a nd s uppl y
nutri ents .
Contraindications i ncl ude
Na s opha ryngea l or es opha gea l obs tructi on
Severe ma xi l l ofa ci a l tra uma
Uncorrected coa gul a ti on a bnorma l i ti es
Es opha gea l va ri ces previ ous l y ha ve been cons i dered a contra i ndi ca ti on, but evi dence of a dvers e effects i s l a cki ng.
Severa l types of tubes a re a va i l a bl e. A Levi n or Sa l em s ump tube i s us ed for ga s tri c decompres s i on or a na l ys i s a nd ra rel y for s hort-term feedi ng. A
va ri ety of l ong, thi n, i ntes ti na l tubes a re us ed for l ong-term entera l feedi ng (s ee p. 21).
For i ntuba ti on, the pa ti ent s i ts upri ght or, i f una bl e, l i es i n the l eft l a tera l decubi tus pos i ti on. A topi ca l a nes theti c s pra yed i n the nos e a nd
pha rynx hel ps reduce di s comfort. Wi th the pa ti ent's hea d pa rti a l l y fl exed, the l ubri ca ted tube i s i ns erted through the na res a nd a i med ba ck a nd
then down to conform to the na s opha rynx. As the ti p rea ches the pos teri or pha ryngea l wa l l , the pa ti ent s houl d s i p wa ter through a s tra w. Vi ol ent
coughi ng wi th fl ow of a i r through the tube duri ng res pi ra ti on i ndi ca tes tha t the tube i s mi s pl a ced i n the tra chea . As pi ra ti on of ga s tri c jui ce veri fi es
entry i nto the s toma ch. The pos i ti on of l a rger tubes ca n be confi rmed by i ns ti l l i ng 20 to 30 mL of a i r a nd l i s teni ng wi th the s tethos cope under the
l eft s ubcos ta l regi on for a rus h of a i r.
Some s ma l l er, more fl exi bl e i ntes ti na l feedi ng tubes requi re the us e of s ti ffeni ng wi res or s tyl ets . Thes e tubes us ua l l y requi re fl uoros copi c or
endos copi c a s s i s ta nce for pa s s a ge through the pyl orus .
Compl i ca ti ons a re ra re a nd i ncl ude na s opha ryngea l tra uma wi th or wi thout hemorrha ge, pul mona ry a s pi ra ti on, tra uma ti c es opha gea l or ga s tri c
hemorrha ge or perfora ti on, a nd (very ra rel y) i ntra cra ni a l or medi a s ti na l penetra ti on.
Anoscopy and Sigmoidoscopy
Anos copy a nd s i gmoi dos copy a re us ed to eva l ua te s ymptoms refera bl e to the rectum or a nus (eg, bri ght recta l bl eedi ng, di s cha rge, protrus i ons ,
pa i n). There a re no a bs ol ute contra i ndi ca ti ons . Pa ti ents wi th ca rdi a c a rrhythmi a s or recent myoca rdi a l i s chemi a s houl d ha ve the procedure
pos tponed unti l the comorbi d condi ti ons i mprove; otherwi s e, pa ti ents wi l l need ca rdi a c moni tori ng. Per cha nges i n Ameri ca n Hea rt As s oci a ti on
gui del i nes , thes e procedures no l onger requi re endoca rdi ti s prophyl a xi s .
The peri a na l a rea a nd di s ta l rectum ca n be exa mi ned wi th a 7-cm a nos cope, a nd the rectum a nd s i gmoi d wi th ei ther a ri gi d 25-cm or a fl exi bl e 60cm i ns trument. Fl exi bl e s i gmoi dos copy i s much more comforta bl e for the pa ti ent a nd rea di l y permi ts photogra phy a nd bi ops y of ti s s ue.
Cons i dera bl e s ki l l i s requi red to pa s s a ri gi d s i gmoi dos cope beyond the rectos i gmoi d juncti on (15 cm) wi thout ca us i ng di s comfort.
Si gmoi dos copy i s done a fter gi vi ng a n enema to empty the rectum. IV drugs a re us ua l l y not needed. The pa ti ent i s pl a ced i n the l eft l a tera l
pos i ti on. After externa l i ns pecti on a nd di gi ta l recta l exa mi na ti on, the l ubri ca ted i ns trument i s gentl y i ns erted 3 to 4 cm pa s t the a na l s phi ncter. At
thi s poi nt, the obtura tor of the ri gi d s i gmoi dos cope i s removed, a nd the i ns trument i s i ns erted further under di rect vi s i on.
Anos copy ma y be done wi thout prepa ra ti on. The a nos cope i s i ns erted i ts ful l l ength a s des cri bed a bove for ri gi d s i gmoi dos copy, us ua l l y wi th the
pa ti ent i n the l eft l a tera l pos i ti on. Compl i ca ti ons a re exceedi ngl y ra re when the procedure i s done properl y.
Abdominal Paracentesis
Abdomi na l pa ra centes i s i s us ed to obta i n a s ci ti c fl ui d for tes ti ng. It a l s o ca n be us ed to remove tens e a s ci tes ca us i ng res pi ra tory di ffi cul ti es or
pa i n or a s a trea tment for chroni c a s ci tes .
Absolute contraindications i ncl ude
Severe, uncorrecta bl e di s orders of bl ood coa gul a ti on
Intes ti na l obs tructi on
An i nfected a bdomi na l wa l l
Poor pa ti ent coopera ti on, s urgi ca l s ca rri ng over the puncture a rea , a nd s evere porta l hypertens i on wi th a bdomi na l col l a tera l ci rcul a ti on a re
rel a ti ve contra i ndi ca ti ons .
CBC, pl a tel et count, a nd coa gul a ti on s tudi es a re done before the procedure. After emptyi ng the bl a dder, the pa ti ent s i ts i n bed wi th the hea d
el eva ted 45 to 90. In pa ti ents wi th obvi ous a nd ma rked a s ci tes , a poi nt i s l oca ted a t the mi dl i ne between the umbi l i cus a nd the pubi c bone a nd
i s cl ea ned wi th a n a nti s epti c s ol uti on a nd a l cohol . In pa ti ents wi th modera te a s ci tes , preci s e l oca ti on of a s ci ti c fl ui d by a bdomi na l ul tra s ound i s
i ndi ca ted. Under s teri l e techni que, the a rea i s a nes theti zed to the peri toneum wi th l i doca i ne 1%. For di a gnos ti c pa ra centes i s , a n 18-ga uge
needl e a tta ched to a 50-mL s yri nge i s i ns erted through the peri toneum (genera l l y a poppi ng s ens a ti on i s noted). Fl ui d i s gentl y a s pi ra ted a nd
s ent for cel l count, protei n or a myl a s e content, cytol ogy, or cul ture a s needed. For thera peuti c (l a rge-vol ume) pa ra centes i s , a 14-ga uge ca nnul a
a tta ched to a va cuum a s pi ra ti on s ys tem i s us ed to col l ect up to 8 L of a s ci ti c fl ui d. Pos tprocedure hypotens i on ca us ed by fl ui d redi s tri buti on i s ra re
a s l ong a s i nters ti ti a l (l eg) edema i s pres ent.
Hemorrha ge i s the mos t common compl i ca ti on. Occa s i ona l l y, wi th tens e a s ci tes , prol onged l ea ka ge of a s ci ti c fl ui d occurs through the needl e s i te.
Other Testing Procedures
Electrogastrography mea s ures ga s tri c el ectri ca l a cti vi ty wi th a dhes i ve cuta neous el ectrodes . Thi s procedure i s us eful i n pa ti ents wi th ga s tropa res i s .
In electrical impedance testing, a n el ectri ca l s ens or i s pl a ced i n the di s ta l es opha gus to a s s es s nona ci d refl ux, whi ch i s common a mong pa ti ents
recei vi ng ga s tri c a nti s ecretory drugs a nd a mong i nfa nts wi th refl ux di s ea s e.
Chapter 10. GI Bleeding

Introduction
GI bl eedi ng ca n ori gi na te a nywhere from the mouth to the a nus a nd ca n be overt or occul t. The ma ni fes ta ti ons depend on the l oca ti on a nd ra te of
bl eedi ng.
Hema temes i s i s vomi ti ng of red bl ood a nd i ndi ca tes upper GI bl eedi ng, us ua l l y from a n a rteri a l s ource or va ri x. Coffee-ground emes i s i s vomi ti ng
of da rk brown, gra nul a r ma teri a l tha t res embl es coffee grounds . It res ul ts from upper GI bl eedi ng tha t ha s s l owed or s topped, wi th convers i on of
red Hb to brown hema ti n by ga s tri c a ci d.
Hema tochezi a i s the pa s s a ge of gros s bl ood from the rectum a nd us ua l l y i ndi ca tes l ower GI bl eedi ng but ma y res ul t from vi gorous upper GI
bl eedi ng wi th ra pi d tra ns i t of bl ood through the i ntes ti nes .
Mel ena i s bl a ck, ta rry s tool a nd typi ca l l y i ndi ca tes upper GI bl eedi ng, but bl eedi ng from a s ource i n the s ma l l bowel or ri ght col on ma y a l s o be the
ca us e. About 100 to 200 mL of bl ood i n the upper GI tra ct i s requi red to ca us e mel ena , whi ch ma y pers i s t for s evera l da ys a fter bl eedi ng ha s
cea s ed. Bl a ck s tool tha t does not conta i n occul t bl ood ma y res ul t from i nges ti on of i ron, bi s muth, or va ri ous foods a nd s houl d not be mi s ta ken for
mel ena .
Chroni c occul t bl eedi ng ca n occur from a nywhere i n the GI tra ct a nd i s detecta bl e by chemi ca l tes ti ng of a s tool s peci men. Acute, s evere bl eedi ng
a l s o ca n occur from a nywhere i n the GI tra ct. Pa ti ents ma y pres ent wi th s i gns of s hock. Thos e wi th underl yi ng i s chemi c hea rt di s ea s e ma y devel op
a ngi na or MI beca us e of hypoperfus i on.
GI bl eedi ng ma y preci pi ta te porta l -s ys temi c encepha l opa thy (s ee p. 220) or hepa torena l s yndrome (ki dney fa i l ure s econda ry to l i ver fa i l ures ee
p. 223).
Etiology
There a re ma ny pos s i bl e ca us es (s ee
Ta bl e 10-1), whi ch a re di vi ded i nto upper GI (a bove the l i ga ment of Trei tz), l ower GI, a nd s ma l l bowel .
Bl eedi ng of a ny ca us e i s more l i kel y, a nd potenti a l l y more s evere, i n pa ti ents wi th chroni c l i ver di s ea s e (eg, ca us ed by a l cohol a bus e or chroni c
hepa ti ti s ), i n thos e wi th heredi ta ry coa gul a ti on di s orders , or i n thos e ta ki ng certa i n drugs . Drugs a s s oci a ted wi th GI bl eedi ng i ncl ude
a nti coa gul a nts (eg, hepa ri n, wa rfa ri n), thos e a ffecti ng pl a tel et functi on (eg, a s pi ri n a nd certa i n other NSAIDs , cl opi dogrel , SSRIs ), a nd thos e
a ffecti ng mucos a l defens es (eg, NSAIDs ).
Evaluation
Sta bi l i za ti on wi th a i rwa y ma na gement, IV fl ui ds , or tra ns fus i ons i s es s enti a l before a nd duri ng di a gnos ti c eva l ua ti on.
History: History of present illness s houl d a ttempt to a s certa i n qua nti ty a nd frequency of bl ood pa s s a ge. However, qua nti ty ca n be di ffi cul t to a s s es s
beca us e even s ma l l a mounts (5 to 10 mL) of bl ood turn wa ter i n a toi l et bowl a n opa que red, a nd modes t a mounts of vomi ted bl ood a ppea r huge
to a n a nxi ous pa ti ent. However, mos t ca n di s ti ngui s h a mong bl ood s trea ks , a few tea s poons , a nd cl ots .
Pa ti ents wi th hema temes i s s houl d be a s ked whether bl ood wa s pa s s ed wi th i ni ti a l vomi ti ng or onl y a fter a n i ni ti a l (or s evera l ) nonbl oody
emes i s .
Pa ti ents wi th recta l bl eedi ng s houl d be a s ked whether pure bl ood wa s pa s s ed; whether i t wa s mi xed wi th s tool , pus , or mucus ; or whether bl ood
s i mpl y coa ted the s tool . Thos e wi th bl oody di a rrhea s houl d be a s ked a bout tra vel or other pos s i bl e expos ure to GI pa thogens .
[Table 10-1. Common Ca us es of GI Bl eedi ng]
Review of symptoms s houl d i ncl ude pres ence of a bdomi na l di s comfort, wei ght l os s , ea s y bl eedi ng or brui s i ng, previ ous col onos copy res ul ts , a nd
s ymptoms of a nemi a (eg, wea knes s , ea s y fa ti ga bi l i ty, di zzi nes s ).
Past medical history s houl d i nqui re a bout previ ous GI bl eedi ng (di a gnos ed or undi a gnos ed); known i nfl a mma tory bowel di s ea s e, bl eedi ng
di a thes es , a nd l i ver di s ea s e; a nd us e of a ny drugs tha t i ncrea s e the l i kel i hood of bl eedi ng or chroni c l i ver di s ea s e (eg, a l cohol ).
Physical examination: Genera l exa mi na ti on focus es on vi ta l s i gns a nd other i ndi ca tors of s hock or hypovol emi a (eg, ta chyca rdi a , ta chypnea , pa l l or,
di a phores i s , ol i guri a , confus i on) a nd a nemi a (eg, pa l l or, di a phores i s ). Pa ti ents wi th l es s er degrees of bl eedi ng ma y s i mpl y ha ve mi l d ta chyca rdi a
(hea rt ra te > 100). Orthos ta ti c cha nges i n pul s e (a cha nge of > 10 bea ts /mi n) or BP (a drop of 10 mm Hg) often devel op a fter a cute l os s of 2 uni ts
of bl ood. However, orthos ta ti c mea s urements a re unwi s e i n pa ti ents wi th s evere bl eedi ng (pos s i bl y ca us i ng s yncope) a nd genera l l y l a ck
s ens i ti vi ty a nd s peci fi ci ty a s a mea s ure of i ntra va s cul a r vol ume, es peci a l l y i n el derl y pa ti ents .
Externa l s ti gma ta of bl eedi ng di s orders (eg, petechi a e, ecchymos es ) a re s ought, a s a re s i gns of chroni c l i ver di s ea s e (eg, s pi der a ngi oma s ,
a s ci tes , pa l ma r erythema ) a nd porta l hypertens i on (eg, s pl enomega l y, di l a ted a bdomi na l wa l l vei ns ).
A di gi ta l recta l exa mi na ti on i s neces s a ry to s ea rch for s tool col or, ma s s es , a nd fi s s ures . Anos copy i s done to di a gnos e hemorrhoi ds . Chemi ca l
tes ti ng of a s tool s peci men for occul t bl ood compl etes the exa mi na ti on i f gros s bl ood i s not pres ent.
Red flags: Severa l fi ndi ngs s ugges t hypovol emi a or hemorrha gi c s hock:
Syncope
Hypotens i on
Pa l l or
Di a phores i s
Ta chyca rdi a
Interpretation of findings: The hi s tory a nd phys i ca l exa mi na ti on s ugges t a di a gnos i s i n a bout 50% of pa ti ents , but fi ndi ngs a re ra rel y di a gnos ti c a nd
confi rma tory tes ti ng i s requi red.
Epi ga s tri c a bdomi na l di s comfort rel i eved by food or a nta ci ds s ugges ts pepti c ul cer di s ea s e. However, ma ny pa ti ents wi th bl eedi ng ul cers ha ve no
hi s tory of pa i n. Wei ght l os s a nd a norexi a , wi th or wi thout a cha nge i n s tool , s ugges t a GI ca ncer. A hi s tory of ci rrhos i s or chroni c hepa ti ti s s ugges ts
es opha gea l va ri ces . Dys pha gi a s ugges ts es opha gea l ca ncer or s tri cture. Vomi ti ng a nd retchi ng before the ons et of bl eedi ng s ugges ts a Ma l l oryWei s s tea r of the es opha gus , a l though a bout 50% of pa ti ents wi th Ma l l ory-Wei s s tea rs do not ha ve thi s hi s tory.
A hi s tory of bl eedi ng (eg, purpura , ecchymos i s , hema turi a ) ma y i ndi ca te a bl eedi ng di a thes i s (eg, hemophi l i a , hepa ti c fa i l ure). Bl oody di a rrhea ,
fever, a nd a bdomi na l pa i n s ugges t i s chemi c col i ti s , i nfl a mma tory bowel di s ea s e (eg, ul cera ti ve col i ti s , Crohn's di s ea s e), or a n i nfecti ous col i ti s
(eg, Shigella, Salmonella, Campylobacter, a mebi a s i s ). Hema tochezi a s ugges ts di verti cul os i s or a ngi odys pl a s i a . Fres h bl ood onl y on toi l et pa per or the
s urfa ce of formed s tool s s ugges ts i nterna l hemorrhoi ds or fi s s ures , wherea s bl ood mi xed wi th the s tool i ndi ca tes a more proxi ma l s ource. Occul t
bl ood i n the s tool ma y be the fi rs t s i gn of col on ca ncer or a pol yp, pa rti cul a rl y i n pa ti ents > 45 yr.
Bl ood i n the nos e or tri ckl i ng down the pha rynx s ugges ts the na s opha rynx a s the s ource. Spi der a ngi oma s , hepa tos pl enomega l y, or a s ci tes i s
cons i s tent wi th chroni c l i ver di s ea s e a nd hence pos s i bl e es opha gea l va ri ces . Arteri ovenous ma l forma ti ons , es peci a l l y of the mucous membra nes ,
s ugges t heredi ta ry hemorrha gi c tel a ngi ecta s i a (Rendu-Os l er-Weber s yndrome). Cuta neous na i l bed a nd GI tel a ngi ecta s i a ma y i ndi ca te s ys temi c
s cl eros i s or mi xed connecti ve ti s s ue di s ea s e.
Testing: Severa l tes ts a re done to hel p confi rm the s us pected di a gnos i s .
CBC a nd often other l a bora tory s tudi es
NGT for a l l but thos e wi th mi ni ma l recta l bl eedi ng
Upper endos copy for s us pected upper GI bl eedi ng
Col onos copy for l ower GI bl eedi ng (unl es s cl ea rl y ca us ed by hemorrhoi ds )
CBC s houl d be obta i ned i n pa ti ents wi th occul t bl ood l os s . Thos e wi th more s i gni fi ca nt bl eedi ng a l s o requi re coa gul a ti on s tudi es (eg, pl a tel et
count, PT, PTT) a nd l i ver functi on tes ts (eg, bi l i rubi n, a l ka l i ne phos pha ta s e, a l bumi n, AST, ALT). Type a nd cros s ma tch a re done i f bl eedi ng i s
ongoi ng. Hb a nd Hct ma y be repea ted up to every 6 h i n pa ti ents wi th s evere bl eedi ng. Addi ti ona l l y, one or more di a gnos ti c procedures a re
typi ca l l y requi red.
Na s oga s tri c a s pi ra ti on a nd l a va ge s houl d be done i n a l l pa ti ents wi th s us pected upper GI bl eedi ng (eg, hema temes i s , coffee-ground emes i s ,
mel ena , ma s s i ve recta l bl eedi ng). Bl oody na s oga s tri c a s pi ra te i ndi ca tes a cti ve upper GI bl eedi ng, but a bout 10% of pa ti ents wi th upper GI
bl eedi ng ha ve no bl ood i n the na s oga s tri c a s pi ra te. Coffee-ground ma teri a l i ndi ca tes bl eedi ng tha t i s s l ow or s topped. If there i s no s i gn of
bl eedi ng, a nd bi l e i s returned, the NGT i s removed; otherwi s e, i t i s l eft i n pl a ce to moni tor conti nui ng or recurrent bl eedi ng. Nonbl oody,
nonbi l i ous return i s cons i dered a nondi a gnos ti c a s pi ra te.
Upper endos copy (exa mi na ti on of the es opha gus , s toma ch, a nd duodenum) s houl d be done for upper GI bl eedi ng. Beca us e endos copy ma y be
thera peuti c a s wel l a s di a gnos ti c, i t s houl d be done ra pi dl y for s i gni fi ca nt bl eedi ng but ma y be deferred for 24 h i f bl eedi ng s tops or i s mi ni ma l .
Upper GI ba ri um x-ra ys ha ve no rol e i n a cute bl eedi ng, a nd the contra s t us ed ma y obs cure s ubs equent a ttempts a t a ngi ogra phy. Angi ogra phy i s
us eful i n the di a gnos i s of upper GI bl eedi ng a nd permi ts certa i n thera peuti c ma neuvers (eg, embol i za ti on, va s ocons tri ctor i nfus i on).
Fl exi bl e s i gmoi dos copy a nd a nos copy ma y be a l l tha t i s requi red a cutel y for pa ti ents wi th s ymptoms typi ca l of hemorrhoi da l bl eedi ng. Al l other
pa ti ents wi th hema tochezi a s houl d ha ve col onos copy, whi ch ca n be done el ecti vel y a fter routi ne prepa ra ti on unl es s there i s s i gni fi ca nt ongoi ng
bl eedi ng. In s uch pa ti ents , a ra pi d prep (5 to 10 L of pol yethyl ene gl ycol s ol uti on del i vered vi a NGT or by mouth over 3 to 4 h) often a l l ows
a dequa te vi s ua l i za ti on. If col onos copy ca nnot vi s ua l i ze the s ource a nd ongoi ng bl eedi ng i s s uffi ci entl y ra pi d (> 0.5 to 1 mL/mi n), a ngi ogra phy ma y
l oca l i ze the s ource. Some a ngi ogra phers fi rs t ta ke a ra di onucl i de s ca n to focus the exa mi na ti on, beca us e a ngi ogra phy i s l es s s ens i ti ve tha n the
ra di onucl i de s ca n.
Di a gnos i s of occul t bl eedi ng ca n be di ffi cul t, beca us e heme-pos i ti ve s tool s ma y res ul t from bl eedi ng a nywhere i n the GI tra ct. Endos copy i s the
preferred method, wi th s ymptoms determi ni ng whether the upper or l ower GI tra ct i s exa mi ned fi rs t. Doubl e-contra s t ba ri um enema a nd
s i gmoi dos copy ca n be us ed for the l ower tra ct when col onos copy i s una va i l a bl e or the pa ti ent refus es i t. If the res ul ts of upper endos copy a nd
col onos copy a re nega ti ve a nd occul t bl ood pers i s ts i n the s tool , a n upper GI s eri es wi th s ma l l -bowel fol l ow-through, s ma l l -bowel endos copy
(enteros copy), ca ps ul e endos copy, techneti um-l a bel ed col l oi d or RBC s ca n, a nd a ngi ogra phy s houl d be cons i dered.
Treatment
Secure a i rwa y i f needed
IV fl ui d res us ci ta ti on
Bl ood tra ns fus i on i f needed
In s ome, a ngi ogra phi c or endos copi c hemos ta s i s
Hema temes i s , hema tochezi a , or mel ena s houl d be cons i dered a n emergency. Admi s s i on to a n ICU, wi th cons ul ta ti on by both a ga s troenterol ogi s t
a nd a s urgeon, i s recommended for a l l pa ti ents wi th s evere GI bl eedi ng. Genera l trea tment i s di rected a t ma i ntena nce of the a i rwa y a nd
res tora ti on of ci rcul a ti ng vol ume. Hemos ta s i s a nd other trea tment depend on the ca us e of the bl eedi ng.
Airway: A ma jor ca us e of morbi di ty a nd morta l i ty i n pa ti ents wi th a cti ve upper GI bl eedi ng i s a s pi ra ti on of bl ood wi th s ubs equent res pi ra tory
compromi s e. To prevent thes e probl ems , endotra chea l i ntuba ti on s houl d be cons i dered i n pa ti ents who ha ve i na dequa te ga g refl exes or a re
obtunded or uncons ci ous pa rti cul a rl y i f they wi l l be undergoi ng upper endos copy.
Fluid resuscitation: IV fl ui ds a re i ni ti a ted a s for a ny pa ti ent wi th hypovol emi a or hemorrha gi c s hock (s ee p. 2297): hea l thy a dul ts a re gi ven norma l
s a l i ne IV i n 500- to 1000-mL a l i quots unti l s i gns of hypovol emi a remi tup to a ma xi mum of 2 L (for chi l dren, 20 mL/kg, tha t ma y be repea ted once).
Pa ti ents requi ri ng further res us ci ta ti on s houl d recei ve tra ns fus i on wi th pa cked RBCs . Tra ns fus i ons conti nue unti l i ntra va s cul a r vol ume i s res tored
a nd then a re gi ven a s needed to repl a ce ongoi ng bl ood l os s . Tra ns fus i ons i n ol der pa ti ents or thos e wi th corona ry a rtery di s ea s e ma y be s topped
when Hct i s s ta bl e a t 30 unl es s the pa ti ent i s s ymptoma ti c. Younger pa ti ents or thos e wi th chroni c bl eedi ng a re us ua l l y not tra ns fus ed unl es s Hct
i s < 23 or they ha ve s ymptoms s uch a s dys pnea or corona ry i s chemi a .
Pl a tel et count s houl d be moni tored cl os el y; pl a tel et tra ns fus i on ma y be requi red wi th s evere bl eedi ng. Pa ti ents who a re ta ki ng a nti pl a tel et drugs
(eg, cl opi dogrel , a s pi ri n) ha ve pl a tel et dys functi on, often res ul ti ng i n i ncrea s ed bl eedi ng. Pl a tel et tra ns fus i on s houl d be cons i dered when
pa ti ents ta ki ng thes e drugs ha ve s evere ongoi ng bl eedi ng, a l though a res i dua l ci rcul a ti ng drug (pa rti cul a rl y cl opi dogrel ) ma y i na cti va te tra ns fus ed
pl a tel ets . Fres h frozen pl a s ma s houl d be tra ns fus ed a fter every 4 uni ts of pa cked RBCs .
Hemostasis: GI bl eedi ng s tops s ponta neous l y i n a bout 80% of pa ti ents . The rema i ni ng pa ti ents requi re s ome type of i nterventi on. Speci fi c thera py
depends on the bl eedi ng s i te. Ea rl y i nterventi on to control bl eedi ng i s i mporta nt to mi ni mi ze morta l i ty, pa rti cul a rl y i n el derl y pa ti ents .
For pepti c ul cer, ongoi ng bl eedi ng or rebl eedi ng i s trea ted wi th endos copi c coa gul a ti on (wi th bi pol a r el ectrocoa gul a ti on, i njecti on s cl erothera py,
hea ter probes , or l a s er). Non-bl eedi ng ves s el s tha t a re vi s i bl e wi thi n a n ul cer cra ter a re a l s o trea ted. If endos copy does not s top the bl eedi ng,
s urgery i s requi red to overs ew the bl eedi ng s i te. If medi ca l ma na gement does not control ga s tri c a ci d s ecreti on, s urgeons do a ci d-reducti on
s urgery (s ee p. 136) a t the s a me ti me.
Acti ve va ri cea l bl eedi ng ca n be trea ted wi th endos copi c ba ndi ng, i njecti on s cl erothera py, or a tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng
(TIPS) procedure.
Severe, ongoi ng l ower GI bl eedi ng ca us ed by di verti cul a or a ngi oma s ca n s ometi mes be control l ed col onos copi ca l l y by el ectroca utery, coa gul a ti on
wi th a hea ter probe, or i njecti on wi th di l ute epi nephri ne. Pol yps ca n be removed by s na re or ca utery. If thes e methods a re i neffecti ve or
unfea s i bl e, a ngi ogra phy wi th embol i za ti on or va s opres s i n i nfus i on ma y be s ucces s ful . However, beca us e col l a tera l bl ood fl ow to the bowel i s
l i mi ted, a ngi ogra phi c techni ques ha ve a s i gni fi ca nt ri s k of bowel i s chemi a or i nfa rcti on unl es s s uper-s el ecti ve ca theteri za ti on techni ques a re
us ed. In mos t s eri es , the ra te of i s chemi c compl i ca ti ons i s < 5%. Va s opres s i n i nfus i on ha s a bout a n 80% s ucces s ra te for s toppi ng bl eedi ng, but
bl eedi ng recurs i n a bout 50% of pa ti ents . Al s o, there i s a ri s k of hypertens i on a nd corona ry i s chemi a . Furthermore, a ngi ogra phy ca n be us ed to
l oca l i ze the s ource of bl eedi ng more a ccura tel y. Surgery ma y be us ed i n pa ti ents wi th conti nued bl eedi ng (requi ri ng > 4 uni ts tra ns fus i on/24 h),
but l oca l i za ti on of the bl eedi ng s i te i s very i mporta nt. Bl i nd hemi col ectomy (wi th no preopera ti ve i denti fi ca ti on of the bl eedi ng s i te) ca rri es a
much hi gher morta l i ty ri s k tha n does di rected s egmenta l res ecti on. However, a s s es s ment mus t be expedi ti ous s o tha t s urgery i s not unneces s a ri l y
del a yed.
Acute or chroni c bl eedi ng of i nterna l hemorrhoi ds s tops s ponta neous l y i n mos t ca s es . Pa ti ents wi th refra ctory bl eedi ng a re trea ted vi a a nos copy
wi th rubber ba nd l i ga ti on, i njecti on, coa gul a ti on, or s urgery.
Geriatrics Essentials
In the el derl y, hemorrhoi ds a nd col orecta l ca ncer a re the mos t common ca us es of mi nor bl eedi ng. Pepti c ul cer, di verti cul a r di s ea s e, a nd
a ngi odys pl a s i a a re the mos t common ca us es of ma jor bl eedi ng. Va ri cea l bl eedi ng i s l es s common tha n i n younger pa ti ents .
Ma s s i ve GI bl eedi ng i s tol era ted poorl y by el derl y pa ti ents . Di a gnos i s mus t be ma de qui ckl y, a nd trea tment mus t be s ta rted s ooner tha n i n
younger pa ti ents , who ca n better tol era te repea ted epi s odes of bl eedi ng.
Key Points
Recta l bl eedi ng ma y res ul t from upper or l ower GI bl eedi ng.
Orthos ta ti c cha nges i n vi ta l s i gns a re unrel i a bl e ma rkers for s eri ous bl eedi ng.
About 80% of pa ti ents s top bl eedi ng s ponta neous l y; va ri ous endos copi c techni ques a re us ua l l y the fi rs t choi ce for the rema i nder.
Varices
Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may
bleed massively but cause no other symptoms. Diagnosis is by upper endoscopy. Treatment is primarily with endoscopic banding and IV octreotide. Sometimes a
transjugular intrahepatic portosystemic shunting procedure is needed.
Porta l hypertens i on (s ee p. 218) res ul ts from a number of condi ti ons , predomi na ntl y l i ver ci rrhos i s . If porta l pres s ure rema i ns hi gher tha n i nferi or
vena ca va l pres s ure for a s i gni fi ca nt peri od, venous col l a tera l s devel op. The mos t da ngerous col l a tera l s occur i n the di s ta l es opha gus a nd ga s tri c
fundus , ca us i ng engorged, s erpenti ne s ubmucos a l ves s el s known a s va ri ces . Thes e va ri ces pa rti a l l y decompres s porta l hypertens i on but ca n
rupture, ca us i ng ma s s i ve GI bl eedi ng. The tri gger for va ri cea l rupture i s unknown, but bl eedi ng a l mos t never occurs unl es s the porta l /s ys temi c
pres s ure gra di ent i s > 12 mm Hg. Coa gul opa thi es ca us ed by l i ver di s ea s e ma y fa ci l i ta te bl eedi ng. NGT pa s s a ge i n a pa ti ent wi th va ri ces ha s not
been s hown to tri gger bl eedi ng.
Symptoms and Signs

Pa ti ents typi ca l l y pres ent wi th s udden, pa i nl es s , upper GI bl eedi ng, often ma s s i ve. Si gns of s hock ma y be pres ent. Bl eedi ng i s us ua l l y from the
di s ta l es opha gus , l es s often from the ga s tri c fundus . Bl eedi ng from ga s tri c va ri ces a l s o ma y be a cute but i s more often s uba cute or chroni c.
Bl eedi ng i nto the GI tra ct ma y preci pi ta te porta l -s ys temi c encepha l opa thy i n pa ti ents wi th i mpa i red hepa ti c functi on.
Diagnosis
Endos copy
Eva l ua ti on for coa gul opa thy
Both es opha gea l a nd ga s tri c va ri ces a re bes t di a gnos ed by endos copy, whi ch ma y a l s o i denti fy va ri ces a t hi gh ri s k of bl eedi ng (eg, thos e wi th red
ma rki ngs ). Endos copy i s a l s o cri ti ca l to excl ude other ca us es of a cute bl eedi ng (eg, pepti c ul cer), even i n pa ti ents known to ha ve va ri ces ; perha ps
a s ma ny a s one thi rd of pa ti ents wi th known va ri ces who ha ve upper GI bl eedi ng ha ve a nonva ri cea l s ource.
Beca us e va ri ces a re typi ca l l y a s s oci a ted wi th s i gni fi ca nt hepa ti c di s ea s e, eva l ua ti on for pos s i bl e coa gul opa thy i s i mporta nt. La bora tory tes ts
i ncl ude CBC wi th pl a tel ets , PT, PTT, a nd l i ver functi on tes ts . Bl eedi ng pa ti ents s houl d ha ve type a nd cros s ma tch for 6 uni ts of pa cked RBCs .
Prognosis
In a bout 80% of pa ti ents , va ri cea l bl eedi ng s tops s ponta neous l y. Neverthel es s , morta l i ty i s hi gh, often > 50%. Morta l i ty depends pri ma ri l y on
s everi ty of the a s s oci a ted l i ver di s ea s e ra ther tha n on the bl eedi ng i ts el f. Bl eedi ng i s often fa ta l i n pa ti ents wi th s evere hepa tocel l ul a r
i mpa i rment (eg, a dva nced ci rrhos i s ), wherea s pa ti ents wi th good hepa ti c res erve us ua l l y recover.
Survi vi ng pa ti ents a re a t hi gh ri s k of further va ri cea l bl eedi ng; typi ca l l y, 50 to 75% ha ve recurrence wi thi n 1 to 2 yr. Ongoi ng endos copi c or drug
thera py s i gni fi ca ntl y l owers thi s ri s k, but the overa l l effect on l ong-term morta l i ty s eems to be ma rgi na l , proba bl y beca us e of the underl yi ng
hepa ti c di s ea s e.
Treatment
Fl ui d res us ci ta ti on
Endos copi c ba ndi ng (s cl erothera py s econd choi ce)
IV octreoti de
Pos s i bl y a tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) procedure
Ma na gement of hypovol emi a a nd hemorrha gi c s hock i s a s des cri bed a bove a nd i n Ch. 226. Pa ti ents wi th coa gul a ti on a bnorma l i ti es (eg, el eva ted
INR) s houl d be gi ven 1 to 2 uni ts of fres h frozen pl a s ma a nd 2.5 to 10 mg vi ta mi n K IM (or IV i f s evere).
Beca us e va ri ces a re i nva ri a bl y di a gnos ed duri ng endos copy, pri ma ry trea tment i s endos copi c. Endos copi c ba ndi ng of va ri ces i s preferred over
i njecti on s cl erothera py. At the s a me ti me, IV octreoti de (a s yntheti c a na l og of s oma tos ta ti n, whi ch ma y a l s o be us ed) s houl d be gi ven. Octreoti de
i ncrea s es s pl a nchni c va s cul a r res i s ta nce by i nhi bi ti ng the rel ea s e of s pl a nchni c va s odi l a tor hormones (eg, gl uca gon, va s oa cti ve i ntes ti na l
pepti de). The us ua l dos e i s a 50 g IV bol us , fol l owed by i nfus i on of 50 g/h. Octreoti de i s preferred over previ ous l y us ed a gents s uch a s
va s opres s i n a nd terl i pres s i n, beca us e i t ha s fewer a dvers e effects .
If bl eedi ng conti nues or recurs des pi te thes e mea s ures , emergency techni ques to s hunt bl ood from the porta l s ys tem to the vena ca va ca n l ower
porta l pres s ure a nd di mi ni s h bl eedi ng. A TIPS procedure i s the emergency i nterventi on of choi ce. TIPS i s a n i nva s i ve ra di ol ogi c procedure i n whi ch
a gui dewi re i s pa s s ed from the vena ca va through the l i ver pa renchyma i nto the porta l ci rcul a ti on. The res ul ta nt pa s s a ge i s di l a ted by a ba l l oon
ca theter, a nd a meta l l i c s tent i s i ns erted, crea ti ng a bypa s s between the porta l a nd hepa ti c venous ci rcul a ti ons . Stent s i ze i s cruci a l . If the s tent i s
too l a rge, porta l -s ys temi c encepha l opa thy res ul ts beca us e of di vers i on of too much porta l bl ood fl ow from the l i ver. If the s tent i s too s ma l l , i t i s
more l i kel y to occl ude. Surgi ca l porta ca va l s hunts , s uch a s the di s ta l s pl eno-rena l s hunt, work by a s i mi l a r mecha ni s m but a re more i nva s i ve a nd
ha ve a hi gher i mmedi a te morta l i ty.
Mecha ni ca l compres s i on of bl eedi ng va ri ces wi th a Sengs ta ken-Bl a kemore tube or one of i ts va ri a nts ca us es cons i dera bl e morbi di ty a nd s houl d
not be us ed a s pri ma ry ma na gement. However, s uch a tube ma y provi de l i fe-s a vi ng ta mpona de pendi ng decompres s i on wi th a TIPS or s urgi ca l
procedure. The tube i s a fl exi bl e NGT wi th one ga s tri c ba l l oon a nd one es opha gea l ba l l oon. After i ns erti on, the ga s tri c ba l l oon i s i nfl a ted wi th a
fi xed vol ume of a i r, a nd tra cti on i s a ppl i ed to the tube to pul l the ba l l oon s nugl y a ga i ns t the ga s troes opha gea l juncti on. Thi s ba l l oon i s often
s uffi ci ent to control bl eedi ng, but i f not, the es opha gea l ba l l oon i s i nfl a ted to a pres s ure of 25 mm Hg. The procedure i s qui te uncomforta bl e a nd
ma y res ul t i n es opha gea l perfora ti on a nd a s pi ra ti on; thus , endotra chea l i ntuba ti on a nd IV s eda ti on a re often recommended.
Li ver tra ns pl a nta ti on ca n a l s o decompres s the porta l s ys tem but i s a pra cti ca l opti on onl y for pa ti ents a l rea dy on a tra ns pl a nt l i s t.
Long-term medi ca l thera py of porta l hypertens i on (wi th -bl ockers a nd ni tra tes ) i s di s cus s ed el s ewhere (s ee p.
219). Trea tment of porta l -s ys temi c encepha l opa thy ma y be needed (s ee p. 220).
Vascular GI Lesions
Several distinct congenital or acquired syndromes involve abnormal mucosal or submucosal blood vessels in the GI tract. These vessels may cause recurrent
bleeding, which is rarely massive. Diagnosis is by endoscopy and sometimes angiography. Treatment is endoscopic hemostasis; occasionally, angiographic
embolization or surgical resection may be needed.

Vascular ectasias (a ngi odys pl a s i a s , a rteri ovenous ma l forma ti ons ) a re di l a ted, tortuous ves s el s tha t typi ca l l y devel op i n the cecum a nd a s cendi ng
col on. They occur ma i nl y i n peopl e > 60 a nd a re the mos t common ca us e of l ower GI bl eedi ng i n tha t a ge group. They a re thought to be
degenera ti ve a nd do not occur i n a s s oci a ti on wi th other va s cul a r a bnorma l i ti es . Mos t pa ti ents ha ve 2 or 3 l es i ons , whi ch a re typi ca l l y 0.5 to 1.0 cm,
bri ght red, fl a t or s l i ghtl y ra i s ed, a nd covered by very thi n epi thel i um. Va s cul a r ecta s i a s a l s o occur i n a s s oci a ti on wi th a number of s ys temi c
di s ea s es (eg, rena l fa i l ure, ci rrhos i s , CREST s yndrome [ca l ci nos i s cuti s , Ra yna ud's phenomenon, es opha gea l dys moti l i ty, s cl eroda ctyl y,
tel a ngi ecta s i a s ]s ee p. 310) a nd a fter ra di a ti on to the bowel .
Gastric antral vascular ectasia (wa termel on s toma ch) cons i s ts of l a rge di l a ted vei ns runni ng l i nea rl y a l ong the s toma ch, crea ti ng a s tri ped
a ppea ra nce s ugges ti ve of a wa termel on. The condi ti on occurs ma i nl y i n ol der women a nd i s of unknown eti ol ogy.
Hereditary hemorrhagic telangiectasia (Rendu-Os l er-Weber s yndromes ee a l s o p. 982) i s a n a utos oma l domi na nt di s order tha t ca us es mul ti pl e
va s cul a r l es i ons i n va ri ous pa rts of the body, i ncl udi ng the enti re GI tra ct. GI bl eedi ng ra rel y occurs before a ge 40.
Dieulafoy's lesion i s a n a bnorma l l y l a rge a rtery tha t penetra tes the gut wa l l , occa s i ona l l y erodi ng through the mucos a a nd ca us i ng ma s s i ve
bl eedi ng. It occurs ma i nl y i n the proxi ma l s toma ch.
Arteriovenous malformations a nd hemangiomas, both congeni ta l di s orders of bl ood ves s el s , ca n occur i n the GI tra ct but a re ra re.
Symptoms and Signs
Va s cul a r l es i ons a re pa i nl es s . Pa ti ents often pres ent wi th heme-pos i ti ve s tool s or modes t a mounts of bri ght red bl ood from the rectum. Bl eedi ng
i s often i ntermi ttent, s ometi mes wi th l ong peri ods between epi s odes . Pa ti ents wi th upper GI l es i ons ma y pres ent wi th mel ena . Ma jor bl eedi ng i s
unus ua l .
Diagnosis
Endos copy
Va s cul a r l es i ons a re mos t commonl y di a gnos ed endos copi ca l l y. If routi ne endos copy i s nondi a gnos ti c, s ma l l -bowel endos copy, ca ps ul e
endos copy, i ntra opera ti ve endos copy, or vi s cera l a ngi ogra phy ma y be requi red. 99mTc-l a bel ed RBC s ca ns a re l es s s peci fi c but ma y hel p l oca l i ze the
l es i on enough to fa ci l i ta te endos copy or a ngi ogra phy.
Treatment
Endos copi c coa gul a ti on
Endos copi c coa gul a ti on (wi th hea ter probe, l a s er, a rgon pl a s ma , or bi pol a r el ectrocoa gul a ti on) i s effecti ve for ma ny va s cul a r l es i ons . Va s cul a r
ecta s i a s often recur, a l though there i s s ome evi dence tha t ora l es trogen-proges terone combi na ti ons ma y l i mi t recurrence.
Mi l d recurrent bl eedi ng ca n be trea ted s i mpl y wi th chroni c i ron thera py. More s i gni fi ca nt bl eedi ng tha t i s unres pons i ve to endos copi c mea s ures
ma y requi re a ngi ogra phi c embol i za ti on or s urgi ca l res ecti on. However, rebl eedi ng occurs i n a bout 15 to 25% of s urgi ca l l y trea ted pa ti ents .
Chapter 11. Acute Abdomen and Surgical Gastroenterology

Introduction
Acute a bdomen refers to a bdomi na l s ymptoms a nd s i gns of s uch s everi ty or concern tha t di s orders requi ri ng s urgery s houl d be cons i dered. The
pri ma ry s ymptom i s a cute a bdomi na l pa i n. Chroni c a bdomi na l pa i n i s di s cus s ed i n Ch. 7.
Acute Abdominal Pain
Abdomi na l pa i n i s common a nd often i ncons equenti a l . Acute a nd s evere a bdomi na l pa i n, however, i s a l mos t a l wa ys a s ymptom of i ntra a bdomi na l di s ea s e. It ma y be the s ol e i ndi ca tor of the need for s urgery a nd mus t be a ttended to s wi ftl y: Ga ngrene a nd perfora ti on of the gut ca n
occur < 6 h from ons et of s ymptoms i n certa i n condi ti ons (eg, i nterrupti on of the i ntes ti na l bl ood s uppl y ca us ed by a s tra ngul a ti ng obs tructi on or
a n a rteri a l embol us ). Abdomi na l pa i n i s of pa rti cul a r concern i n pa ti ents who a re very young or very ol d a nd thos e who ha ve HIV i nfecti on or a re
ta ki ng i mmunos uppres s a nts .
Textbook des cri pti ons of a bdomi na l pa i n ha ve l i mi ta ti ons beca us e peopl e rea ct to pa i n di fferentl y. Some, pa rti cul a rl y el derl y peopl e, a re s toi c,
wherea s others exa ggera te thei r s ymptoms . Infa nts , young chi l dren, a nd s ome el derl y peopl e ma y ha ve di ffi cul ty l oca l i zi ng the pa i n.
Pathophysiology
Visceral pain comes from the a bdomi na l vi s cera , whi ch a re i nnerva ted by a utonomi c nerve fi bers a nd res pond ma i nl y to the s ens a ti ons of
di s tenti on a nd mus cul a r contra cti onnot to cutti ng, tea ri ng, or l oca l i rri ta ti on. Vi s cera l pa i n i s typi ca l l y va gue, dul l , a nd na us ea ti ng. It i s poorl y
l oca l i zed a nd tends to be referred to a rea s corres pondi ng to the embryoni c ori gi n of the a ffected s tructure. Foregut s tructures (s toma ch,
duodenum, l i ver, a nd pa ncrea s ) ca us e upper a bdomi na l pa i n. Mi dgut s tructures (s ma l l bowel , proxi ma l col on, a nd a ppendi x) ca us e peri umbi l i ca l
pa i n. Hi ndgut s tructures (di s ta l col on a nd GU tra ct) ca us e l ower a bdomi na l pa i n.
Somatic pain comes from the pa ri eta l peri toneum, whi ch i s i nnerva ted by s oma ti c nerves , whi ch res pond to i rri ta ti on from i nfecti ous , chemi ca l , or
other i nfl a mma tory proces s es . Soma ti c pa i n i s s ha rp a nd wel l l oca l i zed.
Referred pain i s pa i n percei ved di s ta nt from i ts s ource a nd res ul ts from convergence of nerve fi bers a t the s pi na l cord. Common exa mpl es of
referred pa i n a re s ca pul a r pa i n due to bi l i a ry col i c, groi n pa i n due to rena l col i c, a nd s houl der pa i n due to bl ood or i nfecti on i rri ta ti ng the
di a phra gm.
Peritonitis: Peri toni ti s i s i nfl a mma ti on of the peri tonea l ca vi ty. The mos t s eri ous ca us e i s perfora ti on of the GI tra ct (s ee p. 111), whi ch ca us es
i mmedi a te chemi ca l i nfl a mma ti on fol l owed s hortl y by i nfecti on from i ntes ti na l orga ni s ms . Peri toni ti s ca n a l s o res ul t from a ny a bdomi na l
condi ti on tha t ca us es ma rked i nfl a mma ti on (eg, a ppendi ci ti s , di verti cul i ti s , s tra ngul a ti ng i ntes ti na l obs tructi on, pa ncrea ti ti s , pel vi c i nfl a mma tory
di s ea s e, mes enteri c i s chemi a ). Intra peri tonea l bl ood from a ny s ource (eg, ruptured a neurys m, tra uma , s urgery, ectopi c pregna ncy) i s i rri ta ti ng a nd
res ul ts i n peri toni ti s . Ba ri um ca us es s evere peri toni ti s a nd s houl d never be gi ven to a pa ti ent wi th s us pected GI tra ct perfora ti on. Peri toneos ys temi c s hunts , dra i ns , a nd di a l ys i s ca theters i n the peri tonea l ca vi ty predi s pos e a pa ti ent to i nfecti ous peri toni ti s , a s does a s ci ti c fl ui d. Ra rel y,
s ponta neous ba cteri a l peri toni ti s occurs , i n whi ch the peri tonea l ca vi ty i s i nfected by bl ood-borne ba cteri a .
Peri toni ti s ca us es fl ui d s hi ft i nto the peri tonea l ca vi ty a nd bowel , l ea di ng to s evere dehydra ti on a nd el ectrol yte di s turba nces . Adul t res pi ra tory
di s tres s s yndrome ca n devel op ra pi dl y. Ki dney fa i l ure, l i ver fa i l ure, a nd di s s emi na ted i ntra va s cul a r coa gul a ti on fol l ow. The pa ti ent's fa ce
becomes dra wn i nto the ma s kl i ke a ppea ra nce typi ca l of hi ppocra ti c fa ci es . Dea th occurs wi thi n da ys .
Etiology
Ma ny i ntra -a bdomi na l di s orders ca us e a bdomi na l pa i n (s ee
Fi g. 11-1); s ome a re tri vi a l but s ome a re i mmedi a tel y l i fe threa teni ng, requi ri ng ra pi d di a gnos i s a nd s urgery. Thes e i ncl ude ruptured a bdomi na l
a orti c a neurys m (AAA), perfora ted vi s cus , mes enteri c i s chemi a , a nd ruptured ectopi c pregna ncy. Others (eg, i ntes ti na l obs tructi on, a ppendi ci ti s ,
s evere a cute pa ncrea ti ti s ) a re a l s o s eri ous a nd nea rl y a s urgent. Severa l extra -a bdomi na l di s orders a l s o ca us e a bdomi na l pa i n (s ee
Ta bl e 11-1).
Abdomi na l pa i n i n neona tes , i nfa nts , a nd young chi l dren ha s numerous ca us es not encountered i n a dul ts , i ncl udi ng meconi um peri toni ti s , pyl ori c
s tenos i s , es opha gea l webs , vol vul us of a gut wi th a common mes entery, i mperfora te a nus , i ntus s us cepti on, a nd i ntes ti na l obs tructi on ca us ed by
a tres i a .
Evaluation
Eva l ua ti on of mi l d a nd s evere pa i n fol l ows the s a me proces s , a l though wi th s evere a bdomi na l pa i n, thera py s ometi mes proceeds s i mul ta neous l y
a nd i nvol ves ea rl y cons ul ta ti on wi th a s urgeon. Hi s tory a nd phys i ca l exa mi na ti on us ua l l y excl ude a l l but a few pos s i bl e ca us es , wi th fi na l
di a gnos i s confi rmed by judi ci ous us e of l a bora tory a nd i ma gi ng tes ts . Li fe-threa teni ng ca us es s houl d a l wa ys be rul ed out before focus i ng on l es s
s eri ous di a gnos es . In s eri ous l y i l l pa ti ents wi th s evere a bdomi na l pa i n, the mos t i mporta nt di a gnos ti c mea s ure ma y be expedi ti ous s urgi ca l
expl ora ti on. In mi l dl y i l l pa ti ents , wa tchful wa i ti ng ma y be bes t.
History: A thorough hi s tory us ua l l y s ugges ts the di a gnos i s (s ee
Ta bl e 11-2). Of pa rti cul a r i mporta nce a re pa i n l oca ti on (s ee Fi g. 11-1) a nd cha ra cteri s ti cs , hi s tory of s i mi l a r s ymptoms , a nd a s s oci a ted s ymptoms .
Concomi ta nt s ymptoms s uch a s ga s troes opha gea l refl ux, na us ea , vomi ti ng, di a rrhea , cons ti pa ti on, ja undi ce, mel ena , hema turi a , hema temes i s ,
wei ght l os s , a nd mucus or bl ood i n the s tool hel p di rect s ubs equent eva l ua ti on. A drug hi s tory s houl d i ncl ude deta i l s concerni ng pres cri pti on a nd
i l l i ci t drug us e a s wel l a s a l cohol . Ma ny drugs ca us e GI ups et. Predni s one or i mmunos uppres s a nts ma y i nhi bi t the i nfl a mma tory res pons e to
perfora ti on or peri toni ti s a nd res ul t i n l es s pa i n a nd l eukocytos i s tha n mi ght otherwi s e be expected. Anti coa gul a nts ca n i ncrea s e the cha nces of
bl eedi ng a nd hema toma forma ti on. Al cohol predi s pos es to pa ncrea ti ti s .
Known medi ca l condi ti ons a nd previ ous a bdomi na l s urgeri es a re i mporta nt to a s certa i n. Women s houl d be a s ked whether they a re pregna nt.
Physical examination: The genera l a ppea ra nce i s i mporta nt. A ha ppy, comforta bl e-a ppea ri ng pa ti ent ra rel y ha s a s eri ous probl em, unl i ke one who
i s a nxi ous , pa l e, di a phoreti c, or i n obvi ous pa i n. BP, pul s e, s ta te of cons ci ous nes s , a nd other s i gns of peri phera l perfus i on mus t be eva l ua ted.
However, the focus
[Fig. 11-1. Loca ti on of a bdomi na l pa i n a nd pos s i bl e ca us es .]
[Table 11-1. Extra -Abdomi na l Ca us es of Abdomi na l Pa i n]
of the exa mi na ti on i s the a bdomen, begi nni ng wi th i ns pecti on a nd a us cul ta ti on, fol l owed by pa l pa ti on a nd percus s i on. Recta l exa mi na ti on a nd
pel vi c exa mi na ti on (for women) to l oca te tendernes s , ma s s es , a nd bl ood a re es s enti a l .
Pa l pa ti on begi ns gentl y, a wa y from the a rea of grea tes t pa i n, detecti ng a rea s of pa rti cul a r tendernes s , a s wel l a s the pres ence of gua rdi ng,
ri gi di ty, a nd rebound (a l l s ugges ti ng peri tonea l i rri ta ti on) a nd a ny ma s s es . Gua rdi ng i s a n i nvol unta ry contra cti on of the a bdomi na l mus cl es tha t
i s s l i ghtl y s l ower a nd more s us ta i ned tha n the ra pi d, vol unta ry fl i nch exhi bi ted by s ens i ti ve or a nxi ous pa ti ents . Rebound i s a di s ti nct fl i nch upon
bri s k wi thdra wa l of the exa mi ner's ha nd. The i ngui na l a rea a nd a l l s urgi ca l s ca rs s houl d be pa l pa ted for herni a s .
Red flags: Certa i n fi ndi ngs ra i s e s us pi ci on of a more s eri ous eti ol ogy:
Severe pa i n
Si gns of s hock (eg, ta chyca rdi a , hypotens i on, di a phores i s , confus i on)
Si gns of peri toni ti s
Abdomi na l di s tenti on
Interpretation of findings: Di s tenti on, es peci a l l y when s urgi ca l s ca rs , tympa ny to percus s i on, a nd hi gh-pi tched peri s ta l s i s or borborygmi i n rus hes
a re pres ent, s trongl y s ugges ts bowel obs tructi on. Severe pa i n i n a pa ti ent wi th a s i l ent a bdomen who i s l yi ng a s s ti l l a s pos s i bl e s ugges ts
peri toni ti s ; l oca ti on of tendernes s s ugges ts eti ol ogy (eg, ri ght upper qua dra nt s ugges ts chol ecys ti ti s , ri ght l ower qua dra nt s ugges ts a ppendi ci ti s )
but ma y not be di a gnos ti c. Ba ck pa i n wi th s hock s ugges ts ruptured AAA, pa rti cul a rl y i f there i s a tender, pul s a ti l e ma s s . Shock a nd va gi na l
bl eedi ng i n a pregna nt woma n s ugges t ruptured ectopi c pregna ncy. Ecchymos es of the cos tovertebra l a ngl es (Grey Turner's s i gn) or a round the
umbi l i cus (Cul l en's s i gn) s ugges t hemorrha gi c pa ncrea ti ti s but a re not very s ens i ti ve for thi s di s order.
Hi s tory i s often s ugges ti ve (s ee Ta bl e 11-2). Mi l d to modera te pa i n i n the pres ence of a cti ve peri s ta l s i s of norma l pi tch s ugges ts a nons urgi ca l
di s ea s e (eg, ga s troenteri ti s ) but ma y a l s o be the ea rl y ma ni fes ta ti ons of a more s eri ous di s order. A pa ti ent who i s wri thi ng a round tryi ng to get
comforta bl e i s more l i kel y to ha ve a n obs tructi ve mecha ni s m (eg, rena l or bi l i a ry col i c).
Previ ous a bdomi na l s urgery ma kes obs tructi on from a dhes i ons more l i kel y. Genera l i zed a theros cl eros i s i ncrea s es the pos s i bi l i ty of MI, AAA, a nd
mes enteri c i s chemi a . HIV i nfecti on ma kes i nfecti ous ca us es a nd drug a dvers e effects l i kel y.
Testing: Tes ts a re s el ected ba s ed on cl i ni ca l s us pi ci on.
Uri ne pregna ncy tes t for a l l women of chi l dbea ri ng a ge
Sel ected i ma gi ng tes ts ba s ed on s us pected di a gnos i s
Sta nda rd tes ts (eg, CBC, chemi s tri es , uri na l ys i s ) a re often done but a re of l i ttl e va l ue due to poor s peci fi ci ty; pa ti ents wi th s i gni fi ca nt di s ea s e ma y
ha ve norma l res ul ts . Abnorma l res ul ts do not provi de a s peci fi c di a gnos i s (the uri na l ys i s i n pa rti cul a r ma y s how pyuri a or hema turi a i n a wi de
va ri ety of condi ti ons ), a nd they ca n a l s o occur i n the a bs ence of s i gni fi ca nt di s ea s e. An excepti on i s s erum l i pa s e, whi ch s trongl y s ugges ts a
di a gnos i s of a cute pa ncrea ti ti s . A beds i de uri ne pregna ncy tes t s houl d be done for a l l women of chi l dbea ri ng a ge beca us e a nega ti ve res ul t
effecti vel y excl udes ruptured ectopi c pregna ncy.
An a bdomi na l s eri es , cons i s ti ng of fl a t a nd upri ght a bdomi na l x-ra ys a nd upri ght ches t x-ra ys (l eft l a tera l recumbent a bdomen a nd
a nteropos teri or ches t x-ra y for pa ti ents una bl e to s ta nd), s houl d be done when perfora ti on or obs tructi on i s s us pected. However, thes e pl a i n xra ys a re s el dom di a gnos ti c for other condi ti ons a nd need not be a utoma ti ca l l y done. Ul tra s ound s houl d be done for s us pected bi l i a ry tra ct
di s ea s e or ectopi c pregna ncy (tra ns va gi na l
[Table 11-2. Hi s tory i n Pa ti ents wi th Acute Abdomi na l Pa i n]
probe). Ul tra s ound ca n a l s o detect AAA but ca nnot rel i a bl y i denti fy rupture. Noncontra s t hel i ca l CT i s the moda l i ty of choi ce for s us pected rena l
s tones . CT wi th ora l contra s t i s di a gnos ti c i n a bout 95% of pa ti ents wi th s i gni fi ca nt a bdomi na l pa i n a nd ha s ma rkedl y l owered the nega ti ve
l a pa rotomy ra te. However, a dva nced i ma gi ng mus t not be a l l owed to del a y s urgery i n pa ti ents wi th defi ni ti ve s ymptoms a nd s i gns .
Treatment
Some cl i ni ci a ns feel tha t provi di ng pa i n rel i ef before a di a gnos i s i s ma de i nterferes wi th thei r a bi l i ty to eva l ua te. However, modera te dos es of IV
a na l ges i cs (eg, fenta nyl 50 to 100 g, morphi ne 4 to 6 mg) do not ma s k peri tonea l s i gns a nd, by di mi ni s hi ng a nxi ety a nd di s comfort, often ma ke
exa mi na ti on ea s i er.
Key Points
Li fe-threa teni ng ca us es s houl d be l ooked for fi rs t.
Pregna ncy s houl d be rul ed out i n women of chi l dbea ri ng a ge.
Si gns of peri toni ti s , s hock, a nd obs tructi on s houl d be s ought.

Bl ood tes ts a re of mi ni ma l va l ue.
Acute Mesenteric Ischemia
Acute mesenteric ischemia is interruption of intestinal blood flow by embolism, thrombosis, or a low-flow state. It leads to mediator release, inflammation, and
ultimately infarction. Abdominal pain is out of proportion to physical findings. Early diagnosis is difficult, but angiography and exploratory laparotomy have the
most sensitivity; other imaging modalities often become positive only late in the disease. Treatment is by embolectomy, revascularization of viable segments, or
resection; sometimes vasodilator therapy is successful. Mortality is high.
Pathophysiology
The i ntes ti na l mucos a ha s a hi gh meta bol i c ra te a nd, a ccordi ngl y, a hi gh bl ood fl ow requi rement (norma l l y recei vi ng 20 to 25% of ca rdi a c output),
ma ki ng i t very s ens i ti ve to the effects of decrea s ed perfus i on. Is chemi a di s rupts the mucos a l ba rri er, a l l owi ng rel ea s e of ba cteri a , toxi ns , a nd
va s oa cti ve medi a tors , whi ch i n turn l ea ds to myoca rdi a l depres s i on, s ys temi c i nfl a mma tory res pons e s yndrome (s ee p. 2299), mul ti s ys tem orga n
fa i l ure, a nd dea th. Medi a tor rel ea s e ma y occur even before compl ete i nfa rcti on. Necros i s ca n occur a s s oon a s 10 to 12 h a fter the ons et of
s ymptoms .
Three ma jor ves s el s s erve the a bdomi na l contents : the cel i a c trunk, the s uperi or mes enteri c a rtery (SMA), a nd the i nferi or mes enteri c a rtery (IMA).
The cel i a c trunk s uppl i es the es opha gus , s toma ch, proxi ma l duodenum, l i ver, ga l l bl a dder, pa ncrea s , a nd s pl een. The SMA s uppl i es the di s ta l
duodenum, jejunum, i l eum, a nd col on to the s pl eni c fl exure. The IMA s uppl i es the des cendi ng col on a nd s i gmoi d col on a nd the rectum. Col l a tera l
ves s el s a re a bunda nt i n the s toma ch, duodenum, a nd rectum; thes e a rea s ra rel y devel op i s chemi a . The s pl eni c fl exure i s a wa ters hed between
the SMA a nd IMA a nd i s a t pa rti cul a r ri s k of i s chemi a .
Etiology
Mes enteri c bl ood fl ow ma y be di s rupted on ei ther the venous or a rteri a l s i des . In genera l , pa ti ents > 50 a re a t grea tes t ri s k a nd ha ve the types of
occl us i ons a nd ri s k fa ctors s hown i n
Ta bl e 11-3. However, ma ny pa ti ents ha ve no i denti fi a bl e ri s k fa ctors .
Symptoms and Signs
The ea rl y ha l l ma rk of mes enteri c i s chemi a i s s evere pa i n but mi ni ma l phys i ca l fi ndi ngs . The a bdomen rema i ns s oft, wi th l i ttl e or no tendernes s .
Mi l d ta chyca rdi a ma y be pres ent. La ter, a s necros i s devel ops , s i gns of peri toni ti s a ppea r, wi th ma rked a bdomi na l tendernes s , gua rdi ng, ri gi di ty,
a nd no bowel s ounds . The s tool ma y be heme-pos i ti ve (i ncrea s i ngl y l i kel y a s i s chemi a progres s es ). The us ua l s i gns of s hock devel op a nd a re
frequentl y fol l owed by dea th.
Sudden ons et of pa i n s ugges ts but i s not di a gnos ti c of a n a rteri a l embol i s m, wherea s a more gra dua l ons et i s typi ca l of venous thrombos i s .
Pa ti ents wi th a hi s tory of pos tpra ndi a l a bdomi na l di s comfort (whi ch s ugges ts i ntes ti na l a ngi na ) ma y ha ve a rteri a l thrombos i s .
[Table 11-3. Ca us es of Acute Mes enteri c Is chemi a ]
Diagnosis
Cl i ni ca l di a gnos i s more i mporta nt tha n di a gnos ti c tes ts
Mes enteri c a ngi ogra phy i f di a gnos i s uncl ea r
Ea rl y di a gnos i s i s pa rti cul a rl y i mporta nt beca us e morta l i ty i ncrea s es s i gni fi ca ntl y once i ntes ti na l i nfa rcti on ha s occurred. Mes enteri c i s chemi a
mus t be cons i dered i n a ny pa ti ent > 50 wi th known ri s k fa ctors or predi s pos i ng condi ti ons who devel ops s udden, s evere a bdomi na l pa i n.
Pa ti ents wi th cl ea r peri tonea l s i gns s houl d proceed di rectl y to the opera ti ng room for both di a gnos i s a nd trea tment. For others , s el ecti ve
mes enteri c a ngi ogra phy i s the di a gnos ti c procedure of choi ce. Other i ma gi ng s tudi es a nd s erum ma rkers ca n s how a bnorma l i ti es but l a ck
s ens i ti vi ty a nd s peci fi ci ty ea rl y i n the cours e of the di s ea s e when di a gnos i s i s mos t cri ti ca l . Pl a i n a bdomi na l x-ra ys a re us eful ma i nl y i n rul i ng out
other ca us es of pa i n (eg, perfora ted vi s cus ), a l though porta l venous ga s or pneuma tos i s i ntes ti na l i s ma y be s een l a te i n the di s ea s e. Thes e
fi ndi ngs a l s o a ppea r on CT, whi ch ma y a l s o di rectl y vi s ua l i ze va s cul a r occl us i onmore a ccura tel y on the venous s i de. Doppl er ul tra s onogra phy
ca n s ometi mes i denti fy a rteri a l occl us i on, but s ens i ti vi ty i s l ow. MRI i s very a ccura te i n proxi ma l va s cul a r occl us i on, l es s s o i n di s ta l va s cul a r
occl us i on. Serum ma rkers (eg, crea ti ne ki na s e, l a cta te) ri s e wi th necros i s but a re nons peci fi c fi ndi ngs tha t a re s een l a ter. Intes ti na l fa tty a ci d
bi ndi ng protei n i n the uri ne ma y prove va l ua bl e i n the future a s a n ea rl y ma rker.
Prognosis
If di a gnos i s a nd trea tment ta ke pl a ce before i nfa rcti on occurs , morta l i ty i s l ow; a fter i ntes ti na l i nfa rcti on, morta l i ty a pproa ches 70 to 90%. For thi s
rea s on, cl i ni ca l di a gnos i s of mes enteri c i s chemi a s houl d s upers ede di a gnos ti c tes ts , whi ch ma y del a y trea tment.
Treatment
Surgi ca l : Embol ectomy, reva s cul a ri za ti on, or res ecti on
Angi ogra phi c: Va s odi l a tors or thrombol ys i s
Long-term a nti coa gul a ti on or a nti pl a tel et thera py
If di a gnos i s i s ma de duri ng expl ora tory l a pa rotomy, opti ons a re s urgi ca l embol ectomy, reva s cul a ri za ti on, a nd res ecti on. A "s econd l ook"
l a pa rotomy ma y be needed to rea s s es s the vi a bi l i ty of ques ti ona bl e a rea s of bowel . If di a gnos i s i s ma de by a ngi ogra phy, i nfus i on of the
va s odi l a tor pa pa veri ne through the a ngi ogra phy ca theter ma y i mprove s urvi va l i n both occl us i ve a nd nonoccl us i ve i s chemi a . A 60-mg bol us i s
gi ven over 2 mi n, fol l owed by a n i nfus i on of 30 to 60 mg/h. Pa pa veri ne i s us eful even when s urgi ca l i nterventi on i s pl a nned a nd i s s ometi mes
gi ven duri ng a nd a fter s urgi ca l i nterventi on a s wel l . In a ddi ti on, for a rteri a l occl us i on, thrombol ys i s or s urgi ca l embol ectomy ma y be done. The
devel opment of peri tonea l s i gns a t a ny ti me duri ng the eva l ua ti on s ugges ts the need for i mmedi a te s urgery. Mes enteri c venous thrombos i s
wi thout s i gns of peri toni ti s ca n be trea ted wi th pa pa veri ne fol l owed by a nti coa gul a ti on wi th hepa ri n a nd then wa rfa ri n.
Pa ti ents wi th a rteri a l embol i s m or venous thrombos i s requi re l ong-term a nti coa gul a ti on wi th wa rfa ri n. Pa ti ents wi th nonoccl us i ve i s chemi a ma y
be trea ted wi th a nti pl a tel et thera py.
Acute Perforation
Any part of the GI tract may become perforated, releasing gastric or intestinal contents into the peritoneal space. Causes vary. Symptoms develop suddenly, with
severe pain followed shortly by signs of shock. Diagnosis is usually made by the presence of free air in the abdomen on imaging studies. Treatment is with fluid
resuscitation, antibiotics, and surgery. Mortality is high, varying with the underlying disorder and the patient's general health.
Etiology
Both bl unt a nd penetra ti ng tra uma ca n res ul t i n perfora ti on of a ny pa rt of the GI tra ct (s ee
Ta bl e 11-4). Swa l l owed forei gn bodi es , even s ha rp ones , ra rel y ca us e perfora ti on unl es s they become i mpa cted, ca us i ng i s chemi a a nd necros i s
from l oca l pres s ure. Forei gn bodi es i ns erted vi a the a nus ma y perfora te the rectum.
Symptoms and Signs
Es opha gea l , ga s tri c, a nd duodena l perfora ti on tends to ma ni fes t s uddenl y a nd ca ta s trophi ca l l y, wi th a brupt ons et of a cute a bdomen wi th s evere
genera l i zed a bdomi na l pa i n, tendernes s , a nd peri tonea l s i gns . Pa i n ma y ra di a te to the s houl der.
Perfora ti on a t other GI s i tes often occurs i n the s etti ng of other pa i nful , i nfl a mma tory condi ti ons . Beca us e s uch perfora ti ons a re often s ma l l
i ni ti a l l y a nd frequentl y wa l l ed off by the omentum, pa i n often devel ops gra dua l l y a nd ma y be l oca l i zed. Tendernes s a l s o i s more foca l . Such
fi ndi ngs ca n ma ke i t di ffi cul t to di s ti ngui s h perfora ti on from wors eni ng of the underl yi ng di s order or l a ck of res pons e to trea tment.
In a l l types of perfora ti on, na us ea , vomi ti ng, a nd a norexi a a re common. Bowel s ounds a re qui et to a bs ent.
Diagnosis
Abdomi na l s eri es
If nondi a gnos ti c, a bdomi na l CT
An a bdomi na l s eri es (s upi ne a nd upri ght a bdomi na l x-ra ys a nd ches t x-ra ys ) ma y be di a gnos ti c, s howi ng free a i r under the di a phra gm i n 50 to 75%
of ca s es . As ti me pa s s es , thi s s i gn becomes more common. A l a tera l ches t x-ra y i s more s ens i ti ve for free a i r tha n a pos teroa nteri or x-ra y. If the
a bdomi na l s eri es i s nondi a gnos ti c, a bdomi na l CT us ua l l y wi th ora l a nd IV a nd/or recta l contra s t ma y be hel pful . Ba ri um s houl d not be us ed i f
perfora ti on i s s us pected.
Treatment
Surgery
IV fl ui ds a nd a nti bi oti cs
[Table 11-4. Some Ca us es of GI Tra ct Perfora ti on]
If a perfora ti on i s noted, i mmedi a te s urgery i s neces s a ry beca us e morta l i ty ca us ed by peri toni ti s i ncrea s es ra pi dl y the l onger trea tment i s
del a yed. If a n a bs ces s or a n i nfl a mma tory ma s s ha s formed, the procedure ma y be l i mi ted to dra i na ge of the a bs ces s .
An NGT i s i ns erted before opera ti on. Pa ti ents wi th s i gns of vol ume depl eti on s houl d ha ve uri ne output moni tored wi th a ca theter. Fl ui d s ta tus i s
ma i nta i ned by a dequa te IV fl ui d a nd el ectrol yte repl a cement. IV a nti bi oti cs effecti ve a ga i ns t i ntes ti na l fl ora s houl d be gi ven (eg, cefoteta n 1 to 2
g bi d, or a mi ka ci n 5 mg/kg ti d pl us cl i nda myci n 600 to 900 mg qi d).
Appendicitis
Appendicitis is acute inflammation of the vermiform appendix, typically resulting in abdominal pain, anorexia, and abdominal tenderness. Diagnosis is clinical,
often supplemented by CT or ultrasound. Treatment is surgical removal.
In the US, a cute a ppendi ci ti s i s the mos t common ca us e of a cute a bdomi na l pa i n requi ri ng s urgery. Over 5% of the popul a ti on devel ops
a ppendi ci ti s a t s ome poi nt. It mos t commonl y occurs i n the teens a nd 20s but ma y occur a t a ny a ge.
Other condi ti ons a ffecti ng the a ppendi x i ncl ude ca rci noi ds , ca ncer, vi l l ous a denoma s , a nd di verti cul a . The a ppendi x ma y a l s o be a ffected by
Crohn's di s ea s e or ul cera ti ve col i ti s wi th pa ncol i ti s .
Etiology
Appendi ci ti s i s thought to res ul t from obs tructi on of the a ppendi cea l l umen, typi ca l l y by l ymphoi d hyperpl a s i a , but occa s i ona l l y by a feca l i th,
forei gn body, or even worms . The obs tructi on l ea ds to di s tenti on, ba cteri a l overgrowth, i s chemi a , a nd i nfl a mma ti on. If untrea ted, necros i s ,
ga ngrene, a nd perfora ti on occur. If the perfora ti on i s conta i ned by the omentum, a n a ppendi cea l a bs ces s res ul ts .
Symptoms and Signs
The cl a s s i c s ymptoms of a cute a ppendi ci ti s a re epi ga s tri c or peri umbi l i ca l pa i n fol l owed by bri ef na us ea , vomi ti ng, a nd a norexi a ; a fter a few
hours , the pa i n s hi fts to the ri ght l ower qua dra nt. Pa i n i ncrea s es wi th cough a nd moti on. Cl a s s i c s i gns a re ri ght l ower qua dra nt di rect a nd rebound
tendernes s l oca ted a t McBurney's poi nt (juncti on of the mi ddl e a nd outer thi rds of the l i ne joi ni ng the umbi l i cus to the a nteri or s uperi or s pi ne).
Addi ti ona l s i gns a re pa i n fel t i n the ri ght l ower qua dra nt wi th pa l pa ti on of the l eft l ower qua dra nt (Rovs i ng s i gn), a n i ncrea s e i n pa i n from
pa s s i ve extens i on of the ri ght hi p joi nt tha t s tretches the i l i ops oa s mus cl e (ps oa s s i gn), or pa i n ca us ed by pa s s i ve i nterna l rota ti on of the fl exed
thi gh (obtura tor s i gn). Low-gra de fever (recta l tempera ture 37.7 to 38.3 C [100 to 101 F]) i s common.
Unfortuna tel y, thes e cl a s s i c fi ndi ngs a ppea r i n < 50% of pa ti ents . Ma ny va ri a ti ons of s ymptoms a nd s i gns occur. Pa i n ma y not be l oca l i zed,
pa rti cul a rl y i n i nfa nts a nd chi l dren. Tendernes s ma y be di ffus e or, i n ra re i ns ta nces , a bs ent. Bowel movements a re us ua l l y l es s frequent or
a bs ent; i f di a rrhea i s a s i gn, a retroceca l a ppendi x s houl d be s us pected. RBCs or WBCs ma y be pres ent i n the uri ne. Atypi ca l s ymptoms a re
common a mong el derl y pa ti ents a nd pregna nt women; i n pa rti cul a r, pa i n i s l es s s evere a nd l oca l tendernes s i s l es s ma rked.
Diagnosis
Abdomi na l CT i f neces s a ry
Ul tra s ound a n opti on to CT
When cl a s s i c s ymptoms a nd s i gns a re pres ent, the di a gnos i s i s cl i ni ca l . In s uch pa ti ents , del a yi ng l a pa rotomy to do i ma gi ng tes ts onl y i ncrea s es
the l i kel i hood of perfora ti on a nd s ubs equent compl i ca ti ons . In pa ti ents wi th a typi ca l or equi voca l fi ndi ngs , i ma gi ng s tudi es s houl d be done
wi thout del a y. Contra s t-enha nced CT ha s rea s ona bl e a ccura cy i n di a gnos i ng a ppendi ci ti s a nd ca n a l s o revea l other ca us es of a n a cute a bdomen.
Gra ded compres s i on ul tra s ound ca n us ua l l y be done qui ckl y a nd us es no ra di a ti on (of pa rti cul a r concern i n chi l dren); however, i t i s occa s i ona l l y
l i mi ted by the pres ence of bowel ga s a nd i s l es s us eful for recogni zi ng nona ppendi cea l ca us es of pa i n. Appendi ci ti s rema i ns pri ma ri l y a cl i ni ca l
di a gnos i s . Sel ecti ve a nd judi ci ous us e of ra di ogra phi c s tudi es ma y reduce the ra te of nega ti ve l a pa rotomy.
La pa ros copy ca n be us ed for di a gnos i s a s wel l a s defi ni ti ve trea tment; i t ma y be es peci a l l y hel pful i n women wi th l ower a bdomi na l pa i n of
uncl ea r eti ol ogy. La bora tory s tudi es typi ca l l y s how l eukocytos i s (12,000 to 15,000/L), but thi s fi ndi ng i s hi ghl y va ri a bl e; a norma l WBC count s houl d
not be us ed to excl ude a ppendi ci ti s .
Prognosis
Wi thout s urgery or a nti bi oti cs , morta l i ty i s > 50%.
Wi th ea rl y s urgery, the morta l i ty ra te i s < 1%, a nd conva l es cence i s norma l l y ra pi d a nd compl ete. Wi th compl i ca ti ons (rupture a nd devel opment of
a n a bs ces s or peri toni ti s ), the prognos i s i s wors e: Repea t opera ti ons a nd a l ong conva l es cence ma y fol l ow.
Treatment
Surgi ca l remova l
IV fl ui ds a nd a nti bi oti cs
Trea tment of a cute a ppendi ci ti s i s open or l a pa ros copi c a ppendectomy; beca us e trea tment del a y i ncrea s es morta l i ty, a nega ti ve a ppendectomy
ra te of 15% i s cons i dered a ccepta bl e. The s urgeon ca n us ua l l y remove the a ppendi x even i f perfora ted. Occa s i ona l l y, the a ppendi x i s di ffi cul t to
l oca te: In thes e ca s es , i t us ua l l y l i es behi nd the cecum or the i l eum a nd mes entery of the ri ght col on. A contra i ndi ca ti on to a ppendectomy i s
i nfl a mma tory bowel di s ea s e i nvol vi ng the cecum. However, i n ca s es of termi na l i l ei ti s a nd a norma l cecum, the a ppendi x s houl d be removed.
Appendectomy s houl d be preceded by IV a nti bi oti cs . Thi rd-genera ti on cepha l os pori ns a re preferred. For nonperfora ted a ppendi ci ti s , no further
a nti bi oti cs a re requi red. If the a ppendi x i s perfora ted, a nti bi oti cs s houl d be conti nued unti l the pa ti ent's tempera ture a nd WBC count ha ve
norma l i zed or conti nued for a fi xed cours e, a ccordi ng to the s urgeon's preference. If s urgery i s i mpos s i bl e, a nti bi oti cs a l though not cura ti ve
ma rkedl y i mprove the s urvi va l ra te. When a l a rge i nfl a mma tory ma s s i s found i nvol vi ng the a ppendi x, termi na l i l eum, a nd cecum, res ecti on of the
enti re ma s s a nd i l eocol os tomy a re prefera bl e. In l a te ca s es i n whi ch a peri col i c a bs ces s ha s a l rea dy formed, the a bs ces s i s dra i ned ei ther by a n
ul tra s ound-gui ded percuta neous ca theter or by open opera ti on (wi th a ppendectomy to fol l ow a t a l a ter da te). A Meckel 's di verti cul um i n a pa ti ent
under the a ge of 40 s houl d be removed concomi ta ntl y wi th the a ppendectomy unl es s extens i ve i nfl a mma ti on a round the a ppendi x prevents the
procedure.
Hernias of the Abdominal Wall
A hernia of the abdominal wall is a protrusion of the abdominal contents through an acquired or congenital area of weakness or defect in the wall. Many hernias
are asymptomatic, but some become incarcerated or strangulated, causing pain and requiring immediate surgery. Diagnosis is clinical. Treatment is elective
surgical repair.
Abdomi na l herni a s a re extremel y common, pa rti cul a rl y a mong ma l es , neces s i ta ti ng a bout 700,000 opera ti ons ea ch yea r i n the US.
Classification
Abdomi na l herni a s a re cl a s s i fi ed a s ei ther a bdomi na l wa l l or groi n herni a s . Stra ngul a ted herni a s a re i s chemi c from phys i ca l cons tri cti on of thei r
bl ood s uppl y. Ga ngrene, perfora ti on, a nd peri toni ti s ma y devel op. Inca rcera ted a nd s tra ngul a ted herni a s ca nnot be reduced ma nua l l y.
Abdomi na l wa l l herni a s i ncl ude umbi l i ca l herni a s , epi ga s tri c herni a s , Spi gel i a n herni a s , a nd i nci s i ona l (ventra l ) herni a s . Umbi l i ca l herni a s
(protrus i ons through the umbi l i ca l ri ng) a re mos tl y congeni ta l , but s ome a re a cqui red i n a dul thood s econda ry to obes i ty, a s ci tes , pregna ncy, or
chroni c peri tonea l di a l ys i s . Epi ga s tri c herni a s occur through the l i nea a l ba . Spi gel i a n herni a s occur through defects i n the tra ns vers us a bdomi ni s
mus cl e l a tera l to the rectus s hea th, us ua l l y bel ow the l evel of the umbi l i cus . Inci s i ona l herni a s occur through a n i nci s i on from previ ous
a bdomi na l s urgery.
Groi n herni a s i ncl ude i ngui na l herni a s a nd femora l herni a s . Ingui na l herni a s occur a bove the i ngui na l l i ga ment. Indi rect i ngui na l herni a s
tra vers e the i nterna l i ngui na l ri ng i nto the i ngui na l ca na l , a nd di rect i ngui na l herni a s extend di rectl y forwa rd a nd do not pa s s through the
i ngui na l ca na l . Femora l herni a s occur bel ow the i ngui na l l i ga ment a nd go i nto the femora l ca na l .
About 75% of a l l a bdomi na l herni a s a re i ngui na l . Inci s i ona l herni a s compri s e a nother 10 to 15%. Femora l a nd unus ua l herni a s a ccount for the
rema i ni ng 10 to 15%.
Symptoms and Signs
Mos t pa ti ents compl a i n onl y of a vi s i bl e bul ge, whi ch ma y ca us e va gue di s comfort or be a s ymptoma ti c. Mos t herni a s , even l a rge ones , ca n be
ma nua l l y reduced wi th pers i s tent gentl e pres s ure; pl a ci ng the pa ti ent i n the Trendel enburg pos i ti on ma y hel p. An i nca rcera ted herni a ca nnot be
reduced but ha s no a ddi ti ona l s ymptoms . A s tra ngul a ted herni a ca us es s tea dy, gra dua l l y i ncrea s i ng pa i n, typi ca l l y wi th na us ea a nd vomi ti ng. The
herni a i ts el f i s tender, a nd the overl yi ng s ki n ma y be erythema tous ; peri toni ti s ma y devel op dependi ng on l oca ti on, wi th di ffus e tendernes s ,
gua rdi ng, a nd rebound.
Diagnosis
The di a gnos i s i s cl i ni ca l . Beca us e the herni a ma y be a ppa rent onl y when a bdomi na l pres s ure i s i ncrea s ed, the pa ti ent s houl d be exa mi ned i n a
s ta ndi ng pos i ti on. If no herni a i s pa l pa bl e, the pa ti ent s houl d cough or perform a Va l s a l va ma neuver a s the exa mi ner pa l pa tes the a bdomi na l
wa l l . Exa mi na ti on focus es on the umbi l i cus , the i ngui na l a rea (wi th a fi nger i n the i ngui na l ca na l i n ma l es ), the femora l tri a ngl e, a nd a ny
i nci s i ons tha t a re pres ent.
Ingui na l ma s s es tha t res embl e herni a s ma y be the res ul t of a denopa thy (i nfecti ous or ma l i gna nt), a n ectopi c tes ti s , or l i poma . Thes e ma s s es a re
s ol i d a nd a re not reduci bl e. A s crota l ma s s ma y be a va ri cocel e, hydrocel e, or tes ti cul a r tumor. Ul tra s ound ma y be done i f phys i ca l exa mi na ti on i s
equi voca l .
Prognosis
Congeni ta l umbi l i ca l herni a s ra rel y s tra ngul a te a nd a re not trea ted; mos t res ol ve s ponta neous l y wi thi n s evera l yea rs . Very l a rge defects ma y be
repa i red el ecti vel y a fter a ge 2 yr. Umbi l i ca l herni a s i n a dul ts ca us e cos meti c concerns a nd ca n be el ecti vel y repa i red; s tra ngul a ti on a nd
i nca rcera ti on a re unus ua l but, i f ha ppen, us ua l l y conta i n omentum ra ther tha n i ntes ti ne.
Treatment
Surgi ca l repa i r
Groi n herni a s s houl d be repa i red el ecti vel y beca us e of the ri s k of s tra ngul a ti on, whi ch res ul ts i n hi gher morbi di ty (a nd pos s i bl e morta l i ty i n
el derl y pa ti ents ). Repa i r ma y be through a s ta nda rd i nci s i on or l a pa ros copi ca l l y.
An i nca rcera ted or s tra ngul a ted herni a of a ny ki nd requi res urgent s urgi ca l repa i r.
Ileus
(Pa ra l yti c Il eus ; Adyna mi c Il eus ; Pa res i s )
Ileus is a temporary arrest of intestinal peristalsis. It occurs most commonly after abdominal surgery, particularly when the intestines have been manipulated.
Symptoms are nausea, vomiting, and vague abdominal discomfort. Diagnosis is based on x-ray findings and clinical impression. Treatment is supportive, with
nasogastric suction and IV fluids.
Etiology
In a ddi ti on to pos topera ti ve ca us es , i l eus a l s o res ul ts from i ntra peri tonea l or retroperi tonea l i nfl a mma ti on (eg, a ppendi ci ti s , di verti cul i ti s ,
perfora ted duodena l ul cer), retroperi tonea l or i ntra -a bdomi na l hema toma s (eg, ruptured a bdomi na l a orti c a neurys m, l umba r compres s i on
fra cture), meta bol i c di s turba nces (eg, hypoka l emi a ), or drugs (eg, opi oi ds , a nti chol i nergi cs , s ometi mes Ca cha nnel bl ockers ). Il eus s ometi mes
occurs i n a s s oci a ti on wi th rena l or thora ci c di s ea s e (eg, l ower ri b fra ctures , l ower l obe pneumoni a s , MI).
Ga s tri c a nd col oni c moti l i ty di s turba nces a fter a bdomi na l s urgery a re common. The s ma l l bowel i s typi ca l l y l ea s t a ffected, wi th moti l i ty a nd
a bs orpti on returni ng to norma l wi thi n hours a fter s urgery. Stoma ch emptyi ng i s us ua l l y i mpa i red for a bout 24 h or more. The col on i s often mos t
a ffected a nd ma y rema i n i na cti ve for 48 to 72 h or more.
Symptoms and Signs
Symptoms a nd s i gns i ncl ude a bdomi na l di s tenti on, vomi ti ng, a nd va gue di s comfort. Pa i n ra rel y ha s the cl a s s i c col i cky pa ttern pres ent i n
mecha ni ca l obs tructi on. There ma y be obs ti pa ti on or pa s s a ge of s l i ght a mounts of wa tery s tool . Aus cul ta ti on revea l s a s i l ent a bdomen or
mi ni ma l peri s ta l s i s . The a bdomen i s not tender unl es s the underl yi ng ca us e i s i nfl a mma tory.
Diagnosis
Someti mes x-ra ys
The mos t es s enti a l ta s k i s to di s ti ngui s h i l eus from i ntes ti na l obs tructi on. In both condi ti ons , x-ra ys s how ga s eous di s tenti on of i s ol a ted
s egments of i ntes ti ne. In pos topera ti ve i l eus , however, ga s ma y a ccumul a te more i n the col on tha n i n the s ma l l bowel . Pos topera ti ve
a ccumul a ti on of ga s i n the s ma l l bowel often i mpl i es devel opment of a compl i ca ti on (eg, obs tructi on, peri toni ti s ). In other types of i l eus , x-ra y
fi ndi ngs a re s i mi l a r to obs tructi on; di fferenti a ti on ca n be di ffi cul t unl es s cl i ni ca l fea tures cl ea rl y fa vor one or the other. Wa ter-s ol ubl e contra s t
s tudi es ma y hel p di fferenti a te.
Treatment
NGT
IV fl ui ds
Trea tment i nvol ves conti nuous na s oga s tri c s ucti on, npo s ta tus , IV fl ui ds a nd el ectrol ytes , a mi ni ma l a mount of s eda ti ves , a nd a voi da nce of
opi oi ds a nd a nti chol i nergi c drugs . Ma i nta i ni ng a n a dequa te s erum K l evel (> 4 mEq/L [> 4 mmol /L]) i s es peci a l l y i mporta nt. Il eus pers i s ti ng > 1 wk
proba bl y ha s a mecha ni ca l obs tructi ve ca us e, a nd l a pa rotomy s houl d be cons i dered. Someti mes col oni c i l eus ca n be rel i eved by col onos copi c
decompres s i on; ra rel y, cecos tomy i s requi red. Col onos copi c decompres s i on i s hel pful i n trea ti ng ps eudo-obs tructi on (Ogi l vi e's s yndrome), whi ch
cons i s ts of a ppa rent obs tructi on a t the s pl eni c fl exure, a l though no ca us e ca n be found by contra s t enema or col onos copy for the fa i l ure of ga s
a nd feces to pa s s thi s poi nt. Some cl i ni ci a ns us e IV neos ti gmi ne (requi res ca rdi a c moni tori ng) to trea t Ogi l vi e's s yndrome.
Intestinal Obstruction
Intestinal obstruction is significant mechanical impairment or complete arrest of the passage of contents through the intestine. Symptoms include cramping pain,
vomiting, obstipation, and lack of flatus. Diagnosis is clinical, confirmed by abdominal x-rays. Treatment is fluid resuscitation, nasogastric suction, and, in most
cases of complete obstruction, surgery.
Mecha ni ca l obs tructi on i s di vi ded i nto obs tructi on of the s ma l l bowel (i ncl udi ng the duodenum) a nd obs tructi on of the l a rge bowel . Obs tructi on
ma y be pa rti a l or compl ete. About 85% of pa rti a l s ma l l -bowel obs tructi ons res ol ve wi th nonopera ti ve trea tment, wherea s a bout 85% of compl ete
s ma l l -bowel obs tructi ons requi re opera ti on.
Etiology
Overa l l , the mos t common ca us es of mecha ni ca l obs tructi on a re a dhes i ons , herni a s , a nd tumors . Other genera l ca us es a re di verti cul i ti s , forei gn
bodi es (i ncl udi ng ga l l s tones ), vol vul us (twi s ti ng of bowel on i ts mes entery), i ntus s us cepti on (tel es copi ng of one s egment of bowel i nto a nother
s ee p. 2801), a nd feca l i mpa cti on. Speci fi c s egments of the i ntes ti ne a re a ffected di fferentl y (s ee
Ta bl e 11-5).
Pathophysiology
In s i mpl e mecha ni ca l obs tructi on, bl ocka ge occurs wi thout va s cul a r compromi s e. Inges ted fl ui d a nd food, di ges ti ve s ecreti ons , a nd ga s
a ccumul a te a bove the obs tructi on. The proxi ma l bowel di s tends , a nd the di s ta l s egment col l a ps es . The norma l s ecretory a nd a bs orpti ve functi ons
of the mucos a a re depres s ed, a nd the bowel wa l l becomes edema tous a nd conges ted. Severe i ntes ti na l di s tenti on i s s el f-perpetua ti ng a nd
progres s i ve, i ntens i fyi ng
[Table 11-5. Ca us es of Intes ti na l Obs tructi on]
the peri s ta l ti c a nd s ecretory dera ngements a nd i ncrea s i ng the ri s ks of dehydra ti on a nd progres s i on to s tra ngul a ti ng obs tructi on.
Stra ngul a ti ng obs tructi on i s obs tructi on wi th compromi s ed bl ood fl ow; i t occurs i n nea rl y 25% of pa ti ents wi th s ma l l -bowel obs tructi on. It i s
us ua l l y a s s oci a ted wi th herni a , vol vul us , a nd i ntus s us cepti on. Stra ngul a ti ng obs tructi on ca n progres s to i nfa rcti on a nd ga ngrene i n a s l i ttl e a s 6 h.
Venous obs tructi on occurs fi rs t, fol l owed by a rteri a l occl us i on, res ul ti ng i n ra pi d i s chemi a of the bowel wa l l . The i s chemi c bowel becomes
edema tous a nd i nfa rcts , l ea di ng to ga ngrene a nd perfora ti on. In l a rge-bowel obs tructi on, s tra ngul a ti on i s ra re (except wi th vol vul us ).
Perfora ti on ma y occur i n a n i s chemi c s egment (typi ca l l y s ma l l bowel ) or when ma rked di l a ti on occurs . The ri s k i s hi gh i f the cecum i s di l a ted to a
di a meter 13 cm. Perfora ti on of a tumor or a di verti cul um ma y a l s o occur a t the obs tructi on s i te.
Symptoms and Signs
Obstruction of the small bowel ca us es s ymptoms s hortl y a fter ons et: a bdomi na l cra mps centered a round the umbi l i cus or i n the epi ga s tri um,
vomi ti ng, a ndi n pa ti ents wi th compl ete obs tructi onobs ti pa ti on. Pa ti ents wi th pa rti a l obs tructi on ma y devel op di a rrhea . Severe, s tea dy pa i n
s ugges ts tha t s tra ngul a ti on ha s occurred. In the a bs ence of s tra ngul a ti on, the a bdomen i s not tender. Hypera cti ve, hi gh-pi tched peri s ta l s i s wi th
rus hes coi nci di ng wi th cra mps i s typi ca l . Someti mes , di l a ted l oops of bowel a re pa l pa bl e. Wi th i nfa rcti on, the a bdomen becomes tender a nd
a us cul ta ti on revea l s a s i l ent a bdomen or mi ni ma l peri s ta l s i s . Shock a nd ol i guri a a re s eri ous s i gns tha t i ndi ca te ei ther l a te s i mpl e obs tructi on or
s tra ngul a ti on.
Obstruction of the large bowel us ua l l y ca us es mi l der s ymptoms tha t devel op more gra dua l l y tha n thos e ca us ed by s ma l l -bowel obs tructi on.
Increa s i ng cons ti pa ti on l ea ds to obs ti pa ti on a nd a bdomi na l di s tenti on. Vomi ti ng ma y occur (us ua l l y s evera l hours a fter ons et of other s ymptoms )
but i s not common. Lower a bdomi na l cra mps unproducti ve of feces occur. Phys i ca l exa mi na ti on typi ca l l y s hows a di s tended a bdomen wi th l oud
borborygmi . There i s no tendernes s , a nd the rectum i s us ua l l y empty. A ma s s corres pondi ng to the s i te of a n obs tructi ng tumor ma y be pa l pa bl e.
Sys temi c s ymptoms a re rel a ti vel y mi l d, a nd fl ui d a nd el ectrol yte defi ci ts a re uncommon.
Volvulus often ha s a n a brupt ons et. Pa i n i s conti nuous , s ometi mes wi th s uperi mpos ed wa ves of col i cky pa i n.
Diagnosis
Abdomi na l s eri es
Supi ne a nd upri ght a bdomi na l x-ra ys s houl d be ta ken a nd a re us ua l l y a dequa te to di a gnos e obs tructi on. Al though onl y l a pa rotomy ca n
defi ni ti vel y di a gnos e s tra ngul a ti on, ca reful s eri a l cl i ni ca l exa mi na ti on ma y provi de ea rl y wa rni ng. El eva ted WBCs a nd a ci dos i s ma y i ndi ca te tha t
s tra ngul a ti on ha s a l rea dy occurred.
On pl a i n x-ra ys , a l a dderl i ke s eri es of di s tended s ma l l -bowel l oops i s typi ca l of s ma l l -bowel obs tructi on but ma y a l s o occur wi th obs tructi on of
the ri ght col on. Fl ui d l evel s i n the bowel ca n be s een i n upri ght vi ews . Si mi l a r, a l though perha ps l es s dra ma ti c, x-ra y fi ndi ngs a nd s ymptoms occur
i n i l eus (pa ra l ys i s of the i ntes ti ne wi thout obs tructi ons ee p. 114); di fferenti a ti on ca n be di ffi cul t. Di s tended l oops a nd fl ui d l evel s ma y be
a bs ent wi th a n obs tructi on of the upper jejunum or wi th cl os ed-l oop s tra ngul a ti ng obs tructi ons (a s ma y occur wi th vol vul us ). Infa rcted bowel ma y
produce a ma s s effect on x-ra y. Ga s i n the bowel wa l l (pneuma tos i s i ntes ti na l i s ) i ndi ca tes ga ngrene.
In l a rge-bowel obs tructi on, a bdomi na l x-ra y s hows di s tenti on of the col on proxi ma l to the obs tructi on. In ceca l vol vul us , there ma y be a l a rge ga s
bubbl e i n the mi d-a bdomen or l eft upper qua dra nt. Wi th both ceca l a nd s i gmoi da l vol vul us , a contra s t enema s hows the s i te of obs tructi on by a
typi ca l "bi rd-bea k" deformi ty a t the s i te of the twi s t; the procedure ma y a ctua l l y reduce a s i gmoi d vol vul us . If contra s t enema i s not done,
col onos copy ca n be us ed to decompres s a s i gmoi d vol vul us but ra rel y works wi th a ceca l vol vul us .
Treatment
Na s oga s tri c s ucti on
IV fl ui ds
IV a nti bi oti cs i f bowel i s chemi a s us pected
Pa ti ents wi th pos s i bl e i ntes ti na l obs tructi on s houl d be hos pi ta l i zed. Trea tment of a cute i ntes ti na l obs tructi on mus t proceed s i mul ta neous l y wi th
di a gnos i s . A s urgeon s houl d a l wa ys be i nvol ved.
Supporti ve ca re i s s i mi l a r for s ma l l - a nd l a rge-bowel obs tructi on: na s oga s tri c s ucti on, IV fl ui ds (0.9% s a l i ne or l a cta ted Ri nger's s ol uti on for
i ntra va s cul a r vol ume repl eti on), a nd a uri na ry ca theter to moni tor fl ui d output. El ectrol yte repl a cement s houl d be gui ded by tes t res ul ts , a l though
i n ca s es of repea ted vomi ti ng s erum Na a nd K a re l i kel y to be depl eted. If bowel i s chemi a or i nfa rcti on i s s us pected, a nti bi oti cs s houl d be gi ven
(eg, a 3rd-genera ti on cepha l os pori n, s uch a s cefoteta n 2 g IV) before l a pa rotomy.
Specific measures: Obs tructi on of the duodenum i n a dul ts i s trea ted by res ecti on or, i f the l es i on ca nnot be removed, pa l l i a ti ve ga s trojejunos tomy
(for trea tment i n chi l dren, s ee p. 2978).
Compl ete obs tructi on of the s ma l l bowel i s preferenti a l l y trea ted wi th ea rl y l a pa rotomy, a l though s urgery ca n be del a yed 2 or 3 h to i mprove fl ui d
s ta tus a nd uri ne output i n a very i l l , dehydra ted pa ti ent. The offendi ng l es i on i s removed whenever pos s i bl e. If a ga l l s tone i s the ca us e of
obs tructi on, i t i s removed through a n enterotomy, a nd chol ecys tectomy need not be done. Procedures to prevent recurrence s houl d be done,
i ncl udi ng repa i r of herni a s , remova l of forei gn bodi es , a nd l ys i s of the offendi ng a dhes i ons . In s ome pa ti ents wi th ea rl y pos topera ti ve obs tructi on
or repea ted obs tructi on ca us ed by a dhes i ons , s i mpl e i ntuba ti on wi th a l ong i ntes ti na l tube (ma ny cons i der a s ta nda rd NGT to be equa l l y
effecti ve), ra ther tha n s urgery, ma y be a ttempted i n the a bs ence of peri tonea l s i gns .
Di s s emi na ted i ntra peri tonea l ca ncer obs tructi ng the s ma l l bowel i s a ma jor ca us e of dea th i n a dul t pa ti ents wi th GI tra ct ca ncer. Bypa s s i ng the
obs tructi on, ei ther s urgi ca l l y or wi th endos copi ca l l y pl a ced s tents , ma y pa l l i a te s ymptoms bri efl y.
Obs tructi ng col on ca ncers ca n often be trea ted by a s i ngl e-s ta ge res ecti on a nd a na s tomos i s . Other opti ons i ncl ude a di verti ng i l eos tomy a nd
di s ta l a na s tomos i s . Occa s i ona l l y, a di verti ng col os tomy wi th del a yed res ecti on i s requi red.
When di verti cul i ti s ca us es obs tructi on, perfora ti on i s often pres ent. Remova l of the i nvol ved a rea ma y be very di ffi cul t but i s i ndi ca ted i f
perfora ti on a nd genera l peri toni ti s a re pres ent. Res ecti on a nd col os tomy a re done, a nd a na s tomos i s i s pos tponed.
Feca l i mpa cti on us ua l l y occurs i n the rectum a nd ca n be removed di gi ta l l y a nd wi th enema s . However, a feca l concreti on a l one or i n a mi xture (i e,
wi th ba ri um or a nta ci ds ) tha t ca us es compl ete obs tructi on (us ua l l y i n the s i gmoi d) requi res l a pa rotomy.
Trea tment of ceca l vol vul us cons i s ts of res ecti on a nd a na s tomos i s of the i nvol ved s egment or fi xa ti on of the cecum i n i ts norma l pos i ti on by
cecos tomy i n the fra i l pa ti ent. In s i gmoi da l vol vul us , a n endos cope or a l ong recta l tube ca n often decompres s the l oop, a nd res ecti on a nd
a na s tomos i s ma y be deferred for a few da ys . Wi thout a res ecti on, recurrence i s a l mos t i nevi ta bl e.
Intra-Abdominal Abscesses
Abscesses can occur anywhere in the abdomen and retroperitoneum. They mainly occur after surgery, trauma, or conditions involving abdominal infection and
inflammation, particularly when peritonitis or perforation occurs. Symptoms are malaise, fever, and abdominal pain. Diagnosis is by CT. Treatment is with
drainage, either surgical or percutaneous. Antibiotics are ancillary.
Etiology
Intra -a bdomi na l a bs ces s es a re cl a s s i fi ed a s i ntra peri tonea l , retroperi tonea l , or vi s cera l (s ee
Ta bl e 11-6). Ma ny i ntra -a bdomi na l a bs ces s es devel op a fter perfora ti on of a hol l ow vi s cus or col oni c ca ncer. Others devel op by extens i on of
i nfecti on or i nfl a mma ti on res ul ti ng from condi ti ons s uch a s a ppendi ci ti s , di verti cul i ti s , Crohn's di s ea s e, pa ncrea ti ti s , pel vi c i nfl a mma tory
di s ea s e, or i ndeed a ny condi ti on ca us i ng genera l i zed peri toni ti s . Abdomi na l s urgery, pa rti cul a rl y tha t i nvol vi ng the di ges ti ve or bi l i a ry tra ct, i s
a nother s i gni fi ca nt ri s k fa ctor: The peri toneum ma y be conta mi na ted duri ng or a fter s urgery from s uch events a s a na s tomoti c l ea ks . Tra uma ti c
[Table 11-6. Intra -Abdomi na l Abs ces s es ]
a bdomi na l i njuri es pa rti cul a rl y l a cera ti ons a nd hema toma s of the l i ver, pa ncrea s , s pl een, a nd i ntes ti nes ma y devel op a bs ces s es , whether
trea ted opera ti vel y or not.
The i nfecti ng orga ni s ms typi ca l l y refl ect norma l bowel fl ora a nd a re a compl ex mi xture of a na erobi c a nd a erobi c ba cteri a . Mos t frequent i s ol a tes
a re a erobi c gra m-nega ti ve ba ci l l i (eg, Escherichia coli a nd Klebsiella) a nd a na erobes (es peci a l l y Bacteroides fragilis).
Undra i ned a bs ces s es ma y extend to conti guous s tructures , erode i nto a dja cent ves s el s (ca us i ng hemorrha ge or thrombos i s ), rupture i nto the
peri toneum or bowel , or form a cuta neous fi s tul a . Subdi a phra gma ti c a bs ces s es ma y extend i nto the thora ci c ca vi ty, ca us i ng a n empyema , l ung
a bs ces s , or pneumoni a . An a bs ces s i n the l ower a bdomen ma y tra ck down i nto the thi gh or peri recta l fos s a . Spl eni c a bs ces s i s a ra re ca us e of
s us ta i ned ba cteremi a i n endoca rdi ti s tha t pers i s ts des pi te a ppropri a te a nti mi crobi a l thera py.
Symptoms and Signs
Abs ces s es ma y form wi thi n 1 wk of perfora ti on or s i gni fi ca nt peri toni ti s , wherea s pos topera ti ve a bs ces s es ma y not occur unti l 2 to 3 wk a fter
opera ti on a nd, ra rel y, not for s evera l months . Al though ma ni fes ta ti ons va ry, mos t a bs ces s es ca us e fever a nd a bdomi na l di s comfort ra ngi ng from
mi ni ma l to s evere (us ua l l y nea r the a bs ces s ). Pa ra l yti c i l eus , ei ther genera l i zed or l oca l i zed, ma y devel op. Na us ea , a norexi a , a nd wei ght l os s a re
common.
Abs ces s es i n Dougl a s ' cul -de-s a c, a dja cent to the col on, ma y ca us e di a rrhea . Conti gui ty to the bl a dder ma y res ul t i n uri na ry urgency a nd frequency
a nd, i f ca us ed by di verti cul i ti s , ma y crea te a col oves i ca l fi s tul a .
Subphreni c a bs ces s es ma y ca us e ches t s ymptoms s uch a s nonproducti ve cough, ches t pa i n, dys pnea , a nd s houl der pa i n. Ra l es , rhonchi , or a
fri cti on rub ma y be a udi bl e. Dul l nes s to percus s i on a nd decrea s ed brea th s ounds a re typi ca l when ba s i l a r a tel ecta s i s , pneumoni a , or pl eura l
effus i on occurs .
Genera l l y, there i s tendernes s over the l oca ti on of the a bs ces s . La rge a bs ces s es ma y be pa l pa bl e a s a ma s s .
Diagnosis
Abdomi na l CT
Ra rel y, ra di onucl i de s ca nni ng
CT of the a bdomen a nd pel vi s wi th ora l contra s t i s the preferred di a gnos ti c moda l i ty for s us pected a bs ces s . Other i ma gi ng s tudi es , i f done, ma y
s how a bnorma l i ti es ; pl a i n a bdomi na l x-ra ys ma y revea l extra i ntes ti na l ga s i n the a bs ces s , di s pl a cement of a dja cent orga ns , a s oft-ti s s ue dens i ty
repres enti ng the a bs ces s , or l os s of the ps oa s mus cl e s ha dow. Abs ces s es nea r the di a phra gm ma y res ul t i n ches t x-ra y a bnorma l i ti es s uch a s
i ps i l a tera l pl eura l effus i on, el eva ted or i mmobi l e hemi di a phra gm, l ower l obe i nfi l tra tes , a nd a tel ecta s i s .
CBC a nd bl ood cul tures s houl d be done. Leukocytos i s occurs i n mos t pa ti ents , a nd a nemi a i s common.
Occa s i ona l l y, ra di onucl i de s ca nni ng wi th i ndi um 111 -l a bel ed l eukocytes ma y be hel pful i n i denti fyi ng i ntra -a bdomi na l a bs ces s es .
Prognosis
Intra -a bdomi na l a bs ces s es ha ve a morta l i ty ra te of 10 to 40%. Outcome depends ma i nl y on the pa ti ent's pri ma ry i l l nes s or i njury a nd genera l
medi ca l condi ti on ra ther tha n on the s peci fi c na ture a nd l oca ti on of the a bs ces s .
Treatment
IV a nti bi oti cs
Dra i na ge: Percuta neous or s urgi ca l
Al l i ntra -a bdomi na l a bs ces s es requi re dra i na ge, ei ther by percuta neous ca theters or s urgery. Dra i na ge through ca theters (pl a ced wi th CT or
ul tra s ound gui da nce) ma y be a ppropri a te gi ven the fol l owi ng condi ti ons : Few a bs ces s ca vi ti es a re pres ent; the dra i na ge route does not tra vers e
bowel or unconta mi na ted orga ns , pl eura , or peri toneum; the s ource of conta mi na ti on i s control l ed; a nd the pus i s thi n enough to pa s s through
the ca theter.
Anti bi oti cs a re not cura ti ve but ma y l i mi t hema togenous s prea d a nd s houl d be gi ven before a nd a fter i nterventi on. Thera py requi res drugs a cti ve
a ga i ns t bowel fl ora , s uch a s a combi na ti on of a n a mi nogl ycos i de (eg, genta mi ci n 1.5 mg/kg q 8 h) a nd metroni da zol e 500 mg q 8 h. Si ngl e-a gent
thera py wi th cefoteta n 2 g q 12 h i s a l s o rea s ona bl e. Pa ti ents previ ous l y gi ven a nti bi oti cs or thos e who ha ve hos pi ta l -a cqui red i nfecti ons s houl d
recei ve drugs a cti ve a ga i ns t res i s ta nt a erobi c gra m-nega ti ve ba ci l l i (eg, Pseudomonas) a nd a na erobes .
Nutri ti ona l s upport i s i mporta nt, wi th the entera l route preferred. Pa rentera l nutri ti on s houl d begi n ea rl y i f the entera l route i s not fea s i bl e.
Ischemic Colitis
Ischemic colitis is a transient reduction in blood flow to the colon.
Necros i s ma y occur but i s us ua l l y l i mi ted to the mucos a a nd s ubmucos a , onl y occa s i ona l l y ca us i ng ful l -thi cknes s necros i s neces s i ta ti ng s urgery. It
occurs ma i nl y i n ol der peopl e (> 60) a nd i s thought to be ca us ed by s ma l l -ves s el a theros cl eros i s .
Symptoms a re mi l der a nd of s l ower ons et tha n thos e of a cute mes enteri c i s chemi a a nd cons i s t of l eft l ower qua dra nt pa i n fol l owed by recta l
bl eedi ng. Di a gnos i s i s ma de by col onos copy; a ngi ogra phy or ma gneti c res ona nce a ngi ogra phy i s not i ndi ca ted. Trea tment i s s upporti ve wi th IV
fl ui ds , bowel res t, a nd a nti bi oti cs . Surgery i s ra rel y requi red. About 5% of pa ti ents ha ve a recurrence. Occa s i ona l l y, s tri ctures devel op a t the s i te of
the i s chemi a s evera l weeks l a ter, neces s i ta ti ng s urgi ca l res ecti on.
Chapter 12. Esophageal and Swallowing Disorders

Introduction
(See a l s o Es opha gea l Ca ncer on p. 186 a nd Es opha gea l Atres i a on p. 2975.)
The s wa l l owi ng a ppa ra tus cons i s ts of the pha rynx, upper es opha gea l (cri copha ryngea l ) s phi ncter, the body of the es opha gus , a nd the l ower
es opha gea l s phi ncter (LES). The upper thi rd of the es opha gus a nd the s tructures proxi ma l to i t a re compos ed of s kel eta l mus cl e; the di s ta l
es opha gus a nd LES a re compos ed of s mooth mus cl e. Thes e components work a s a n i ntegra ted s ys tem tha t tra ns ports ma teri a l from the mouth to
the s toma ch a nd prevents i ts refl ux i nto the es opha gus . Phys i ca l obs tructi on or di s orders tha t i nterfere wi th motor functi on (moti l i ty di s orders )
ca n a ffect the s ys tem.
The pa ti ent's hi s tory s ugges ts the di a gnos i s a l mos t 80% of the ti me. The onl y phys i ca l fi ndi ngs i n es opha gea l di s orders a re cervi ca l a nd
s upra cl a vi cul a r l ympha denopa thy ca us ed by meta s ta s i s , s wel l i ngs i n the neck ca us ed by l a rge pha ryngea l di verti cul a or thyromega l y, a nd
prol onged s wa l l owi ng ti me (the ti me from the a ct of s wa l l owi ng to the s ound of the bol us of fl ui d a nd a i r enteri ng the s toma chnorma l l y 12 s ec
hea rd by a us cul ta ti on wi th the s tethos cope over the epi ga s tri um). Wa tchi ng the pa ti ent s wa l l ow ma y hel p di a gnos e a s pi ra ti on or na s a l
regurgi ta ti on. Mos t es opha gea l di s orders requi re s peci fi c tes ts for di a gnos i s .
Dysphagia
Dys pha gi a i s di ffi cul ty s wa l l owi ng. The condi ti on res ul ts from i mpeded tra ns port of l i qui ds , s ol i ds , or both from the pha rynx to the s toma ch.
Dys pha gi a s houl d not be confus ed wi th gl obus s ens a ti on (s ee p. 78), a feel i ng of ha vi ng a l ump i n the throa t, whi ch i s unrel a ted to s wa l l owi ng
a nd occurs wi thout i mpa i red tra ns port.
Complications: Dys pha gi a ca n l ea d to tra chea l a s pi ra ti on of i nges ted ma teri a l , ora l s ecreti ons , or both. As pi ra ti on ca n ca us e a cute pneumoni a ;
recurrent a s pi ra ti on ma y eventua l l y l ea d to chroni c l ung di s ea s e. Prol onged dys pha gi a often l ea ds to i na dequa te nutri ti on a nd wei ght l os s .
Etiology
Dys pha gi a i s cl a s s i fi ed a s oropha ryngea l or es opha gea l , dependi ng on where i t occurs .
Oropharyngeal dysphagia: Oropha ryngea l dys pha gi a i s di ffi cul ty emptyi ng ma teri a l from the oropha rynx i nto the es opha gus ; i t res ul ts from a bnorma l
functi on proxi ma l to the es opha gus . Pa ti ents compl a i n of di ffi cul ty i ni ti a ti ng s wa l l owi ng, na s a l regurgi ta ti on, a nd tra chea l a s pi ra ti on fol l owed by
coughi ng.
Mos t often, oropha ryngea l dys pha gi a occurs i n pa ti ents wi th neurol ogi c condi ti ons or mus cul a r di s orders tha t a ffect s kel eta l mus cl es (s ee
Ta bl e 12-1).
Esophageal dysphagia: Es opha gea l dys pha gi a i s di ffi cul ty pa s s i ng food down the es opha gus . It res ul ts from ei ther a moti l i ty di s order or a
mecha ni ca l obs tructi on (s ee
Ta bl e 12-2).
Evaluation
History: History of present illness begi ns wi th dura ti on of s ymptoms a nd a cui ty of ons et. Pa ti ents s houl d des cri be wha t s ubs ta nces ca us e di ffi cul ty
a nd where they feel the di s turba nce i s l oca ted. Speci fi c concerns i ncl ude whether pa ti ents ha ve di ffi cul ty s wa l l owi ng s ol i ds , l i qui ds , or both;
whether food comes out thei r nos e; whether they drool or ha ve food s pi l l from thei r mouth; a nd whether they cough or choke whi l e ea ti ng.
[Table 12-1. Some Ca us es of Oropha ryngea l Dys pha gi a ]
Review of symptoms s houl d focus on s ymptoms s ugges ti ve of neuromus cul a r, GI, a nd connecti ve ti s s ue di s orders a nd on the pres ence of
compl i ca ti ons . Importa nt neuromus cul a r s ymptoms i ncl ude wea knes s a nd ea s y fa ti ga bi l i ty, ga i t or ba l a nce di s turba nce, tremor, a nd di ffi cul ty
s pea ki ng. Importa nt GI s ymptoms i ncl ude hea rtburn or other ches t di s comfort s ugges ti ve of refl ux. Symptoms of connecti ve ti s s ue di s orders
i ncl ude mus cl e a nd joi nt pa i n, Ra yna ud's phenomenon, a nd s ki n cha nges (eg, ra s h, s wel l i ng, thi ckeni ng).
Past medical history s houl d a s certa i n known di s ea s es tha t ma y ca us e dys pha gi a (s ee Ta bl es 12-1 a nd 12-2).
Physical examination: Exa mi na ti on focus es on fi ndi ngs s ugges ti ve of neuromus cul a r, GI, a nd connecti ve ti s s ue di s orders a nd on the pres ence of
compl i ca ti ons .
Genera l exa mi na ti on s houl d eva l ua te nutri ti ona l s ta tus (i ncl udi ng body wei ght). A compl ete neurol ogi c exa mi na ti on i s es s enti a l , wi th a ttenti on
to a ny res ti ng tremor, the cra ni a l nerves (note the ga g refl ex ma y norma l l y be a bs ent; thi s a bs ence i s thus not a good ma rker of s wa l l owi ng
dys functi on), a nd mus cl e s trength. Pa ti ents who des cri be ea s y fa ti ga bi l i ty s houl d be obs erved performi ng a repeti ti ve a cti on (eg, bl i nki ng,
counti ng a l oud) for a ra pi d decrement i n performa nce.
[Table 12-2. Some Ca us es of Es opha gea l Dys pha gi a ]
The pa ti ent's ga i t s houl d be obs erved, a nd ba l a nce s houl d be tes ted. Ski n i s exa mi ned for ra s h a nd thi ckeni ng or texture cha nges , pa rti cul a rl y on
the fi ngerti ps . Mus cl es a re i ns pected for wa s ti ng a nd fa s ci cul a ti ons a nd a re pa l pa ted for tendernes s . The neck i s eva l ua ted for thyromega l y or
other ma s s .
Red flags: Any dys pha gi a i s of concern, but certa i n fi ndi ngs a re more urgent:
Symptoms of compl ete obs tructi on (eg, drool i ng, i na bi l i ty to s wa l l ow a nythi ng)
Dys pha gi a res ul ti ng i n wei ght l os s

New foca l neurol ogi c defi ci t, pa rti cul a rl y a ny objecti ve wea knes s
Interpretation of findings: Dys pha gi a tha t occurs i n conjuncti on wi th a n a cute neurol ogi c event i s l i kel y the res ul t of tha t event; new dys pha gi a i n a
pa ti ent wi th a s ta bl e, l ong-s ta ndi ng neurol ogi c di s order ma y ha ve a nother eti ol ogy. Dys pha gi a for s ol i ds a l one s ugges ts mecha ni ca l obs tructi on;
however, a probl em wi th both s ol i ds a nd l i qui ds i s nons peci fi c. Drool i ng a nd s pi l l i ng food from the mouth whi l e ea ti ng or na s a l regurgi ta ti on
s ugges ts a n oropha ryngea l di s order. Regurgi ta ti on of a s ma l l a mount of food on l a tera l compres s i on of the neck i s vi rtua l l y di a gnos ti c of
pha ryngea l di verti cul um.
Pa ti ents who compl a i n of di ffi cul ty getti ng food to l ea ve the mouth or of food s ti cki ng i n the l ower es opha gus a re us ua l l y correct a bout the
condi ti on's l oca ti on; the s ens a ti on of dys pha gi a i n the upper es opha gus i s l es s s peci fi c.
Ma ny fi ndi ngs s ugges t s peci fi c di s orders (s ee
Ta bl e 12-3) but a re of va ryi ng s ens i ti vi ty a nd s peci fi ci ty a nd thus do not rul e i n or out a gi ven ca us e; however, they ca n gui de tes ti ng.
Testing: A ba ri um s wa l l ow (wi th a s ol i d bol us , us ua l l y a ma rs hma l l ow or ta bl et) s houl d be done. If thi s tes t s hows obs tructi on, endos copy (a nd
pos s i bl y bi ops y) s houl d be done to rul e out ma l i gna ncy. If the ba ri um s wa l l ow i s nega ti ve or s ugges ti ve of a moti l i ty di s order, es opha gea l
moti l i ty s tudi es s houl d be done. Other tes ts for s peci fi c ca us es a re done a s s ugges ted by fi ndi ngs .
Treatment
Trea tment i s di rected a t the s peci fi c ca us e. If compl ete obs tructi on occurs , emergent upper endos copy i s es s enti a l . If a s tri cture, ri ng, or web i s
found, ca reful endos copi c di l a ti on i s performed. Pendi ng res ol uti on, pa ti ents wi th oropha ryngea l dys pha gi a ma y benefi t
[Table 12-3. Some Hel pful Fi ndi ngs i n Dys pha gi a ]
from eva l ua ti on by a reha bi l i ta ti on s peci a l i s t. Someti mes pa ti ents benefi t from cha ngi ng hea d pos i ti on whi l e ea ti ng, retra i ni ng the s wa l l owi ng
mus cl es , doi ng exerci s es tha t i mprove the a bi l i ty to a ccommoda te a food bol us i n the ora l ca vi ty, or doi ng s trength a nd coordi na ti on exerci s es for
the tongue. Pa ti ents wi th s evere dys pha gi a a nd recurrent a s pi ra ti on ma y requi re a ga s tros tomy tube.
Chewi ng, s wa l l owi ng, ta s ti ng, a nd communi ca ti ng requi re i nta ct, coordi na ted neuromus cul a r functi on i n the mouth, fa ce, a nd neck. Ora l motor
functi on i n pa rti cul a r decl i nes mea s ura bl y wi th a gi ng, even i n hea l thy peopl e. Decl i ne i n functi on ma y ha ve ma ny ma ni fes ta ti ons :
Reducti on i n ma s ti ca tory mus cl e s trength a nd coordi na ti on i s common, es peci a l l y a mong pa ti ents wi th pa rti a l or compl ete dentures , a nd ma y
l ea d to a tendency to s wa l l ow l a rger food pa rti cl es , whi ch ca n i ncrea s e the ri s k of choki ng or a s pi ra ti on.
Droopi ng of the l ower fa ce a nd l i ps ca us ed by decrea s ed ci rcumora l mus cl e tone a nd, i n edentul ous peopl e, reduced bone s upport, i s a n
a es theti c concern a nd ca n l ea d to drool i ng, s pi l l i ng of food a nd l i qui ds , a nd di ffi cul ty cl os i ng the l i ps whi l e ea ti ng, s l eepi ng, or res ti ng.
Si a l orrhea (s a l i va l ea ka ge) i s often the fi rs t s ymptom.
Swa l l owi ng di ffi cul ti es i ncrea s e. It ta kes l onger to move food from mouth to oropha rynx, whi ch i ncrea s es the l i kel i hood of a s pi ra ti on.
After a ge-rel a ted cha nges , the mos t common ca us es of ora l motor di s orders a re neuromus cul a r di s orders (eg, cra ni a l neuropa thi es ca us ed by
di a betes , s troke, Pa rki ns on's di s ea s e, a myotrophi c l a tera l s cl eros i s , mul ti pl e s cl eros i s ). Ia trogeni c ca us es a l s o contri bute. Drugs (eg,
a nti chol i nergi cs , di ureti cs ), ra di a ti on thera py to the hea d a nd neck, a nd chemothera py ca n grea tl y i mpa i r s a l i va producti on. Hypos a l i va ti on i s a
ma jor ca us e of del a yed a nd i mpa i red s wa l l owi ng.
Ora l motor dys functi on i s bes t ma na ged wi th a mul ti di s ci pl i na ry a pproa ch. Coordi na ted referra l s to s peci a l i s ts i n pros theti c denti s try,
reha bi l i ta ti ve medi ci ne, s peech pa thol ogy, otol a ryngol ogy, a nd ga s troenterol ogy ma y be needed.
Key Points
Al l pa ti ents compl a i ni ng of es opha gea l dys pha gi a s houl d undergo upper endos copy to rul e out ca ncer.
If the upper endos copy i s norma l , bi ops i es s houl d be obta i ned to rul e out eos i nophi l i c es opha gi ti s .
Trea tment i s gea red towa rd the ca us e.
Cricopharyngeal Incoordination
In cri copha ryngea l i ncoordi na ti on, the cri copha ryngea l mus cl e (the upper es opha gea l s phi ncter) i s uncoordi na ted. It ca n ca us e a Zenker's
di verti cul um (s ee p. 125). Repea ted a s pi ra ti on of ma teri a l from the di verti cul um ca n l ea d to chroni c l ung di s ea s e. The condi ti on ca n be trea ted by
s urgi ca l s ecti on of the cri copha ryngea l mus cl e.
Obstructive Disorders
(See a l s o Beni gn Es opha gea l Tumors a nd Es opha gea l Ca ncer on p. 186.)
Lower Esophageal Ring
(Scha tzki 's Ri ng, B Ri ng)
A lower esophageal ring is a 2- to 4-mm mucosal stricture, probably congenital, causing a ringlike narrowing of the distal esophagus at the squamocolumnar
junction.
Thes e ri ngs ca us e i ntermi ttent dys pha gi a for s ol i ds . Thi s s ymptom ca n begi n a t a ny a ge but us ua l l y does not begi n unti l a fter a ge 25. The
s wa l l owi ng di ffi cul ty comes a nd goes a nd i s es peci a l l y a ggra va ted by mea t a nd dry brea d. Symptoms us ua l l y occur onl y when the es opha gea l
l umen i s < 12 mm i n di a meter a nd never when i t i s > 20 mm. If the di s ta l es opha gus i s a dequa tel y di s tended, ba ri um x-ra ys us ua l l y s how the ri ng.
Ins tructi ng the pa ti ent to chew food thoroughl y i s us ua l l y the onl y trea tment requi red i n wi der ri ngs , but na rrow-l umen ri ngs requi re di l a ti on by
endos copy or bougi ena ge. Surgi ca l res ecti on i s ra rel y requi red.
Esophageal Web
(Pl ummer-Vi ns on Syndrome; Pa ters on-Kel l y Syndrome; Si deropeni c Dys pha gi a )
An esophageal web is a thin mucosal membrane that grows across the lumen.
Ra rel y, webs devel op i n pa ti ents wi th untrea ted s evere i ron-defi ci ency a nemi a ; they devel op even more ra rel y i n pa ti ents wi thout a nemi a . Webs
us ua l l y occur i n the upper es opha gus , ca us i ng dys pha gi a for s ol i ds . They a re bes t di a gnos ed by ba ri um s wa l l ow. Webs res ol ve wi th trea tment of
the a nemi a but ca n be ea s i l y ruptured duri ng es opha gos copy.
Dysphagia Lusoria
Dysphagia lusoria is caused by compression of the esophagus from any of several congenital vascular abnormalities.
The va s cul a r a bnorma l i ty i s us ua l l y a n a berra nt ri ght s ubcl a vi a n a rtery a ri s i ng from the l eft s i de of the a orti c a rch, a doubl e a orti c a rch, or a ri ght
a orti c a rch wi th l eft l i ga mentum a rteri os um. The dys pha gi a ma y devel op i n chi l dhood or l a ter i n l i fe a s a res ul t of a rteri os cl eroti c cha nges i n the
a berra nt ves s el . Ba ri um s wa l l ow s hows the extri ns i c compres s i on, but a rteri ogra phy i s neces s a ry for a bs ol ute di a gnos i s . Mos t pa ti ents requi re no
trea tment, but s urgi ca l repa i r i s s ometi mes done.
Motility Disorders
Achalasia
(Ca rdi os pa s m; Es opha gea l Aperi s ta l s i s ; Mega es opha gus )
Achalasia is a neurogenic esophageal motility disorder characterized by impaired esophageal peristalsis, a lack of lower esophageal sphincter relaxation during
swallowing, and an elevation of lower esophageal sphincter resting pressure. Symptoms are slowly progressive dysphagia, usually to both liquids and solids, and
regurgitation of undigested food. Evaluation typically includes barium swallow, endoscopy, and sometimes manometry. Treatments include dilation, chemical
denervation, and surgical myotomy.
Acha l a s i a i s thought to be ca us ed by a l os s of ga ngl i on cel l s i n the myenteri c pl exus of the es opha gus , res ul ti ng i n denerva ti on of es opha gea l
mus cl e. Eti ol ogy of the denerva ti on i s unknown, a l though a vi ra l ca us e i s s us pected, a nd certa i n tumors ma y ca us e a cha l a s i a ei ther by di rect
obs tructi on or a s a pa ra neopl a s ti c proces s . Cha ga s di s ea s e, whi ch ca us es des tructi on of a utonomi c ga ngl i a , ma y res ul t i n a cha l a s i a .
Increa s ed pres s ure a t the l ower es opha gea l s phi ncter (LES) ca us es obs tructi on wi th s econda ry di l a ti on of the es opha gus . Es opha gea l retenti on of
undi ges ted food i s common.
Symptoms and Signs
Acha l a s i a occurs a t a ny a ge but us ua l l y begi ns between a ges 20 a nd 60. Ons et i s i ns i di ous , a nd progres s i on i s gra dua l over months or yea rs .
Dys pha gi a for both s ol i ds a nd l i qui ds i s the ma jor s ymptom. Nocturna l regurgi ta ti on of undi ges ted food occurs i n a bout 33% of pa ti ents a nd ma y
ca us e cough a nd pul mona ry a s pi ra ti on. Ches t pa i n i s l es s common but ma y occur on s wa l l owi ng or s ponta neous l y. Mi l d to modera te wei ght l os s
occurs ; when wei ght l os s i s pronounced, pa rti cul a rl y i n el derl y pa ti ents whos e s ymptoms of dys pha gi a devel oped ra pi dl y, a cha l a s i a s econda ry to
a tumor of the ga s troes opha gea l juncti on s houl d be cons i dered.
Diagnosis
Ba ri um s wa l l ow
Es opha gea l ma nometry
The preferred tes t i s ba ri um s wa l l ow, whi ch s hows a bs ence of progres s i ve peri s ta l ti c contra cti ons duri ng s wa l l owi ng. The es opha gus i s di l a ted,
often enormous l y, but i s na rrowed a nd bea kl i ke a t the LES. If es opha gos copy i s done, there i s di l a ti on but no obs tructi ng l es i on. The
es opha gos cope us ua l l y pa s s es rea di l y i nto the s toma ch; res i s ta nce ra i s es the pos s i bi l i ty of a n i na ppa rent ca ncer or s tri cture. To excl ude ca ncer, a
retrofl exed vi ew of the ga s tri c ca rdi a , bi ops i es , a nd brus hi ngs for cytol ogy s houl d be obta i ned. Es opha gea l ma nometry i s us ua l l y done a nd
typi ca l l y s hows a peri s ta l s i s , i ncrea s ed LES pres s ure, a nd i ncompl ete s phi ncteri c rel a xa ti on duri ng s wa l l owi ng.
Acha l a s i a mus t be di fferenti a ted from a di s ta l s tenos i ng ca rci noma a nd a pepti c s tri cture, pa rti cul a rl y i n pa ti ents wi th s ys temi c s cl eros i s (s ee p.
309), i n whom es opha gea l ma nometry ma y a l s o s how a peri s ta l s i s . Sys temi c s cl eros i s i s us ua l l y a ccompa ni ed by a hi s tory of Ra yna ud's
phenomenon a nd s ymptoms of ga s troes opha gea l refl ux di s ea s e (GERD), due to l ow or a bs ent LES pres s ure.
Acha l a s i a due to ca ncer a t the ga s troes opha gea l juncti on ca n be di a gnos ed by CT of the ches t a nd a bdomen or by endos copi c ul tra s ound.
Prognosis
Pul mona ry a s pi ra ti on a nd the pres ence of ca ncer a re the determi ni ng prognos ti c fa ctors . Nocturna l regurgi ta ti on a nd coughi ng s ugges t a s pi ra ti on.
Pul mona ry compl i ca ti ons s econda ry to a s pi ra ti on a re di ffi cul t to ma na ge. Inci dence of es opha gea l ca ncer i n pa ti ents wi th a cha l a s i a ma y be
i ncrea s ed; thi s poi nt i s controvers i a l .
Treatment
Ba l l oon di l a ti on of the LES
Al terna ti vel y, botul i num toxi n i njecti on or s urgi ca l myotomy
No thera py res tores peri s ta l s i s ; trea tment a i ms a t reduci ng the pres s ure (a nd thus the obs tructi on) a t the LES. Pneuma ti c ba l l oon di l a ti on of the
LES i s i ndi ca ted i ni ti a l l y. Res ul ts a re s a ti s fa ctory i n a bout 85% of pa ti ents , but repea ted di l a ti ons ma y be needed. Es opha gea l rupture a nd
s econda ry medi a s ti ni ti s requi ri ng s urgi ca l repa i r occur i n < 2% of pa ti ents . Ni tra tes (eg, i s os orbi de di ni tra te 5 to 10 mg s ubl i ngua l l y before mea l s )
or Ca cha nnel bl ockers (eg, ni fedi pi ne 10 mg po ti d) a re of l i mi ted effecti venes s but ma y reduce LES pres s ure enough to prol ong the ti me between
di l a ti ons .
Acha l a s i a ca n a l s o be trea ted by chemi ca l denerva ti on of chol i nergi c nerves i n the di s ta l es opha gus by di rect i njecti on of botul i num toxi n type A
i nto the LES. Cl i ni ca l i mprovement occurs i n 70 to 80% of pa ti ents , but res ul ts ma y l a s t onl y 6 mo to 1 yr.
A Hel l er myotomy, i n whi ch the mus cul a r fi bers i n the LES a re cut, i s us ua l l y res erved for pa ti ents who do not res pond to di l a ti on; i ts s ucces s ra te
i s a bout 85%. It ca n be done vi a l a pa ros copy or thora cos copy a nd ma y be a vi a bl e a l terna ti ve to di l a ti on a s pri ma ry thera py. Symptoma ti c GERD
occurs a fter s urgery i n a bout 15% of pa ti ents .
Symptomatic Diffuse Esophageal Spasm
(Spa s ti c Ps eudodi verti cul os i s ; Ros a ry Bea d or Corks crew Es opha gus )
Symptomatic diffuse esophageal spasm is part of a spectrum of motility disorders characterized variously by nonpropulsive contractions, hyperdynamic
contractions, or elevated lower esophageal sphincter pressure. Symptoms are chest pain and sometimes dysphagia. Diagnosis is by barium swallow or
manometry. Treatment is difficult but includes nitrates, Ca channel blockers, botulinum toxin injection, and antireflux therapy.
Abnorma l i ti es i n es opha gea l moti l i ty correl a te poorl y wi th pa ti ent s ymptoms ; s i mi l a r a bnorma l i ti es ma y ca us e di fferent or no s ymptoms i n
di fferent peopl e. Furthermore, nei ther s ymptoms nor a bnorma l contra cti ons a re defi ni ti vel y a s s oci a ted wi th hi s topa thol ogi c a bnorma l i ti es of the
es opha gus .
Symptoms and Signs
Di ffus e es opha gea l s pa s m typi ca l l y ca us es s ubs terna l ches t pa i n wi th dys pha gi a for both l i qui ds a nd s ol i ds . The pa i n ma y wa ken the pa ti ent
from s l eep. Very hot or col d l i qui ds ma y a ggra va te the pa i n. Over ma ny yea rs , thi s di s order ma y evol ve i nto a cha l a s i a .
Es opha gea l s pa s ms ca n ca us e s evere pa i n wi thout dys pha gi a . Thi s pa i n i s often des cri bed a s a s ubs terna l s queezi ng pa i n a nd ma y occur i n
a s s oci a ti on wi th exerci s e. Such pa i n ma y be i ndi s ti ngui s ha bl e from a ngi na pectori s .
Some pa ti ents ha ve s ymptoms tha t combi ne thos e of a cha l a s i a a nd di ffus e s pa s m. One s uch combi na ti on ha s been ca l l ed vi gorous a cha l a s i a
beca us e i t fea tures both the food retenti on a nd a s pi ra ti on of a cha l a s i a a nd the s evere pa i n a nd s pa s m of di ffus e s pa s m.
Diagnosis
Es opha gea l ma nometry
Pos s i bl y tes ti ng for corona ry i s chemi a
Al terna ti ve di a gnos es i ncl ude corona ry i s chemi a . Defi ni ti ve confi rma ti on of a n es opha gea l ori gi n for s ymptoms i s di ffi cul t. Ba ri um s wa l l ow ma y
s how poor progres s i on of a bol us a nd di s ordered, s i mul ta neous contra cti ons or terti a ry contra cti ons . Severe s pa s ms ma y mi mi c the ra di ogra phi c
a ppea ra nce of di verti cul a but va ry i n s i ze a nd pos i ti on. Es opha gea l ma nometry (s ee p. 96) provi des the mos t s peci fi c des cri pti on of the s pa s ms .
Contra cti ons a re us ua l l y s i mul ta neous , prol onged or mul ti pha s i c, a nd pos s i bl y of very hi gh a mpl i tude ("nutcra cker es opha gus "). However, s pa s ms
ma y not occur duri ng tes ti ng. Lower es opha gea l s phi ncter (LES) pres s ure el eva ti on or i mpa i red rel a xa ti on i s pres ent i n 30% of pa ti ents .
Es opha gea l s ci nti gra phy a nd provoca ti ve tes ts wi th drugs (eg, edrophoni um chl ori de 10 mg IV) ha ve not proved hel pful .
Treatment
Ca cha nnel bl ockers
Botul i num toxi n i njecti on
Es opha gea l s pa s ms a re often di ffi cul t to trea t, a nd control l ed s tudi es of trea tment methods a re l a cki ng. Anti chol i nergi cs , ni trogl yceri n, a nd l onga cti ng ni tra tes ha ve ha d l i mi ted s ucces s . Ca cha nnel bl ockers gi ven ora l l y (eg, vera pa mi l 80 mg ti d, ni fedi pi ne 10 mg ti d) ma y be us eful , a s ma y
i njecti on of botul i num toxi n type A i nto the LES.
Medi ca l ma na gement i s us ua l l y s uffi ci ent, but pneuma ti c di l a ti on a nd bougi ena ge, or even s urgi ca l myotomy a l ong the ful l l ength of the
es opha gus , ma y be tri ed i n i ntra cta bl e ca s es .
Esophageal Diverticula
An esophageal diverticulum is an outpouching of mucosa through the muscular layer of the esophagus. It can be asymptomatic or cause dysphagia and
regurgitation. Diagnosis is made by barium swallow; surgical repair is rarely required.
There a re s evera l types of es opha gea l di verti cul a , ea ch of di fferent ori gi n.
Zenker's (pha ryngea l ) di verti cul a a re pos teri or outpouchi ngs of mucos a a nd s ubmucos a through the cri copha ryngea l mus cl e, proba bl y res ul ti ng
from a n i ncoordi na ti on between pha ryngea l propul s i on a nd cri copha ryngea l rel a xa ti on.
Mi des opha gea l (tra cti on) di verti cul a a re ca us ed by tra cti on from medi a s ti na l i nfl a mma tory l es i ons or, s econda ri l y, by moti l i ty di s orders .
Epi phreni c di verti cul a occur jus t a bove the di a phra gm a nd us ua l l y a ccompa ny a moti l i ty di s order (a cha l a s i a , di ffus e es opha gea l s pa s m).
Symptoms and Signs
A Zenker's di verti cul um fi l l s wi th food tha t mi ght be regurgi ta ted when the pa ti ent bends or l i es down. As pi ra ti on pneumoni ti s ma y res ul t i f
regurgi ta ti on i s nocturna l . Ra rel y, the pouch becomes l a rge, ca us i ng dys pha gi a a nd s ometi mes a pa l pa bl e neck ma s s .
Tra cti on a nd epi phreni c di verti cul a a re ra rel y s ymptoma ti c, a l though thei r underl yi ng ca us e ma y be.
Diagnosis
Al l di verti cul a a re di a gnos ed by vi deota ped ba ri um s wa l l ow.
Treatment
Us ua l l y none
Someti mes s urgi ca l res ecti on
Speci fi c trea tment i s us ua l l y not requi red, a l though res ecti on i s occa s i ona l l y neces s a ry for l a rge or s ymptoma ti c di verti cul a . Di verti cul a a s s oci a ted
wi th moti l i ty di s orders requi re trea tment of the pri ma ry di s order. For exa mpl e, ca s e reports s ugges t doi ng a cri copha ryngea l myotomy when
res ecti ng a Zenker's di verti cul um.
Gastroesophageal Reflux Disease
Incompetence of the lower esophageal sphincter allows reflux of gastric contents into the esophagus, causing burning pain. Prolonged reflux may lead to
esophagitis, stricture, and rarely metaplasia or cancer. Diagnosis is clinical, sometimes with endoscopy, with or without acid testing. Treatment involves lifestyle
modification, acid suppression using proton pump inhibitors, and sometimes surgical repair.
Ga s troes opha gea l refl ux di s ea s e (GERD) i s common, occurri ng i n 30 to 40% of a dul ts . It a l s o occurs frequentl y i n i nfa nts , typi ca l l y begi nni ng a t
bi rth.
Etiology
The pres ence of refl ux i mpl i es l ower es opha gea l s phi ncter (LES) i ncompetence, whi ch ma y res ul t from a genera l i zed l os s of i ntri ns i c s phi ncter
tone or from recurrent i na ppropri a te tra ns i ent rel a xa ti ons (i e, unrel a ted to s wa l l owi ng). Tra ns i ent LES rel a xa ti ons a re tri ggered by ga s tri c
di s tenti on or s ubthres hol d pha ryngea l s ti mul a ti on.
Fa ctors tha t contri bute to the competence of the ga s troes opha gea l juncti on i ncl ude the a ngl e of the ca rdi oes opha gea l juncti on, the a cti on of the
di a phra gm, a nd gra vi ty (i e, a n upri ght pos i ti on). Fa ctors contri buti ng to refl ux i ncl ude wei ght ga i n, fa tty foods , ca ffei na ted or ca rbona ted
bevera ges , a l cohol , toba cco s moki ng, a nd drugs . Drugs tha t l ower LES pres s ure i ncl ude a nti chol i nergi cs , a nti hi s ta mi nes , tri cycl i c a nti depres s a nts ,
Ca cha nnel bl ockers , proges terone, a nd ni tra tes .
Complications: GERD ma y l ea d to es opha gi ti s , pepti c es opha gea l ul cer, es opha gea l s tri cture, Ba rrett's es opha gus , a nd es opha gea l a denoca rci noma
(s ee p. 186). Fa ctors tha t contri bute to the devel opment of es opha gi ti s i ncl ude the ca us ti c na ture of the refl uxa te, the i na bi l i ty to cl ea r the
refl uxa te from the es opha gus , the vol ume of ga s tri c contents , a nd l oca l mucos a l protecti ve functi ons . Some pa ti ents , pa rti cul a rl y i nfa nts , a s pi ra te
the refl ux ma teri a l .
Symptoms and Signs
The mos t promi nent s ymptom of GERD i s hea rtburn, wi th or wi thout regurgi ta ti on of ga s tri c contents i nto the mouth. Infa nts pres ent wi th vomi ti ng,
i rri ta bi l i ty, a norexi a , a nd s ometi mes s ymptoms of chroni c a s pi ra ti on. Both a dul ts a nd i nfa nts wi th chroni c a s pi ra ti on ma y ha ve cough, hoa rs enes s ,
or wheezi ng.
Es opha gi ti s ma y ca us e odynopha gi a a nd even es opha gea l hemorrha ge, whi ch i s us ua l l y occul t but ca n be ma s s i ve. Pepti c s tri cture ca us es a
gra dua l l y progres s i ve dys pha gi a for s ol i d foods . Pepti c es opha gea l ul cers ca us e the s a me type of pa i n a s ga s tri c or duodena l ul cers , but the pa i n
i s us ua l l y l oca l i zed to the xi phoi d or hi gh s ubs terna l regi on. Pepti c es opha gea l ul cers hea l s l owl y, tend to recur, a nd us ua l l y l ea ve a s tri cture on
hea l i ng.
Diagnosis
Cl i ni ca l di a gnos i s
Endos copy for thos e not res pondi ng to empi ri c trea tment
24-h pH tes ti ng for thos e wi th typi ca l s ymptoms but norma l endos copy
A deta i l ed hi s tory poi nts to the di a gnos i s . Pa ti ents wi th typi ca l s ymptoms of GERD ma y be gi ven a tri a l of thera py. Pa ti ents who do not i mprove, or
ha ve l ong-s ta ndi ng s ymptoms or s ymptoms of compl i ca ti ons , s houl d be s tudi ed. Endos copy, wi th cytol ogi c wa s hi ngs a nd bi ops y of a bnorma l
a rea s , i s the tes t of choi ce. Endos copi c bi ops y i s the onl y tes t tha t cons i s tentl y detects the col umna r mucos a l cha nges of Ba rrett's es opha gus .
Pa ti ents wi th unrema rka bl e endos copy fi ndi ngs who ha ve typi ca l s ymptoms des pi te trea tment wi th proton pump i nhi bi tors s houl d undergo 24-h
pH tes ti ng (s ee p. 95). Al though ba ri um s wa l l ow rea di l y s hows es opha gea l ul cers a nd pepti c s tri ctures , i t i s l es s us eful for mi l d to modera te
refl ux; i n a ddi ti on, mos t pa ti ents wi th a bnorma l i ti es requi re s ubs equent endos copy. Es opha gea l ma nometry ma y be us ed to gui de pH probe
pl a cement a nd to eva l ua te es opha gea l peri s ta l s i s before s urgi ca l trea tment.
Treatment
Hea d of bed el eva ted
Coffee, a l cohol , fa ts , a nd s moki ng a voi ded
Proton pump i nhi bi tors
Ma na gement of uncompl i ca ted GERD cons i s ts of el eva ti ng the hea d of the bed a bout 15 cm (6 i n) a nd a voi di ng the fol l owi ng: ea ti ng wi thi n 2 to 3 h
of bedti me, s trong s ti mul a nts of a ci d s ecreti on (eg, coffee, a l cohol ), certa i n drugs (eg, a nti chol i nergi cs ), s peci fi c foods (eg, fa ts , chocol a te), a nd
s moki ng.
Drug thera py i s wi th a proton pump i nhi bi tor. For exa mpl e, a dul ts ca n be gi ven omepra zol e 20 mg, l a ns opra zol e 30 mg, or es omepra zol e 40 mg 30
mi n before brea kfa s t. In s ome ca s es , proton pump i nhi bi tors ma y be gi ven bi d. Infa nts a nd chi l dren ma y be gi ven thes e drugs a t a n a ppropri a te
l ower s i ngl e da i l y dos e (i e, omepra zol e 20 mg i n chi l dren > 3 yr, 10 mg i n chi l dren < 3 yr; l a ns opra zol e 15 mg i n chi l dren 30 kg, 30 mg i n chi l dren >
30 kg). Thes e drugs ma y be conti nued l ong-term, but the dos e s houl d be a djus ted to the mi ni mum requi red to prevent s ymptoms . H 2 bl ockers (eg,
ra ni ti di ne 150 mg a t bedti me) or promoti l i ty a gents (eg, metocl opra mi de 10 mg po 30 mi n before mea l s a nd a t bedti me) a re l es s effecti ve.
Anti refl ux s urgery (us ua l l y vi a l a pa ros copy) i s done on pa ti ents wi th s eri ous es opha gi ti s , l a rge hi a ta l herni a s , hemorrha ge, s tri cture, or ul cers .
Es opha gea l s tri ctures a re ma na ged by repea ted ba l l oon di l a ti on.
Ba rrett's es opha gus ma y or ma y not regres s wi th medi ca l or s urgi ca l thera py. Beca us e Ba rrett's es opha gus i s a precurs or to a denoca rci noma ,
endos copi c s urvei l l a nce for ma l i gna nt tra ns forma ti on i s recommended every 1 to 2 yr. Survei l l a nce ha s uncerta i n cos t-effecti venes s i n pa ti ents
wi th l ow-gra de dys pl a s i a but i s i mporta nt i n hi gh-gra de dys pl a s i a i n pa ti ents who a re una bl e to undergo s urgi ca l res ecti on. Al terna ti vel y,
Ba rrett's es opha gus ma y be trea ted wi th endos copi c mucos a l res ecti on, photodyna mi c thera py, cryothera py, or l a s er a bl a ti on.
Hiatus Hernia
Hiatus hernia is a protrusion of the stomach through the diaphragmatic hiatus. Most hernias are asymptomatic, but an increased incidence of acid reflux may lead
to symptoms of gastroesophageal reflux disease (GERD). Diagnosis is by barium swallow. Treatment is directed at symptoms of GERD if present.
Etiology
Eti ol ogy i s us ua l l y unknown, but a hi a tus herni a i s thought to be a cqui red through s tretchi ng of the fa s ci a l a tta chments between the es opha gus
a nd di a phra gm a t the hi a tus (the openi ng through whi ch the es opha gus tra vers es the di a phra gm).
Pathophysiology
In a s l i di ng hi a tus herni a (the mos t common type), the ga s troes opha gea l juncti on a nd a porti on of the s toma ch a re a bove the di a phra gm. In a
pa ra es opha gea l hi a tus herni a , the ga s troes opha gea l juncti on i s i n the norma l l oca ti on, but a porti on of the s toma ch i s a dja cent to the es opha gus
i n the di a phra gma ti c hi a tus . Herni a s ma y a l s o occur through other pa rts of the di a phra gm (s ee p. 2977).
A s l i di ng hi a tus herni a i s common a nd i s a n i nci denta l fi ndi ng on x-ra y i n > 40% of the popul a ti on; therefore, the rel a ti ons hi p of herni a to
s ymptoms i s uncl ea r. Al though mos t pa ti ents wi th GERD ha ve s ome degree of hi a tus herni a , < 50% of pa ti ents wi th hi a tus herni a ha ve GERD.
Symptoms and Signs
Mos t pa ti ents wi th a s l i di ng hi a tus herni a a re a s ymptoma ti c, but ches t pa i n a nd other refl ux s ymptoms ca n occur. A pa ra es opha gea l hi a tus herni a
i s genera l l y a s ymptoma ti c but, unl i ke a s l i di ng hi a tus herni a , ma y i nca rcera te a nd s tra ngul a te. Occul t or ma s s i ve GI hemorrha ge ma y occur wi th
ei ther type.
Diagnosis
A l a rge hi a tus herni a i s often di s covered i nci denta l l y on ches t x-ra y. Sma l l er herni a s a re di a gnos ed wi th a ba ri um s wa l l ow.
Treatment
Someti mes a proton pump i nhi bi tor
An a s ymptoma ti c s l i di ng hi a tus herni a requi res no s peci fi c thera py. Pa ti ents wi th a ccompa nyi ng GERD s houl d be trea ted wi th a proton pump
i nhi bi tor. A pa ra es opha gea l herni a s houl d be reduced s urgi ca l l y beca us e of the ri s k of s tra ngul a ti on.
Infectious Esophageal Disorders
Esophageal infection occurs mainly in patients with impaired host defenses. Primary agents include Candida albicans, herpes simplex virus, and cytomegalovirus.
Symptoms are odynophagia and chest pain. Diagnosis is by endoscopic visualization and culture. Treatment is with antifungal or antiviral drugs.
Es opha gea l i nfecti on i s ra re i n pa ti ents wi th norma l hos t defens es . Pri ma ry es opha gea l defens es i ncl ude s a l i va , es opha gea l moti l i ty, a nd
cel l ul a r i mmuni ty. Thus , a t-ri s k pa ti ents i ncl ude thos e wi th AIDS, orga n tra ns pl a nts , a l cohol i s m, di a betes , undernutri ti on, ca ncer, a nd moti l i ty
di s orders . Candida i nfecti on ma y occur i n a ny of thes e pa ti ents . Herpes s i mpl ex vi rus (HSV) a nd cytomega l ovi rus (CMV) i nfecti ons occur ma i nl y i n
AIDS a nd tra ns pl a nt pa ti ents .
Candida: Pa ti ents wi th Candida es opha gi ti s us ua l l y compl a i n of odynopha gi a a nd, l es s commonl y, dys pha gi a . About two thi rds of pa ti ents ha ve
s i gns of ora l thrus h (thus i ts a bs ence does not excl ude es opha gea l i nvol vement). Pa ti ents wi th odynopha gi a a nd typi ca l thrus h ma y be gi ven
empi ri c trea tment, but i f s i gni fi ca nt i mprovement does not occur i n 5 to 7 da ys , endos copi c eva l ua ti on i s requi red. Ba ri um s wa l l ow i s l es s
a ccura te.
Trea tment i s wi th fl ucona zol e 200 mg po or IV for one dos e, then 100 mg po or IV q 24 h for 14 to 21 da ys . Al terna ti ves i ncl ude the a zol es (eg,
i tra cona zol e, vori cona zol e, ketocona zol e) or echi noca ndi ns (eg, ca s pofungi n). Topi ca l thera py ha s no rol e.
HSV and CMV: Thes e i nfecti ons a re equa l l y l i kel y i n tra ns pl a nt pa ti ents , but HSV occurs ea rl y a fter tra ns pl a nta ti on (rea cti va ti on) a nd CMV occurs 2
to 6 mo a fter. Among AIDS pa ti ents , CMV i s much more common tha n HSV, a nd vi ra l es opha gi ti s occurs ma i nl y when the CD4+ count i s < 200/L.
Severe odynopha gi a res ul ts from ei ther i nfecti on.
Endos copy, wi th cytol ogy or bi ops y, i s us ua l l y neces s a ry for di a gnos i s . HSV i s trea ted wi th IV a cycl ovi r 5 mg/kg q 8 h for 7 da ys or va l a cycl ovi r 1 g po
ti d. CMV i s trea ted wi th ga nci cl ovi r 5 mg/kg IV q 12 h for 14 to 21 da ys wi th ma i ntena nce a t 5 mg/kg IV 5 da ys /wk i n i mmunocompromi s ed pa ti ents .
Al terna ti ves i ncl ude fos ca rnet a nd ci dofovi r.
Mallory-Weiss Syndrome
Mallory-Weiss syndrome is a nonpenetrating mucosal laceration of the distal esophagus and proximal stomach caused by vomiting, retching, or hiccuping.
Ini ti a l l y des cri bed i n a l cohol i cs , Ma l l ory-Wei s s s yndrome ca n occur i n a ny pa ti ent who vomi ts forceful l y. It i s the ca us e of a bout 5% of epi s odes of
upper GI hemorrha ge. Mos t epi s odes of bl eedi ng s top s ponta neous l y; s evere bl eedi ng occurs i n a bout 10% of pa ti ents who requi re s i gni fi ca nt
i nterventi on, s uch a s tra ns fus i on or endos copi c hemos ta s i s (by i njecti on of etha nol , pol i doca nol , or epi nephri ne or by el ectroca utery). Intra a rteri a l i nfus i on of pi tres s i n or thera peuti c embol i za ti on i nto the l eft ga s tri c a rtery duri ng a ngi ogra phy ma y a l s o be us ed to control bl eedi ng.
Surgi ca l repa i r i s ra rel y requi red.
Esophageal Rupture
Esophageal rupture may be iatrogenic during endoscopic procedures or other instrumentation or may be spontaneous (Boerhaave's syndrome). Patients are
seriously ill, with symptoms of mediastinitis. Diagnosis is by esophagography with a water-soluble contrast agent. Immediate surgical repair and drainage are
required.
Endos copi c procedures a re the pri ma ry ca us e of es opha gea l rupture, but s ponta neous rupture ma y occur, typi ca l l y rel a ted to vomi ti ng, retchi ng, or
s wa l l owi ng a l a rge food bol us . The mos t common s i te of rupture i s the di s ta l es opha gus on the l eft s i de. Aci d a nd other s toma ch contents ca us e a
ful mi na nt medi a s ti ni ti s a nd s hock. Pneumomedi a s ti num i s common.
Symptoms and Signs
Symptoms i ncl ude ches t a nd a bdomi na l pa i n, vomi ti ng, hema temes i s , a nd s hock. Subcuta neous emphys ema i s pa l pa bl e i n a bout 30% of pa ti ents .
Medi a s ti na l crunch (Ha mma n's s i gn), a cra ckl i ng s ound s ynchronous wi th the hea rtbea t, ma y be pres ent.
Diagnosis
Ches t a nd a bdomi na l x-ra ys
Es opha gogra phy
Ches t a nd a bdomi na l x-ra ys s howi ng medi a s ti na l a i r, pl eura l effus i on, or medi a s ti na l wi deni ng s ugges t the di a gnos i s . Di a gnos i s i s confi rmed by
es opha gogra phy wi th a wa ter-s ol ubl e contra s t a gent, whi ch a voi ds potenti a l medi a s ti na l i rri ta ti on from ba ri um. CT of the thora x detects
medi a s ti na l a i r a nd fl ui d but does not l oca l i ze the perfora ti on wel l . Endos copy ma y mi s s a s ma l l perfora ti on.
Treatment
Surgi ca l repa i r
Pendi ng s urgi ca l repa i r, pa ti ents s houl d recei ve broa d-s pectrum a nti bi oti cs (eg, genta mi ci n pl us metroni da zol e or pi pera ci l l i n/ta zoba cta m) a nd
fl ui d res us ci ta ti on a s needed for s hock. Even wi th trea tment, morta l i ty i s hi gh.
Chapter 13. Gastritis and Peptic Ulcer Disease

Introduction
Aci d i s s ecreted by pa ri eta l cel l s i n the proxi ma l two thi rds (body) of the s toma ch. Ga s tri c a ci d a i ds di ges ti on by crea ti ng the opti ma l pH for peps i n
a nd ga s tri c l i pa s e a nd by s ti mul a ti ng pa ncrea ti c bi ca rbona te s ecreti on. Aci d s ecreti on i s i ni ti a ted by food: the thought, s mel l , or ta s te of food
effects va ga l s ti mul a ti on of the ga s tri n-s ecreti ng G cel l s l oca ted i n the di s ta l one thi rd (a ntrum) of the s toma ch. The a rri va l of protei n to the
s toma ch further s ti mul a tes ga s tri n output. Ci rcul a ti ng ga s tri n tri ggers the rel ea s e of hi s ta mi ne from enterochroma ffi n-l i ke cel l s i n the body of the
s toma ch. Hi s ta mi ne s ti mul a tes the pa ri eta l cel l s vi a thei r H 2 receptors . The pa ri eta l cel l s s ecrete a ci d, a nd the res ul ti ng drop i n pH ca us es the
a ntra l D cel l s to rel ea s e s oma tos ta ti n, whi ch i nhi bi ts ga s tri n rel ea s e (nega ti ve feedba ck control ).
Aci d s ecreti on i s pres ent a t bi rth a nd rea ches a dul t l evel s (on a wei ght ba s i s ) by a ge 2. There i s a decl i ne i n a ci d output i n el derl y pa ti ents who
devel op chroni c ga s tri ti s , but a ci d output i s otherwi s e ma i nta i ned throughout l i fe.
Norma l l y, the GI mucos a i s protected by s evera l di s ti nct mecha ni s ms : (1) Mucos a l producti on of mucus a nd HCO3 crea tes a pH gra di ent from the
ga s tri c l umen (l ow pH) to the mucos a (neutra l pH). The mucus s erves a s a ba rri er to the di ffus i on of a ci d a nd peps i n. (2) Epi thel i a l cel l s remove
exces s hydrogen i ons (H +) vi a membra ne tra ns port s ys tems a nd ha ve ti ght juncti ons , whi ch prevent ba ck di ffus i on of H + i ons . (3) Mucos a l bl ood
fl ow removes exces s a ci d tha t ha s di ffus ed a cros s the epi thel i a l l a yer. Severa l growth fa ctors (eg, epi derma l growth fa ctor, i ns ul i n-l i ke growth
fa ctor I) a nd pros ta gl a ndi ns ha ve been l i nked to mucos a l repa i r a nd ma i ntena nce of mucos a l i ntegri ty.
Fa ctors tha t i nterfere wi th thes e mucos a l defens es (pa rti cul a rl y NSAIDs a nd Helicobacter pylori i nfecti on) predi s pos e to ga s tri ti s a nd pepti c ul cer
di s ea s e.
NSAIDs promote mucos a l i nfl a mma ti on a nd ul cer forma ti on (s ometi mes wi th GI bl eedi ng) both topi ca l l y a nd s ys temi ca l l y. By i nhi bi ti ng
pros ta gl a ndi n producti on vi a bl ocka ge of the enzyme cycl ooxygena s e (COX), NSAIDs reduce ga s tri c bl ood fl ow, reduce mucus a nd HCO3 s ecreti on,
a nd decrea s e cel l repa i r a nd repl i ca ti on. Al s o, beca us e NSAIDs a re wea k a ci ds a nd a re noni oni zed a t ga s tri c pH, they di ffus e freel y a cros s the
mucus ba rri er i nto ga s tri c epi thel i a l cel l s , where H + i ons a re l i bera ted, l ea di ng to cel l ul a r da ma ge. Beca us e ga s tri c pros ta gl a ndi n producti on
i nvol ves the COX-1 i s oform, NSAIDs tha t a re s el ecti ve COX-2 i nhi bi tors ha ve fewer a dvers e ga s tri c effects tha n other NSAIDs .
Helicobacter pylori Infection
H. pylori is a common gastric pathogen that causes gastritis, peptic ulcer disease, gastric adenocarcinoma, and low-grade gastric lymphoma. Infection may be
asymptomatic or result in varying degrees of dyspepsia. Diagnosis is by urea breath test and testing of endoscopic biopsy samples. Treatment is with a proton
pump inhibitor plus two antibiotics.
H. pylori i s a s pi ra l -s ha ped, gra m-nega ti ve orga ni s m tha t ha s a da pted to thri ve i n a ci d. In devel opi ng countri es , i t commonl y ca us es chroni c
i nfecti ons a nd i s us ua l l y a cqui red duri ng chi l dhood. In the US, i nfecti on i s l es s common a mong chi l dren but i ncrea s es wi th a ge: by a ge 60, a bout
50% of peopl e a re i nfected. Infecti on i s mos t common a mong bl a cks , Hi s pa ni cs , a nd As i a ns .
The orga ni s m ha s been cul tured from s tool , s a l i va , a nd denta l pl a que, whi ch s ugges ts ora l -ora l or feca l -ora l tra ns mi s s i on. Infecti ons tend to
cl us ter i n fa mi l i es a nd i n res i dents of cus todi a l i ns ti tuti ons . Nurs es a nd ga s troenterol ogi s ts s eem to be a t hi gh ri s k beca us e ba cteri a ca n be
tra ns mi tted by i mproperl y di s i nfected endos copes .
Pathophysiology
Effects of H. pylori i nfecti on va ry dependi ng on the l oca ti on wi thi n the s toma ch. Antra l -predomi na nt i nfecti on res ul ts i n i ncrea s ed ga s tri n
producti on, proba bl y vi a l oca l i mpa i rment of s oma tos ta ti n rel ea s e. Res ul ta nt hypers ecreti on of a ci d predi s pos es to prepyl ori c a nd duodena l
ul cer. Body-predomi na nt i nfecti on l ea ds to ga s tri c a trophy a nd decrea s ed a ci d producti on, pos s i bl y vi a i ncrea s ed l oca l producti on of IL-1.
Pa ti ents wi th body-predomi na nt i nfecti on a re predi s pos ed to ga s tri c ul cer a nd a denoca rci noma . Some pa ti ents ha ve mi xed i nfecti on of both
a ntrum a nd body wi th va ryi ng cl i ni ca l effects . Ma ny pa ti ents wi th H. pylori i nfecti on ha ve no noti cea bl e cl i ni ca l effects .
Ammoni a produced by H. pylori ena bl es the orga ni s m to s urvi ve i n the a ci di c envi ronment of the s toma ch a nd ma y erode the mucus ba rri er.
Cytotoxi ns a nd mucol yti c enzymes (eg, ba cteri a l protea s e, l i pa s e) produced by H. pylori ma y pl a y a rol e i n mucos a l da ma ge a nd s ubs equent
ul cerogenes i s .
Infected peopl e a re 3 to 6 ti mes more l i kel y to devel op s toma ch ca ncer. H. pylori i nfecti on i s a s s oci a ted wi th i ntes ti na l -type a denoca rci noma of the
ga s tri c body a nd a ntrum but not ca ncer of the ga s tri c ca rdi a . Other a s s oci a ted ca ncers i ncl ude ga s tri c l ymphoma a nd mucos a -a s s oci a ted l ymphoi d
ti s s ue (MALT) l ymphoma , a monocl ona l l y res tri cted B-cel l tumor.
Diagnosis
For i ni ti a l di a gnos i s : Serol ogi c tes ts
For confi rma ti on of cure: Urea brea th tes t or s tool a nti gen a s s a y
Screeni ng of a s ymptoma ti c pa ti ents i s not wa rra nted. Tes ts a re done duri ng eva l ua ti on for pepti c ul cer a nd ga s tri ti s . Pos ttrea tment tes ti ng i s
typi ca l l y done to confi rm era di ca ti on of the orga ni s m. Di fferent tes ts a re preferred for i ni ti a l di a gnos i s a nd pos ttrea tment.
Noninvasive tests: La bora tory a nd offi ce-ba s ed s erol ogi c a s s a ys for a nti bodi es to H. pylori ha ve s ens i ti vi ty a nd s peci fi ci ty of > 85% a nd a re
cons i dered the noni nva s i ve tes ts of choi ce for i ni ti a l documenta ti on of H. pylori i nfecti on. However, beca us e qua l i ta ti ve a s s a ys rema i n pos i ti ve for
up to 3 yr a fter s ucces s ful trea tment a nd beca us e qua nti ta ti ve a nti body l evel s do not decl i ne s i gni fi ca ntl y for 6 to 12 mo a fter trea tment, s erol ogi c
a s s a ys a re not us ua l l y us ed to a s s es s cure.
Urea brea th tes ts us e a n ora l dos e of 13 C- or 14 C-l a bel ed urea . In a n i nfected pa ti ent, the orga ni s m meta bol i zes the urea a nd l i bera tes l a bel ed
CO2 , whi ch i s exha l ed a nd ca n be qua nti fi ed i n brea th s a mpl es ta ken 20 to 30 mi n a fter i nges ti on of the urea . Sens i ti vi ty a nd s peci fi ci ty a re > 90%.
Urea brea th tes ts a re wel l s ui ted for confi rmi ng era di ca ti on of the orga ni s m a fter thera py. Fa l s e-nega ti ve res ul ts a re pos s i bl e wi th recent
a nti bi oti c us e or concomi ta nt proton pump i nhi bi tor thera py; therefore, fol l ow-up tes ti ng s houl d be del a yed 4 wk a fter a nti bi oti c thera py a nd 1
wk a fter proton pump i nhi bi tor thera py. H 2 bl ockers do not a ffect the tes t.
Stool a nti gen a s s a ys s eem to ha ve a s ens i ti vi ty a nd s peci fi ci ty nea r tha t of urea brea th tes ts , pa rti cul a rl y for i ni ti a l di a gnos i s ; a n offi ce-ba s ed tes t
i s under devel opment.
Invasive tests: Endos copy i s us ed to obta i n mucos a l bi ops y s a mpl es for a ra pi d urea s e tes t (RUT) or hi s tol ogi c s ta i ni ng. Ba cteri a l cul ture i s of
l i mi ted us e beca us e of the fa s ti di ous na ture of the orga ni s m. Endos copy i s not recommended s ol el y for di a gnos i s of H. pylori; noni nva s i ve tes ts
a re preferred unl es s endos copy i s i ndi ca ted for other rea s ons .
The RUT, i n whi ch pres ence of ba cteri a l urea s e i n the bi ops y s a mpl e ca us es a col or cha nge on a s peci a l medi um, i s the di a gnos ti c method of
choi ce on ti s s ue s a mpl es . Hi s tol ogi c s ta i ni ng of bi ops y s a mpl es s houl d be done for pa ti ents wi th nega ti ve RUT res ul ts but s us pi ci ous cl i ni ca l
fi ndi ngs , recent a nti bi oti c us e, or trea tment wi th proton pump i nhi bi tors . RUT a nd hi s tol ogi c s ta i ni ng ea ch ha ve a s ens i ti vi ty a nd s peci fi ci ty of >
90%.
Treatment
Anti bi oti cs (va ri ous regi mens ) pl us a proton pump i nhi bi tor
Pa ti ents wi th compl i ca ti ons (eg, ga s tri ti s , ul cer, ca ncer) s houl d ha ve the orga ni s m era di ca ted. Era di ca ti on of H. pylori ca n even cure s ome ca s es of
MALT l ymphoma (but not other i nfecti on-rel a ted ca ncers ). Trea tment of a s ymptoma ti c i nfecti on ha s been controvers i a l , but the recogni ti on of the
rol e of H. pylori i n ca ncer ha s l ed to a recommenda ti on for trea tment. Va cci nes , both preventi ve a nd thera peuti c (i e, a s a n a djunct to trea tment of
i nfected pa ti ents ), a re under devel opment.
H. pylori era di ca ti on requi res mul ti drug thera py, typi ca l l y a nti bi oti cs pl us a ci d s uppres s a nts . Proton pump i nhi bi tors s uppres s H. pylori, a nd the
i ncrea s ed ga s tri c pH a ccompa nyi ng thei r us e ca n enha nce ti s s ue concentra ti on a nd effi ca cy of a nti mi crobi a l s , crea ti ng a hos ti l e envi ronment for H.
pylori.
Tri pl e thera py i s recommended. Ora l omepra zol e 20 mg bi d or l a ns opra zol e 30 mg bi d, pl us cl a ri thromyci n 500 mg bi d, pl us a moxi ci l l i n 1 g bi d (or,
for peni ci l l i n-a l l ergi c pa ti ents , metroni da zol e 500 mg bi d) for 14 da ys , cures i nfecti on i n > 95% of ca s es . Thi s regi men ha s excel l ent tol era bi l i ty.
Ra ni ti di ne bi s muth ci tra te 400 mg po bi d ma y be s ubs ti tuted for the proton pump i nhi bi tor.
Qua drupl e thera py wi th a proton pump i nhi bi tor bi d, tetra cycl i ne 500 mg a nd bi s muth s ubs a l i cyl a te or s ubci tra te 525 mg qi d, a nd metroni da zol e
500 mg ti d i s a l s o effecti ve but more cumbers ome.
Infected pa ti ents wi th duodena l or ga s tri c ul cer requi re conti nua ti on of the a ci d s uppres s i on for a t l ea s t 4 wk.
Trea tment i s repea ted i f H. pylori i s not era di ca ted. If two cours es a re uns ucces s ful , s ome a uthori ti es recommend endos copy to obta i n cul tures for
s ens i ti vi ty tes ti ng.
Gastritis
Gastritis is inflammation of the gastric mucosa caused by any of several conditions, including infection (Helicobacter pylori), drugs (NSAIDs, alcohol), stress, and
autoimmune phenomena (atrophic gastritis). Many cases are asymptomatic, but dyspepsia and GI bleeding sometimes occur. Diagnosis is by endoscopy.
Treatment is directed at the cause but often includes acid suppression and, for H. pylori infection, antibiotics.
Ga s tri ti s i s cl a s s i fi ed a s eros i ve or noneros i ve ba s ed on the s everi ty of mucos a l i njury. It i s a l s o cl a s s i fi ed a ccordi ng to the s i te of i nvol vement (i e,
ca rdi a , body, a ntrum). Ga s tri ti s ca n be further cl a s s i fi ed hi s tol ogi ca l l y a s a cute or chroni c ba s ed on the i nfl a mma tory cel l type. No cl a s s i fi ca ti on
s cheme ma tches perfectl y wi th the pa thophys i ol ogy; a l a rge degree of overl a p exi s ts . Some forms of ga s tri ti s i nvol ve a ci d-pepti c a nd H. pylori
di s ea s e. Addi ti ona l l y, the term i s often l oos el y a ppl i ed to nons peci fi c (a nd often undi a gnos ed) a bdomi na l di s comfort a nd ga s troenteri ti s .
Acute ga s tri ti s i s cha ra cteri zed by PMN i nfi l tra ti on of the mucos a of the a ntrum a nd body.
Chroni c ga s tri ti s i mpl i es s ome degree of a trophy (wi th l os s of functi on of the mucos a ) or meta pl a s i a . It predomi na ntl y i nvol ves the a ntrum (wi th
s ubs equent l os s of G cel l s a nd decrea s ed ga s tri n s ecreti on) or the corpus (wi th l os s of oxynti c gl a nds , l ea di ng to reduced a ci d, peps i n, a nd
i ntri ns i c fa ctor).
Erosive Gastritis
Erosive gastritis is gastric mucosal erosion caused by damage to mucosal defenses. It is typically acute, manifesting with bleeding, but may be subacute or
chronic with few or no symptoms. Diagnosis is by endoscopy. Treatment is supportive, with removal of the inciting cause. Certain ICU patients (eg, ventilatorbound, head trauma, burn, multisystem trauma) benefit from prophylaxis with acid suppressants.
Ca us es of eros i ve ga s tri ti s i ncl ude NSAIDs , a l cohol , s tres s , a nd l es s commonl y ra di a ti on, vi ra l i nfecti on (eg, cytomega l ovi rus ), va s cul a r i njury, a nd
di rect tra uma (eg, na s oga s tri c tubes ).
Superfi ci a l eros i ons a nd puncta te mucos a l l es i ons occur. Thes e ma y devel op a s s oon a s 12 h a fter the i ni ti a l i ns ul t. Deep eros i ons , ul cers , a nd
s ometi mes perfora ti on ma y occur i n s evere or untrea ted ca s es . Les i ons typi ca l l y occur i n the body, but the a ntrum ma y a l s o be i nvol ved.
Acute stress gastritis, a form of eros i ve ga s tri ti s , occurs i n a bout 5% of cri ti ca l l y i l l pa ti ents . The i nci dence i ncrea s es wi th dura ti on of ICU s ta y a nd
l ength of ti me the pa ti ent i s not recei vi ng entera l feedi ng. Pa thogenes i s l i kel y i nvol ves hypoperfus i on of the GI mucos a , res ul ti ng i n i mpa i red
mucos a l defens es . Pa ti ents wi th hea d i njury or burns ma y a l s o ha ve i ncrea s ed s ecreti on of a ci d.
Symptoms and Signs

Pa ti ents wi th mi l d eros i ve ga s tri ti s a re often a s ymptoma ti c, a l though s ome compl a i n of dys peps i a , na us ea , or vomi ti ng. Often, the fi rs t s i gn i s
hema temes i s , mel ena , or bl ood i n the na s oga s tri c a s pi ra te, us ua l l y wi thi n 2 to 5 da ys of the i nci ti ng event. Bl eedi ng i s us ua l l y mi l d to modera te,
a l though i t ca n be ma s s i ve i f deep ul cera ti on i s pres ent, pa rti cul a rl y i n a cute s tres s ga s tri ti s . Acute a nd chroni c eros i ve ga s tri ti s a re di a gnos ed
endos copi ca l l y.
Diagnosis
Acute a nd chroni c eros i ve ga s tri ti s a re di a gnos ed endos copi ca l l y.
Treatment
For bl eedi ng: Endos copi c hemos ta s i s
For a ci d s uppres s i on: A proton pump i nhi bi tor or H 2 bl ocker
In s evere ga s tri ti s , bl eedi ng i s ma na ged wi th IV fl ui ds a nd bl ood tra ns fus i on a s needed. Endos copi c hemos ta s i s s houl d be a ttempted, wi th
s urgery (tota l ga s trectomy) a fa l l ba ck procedure. Angi ogra phy i s unl i kel y to s top s evere ga s tri c bl eedi ng beca us e of the ma ny col l a tera l ves s el s
s uppl yi ng the s toma ch. Aci d s uppres s i on s houl d be s ta rted i f the pa ti ent i s not a l rea dy recei vi ng i t.
For mi l der ga s tri ti s , removi ng the offendi ng a gent a nd us i ng drugs to reduce ga s tri c a ci di ty (s ee p. 136) ma y be a l l tha t i s requi red.
Prevention
Prophyl a xi s wi th a ci d-s uppres s i ve drugs ca n reduce the i nci dence of a cute s tres s ga s tri ti s . However, i t ma i nl y benefi ts certa i n hi gh-ri s k ICU
pa ti ents , i ncl udi ng thos e wi th s evere burns , CNS tra uma , coa gul opa thy, s eps i s , s hock, mul ti pl e tra uma , mecha ni ca l venti l a ti on for > 48 h, hepa ti c
or rena l fa i l ure, mul ti orga n dys functi on, a nd hi s tory of pepti c ul cer or GI bl eedi ng.
Prophyl a xi s cons i s ts of IV H 2 bl ockers , proton pump i nhi bi tors , or ora l a nta ci ds to ra i s e i ntra ga s tri c pH > 4.0. Repea ted pH mea s urement a nd
ti tra ti on of thera py a re not requi red. Ea rl y entera l feedi ng a l s o ca n decrea s e the i nci dence of bl eedi ng.
Aci d s uppres s i on i s not recommended for pa ti ents s i mpl y ta ki ng NSAIDs unl es s they ha ve previ ous l y ha d a n ul cer.
Nonerosive Gastritis
Nonerosive gastritis refers to a variety of histologic abnormalities that are mainly the result of H. pylori infection. Most patients are asymptomatic. Diagnosis is
by endoscopy. Treatment is eradication of H. pylori and sometimes acid suppression.
Pathology
Superficial gastritis: Lymphocytes a nd pl a s ma cel l s mi xed wi th neutrophi l s a re the predomi na nt i nfi l tra ti ng i nfl a mma tory cel l s . Infl a mma ti on i s
s uperfi ci a l a nd ma y i nvol ve the a ntrum, body, or both. It i s us ua l l y not a ccompa ni ed by a trophy or meta pl a s i a . Preva l ence i ncrea s es wi th a ge.
Deep gastritis: Deep ga s tri ti s i s more l i kel y to be s ymptoma ti c (eg, va gue dys peps i a ). Mononucl ea r cel l s a nd neutrophi l s i nfi l tra te the enti re
mucos a to the l evel of the mus cul a ri s , but exuda te or crypt a bs ces s es s el dom res ul t, a s mi ght be expected by s uch i nfi l tra ti on. Di s tri buti on ma y be
pa tchy. Superfi ci a l ga s tri ti s ma y be pres ent, a s ma y pa rti a l gl a nd a trophy a nd meta pl a s i a .
Gastric atrophy: Atrophy of ga s tri c gl a nds ma y fol l ow i n ga s tri ti s , mos t often l ongs ta ndi ng a ntra l (s ometi mes referred to a s type B) ga s tri ti s . Some
pa ti ents wi th ga s tri c a trophy ha ve a utoa nti bodi es to pa ri eta l cel l s , us ua l l y i n a s s oci a ti on wi th corpus (type A) ga s tri ti s a nd perni ci ous a nemi a .
Atrophy ma y occur wi thout s peci fi c s ymptoms . Endos copi ca l l y, the mucos a ma y a ppea r norma l unti l a trophy i s a dva nced, when s ubmucos a l
va s cul a ri ty ma y be vi s i bl e. As a trophy becomes compl ete, s ecreti on of a ci d a nd peps i n di mi ni s hes a nd i ntri ns i c fa ctor ma y be l os t, res ul ti ng i n
vi ta mi n B 12 ma l a bs orpti on.
Metaplasia: Two types of meta pl a s i a a re common i n chroni c noneros i ve ga s tri ti s : mucous gl a nd a nd i ntes ti na l .
Mucous gl a nd meta pl a s i a (ps eudopyl ori c meta pl a s i a ) occurs i n the s etti ng of s evere a trophy of the ga s tri c gl a nds , whi ch a re progres s i vel y
repl a ced by mucous gl a nds (a ntra l mucos a ), es peci a l l y a l ong the l es s er curve. Ga s tri c ul cers ma y be pres ent (typi ca l l y a t the juncti on of a ntra l a nd
corpus mucos a ), but whether they a re the ca us e or cons equence of thes e meta pl a s ti c cha nges i s not cl ea r.
Intes ti na l meta pl a s i a typi ca l l y begi ns i n the a ntrum i n res pons e to chroni c mucos a l i njury a nd ma y extend to the body. Ga s tri c mucos a cel l s
cha nge to res embl e i ntes ti na l mucos a wi th gobl et cel l s , endocri ne (enterochroma ffi n or enterochroma ffi n-l i ke) cel l s , a nd rudi menta ry vi l l i a nd
ma y even a s s ume functi ona l (a bs orpti ve) cha ra cteri s ti cs . Intes ti na l meta pl a s i a i s cl a s s i fi ed hi s tol ogi ca l l y a s compl ete (mos t common) or
i ncompl ete. Wi th compl ete meta pl a s i a , ga s tri c mucos a i s compl etel y tra ns formed i nto s ma l l -bowel mucos a , both hi s tol ogi ca l l y a nd functi ona l l y,
wi th the a bi l i ty to a bs orb nutri ents a nd s ecrete pepti des . In i ncompl ete meta pl a s i a , the epi thel i um a s s umes a hi s tol ogi c a ppea ra nce cl os er to
tha t of the l a rge i ntes ti ne a nd frequentl y exhi bi ts dys pl a s i a . Intes ti na l meta pl a s i a ma y l ea d to s toma ch ca ncer.
Symptoms and Signs
Mos t pa ti ents wi th H. pylori-a s s oci a ted ga s tri ti s a re a s ymptoma ti c, a l though s ome ha ve mi l d dys peps i a or other va gue s ymptoms .
Diagnosis
Endos copy
Often, the condi ti on i s di s covered duri ng endos copy done for other purpos es . Tes ti ng of a s ymptoma ti c pa ti ents i s not i ndi ca ted. Once ga s tri ti s i s
i denti fi ed, tes ti ng for H. pylori i s a ppropri a te.
Treatment
Era di ca ti on of H. pylori
Someti mes a ci d-s uppres s i ve drugs
Trea tment of chroni c noneros i ve ga s tri ti s i s H. pylori era di ca ti on (s ee p. 130). Trea tment of a s ymptoma ti c pa ti ents i s s omewha t controvers i a l gi ven
the hi gh preva l ence of H. pylori-a s s oci a ted s uperfi ci a l ga s tri ti s a nd the rel a ti vel y l ow i nci dence of cl i ni ca l s equel a e (i e, pepti c ul cer di s ea s e).
However, H. pylori i s a cl a s s J ca rci nogen; era di ca ti on removes the ca ncer ri s k. In H. pylori-nega ti ve pa ti ents , trea tment i s di rected a t s ymptoms
us i ng a ci d-s uppres s i ve drugs (eg, H 2 bl ockers , proton pump i nhi bi tors ) or a nta ci ds .
Postgastrectomy Gastritis
Postgastrectomy gastritis is gastric atrophy developing after partial or subtotal gastrectomy (except in cases of gastrinoma).
Meta pl a s i a of the rema i ni ng corpus mucos a i s common. The degree of ga s tri ti s i s us ua l l y grea tes t a t the l i nes of a na s tomos i s .
Severa l mecha ni s ms a re res pons i bl e: bi l e refl ux, whi ch i s common a fter s uch s urgery, da ma ges the ga s tri c mucos a ; l os s of a ntra l ga s tri n
decrea s es s ti mul a ti on of pa ri eta l a nd pepti c cel l s , ca us i ng a trophy; a nd va gotomy ma y res ul t i n a l os s of va ga l trophi c a cti on.
There a re no s peci fi c s ymptoms of ga s tri ti s . Pos tga s trectomy ga s tri ti s often progres s es to s evere a trophy a nd a chl orhydri a . Producti on of i ntri ns i c
fa ctor ma y cea s e wi th res ul ta nt vi ta mi n B 12 defi ci ency (whi ch ma y be wors ened by ba cteri a l overgrowth i n the a fferent l oop). The rel a ti ve ri s k of
ga s tri c a denoca rci noma s eems to i ncrea s e 15 to 20 yr a fter pa rti a l ga s trectomy; however, gi ven the l ow a bs ol ute i nci dence of pos tga s trectomy
ca ncer, routi ne endos copi c s urvei l l a nce i s proba bl y not cos t effecti ve, but upper GI s ymptoms or a nemi a i n s uch pa ti ents s houl d prompt
endos copy.
Uncommon Gastritis Syndromes
Menetrier's disease: Thi s ra re i di opa thi c di s order a ffects a dul ts a ged 30 to 60 a nd i s more common a mong men. It ma ni fes ts a s a s i gni fi ca nt
thi ckeni ng of the ga s tri c fol ds of the ga s tri c body but not the a ntrum. Gl a nd a trophy a nd ma rked foveol a r pi t hyperpl a s i a occur, often a ccompa ni ed
by mucous gl a nd meta pl a s i a a nd i ncrea s ed mucos a l thi cknes s wi th l i ttl e i nfl a mma ti on. Hypoa l bumi nemi a (the mos t cons i s tent l a bora tory
a bnorma l i ty) ca us ed by GI protei n l os s ma y be pres ent (protei n-l os i ng ga s tropa thy). As the di s ea s e progres s es , the s ecreti on of a ci d a nd peps i n
decrea s es , ca us i ng hypochl orhydri a .
Symptoms a re nons peci fi c a nd commonl y i ncl ude epi ga s tri c pa i n, na us ea , wei ght l os s , edema , a nd di a rrhea . Di fferenti a l di a gnos i s i ncl udes (1)
l ymphoma , i n whi ch mul ti pl e ga s tri c ul cers ma y occur; (2) mucos a -a s s oci a ted l ymphoi d ti s s ue (MALT) l ymphoma , wi th extens i ve i nfi l tra ti on of
monocl ona l B l ymphocytes ; (3) Zol l i nger-El l i s on s yndrome wi th a s s oci a ted ga s tri c fol d hypertrophy; a nd (4) Cronkhi te-Ca na da s yndrome, a mucos a l
pol ypoi d protei n-l os i ng s yndrome a s s oci a ted wi th di a rrhea . Di a gnos i s i s ma de by endos copy wi th deep mucos a l bi ops y or ful l -thi cknes s
l a pa ros copi c ga s tri c bi ops y.
Va ri ous trea tments ha ve been us ed, i ncl udi ng a nti chol i nergi cs , a nti s ecretory drugs , a nd corti cos teroi ds , but none ha ve proved ful l y effecti ve.
Pa rti a l or compl ete ga s tri c res ecti on ma y be neces s a ry i n ca s es of s evere hypoa l bumi nemi a .
Eosinophilic gastritis: Extens i ve i nfi l tra ti on of the mucos a , s ubmucos a , a nd mus cl e l a yers wi th eos i nophi l s often occurs i n the a ntrum. It i s us ua l l y
i di opa thi c but ma y res ul t from nema tode i nfes ta ti on. Symptoms i ncl ude na us ea , vomi ti ng, a nd ea rl y s a ti ety. Di a gnos i s i s by endos copi c bi ops y of
i nvol ved a rea s . Corti cos teroi ds ca n be s ucces s ful i n i di opa thi c ca s es ; however, i f pyl ori c obs tructi on devel ops , s urgery ma y be requi red.
Mucosa-associated lymphoid tissue (MALT) lymphoma: Thi s ra re condi ti on i s cha ra cteri zed by ma s s i ve l ymphoi d i nfi l tra ti on of the ga s tri c mucos a ,
whi ch ca n res embl e Menetri er's di s ea s e.
Gastritis caused by systemic disorders: Sa rcoi dos i s , TB, a myl oi dos i s , a nd other gra nul oma tous di s ea s es ca n ca us e ga s tri ti s , whi ch i s s el dom of
pri ma ry i mporta nce.
Gastritis caused by physical agents: Ra di a ti on a nd i nges ti on of corros i ves (es peci a l l y a ci di c compounds ) ca n ca us e ga s tri ti s . Expos ure to > 16 Gy of
ra di a ti on ca us es ma rked deep ga s tri ti s , us ua l l y i nvol vi ng the a ntrum more tha n the corpus . Pyl ori c s tenos i s a nd perfora ti on a re pos s i bl e
compl i ca ti ons of ra di a ti on-i nduced ga s tri ti s .
Infectious (septic) gastritis: Except for H. pylori i nfecti on, ba cteri a l i nva s i on of the s toma ch i s ra re a nd ma i nl y occurs a fter i s chemi a , i nges ti on of
corros i ves , or expos ure to ra di a ti on. On x-ra y, ga s outl i nes the mucos a . The condi ti on ca n ma ni fes t a s a n a cute s urgi ca l a bdomen a nd ha s a very
hi gh morta l i ty ra te. Surgery i s often neces s a ry.
Debi l i ta ted or i mmunocompromi s ed pa ti ents ma y devel op vi ra l or funga l ga s tri ti s wi th cytomega l ovi rus , Candida, hi s topl a s mos i s , or mucormycos i s ;
thes e di a gnos es s houl d be cons i dered i n pa ti ents wi th exuda ti ve ga s tri ti s , es opha gi ti s , or duodeni ti s .
Autoimmune Metaplastic Atrophic Gastritis
Autoimmune metaplastic atrophic gastritis (AMAG) is an inherited autoimmune disease that attacks parietal cells, resulting in hypochlorhydria and decreased
production of intrinsic factor. Consequences include atrophic gastritis, B12 malabsorption, and, frequently, pernicious anemia. Risk of gastric adenocarcinoma
increases 3-fold. Diagnosis is by endoscopy. Treatment is with parenteral vitamin B12 .

Pa ti ents wi th AMAG ha ve a nti bodi es to pa ri eta l cel l s a nd thei r components (whi ch i ncl ude i ntri ns i c fa ctor a nd the proton pump H +,K+-ATPa s e).
AMAG i s i nheri ted a s a n a utos oma l domi na nt tra i t. Some pa ti ents a l s o devel op Ha s hi moto's thyroi di ti s a nd 50% ha ve thyroi d a nti bodi es ;
convers el y, pa ri eta l cel l a nti bodi es a re found i n 30% of pa ti ents wi th thyroi di ti s .
The l a ck of i ntri ns i c fa ctor l ea ds to vi ta mi n B 12 defi ci ency tha t ca n res ul t i n a mega l obl a s ti c a nemi a (perni ci ous a nemi a s ee p. 932) or neurol ogi c
s ymptoms (s uba cute combi ned degenera ti ons ee p.
38).
Hypochl orhydri a l ea ds to G-cel l hyperpl a s i a a nd el eva ted s erum ga s tri n l evel s (often >1000 pg/mL). El eva ted ga s tri n l evel s l ea d to
enterochroma ffi n-l i ke cel l hyperpl a s i a , whi ch occa s i ona l l y undergoes tra ns forma ti on to a ca rci noi d tumor.
In s ome pa ti ents , AMAG ma y be a s s oci a ted wi th chroni c Helicobacter pylori i nfecti on, a l though the rel a ti ons hi p i s not cl ea r. Ga s trectomy a nd
chroni c a ci d s uppres s i on wi th proton pump i nhi bi tors ca us e s i mi l a r defi ci enci es of i ntri ns i c fa ctor s ecreti on.
The a rea s of a trophi c ga s tri ti s i n the body a nd fundus ma y ma ni fes t meta pl a s i a . Pa ti ents wi th AMAG ha ve a 3-fol d i ncrea s ed rel a ti ve ri s k of
devel opi ng ga s tri c a denoca rci noma .
Di a gnos i s i s ma de by endos copi c bi ops y. Serum B 12 l evel s s houl d be obta i ned. Pa ri eta l cel l a nti bodi es ca n be detected but a re not mea s ured
routi nel y. The i s s ue of s urvei l l a nce endos copy for ca ncer s creeni ng i s uns ettl ed; fol l ow-up exa mi na ti ons a re unneces s a ry unl es s hi s tol ogi c
a bnorma l i ti es (eg, dys pl a s i a ) a re pres ent on i ni ti a l bi ops y or s ymptoms devel op. No trea tment i s needed other tha n pa rentera l repl a cement of
vi ta mi n B 12 .
Peptic Ulcer Disease
A peptic ulcer is an erosion in a segment of the GI mucosa, typically in the stomach (gastric ulcer) or the first few centimeters of the duodenum (duodenal ulcer),
that penetrates through the muscularis mucosae. Nearly all ulcers are caused by Helicobacter pylori infection or NSAID use. Symptoms typically include burning
epigastric pain that is often relieved by food. Diagnosis is by endoscopy and testing for H. pylori. Treatment involves acid suppression, eradication of H. pylori (if
present), and avoidance of NSAIDs.
Ul cers ma y ra nge i n s i ze from s evera l mi l l i meters to s evera l centi meters . Ul cers a re del i nea ted from eros i ons by the depth of penetra ti on;
eros i ons a re more s uperfi ci a l a nd do not i nvol ve the mus cul a ri s mucos a e. Ul cers ca n occur a t a ny a ge, i ncl udi ng i nfa ncy a nd chi l dhood, but a re
mos t common a mong mi ddl e-a ged a dul ts .
Etiology
H. pylori a nd NSAIDs di s rupt norma l mucos a l defens e a nd repa i r, ma ki ng the mucos a more s us cepti bl e to a ci d. H. pylori i nfecti on i s pres ent i n 50 to
70% of pa ti ents wi th duodena l ul cers a nd 30 to 50% of pa ti ents wi th ga s tri c ul cers . If H. pylori i s era di ca ted, onl y 10% of pa ti ents ha ve recurrence of
pepti c ul cer di s ea s e, compa red wi th 70% recurrence i n pa ti ents trea ted wi th a ci d s uppres s i on a l one. NSAIDs now a ccount for > 50% of pepti c
ul cers .
Ci ga rette s moki ng i s a ri s k fa ctor for the devel opment of ul cers a nd thei r compl i ca ti ons . Al s o, s moki ng i mpa i rs ul cer hea l i ng a nd i ncrea s es the
i nci dence of recurrence. Ri s k correl a tes wi th the number of ci ga rettes s moked per da y. Al though a l cohol i s a s trong promoter of a ci d s ecreti on, no
defi ni ti ve da ta l i nk modera te a mounts of a l cohol to the devel opment or del a yed hea l i ng of ul cers . Very few pa ti ents ha ve hypers ecreti on of
ga s tri n (Zol l i nger-El l i s on s yndromes ee p. 200).
A fa mi l y hi s tory exi s ts i n 50 to 60% of chi l dren wi th duodena l ul cer.
Symptoms and Signs
Symptoms depend on ul cer l oca ti on a nd pa ti ent a ge; ma ny pa ti ents , pa rti cul a rl y el derl y pa ti ents , ha ve few or no s ymptoms . Pa i n i s mos t common,
often l oca l i zed to the epi ga s tri um a nd rel i eved by food or a nta ci ds . The pa i n i s des cri bed a s burni ng or gna wi ng, or s ometi mes a s a s ens a ti on of
hunger. The cours e i s us ua l l y chroni c a nd recurrent. Onl y a bout ha l f of pa ti ents pres ent wi th the cha ra cteri s ti c pa ttern of s ymptoms .
Gastric ulcer s ymptoms often do not fol l ow a cons i s tent pa ttern (eg, ea ti ng s ometi mes exa cerba tes ra ther tha n rel i eves pa i n). Thi s i s es peci a l l y
true for pyl ori c cha nnel ul cers , whi ch a re often a s s oci a ted wi th s ymptoms of obs tructi on (eg, bl oa ti ng, na us ea , vomi ti ng) ca us ed by edema a nd
s ca rri ng.
Duodenal ulcers tend to ca us e more cons i s tent pa i n. Pa i n i s a bs ent when the pa ti ent a wa kens but a ppea rs i n mi d-morni ng, i s rel i eved by food, but
recurs 2 to 3 h a fter a mea l . Pa i n tha t a wa kens a pa ti ent a t ni ght i s common a nd i s hi ghl y s ugges ti ve of duodena l ul cer. In neona tes , perfora ti on
a nd hemorrha ge ma y be the fi rs t ma ni fes ta ti on of duodena l ul cer. Hemorrha ge ma y a l s o be the fi rs t recogni zed s i gn i n l a ter i nfa ncy a nd ea rl y
chi l dhood, a l though repea ted vomi ti ng or evi dence of a bdomi na l pa i n ma y be a cl ue.
Diagnosis
Endos copy
Someti mes s erum ga s tri n l evel s
Di a gnos i s of pepti c ul cer i s s ugges ted by pa ti ent hi s tory a nd confi rmed by endos copy. Empi ri c thera py i s often begun wi thout defi ni ti ve di a gnos i s .
However, endos copy a l l ows for bi ops y or cytol ogi c brus hi ng of ga s tri c a nd es opha gea l l es i ons to di s ti ngui s h between s i mpl e ul cera ti on a nd
ul cera ti ng s toma ch ca ncer. Stoma ch ca ncer ma y ma ni fes t wi th s i mi l a r ma ni fes ta ti ons a nd mus t be excl uded, es peci a l l y i n pa ti ents who a re > 45,
ha ve l os t wei ght, or report s evere or refra ctory s ymptoms . The i nci dence of ma l i gna nt duodena l ul cer i s extremel y l ow, s o bi ops i es of l es i ons i n
tha t a rea a re genera l l y not wa rra nted. Endos copy ca n a l s o be us ed to defi ni ti vel y di a gnos e H. pylori i nfecti on, whi ch s houl d be s ought when a n
ul cer i s detected.
Ga s tri n-s ecreti ng ca ncer a nd Zol l i nger-El l i s on s yndrome s houl d be cons i dered when there a re mul ti pl e ul cers , when ul cers devel op i n a typi ca l
l oca ti ons (eg, pos tbul ba r) or a re refra ctory to trea tment, or when the pa ti ent ha s promi nent di a rrhea or wei ght l os s . Serum ga s tri n l evel s s houl d
be mea s ured i n thes e pa ti ents .
Complications
Hemorrhage: Mi l d to s evere hemorrha ge i s the mos t common compl i ca ti on of pepti c ul cer di s ea s e. Symptoms i ncl ude hema temes i s (vomi ti ng of
fres h bl ood or "coffee ground" ma teri a l ); pa s s a ge of bl oody s tool s (hema tochezi a ) or bl a ck ta rry s tool s (mel ena ); a nd wea knes s , orthos ta s i s ,
s yncope, thi rs t, a nd s wea ti ng ca us ed by bl ood l os s .
Penetration (confined perforation): A pepti c ul cer ma y penetra te the wa l l of the s toma ch. If a dhes i ons prevent l ea ka ge i nto the peri tonea l ca vi ty, free
penetra ti on i s a voi ded a nd confi ned perfora ti on occurs . Sti l l , the ul cer ma y penetra te i nto the duodenum a nd enter the a dja cent confi ned s pa ce
(l es s er s a c) or a nother orga n (eg, pa ncrea s , l i ver). Pa i n ma y be i ntens e, pers i s tent, referred to s i tes other tha n the a bdomen (us ua l l y the ba ck
when ca us ed by penetra ti on of a pos teri or duodena l ul cer i nto the pa ncrea s ), a nd modi fi ed by body pos i ti on. CT or MRI i s us ua l l y needed to
confi rm the di a gnos i s . When thera py does not res ul t i n hea l i ng, s urgery i s requi red.
Free perforation: Ul cers tha t perfora te i nto the peri tonea l ca vi ty unchecked by a dhes i ons a re us ua l l y l oca ted i n the a nteri or wa l l of the duodenum
or, l es s commonl y, i n the s toma ch. The pa ti ent pres ents wi th a n a cute a bdomen. There i s s udden, i ntens e, conti nuous epi ga s tri c pa i n tha t
s prea ds ra pi dl y throughout the a bdomen, often becomi ng promi nent i n the ri ght l ower qua dra nt a nd a t ti mes referred to one or both s houl ders .
The pa ti ent us ua l l y l i es s ti l l beca us e even deep brea thi ng wors ens the pa i n. Pa l pa ti on of the a bdomen i s pa i nful , rebound tendernes s i s
promi nent, a bdomi na l mus cl es a re ri gi d (boa rdl i ke), a nd bowel s ounds a re di mi ni s hed or a bs ent. Shock ma y ens ue, hera l ded by i ncrea s ed pul s e
ra te a nd decrea s ed BP a nd uri ne output. Symptoms ma y be l es s s tri ki ng i n el derl y or mori bund pa ti ents a nd thos e recei vi ng corti cos teroi ds or
i mmunos uppres s a nts .
Di a gnos i s i s confi rmed i f a n x-ra y or CT s hows free a i r under the di a phra gm or i n the peri tonea l ca vi ty. Upri ght vi ews of the ches t a nd a bdomen a re
preferred. The mos t s ens i ti ve vi ew i s the l a tera l x-ra y of the ches t. Severel y i l l pa ti ents ma y be una bl e to s i t upri ght a nd s houl d ha ve a l a tera l
decubi tus x-ra y of the a bdomen. Fa i l ure to detect free a i r does not excl ude the di a gnos i s .
Immedi a te s urgery i s requi red. The l onger the del a y, the poorer i s the prognos i s . When s urgery i s contra i ndi ca ted, the a l terna ti ves a re conti nuous
na s oga s tri c s ucti on a nd broa d-s pectrum a nti bi oti cs .
Gastric outlet obstruction: Obs tructi on ma y be ca us ed by s ca rri ng, s pa s m, or i nfl a mma ti on from a n ul cer. Symptoms i ncl ude recurrent, l a rge-vol ume
vomi ti ng, occurri ng more frequentl y a t the end of the da y a nd often a s l a te a s 6 h a fter the l a s t mea l . Los s of a ppeti te wi th pers i s tent bl oa ti ng or
ful l nes s a fter ea ti ng a l s o s ugges ts ga s tri c outl et obs tructi on. Prol onged vomi ti ng ma y ca us e wei ght l os s , dehydra ti on, a nd a l ka l os i s .
If the pa ti ent's hi s tory s ugges ts obs tructi on, phys i ca l exa mi na ti on, ga s tri c a s pi ra ti on, or x-ra ys ma y provi de evi dence of reta i ned ga s tri c contents . A
s uccus s i on s pl a s h hea rd > 6 h a fter a mea l or a s pi ra ti on of fl ui d or food res i due > 200 mL a fter a n overni ght fa s t s ugges ts ga s tri c retenti on. If
ga s tri c a s pi ra ti on s hows ma rked retenti on, the s toma ch s houl d be empti ed a nd endos copy done or x-ra ys ta ken to determi ne s i te, ca us e, a nd
degree of obs tructi on.
Edema or s pa s m ca us ed by a n a cti ve pyl ori c cha nnel ul cer i s trea ted wi th ga s tri c decompres s i on by na s oga s tri c s ucti on a nd a ci d s uppres s i on (eg,
IV H 2 bl ockers ). Dehydra ti on a nd el ectrol yte i mba l a nces res ul ti ng from protra cted vomi ti ng or conti nued na s oga s tri c s ucti oni ng s houl d be
vi gorous l y s ought a nd corrected. Proki neti c a gents a re not i ndi ca ted. Genera l l y, obs tructi on res ol ves wi thi n 2 to 5 da ys of trea tment. Prol onged
obs tructi on ma y res ul t from pepti c s ca rri ng a nd ma y res pond to endos copi c pyl ori c ba l l oon di l a ti on. Surgery i s neces s a ry to rel i eve obs tructi on i n
s el ected ca s es .
Recurrence: Fa ctors tha t a ffect recurrence of ul cer i ncl ude fa i l ure to era di ca te H. pylori, conti nued NSAID us e, a nd s moki ng. Les s commonl y, a
ga s tri noma (Zol l i nger-El l i s on s yndrome) ma y be the ca us e. The 3-yr recurrence ra te for ga s tri c a nd duodena l ul cers i s < 10% when H. pylori i s
s ucces s ful l y era di ca ted but > 50% when i t i s not. Thus , a pa ti ent wi th recurrent di s ea s e s houl d be tes ted for H. pylori a nd trea ted a ga i n i f the tes ts
a re pos i ti ve.
Al though l ong-term trea tment wi th H 2 bl ockers , proton pump i nhi bi tors , or mi s opros tol reduces the ri s k of recurrence, thei r routi ne us e for thi s
purpos e i s not recommended. However, pa ti ents who requi re NSAIDs a fter ha vi ng ha d a pepti c ul cer a re ca ndi da tes for l ong-term thera py, a s a re
thos e wi th a ma rgi na l ul cer or pri or perfora ti on or bl eedi ng.
Stomach cancer: Pa ti ents wi th H. pylori-a s s oci a ted ul cers ha ve a 3- to 6-fol d i ncrea s ed ri s k of ga s tri c ca ncer l a ter i n l i fe. There i s no i ncrea s ed ri s k of
ca ncer wi th ul cers of other eti ol ogy.
Treatment
Era di ca ti on of H. pylori (when pres ent)
Aci d-s uppres s i ve drugs
Trea tment of ga s tri c a nd duodena l ul cers requi res era di ca ti on of H. pylori when pres ent (s ee p. 130) a nd a reducti on of ga s tri c a ci di ty. For duodena l
ul cers , i t i s pa rti cul a rl y i mporta nt to s uppres s nocturna l a ci d s ecreti on.
Methods of decrea s i ng a ci di ty i ncl ude a number of drugs , a l l of whi ch a re effecti ve but whi ch va ry i n cos t, dura ti on of thera py, a nd conveni ence of
dos i ng. In a ddi ti on, mucos a l protecti ve drugs (eg, s ucra l fa te) a nd a ci d-reduci ng s urgi ca l procedures ma y be us ed. Drug thera py i s di s cus s ed on p.
136.
Adjuncts: Smoki ng s houl d be s topped, a nd a l cohol cons umpti on s topped or l i mi ted to s ma l l a mounts of di l ute a l cohol . There i s no evi dence tha t
cha ngi ng the di et s peeds ul cer hea l i ng or prevents recurrence. Thus , ma ny phys i ci a ns recommend el i mi na ti ng onl y foods tha t ca us e di s tres s .
Surgery: Wi th current drug thera py, the number of pa ti ents requi ri ng s urgery ha s decl i ned dra ma ti ca l l y. Indi ca ti ons i ncl ude perfora ti on,
obs tructi on, uncontrol l ed or recurrent bl eedi ng, a nd, a l though ra re, s ymptoms tha t do not res pond to drug thera py.
Surgery cons i s ts of a procedure to reduce a ci d s ecreti on, often combi ned wi th a procedure to ens ure ga s tri c dra i na ge. The recommended opera ti on
for duodena l ul cer i s hi ghl y s el ecti ve, or pa ri eta l cel l , va gotomy (whi ch i s l i mi ted to nerves a t the ga s tri c body a nd s pa res a ntra l i nnerva ti on,
thereby obvi a ti ng the need for a dra i na ge procedure). Thi s procedure ha s a very l ow morta l i ty ra te a nd a voi ds the morbi di ty a s s oci a ted wi th
res ecti on a nd tra di ti ona l va gotomy. Other a ci d-reduci ng s urgi ca l procedures i ncl ude a ntrectomy, hemi ga s trectomy, pa rti a l ga s trectomy, a nd
s ubtota l ga s trectomy (i e, res ecti on of 30 to 90% of the di s ta l s toma ch). Thes e a re typi ca l l y combi ned wi th trunca l va gotomy. Pa ti ents who undergo
a res ecti ve procedure or who ha ve a n obs tructi on requi re ga s tri c dra i na ge vi a a ga s troduodenos tomy (Bi l l roth I) or ga s trojejunos tomy (Bi l l roth II).
The i nci dence a nd type of pos ts urgi ca l s ymptoms va ry wi th the type of opera ti on. After res ecti ve s urgery, up to 30% of pa ti ents ha ve s i gni fi ca nt
s ymptoms , i ncl udi ng wei ght l os s , ma l di ges ti on, a nemi a , dumpi ng s yndrome, rea cti ve hypogl ycemi a , bi l i ous vomi ti ng, mecha ni ca l probl ems , a nd
ul cer recurrence.
Weight loss i s common a fter s ubtota l ga s trectomy; the pa ti ent ma y l i mi t food i nta ke beca us e of ea rl y s a ti ety (beca us e the res i dua l ga s tri c pouch i s
s ma l l ) or to prevent dumpi ng s yndrome a nd other pos tpra ndi a l s yndromes . Wi th a s ma l l ga s tri c pouch, di s tenti on or di s comfort ma y occur a fter a
mea l of even modera te s i ze; pa ti ents s houl d be encoura ged to ea t s ma l l er a nd more frequent mea l s .
Maldigestion a nd s tea torrhea ca us ed by pa ncrea ti cobi l i a ry bypa s s , es peci a l l y wi th Bi l l roth II a na s tomos i s , ma y contri bute to wei ght l os s .
Anemia i s common (us ua l l y from i ron defi ci ency, but occa s i ona l l y from vi ta mi n B 12 defi ci ency ca us ed by l os s of i ntri ns i c fa ctor or ba cteri a l
overgrowth) i n the a fferent l i mb, a nd os teoma l a ci a ma y occur. IM vi ta mi n B 12 s uppl ementa ti on i s recommended for a l l pa ti ents wi th tota l
ga s trectomy but ma y a l s o be gi ven to pa ti ents wi th s ubtota l ga s trectomy i f defi ci ency i s s us pected.
Dumping syndrome ma y fol l ow ga s tri c s urgi ca l procedures , pa rti cul a rl y res ecti ons . Wea knes s , di zzi nes s , s wea ti ng, na us ea , vomi ti ng, a nd
pa l pi ta ti on occur s oon a fter ea ti ng, es peci a l l y hyperos mol a r foods . Thi s phenomenon i s referred to a s ea rl y dumpi ng, the ca us e of whi ch rema i ns
uncl ea r but l i kel y i nvol ves a utonomi c refl exes , i ntra va s cul a r vol ume contra cti on, a nd rel ea s e of va s oa cti ve pepti des from the s ma l l i ntes ti ne.
Di eta ry modi fi ca ti ons , wi th s ma l l er, more frequent mea l s a nd decrea s ed ca rbohydra te i nta ke, us ua l l y hel p.
Reactive hypoglycemia or late dumping (a nother form of the s yndrome) res ul ts from ra pi d emptyi ng of ca rbohydra tes from the ga s tri c pouch. Ea rl y
hi gh pea ks i n bl ood gl ucos e s ti mul a te exces s rel ea s e of i ns ul i n, whi ch l ea ds to s ymptoma ti c hypogl ycemi a s evera l hours a fter the mea l . A hi ghprotei n, l ow-ca rbohydra te di et a nd a dequa te ca l ori c i nta ke (i n frequent s ma l l feedi ngs ) a re recommended.
Mechanical problems (i ncl udi ng ga s tropa res i s a nd bezoa r forma ti ons ee p. 138) ma y occur s econda ry to a decrea s e i n pha s e III ga s tri c motor
contra cti ons , whi ch a re a l tered a fter a ntrectomy a nd va gotomy. Di a rrhea i s es peci a l l y common a fter va gotomy, even wi thout a res ecti on
(pyl oropl a s ty).
Ulcer recurrence, a ccordi ng to ol der s tudi es , occurs i n 5 to 12% a fter hi ghl y s el ecti ve va gotomy a nd i n 2 to 5% a fter res ecti ve s urgery. Recurrent ul cers
a re di a gnos ed by endos copy a nd genera l l y res pond to ei ther proton pump i nhi bi tors or H 2 bl ockers . For ul cers tha t conti nue to recur, the
compl etenes s of va gotomy s houl d be tes ted by ga s tri c a na l ys i s , H. pylori el i mi na ted i f pres ent, a nd Zol l i nger-El l i s on s yndrome rul ed out by s erum
ga s tri n s tudi es .
Drug Treatment of Gastric Acidity
Drugs for decrea s i ng a ci di ty a re us ed for pepti c ul cer, ga s troes opha gea l refl ux di s ea s e (GERDs ee p. 125), a nd ma ny forms of ga s tri ti s . Some
drugs a re us ed i n regi mens for trea ti ng H. pylori i nfecti on. Drugs i ncl ude proton pump i nhi bi tors , H 2 bl ockers , a nta ci ds , a nd pros ta gl a ndi ns .
Proton pump inhibitors: Thes e drugs a re potent i nhi bi tors of H +,K+-ATPa s e. Thi s enzyme, l oca ted i n the a pi ca l s ecretory membra ne of the pa ri eta l cel l ,
pl a ys a key rol e i n the s ecreti on of H + (protons ). Thes e drugs ca n compl etel y i nhi bi t a ci d s ecreti on a nd ha ve a l ong dura ti on of a cti on. They
promote ul cer hea l i ng a nd a re a l s o key components of H. pylori era di ca ti on regi mens . Proton pump i nhi bi tors ha ve repl a ced H 2 bl ockers i n mos t
cl i ni ca l s i tua ti ons beca us e of grea ter ra pi di ty of a cti on a nd effi ca cy.
Proton pump i nhi bi tors i ncl ude es omepra zol e, l a ns opra zol e, a nd pa ntopra zol e, a l l a va i l a bl e ora l l y a nd IV, a nd omepra zol e a nd ra bepra zol e,
a va i l a bl e onl y ora l l y i n the US (s ee
Ta bl e 13-1). Omepra zol e i s a va i l a bl e wi thout a pres cri pti on i n the US. For uncompl i ca ted duodena l ul cers , omepra zol e 20 mg po once/da y or
l a ns opra zol e 30 mg po once/da y i s gi ven for 4 wk. Compl i ca ted duodena l ul cers (i e, mul ti pl e
[Table 13-1. Proton Pump Inhi bi tors ]
ul cers , bl eedi ng ul cers , thos e > 1.5 cm, or thos e occurri ng i n pa ti ents wi th s eri ous underl yi ng i l l nes s ) res pond better to hi gher dos es (omepra zol e
40 mg once/da y, l a ns opra zol e 60 mg once/da y or 30 mg bi d). Ga s tri c ul cers requi re trea tment for 6 to 8 wk. Ga s tri ti s a nd GERD requi re 8 to 12 wk of
thera py; GERD a ddi ti ona l l y requi res l ong-term ma i ntena nce.
Long-term proton pump i nhi bi tor thera py produces el eva ted ga s tri n l evel s , whi ch l ea d to enterochroma ffi n-l i ke cel l hyperpl a s i a . However, there i s
no evi dence of dys pl a s i a or ma l i gna nt tra ns forma ti on i n pa ti ents recei vi ng thi s trea tment. Some ma y devel op vi ta mi n B 12 ma l a bs orpti on.
H 2 blockers: Thes e drugs (ci meti di ne, ra ni ti di ne, fa moti di ne, a va i l a bl e IV a nd ora l l y; a nd ni za ti di ne a va i l a bl e ora l l y) a re competi ti ve i nhi bi tors of
hi s ta mi ne a t the H 2 receptor, thus s uppres s i ng ga s tri n-s ti mul a ted a ci d s ecreti on a nd proporti ona tel y reduci ng ga s tri c jui ce vol ume. Hi s ta mi nemedi a ted peps i n s ecreti on i s a l s o decrea s ed.
H 2 bl ockers a re wel l a bs orbed from the GI tra ct, wi th ons et of a cti on 30 to 60 mi n a fter i nges ti on a nd pea k effects a t 1 to 2 h. IV a dmi ni s tra ti on
produces a more ra pi d ons et of a cti on. Dura ti on of a cti on i s proporti ona l to dos e a nd ra nges from 6 to 20 h. Dos es s houl d often be reduced i n
el derl y pa ti ents .
For duodena l ul cers , once da i l y ora l a dmi ni s tra ti on of ci meti di ne 800 mg, ra ni ti di ne 300 mg, fa moti di ne 40 mg, or ni za ti di ne 300 mg gi ven a t
bedti me or a fter di nner for 6 to 8 wk i s effecti ve. Ga s tri c ul cers ma y res pond to the s a me regi men conti nued for 8 to 12 wk, but beca us e nocturna l
a ci d s ecreti on i s l es s i mporta nt, morni ng a dmi ni s tra ti on ma y be equa l l y or more effecti ve. Chi l dren 40 kg ma y recei ve a dul t dos es . Bel ow tha t
wei ght, the ora l dos a ge i s ra ni ti di ne 2 mg/kg q 12 h a nd ci meti di ne 10 mg/kg q 12 h. For GERD, H 2 bl ockers a re now mos tl y us ed for pa i n
ma na gement. Ga s tri ti s hea l s wi th fa moti di ne or ra ni ti di ne gi ven bi d for 8 to 12 wk.
Ci meti di ne ha s mi nor a nti a ndrogen effects expres s ed a s revers i bl e gynecoma s ti a a nd, l es s commonl y, erecti l e dys functi on wi th prol onged us e.
Menta l s ta tus cha nges , di a rrhea , ra s h, drug fever, mya l gi a s , thrombocytopeni a , a nd s i nus bra dyca rdi a a nd hypotens i on a fter ra pi d IV
a dmi ni s tra ti on ha ve been reported wi th a l l H 2 bl ockers , genera l l y i n < 1% of trea ted pa ti ents but more commonl y i n el derl y pa ti ents .
Ci meti di ne a nd, to a l es s er extent, other H 2 bl ockers i ntera ct wi th the P-450 mi cros oma l enzyme s ys tem a nd ma y del a y meta bol i s m of other drugs
el i mi na ted through thi s s ys tem (eg, phenytoi n, wa rfa ri n, theophyl l i ne, di a zepa m, l i doca i ne).
Antacids: Thes e a gents neutra l i ze ga s tri c a ci d a nd reduce peps i n a cti vi ty (whi ch di mi ni s hes a s ga s tri c pH ri s es to > 4.0). In a ddi ti on, s ome a nta ci ds
a ds orb peps i n. Anta ci ds ma y i nterfere wi th the a bs orpti on of other drugs (eg, tetra cycl i ne, di goxi n, i ron).
Anta ci ds rel i eve s ymptoms , promote ul cer hea l i ng, a nd reduce recurrence. They a re rel a ti vel y i nexpens i ve but mus t be ta ken 5 to 7 ti mes /da y. The
opti ma l a nta ci d regi men for ul cer hea l i ng s eems to be 15 to 30 mL of l i qui d or 2 to 4 ta bl ets 1 h a nd 3 h a fter ea ch mea l a nd a t bedti me. The tota l
da i l y dos a ge of a nta ci ds s houl d provi de 200 to 400 mEq neutra l i zi ng ca pa ci ty. However, a nta ci ds ha ve been s upers eded by a ci d-s uppres s i ve
thera py i n the trea tment of pepti c ul cer a nd a re us ed onl y for s hort-term s ymptom rel i ef.
In genera l , there a re 2 types of a nta ci ds : a bs orba bl e a nd nona bs orba bl e. Abs orba bl e a nta ci ds (eg, Na bi ca rbona te, Ca ca rbona te) provi de ra pi d,
compl ete neutra l i za ti on but ma y ca us e a l ka l os i s a nd s houl d be us ed onl y bri efl y (1 or 2 da ys ). Nona bs orba bl e a nta ci ds (eg, a l umi num or Mg
hydroxi de) ha ve fewer s ys temi c a dvers e effects a nd a re preferred.
Al umi num hydroxi de i s a rel a ti vel y s a fe, commonl y us ed a nta ci d. Wi th chroni c us e, phos pha te depl eti on occa s i ona l l y devel ops a s a res ul t of
bi ndi ng of phos pha te by a l umi num i n the GI tra ct. The ri s k of phos pha te depl eti on i ncrea s es i n a l cohol i cs , undernouri s hed pa ti ents , a nd pa ti ents
wi th rena l di s ea s e (i ncl udi ng thos e recei vi ng hemodi a l ys i s ). Al umi num hydroxi de ca us es cons ti pa ti on.
Mg hydroxi de i s a more effecti ve a nta ci d tha n a l umi num but ma y ca us e di a rrhea . To l i mi t di a rrhea , ma ny propri eta ry a nta ci ds combi ne Mg a nd
a l umi num a nta ci ds . Beca us e s ma l l a mounts of Mg a re a bs orbed, Mg prepa ra ti ons s houl d be us ed wi th ca uti on i n pa ti ents wi th rena l di s ea s e.
Prostaglandins: Certa i n pros ta gl a ndi ns (es peci a l l y mi s opros tol ) i nhi bi t a ci d s ecreti on by decrea s i ng the genera ti on of cycl i c AMP tha t i s tri ggered by
hi s ta mi ne s ti mul a ti on of the pa ri eta l cel l , a nd enha nce mucos a l defens e. Syntheti c pros ta gl a ndi n deri va ti ves a re us ed predomi na ntl y to
decrea s e the ri s k of NSAID-i nduced mucos a l i njury. Pa ti ents a t hi gh ri s k of NSAID-i nduced ul cers (i e, el derl y pa ti ents , thos e wi th a hi s tory of ul cer
or ul cer compl i ca ti on, thos e a l s o ta ki ng corti cos teroi ds ) a re ca ndi da tes to ta ke mi s opros tol 200 g po qi d wi th food a l ong wi th thei r NSAID.
Common a dvers e effects of mi s opros tol a re a bdomi na l cra mpi ng a nd di a rrhea , whi ch occur i n 30% of pa ti ents . Mi s opros tol i s a powerful
a borti fa ci ent a nd i s a bs ol utel y contra i ndi ca ted i n women of chi l dbea ri ng a ge who a re not us i ng contra cepti on.
Sucralfate: Thi s drug i s a s ucros e-a l umi num compl ex tha t di s s oci a tes i n s toma ch a ci d a nd forms a phys i ca l ba rri er over a n i nfl a med a rea ,
protecti ng i t from a ci d, peps i n, a nd bi l e s a l ts . It a l s o i nhi bi ts peps i n-s ubs tra te i ntera cti on, s ti mul a tes mucos a l pros ta gl a ndi n producti on, a nd
bi nds bi l e s a l ts . It ha s no effect on a ci d output or ga s tri n s ecreti on. Sucra l fa te s eems to ha ve trophi c effects on the ul cera ted mucos a , pos s i bl y by
bi ndi ng growth fa ctors a nd concentra ti ng them a t a n ul cer s i te. Sys temi c a bs orpti on of s ucra l fa te i s negl i gi bl e. Cons ti pa ti on occurs i n 3 to 5% of
pa ti ents . Sucra l fa te ma y bi nd to other drugs a nd i nterfere wi th thei r a bs orpti on.
Chapter 14. Bezoars and Foreign Bodies

Introduction
Food a nd other i nges ted ma teri a l s ma y col l ect a nd form s ol i d ma s s es wi thi n the GI tra ct.
Bezoars
A bezoar is a tightly packed collection of partially digested or undigested material that is unable to exit the stomach. It often occurs in patients with abnormal
gastric emptying, especially those that have diabetic gastroparesis, as well as after gastric surgery. Many bezoars are asymptomatic, but some cause symptoms
of gastric outlet obstruction. Some can be dissolved enzymatically, others removed endoscopically, and some require surgery.
Pa rti a l l y di ges ted a ggl omera ti ons of vegeta bl e ma tter a re ca l l ed phytobezoa rs ; a ggl omera ti ons of ha i r a re ca l l ed tri chobezoa rs . Pha rma cobezoa rs
a re concreti ons of medi ca ti on (pa rti cul a rl y common wi th s ucra l fa te a nd a l umi num hydroxi de gel ). Ma ny other s ubs ta nces ha ve been found i n
bezoa rs .
Etiology
Tri chobezoa rs , whi ch ca n wei gh s evera l kg, mos t commonl y occur i n pa ti ents wi th ps ychi a tri c di s turba nces who chew a nd s wa l l ow thei r own ha i r.
Phytobezoa rs often occur i n pa ti ents who ha ve undergone a Bi l l roth I or II pa rti a l ga s trectomy, es peci a l l y when a ccompa ni ed by va gotomy.
Hypochl orhydri a , di mi ni s hed a ntra l moti l i ty, a nd i ncompl ete ma s ti ca ti on a re the ma i n predi s pos i ng fa ctors ; thes e fa ctors a re more common
a mong the el derl y, who a re thus a t hi gher ri s k of bezoa r forma ti on. Others i ncl ude di a beti c ga s tropa res i s a nd ga s tropl a s ty for morbi d obes i ty.
Cons umpti on of pers i mmons (a frui t conta i ni ng the ta nni n s hi buol , whi ch pol ymeri zes i n the s toma ch) ha s been known to ca us e bezoa rs tha t
requi re s urgery i n > 90% of ca s es . Pers i mmon bezoa rs often occur i n epi demi cs i n regi ons where the frui t i s grown.
Symptoms and Signs
Mos t bezoa rs ca us e no s ymptoms , a l though pos tpra ndi a l ful l nes s , na us ea a nd vomi ti ng, pa i n, a nd GI bl eedi ng ma y occur.
Diagnosis
Endos copy
Bezoa rs a re detecta bl e a s a ma s s l es i on on mos t tes ts (eg, x-ra y, ul tra s ound, CT) tha t ma y be done to eva l ua te upper GI s ymptoms . They ma y be
mi s ta ken for tumors ; upper endos copy i s us ua l l y done. On endos copy, bezoa rs ha ve a n unmi s ta ka bl e i rregul a r s urfa ce a nd ma y ra nge i n col or from
yel l ow-green to gra y-bl a ck. An endos copi c bi ops y tha t yi el ds ha i r or pl a nt ma teri a l i s di a gnos ti c.
Treatment
Obs erva ti on
Someti mes ma nua l remova l vi a endos copy
Someti mes enzyma ti c thera py
If i ni ti a l di a gnos i s i s ma de by endos copy, remova l ca n be a ttempted a t tha t ti me. Fra gmenta ti on wi th forceps , wi re s na re, jet s pra y, or even l a s er
ma y brea k up bezoa rs , a l l owi ng them to pa s s or be extra cted. Metocl opra mi de 40 mg IV over 24 h or 10 mg IM q 4 h for s evera l da ys ma y i ncrea s e
peri s ta l s i s a nd a i d ga s tri c emptyi ng of fra gmented ma teri a l .
If endos copy wa s not i ni ti a l l y done, trea tment i s ba s ed on s ymptoms . As ymptoma ti c pa ti ents tha t ha ve a bezoa r di s covered i nci denta l l y duri ng
tes ti ng for other rea s ons do not neces s a ri l y requi re i nterventi on. In s ome ca s es , a tri a l of enzyma ti c thera py ca n be a ttempted. Enzymes i ncl ude
pa pa i n (10,000 U wi th ea ch mea l ), mea t tenderi zer (5 mL [1 ts p] i n 8 oz of cl ea r l i qui d before ea ch mea l ), or cel l ul a s e (10 g di s s ol ved i n 1 L wa ter,
cons umed over 24 h for 2 to 3 da ys ). If enzyma ti c thera py i s uns ucces s ful , or i f pa ti ents a re s ymptoma ti c, endos copi c remova l ma y be tri ed. Rockl i ke
concreti ons a nd tri chobezoa rs us ua l l y requi re l a pa rotomy.
Foreign Bodies
A variety of foreign bodies may enter the GI tract. Many pass spontaneously, but some become impacted, causing symptoms of obstruction. Perforation may
occur. The esophagus is the most common (75%) site of impaction. Nearly all impacted objects can be removed endoscopically, but surgery is occasionally
necessary.
Undi ges ti bl e objects ma y be i ntenti ona l l y s wa l l owed by chi l dren a nd demented a dul ts . Denture wea rers , the el derl y, a nd i nebri a ted peopl e a re
prone to a cci denta l l y s wa l l owi ng i na dequa tel y ma s ti ca ted food (pa rti cul a rl y mea t), whi ch ma y become i mpa cted i n the es opha gus . Smuggl ers
who s wa l l ow drug-fi l l ed ba l l oons , vi a l s , or pa cka ges to es ca pe detecti on (body pa ckers or body s tuffers ) ma y devel op i ntes ti na l obs tructi on. The
pa cka gi ng ma y rupture, l ea di ng to drug overdos e.
Esophageal foreign bodies: Forei gn bodi es us ua l l y l odge i n a n a rea of es opha gea l na rrowi ng s uch a s a t the cri copha ryngeus or a orti c a rch or jus t
a bove the ga s troes opha gea l juncti on. If obs tructi on i s compl ete, pa ti ents retch or vomi t. Some pa ti ents drool beca us e they a re una bl e to s wa l l ow
s ecreti ons .
Immedi a te endos copi c remova l i s requi red for s ha rp objects , coi ns i n the proxi ma l es opha gus , a nd a ny obs tructi on ca us i ng s i gni fi ca nt s ymptoms .
Al s o, button ba tteri es l odged i n the es opha gus ma y ca us e di rect corros i ve da ma ge, l ow-vol ta ge burns , a nd pres s ure necros i s a nd thus requi re
prompt remova l .
Other es opha gea l forei gn bodi es ma y be obs erved for a ma xi mum of 12 to 24 h. Gl uca gon 1 mg IV s ometi mes rel a xes the es opha gus enough to
a l l ow s ponta neous pa s s a ge. Other methods , s uch a s us e of efferves cent a gents , mea t tenderi zer, a nd bougi ena ge, a re not recommended.
Endos copi c remova l i s the trea tment of choi ce. Remova l i s bes t a chi eved us i ng a forceps , ba s ket, or s na re wi th a n overtube pl a ced i n the
es opha gus to prevent a s pi ra ti on.
Someti mes , forei gn bodi es s cra tch the es opha gus but do not become l odged. In s uch ca s es , pa ti ents ma y report a forei gn body s ens a ti on even
though no forei gn body i s pres ent.
Gastric and intestinal foreign bodies: Forei gn bodi es tha t pa s s through the es opha gus a re a s ymptoma ti c unl es s obs tructi on or perfora ti on occurs . Of
the forei gn bodi es tha t rea ch the s toma ch, 80 to 90% pa s s s ponta neous l y, 10 to 20% requi re nonopera ti ve i nterventi on, a nd 1% requi re s urgery.
Thus , mos t i ntra ga s tri c forei gn bodi es ca n be i gnored. However, objects l a rger tha n 5 2 cm ra rel y pa s s the s toma ch. Sha rp objects s houl d be
retri eved from the s toma ch beca us e 15 to 35% wi l l ca us e i ntes ti na l perfora ti on, but s ma l l round objects (eg, coi ns a nd button ba tteri es ) ca n
s i mpl y be obs erved. The pa ti ent's s tool s s houl d be s ea rched, a nd i f the object does not a ppea r, x-ra ys a re ta ken a t 48-h i nterva l s . A coi n tha t
rema i ns i n the s toma ch for > 4 wk or a ba ttery s howi ng s i gns of corros i on on x-ra y tha t rema i ns i n the s toma ch for > 48 h s houl d be removed. A
ha nd-hel d meta l detector ca n l oca l i ze meta l l i c forei gn bodi es a nd provi de i nforma ti on compa ra bl e to tha t yi el ded by pl a i n x-ra ys .
Pa ti ents wi th s ymptoms of obs tructi on or perfora ti on requi re l a pa rotomy. Inges ted drug pa cka ges a re of grea t concern beca us e of the ri s k of
l ea ka ge a nd cons equent drug overdos e. Pa ti ents wi th s ymptoms of drug toxi ci ty s houl d ha ve i mmedi a te l a pa rotomy wi th i nteri m medi ca l
ma na gement of s ymptoms (eg, benzodi a zepi nes for coca i ne toxi ci ty). As ymptoma ti c pa ti ents s houl d be a dmi tted to the hos pi ta l . Some cl i ni ci a ns
a dvoca te ora l pol yethyl ene gl ycol s ol uti on a s a ca tha rti c to enha nce pa s s a ge of the ma teri a l ; others s ugges t s urgi ca l remova l . The bes t pra cti ce i s
uncl ea r.
Mos t forei gn objects tha t ha ve pa s s ed i nto the s ma l l i ntes ti ne us ua l l y tra vers e the GI tra ct wi thout probl em, even i f they ta ke weeks or months to
do s o. They tend to be hel d up jus t before the i l eoceca l va l ve or a t a ny s i te of na rrowi ng, a s i s pres ent i n Crohn's di s ea s e. Someti mes objects s uch
a s toothpi cks rema i n wi thi n the GI tra ct for ma ny yea rs , onl y to turn up i n a gra nul oma or a bs ces s .
Rectal foreign bodies: Ga l l s tones , feca l i ths , a nd s wa l l owed forei gn bodi es (i ncl udi ng toothpi cks a nd chi cken a nd fi s h bones ) ma y l odge a t the
a norecta l juncti on. Uri na ry ca l cul i , va gi na l pes s a ri es , or s urgi ca l s ponges or i ns truments ma y erode i nto the rectum. Forei gn bodi es , s ometi mes
bi za rre a nd/or rel a ted to s exua l pl a y, ma y be i ntroduced i ntenti ona l l y but become l odged uni ntenti ona l l y. Some objects a re ca ught i n the recta l
wa l l , a nd others a re tra pped jus t a bove the a na l s phi ncter.
Sudden, excruci a ti ng pa i n duri ng defeca ti on s houl d a rous e s us pi ci on of a penetra ti ng forei gn body, us ua l l y l odged a t or jus t a bove the a norecta l
juncti on. Other ma ni fes ta ti ons depend on the s i ze a nd s ha pe of the forei gn body, i ts dura ti on i n s i tu, a nd the pres ence of i nfecti on or perfora ti on.
Forei gn bodi es us ua l l y become l odged i n the mi d rectum, where they ca nnot negoti a te the a nteri or a ngul a ti on of the rectum. They ca n be fel t on
di gi ta l exa mi na ti on. Abdomi na l exa mi na ti on a nd ches t x-ra ys ma y be neces s a ry to excl ude pos s i bl e i ntra peri tonea l recta l perfora ti on.
If the object ca n be pa l pa ted, a l oca l a nes theti c i s gi ven by s c a nd s ubmucos a l i njecti ons of 0.5% l i doca i ne or bupi va ca i ne. The a nus i s di l a ted
wi th a recta l retra ctor, a nd the forei gn body i s gra s ped a nd removed. If the object ca nnot be pa l pa ted, the pa ti ent s houl d be hos pi ta l i zed.
Peri s ta l s i s us ua l l y moves the forei gn body down to the mi d rectum, a nd the a bove routi ne ca n be fol l owed. Remova l vi a a s i gmoi dos cope or
proctos cope i s ra rel y s ucces s ful , a nd s i gmoi dos copy us ua l l y forces the forei gn body proxi ma l l y, del a yi ng i ts extra cti on. Regi ona l or genera l
a nes thes i a i s i nfrequentl y neces s a ry, a nd l a pa rotomy wi th mi l ki ng of the forei gn body towa rd the a nus or col otomy wi th extra cti on of the forei gn
body i s ra rel y neces s a ry. After extra cti on, s i gmoi dos copy s houl d be done to rul e out s i gni fi ca nt recta l tra uma or perfora ti on. Remova l of a recta l
forei gn body ma y be of hi gh ri s k a nd s houl d be done by a s urgeon or ga s troenterol ogi s t s ki l l ed i n forei gn body remova l .
Chapter 15. Pancreatitis

Introduction
Pa ncrea ti ti s i s cl a s s i fi ed a s ei ther a cute or chroni c. Acute pa ncrea ti ti s i s i nfl a mma ti on tha t res ol ves both cl i ni ca l l y a nd hi s tol ogi ca l l y. Chroni c
pa ncrea ti ti s i s cha ra cteri zed by hi s tol ogi c cha nges tha t a re i rrevers i bl e a nd progres s i ve a nd tha t res ul t i n cons i dera bl e l os s of exocri ne a nd
endocri ne pa ncrea ti c functi on. Pa ti ents wi th chroni c pa ncrea ti ti s ma y ha ve a fl a re-up of a cute di s ea s e.
Pa ncrea ti ti s ca n a ffect both the exocri ne a nd endocri ne functi ons of the pa ncrea s . Pa ncrea ti c a ci na r cel l s s ecrete bi ca rbona te a nd di ges ti ve
enzymes i nto ducts tha t connect the pa ncrea s to the duodenum a t the a mpul l a of Va ter (exocri ne functi on). Pa ncrea ti c -cel l s s ecrete i ns ul i n
di rectl y i nto the bl oods trea m (endocri ne functi on).
Acute Pancreatitis
Acute pancreatitis is inflammation of the pancreas (and, sometimes, adjacent tissues) caused by the release of activated pancreatic enzymes. The most common
triggers are biliary tract disease and chronic heavy alcohol intake. The condition ranges from mild (abdominal pain and vomiting) to severe (pancreatic necrosis
and a systemic inflammatory process with shock and multiorgan failure). Diagnosis is based on clinical presentation and serum amylase and lipase levels.
Treatment is supportive, with IV fluids, analgesics, and fasting.
Etiology
Bi l i a ry tra ct di s ea s e a nd a l cohol i s m a ccount for 80% of a cute pa ncrea ti ti s ca s es . The rema i ni ng 20% res ul t from myri a d ca us es (s ee
Ta bl e 15-1).
Pathophysiology
The preci s e mecha ni s m by whi ch obs tructi on of the s phi ncter of Oddi by a ga l l s tone or mi crol i thi a s i s (s l udge) ca us es pa ncrea ti ti s i s uncl ea r,
a l though i t proba bl y i nvol ves i ncrea s ed ducta l pres s ure. Prol onged a l cohol i nta ke (> 100 g/da y for > 3 to 5 yr) ma y ca us e the protei n of pa ncrea ti c
enzymes to preci pi ta te wi thi n s ma l l pa ncrea ti c ductul es . Ducta l obs tructi on by thes e protei n pl ugs ma y ca us e prema ture a cti va ti on of pa ncrea ti c
enzymes . An a l cohol bi nge i n s uch pa ti ents ca n tri gger pa ncrea ti ti s , but the exa ct mecha ni s m i s not known.
A number of geneti c muta ti ons predi s pos i ng to pa ncrea ti ti s ha ve been i denti fi ed. One, a n a utos oma l domi na nt muta ti on of the ca ti oni c
tryps i nogen gene, ca us es pa ncrea ti ti s i n 80% of ca rri ers ; a n obvi ous fa mi l i a l pa ttern i s pres ent. Other muta ti ons ha ve l es s er penetra nce a nd a re
not rea di l y a ppa rent cl i ni ca l l y except through geneti c tes ti ng. The geneti c a bnorma l i ty res pons i bl e for cys ti c fi bros i s i ncrea s es the ri s k of recurrent
a cute a s wel l a s chroni c pa ncrea ti ti s .
Rega rdl es s of the eti ol ogy, pa ncrea ti c enzymes (i ncl udi ng tryps i n, phos phol i pa s e A2 , a nd el a s ta s e) become a cti va ted wi thi n the gl a nd i ts el f. The
enzymes ca n da ma ge ti s s ue a nd a cti va te compl ement a nd the i nfl a mma tory ca s ca de, produci ng cytoki nes . Thi s proces s ca us es i nfl a mma ti on,
edema , a nd s ometi mes necros i s . In mi l d pa ncrea ti ti s , i nfl a mma ti on i s confi ned to the pa ncrea s ; the morta l i ty ra te i s < 5%. In s evere pa ncrea ti ti s ,
there i s s i gni fi ca nt i nfl a mma ti on, wi th necros i s a nd hemorrha ge of the gl a nd a nd a s ys temi c i nfl a mma tory res pons e; the morta l i ty ra te i s 10 to
50%. After 5 to 7 da ys , necroti c pa ncrea ti c ti s s ue ma y become i nfected by enteri c ba cteri a .
[Table 15-1. Some Ca us es of Acute Pa ncrea ti ti s ]
Acti va ted enzymes a nd cytoki nes tha t enter the peri tonea l ca vi ty ca us e a chemi ca l burn a nd thi rd s pa ci ng of fl ui d; thos e tha t enter the s ys temi c
ci rcul a ti on ca us e a s ys temi c i nfl a mma tory res pons e tha t ca n res ul t i n a cute res pi ra tory di s tres s s yndrome a nd rena l fa i l ure. The s ys temi c effects
a re ma i nl y the res ul t of i ncrea s ed ca pi l l a ry permea bi l i ty a nd decrea s ed va s cul a r tone, whi ch res ul t from the rel ea s ed cytoki nes a nd chemoki nes .
Phos phol i pa s e A2 i s thought to i njure a l veol a r membra nes of the l ungs .
In a bout 40% of pa ti ents , col l ecti ons of enzyme-ri ch pa ncrea ti c fl ui d a nd ti s s ue debri s form i n a nd a round the pa ncrea s . In a bout ha l f, the
col l ecti ons res ol ve s ponta neous l y. In others , the col l ecti ons become i nfected or form ps eudocys ts . Ps eudocys ts ha ve a fi brous ca ps ul e wi thout a n
epi thel i a l l i ni ng. Ps eudocys ts ma y hemorrha ge, rupture, or become i nfected.
Dea th duri ng the fi rs t s evera l da ys i s us ua l l y ca us ed by ca rdi ova s cul a r i ns ta bi l i ty (wi th refra ctory s hock a nd rena l fa i l ure) or res pi ra tory fa i l ure
(wi th hypoxemi a a nd a t ti mes a dul t res pi ra tory di s tres s s yndrome). Occa s i ona l l y, dea th res ul ts from hea rt fa i l ure s econda ry to a n uni denti fi ed
myoca rdi a l depres s a nt fa ctor. Dea th a fter the fi rs t week i s us ua l l y ca us ed by mul ti orga n s ys tem fa i l ure.
Symptoms and Signs
An a cute a tta ck ca us es s tea dy, bori ng upper a bdomi na l pa i n, typi ca l l y s evere enough to requi re l a rge dos es of pa rentera l opi oi ds . The pa i n
ra di a tes through to the ba ck i n a bout 50% of pa ti ents ; ra rel y, pa i n i s fi rs t fel t i n the l ower a bdomen. Pa i n us ua l l y devel ops s uddenl y i n ga l l s tone
pa ncrea ti ti s ; i n a l cohol i c pa ncrea ti ti s , pa i n devel ops over a few da ys . The pa i n us ua l l y pers i s ts for s evera l da ys . Si tti ng up a nd l ea ni ng forwa rd
ma y reduce pa i n, but coughi ng, vi gorous movement, a nd deep brea thi ng ma y a ccentua te i t. Na us ea a nd vomi ti ng a re common.
The pa ti ent a ppea rs a cutel y i l l a nd s wea ty. Pul s e ra te i s us ua l l y 100 to 140 bea ts /mi n. Res pi ra ti on i s s ha l l ow a nd ra pi d. BP ma y be tra ns i entl y
hi gh or l ow, wi th s i gni fi ca nt pos tura l hypotens i on. Tempera ture ma y be norma l or even s ubnorma l a t fi rs t but ma y i ncrea s e to 37.7 to 38.3 C (100 to
101 F) wi thi n a few hours . Sens ori um ma y be bl unted to the poi nt of s emi coma . Scl era l i cterus i s occa s i ona l l y pres ent. The l ungs ma y ha ve l i mi ted
di a phra gma ti c excurs i on a nd evi dence of a tel ecta s i s .
About 20% of pa ti ents experi ence upper a bdomi na l di s tenti on ca us ed by ga s tri c di s tenti on or di s pl a cement of the s toma ch by a pa ncrea ti c
i nfl a mma tory ma s s . Pa ncrea ti c duct di s rupti on ma y ca us e a s ci tes (pa ncrea ti c a s ci tes ). Ma rked a bdomi na l tendernes s occurs , mos t often i n the
upper a bdomen. There ma y be mi l d tendernes s i n the l ower a bdomen, but the rectum i s not tender a nd the s tool i s us ua l l y nega ti ve for occul t
bl ood. Mi l d-to-modera te mus cul a r ri gi di ty ma y be pres ent i n the upper a bdomen but i s ra re i n the l ower a bdomen. Ra rel y, s evere peri tonea l
i rri ta ti on res ul ts i n a ri gi d a nd boa rdl i ke a bdomen. Bowel s ounds ma y be hypoa cti ve. Grey Turner's s i gn (ecchymos es of the fl a nks ) a nd Cul l en's
s i gn (ecchymos es of the umbi l i ca l regi on) i ndi ca te extra va s a ti on of hemorrha gi c exuda te.
Infecti on i n the pa ncrea s or i n a n a dja cent fl ui d col l ecti on s houl d be s us pected i f the pa ti ent ha s a genera l l y toxi c a ppea ra nce wi th el eva ted
tempera ture a nd WBC count or i f deteri ora ti on fol l ows a n i ni ti a l peri od of s ta bi l i za ti on.
Diagnosis
Serum ma rkers (a myl a s e, l i pa s e)
Once pa ncrea ti ti s i s di a gnos ed, CT us ua l l y done
Pa ncrea ti ti s i s s us pected whenever s evere a bdomi na l pa i n occurs , es peci a l l y i n a pa ti ent wi th s i gni fi ca nt a l cohol us e or known ga l l s tones .
Condi ti ons ca us i ng s i mi l a r s ymptoms i ncl ude perfora ted ga s tri c or duodena l ul cer, mes enteri c i nfa rcti on, s tra ngul a ti ng i ntes ti na l obs tructi on,
di s s ecti ng a neurys m, bi l i a ry col i c, a ppendi ci ti s , di verti cul i ti s , i nferi or wa l l MI, a nd hema toma of the a bdomi na l mus cl es or s pl een.
Di a gnos i s i s ma de by cl i ni ca l s us pi ci on, s erum ma rkers (a myl a s e a nd l i pa s e), a nd the a bs ence of other ca us es for the pa ti ent's s ymptoms . Thus , a
broa d ra nge of tes ts i s done, typi ca l l y i ncl udi ng CBC, el ectrol ytes , Ca , Mg, gl ucos e, BUN, crea ti ni ne, a myl a s e, a nd l i pa s e. Other routi ne tes ts
i ncl ude ECG a nd a n a bdomi na l s eri es (ches t, fl a t, a nd upri ght a bdomen). A uri ne di ps ti ck for tryps i nogen-2 ha s s ens i ti vi ty a nd s peci fi ci ty of > 90%
for a cute pa ncrea ti ti s . Ul tra s ound a nd CT a re not genera l l y done s peci fi ca l l y to di a gnos e pa ncrea ti ti s but a re often us ed to eva l ua te a cute
a bdomi na l pa i n (s ee p.
108).
Laboratory tests: Serum a myl a s e a nd l i pa s e concentra ti ons i ncrea s e on the fi rs t da y of a cute pa ncrea ti ti s a nd return to norma l i n 3 to 7 da ys . Li pa s e
i s more s peci fi c for pa ncrea ti ti s , but both enzymes ma y be i ncrea s ed i n rena l fa i l ure a nd va ri ous a bdomi na l condi ti ons (eg, perfora ted ul cer,
mes enteri c va s cul a r occl us i on, i ntes ti na l obs tructi on). Other ca us es of i ncrea s ed s erum a myl a s e i ncl ude s a l i va ry gl a nd dys functi on,
ma croa myl a s emi a , a nd tumors tha t s ecrete a myl a s e. Both a myl a s e a nd l i pa s e l evel s ma y rema i n norma l i f des tructi on of a ci na r ti s s ue duri ng
previ ous epi s odes precl udes rel ea s e of s uffi ci ent a mounts of enzymes . The s erum of pa ti ents wi th hypertri gl yceri demi a ma y conta i n a ci rcul a ti ng
i nhi bi tor tha t mus t be di l uted before a n el eva ti on i n s erum a myl a s e ca n be detected.
Amyl a s e:crea ti ni ne cl ea ra nce ra ti o does not ha ve s uffi ci ent s ens i ti vi ty or s peci fi ci ty to di a gnos e pa ncrea ti ti s . It i s genera l l y us ed to di a gnos e
ma croa myl a s emi a when no pa ncrea ti ti s exi s ts . In ma croa myl a s emi a , a myl a s e bound to s erum i mmunogl obul i n fa l s el y el eva tes the s erum
a myl a s e l evel .
Fra cti ona ti on of tota l s erum a myl a s e i nto pa ncrea ti c type (p-type) i s oa myl a s e a nd s a l i va ry-type (s -type) i s oa myl a s e i ncrea s es the a ccura cy of
s erum a myl a s e. However, the l evel of p-type a l s o i ncrea s es i n rena l fa i l ure a nd i n other s evere a bdomi na l condi ti ons i n whi ch a myl a s e cl ea ra nce
i s a l tered.
The WBC count us ua l l y i ncrea s es to 12,000 to 20,000/L. Thi rd-s pa ce fl ui d l os s es ma y i ncrea s e the Hct to a s hi gh a s 50 to 55%, i ndi ca ti ng s evere
i nfl a mma ti on. Hypergl ycemi a ma y occur. Serum Ca concentra ti on fa l l s a s ea rl y a s the fi rs t da y beca us e of the forma ti on of Ca "s oa ps " s econda ry to
exces s genera ti on of free fa tty a ci ds , es peci a l l y by pa ncrea ti c l i pa s e. Serum bi l i rubi n i ncrea s es i n 15 to 25% of pa ti ents beca us e pa ncrea ti c edema
compres s es the common bi l e duct.
Imaging: Pl a i n x-ra ys of the a bdomen ma y di s cl os e ca l ci fi ca ti ons wi thi n pa ncrea ti c ducts (evi dence of pri or i nfl a mma ti on a nd hence chroni c
pa ncrea ti ti s ), ca l ci fi ed ga l l s tones , or l oca l i zed i l eus i n the l eft upper qua dra nt or the center of the a bdomen (a "s enti nel l oop" of s ma l l bowel ,
di l a ti on of the tra ns vers e col on, or duodena l i l eus ). Ches t x-ra y ma y revea l a tel ecta s i s or a pl eura l effus i on (us ua l l y l eft-s i ded or bi l a tera l but
ra rel y confi ned to the ri ght pl eura l s pa ce).
Ul tra s ound s houl d be done i f ga l l s tone pa ncrea ti ti s i s s us pected (a nd a nother eti ol ogy i s not obvi ous ) to detect ga l l s tones or di l a ti on of the
common bi l e duct (whi ch i ndi ca tes bi l i a ry tra ct obs tructi on). Edema of the pa ncrea s ma y be vi s ua l i zed, but overl yi ng ga s frequentl y obs cures the
pa ncrea s .
CT wi th IV contra s t i s genera l l y done to i denti fy necros i s , fl ui d col l ecti ons , or ps eudocys ts once pa ncrea ti ti s ha s been di a gnos ed. It i s pa rti cul a rl y
recommended for s evere pa ncrea ti ti s or i f a compl i ca ti on ens ues (eg, hypotens i on or progres s i ve l eukocytos i s a nd el eva ti on of tempera ture). IV
contra s t fa ci l i ta tes the recogni ti on of pa ncrea ti c necros i s ; however, i t ma y ca us e pa ncrea ti c necros i s i n a rea s of l ow perfus i on (i e, i s chemi a ).
Thus , contra s t-enha nced CT s houl d be done onl y a fter the pa ti ent ha s been a dequa tel y hydra ted.
If pa ncrea ti c i nfecti on i s s us pected, fl ui d obta i ned by percuta neous CT-gui ded needl e a s pi ra ti on of cys ts or a rea s of fl ui d col l ecti on or necros i s
ma y revea l orga ni s ms on Gra m s ta i n or cul ture. The di a gnos i s i s s upported by pos i ti ve bl ood cul tures a nd, pa rti cul a rl y, by the pres ence of a i r
bubbl es i n the retroperi toneum on a bdomi na l CT. The a dvent of ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP) ma y ma ke the s el ecti on of
pa ncrea ti c i ma gi ng s i mpl er.
Prognosis
In edema tous pa ncrea ti ti s , morta l i ty i s < 5%. In pa ncrea ti ti s wi th necros i s a nd hemorrha ge, morta l i ty i s 10 to 50%. In pa ncrea ti c i nfecti on, morta l i ty
i s us ua l l y 100% wi thout extens i ve s urgi ca l debri dement or dra i na ge of the i nfected a rea .
CT fi ndi ngs correl a te wi th prognos i s . If CT i s norma l or s hows onl y mi l d pa ncrea ti c edema (Ba l tha za r cl a s s A or B), the prognos i s i s excel l ent.
Pa ti ents wi th peri pa ncrea ti c i nfl a mma ti on or one a rea of fl ui d col l ecti on (cl a s s es C a nd D) ha ve a 10 to 15% i nci dence of a bs ces s forma ti on; the
i nci dence i s over 60% i n pa ti ents wi th two or more a rea s of fl ui d col l ecti on (cl a s s E).
Ranson's prognostic signs hel p predi ct the prognos i s of a cute pa ncrea ti ti s . Fi ve of Ra ns on's s i gns ca n be documented a t a dmi s s i on:
Age > 55 yr
Pl a s ma gl ucos e > 200 mg/dL (> 11.1 mmol /L)
Serum LDH > 350 IU/L

AST > 250 UL
WBC count > 16,000/L
The res t of Ra ns on's s i gns a re determi ned wi thi n 48 h of a dmi s s i on:
Hct decrea s e > 10%
BUN i ncrea s e > 5 mg/dL (> 1.78 mmol /L)
Serum Ca < 8 mg/dL (< 2 mmol /L)
Pa o 2 < 60 mm Hg (< 7.98 kPa )
Ba s e defi ci t > 4 mEq/L (> 4 mmol /L)
Es ti ma ted fl ui d s eques tra ti on > 6 L
Morta l i ty i ncrea s es wi th the number of pos i ti ve s i gns : If < 3 s i gns a re pos i ti ve, the morta l i ty ra te i s < 5%; i f 3 a re pos i ti ve, morta l i ty i s 15 to 20%.
The APACHE II i ndex (s ee
Ta bl e 222-4 on p. 2248), ca l cul a ted on the s econd hos pi ta l da y, a l s o correl a tes wi th prognos i s .
Treatment
Fl ui d res us ci ta ti on
Fa s ti ng
Drugs , i ncl udi ng a dequa te a na l ges i a a nd a ci d bl ockers
Anti bi oti cs for pa ncrea ti c necros i s
Dra i na ge of i nfected ps eudocys ts or a rea s of necros i s
Adequa te fl ui d res us ci ta ti on i s es s enti a l ; up to 6 to 8 L/da y of fl ui d conta i ni ng a ppropri a te el ectrol ytes ma y be requi red. Ina dequa te fl ui d thera py
i ncrea s es the ri s k of pa ncrea ti c necros i s .
Fa s ti ng i s i ndi ca ted unti l a cute i nfl a mma ti on s ubs i des (i e, ces s a ti on of a bdomi na l tendernes s a nd pa i n, norma l i za ti on of s erum a myl a s e, return
of a ppeti te, feel i ng better). Fa s ti ng ca n l a s t from a few da ys i n mi l d pa ncrea ti ti s to s evera l weeks . TPN s houl d be i ni ti a ted i n s evere ca s es wi thi n
the fi rs t few da ys to prevent undernutri ti on.
Pa i n rel i ef requi res pa rentera l opi oi ds , whi ch s houl d be gi ven i n a dequa te dos es . Al though morphi ne ma y ca us e the s phi ncter of Oddi to contra ct,
thi s i s of doubtful cl i ni ca l s i gni fi ca nce. Anti emeti c a gents (eg, prochl orpera zi ne 5 to 10 mg IV q 6 h) s houl d be gi ven to a l l evi a te vomi ti ng. An NGT
i s requi red onl y i f s i gni fi ca nt vomi ti ng pers i s ts or i l eus i s pres ent.
Pa rentera l H 2 bl ockers or proton pump i nhi bi tors a re gi ven. Efforts to reduce pa ncrea ti c s ecreti on wi th drugs (eg, a nti chol i nergi cs , gl uca gon,
s oma tos ta ti n, octreoti de) ha ve no proven benefi t.
Severe a cute pa ncrea ti ti s s houl d be trea ted i n a n ICU, pa rti cul a rl y i n pa ti ents wi th hypotens i on, ol i guri a , Ra ns on's s core 3, APACHE II 8, or
pa ncrea ti c necros i s on CT > 30%. In the ICU, vi ta l s i gns a nd uri ne output a re moni tored hourl y; meta bol i c pa ra meters (Hct, gl ucos e, a nd
el ectrol ytes ) a re rea s s es s ed every 8 h; ABG i s determi ned a s needed; centra l venous pres s ure l i ne or Swa n-Ga nz ca theter mea s urements a re
determi ned every 6 h i f the pa ti ent i s hemodyna mi ca l l y uns ta bl e or i f fl ui d requi rements a re uncl ea r. CBC, pl a tel et count, coa gul a ti on pa ra meters ,
tota l protei n wi th a l bumi n, BUN, crea ti ni ne, Ca , a nd Mg a re mea s ured da i l y.
Hypoxemi a i s trea ted wi th humi di fi ed O2 vi a ma s k or na s a l prongs . If hypoxemi a pers i s ts or a dul t res pi ra tory di s tres s s yndrome devel ops ,
a s s i s ted venti l a ti on ma y be requi red. Gl ucos e > 170 to 200 mg/dL (9.4 to 11.1 mmol /L) s houl d be trea ted ca uti ous l y wi th s c or IV i ns ul i n a nd
ca reful l y moni tored. Hypoca l cemi a genera l l y i s not trea ted unl es s neuromus cul a r i rri ta bi l i ty occurs ; 10 to 20 mL of 10% Ca gl ucona te i n 1 L of IV
fl ui d i s gi ven over 4 to 6 h. Chroni c a l cohol i cs a nd pa ti ents wi th documented hypoma gnes emi a s houl d recei ve Mg s ul fa te 1 g/L of repl a cement
fl ui d for a tota l of 2 to 4 g, or unti l l evel s norma l i ze. If rena l fa i l ure occurs , s erum Mg l evel s a re moni tored a nd IV Mg i s gi ven ca uti ous l y. Wi th
res tora ti on of norma l Mg l evel s , s erum Ca l evel s us ua l l y return to norma l .
Hea rt fa i l ure s houl d be trea ted (s ee p. 2126). Prerena l a zotemi a s houl d be trea ted by i ncrea s ed fl ui d repl a cement. Rena l fa i l ure ma y requi re
di a l ys i s (us ua l l y peri tonea l ).
Anti bi oti c prophyl a xi s wi th i mi penem ca n prevent i nfecti on of s teri l e pa ncrea ti c necros i s , a l though the effect on reduci ng morta l i ty i s uncl ea r.
Infected a rea s of pa ncrea ti c necros i s requi re s urgi ca l debri dement, but i nfected fl ui d col l ecti ons outs i de the pa ncrea s ma y be dra i ned
percuta neous l y. A ps eudocys t tha t i s expa ndi ng ra pi dl y, i nfected, bl eedi ng, or l i kel y to rupture requi res dra i na ge. Whether dra i na ge i s
percuta neous , s urgi ca l , or endos copi c depends on l oca ti on of the ps eudocys t a nd i ns ti tuti ona l experti s e. Peri tonea l l a va ge to wa s h out a cti va ted
pa ncrea ti c enzymes a nd i nfl a mma tory medi a tors ha s no proven benefi t.
Surgi ca l i nterventi on duri ng the fi rs t s evera l da ys i s jus ti fi ed for s evere bl unt or penetra ti ng tra uma or uncontrol l ed bi l i a ry s eps i s . Al though > 80%
of pa ti ents wi th ga l l s tone pa ncrea ti ti s pa s s the s tone s ponta neous l y, ERCP wi th s phi ncterotomy a nd s tone remova l i s i ndi ca ted for pa ti ents who
do not i mprove a fter 24 h of trea tment. Pa ti ents who s ponta neous l y i mprove genera l l y undergo el ecti ve l a pa ros copi c chol ecys tectomy. El ecti ve
chol a ngi ogra phy rema i ns controvers i a l .
Chronic Pancreatitis
Chronic pancreatitis is persistent inflammation of the pancreas that results in permanent structural damage with fibrosis and ductal strictures, followed by a
decline in exocrine and endocrine function. It can occur as the result of chronic alcohol abuse but may be idiopathic. Initial symptoms are recurrent attacks of pain.
Later in the disease, some patients develop malabsorption and glucose intolerance. Diagnosis is usually made by imaging studies such as ERCP, endoscopic
ultrasound, or secretin pancreatic function testing. Treatment is supportive, with dietary modification, analgesics, and enzyme supplements. In some cases,
surgical treatment is helpful.
Etiology
In the US, 70 to 80% of ca s es res ul t from a l cohol i s m, a nd 15 to 25% a re i di opa thi c. However, recent da ta s ugges t tha t a l cohol i s becomi ng l es s of a
ca us e. Les s common ca us es i ncl ude heredi ta ry pa ncrea ti ti s , hyperpa ra thyroi di s m, a nd obs tructi on of the ma i n pa ncrea ti c duct ca us ed by s tenos i s ,
s tones , or ca ncer. In Indi a , Indones i a , a nd Ni geri a , i di opa thi c ca l ci fi c pa ncrea ti ti s occurs a mong chi l dren a nd young a dul ts (tropi ca l pa ncrea ti ti s ).
Pathophysiology
Si mi l a r to a cute pa ncrea ti ti s , the mecha ni s m of di s ea s e ma y be ducta l obs tructi on by protei n pl ugs . The protei n pl ugs ma y res ul t from exces s
s ecreti on of gl ycoprotei n-2 or a defi ci ency of l i thos ta ti n, a protei n i n pa ncrea ti c fl ui d tha t i nhi bi ts Ca preci pi ta ti on. If obs tructi on i s chroni c,
pers i s tent i nfl a mma ti on l ea ds to fi bros i s a nd a l terna ti ng a rea s of ducta l di l a ti on a nd s tri cture, whi ch ma y become ca l ci fi ed. Neurona l s hea th
hypertrophy a nd peri neura l i nfl a mma ti on occur a nd ma y contri bute to chroni c pa i n.
After s evera l yea rs , progres s i ve fi bros i s l ea ds to l os s of exocri ne a nd endocri ne functi on. Di a betes devel ops i n 20 to 30% of pa ti ents wi thi n 10 to
15 yr of ons et.
Symptoms and Signs
Mos t pa ti ents pres ent wi th epi s odi c a bdomi na l pa i n. About 10 to 15% ha ve no pa i n a nd pres ent wi th ma l a bs orpti on. Pa i n i s epi ga s tri c, s evere,
a nd ma y l a s t ma ny hours or s evera l da ys . Epi s odes typi ca l l y s ubs i de s ponta neous l y a fter 6 to 10 yr a s the a ci na r cel l s tha t s ecrete pa ncrea ti c
di ges ti ve enzymes a re progres s i vel y des troyed. When l i pa s e a nd protea s e s ecreti ons a re reduced to < 10% of norma l , the pa ti ent devel ops
s tea torrhea , pa s s i ng grea s y s tool s or even oi l dropl ets , a nd crea torrhea (the pres ence of undi ges ted mus cl e fi bers i n the feces ). Symptoms of
gl ucos e i ntol era nce ma y a ppea r a t thi s ti me.
Diagnosis
Cl i ni ca l s us pi ci on
Abdomi na l CT
Someti mes ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP), endos copi c ul tra s onogra phy, or ERCP
Di a gnos i s ca n be di ffi cul t beca us e a myl a s e a nd l i pa s e l evel s a re frequentl y norma l beca us e of s i gni fi ca nt l os s of pa ncrea ti c functi on. In a pa ti ent
wi th a typi ca l hi s tory of a l cohol a bus e a nd recurrent epi s odes of a cute pa ncrea ti ti s , detecti on of pa ncrea ti c ca l ci fi ca ti on on pl a i n x-ra y of the
a bdomen ma y be s uffi ci ent. However, s uch ca l ci fi ca ti ons typi ca l l y occur l a te i n the di s ea s e a nd then a re vi s i bl e i n onl y a bout 30% of pa ti ents . In
pa ti ents wi thout a typi ca l hi s tory, pa ncrea ti c ca ncer mus t be excl uded a s the ca us e of pa i n: a bdomi na l CT i s recommended. CT ca n s how
ca l ci fi ca ti ons a nd other pa ncrea ti c a bnorma l i ti es (eg, ps eudocys t or di l a ted ducts ) but s ti l l ma y be norma l ea rl y i n the di s ea s e.
The pri ma ry opti ons for pa ti ents wi th norma l CT fi ndi ngs i ncl ude ERCP, endos copi c ul tra s onogra phy, a nd s ecreti n pa ncrea ti c functi on tes ti ng.
Thes e tes ts a re qui te s ens i ti ve, but ERCP preci pi ta tes a cute pa ncrea ti ti s i n a bout 5% of pa ti ents . MRCP ma y prove a n a ccepta bl e a l terna ti ve.
La te i n the di s ea s e, tes ts of pa ncrea ti c exocri ne functi on become a bnorma l . A 72-h tes t for s tool fa t i s di a gnos ti c for s tea torrhea but ca nnot
es ta bl i s h a ca us e. The s ecreti n tes t col l ects pa ncrea ti c s ecreti ons vi a a duodena l tube for a na l ys i s but i s done i n onl y a few centers . Level s of
s erum tryps i nogen a nd feca l chymotryps i n a nd el a s ta s e ma y be decrea s ed. In the benti romi de tes t a nd the pa ncreol a uryl tes t, s ubs ta nces a re
gi ven ora l l y, a nd uri ne i s a na l yzed for cl ea va ge products genera ted by pa ncrea ti c enzymes . Al l s uch exocri ne tes ts a re l es s s ens i ti ve tha n ERCP or
endos copi c ul tra s onogra phy ea rl y i n the di s ea s e.
Treatment
IV fl ui ds
Fa s ti ng
Drugs , i ncl udi ng a dequa te a na l ges i a a nd a ci d bl ockers
Pa ncrea ti c enzyme s uppl ements
Someti mes dra i na ge of ps eudocys ts (s urgi ca l or endos copi c)
A rel a ps e requi res trea tment s i mi l a r to a cute pa ncrea ti ti s wi th fa s ti ng, IV fl ui ds , a nd a na l ges i cs . When feedi ng res umes , the pa ti ent mus t es chew
a l cohol a nd cons ume a l ow-fa t (< 25 g/da y) di et (to reduce s ecreti on of pa ncrea ti c enzymes ). An H 2 bl ocker or proton pump i nhi bi tor ma y reduce
a ci d-s ti mul a ted rel ea s e of s ecreti n, thereby decrea s i ng the fl ow of pa ncrea ti c s ecreti ons . Too often, thes e mea s ures do not rel i eve pa i n, requi ri ng
i ncrea s ed a mounts of opi oi ds , wi th the threa t of a ddi cti on. Medi ca l trea tment of chroni c pa ncrea ti c pa i n i s often uns a ti s fa ctory.
Pa ncrea ti c enzyme s uppl ementa ti on ma y reduce chroni c pa i n by i nhi bi ti ng the rel ea s e of chol ecys toki ni n, thereby reduci ng the s ecreti on of
pa ncrea ti c enzymes . Suppl ementa ti on i s more l i kel y to be s ucces s ful i n mi l d i di opa thi c pa ncrea ti ti s tha n i n a l cohol i c pa ncrea ti ti s . Enzymes a re
a l s o us ed to trea t s tea torrhea . Va ri ous prepa ra ti ons a re a va i l a bl e, a nd a dos e provi di ng a t l ea s t 30,000 U of l i pa s e s houl d be us ed. Non-enteri c
coa ted ta bl ets s houl d be us ed, a nd they s houl d be ta ken wi th mea l s . An H 2 bl ocker or proton pump i nhi bi tor s houl d be gi ven to prevent a ci d
brea kdown of the enzymes .
Fa vora bl e cl i ni ca l res pons es i ncl ude wei ght ga i n, fewer bowel movements , el i mi na ti on of oi l dropl et s eepa ge, a nd i mproved wel l -bei ng. Cl i ni ca l
res pons e ca n be documented by s howi ng a decrea s e i n s tool fa t a fter enzyme thera py. If s tea torrhea i s pa rti cul a rl y s evere a nd refra ctory to thes e
mea s ures , medi um-cha i n tri gl yceri des ca n be provi ded a s a s ource of fa t (they a re a bs orbed wi thout pa ncrea ti c enzymes ), reduci ng other di eta ry
fa ts proporti ona l l y. Suppl ementa ti on wi th fa t-s ol ubl e vi ta mi ns (A, D, K) s houl d be gi ven, i ncl udi ng vi ta mi n E, whi ch ma y mi ni mi ze i nfl a mma ti on.
Surgi ca l trea tment ma y be effecti ve for pa i n rel i ef. A pa ncrea ti c ps eudocys t, whi ch ma y ca us e chroni c pa i n, ca n be decompres s ed i nto a nea rby
s tructure to whi ch i t fi rml y a dheres (eg, the s toma ch) or i nto a defuncti ona l i zed l oop of jejunum (vi a a Roux-en-Y cys tojejunos tomy). If the ma i n
pa ncrea ti c duct i s di l a ted > 5 to 8 mm, a l a tera l pa ncrea ti cojejunos tomy (Pues tow procedure) rel i eves pa i n i n a bout 70 to 80% of pa ti ents . If the
duct i s not di l a ted, a pa rti a l res ecti on i s s i mi l a rl y effecti ve; ei ther di s ta l pa ncrea tectomy (for extens i ve di s ea s e a t the ta i l of the pa ncrea s ) or
Whi ppl e procedure (for extens i ve di s ea s e a t the hea d of the pa ncrea s ) i s done. Opera ti ve a pproa ches s houl d be res erved for pa ti ents who ha ve
s topped us i ng a l cohol a nd who ca n ma na ge di a betes tha t ma y be i ntens i fi ed by pa ncrea ti c res ecti on.
Some ps eudocys ts ca n be dra i ned endos copi ca l l y. Endos copi c ul tra s ound-gui ded denerva ti on of the cel i a c pl exus wi th a l cohol a nd bupi va ca i ne
ma y provi de pa i n rel i ef. If there i s s i gni fi ca nt s tri cture a t the pa pi l l a or di s ta l pa ncrea ti c duct, ERCP wi th s phi ncterotomy, s tent pl a cement, or
di l a ta ti on ma y be effecti ve.
Ora l hypogl ycemi c drugs ra rel y hel p trea t di a betes ca us ed by chroni c pa ncrea ti ti s . Ins ul i n s houl d be gi ven ca uti ous l y beca us e the coexi s ti ng
defi ci ency of gl uca gon s ecreti on by -cel l s mea ns tha t the hypogl ycemi c effects of i ns ul i n a re unoppos ed a nd prol onged hypogl ycemi a ma y occur.
Pa ti ents a re a t i ncrea s ed ri s k of pa ncrea ti c ca ncer. Wors eni ng of s ymptoms , es peci a l l y wi th devel opment of a pa ncrea ti c duct s tri cture, s houl d
prompt a n eva l ua ti on for ca ncer. Eva l ua ti on ma y i ncl ude brus hi ng s tri ctures for cytol ogi c a na l ys i s or mea s uri ng s erum ma rkers (eg, CA 19-9,
ca rci noembryoni c a nti gen).
Chapter 16. Gastroenteritis

Introduction
(See a l s o Food Al l ergy on p. 1118 a nd Mus hroom Poi s oni ng on p. 3336.)
Gastroenteritis is inflammation of the lining of the stomach and small and large intestines. Most cases are infectious, although gastroenteritis may occur after
ingestion of drugs and chemical toxins (eg, metals, plant substances). Symptoms include anorexia, nausea, vomiting, diarrhea, and abdominal discomfort.
Diagnosis is clinical or by stool culture, although immunoassays are increasingly used. Treatment is symptomatic, although parasitic and some bacterial infections
require specific anti-infective therapy.
Ga s troenteri ti s i s us ua l l y uncomforta bl e but s el f-l i mi ted. El ectrol yte a nd fl ui d l os s i s us ua l l y l i ttl e more tha n a n i nconveni ence to a n otherwi s e
hea l thy a dul t but ca n be gra ve for peopl e who a re very young (s ee p. 2806), el derl y, or debi l i ta ted or who ha ve s eri ous concomi ta nt i l l nes s es .
Worl dwi de, a n es ti ma ted 3 to 6 mi l l i on chi l dren di e ea ch yea r from i nfecti ous ga s troenteri ti s .
Etiology
Infecti ous ga s troenteri ti s ma y be ca us ed by vi rus es , ba cteri a , or pa ra s i tes . Ma ny s peci fi c orga ni s ms a re di s cus s ed further i n the Infecti ous
Di s ea s es s ecti on.
Viruses: The vi rus es mos t commonl y i mpl i ca ted a re
Rota vi rus
Norovi rus
Vi rus es a re the mos t common ca us e of ga s troenteri ti s i n the US. They i nfect enterocytes i n the vi l l ous epi thel i um of the s ma l l bowel . The res ul t i s
tra ns uda ti on of fl ui d a nd s a l ts i nto the i ntes ti na l l umen; s ometi mes , ma l a bs orpti on of ca rbohydra tes wors ens s ymptoms by ca us i ng os moti c
di a rrhea . Di a rrhea i s wa tery. Infl a mma tory di a rrhea (dys entery), wi th feca l WBCs a nd RBCs or gros s bl ood, i s uncommon. Four ca tegori es of vi rus es
ca us e mos t ga s troenteri ti s : rota vi rus a nd ca l i ci vi rus (predomi na ntl y the norovi rus [formerl y Norwa l k vi rus ]) ca us e the ma jori ty of vi ra l
ga s troenteri ti s , fol l owed by a s trovi rus a nd enteri c a denovi rus .
Rota vi rus i s the mos t common ca us e of s pora di c, s evere, dehydra ti ng di a rrhea i n young chi l dren (pea k i nci dence, 3 to 15 mo). Rota vi rus i s hi ghl y
conta gi ous ; mos t i nfecti ons occur by the feca l -ora l route. Adul ts ma y be i nfected a fter cl os e conta ct wi th a n i nfected i nfa nt. The i l l nes s i n a dul ts i s
genera l l y mi l d. Incuba ti on i s 1 to 3 da ys . In tempera te cl i ma tes , mos t i nfecti ons occur i n the wi nter. Ea ch yea r i n the US, a wa ve of rota vi rus i l l nes s
begi ns i n the Southwes t i n November a nd ends i n the Northea s t i n Ma rch.
Norovi rus mos t commonl y i nfects ol der chi l dren a nd a dul ts . Infecti ons occur yea r-round. Norovi rus i s the pri nci pa l ca us e of s pora di c vi ra l
ga s troenteri ti s i n a dul ts a nd of epi demi c vi ra l ga s troenteri ti s i n a l l a ge groups ; l a rge wa terborne a nd food-borne outbrea ks occur. Pers on-topers on tra ns mi s s i on a l s o occurs beca us e the vi rus i s hi ghl y conta gi ous . Incuba ti on i s 24 to 48 h.
As trovi rus ca n i nfect peopl e of a l l a ges but us ua l l y i nfects i nfa nts a nd young chi l dren. Infecti on i s mos t common i n wi nter. Tra ns mi s s i on i s by the
feca l -ora l route. Incuba ti on i s 3 to 4 da ys .
Adenovi rus es a re the 4th mos t common ca us e of chi l dhood vi ra l ga s troenteri ti s . Infecti ons occur yea r-round, wi th a s l i ght i ncrea s e i n s ummer.
Chi l dren < 2 yr a re pri ma ri l y a ffected. Tra ns mi s s i on i s by the feca l -ora l route. Incuba ti on i s 3 to 10 da ys .
In i mmunocompromi s ed pa ti ents , a ddi ti ona l vi rus es (eg, cytomega l ovi rus , enterovi rus ) ca n ca us e ga s troenteri ti s .
Bacteria: The ba cteri a mos t commonl y i mpl i ca ted a re
Salmonella
Campylobacter
Shigella
Escherichia coli (es peci a l l y s erotype O157:H7)
Ba cteri a l ga s troenteri ti s i s l es s common tha n vi ra l . Ba cteri a ca us e ga s troenteri ti s by s evera l mecha ni s ms . Certa i n s peci es (eg, Vibrio cholerae,
enterotoxi geni c s tra i ns of E. coli) a dhere to i ntes ti na l mucos a wi thout i nva di ng a nd produce enterotoxi ns . Thes e toxi ns i mpa i r i ntes ti na l
a bs orpti on a nd ca us e s ecreti on of el ectrol ytes a nd wa ter by s ti mul a ti ng a denyl a te cycl a s e, res ul ti ng i n wa tery di a rrhea . Clostridium difficile
produces a s i mi l a r toxi n when overgrowth fol l ows a nti bi oti c us e (s ee p. 1292).
Some ba cteri a (eg, Staphylococcus aureus, Bacillus cereus, Clostridium perfringens) produce a n exotoxi n tha t i s i nges ted i n conta mi na ted food. The
exotoxi n ca n ca us e ga s troenteri ti s wi thout ba cteri a l i nfecti on. Thes e toxi ns genera l l y ca us e a cute na us ea , vomi ti ng, a nd di a rrhea wi thi n 12 h of
i nges ti on of conta mi na ted food. Symptoms a ba te wi thi n 36 h.
Other ba cteri a (eg, Shigella, Salmonella, Campylobacter, s ome E. coli s ubtypes ) i nva de the mucos a of the s ma l l bowel or col on a nd ca us e mi cros copi c
ul cera ti on, bl eedi ng, exuda ti on of protei n-ri ch fl ui d, a nd s ecreti on of el ectrol ytes a nd wa ter. The i nva s i ve proces s a nd i ts res ul ts ca n occur
whether or not the orga ni s m produces a n enterotoxi n. The res ul ti ng di a rrhea conta i ns WBCs a nd RBCs a nd s ometi mes gros s bl ood.
Salmonella a nd Campylobacter a re the mos t common ba cteri a l ca us es of di a rrhea l i l l nes s i n the US. Both i nfecti ons a re mos t frequentl y a cqui red
through undercooked poul try; unpa s teuri zed mi l k i s a l s o a pos s i bl e s ource. Campylobacter i s occa s i ona l l y tra ns mi tted from dogs or ca ts wi th
di a rrhea . Salmonella ca n be tra ns mi tted by undercooked eggs a nd by conta ct wi th repti l es . Speci es of Shigella a re the 3rd mos t common ba cteri a l
ca us e of di a rrhea i n the US a nd a re us ua l l y tra ns mi tted pers on to pers on, a l though food-borne epi demi cs occur. Shigella dysenteriae type 1 (not
pres ent i n the US) produces Shi ga toxi n, whi ch ca n ca us e hemol yti c-uremi c s yndrome (s ee p. 961).
Severa l di fferent s ubtypes of E. coli ca us e di a rrhea . The epi demi ol ogy a nd cl i ni ca l ma ni fes ta ti ons va ry grea tl y dependi ng on the s ubtype: (1)
Enterohemorrha gi c E. coli i s the mos t cl i ni ca l l y s i gni fi ca nt s ubtype i n the US. It produces Shi ga toxi n, whi ch ca us es bl oody di a rrhea (hemorrha gi c
col i ti s ). E. coli O157:H7 i s the mos t common s tra i n of thi s s ubtype i n the US. Undercooked ground beef, unpa s teuri zed mi l k a nd jui ce, a nd
conta mi na ted wa ter a re pos s i bl e s ources . Pers on-to-pers on tra ns mi s s i on i s common i n the da y ca re s etti ng. Hemol yti c-uremi c s yndrome i s a
s eri ous compl i ca ti on tha t devel ops i n 2 to 7% of ca s es , mos t commonl y a mong the young a nd ol d. (2) Enterotoxi geni c E. coli produces two toxi ns
(one s i mi l a r to chol era toxi n) tha t ca us e wa tery di a rrhea . Thi s s ubtype i s the mos t common ca us e of tra vel er's di a rrhea . (3) Enteropa thogeni c E. coli
ca us es wa tery di a rrhea . Once a common ca us e of di a rrhea outbrea ks i n nurs eri es , thi s s ubtype i s now ra re. (4) Enteroi nva s i ve E. coli ca us es bl oody
or nonbl oody di a rrhea , pri ma ri l y i n the devel opi ng worl d. It i s ra re i n the US.
Severa l other ba cteri a ca us e ga s troenteri ti s , but mos t a re uncommon i n the US. Yersinia enterocolitica ca n ca us e ga s troenteri ti s or a s yndrome tha t
mi mi cs a ppendi ci ti s . It i s tra ns mi tted by undercooked pork, unpa s teuri zed mi l k, or conta mi na ted wa ter. Severa l Vibrio s peci es (eg, V.
parahaemolyticus) ca us e di a rrhea a fter i nges ti on of undercooked s ea food. V. cholerae s ometi mes ca us es s evere dehydra ti ng di a rrhea i n the
devel opi ng worl d. Listeria ca us es food-borne ga s troenteri ti s . Aeromonas i s a cqui red from s wi mmi ng i n or dri nki ng conta mi na ted fres h or bra cki s h
wa ter. Plesiomonas shigelloides ca n ca us e di a rrhea i n pa ti ents who ha ve ea ten ra w s hel l fi s h or tra vel ed to tropi ca l regi ons of the devel opi ng worl d.
Parasites: The pa ra s i tes mos t commonl y i mpl i ca ted a re
Giardia
Cryptosporidium
Certa i n i ntes ti na l pa ra s i tes , nota bl y Giardia intestinalis (lamblias ee p. 1371), a dhere to or i nva de the i ntes ti na l mucos a , ca us i ng na us ea , vomi ti ng,
di a rrhea , a nd genera l ma l a i s e. Gi a rdi a s i s occurs i n every regi on of the US a nd throughout the worl d. The i nfecti on ca n become chroni c a nd ca us e
a ma l a bs orpti on s yndrome. It i s us ua l l y a cqui red vi a pers on-to-pers on tra ns mi s s i on (often i n da y ca re centers ) or from conta mi na ted wa ter.
Cryptosporidium parvum ca us es wa tery di a rrhea s ometi mes a ccompa ni ed by a bdomi na l cra mps , na us ea , a nd vomi ti ng. In hea l thy peopl e, the
i l l nes s i s s el f-l i mi ted, l a s ti ng a bout 2 wk. In i mmunocompromi s ed pa ti ents , i l l nes s ma y be s evere, ca us i ng s ubs ta nti a l el ectrol yte a nd fl ui d l os s .
Cryptosporidium i s us ua l l y a cqui red through conta mi na ted wa ter.
Other pa ra s i tes tha t ca n ca us e s ymptoms s i mi l a r to thos e of cryptos pori di os i s i ncl ude Cyclospora cayetanensis a nd, i n i mmunocompromi s ed
pa ti ents , Cystoisospora (Isospora) belli, a nd a col l ecti on of orga ni s ms referred to a s mi cros pori di a (eg, Enterocytozoon bieneusi, Encephalitozoon
intestinalis). Entamoeba histolytica (a mebi a s i s ) i s a common ca us e of s uba cute bl oody di a rrhea i n the devel opi ng worl d a nd occa s i ona l l y occurs i n
the US.
Symptoms and Signs
The cha ra cter a nd s everi ty of s ymptoms va ry. Genera l l y, ons et i s s udden, wi th a norexi a , na us ea , vomi ti ng, borborygmi , a bdomi na l cra mps , a nd
di a rrhea (wi th or wi thout bl ood a nd mucus ). Ma l a i s e, mya l gi a s , a nd pros tra ti on ma y occur. The a bdomen ma y be di s tended a nd mi l dl y tender; i n
s evere ca s es , mus cl e gua rdi ng ma y be pres ent. Ga s -di s tended i ntes ti na l l oops ma y be pa l pa bl e. Borborygmi a re pres ent even wi thout di a rrhea
(a n i mporta nt di fferenti a l fea ture from pa ra l yti c i l eus ). Pers i s tent vomi ti ng a nd di a rrhea ca n res ul t i n i ntra va s cul a r fl ui d depl eti on wi th
hypotens i on a nd ta chyca rdi a . In s evere ca s es , s hock, wi th va s cul a r col l a ps e a nd ol i guri c rena l fa i l ure, occurs .
If vomi ti ng i s the ma i n ca us e of fl ui d l os s , meta bol i c a l ka l os i s wi th hypochl oremi a ca n occur. If di a rrhea i s more promi nent, a ci dos i s i s more
l i kel y. Both vomi ti ng a nd di a rrhea ca n ca us e hypoka l emi a . Hypona tremi a ma y devel op, pa rti cul a rl y i f hypotoni c fl ui ds a re us ed i n repl a cement
thera py.
In vi ra l i nfecti ons , wa tery di a rrhea i s the mos t common s ymptom; s tool s ra rel y conta i n mucus or bl ood. Rota vi rus ga s troenteri ti s i n i nfa nts a nd
young chi l dren ma y l a s t 5 to 7 da ys . Vomi ti ng occurs i n 90% of pa ti ents , a nd fever > 39 C (> 102.2 F) occurs i n a bout 30%. Norovi rus typi ca l l y ca us es
a cute ons et of vomi ti ng, a bdomi na l cra mps , a nd di a rrhea , wi th s ymptoms l a s ti ng onl y 1 to 2 da ys . In chi l dren, vomi ti ng i s more promi nent tha n
di a rrhea , wherea s i n a dul ts , di a rrhea us ua l l y predomi na tes . Pa ti ents ma y a l s o experi ence fever, hea da che, a nd mya l gi a s . The ha l l ma rk of
a denovi rus ga s troenteri ti s i s di a rrhea l a s ti ng 1 to 2 wk. Affected i nfa nts a nd chi l dren ma y ha ve mi l d vomi ti ng tha t typi ca l l y s ta rts 1 to 2 da ys a fter
the ons et of di a rrhea . Low-gra de fever occurs i n a bout 50% of pa ti ents . As trovi rus ca us es a s yndrome s i mi l a r to mi l d rota vi rus i nfecti on.
Ba cteri a tha t ca us e i nva s i ve di s ea s e (eg, Shigella, Salmonella) a re more l i kel y to res ul t i n fever, pros tra ti on, a nd bl oody di a rrhea . Ba cteri a tha t
produce a n enterotoxi n (eg, S. aureus, B. cereus, C. perfringens) us ua l l y ca us e wa tery di a rrhea .
Pa ra s i ti c i nfecti ons typi ca l l y ca us e s uba cute or chroni c di a rrhea . Mos t ca us e nonbl oody di a rrhea ; a n excepti on i s E. histolytica, whi ch ca us es
a mebi c dys entery. Fa ti gue a nd wei ght l os s a re common when di a rrhea i s pers i s tent.
Diagnosis
Stool tes ti ng i n s el ect ca s es
Other GI di s orders tha t ca us e s i mi l a r s ymptoms (eg, a ppendi ci ti s , chol ecys ti ti s , ul cera ti ve col i ti s ) mus t be excl uded. Fi ndi ngs s ugges ti ve of
ga s troenteri ti s i ncl ude copi ous , wa tery di a rrhea ; i nges ti on of potenti a l l y conta mi na ted food (pa rti cul a rl y duri ng a known outbrea k), untrea ted
s urfa ce wa ter, or a known GI i rri ta nt; recent tra vel ; or conta ct wi th s i mi l a rl y i l l peopl e. E. coli O157:H7-i nduced di a rrhea i s notori ous for a ppea ri ng
to be a hemorrha gi c ra ther tha n a n i nfecti ous proces s , ma ni fes ti ng a s GI bl eedi ng wi th l i ttl e or no s tool . Hemol yti curemi c s yndrome ma y fol l ow a s
evi denced by rena l fa i l ure a nd hemol yti c a nemi a (s ee p. 961). Recent ora l a nti bi oti c us e (wi thi n 3 mo) mus t ra i s e s us pi ci on for C. difficile i nfecti on
(s ee p. 1292).
Stool testing: If a recta l exa mi na ti on s hows occul t bl ood or i f wa tery di a rrhea pers i s ts > 48 h, s tool exa mi na ti on (feca l WBCs , ova , pa ra s i tes ) a nd
cul ture a re i ndi ca ted. However, for the di a gnos i s of gi a rdi a s i s or cryptos pori di os i s , s tool a nti gen detecti on us i ng a n enzyme i mmunoa s s a y ha s a
hi gher s ens i ti vi ty. Rota vi rus a nd enteri c a denovi rus i nfecti ons ca n be di a gnos ed us i ng commerci a l l y a va i l a bl e ra pi d a s s a ys tha t detect vi ra l
a nti gen i n the s tool , but thes e a re us ua l l y done onl y to document a n outbrea k.
Al l pa ti ents wi th gros s l y bl oody di a rrhea s houl d be tes ted for E. coli O157:H7, a s s houl d pa ti ents wi th nonbl oody di a rrhea duri ng a known
outbrea k. Speci fi c cul tures mus t be reques ted beca us e thi s orga ni s m i s not detected on s ta nda rd s tool cul ture medi a . Al terna ti vel y, a ra pi d
enzyme a s s a y for the detecti on of Shi ga toxi n i n s tool ca n be done; a pos i ti ve tes t i ndi ca tes i nfecti on wi th E. coli O157:H7 or one of the other
s erotypes of enterohemorrha gi c E. coli. (NOTE: Shigella s peci es i n the US do not produce Shi ga toxi n.)
Adul ts wi th gros s l y bl oody di a rrhea s houl d us ua l l y ha ve s i gmoi dos copy wi th cul tures a nd bi ops y. Appea ra nce of the col oni c mucos a ma y hel p
di a gnos e a mebi c dys entery, s hi gel l os i s , a nd E. coli O157:H7 i nfecti on, a l though ul cera ti ve col i ti s ma y ca us e s i mi l a r l es i ons . Pa ti ents wi th recent
a nti bi oti c us e s houl d ha ve a s tool a s s a y for C. difficile toxi n.
General tests: Serum el ectrol ytes , BUN, a nd crea ti ni ne s houl d be obta i ned to eva l ua te hydra ti on a nd a ci d-ba s e s ta tus i n pa ti ents who a ppea r
s eri ous l y i l l . CBC i s nons peci fi c, a l though eos i nophi l i a ma y i ndi ca te pa ra s i ti c i nfecti on.
Treatment
Ora l or IV rehydra ti on
Cons i dera ti on of a nti di a rrhea l a gents i f there i s no s us pi ci on of C. difficile or E. coli O157:H7 i nfecti on
Anti bi oti cs onl y i n s el ect ca s es
Supporti ve trea tment i s a l l tha t i s needed for mos t pa ti ents . Bed res t wi th conveni ent a cces s to a toi l et or bedpa n i s des i ra bl e. Ora l gl ucos eel ectrol yte s ol uti ons , broth, or boui l l on ma y prevent dehydra ti on or trea t mi l d dehydra ti on. Even i f vomi ti ng, the pa ti ent s houl d ta ke frequent
s ma l l s i ps of s uch fl ui ds : vomi ti ng ma y a ba te wi th vol ume repl a cement. For pa ti ents wi th E. coli O157:H7 i nfecti on, rehydra ti on wi th i s otoni c IV
fl ui ds ma y a ttenua te the s everi ty of a ny rena l i njury s houl d hemol yti c-uremi c s yndrome devel op. Chi l dren ma y become dehydra ted more qui ckl y
a nd s houl d be gi ven a n a ppropri a te rehydra ti on s ol uti on (s evera l a re a va i l a bl e commerci a l l ys ee a l s o p.
2809). Ca rbona ted bevera ges a nd s ports dri nks l a ck the correct ra ti o of gl ucos e to Na a nd thus a re not a ppropri a te for chi l dren < 5 yr. If the chi l d i s
brea s tfed, brea s tfeedi ng s houl d conti nue. If vomi ti ng i s protra cted or i f s evere dehydra ti on i s promi nent, IV repl a cement of vol ume a nd
el ectrol ytes i s neces s a ry (s ee p. 2297).
When the pa ti ent ca n tol era te fl ui ds wi thout vomi ti ng a nd the a ppeti te ha s begun to return, food ma y be gra dua l l y res ta rted. There i s no
demons tra ted benefi t from res tri cti on to bl a nd food (eg, cerea l , gel a ti n, ba na na s , toa s t). Some pa ti ents ha ve tempora ry l a ctos e i ntol era nce.
Anti di a rrhea l a gents a re s a fe for pa ti ents > 5 yr wi th wa tery di a rrhea (a s s hown by heme-nega ti ve s tool ). However, a nti di a rrhea l s ma y ca us e
deteri ora ti on of pa ti ents wi th C. difficile or E. coli O157:H7 i nfecti on a nd thus s houl d not be gi ven to a ny pa ti ent wi th recent a nti bi oti c us e or hemepos i ti ve s tool , pendi ng s peci fi c di a gnos i s . Effecti ve a nti di a rrhea l s i ncl ude l opera mi de 4 mg po i ni ti a l l y, fol l owed by 2 mg po for ea ch s ubs equent
epi s ode of di a rrhea (ma xi mum of 6 dos es /da y or 16 mg/da y), or di phenoxyl a te 2.5 to 5 mg ti d or qi d i n ta bl et or l i qui d form.
If vomi ti ng i s s evere a nd a s urgi ca l condi ti on ha s been excl uded, a n a nti emeti c ma y be benefi ci a l . Agents us eful i n a dul ts i ncl ude
prochl orpera zi ne 5 to 10 mg IV ti d or qi d, or 25 mg per rectum bi d; a nd prometha zi ne 12.5 to 25 mg IM ti d or qi d, or 25 to 50 mg per rectum qi d. Thes e
drugs a re us ua l l y a voi ded i n chi l dren beca us e of l a ck of demons tra ted effi ca cy a nd the hi gh i nci dence of dys toni c rea cti ons .
Antimicrobials: Empi ri c a nti bi oti cs a re genera l l y not recommended except for certa i n ca s es of tra vel er's di a rrhea or when s us pi ci on of Shigella or
Campylobacter i nfecti on i s hi gh (eg, conta ct wi th a known ca s e). Otherwi s e, a nti bi oti cs s houl d not be gi ven unti l s tool cul ture res ul ts a re known,
pa rti cul a rl y i n chi l dren, who ha ve a hi gher ra te of i nfecti on wi th E. coli O157:H7 (a nti bi oti cs i ncrea s e the ri s k of hemol yti c-uremi c s yndrome i n
pa ti ents i nfected wi th E. coli O157:H7).
In proven ba cteri a l ga s troenteri ti s , a nti bi oti cs a re not a l wa ys requi red. They do not hel p wi th Salmonella a nd prol ong the dura ti on of s heddi ng i n
the s tool . Excepti ons i ncl ude i mmunocompromi s ed pa ti ents , neona tes , a nd pa ti ents wi th Salmonella ba cteremi a . Anti bi oti cs a re a l s o i neffecti ve
a ga i ns t toxi c ga s troenteri ti s (eg, S. aureus, B. cereus, C. perfringens). Indi s cri mi na te us e of a nti bi oti cs fos ters the emergence of drug-res i s ta nt
orga ni s ms . However, certa i n i nfecti ons do requi re a nti bi oti cs (s ee
Ta bl e 16-1).
The us e of probi oti cs , s uch a s l a ctoba ci l l us , i s genera l l y s a fe a nd ma y ha ve s ome benefi t i n rel i evi ng s ymptoms . They ca n be gi ven i n the form of
yogurt wi th a cti ve cul tures .
[Table 16-1. Sel ected Ora l Anti bi oti cs for Infecti ous Ga s troenteri ti s *]
For cryptos pori di os i s , ni ta zoxa ni de ma y be hel pful i n i mmunocompetent pa ti ents . The dos e i s 100 mg po bi d for chi l dren 1 to 3 yr, 200 mg po bi d
for chi l dren 4 to 11 yr, a nd 500 mg po bi d for chi l dren 12 yr a nd a dul ts .
Prevention
A new ora l penta va l ent rota vi rus va cci ne i s a va i l a bl e tha t i s s a fe a nd effecti ve a ga i ns t the ma jori ty of s tra i ns res pons i bl e for di s ea s e. Thi s
va cci ne i s now pa rt of the recommended i nfa nt va cci na ti on s chedul e a nd i s gi ven a t 2, 4, a nd 6 mo of a ge (s ee p.
2718).
Preventi on of i nfecti on i s compl i ca ted by the frequency of a s ymptoma ti c i nfecti on a nd the ea s e wi th whi ch ma ny a gents , pa rti cul a rl y vi rus es , a re
tra ns mi tted from pers on to pers on. In genera l , proper procedures for ha ndl i ng a nd prepa ri ng food mus t be fol l owed. Tra vel ers mus t a voi d
potenti a l l y conta mi na ted food a nd dri nk.

Brea s tfeedi ng a ffords s ome protecti on to neona tes a nd i nfa nts . Ca regi vers s houl d wa s h thei r ha nds thoroughl y wi th s oa p a nd wa ter a fter
cha ngi ng di a pers , a nd di a per-cha ngi ng a rea s s houl d be di s i nfected wi th a fres hl y prepa red s ol uti on of 1:64 hous ehol d bl ea ch (one fourth cup
di l uted i n 1 ga l l on of wa ter). Chi l dren wi th di a rrhea s houl d be excl uded from chi l d ca re fa ci l i ti es for the dura ti on of s ymptoms . Chi l dren i nfected
wi th enterohemorrha gi c E. coli or Shigella s houl d a l s o ha ve two nega ti ve s tool cul tures before rea dmi s s i on to the fa ci l i ty.
Traveler's Diarrhea
(Turi s ta )
Traveler's diarrhea is gastroenteritis that is usually caused by bacteria endemic to local water. Symptoms include vomiting and diarrhea. Diagnosis is mainly
clinical. Treatment is with ciprofloxacin or azithromycin, loperamide, and replacement fluids.
Etiology
Tra vel er's di a rrhea ma y be ca us ed by a ny of s evera l ba cteri a , vi rus es , or, l es s commonl y, pa ra s i tes . However, enterotoxi geni c Escherichia coli i s
mos t common. E. coli i s common i n the wa ter s uppl i es of a rea s tha t l a ck a dequa te puri fi ca ti on. Infecti on i s common a mong peopl e tra vel i ng to
devel opi ng countri es . Norovi rus i nfecti on ha s been a pa rti cul a r probl em on s ome crui s e s hi ps .
Both food a nd wa ter ca n be the s ource of i nfecti on. Tra vel ers who a voi d dri nki ng l oca l wa ter ma y s ti l l become i nfected by brus hi ng thei r teeth
wi th a n i mproperl y ri ns ed toothbrus h, dri nki ng bottl ed dri nks wi th i ce ma de from l oca l wa ter, or ea ti ng food tha t i s i mproperl y ha ndl ed or wa s hed
wi th l oca l wa ter. Peopl e ta ki ng drugs tha t decrea s e s toma ch a ci d (a nta ci ds , H 2 bl ockers , a nd proton pump i nhi bi tors ) a re a t ri s k of more s evere
i l l nes s .
Symptoms and Signs
Na us ea , vomi ti ng, borborygmi , a bdomi na l cra mps , a nd di a rrhea begi n 12 to 72 h a fter i nges ti ng conta mi na ted food or wa ter. Severi ty i s va ri a bl e.
Some peopl e devel op fever a nd mya l gi a s . Mos t ca s es a re mi l d a nd s el f-l i mi ted, a l though dehydra ti on ca n occur, es peci a l l y i n wa rm cl i ma tes .
Diagnosis
Speci fi c di a gnos ti c mea s ures a re us ua l l y not neces s a ry. However, fever, s evere a bdomi na l pa i n, a nd bl oody di a rrhea s ugges t more s eri ous
di s ea s e a nd s houl d prompt i mmedi a te eva l ua ti on.
Treatment
Fl ui d repl a cement
Someti mes a nti moti l i ty drugs
Ra rel y a nti bi oti cs (eg, ci profl oxa ci n, a zi thromyci n)
The ma i ns ta y of trea tment i s fl ui d repl a cement a nd a n a nti moti l i ty drug s uch a s l opera mi de 4 mg po i ni ti a l l y, fol l owed by 2 mg po for ea ch
s ubs equent epi s ode of di a rrhea (ma xi mum of 6 dos es /da y or 16 mg/da y), or di phenoxyl a te 2.5 to 5 mg po ti d or qi d i n ta bl et or l i qui d form.
Anti moti l i ty drugs a re contra i ndi ca ted i n pa ti ents wi th fever or bl oody s tool s a nd i n chi l dren < 2 yr. Iodochl orhydroxyqui n, whi ch ma y be a va i l a bl e
i n s ome devel opi ng countri es , s houl d not be us ed beca us e i t ma y ca us e neurol ogi c da ma ge.
Genera l l y, a nti bi oti cs a re not neces s a ry for mi l d di a rrhea . In pa ti ents wi th modera te to s evere di a rrhea ( 3 l oos e s tool s over 8 h), a nti bi oti cs a re
gi ven, es peci a l l y i f vomi ti ng, a bdomi na l cra mps , fever, or bl oody s tool s a re pres ent. For a dul ts , ci profl oxa ci n 500 mg po bi d for 3 da ys or
l evofl oxa ci n 500 mg po once/da y for 3 da ys i s recommended. Azi thromyci n 250 mg po once/da y for 3 da ys or ri fa xi mi n 200 mg po ti d for 3 da ys ma y
a l s o be us ed. For chi l dren, a zi thromyci n 5 to 10 mg/kg po once/da y for 3 da ys i s preferred.
Prevention
Tra vel ers s houl d di ne a t res ta ura nts wi th a reputa ti on for s a fety a nd a voi d foods a nd bevera ges from s treet vendors . They s houl d cons ume onl y
cooked foods tha t a re s ti l l s tea mi ng hot, frui t tha t ca n be peel ed, a nd ca rbona ted bevera ges wi thout i ce s erved i n s ea l ed bottl es (bottl es of
nonca rbona ted bevera ges ca n conta i n ta p wa ter a dded by uns crupul ous vendors ); uncooked vegeta bl es s houl d be a voi ded. Buffets a nd fa s t food
res ta ura nts pos e a n i ncrea s ed ri s k.
Prophyl a cti c a nti bi oti cs a re effecti ve i n preventi ng di a rrhea , but beca us e of concerns a bout a dvers e effects a nd devel opment of res i s ta nce, they
s houl d proba bl y be res erved for i mmunocompromi s ed pa ti ents .
Drug- and Chemical-Related Gastroenteritis
Ma ny drugs ca us e na us ea , vomi ti ng, a nd di a rrhea a s a dvers e effects . A deta i l ed drug hi s tory mus t be obta i ned. In mi l d ca s es , ces s a ti on fol l owed
by reus e of the drug ma y es ta bl i s h a ca us a l rel a ti ons hi p. Commonl y res pons i bl e drugs i ncl ude a nta ci ds conta i ni ng Mg, a nti bi oti cs ,
a nti hel mi nthi cs , cytotoxi cs (us ed i n ca ncer thera py), col chi ci ne, di goxi n, hea vy meta l s , l a xa ti ves , a nd ra di a ti on thera py. Us e of a nti bi oti cs ma y l ea d
to Clostridium difficile-i nduced di a rrhea (s ee p. 1292).
Ia trogeni c, a cci denta l , or i ntenti ona l hea vy-meta l poi s oni ng frequentl y ca us es na us ea , vomi ti ng, a bdomi na l pa i n, a nd di a rrhea .
La xa ti ve a bus e, s ometi mes deni ed by pa ti ents , ma y l ea d to wea knes s , vomi ti ng, di a rrhea , el ectrol yte depl eti on, a nd meta bol i c di s turba nces .
Va ri ous pl a nts a nd mus hrooms ca us e a s yndrome of ga s troenteri ti s (s ee p. 3336).
Chapter 17. Malabsorption Syndromes

Introduction
Ma l a bs orpti on i s i na dequa te a s s i mi l a ti on of di eta ry s ubs ta nces due to defects i n di ges ti on, a bs orpti on, or tra ns port. Ma l a bs orpti on ca n a ffect
ma cronutri ents (eg, protei ns , ca rbohydra tes , fa ts ), mi cronutri ents (eg, vi ta mi ns , mi nera l s ), or both, ca us i ng exces s i ve feca l excreti on, nutri ti ona l
defi ci enci es , a nd GI s ymptoms .
Pathophysiology
Di ges ti on a nd a bs orpti on occur i n three pha s es : (1) i ntra l umi na l hydrol ys i s of fa ts , protei ns , a nd ca rbohydra tes by enzymes bi l e s a l ts enha nce
the s ol ubi l i za ti on of fa t i n thi s pha s e; (2) di ges ti on by brus h border enzymes a nd upta ke of end-products ; a nd (3) l ympha ti c tra ns port of nutri ents .
Ma l a bs orpti on occurs when a ny of thes e pha s es i s i mpa i red.
Fats: Pa ncrea ti c enzymes s pl i t l ong-cha i n tri gl yceri des i nto fa tty a ci ds a nd monogl yceri des , whi ch combi ne wi th bi l e a ci ds a nd phos phol i pi ds to
form mi cel l es tha t pa s s through jejuna l enterocytes . Abs orbed fa tty a ci ds a re res ynthes i zed a nd combi ned wi th protei n, chol es terol , a nd
phos phol i pi d to form chyl omi crons , whi ch a re tra ns ported by the l ympha ti c s ys tem. Medi um-cha i n tri gl yceri des a re a bs orbed di rectl y.
Una bs orbed fa ts tra p fa t-s ol ubl e vi ta mi ns (A, D, E, K) a nd pos s i bl y s ome mi nera l s , ca us i ng defi ci ency. Ba cteri a l overgrowth res ul ts i n
deconjuga ti on a nd dehydroxyl a ti on of bi l e s a l ts , l i mi ti ng the a bs orpti on of fa ts . Una bs orbed bi l e s a l ts s ti mul a te the col on, ca us i ng di a rrhea .
Carbohydrates: Enzymes on mi crovi l l i l ys e ca rbohydra tes a nd di s a ccha ri des i nto cons ti tuent monos a ccha ri des . Col oni c ba cteri a ferment una bs orbed
ca rbohydra tes i nto CO2 , metha ne, H 2 , a nd s hort-cha i n fa tty a ci ds (butyra te, propi ona te, a ceta te, a nd l a cta te). Thes e fa tty a ci ds ca us e di a rrhea . The
ga s es ca us e a bdomi na l di s tenti on a nd bl oa ti ng.
Proteins: Enteroki na s e, a brus h border enzyme, a cti va tes tryps i nogen i nto tryps i n, whi ch converts ma ny pa ncrea ti c protea s es i nto thei r a cti ve forms .
Acti ve pa ncrea ti c enzymes hydrol yze protei ns i nto ol i gopepti des , whi ch a re a bs orbed di rectl y or hydrol yzed i nto a mi no a ci ds .
Etiology
Ma l a bs orpti on ha s ma ny ca us es (s ee
Ta bl e 17-1). Some ma l a bs orpti ve di s orders (eg, cel i a c s prue) i mpa i r the a bs orpti on of mos t nutri ents , vi ta mi ns , a nd tra ce mi nera l s (gl oba l
ma l a bs orpti on); others (eg, perni ci ous a nemi a ) a re more s el ecti ve.
[Table 17-1. Ca us es of Ma l a bs orpti on]
Pa ncrea ti c i ns uffi ci ency ca us es ma l a bs orpti on i f > 90% of functi on i s l os t. Increa s ed l umi na l a ci di ty (eg, Zol l i nger-El l i s on s yndrome) i nhi bi ts
l i pa s e a nd fa t di ges ti on. Ci rrhos i s a nd chol es ta s i s reduce hepa ti c bi l e s ynthes i s or del i very of bi l e s a l ts to the duodenum, ca us i ng
ma l a bs orpti on. Other ca us es a re di s cus s ed el s ewhere i n thi s cha pter.
Symptoms and Signs
The effects of una bs orbed s ubs ta nces i ncl ude di a rrhea , s tea torrhea , a bdomi na l bl oa ti ng, a nd ga s . Other s ymptoms res ul t from nutri ti ona l
defi ci enci es . Pa ti ents often l os e wei ght des pi te a dequa te food i nta ke.
Chroni c di a rrhea i s the mos t common s ymptom a nd i s wha t us ua l l y prompts eva l ua ti on of the pa ti ent. Stea torrhea fa tty s tool , the ha l l ma rk of
ma l a bs orpti onoccurs when > 7 g/da y of fa t a re excreted. Stea torrhea ca us es foul -s mel l i ng, pa l e, bul ky, a nd grea s y s tool s .
Severe vi ta mi n a nd mi nera l defi ci enci es occur i n a dva nced ma l a bs orpti on; s ymptoms a re rel a ted to the s peci fi c nutri ent defi ci ency (s ee
Ta bl e 17-2). Vi ta mi n B 12 defi ci ency ma y occur i n bl i nd l oop s yndrome or a fter extens i ve res ecti on of the di s ta l i l eum or s toma ch.
Amenorrhea ma y res ul t from undernutri ti on a nd i s a n i mporta nt ma ni fes ta ti on of cel i a c s prue i n young women.
Diagnosis
Di a gnos i s typi ca l l y cl i ni ca l l y a ppa rent
Bl ood tes ts to s creen for cons equences of ma l a bs orpti on
Stool fa t tes ti ng to confi rm ma l a bs orpti on (i f uncl ea r)
Ca us e di a gnos ed wi th endos copy, contra s t x-ra ys , or other tes ts ba s ed on fi ndi ngs
Ma l a bs orpti on i s s us pected i n a pa ti ent wi th chroni c di a rrhea , wei ght l os s , a nd a nemi a . The eti ol ogy i s s ometi mes obvi ous . For exa mpl e, thos e
wi th ma l a bs orpti on due to chroni c pa ncrea ti ti s us ua l l y ha ve ha d pri or bouts of a cute pa ncrea ti ti s . Pa ti ents wi th cel i a c s prue ca n pres ent wi th
cl a s s i c l i fel ong di a rrhea exa cerba ted by gl uten products a nd ma y ha ve derma ti ti s herpeti formi s . Thos e wi th ci rrhos i s a nd pa ncrea ti c ca ncer ca n
pres ent wi th ja undi ce. Abdomi na l di s tenti on, exces s i ve fl a tus , a nd wa tery di a rrhea occurri ng 30 to 90 mi n a fter ca rbohydra te i nges ti on s ugges t
defi ci ency of a di s a ccha ri da s e enzyme, us ua l l y l a cta s e. Previ ous extens i ve a bdomi na l opera ti ons s ugges t s hort bowel s yndrome.
If the hi s tory s ugges ts a s peci fi c ca us e, tes ti ng s houl d be di rected to tha t condi ti on (s ee
Fi g. 17-1). If no ca us e i s rea di l y a ppa rent, bl ood tes ts ca n be us ed a s s creeni ng tool s (eg, CBC, RBC i ndi ces , ferri ti n, vi ta mi n B 12 , fol a te, Ca , a l bumi n,
chol es terol , PT). Thes e res ul ts ma y s ugges t a di a gnos i s a nd di rect further i nves ti ga ti on.
[Table 17-2. Symptoms of Ma l a bs orpti on]
Ma crocyti c a nemi a s houl d prompt mea s urement of s erum fol a te a nd B 12 l evel s . Fol a te defi ci ency i s common i n mucos a l di s orders i nvol vi ng the
proxi ma l s ma l l bowel (eg, cel i a c s prue, tropi ca l s prue, Whi ppl e's di s ea s e). Low B 12 l evel s ca n occur i n perni ci ous a nemi a , chroni c pa ncrea ti ti s ,
ba cteri a l overgrowth, a nd termi na l i l ea l di s ea s e. A combi na ti on of l ow B 12 a nd hi gh fol a te l evel s i s s ugges ti ve of ba cteri a l overgrowth, beca us e
i ntes ti na l ba cteri a us e vi ta mi n B 12 a nd s ynthes i ze fol a te.
Mi crocyti c a nemi a s ugges ts i ron defi ci ency, whi ch ma y occur wi th cel i a c s prue. Al bumi n i s a genera l i ndi ca tor of nutri ti ona l s ta te. Low a l bumi n ca n
res ul t from poor i nta ke, decrea s ed s ynthes i s i n ci rrhos i s , or protei n wa s ti ng. Low s erum ca rotene (a precurs or of vi ta mi n A) s ugges ts
ma l a bs orpti on i f i nta ke i s a dequa te.
Confirming malabsorption: Tes ts to confi rm ma l a bs orpti on a re a ppropri a te when s ymptoms a re va gue a nd the eti ol ogy i s not a ppa rent. Mos t tes ts
for ma l a bs orpti on a s s es s fa t ma l a bs orpti on beca us e i t i s rel a ti vel y ea s y to mea s ure. Confi rma ti on of ca rbohydra te ma l a bs orpti on i s not hel pful
once s tea torrhea i s documented. Tes ts for protei n ma l a bs orpti on a re ra rel y us ed beca us e feca l ni trogen i s di ffi cul t to mea s ure.
[Fig. 17-1. Sugges ted eva l ua ti on for ma l a bs orpti on.]
[
Table 17-3. Sma l l -Bowel Mucos a l Hi s tol ogy i n Certa i n Ma l a bs orpti ve Di s orders ]
Di rect mea s urement of feca l fa t from a 72-h s tool col l ecti on i s the gol d s ta nda rd for es ta bl i s hi ng s tea torrhea but unneces s a ry wi th gros s
s tea torrhea of obvi ous ca us e. However, thi s tes t i s a va i l a bl e routi nel y i n onl y a few centers . Stool i s col l ected for a 3-da y peri od duri ng whi ch the
pa ti ent cons umes 100 g fa t/da y. Tota l fa t i n the s tool i s mea s ured. Feca l fa t > 7 g/da y i s a bnorma l . Al though s evere fa t ma l a bs orpti on (feca l fa t
40 g/da y) s ugges ts pa ncrea ti c i ns uffi ci ency or s ma l l -bowel mucos a l di s ea s e, thi s tes t ca nnot determi ne the s peci fi c ca us e of ma l a bs orpti on.
Beca us e the tes t i s mes s y, unpl ea s a nt, a nd ti me cons umi ng, i t i s una ccepta bl e to mos t pa ti ents a nd di ffi cul t to do.
Suda n III s ta i ni ng of a s tool s mea r i s a s i mpl e a nd di rect, but nonqua nti ta ti ve, s creeni ng tes t for feca l fa t. Aci d s tea tocri t i s a gra vi metri c a s s a y
done on a s i ngl e s tool s a mpl e; i t ha s a reported hi gh s ens i ti vi ty a nd s peci fi ci ty (us i ng 72-h col l ecti on a s the s ta nda rd). Nea r-i nfra red refl ecta nce
a na l ys i s (NIRA) s i mul ta neous l y tes ts s tool for fa t, ni trogen, a nd ca rbohydra tes a nd ma y become the preferred tes t i n the future.
Mea s urement of el a s ta s e a nd chymotryps i n i n the s tool ca n a l s o hel p di fferenti a te pa ncrea ti c a nd i ntes ti na l ca us es of ma l a bs orpti on; both a re
decrea s ed i n pa ncrea ti c exocri ne i ns uffi ci ency.
The D-xyl os e a bs orpti on tes t, i f a va i l a bl e, ca n be done i f the eti ol ogy i s not obvi ous . It i s the bes t noni nva s i ve tes t to a s s es s i ntes ti na l mucos a l
i ntegri ty a nd di fferenti a te mucos a l from pa ncrea ti c di s ea s e. Thi s tes t ha s a reported s peci fi ci ty of 98% a nd s ens i ti vi ty of 91% for s ma l l -bowel
ma l a bs orpti on.
D-Xyl os e i s a bs orbed by pa s s i ve di ffus i on a nd does not requi re pa ncrea ti c enzymes for di ges ti on. A norma l D-xyl os e tes t i n the pres ence of
modera te to s evere s tea torrhea i ndi ca tes pa ncrea ti c exocri ne i ns uffi ci ency ra ther tha n s ma l l -bowel mucos a l di s ea s e. Ba cteri a l overgrowth
s yndrome ca n ca us e a bnorma l res ul ts beca us e the enteri c ba cteri a meta bol i ze pentos e, thus decrea s i ng the D-xyl os e a va i l a bl e for a bs orpti on.
After fa s ti ng, the pa ti ent i s gi ven 25 g of D-xyl os e i n 200 to 300 mL of wa ter po. Uri ne i s col l ected over 5 h, a nd a venous s a mpl e i s obta i ned a fter 1
h. Serum D-xyl os e < 20 mg/dL or < 4 g i n the uri ne s a mpl e i ndi ca tes a bnorma l a bs orpti on. Fa l s el y l ow l evel s ca n a l s o occur i n rena l di s ea s es ,
porta l hypertens i on, a s ci tes , or del a yed ga s tri c emptyi ng ti me. Thi s tes t i s ra rel y us ed toda y. In a ddi ti on, a n a bnorma l D-xyl os e tes t wi l l requi re a n
endos copi c exa mi na ti on wi th bi ops i es of the s ma l l -bowel mucos a . As a res ul t, s ma l l -bowel bi ops y ha s repl a ced thi s tes t to es ta bl i s h i ntes ti na l
mucos a l di s ea s e.
Diagnosing the cause of malabsorption: More s peci fi c di a gnos ti c tes ts (eg, upper endos copy, col onos copy, ba ri um x-ra ys ) a re i ndi ca ted to di a gnos e
s evera l ca us es of ma l a bs orpti on.
Endos copy wi th s ma l l -bowel bi ops y i s done when mucos a l di s ea s e of the s ma l l bowel i s s us pected or i f the D-xyl os e tes t i s a bnorma l i n a
pa ti ent wi th ma s s i ve s tea torrhea . As pi ra te from the s ma l l bowel ca n be s ent for ba cteri a l cul ture a nd col ony count to document ba cteri a l
overgrowth. Hi s tol ogi c fea tures on s ma l l -bowel bi ops y (s ee Ta bl e 17-3) ca n es ta bl i s h the s peci fi c mucos a l di s ea s e.
Sma l l -bowel x-ra ys (eg, s ma l l -bowel fol l ow-through, enterocl ys i s ) ca n detect a na tomi c condi ti ons tha t predi s pos e to ba cteri a l overgrowth. Thes e
i ncl ude jejuna l di verti cul a , fi s tul a s , s urgi ca l l y crea ted bl i nd l oops a nd a na s tomos es , ul cera ti ons , a nd s tri ctures . Abdomi na l fl a t pl a te x-ra y ma y
s how pa ncrea ti c ca l ci fi ca ti ons i ndi ca ti ve of chroni c pa ncrea ti ti s . Ba ri um contra s t s tudi es of the s ma l l bowel a re nei ther s ens i ti ve nor s peci fi c but
ma y ha ve fi ndi ngs s ugges ti ve of mucos a l di s ea s e (eg, di l a ted s ma l l -bowel l oops , thi nned or thi ckened mucos a l fol ds , coa rs e fra gmenta ti on of the
ba ri um col umn).
Tes ts for pa ncrea ti c i ns uffi ci ency (eg, s ecreti n s ti mul a ti on tes t, benti romi de tes t, pa ncreol a uryl tes t, s erum tryps i nogen, feca l el a s ta s e, feca l
chymotryps i ns ee p. 145) a re done i f hi s tory i s s ugges ti ve but a re not s ens i ti ve for mi l d pa ncrea ti c di s ea s e.
The
14
C-xyl os e brea th tes t hel ps di a gnos e ba cteri a l overgrowth. 14 C-xyl os e i s gi ven ora l l y, a nd the exha l ed
Ca ta bol i s m of i nges ted xyl os e by the overgrowth fl ora ca us es
14
14
CO2 concentra ti on i s mea s ured.
CO2 to a ppea r i n exha l ed brea th.
The H 2 brea th tes t mea s ures the exha l ed H 2 produced by the ba cteri a l degra da ti on of ca rbohydra tes . In pa ti ents wi th di s a ccha ri da s e defi ci enci es ,
enteri c ba cteri a degra de nona bs orbed ca rbohydra tes i n the col on, i ncrea s i ng exha l ed H 2 . The l a ctos e-H 2 brea th tes t i s us eful onl y to confi rm
l a cta s e defi ci ency (s ee p. 158) a nd i s not us ed a s a n i ni ti a l di a gnos ti c tes t i n the work-up of ma l a bs orpti on.
The Schi l l i ng tes t a s s es s es ma l a bs orpti on of vi ta mi n B 12 . Its 4 s ta ges determi ne whether the defi ci ency res ul ts from perni ci ous a nemi a ,
pa ncrea ti c exocri ne i ns uffi ci ency, ba cteri a l overgrowth, or i l ea l di s ea s e.
Sta ge 1: The pa ti ent i s gi ven 1 g of ra di ol a bel ed cya nocoba l a mi n po concurrent wi th 1000 g of nonl a bel ed coba l a mi n IM to s a tura te hepa ti c
bi ndi ng s i tes . A 24-h uri ne col l ecti on i s a na l yzed for ra di oa cti vi ty; uri na ry excreti on of < 8% of the ora l dos e i ndi ca tes ma l a bs orpti on of
coba l a mi n.
Sta ge 2: If s ta ge 1 i s a bnorma l , the tes t i s repea ted wi th the a ddi ti on of i ntri ns i c fa ctor. Perni ci ous a nemi a i s pres ent i f thi s norma l i zes
a bs orpti on.
Sta ge 3: Sta ge 3 i s done a fter a ddi ng pa ncrea ti c enzymes ; norma l i za ti on i n thi s s ta ge i ndi ca tes coba l a mi n ma l a bs orpti on s econda ry to
pa ncrea ti c i ns uffi ci ency.
Sta ge 4: Sta ge 4 i s done a fter a nti mi crobi a l thera py wi th a na erobi c covera ge; norma l i za ti on a fter a nti bi oti cs s ugges ts ba cteri a l overgrowth.
Coba l a mi n defi ci ency s econda ry to i l ea l di s ea s e or i l ea l res ecti on res ul ts i n a bnorma l i ti es i n a l l s ta ges .
Tes ts for l es s common ca us es of ma l a bs orpti on i ncl ude s erum ga s tri n (Zol l i nger-El l i s on s yndrome), i ntri ns i c fa ctor a nd pa ri eta l cel l a nti bodi es
(perni ci ous a nemi a ), s wea t chl ori de (cys ti c fi bros i s ), l i poprotei n el ectrophores i s (a beta l i poprotei nemi a ), a nd s erum corti s ol (Addi s on's di s ea s e).
Bacterial Overgrowth Syndrome
Small-bowel bacterial overgrowth can occur from alterations in intestinal anatomy or GI motility, or lack of gastric acid secretion. This condition can lead to
vitamin deficiencies, fat malabsorption, and undernutrition. Diagnosis is by breath test or quantitative culture of intestinal fluid aspirate. Treatment is with oral
antibiotics.
Under norma l condi ti ons , the proxi ma l s ma l l bowel conta i ns < 105 ba cteri a /mL, ma i nl y gra m-pos i ti ve a erobi c ba cteri a . Thi s l ow ba cteri a l count i s
ma i nta i ned by norma l peri s ta l s i s , norma l ga s tri c a ci d s ecreti on, mucus , s ecretory IgA, a nd a n i nta ct i l eoceca l va l ve.
Etiology
Us ua l l y, ba cteri a l overgrowth occurs when a na tomi c a l tera ti ons promote s ta s i s of i ntes ti na l contents . Thes e condi ti ons i ncl ude s ma l l -bowel
di verti cul os i s , s urgi ca l bl i nd l oops , pos tga s trectomy s ta tes (es peci a l l y i n the a fferent l oop of a Bi l l roth II), s tri ctures , or pa rti a l obs tructi on.
Intes ti na l moti l i ty di s orders a s s oci a ted wi th di a beti c neuropa thy, s ys temi c s cl eros i s , a myl oi dos i s , a nd i di opa thi c i ntes ti na l ps eudo-obs tructi on
ca n a l s o i mpa i r ba cteri a l cl ea ra nce. Achl orhydri a a nd i di opa thi c cha nges i n i ntes ti na l moti l i ty ma y ca us e ba cteri a l overgrowth i n el derl y peopl e.
Pathophysiology
The exces s ba cteri a cons ume nutri ents , i ncl udi ng vi ta mi n B 12 a nd ca rbohydra tes , l ea di ng to ca l ori c depri va ti on a nd vi ta mi n B 12 defi ci ency.
However, beca us e the ba cteri a produce fol a te, thi s defi ci ency i s ra re. The ba cteri a deconjuga te bi l e s a l ts , ca us i ng fa i l ure of mi cel l e forma ti on a nd
s ubs equent fa t ma l a bs orpti on. Severe ba cteri a l overgrowth a l s o da ma ges the i ntes ti na l mucos a . Fa t ma l a bs orpti on a nd mucos a l da ma ge ca n
ca us e di a rrhea .
Symptoms and Signs
Ma ny pa ti ents a re a s ymptoma ti c a nd pres ent wi th onl y wei ght l os s or nutri ent defi ci enci es . Some ha ve s i gni fi ca nt di a rrhea or s tea torrhea .
Diagnosis
14 C-xyl os e brea th tes t or qua nti ta ti ve cul ture of i ntes ti na l a s pi ra te
Upper GI s eri es wi th s ma l l -bowel fol l ow-through
Some cl i ni ci a ns a dvoca te res pons e to empi ri c a nti bi oti c thera py a s a di a gnos ti c tes t. However, beca us e ba cteri a l overgrowth ca n mi mi c other
ma l a bs orpti ve di s orders (eg, Crohn's di s ea s e) a nd a dvers e effects of the a nti bi oti cs ca n wors en s ymptoms , es ta bl i s hi ng a defi ni ti ve eti ol ogy i s
preferred.
The s ta nda rd for di a gnos i s i s qua nti ta ti ve cul ture of i ntes ti na l fl ui d a s pi ra te s howi ng ba cteri a l count > 105 /mL. Thi s method, however, requi res
endos copy. Brea th tes ts , us i ng s ubs tra tes l i ke gl ucos e, l a ctul os e, a nd xyl os e, a re noni nva s i ve a nd ea s y to do. The 14 C-xyl os e brea th tes t s eems to
perform better tha n the other brea th tes ts . In a ddi ti on, a n upper GI s eri es wi th s ma l l -bowel fol l ow-through s houl d be done to i denti fy
predi s pos i ng a na tomi c l es i ons .
Treatment
Ora l a nti bi oti cs (va ri ous )
Trea tment i s wi th 10 to 14 da ys of ora l a nti bi oti cs . Empi ri c regi mens i ncl ude tetra cycl i ne 250 mg qi d, a moxi ci l l i n/cl a vul a ni c a ci d 250 to 500 mg ti d,
cepha l exi n 250 mg qi d, tri methopri m/s ul fa methoxa zol e 160/800 mg bi d, a nd metroni da zol e 250 to 500 mg ti d or qi d. Anti bi oti cs s houl d be cha nged
ba s ed on cul ture a nd s ens i ti vi ty res ul ts . Underl yi ng condi ti ons a nd nutri ti ona l defi ci enci es (eg, vi ta mi n B 12 ) s houl d be corrected.
Carbohydrate Intolerance
Carbohydrate intolerance is the inability to digest certain carbohydrates due to a lack of one or more intestinal enzymes. Symptoms include diarrhea, abdominal
distention, and flatulence. Diagnosis is clinical and by an H 2 breath test. Treatment is removal of the causative disaccharide from the diet.
Pathophysiology
Di s a ccha ri des a re norma l l y s pl i t i nto monos a ccha ri des by di s a ccha ri da s es (eg, l a cta s e, ma l ta s e, i s oma l ta s e, s ucra s e [i nverta s e]) l oca ted i n the
brus h border of s ma l l -bowel enterocytes . Undi ges ted di s a ccha ri des ca us e a n os moti c l oa d tha t a ttra cts wa ter a nd el ectrol ytes i nto the bowel ,
ca us i ng wa tery di a rrhea . Ba cteri a l fermenta ti on of ca rbohydra tes i n the col on produces ga s es (H 2 , CO2 , a nd metha ne), res ul ti ng i n exces s i ve
fl a tus , bl oa ti ng a nd di s tenti on, a nd a bdomi na l pa i n.
Etiology
Enzyme defi ci enci es ca n be congeni ta l , a cqui red (pri ma ry), or s econda ry. Congeni ta l defi ci enci es a re ra re.
Acqui red l a cta s e defi ci ency (pri ma ry a dul t hypol a cta s i a ) i s the mos t common form of ca rbohydra te i ntol era nce. La cta s e l evel s a re hi gh i n
neona tes , permi tti ng di ges ti on of mi l k; i n mos t ethni c groups (80% of bl a cks a nd Hi s pa ni cs , a l mos t 100% of As i a ns ), the l evel s decrea s e i n the
pos t-wea ni ng peri od renderi ng ol der chi l dren a nd a dul ts una bl e to di ges t s i gni fi ca nt a mounts of l a ctos e. However, 80 to 85% of whi tes of
Northwes t Europea n des cent produce l a cta s e throughout l i fe a nd a re thus a bl e to di ges t mi l k a nd mi l k products . It i s uncl ea r why the norma l s ta te
of > 75% of the worl d's popul a ti on s houl d be l a bel ed a "defi ci ency."
Seconda ry l a cta s e defi ci ency occurs i n condi ti ons tha t da ma ge the s ma l l -bowel mucos a (eg, cel i a c s prue, tropi ca l s prue, a cute i ntes ti na l
i nfecti ons ). In i nfa nts , tempora ry s econda ry di s a ccha ri da s e defi ci ency ma y compl i ca te enteri c i nfecti ons or a bdomi na l s urgery. Recovery from the
underl yi ng di s ea s e i s fol l owed by a n i ncrea s e i n a cti vi ty of the enzyme.
Symptoms and Signs
Symptoms a nd s i gns a re s i mi l a r i n a l l di s a ccha ri da s e defi ci enci es . A chi l d who ca nnot tol era te l a ctos e devel ops di a rrhea a fter i nges ti ng
s i gni fi ca nt a mounts of mi l k a nd ma y not ga i n wei ght. An a ffected a dul t ma y ha ve wa tery di a rrhea , bl oa ti ng, exces s i ve fl a tus , na us ea , borborygmi ,
a nd a bdomi na l cra mps a fter i nges ti ng l a ctos e. The pa ti ent often recogni zes thi s ea rl y i n l i fe a nd a voi ds ea ti ng da i ry products . Symptoms typi ca l l y
requi re i nges ti on of more tha n the equi va l ent of 8 to 12 oz of mi l k. Di a rrhea ma y be s evere enough to purge other nutri ents before they ca n be
a bs orbed. Symptoms ma y be s i mi l a r to a nd ca n be confus ed wi th i rri ta bl e bowel s yndrome (s ee p. 162).
Diagnosis
Cl i ni ca l di a gnos i s
H 2 brea th tes t for confi rma ti on
La ctos e i ntol era nce ca n us ua l l y be di a gnos ed wi th a ca reful hi s tory s upported by di eta ry cha l l enge. Pa ti ents us ua l l y ha ve a hi s tory of i ntol era nce
to mi l k a nd da i ry foods . The di a gnos i s i s a l s o s ugges ted i f the s tool from chroni c or i ntermi ttent di a rrhea i s a ci di c (pH < 6) a nd ca n be confi rmed
by a n H 2 brea th or a l a ctos e tol era nce tes t.
In the H 2 brea th tes t, 50 g of l a ctos e i s gi ven ora l l y a nd the H 2 produced by ba cteri a l meta bol i s m of undi ges ted l a ctos e i s mea s ured wi th a brea th
meter a t 2, 3, a nd 4 h pos ti nges ti on. Mos t a ffected pa ti ents ha ve a n i ncrea s e i n expi red H 2 of > 20 ppm over ba s el i ne. Sens i ti vi ty a nd s peci fi ci ty a re
> 95%.
The l a ctos e tol era nce tes t i s l es s s peci fi c. Ora l l a ctos e (1.0 to 1.5 g/kg body wei ght) i s gi ven. Serum gl ucos e i s mea s ured before i nges ti on a nd 60
a nd 120 mi n a fter. La ctos e-i ntol era nt pa ti ents devel op di a rrhea , a bdomi na l bl oa ti ng, a nd di s comfort wi thi n 20 to 30 mi n, a nd thei r s erum gl ucos e
l evel s do not ri s e > 20 mg/dL (< 1.1 mmol /L) a bove ba s el i ne. Low l a cta s e a cti vi ty i n a jejuna l bi ops y s peci men i s di a gnos ti c, but endos copy i s
needed to obta i n a s peci men a nd i s not routi ne.
Treatment
Di eta ry res tri cti on
Ca rbohydra te ma l a bs orpti on i s rea di l y control l ed by a voi di ng di eta ry s uga rs tha t ca nnot be a bs orbed (i e, fol l owi ng a l a ctos e-free di et i n ca s es of
l a cta s e defi ci ency). However, beca us e the degree of l a ctos e ma l a bs orpti on va ri es grea tl y, ma ny pa ti ents ca n i nges t up to 12 oz (18 g of l a ctos e) of
mi l k da i l y wi thout s ymptoms . Yogurt i s us ua l l y tol era ted beca us e i t conta i ns a n a ppreci a bl e a mount of l a cta s e produced by i ntri ns i c Lactobacilli.
For s ymptoma ti c pa ti ents wi s hi ng to dri nk mi l k, l a ctos e i n mi l k ca n be predi ges ted by the a ddi ti on of a commerci a l l y prepa red l a cta s e, a nd
pretrea ted mi l k i s now a va i l a bl e. Enzyme s uppl ements s houl d be a n a djunct to, not a s ubs ti tute for, di eta ry res tri cti on. La ctos e-i ntol era nt
pa ti ents mus t ta ke Ca s uppl ements (1200 to 1500 mg/da y).
Celiac Sprue
(Nontropi ca l Sprue; Gl uten Enteropa thy; Cel i a c Di s ea s e)
Celiac sprue is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation, which
causes malabsorption. Symptoms usually include diarrhea and abdominal discomfort. Diagnosis is by small-bowel biopsies showing characteristic though not
specific pathologic changes of villous atrophy that resolve with a strict gluten-free diet.
Etiology
Cel i a c s prue i s a heredi ta ry di s order ca us ed by s ens i ti vi ty to the gl i a di n fra cti on of gl uten, a protei n found i n whea t; s i mi l a r protei ns a re pres ent
i n rye a nd ba rl ey. In a geneti ca l l y s us cepti bl e pers on, gl uten-s ens i ti ve T cel l s a re a cti va ted when gl uten-deri ved pepti de epi topes a re pres ented.
The i nfl a mma tory res pons e ca us es cha ra cteri s ti c mucos a l vi l l ous a trophy i n the s ma l l bowel .
Epidemiology: Cel i a c s prue ma i nl y a ffects whi tes of northern Europea n des cent. Preva l ence es ti ma tes ba s ed on s erol ogi c s creens (s ometi mes
confi rmed by bi ops y) i ndi ca te the di s order i s pres ent i n a bout 1/300 i n Europe a nd perha ps 1/250 i n the US overa l l (but there ma y be s i gni fi ca nt
va ri a ti on a mong regi ons i n the US).
The di s ea s e a ffects a bout 10 to 20% of 1s t-degree rel a ti ves . Fema l e:ma l e ra ti o i s 2:1. Ons et i s genera l l y i n chi l dhood but ma y occur l a ter.
Symptoms and Signs
The cl i ni ca l pres enta ti on va ri es ; no typi ca l pres enta ti on exi s ts . Some pa ti ents a re a s ymptoma ti c or ha ve onl y s i gns of nutri ti ona l defi ci ency.
Others ha ve s i gni fi ca nt GI s ymptoms .
Cel i a c s prue ca n ma ni fes t i n i nfa ncy a nd chi l dhood a fter i ntroducti on of cerea l s i nto the di et. The chi l d ha s fa i l ure to thri ve, a pa thy, a norexi a ,
pa l l or, genera l i zed hypotoni a , a bdomi na l di s tenti on, a nd mus cl e wa s ti ng. Stool s a re s oft, bul ky, cl a y-col ored, a nd offens i ve. Ol der chi l dren ma y
pres ent wi th a nemi a or fa i l ure to grow norma l l y.
In a dul ts , l a s s i tude, wea knes s , a nd a norexi a a re mos t common. Mi l d a nd i ntermi ttent di a rrhea i s s ometi mes the pres enti ng s ymptom.
Stea torrhea ra nges from mi l d to s evere (7 to 50 g fa t/da y). Some pa ti ents ha ve wei ght l os s , ra rel y enough to become underwei ght. Anemi a ,
gl os s i ti s , a ngul a r s toma ti ti s , a nd a phthous ul cers a re us ua l l y s een i n thes e pa ti ents . Ma ni fes ta ti ons of vi ta mi n D a nd Ca defi ci enci es (eg,
os teoma l a ci a , os teopeni a , os teoporos i s ) a re common. Both men a nd women ma y ha ve reduced ferti l i ty.
About 10% ha ve derma ti ti s herpeti formi s , a n i ntens el y pruri ti c pa pul oves i cul a r ra s h tha t i s s ymmetri ca l l y di s tri buted over the extens or a rea s of
the el bows , knees , buttocks , s houl ders , a nd s ca l p. Thi s ra s h ca n be i nduced by a hi gh-gl uten di et. Cel i a c s prue i s a l s o a s s oci a ted wi th di a betes
mel l i tus , a utoi mmune thyroi d di s ea s e, a nd Down s yndrome.
Diagnosis
Serol ogi c ma rkers
Sma l l -bowel bi ops y
The di a gnos i s i s s us pected cl i ni ca l l y a nd by l a bora tory a bnorma l i ti es s ugges ti ve of ma l a bs orpti on. Fa mi l y i nci dence i s a va l ua bl e cl ue. Cel i a c
s prue s houl d be s trongl y cons i dered i n a pa ti ent wi th i ron defi ci ency wi thout obvi ous GI bl eedi ng.
Confi rma ti on requi res a s ma l l -bowel bi ops y from the s econd porti on of the duodenum. Fi ndi ngs i ncl ude l a ck or s horteni ng of vi l l i (vi l l ous
a trophy), i ncrea s ed i ntra epi thel i a l cel l s , a nd crypt hyperpl a s i a . However, s uch fi ndi ngs ca n a l s o occur i n tropi ca l s prue, s evere i ntes ti na l ba cteri a l
overgrowth, eos i nophi l i c enteri ti s , l a ctos e i ntol era nce, a nd l ymphoma .
Beca us e bi ops y l a cks s peci fi ci ty, s erol ogi c ma rkers ca n a i d di a gnos i s . Anti -ti s s ue tra ns gl uta mi na s e a nti body (AGA) a nd a nti -endomys i a l a nti body
(EMAa n a nti body a ga i ns t a n i ntes ti na l connecti ve ti s s ue protei n) ea ch ha ve s ens i ti vi ty a nd s peci fi ci ty > 90%. Thes e ma rkers ca n a l s o be us ed to
s creen popul a ti ons wi th hi gh preva l ence of cel i a c s prue, i ncl udi ng 1s t-degree rel a ti ves of a ffected pa ti ents a nd pa ti ents wi th di s ea s es tha t occur
a t a grea ter frequency i n a s s oci a ti on wi th cel i a c s prue. If ei ther tes t i s pos i ti ve, the pa ti ent s houl d ha ve a di a gnos ti c s ma l l -bowel bi ops y. If both
a re nega ti ve, cel i a c s prue i s extremel y unl i kel y. Thes e a nti bodi es decrea s e i n ti ter i n pa ti ents on a gl uten-free di et a nd thus a re us eful i n
moni tori ng di eta ry compl i a nce.
Other l a bora tory a bnorma l i ti es often occur a nd s houl d be s ought. They i ncl ude a nemi a (i ron-defi ci ency a nemi a i n chi l dren a nd fol a te-defi ci ency
a nemi a i n a dul ts ); l ow a l bumi n, Ca , K, a nd Na ; a nd el eva ted a l ka l i ne phos pha ta s e a nd PT.
Ma l a bs orpti on tes ts a re not s peci fi c for cel i a c s prue. If done, common fi ndi ngs i ncl ude s tea torrhea of 10 to 40 g/da y a nd a bnorma l res ul ts wi th Dxyl os e a nd (i n s evere i l ea l di s ea s e) Schi l l i ng tes ts .
Prognosis
Morta l i ty i s 10 to 30% wi thout a gl uten-free di et. Wi th proper di et, morta l i ty i s < 1%, ma i nl y i n a dul ts who ha ve s evere di s ea s e a t the outs et.
Compl i ca ti ons i ncl ude refra ctory s prue, col l a genous s prue, a nd i ntes ti na l l ymphoma s . Intes ti na l l ymphoma s a ffect 6 to 8% of pa ti ents wi th cel i a c
s prue, us ua l l y ma ni fes ti ng a fter 20 to 40 yr of di s ea s e. The i nci dence of other GI ca ncers (eg, ca rci noma of the es opha gus or oropha rynx, s ma l l bowel a denoca rci noma ) a l s o i ncrea s es . Adherence to a gl uten-free di et ca n s i gni fi ca ntl y reduce the ri s k of ca ncer.
Treatment
Gl uten-free di et
Suppl ements to repl a ce a ny s eri ous defi ci enci es
Trea tment i s a gl uten-free di et (a voi di ng foods conta i ni ng whea t, rye, or ba rl ey). Gl uten i s s o wi del y us ed (eg, i n commerci a l s oups , s a uces , i ce
crea ms , hot dogs ) tha t a pa ti ent needs a deta i l ed l i s t of foods to a voi d. Pa ti ents a re encoura ged to cons ul t a di eti ti a n a nd joi n a cel i a c s upport
group. The res pons e to a gl uten-free di et i s us ua l l y ra pi d, a nd s ymptoms res ol ve i n 1 to 2 wk. Inges ti ng even s ma l l a mounts of food conta i ni ng
gl uten ma y prevent remi s s i on or i nduce rel a ps e.
Sma l l -bowel bi ops y s houl d be repea ted a fter 3 to 4 mo of a gl uten-free di et. If a bnorma l i ti es pers i s t, other ca us es of vi l l ous a trophy (eg,
l ymphoma ) s houl d be cons i dered. Les s eni ng of s ymptoms a nd i mprovement i n s ma l l -bowel morphol ogy a re a ccompa ni ed by a decrea s e i n AGA
a nd EMA ti ters .
Suppl ementa ry vi ta mi ns , mi nera l s , a nd hema ti ni cs ma y be gi ven, dependi ng on the defi ci enci es . Mi l d ca s es ma y not requi re s uppl ementa ti on,
wherea s s evere ca s es ma y requi re comprehens i ve repl a cement. For a dul ts , repl a cement i ncl udes ferrous s ul fa te 300 mg po once/da y to ti d, fol a te
5 to 10 mg po once/da y, Ca s uppl ements , a nd a ny s ta nda rd mul ti vi ta mi n. Someti mes chi l dren (but ra rel y a dul ts ) who a re s eri ous l y i l l on i ni ti a l
di a gnos i s requi re bowel res t a nd TPN.

If a pa ti ent res ponds poorl y to gl uten wi thdra wa l , ei ther the di a gnos i s i s i ncorrect or the di s ea s e ha s become refra ctory. Corti cos teroi ds ca n
control s ymptoms i n the l a tter ca s e.
Infection and Infestation
Acute ba cteri a l , vi ra l , a nd pa ra s i ti c i nfecti ons ma y ca us e tra ns i ent ma l a bs orpti on, proba bl y a s a res ul t of tempora ry, s uperfi ci a l da ma ge to the
vi l l i a nd mi crovi l l i . Chroni c ba cteri a l i nfecti ons of the s ma l l bowel a re uncommon, a pa rt from bl i nd l oops , s ys temi c s cl eros i s , a nd di verti cul a .
Intes ti na l ba cteri a ma y us e up di eta ry vi ta mi n B 12 a nd other nutri ents , perha ps i nterfere wi th enzyme s ys tems , a nd ca us e mucos a l i njury.
Intestinal Lymphangiectasia
(Idi opa thi c Hypoprotei nemi a )
Intestinal lymphangiectasia is obstruction or malformation of the intramucosal lymphatics of the small bowel. It primarily affects children and young adults.
Symptoms include those of malabsorption, with edema and growth retardation. Diagnosis is by small-bowel biopsy. Treatment is usually supportive.
Ma l forma ti on of the l ympha ti c s ys tem i s congeni ta l or a cqui red. Congeni ta l ca s es us ua l l y ma ni fes t i n chi l dren a nd young a dul ts (mea n a ge of
ons et: 11 yr). Ma l es a nd fema l es a re equa l l y a ffected. In a cqui red ca s es , the defect ma y be s econda ry to retroperi tonea l fi bros i s , cons tri cti ve
peri ca rdi ti s , pa ncrea ti ti s , neopl a s ti c tumors , a nd i nfi l tra ti ve di s orders tha t bl ock the l ympha ti cs .
Impa i red l ympha ti c dra i na ge l ea ds to i ncrea s ed pres s ure a nd l ea ka ge of l ymph i nto the i ntes ti na l l umen. Impa i rment of chyl omi cron a nd
l i poprotei n a bs orpti on res ul ts i n ma l a bs orpti on of fa ts a nd protei n. Beca us e ca rbohydra tes a re not a bs orbed through the l ympha ti c s ys tem, thei r
upta ke i s not i mpa i red.
Symptoms and Signs
Ea rl y ma ni fes ta ti ons i ncl ude ma s s i ve a nd often a s ymmetri c peri phera l edema , i ntermi ttent di a rrhea , na us ea , vomi ti ng, a nd a bdomi na l pa i n.
Some pa ti ents ha ve mi l d to modera te s tea torrhea . Chyl ous pl eura l effus i ons (chyl othora x) a nd chyl ous a s ci tes ma y be pres ent. Growth i s reta rded
i f ons et i s i n the fi rs t deca de of l i fe.
Diagnosis
Endos copi c s ma l l -bowel bi ops y
Someti mes contra s t l ympha ngi ogra phy
Di a gnos i s us ua l l y requi res endos copi c s ma l l -bowel bi ops y, whi ch s hows ma rked di l a ti on a nd ecta s i a of the mucos a l a nd s ubmucos a l l ympha ti c
ves s el s . Al terna ti vel y, contra s t l ympha ngi ogra phy (i njecti on of contra s t ma teri a l vi a the peda l vei n) ca n s how a bnorma l i ntes ti na l l ympha ti cs .
La bora tory a bnorma l i ti es i ncl ude l ymphocytopeni a a nd l ow l evel s of s erum a l bumi n, chol es terol , IgA, IgM, IgG, tra ns ferri n, a nd cerul opl a s mi n.
Ba ri um s tudi es ma y s how thi ckened, nodul a r mucos a l fol ds tha t res embl e s ta cked coi ns . D-Xyl os e a bs orpti on i s norma l . Intes ti na l protei n l os s
ca n be s hown by us i ng chromi um-51-l a bel ed a l bumi n.
Treatment
Supporti ve ca re
Someti mes s urgi ca l res ecti on or repa i r
Abnorma l l ympha ti cs ca nnot be corrected. Supporti ve trea tment i ncl udes a l ow-fa t (< 30 g/da y), hi gh-protei n di et conta i ni ng medi um-cha i n
tri gl yceri de s uppl ements . Suppl ementa l Ca a nd fa t-s ol ubl e vi ta mi ns a re gi ven. Intes ti na l res ecti on or a na s tomos i s of the a bnorma l l ympha ti cs to
the venous cha nnel s ma y be benefi ci a l . Pl eura l effus i ons s houl d be dra i ned by thora centes i s .
Short Bowel Syndrome
Short bowel syndrome is malabsorption resulting from extensive resection of the small bowel. Symptoms depend on the length and function of the remaining
small bowel, but diarrhea can be severe, and nutritional deficiencies are common. Treatment is with small feedings, antidiarrheals, and sometimes TPN or
intestinal transplantation.
Common rea s ons for extens i ve res ecti on a re Crohn's di s ea s e, mes enteri c i nfa rcti on, ra di a ti on enteri ti s , ca ncer, vol vul us , a nd congeni ta l
a noma l i es .
Beca us e the jejunum i s the pri ma ry di ges ti ve a nd a bs orpti ve s i te for mos t nutri ents , jejuna l res ecti on s i gni fi ca ntl y reduces nutri ent a bs orpti on. In
res pons e, the i l eum a da pts by i ncrea s i ng the l ength a nd a bs orpti ve functi on of i ts vi l l i , res ul ti ng i n gra dua l i mprovement of nutri ent a bs orpti on.
The i l eum i s the s i te of vi ta mi n B 12 a nd bi l e a ci d a bs orpti on. Severe di a rrhea a nd bi l e a ci d ma l a bs orpti on res ul t when > 100 cm of the i l eum i s
res ected. Nota bl y, there i s no compens a tory a da pta ti on of the rema i ni ng jejunum. Cons equentl y, ma l a bs orpti on of fa t, fa t-s ol ubl e vi ta mi ns , a nd
vi ta mi n B 12 occurs . In a ddi ti on, una bs orbed bi l e a ci ds i n the col on res ul t i n s ecretory di a rrhea . Pres erva ti on of the col on ca n s i gni fi ca ntl y reduce
wa ter a nd el ectrol yte l os s es . Res ecti on of the termi na l i l eum a nd i l eoceca l va l ve ca n predi s pos e to ba cteri a l overgrowth.
Treatment
TPN
Eventua l ora l feedi ng i f > 100 cm of jejunum rema i n
Anti di a rrhea l s , chol es tyra mi ne, proton pump i nhi bi tors , vi ta mi n s uppl ements
In the i mmedi a te pos topera ti ve peri od, di a rrhea i s typi ca l l y s evere, wi th s i gni fi ca nt el ectrol yte l os s es . Pa ti ents typi ca l l y requi re TPN a nd i ntens i ve
moni tori ng of fl ui d a nd el ectrol ytes (i ncl udi ng Ca a nd Mg). An ora l i s o-os moti c s ol uti on of Na a nd gl ucos e (s i mi l a r to WHO ora l rehydra ti on
formul a s ee p.
2809) i s s l owl y i ntroduced i n the pos topera ti ve pha s e once the pa ti ent s ta bi l i zes a nd s tool output i s < 2 L/da y.
Pa ti ents wi th extens i ve res ecti on (< 100 cm of rema i ni ng jejunum) a nd thos e wi th exces s i ve fl ui d a nd el ectrol yte l os s es requi re TPN for l i fe.
Pa ti ents wi th > 100 cm of jejunum l eft ca n a chi eve a dequa te nutri ti on through ora l feedi ng. Fa t a nd protei n i n the di et a re us ua l l y wel l tol era ted,
unl i ke ca rbohydra tes , whi ch contri bute a s i gni fi ca nt os moti c l oa d. Sma l l feedi ngs reduce the os moti c l oa d. Idea l l y, 40% of ca l ori es s houl d cons i s t
of fa t.
Pa ti ents who ha ve di a rrhea a fter mea l s s houl d ta ke a nti di a rrhea l s (eg, l opera mi de) 1 h before ea ti ng. Chol es tyra mi ne 2 to 4 g ta ken wi th mea l s
reduces di a rrhea a s s oci a ted wi th bi l e a ci d ma l a bs orpti on. Monthl y IM i njecti ons of vi ta mi n B 12 s houl d be gi ven to pa ti ents wi th a documented
defi ci ency. Mos t pa ti ents s houl d ta ke s uppl ementa l vi ta mi ns , Ca , a nd Mg.
Ga s tri c a ci d hypers ecreti on ca n devel op, whi ch ca n dea cti va te pa ncrea ti c enzymes ; thus , mos t pa ti ents a re gi ven H 2 bl ockers or proton pump
i nhi bi tors .
Sma l l -bowel tra ns pl a nta ti on i s a dvoca ted for pa ti ents who a re not ca ndi da tes for l ong-term TPN a nd i n whom a da pta ti on does not occur.
Tropical Sprue
Tropical sprue is an acquired disease, probably of infectious etiology, characterized by malabsorption and megaloblastic anemia. Diagnosis is clinical and by
small-bowel biopsy. Treatment is with tetracycline and folate for 6 mo.
Etiology
Tropi ca l s prue occurs chi efl y i n the Ca ri bbea n, s outhern Indi a , a nd Southea s t As i a , a ffecti ng both na ti ves a nd vi s i tors . The i l l nes s i s ra re i n
vi s i tors s pendi ng < 1 mo i n a rea s where the di s ea s e i s endemi c. Al though eti ol ogy i s uncl ea r, i t i s thought to res ul t from chroni c i nfecti on of the
s ma l l bowel by toxi geni c s tra i ns of col i form ba cteri a . Ma l a bs orpti on of fol a te a nd vi ta mi n B 12 defi ci ency res ul t i n mega l obl a s ti c a nemi a . The
i nci dence of tropi ca l s prue i s decrea s i ng, perha ps beca us e of i ncrea s i ng us e of a nti bi oti cs for a cute tra vel er's di a rrhea .
Symptoms and Signs
Pa ti ents commonl y ha ve a cute di a rrhea wi th fever a nd ma l a i s e. A chroni c pha s e of mi l der di a rrhea , na us ea , a norexi a , a bdomi na l cra mps , a nd
fa ti gue fol l ows . Stea torrhea i s common. Nutri ti ona l defi ci enci es , es peci a l l y of fol a te a nd vi ta mi n B 12 , eventua l l y devel op a fter s evera l months to
yea rs . The pa ti ent ma y a l s o ha ve wei ght l os s , gl os s i ti s , s toma ti ti s , a nd peri phera l edema .
Diagnosis
Endos copy wi th s ma l l -bowel bi ops y
Bl ood tes ts to s creen for cons equences of ma l a bs orpti on
Tropi ca l s prue i s s us pected i n peopl e who l i ve i n or ha ve vi s i ted a rea s where the di s ea s e i s endemi c a nd who ha ve mega l obl a s ti c a nemi a a nd
s ymptoms of ma l a bs orpti on. The defi ni ti ve tes t i s upper GI endos copy wi th s ma l l -bowel bi ops y. Cha ra cteri s ti c hi s tol ogi c cha nges (s ee Ta bl e 17-3)
us ua l l y i nvol ve the enti re s ma l l bowel a nd i ncl ude bl unti ng of the vi l l i wi th i nfi l tra ti on of chroni c i nfl a mma tory cel l s i n the epi thel i um a nd
l a mi na propri a . Cel i a c di s ea s e a nd pa ra s i ti c i nfecti on mus t be rul ed out.
Addi ti ona l l a bora tory s tudi es (eg, CBC; a l bumi n; Ca ; PT; i ron, fol a te, a nd B 12 l evel s ) hel p eva l ua te nutri ti ona l s ta tus . Ba ri um s ma l l -bowel fol l owthrough ma y s how s egmenta ti on of the ba ri um, di l a ti on of the l umen, a nd thi ckeni ng of the mucos a l fol ds . D-Xyl os e a bs orpti on i s a bnorma l i n >
90% of ca s es . However, thes e tes ts a re not s peci fi c or es s enti a l for di a gnos i s .
Treatment
Long-term tetra cycl i ne
Trea tment i s tetra cycl i ne 250 mg po qi d for 1 or 2 mo, then bi d for up to 6 mo, dependi ng on di s ea s e s everi ty a nd res pons e to trea tment. Fol a te 5 to
10 mg po once/da y s houl d be gi ven for the fi rs t month a l ong wi th vi ta mi n B 12 1 mg IM weekl y for s evera l weeks . Mega l obl a s ti c a nemi a promptl y
a ba tes , a nd the cl i ni ca l res pons e i s dra ma ti c. Other nutri ti ona l repl a cements a re gi ven a s needed. Rel a ps e ma y occur i n 20%. Fa i l ure to res pond
a fter 4 wk of thera py s ugges ts a nother condi ti on.
Whipple's Disease
(Intes ti na l Li podys trophy)
Whipple's disease is a rare systemic illness caused by the bacterium Tropheryma whippelii. Main symptoms are arthritis, weight loss, and diarrhea. Diagnosis is
by small-bowel biopsy. Treatment is with a minimum 1 yr of trimethoprim/sulfamethoxazole.

Whi ppl e's di s ea s e predomi na tel y a ffects whi te men a ged 30 to 60. Al though i t a ffects ma ny pa rts of the body (eg, hea rt, l ung, bra i n, s erous
ca vi ti es , joi nts , eye, GI tra ct), the mucos a of the s ma l l bowel i s a l mos t a l wa ys i nvol ved. Affected pa ti ents ma y ha ve s ubtl e defects of cel l medi a ted i mmuni ty tha t predi s pos e to i nfecti on wi th T. whippelii. About 30% of pa ti ents ha ve HLA-B27.
Symptoms and Signs
Cl i ni ca l pres enta ti on va ri es dependi ng on the orga n s ys tems a ffected. Us ua l l y, the fi rs t s ymptoms a re a rthri ti s a nd fever. Intes ti na l s ymptoms (eg,
wa tery di a rrhea , s tea torrhea , a bdomi na l pa i n, a norexi a , wei ght l os s ) us ua l l y ma ni fes t l a ter, s ometi mes yea rs a fter the i ni ti a l compl a i nt. Gros s or
occul t i ntes ti na l bl eedi ng ma y occur. Severe ma l a bs orpti on ma y be pres ent i n pa ti ents di a gnos ed l a te i n the cl i ni ca l cours e. Other fi ndi ngs
i ncl ude i ncrea s ed s ki n pi gmenta ti on, a nemi a , l ympha denopa thy, chroni c cough, s eros i ti s , peri phera l edema , a nd CNS s ymptoms .
Diagnosis
Endos copy wi th s ma l l -bowel bi ops y
The di a gnos i s ma y be mi s s ed i n pa ti ents wi thout promi nent GI s ymptoms . Whi ppl e's di s ea s e s houl d be s us pected i n mi ddl e-a ged whi te men
who ha ve a rthri ti s a nd a bdomi na l pa i n, di a rrhea , wei ght l os s , or other s ymptoms of ma l a bs orpti on. Such pa ti ents s houl d ha ve upper endos copy
wi th s ma l l -bowel bi ops y; the i ntes ti na l l es i ons a re s peci fi c a nd di a gnos ti c. The mos t s evere a nd cons i s tent cha nges a re i n the proxi ma l s ma l l
bowel . Li ght mi cros copy s hows peri odi c a ci d-Schi ff-pos i ti ve ma cropha ges tha t di s tort the vi l l us a rchi tecture. Gra m-pos i ti ve, a ci d fa s t-nega ti ve
ba ci l l i (T. whippelii) a re s een i n the l a mi na propri a a nd i n the ma cropha ges . Confi rma ti on by el ectron mi cros copy i s recommended.
Whi ppl e's di s ea s e s houl d be di fferenti a ted from i ntes ti na l i nfecti on wi th Mycobacterium avium-intracellulare (MAI), whi ch ha s s i mi l a r hi s tol ogi c
fi ndi ngs . However, MAI s ta i ns pos i ti ve wi th a ci d fa s t. PCR tes ti ng ma y be us eful for confi rma ti on.
Treatment
Anti bi oti cs
La te rel a ps e a pos s i bi l i ty
Untrea ted di s ea s e i s progres s i ve a nd fa ta l . Ma ny a nti bi oti cs a re cura ti ve (eg, tetra cycl i ne, tri methopri m/s ul fa methoxa zol e, chl ora mpheni col ,
a mpi ci l l i n, peni ci l l i n, cepha l os pori ns ). Trea tment i s i ni ti a ted wi th ceftri a xone (2 g IV da i l y) or wi th proca i ne (1.2 mi l l i on uni ts IM once/da y) or
peni ci l l i n G (1.5 to 6 mi l l i on uni ts IV q 6 h) pl us s treptomyci n (1.0 g IM once/da y for 10 to 14 da ys ). Thi s regi men i s fol l owed by a l ong-term cours e
of tri methopri m/s ul fa methoxa zol e (160/800 mg po bi d for 1 yr). Sul fa -a l l ergi c pa ti ents ma y s ubs ti tute ora l peni ci l l i n VK or a mpi ci l l i n. Prompt
cl i ni ca l i mprovement occurs , wi th fever a nd joi nt pa i ns res ol vi ng i n a few da ys . Intes ti na l s ymptoms us ua l l y a ba te wi thi n 1 to 4 wk.
Some a uthori ti es do not recommend repea t s ma l l -bowel bi ops i es beca us e ma cropha ges ma y pers i s t for yea rs a fter trea tment. However, others
recommend repea t bi ops y a fter 1 yr. In the l a tter a pproa ch, el ectron mi cros copy i s needed to document ba ci l l i (not jus t ma cropha ges ). Rel a ps es
a re common a nd ma y occur yea rs l a ter. If rel a ps e i s s us pected, s ma l l -bowel bi ops i es s houl d be done (rega rdl es s of a ffected orga n s ys tems ) to
determi ne pres ence of free ba ci l l i .
Chapter 18. Irritable Bowel Syndrome

(Spa s ti c Col on)
Irritable bowel syndrome (IBS) is characterized by abdominal discomfort or pain that is accompanied by at least two of the following: relief by defecation, change
in frequency of stool, or change in consistency of stool. The cause is unknown, and the pathophysiology is incompletely understood. Diagnosis is clinical.
Treatment is symptomatic, consisting of dietary management and drugs, including anticholinergics and agents active at serotonin receptors.
Etiology
The ca us e of IBS i s unknown. No a na tomi c ca us e ca n be found on l a bora tory tes ts , x-ra ys , a nd bi ops i es . Emoti ona l fa ctors , di et, drugs , or
hormones ma y preci pi ta te or a ggra va te GI s ymptoms . Hi s tori ca l l y, the di s order wa s often cons i dered a s purel y ps ychos oma ti c. Al though
ps ychos oci a l fa ctors a re i nvol ved, IBS i s better unders tood a s a combi na ti on of ps ychos oci a l a nd phys i ol ogi c fa ctors .
Psychosocial factors: Ps ychol ogi c di s tres s i s common a mong pa ti ents wi th IBS, es peci a l l y a mong thos e who s eek medi ca l ca re. Some pa ti ents ha ve
a nxi ety di s orders , depres s i on, or a s oma ti za ti on di s order. Sl eep di s turba nces a l s o coexi s t. However, s tres s a nd emoti ona l confl i ct do not a l wa ys
coi nci de wi th s ymptom ons et a nd recurrence. Some pa ti ents wi th IBS s eem to ha ve a l ea rned a berra nt i l l nes s beha vi or (i e, they expres s
emoti ona l confl i ct a s a GI compl a i nt, us ua l l y a bdomi na l pa i n). The phys i ci a n eva l ua ti ng pa ti ents wi th IBS, pa rti cul a rl y thos e wi th refra ctory
s ymptoms , s houl d i nves ti ga te for unres ol ved ps ychol ogi c i s s ues , i ncl udi ng the pos s i bi l i ty of s exua l or phys i ca l a bus e. Ps ychos oci a l fa ctors a l s o
a ffect the outcome i n IBS.
Physiologic factors: A va ri ety of phys i ol ogi c fa ctors s eem to be i nvol ved i n IBS s ymptoms . Fa ctors i ncl ude a l tered moti l i ty, vi s cera l hypera l ges i a , a nd
va ri ous geneti c a nd envi ronmenta l fa ctors .
Vi s cera l hypera l ges i a refers to hypers ens i ti vi ty to norma l a mounts of i ntra l umi na l di s tenti on a nd hei ghtened percepti on of pa i n i n the pres ence
of norma l qua nti ti es of i ntes ti na l ga s ; i t ma y res ul t from remodel i ng of neura l pa thwa ys i n the bra i n-gut a xi s . Some pa ti ents (perha ps 1 i n 7) ha ve
reported thei r IBS s ymptoms bega n a fter a n epi s ode of a cute ga s troenteri ti s (termed pos ti nfecti ous IBS). A s ubs et of pa ti ents wi th IBS ha s
a utonomi c dys functi ons . However, ma ny pa ti ents ha ve no demons tra bl e phys i ol ogi c a bnorma l i ti es , a nd even i n thos e tha t do, the a bnorma l i ti es
ma y not correl a te wi th s ymptoms .
Cons ti pa ti on ma y be expl a i ned by s l ower col oni c tra ns i t, a nd di a rrhea ma y be expl a i ned by fa s ter col oni c tra ns i t. Some pa ti ents wi th cons ti pa ti on
ha ve fewer col oni c hi gh a mpl i tude-propa ga ted contra cti ons , whi ch propel col oni c contents over s evera l s egments . Convers el y, exces s s i gmoi d
motor a cti vi ty ma y reta rd tra ns i t i n functi ona l cons ti pa ti on.
Pos tpra ndi a l a bdomi na l di s comfort ma y be a ttri buted to a n exa ggera ted ga s tro-col oni c refl ex (the col oni c contra cti l e res pons e to a mea l ), the
pres ence of col oni c hi gh a mpl i tude-propa ga ted contra cti ons , i ncrea s ed i ntes ti na l s ens i ti vi ty (vi s cera l hypera l ges i a ), or a combi na ti on of thes e.
Fa t i nges ti on ma y exa ggera te hypers ens i ti vi ty.
Hormona l fl uctua ti ons a ffect bowel functi ons i n women. Recta l s ens i ti vi ty i s i ncrea s ed duri ng mens es but not duri ng other pha s es of the
mens trua l cycl e. The effects of s ex s teroi ds on GI tra ns i t a re s ubtl e. The rol e of s ma l l -bowel ba cteri a l overgrowth i n IBS i s controvers i a l .
Symptoms and Signs
IBS tends to begi n i n the teens a nd 20s , ca us i ng bouts of s ymptoms tha t recur a t i rregul a r peri ods . Ons et i n l a te a dul t l i fe i s l es s common but not
ra re. Symptoms ra rel y rous e the s l eepi ng pa ti ent. Symptoms a re often tri ggered by food, pa rti cul a rl y fa ts , or by s tres s .
Pa ti ents ha ve a bdomi na l di s comfort, whi ch va ri es cons i dera bl y but i s often l oca ted i n the l ower qua dra nt, s tea dy or cra mpi ng i n na ture, a nd
rel i eved by defeca ti on. In a ddi ti on, a bdomi na l di s comfort i s tempora l l y a s s oci a ted wi th a l tera ti ons i n s tool frequency (i ncrea s ed i n di a rrhea predomi na nt IBS a nd decrea s ed i n cons ti pa ti on-predomi na nt IBS) a nd cons i s tency (i e, l oos e or l umpy a nd ha rd). Pa i n or di s comfort rel a ted to
defeca ti on i s l i kel y to be of bowel ori gi n; tha t a s s oci a ted wi th exerci s e, movement, uri na ti on, or mens trua ti on us ua l l y ha s a di fferent ca us e.
Al though bowel pa tterns a re rel a ti vel y cons i s tent i n mos t pa ti ents , i t i s not unus ua l for pa ti ents to a l terna te between cons ti pa ti on a nd di a rrhea .
Pa ti ents ma y a l s o ha ve s ymptoms of a bnorma l s tool pa s s a ge (s tra i ni ng, urgency, or feel i ng of i ncompl ete eva cua ti on), pa s s mucus , or compl a i n of
bl oa ti ng or a bdomi na l di s tenti on. Ma ny pa ti ents a l s o ha ve s ymptoms of dys peps i a . Extra i ntes ti na l s ymptoms (eg, fa ti gue, fi bromya l gi a , s l eep
di s turba nces , chroni c hea da ches ) a re common.
Diagnosis
Cl i ni ca l eva l ua ti on, ba s ed on Rome cri teri a
Screeni ng for orga ni c ca us es wi th ba s i c l a bora tory tes ts a nd s i gmoi dos copy or col onos copy
Other tes ts for pa ti ents wi th red fl a g fi ndi ngs (recta l bl ood, wei ght l os s , fever)
Di a gnos i s i s ba s ed on cha ra cteri s ti c bowel pa tterns , ti me a nd cha ra cter of pa i n, a nd excl us i on of other di s ea s e proces s es through phys i ca l
exa mi na ti on a nd routi ne di a gnos ti c tes ts . Di a gnos ti c tes ti ng s houl d be more i ntens i ve when the fol l owi ng red fl a g fi ndi ngs a re pres ent ei ther a t
i ni ti a l pres enta ti on or a t a ny ti me a fter di a gnos i s : ol der a ge, fever, wei ght l os s , recta l bl eedi ng, vomi ti ng. Beca us e pa ti ents wi th IBS ca n devel op
orga ni c condi ti ons , tes ti ng for other condi ti ons s houl d a l s o be cons i dered i n pa ti ents who devel op a l a rm s ymptoms or ma rkedl y di fferent
s ymptoms duri ng the cours e of IBS. Common i l l nes s es tha t ma y be confus ed wi th IBS i ncl ude l a ctos e i ntol era nce, drug-i nduced di a rrhea , pos tchol ecys tectomy di a rrhea , l a xa ti ve a bus e, pa ra s i ti c di s ea s es (eg, gi a rdi a s i s ), eos i nophi l i c ga s tri ti s or enteri ti s , mi cros copi c col i ti s , a nd ea rl y
i nfl a mma tory bowel di s ea s e. However, uni nfl a med col oni c di verti cul a do not ca us e s ymptoms , a nd thei r pres ence s houl d not be cons i dered
expl a na tory.
The bi moda l a ge di s tri buti on of pa ti ents wi th i nfl a mma tory bowel di s ea s e ma kes i t i mpera ti ve to eva l ua te both younger a nd ol der pa ti ents . In
pa ti ents > 60 wi th a cute s ymptoms , i s chemi c col i ti s s houl d be cons i dered. Pa ti ents wi th cons ti pa ti on a nd no a na tomi c l es i on s houl d be eva l ua ted
for hypothyroi di s m a nd hyperpa ra thyroi di s m. If the pa ti ent's s ymptoms s ugges t ma l a bs orpti on, tropi ca l s prue, cel i a c di s ea s e, a nd Whi ppl e's
di s ea s e mus t be cons i dered. Defeca tory di s orders s houl d be cons i dered a s a ca us e of cons ti pa ti on i n pa ti ents who report s ymptoms of di ffi cul t
defeca ti on. Ra re ca us es of di a rrhea i ncl ude hyperthyroi di s m, medul l a ry ca ncer of the thyroi d, or ca rci noi d s yndrome, ga s tri noma , vi poma , a nd
Zol l i nger-El l i s on s yndrome. However, s ecretory di a rrhea ca us ed by va s oa cti ve i ntes ti na l pepti de (VIP), ca l ci toni n, or ga s tri n i s typi ca l l y
a ccompa ni ed by s tool vol umes > 1000 mL da i l y.
History: Pa rti cul a r a ttenti on s houl d be gi ven to the cha ra cter of the pa i n, bowel ha bi ts , fa mi l i a l i nterrel a ti ons hi ps , a nd drug a nd di eta ry hi s tori es .
Equa l l y i mporta nt a re the pa ti ent's overa l l emoti ona l s ta te, i nterpreta ti on of pers ona l probl ems a nd qua l i ty of l i fe. The qua l i ty of the pa ti entphys i ci a n i ntera cti on i s key to di a gnos ti c a nd thera peuti c effi ca cy.
The Rome criteria a re s ta nda rdi zed s ymptom-ba s ed cri teri a for di a gnos i ng IBS. The Rome cri teri a requi re the pres ence of a bdomi na l pa i n or
di s comfort for a t l ea s t 3 da ys /mo i n the l a s t 3 mo a l ong wi th 2 of the fol l owi ng: (1) i mprovement wi th defeca ti on, (2) ons et (of ea ch epi s ode of
di s comfort) a s s oci a ted wi th a cha nge i n frequency of defeca ti on, or (3) cha nge i n cons i s tency of s tool .
Physical examination: Pa ti ents genera l l y a ppea r to be hea l thy. Pa l pa ti on of the a bdomen ma y revea l tendernes s , pa rti cul a rl y i n the l eft l ower
qua dra nt, a t ti mes a s s oci a ted wi th a pa l pa bl e, tender s i gmoi d. A di gi ta l recta l exa mi na ti on, i ncl udi ng a tes t for occul t bl ood, s houl d be done on
a l l pa ti ents . In women, a pel vi c exa mi na ti on hel ps rul e out ova ri a n tumors a nd cys ts or endometri os i s , whi ch ma y mi mi c IBS.
Testing: The di a gnos i s of IBS ca n rea s ona bl y be ma de us i ng the Rome cri teri a a s l ong a s pa ti ents ha ve no red fl a g fi ndi ngs , s uch a s recta l
bl eedi ng, wei ght l os s , a nd fever, or other fi ndi ngs tha t mi ght s ugges t a nother eti ol ogy. Ma ny pa ti ents wi th IBS a re overtes ted; however, CBC,
bi ochemi ca l profi l e (i ncl udi ng l i ver tes ts ), ESR, s tool exa mi na ti on for ova a nd pa ra s i tes (i n thos e wi th di a rrhea predomi na nce), thyroi ds ti mul a ti ng hormone a nd Ca for thos e wi th cons ti pa ti on, a nd fl exi bl e s i gmoi dos copy or col onos copy s houl d be done. Duri ng fl exi bl e fi ber-opti c
proctos i gmoi dos copy, i ntroducti on of the i ns trument a nd a i r i ns uffl a ti on frequentl y tri gger bowel s pa s m a nd pa i n. The mucos a l a nd va s cul a r
pa tterns i n IBS us ua l l y a ppea r norma l . Col onos copy i s preferred for pa ti ents > 50 wi th a cha nge i n bowel ha bi ts , pa rti cul a rl y thos e wi th no
previ ous IBS s ymptoms , to excl ude col oni c pol yps a nd tumors . In pa ti ents wi th chroni c di a rrhea , pa rti cul a rl y ol der women, mucos a l bi ops y ca n rul e
out pos s i bl e mi cros copi c col i ti s .
Addi ti ona l s tudi es (s uch a s ul tra s ound, CT, ba ri um enema x-ra y, upper GI es opha goga s troduodenos copy, a nd s ma l l -bowel x-ra ys ) s houl d be
underta ken onl y when there a re other objecti ve a bnorma l i ti es . Feca l fa t excreti on s houl d be mea s ured when there i s a concern a bout s tea torrhea .
Tes ti ng for cel i a c s prue a nd s ma l l -bowel x-ra ys a re recommended when ma l a bs orpti on i s s us pected. Tes ti ng for ca rbohydra te i ntol era nce s houl d
be cons i dered i n a ppropri a te ci rcums ta nces .
Intercurrent disease: Pa ti ents wi th IBS ma y s ubs equentl y devel op a ddi ti ona l GI di s orders , a nd the cl i ni ci a n mus t not s umma ri l y di s mi s s thei r
compl a i nts . Cha nges i n s ymptoms (eg, i n the l oca ti on, type, or i ntens i ty of pa i n; i n bowel ha bi ts ; i n cons ti pa ti on a nd di a rrhea ) a nd new s ymptoms
or compl a i nts (eg, nocturna l di a rrhea ) ma y s i gna l a nother di s ea s e proces s . Other s ymptoms tha t requi re i nves ti ga ti on i ncl ude fres h bl ood i n the
s tool , wei ght l os s , very s evere a bdomi na l pa i n or unus ua l a bdomi na l di s tenti on, s tea torrhea or noti cea bl y foul -s mel l i ng s tool s , fever or chi l l s ,
pers i s tent vomi ti ng, hema temes i s , s ymptoms tha t wa ke the pa ti ent from s l eep (eg, pa i n, the urge to defeca te), a nd a s tea dy progres s i ve
wors eni ng of s ymptoms . Pa ti ents > 40 a re more l i kel y tha n younger pa ti ents to devel op a n i ntercurrent phys i ol ogi c i l l nes s .
Treatment
Support a nd unders ta ndi ng
Norma l di et, a voi di ng ga s -produci ng a nd di a rrhea -produci ng foods
Increa s ed fi ber i nta ke cons ti pa ti on
Lopera mi de for di a rrhea
Pos s i bl y tri cycl i c a nti depres s a nts
Thera py i s di rected a t s peci fi c s ymptoms . An effecti ve thera peuti c rel a ti ons hi p i s es s enti a l for effecti vel y ma na gi ng IBS. Pa ti ents s houl d be i nvi ted
to expres s not onl y thei r s ymptoms but a l s o thei r unders ta ndi ng of thei r s ymptoms a nd the rea s ons prompti ng a vi s i t to the hea l th ca re
pra cti ti oner (eg, fea r of s eri ous di s ea s e). Pa ti ents s houl d be educa ted a bout the di s order (eg, norma l bowel phys i ol ogy a nd the bowel 's
hypers ens i ti vi ty to s tres s a nd food) a nd rea s s ured, a fter a ppropri a te tes ts , a bout the a bs ence of a s eri ous or l i fe-threa teni ng di s ea s e.
Appropri a te thera peuti c goa l s (eg, expecta ti ons rega rdi ng the norma l cours e or va ri a bi l i ty i n s ymptoms , a dvers e effects of drugs , the a ppropri a te
a nd a va i l a bl e worki ng rel a ti ons hi p between the phys i ci a n a nd the pa ti ent) s houl d be es ta bl i s hed. Fi na l l y, pa ti ents ca n benefi t by bei ng a cti vel y
i nvol ved i n the ma na gement of thei r condi ti on. When s ucces s ful , thi s ca n enha nce the pa ti ent's moti va ti on to a dhere to trea tment, fos ter a more
pos i ti ve phys i ci a n-pa ti ent rel a ti ons hi p, a nd mobi l i ze the copi ng res ources of even the mos t chroni ca l l y pa s s i ve pa ti ents . Ps ychol ogi c s tres s ,
a nxi ety, or mood di s orders s houl d be i denti fi ed, eva l ua ted, a nd trea ted. Regul a r phys i ca l a cti vi ty hel ps rel i eve s tres s a nd a s s i s ts i n bowel
functi on, pa rti cul a rl y i n pa ti ents wi th cons ti pa ti on.
Diet: In genera l , a norma l di et s houl d be fol l owed. Mea l s s houl d not be overl y l a rge, a nd ea ti ng s houl d be s l ow a nd pa ced. Pa ti ents wi th
a bdomi na l di s tenti on a nd i ncrea s ed fl a tul ence ma y benefi t from reduci ng or el i mi na ti ng bea ns , ca bba ge, a nd other foods conta i ni ng
fermenta bl e ca rbohydra tes . Reduced i nta ke of s weeteners (eg, s orbi tol , ma nni tol , fructos e), whi ch a re cons ti tuents of na tura l a nd proces s ed
foods (eg, a ppl e a nd gra pe jui ce, ba na na s , nuts , a nd ra i s i ns ), ma y a l l evi a te fl a tul ence, bl oa ti ng, a nd di a rrhea . Pa ti ents wi th evi dence of l a ctos e
i ntol era nce s houl d reduce thei r i nta ke of mi l k a nd da i ry products . A l ow-fa t di et ma y reduce pos tpra ndi a l a bdomi na l s ymptoms .
Di eta ry fi ber s uppl ements ma y s often s tool a nd i mprove the ea s e of eva cua ti on. A bl a nd bul k-produci ng a gent ma y be us ed (eg, ra w bra n, s ta rti ng
wi th 15 mL [1 tbs p] wi th ea ch mea l , s uppl emented wi th i ncrea s ed fl ui d i nta ke). Al terna ti vel y, ps yl l i um hydrophi l i c muci l l oi d wi th two gl a s s es of
wa ter ma y be us ed. However, exces s i ve us e of fi ber ca n l ea d to bl oa ti ng a nd di a rrhea , s o fi ber dos es mus t be i ndi vi dua l i zed. Occa s i ona l l y,
fl a tul ence ma y be reduced by s wi tchi ng to a s yntheti c fi ber prepa ra ti on (eg, methyl cel l ul os e).
Drug therapy: Drug thera py i s di rected towa rd the domi na nt s ymptoms . Anti chol i nergi c drugs (eg, hyos cya mi ne 0.125 mg po 30 to 60 mi n before
mea l s ) ma y be us ed for thei r a nti s pa s modi c effects .
Serotoni n receptor modul a ti on ma y be of benefi t. Tega s erod, a 5HT4 a goni s t, s ti mul a tes moti l i ty a nd a l l evi a tes cons ti pa ti on. In 2007, tega s erod
wa s wi thdra wn from the ma rket beca us e, i n cl i ni ca l tri a l s , i t s l i ghtl y i ncrea s ed the i nci dence of ca rdi ova s cul a r i s chemi c events (i e, MI, uns ta bl e
a ngi na pectori s , s troke) compa red wi th pl a cebo. Tega s erod ha s s i nce been rei ntroduced under a res tri cted progra m. The chl ori de cha nnel
a cti va tor l ubi pros tone ma y hel p pa ti ents wi th cons ti pa ti on.
In pa ti ents wi th di a rrhea , ora l di phenoxyl a te 2.5 to 5 mg or l opera mi de 2 to 4 mg ma y be gi ven before mea l s . The dos e of l opera mi de s houl d be
ti tra ted upwa rd to reduce di a rrhea whi l e a voi di ng cons ti pa ti on. For ma ny pa ti ents , tri cycl i c a nti depres s a nts (TCAs ) hel p rel i eve s ymptoms of
di a rrhea , a bdomi na l pa i n, a nd bl oa ti ng. Thes e drugs a re thought to reduce pa i n by down-regul a ti ng the a cti vi ty of s pi na l cord a nd corti ca l a fferent
pa thwa ys a rri vi ng from the i ntes ti ne. Seconda ry a mi ne TCAs (eg, nortri ptyl i ne, des i pra mi ne) a re often better tol era ted tha n pa rent terti a ry a mi nes
(eg, a mi tri ptyl i ne, i mi pra mi ne, doxepi n) beca us e of fewer a nti chol i nergi c, s eda ti ng a nti hi s ta mi ni c, a nd -a drenergi c a dvers e effects . Trea tment
s houl d begi n wi th a very l ow dos e of a TCA (eg, des i pra mi ne 10 to 25 mg once/da y a t bedti me), i ncrea s i ng a s neces s a ry a nd tol era ted up to a bout
100 to 150 mg once/da y. SSRIs a re a l s o us eful , pa rti cul a rl y for pa ti ents wi th a nxi ety or a n a ffecti ve di s order, but ma y exa cerba te di a rrhea . 5HT3
a nta goni s ts (eg, a l os etron) ma y benefi t fema l e pa ti ents wi th s evere di a rrhea refra ctory to other drugs . Beca us e a l os etron i s a s s oci a ted wi th
i s chemi c col i ti s , i ts us e i s res tri cted.
Prel i mi na ry da ta s ugges t tha t certa i n probi oti cs (eg, Bifidobacterium infantis) a l l evi a te IBS s ymptoms , pa rti cul a rl y bl oa ti ng. The benefi ci a l effects of
probi oti cs a re not generi c to the enti re s peci es but s peci fi c to certa i n s tra i ns . Certa i n a roma ti c oi l s (ca rmi na ti ves ) ca n rel a x s mooth mus cl e a nd
rel i eve pa i n ca us ed by cra mps i n s ome pa ti ents . Peppermi nt oi l i s the mos t commonl y us ed a gent i n thi s cl a s s .
Psychologic therapies: Cogni ti ve-beha vi ora l thera py, s ta nda rd ps ychothera py, a nd hypnothera py ma y hel p s ome IBS pa ti ents .
Chapter 19. Inflammatory Bowel Disease

Introduction
Infl a mma tory bowel di s ea s e (IBD), whi ch i ncl udes Crohn's di s ea s e a nd ul cera ti ve col i ti s (UC), i s a rel a ps i ng a nd remi tti ng condi ti on cha ra cteri zed
by chroni c i nfl a mma ti on a t va ri ous s i tes i n the GI tra ct, whi ch res ul ts i n di a rrhea a nd a bdomi na l pa i n.
Infl a mma ti on res ul ts from a cel l -medi a ted i mmune res pons e i n the GI mucos a . The preci s e eti ol ogy i s unknown, but evi dence s ugges ts tha t the
norma l i ntes ti na l fl ora tri gger a n i mmune rea cti on i n pa ti ents wi th a mul ti fa ctori a l geneti c predi s pos i ti on (perha ps i nvol vi ng a bnorma l epi thel i a l
ba rri ers a nd mucos a l i mmune defens es ). No s peci fi c envi ronmenta l , di eta ry, or i nfecti ous ca us es ha ve been i denti fi ed. The i mmune rea cti on
i nvol ves the rel ea s e of i nfl a mma tory medi a tors , i ncl udi ng cytoki nes , i nterl euki ns , a nd tumor necros i s fa ctor (TNF).
Al though Crohn's di s ea s e a nd UC a re s i mi l a r, they ca n be di s ti ngui s hed i n mos t ca s es (s ee
Ta bl e 19-1). About 10% of col i ti s ca s es a re cons i dered i ndetermi na te. The term col i ti s a ppl i es onl y to i nfl a mma tory di s ea s e of the col on (eg,
ul cera ti ve, gra nul oma tous , i s chemi c, ra di a ti on-i nduced, i nfecti ous ). Spa s ti c (mucous ) col i ti s i s a mi s nomer s ometi mes a ppl i ed to a functi ona l
di s order, i rri ta bl e bowel s yndrome (s ee p. 162).
Epidemiology: IBD a ffects peopl e of a l l a ges but us ua l l y begi ns before a ge 30, wi th pea k i nci dence from 14 to 24. IBD ma y ha ve a s econd s ma l l er
pea k between a ges 50 a nd 70; however, thi s l a ter pea k ma y i ncl ude s ome ca s es of i s chemi c col i ti s .
IBD i s mos t common a mong peopl e of Northern Europea n a nd Angl o-Sa xon ori gi n a nd i s 2 to 4 ti mes more common a mong As hkena zi Jews tha n i n
non-Jewi s h whi tes . The i nci dence i s l ower i n centra l a nd s outhern Europe a nd l ower s ti l l i n South Ameri ca , As i a , a nd Afri ca . However, the
i nci dence i s i ncrea s i ng a mong bl a cks a nd La ti n Ameri ca ns l i vi ng i n North Ameri ca . Both s exes a re equa l l y a ffected. Fi rs t-degree rel a ti ves of
pa ti ents wi th IBD ha ve a 4- to 20-fol d i ncrea s ed ri s k; thei r a bs ol ute ri s k ma y be a s hi gh a s 7%. Fa mi l i a l tendency i s much hi gher i n Crohn's di s ea s e
tha n i n UC.
[Table 19-1. Di fferenti a ti ng Crohn's Di s ea s e a nd Ul cera ti ve Col i ti s ]
Severa l gene muta ti ons conferri ng a hi gher ri s k of Crohn's di s ea s e (a nd s ome pos s i bl y rel a ted to UC) ha ve been i denti fi ed.
Ci ga rette s moki ng s eems to contri bute to devel opment or exa cerba ti on of Crohn's di s ea s e but decrea s es ri s k of UC. NSAIDs ma y exa cerba te IBD.
Extraintestinal Manifestations
Crohn's di s ea s e a nd UC both a ffect orga ns other tha n the i ntes ti nes . Mos t extra i ntes ti na l ma ni fes ta ti ons a re more common i n UC a nd Crohn's
col i ti s tha n i n Crohn's di s ea s e l i mi ted to the s ma l l bowel . Extra i ntes ti na l ma ni fes ta ti ons a re ca tegori zed i n 3 wa ys :
1. Di s orders tha t us ua l l y pa ra l l el (i e, wa x a nd wa ne wi th) IBD fl a re-ups . Thes e di s orders i ncl ude peri phera l a rthri ti s , epi s cl eri ti s , a phthous
s toma ti ti s , erythema nodos um, a nd pyoderma ga ngrenos um. Arthri ti s tends to i nvol ve l a rge joi nts a nd be mi gra tory a nd tra ns i ent. One or more
of thes e pa ra l l el di s orders devel ops i n more tha n one thi rd of pa ti ents hos pi ta l i zed wi th IBD.
2. Di s orders tha t a re cl ea rl y a s s oci a ted wi th IBD but a ppea r i ndependentl y of IBD a cti vi ty. Thes e di s orders i ncl ude a nkyl os i ng s pondyl i ti s ,
s a croi l i i ti s , uvei ti s , a nd pri ma ry s cl eros i ng chol a ngi ti s . Ankyl os i ng s pondyl i ti s occurs more commonl y i n IBD pa ti ents wi th the HLA-B27 a nti gen.
Mos t pa ti ents wi th s pi na l or s a croi l i a c i nvol vement ha ve evi dence of uvei ti s a nd vi ce vers a . Pri ma ry s cl eros i ng chol a ngi ti s , whi ch i s a ri s k fa ctor
for ca ncer of the bi l i a ry tra ct, i s s trongl y a s s oci a ted wi th UC or Crohn's col i ti s . Chol a ngi ti s ma y a ppea r before or concurrentl y wi th the bowel
di s ea s e or even 20 yr a fter col ectomy. Li ver di s ea s e (eg, fa tty l i ver, a utoi mmune hepa ti ti s , peri chol a ngi ti s , ci rrhos i s ) occurs i n 3 to 5% of
pa ti ents , a l though mi nor a bnorma l i ti es i n l i ver functi on tes ts a re more common. Some of thes e condi ti ons (eg, pri ma ry s cl eros i ng chol a ngi ti s )
ma y precede IBD by ma ny yea rs a nd, when di a gnos ed, s houl d prompt a n eva l ua ti on for IBD.
3. Di s orders tha t a re cons equences of di s rupted bowel phys i ol ogy. Thes e di s orders occur ma i nl y i n s evere Crohn's di s ea s e of the s ma l l bowel .
Ma l a bs orpti on ma y res ul t from extens i ve i l ea l res ecti on a nd ca us e defi ci enci es of fa t-s ol ubl e vi ta mi ns , vi ta mi n B 12 , or mi nera l s , res ul ti ng i n
a nemi a , hypoca l cemi a , hypoma gnes emi a , cl otti ng di s orders , a nd bone demi nera l i za ti on. In chi l dren, ma l a bs orpti on reta rds growth a nd
devel opment. Other di s orders i ncl ude ki dney s tones from exces s i ve di eta ry oxa l a te a bs orpti on, hydroureter a nd hydronephros i s from uretera l
compres s i on by the i ntes ti na l i nfl a mma tory proces s , ga l l s tones from i mpa i red i l ea l rea bs orpti on of bi l e s a l ts , a nd a myl oi dos i s s econda ry to
l ong-s ta ndi ng i nfl a mma tory a nd s uppura ti ve di s ea s e.
Thromboembol i c di s ea s e ma y occur a s a res ul t of mul ti pl e fa ctors i n a l l 3 ca tegori es .
Treatment
Supporti ve ca re
5-Ami nos a l i cyl i c a ci d
Corti cos teroi ds
Immunomodul a ti ng drugs
Anti cytoki ne drugs
Someti mes a nti bi oti cs (eg, metroni da zol e, ci profl oxa ci n) a nd probi oti cs
Severa l cl a s s es of drugs a re hel pful for IBD. Deta i l s of thei r s el ecti on a nd us e a re di s cus s ed under ea ch di s order.
5-Aminosalicylic acid (5-ASA, mesalamine): 5-ASA bl ocks producti on of pros ta gl a ndi ns a nd l eukotri enes a nd ha s other benefi ci a l effects on the
i nfl a mma tory ca s ca de. Beca us e 5-ASA i s a cti ve onl y i ntra l umi na l l y a nd i s ra pi dl y a bs orbed by the proxi ma l s ma l l bowel , i t mus t be formul a ted for
del a yed a bs orpti on when gi ven ora l l y. Sul fa s a l a zi ne, the ori gi na l a gent i n thi s cl a s s , del a ys a bs orpti on by compl exi ng 5-ASA wi th a s ul fa moi ety,
s ul fa pyri di ne. The compl ex i s cl ea ved by ba cteri a l fl ora i n the l ower i l eum a nd col on, rel ea s i ng the 5-ASA. The s ul fa moi ety, however, ca us es
numerous a dvers e effects (eg, na us ea , dys peps i a , hea da che), i nterferes wi th fol a te (fol i c a ci d) a bs orpti on, a nd occa s i ona l l y ca us es s eri ous
a dvers e rea cti ons (eg, hemol yti c a nemi a or a gra nul ocytos i s a nd, ra rel y, hepa ti ti s or pneumoni ti s ). Revers i bl e decrea s es i n s perm count a nd
moti l i ty occur i n up to 80% of men. If us ed, s ul fa s a l a zi ne s houl d be gi ven wi th food, i ni ti a l l y i n a l ow dos a ge (eg, 0.5 g po bi d) a nd gra dua l l y
i ncrea s ed over s evera l da ys to 1 to 2 g bi d to ti d. Pa ti ents s houl d ta ke da i l y fol a te s uppl ements 1 mg po a nd ha ve CBC a nd l i ver tes ts every 6 to 12
mo. Acute i nters ti ti a l nephri ti s s econda ry to mes a l a mi ne occurs ra rel y; peri odi c moni tori ng of rena l functi on i s a dvi s a bl e beca us e mos t ca s es a re
revers i bl e i f recogni zed ea rl y.
Newer drugs tha t compl ex 5-ASA wi th other vehi cl es s eem a l mos t equa l l y effecti ve but ha ve fewer a dvers e effects . Ol s a l a zi ne (a 5-ASA di mer) a nd
ba l s a l a zi de (5-ASA conjuga ted to a n i na cti ve compound) a re cl ea ved by ba cteri a l a zoreducta s es (a s i s s ul fa s a l a zi ne). Thes e drugs a re a cti va ted
ma i nl y i n the col on a nd a re l es s effecti ve for proxi ma l s ma l l -bowel di s ea s e. Ol s a l a zi ne dos a ge i s 500 to 1500 mg po bi d, a nd ba l s a l a zi de i s 2.25 g
po ti d. Ol s a l a zi ne s ometi mes ca us es di a rrhea , es peci a l l y i n pa ti ents wi th pa ncol i ti s . Thi s probl em i s mi ni mi zed by gra dua l es ca l a ti on of dos e
a nd a dmi ni s tra ti on wi th mea l s .
Other forms of 5-ASA us e del a yed-rel ea s e coa ti ngs . As a col (typi ca l dos e 800 to 1200 mg po ti d) i s 5-ASA coa ted wi th a n a cryl i c pol ymer whos e pH
s ol ubi l i ty del a ys rel ea s e of the drug unti l entry i nto the di s ta l i l eum a nd col on. Penta s a (1 g po qi d) i s 5-ASA enca ps ul a ted i n ethyl cel l ul os e
mi crogra nul es tha t rel ea s e 35% of the drug i n the s ma l l bowel . Two once/da y formul a ti ons of mes a l a mi ne (Li a l da , Apri s o) a re a va i l a bl e; thi s l es s
frequent dos i ng ma y i mprove a dherence.
5-ASA i s a l s o a va i l a bl e a s a s uppos i tory (500 or 1000 mg a t bedti me or bi d) or enema (4 g a t bedti me or bi d) for procti ti s a nd l eft-s i ded col on
di s ea s e. Thes e recta l prepa ra ti ons a re effecti ve for both a cute trea tment a nd l ong-term ma i ntena nce i n procti ti s a nd l eft-s i ded col on di s ea s e,
a nd they ha ve i ncrementa l benefi t i n combi na ti on wi th ora l 5-ASA.
Corticosteroids: Corti cos teroi ds a re us eful for a cute fl a re-ups of mos t forms of IBD when 5-ASA compounds a re i na dequa te. However, corti cos teroi ds
a re not a ppropri a te for ma i ntena nce. IV hydrocorti s one 300 mg/da y or methyl predni s ol one 60 to 80 mg/da y by conti nuous dri p or i n di vi ded dos es
i s us ed for s evere di s ea s e; ora l predni s one or predni s ol one 40 to 60 mg once/da y ma y be us ed for modera te di s ea s e. Trea tment i s conti nued unti l
s ymptoms remi t (us ua l l y 7 to 28 da ys ) a nd then ta pered by 5 to 10 mg weekl y to 20 mg once/da y. Trea tment i s then further ta pered by 2.5 to 5 mg
weekl y whi l e i ns ti tuti ng ma i ntena nce thera py wi th 5-ASA or i mmunomodul a tors . Advers e effects of s hort-term corti cos teroi ds i n hi gh dos es
i ncl ude hypergl ycemi a , hypertens i on, i ns omni a , hypera cti vi ty, a nd a cute ps ychoti c epi s odes .
Hydrocorti s one enema s or foa m ma y be us ed for procti ti s a nd l eft-s i ded col on di s ea s e; a s a n enema , 100 mg i n 60 mL of i s otoni c s ol uti on i s gi ven
once/da y or bi d. The enema s houl d be reta i ned i n the bowel a s l ong a s pos s i bl e; i ns ti l l a ti on a t ni ght, wi th the pa ti ent l yi ng on the l eft s i de wi th
hi ps el eva ted, ma y prol ong retenti on a nd extend di s tri buti on. Trea tment, i f effecti ve, s houl d be conti nued da i l y for a bout 2 to 4 wk, then every
other da y for 1 to 2 wk, a nd then gra dua l l y di s conti nued over 1 to 2 wk.
Budes oni de i s a corti cos teroi d wi th a hi gh (> 90%) fi rs t-pa s s l i ver meta bol i s m; thus , ora l a dmi ni s tra ti on ma y ha ve a s i gni fi ca nt effect on GI tra ct
di s ea s e but mi ni ma l a drena l s uppres s i on. Ora l budes oni de ha s fewer a dvers e effects tha n predni s ol one but i s not a s ra pi dl y effecti ve a nd i s
typi ca l l y us ed for l es s s evere di s ea s e. Budes oni de ma y be effecti ve i n ma i nta i ni ng remi s s i on for 3 to 6 mo but ha s not yet proved effecti ve for
l ong-term ma i ntena nce. Dos a ge i s 9 mg once/da y. It i s a l s o a va i l a bl e outs i de the US a s a n enema .
Immunomodulating drugs: Aza thi opri ne a nd i ts meta bol i te 6-merca ptopuri ne i nhi bi t T-cel l functi on. They a re effecti ve l ong-term a nd ma y di mi ni s h
corti cos teroi d requi rements a nd ma i nta i n remi s s i on for yea rs . Thes e drugs often requi re 1 to 3 mo to produce cl i ni ca l benefi ts , s o corti cos teroi ds
ca nnot be wi thdra wn unti l a t l ea s t the 2nd month. Dos a ge of a za thi opri ne i s us ua l l y 2.5 to 3.0 mg/kg po once/da y a nd 6-merca ptopuri ne 1.5 to 2.5
mg/kg po once/da y but va ri es dependi ng on i ndi vi dua l meta bol i s m. Si gns of bone ma rrow s uppres s i on mus t be moni tored wi th regul a r WBC count
(bi weekl y for 1 mo, then every 1 to 2 mo). Pa ncrea ti ti s or hi gh fever occurs i n a bout 3 to 5% of pa ti ents ; ei ther i s a n a bs ol ute contra i ndi ca ti on to
recha l l enge. Hepa totoxi ci ty i s ra rer a nd ca n be s creened by bl ood tes ts every 6 to 12 mo. Newl y a va i l a bl e bl ood tes ts tha t mea s ure the a cti vi ty of
one of the enzymes tha t meta bol i ze a za thi opri ne a nd 6-merca ptopuri ne a nd tha t di rectl y mea s ure meta bol i te l evel s ma y s ometi mes be hel pful i n
ens uri ng s a fe a nd effecti ve drug dos a ges .
Methotrexa te 15 to 25 mg po or s c weekl y i s of benefi t to ma ny pa ti ents wi th corti cos teroi d-refra ctory or corti cos teroi d-dependent Crohn's di s ea s e,
even thos e who ha ve not res ponded to a za thi opri ne or 6-merca ptopuri ne. Advers e effects i ncl ude na us ea , vomi ti ng, a nd a s ymptoma ti c l i ver
functi on tes t a bnorma l i ti es . Fol a te 1 mg po once/da y ma y di mi ni s h s ome of the a dvers e effects . Al cohol us e, obes i ty, di a betes , a nd pos s i bl y
ps ori a s i s a re ri s k fa ctors for hepa totoxi ci ty. Pa ti ents wi th thes e condi ti ons s houl d ha ve a l i ver bi ops y a fter a tota l dos e of 1.5 g, but otherwi s e,
concerns over hepa totoxi ci ty a re too often exa ggera ted. Pul mona ry toxi ci ty ca n a l s o occur wi th methotrexa te thera py.
Cycl os pori ne, whi ch bl ocks l ymphocyte a cti va ti on, ma y benefi t pa ti ents wi th s evere UC unres pons i ve to corti cos teroi ds a nd who ma y otherwi s e
requi re col ectomy. Its onl y wel l -documented us e i n Crohn's di s ea s e i s for pa ti ents wi th refra ctory fi s tul a s or pyoderma . Ini ti a l dos e i s 4 mg/kg IV
i n conti nuous i nfus i on over 24 h; res ponders a re converted to a n ora l dos e of 6 to 8 mg/kg once/da y wi th ea rl y i ntroducti on of a za thi opri ne or 6merca ptopuri ne. Long-term us e (> 6 mo) i s contra i ndi ca ted by mul ti pl e a dvers e effects (eg, rena l toxi ci ty, s ei zures , opportuni s ti c i nfecti ons ,
hypertens i on, neuropa thy). Genera l l y, pa ti ents a re not offered cycl os pori ne unl es s there i s a rea s on to a voi d the s a fer cura ti ve opti on of
col ectomy. If the drug i s us ed, trough bl ood l evel s s houl d be kept between 200 to 400 ng/mL a nd Pneumocystis jirovecii prophyl a xi s s houl d be
cons i dered duri ng the peri od of concomi ta nt corti cos teroi d, cycl os pori ne, a nd a nti meta bol i te trea tment. Ta crol i mus , a n i mmunos uppres s a nt a l s o
us ed i n tra ns pl a nt pa ti ents , s eems a s effecti ve a s cycl os pori ne.
Anticytokine drugs: Infl i xi ma b, certol i zuma b, a nd a da l i muma b a re a nti bodi es to TNF. Thes e a gents ma y be us eful i n Crohn's di s ea s e; a ddi ti ona l l y
i nfl i xi ma b ma y be benefi ci a l i n UC for refra ctory or corti cos teroi d-dependent di s ea s e. Severa l a nti -i nterl euki n a nti bodi es a nd i nterl euki ns ma y
decrea s e the i nfl a mma tory res pons e a nd a re bei ng s tudi ed for Crohn's di s ea s e. An a nti body to l eukocyte a dhes i on mol ecul es (na ta l i zuma b) i s
a pproved a s monothera py for the mos t refra ctory ca s es of Crohn's di s ea s e; other a na l ogs (eg, vedol i zuma b) a re a l s o bei ng s tudi ed.
Infl i xi ma b i s gi ven a s a s i ngl e IV i nfus i on of 5 mg/kg over 2 h. Monothera py wi th i nfl i xi ma b i s cl ea rl y effecti ve for both i nducti on a nd ma i ntena nce
of remi s s i on, but s ome s tudi es s ugges t better s hort-term res ul ts when i nfl i xi ma b i s i ni ti a ted i n combi na ti on wi th a thi opuri ne (eg, a za thi opri ne).
Idea l l y, i nfl i xi ma b woul d eventua l l y be s topped a nd pa ti ents woul d be ma i nta i ned on the a nti meta bol i te, but thi s s tra tegy ha s not been
va l i da ted i n control l ed s tudi es . Corti cos teroi d ta peri ng ma y begi n a fter 2 wk. The i ni ti a l i nfl i xi ma b i nfus i on i s us ua l l y fol l owed by repea t
i nfus i ons a t weeks 2 a nd 6. Subs equentl y, i t i s gi ven every 8 wk or a t i nterva l s determi ned by the pa ti ent's cl i ni ca l cours e. Advers e effects duri ng
i nfus i on (i nfus i on rea cti on) i ncl ude i mmedi a te hypers ens i ti vi ty rea cti ons (eg, ra s h, i tchi ng, s ometi mes a na phyl a ctoi d rea cti ons ), fever, chi l l s ,
hea da che, a nd na us ea . Del a yed hypers ens i ti vi ty rea cti ons ha ve a l s o occurred. Anti -TNF drugs gi ven s ubcuta neous l y (eg, a da l i muma b) do not
ca us e i nfus i on rea cti ons , a l though they ma y ca us e l oca l erythema , pa i n, a nd i tchi ng (i njecti on s i te rea cti on). Pa ti ents who a re i ntol era nt or who
ha ve l os t thei r i ni ti a l res pons e to i nfl i xi ma b ma y res pond to a da l i muma b thera py.
Severa l pa ti ents ha ve di ed of s eps i s a fter i nfl i xi ma b us e, s o i t i s contra i ndi ca ted when uncontrol l ed ba cteri a l i nfecti on i s pres ent. Furthermore,
TB rea cti va ti on ha s been a ttri buted to thi s drug; therefore, s creeni ng by PPD a nd ches t x-ra y i s requi red before i ts us e. Lymphoma , demyel i na ti ng
di s ea s e, a nd l i ver a nd hema tol ogi c toxi ci ty a re other potenti a l concerns wi th a nti -TNF a nti body trea tment. Other a nti cytoki ne, a nti -i ntegri n, a nd
growth fa ctors a re under i nves ti ga ti on, a s i s l eukopheres i s thera py to depl ete a cti va ted i mmunocytes .
Antibiotics and probiotics: Anti bi oti cs ma y be hel pful i n Crohn's di s ea s e but a re of l i mi ted us e i n UC. Metroni da zol e 500 to 750 mg po ti d for 4 to 8 wk
ma y control mi l d Crohn's di s ea s e a nd hel p hea l fi s tul a s . However, a dvers e effects (pa rti cul a rl y neurotoxi ci ty) often precl ude compl eti on of
trea tment. Ci profl oxa ci n 500 to 750 mg po bi d ma y prove l es s toxi c. Ma ny experts recommend metroni da zol e a nd ci profl oxa ci n i n combi na ti on.
Ri fa xi mi n, a nona bs orba bl e a nti bi oti c, a t a dos e of 200 mg po ti d i s a l s o bei ng s tudi ed a s trea tment for a cti ve Crohn's di s ea s e.
Va ri ous nonpa thogeni c mi croorga ni s ms (eg, commens a l Escherichia coli, Lactobacillus s peci es , Saccharomyces) gi ven da i l y s erve a s probi oti cs a nd ma y
be effecti ve i n preventi ng pouchi ti s (s ee p. 176), but other thera peuti c rol es ha ve yet to be cl ea rl y defi ned. Thera peuti c i nfes ta ti on wi th the
pa ra s i te Trichuris suis ha s been tri ed i n a n effort to s ti mul a te T2-hel per cel l i mmuni ty a nd ma y decrea s e di s ea s e a cti vi ty i n UC.
Supportive care: Mos t pa ti ents a nd thei r fa mi l i es a re i nteres ted i n di et a nd s tres s ma na gement. Al though there a re a necdota l reports of cl i ni ca l
i mprovement on certa i n di ets , i ncl udi ng one wi th ri gi d ca rbohydra te res tri cti ons , control l ed tri a l s ha ve s hown no benefi t. Stres s ma na gement ma y
be hel pful .
Crohn's Disease
(Regi ona l Enteri ti s ; Gra nul oma tous Il ei ti s or Il eocol i ti s )
Crohn's disease is a chronic transmural inflammatory disease that usually affects the distal ileum and colon but may occur in any part of the GI tract. Symptoms
include diarrhea and abdominal pain. Abscesses, internal and external fistulas, and bowel obstruction may arise. Extraintestinal symptoms, particularly arthritis,
may occur. Diagnosis is by colonoscopy and barium contrast studies. Treatment is with 5-aminosalicylic acid, corticosteroids, immunomodulators, anticytokines,
antibiotics, and often surgery.
Pathophysiology
Crohn's di s ea s e begi ns wi th crypt i nfl a mma ti on a nd a bs ces s es , whi ch progres s to ti ny foca l a phthoi d ul cers . Thes e mucos a l l es i ons ma y devel op
i nto deep l ongi tudi na l a nd tra ns vers e ul cers wi th i nterveni ng mucos a l edema , crea ti ng a cha ra cteri s ti c cobbl es toned a ppea ra nce to the bowel .
Tra ns mura l s prea d of i nfl a mma ti on l ea ds to l ymphedema a nd thi ckeni ng of the bowel wa l l a nd mes entery. Mes enteri c fa t typi ca l l y extends onto
the s eros a l s urfa ce of the bowel . Mes enteri c l ymph nodes often enl a rge. Extens i ve i nfl a mma ti on ma y res ul t i n hypertrophy of the mus cul a ri s
mucos a e, fi bros i s , a nd s tri cture forma ti on, whi ch ca n l ea d to bowel obs tructi on. Abs ces s es a re common, a nd fi s tul a s often penetra te i nto
a djoi ni ng s tructures , i ncl udi ng other l oops of bowel , the bl a dder, or ps oa s mus cl e. Fi s tul a s ma y even extend to the s ki n of the a nteri or a bdomen
or fl a nks . Independentl y of i ntra -a bdomi na l di s ea s e a cti vi ty, peri a na l fi s tul a s a nd a bs ces s es occur i n 25 to 33% of ca s es ; thes e compl i ca ti ons a re
frequentl y the mos t troubl es ome a s pects of Crohn's di s ea s e.
Nonca s ea ti ng gra nul oma s ca n occur i n l ymph nodes , peri toneum, the l i ver, a nd a l l l a yers of the bowel wa l l . Al though pa thognomoni c when
pres ent, gra nul oma s a re not detected i n a bout ha l f of pa ti ents wi th Crohn's di s ea s e. The pres ence of gra nul oma s does not s eem to be rel a ted to
the cl i ni ca l cours e.
Segments of di s ea s ed bowel a re s ha rpl y dema rca ted from a dja cent norma l bowel ("s ki p a rea s "); hence, the na me regi ona l enteri ti s . About 35% of
Crohn's di s ea s e ca s es i nvol ve the i l eum a l one (i l ei ti s ); a bout 45% i nvol ve the i l eum a nd col on (i l eocol i ti s ), wi th a predi l ecti on for the ri ght s i de of
the col on; a nd a bout 20% i nvol ve the col on a l one (gra nul oma tous col i ti s ), mos t of whi ch, unl i ke ul cera ti ve col i ti s (UC), s pa re the rectum.
Occa s i ona l l y, the enti re s ma l l bowel i s i nvol ved (jejunoi l ei ti s ). The s toma ch, duodenum, or es opha gus i s cl i ni ca l l y i nvol ved onl y ra rel y, a l though
mi cros copi c evi dence of di s ea s e i s often detecta bl e i n the ga s tri c a ntrum, es peci a l l y i n younger pa ti ents . In the a bs ence of s urgi ca l i nterventi on,
the di s ea s e a l mos t never extends i nto a rea s of s ma l l bowel tha t a re not i nvol ved a t fi rs t di a gnos i s .
There i s a n i ncrea s ed ri s k of ca ncer i n a ffected s ma l l -bowel s egments . Pa ti ents wi th col oni c i nvol vement ha ve a l ong-term ri s k of col orecta l ca ncer
equa l to tha t of UC, gi ven the s a me extent a nd dura ti on of di s ea s e.
Symptoms and Signs
The mos t common i ni ti a l ma ni fes ta ti on i s chroni c di a rrhea wi th a bdomi na l pa i n, fever, a norexi a , a nd wei ght l os s . The a bdomen i s tender, a nd a
ma s s or ful l nes s ma y be pa l pa bl e. Gros s recta l bl eedi ng i s unus ua l except i n i s ol a ted col oni c di s ea s e, whi ch ma y ma ni fes t s i mi l a rl y to UC. Some
pa ti ents pres ent wi th a n a cute a bdomen tha t s i mul a tes a cute a ppendi ci ti s or i ntes ti na l obs tructi on. About 33% of pa ti ents ha ve peri a na l di s ea s e
(es peci a l l y fi s s ures a nd fi s tul a s ), whi ch i s s ometi mes the mos t promi nent or even i ni ti a l compl a i nt. In chi l dren, extra i ntes ti na l ma ni fes ta ti ons
frequentl y predomi na te over GI s ymptoms ; a rthri ti s , FUO, a nemi a , or growth reta rda ti on ma y be a pres enti ng s ymptom, wherea s a bdomi na l pa i n
or di a rrhea ma y be a bs ent.
Wi th recurrent di s ea s e, s ymptoms va ry. Pa i n i s mos t common a nd occurs wi th both s i mpl e recurrence a nd a bs ces s forma ti on. Pa ti ents wi th s evere
fl a re-up or a bs ces s a re l i kel y to ha ve ma rked tendernes s , gua rdi ng, rebound, a nd a genera l toxi c a ppea ra nce. Stenoti c s egments ma y ca us e bowel
obs tructi on, wi th col i cky pa i n, di s tenti on, obs ti pa ti on, a nd vomi ti ng. Adhes i ons from previ ous s urgery ma y a l s o ca us e bowel obs tructi on, whi ch
begi ns ra pi dl y, wi thout the prodrome of fever, pa i n, a nd ma l a i s e typi ca l of obs tructi on due to a Crohn's di s ea s e fl a re-up. An enteroves i ca l fi s tul a
ma y produce a i r bubbl es i n the uri ne (pneuma turi a ). Dra i ni ng cuta neous fi s tul a s ma y occur. Free perfora ti on i nto the peri tonea l ca vi ty i s unus ua l .
Chroni c di s ea s e ca us es a va ri ety of s ys temi c s ymptoms , i ncl udi ng fever, wei ght l os s , undernutri ti on, a nd extra i ntes ti na l ma ni fes ta ti ons (s ee p.
166).
The Vi enna Cl a s s i fi ca ti on a nd i ts recent Montrea l modi fi ca ti on ca tegori ze Crohn's di s ea s e i nto 3 pri nci pa l pa tterns : (1) pri ma ri l y i nfl a mma tory,
whi ch a fter s evera l yea rs commonl y evol ves i nto ei ther (2) pri ma ri l y s tenoti c or obs tructi ng or (3) pri ma ri l y penetra ti ng or fi s tul i zi ng. Thes e
di fferent cl i ni ca l pa tterns di cta te di fferent thera peuti c a pproa ches . Some geneti c s tudi es s ugges t a mol ecul a r ba s i s for thi s cl a s s i fi ca ti on.
Diagnosis
Ba ri um x-ra ys of the s toma ch, s ma l l bowel , a nd col on
Abdomi na l CT (conventi ona l or CT enterogra phy)
Someti mes ma gneti c res ona nce (MR) enterogra phy, upper endos copy, a nd/or col onos copy
Crohn's di s ea s e s houl d be s us pected i n a pa ti ent wi th i nfl a mma tory or obs tructi ve s ymptoms or i n a pa ti ent wi thout promi nent GI s ymptoms but
wi th peri a na l fi s tul a s or a bs ces s es or wi th otherwi s e unexpl a i ned a rthri ti s , erythema nodos um, fever, a nemi a , or (i n a chi l d) s tunted growth. A
fa mi l y hi s tory of Crohn's di s ea s e a l s o i ncrea s es the i ndex of s us pi ci on. Si mi l a r s ymptoms a nd s i gns (eg, a bdomi na l pa i n, di a rrhea ) ma y be ca us ed
by other GI di s orders . Di fferenti a ti on from UC (s ee Ta bl e 19-1) ma y be a n i s s ue i n the 20% of ca s es i n whi ch Crohn's di s ea s e i s confi ned to the
col on. However, beca us e trea tment i s s i mi l a r, thi s di s ti ncti on i s cri ti ca l onl y when s urgery or experi menta l thera py i s contempl a ted.
Pa ti ents pres enti ng wi th a n a cute a bdomen (ei ther i ni ti a l l y or on rel a ps e) s houl d ha ve fl a t a nd upri ght a bdomi na l x-ra ys a nd a n a bdomi na l CT
s ca n. Thes e s tudi es ma y s how obs tructi on, a bs ces s es or fi s tul a s , a nd other pos s i bl e ca us es of a n a cute a bdomen (eg, a ppendi ci ti s ). Ul tra s ound
ma y better del i nea te gynecol ogi c pa thol ogy i n women wi th l ower a bdomi na l a nd pel vi c pa i n.
If i ni ti a l pres enta ti on i s l es s a cute, a n upper GI s eri es wi th s ma l l -bowel fol l ow-through a nd s pot fi l ms of the termi na l i l eum i s preferred over
conventi ona l CT. However, newer techni ques of CT or MR enterogra phy, whi ch combi ne hi gh-res ol uti on CT or MR i ma gi ng wi th l a rge vol umes of
i nges ted contra s t, a re becomi ng the procedures of choi ce i n s ome centers . Thes e i ma gi ng s tudi es a re vi rtua l l y di a gnos ti c i f they s how
cha ra cteri s ti c s tri ctures or fi s tul a s wi th a ccompa nyi ng s epa ra ti on of bowel l oops . If fi ndi ngs a re ques ti ona bl e, CT enterocl ys i s or vi deo ca ps ul e
enteros copy ma y s how s uperfi ci a l a phthous a nd l i nea r ul cers . Ba ri um enema x-ra y ma y be us ed i f s ymptoms s eem predomi na ntl y col oni c (eg,
di a rrhea ) a nd ma y s how refl ux of ba ri um i nto the termi na l i l eum wi th i rregul a ri ty, nodul a ri ty, s ti ffnes s , wa l l thi ckeni ng, a nd a na rrowed l umen.
Di fferenti a l di a gnos es i n pa ti ents wi th s i mi l a r x-ra y fi ndi ngs i ncl ude ca ncer of the cecum, i l ea l ca rci noi d, l ymphoma , s ys temi c va s cul i ti s , ra di a ti on
enteri ti s , i l eoceca l TB, a nd a meboma .
In a typi ca l ca s es (eg, predomi na ntl y di a rrhea , wi th mi ni ma l pa i n), eva l ua ti on i s s i mi l a r to s us pected UC, wi th col onos copy (i ncl udi ng bi ops y,
s a mpl i ng for enteri c pa thogens , a nd, when pos s i bl e, vi s ua l i za ti on of the termi na l i l eum). Upper GI endos copy ma y i denti fy s ubtl e ga s troduodena l
i nvol vement even i n the a bs ence of upper GI s ymptoms .
La bora tory tes ts s houl d be done to s creen for a nemi a , hypoa l bumi nemi a , a nd el ectrol yte a bnorma l i ti es . Li ver functi on tes ts s houl d be done;
el eva ted a l ka l i ne phos pha ta s e a nd -gl uta myl tra ns pepti da s e l evel s i n pa ti ents wi th ma jor col oni c i nvol vement s ugges t pos s i bl e pri ma ry
s cl eros i ng chol a ngi ti s . Leukocytos i s or i ncrea s ed l evel s of a cute-pha s e rea cta nts (eg, ESR, C-rea cti ve protei n) a re nons peci fi c but ma y be us ed
s eri a l l y to moni tor di s ea s e a cti vi ty.
Peri nucl ea r a nti neutrophi l cytopl a s mi c a nti bodi es a re pres ent i n 60 to 70% of pa ti ents wi th UC a nd i n onl y 5 to 20% of pa ti ents wi th Crohn's
di s ea s e. Anti -Saccharomyces cerevisiae a nti bodi es a re rel a ti vel y s peci fi c for Crohn's di s ea s e. However, thes e tes ts do not rel i a bl y s epa ra te the 2
di s ea s es . They ha ve uncerta i n va l ue i n ca s es of i ndetermi na te col i ti s a nd a re not recommended for routi ne di a gnos i s .
Prognosis
Es ta bl i s hed Crohn's di s ea s e i s ra rel y cured but i s cha ra cteri zed by i ntermi ttent exa cerba ti ons a nd remi s s i ons . Some pa ti ents ha ve s evere di s ea s e
wi th frequent, debi l i ta ti ng peri ods of pa i n. However, wi th judi ci ous medi ca l thera py a nd, where a ppropri a te, s urgi ca l thera py, mos t pa ti ents
functi on wel l a nd a da pt s ucces s ful l y. Di s ea s e-rel a ted morta l i ty i s very l ow. GI ca ncer, i ncl udi ng ca ncer of the col on a nd s ma l l bowel , i s the
l ea di ng ca us e of exces s Crohn's di s ea s e-rel a ted morta l i ty.
Treatment
Lopera mi de or a nti s pa s modi cs for s ymptom rel i ef
5-Ami nos a l i cyl i c a ci d (5-ASA) or a nti bi oti cs
Other drugs dependi ng on s ymptoms a nd s everi ty
Someti mes s urgery
Deta i l s of s peci fi c drugs a nd dos a ges a re di s cus s ed on p. 167.
General management: Cra mps a nd di a rrhea ma y be rel i eved by ora l a dmi ni s tra ti on of l opera mi de 2 to 4 mg or a nti s pa s modi c drugs up to 4
ti mes /da y (i dea l l y before mea l s ). Such s ymptoma ti c trea tment i s s a fe, except i n ca s es of s evere, a cute Crohn's col i ti s , whi ch ma y progres s to toxi c
mega col on a s i n UC. Hydrophi l i c muci l l oi ds (eg, methyl cel l ul os e or ps yl l i um prepa ra ti ons ) s ometi mes hel p prevent a na l i rri ta ti on by i ncrea s i ng
s tool fi rmnes s . Di eta ry rougha ge i s to be a voi ded i n s tri cturi ng di s ea s e or a cti ve col oni c i nfl a mma ti on.
Mild to moderate disease: Thi s ca tegory i ncl udes a mbul a tory pa ti ents who tol era te ora l i nta ke a nd ha ve no s i gns of toxi ci ty, tendernes s , ma s s , or
obs tructi on. 5-ASA (mes a l a mi ne) i s commonl y us ed a s fi rs t-l i ne trea tment, a l though i ts benefi ts for s ma l l -bowel di s ea s e a re modes t a t bes t.
Penta s a i s the mos t effecti ve formul a ti on for di s ea s e proxi ma l to the termi na l i l eum; As a col i s effecti ve i n di s ta l i l ea l di s ea s e. Al l formul a ti ons
a re roughl y equi va l ent for Crohn's col i ti s , a l though none of the newer prepa ra ti ons ri va l s ul fa s a l a zi ne for effi ca cy on a dos e-for-dos e ba s i s .
Anti bi oti cs a re cons i dered a fi rs t-l i ne a gent by s ome cl i ni ci a ns , or they ma y be res erved for pa ti ents not res pondi ng to 4 wk of 5-ASA; thei r us e i s
s tri ctl y empi ri c. Wi th a ny of thes e drugs , 8 to 16 wk of trea tment ma y be requi red.
Res ponders s houl d recei ve ma i ntena nce thera py.
Moderate to severe disease: Pa ti ents wi thout fi s tul a s or a bs ces s es but wi th s i gni fi ca nt pa i n, tendernes s , fever, or vomi ti ng, or thos e who ha ve not
res ponded to trea tment for mi l d di s ea s e, requi re corti cos teroi ds , ei ther ora l or pa rentera l , dependi ng on s everi ty of s ymptoms a nd frequency of
vomi ti ng. Ora l predni s one or predni s ol one ma y a ct more ra pi dl y a nd rel i a bl y tha n ora l budes oni de, but budes oni de ha s s omewha t fewer a dvers e
effects a nd i s cons i dered the corti cos teroi d of choi ce i n ma ny centers , es peci a l l y i n Europe. Pa ti ents not res pondi ng to corti cos teroi ds , or thos e
whos e dos es ca nnot be ta pered, s houl d recei ve a za thi opri ne, 6-merca ptopuri ne, or pos s i bl y methotrexa te. Infl i xi ma b i s preferred by s ome a s a
s econd-l i ne a gent a fter corti cos teroi ds , a nd even a s a fi rs t-l i ne a gent i n preference to corti cos teroi ds , but i t i s contra i ndi ca ted i n a cti ve
uncontrol l ed i nfecti on.
Obs tructi on i s ma na ged i ni ti a l l y wi th na s oga s tri c s ucti on a nd IV fl ui ds . Obs tructi on due to uncompl i ca ted Crohn's di s ea s e s houl d res ol ve wi thi n a
few da ys a nd therefore does not requi re pa rentera l nutri ti on; a bs ence of prompt res pons e i ndi ca tes a compl i ca ti on or a nother eti ol ogy a nd
dema nds i mmedi a te s urgery.
Fulminant disease or abscess: Pa ti ents wi th toxi c a ppea ra nce, hi gh fever, pers i s tent vomi ti ng, rebound, or a tender or pa l pa bl e ma s s mus t be
hos pi ta l i zed for a dmi ni s tra ti on of IV fl ui ds a nd a nti bi oti cs . Abs ces s es mus t be dra i ned, ei ther percuta neous l y or s urgi ca l l y. IV corti cos teroi ds
s houl d be gi ven onl y when i nfecti on ha s been rul ed out or control l ed. If there i s no res pons e to corti cos teroi ds a nd a nti bi oti cs wi thi n 5 to 7 da ys ,
s urgery i s us ua l l y i ndi ca ted.
Fistulas: Fi s tul a s a re trea ted i ni ti a l l y wi th metroni da zol e a nd ci profl oxa ci n. Pa ti ents who do not res pond i n 3 to 4 wk ma y recei ve a n
i mmunomodul a tor (eg, a za thi opri ne, 6-merca ptopuri ne), wi th or wi thout a n i nducti on regi men of i nfl i xi ma b for more ra pi d res pons e. Cycl os pori ne
i s a n a l terna ti ve, but fi s tul a s often rel a ps e a fter trea tment. Severe refra ctory peri a na l fi s tul a s ma y requi re tempora ry di verti ng col os tomy but
a l mos t i nva ri a bl y recur a fter reconnecti on; hence, di vers i on i s more a ppropri a tel y cons i dered a prepa ra ti on for defi ni ti ve s urgery or a t bes t a n
a djunct to i nfl i xi ma b ra ther tha n a pri ma ry trea tment.
Maintenance therapy: Pa ti ents who requi re onl y 5-ASA or a n a nti bi oti c to a chi eve remi s s i on ca n be ma i nta i ned on thi s drug. Pa ti ents requi ri ng a cute
trea tment wi th corti cos teroi ds or i nfl i xi ma b genera l l y requi re a za thi opri ne, 6-merca ptopuri ne, methotrexa te, or i nfl i xi ma b for ma i ntena nce.
Sys temi ca l l y a cti ve corti cos teroi ds a re nei ther s a fe nor effecti ve for l ong-term ma i ntena nce, a l though budes oni de ha s been s hown to del a y
rel a ps e wi th fewer a dvers e effects . Pa ti ents who res pond to i nfl i xi ma b for a cute di s ea s e but who a re not wel l ma i nta i ned on a nti meta bol i tes
ma y s ta y i n remi s s i on wi th repea t dos es of i nfl i xi ma b 5 to 10 mg/kg a t 8-wk i nterva l s . Moni tori ng duri ng remi s s i on ca n be done by fol l owi ng
s ymptoms a nd bl ood tes ts a nd does not requi re routi ne x-ra ys or col onos copy (other tha n regul a r s urvei l l a nce for dys pl a s i a a fter 7 to 8 yr of
di s ea s e).
Surgery: Even though a bout 70% of pa ti ents ul ti ma tel y requi re a n opera ti on, s urgery i s a l wa ys done rel ucta ntl y. It i s bes t res erved for recurrent
i ntes ti na l obs tructi on or i ntra cta bl e fi s tul a s or a bs ces s es . Res ecti on of the i nvol ved bowel ma y a mel i ora te s ymptoms but does not cure the
di s ea s e, whi ch i s l i kel y to recur even a fter res ecti on of a l l cl i ni ca l l y a ppa rent l es i ons . The recurrence ra te, defi ned by endos copi c l es i ons a t the
a na s tomoti c s i te, i s > 70% a t 1 yr a nd > 85% a t 3 yr; defi ned by cl i ni ca l s ymptoms , i t i s a bout 25 to 30% a t 3 yr a nd 40 to 50% a t 5 yr. Ul ti ma tel y,
further s urgery i s requi red i n nea rl y 50% of ca s es . However, recurrence ra tes s eem to be reduced by ea rl y pos topera ti ve prophyl a xi s wi th 6merca ptopuri ne, metroni da zol e, or pos s i bl y i nfl i xi ma b or 5-ASA. Moreover, when s urgery i s done for a ppropri a te i ndi ca ti ons , a l mos t a l l pa ti ents
ha ve i mproved qua l i ty of l i fe.
Ulcerative Colitis
Ulcerative colitis (UC) is a chronic inflammatory and ulcerative disease arising in the colonic mucosa, characterized most often by bloody diarrhea. Extraintestinal
symptoms, particularly arthritis, may occur. Long-term risk of colon cancer is high. Diagnosis is by colonoscopy. Treatment is with 5-aminosalicylic acid,
corticosteroids, immunomodulators, anticytokines, antibiotics, and occasionally surgery.
Pathophysiology
UC us ua l l y begi ns i n the rectum. It ma y rema i n l oca l i zed to the rectum (ul cera ti ve procti ti s ) or extend proxi ma l l y, s ometi mes i nvol vi ng the enti re
col on. Ra rel y, i t i nvol ves mos t of the l a rge bowel a t once.
The i nfl a mma ti on ca us ed by UC a ffects the mucos a a nd s ubmucos a , a nd there i s a s ha rp border between norma l a nd a ffected ti s s ue. Onl y i n
s evere di s ea s e i s the mus cul a ri s i nvol ved. In ea rl y ca s es , the mucous membra ne i s erythema tous , fi nel y gra nul a r, a nd fri a bl e, wi th l os s of the
norma l va s cul a r pa ttern a nd often wi th s ca ttered hemorrha gi c a rea s . La rge mucos a l ul cers wi th copi ous purul ent exuda te cha ra cteri ze s evere
di s ea s e. Is l a nds of rel a ti vel y norma l or hyperpl a s ti c i nfl a mma tory mucos a (ps eudopol yps ) project a bove a rea s of ul cera ted mucos a . Fi s tul a s a nd
a bs ces s es do not occur.
Toxic or fulminant colitis occurs when tra ns mura l extens i on of ul cera ti on res ul ts i n l oca l i zed i l eus a nd peri toni ti s . Wi thi n hours to da ys , the col on
l os es mus cul a r tone a nd begi ns to di l a te. The terms toxi c mega col on or toxi c di l a ti on a re di s coura ged beca us e the toxi c i nfl a mma tory s ta te a nd
i ts compl i ca ti ons ca n occur wi thout fra nk mega col on (defi ned a s tra ns vers e col on > 6 cm di a meter duri ng a n exa cerba ti on). Toxi c col i ti s i s a
medi ca l emergency tha t us ua l l y occurs s ponta neous l y i n the cours e of very s evere col i ti s but i s s ometi mes preci pi ta ted by opi oi d or
a nti chol i nergi c a nti di a rrhea l drugs . Col oni c perfora ti on ma y occur, whi ch i ncrea s es morta l i ty s i gni fi ca ntl y.
Symptoms and Signs
Bl oody di a rrhea of va ri ed i ntens i ty a nd dura ti on i s i nters pers ed wi th a s ymptoma ti c i nterva l s . Us ua l l y a n a tta ck begi ns i ns i di ous l y, wi th i ncrea s ed
urgency to defeca te, mi l d l ower a bdomi na l cra mps , a nd bl ood a nd mucus i n the s tool s . Some ca s es devel op a fter a n i nfecti on (eg, a mebi a s i s ,
ba ci l l a ry dys entery).
When ul cera ti on i s confi ned to the rectos i gmoi d, the s tool ma y be norma l or ha rd a nd dry, but recta l di s cha rges of mucus l oa ded wi th RBCs a nd
WBCs a ccompa ny or occur between bowel movements . Sys temi c s ymptoms a re a bs ent or mi l d. If ul cera ti on extends proxi ma l l y, s tool s become
l oos er a nd the pa ti ent ma y ha ve > 10 bowel movements per da y, often wi th s evere cra mps a nd di s tres s i ng recta l tenes mus , wi thout res pi te a t
ni ght. The s tool s ma y be wa tery or conta i n mucus a nd frequentl y cons i s t a l mos t enti rel y of bl ood a nd pus .
Toxi c or ful mi na nt col i ti s ma ni fes ts i ni ti a l l y wi th s udden vi ol ent di a rrhea , fever to 40 C (104 F), a bdomi na l pa i n, s i gns of peri toni ti s (eg, rebound
tendernes s ), a nd profound toxemi a .
Sys temi c s ymptoms a nd s i gns , more common wi th extens i ve UC, i ncl ude ma l a i s e, fever, a nemi a , a norexi a , a nd wei ght l os s . Extra i ntes ti na l
ma ni fes ta ti ons (pa rti cul a rl y joi nt a nd s ki n compl i ca ti ons s ee p. 167) a re mos t common when s ys temi c s ymptoms a re pres ent.
Diagnosis
Stool cul tures a nd mi cros copy (to excl ude i nfecti ous ca us es )
Si gmoi dos copy wi th bi ops y
Initial presentation: Di a gnos i s i s s ugges ted by typi ca l s ymptoms a nd s i gns , pa rti cul a rl y when a ccompa ni ed by extra i ntes ti na l ma ni fes ta ti ons or a
hi s tory of previ ous s i mi l a r a tta cks . UC s houl d be di s ti ngui s hed from Crohn's di s ea s e (s ee Ta bl e 19-1) but more i mporta ntl y from other ca us es of
a cute col i ti s (eg, i nfecti on; i n el derl y pa ti ents , i s chemi a ).
In a l l pa ti ents , s tool cul tures for enteri c pa thogens s houl d be done, a nd Entamoeba histolytica s houl d be excl uded by exa mi na ti on of fres h s tool
s peci mens . When a mebi a s i s i s s us pected beca us e of epi demi ol ogi c or tra vel hi s tory, s erol ogi c ti ters a nd bi ops i es s houl d be done. Hi s tory of
pri or a nti bi oti c us e or recent hos pi ta l i za ti on s houl d prompt s tool a s s a y for Clostridium difficile toxi n. Pa ti ents a t ri s k s houl d be tes ted for HIV,
gonorrhea , herpes vi rus , chl a mydi a , a nd a mebi a s i s . Opportuni s ti c i nfecti ons (eg, cytomega l ovi rus , Mycobacterium avium-intracellulare) or Ka pos i 's
s a rcoma mus t a l s o be cons i dered i n i mmunos uppres s ed pa ti ents . In women us i ng ora l contra cepti ves , contra cepti ve-i nduced col i ti s i s pos s i bl e;
i t us ua l l y res ol ves s ponta neous l y a fter hormone thera py i s s topped.
Si gmoi dos copy s houl d be done; i t a l l ows vi s ua l confi rma ti on of col i ti s a nd permi ts di rect s a mpl i ng of s tool or mucus for cul ture a nd mi cros copi c
eva l ua ti on, a s wel l a s bi ops y of a ffected a rea s . Al though vi s ua l i ns pecti on a nd bi ops i es ma y be nondi a gnos ti c, beca us e there i s much overl a p i n
a ppea ra nce a mong di fferent types of col i ti s , a cute, s el f-l i mi ted, i nfecti ous col i ti s ca n us ua l l y be di s ti ngui s hed hi s tol ogi ca l l y from chroni c
i di opa thi c UC or Crohn's col i ti s . Severe peri a na l di s ea s e, recta l s pa ri ng, a bs ence of bl eedi ng, a nd a s ymmetri c or s egmenta l i nvol vement of the
col on i ndi ca te Crohn's di s ea s e ra ther tha n UC (s ee Ta bl e 19-1). Col onos copy i s us ua l l y unneces s a ry i ni ti a l l y but s houl d be done el ecti vel y i f
i nfl a mma ti on ha s extended proxi ma l to the rea ch of the s i gmoi dos cope.
La bora tory tes ts s houl d be done to s creen for a nemi a , hypoa l bumi nemi a , a nd el ectrol yte a bnorma l i ti es . Li ver functi on tes ts s houl d be done;
el eva ted a l ka l i ne phos pha ta s e a nd -gl uta myl tra ns pepti da s e l evel s s ugges t pos s i bl e pri ma ry s cl eros i ng chol a ngi ti s . Peri nucl ea r a nti neutrophi l
cytopl a s mi c a nti bodi es a re rel a ti vel y s peci fi c (60 to 70%) for UC. Anti -Saccharomyces cerevisiae a nti bodi es a re rel a ti vel y s peci fi c for Crohn's di s ea s e.
However, thes e tes ts do not rel i a bl y s epa ra te the 2 di s ea s es a nd a re not recommended for routi ne di a gnos i s . Other pos s i bl e l a bora tory
a bnorma l i ti es i ncl ude l eukocytos i s , thrombocytos i s , a nd el eva ted a cute-pha s e rea cta nts (eg, ESR, C-rea cti ve protei n).
X-ra ys a re not di a gnos ti c but occa s i ona l l y s how a bnorma l i ti es . Pl a i n x-ra ys of the a bdomen ma y s how mucos a l edema , l os s of ha us tra ti on, a nd
a bs ence of formed s tool i n the di s ea s ed bowel . Ba ri um enema s hows s i mi l a r cha nges , a l bei t more cl ea rl y, a nd ma y a l s o s how ul cera ti ons , but
the enema s houl d not be done duri ng a n a cute pres enta ti on. A s hortened, ri gi d col on wi th a n a trophi c or ps eudopol ypoi d mucos a i s often s een
a fter s evera l yea rs ' i l l nes s . X-ra y fi ndi ngs of thumbpri nti ng a nd s egmenta l di s tri buti on a re more s ugges ti ve of i ntes ti na l i s chemi a or pos s i bl y
Crohn's col i ti s ra ther tha n of UC.
Recurrent symptoms: Pa ti ents wi th known di s ea s e a nd a recurrence of typi ca l s ymptoms s houl d be exa mi ned, but extens i ve tes ti ng i s not a l wa ys
requi red. Dependi ng on dura ti on a nd s everi ty of s ymptoms , s i gmoi dos copy or col onos copy ma y be done a nd a CBC obta i ned. Cul tures , ova a nd
pa ra s i te exa mi na ti on, a nd C. difficile toxi n a s s a y s houl d be done when there a re a typi ca l fea tures to the rel a ps e or when there i s a n exa cerba ti on
a fter prol onged remi s s i on, duri ng a conta gi ous outbrea k, a fter a nti bi oti c expos ure, or whenever the cl i ni ci a n i s s us pi ci ous .
Fulminant symptoms: Pa ti ents requi re further eva l ua ti on duri ng s evere fl a re-ups . Fl a t a nd upri ght a bdomi na l x-ra ys s houl d be ta ken; they ma y s how
mega col on or i ntra l umi na l ga s a ccumul a ted over a l ong, conti nuous , pa ra l yzed s egment of col ona res ul t of l os t mus cl e tone. Col onos copy a nd
ba ri um enema s houl d be a voi ded beca us e of the ri s k of perfora ti on. CBC, ESR, el ectrol ytes , PT, PTT, a nd type a nd cros s ma tch s houl d be obta i ned.
The pa ti ent mus t be wa tched cl os el y for progres s i ve peri toni ti s or perfora ti on. Percus s i on over the l i ver i s i mporta nt beca us e l os s of hepa ti c
dul l nes s ma y be the fi rs t cl i ni ca l s i gn of free perfora ti on, es peci a l l y i n a pa ti ent whos e peri tonea l s i gns a re s uppres s ed by hi gh-dos e
corti cos teroi ds . Abdomi na l x-ra ys a re ta ken every 1 or 2 da ys to fol l ow the cours e of col oni c di s tenti on a nd to detect free or i ntra mura l a i r.
Prognosis
Us ua l l y, UC i s chroni c wi th repea ted exa cerba ti ons a nd remi s s i ons . In a bout 10% of pa ti ents , a n i ni ti a l a tta ck becomes ful mi na nt wi th ma s s i ve
hemorrha ge, perfora ti on, or s eps i s a nd toxemi a . Compl ete recovery a fter a s i ngl e a tta ck occurs i n a nother 10%.
Pa ti ents wi th l oca l i zed ul cera ti ve procti ti s ha ve the bes t prognos i s . Severe s ys temi c ma ni fes ta ti ons , toxi c compl i ca ti ons , a nd ma l i gna nt
degenera ti on a re unl i kel y, a nd l a te extens i on of the di s ea s e occurs i n onl y a bout 20 to 30%. Surgery i s ra rel y requi red, a nd l i fe expecta ncy i s
norma l . The s ymptoms , however, ma y prove s tubborn a nd refra ctory. Moreover, beca us e extens i ve UC ma y begi n i n the rectum a nd s prea d
proxi ma l l y, procti ti s s houl d not be cons i dered l oca l i zed unti l i t ha s been obs erved for 6 mo. Loca l i zed di s ea s e tha t l a ter extends i s often more
s evere a nd more refra ctory to thera py.
Colon cancer: The ri s k of col on ca ncer i s proporti ona l to the dura ti on of di s ea s e a nd a mount of col on a ffected, but not neces s a ri l y to the cl i ni ca l
s everi ty of the a tta cks . Some recent s tudi es s ugges t tha t s us ta i ned mi cros copi c i nfl a mma ti on i s a ri s k fa ctor, a nd tha t us e of a mi nos a l i cyl a te to
control i nfl a mma ti on i s protecti ve. Ca ncer begi ns to a ppea r by 7 yr from ons et of i l l nes s i n pa ti ents wi th extens i ve col i ti s . The cumul a ti ve
l i kel i hood of ca ncer i s a bout 3% a t 15 yr, 5% a t 20 yr, a nd 9% a t 25 yr, repres enti ng a n a nnua l ri s k of a bout 0.5 to 1% a fter the 10th yr. There i s
proba bl y no hi gher a bs ol ute ca ncer ri s k a mong pa ti ents wi th chi l dhood-ons et col i ti s i ndependent of the l onger dura ti on of di s ea s e. However,
pa ti ents who ha ve i nfl a mma tory bowel di s ea s e a nd pri ma ry s cl eros i ng chol a ngi ti s a re a t a hi gher ri s k of ca ncer from the ti me of col i ti s di a gnos i s .
Regul a r col onos copi c s urvei l l a nce, prefera bl y duri ng remi s s i on, i s a dvi s ed for pa ti ents wi th di s ea s e dura ti on > 8 to 10 yr (except for thos e wi th
i s ol a ted procti ti s ). Endos copi c bi ops i es s houl d be ta ken every 10 cm throughout the col on. Newer techni ques , es peci a l l y chromoendos copy, ma y
better i denti fy a rea s of s us pi ci on i n preference to tota l l y ra ndom bi ops i es . Any gra de of defi ni te dys pl a s i a wi thi n a n a rea a ffected by col i ti s i s
l i a bl e to progres s to more a dva nced neopl a s i a a nd even ca ncer a nd i s a s trong i ndi ca ti on for tota l col ectomy unl es s the dys pl a s i a i s s tri ctl y
confi ned to a di s crete, compl etel y exci s a bl e pol yp. It i s i mporta nt to di s ti ngui s h defi ni te neopl a s ti c dys pl a s i a from rea cti ve or regenera ti ve a typi a
s econda ry to i nfl a mma ti on. However, i f the dys pl a s i a i s unequi voca l , del a yi ng col ectomy i n fa vor of repea ted fol l ow-up s urvei l l a nce i s a ri s ky
s tra tegy. Ps eudopol yps ha ve no prognos ti c s i gni fi ca nce but ma y be di ffi cul t to di s ti ngui s h from neopl a s ti c pol yps ; thus , a ny s us pect pol yp s houl d
undergo exci s i on bi ops y.
The opti ma l frequency of col onos copi c s urvei l l a nce ha s not been es ta bl i s hed, but s ome a uthori ti es recommend every 2 yr duri ng the 2nd deca de
of di s ea s e a nd a nnua l l y therea fter.
Long-term s urvi va l a fter di a gnos i s of col i ti s -rel a ted ca ncer i s a bout 50%, a fi gure compa ra bl e to tha t for col orecta l ca ncer i n the genera l
popul a ti on.
Treatment
Lopera mi de a nd di eta ry ma na gement for s ymptom rel i ef
5-Ami nos a l i cyl i c a ci d (5-ASA)
Corti cos teroi ds a nd other drugs dependi ng on s ymptoms a nd s everi ty
Anti cytoki ne drugs
Someti mes s urgery
Deta i l s of s peci fi c drugs a nd regi mens a re di s cus s ed on p. 167.
General management: Avoi di ng ra w frui ts a nd vegeta bl es l i mi ts tra uma to the i nfl a med col oni c mucos a a nd ma y l es s en s ymptoms . A mi l k-free di et
ma y hel p but need not be conti nued i f no benefi t i s noted. Lopera mi de 2 mg po bi d to qi d i s i ndi ca ted for rel a ti vel y mi l d di a rrhea ; hi gher ora l
dos es (4 mg i n the morni ng a nd 2 mg a fter ea ch bowel movement) ma y be requi red for more i ntens e di a rrhea . Anti di a rrhea l drugs mus t be us ed
wi th extreme ca uti on i n s evere ca s es beca us e they ma y preci pi ta te toxi c di l a ti on.
Mild left-sided disease: Pa ti ents wi th procti ti s , or col i ti s tha t does not extend proxi ma l l y beyond the s pl eni c fl exure, a re trea ted wi th 5-ASA
(mes a l a mi ne) enema s once/da y or bi d dependi ng on s everi ty. Suppos i tori es a re effecti ve for more di s ta l di s ea s e a nd a re us ua l l y preferred by
pa ti ents . Corti cos teroi d a nd budes oni de enema s a re s l i ghtl y l es s effecti ve but s houl d be us ed i f 5-ASA i s uns ucces s ful or not tol era ted. Once
remi s s i on i s a chi eved, dos a ge i s s l owl y ta pered to ma i ntena nce l evel s . Ora l 5-ASA drugs theoreti ca l l y ha ve s ome i ncrementa l benefi t i n l es s eni ng
the proba bi l i ty of proxi ma l s prea d of di s ea s e.
Moderate or extensive disease: Pa ti ents wi th i nfl a mma ti on proxi ma l to the s pl eni c fl exure or l eft-s i ded di s ea s e unres pons i ve to topi ca l a gents
s houl d recei ve a n ora l 5-ASA formul a ti on i n a ddi ti on to 5-ASA enema s . Hi gh-dos e corti cos teroi ds a re a dded for more s evere s ymptoms ; a fter 1 to 2
wk, the da i l y dos e i s reduced by a bout 5 to 10 mg ea ch wk. Immunomodul a ter thera py wi th a za thi opri ne or 6-merca ptopuri ne ca n be us ed i n
pa ti ents who a re refra ctory to ma xi ma l dos es of 5-ASA a nd woul d otherwi s e need l ong-term corti cos teroi d thera py. Addi ti ona l l y, i nfl i xi ma b i s
benefi ci a l i n s ome pa ti ents a nd ma y be cons i dered for thos e refra ctory to i mmunomodul a tor or corti cos teroi d thera py a s wel l a s thos e who a re
corti cos teroi d dependent.
Severe disease: Pa ti ents wi th > 10 bl oody bowel movements per da y, ta chyca rdi a , hi gh fever, or s evere a bdomi na l pa i n requi re hos pi ta l i za ti on to
recei ve hi gh-dos e IV corti cos teroi ds . 5-ASA ma y be conti nued. IV fl ui ds a nd bl ood tra ns fus i on a re gi ven a s needed for dehydra ti on a nd a nemi a .
The pa ti ent mus t be obs erved cl os el y for the devel opment of toxi c mega col on. Pa rentera l hypera l i menta ti on i s s ometi mes us ed for nutri ti ona l
s upport but i s of no va l ue a s pri ma ry thera py; pa ti ents who ca n tol era te food s houl d ea t.
Pa ti ents who do not res pond wi thi n 3 to 7 da ys s houl d be cons i dered for IV cycl os pori ne or i nfl i xi ma b or el s e for s urgery. Pa ti ents who do res pond
to a corti cos teroi d regi men a re s wi tched wi thi n a week or s o to predni s one 60 mg po once/da y, whi ch ma y be gra dua l l y reduced a t home ba s ed on
cl i ni ca l res pons e. Pa ti ents who a re s ta rted on IV cycl os pori ne a nd res pond to thera py a re s wi tched to ora l cycl os pori ne a nd concomi ta nt
a za thi opri ne or 6-merca ptopuri ne. Ora l cycl os pori ne i s conti nued for a bout 3 to 4 mo, duri ng whi ch ti me corti cos teroi ds a re ta pered a nd
cycl os pori ne l evel s a re cl os el y moni tored. Some cl i ni ci a ns recommend prophyl a xi s a ga i ns t Pneumocystis jirovecii pneumoni a duri ng the i nterva l of
overl a ppi ng trea tment wi th corti cos teroi ds , cycl os pori ne, a nd a n a nti meta bol i te.
Fulminant colitis: If ful mi na nt col i ti s or toxi c mega col on i s s us pected, the pa ti ent s houl d (1) s top a l l a nti di a rrhea l drugs ; (2) ta ke nothi ng by mouth
a nd ha ve i ns erted a l ong i ntes ti na l tube a tta ched to i ntermi ttent s ucti on; (3) recei ve a ggres s i ve IV fl ui d a nd el ectrol yte thera py wi th 0.9% Na Cl ,
a nd pota s s i um chl ori de a nd bl ood a s needed; (4) be trea ted wi th hi gh-dos e IV corti cos teroi d or cycl os pori ne; a nd (5) recei ve a nti bi oti cs (eg,
metroni da zol e 500 mg IV q 8 h a nd ci profl oxa ci n 500 mg IV q 12 h).
Ha vi ng the pa ti ent rol l over i n bed from the s upi ne to prone pos i ti on every 2 to 3 h ma y hel p redi s tri bute col oni c ga s a nd prevent progres s i ve
di s tenti on. Pa s s a ge of a s oft recta l tube ma y a l s o be hel pful but mus t be done wi th extreme ca uti on to a voi d bowel perfora ti on.
If i ntens i ve medi ca l mea s ures do not produce defi ni te i mprovement wi thi n 24 to 48 h, i mmedi a te s urgery i s requi red or the pa ti ent ma y di e of
s eps i s ca us ed by ba cteri a l tra ns l oca ti on or even perfora ti on.

Maintenance therapy: After effecti ve trea tment of a fl a re-up, corti cos teroi ds a re ta pered ba s ed on cl i ni ca l res pons e a nd then s topped beca us e they
a re i neffecti ve a s ma i ntena nce. Pa ti ents s houl d rema i n on 5-ASA drugs i ndefi ni tel yora l or recta l , dependi ng on l oca ti on of di s ea s ebeca us e
s toppi ng ma i ntena nce thera py often a l l ows di s ea s e rel a ps e. Dos a ge i nterva l s for recta l prepa ra ti ons ma y be gra dua l l y l engthened to every 2nd or
3rd da y.
Pa ti ents who ca nnot be wi thdra wn from corti cos teroi ds s houl d be gi ven a za thi opri ne or 6-merca ptopuri ne. Al s o, i nfl i xi ma b i s becomi ng more
wi del y a ccepted a s ma i ntena nce thera py for UC a s wel l a s for Crohn's di s ea s e.
Surgery: Nea rl y one thi rd of pa ti ents wi th extens i ve UC ul ti ma tel y requi re s urgery. Tota l proctocol ectomy i s cura ti ve: Li fe expecta ncy a nd qua l i ty of
l i fe a re res tored to norma l , the di s ea s e does not recur (unl i ke Crohn's di s ea s e), a nd the ri s k of col on ca ncer i s el i mi na ted.
Emergency col ectomy i s i ndi ca ted for ma s s i ve hemorrha ge, ful mi na ti ng toxi c col i ti s , or perfora ti on. Subtota l col ectomy wi th i l eos tomy a nd
rectos i gmoi d cl os ure or mucous fi s tul a i s us ua l l y the procedure of choi ce beca us e mos t cri ti ca l l y i l l pa ti ents ca nnot tol era te more extens i ve
s urgery. The rectos i gmoi d s tump ma y be el ecti vel y removed l a ter or ma y be us ed for i l eoa na l a na s tomos i s wi th a pouch. The i nta ct recta l s tump
s houl d not be a l l owed to rema i n i ndefi ni tel y beca us e of the ri s k of di s ea s e a cti va ti on a nd ma l i gna nt tra ns forma ti on.
El ecti ve s urgery i s i ndi ca ted for ca ncer, s ymptoma ti c s tri ctures , growth reta rda ti on i n chi l dren, or, mos t commonl y, i ntra cta bl e chroni c di s ea s e
res ul ti ng i n i nva l i di s m or corti cos teroi d dependence. Col ectomy i s a l s o done for hi gh-gra de a nd perha ps even l ow-gra de mucos a l dys pl a s i a
confi rmed on pa thol ogi c cons ul ta ti on, unl es s the dys pl a s i a i s l i mi ted excl us i vel y to a compl etel y exci s a bl e pol yp. Severe col i ti s -rel a ted
extra i ntes ti na l ma ni fes ta ti ons (eg, pyoderma ga ngrenos um), now better control l ed by i ntens i ve medi ca l thera pi es , a re onl y ra rel y i ndi ca ti ons for
s urgery.
The el ecti ve procedure of choi ce i n pa ti ents wi th norma l s phi ncter functi on i s res tora ti ve proctocol ectomy wi th i l eoa na l a na s tomos i s . Thi s
procedure crea tes a pel vi c res ervoi r or pouch from di s ta l i l eum, whi ch i s connected to the a nus . The i nta ct s phi ncter a l l ows conti nence, typi ca l l y
wi th 8 to 10 bowel movements /da y. Pouchi ti s i s a n i nfl a mma tory rea cti on occurri ng a fter thi s procedure i n a bout 50% of pa ti ents . It i s thought to
be rel a ted to ba cteri a l overgrowth a nd i s trea ted wi th a nti bi oti cs (eg, qui nol ones ). Probi oti cs ma y be protecti ve. Mos t ca s es of pouchi ti s a re
rea di l y control l ed, but 5 to 10% prove refra ctory to a l l medi ca l thera py a nd requi re convers i on to a conventi ona l (Brooke) i l eos tomy. For a mi nori ty
of pa ti ents who a re ol der, who ha ve wel l -es ta bl i s hed fa mi l i es a nd l i fes tyl es , who ha ve poor s phi ncter tone or ca nnot tol era te frequent bowel
movements , or who a re s i mpl y una bl e or unwi l l i ng to fa ce the cons equences of frequent or chroni c pouchi ti s , the Brooke i l eos tomy rema i ns the
procedure of choi ce.
In a ny event, the phys i ca l a nd emoti ona l burdens i mpos ed by a ny form of col on res ecti on mus t be recogni zed, a nd ca re s houl d be ta ken to s ee
tha t the pa ti ent recei ves a l l the i ns tructi ons a nd a l l the medi ca l a nd ps ychol ogi c s upport tha t i s neces s a ry before a nd a fter s urgery.
Chapter 20. Diverticular Disease

Introduction
Di verti cul a a re s a cl i ke mucos a l outpouchi ngs tha t protrude from a tubul a r s tructure. True di verti cul a conta i n a l l l a yers of the pa rent s tructure.
Fa l s e or ps eudodi verti cul a a re mucos a l projecti ons through the mus cul a r l a yer. Es opha gea l (s ee p. 125) a nd Meckel 's di verti cul a a re true
di verti cul a . Col oni c di verti cul a a re ps eudodi verti cul a ; they ca us e s ymptoms by tra ppi ng feces a nd becomi ng i nfl a med or i nfected, bl eedi ng, or
rupturi ng.
Diverticulosis
Diverticulosis is the presence of multiple diverticula in the colon, probably resulting from a lifelong low-fiber diet. Most diverticula are asymptomatic, but some
become inflamed or bleed. Diagnosis is by colonoscopy or barium enema. Treatment varies depending on manifestation.
Di verti cul a occur a nywhere i n the l a rge bowel us ua l l y i n the s i gmoi d but ra rel y bel ow the peri tonea l refl ecti on of the rectum. They va ry i n
di a meter from 3 mm to > 3 cm. Pa ti ents wi th di verti cul a us ua l l y ha ve s evera l of them. Di verti cul os i s i s uncommon i n peopl e < 40 but becomes
common ra pi dl y therea fter; es s enti a l l y every 90-yr-ol d pers on ha s ma ny di verti cul a . Gi a nt di verti cul a , whi ch a re ra re, ra nge i n di a meter from 3 to
15 cm a nd ma y be s i ngl e.
Pathophysiology
Di verti cul a a re proba bl y ca us ed by i ncrea s ed i ntra l umi na l pres s ure l ea di ng to mucos a l extrus i on through the wea kes t poi nts of the mus cul a r
l a yer of the bowel a rea s a dja cent to i ntra mura l bl ood ves s el s . Di verti cul a a re more common a mong peopl e who ea t a l ow-fi ber di et; however,
the mecha ni s m i s not cl ea r. One theory i s tha t i ncrea s ed i ntra l umi na l pres s ure i s requi red to move l ow-bul k s tool through the col on. Another
theory i s tha t l ow-s tool bul k ca us es a s ma l l er di a meter col on, whi ch by La pl a ce's l a w woul d ha ve i ncrea s ed pres s ure.
The eti ol ogy of gi a nt di verti cul a i s uncl ea r. One theory i s tha t a va l vel i ke a bnorma l i ty exi s ts a t the ba s e of the di verti cul um, s o bowel ga s ca n
enter but es ca pes l es s freel y.
Symptoms and Signs
Mos t (70%) di verti cul a a re a s ymptoma ti c, 15 to 25% become pa i nful l y i nfl a med (di verti cul i ti s ), a nd 10 to 15% bl eed pa i nl es s l y. The bl eedi ng i s
proba bl y ca us ed by eros i on of the a dja cent ves s el by l oca l tra uma from i mpa cted feces i n the di verti cul um. Al though mos t di verti cul a a re di s ta l ,
75% of bl eedi ng occurs from di verti cul a proxi ma l to the s pl eni c fl exure. In 33% of pa ti ents (5% overa l l ), bl eedi ng i s s eri ous enough to requi re
tra ns fus i on.
Diagnosis
Us ua l l y col onos copy
As ymptoma ti c di verti cul a a re us ua l l y found i nci denta l l y duri ng ba ri um enema or col onos copy. Di verti cul os i s i s s us pected when pa i nl es s recta l
bl eedi ng devel ops , pa rti cul a rl y i n a n el derl y pa ti ent. Eva l ua ti on of recta l bl eedi ng typi ca l l y i ncl udes col onos copy, whi ch ca n be done el ecti vel y
a fter routi ne prepa ra ti on unl es s there i s s i gni fi ca nt ongoi ng bl eedi ng. In s uch pa ti ents , a ra pi d prepa ra ti on (5 to 10 L of pol yethyl ene gl ycol
s ol uti on del i vered vi a NGT over 3 to 4 h) often a l l ows a dequa te vi s ua l i za ti on. If col onos copy ca nnot vi s ua l i ze the s ource a nd ongoi ng bl eedi ng i s
s uffi ci entl y ra pi d (> 0.5 to 1 mL/mi n), a ngi ogra phy ma y l oca l i ze the s ource. Some a ngi ogra phers fi rs t do a ra di onucl i de s ca n to focus the
exa mi na ti on.
Treatment
Hi gh-fi ber di et
Someti mes a ngi ogra phi c or endos copi c trea tment of bl eedi ng
Trea tment of di verti cul os i s a i ms a t reduci ng s egmenta l s pa s m. A hi gh-fi ber di et hel ps a nd ma y be s uppl emented by ps yl l i um s eed prepa ra ti ons
or bra n. Low-fi ber di ets a re contra i ndi ca ted. The i ntui ti ve i njuncti on to a voi d s eeds or other di eta ry ma teri a l tha t mi ght become i mpa cted i n a
di verti cul um ha s no es ta bl i s hed medi ca l ba s i s . Anti s pa s modi cs (eg, bel l a donna ) a re not of benefi t a nd ma y ca us e a dvers e effects . Surgery i s
unwa rra nted for uncompl i ca ted di s ea s e. Gi a nt di verti cul a , however, requi re s urgery.
Di verti cul a r bl eedi ng s tops s ponta neous l y i n 75% of pa ti ents . Trea tment i s often gi ven duri ng di a gnos ti c procedures . If a ngi ogra phy wa s done for
di a gnos i s , ongoi ng bl eedi ng ca n be control l ed i n 70 to 90% of pa ti ents by i ntra a rteri a l i njecti on of va s opres s i n. In s ome ca s es , bl eedi ng recurs
wi thi n a few da ys a nd requi res s urgery. Angi ogra phi c embol i za ti on effecti vel y s tops bl eedi ng but l ea ds to bowel i nfa rcti on i n up to 20% of
pa ti ents a nd i s not recommended. Col onos copy a l l ows hea t or l a s er coa gul a ti on of ves s el s or i njecti on of epi nephri ne. If thes e mea s ures fa i l to
s top bl eedi ng, s egmenta l res ecti on or s ubtota l col ectomy i s i ndi ca ted.
Diverticulitis
Diverticulitis is inflammation of a diverticulum, which can result in phlegmon of the bowel wall, peritonitis, perforation, fistula, or abscess. The primary symptom
is abdominal pain. Diagnosis is by CT. Treatment is with antibiotics (ciprofloxacin, or a 3rd-generation cephalosporin plus metronidazole) and occasionally surgery.
Di verti cul i ti s occurs when a mi cro or ma cro perfora ti on devel ops i n a di verti cul um, rel ea s i ng i ntes ti na l ba cteri a . The res ul ta nt i nfl a mma ti on
rema i ns l oca l i zed i n a bout 75% of pa ti ents . The rema i ni ng 25% ma y devel op a bs ces s , free i ntra peri tonea l perfora ti on, bowel obs tructi on, or
fi s tul a s . The mos t common fi s tul a s i nvol ve the bl a dder but ma y a l s o i nvol ve the s ma l l bowel , uterus , va gi na , a bdomi na l wa l l , or even the thi gh.
Di verti cul i ti s i s mos t s eri ous i n el derl y pa ti ents , es peci a l l y thos e ta ki ng predni s one or other drugs tha t i ncrea s e the ri s k of i nfecti on. Nea rl y a l l
s eri ous di verti cul i ti s occurs i n the s i gmoi d.
Symptoms and Signs

Di verti cul i ti s us ua l l y ma ni fes ts wi th pa i n or tendernes s i n the l eft l ower qua dra nt of the a bdomen a nd fever. Peri tonea l s i gns (eg, rebound or
gua rdi ng) ma y be pres ent, pa rti cul a rl y wi th a bs ces s or free perfora ti on. Fi s tul a s ma y ma ni fes t a s pneuma turi a , fecul ent va gi na l di s cha rge, or a
cuta neous or myofa s ci a l i nfecti on of the a bdomi na l wa l l , peri neum, or upper l eg. Pa ti ents wi th bowel obs tructi on ha ve na us ea , vomi ti ng, a nd
a bdomi na l di s tenti on. Bl eedi ng i s uncommon.
Diagnosis
Abdomi na l CT
Col onos copy a fter res ol uti on
Cl i ni ca l s us pi ci on i s hi gh i n pa ti ents wi th known di verti cul os i s . However, beca us e other di s orders (eg, a ppendi ci ti s , col on or ova ri a n ca ncer) ma y
ca us e s i mi l a r s ymptoms , tes ti ng i s requi red. Abdomi na l CT wi th ora l a nd IV contra s t i s preferred, a l though fi ndi ngs i n a bout 10% of pa ti ents
ca nnot be di s ti ngui s hed from col on ca ncer. Col onos copy, a fter res ol uti on of the a cute i nfecti on, i s neces s a ry for defi ni ti ve di a gnos i s .
Treatment
Va ri es wi th s everi ty
Li qui d di et, ora l a nti bi oti cs for mi l d di s ea s e
IV a nti bi oti cs , npo for more s evere di s ea s e
CT-gui ded percuta neous dra i na ge of a bs ces s
Someti mes s urgery
A pa ti ent who i s not very i l l i s trea ted a t home wi th res t, a l i qui d di et, a nd ora l a nti bi oti cs (eg, ci profl oxa ci n 500 mg bi d a moxi ci l l i n/cl a vul a na te
500 mg ti d pl us metroni da zol e 500 mg qi d). Symptoms us ua l l y s ubs i de ra pi dl y. The pa ti ent gra dua l l y a dva nces to a s oft l ow-fi ber di et a nd a da i l y
ps yl l i um s eed prepa ra ti on. The col on s houl d be eva l ua ted a fter 2 to 4 wk wi th a col onos copy or ba ri um enema . After 1 mo, a hi gh-fi ber di et i s
res umed.
Pa ti ents wi th more s evere s ymptoms (eg, pa i n, fever, ma rked l eukocytos i s ) s houl d be hos pi ta l i zed, a s s houl d pa ti ents ta ki ng predni s one (who a re
a t hi gher ri s k of perfora ti on a nd genera l peri toni ti s ). Trea tment i s bed res t, npo, IV fl ui ds , a nd IV a nti bi oti cs (eg, cefta zi di me 1 g IV q 8 h pl us
metroni da zol e 500 mg IV q 6 to 8 h).
About 80% of pa ti ents ca n be trea ted s ucces s ful l y wi thout s urgery. An a bs ces s ma y res pond to percuta neous dra i na ge (CT gui ded). If res pons e i s
s a ti s fa ctory, the pa ti ent rema i ns hos pi ta l i zed unti l s ymptoms a re rel i eved a nd a s oft di et i s res umed. A col onos copy or ba ri um enema i s done 2
wk a fter s ymptoms ha ve res ol ved.
Surgery: Surgery i s requi red i mmedi a tel y for pa ti ents wi th free perfora ti on or genera l peri toni ti s a nd for pa ti ents wi th s evere s ymptoms tha t do not
res pond to nons urgi ca l trea tment wi thi n 48 h. Increa s i ng pa i n, tendernes s , a nd fever a re other s i gns tha t s urgery i s needed. Surgery s houl d a l s o
be cons i dered i n pa ti ents wi th a ny of the fol l owi ng: 2 previ ous a tta cks of mi l d di verti cul i ti s (or one a tta ck i n a pa ti ent < 50); a pers i s tent tender
ma s s ; cl i ni ca l , endos copi c, or x-ra y s i gns s ugges ti ve of ca ncer; a nd dys uri a a s s oci a ted wi th di verti cul i ti s i n men (or i n women who ha ve ha d a
hys terectomy), beca us e thi s s ymptom ma y pres a ge perfora ti on i nto the bl a dder.
The i nvol ved s ecti on of the col on i s res ected. The ends ca n be rea na s tomos ed i mmedi a tel y i n hea l thy pa ti ents wi thout perfora ti on, a bs ces s , or
s i gni fi ca nt i nfl a mma ti on. Other pa ti ents ha ve a tempora ry col os tomy wi th a na s tomos i s ca rri ed out i n a s ubs equent opera ti on a fter i nfl a mma ti on
res ol ves a nd the pa ti ent's genera l condi ti on i mproves .
Meckel's Diverticulum
Meckel's diverticulum is a congenital sacculation of the distal ileum occurring in 2 to 3% of people. It is usually located within 100 cm of the ileocecal valve and
often contains heterotopic gastric tissue, pancreatic tissue, or both. Symptoms are uncommon but include bleeding, bowel obstruction, and inflammation
(diverticulitis). Diagnosis is difficult and often involves radionuclide scanning and barium studies. Treatment is surgical resection.
Pathophysiology
In ea rl y feta l l i fe, the vi tel l i ne duct runni ng from the termi na l i l eum to the umbi l i cus a nd yol k s a c i s norma l l y obl i tera ted by the 7th wk. If the
porti on connecti ng to the i l eum fa i l s to a trophy, a Meckel 's di verti cul um res ul ts . Thi s congeni ta l di verti cul um a ri s es from the a nti mes enteri c
ma rgi n of the i ntes ti ne a nd conta i ns a l l l a yers of the norma l bowel . About 50% of di verti cul a a l s o conta i n heterotopi c ti s s ue of the s toma ch (a nd
thus conta i n pa ri eta l cel l s tha t s ecrete HCl ), pa ncrea s , or both.
Onl y a bout 2% of peopl e wi th Meckel 's di verti cul um devel op compl i ca ti ons . Al though di verti cul a a re equa l l y common a mong ma l es a nd fema l es ,
ma l es a re 2 to 3 ti mes more l i kel y to ha ve compl i ca ti ons . Compl i ca ti ons i ncl ude the fol l owi ng:
Bl eedi ng
Obs tructi on
Di verti cul i ti s
Tumors
Bl eedi ng i s more common a mong young chi l dren (< 5 yr) a nd occurs when a ci d s ecreted from ectopi c ga s tri c mucos a i n the di verti cul um ul cera tes
the a dja cent i l eum. Obs tructi on ca n occur a t a ny a ge but i s more common a mong ol der chi l dren a nd a dul ts . In chi l dren, obs tructi on i s mos t l i kel y
ca us ed by i ntus s us cepti on of the di verti cul um. Obs tructi on ma y a l s o res ul t from a dhes i ons , vol vul us , reta i ned forei gn bodi es , tumors , or
i nca rcera ti on i n a herni a (Li ttre's herni a ). Acute Meckel 's di verti cul i ti s ca n occur a t a ny a ge, but i ts i nci dence pea ks i n ol der chi l dren. Tumors ,
i ncl udi ng ca rci noi ds , a re ra re a nd occur ma i nl y i n a dul ts .
Symptoms and Signs
In a l l a ges , i ntes ti na l obs tructi on i s ma ni fes ted by cra mpi ng a bdomi na l pa i n, na us ea , a nd vomi ti ng. Acute Meckel 's di verti cul i ti s i s cha ra cteri zed
by a bdomi na l pa i n a nd tendernes s typi ca l l y l oca l i zed bel ow or to the l eft of the umbi l i cus ; i t i s often a ccompa ni ed by vomi ti ng a nd i s s i mi l a r to
a ppendi ci ti s except for l oca ti on of pa i n.
Chi l dren ma y pres ent wi th repea ted epi s odes of pa i nl es s , bri ght red recta l bl eedi ng, whi ch i s us ua l l y not s evere enough to ca us e s hock. Adul ts
ma y a l s o bl eed, typi ca l l y res ul ti ng i n mel ena ra ther tha n fra nk bl ood.
Diagnosis
Ba s ed on s ymptoms
Ra di onucl i de s ca n for bl eedi ng
CT for pa i n
Di a gnos i s i s di ffi cul t, a nd tes ts a re chos en ba s ed on pres enti ng s ymptoms . If recta l bl eedi ng i s s us pected to ori gi na te from a Meckel 's
di verti cul um, a 99mTc pertechneta te s ca n ma y i denti fy ectopi c ga s tri c mucos a a nd hence the di verti cul um. Pa ti ents pres enti ng wi th a bdomi na l pa i n
a nd foca l tendernes s s houl d ha ve a CT s ca n wi th ora l contra s t. If vomi ti ng a nd s i gns of obs tructi on a re predomi na nt, fl a t a nd upri ght x-ra ys of the
a bdomen a re done. Someti mes di a gnos i s i s ma de onl y duri ng s urgi ca l expl ora ti on for pres umed a ppendi ci ti s ; whenever a norma l a ppendi x i s
found, Meckel 's di verti cul um s houl d be s us pected.
Treatment
Surgery
Pa ti ents wi th i ntes ti na l obs tructi on ca us ed by Meckel 's di verti cul um requi re ea rl y s urgery. For deta i l ed trea tment of i ntes ti na l obs tructi on, s ee p.
117.
A bl eedi ng di verti cul um wi th a n i ndura ted a rea i n the a dja cent i l eum requi res res ecti on of thi s s ecti on of the bowel a nd the di verti cul um. A
bl eedi ng di verti cul um wi thout i l ea l i ndura ti on requi res onl y res ecti on of the di verti cul um.
Meckel 's di verti cul i ti s a l s o requi res res ecti on. Sma l l , a s ymptoma ti c di verti cul a encountered i nci denta l l y a t l a pa rotomy need not be removed.
Diverticular Disease of the Stomach and Small Bowel
Di verti cul a ra rel y i nvol ve the s toma ch but occur i n the duodenum i n up to 25% of peopl e. Mos t duodena l di verti cul a a re s ol i ta ry a nd occur i n the
s econd porti on of the duodenum nea r the a mpul l a of Va ter (peri a mpul l a ry). Jejuna l di verti cul a occur i n a bout 0.26% of pa ti ents a nd a re more
common a mong pa ti ents wi th di s orders of i ntes ti na l moti l i ty. Meckel 's di verti cul um occurs i n the di s ta l i l eum.
Duodena l a nd jejuna l di verti cul a a re a s ymptoma ti c i n > 90% of ca s es a nd a re us ua l l y detected i nci denta l l y duri ng ra di ol ogi c or endos copi c
i nves ti ga ti on of the upper GI tra ct for a n unrel a ted di s ea s e. Ra rel y, s ma l l -bowel di verti cul a bl eed or become i nfl a med, ca us i ng pa i n a nd na us ea .
Some even perfora te. For poorl y unders tood rea s ons , pa ti ents wi th peri a mpul l a ry di verti cul a a re a t i ncrea s ed ri s k of ga l l s tones a nd pa ncrea ti ti s .
Trea tment i s s urgi ca l res ecti on; however, the cl i ni ci a n s houl d be ca uti ous of recommendi ng s urgery for pa ti ents wi th a di verti cul um a nd va gue GI
s ymptoms (eg, dys peps i a ).
Chapter 21. Anorectal Disorders

Introduction
(See a l s o Forei gn Bodi es on p. 139 a nd Anorecta l Ca ncer on p. 195.)
The a na l ca na l begi ns a t the a na l s phi ncter a nd ends a t the a norecta l juncti on (pecti na te l i ne, mucocuta neous juncti on, denta te l i ne), where
there a re 8 to 12 a na l crypts a nd 5 to 8 pa pi l l a e. The ca na l i s l i ned wi th a noderm, a conti nua ti on of the externa l s ki n. The a na l ca na l a nd a dja cent
s ki n a re i nnerva ted by s oma ti c s ens ory nerves a nd a re hi ghl y s us cepti bl e to pa i nful s ti mul i . Venous dra i na ge from the a na l ca na l occurs through
the ca va l s ys tem, but the a norecta l juncti on ca n dra i n i nto both the porta l a nd ca va l s ys tems . Lympha ti cs from the a na l ca na l pa s s to the i nterna l
i l i a c nodes , the pos teri or va gi na l wa l l , a nd the i ngui na l nodes . The venous a nd l ympha ti c di s tri buti ons determi ne how ma l i gna nt di s ea s e a nd
i nfecti on s prea d.
The rectum i s a conti nua ti on of the s i gmoi d col on begi nni ng a t the l evel of the 3rd s a cra l vertebra a nd conti nui ng to the a norecta l juncti on. The
recta l l i ni ng cons i s ts of red, gl i s teni ng gl a ndul a r mucos a , whi ch ha s a n a utonomi c nerve s uppl y a nd i s rel a ti vel y i ns ens i ti ve to pa i n. Venous
dra i na ge occurs through the porta l s ys tem. Lympha ti c return from the rectum occurs a l ong the s uperi or hemorrhoi da l va s cul a r pedi cl e to the
i nferi or mes enteri c a nd a orti c nodes .
The s phi ncteri c ri ng enci rcl i ng the a na l ca na l i s compos ed of the i nterna l s phi ncter, the centra l porti on of the l eva tors , a nd components of the
externa l s phi ncter. Anteri orl y, i t i s more vul nera bl e to tra uma , whi ch ca n res ul t i n i nconti nence. The puborecta l i s forms a mus cul a r s l i ng a round
the rectum for s upport a nd a s s i s ta nce i n defeca ti on.
History: Hi s tory s houl d i ncl ude the deta i l s of bl eedi ng, pa i n, protrus i on, di s cha rge, s wel l i ng, a bnorma l s ens a ti ons , bowel movements ,
i nconti nence, s tool cha ra cteri s ti cs , us e of ca tha rti cs a nd enema s , a nd a bdomi na l a nd uri na ry s ymptoms . Al l pa ti ents s houl d be a s ked a bout a na l
i ntercours e a nd other pos s i bl e ca us es of tra uma a nd i nfecti on.
Physical examination: Exa mi na ti on s houl d be done gentl y a nd wi th good l i ghti ng. It cons i s ts of externa l i ns pecti on, peri a na l a nd i ntra recta l di gi ta l
pa l pa ti on, a bdomi na l exa mi na ti on, a nd rectova gi na l bi di gi ta l pa l pa ti on. Anos copy a nd ri gi d or fl exi bl e s i gmoi dos copy to 15 to 60 cm a bove the
a na l verge a re often i ncl uded (s ee p. 98). Ins pecti on, pa l pa ti on, a nd a nos copy a nd s i gmoi dos copy a re bes t done wi th the pa ti ent i n the l eft l a tera l
(Si ms ') pos i ti on or i nverted on a ti l t ta bl e. In ca s es of pa i nful a na l l es i ons , topi ca l (l i doca i ne 5% oi ntment), regi ona l , or even genera l a nes thes i a
ma y be requi red. If i t ca n be tol era ted, a cl ea ns i ng phos pha te enema ma y fa ci l i ta te s i gmoi dos copy. Bi ops i es , s mea rs , a nd cul tures ma y be ta ken,
a nd x-ra y exa mi na ti on done i f i ndi ca ted.
Anal Fissure
(Fi s s ure i n Ano; Ana l Ul cer)
An anal fissure is an acute longitudinal tear or a chronic ovoid ulcer in the squamous epithelium of the anal canal. It causes severe pain, sometimes with bleeding,
particularly with defecation. Diagnosis is by inspection. Treatment is local hygiene, stool softeners, and sometimes botulinum toxin injection.
Ana l fi s s ures a re bel i eved to res ul t from l a cera ti on by a ha rd or l a rge s tool , wi th s econda ry i nfecti on. Tra uma (eg, a na l i ntercours e) i s a ra re
ca us e. The fi s s ure ma y ca us e i nterna l s phi ncter s pa s m, decrea s i ng bl ood s uppl y a nd perpetua ti ng the fi s s ure.
Symptoms and Signs
Ana l fi s s ures us ua l l y l i e i n the pos teri or mi dl i ne but ma y occur i n the a nteri or mi dl i ne. Thos e off the mi dl i ne ma y ha ve s peci fi c eti ol ogi es ,
pa rti cul a rl y Crohn's di s ea s e. An externa l s ki n ta g (the s enti nel pi l e) ma y be pres ent a t the l ower end of the fi s s ure, a nd a n enl a rged (hypertrophi c)
pa pi l l a ma y be pres ent a t the upper end.
Infa nts ma y devel op a cute fi s s ures , but chroni c fi s s ures a re ra re. Chroni c fi s s ures mus t be di fferenti a ted from ca ncer, pri ma ry l es i ons of s yphi l i s ,
TB, a nd ul cera ti on ca us ed by Crohn's di s ea s e.
Fi s s ures ca us e pa i n a nd bl eedi ng. The pa i n typi ca l l y occurs wi th or s hortl y a fter defeca ti on, l a s ts for s evera l hours , a nd s ubs i des unti l the next
bowel movement. Exa mi na ti on mus t be gentl e but wi th a dequa te s prea di ng of the buttocks to a l l ow vi s ua l i za ti on.
Diagnosis
Di a gnos i s i s ma de by i ns pecti on. Unl es s fi ndi ngs s ugges t a s peci fi c ca us e, further s tudi es a re not requi red.
Treatment
Stool s ofteners
Protecti ve oi ntments , s i tz ba ths
Ni trogl yceri n oi ntment or botul i num toxi n type A i njecti on
Fi s s ures often res pond to cons erva ti ve mea s ures tha t mi ni mi ze tra uma duri ng defeca ti on (eg, s tool s ofteners , ps yl l i um, fi ber). Hea l i ng i s a i ded by
us e of protecti ve zi nc oxi de oi ntments or bl a nd s uppos i tori es (eg, gl yceri n) tha t l ubri ca te the l ower rectum a nd s often s tool . Topi ca l a nes theti cs
(eg, benzoca i ne, l i doca i ne) a nd wa rm (not hot) s i tz ba ths for 10 or 15 mi n a fter ea ch bowel movement a nd prn gi ve tempora ry rel i ef.
Topi ca l ni trogl yceri n 0.2% oi ntment, ni fedi pi ne crea m 0.2% or 0.3%, a rgi ni ne gel , a nd i njecti ons of botul i num toxi n type A i nto the i nterna l
s phi ncter rel a x the a na l s phi ncter a nd decrea s e ma xi mum a na l res ti ng pres s ure, a l l owi ng hea l i ng. When cons erva ti ve mea s ures fa i l , s urgery
(i nterna l a na l s phi ncterotomy or control l ed a na l di l a ti on) i s needed to i nterfere wi th the cycl e of i nterna l a na l s phi ncter s pa s m.
Anorectal Abscess
An anorectal abscess is a localized collection of pus in the perirectal spaces. Abscesses usually originate in an anal crypt. Symptoms are pain and swelling.
Diagnosis is primarily by examination and CT or pelvic MRI for deeper abscesses. Treatment is surgical drainage.
An a bs ces s ma y be l oca ted i n va ri ous s pa ces s urroundi ng the rectum a nd ma y be s uperfi ci a l or deep. A peri a na l a bs ces s i s s uperfi ci a l a nd poi nts
to the s ki n. An i s chi orecta l a bs ces s i s deeper, extendi ng a cros s the s phi ncter i nto the i s chi orecta l s pa ce bel ow the l eva tor a ni ; i t ma y penetra te to
the contra l a tera l s i de, formi ng a "hors es hoe" a bs ces s . An a bs ces s a bove the l eva tor a ni (i e, s upra l eva tor a bs ces s ) i s qui te deep a nd ma y extend
to the peri toneum or a bdomi na l orga ns ; thi s a bs ces s often res ul ts from di verti cul i ti s or pel vi c i nfl a mma tory di s ea s e. Crohn's di s ea s e (es peci a l l y
of the col on) s ometi mes ca us es a norecta l a bs ces s . A mi xed i nfecti on us ua l l y occurs , wi th Escherichia coli, Proteus vulgaris, Bacteroides, s treptococci ,
a nd s ta phyl ococci predomi na ti ng.
Symptoms and Signs
Superfi ci a l a bs ces s es ca n be very pa i nful ; peri a na l s wel l i ng, rednes s , a nd tendernes s a re cha ra cteri s ti c. Deeper a bs ces s es ma y be l es s pa i nful
but ca us e toxi c s ymptoms (eg, fever, chi l l s , ma l a i s e). There ma y be no peri a na l fi ndi ngs , but di gi ta l recta l exa mi na ti on ma y revea l a tender,
fl uctua nt s wel l i ng of the recta l wa l l . Hi gh pel vi recta l a bs ces s es ma y ca us e l ower a bdomi na l pa i n a nd fever wi thout recta l s ymptoms . Someti mes
fever i s the onl y s ymptom.
Diagnosis
Ra rel y exa mi na ti on under a nes thes i a or CT
Pa ti ents who ha ve a poi nti ng cuta neous a bs ces s , a norma l di gi ta l recta l exa mi na ti on, a nd no s i gns of s ys temi c i l l nes s do not requi re i ma gi ng.
Thos e wi th a ny fi ndi ngs s ugges ti ve of a deeper a bs ces s or Crohn's di s ea s e s houl d ha ve a n exa mi na ti on under a nes thes i a a t the ti me of dra i na ge.
Hi gher (s upra l eva tor) a bs ces s es requi re CT to determi ne the i ntra -a bdomi na l s ource of s eps i s .
Treatment
Inci s i on a nd dra i na ge
Anti bi oti cs for hi gh-ri s k pa ti ents
Prompt i nci s i on a nd a dequa te dra i na ge a re requi red a nd s houl d not wa i t unti l the a bs ces s poi nts . Ma ny a bs ces s es ca n be dra i ned a s a n i n-offi ce
procedure; deeper a bs ces s es ma y requi re dra i na ge i n the opera ti ng room. Febri l e, neutropeni c, or di a beti c pa ti ents or thos e wi th ma rked
cel l ul i ti s s houl d a l s o recei ve a nti bi oti cs (eg, ci profl oxa ci n 500 mg IV q 12 h a nd metroni da zol e 500 mg IV q 8 h, a mpi ci l l i n/s ul ba cta m 1.5 g IV q 8 h).
Anti bi oti cs a re not i ndi ca ted for hea l thy pa ti ents wi th s uperfi ci a l a bs ces s es . Anorecta l fi s tul a s ma y devel op a fter dra i na ge.
Anorectal Fistula
(Fi s tul a i n Ano)
An anorectal fistula is a tubelike tract with one opening in the anal canal and the other usually in the perianal skin. Symptoms are discharge and sometimes pain.
Diagnosis is by examination and sigmoidoscopy. Treatment often requires surgery.
Fi s tul a s a ri s e s ponta neous l y or occur s econda ry to dra i na ge of a peri recta l a bs ces s . Predi s pos i ng ca us es i ncl ude Crohn's di s ea s e a nd TB. Mos t
fi s tul a s ori gi na te i n the a norecta l crypts ; others ma y res ul t from di verti cul i ti s , tumors , or tra uma . Fi s tul a s i n i nfa nts a re congeni ta l a nd a re more
common a mong boys . Rectova gi na l fi s tul a s ma y be s econda ry to Crohn's di s ea s e, obs tetri c i njuri es , ra di a ti on thera py, or ca ncer.
Symptoms and Signs
A hi s tory of recurrent a bs ces s fol l owed by i ntermi ttent or cons ta nt di s cha rge i s us ua l . Di s cha rge ma teri a l i s purul ent, s eros a ngui neous , or both.
Pa i n ma y be pres ent i f there i s i nfecti on. On i ns pecti on, one or more s econda ry openi ngs ca n be s een. A cordl i ke tra ct ca n often be pa l pa ted. A
probe i ns erted i nto the tra ct ca n determi ne the depth a nd di recti on a nd often the pri ma ry openi ng.
Diagnosis
Si gmoi dos copy
Di a gnos i s i s by exa mi na ti on. Si gmoi dos copy s houl d fol l ow to rul e out Crohn's di s ea s e. Hi dra deni ti s s uppura ti va , pi l oni da l s i nus , derma l
s uppura ti ve s i nus es , a nd urethro-peri nea l fi s tul a s mus t be di fferenti a ted from cryptogeni c fi s tul a s .
Treatment
Va ri ous s urgi ca l procedures
Medi ca l trea tment i f ca us ed by Crohn's di s ea s e
In the pa s t, the onl y effecti ve trea tment wa s s urgery, i n whi ch the pri ma ry openi ng a nd the enti re tra ct a re unroofed a nd converted i nto a "di tch."
Pa rti a l di vi s i on of the s phi ncters ma y be neces s a ry. Some degree of i nconti nence ma y occur i f a cons i dera bl e porti on of the s phi ncteri c ri ng i s
di vi ded. Al terna ti ves to conventi ona l s urgery i ncl ude a dva ncement fl a ps , bi ol ogi c pl ugs , a nd fi bri n gl ue i ns ti l l a ti ons i nto the fi s tul ous tra ct.
If di a rrhea or Crohn's di s ea s e i s pres ent, fi s tul otomy i s i na dvi s a bl e beca us e of del a yed wound hea l i ng. For pa ti ents wi th Crohn's di s ea s e,
metroni da zol e, other a ppropri a te a nti bi oti cs , a nd s uppres s i ve thera pi es ca n be gi ven (s ee p. 171). Infl i xi ma b i s very effecti ve i n cl os i ng fi s tul a s
ca us ed by Crohn's di s ea s e.
Fecal Incontinence
Fecal incontinence is involuntary defecation.
Feca l i nconti nence ca n res ul t from i njuri es or di s ea s es of the s pi na l cord, congeni ta l a bnorma l i ti es , a cci denta l i njuri es to the rectum a nd a nus ,
proci denti a , di a betes , s evere dementi a , feca l i mpa cti on, extens i ve i nfl a mma tory proces s es , tumors , obs tetri c i njuri es , a nd opera ti ons i nvol vi ng
di vi s i on or di l a ti on of the a na l s phi ncters .
Phys i ca l exa mi na ti on s houl d eva l ua te gros s s phi ncter functi on a nd peri a na l s ens a ti on a nd rul e out feca l i mpa cti on. Ana l s phi ncter
ul tra s onogra phy, pel vi c a nd peri nea l MRIs , pel vi c fl oor el ectromyogra phy, a nd a norecta l ma nometry a re a l s o us eful .
Treatment
Progra m of s tool regul a ti on
Peri nea l exerci s es , s ometi mes wi th bi ofeedba ck
Someti mes a s urgi ca l procedure
Trea tment i ncl udes a bowel ma na gement progra m to devel op a predi cta bl e pa ttern of defeca ti on. The progra m i ncl udes i nta ke of a dequa te fl ui d
a nd s uffi ci ent di eta ry bul k. Si tti ng on a toi l et or us i ng a nother cus toma ry defeca tory s ti mul a nt (eg, coffee) encoura ges defeca ti on. A s uppos i tory
(eg, gl yceri n, bi s a codyl ) or a phos pha te enema ma y a l s o be us ed. If a regul a r defeca tory pa ttern does not devel op, a l ow-res i due di et a nd ora l
l opera mi de ma y reduce the frequency of defeca ti on.
Si mpl e peri nea l exerci s es , i n whi ch the pa ti ent repea tedl y contra cts the s phi ncters , peri nea l mus cl es , a nd buttocks , ma y s trengthen thes e
s tructures a nd contri bute to conti nence, pa rti cul a rl y i n mi l d ca s es . Bi ofeedba ck (to tra i n the pa ti ent to us e the s phi ncters ma xi ma l l y a nd to better
a ppreci a te phys i ol ogi c s ti mul i ) s houl d be cons i dered before recommendi ng s urgery i n wel l -moti va ted pa ti ents who ca n unders ta nd a nd fol l ow
i ns tructi ons a nd who ha ve a n a na l s phi ncter ca pa bl e of recogni zi ng the cue of recta l di s tenti on. About 70% of s uch pa ti ents res pond to
bi ofeedba ck.
A defect i n the s phi ncter ca n be s utured di rectl y. When there i s i ns uffi ci ent res i dua l s phi ncter for repa i r, pa rti cul a rl y i n pa ti ents < 50 yr of a ge, a
gra ci l i s mus cl e ca n be tra ns pos ed. Some centers a tta ch a pa cema ker to the gra ci l i s mus cl e, a s wel l a s a n a rti fi ci a l s phi ncter; thes e or other
experi menta l procedures a re a va i l a bl e i n onl y a few centers i n the US, a s res ea rch protocol s . Al terna ti vel y, a Thi ers ch wi re or other ma teri a l ca n
be us ed to enci rcl e the a nus . When a l l el s e fa i l s , a col os tomy ca n be cons i dered.
Hemorrhoids
(Pi l es )
Hemorrhoids are dilated veins of the hemorrhoidal plexus in the lower rectum. Symptoms include irritation and bleeding. Thrombosed hemorrhoids are painful.
Diagnosis is by inspection or anoscopy. Treatment is symptomatic or with endoscopic banding, injection sclerotherapy, or sometimes surgery.
Externa l hemorrhoi ds a re l oca ted bel ow the denta te l i ne a nd a re covered by s qua mous epi thel i um. Interna l hemorrhoi ds a re l oca ted a bove the
denta te l i ne a nd a re l i ned by recta l mucos a . Hemorrhoi ds typi ca l l y occur i n the ri ght a nteri or, ri ght pos teri or, a nd l eft l a tera l zones . They occur i n
a dul ts a nd chi l dren.
Symptoms and Signs
Hemorrhoi ds a re often a s ymptoma ti c, or they ma y s i mpl y protrude. Pruri tus a ni i s not commonl y ca us ed by hemorrhoi ds .
Externa l hemorrhoi ds ma y become thrombos ed, res ul ti ng i n a pa i nful , purpl i s h s wel l i ng. Ra rel y, they ul cera te a nd ca us e mi nor bl eedi ng.
Cl ea ns i ng the a na l regi on ma y be di ffi cul t.
Interna l hemorrhoi ds typi ca l l y ma ni fes t wi th bl eedi ng a fter defeca ti on; bl ood i s noted on toi l et ti s s ue a nd s ometi mes i n the toi l et bowl . Interna l
hemorrhoi ds ma y be uncomforta bl e but a re not a s pa i nful a s thrombos ed externa l hemorrhoi ds . Interna l hemorrhoi ds s ometi mes ca us e mucus
di s cha rge a nd a s ens a ti on of i ncompl ete eva cua ti on.
Stra ngul a ted hemorrhoi ds occur when protrus i on a nd cons tri cti on occl ude the bl ood s uppl y. They ca us e pa i n tha t i s occa s i ona l l y fol l owed by
necros i s a nd ul cera ti on.
Diagnosis
Anos copy
Someti mes s i gmoi dos copy or col onos copy
Mos t pa i nful hemorrhoi ds , thrombos ed, ul cera ted or not, a re s een on i ns pecti on of the a nus a nd rectum. Anos copy i s es s enti a l i n eva l ua ti ng
pa i nl es s or bl eedi ng hemorrhoi ds . Recta l bl eedi ng s houl d be a ttri buted to hemorrhoi ds onl y a fter more s eri ous condi ti ons a re excl uded (eg, by
s i gmoi dos copy or col onos copy).

Treatment
Stool s ofteners , s i tz ba ths
Ra rel y exci s i on for thrombos ed externa l hemorrhoi ds
Injecti on s cl erothera py or rubber ba nd l i ga ti on for i nterna l hemorrhoi ds
Symptoma ti c trea tment i s us ua l l y a l l tha t i s needed. It i s a ccompl i s hed wi th s tool s ofteners (eg, docus a te, ps yl l i um), wa rm s i tz ba ths (i e, s i tti ng i n
a tub of tol era bl y hot wa ter for 10 mi n) a fter ea ch bowel movement a nd prn, a nes theti c oi ntments conta i ni ng l i doca i ne, or wi tch ha zel
(ha ma mel i s ) compres s es (whi ch s oothe by a n unknown mecha ni s m). Pa i n ca us ed by a thrombos ed hemorrhoi d ca n be trea ted wi th NSAIDs .
Infrequentl y, s i mpl e exci s i on of the hemorrhoi d ma y rel i eve pa i n ra pi dl y; a fter i nfi l tra ti on wi th 1% l i doca i ne, the thrombos ed porti on of the
hemorrhoi d i s exci s ed, a nd the defect i s cl os ed wi th a n a bs orba bl e s uture. Bl eedi ng hemorrhoi ds ca n be trea ted by i njecti on s cl erothera py wi th
5% phenol i n vegeta bl e oi l . Bl eedi ng s houl d cea s e a t l ea s t tempora ri l y.
Rubber ba nd l i ga ti on i s us ed for l a rger, prol a ps i ng i nterna l hemorrhoi ds or thos e tha t do not res pond to cons erva ti ve ma na gement. Wi th mi xed
i nterna l a nd externa l hemorrhoi ds , onl y the i nterna l component s houl d be rubber ba nd l i ga ted. The i nterna l hemorrhoi d i s gra s ped a nd
wi thdra wn through a s tretched 1/2-cm di a meter ba nd, whi ch i s rel ea s ed to l i ga te the hemorrhoi d, res ul ti ng i n i ts necros i s a nd s l oughi ng. One
hemorrhoi d i s l i ga ted every 2 wk; 3 to 6 trea tments ma y be requi red. Someti mes , mul ti pl e hemorrhoi ds ca n be l i ga ted a t a s i ngl e vi s i t.
Infra red photocoa gul a ti on i s us eful for a bl a ti ng s ma l l i nterna l hemorrhoi ds , hemorrhoi ds tha t ca nnot be rubber ba nd l i ga ted beca us e of pa i n
s ens i ti vi ty, or hemorrhoi ds tha t a re not cured wi th rubber ba nd l i ga ti on. La s er des tructi on, cryothera py, a nd va ri ous types of el ectrodes tructi on a re
of unproven effi ca cy.
Surgi ca l hemorrhoi dectomy i s requi red for pa ti ents who do not res pond to other forms of thera py. Si gni fi ca nt pos topera ti ve pa i n i s common, a s i s
uri na ry retenti on a nd cons ti pa ti on. Sta pl ed hemorrhoi dopexy i s a n a l terna ti ve procedure for ci rcumferenti a l hemorrhoi ds , a l though i ts a dva nta ges
a nd the i ndi ca ti ons ha ve yet to be defi ned.
Levator Syndrome
Episodic rectal pain caused by spasm of the levator ani muscle.
Proctalgia fugax (fl eeti ng pa i n i n the rectum) a nd coccydynia (pa i n i n the coccygea l regi on) a re va ri a nts of l eva tor s yndrome. Recta l s pa s m ca us es
pa i n, typi ca l l y unrel a ted to defeca ti on, us ua l l y l a s ti ng < 20 mi n. The pa i n ma y be bri ef a nd i ntens e or a va gue a che hi gh i n the rectum. It ma y occur
s ponta neous l y or wi th s i tti ng a nd ca n wa ken the pa ti ent from s l eep. The pa i n ma y feel a s i f i t woul d be rel i eved by the pa s s a ge of ga s or a bowel
movement. In s evere ca s es , the pa i n ca n pers i s t for ma ny hours a nd recur frequentl y. The pa ti ent ma y ha ve undergone va ri ous recta l opera ti ons
for thes e s ymptoms , wi th no benefi t.
Diagnosis
Phys i ca l exa mi na ti on ca n excl ude other pa i nful recta l condi ti ons (eg, thrombos ed hemorrhoi ds , fi s s ures , a bs ces s es ). Phys i ca l exa mi na ti on i s
often norma l , a l though tendernes s or ti ghtnes s of the l eva tor mus cl e, us ua l l y on the l eft, ma y be pres ent. Occa s i ona l ca s es a re ca us ed by l ow
ba ck or pros ta te di s orders .
Treatment
Ana l ges i cs , s i tz ba ths
Someti mes el ectroga l va ni c s ti mul a ti on
Trea tment cons i s ts of expl a na ti ons to the pa ti ent of the beni gn na ture of the condi ti on. An a cute epi s ode ma y be rel i eved by the pa s s a ge of ga s
or a bowel movement, by a s i tz ba th, or by a mi l d a na l ges i c. When the s ymptoms a re more i ntens e, phys i ca l thera py wi th el ectroga l va ni c
s ti mul a ti on a ppl i ed to the l ower rectum i s us ua l l y effecti ve. Skel eta l mus cl e rel a xa nts or a na l s phi ncter ma s s a ge under l oca l or regi ona l
a nes thes i a ca n be tri ed, but the benefi t i s uncl ea r.
Pilonidal Disease
Pilonidal disease refers to an acute abscess or chronic draining sinus in the sacrococcygeal area.
Pi l oni da l di s ea s e us ua l l y occurs i n young, hi rs ute, whi te ma l es but ca n a l s o occur i n women. One or s evera l mi dl i ne or a dja cent-to-the-mi dl i ne
pi ts or s i nus es occur i n the s ki n of the s a cra l regi on a nd ma y form a ca vi ty, often conta i ni ng ha i r. The l es i on i s us ua l l y a s ymptoma ti c; i nfected
l es i ons a re pa i nful .
Trea tment of a n a cute a bs ces s i s by i nci s i on a nd dra i na ge. Us ua l l y, one or more chroni c dra i ni ng s i nus es pers i s t a nd mus t be exti rpa ted by
exci s i on a nd pri ma ry cl os ure or, prefera bl y, by a n open techni que (eg, cys totomy, ma rs upi a l i za ti on). Anti bi oti cs a re genera l l y not needed.
Proctitis
Proctitis is inflammation of the rectal mucosa, which may result from infection, inflammatory bowel disease, or radiation. Symptoms are rectal discomfort and
bleeding. Diagnosis is by sigmoidoscopy, usually with cultures and biopsy. Treatment depends on etiology.
Procti ti s ma y be a ma ni fes ta ti on of s exua l l y tra ns mi tted di s ea s e, certa i n enteri c i nfecti ons (eg, Campylobacter, Shigella, Salmonella), i nfl a mma tory
bowel di s ea s e, or ra di a ti on trea tments ; i t ma y be a s s oci a ted wi th pri or a nti bi oti c us e. Sexua l l y tra ns mi tted pa thogens ca us e procti ti s more
commonl y a mong homos exua l men. Immunocompromi s ed pa ti ents a re a t pa rti cul a r ri s k of i nfecti ons wi th herpes s i mpl ex a nd cytomega l ovi rus .
Symptoms and Signs
Typi ca l l y, pa ti ents report recta l bl eedi ng or pa s s a ge of mucus . Procti ti s res ul ti ng from gonorrhea , herpes s i mpl ex, or cytomega l ovi rus ma y ca us e
i ntens e a norecta l pa i n.
Diagnosis
Proctos copy or s i gmoi dos copy
Tes ts for s yphi l i s a nd Clostridium difficile
Di a gnos i s requi res proctos copy or s i gmoi dos copy, whi ch ma y revea l a n i nfl a med recta l mucos a . Sma l l di s crete ul cers a nd ves i cl es s ugges t herpes
i nfecti on. Smea rs s houl d be s ent for cul ture of Neisseria gonorrhoeae, Chlamydia s p, enteri c pa thogens , a nd vi ra l pa thogens . Serol ogi c tes ts for
s yphi l i s a nd s tool tes ts for C. difficile toxi n a re done. Someti mes mucos a l bi ops y i s needed. Col onos copy ma y be va l ua bl e i n s ome pa ti ents .
Treatment
Va ri ous trea tments dependi ng on ca us e
Infecti ve procti ti s ca n be trea ted wi th a nti bi oti cs . Homos exua l men wi th nons peci fi c procti ti s ma y be trea ted empi ri ca l l y wi th ceftri a xone 125 mg
IM once (or ci profl oxa ci n 500 mg po bi d for 7 da ys ), pl us doxycycl i ne 100 mg po bi d for 7 da ys . Anti bi oti c-a s s oci a ted procti ti s i s trea ted wi th
metroni da zol e (250 mg po qi d) or va ncomyci n (125 mg po qi d) for 7 to 10 da ys .
Ra di a ti on procti ti s i s us ua l l y effecti vel y trea ted wi th topi ca l forma l i n ca reful l y a ppl i ed to the a ffected mucos a . Al terna ti ve trea tments i ncl ude
topi ca l corti cos teroi ds a s foa m (hydrocorti s one 90 mg) or enema s (hydrocorti s one 100 mg or methyl predni s ol one 40 mg) bi d for 3 wk, or
mes a l a mi ne (4 g) enema a t bedti me for 3 to 6 wk. Mes a l a mi ne s uppos i tori es 500 mg once/da y or bi d, mes a l a mi ne 800 mg po ti d, or s ul fa s a l a zi ne
500 to 1000 mg po qi d for 3 wk a l one or i n combi na ti on wi th topi ca l thera py ma y a l s o be effecti ve. Pa ti ents unres pons i ve to thes e forms of
thera py ma y benefi t from a cours e of s ys temi c corti cos teroi ds .
Pruritus Ani
Pruritus ani is anal and perianal itching.
The peri a na l s ki n tends to i tch, whi ch ca n res ul t from numerous ca us es (s ee
Ta bl e 21-1).
[Table 21-1. Ca us es of Pruri tus Ani ]
Occa s i ona l l y, the i rri ta ti on i s mi s i nterpreted by the pa ti ent a s pa i n, s o other ca us es of peri a na l pa i n (eg, a bs ces s ) s houl d be rul ed out.
Di a gnos i s i s ba s ed on the a ppea ra nce of the a na l s ki n a nd rel eva nt i nforma ti on from the hi s tory. The s ki n typi ca l l y s hows dul l nes s a nd
thi ckeni ng, a l though the underl yi ng pa thol ogy i s often obs cured by excori a ti on ca us ed by s cra tchi ng a nd s econda ry i nfecti on. A s cra pi ng of l oca l
s ki n i s ta ken to rul e out a funga l i nfecti on, a nd a s tool s a mpl e s houl d be exa mi ned for ova a nd pa ra s i tes . Vi s i bl e l es i ons s houl d be bi ops i ed.
Foods s us pected of ca us i ng pruri tus a ni s houl d be el i mi na ted from the di et. Cl othi ng s houl d be l oos e, a nd bed cl othi ng l i ght. After bowel
movements , the pa ti ent s houl d cl ea ns e the a na l a rea wi th a bs orbent cotton or pl a i n s oft ti s s ue moi s tened wi th wa ter. Li bera l , frequent dus ti ng
wi th nonmedi ca ted ta l cum powder or corns ta rch hel ps comba t moi s ture. Hydrocorti s one a ceta te 1% oi ntment, a ppl i ed s pa ri ngl y qi d, ma y rel i eve
s ymptoms . Sys temi c ca us es a nd pa ra s i ti c or funga l i nfecti ons mus t be trea ted s peci fi ca l l y.
Rectal Prolapse and Procidentia
Rectal prolapse is painless protrusion of the rectum through the anus. Procidentia is complete prolapse of the entire thickness of the rectum. Diagnosis is by
inspection. Surgery is usually required in adults.
Tra ns i ent, mi nor prol a ps e of jus t the recta l mucos a often occurs i n otherwi s e norma l i nfa nts . Mucos a l prol a ps e i n a dul ts pers i s ts a nd ma y
progres s i vel y wors en.
Proci denti a i s compl ete prol a ps e of the enti re thi cknes s of the rectum. The pri ma ry ca us e i s uncl ea r. Mos t pa ti ents a re women > 60.
Symptoms and Signs
The mos t promi nent s ymptom i s protrus i on. It ma y onl y occur whi l e s tra i ni ng or whi l e wa l ki ng or s ta ndi ng. Recta l bl eedi ng ca n occur, a nd
i nconti nence i s frequent. Pa i n i s uncommon unl es s i nca rcera ti on occurs .
Diagnosis
Si gmoi dos copy, col onos copy, or ba ri um enema
To determi ne the ful l extent of the prol a ps e, the cl i ni ci a n s houl d exa mi ne the pa ti ent whi l e the pa ti ent i s s ta ndi ng or s qua tti ng a nd s tra i ni ng.
Recta l proci denti a ca n be di s ti ngui s hed from hemorrhoi ds by the pres ence of ci rcumferenti a l mucos a l fol ds . Ana l s phi ncter tone i s us ua l l y
di mi ni s hed. Si gmoi dos copy, col onos copy, or ba ri um enema x-ra ys of the col on mus t be done to s ea rch for other di s ea s e. Pri ma ry neurol ogi c
di s orders (eg, s pi na l cord tumors ) mus t be rul ed out.
Treatment
El i mi na ti on of ca us es of s tra i ni ng
For i nfa nts a nd chi l dren: Someti mes s tra ppi ng buttocks together
For a dul ts : Someti mes s urgery
In i nfa nts a nd chi l dren, cons erva ti ve trea tment i s mos t s a ti s fa ctory. Ca us es of s tra i ni ng s houl d be el i mi na ted. Fi rml y s tra ppi ng the buttocks
together wi th ta pe between bowel movements us ua l l y fa ci l i ta tes s ponta neous res ol uti on of the prol a ps e. For s i mpl e mucos a l prol a ps e i n a dul ts ,
the exces s mucos a ca n be exci s ed. For proci denti a , a n a bdomi na l opera ti on ma y be requi red. In pa ti ents who a re very ol d or i n poor hea l th, a wi re
or s yntheti c pl a s ti c l oop ca n enci rcl e the s phi ncteri c ri ng (Thi ers ch's procedure). Other peri nea l opera ti ons (eg, Del orme or Al temei er procedure)
ca n be cons i dered.
Chapter 22. Tumors of the GI Tract

Introduction
Va ri ous beni gn a nd ma l i gna nt tumors ca n devel op a nywhere i n the GI tra ct. Tumors of the mouth a re di s cus s ed i n Ch. 55.
Benign Esophageal Tumors
Al though there a re ma ny types of beni gn es opha gea l tumors , mos t a re of l i ttl e cons equence except for ca us i ng a nnoyi ng s wa l l owi ng s ymptoms
(s ee p. 120) a nd ra rel y ul cera ti on or bl eedi ng. Lei omyoma , the mos t common, ma y be mul ti pl e but us ua l l y ha s a n excel l ent prognos i s .
Esophageal Cancer
The most common malignant tumor in the proximal two thirds of the esophagus is squamous cell carcinoma; adenocarcinoma is the most common in the distal
one third. Symptoms are progressive dysphagia and weight loss. Diagnosis is by endoscopy, followed by CT and endoscopic ultrasound for staging. Treatment
varies with stage and generally includes surgery with or without chemotherapy and radiation. Long-term survival is poor except for those with local disease.
Es opha gea l ca ncer a ccounts for a n es ti ma ted 15,500 ca s es a nd 13,900 dea ths i n the US a nnua l l y.
Squamous cell carcinoma: About 8000 ca s es occur a nnua l l y i n the US. It i s more common i n pa rts of As i a a nd i n South Afri ca . In the US, i t i s 4 to 5
ti mes more common a mong bl a cks tha n whi tes , a nd 2 to 3 ti mes more common a mong men tha n women.
The pri ma ry ri s k fa ctors a re a l cohol i nges ti on a nd toba cco us e (i n a ny form). Other fa ctors i ncl ude a cha l a s i a , huma n pa pi l l oma vi rus , l ye i nges ti on
(res ul ti ng i n s tri cture), s cl erothera py, Pl ummer-Vi ns on s yndrome, i rra di a ti on of the es opha gus , a nd es opha gea l webs . Geneti c ca us es a re uncl ea r,
but 50% of pa ti ents wi th tyl os i s (hyperkera tos i s pa l ma ri s et pl a nta ri s ), a n a utos oma l domi na nt di s order, ha ve es opha gea l ca ncer by a ge 45, a nd
95% ha ve i t by a ge 55.
Adenocarcinoma: Adenoca rci noma occurs i n the di s ta l es opha gus . Its i nci dence i s i ncrea s i ng; i t a ccounts for 50% of es opha gea l ca rci noma i n
whi tes . It i s 4 ti mes more common a mong whi tes tha n bl a cks . Al cohol i s not a n i mporta nt ri s k fa ctor, but s moki ng i s contri butory. Adenoca rci noma
of the di s ta l es opha gus i s di ffi cul t to di s ti ngui s h from a denoca rci noma of the ga s tri c ca rdi a i nva di ng the di s ta l es opha gus .
Mos t a denoca rci noma s a ri s e i n Ba rrett's es opha gus , whi ch res ul ts from chroni c ga s troes opha gea l refl ux di s ea s e a nd refl ux es opha gi ti s . In
Ba rrett's es opha gus , a meta pl a s ti c, col umna r, gl a ndul a r, i ntes ti ne-l i ke mucos a wi th brus h border a nd gobl et cel l s repl a ces the norma l s tra ti fi ed
s qua mous epi thel i um of the di s ta l es opha gus duri ng the hea l i ng pha s e of a cute es opha gi ti s when hea l i ng ta kes pl a ce i n the conti nued pres ence
of s toma ch a ci d.
Other malignant tumors: Les s common ma l i gna nt tumors i ncl ude s pi ndl e cel l ca rci noma (a poorl y di fferenti a ted va ri a nt of s qua mous cel l
ca rci noma ), verrucous ca rci noma (a wel l -di fferenti a ted va ri a nt of s qua mous cel l ca rci noma ), ps eudos a rcoma , mucoepi dermoi d ca rci noma ,
a denos qua mous ca rci noma , cyl i ndroma (a denoi d cys ti c ca rci noma ), pri ma ry oa t cel l ca rci noma , chori oca rci noma , ca rci noi d tumor, s a rcoma , a nd
pri ma ry ma l i gna nt mel a noma .
Meta s ta ti c ca ncer cons ti tutes 3% of es opha gea l ca ncer. Mel a noma a nd brea s t ca ncer a re mos t l i kel y to meta s ta s i ze to the es opha gus ; others
i ncl ude ca ncers of the hea d a nd neck, l ung, s toma ch, l i ver, ki dney, pros ta te, tes ti s , a nd bone. Thes e tumors us ua l l y s eed the l oos e connecti ve
ti s s ue s troma a round the es opha gus , wherea s pri ma ry es opha gea l ca ncers begi n i n the mucos a or s ubmucos a .
Symptoms and Signs
Ea rl y-s ta ge es opha gea l ca ncer tends to be a s ymptoma ti c. When the l umen of the es opha gus becomes cons tri cted to < 14 mm, dys pha gi a
commonl y occurs . The pa ti ent fi rs t ha s di ffi cul ty s wa l l owi ng s ol i d food, then s emi s ol i d food, a nd fi na l l y l i qui d food a nd s a l i va ; thi s s tea dy
progres s i on s ugges ts a growi ng ma l i gna nt proces s ra ther tha n a s pa s m, beni gn ri ng, or pepti c s tri cture. Ches t pa i n ma y be pres ent, us ua l l y
ra di a ti ng to the ba ck.
Wei ght l os s , even when the pa ti ent ma i nta i ns a good a ppeti te, i s a l mos t uni vers a l . Compres s i on of the recurrent l a ryngea l nerve ma y l ea d to
voca l cord pa ra l ys i s a nd hoa rs enes s . Compres s i on of s ympa theti c nerves ma y l ea d to Horner's s yndrome, a nd nerve compres s i on el s ewhere ma y
ca us e s pi na l pa i n, hi ccups , or pa ra l ys i s of the di a phra gm. Ma l i gna nt pl eura l effus i ons or pul mona ry meta s ta s i s ma y ca us e dys pnea . Intra l umi na l
tumor i nvol vement ma y ca us e odynopha gi a , vomi ti ng, hema temes i s , mel ena , i ron defi ci ency a nemi a , a s pi ra ti on, a nd cough. Fi s tul a s between the
es opha gus a nd tra cheobronchi a l tree ma y ca us e l ung a bs ces s a nd pneumoni a . Other fi ndi ngs ma y i ncl ude s uperi or vena ca va s yndrome,
ma l i gna nt a s ci tes , a nd bone pa i n.
Lympha ti c s prea d to i nterna l jugul a r, cervi ca l , s upra cl a vi cul a r, medi a s ti na l , a nd cel i a c nodes i s common. The tumor us ua l l y meta s ta s i zes to l ung
a nd l i ver a nd occa s i ona l l y to di s ta nt s i tes (eg, bone, hea rt, bra i n, a drena l gl a nds , ki dneys , peri toneum).
Diagnosis
Endos copy wi th bi ops y
Then CT a nd endos copi c ul tra s ound
There a re no s creeni ng tes ts . Pa ti ents s us pected of ha vi ng es opha gea l ca ncer s houl d ha ve endos copy wi th cytol ogy a nd bi ops y. Al though ba ri um xra y ma y s how a n obs tructi ve l es i on, endos copy i s requi red for bi ops y a nd ti s s ue di a gnos i s .
Pa ti ents i n whom es opha gea l ca ncer i s i denti fi ed requi re CT of the ches t a nd a bdomen to determi ne extent of tumor s prea d. If CT res ul ts a re
nega ti ve for meta s ta s i s , endos copi c ul tra s ound s houl d be done to determi ne the depth of the tumor i n the es opha gea l wa l l a nd regi ona l l ymph
node i nvol vement. Fi ndi ngs gui de thera py a nd hel p determi ne prognos i s .
Ba s i c bl ood tes ts , i ncl udi ng CBC, el ectrol ytes , a nd l i ver functi on, s houl d be done.
Prognosis
Prognos i s depends grea tl y on s ta ge, but overa l l i s poor (5-yr s urvi va l : < 5%) beca us e ma ny pa ti ents pres ent wi th a dva nced di s ea s e. Pa ti ents wi th
ca ncer res tri cted to the mucos a ha ve a bout a n 80% s urvi va l ra te, whi ch drops to < 50% wi th s ubmucos a l i nvol vement, 20% wi th extens i on to the
mus cul a ri s propri a , 7% wi th extens i on to a dja cent s tructures , a nd < 3% wi th di s ta nt meta s ta s es .
Treatment
Surgi ca l res ecti on, often combi ned wi th chemothera py a nd ra di a ti on
Trea tment deci s i ons depend on tumor s ta gi ng, s i ze, l oca ti on, a nd the pa ti ent's wi s hes (ma ny choos e to forgo a ggres s i ve trea tment).
General principles: Pa ti ents wi th s ta ge 0, I, or IIa di s ea s e (s ee
Ta bl e 22-1) res pond wel l to s urgi ca l res ecti on; preopera ti ve chemothera py a nd ra di a ti on provi de a ddi ti ona l benefi t. Thos e wi th s ta ge IIb a nd III
ha ve poor s urvi va l wi th s urgery a l one; res pons e a nd s urvi va l a re enha nced by preopera ti ve (neoa djuva nt) us e of ra di a ti on a nd chemothera py to
reduce tumor vol ume before s urgery. Pa ti ents una bl e or unwi l l i ng to undergo s urgery ma y recei ve s ome benefi t from combi ned ra di a ti on a nd
chemothera py. Ra di a ti on or chemothera py a l one i s of l i ttl e benefi t. Pa ti ents wi th s ta ge IV di s ea s e requi re pa l l i a ti on a nd s houl d not undergo
s urgery.
After trea tment, pa ti ents a re s creened for recurrence by endos copy a nd CT of the neck, ches t, a nd a bdomen a t 6-mo i nterva l s for 3 yr a nd a nnua l l y
therea fter.
Pa ti ents wi th Ba rrett's es opha gus requi re i ntens e l ong-term trea tment for ga s troes opha gea l refl ux di s ea s e (s ee p. 125) a nd endos copi c
s urvei l l a nce for ma l i gna nt tra ns forma ti on a t 3- to 12-mo i nterva l s dependi ng on the degree of meta pl a s i a .
Surgery: En bl oc res ecti on for cure requi res remova l of the enti re tumor, proxi ma l a nd di s ta l ma rgi ns of norma l ti s s ue, a l l potenti a l l y ma l i gna nt
l ymph nodes , a nd a porti on of the proxi ma l s toma ch s uffi ci ent to conta i n the di s ta l dra i ni ng l ympha ti cs . The procedure requi res ga s tri c pul l -up
wi th es opha goga s tri c a na s tomos i s , s ma l l -bowel i nterpos i ti on, or col oni c i nterpos i ti on. Pyl oropl a s ty i s requi red to ens ure proper ga s tri c dra i na ge
beca us e es opha gectomy neces s a ri l y res ul ts i n bi l a tera l va gotomy. Thi s extens i ve s urgery ma y be poorl y tol era ted by pa ti ents > 75 yr, pa rti cul a rl y
thos e
[Table 22-1. Sta gi ng Es opha gea l Ca ncer*]
wi th underl yi ng ca rdi a c or pul mona ry di s ea s e (ejecti on fra cti on < 40%, or forced expi ra tory vol ume i n 1 s ec [FEV1 ] < 1.5 L/mi n). Overa l l , opera ti ve
morta l i ty i s a bout 5%.
Compl i ca ti ons of s urgery i ncl ude a na s tomoti c l ea ks , fi s tul a s , a nd s tri ctures ; bi l i ous ga s troes opha gea l refl ux; a nd dumpi ng s yndrome. The burni ng
ches t pa i n of bi l e refl ux a fter di s ta l es opha gectomy ca n be more a nnoyi ng tha n the ori gi na l s ymptom of dys pha gi a a nd ma y requi re s ubs equent
Roux-en-Y jejunos tomy for bi l e di vers i on. An i nterpos ed s egment of s ma l l bowel or col on i n the ches t ha s a tenuous bl ood s uppl y, a nd tors i on,
i s chemi a , or ga ngrene of the i nterpos ed bowel ma y res ul t.
External beam radiation therapy: Ra di a ti on i s us ua l l y us ed i n combi na ti on wi th chemothera py for pa ti ents who a re poor ca ndi da tes for cura ti ve
s urgery, i ncl udi ng thos e wi th a dva nced di s ea s e. Ra di a ti on i s contra i ndi ca ted i n pa ti ents wi th tra cheoes opha gea l fi s tul a beca us e tumor s hri nka ge
enl a rges the fi s tul a . Si mi l a rl y, pa ti ents wi th va s cul a r enca s ement by tumor ma y experi ence ma s s i ve hemorrha ge wi th tumor s hri nka ge. Duri ng the
ea rl y s ta ges of ra di a ti on thera py, edema ma y wors en es opha gea l obs tructi on, dys pha gi a , a nd odynopha gi a . Thi s probl em ma y requi re es opha gea l
di l a ti on or prera di a ti on pl a cement of a percuta neous ga s tros tomy feedi ng tube. Other a dvers e effects of ra di a ti on thera py i ncl ude na us ea ,
vomi ti ng, a norexi a , fa ti gue, es opha gi ti s , exces s es opha gea l mucus producti on, xeros tomi a , s tri cture, ra di a ti on pneumoni ti s , ra di a ti on
peri ca rdi ti s , myoca rdi ti s , a nd myel i ti s (s pi na l cord i nfl a mma ti on).
Chemotherapy: Tumors a re poorl y res pons i ve to chemothera py a l one. Res pons e ra tes (defi ned a s 50% reducti on i n a l l mea s ura bl e a rea s of
tumor) va ry from 10 to 40%, but res pons es genera l l y a re i ncompl ete (mi nor s hri nka ge of tumor) a nd tempora ry. No drug i s nota bl y more effecti ve
tha n a nother.
Mos t commonl y, ci s pl a ti n a nd 5-fl uoroura ci l a re us ed i n combi na ti on. However, s evera l other drugs , i ncl udi ng mi tomyci n, doxorubi ci n, vi ndes i ne,
bl eomyci n, a nd methotrexa te, a l s o a re a cti ve a ga i ns t s qua mous cel l ca rci noma .
Palliation: Pa l l i a ti on i s di rected a t reduci ng es opha gea l obs tructi on s uffi ci entl y to a l l ow ora l i nta ke. Sufferi ng ca us ed by es opha gea l obs tructi on
ca n be s i gni fi ca nt, wi th s a l i va ti on a nd recurrent a s pi ra ti on. Opti ons i ncl ude ma nua l di l a ti on procedures (bougi ena ge), ora l l y i ns erted s tents ,
ra di a ti on thera py, l a s er photocoa gul a ti on, a nd photodyna mi c thera py. In s ome ca s es , cervi ca l es opha gos tomy wi th feedi ng jejunos tomy i s
requi red.
Rel i ef provi ded by es opha gea l di l a ti on ra rel y l a s ts more tha n a few da ys . Fl exi bl e meta l mes h s tents a re more effecti ve a t ma i nta i ni ng
es opha gea l pa tency. Some pl a s ti c-coa ted model s ca n a l s o be us ed to occl ude tra cheoes opha gea l fi s tul a s , a nd s ome a re a va i l a bl e wi th a va l ve
tha t prevents refl ux when the s tent mus t be pl a ced nea r the l ower es opha gea l s phi ncter.
Endos copi c l a s er thera py ca n pa l l i a te dys pha gi a by burni ng a centra l cha nnel through the tumor a nd ca n be repea ted i f needed. Photodyna mi c
thera py us es a n i njecti on of porfi mer s odi um, a hema toporphyri n deri va ti ve tha t i s ta ken up by ti s s ues a nd a cts a s a photos ens i ti zer. When
a cti va ted by a l a s er bea m di rected on the tumor, thi s s ubs ta nce rel ea s es cytotoxi c oxygen s i ngl ets tha t des troy tumor cel l s . Pa ti ents recei vi ng thi s
trea tment mus t a voi d s un expos ure for 6 wk a fter trea tment beca us e the s ki n i s a l s o s ens i ti zed to l i ght.
Supportive care: Nutri ti ona l s upport by entera l or pa rentera l s uppl ementa ti on enha nces the tol era bi l i ty a nd fea s i bi l i ty of a l l trea tments . An
endos copi ca l l y or s urgi ca l l y pl a ced feedi ng tube provi des a more di s ta l route for feedi ng when the es opha gus i s obs tructed.
Beca us e nea rl y a l l ca s es of es opha gea l ca ncer a re fa ta l , end-of-l i fe ca re s houl d a l wa ys a i m to control s ymptoms , es peci a l l y pa i n a nd i na bi l i ty to
s wa l l ow s ecreti ons (s ee a l s o p. 3483). At s ome poi nt, ma ny pa ti ents need s ubs ta nti a l dos es of opi oi ds . Pa ti ents s houl d be a dvi s ed to ma ke endof-l i fe ca re deci s i ons ea rl y i n the cours e of di s ea s e a nd to record thei r wi s hes i n a n a dva nce di recti ve (s ee p. 3471).
Stomach Cancer
Etiology of stomach cancer is multifactorial, but Helicobacter pylori plays a significant role. Symptoms include early satiety, obstruction, and bleeding but tend to
occur late in the disease. Diagnosis is by endoscopy, followed by CT and endoscopic ultrasound for staging. Treatment is mainly surgery; chemotherapy may
provide a temporary response. Long-term survival is poor except for those with local disease.
Stoma ch ca ncer a ccounts for a n es ti ma ted 21,000 ca s es a nd over 11,000 dea ths i n the US a nnua l l y. Ga s tri c a denoca rci noma a ccounts for 95% of
ma l i gna nt tumors of the s toma ch; l es s common a re l oca l i zed ga s tri c l ymphoma s (s ee p. 1016) a nd l ei omyos a rcoma s . Stoma ch ca ncer i s the 2nd
mos t common ca ncer worl dwi de, but the i nci dence va ri es wi del y; i nci dence i s extremel y hi gh i n Ja pa n, Chi na , Chi l e, a nd Icel a nd. In the US,
i nci dence ha s decl i ned i n recent deca des to the 7th mos t common ca us e of dea th from ca ncer. In the US, i t i s mos t common a mong bl a cks ,
Hi s pa ni cs , a nd Ameri ca n Indi a ns . Its i nci dence i ncrea s es wi th a ge; > 75% of pa ti ents a re > 50 yr.
Etiology
Helicobacter pylori i nfecti on i s the ca us e of mos t s toma ch ca ncer. Autoi mmune a trophi c ga s tri ti s (s ee p. 133) a nd va ri ous geneti c fa ctors (s ee
Ga s troi ntes ti na l Stroma l Tumors on p. 190) a re a l s o ri s k fa ctors . Di eta ry fa ctors a re not proven ca us es .
Ga s tri c pol yps ca n be precurs ors of ca ncer. Infl a mma tory pol yps ma y devel op i n pa ti ents ta ki ng NSAIDs , a nd fundi c foveol a r pol yps a re common
a mong pa ti ents ta ki ng proton pump i nhi bi tors . Adenoma tous pol yps , pa rti cul a rl y mul ti pl e ones , a l though ra re, a re the mos t l i kel y to devel op
ca ncer. Ca ncer i s pa rti cul a rl y l i kel y i f a n a denoma tous pol yp i s > 2 cm i n di a meter or ha s a vi l l ous hi s tol ogy. Beca us e ma l i gna nt tra ns forma ti on
ca nnot be detected by i ns pecti on, a l l pol yps s een a t endos copy s houl d be removed. The i nci dence of s toma ch ca ncer i s genera l l y decrea s ed i n
pa ti ents wi th duodena l ul cer.
Pathophysiology
Ga s tri c a denoca rci noma s ca n be cl a s s i fi ed by gros s a ppea ra nce:
Protrudi ng: The tumor i s pol ypoi d or funga ti ng.
Penetra ti ng: The tumor i s ul cera ted.
Superfi ci a l s prea di ng: The tumor s prea ds a l ong the mucos a or i nfi l tra tes s uperfi ci a l l y wi thi n the wa l l of the s toma ch.
Li ni ti s pl a s ti ca : The tumor i nfi l tra tes the s toma ch wa l l wi th a n a s s oci a ted fi brous rea cti on tha t ca us es a ri gi d "l ea ther bottl e" s toma ch.
Mi s cel l a neous : The tumor s hows cha ra cteri s ti cs of 2 of the other types ; thi s cl a s s i fi ca ti on i s the l a rges t.
Prognos i s i s better wi th protrudi ng tumors tha n wi th s prea di ng tumors beca us e protrudi ng tumors become s ymptoma ti c ea rl i er.
Symptoms and Signs
Ini ti a l s ymptoms a re nons peci fi c, often cons i s ti ng of dys peps i a s ugges ti ve of pepti c ul cer. Pa ti ents a nd phys i ci a ns a l i ke tend to di s mi s s
s ymptoms or trea t the pa ti ent for a ci d di s ea s e. La ter, ea rl y s a ti ety (ful l nes s a fter i nges ti ng a s ma l l a mount of food) ma y occur i f the ca ncer
obs tructs the pyl ori c regi on or i f the s toma ch becomes nondi s tens i bl e s econda ry to l i ni ti s pl a s ti ca . Dys pha gi a ma y res ul t i f ca ncer i n the ca rdi a c
regi on of the s toma ch obs tructs the es opha gea l outl et. Los s of wei ght or s trength, us ua l l y res ul ti ng from di eta ry res tri cti on, i s common. Ma s s i ve
hema temes i s or mel ena i s uncommon, but s econda ry a nemi a ma y fol l ow occul t bl ood l os s . Occa s i ona l l y, the fi rs t s ymptoms a re ca us ed by
meta s ta s i s (eg, ja undi ce, a s ci tes , fra ctures ).
Phys i ca l fi ndi ngs ma y be unrema rka bl e or l i mi ted to heme-pos i ti ve s tool s . La te i n the cours e, a bnorma l i ti es i ncl ude a n epi ga s tri c ma s s ;
umbi l i ca l , l eft s upra cl a vi cul a r, or l eft a xi l l a ry l ymph nodes ; hepa tomega l y; a nd a n ova ri a n or recta l ma s s . Pul mona ry, CNS, a nd bone l es i ons ma y
occur.
Diagnosis
Endos copy wi th bi ops y
Then CT a nd endos copi c ul tra s ound
Di fferenti a l di a gnos i s commonl y i ncl udes pepti c ul cer a nd i ts compl i ca ti ons .
Pa ti ents s us pected of ha vi ng s toma ch ca ncer s houl d ha ve endos copy wi th mul ti pl e bi ops i es a nd brus h cytol ogy. Occa s i ona l l y, a bi ops y l i mi ted to
the mucos a mi s s es tumor ti s s ue i n the s ubmucos a . X-ra ys , pa rti cul a rl y doubl e-contra s t ba ri um s tudi es , ma y s how l es i ons but ra rel y obvi a te the
need for s ubs equent endos copy.
Pa ti ents i n whom ca ncer i s i denti fi ed requi re CT of the ches t a nd a bdomen to determi ne extent of tumor s prea d. If CT i s nega ti ve for meta s ta s i s ,
endos copi c ul tra s ound s houl d be done to determi ne the depth of the tumor a nd regi ona l l ymph node i nvol vement. Fi ndi ngs gui de thera py a nd
hel p determi ne prognos i s .
Ba s i c bl ood tes ts , i ncl udi ng CBC, el ectrol ytes , a nd l i ver functi on tes ts , s houl d be done to a s s es s a nemi a , hydra ti on, genera l condi ti on, a nd
pos s i bl e l i ver meta s ta s es . Ca rci noembryoni c a nti gen (CEA) s houl d be mea s ured before a nd a fter s urgery.
Screening: Screeni ng wi th endos copy i s us ed i n hi gh-ri s k popul a ti ons (eg, Ja pa nes e) but i s not recommended i n the US. Fol l ow-up s creeni ng for
recurrence i n trea ted pa ti ents cons i s ts of endos copy a nd CT of the ches t, a bdomen, a nd pel vi s . If a n el eva ted CEA dropped a fter s urgery, fol l ow-up
s houl d i ncl ude CEA l evel s ; a ri s e s i gni fi es recurrence.
Prognosis
Prognos i s depends grea tl y on s ta ge but overa l l i s poor (5-yr s urvi va l : < 5 to 15%) beca us e mos t pa ti ents pres ent wi th a dva nced di s ea s e. If the
tumor i s l i mi ted to the mucos a or s ubmucos a , 5-yr s urvi va l ma y be a s hi gh a s 80%. For tumors i nvol vi ng l oca l l ymph nodes , s urvi va l i s 20 to 40%.
More wi des prea d di s ea s e i s a l mos t a l wa ys fa ta l wi thi n 1 yr. Ga s tri c l ymphoma s ha ve a better prognos i s a nd a re di s cus s ed i n Ch. 118.
Treatment
Surgi ca l res ecti on, s ometi mes combi ned wi th chemothera py, ra di a ti on, or both
Trea tment deci s i ons depend on tumor s ta gi ng a nd the pa ti ent's wi s hes (s ome ma y choos e to forgo a ggres s i ve trea tments ee p. 3471).
Cura ti ve s urgery i nvol ves remova l of mos t or a l l of the s toma ch a nd a dja cent l ymph nodes a nd i s rea s ona bl e i n pa ti ents wi th di s ea s e l i mi ted to
the s toma ch a nd perha ps the regi ona l l ymph nodes (< 50% of pa ti ents ). Adjuva nt chemothera py or combi ned chemothera py a nd ra di a ti on thera py
a fter s urgery ma y be benefi ci a l i f the tumor i s res ecta bl e.
Res ecti on of l oca l l y a dva nced regi ona l di s ea s e res ul ts i n a 10-mo medi a n s urvi va l (vs 3 to 4 mo wi thout res ecti on).
Meta s ta s i s or extens i ve noda l i nvol vement precl udes cura ti ve s urgery, a nd a t mos t, pa l l i a ti ve procedures s houl d be underta ken. However, the true
extent of tumor s prea d often i s not recogni zed unti l cura ti ve s urgery i s a ttempted. Pa l l i a ti ve s urgery typi ca l l y cons i s ts of a ga s troenteros tomy to
bypa s s a pyl ori c obs tructi on a nd s houl d be done onl y i f the pa ti ent's qua l i ty of l i fe ca n be i mproved. In pa ti ents not undergoi ng s urgery,
combi na ti on chemothera py regi mens (5-fl uoroura ci l , doxorubi ci n, mi tomyci n, ci s pl a ti n, or l eucovori n i n va ri ous combi na ti ons ) ma y produce
tempora ry res pons e but l i ttl e i mprovement i n 5-yr s urvi va l . Ra di a ti on thera py i s of l i mi ted benefi t.
Gastrointestinal Stromal Tumors
Ga s troi ntes ti na l s troma l tumors a re tumors of the GI tra ct deri ved from mes enchyma l precurs or cel l s i n the gut wa l l . They res ul t from muta ti ons of
a growth fa ctor receptor gene, CKIT. Some a re ca us ed by previ ous ra di a ti on thera py to the a bdomen for other tumors .
Tumors a re s l ow growi ng, a nd ma l i gna nt potenti a l va ri es from mi ni ma l to s i gni fi ca nt. Mos t (60 to 70%) occur i n the s toma ch, 20 to 25% i n the s ma l l
bowel , a nd a s ma l l number i n the es opha gus , col on, a nd rectum. Avera ge a ge a t pres enta ti on i s 50 to 60.
Symptoms va ry wi th l oca ti on but i ncl ude bl eedi ng, dys peps i a , a nd obs tructi on. Di a gnos i s i s us ua l l y by endos copy, wi th bi ops y a nd endos copi c
ul tra s ound for s ta gi ng. Trea tment i s s urgi ca l remova l . The rol e of ra di a ti on a nd chemothera py i s uncl ea r, but the tyros i ne ki na s e i nhi bi tor
i ma ti ni b ha s been benefi ci a l .
Small-Bowel Tumors
Sma l l -bowel tumors a ccount for 1 to 5% of GI tumors (over 5000 ca s es i n the US a nnua l l y).
Benign tumors i ncl ude l ei omyoma s , l i poma s , neurofi broma s , a nd fi broma s . Al l ma y ca us e a bdomi na l di s tenti on, pa i n, bl eedi ng, di a rrhea , a nd, i f
obs tructi on devel ops , vomi ti ng. Pol yps a re not a s common a s i n the col on.
Adenocarcinoma, a ma l i gna nt tumor, i s uncommon. Us ua l l y i t a ri s es i n the duodenum or proxi ma l jejunum a nd ca us es mi ni ma l s ymptoms . In
pa ti ents wi th Crohn's di s ea s e, the tumors tend to occur di s ta l l y a nd i n bypa s s ed or i nfl a med l oops of bowel ; a denoca rci noma occurs more often
i n Crohn's di s ea s e of the s ma l l bowel tha n i n Crohn's di s ea s e of the col on.
Pri ma ry ma l i gna nt lymphoma (s ee p. 1016) a ri s i ng i n the i l eum ma y ca us e a l ong, ri gi d s egment. Sma l l -bowel l ymphoma s a ri s e often i n l ongs ta ndi ng untrea ted cel i a c s prue.
Carcinoid tumors (s ee p. 907) occur mos t often i n the s ma l l bowel , pa rti cul a rl y the i l eum, a nd the a ppendi x, a nd i n thes e l oca ti ons a re often
ma l i gna nt. Mul ti pl e tumors occur i n 50% of ca s es . Of thos e > 2 cm i n di a meter, 80% ha ve meta s ta s i zed l oca l l y or to the l i ver by the ti me of
opera ti on. About 30% of s ma l l -bowel ca rci noi ds ca us e obs tructi on, pa i n, bl eedi ng, or ca rci noi d s yndrome. Trea tment i s s urgi ca l res ecti on; repea t
opera ti ons ma y be requi red.
Kaposi's sarcoma (s ee p. 753), fi rs t des cri bed a s a di s ea s e of el derl y Jewi s h a nd Ita l i a n men, occurs i n a n a ggres s i ve form i n Afri ca ns , tra ns pl a nt
reci pi ents , a nd AIDS pa ti ents , who ha ve GI tra ct i nvol vement 40 to 60% of the ti me. Les i ons ma y occur a nywhere i n the GI tra ct but us ua l l y i n the
s toma ch, s ma l l bowel , or di s ta l col on. GI l es i ons us ua l l y a re a s ymptoma ti c, but bl eedi ng, di a rrhea , protei nl os i ng enteropa thy, a nd
i ntus s us cepti on ma y occur. A s econd pri ma ry i ntes ti na l ca ncer occurs i n 20% of pa ti ents ; mos t often i t i s l ymphocyti c l eukemi a , non-Hodgki n
l ymphoma , Hodgki n l ymphoma , or a denoca rci noma of the GI tra ct. Trea tment depends on the cel l type a nd l oca ti on a nd extent of the l es i ons .
Diagnosis
Enterocl ys i s
Someti mes pus h endos copy or ca ps ul e vi deo endos copy
Enterocl ys i s (s ometi mes CT enterocl ys i s ) i s proba bl y the mos t common s tudy for ma s s l es i ons of the s ma l l bowel . Pus h endos copy of the s ma l l
bowel wi th a n enteros cope ma y be us ed to vi s ua l i ze a nd bi ops y tumors . Ca ps ul e vi deo endos copy ca n hel p i denti fy s ma l l -bowel l es i ons ,
pa rti cul a rl y bl eedi ng s i tes ; a s wa l l owed ca ps ul e tra ns mi ts 2 i ma ges /s ec to a n externa l recorder. The ori gi na l ca ps ul e i s not us eful i n the s toma ch
or col on beca us e i t tumbl es i n thes e l a rger orga ns ; a col on ca ps ul e ca mera wi th better opti cs a nd i l l umi na ti on i s under devel opment for us e i n
thes e l a rger-di a meter orga ns .
Treatment
Surgi ca l res ecti on
Trea tment i s s urgi ca l res ecti on. El ectroca utery, therma l obl i tera ti on, or l a s er photothera py a t the ti me of enteros copy or s urgery ma y be a n
a l terna ti ve to res ecti on.
Polyps of the Colon and Rectum
An intestinal polyp is any mass of tissue that arises from the bowel wall and protrudes into the lumen. Most are asymptomatic except for minor bleeding, which
is usually occult. The main concern is malignant transformation; most colon cancers arise in a previously benign adenomatous polyp. Diagnosis is by endoscopy.
Treatment is endoscopic removal.
Pol yps ma y be s es s i l e or peduncul a ted a nd va ry cons i dera bl y i n s i ze. Inci dence of pol yps ra nges from 7 to 50%; the hi gher fi gure i ncl udes very
s ma l l pol yps (us ua l l y hyperpl a s ti c pol yps or a denoma s ) found a t a utops y. Pol yps , often mul ti pl e, occur mos t commonl y i n the rectum a nd s i gmoi d
a nd decrea s e i n frequency towa rd the cecum. Mul ti pl e pol yps ma y repres ent fa mi l i a l a denoma tous pol ypos i s (s ee p. 192). About 25% of pa ti ents
wi th ca ncer of the l a rge bowel a l s o ha ve s a tel l i te a denoma tous pol yps .
Adenomatous (neoplastic) polyps a re of grea tes t concern. Such l es i ons a re cl a s s i fi ed hi s tol ogi ca l l y a s tubul a r a denoma s , tubul o-vi l l ous a denoma s
(vi l l ogl a ndul a r pol yps ), or vi l l ous a denoma s . The l i kel i hood of ca ncer i n a n a denoma tous pol yp a t the ti me of di s covery i s rel a ted to s i ze,
hi s tol ogi c type, a nd degree of dys pl a s i a ; a 1.5-cm tubul a r a denoma ha s a 2% ri s k of conta i ni ng a ca ncer vs a 35% ri s k i n 3-cm vi l l ous a denoma s .
Serra ted a denoma s , a s omewha t more a ggres s i ve type of a denoma , ma y devel op from hyperpl a s ti c pol yps .
Nonadenomatous (nonneoplastic) polyps i ncl ude hyperpl a s ti c pol yps , ha ma rtoma s , juveni l e pol yps , ps eudopol yps , l i poma s , l ei omyoma s , a nd other
ra rer tumors . Juveni l e pol yps occur i n chi l dren, typi ca l l y outgrow thei r bl ood s uppl y, a nd a utoa mputa te s ome ti me duri ng or a fter puberty.
Trea tment i s requi red onl y for uncontrol l a bl e bl eedi ng or i ntus s us cepti on. Infl a mma tory pol yps a nd ps eudopol yps occur i n chroni c ul cera ti ve
col i ti s a nd i n Crohn's di s ea s e of the col on. Mul ti pl e juveni l e pol yps (but not s pora di c ones ) convey a n i ncrea s ed ca ncer ri s k. The s peci fi c number
of pol yps res ul ti ng i n i ncrea s ed ri s k i s not known.
Symptoms and Signs
Mos t pol yps a re a s ymptoma ti c. Recta l bl eedi ng, us ua l l y occul t a nd ra rel y ma s s i ve, i s the mos t frequent compl a i nt. Cra mps , a bdomi na l pa i n, or
obs tructi on ma y occur wi th a l a rge l es i on. Recta l pol yps ma y be pa l pa bl e by di gi ta l exa mi na ti on. Occa s i ona l l y, a pol yp on a l ong pedi cl e ma y
prol a ps e through the a nus . La rge vi l l ous a denoma s ma y ra rel y ca us e wa tery di a rrhea tha t ma y res ul t i n hypoka l emi a .
Diagnosis
Col onos copy
Di a gnos i s i s us ua l l y ma de by col onos copy. Ba ri um enema , pa rti cul a rl y doubl e-contra s t exa mi na ti on, i s effecti ve, but col onos copy i s preferred
beca us e pol yps a l s o ma y be removed duri ng tha t procedure. Beca us e recta l pol yps a re often mul ti pl e a nd ma y coexi s t wi th ca ncer, compl ete
col onos copy to the cecum i s ma nda tory even i f a di s ta l l es i on i s found by fl exi bl e s i gmoi dos copy.
Treatment
Compl ete remova l duri ng col onos copy
Someti mes fol l ow wi th s urgi ca l res ecti on
Fol l ow-up s urvei l l a nce col onos copy
Pol yps s houl d be removed compl etel y wi th a s na re or el ectros urgi ca l bi ops y forceps duri ng tota l col onos copy; compl ete exci s i on i s pa rti cul a rl y
i mporta nt for l a rge vi l l ous a denoma s , whi ch ha ve a hi gh potenti a l for ca ncer. If col onos copi c remova l i s uns ucces s ful , l a pa rotomy s houl d be done.
Subs equent trea tment depends on the hi s tol ogy of the pol yp. If dys pl a s ti c epi thel i um does not i nva de the mus cul a ri s mucos a , the l i ne of
res ecti on i n the pol yp's s ta l k i s cl ea r, a nd the l es i on i s wel l di fferenti a ted, endos copi c exci s i on a nd cl os e endos copi c fol l ow-up s houl d s uffi ce.
Pa ti ents wi th deeper i nva s i on, a n uncl ea r res ecti on l i ne, or a poorl y di fferenti a ted l es i on s houl d ha ve s egmenta l res ecti on of the col on. Beca us e
i nva s i on through the mus cul a ri s mucos a provi des a cces s to l ympha ti cs a nd i ncrea s es the potenti a l for l ymph node meta s ta s i s , s uch pa ti ents
s houl d ha ve further eva l ua ti on (a s i n col on ca ncers ee p. 193).
The s chedul i ng of fol l ow-up exa mi na ti ons a fter pol ypectomy i s controvers i a l . Mos t a uthori ti es recommend tota l col onos copy a nnua l l y for 2 yr (or
ba ri um enema i f tota l col onos copy i s i mpos s i bl e), wi th remova l of newl y di s covered l es i ons . If 2 a nnua l exa mi na ti ons a re nega ti ve for new
l es i ons , col onos copy i s recommended every 2 to 3 yr.
Prevention
As pi ri n a nd COX-2 i nhi bi tors ma y hel p prevent forma ti on of new pol yps i n pa ti ents wi th pol yps or col on ca ncer.
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is a hereditary disorder causing numerous colonic polyps and resulting in colon carcinoma by age 40. Patients are usually
asymptomatic but may have heme-positive stool. Diagnosis is by colonoscopy and genetic testing. Treatment is colectomy.
FAP i s a n a utos oma l domi na nt di s ea s e i n whi ch 100 a denoma tous pol yps ca rpet the col on a nd rectum. The di s order occurs i n 1 i n 8,000 to 14,000
peopl e. Pol yps a re pres ent i n 50% of pa ti ents by a ge 15, a nd 95% by 35. Ca ncer devel ops before a ge 40 i n nea rl y a l l untrea ted pa ti ents .
Pa ti ents a l s o ca n devel op va ri ous extra col oni c ma ni fes ta ti ons (previ ous l y termed Ga rdner's s yndrome), both beni gn a nd ma l i gna nt. Beni gn
ma ni fes ta ti ons i ncl ude des moi d tumors , os teoma s of the s kul l or ma ndi bl e, s eba ceous cys ts , a nd a denoma s i n other pa rts of the GI tra ct.
Pa ti ents a re a t i ncrea s ed ri s k of ca ncer i n the duodenum (5 to 11%), pa ncrea s (2%), thyroi d (2%), bra i n (medul l obl a s toma i n < 1%), a nd l i ver
(hepa tobl a s toma i n 0.7% of chi l dren < 5).
Symptoms and Signs
Ma ny pa ti ents a re a s ymptoma ti c, but recta l bl eedi ng, typi ca l l y occul t, occurs .
Diagnosis
Col onos copy
Geneti c tes ti ng of pa ti ent a nd 1s t-degree rel a ti ves
Offs pri ng s creened for hepa tobl a s toma
Di a gnos i s i s ma de by fi ndi ng > 100 pol yps on col onos copy. Di a gnos ed pa ti ents s houl d ha ve geneti c tes ti ng to i denti fy the s peci fi c muta ti on, whi ch
s houl d then be s ought i n 1s t-degree rel a ti ves . If geneti c tes ti ng i s una va i l a bl e, rel a ti ves s houl d be s creened wi th a nnua l s i gmoi dos copy
begi nni ng a t a ge 12, reduci ng frequency wi th ea ch deca de. If no pol yps a re evi dent by a ge 50, s creeni ng frequency i s then the s a me a s for a vera geri s k pa ti ents .
Chi l dren of pa rents wi th FAP s houl d be s creened for hepa tobl a s toma from bi rth to a ge 5 yr wi th a nnua l s erum fetoprotei n l evel s a nd pos s i bl y l i ver
ul tra s ound.
Treatment
Col ectomy
Endos copi c s urvei l l a nce of rema i nder of GI tra ct
Perha ps a s pi ri n or coxi bs
Col ectomy s houl d be done a t the ti me of di a gnos i s . Tota l proctocol ectomy, ei ther wi th i l eos tomy or mucos a l proctectomy a nd i l eoa na l pouch,
el i mi na tes the ri s k of ca ncer. If s ubtota l col ectomy (remova l of mos t of the col on, l ea vi ng the rectum) wi th i l eorecta l a na s tomos i s i s done, the
recta l remna nt mus t be i ns pected every 3 to 6 mo; new pol yps mus t be exci s ed or ful gura ted. As pi ri n or coxi bs ma y i nhi bi t new pol yp forma ti on. If
new ones a ppea r too ra pi dl y or prol i fi ca l l y to remove, exci s i on of the rectum a nd perma nent i l eos tomy a re needed.
After col ectomy, pa ti ents s houl d ha ve upper endos copy every 6 mo to 4 yr, dependi ng on the number of pol yps (i f a ny) i n the s toma ch a nd
duodenum. Annua l phys i ca l exa mi na ti on of the thyroi d, a nd pos s i bl y ul tra s ound, a l s o i s recommended.
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome is an autosomal dominant disease with multiple hamartomatous polyps in the stomach, small bowel, and colon along with distinctive
pigmented skin lesions.
Pa ti ents a re a t a s i gni fi ca ntl y i ncrea s ed ri s k of GI a nd non-GI ca ncers ; pos s i bl y the geneti c defect i nvol ves a tumor s uppres s or gene. GI ca ncers
i ncl ude thos e of the pa ncrea s , s ma l l i ntes ti ne, a nd col on. Non-GI ca ncers i ncl ude thos e of the brea s t, l ung, uterus , a nd ova ri es .
The s ki n l es i ons a re mel a noti c ma cul es of the s ki n a nd mucous membra nes , es peci a l l y of the peri ora l regi on, l i ps a nd gums , ha nds , a nd feet. Al l
but the bucca l l es i ons tend to fa de by puberty. Pol yps ma y bl eed a nd often ca us e obs tructi on or i ntus s us cepti on.
Di a gnos i s i s s ugges ted by the cl i ni ca l pi cture. Geneti c tes ti ng i s not routi nel y a va i l a bl e but s houl d be cons i dered. Fi rs t-degree rel a ti ves s houl d
be eva l ua ted a nd ha ve routi ne s urvei l l a nce for ca ncers , but there i s no fi rm cons ens us on s peci fi c tes ts a nd i nterva l s .
Col oni c pol yps l a rger tha n 1 cm typi ca l l y a re removed.
Colorectal Cancer
Colorectal cancer (CRC) is extremely common. Symptoms include blood in the stool or change in bowel habits. Screening is with fecal occult blood testing.
Diagnosis is by colonoscopy. Treatment is surgical resection and chemotherapy for nodal involvement.
CRC a ccounts for a n es ti ma ted 153,000 ca s es a nd 52,000 dea ths i n the US a nnua l l y. In Wes tern countri es , the col on a nd rectum a ccount for more
new ca s es of ca ncer per yea r tha n a ny a na tomi c s i te except the l ung. Inci dence begi ns to ri s e a t a ge 40 a nd pea ks a t a ge 60 to 75. Overa l l , 70% of
ca s es occur i n the rectum a nd s i gmoi d, a nd 95% a re a denoca rci noma s . Col on ca ncer i s more common a mong women; recta l ca ncer i s more common
a mong men. Synchronous ca ncers (more tha n one) occur i n 5% of pa ti ents .
Etiology
CRC mos t often occurs a s tra ns forma ti on wi thi n a denoma tous pol yps . Serra ted a denoma s a re pa rti cul a rl y a ggres s i ve i n thei r ma l i gna nt
tra ns forma ti on. About 80% of ca s es a re s pora di c, a nd 20% ha ve a n i nheri ta bl e component. Predi s pos i ng fa ctors i ncl ude chroni c ul cera ti ve col i ti s
a nd gra nul oma tous col i ti s ; the ri s k of ca ncer i ncrea s es wi th the dura ti on of thes e di s orders .
Popul a ti ons wi th a hi gh i nci dence of CRC ea t l ow-fi ber di ets tha t a re hi gh i n a ni ma l protei n, fa t, a nd refi ned ca rbohydra tes . Ca rci nogens ma y be
i nges ted i n the di et but a re more l i kel y produced by ba cteri a l a cti on on di eta ry s ubs ta nces or bi l i a ry or i ntes ti na l s ecreti ons . The exa ct
mecha ni s m i s unknown.
CRC s prea ds by di rect extens i on through the bowel wa l l , hema togenous meta s ta s i s , regi ona l l ymph node meta s ta s i s , peri neura l s prea d, a nd
i ntra l umi na l meta s ta s i s .
Symptoms and Signs
Col orecta l a denoca rci noma grows s l owl y, a nd a l ong i nterva l el a ps es before i t i s l a rge enough to ca us e s ymptoms . Symptoms depend on l es i on
l oca ti on, type, extent, a nd compl i ca ti ons .
The ri ght col on ha s a l a rge ca l i ber, a thi n wa l l , a nd i ts contents a re l i qui d; thus , obs tructi on i s a l a te event. Bl eedi ng i s us ua l l y occul t. Fa ti gue a nd
wea knes s ca us ed by s evere a nemi a ma y be the onl y compl a i nts . Tumors s ometi mes grow l a rge enough to be pa l pa bl e through the a bdomi na l
wa l l before other s ymptoms a ppea r.
The l eft col on ha s a s ma l l er l umen, the feces a re s emi s ol i d, a nd ca ncer tends to enci rcl e the bowel , ca us i ng a l terna ti ng cons ti pa ti on a nd
i ncrea s ed s tool frequency or di a rrhea . Pa rti a l obs tructi on wi th col i cky a bdomi na l pa i n or compl ete obs tructi on ma y be the i ni ti a l ma ni fes ta ti on.
The s tool ma y be s trea ked or mi xed wi th bl ood. Some pa ti ents pres ent wi th s ymptoms of perfora ti on, us ua l l y wa l l ed off (foca l pa i n a nd
tendernes s ), or ra rel y wi th di ffus e peri toni ti s .
In recta l ca ncer, the mos t common i ni ti a l s ymptom i s bl eedi ng wi th defeca ti on. Whenever
[
Table 22-2. Sta gi ng Col orecta l Ca ncer*]
recta l bl eedi ng occurs , even wi th obvi ous hemorrhoi ds or known di verti cul a r di s ea s e, coexi s ti ng ca ncer mus t be rul ed out. Tenes mus or a
s ens a ti on of i ncompl ete eva cua ti on ma y be pres ent. Pa i n i s common wi th peri recta l i nvol vement.
Some pa ti ents fi rs t pres ent wi th s ymptoms a nd s i gns of meta s ta ti c di s ea s e (eg, hepa tomega l y, a s ci tes , s upra cl a vi cul a r l ymph node enl a rgement).
Diagnosis
Col onos copy
Screening tests: Ea rl y di a gnos i s depends on routi ne exa mi na ti on, pa rti cul a rl y feca l occul t bl ood (FOB) tes ti ng. Ca ncer detected by thi s method tends
to be a t a n ea rl i er s ta ge a nd hence more cura bl e. For a vera ge-ri s k pa ti ents , FOB tes ti ng s houl d be done a nnua l l y a fter a ge 50, wi th fl exi bl e
s i gmoi dos copy every 5 yr. Some a uthori ti es recommend col onos copy every 10 yr i ns tea d of s i gmoi dos copy. Col onos copy every 3 yr ma y be even
better. Screeni ng of pa ti ents wi th hi gh-ri s k condi ti ons (eg, ul cera ti ve col i ti s ) i s di s cus s ed under the s peci fi c condi ti on.
CT col onogra phy (vi rtua l col onos copy) genera tes 3D a nd 2D i ma ges of the col on us i ng mul ti detector row CT a nd a combi na ti on of ora l contra s t a nd
ga s di s tenti on of the col on. Vi ewi ng the hi gh-res ol uti on 3D i ma ges s omewha t s i mul a tes the a ppea ra nce of opti ca l endos copy, hence the na me. It
ha s s ome promi s e a s a s creeni ng tes t for peopl e who a re una bl e or unwi l l i ng to undergo endos copi c col onos copy but i s l es s s ens i ti ve a nd hi ghl y
i nterpreter dependent. It a voi ds the need for s eda ti on but s ti l l requi res thorough bowel prepa ra ti on, a nd the ga s di s tenti on ma y be
uncomforta bl e. Addi ti ona l l y, unl i ke wi th opti ca l col onos copy, l es i ons ca nnot be bi ops i ed duri ng the di a gnos ti c procedure.
Vi deo ca ps ul e endos copy of the col on ha s ma ny techni ca l probl ems a nd i s not currentl y a ccepta bl e a s a s creeni ng tes t.
Diagnostic tests: Pa ti ents wi th pos i ti ve FOB tes ts requi re col onos copy, a s do thos e wi th l es i ons s een on s i gmoi dos copy or i ma gi ng s tudy. Al l
l es i ons s houl d be compl etel y removed for hi s tol ogi c exa mi na ti on. If a l es i on i s s es s i l e or not remova bl e a t col onos copy, s urgi ca l exci s i on s houl d
be s trongl y cons i dered.
Ba ri um enema x-ra y, pa rti cul a rl y a doubl e-contra s t s tudy, ca n detect ma ny l es i ons but i s s omewha t l es s a ccura te tha n col onos copy a nd i s not
preferred a s fol l ow up to a pos i ti ve FOB tes t.
Once ca ncer i s di a gnos ed, pa ti ents s houl d ha ve a bdomi na l CT, ches t x-ra y, a nd routi ne l a bora tory tes ts to s eek meta s ta ti c di s ea s e a nd a nemi a
a nd to eva l ua te overa l l condi ti on.
El eva ted s erum ca rci noembryoni c a nti gen (CEA) l evel s a re pres ent i n 70% of pa ti ents wi th CRC, but thi s tes t i s not s peci fi c a nd therefore i s not
recommended for s creeni ng. However, i f CEA i s hi gh preopera ti vel y a nd l ow a fter remova l of a col on tumor, moni tori ng CEA ma y hel p to detect
recurrence ea rl i er. CA 199 a nd CA 125 a re other tumor ma rkers tha t ma y be s i mi l a rl y us ed.
Prognosis
Prognos i s depends grea tl y on s ta ge (s ee Ta bl e 22-2). The 10-yr s urvi va l ra te for ca ncer l i mi ted to the mucos a a pproa ches 90%; wi th extens i on
through the bowel wa l l , 70 to 80%; wi th pos i ti ve l ymph nodes , 30 to 50%; a nd wi th meta s ta ti c di s ea s e, < 20%.
Treatment
Surgi ca l res ecti on, s ometi mes combi ned wi th chemothera py, ra di a ti on, or both
Surgery: Surgery for cure ca n be a ttempted i n the 70% of pa ti ents pres enti ng wi thout meta s ta ti c di s ea s e. Attempt to cure cons i s ts of wi de res ecti on
of the tumor a nd i ts regi ona l l ympha ti c dra i na ge wi th rea na s tomos i s of bowel s egments . If there i s 5 cm of norma l bowel pres ent between the
l es i on a nd the a na l verge, a n a bdomi noperi nea l res ecti on i s done, wi th perma nent col os tomy.
Res ecti on of a l i mi ted number (1 to 3) of l i ver meta s ta s es i s recommended i n s el ect nondebi l i ta ted pa ti ents a s a s ubs equent procedure. Cri teri a
i ncl ude thos e whos e pri ma ry tumor ha s been res ected, whos e l i ver meta s ta s es a re i n one hepa ti c l obe, a nd who ha ve no extra hepa ti c
meta s ta s es . Onl y a s ma l l number of pa ti ents wi th l i ver meta s ta s es meet thes e cri teri a , but 5-yr pos topera ti ve s urvi va l i s 25%.
Adjuvant therapy: Chemothera py (typi ca l l y 5-fl uoroura ci l a nd l eucovori n) i mproves s urvi va l by 10 to 30% i n col on ca ncer pa ti ents wi th pos i ti ve l ymph
nodes . Recta l ca ncer pa ti ents wi th 1 to 4 pos i ti ve l ymph nodes benefi t from combi ned ra di a ti on a nd chemothera py; when > 4 pos i ti ve l ymph nodes
a re found, combi ned moda l i ti es a re l es s effecti ve. Preopera ti ve ra di a ti on thera py a nd chemothera py to i mprove the res ecta bi l i ty ra te of recta l
ca ncer or decrea s e the i nci dence of l ymph node meta s ta s i s a re ga i ni ng fa vor.
Follow-up: Pos topera ti vel y, col onos copy s houl d be done a nnua l l y for 5 yr a nd every 3 yr therea fter i f no pol yps or tumors a re found. If preopera ti ve
col onos copy wa s i ncompl ete beca us e of a n obs tructi ng ca ncer, a "compl eti on" col onos copy s houl d be done 3 mo a fter s urgery.
Addi ti ona l s creeni ng for recurrence s houl d i ncl ude hi s tory, phys i ca l exa mi na ti on, a nd l a bora tory tes ts (eg, CBC, l i ver functi on tes ts ) every 3 mo for 3
yr a nd then every 6 mo for 2 yr. Ima gi ng s tudi es (CT or MRI) a re often recommended a t 1-yr i nterva l s but a re of uncerta i n benefi t for routi ne fol l ow
up i n the a bs ence of a bnorma l i ti es on exa mi na ti on or bl ood tes ts .
Palliation: When cura ti ve s urgery i s not pos s i bl e or the pa ti ent i s a n una ccepta bl e s urgi ca l ri s k, l i mi ted pa l l i a ti ve s urgery (eg, to rel i eve obs tructi on
or res ect a perfora ted a rea ) ma y be i ndi ca ted; medi a n s urvi va l i s 7 mo. Some obs tructi ng tumors ca n be debul ked by endos copi c l a s er trea tment or
el ectrocoa gul a ti on or hel d open by s tents . Chemothera py ma y s hri nk tumors a nd prol ong l i fe for s evera l months .
Newer drugs us ed s i ngl y or i n drug combi na ti ons i ncl ude ca peci ta bi ne (a 5-fl uoroura ci l precurs or), i ri noteca n, a nd oxa l i pl a ti n. Monocl ona l
a nti bodi es s uch a s beva ci zuma b, cetuxi ma b, a nd pa ni tumuma b a re a l s o bei ng us ed wi th s ome effecti venes s . No regi men i s cl ea rl y more effecti ve
for prol ongi ng l i fe i n pa ti ents wi th meta s ta ti c CRC, a l though s ome ha ve been s hown to del a y di s ea s e progres s i on. Chemothera py for a dva nced
col on ca ncer s houl d be ma na ged by a n experi enced chemothera pi s t who ha s a cces s to i nves ti ga ti ona l drugs .
When meta s ta s es a re confi ned to the l i ver, a mbul a tory hepa ti c a rtery i nfus i on wi th fl oxuri di ne or ra di oa cti ve mi cros pheres vi a a n i mpl a nta bl e s c
pump or a n externa l pump worn on the bel t ma y offer more benefi t tha n s ys temi c chemothera py; however, thes e thera pi es a re of uncerta i n
benefi t. When meta s ta s es a re a l s o extra hepa ti c, i ntra hepa ti c a rteri a l chemothera py offers no a dva nta ge over s ys temi c chemothera py.
Anorectal Cancer
The mos t common a norecta l ca ncer i s a denoca rci noma . Squa mous cel l (nonkera ti ni zi ng s qua mous cel l or ba s a l oi d) ca rci noma of the a norectum
a ccounts for 3 to 5% of di s ta l l a rge-bowel ca ncers . Ba s a l cel l ca rci noma , Bowen's di s ea s e (i ntra derma l ca rci noma ), extra ma mma ry Pa get's di s ea s e,
cl oa cogeni c ca rci noma , a nd ma l i gna nt mel a noma a re l es s common. Other tumors i ncl ude l ymphoma a nd va ri ous s a rcoma s . Meta s ta s i s occurs
a l ong the l ympha ti cs of the rectum a nd i nto the i ngui na l l ymph nodes .
Ri s k fa ctors i ncl ude i nfecti on wi th huma n pa pi l l oma vi rus (HPV), chroni c fi s tul a s , i rra di a ted a na l s ki n, l eukopl a ki a , l ymphogra nul oma venereum,
a nd condyl oma a cumi na tum. Ga y men pra cti ci ng recepti ve a na l i ntercours e a re a t i ncrea s ed ri s k. Pa ti ents wi th HPV i nfecti on ma y ma ni fes t
dys pl a s i a i n s l i ghtl y a bnorma l or norma l -a ppea ri ng a na l epi thel i um (a na l i ntra epi thel i a l neopl a s i a hi s tol ogi ca l l y gra ded I, II, or III). Thes e
cha nges a re more common a mong HIV-i nfected pa ti ents , pa rti cul a rl y ga y men. Hi gher gra des ma y progres s to i nva s i ve ca rci noma . It i s uncl ea r
whether ea rl y recogni ti on a nd era di ca ti on i mprove l ong-term outcome; hence, s creeni ng recommenda ti ons a re uncl ea r.
Wi de l oca l exci s i on i s often s a ti s fa ctory trea tment of peri a na l ca rci noma s . Combi na ti on chemothera py a nd ra di a ti on thera py res ul t i n a hi gh ra te
of cure when us ed for a na l s qua mous a nd cl oa cogeni c tumors . Abdomi noperi nea l res ecti on i s i ndi ca ted when ra di a ti on a nd chemothera py do not
res ul t i n compl ete regres s i on of tumor a nd there a re no meta s ta s es outs i de of the ra di a ti on fi el d.
Hereditary Nonpolyposis Colorectal Carcinoma
Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder responsible for 3 to 5% of cases of colorectal cancer (CRC). Symptoms,
initial diagnosis, and treatment are similar to other forms of CRC. HNPCC is suspected by history and is confirmed by genetic testing. Patients also require
surveillance for other cancer, particularly endometrial and ovarian cancer.
Pa ti ents wi th one of s evera l known muta ti ons ha ve a 70 to 80% l i feti me ri s k of devel opi ng CRC. Compa red to s pora di c forms of col on ca ncer, HNPCC
occurs a t a younger a ge (mi d 40s ), a nd the l es i on i s more l i kel y to be proxi ma l to the s pl eni c fl exure. The precurs or l es i on i s us ua l l y a s i ngl e
col oni c a denoma , unl i ke the mul ti pl e a denoma s pres ent i n pa ti ents wi th fa mi l i a l a denoma tous pol ypos i s (FAP), the other ma i n heredi ta ry form
of CRC.
However, s i mi l a r to FAP, numerous extra col oni c ma ni fes ta ti ons occur. Nonma l i gna nt di s orders i ncl ude ca fe-a u-l a i t s pots , s eba ceous gl a nd
tumors , a nd kera toa ca nthoma s . Common a s s oci a ted ca ncers i ncl ude endometri a l a nd ova ri a n tumors (39% ri s k of endometri a l a nd 9% ri s k of
ova ri a n by a ge 70). Pa ti ents a l s o ha ve a n el eva ted ri s k of ca ncer of the ureter, rena l pel vi s , s toma ch, bi l i a ry tree, a nd s ma l l bowel .
Symptoms and Signs
Symptoms a nd s i gns a re s i mi l a r to other forms of CRC, a nd di a gnos i s a nd ma na gement of the tumor i ts el f a re the s a me. The s peci fi c di a gnos i s of
HNPCC i s confi rmed by geneti c tes ti ng. However, deci di ng who to tes t i s di ffi cul t beca us e (unl i ke FAP) there i s no typi ca l cl i ni ca l a ppea ra nce. Thus ,
s us pi ci on of HNPCC requi res a deta i l ed fa mi l y hi s tory, whi ch s houl d be obta i ned i n a l l younger pa ti ents i denti fi ed wi th CRC.
Diagnosis
Cl i ni ca l cri teri a fol l owed by tes ti ng for mi cros a tel l i te i ns ta bi l i ty (MSI)
Geneti c tes ti ng for confi rma ti on
To meet the Ams terda m II cri teri a for HNPCC, a l l three of the fol l owi ng hi s tori ca l el ements mus t be pres ent:
Three or more rel a ti ves wi th CRC or a n HNPCC-a s s oci a ted ca ncer
CRC i nvol vi ng a t l ea s t two genera ti ons
At l ea s t one ca s e of CRC before a ge 50
Pa ti ents meeti ng thes e cri teri a s houl d ha ve thei r tumor ti s s ue tes ted for MSI, a DNA a bnorma l i ty. If MSI i s pres ent, geneti c tes ti ng for s peci fi c
HNPCC muta ti ons i s i ndi ca ted. Other a uthori ti es us e a ddi ti ona l cri teri a (eg, Bethes da cri teri a ) to i ni ti a te MSI tes ti ng. If MSI tes ti ng i s not a va i l a bl e
l oca l l y, the pa ti ent s houl d be referred to a n a ppropri a te center.
Pa ti ents wi th confi rmed HNPCC requi re ongoi ng s creeni ng for other ca ncers . For endometri a l ca ncer, a nnua l endometri a l a s pi ra ti on or tra ns va gi na l
ul tra s ound i s recommended. For ova ri a n ca ncer, opti ons i ncl ude a nnua l tra ns va gi na l ul tra s ound a nd s erum CA 125 l evel s . Prophyl a cti c
hys terectomy a nd oophorectomy a re a l s o opti ons . Uri na l ys i s ma y be us ed to s creen for rena l tumors .
Fi rs t-degree rel a ti ves of pa ti ents wi th HNPCC s houl d ha ve col onos copy every 1 to 2 yr begi nni ng i n thei r 20s , a nd a nnua l l y a fter a ge 40. Fema l e 1s tdegree rel a ti ves s houl d be tes ted a nnua l l y for endometri a l a nd ova ri a n ca ncer. More di s ta nt bl ood rel a ti ves s houl d ha ve geneti c tes ti ng; i f
res ul ts a re nega ti ve, they s houl d ha ve col onos copy a t the frequency for a vera ge-ri s k pa ti ents .
Treatment
The mos t common trea tment i s res ecti on of the i ndex l es i on wi th frequent s urvei l l a nce for a nother col on ca ncer a nd a ny a s s oci a ted tumors i n
other orga ns . Beca us e mos t HNPCC tumors occur proxi ma l to the s pl eni c fl exure, s ubtota l col ectomy, l ea vi ng the rectos i gmoi d i nta ct, ha s been
s ugges ted a s a n a l terna ti ve. In ei ther ca s e, cl os e fol l ow up i s needed.
Pancreatic Cancer
Pancreatic cancer, primarily ductal adenocarcinoma, accounts for an estimated 37,000 cases and 33,000 deaths in the US annually. Symptoms include weight loss,
abdominal pain, and jaundice. Diagnosis is by CT. Treatment is surgical resection and adjuvant chemotherapy and radiation therapy. Prognosis is poor because
disease is often advanced at the time of diagnosis.
Mos t pa ncrea ti c ca ncers a re exocri ne tumors tha t devel op from ducta l a nd a ci na r cel l s . Pa ncrea ti c endocri ne tumors a re di s cus s ed bel ow.
Adenoca rci noma s of the exocri ne pa ncrea s a ri s e from duct cel l s 9 ti mes more often tha n from a ci na r cel l s ; 80% occur i n the hea d of the gl a nd.
Adenoca rci noma s a ppea r a t the mea n a ge of 55 yr a nd occur 1.5 to 2 ti mes more often i n men. Promi nent ri s k fa ctors i ncl ude s moki ng, a hi s tory of
chroni c pa ncrea ti ti s , a nd pos s i bl y l ong-s ta ndi ng di a betes mel l i tus (pri ma ri l y i n women). Heredi ty pl a ys s ome rol e. Al cohol a nd ca ffei ne
cons umpti on do not s eem to be ri s k fa ctors .
Symptoms and Signs
Symptoms occur l a te. By di a gnos i s , 90% of pa ti ents ha ve l oca l l y a dva nced tumors tha t ha ve i nvol ved retroperi tonea l s tructures , s prea d to regi ona l
l ymph nodes , or meta s ta s i zed to the l i ver or l ung.
Mos t pa ti ents ha ve s evere upper a bdomi na l pa i n, whi ch us ua l l y ra di a tes to the ba ck. The pa i n ma y be rel i eved by bendi ng forwa rd or a s s umi ng
the feta l pos i ti on. Wei ght l os s i s common. Adenoca rci noma s of the hea d of the pa ncrea s ca us e obs tructi ve ja undi ce (often ca us i ng pruri tus ) i n 80
to 90% of pa ti ents . Ca ncer i n the body a nd ta i l ma y ca us e s pl eni c vei n obs tructi on, res ul ti ng i n s pl enomega l y, ga s tri c a nd es opha gea l va ri ces , a nd
GI hemorrha ge. The ca ncer ca us es di a betes i n 25 to 50% of pa ti ents , l ea di ng to s ymptoms of gl ucos e i ntol era nce (eg, pol yuri a a nd pol ydi ps i a ).
Diagnosis
CT or ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP)
CA 19-9 a nti gen to fol l ow (not for s creeni ng)
The preferred tes ts a re a n a bdomi na l hel i ca l CT or MRCP. If CT or MRCP s hows a ppa rent unres ecta bl e or meta s ta ti c di s ea s e, a percuta neous
needl e a s pi ra ti on of a n a cces s i bl e l es i on mi ght be cons i dered to obta i n a ti s s ue di a gnos i s . If CT s hows a potenti a l l y res ecta bl e tumor or no
tumor, MRCP or endos copi c ul tra s ound ma y be us ed to s ta ge di s ea s e or detect s ma l l tumors not vi s i bl e wi th CT. Pa ti ents wi th obs tructi ve ja undi ce
ma y ha ve ERCP a s the fi rs t di a gnos ti c procedure.
Routi ne l a bora tory tes ts s houl d be done. El eva ti on of a l ka l i ne phos pha ta s e a nd bi l i rubi n i ndi ca te bi l e duct obs tructi on or l i ver meta s ta s es .
Pa ncrea s -a s s oci a ted a nti gen CA 19-9 ma y be us ed to moni tor pa ti ents di a gnos ed wi th pa ncrea ti c ca rci noma a nd to s creen thos e a t hi gh ri s k.
However, thi s tes t i s not s ens i ti ve or s peci fi c enough to be us ed for popul a ti on s creeni ng. El eva ted l evel s s houl d drop wi th s ucces s ful trea tment;
s ubs equent i ncrea s es i ndi ca te progres s i on. Amyl a s e a nd l i pa s e l evel s a re us ua l l y norma l .
Prognosis
Prognos i s va ri es wi th s ta ge but overa l l i s poor (5-yr s urvi va l : < 2%), beca us e ma ny pa ti ents ha ve a dva nced di s ea s e a t the ti me of di a gnos i s .
Treatment
Whi ppl e procedure
Adjuva nt chemothera py a nd ra di a ti on thera py
Symptom control
About 80 to 90% of ca ncers a re cons i dered s urgi ca l l y unres ecta bl e a t ti me of di a gnos i s beca us e of meta s ta s es or i nva s i on of ma jor bl ood ves s el s .
Dependi ng on l oca ti on of the tumor, the procedure of choi ce i s mos t commonl y a Whi ppl e procedure (pa ncrea toduodenectomy). Adjuva nt thera py
wi th 5-fl uoroura ci l (5-FU) a nd externa l bea m ra di a ti on thera py i s typi ca l l y gi ven, res ul ti ng i n a bout 40% 2-yr a nd 25% 5-yr s urvi va l . Thi s combi na ti on
i s a l s o us ed for pa ti ents wi th l oca l i zed but unres ecta bl e tumors a nd res ul ts i n medi a n s urvi va l of a bout 1 yr. Newer drugs (eg, gemci ta bi ne,
i ri noteca n, pa cl i ta xel , oxa l i pl a ti n, ca rbopl a ti n) ma y be more effecti ve tha n 5-FU-ba s ed chemothera py, but no drug, s i ngl y or i n combi na ti on, i s
cl ea rl y s uperi or i n prol ongi ng s urvi va l . Pa ti ents wi th hepa ti c or di s ta nt meta s ta s es ma y be offered chemothera py a s pa rt of a n i nves ti ga ti ona l
progra m, but the outl ook i s di s ma l wi th or wi thout s uch trea tment a nd s ome pa ti ents ma y choos e to forego i t.
If a n unres ecta bl e tumor i s found a t opera ti on a nd ga s troduodena l or bi l e duct obs tructi on i s pres ent or pendi ng, a doubl e ga s tri c a nd bi l i a ry
bypa s s opera ti on i s us ua l l y done to rel i eve obs tructi on. In pa ti ents wi th i nopera bl e l es i ons a nd ja undi ce, endos copi c pl a cement of a bi l e duct
s tent rel i eves ja undi ce. However, s urgi ca l bypa s s s houl d be cons i dered i n pa ti ents wi th unres ecta bl e l es i ons i f l i fe expecta ncy i s > 6 to 7 mo
beca us e of compl i ca ti ons a s s oci a ted wi th s tents .
Symptomatic treatment: Ul ti ma tel y, mos t pa ti ents experi ence pa i n a nd di e. Thus , s ymptoma ti c trea tment i s a s i mporta nt a s control l i ng di s ea s e.
Appropri a te end-of-l i fe ca re s houl d be di s cus s ed (s ee a l s o p. 3480).
Pa ti ents wi th modera te to s evere pa i n s houl d recei ve a n ora l opi oi d i n dos es a dequa te to provi de rel i ef. Concern a bout a ddi cti on s houl d not be a
ba rri er to effecti ve pa i n control . For chroni c pa i n, l ong-a cti ng prepa ra ti ons (eg, tra ns derma l fenta nyl , oxycodone, oxymorphone) a re us ua l l y bes t.
Percuta neous or opera ti ve s pl a nchni c (cel i a c) bl ock effecti vel y control s pa i n i n mos t pa ti ents . In ca s es of i ntol era bl e pa i n, opi oi ds gi ven s c or by
IV, epi dura l , or i ntra theca l i nfus i on provi des a ddi ti ona l rel i ef.
If pa l l i a ti ve s urgery or endos copi c pl a cement of a bi l i a ry s tent fa i l s to rel i eve pruri tus s econda ry to obs tructi ve ja undi ce, the pa ti ent ca n be
ma na ged wi th chol es tyra mi ne (4 g po once/da y to qi d). Phenoba rbi ta l 30 to 60 mg po ti d to qi d ma y be hel pful .
Exocri ne pa ncrea ti c i ns uffi ci ency i s trea ted wi th ta bl ets of porci ne pa ncrea ti c enzymes (pa ncrel i pa s e). The pa ti ent s houl d ta ke enough to s uppl y
16,000 to 20,000 l i pa s e uni ts before ea ch mea l or s na ck. If a mea l i s prol onged (a s i n a res ta ura nt), s ome of the ta bl ets s houl d be ta ken duri ng the
mea l . Opti ma l i ntra l umi na l pH for the enzymes i s 8; thus , s ome cl i ni ci a ns gi ve a proton pump i nhi bi tor or H 2 bl ocker 2 ti mes /da y. Di a betes
mel l i tus s houl d be cl os el y moni tored a nd control l ed.
Cystadenocarcinoma
Cys ta denoca rci noma i s a ra re a denoma tous pa ncrea ti c ca ncer tha t a ri s es a s a ma l i gna nt degenera ti on of a mucous cys ta denoma a nd ma ni fes ts
a s upper a bdomi na l pa i n a nd a pa l pa bl e a bdomi na l ma s s . Di a gnos i s i s ma de by a bdomi na l CT or MRI, whi ch typi ca l l y s hows a cys ti c ma s s
conta i ni ng debri s ; the ma s s ma y be mi s i nterpreted a s necroti c a denoca rci noma or pa ncrea ti c ps eudocys t. Unl i ke ducta l a denoca rci noma ,
cys ta denoca rci noma ha s a rel a ti vel y good prognos i s . Onl y 20% of pa ti ents ha ve meta s ta s i s a t the ti me of opera ti on; compl ete exci s i on of the
tumor by di s ta l or tota l pa ncrea tectomy or by a Whi ppl e procedure res ul ts i n a 65% 5-yr s urvi va l .
Intraductal Papillary-Mucinous Tumor
Intra ducta l pa pi l l a ry-muci nous tumor (IPMT) i s a ra re ca ncer res ul ti ng i n mucus hypers ecreti on a nd ducta l obs tructi on. Hi s tol ogy ma y be beni gn,
borderl i ne, or ma l i gna nt. Mos t (80%) occur i n women a nd i n the ta i l of the pa ncrea s (66%).
Symptoms cons i s t of pa i n a nd recurrent bouts of pa ncrea ti ti s . Di a gnos i s i s ma de by CT, s ometi mes a l ong wi th endos copi c ul tra s onogra phy,
ma gneti c res ona nce chol a ngi opa ncrea togra phy, or ERCP. Beni gn a nd ma l i gna nt di s ea s e ca nnot be di fferenti a ted wi thout s urgi ca l remova l , whi ch
i s the trea tment of choi ce. Wi th s urgery, 5-yr s urvi va l i s > 95% for beni gn or borderl i ne ca s es , but 50 to 75% for ma l i gna nt tumors .
Pancreatic Endocrine Tumors
Pa ncrea ti c endocri ne tumors a ri s e from i s l et a nd ga s tri n-produci ng cel l s a nd often produce ma ny hormones . They ha ve 2 genera l ma ni fes ta ti ons .
Nonfuncti oni ng tumors ma y ca us e obs tructi ve s ymptoms of the bi l i a ry tra ct or duodenum, bl eedi ng i nto the GI tra ct, or a bdomi na l ma s s es .
Functi oni ng tumors hypers ecrete a pa rti cul a r hormone, ca us i ng va ri ous s yndromes (s ee
Ta bl e 22-3). Thes e cl i ni ca l s yndromes ca n a l s o occur i n mul ti pl e endocri ne neopl a s i a , i n whi ch tumors or hyperpl a s i a a ffects two or more
endocri ne gl a nds , us ua l l y the pa ra thyroi d, pi tui ta ry, thyroi d, or a drena l s (s ee p. 909).
Trea tment for functi oni ng a nd nonfuncti oni ng tumors i s s urgi ca l res ecti on. If meta s ta s es precl ude cura ti ve s urgery, va ri ous a nti hormone
trea tments ma y be tri ed for functi oni ng tumors . Beca us e of tumor ra ri ty, chemothera py tri a l s ha ve not i denti fi ed defi ni ti ve trea tment. However,
s treptozotoci n ha s s el ecti ve a cti vi ty a ga i ns t pa ncrea ti c i s l et cel l s a nd i s commonl y us ed, ei ther a l one or i n combi na ti on wi th 5-fl uoroura ci l or
doxorubi ci n. Some centers us e chl orozotoci n a nd i nterferon.
Insulinoma
An insulinoma is a rare pancreatic -cell tumor that hypersecretes insulin. The main symptom is fasting hypoglycemia. Diagnosis is by a 48- or 72-h fast with
measurement of glucose and insulin levels, followed by endoscopic ultrasound. Treatment is surgery when possible. Drugs that block insulin secretion (eg,
diazoxide, octreotide, Ca channel blockers, -blockers, phenytoin) are used for patients not responding to surgery.
Of a l l i ns ul i noma s , 80% a re s i ngl e a nd ma y be cura ti vel y res ected i f i denti fi ed. Onl y 10% of i ns ul i noma s a re ma l i gna nt. Ins ul i noma occurs i n
1/250,000 a t a medi a n a ge of 50 yr, except i n mul ti pl e endocri ne neopl a s i a (MEN) type I (a bout 10% of i ns ul i noma s ), when i t occurs i n the 20s .
Ins ul i noma s a s s oci a ted wi th MEN type I a re more l i kel y to be mul ti pl e.
Surrepti ti ous a dmi ni s tra ti on of exogenous i ns ul i n ca n ca us e epi s odi c hypogl ycemi a mi mi cki ng i ns ul i noma .
Symptoms and Signs
Hypogl ycemi a s econda ry to a n i ns ul i noma occurs duri ng fa s ti ng. Symptoms a re i ns i di ous a nd ma y mi mi c va ri ous ps ychi a tri c a nd
[Table 22-3. Pa ncrea ti c Endocri ne Tumors ]
neurol ogi c di s orders . CNS di s turba nces i ncl ude hea da che, confus i on, vi s ua l di s turba nces , motor wea knes s , pa l s y, a ta xi a , ma rked pers ona l i ty
cha nges , a nd pos s i bl e progres s i on to l os s of cons ci ous nes s , s ei zures , a nd coma . Symptoms of s ympa theti c s ti mul a ti on (fa i ntnes s , wea knes s ,
tremul ous nes s , pa l pi ta ti on, s wea ti ng, hunger, nervous nes s ) a re often pres ent.
Diagnosis
Ins ul i n l evel
Someti mes C-pepti de or proi ns ul i n l evel s
Endos copi c ul tra s ound
Pl a s ma gl ucos e s houl d be mea s ured duri ng s ymptoms . If hypogl ycemi a i s pres ent (gl ucos e < 40 mg/dL [2.78 mmol /L]), a n i ns ul i n l evel s houl d be
mea s ured on a s i mul ta neous s a mpl e. Hyperi ns ul i nemi a of > 6 U/mL (42 pmol /L) s ugges ts a n i ns ul i n-medi a ted ca us e, a s does a s erum i ns ul i n to
pl a s ma gl ucos e ra ti o > 0.3 (U/mL)/(mg/dL).
Ins ul i n i s s ecreted a s proi ns ul i n, cons i s ti ng of a n cha i n a nd cha i n connected by a C pepti de. Beca us e pha rma ceuti ca l i ns ul i n cons i s ts onl y of
the cha i n, s urrepti ti ous i ns ul i n a dmi ni s tra ti on ca n be detected by mea s uri ng C-pepti de a nd proi ns ul i n l evel s . In pa ti ents wi th i ns ul i noma , C
pepti de i s 0.2 nmol /L a nd proi ns ul i n i s 5 pmol /L. Thes e l evel s a re norma l or l ow i n pa ti ents wi th s urrepti ti ous i ns ul i n a dmi ni s tra ti on.
Beca us e ma ny pa ti ents ha ve no s ymptoms (a nd hence no hypogl ycemi a ) a t the ti me of eva l ua ti on, di a gnos i s requi res a dmi s s i on to the hos pi ta l
for a 48- or 72-h fa s t. Nea rl y a l l (98%) wi th i ns ul i noma devel op s ymptoms wi thi n 48 h of fa s ti ng; 70 to 80% wi thi n 24 h. Hypogl ycemi a a s the ca us e
of the s ymptoms i s es ta bl i s hed by Whi ppl e's tri a d: (1) Symptoms occur duri ng the fa s t; (2) s ymptoms occur i n the pres ence of hypogl ycemi a ; a nd (3)
i nges ti on of ca rbohydra tes rel i eves the s ymptoms . Hormone l evel s a re obta i ned a s des cri bed a bove when the pa ti ent i s ha vi ng s ymptoms .
If Whi ppl e's tri a d i s not obs erved a fter prol onged fa s ti ng a nd the pl a s ma gl ucos e a fter a n overni ght fa s t i s > 50 mg/dL (> 2.78 mmol /L), a C-pepti de
s uppres s i on tes t ca n be done. Duri ng i ns ul i n i nfus i on (0.1 U/kg/h), pa ti ents wi th i ns ul i noma fa i l to s uppres s C pepti de to norma l l evel s ( 1.2
ng/mL [ 0.40 nmol /L]).
Endos copi c ul tra s onogra phy ha s > 90% s ens i ti vi ty a nd hel ps l oca l i ze the tumor. PET a l s o ma y be us ed. CT ha s not proved us eful , a nd a rteri ogra phy
or s el ecti ve porta l a nd s pl eni c vei n ca theteri za ti on i s genera l l y unneces s a ry.
Treatment
Di a zoxi de or s ometi mes octreoti de for hypogl ycemi a
Overa l l s urgi ca l cure ra tes a pproa ch 90%. A s ma l l , s i ngl e i ns ul i noma a t or nea r the s urfa ce of the pa ncrea s ca n us ua l l y be enucl ea ted s urgi ca l l y. If
a s i ngl e l a rge or deep a denoma i s wi thi n the pa ncrea ti c body or ta i l , i f there a re mul ti pl e l es i ons of the body or ta i l (or both), or i f no i ns ul i noma
i s found (a n unus ua l ci rcums ta nce), a di s ta l , s ubtota l pa ncrea tectomy i s done. In < 1% of ca s es , the i ns ul i noma i s ectopi ca l l y l oca ted i n
peri pa ncrea ti c s i tes of the duodena l wa l l or peri duodena l a rea a nd ca n be found onl y by di l i gent s ea rch duri ng s urgery. Pa ncrea toduodenectomy
(Whi ppl e procedure) i s done for res ecta bl e ma l i gna nt i ns ul i noma s of the proxi ma l pa ncrea s . Tota l pa ncrea tectomy i s done i f a previ ous s ubtota l
pa ncrea tectomy proves i na dequa te.
If hypogl ycemi a conti nues , di a zoxi de s ta rti ng a t 1.5 mg/kg po bi d wi th a na tri ureti c ca n be us ed. Dos es ca n be i ncrea s ed up to 4 mg/kg. A
s oma tos ta ti n a na l og, octreoti de (100 to 500 g s c bi d to ti d), i s va ri a bl y effecti ve a nd s houl d be cons i dered for pa ti ents wi th conti nui ng
hypogl ycemi a refra ctory to di a zoxi de. Pa ti ents who res pond ma y be converted to a l ong-a cti ng octreoti de formul a ti on gi ven a s 20 to 30 mg IM
once/mo. Pa ti ents us i ng octreoti de ma y a l s o need to ta ke s uppl ementa l pa ncrea ti c enzymes beca us e octreoti de s uppres s es pa ncrea ti c enzyme
s ecreti on. Other drugs tha t ha ve modes t a nd va ri a bl e effect on i ns ul i n s ecreti on i ncl ude vera pa mi l , di l ti a zem, a nd phenytoi n.
If s ymptoms a re not control l ed, chemothera py ma y be tri ed, but res pons e i s l i mi ted. Streptozotoci n ha s a 30 to 40% res pons e ra te, a nd when
combi ned wi th 5-fl uoroura ci l , a 60% res pons e ra te l a s ti ng up to 2 yr. Other a gents i ncl ude doxorubi ci n, chl orozotoci n, a nd i nterferon.
Zollinger-Ellison Syndrome
(Z-E Syndrome; Ga s tri noma )
Zollinger-Ellison syndrome is caused by a gastrin-producing tumor usually located in the pancreas or the duodenal wall. Gastric acid hypersecretion and peptic
ulceration result. Diagnosis is by measuring serum gastrin levels. Treatment is proton pump inhibitors and surgical removal.
Ga s tri noma s occur i n the pa ncrea s or duodena l wa l l 80 to 90% of the ti me. The rema i nder occur i n the s pl eni c hi l um, mes entery, s toma ch, l ymph
node, or ova ry. About 50% of pa ti ents ha ve mul ti pl e tumors . Ga s tri noma s us ua l l y a re s ma l l (< 1 cm i n di a meter) a nd grow s l owl y. About 50% a re
ma l i gna nt. About 40 to 60% of pa ti ents wi th ga s tri noma ha ve mul ti pl e endocri ne neopl a s i a (s ee p. 909).
Symptoms and Signs
Zol l i nger-El l i s on s yndrome typi ca l l y ma ni fes ts a s a ggres s i ve pepti c ul cer di s ea s e, wi th ul cers occurri ng i n a typi ca l l oca ti ons (up to 25% a re l oca ted
di s ta l to the duodena l bul b). However, a s ma ny a s 25% do not ha ve a n ul cer a t di a gnos i s . Typi ca l ul cer s ymptoms a nd compl i ca ti ons (eg,
perfora ti on, bl eedi ng, obs tructi on) ca n occur. Di a rrhea i s the i ni ti a l s ymptom i n 25 to 40% of pa ti ents .
Diagnosis
Serum ga s tri n l evel
CT, s ci nti gra phy, or PET to l oca l i ze
The s yndrome i s s us pected by hi s tory, pa rti cul a rl y when s ymptoms a re refra ctory to s ta nda rd a ci d s uppres s a nt thera py.
The mos t rel i a bl e tes t i s s erum ga s tri n. Al l pa ti ents ha ve l evel s > 150 pg/mL; ma rkedl y el eva ted l evel s of > 1000 pg/mL i n a pa ti ent wi th
compa ti bl e cl i ni ca l fea tures a nd ga s tri c a ci d hypers ecreti on of > 15 mEq/h es ta bl i s h the di a gnos i s . However, modera te hyperga s tri nemi a ca n occur
wi th hypochl orhydri c s ta tes (eg, perni ci ous a nemi a , chroni c ga s tri ti s , us e of proton pump i nhi bi tors ), i n rena l i ns uffi ci ency wi th decrea s ed
cl ea ra nce of ga s tri ns , i n ma s s i ve i ntes ti na l res ecti on, a nd i n pheochromocytoma .
A s ecreti n provoca ti ve tes t ma y be us eful i n pa ti ents wi th ga s tri n l evel s < 1000 pg/mL. An IV bol us of s ecreti n 2 g/kg i s gi ven wi th s eri a l
mea s urements of s erum ga s tri n (10 a nd 1 mi n before, a nd 2, 5, 10, 15, 20, a nd 30 mi n a fter i njecti on). The cha ra cteri s ti c res pons e i n ga s tri noma i s
a n i ncrea s e i n ga s tri n l evel s , the oppos i te of wha t occurs i n thos e wi th a ntra l G-cel l hyperpl a s i a or typi ca l pepti c ul cer di s ea s e. Pa ti ents a l s o
s houl d be eva l ua ted for Helicobacter pylori i nfecti on, whi ch commonl y res ul ts i n pepti c ul cera ti on a nd modera te exces s ga s tri n s ecreti on.
Once the di a gnos i s ha s been es ta bl i s hed, the tumor or tumors mus t be l oca l i zed. The fi rs t tes t i s a bdomi na l CT or s oma tos ta ti n receptor
s ci nti gra phy, whi ch ma y i denti fy the pri ma ry tumor a nd meta s ta ti c di s ea s e. PET or s el ecti ve a rteri ogra phy wi th ma gni fi ca ti on a nd s ubtra cti on i s
a l s o hel pful . If no s i gns of meta s ta s es a re pres ent a nd the pri ma ry i s uncerta i n, endos copi c ul tra s onogra phy s houl d be done. Sel ecti ve a rteri a l
s ecreti n i njecti on i s a n a l terna ti ve.
Prognosis
Fi ve- a nd 10-yr s urvi va l i s > 90% when a n i s ol a ted tumor i s removed s urgi ca l l y vs 43% a t 5 yr a nd 25% a t 10 yr wi th i ncompl ete remova l .
Treatment
Aci d s uppres s i on
Surgi ca l res ecti on for l oca l i zed di s ea s e
Chemothera py for meta s ta ti c di s ea s e
Acid suppression: Proton pump i nhi bi tors a re the drugs of choi ce: omepra zol e or es omepra zol e 40 mg po bi d. The dos e ma y be decrea s ed gra dua l l y
once s ymptoms res ol ve a nd a ci d output decl i nes . A ma i ntena nce dos e i s needed; pa ti ents need to ta ke thes e drugs i ndefi ni tel y unl es s they
undergo s urgery.
Octreoti de i njecti ons , 100 to 500 g s c bi d to ti d, ma y a l s o decrea s e ga s tri c a ci d producti on a nd ma y be pa l l i a ti ve i n pa ti ents not res pondi ng wel l
to proton pump i nhi bi tors . A l ong-a cti ng form of octreoti de ca n be us ed 20 to 30 mg IM once/mo.
Surgery: Surgi ca l remova l s houl d be a ttempted i n pa ti ents wi thout a ppa rent meta s ta s es . At s urgery, duodenotomy a nd i ntra opera ti ve endos copi c
tra ns i l l umi na ti on or ul tra s ound hel p l oca l i ze tumors . Surgi ca l cure i s pos s i bl e i n 20% of pa ti ents i f the ga s tri noma i s not pa rt of a mul ti pl e
endocri ne neopl a s i a s yndrome.
Chemotherapy: In pa ti ents wi th meta s ta ti c di s ea s e, s treptozoci n i n combi na ti on wi th 5-fl uoroura ci l or doxorubi ci n i s the preferred chemothera py
for i s l et cel l tumors . It ma y reduce tumor ma s s (i n 50 to 60%) a nd s erum ga s tri n l evel s a nd i s a us eful a djunct to omepra zol e. Pa ti ents wi th
meta s ta ti c di s ea s e a re not cured by chemothera py.
Vipoma
A vipoma is a non- pancreatic islet cell tumor secreting vasoactive intestinal peptide (VIP), resulting in a syndrome of watery diarrhea, hypokalemia, and
achlorhydria (WDHA syndrome). Diagnosis is by serum VIP levels. Tumor is localized with CT and endoscopic ultrasound. Treatment is surgical resection.
Of thes e tumors , 50 to 75% a re ma l i gna nt, a nd s ome ma y be qui te l a rge (7 cm) a t di a gnos i s . In a bout 6%, vi poma occurs a s pa rt of mul ti pl e
endocri ne neopl a s i a (s ee p. 909).
Symptoms and Signs
The ma jor s ymptoms a re prol onged ma s s i ve wa tery di a rrhea (fa s ti ng s tool vol ume > 750 to 1000 mL/da y a nd nonfa s ti ng vol umes of > 3000 mL/da y)
a nd s ymptoms of hypoka l emi a , a ci dos i s , a nd dehydra ti on. In ha l f, di a rrhea i s cons ta nt; i n the res t, di a rrhea s everi ty va ri es over ti me. About 33%
ha ve di a rrhea < 1 yr before di a gnos i s , but 25% ha ve di a rrhea 5 yr before di a gnos i s . Letha rgy, mus cul a r wea knes s , na us ea , vomi ti ng, a nd cra mpy
a bdomi na l pa i n occur frequentl y. Fl us hi ng s i mi l a r to the ca rci noi d s yndrome occurs i n 20% of pa ti ents duri ng a tta cks of di a rrhea .
Diagnosis
Confi rma ti on of s ecretory di a rrhea
Serum VIP l evel s
Endos copi c ul tra s onogra phy, PET, or s ci nti gra phy ca n l oca l i ze
Di a gnos i s requi res demons tra ti on of s ecretory di a rrhea (s tool os mol a l i ty i s cl os e to pl a s ma os mol a l i ty, a nd twi ce the s um of Na a nd K
concentra ti on i n the s tool a ccounts for a l l mea s ured s tool os mol a l i ty). Other ca us es of s ecretory di a rrhea a nd, i n pa rti cul a r, l a xa ti ve a bus e mus t
be excl uded (s ee p. 88). In s uch pa ti ents , s erum VIP l evel s s houl d be mea s ured (i dea l l y duri ng a bout of di a rrhea ). Ma rkedl y el eva ted l evel s
es ta bl i s h the di a gnos i s , but mi l d el eva ti ons ma y occur wi th s hort bowel s yndrome a nd i nfl a mma tory di s ea s es . Pa ti ents wi th el eva ted VIP l evel s
s houl d ha ve tumor l oca l i za ti on s tudi es , s uch a s endos copi c ul tra s onogra phy, PET, a nd octreoti de s ci nti gra phy or a rteri ogra phy to l oca l i ze
meta s ta s es .
El ectrol ytes a nd CBC s houl d be mea s ured. Hypergl ycemi a a nd i mpa i red gl ucos e tol era nce occur i n 50% of pa ti ents . Hyperca l cemi a occurs i n 50%
of pa ti ents .
Treatment
Fl ui d a nd el ectrol yte repl a cement
Octreoti de
Ini ti a l l y, fl ui ds a nd el ectrol ytes mus t be repl a ced. Bi ca rbona te mus t be gi ven to repl a ce feca l l os s a nd a voi d a ci dos i s . Beca us e feca l l os s es of
wa ter a nd el ectrol ytes i ncrea s e a s rehydra ti on i s a chi eved, conti nua l IV repl a cement ma y become di ffi cul t.
Octreoti de us ua l l y control s di a rrhea , but l a rge dos es ma y be needed. Res ponders ma y benefi t from a l ong-a cti ng octreoti de formul a ti on gi ven 20
to 30 mg IM once/mo. Pa ti ents us i ng octreoti de ma y a l s o need to ta ke s uppl ementa l pa ncrea ti c enzymes beca us e octreoti de s uppres s es
pa ncrea ti c enzyme s ecreti on.
Tumor res ecti on i s cura ti ve i n 50% of pa ti ents wi th a l oca l i zed tumor. In thos e wi th meta s ta ti c tumor, res ecti on of a l l vi s i bl e tumor ma y provi de
tempora ry rel i ef of s ymptoms . The combi na ti on of s treptozoci n a nd doxorubi ci n ma y reduce di a rrhea a nd tumor ma s s i f objecti ve res pons e occurs
(i n 50 to 60%). Chemothera py i s not cura ti ve.
Glucagonoma
A glucagonoma is a pancreatic -cell tumor that secretes glucagon, causing hyperglycemia and a characteristic skin rash. Diagnosis is by elevated glucagon levels
and imaging studies. Tumor is localized with CT and endoscopic ultrasound. Treatment is surgical resection.
Gl uca gonoma s a re very ra re but s i mi l a r to other i s l et cel l tumors i n tha t the pri ma ry a nd meta s ta ti c l es i ons a re s l ow-growi ng: 15-yr s urvi va l i s
common. Ei ghty percent of gl uca gonoma s a re ma l i gna nt. The a vera ge a ge a t s ymptom ons et i s 50 yr; 80% of pa ti ents a re women. A few pa ti ents
ha ve mul ti pl e endocri ne neopl a s i a type I.
Symptoms and Signs
Beca us e gl uca gonoma s produce gl uca gon, the s ymptoms a re the s a me a s thos e of di a betes . Frequentl y, wei ght l os s , normochromi c a nemi a ,
hypoa mi noa ci demi a , a nd hypol i pi demi a a re pres ent, but the mos t di s ti ncti ve cl i ni ca l fea ture i s a chroni c erupti on i nvol vi ng the extremi ti es , often
a s s oci a ted wi th a s mooth, s hi ny, vermi l i on tongue a nd chei l i ti s . The exfol i a ti ng, browni s h red, erythema tous l es i on wi th s uperfi ci a l necrol ys i s i s
termed necrol yti c mi gra tory erythema .
Diagnosis
Serum gl uca gon l evel
CT a nd endos copi c ul tra s onogra phy to l oca l i ze
Mos t pa ti ents wi th gl uca gonoma ha ve gl uca gon l evel s > 1000 pg/mL (norma l < 200). However, modera te el eva ti ons occur i n rena l i ns uffi ci ency,
a cute pa ncrea ti ti s , s evere s tres s , a nd fa s ti ng. Correl a ti on wi th s ymptoms i s requi red. Pa ti ents s houl d ha ve a bdomi na l CT fol l owed by endos copi c
ul tra s onogra phy; MRI or PET ma y be us ed i f CT i s unrevea l i ng.
Treatment
Chemothera py for meta s ta ti c di s ea s e
Octreoti de to s uppres s gl uca gon producti on
Res ecti on of the tumor a l l evi a tes a l l s ymptoms . Unres ecta bl e, meta s ta ti c, or recurrent tumors a re trea ted wi th combi na ti on s treptozoci n a nd
doxorubi ci n, whi ch ma y decrea s e l evel s of ci rcul a ti ng i mmunorea cti ve gl uca gon, l es s en s ymptoms , a nd i mprove res pons e ra tes (50%) but a re
unl i kel y to i mprove s urvi va l . Octreoti de i njecti ons pa rti a l l y s uppres s gl uca gon producti on a nd rel i eve the erythema , but gl ucos e tol era nce ma y
a l s o decrea s e beca us e octreoti de decrea s es i ns ul i n s ecreti on. Octreoti de ma y qui ckl y revers e a norexi a a nd wei ght l os s ca us ed by the ca ta bol i c
effect of gl uca gon exces s . Pa ti ents who res pond ma y be converted to a l ong-a cti ng octreoti de formul a ti on gi ven 20 to 30 mg IM once/mo. Pa ti ents
us i ng octreoti de ma y a l s o need to ta ke s uppl ementa l pa ncrea ti c enzymes beca us e octreoti de s uppres s es pa ncrea ti c enzyme s ecreti on.
Loca l l y a ppl i ed, ora l , or pa rentera l zi nc ma y ca us e the erythema to di s a ppea r, but res ol uti on ma y occur a fter s i mpl e hydra ti on or IV a dmi ni s tra ti on
of a mi no or fa tty a ci ds , s ugges ti ng tha t the erythema i s not s ol el y ca us ed by zi nc defi ci ency.
3 - Hepatic and Biliary Disorders

Chapter 23. Approach to the Patient With Liver Disease
Introduction
The l i ver i s the mos t meta bol i ca l l y compl ex orga n. Hepa tocytes (l i ver pa renchyma l cel l s ) perform the l i ver's meta bol i c functi ons :
Forma ti on a nd excreti on of bi l e duri ng bi l i rubi n meta bol i s m (s ee Si deba r 23-1)
Regul a ti on of ca rbohydra te homeos ta s i s
Li pi d s ynthes i s a nd s ecreti on of pl a s ma l i poprotei ns
Control of chol es terol meta bol i s m
Forma ti on of urea , s erum a l bumi n, cl otti ng fa ctors , enzymes , a nd numerous other protei ns
Meta bol i s m or detoxi fi ca ti on of drugs a nd other forei gn s ubs ta nces
At the cel l ul a r l evel , porta l tri a ds cons i s t of a dja cent a nd pa ra l l el termi na l bra nches of bi l e ducts , porta l vei ns , a nd hepa ti c a rteri es tha t border
the hepa tocytes (s ee
Fi g. 23-1). Termi na l bra nches of the hepa ti c vei ns a re i n the center of hepa ti c l obul es . Beca us e bl ood fl ows from the porta l tri a ds pa s t the
hepa tocytes a nd dra i ns vi a vei n bra nches i n the center of the l obul e, the center of the l obul e i s the a rea mos t s us cepti bl e to i s chemi a .
Pathophysiology
Li ver di s orders ca n res ul t from a wi de va ri ety of i ns ul ts , i ncl udi ng i nfecti ons , drugs , toxi ns , i s chemi a , a nd a utoi mmune di s orders . Occa s i ona l l y,
l i ver di s orders occur pos topera ti vel y (s ee p. 223). Mos t l i ver di s orders ca us e s ome degree of hepa tocel l ul a r i njury a nd necros i s , res ul ti ng i n
va ri ous a bnorma l l a bora tory tes t res ul ts a nd, s ometi mes , s ymptoms .
[Fig. 23-1. Orga ni za ti on of the l i ver.]
Symptoms ma y be due to l i ver di s ea s e i ts el f (eg, ja undi ce due to a cute hepa ti ti s ) or to compl i ca ti ons of l i ver di s ea s e (eg, a cute GI bl eedi ng due to
ci rrhos i s a nd porta l hypertens i on).
Sidebar 23-1 Overview of Bilirubin Metabolism

The brea kdown of heme produces bi l i rubi n (a n i ns ol ubl e wa s te product) a nd other bi l e pi gments . Bi l i rubi n mus t be ma de wa ter s ol ubl e to be
excreted. Thi s tra ns forma ti on occurs i n 5 s teps : forma ti on, pl a s ma tra ns port, l i ver upta ke, conjuga ti on, a nd bi l i a ry excreti on.
Formation: About 250 to 350 mg of unconjuga ted bi l i rubi n forms da i l y; 70 to 80% deri ves from the brea kdown of degenera ti ng RBCs , a nd 20 to 30%
(ea rl y-l a bel ed bi l i rubi n) deri ves pri ma ri l y from other heme protei ns i n the bone ma rrow a nd l i ver. Hb i s degra ded to i ron a nd bi l i verdi n, whi ch i s
converted to bi l i rubi n.
Plasma transport: Unconjuga ted (i ndi rect-rea cti ng) bi l i rubi n i s not wa ter s ol ubl e a nd s o i s tra ns ported i n the pl a s ma bound to a l bumi n. It ca nnot
pa s s through the gl omerul a r membra ne i nto the uri ne. Al bumi n bi ndi ng wea kens under certa i n condi ti ons (eg, a ci dos i s ), a nd s ome s ubs ta nces
(eg, s a l i cyl a tes , certa i n a nti bi oti cs ) compete for the bi ndi ng s i tes .
Liver uptake: The l i ver ta kes up bi l i rubi n ra pi dl y but does not ta ke up the a tta ched s erum a l bumi n.
Conjugation: Unconjuga ted bi l i rubi n i n the l i ver i s conjuga ted to form ma i nl y bi l i rubi n di gl ucuroni de, or conjuga ted (di rect-rea cti ng) bi l i rubi n. Thi s
rea cti on, ca ta l yzed by the mi cros oma l enzyme gl ucuronyl tra ns fera s e, renders the bi l i rubi n wa ter s ol ubl e.
Biliary excretion: Ti ny ca na l i cul i formed by a dja cent hepa tocytes progres s i vel y coa l es ce i nto ductul es , i nterl obul a r bi l e ducts , a nd l a rger hepa ti c
ducts . Outs i de the porta hepa ti s , the ma i n hepa ti c duct joi ns the cys ti c duct from the ga l l bl a dder to form the common bi l e duct, whi ch dra i ns i nto
the duodenum a t the a mpul l a of Va ter.
Conjuga ted bi l i rubi n i s s ecreted i nto the bi l e ca na l i cul us wi th other bi l e cons ti tuents . In the i ntes ti ne, ba cteri a meta bol i ze bi l i rubi n to form
urobi l i nogen, much of whi ch i s further meta bol i zed to s tercobi l i ns , whi ch render the s tool brown. In compl ete bi l i a ry obs tructi on, s tool s l os e thei r
norma l col or a nd become l i ght gra y (cl a y-col ored s tool ). Some urobi l i nogen i s rea bs orbed, extra cted by hepa tocytes , a nd re-excreted i n bi l e
(enterohepa ti c ci rcul a ti on). A s ma l l a mount i s excreted i n uri ne.
Beca us e conjuga ted bi l i rubi n i s excreted i n uri ne a nd unconjuga ted bi l i rubi n i s not, onl y conjuga ted hyperbi l i rubi nemi a (eg, due to hepa tocel l ul a r
or chol es ta ti c ja undi ce) ca us es bi l i rubi nuri a .
Des pi te necros i s , the l i ver ca n regenera te i ts el f. Even extens i ve pa tchy necros i s ca n res ol ve compl etel y (eg, i n a cute vi ra l hepa ti ti s ). Incompl ete
regenera ti on a nd fi bros i s , however, ma y res ul t from i njury tha t bri dges enti re l obul es or from l es s pronounced but ongoi ng da ma ge.
Speci fi c di s ea s es preferenti a l l y a ffect certa i n hepa tobi l i a ry s tructures or functi ons (eg, a cute vi ra l hepa ti ti s i s pri ma ri l y ma ni fes ted by da ma ge to
hepa tocytes or hepa tocel l ul a r i njury; pri ma ry bi l i a ry ci rrhos i s , by i mpa i rment of bi l i a ry s ecreti on; a nd cryptogeni c ci rrhos i s , by l i ver fi bros i s a nd
res ul ta nt porta l venous hypertens i on). The pa rt of the hepa tobi l i a ry s ys tem a ffected determi nes the s ymptoms , s i gns , a nd l a bora tory
a bnorma l i ti es (s ee a l s o Ch. 24). Some di s orders (eg, s evere a l cohol i c l i ver di s ea s e) a ffect mul ti pl e l i ver s tructures , res ul ti ng i n a combi na ti on of
pa tterns of s ymptoms , s i gns , a nd l a bora tory a bnorma l i ti es .

The prognos i s of s eri ous compl i ca ti ons i s wors e i n ol der a dul ts , who a re l es s a bl e to recover from s evere phys i ol ogi c s tres s es a nd to tol era te
toxi c a ccumul a ti ons .
Evaluation
History: Va ri ous s ymptoms ma y devel op, but few a re s peci fi c for l i ver di s orders :
Common nons peci fi c s ymptoms i ncl ude fa ti gue, a norexi a , na us ea , a nd, occa s i ona l l y, vomi ti ng, pa rti cul a rl y i n s evere di s orders .
Loos e, fa tty s tool s (s tea torrhea ) ca n occur when chol es ta s i s prevents s uffi ci ent bi l e from rea chi ng the i ntes ti nes . Pa ti ents wi th s tea torrhea a re
a t ri s k of defi ci enci es of fa t-s ol ubl e vi ta mi ns (A, D, E, K). Common cl i ni ca l cons equences ma y i ncl ude os teoporos i s a nd bl eedi ng.
Fever ca n devel op i n vi ra l or a l cohol i c hepa ti ti s .
Ja undi ce (s ee p. 212), occurri ng i n both hepa tocel l ul a r dys functi on a nd chol es ta ti c di s orders , i s the mos t s peci fi c s ymptom. It i s often
a ccompa ni ed by da rk uri ne a nd l i ght s tool s .
Ri ght upper qua dra nt pa i n due to l i ver di s orders us ua l l y res ul ts from di s tenti on (eg, by pa s s i ve venous conges ti on or tumor) or i nfl a mma ti on of
the l i ver ca ps ul e.
Erecti l e dys functi on a nd femi ni za ti on devel op; however, thes e s ymptoms ma y refl ect the effects of a l cohol more tha n l i ver di s orders .
Fa mi l y hi s tory, s oci a l hi s tory, a nd drug a nd s ubs ta nce us e hi s tory s houl d note ri s k fa ctors for l i ver di s orders (s ee
Ta bl e 23-1).
Physical examination: Abnorma l i ti es detecta bl e on a phys i ca l exa mi na ti on us ua l l y do not devel op unti l l a te i n the cours e of the di s ea s e. Some
common fi ndi ngs s ugges t a ca us e (s ee
Ta bl e 23-2).
Ascites
Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is
based on physical examination and often ultrasonography or CT. Treatments include bed rest, dietary Na restriction, diuretics, and therapeutic paracentesis.
Ascitic fluid can become infected (spontaneous bacterial peritonitis), often with pain and fever. Diagnosis of infection involves analysis and culture of ascitic fluid.
Infection is treated with antibiotics.
[Table 23-1. Ri s k Fa ctors for Li ver Di s orders ]
Etiology
As ci tes ca n res ul t from chroni c, but not a cute, l i ver di s ea s es .
Hepatic causes i ncl ude the fol l owi ng:
Porta l hypertens i on (a ccounts for > 90% of hepa ti c ca s es ), us ua l l y due to ci rrhos i s
Chroni c hepa ti ti s
Severe a l cohol i c hepa ti ti s wi thout ci rrhos i s
Hepa ti c vei n obs tructi on (Budd-Chi a ri s yndrome)
Porta l vei n thrombos i s does not us ua l l y ca us e a s ci tes unl es s hepa tocel l ul a r da ma ge i s a l s o pres ent.
Nonhepatic causes i ncl ude the fol l owi ng:
Genera l i zed fl ui d retenti on a s s oci a ted wi th s ys temi c di s ea s es (eg, hea rt fa i l ure, nephroti c s yndrome, s evere hypoa l bumi nemi a , cons tri cti ve
peri ca rdi ti s )
Peri tonea l di s orders (eg, ca rci noma tous or i nfecti ous peri toni ti s , bi l i a ry l ea k due to s urgery or a nother medi ca l procedure)
Les s common ca us es , s uch a s rena l di a l ys i s , pa ncrea ti ti s , SLE, a nd endocri ne di s orders (eg, myxedema )
Pathophysiology
Mecha ni s ms a re compl ex a nd i ncompl etel y unders tood. Fa ctors i ncl ude a l tered Sta rl i ng's forces i n the porta l ves s el s (l ow oncoti c pres s ure due to
hypoa l bumi nemi a pl us i ncrea s ed porta l venous pres s ure), a vi d rena l Na retenti on (uri na ry Na concentra ti on i s typi ca l l y < 5 mEq/L), a nd pos s i bl y
i ncrea s ed hepa ti c l ymph forma ti on.
Mecha ni s ms tha t s eem to contri bute to rena l Na retenti on i ncl ude a cti va ti on of the reni n-a ngi otens i n-a l dos terone s ys tem; i ncrea s ed s ympa theti c
tone; i ntra rena l s hunti ng of bl ood a wa y from the cortex; i ncrea s ed forma ti on of ni tri c oxi de; a nd a l tered forma ti on or meta bol i s m of ADH, ki ni ns ,
pros ta gl a ndi ns , a nd a tri a l na tri ureti c fa ctor. Va s odi l a ti on i n the s pl a nchni c a rteri a l ci rcul a ti on ma y be a tri gger, but the s peci fi c rol es a nd
i nterrel a ti ons hi ps of thes e a bnorma l i ti es rema i n uncerta i n.

Symptoms and Signs
Sma l l a mounts of a s ci ti c fl ui d ca us e no s ymptoms . Modera te a mounts ca us e i ncrea s ed a bdomi na l gi rth a nd wei ght ga i n. Ma s s i ve a mounts ma y
ca us e nons peci fi c di ffus e a bdomi na l pres s ure, but a ctua l pa i n i s uncommon a nd s ugges ts a nother ca us e of a cute a bdomi na l pa i n (s ee p. 106). If
a s ci tes res ul ts i n el eva ti on of the di a phra gm, dys pnea ma y occur. Symptoms of s ponta neous ba cteri a l peri toni ti s (SBP) ma y i ncl ude new
a bdomi na l di s comfort a nd fever.
Si gns i ncl ude s hi fti ng dul l nes s on a bdomi na l percus s i on a nd a fl ui d wa ve. Vol umes < 1500 mL ma y not ca us e phys i ca l fi ndi ngs . Ma s s i ve a s ci tes
ca us es ta utnes s of the a bdomi na l wa l l a nd fl a tteni ng of the umbi l i cus . In l i ver di s ea s es or peri tonea l di s orders , a s ci tes i s us ua l l y i s ol a ted or
di s proporti ona te to peri phera l edema ; i n s ys temi c di s ea s es (eg, hea rt fa i l ure), the revers e i s us ua l l y true.
Diagnosis
Ul tra s onogra phy or CT unl es s phys i ca l fi ndi ngs ma ke di a gnos i s obvi ous
Often tes ts of a s ci ti c fl ui d
Di a gnos i s ma y be ba s ed on phys i ca l exa mi na ti on i f there i s a l a rge a mount of fl ui d, but i ma gi ng tes ts a re more s ens i ti ve. Ul tra s onogra phy a nd CT
revea l much s ma l l er vol umes of fl ui d (100 to 200 mL) tha n does phys i ca l exa mi na ti on. SBP i s s us pected i f a pa ti ent wi th a s ci tes a l s o ha s
a bdomi na l pa i n, fever, or unexpl a i ned deteri ora ti on.
Di a gnos ti c pa ra centes i s (s ee p. 99) s houl d be done i f a ny of the fol l owi ng occur:
As ci tes i s newl y di a gnos ed.
Its ca us e i s unknown.
SBP i s s us pected.
[Table 23-2. Interpreta ti on of Some Phys i ca l Fi ndi ngs ]
About 50 to 100 mL of fl ui d i s removed a nd a na l yzed for gros s a ppea ra nce, protei n content, cel l count a nd di fferenti a l , cytol ogy, cul ture, a nd, a s
cl i ni ca l l y i ndi ca ted, a ci d-fa s t s ta i n, a myl a s e, or both. In contra s t to a s ci tes due to i nfl a mma ti on or i nfecti on, a s ci tes due to porta l hypertens i on
produces fl ui d tha t i s cl ea r a nd s tra w-col ored, ha s a l ow protei n concentra ti on, a l ow PMN count (< 250 cel l s /L), a nd, mos t rel i a bl y, a hi gh s erumto-a s ci tes a l bumi n concentra ti on gra di ent, whi ch i s the s erum a l bumi n concentra ti on mi nus the a s ci ti c a l bumi n concentra ti on. Gra di ents > 1.1
g/dL a re rel a ti vel y s peci fi c for a s ci tes due to porta l hypertens i on. In a s ci ti c fl ui d, turbi di ty a nd a PMN count > 250 cel l s /L i ndi ca te SBP, wherea s
bl oody fl ui d ca n s ugges t a tumor or TB. The ra re mi l ky (chyl ous ) a s ci tes i s mos t common wi th l ymphoma .
Treatment
Bed res t a nd di eta ry Na res tri cti on
Someti mes s pi ronol a ctone, pos s i bl y pl us furos emi de
Someti mes thera peuti c pa ra centes i s
Bed res t a nd di eta ry Na res tri cti on (2000 mg/da y) a re the fi rs t a nd l ea s t ri s ky trea tments for a s ci tes due to porta l hypertens i on. Di ureti cs s houl d be
us ed i f ri gi d Na res tri cti on fa i l s to i ni ti a te di ures i s wi thi n a few da ys . Spi ronol a ctone i s us ua l l y effecti ve (i n ora l dos es ra ngi ng from 50 mg
once/da y to 200 mg bi d). A l oop di ureti c (eg, furos emi de 20 to 160 mg po us ua l l y once/da y or 20 to 80 mg po bi d) s houl d be a dded i f s pi ronol a ctone
i s i ns uffi ci ent. Beca us e s pi ronol a ctone ca n ca us e K retenti on a nd furos emi de K depl eti on, the combi na ti on of thes e drugs often provi des opti ma l
di ures i s wi th a l ower ri s k of K a bnorma l i ti es . Fl ui d res tri cti on i s i ndi ca ted onl y for trea tment of hypona tremi a (s erum Na < 120 mEq/L). Cha nges i n
body wei ght a nd uri na ry Na determi na ti ons refl ect res pons e to trea tment. Wei ght l os s of a bout 0.5 kg/da y i s opti ma l beca us e the a s ci ti c
compa rtment ca nnot be mobi l i zed much more ra pi dl y. More a ggres s i ve di ures i s depl etes fl ui d from the i ntra va s cul a r compa rtment, es peci a l l y
when peri phera l edema i s a bs ent; thi s depl eti on ma y ca us e rena l fa i l ure or el ectrol yte i mba l a nce (eg, hypoka l emi a ) tha t ma y preci pi ta te porta l s ys temi c encepha l opa thy. Ina dequa te di eta ry Na res tri cti on i s the us ua l ca us e of pers i s tent a s ci tes .
Thera peuti c pa ra centes i s i s a n a l terna ti ve. Remova l of 4 L/da y i s s a fe; ma ny cl i ni ci a ns i nfus e IV s a l t-poor a l bumi n (a bout 40 g/pa ra centes i s ) a t
a bout the s a me ti me to prevent i ntra va s cul a r vol ume depl eti on. Even s i ngl e tota l pa ra centes i s ma y be s a fe. Thera peuti c pa ra centes i s s hortens
the hos pi ta l s ta y wi th rel a ti vel y l i ttl e ri s k of el ectrol yte i mba l a nce or rena l fa i l ure; neverthel es s , pa ti ents requi re ongoi ng di ureti cs a nd tend to
rea ccumul a te fl ui d more ra pi dl y tha n thos e trea ted wi thout pa ra centes i s .
Techni ques for the a utol ogous i nfus i on of a s ci ti c fl ui d (eg, the LeVeen peri toneovenous s hunt) often ca us e compl i ca ti ons a nd a re genera l l y no
l onger us ed. Tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) ca n l ower porta l pres s ure a nd s ucces s ful l y trea t a s ci tes res i s ta nt to other
trea tments , but TIPS i s i nva s i ve a nd ma y ca us e compl i ca ti ons , i ncl udi ng porta l -s ys temi c encepha l opa thy a nd wors eni ng hepa tocel l ul a r functi on.
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis (SBP) is infection of ascitic fluid without an apparent source. Manifestations may include fever, malaise, and symptoms of
ascites and worsening hepatic failure. Diagnosis is by examination of ascitic fluid. Treatment is with cefotaxime or another antibiotic.
SBP i s pa rti cul a rl y common i n ci rrhoti c a s ci tes , es peci a l l y a mong a l cohol i cs . Thi s i nfecti on ca n ca us e s eri ous s equel a e or dea th. The mos t
common ba cteri a ca us i ng SBP a re gra m-nega ti ve Escherichia coli a nd Klebsiella pneumoniae a nd gra m-pos i ti ve Streptococcus pneumoniae; us ua l l y onl y a
s i ngl e orga ni s m i s i nvol ved.

Symptoms and Signs
Pa ti ents ha ve s ymptoms a nd s i gns of a s ci tes . Di s comfort i s us ua l l y pres ent; i t typi ca l l y i s di ffus e, cons ta nt, a nd mi l d to modera te i n s everi ty.
Si gns of SBP ma y i ncl ude fever, ma l a i s e, encepha l opa thy, wors eni ng hepa ti c fa i l ure, a nd unexpl a i ned cl i ni ca l deteri ora ti on. Peri tonea l s i gns (eg,
a bdomi na l tendernes s a nd rebound) a re pres ent but ma y be s omewha t di mi ni s hed by the pres ence of a s ci ti c fl ui d.
Diagnosis
Di a gnos ti c pa ra centes i s
Cl i ni ca l di a gnos i s of SBP ca n be di ffi cul t; di a gnos i s requi res a hi gh i ndex of s us pi ci on a nd l i bera l us e of di a gnos ti c pa ra centes i s , i ncl udi ng
cul ture. Tra ns ferri ng a s ci ti c fl ui d to bl ood cul ture medi a before i ncuba ti on i ncrea s es the s ens i ti vi ty of cul ture to a l mos t 70%. PMN count of > 250
cel l s /L i s di a gnos ti c of SBP. Bl ood cul tures a re a l s o i ndi ca ted. Beca us e SBP us ua l l y res ul ts from a s i ngl e orga ni s m, fi ndi ng mi xed fl ora on cul ture
s ugges ts a perfora ted a bdomi na l vi s cus or conta mi na ted s peci men.
Treatment
Cefota xi me or a nother a nti bi oti c
If SBP i s di a gnos ed, a n a nti bi oti c s uch a s cefota xi me 2 g IV q 4 to 8 h (pendi ng Gra m s ta i n a nd cul ture res ul ts ) i s gi ven for a t l ea s t 5 da ys a nd unti l
a s ci ti c fl ui d s hows < 250 PMNs /L. Anti bi oti cs i ncrea s e the cha nce of s urvi va l . Beca us e SBP recurs wi thi n a yea r i n up to 70% of pa ti ents ,
prophyl a cti c a nti bi oti cs a re i ndi ca ted; qui nol ones (eg, norfl oxa ci n 400 mg po once/da y) a re mos t wi del y us ed.
Anti bi oti c prophyl a xi s i n a s ci ti c pa ti ents wi th va ri cea l hemorrha ge decrea s es the ri s k of SBP.
Fatty Liver
(Hepa ti c Stea tos i s )
Fatty liver is excessive accumulation of lipid in hepatocytes, the most common liver response to injury.
Fa tty l i ver devel ops for ma ny rea s ons , i nvol ves ma ny di fferent bi ochemi ca l mecha ni s ms , a nd ca us es di fferent types of l i ver da ma ge. Cl i ni ca l l y, i t
i s mos t us eful to di s ti ngui s h fa tty l i ver due to pregna ncy or a l cohol i c l i ver di s ea s e (s ee p. 235) from tha t occurri ng i n the a bs ence of pregna ncy a nd
a l cohol i s m (nona l cohol i c fa tty l i ver di s ea s e [NAFLD]). NAFLD i ncl udes s i mpl e fa tty i nfi l tra ti on (a beni gn condi ti on) a nd nona l cohol i c
s tea tohepa ti ti s , a l es s common but more i mporta nt va ri a nt.
(See a l s o the Ameri ca n Ga s troenterol ogi ca l As s oci a ti on's Medi ca l Pos i ti on Sta tement a nd Techni ca l Revi ew on nona l cohol i c fa tty l i ver di s ea s e.)
Nonalcoholic Steatohepatitis
Nonalcoholic steatohepatitis (NASH) is a syndrome that develops in patients who are not alcoholics; it causes liver damage that is histologically indistinguishable
from alcoholic hepatitis. It develops most often in patients with at least one of the following risk factors: obesity, dyslipidemia, and glucose intolerance.
Pathogenesis is poorly understood but seems to be linked to insulin resistance (eg, as in obesity or metabolic syndrome). Most patients are asymptomatic.
Laboratory findings include elevations in aminotransferase levels. Biopsy is required to confirm the diagnosis. Treatment includes elimination of causes and risk
factors.
NASH (s ometi mes ca l l ed s tea tonecros i s ) i s di a gnos ed mos t often i n pa ti ents between 40 yr a nd 60 yr but ca n occur i n a l l a ge groups . Ma ny
a ffected pa ti ents ha ve obes i ty, type 2 di a betes mel l i tus , or dys l i pi demi a .
Pathophysiology
Pa thophys i ol ogy i nvol ves fa t a ccumul a ti on (s tea tos i s ), i nfl a mma ti on, a nd, va ri a bl y, fi bros i s . Stea tos i s res ul ts from hepa ti c tri gl yceri de
a ccumul a ti on. Pos s i bl e mecha ni s ms for s tea tos i s i ncl ude reduced s ynthes i s of very l ow dens i ty l i poprotei n (VLDL) a nd i ncrea s ed hepa ti c
tri gl yceri de s ynthes i s (pos s i bl y due to decrea s ed oxi da ti on of fa tty a ci ds or i ncrea s ed free fa tty a ci ds bei ng del i vered to the l i ver). Infl a mma ti on
ma y res ul t from l i pi d peroxi da ti ve da ma ge to cel l membra nes . Thes e cha nges ca n s ti mul a te hepa ti c s tel l a te cel l s , res ul ti ng i n fi bros i s . If
a dva nced, NASH ca n ca us e ci rrhos i s a nd porta l hypertens i on.
Symptoms and Signs
Mos t pa ti ents a re a s ymptoma ti c. However, s ome ha ve fa ti gue, ma l a i s e, or ri ght upper qua dra nt a bdomi na l di s comfort. Hepa tomega l y devel ops i n
a bout 75% of pa ti ents . Spl enomega l y ma y devel op i f a dva nced hepa ti c fi bros i s i s pres ent a nd i s us ua l l y the fi rs t i ndi ca ti on tha t porta l
hypertens i on ha s devel oped. Pa ti ents wi th ci rrhos i s due to NASH ca n be a s ymptoma ti c a nd ma y l a ck the us ua l s i gns of chroni c l i ver di s ea s e.
Diagnosis
Pres ence of ri s k fa ctors
Abs ence of hepa ti ti s B a nd C a nd exces s i ve a l cohol i nta ke
Li ver bi ops y
The di a gnos i s s houl d be s us pected i n pa ti ents wi th ri s k fa ctors s uch a s obes i ty, type 2 di a betes mel l i tus , or dys l i pi demi a a nd i n pa ti ents wi th
unexpl a i ned l a bora tory a bnorma l i ti es s ugges ti ng l i ver di s ea s e. The mos t common l a bora tory a bnorma l i ti es a re el eva ti ons i n a mi notra ns fera s e
l evel s . Unl i ke i n a l cohol i c l i ver di s ea s e, the ra ti o of AST/ALT i n NASH i s us ua l l y < 1. Al ka l i ne phos pha ta s e a nd -gl uta myl tra ns pepti da s e (GGT)
occa s i ona l l y i ncrea s e. Hyperbi l i rubi nemi a , prol onga ti on of PT, a nd hypoa l bumi nemi a a re uncommon.
For di a gnos i s , s trong evi dence (s uch a s a hi s tory corrobora ted by fri ends a nd rel a ti ves ) tha t a l cohol i nta ke i s not exces s i ve (eg, i s < 20 g/da y) i s
needed. Serol ogi c tes ts s houl d s how a bs ence of hepa ti ti s B a nd C i nfecti on (i e, hepa ti ti s B s urfa ce a nti gen a nd hepa ti ti s C vi rus a nti body s houl d
be nega ti ve). Li ver bi ops y s houl d revea l da ma ge s i mi l a r to tha t s een i n a l cohol i c hepa ti ti s , us ua l l y i ncl udi ng l a rge fa t dropl ets (ma croves i cul a r
fa tty i nfi l tra ti on). Indi ca ti ons for bi ops y i ncl ude unexpl a i ned s i gns of porta l hypertens i on (i ncl udi ng s pl enomega l y or cytopeni a ) a nd unexpl a i ned
el eva ti ons i n a mi notra ns fera s e l evel s tha t pers i s t for > 6 mo i n a pa ti ent wi th di a betes , obes i ty, or dys l i pi demi a .
Ima gi ng tes ts , i ncl udi ng ul tra s onogra phy, CT, a nd pa rti cul a rl y MRI, ma y i denti fy hepa ti c s tea tos i s . However, thes e tes ts ca nnot i denti fy the
i nfl a mma ti on typi ca l of NASH a nd ca nnot di fferenti a te NASH from other ca us es of hepa ti c s tea tos i s .
Prognosis
Prognos i s i s controvers i a l . Proba bl y, mos t pa ti ents do not devel op hepa ti c i ns uffi ci ency or ci rrhos i s . However, s ome drugs (eg, cytotoxi c drugs ) a nd
meta bol i c di s orders a re a s s oci a ted wi th a ccel era ti on of NASH. Prognos i s i s often good unl es s compl i ca ti ons (eg, va ri cea l hemorrha ge) devel op.
Treatment
El i mi na ti on of ca us es a nd control of ri s k fa ctors
The onl y wi del y a ccepted trea tment goa l i s to el i mi na te potenti a l ca us es a nd ri s k fa ctors . Such a goa l ma y i ncl ude di s conti nua ti on of drugs or
toxi ns , wei ght l os s , a nd trea tment for dys l i pi demi a or hypergl ycemi a . Prel i mi na ry evi dence s ugges ts tha t thi a zol i di nedi ones ca n hel p correct
bi ochemi ca l a nd hi s tol ogi c a bnorma l i ti es i n NASH. Ma ny other trea tments (eg, urs odeoxychol i c a ci d, vi ta mi n E, metroni da zol e, metformi n,
beta i ne, gl uca gon, gl uta mi ne i nfus i on) ha ve not been proved effecti ve.
Jaundice
Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about
2 to 3 mg/dL (34 to 51 mol/L).
Pathophysiology
Mos t bi l i rubi n i s produced when Hb i s broken down i nto unconjuga ted bi l i rubi n (a nd other s ubs ta nces ). Unconjuga ted bi l i rubi n bi nds to a l bumi n
i n the bl ood for tra ns port to the l i ver, where i t i s ta ken up by hepa tocytes a nd conjuga ted wi th gl ucuroni c a ci d to ma ke i t wa ter s ol ubl e.
Conjuga ted bi l i rubi n i s excreted i n bi l e i nto the duodenum. In the i ntes ti ne, ba cteri a meta bol i ze bi l i rubi n to form urobi l i nogen. Some
urobi l i nogen i s el i mi na ted i n the feces , a nd s ome i s rea bs orbed, extra cted by hepa tocytes , reproces s ed, a nd re-excreted i n bi l e (enterohepa ti c
ci rcul a ti ons ee p. 205).
Mechanisms of hyperbilirubinemia: Hyperbi l i rubi nemi a ma y i nvol ve predomi na ntl y unconjuga ted or conjuga ted bi l i rubi n.
Unconjugated hyperbilirubinemia i s mos t often ca us ed by 1 of the fol l owi ng:
Increa s ed producti on
Decrea s ed hepa ti c upta ke
Decrea s ed conjuga ti on
Conjugated hyperbilirubinemia i s mos t often ca us ed by 1 of the fol l owi ng:
Dys functi on of hepa tocytes (hepa tocel l ul a r dys functi on)
Sl owi ng of bi l e egres s from the l i ver (i ntra hepa ti c chol es ta s i s )
Obs tructi on of extra hepa ti c bi l e fl ow (extra -hepa ti c chol es ta s i s )
Consequences: Outcome i s determi ned pri ma ri l y by the ca us e of ja undi ce a nd the pres ence a nd s everi ty of hepa ti c dys functi on. Hepa ti c dys functi on
ca n res ul t i n coa gul opa thy, encepha l opa thy, a nd porta l hypertens i on (whi ch ca n l ea d to GI bl eedi ng).
Etiology
Al though hyperbi l i rubi nemi a ca n be cl a s s i fi ed a s predomi na ntl y unconjuga ted or conjuga ted, ma ny hepa tobi l i a ry di s orders ca us e both forms .
Ma ny condi ti ons (s ee
Ta bl e 23-3), i ncl udi ng us e of certa i n drugs (s ee
Ta bl e 23-4), ca n ca us e ja undi ce, but the mos t common ca us es overa l l a re
Infl a mma tory hepa ti ti s (vi ra l hepa ti ti s , a utoi mmune hepa ti ti s , toxi c hepa ti c i njury)
Al cohol i c l i ver di s ea s e
Bi l i a ry obs tructi on
Evaluation
History: History of present illness s houl d i ncl ude ons et a nd dura ti on of ja undi ce. Hyperbi l i rubi nemi a ca n ca us e uri ne to da rken before
[Table 23-3. Mecha ni s ms a nd Some Ca us es of Ja undi ce i n Adul ts ]
ja undi ce i s vi s i bl e. Therefore, the ons et of da rk uri ne i ndi ca tes ons et of hyperbi l i rubi nemi a more a ccura tel y tha n ons et of ja undi ce. Importa nt
a s s oci a ted s ymptoms i ncl ude fever, prodroma l s ymptoms (eg, fever, ma l a i s e, mya l gi a s ) before ja undi ce, uri ne a nd s tool col or, pruri tus ,
s tea torrhea , a nd a bdomi na l pa i n (i ncl udi ng l oca ti on, s everi ty, dura ti on, a nd ra di a ti on). Importa nt s ymptoms s ugges ti ng s evere di s ea s e i ncl ude
na us ea a nd vomi ti ng, wei ght l os s , a nd pos s i bl e s ymptoms of coa gul opa thy (eg, ea s y brui s i ng or bl eedi ng, ta rry or bl oody s tool s ).
Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng wei ght l os s a nd a bdomi na l pa i n (ca ncer); joi nt pa i n a nd s wel l i ng
[Table 23-4. Some Drugs a nd Toxi ns tha t Ca n Ca us e Ja undi ce]
(a utoi mmune or vi ra l hepa ti ti s , hemochroma tos i s , pri ma ry s cl eros i ng chol a ngi ti s , s a rcoi dos i s ); a nd mi s s ed mens es (pregna ncy).
Past medical history s houl d i denti fy known ca us a ti ve di s orders , s uch a s hepa tobi l i a ry di s ea s e (eg, ga l l s tones , hepa ti ti s , ci rrhos i s ); di s orders tha t
ca n ca us e hemol ys i s (eg, hemogl obi nopa thy, G6PD defi ci ency); a nd di s orders a s s oci a ted wi th l i ver or bi l i a ry di s ea s e, i ncl udi ng i nfl a mma tory
bowel di s ea s e, i nfi l tra ti ve di s orders (eg, a myl oi dos i s , l ymphoma , s a rcoi dos i s , TB), a nd HIV i nfecti on or AIDS.
Drug hi s tory s houl d i ncl ude ques ti ons a bout us e of drugs or expos ure to toxi ns known to a ffect the l i ver (s ee Ta bl e 23-4) a nd a bout va cci na ti on
a ga i ns t hepa ti ti s .
Surgi ca l hi s tory s houl d i ncl ude ques ti ons a bout previ ous s urgery on the bi l i a ry tra ct (a potenti a l ca us e of s tri ctures ).
Soci a l hi s tory s houl d i ncl ude ques ti ons a bout ri s k fa ctors for hepa ti ti s (s ee
Ta bl e 23-5), a mount a nd dura ti on of a l cohol us e, i njecti on drug us e, a nd s exua l hi s tory.
Fa mi l y hi s tory s houl d i ncl ude ques ti ons a bout recurrent, mi l d ja undi ce i n fa mi l y members a nd di a gnos ed heredi ta ry l i ver di s orders . The pa ti ent's
hi s tory of recrea ti ona l drug a nd a l cohol us e s houl d be corrobora ted by fri ends or fa mi l y members when pos s i bl e.
Physical examination: Vi ta l s i gns a re revi ewed for fever a nd s i gns of s ys temi c toxi ci ty (eg, hypotens i on, ta chyca rdi a ).
Genera l a ppea ra nce i s noted, pa rti cul a rl y for ca chexi a a nd l etha rgy.
Hea d a nd neck exa mi na ti on i ncl udes i ns pecti on of the s cl era e a nd tongue for i cterus a nd the eyes for Ka ys er-Fl ei s cher ri ngs . Mi l d ja undi ce i s bes t
s een by exa mi ni ng the s cl era e i n na tura l l i ght; i t i s us ua l l y detecta bl e when s erum bi l i rubi n rea ches 2 to 2.5 mg/dL (34 to 43 mol /L). Brea th odor
s houl d be noted (eg, for fetor hepa ti cus ).
The a bdomen i s i ns pected for col l a tera l va s cul a ture, a s ci tes , a nd s urgi ca l s ca rs . The l i ver i s pa l pa ted for hepa tomega l y, ma s s es , nodul a ri ty, a nd
tendernes s . The s pl een i s pa l pa ted for s pl enomega l y. The a bdomen i s exa mi ned for umbi l i ca l herni a , s hi fti ng dul l nes s , fl ui d wa ve, ma s s es , a nd
tendernes s . The rectum i s exa mi ned for gros s or occul t bl ood.
Men a re checked for tes ti cul a r a trophy a nd gynecoma s ti a .
The upper extremi ti es a re exa mi ned for Dupuytren's contra ctures .
Neurol ogi c exa mi na ti on i ncl udes menta l s ta tus a s s es s ment a nd eva l ua ti on for a s teri xi s .
The s ki n i s exa mi ned for ja undi ce, pa l ma r erythema , needl e tra cks , va s cul a r s pi ders , excori a ti ons , xa nthoma s (cons i s tent wi th pri ma ry bi l i a ry
ci rrhos i s ), pa uci ty of a xi l l a ry a nd pubi c ha i r, hyperpi gmenta ti on, ecchymos es , petechi a e, a nd purpura .
Ma rked a bdomi na l pa i n a nd tendernes s
Al tered menta l s ta tus
GI bl eedi ng (occul t or gros s )
Ecchymos es , petechi a e, or purpura
Interpretation of findings: Severity of illness i s i ndi ca ted ma i nl y by the degree (i f a ny) of hepa ti c dys functi on. As cendi ng chol a ngi ti s i s a concern
beca us e i t requi res emergency trea tment.
Severe hepa ti c dys functi on i s i ndi ca ted by encepha l opa thy (eg, menta l s ta tus cha nge, a s teri xi s ) or coa gul opa thy (eg, ea s y bl eedi ng, purpura , ta rry
or heme-pos i ti ve s tool ), pa rti cul a rl y i n pa ti ents wi th s i gns of porta l hypertens i on
[Table 23-5. Some Ri s k Fa ctors for Hepa ti ti s ]
(eg, a bdomi na l col l a tera l va s cul a ture, a s ci tes , s pl enomega l y). Ma s s i ve upper GI bl eedi ng s ugges ts va ri cea l bl eedi ng due to porta l hypertens i on
(a nd pos s i bl y coa gul opa thy).

As cendi ng chol a ngi ti s i s s ugges ted by fever a nd ma rked, conti nuous ri ght upper qua dra nt a bdomi na l pa i n; a cute pa ncrea ti ti s wi th bi l i a ry
obs tructi on (eg, due to a common duct s tone or pa ncrea ti c ps eudocys t) ma y ma ni fes t s i mi l a rl y.
Cause of jaundice ma y be s ugges ted by the fol l owi ng:
Acute ja undi ce i n the young a nd hea l thy s ugges ts a cute vi ra l hepa ti ti s , pa rti cul a rl y when a vi ra l prodrome, ri s k fa ctors , or both a re pres ent;
however, a ceta mi nophen overdos e i s a l s o common.
Acute ja undi ce a fter a cute drug or toxi n expos ure i n hea l thy pa ti ents i s l i kel y due to tha t s ubs ta nce.
A l ong hi s tory of hea vy a l cohol us e s ugges ts a l cohol i c l i ver di s ea s e, pa rti cul a rl y when typi ca l s ti gma ta a re pres ent.
A pers ona l or fa mi l y hi s tory of recurrent, mi l d ja undi ce wi thout fi ndi ngs of hepa tobi l i a ry dys functi on s ugges ts a heredi ta ry di s order, us ua l l y
Gi l bert s yndrome.
Gra dua l ons et of ja undi ce wi th pruri tus , wei ght l os s , a nd cl a y-col ored s tool s s ugges ts i ntra hepa ti c or extra hepa ti c chol es ta s i s .
Pa i nl es s ja undi ce i n el derl y pa ti ents wi th wei ght l os s a nd a ma s s but wi th mi ni ma l pruri tus s ugges ts bi l i a ry obs tructi on ca us ed by ca ncer.
Other exa mi na ti on fi ndi ngs ca n a l s o be hel pful (s ee
Ta bl e 23-6).
Testing: The fol l owi ng a re done:
Bl ood tes ts (bi l i rubi n, a mi notra ns fera s e, a l ka l i ne phos pha ta s e)
Us ua l l y i ma gi ng
Someti mes bi ops y or l a pa ros copy
Bl ood tes ts i ncl ude mea s urement of tota l a nd di rect bi l i rubi n, a mi notra ns fera s e, a nd a l ka l i ne phos pha ta s e l evel s i n a l l pa ti ents . Res ul ts hel p
di fferenti a te chol es ta s i s from hepa tocel l ul a r dys functi on (i mporta nt beca us e pa ti ents wi th chol es ta s i s us ua l l y requi re i ma gi ng tes ts ):
Hepa tocel l ul a r dys functi on: Ma rked a mi notra ns fera s e el eva ti on (> 500 U/L) a nd modera te a l ka l i ne phos pha ta s e el eva ti on (< 3 ti mes norma l )
Chol es ta s i s : Modera te a mi notra ns fera s e el eva ti on (< 200 U/L) a nd ma rked a l ka l i ne phos pha ta s e el eva ti on (> 3 ti mes norma l )
Hyperbi l i rubi nemi a wi thout hepa tobi l i a ry dys functi on: Mi l d hyperbi l i rubi nemi a (eg, < 3.5 mg/dL [< 59 mol /L]) wi th norma l a mi notra ns fera s e
a nd a l ka l i ne phos pha ta s e l evel s
Al s o, pa ti ents wi th hepa tocel l ul a r dys functi on or chol es ta s i s ha ve da rk uri ne due to bi l i rubi nuri a beca us e conjuga ted bi l i rubi n i s excreted i n
uri ne; unconjuga ted bi l i rubi n i s not. Bi l i rubi n fra cti ona ti on a l s o di fferenti a tes conjuga ted from unconjuga ted forms . When a mi notra ns fera s e a nd
a l ka l i ne phos pha ta s e l evel s a re norma l , fra cti ona ti on of bi l i rubi n ca n hel p s ugges t ca us es , s uch a s Gi l bert s yndrome or hemol ys i s (unconjuga ted)
vs Dubi n-Johns on s yndrome or Rotor's s yndrome (conjuga ted).
Other bl ood tes ts a re done ba s ed on cl i ni ca l s us pi ci on a nd i ni ti a l tes t fi ndi ngs , a s for the fol l owi ng:
Si gns of hepa ti c i ns uffi ci ency (eg, encepha l opa thy, a s ci tes , ecchymos es ) or GI bl eedi ng: Coa gul a ti on profi l e (PT/PTT)
Hepa ti ti s ri s k fa ctors (s ee Ta bl e 23-5) or a hepa tocel l ul a r mecha ni s m s ugges ted by bl ood tes t res ul ts : Hepa ti ti s vi ra l a nd a utoi mmune s erol ogi c
tes ts
Fever, a bdomi na l pa i n, a nd tendernes s : CBC a nd, i f pa ti ents a ppea r i l l , bl ood cul tures
[Table 23-6. Fi ndi ngs Sugges ti ng a Ca us e of Ja undi ce]
Sus pi ci on of hemol ys i s ca n be confi rmed by a peri phera l bl ood s mea r.
Ima gi ng i s done i f pa i n s ugges ts extra hepa ti c obs tructi on or chol a ngi ti s or i f bl ood tes t res ul ts s ugges t chol es ta s i s .
Abdomi na l ul tra s onogra phy us ua l l y i s done fi rs t; us ua l l y, i t i s hi ghl y a ccura te i n detecti ng extra hepa ti c obs tructi on. CT a nd MRI a re a l terna ti ves .
Ul tra s onogra phy i s us ua l l y more a ccura te for ga l l s tones , a nd CT i s more a ccura te for pa ncrea ti c l es i ons . Al l thes e tes ts ca n detect a bnorma l i ti es
i n the bi l i a ry tree a nd foca l l i ver l es i ons but a re l es s a ccura te i n detecti ng di ffus e hepa tocel l ul a r di s orders (eg, hepa ti ti s , ci rrhos i s ).
If ul tra s onogra phy s hows extra hepa ti c chol es ta s i s , other tes ts ma y be neces s a ry to determi ne the ca us e; us ua l l y, ma gneti c res ona nce
chol a ngi opa ncrea togra phy (MRCP) or ERCP i s us ed. ERCP i s more i nva s i ve but a l l ows trea tment of s ome obs tructi ve l es i ons (eg, s tone remova l ,
s tenti ng of s tri ctures ).
Li ver bi ops y i s not commonl y requi red but ca n hel p di a gnos e certa i n di s orders (eg, di s orders ca us i ng i ntra hepa ti c chol es ta s i s , s ome ki nds of
hepa ti ti s , s ome i nfi l tra ti ve di s orders , Dubi n-Johns on s yndrome, hemochroma tos i s , Wi l s on's di s ea s e). Bi ops y ca n a l s o hel p when l i ver enzyme
a bnorma l i ti es a re unexpl a i ned by other tes ts .
La pa ros copy (peri toneos copy) a l l ows di rect i ns pecti on of the l i ver a nd ga l l bl a dder wi thout the tra uma of a ful l l a pa rotomy. Unexpl a i ned
chol es ta ti c ja undi ce wa rra nts l a pa ros copy occa s i ona l l y a nd di a gnos ti c l a pa rotomy ra rel y.
Treatment
The ca us e a nd a ny compl i ca ti ons a re trea ted. Ja undi ce i ts el f requi res no trea tment i n a dul ts (unl i ke i n neona tes s ee p. 2788). Itchi ng, i f
bothers ome, ma y be rel i eved wi th chol es tyra mi ne 2 to 8 g po bi d. However, chol es tyra mi ne i s i neffecti ve i n pa ti ents wi th compl ete bi l i a ry
obs tructi on.
Symptoms ma y be a ttenua ted or mi s s ed i n the el derl y; eg, a bdomi na l pa i n ma y be mi l d or a bs ent i n a cute vi ra l hepa ti ti s . A s l eep di s turba nce or
mi l d confus i on res ul ti ng from portos ys temi c encepha l opa thy ma y be mi s a ttri buted to dementi a .
Key Points
Acute ja undi ce, pa rti cul a rl y wi th a vi ra l prodrome, i n the young a nd hea l thy s ugges ts a cute vi ra l hepa ti ti s .
Pa i nl es s ja undi ce i n el derl y pa ti ents wi th wei ght l os s , a n a bdomi na l ma s s , a nd mi ni ma l pruri tus s ugges ts bi l i a ry obs tructi on ca us ed by ca ncer.
Ami notra ns fera s e l evel s of > 500 U/L a nd a l ka l i ne phos pha ta s e el eva ti on < 3 ti mes norma l s ugges t hepa tocel l ul a r dys functi on.
Ami notra ns fera s e l evel s of < 200 U/L a nd a l ka l i ne phos pha ta s e el eva ti on > 3 ti mes norma l s ugges t chol es ta s i s .
Si gni fi ca nt hepa ti c dys functi on i s i ndi ca ted by a l tered menta l s ta tus a nd coa gul opa thy.
Inborn Metabolic Disorders Causing Hyperbilirubinemia
Heredi ta ry or i nborn meta bol i c di s orders ma y ca us e unconjuga ted or conjuga ted hyperbi l i rubi nemi a .
Unconjuga ted hyperbi l i rubi nemi a : Gi l bert s yndrome, Cri gl er-Na jja r s yndrome, a nd pri ma ry s hunt hyperbi l i rubi nemi a
Conjuga ted hyperbi l i rubi nemi a : Dubi n-Johns on s yndrome a nd Rotor's s yndrome
Gilbert Syndrome
Gi l bert s yndrome i s a pres uma bl y l i fel ong di s order i n whi ch the onl y s i gni fi ca nt a bnorma l i ty i s a s ymptoma ti c, mi l d, unconjuga ted
hyperbi l i rubi nemi a . It ca n be mi s ta ken for chroni c hepa ti ti s or other l i ver di s orders . Gi l bert s yndrome ma y a ffect a s ma ny a s 5% of peopl e.
Al though fa mi l y members ma y be a ffected, a cl ea r geneti c pa ttern i s di ffi cul t to es ta bl i s h.
Pa thogenes i s ma y i nvol ve compl ex defects i n the l i ver's upta ke of bi l i rubi n. Gl ucuronyl tra ns fera s e a cti vi ty i s l ow, though not a s l ow a s i n Cri gl erNa jja r s yndrome type II. In ma ny pa ti ents , RBC des tructi on i s a l s o s l i ghtl y a ccel era ted, but thi s a ccel era ti on does not expl a i n hyperbi l i rubi nemi a .
Li ver hi s tol ogy i s norma l .
Gi l bert s yndrome i s mos t often detected i n young a dul ts s erendi pi tous l y by fi ndi ng a n el eva ted bi l i rubi n l evel , whi ch us ua l l y fl uctua tes between
2 a nd 5 mg/dL (34 a nd 86 mol /L) a nd tends to i ncrea s e wi th fa s ti ng a nd other s tres s es .
Gi l bert s yndrome i s di fferenti a ted from hepa ti ti s by fra cti ona ti on tha t s hows predomi na ntl y unconjuga ted bi l i rubi n, otherwi s e norma l l i ver
functi on tes t res ul ts , a nd a bs ence of uri na ry bi l i rubi n. It i s di fferenti a ted from hemol ys i s by the a bs ence of a nemi a a nd reti cul ocytos i s . Trea tment
i s unneces s a ry. Pa ti ents s houl d be rea s s ured tha t they do not ha ve l i ver di s ea s e.
Crigler-Najjar Syndrome
Thi s ra re i nheri ted di s order i s ca us ed by defi ci ency of the enzyme gl ucuronyl tra ns fera s e. Pa ti ents wi th a utos oma l reces s i ve type I (compl ete)
di s ea s e ha ve s evere hyperbi l i rubi nemi a . They us ua l l y di e of kerni cterus by a ge 1 yr but ma y s urvi ve i nto a dul thood. Trea tment ma y i ncl ude
photothera py a nd l i ver tra ns pl a nta ti on. Pa ti ents wi th a utos oma l domi na nt type II (pa rti a l ) di s ea s e (whi ch ha s va ri a bl e penetra nce) often ha ve
l es s s evere hyperbi l i rubi nemi a (< 20 mg/dL [< 342 mol /L]) a nd us ua l l y l i ve i nto a dul thood wi thout neurol ogi c da ma ge. Phenoba rbi ta l 1.5 to 2
mg/kg po ti d, whi ch i nduces the pa rti a l l y defi ci ent gl ucuronyl tra ns fera s e, ma y be effecti ve.
Primary Shunt Hyperbilirubinemia
Thi s ra re, fa mi l i a l , beni gn condi ti on i s cha ra cteri zed by overproducti on of ea rl y-l a bel ed bi l i rubi n.
Dubin-Johnson Syndrome and Rotor's Syndrome
Dubi n-Johns on s yndrome a nd Rotor's s yndrome ca us e conjuga ted hyperbi l i rubi nemi a , but wi thout chol es ta s i s , ca us i ng no s ymptoms or s equel a e
other tha n ja undi ce. In contra s t to unconjuga ted hyperbi l i rubi nemi a i n Gi l bert s yndrome (whi ch a l s o ca us es no other s ymptoms ), bi l i rubi n ma y
a ppea r i n the uri ne. Ami notra ns fera s e a nd a l ka l i ne phos pha ta s e l evel s a re us ua l l y norma l . Trea tment i s unneces s a ry.
Dubin-Johnson syndrome: Thi s ra re a utos oma l reces s i ve di s order i nvol ves i mpa i red excreti on of bi l i rubi n gl ucuroni des . It i s us ua l l y di a gnos ed by
l i ver bi ops y; the l i ver i s deepl y pi gmented a s a res ul t of a n i ntra cel l ul a r mel a ni n-l i ke s ubs ta nce but i s otherwi s e hi s tol ogi ca l l y norma l .
Rotor's syndrome: Thi s ra re di s order i s cl i ni ca l l y s i mi l a r to Dubi n-Johns on s yndrome, but the l i ver i s not pi gmented, a nd other s ubtl e meta bol i c
di fferences a re pres ent.
Portal Hypertension
Portal hypertension is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities.
Consequences include esophageal varices and portal-systemic encephalopathy. Diagnosis is based on clinical criteria, often in conjunction with imaging tests and
endoscopy. Treatment involves prevention of GI bleeding with endoscopy, drugs, or both and sometimes with portocaval shunting.
The porta l vei n, formed by the s uperi or mes enteri c a nd s pl eni c vei ns , dra i ns bl ood from the a bdomi na l GI tra ct, s pl een, a nd pa ncrea s i nto the
l i ver. Wi thi n reti cul oendothel i uml i ned bl ood cha nnel s (s i nus oi ds ), bl ood from the termi na l porta l venul es merges wi th hepa ti c a rteri a l bl ood.
Bl ood fl ows out of the s i nus oi ds vi a the hepa ti c vei ns i nto the i nferi or vena ca va .
Norma l porta l pres s ure i s 5 to 10 mm Hg (7 to 14 cm H 2 O), whi ch exceeds i nferi or vena ca va l pres s ure by 4 to 5 mm Hg (porta l venous gra di ent).
Hi gher va l ues a re defi ned a s porta l hypertens i on.
Etiology
Porta l hypertens i on res ul ts ma i nl y from i ncrea s ed res i s ta nce to fl ow, whi ch commonl y a ri s es from di s ea s e wi thi n the l i ver i ts el f or uncommonl y
from bl ocka ge of the s pl eni c or porta l vei n or i mpa i red hepa ti c venous outfl ow (s ee
Ta bl e 23-7). Increa s ed fl ow vol ume i s a ra re ca us e, a l though i t often contri butes to porta l hypertens i on i n ci rrhos i s a nd i n hema tol ogi c di s orders
tha t ca us e ma s s i ve s pl enomega l y.
Pathophysiology
In ci rrhos i s , ti s s ue fi bros i s a nd regenera ti on i ncrea s e res i s ta nce i n the s i nus oi ds a nd termi na l porta l venul es . However, other potenti a l l y
revers i bl e fa ctors contri bute; they i ncl ude contra cti l i ty of s i nus oi da l l i ni ng cel l s , producti on of va s oa cti ve s ubs ta nces (eg, endothel i ns , ni tri c
oxi de), va ri ous s ys temi c medi a tors of a rteri ol a r res i s ta nce, a nd pos s i bl y s wel l i ng of hepa tocytes .
Over ti me, porta l hypertens i on crea tes porta l -s ys temi c venous col l a tera l s . They ma y s l i ghtl y decrea s e porta l vei n pres s ure but ca n ca us e
compl i ca ti ons . Engorged s erpenti ne s ubmucos a l ves s el s (va ri ces ) i n the di s ta l es opha gus a nd s ometi mes i n the ga s tri c fundus ca n rupture,
ca us i ng s udden, ca ta s trophi c GI bl eedi ng. Bl eedi ng ra rel y occurs unl es s the porta l pres s ure gra di ent i s > 12 mm Hg. Ga s tri c mucos a l va s cul a r
conges ti on (porta l hypertens i ve ga s tropa thy) ca n ca us e a cute or chroni c bl eedi ng i ndependent of va ri ces . Vi s i bl e a bdomi na l wa l l col l a tera l s a re
common; vei ns ra di a ti ng from the umbi l i cus (ca put medus a e) a re much ra rer a nd i ndi ca te extens i ve fl ow i n the umbi l i ca l a nd peri umbi l i ca l vei ns .
[Table 23-7. Mos t Common Ca us es of Porta l Hypertens i on]
Col l a tera l s a round the rectum ca n ca us e recta l va ri ces tha t ca n bl eed.
Porta l -s ys temi c col l a tera l s s hunt bl ood a wa y from the l i ver. Thus , l es s bl ood rea ches the l i ver when porta l fl ow i ncrea s es (di mi ni s hed hepa ti c
res erve). In a ddi ti on, toxi c s ubs ta nces from the i ntes ti ne a re s hunted di rectl y to the s ys temi c ci rcul a ti on, contri buti ng to porta l -s ys temi c
encepha l opa thy (s ee p. 220). Venous conges ti on wi thi n vi s cera l orga ns due to porta l hypertens i on contri butes to a s ci tes vi a a l tered Sta rl i ng's
forces . Spl enomega l y a nd hypers pl eni s m (s ee p. 984) commonl y occur a s a res ul t of i ncrea s ed s pl eni c vei n pres s ure. Thrombocytopeni a ,
l eukopeni a , a nd, l es s commonl y, hemol yti c a nemi a ma y res ul t.
Porta l hypertens i on i s often a s s oci a ted wi th a hyperdyna mi c ci rcul a ti on. Mecha ni s ms a re compl ex a nd s eem to i nvol ve a l tered s ympa theti c tone,
producti on of ni tri c oxi de a nd other endogenous va s odi l a tors , a nd enha nced a cti vi ty of humora l fa ctors (eg, gl uca gon).
Symptoms and Signs
Porta l hypertens i on i s a s ymptoma ti c; s ymptoms a nd s i gns res ul t from i ts compl i ca ti ons . The mos t da ngerous i s a cute va ri cea l bl eedi ng (s ee p.
103). Pa ti ents typi ca l l y pres ent wi th s udden pa i nl es s upper GI bl eedi ng, often ma s s i ve. Bl eedi ng from porta l hypertens i ve ga s tropa thy i s often
s uba cute or chroni c. As ci tes , s pl enomega l y, or porta l -s ys temi c encepha l opa thy ma y be pres ent.
Diagnosis
Us ua l l y, cl i ni ca l eva l ua ti on
Porta l hypertens i on i s i nferred i n a pa ti ent wi th chroni c l i ver di s ea s e by the pres ence of col l a tera l ci rcul a ti on, s pl enomega l y, a s ci tes , or porta l s ys temi c encepha l opa thy. Proof requi res di rect porta l pres s ure mea s urement by a tra ns jugul a r ca theter, whi ch i s i nva s i ve a nd us ua l l y not done.
Ima gi ng ma y hel p when ci rrhos i s i s s us pected. Ul tra s onogra phy or CT often revea l s di l a ted i ntra -a bdomi na l col l a tera l s , a nd Doppl er
ul tra s onogra phy ca n determi ne porta l vei n pa tency a nd fl ow.
Es opha goga s tri c va ri ces a nd porta l hypertens i ve ga s tropa thy a re bes t di a gnos ed by endos copy, whi ch ma y a l s o i denti fy predi ctors of
es opha goga s tri c va ri cea l bl eedi ng (eg, red ma rki ngs on a va ri x).
Prognosis
Morta l i ty duri ng a cute va ri cea l hemorrha ge ma y exceed 50%. Prognos i s i s predi cted by the degree of hepa ti c res erve a nd the degree of bl eedi ng.
For s urvi vors , the bl eedi ng ri s k wi thi n the next 1 to 2 yr i s 50 to 75%. Ongoi ng endos copi c or drug thera py l owers the bl eedi ng ri s k but decrea s es
l ong-term morta l i ty onl y ma rgi na l l y. For trea tment of a cute bl eedi ng, s ee pp. 102 a nd 104.
Treatment
Ongoi ng endos copi c thera py a nd s urvei l l a nce
-Bl ockers wi th or wi thout i s os orbi de mononi tra te

Someti mes porta l vei n s hunti ng
When pos s i bl e, the underl yi ng di s order i s trea ted. Long-term trea tment of es opha goga s tri c va ri ces tha t ha ve bl ed i s a s eri es of endos copi c
ba ndi ng s es s i ons to obl i tera te res i dua l va ri ces , then peri odi c s urvei l l a nce endos copy for recurrent va ri ces .
Long-term drug thera py for va ri ces tha t ha ve bl ed i nvol ves -bl ockers ; thes e drugs l ower porta l pres s ure pri ma ri l y by di mi ni s hi ng porta l fl ow,
a l though the effects va ry. Propra nol ol (40 to 80 mg po bi d) or na dol ol (40 to 160 mg po once/da y) i s preferred, wi th dos a ge ti tra ted to decrea s e
hea rt ra te by a bout 25%. Addi ng i s os orbi de mononi tra te 10 to 20 mg po bi d ma y further reduce porta l pres s ure. Combi ned l ong-term endos copi c
a nd drug thera py ma y be s l i ghtl y more effecti ve tha n ei ther a l one. Pa ti ents who do not a dequa tel y res pond to ei ther trea tment s houl d be
cons i dered for tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) or, l es s frequentl y, a s urgi ca l portoca va l s hunt. TIPS crea tes a s tent between
the porta l a nd hepa ti c venous ci rcul a ti on wi thi n the l i ver. Al though TIPS ma y res ul t i n fewer i mmedi a te dea ths tha n s urgi ca l s hunti ng, pa rti cul a rl y
duri ng a cute bl eedi ng, ma i ntena nce of pa tency ma y requi re repea t procedures beca us e the s tent ma y become s tenos ed or occl uded over ti me.
Long-term benefi ts a re unknown. Li ver tra ns pl a nta ti on ma y hel p s ome pa ti ents .
For pa ti ents wi th va ri ces tha t ha ve not yet bl ed, -bl ockers l ower the ri s k of bl eedi ng.
For bl eedi ng due to porta l hypertens i ve ga s tropa thy, drugs ca n be us ed to decrea s e porta l pres s ure. A s hunt s houl d be cons i dered i f drugs a re
i neffecti ve, but res ul ts ma y be l es s s ucces s ful tha n for es opha gea l va ri cea l bl eedi ng.
Beca us e i t ra rel y ca us es cl i ni ca l probl ems , hypers pl eni s m requi res no s peci fi c trea tment, a nd s pl enectomy s houl d be a voi ded.
Portal-Systemic Encephalopathy
Portal-systemic encephalopathy is a neuropsychiatric syndrome. It most often results from high gut protein or acute metabolic stress (eg, GI bleeding, infection,
electrolyte abnormality) in a patient with portal-systemic shunting. Symptoms are mainly neuropsychiatric (eg, confusion, flapping tremor, coma). Diagnosis is
based on clinical findings. Treatment usually is correction of the acute cause, restriction of dietary protein, and oral lactulose.
Porta l -s ys temi c encepha l opa thy better des cri bes the pa thophys i ol ogy tha n hepa ti c encepha l opa thy or hepa ti c coma , but a l l 3 terms a re us ed
i ntercha ngea bl y.
Etiology
Porta l -s ys temi c encepha l opa thy ma y occur i n ful mi na nt hepa ti ti s ca us ed by vi rus es , drugs , or toxi ns , but i t more commonl y occurs i n ci rrhos i s or
other chroni c di s orders when extens i ve porta l -s ys temi c col l a tera l s ha ve devel oped a s a res ul t of porta l hypertens i on. Encepha l opa thy a l s o
fol l ows porta l -s ys temi c a na s tomos es , s uch a s s urgi ca l l y crea ted a na s tomos es connecti ng the porta l vei n a nd vena ca va (porta ca va l s hunts ,
tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng [TIPS]).
Precipitants: In pa ti ents wi th chroni c l i ver di s ea s e, a cute epi s odes of encepha l opa thy a re us ua l l y preci pi ta ted by revers i bl e ca us es . The mos t
common a re the fol l owi ng:
Meta bol i c s tres s (eg, i nfecti on; el ectrol yte i mba l a nce, es peci a l l y hypoka l emi a ; dehydra ti on; us e of di ureti c drugs )
Di s orders tha t i ncrea s e gut protei n (eg, GI bl eedi ng, hi gh-protei n di et)
Nons peci fi c cerebra l depres s a nts (eg, a l cohol , s eda ti ves , a na l ges i cs )
Pathophysiology
In porta l -s ys temi c s hunti ng, a bs orbed products tha t woul d otherwi s e be detoxi fi ed by the l i ver enter the s ys temi c ci rcul a ti on, where they ma y be
toxi c to the bra i n, pa rti cul a rl y the cerebra l cortex. The s ubs ta nces ca us i ng bra i n toxi ci ty a re not preci s el y known. Ammoni a , a product of protei n
di ges ti on, i s a n i mporta nt ca us e, but other fa ctors (eg, a l tera ti ons i n cerebra l benzodi a zepi ne receptors a nd neurotra ns mi s s i on by -a mi nobutyri c
a ci d [GABA]) ma y a l s o contri bute. Aroma ti c a mi no a ci d l evel s i n s erum a re us ua l l y hi gh a nd bra nched-cha i n l evel s a re l ow, but thes e l evel s
proba bl y do not ca us e encepha l opa thy.
Symptoms and Signs
Symptoms a nd s i gns of encepha l opa thy tend to devel op i n progres s i ve s ta ges (s ee
Ta bl e 23-8).
Symptoms us ua l l y do not become a ppa rent unti l bra i n functi on i s modera tel y i mpa i red. Cons tructi ona l a pra xi a , i n whi ch pa ti ents ca nnot
reproduce s i mpl e des i gns (eg, a s ta r), devel ops ea rl y. Agi ta ti on a nd ma ni a ca n devel op but a re uncommon. A cha ra cteri s ti c fl a ppi ng tremor
(a s teri xi s ) i s el i ci ted when pa ti ents hol d thei r a rms outs tretched wi th wri s ts dors i fl exed. Neurol ogi c defi ci ts a re s ymmetri c. Neurol ogi c s i gns i n
coma us ua l l y refl ect bi l a tera l di ffus e hemi s pheri c dys functi on. Si gns of bra i n s tem dys functi on devel op onl y i n a dva nced coma , often duri ng the
hours or da ys before dea th. A mus ty, s weet brea th odor (fetor hepa ti cus ) ca n occur rega rdl es s of the s ta ge of encepha l opa thy.
Diagnosis
Often a djuncti ve tes ti ng wi th ps ychometri c eva l ua ti on, a mmoni a l evel , EEG, or a combi na ti on
Excl us i on of other trea ta bl e di s orders
[Table 23-8. Cl i ni ca l Sta ges of Porta l -Sys temi c Encepha l opa thy]
Di a gnos i s i s ul ti ma tel y ba s ed on cl i ni ca l fi ndi ngs , but tes ti ng ma y hel p:
Ps ychometri c tes ti ng ma y revea l s ubtl e neurops ychi a tri c defi ci ts , whi ch ca n hel p confi rm ea rl y encepha l opa thy.
Ammoni a l evel s a re us ua l l y done.
An EEG us ua l l y s hows di ffus e s l ow-wa ve a cti vi ty, even i n mi l d ca s es , a nd ma y be s ens i ti ve but i s not s peci fi c for ea rl y encepha l opa thy.
CSF exa mi na ti on i s not routi nel y neces s a ry; the onl y us ua l a bnorma l i ty i s mi l d protei n el eva ti on.
Other potenti a l l y revers i bl e di s orders tha t coul d ca us e s i mi l a r ma ni fes ta ti ons (eg, i nfecti on, s ubdura l hema toma , hypogl ycemi a , i ntoxi ca ti on)
s houl d be rul ed out. If porta l -s ys temi c encepha l opa thy i s confi rmed, the preci pi ta ti ng ca us e s houl d be s ought.
Prognosis
In chroni c l i ver di s ea s e, correcti on of the preci pi ta ti ng ca us e us ua l l y ca us es encepha l opa thy to regres s wi thout perma nent neurol ogi c s equel a e.
Some pa ti ents , es peci a l l y thos e wi th porta ca va l s hunts or TIPS, requi re conti nuous thera py, a nd i rrevers i bl e extra pyra mi da l s i gns or s pa s ti c
pa ra pa res i s ra rel y devel ops . Coma (s ta ge 4 encepha l opa thy) a s s oci a ted wi th ful mi na nt hepa ti ti s i s fa ta l i n up to 80% of pa ti ents des pi te
i ntens i ve thera py; the combi na ti on of a dva nced chroni c l i ver fa i l ure a nd porta l -s ys temi c encepha l opa thy i s often fa ta l .
Treatment
Trea tment of the ca us e
Bowel cl ea ns i ng us i ng ora l l a ctul os e or enema s
Di eta ry protei n res tri cti on
Trea ti ng the ca us e us ua l l y revers es mi l d ca s es . El i mi na ti ng toxi c enteri c products i s the other goa l a nd i s a ccompl i s hed us i ng s evera l methods .
The bowel s s houl d be cl ea red us i ng enema s or, more often, ora l l a ctul os e s yrup, whi ch ca n be tube-fed to coma tos e pa ti ents . Thi s s yntheti c
di s a ccha ri de i s a n os moti c ca tha rti c. It a l s o l owers col oni c pH, decrea s i ng feca l a mmoni a producti on. The i ni ti a l dos a ge, 30 to 45 mL po ti d, s houl d
be a djus ted to produce 2 or 3 s oft s tool s da i l y. Di eta ry protei n s houl d be a bout 1.0 mg/kg/da y, pri ma ri l y from vegeta bl e s ources . Ora l
nona bs orba bl e a nti bi oti cs s uch a s neomyci n a nd ri fa xi mi n a re effecti ve for hepa ti c encepha l opa thy. Ri fa xi mi n i s us ua l l y preferred beca us e
neomyci n i s a n a mi nogl ycos i de, whi ch ca n preci pi ta te ototoxi ci ty or nephrotoxi ci ty.
Seda ti on deepens encepha l opa thy a nd s houl d be a voi ded whenever pos s i bl e. For coma ca us ed by ful mi na nt hepa ti ti s , meti cul ous s upporti ve
a nd nurs i ng ca re coupl ed wi th preventi on a nd trea tment of compl i ca ti ons i ncrea s e the cha nce of s urvi va l . Hi gh-dos e corti cos teroi ds , excha nge
tra ns fus i on, a nd other compl ex procedures des i gned to remove ci rcul a ti ng toxi ns genera l l y do not i mprove outcome. Pa ti ents deteri ora ti ng
beca us e of ful mi na nt hepa ti c fa i l ure ma y be s a ved by l i ver tra ns pl a nta ti on.
Other potenti a l thera pi es , i ncl udi ng l evodopa , bromocri pti ne, fl uma zeni l , Na benzoa te, i nfus i ons of bra nched-cha i n a mi no a ci ds , keto-a na l ogs of
es s enti a l a mi no a ci ds , a nd pros ta gl a ndi ns , ha ve not proved effecti ve. Compl ex pl a s ma -fi l teri ng s ys tems (a rti fi ci a l l i ver) s how s ome promi s e but
requi re much more s tudy.
Systemic Abnormalities in Liver Disease
Li ver di s ea s e often ca us es s ys temi c s ymptoms a nd a bnorma l i ti es (s ee Porta l -Sys temi c Encepha l opa thy on p. 220).
Circulatory Abnormalities
Hypotens i on i n a dva nced l i ver fa i l ure ma y contri bute to rena l dys functi on. The pa thogenes i s of the hyperdyna mi c ci rcul a ti on (i ncrea s ed ca rdi a c
output a nd hea rt ra te) a nd hypotens i on tha t devel op i n a dva nced l i ver fa i l ure or ci rrhos i s i s poorl y unders tood. However, peri phera l a rteri a l
va s odi l a ti on proba bl y contri butes to both. Fa ctors tha t ma y contri bute i n ci rrhos i s ma y i ncl ude a l tered s ympa theti c tone, producti on of ni tri c oxi de
a nd other endogenous va s odi l a tors , a nd enha nced a cti vi ty of humora l fa ctors (eg, gl uca gon).
For s peci fi c di s orders of hepa ti c ci rcul a ti on (eg, Budd-Chi a ri s yndrome), s ee Ch. 29.
Endocrine Abnormalities
Gl ucos e i ntol era nce, hyperi ns ul i ni s m, i ns ul i n res i s ta nce, a nd hypergl uca gonemi a a re often pres ent i n pa ti ents wi th ci rrhos i s ; the el eva ted
i ns ul i n l evel s refl ect decrea s ed hepa ti c degra da ti on ra ther tha n i ncrea s ed s ecreti on, wherea s the oppos i te i s true for hypergl uca gonemi a .
Abnorma l thyroi d functi on tes ts ma y refl ect a l tered hepa ti c ha ndl i ng of thyroi d hormones a nd cha nges i n pl a s ma bi ndi ng protei ns ra ther tha n
thyroi d a bnorma l i ti es .
Sexual effects a re common. Chroni c l i ver di s ea s e commonl y i mpa i rs mens trua ti on a nd ferti l i ty. Ma l es wi th ci rrhos i s , es peci a l l y a l cohol i cs , often
ha ve both hypogona di s m (i ncl udi ng tes ti cul a r a trophy, erecti l e dys functi on, decrea s ed s perma togenes i s ) a nd femi ni za ti on (gynecoma s ti a , fema l e
ha bi tus ). The bi ochemi ca l ba s i s i s not ful l y unders tood. Gona dotropi n res erve of the hypotha l a mi cpi tui ta ry a xi s i s often bl unted. Ci rcul a ti ng
tes tos terone l evel s a re l ow, res ul ti ng ma i nl y from decrea s ed s ynthes i s but a l s o from i ncrea s ed peri phera l convers i on to es trogens . Level s of
es trogens other tha n es tra di ol a re us ua l l y i ncrea s ed, but the rel a ti ons hi p between es trogens a nd femi ni za ti on i s compl ex. Thes e cha nges a re
more preva l ent i n a l cohol i c l i ver di s ea s e tha n i n ci rrhos i s of other eti ol ogi es , s ugges ti ng tha t a l cohol , ra ther tha n l i ver di s ea s e, ma y be the ca us e.
In fa ct, evi dence i ndi ca tes tha t a l cohol i ts el f i s toxi c to the tes tes .
Hematologic Abnormalities
Anemia i s common a mong pa ti ents wi th l i ver di s ea s e. Contri buti ng fa ctors ma y i ncl ude bl ood l os s , fol a te (fol i c a ci d) defi ci ency, hemol ys i s , ma rrow
s uppres s i on by a l cohol , a nd a di rect effect of chroni c l i ver di s ea s e.
Leukopenia a nd thrombocytopenia often a ccompa ny s pl enomega l y i n a dva nced porta l hypertens i on.
Clotting and coagulation abnormalities a re common a nd compl ex. Hepa tocel l ul a r dys functi on a nd i na dequa te a bs orpti on of vi ta mi n K ma y i mpa i r l i ver
s ynthes i s of cl otti ng fa ctors . An a bnorma l PT, dependi ng on the s everi ty of hepa tocel l ul a r dys functi on, ma y res pond to pa rentera l phytona di one
(vi ta mi n K1 ) 5 to 10 mg once/da y for 2 to 3 da ys . Thrombocytopeni a , di s s emi na ted i ntra va s cul a r coa gul a ti on, a nd fi bri nogen a bnorma l i ti es a l s o
contri bute to cl otti ng di s turba nces i n ma ny pa ti ents .
Renal and Electrolyte Abnormalities
Rena l a nd el ectrol yte a bnorma l i ti es a re common, es peci a l l y a mong pa ti ents wi th a s ci tes .
Hypokalemia ma y res ul t from exces s uri na ry K l os s due to i ncrea s ed ci rcul a ti ng a l dos terone, rena l retenti on of a mmoni um i on i n excha nge for K,
s econda ry rena l tubul a r a ci dos i s , or di ureti c thera py. Ma na gement cons i s ts of gi vi ng ora l KCl s uppl ements a nd wi thhol di ng K-wa s ti ng di ureti cs .
Hyponatremia i s common even though the ki dneys ma y a vi dl y reta i n Na (s ee As ci tes on p. 206); i t us ua l l y occurs wi th a dva nced hepa tocel l ul a r
di s ea s e a nd i s di ffi cul t to correct. Rel a ti ve wa ter overl oa d i s more often res pons i bl e tha n tota l body Na depl eti on; K depl eti on ma y a l s o
contri bute. Wa ter res tri cti on a nd K s uppl ements ma y hel p; us e of di ureti cs tha t i ncrea s e free wa ter cl ea ra nce i s controvers i a l . Sa l i ne s ol uti on IV i s
i ndi ca ted onl y i f profound hypona tremi a ca us es s ei zures or i f tota l body Na depl eti on i s s us pected; i t s houl d be a voi ded i n pa ti ents wi th ci rrhos i s
a nd fl ui d retenti on beca us e i t wors ens a s ci tes a nd onl y tempora ri l y i ncrea s es s erum Na l evel s .
Adva nced l i ver fa i l ure ca n a l ter a ci d-ba s e ba l a nce, us ua l l y ca us i ng meta bol i c a l ka l os i s . BUN l evel s a re often l ow beca us e of i mpa i red l i ver
s ynthes i s ; GI bl eedi ng ca us es el eva ti ons beca us e of a n i ncrea s ed enteri c l oa d ra ther tha n rena l i mpa i rment. When GI bl eedi ng el eva tes BUN,
norma l crea ti ni ne va l ues tend to confi rm norma l ki dney functi on.
Renal failure i n l i ver di s ea s e ma y refl ect
Ra re di s orders tha t di rectl y a ffect both the ki dneys a nd the l i ver (eg, ca rbon tetra chl ori de toxi ci ty)
Ci rcul a tory fa i l ure wi th decrea s ed rena l perfus i on, wi th or wi thout fra nk a cute tubul a r necros i s
Functi ona l rena l fa i l ure, often ca l l ed hepa torena l s yndrome
Hepatorenal syndrome: Thi s s yndrome cons i s ts of progres s i ve ol i guri a a nd a zotemi a i n the a bs ence of s tructura l da ma ge to the ki dney; i t us ua l l y
occurs i n pa ti ents wi th ful mi na nt hepa ti ti s or a dva nced ci rrhos i s wi th a s ci tes . Its unknown pa thogenes i s proba bl y i nvol ves extreme va s odi l a ti on
of the s pl a nchni c a rteri a l ci rcul a ti on, l ea di ng to decrea s ed centra l a rteri a l vol ume. Neura l or humora l reducti ons i n renocorti ca l bl ood fl ow
fol l ow, res ul ti ng i n a di mi ni s hed gl omerul a r fi l tra ti on ra te. Low uri na ry Na concentra ti on a nd beni gn s edi ment us ua l l y di s ti ngui s h i t from tubul a r
necros i s , but prerena l a zotemi a ma y be more di ffi cul t to di s ti ngui s h; i n equi voca l ca s es , res pons e to a vol ume l oa d s houl d be a s s es s ed.
Once es ta bl i s hed, rena l fa i l ure due to hepa torena l s yndrome i s us ua l l y ra pi dl y progres s i ve a nd fa ta l (type 1 hepa torena l s yndrome), a l though
s ome ca s es a re l es s s evere, wi th s ta bl e l ow-gra de rena l i ns uffi ci ency (type 2).
Li ver tra ns pl a nta ti on i s the onl y a ccepted trea tment for type 1 hepa torena l s yndrome; tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) a nd
va s ocons tri ctors s how s ome promi s e, but more s tudy i s needed.
The Asymptomatic Patient With Abnormal Laboratory Test Results
Beca us e a mi notra ns fera s es a nd a l ka l i ne phos pha ta s e a re i ncl uded i n commonl y done l a bora tory tes t pa nel s , a bnorma l i ti es a re often detected
i n pa ti ents wi thout s ymptoms or s i gns of l i ver di s ea s e. In s uch pa ti ents , the phys i ci a n s houl d obta i n a hi s tory of expos ure to pos s i bl e l i ver toxi ns ,
i ncl udi ng a l cohol , pres cri pti on a nd nonpres cri pti on drugs , herba l tea s a nd remedi es , a nd occupa ti ona l or other chemi ca l expos ures .
Aminotransferases: Mi l d i s ol a ted el eva ti ons of ALT or AST (< 2 ti mes norma l ) ma y requi re onl y repea t tes ti ng; they res ol ve i n a bout one thi rd of
ca s es . If a bnorma l i ti es a re pres ent i n other l a bora tory tes ts , a re s evere, or pers i s t on s ubs equent tes ti ng, further eva l ua ti on i s i ndi ca ted a s
fol l ows :
Fa tty l i ver s houl d be cons i dered; i t ca n often be recogni zed cl i ni ca l l y (s ee p. 211).
Pa ti ents s houl d be s creened for hepa ti ti s B a nd C (s ee p. 251).
Pa ti ents > 40 s houl d be s creened for hemochroma tos i s (s ee p. 1032).
Pa ti ents < 30 s houl d be s creened for Wi l s on's di s ea s e (s ee p. 51).
Mos t pa ti ents , es peci a l l y young or mi ddl e-a ged women, s houl d be s creened for a utoi mmune di s orders .
Pa ti ents a t ri s k s houl d be s creened for ma l a ri a a nd s chi s tos omi a s i s .
If a t thi s poi nt the res ul ts a re nega ti ve, s creeni ng for 1 -a nti tryps i n defi ci ency (s ee p. 1901) i s i ndi ca ted. If the enti re eva l ua ti on revea l s no ca us e,
l i ver bi ops y ma y be wa rra nted.
Alkaline phosphatase: Is ol a ted el eva ti on of a l ka l i ne phos pha ta s e l evel s i n a n a s ymptoma ti c pa ti ent requi res confi rma ti on of hepa ti c ori gi n by
s howi ng el eva ti on of 5-nucl eoti da s e or -gl uta myl tra ns pepti da s e. If hepa ti c ori gi n i s confi rmed, l i ver i ma gi ng, us ua l l y wi th ul tra s onogra phy or
ma gneti c res ona nce chol a ngi opa ncrea togra phy, i s i ndi ca ted. If no s tructura l a bnorma l i ty i s found on i ma gi ng, i ntra hepa ti c chol es ta s i s i s pos s i bl e
a nd ma y be s ugges ted by a hi s tory of expos ure to drugs or toxi ns . Infi l tra ti ve di s ea s es a nd l i ver meta s ta s es (eg, due to col on ca ncer) s houl d a l s o
be cons i dered. In women, a nti mi tochondri a l a nti body s houl d be obta i ned. Pers i s tent unexpl a i ned el eva ti ons or s us pi ci on of i ntra hepa ti c
chol es ta s i s wa rra nts cons i dera ti on of l i ver bi ops y.
Postoperative Liver Dysfunction
Mi l d l i ver dys functi on s ometi mes occurs a fter ma jor s urgery even i n the a bs ence of preexi s ti ng l i ver di s orders . Thi s dys functi on us ua l l y res ul ts
from hepa ti c i s chemi a or poorl y unders tood effects of a nes thes i a . Pa ti ents wi th preexi s ti ng wel l -compens a ted l i ver di s ea s e (eg, ci rrhos i s wi th
norma l l i ver functi on) us ua l l y tol era te s urgery wel l . However, s urgery ca n i ncrea s e the s everi ty of s ome preexi s ti ng l i ver di s orders ; eg, l a pa rotomy
ma y preci pi ta te a cute l i ver fa i l ure i n a pa ti ent wi th vi ra l or a l cohol i c hepa ti ti s .
Postoperative jaundice: Di a gnos i s of pos topera ti ve ja undi ce requi res l i ver l a bora tory tes ts . Ti mi ng of s ymptoms a l s o a i ds i n di a gnos i s .
Mul ti fa ctori a l mi xed hyperbi l i rubi nemi a i s the mos t common rea s on for pos topera ti ve ja undi ce. It i s ca us ed by i ncrea s ed forma ti on of bi l i rubi n
a nd decrea s ed hepa ti c cl ea ra nce. Thi s di s order mos t often occurs a fter ma jor s urgery or tra uma requi ri ng mul ti pl e tra ns fus i ons . Hemol ys i s ,
s eps i s , res orpti on of hema toma s , a nd bl ood tra ns fus i ons ca n i ncrea s e the bi l i rubi n l oa d; s i mul ta neous l y, hypoxemi a , hepa ti c i s chemi a , a nd
other poorl y unders tood fa ctors i mpa i r hepa ti c functi on. Thi s condi ti on i s us ua l l y ma xi ma l wi thi n a few da ys of opera ti on. Hepa ti c i ns uffi ci ency i s
ra re, a nd hyperbi l i rubi nemi a typi ca l l y res ol ves s l owl y but compl etel y. Li ver l a bora tory tes ts ca n often di fferenti a te mul ti fa ctori a l mi xed
hyperbi l i rubi nemi a from hepa ti ti s . In mul ti fa ctori a l mi xed hyperbi l i rubi nemi a , s evere hyperbi l i rubi nemi a wi th mi l d a mi notra ns fera s e a nd
a l ka l i ne phos pha ta s e el eva ti ons a re common. In hepa ti ti s , a mi notra ns fera s e l evel s a re us ua l l y very hi gh.
Postoperative hepatitis: Is chemi c pos topera ti ve "hepa ti ti s " res ul ts from i ns uffi ci ent l i ver perfus i on, not i nfl a mma ti on. The ca us e i s tra ns i ent
peri opera ti ve hypotens i on or hypoxi a . Typi ca l l y, a mi notra ns fera s e l evel s i ncrea s e ra pi dl y (often > 1000 uni ts /L), but bi l i rubi n i s onl y mi l dl y
el eva ted. Is chemi c hepa ti ti s i s us ua l l y ma xi ma l wi thi n a few da ys of opera ti on a nd res ol ves wi thi n a few da ys .
Ha l otha ne-rel a ted hepa ti ti s ca n res ul t from us e of a nes theti cs conta i ni ng ha l otha ne or rel a ted a gents . It us ua l l y devel ops wi thi n 2 wk, i s often
preceded by fever, a nd i s s ometi mes a ccompa ni ed by a s ki n ra s h a nd eos i nophi l i a .
True pos topera ti ve hepa ti ti s i s now ra re. It us ed to res ul t ma i nl y from tra ns mi s s i on of hepa ti ti s C vi rus duri ng bl ood tra ns fus i on.
Postoperative cholestasis: The mos t common ca us e of pos topera ti ve chol es ta s i s i s extra hepa ti c bi l i a ry obs tructi on due to i ntra -a bdomi na l
compl i ca ti ons or drugs gi ven pos topera ti vel y. Intra hepa ti c chol es ta s i s occa s i ona l l y devel ops a fter ma jor s urgery, es peci a l l y a fter a bdomi na l or
ca rdi ova s cul a r procedures (beni gn pos topera ti ve i ntra hepa ti c chol es ta s i s ). The pa thogenes i s i s unknown, but the condi ti on us ua l l y res ol ves
s l owl y a nd s ponta neous l y. Occa s i ona l l y, pos topera ti ve chol es ta s i s res ul ts from a cute a ca l cul ous chol ecys ti ti s or pa ncrea ti ti s .
Chapter 24. Testing for Hepatic and Biliary Disorders

Introduction
Di a gnos i s of l i ver a nd bi l i a ry s ys tem di s orders ma y i ncl ude l a bora tory tes ts , i ma gi ng tes ts , a nd l i ver bi ops y. Indi vi dua l tes ts , pa rti cul a rl y thos e of
l i ver bi ochemi s try a nd excreti on, often ha ve l i mi ted s ens i ti vi ty a nd s peci fi ci ty. A combi na ti on of tes ts often bes t defi nes the ca us e a nd s everi ty of
di s ea s e. Us eful a l gori thms (eg, Model of End-Sta ge Li ver Di s ea s e [MELD], Chi l d-Pugh s core) ha ve i ncorpora ted cl i ni ca l a nd l a bora tory fea tures to
predi ct s urvi va l i n pa ti ents wi th decompens a ted ci rrhos i s .
Laboratory Tests
La bora tory tes ts a re genera l l y effecti ve for the fol l owi ng:
Detecti ng hepa ti c dys functi on
As s es s i ng the s everi ty of l i ver i njury
Moni tori ng the cours e of l i ver di s ea s es a nd the res pons e to trea tment
Refi ni ng the di a gnos i s
Ma ny tes ts of l i ver bi ochemi s try a nd excretory performa nce a re ca l l ed l i ver functi on tes ts . However, ra ther tha n a s s es s i ng l i ver functi on, s evera l of
thes e tes ts mea s ure l i ver enzymes tha t a re rel ea s ed i nto the bl oods trea m (eg, rel ea s e of a mi notra ns fera s es from i njured l i ver cel l s or of a l ka l i ne
phos pha ta s e due to chol es ta s i s ). Onl y certa i n tes ts a ctua l l y a s s es s l i ver functi on by eva l ua ti ng hepa tobi l i a ry excreti on (eg, bi l i rubi n) or the l i ver's
s yntheti c ca pa bi l i ty (eg, PT, us ua l l y reported a s the INR; a l bumi n).
The mos t us eful l a bora tory tes ts to s creen for l i ver di s orders a re s erum a mi notra ns fera s es (the mos t commonl y us ed l i ver functi on tes ts ),
bi l i rubi n, a nd a l ka l i ne phos pha ta s e. Certa i n pa tterns of bi ochemi ca l a bnorma l i ti es hel p di s ti ngui s h hepa tocel l ul a r i njury from i mpa i red bi l e
excreti on (chol es ta s i s s ee
Ta bl e 24-1). Tes ts tha t detect vi ra l hepa ti ti s , l i ver i nfl a mma ti on, or a l tered i mmunoregul a ti on i ncl ude hepa ti ti s s erol ogi c tes ts (s ee p. 251) a nd
mea s urement of i mmunogl obul i ns , a nti bodi es , a nd a utoa nti bodi es .
A few l a bora tory tes ts a re di a gnos ti c by thems el ves ; they i ncl ude the fol l owi ng:
IgM a nti body to hepa ti ti s A vi rus (a nti -HAV) for a cute hepa ti ti s A
Hepa ti ti s B s urfa ce a nti gen (HBs Ag) for hepa ti ti s B
Anti body to hepa ti ti s C vi rus (a nti -HCV) a nd HCV-RNA for hepa ti ti s C
Anti mi tochondri a l a nti body for pri ma ry bi l i a ry ci rrhos i s
Serum cerul opl a s mi n (reduced) a nd uri na ry copper (el eva ted) for Wi l s on's di s ea s e
Serum 1 -a nti tryps i n for 1 -a nti tryps i n defi ci ency
-Fetoprotei n for hepa tocel l ul a r ca rci noma
Tests for Liver Injury
Aminotransferases: Al a ni ne a mi notra ns fera s e (ALT) a nd a s pa rta te a mi notra ns fera s e (AST) l ea k from da ma ged cel l s ; thus , thes e enzymes a re
s ens i ti ve i ndi ca tors of l i ver i njury. Ma rkedl y hi gh va l ues (> 500 IU/L; norma l , 40 IU/L), whi ch i ndi ca te a cute hepa tocel l ul a r necros i s or i njury,
us ua l l y res ul t from the fol l owi ng:
Acute vi ra l hepa ti ti s
Toxi n- or drug-i nduced hepa ti ti s
Is chemi c hepa ti ti s or hepa ti c i nfa rcti on
Hi gh l evel s conti nue us ua l l y for da ys or, i n vi ra l hepa ti ti s , for weeks . The degree of el eva ti on ma y not refl ect the extent of l i ver i njury. Seri a l
mea s urements better refl ect s everi ty a nd prognos i s tha n does a s i ngl e mea s urement. A fa l l to norma l i ndi ca tes recovery unl es s a ccompa ni ed by
a n i ncrea s e i n bi l i rubi n a nd i n PT or INR (whi ch i ndi ca tes ful mi na nt l i ver fa i l ure). Ful mi na nt l i ver fa i l ure res ul ts i n fewer l i ver cel l s tha t ca n l ea k
enzymes .
Ami notra ns fera s e l evel s ma y a l s o be ma rkedl y hi gh i n the fol l owi ng:
Acute exa cerba ti on of a utoi mmune hepa ti ti s
Rea cti va ti on of chroni c hepa ti ti s B
Acute Budd-Chi a ri s yndrome
Acute fa tty l i ver of pregna ncy
Pa s s a ge of a common duct s tone

Modes t el eva ti ons (300 to 500 IU/L) pers i s t i n chroni c l i ver di s orders (eg, chroni c hepa ti ti s , a l cohol i c hepa ti ti s ) a nd i n bi l i a ry obs tructi on, except
when pa s s a ge of a common duct s tone ca n tra ns i entl y res ul t i n ma rkedl y hi gh l evel s , s ometi mes i nto the thous a nds .
Mi l d i ncrea s es (< 300 IU/L) a re nons peci fi c a nd often pres ent i n di s orders s uch a s
[Table 24-1. Common Pa tterns of La bora tory Tes t Abnorma l i ti es ]
Ci rrhos i s s econda ry to vi ra l hepa ti ti s
Nona l cohol i c fa tty l i ver di s ea s e (NAFLD)
Chol es ta ti c l i ver di s orders
Hepa tocel l ul a r ca ncer
Ami notra ns fera s es ca n be norma l i n certa i n l i ver di s orders , s uch a s
Hemochroma tos i s
Methotrexa te- or a mi oda rone-i nduced l i ver i njury
Chroni c hepa ti ti s C
NAFLD
El eva ted ALT i s s omewha t s peci fi c for l i ver i njury. Beca us e AST i s pres ent i n the hea rt, s kel eta l mus cl e, ki dneys , a nd pa ncrea s , el eva ted AST ma y
refl ect rha bdomyol ys i s or i njury to one of thes e orga ns . In mos t l i ver di s orders , the ra ti o of AST to ALT i s < 1. However, i n a l cohol -rel a ted l i ver
di s ea s e, the ra ti o i s cha ra cteri s ti ca l l y > 2 beca us e pyri doxa l -5-phos pha te i s defi ci ent i n a l cohol i c pa ti ents ; i t i s requi red for ALT s ynthes i s but i s
l es s es s enti a l for AST s ynthes i s . Thi s defi ci ency a l s o expl a i ns why el eva ti ons of ALT a nd AST a re l ow (< 300 IU/L) i n a l cohol i c pa ti ents .
Lactate dehydrogenase: LDH, commonl y i ncl uded i n routi ne a na l ys i s , i s pres ent i n ma ny other ti s s ues a nd i s i ns ens i ti ve a nd nons peci fi c for
hepa tocel l ul a r i njury. LDH i s typi ca l l y el eva ted i n i s chemi c hepa ti ti s a nd ca ncers tha t extens i vel y i nfi l tra te the l i ver.
Tests for Cholestasis
Bilirubin: Bi l i rubi n, the pi gment i n bi l e, i s produced from the brea kdown of heme protei ns , mos tl y from the heme moi ety of hemogl obi n i n
s enes cent RBCs . Unconjuga ted (free) bi l i rubi n i s i ns ol ubl e i n wa ter a nd thus ca nnot be excreted i n uri ne; mos t unconjuga ted bi l i rubi n i s bound to
a l bumi n i n pl a s ma . Bi l i rubi n i s conjuga ted i n the l i ver wi th gl ucuroni c a ci d to form the more wa ter-s ol ubl e bi l i rubi n di gl ucuroni de. Conjuga ted
bi l i rubi n i s then excreted through the bi l i a ry tra ct i nto the duodenum, where i t i s meta bol i zed i nto urobi l i nogens (s ome of whi ch a re rea bs orbed
a nd res ecreted i nto bi l e), then i nto ora nge-col ored urobi l i ns (mos t of whi ch a re el i mi na ted i n feces ). Thes e bi l e pi gments gi ve s tool i ts typi ca l
col or.
Hyperbi l i rubi nemi a res ul ts from one or more of the fol l owi ng:
Increa s ed bi l i rubi n producti on
Decrea s ed l i ver upta ke or conjuga ti on
Decrea s ed bi l i a ry excreti on (s ee p. 212)
Norma l l y, tota l bi l i rubi n i s mos tl y unconjuga ted, wi th va l ues of < 1.2 mg/dL (< 20 mol /L). Fra cti ona ti on mea s ures the proporti on of bi l i rubi n tha t
i s conjuga ted (i e, di rect, s o-ca l l ed beca us e i t i s mea s ured di rectl y, wi thout the need for s ol vents ). Fra cti ona ti on i s mos t hel pful for eva l ua ti ng
neona ta l ja undi ce a nd for eva l ua ti ng el eva ted bi l i rubi n when other l i ver tes t res ul ts a re norma l , s ugges ti ng tha t hepa tobi l i a ry dys functi on i s not
the ca us e.
Unconjugated hyperbilirubinemia (i ndi rect bi l i rubi n fra cti on > 85%) refl ects i ncrea s ed bi l i rubi n producti on (eg, i n hemol ys i s ) or defecti ve l i ver upta ke
or conjuga ti on (eg, i n Gi l bert s yndrome). Such i ncrea s es i n unconjuga ted bi l i rubi n a re us ua l l y < 5 ti mes norma l (to < 6 mg/dL [<100 mol /L]) unl es s
there i s concurrent l i ver i njury.
Conjugated hyperbilirubinemia (di rect bi l i rubi n fra cti on > 50%) res ul ts from decrea s ed bi l e forma ti on or excreti on (chol es ta s i s ). When a s s oci a ted
wi th other l i ver functi on tes t a bnorma l i ti es , a hi gh s erum bi l i rubi n i ndi ca tes hepa tocel l ul a r dys functi on. Serum bi l i rubi n i s s omewha t i ns ens i ti ve
for l i ver dys functi on. However, the devel opment of s evere hyperbi l i rubi nemi a i n pri ma ry bi l i a ry ci rrhos i s , a l cohol i c hepa ti ti s , a nd a cute l i ver
fa i l ure s ugges ts a poor prognos i s .
Bilirubinuria refl ects the pres ence of conjuga ted bi l i rubi n i n uri ne; bi l i rubi n s pi l l s i nto uri ne beca us e bl ood l evel s a re ma rkedl y el eva ted,
i ndi ca ti ng s evere di s ea s e. Unconjuga ted bi l i rubi n i s wa ter i ns ol ubl e a nd bound to a l bumi n a nd s o ca nnot be excreted i n uri ne. Bi l i rubi nuri a ca n
be detected a t the beds i de wi th commerci a l uri ne tes t s tri ps i n a cute vi ra l hepa ti ti s or other hepa tobi l i a ry di s orders , even before ja undi ce
a ppea rs . However, the di a gnos ti c a ccura cy of s uch uri ne tes ts i s l i mi ted. Res ul ts ca n be fa l s el y nega ti ve when the uri ne s peci men ha s been s tored
a l ong ti me, vi ta mi n C ha s been i nges ted, or uri ne conta i ns ni tra tes (eg, due to UTIs ). Si mi l a rl y, i ncrea s es i n urobi l i nogen a re nei ther s peci fi c nor
s ens i ti ve.
Alkaline phosphatase: Increa s ed l evel s of thi s hepa tocyte enzyme s ugges t chol es ta s i s . Res ul ts ma y not be s peci fi c beca us e a l ka l i ne phos pha ta s e
cons i s ts of s evera l i s oenzymes a nd ha s a wi des prea d extra hepa ti c di s tri buti on (eg, i n the pl a centa , the s ma l l i ntes ti ne, WBCs , ki dneys , a nd
pa rti cul a rl y bone).
Al ka l i ne phos pha ta s e l evel s i ncrea s e to 4 ti mes norma l 1 to 2 da ys a fter ons et of bi l i a ry obs tructi on, rega rdl es s of the s i te of obs tructi on. Level s
ma y rema i n el eva ted for s evera l da ys a fter the obs tructi on res ol ves beca us e the ha l f-l i fe of a l ka l i ne phos pha ta s e i s a bout 7 da ys . Increa s es of up
to 3 ti mes norma l occur i n ma ny l i ver di s orders , i ncl udi ng
Hepa ti ti s
Ci rrhos i s
Spa ce-occupyi ng l es i ons (eg, ca rci noma )
Infi l tra ti ve di s orders (eg, a myl oi dos i s , s a rcoi dos i s , TB, meta s ta s es , a bs ces s es )
Syphi l i ti c hepa ti ti s (a l ka l i ne phos pha ta s e ma y be di s proporti ona tel y el eva ted compa red wi th the modes t cha nges i n other l i ver tes ts )
Is ol a ted el eva ti ons (i e, when other l i ver tes t res ul ts a re norma l ) ma y a ccompa ny
Foca l l i ver l es i ons (eg, a bs ces s , tumor)
Pa rti a l or i ntermi ttent bi l e duct obs tructi on (eg, s tone, s tri cture, chol a ngi oca rci noma )
Syphi l i ti c hepa ti ti s
Occa s i ona l l y, i nfi l tra ti ve di s orders
Is ol a ted el eva ti ons a l s o occur i n the a bs ence of a ny a ppa rent l i ver or bi l i a ry di s order, a s i n the fol l owi ng:
Some ca ncers wi thout a ppa rent l i ver i nvol vement (eg, bronchogeni c ca rci noma , Hodgki n l ymphoma , rena l cel l ca rci noma )
After i nges ti on of fa tty mea l s (beca us e of a n enzyme produced i n the s ma l l i ntes ti ne)
Pregna ncy (beca us e of a n enzyme produced i n the pl a centa )
Chi l dren a nd a dol es cents who a re s ti l l growi ng (beca us e of bone growth)
Chroni c rena l fa i l ure (beca us e of a n enzyme produced i n the i ntes ti ne a nd bone)
Level s of -gl uta myl tra ns pepti da s e or 5-nucl eoti da s e, whi ch a re more s peci fi c to the l i ver, ca n di fferenti a te hepa ti c from extra hepa ti c s ources of
a l ka l i ne phos pha ta s e better tha n fra cti ona ti on of a l ka l i ne phos pha ta s e, whi ch i s techni ca l l y di ffi cul t. Al s o, i n otherwi s e a s ymptoma ti c el derl y
peopl e, a n i ncrea s e i n a l ka l i ne phos pha ta s e us ua l l y ori gi na tes i n bone (eg, i n Pa get's di s ea s e) a nd does not requi re further i nves ti ga ti on for
l i ver i njury.
5-Nucleotidase: Increa s es i n l evel s of thi s enzyme a re a s s ens i ti ve a s a l ka l i ne phos pha ta s e for detecti ng chol es ta s i s a nd bi l i a ry obs tructi on but
a re more s peci fi c, a l mos t a l wa ys i ndi ca ti ng hepa tobi l i a ry dys functi on. Beca us e l evel s of a l ka l i ne phos pha ta s e a nd 5-nucl eoti da s e do not a l wa ys
correl a te, one ca n be norma l whi l e the other i s i ncrea s ed.
-Glutamyl transpeptidase (GGT): Level s of thi s enzyme i ncrea s e i n hepa tobi l i a ry dys functi on, es peci a l l y chol es ta s i s , a nd correl a te l oos el y wi th
l evel s of a l ka l i ne phos pha ta s e a nd 5-nucl eoti da s e. Level s do not i ncrea s e beca us e of bone l es i ons , duri ng chi l dhood, or duri ng pregna ncy.
However, a l cohol a nd certa i n drugs (eg, s ome a nti convul s a nts , wa rfa ri n) ca n i nduce hepa ti c mi cros oma l (cytochrome P-450) enzymes , ma rkedl y
i ncrea s i ng GGT a nd thus s omewha t l i mi ti ng i ts s peci fi ci ty.
Tests of Hepatic Synthetic Capacity
PT and INR: PT ma y be expres s ed i n ti me (s ec) or, prefera bl y, a s a ra ti o of the pa ti ent's mea s ured PT to the l a bora tory's control va l ue (INRs ee p.
971). The INR i s more a ccura te tha n PT for moni tori ng a nti coa gul a ti on. PT or INR i s a va l ua bl e mea s ure of the l i ver's a bi l i ty to s ynthes i ze fi bri nogen
a nd vi ta mi n K-dependent cl otti ng fa ctors : fa ctors II (prothrombi n), V, VII, a nd X. Cha nges ca n occur ra pi dl y beca us e s ome of the i nvol ved cl otti ng
fa ctors ha ve s hort bi ol ogi c ha l f-l i ves (eg, 6 h for fa ctor VII). Abnorma l i ti es i ndi ca te s evere hepa tocel l ul a r dys functi on, a n omi nous s i gn i n a cute
l i ver di s orders . In chroni c l i ver di s orders , a n i ncrea s i ng PT or INR i ndi ca tes progres s i on to l i ver fa i l ure. The PT or INR does not i ncrea s e i n mi l d
hepa tocel l ul a r dys functi on a nd i s often norma l i n ci rrhos i s .
A prol onged PT a nd a n a bnorma l INR ca n res ul t from coa gul a ti on di s orders s uch a s a cons umpti ve coa gul opa thy or vi ta mi n K defi ci ency. Fa t
ma l a bs orpti on, i ncl udi ng chol es ta s i s , ca n ca us e vi ta mi n K defi ci ency. In chroni c chol es ta s i s , ma rked hepa tocel l ul a r dys functi on ca n be rul ed out i f
vi ta mi n K repl a cement (10 mg s c) corrects PT by 30% wi thi n 24 h.
Serum proteins: Hepa tocytes s ynthes i ze mos t s erum protei ns , i ncl udi ng - a nd -gl obul i ns , a l bumi n, a nd mos t cl otti ng fa ctors (but not fa ctor VIII,
produced by the va s cul a r endothel i um, or -gl obul i n, produced by B cel l s ). Hepa tocytes a l s o ma ke protei ns tha t a i d i n the di a gnos i s of s peci fi c
di s orders :
1 -Anti tryps i n (a bs ent i n 1 -a nti tryps i n defi ci ency)
Cerul opl a s mi n (reduced i n Wi l s on's di s ea s e)
Tra ns ferri n (s a tura ted wi th i ron i n hemochroma tos i s )

Ferri ti n (grea tl y i ncrea s ed i n hemochroma tos i s )
Thes e protei ns us ua l l y i ncrea s e i n res pons e to da ma ge (eg, i nfl a mma ti on) to va ri ous ti s s ues , s o tha t el eva ti ons ma y not s peci fi ca l l y refl ect l i ver
di s orders .
Serum albumin commonl y decrea s es i n chroni c l i ver di s orders beca us e of a n i ncrea s e i n vol ume of di s tri buti on (eg, due to a s ci tes ), a decrea s e i n
hepa ti c s ynthes i s , or both. Va l ues < 3 g/dL (< 30 g/L) s ugges t decrea s ed s ynthes i s , ca us ed by one of the fol l owi ng:
Adva nced ci rrhos i s (the mos t common ca us e)
Al cohol i s m
Chroni c i nfl a mma ti on
Protei n undernutri ti on
Hypoa l bumi nemi a ca n a l s o res ul t from exces s i ve l os s of a l bumi n from the ki dneys (i e, nephroti c s yndrome), gut (eg, due to protei nl os i ng
ga s troenteropa thi es ), or s ki n (eg, due to burns or exfol i a ti ve derma ti ti s ).
Beca us e a l bumi n ha s a ha l f-l i fe of a bout 20 da ys , s erum l evel s ta ke weeks to i ncrea s e or decrea s e.
Other Laboratory Tests
Ammonia: Ni trogen compounds tha t enter the col on (eg, i nges ted protei n, s ecreted urea ) a re degra ded by res i dent ba cteri a , l i bera ti ng a mmoni a .
The a mmoni a i s then a bs orbed a nd tra ns ported vi a the porta l vei n to the l i ver. The hea l thy l i ver rea di l y cl ea rs the a mmoni a from the porta l vei n
a nd converts i t to gl uta mi ne, whi ch i s meta bol i zed by the ki dneys i nto urea to be excreted. In pa ti ents wi th porta l -s ys temi c s hunti ng, the di s ea s ed
l i ver does not cl ea r a mmoni a , whi ch then enters the s ys temi c ci rcul a ti on, pos s i bl y contri buti ng to porta l -s ys temi c (hepa ti c) encepha l opa thy.
El eva ted a mmoni a l evel s occur i n hepa ti c encepha l opa thy, but l evel s ma y be fa l s el y l ow or hi gh. In a dva nced l i ver di s orders , the fol l owi ng ma y
i ncrea s e a mmoni a l evel s :
Hi gh-protei n mea l s
GI bl eedi ng
Hypoka l emi a
Meta bol i c a l ka l os i s
Certa i n drugs (eg, a l cohol , ba rbi tura tes , di ureti cs , opi oi ds , va l proa te)
Hi gh-dos e chemothera py
Pa rentera l nutri ti on
Rena l i ns uffi ci ency
Extreme mus cl e exerti on a nd mus cl e wa s ti ng
Sa l i cyl a te i ntoxi ca ti on
Shock
Ureteros i gmoi dos tomy
UTI wi th a urea s e-produci ng orga ni s m (eg, Proteus mirabilis)
Beca us e the degree of el eva ti on i n the a mmoni a l evel correl a tes poorl y wi th s everi ty of hepa ti c encepha l opa thy, thi s l evel ha s l i mi ted us eful nes s
i n moni tori ng thera py.
Serum immunoglobulins: In chroni c l i ver di s orders , s erum i mmunogl obul i ns often i ncrea s e. However, el eva ti ons a re not s peci fi c a nd a re us ua l l y not
hel pful cl i ni ca l l y. Level s i ncrea s e s l i ghtl y i n a cute hepa ti ti s , modera tel y i n chroni c a cti ve hepa ti ti s , a nd ma rkedl y i n a utoi mmune hepa ti ti s . The
pa ttern of i mmunogl obul i n el eva ti on a dds l i ttl e i nforma ti on, a l though di fferent i mmunogl obul i ns a re us ua l l y very hi gh i n di fferent di s orders :
IgM i n pri ma ry bi l i a ry ci rrhos i s
IgA i n a l cohol i c l i ver di s ea s e
IgG i n a utoi mmune hepa ti ti s
Antimitochondrial antibodies: Thes e heterogeneous a nti bodi es a re pos i ti ve, us ua l l y i n hi gh ti ters , i n > 95% of pa ti ents wi th pri ma ry bi l i a ry ci rrhos i s .
They a re a l s o occa s i ona l l y pres ent i n the fol l owi ng:
Autoi mmune hepa ti ti s

Drug-i nduced hepa ti ti s
Other a utoi mmune di s orders , s uch a s connecti ve ti s s ue di s orders , mya s theni a gra vi s , a utoi mmune thyroi di ti s , Addi s on's di s ea s e, a nd
a utoi mmune hemol yti c a nemi a
Anti mi tochondri a l a nti bodi es ca n hel p determi ne the ca us e of chol es ta s i s beca us e they a re us ua l l y a bs ent i n extra hepa ti c bi l i a ry obs tructi on a nd
pri ma ry s cl eros i ng chol a ngi ti s .
Other antibodies: Other a nti bodi es ma y hel p i n di a gnos i s of the fol l owi ng:
Autoi mmune hepa ti ti s : Smooth mus cl e a nti bodi es a ga i ns t a cti n, a nti nucl ea r a nti bodi es (ANA) tha t provi de a homogeneous (di ffus e)
fl uores cence, a nd a nti bodi es to l i ver-ki dney mi cros ome type 1 (a nti -LKM1) a re often pres ent.
Pri ma ry bi l i a ry ci rrhos i s : Anti mi tochondri a l a nti body i s key to the di a gnos i s .
Pri ma ry s cl eros i ng chol a ngi ti s : Peri nucl ea r a nti neutrophi l cytopl a s mi c a nti bodi es (p-ANCA) ca n hel p ra i s e the i ndex of s us pi ci on.
Is ol a ted a bnorma l i ti es of a ny of thes e a nti bodi es a re never di a gnos ti c a nd do not el uci da te pa thogenes i s .
-Fetoprotein (AFP): AFP, a gl ycoprotei n norma l l y s ynthes i zed by the yol k s a c i n the embryo a nd then by the feta l l i ver, i s el eva ted i n neona tes a nd
hence the pregna nt mother. AFP decrea s es ra pi dl y duri ng the fi rs t yea r of l i fe, rea chi ng a dul t va l ues (norma l l y, < 10 to 20 ng/mL or < 10 to 20 mg/L
dependi ng on the l a bora tory) by the a ge of 1 yr. An i ncrea s e i n AFP, no ma tter how s ma l l , s houl d prompt cons i dera ti on of pri ma ry hepa tocel l ul a r
ca rci noma (HCC). Serum AFP genera l l y correl a tes wi th tumor s i ze, di fferenti a ti on a nd meta s ta ti c i nvol vement. Beca us e s ma l l tumors ma y produce
l ow l evel s of AFP, i ncrea s i ng va l ues s ugges t the pres ence of HCC, es peci a l l y when tumors a re > 3 cm di a meter. AFP a l s o hel ps predi ct prognos i s .
Mi l d AFP el eva ti ons a l s o occur i n a cute a nd chroni c hepa ti ti s , proba bl y refl ecti ng l i ver regenera ti on; AFP ca n occa s i ona l l y i ncrea s e to 500 ng/mL i n
ful mi na nt hepa ti ti s . Hi gh AFP l evel s ca n occur i n a few other di s orders (eg, embryoni c tera toca rci noma s , hepa tobl a s toma s i n chi l dren, s ome
hepa ti c meta s ta s es from GI tra ct ca ncers , s ome chol a ngi oca rci noma s ), but thes e ci rcums ta nces a re not common a nd us ua l l y ca n be di fferenti a ted
ba s ed on cl i ni ca l a nd hi s topa thol ogi c grounds .
Sens i ti vi ty, s peci fi ci ty, a nd pea k l evel s of AFP i n pa ti ents wi th HCC va ry by popul a ti on, refl ecti ng di fferences i n fa ctors s uch a s hepa ti ti s preva l ence
a nd ethni ci ty. In a rea s wi th a rel a ti vel y l ow preva l ence of hepa ti ti s (eg, North Ameri ca a nd wes tern Europe), AFP cutoff va l ues of 20 ng/mL ha ve a
s ens i ti vi ty of 39 to 64% a nd a s peci fi ci ty of 76 to 91%. However, not a l l HCCs produce AFP. Thus , AFP i s not a n i dea l s creeni ng tes t but does ha ve a
rol e i n detecti ng HCC. Level s exceedi ng norma l (> 20 ng/mL), es peci a l l y when i ncrea s i ng, s trongl y s ugges t HCC. In ci rrhoti c pa ti ents wi th a ma s s a nd
a hi gh va l ue (eg, > 200 ng/mL), the predi cti ve va l ue i s hi gh. The combi ned us e of AFP a nd ul tra s onogra phy currentl y provi des the bes t s urvei l l a nce.
Imaging Tests
Ima gi ng i s es s enti a l for a ccura tel y di a gnos i ng bi l i a ry tra ct di s orders a nd i s i mporta nt for detecti ng foca l l i ver l es i ons (eg, a bs ces s , tumor). It i s
l i mi ted i n detecti ng a nd di a gnos i ng di ffus e hepa tocel l ul a r di s ea s e (eg, hepa ti ti s , ci rrhos i s ).
Ultrasonography: Ul tra s onogra phy, tra di ti ona l l y done tra ns a bdomi na l l y a nd requi ri ng a peri od of fa s ti ng, provi des s tructura l , but not functi ona l ,
i nforma ti on. It i s the l ea s t expens i ve, s a fes t, a nd mos t s ens i ti ve techni que for i ma gi ng the bi l i a ry s ys tem, es peci a l l y the ga l l bl a dder.
Ul tra s onogra phy i s the procedure of choi ce for
Screeni ng for bi l i a ry tra ct a bnorma l i ti es
Eva l ua ti ng the hepa tobi l i a ry tra ct i n pa ti ents wi th ri ght upper qua dra nt a bdomi na l pa i n
Di fferenti a ti ng i ntra hepa ti c from extra hepa ti c ca us es of ja undi ce
Detecti ng l i ver ma s s es
The ki dneys , pa ncrea s , a nd bl ood ves s el s a re a l s o often vi s i bl e on hepa tobi l i a ry ul tra s ounds . Ul tra s onogra phy ca n mea s ure s pl een s i ze a nd thus
hel p di a gnos e s pl enomega l y, whi ch s ugges ts porta l hypertens i on.
Us e of endos copi c ul tra s onogra phy ma y further refi ne the a pproa ches to hepa tobi l i a ry a bnorma l i ti es .
Ul tra s onogra phy ca n be di ffi cul t i n pa ti ents wi th i ntes ti na l ga s or obes i ty a nd i s opera tor-dependent. Endos copi c ul tra s onogra phy i ncorpora tes a n
ul tra s ound tra ns ducer i nto the ti p of a n endos cope a nd thus provi des grea ter i ma ge res ol uti on even when i ntes ti na l ga s i s pres ent.
Gallstones ca s t i ntens e echoes wi th di s ta l a cous ti c s ha dowi ng tha t move wi th gra vi ty. Tra ns a bdomi na l ul tra s onogra phy i s extremel y a ccura te
(s ens i ti vi ty > 95%) for ga l l s tones > 2 mm i n di a meter. Endos copi c ul tra s onogra phy ca n detect s tones a s s ma l l a s 0.5 mm (mi crol i thi a s i s ) i n the
ga l l bl a dder or bi l i a ry s ys tem. Tra ns a bdomi na l a nd endos copi c ul tra s onogra phy ca n a l s o i denti fy bi l i a ry s l udge (a mi xture of pa rti cul a te ma teri a l
a nd bi l e) a s l ow-l evel echoes tha t l a yer i n the dependent porti on of the ga l l bl a dder wi thout a cous ti c s ha dowi ng.
Cholecystitis typi ca l l y ca us es
A thi ckened ga l l bl a dder wa l l (> 3 mm)
Peri chol ecys ti c fl ui d
An i mpa cted s tone i n the ga l l bl a dder neck

Tendernes s on pa l pa ti on of the ga l l bl a dder wi th the ul tra s ound probe (ul tra s onogra phi c Murphy's s i gn)
Extrahepatic obstruction i s i ndi ca ted by di l a ted bi l e ducts . On tra ns a bdomi na l a nd endos copi c ul tra s ounds , bi l e ducts s ta nd out a s echo-free
tubul a r s tructures . The di a meter of the common duct i s norma l l y < 6 mm, i ncrea s es s l i ghtl y wi th a ge, a nd ca n rea ch 10 mm a fter chol ecys tectomy.
Di l a ted ducts a re vi rtua l l y pa thognomoni c for extra hepa ti c obs tructi on i n the a ppropri a te cl i ni ca l s etti ng. Ul tra s onogra phy ca n mi s s ea rl y or
i ntermi ttent obs tructi on tha t does not di l a te the ducts . Tra ns a bdomi na l ul tra s onogra phy ma y not revea l the l evel or ca us e of bi l i a ry obs tructi on
(eg, s ens i ti vi ty for common duct s tones i s < 40%). Endos copi c ul tra s onogra phy ha s a better yi el d.
Focal liver lesions > 1 cm i n di a meter ca n us ua l l y be detected by tra ns a bdomi na l ul tra s onogra phy. In genera l , cys ts a re echo-free; s ol i d l es i ons (eg,
tumors , a bs ces s es ) tend to be echogeni c. Ca rci noma a ppea rs a s a nons peci fi c s ol i d ma s s . Ul tra s onogra phy ha s been us ed to s creen for
hepa tocel l ul a r ca rci noma i n pa ti ents a t hi gh ri s k (eg, wi th chroni c hepa ti ti s B, ci rrhos i s , or hemochroma tos i s ). Beca us e ul tra s onogra phy ca n
l oca l i ze foca l l es i ons , i t ca n be us ed to gui de a s pi ra ti on a nd bi ops y.
Diffuse disorders (eg, ci rrhos i s , s ometi mes fa tty l i ver) ca n be detected wi th ul tra s onogra phy. Ul tra s ound el a s togra phy ca n mea s ure l i ver s ti ffnes s a s
a n i ndex of hepa ti c fi bros i s . In thi s procedure, the tra ns ducer emi ts a vi bra ti on tha t i nduces a n el a s ti c s hea r wa ve. The ra te a t whi ch the wa ve i s
propa ga ted through the l i ver i s mea s ured; l i ver s ti ffnes s s peeds thi s propa ga ti on.
Doppler ultrasonography: Thi s noni nva s i ve method i s us ed to a s s es s di recti on of bl ood fl ow a nd pa tency of bl ood ves s el s a round the l i ver,
pa rti cul a rl y the porta l vei n. Cl i ni ca l us es i ncl ude
Detecti ng porta l hypertens i on, (eg, i ndi ca ted by s i gni fi ca nt col l a tera l fl ow a nd the di recti on of fl ow)
As s es s i ng the pa tency of l i ver s hunts (eg, s urgi ca l portoca va l , percuta neous tra ns hepa ti c)
Eva l ua ti ng porta l vei n pa tency before l i ver tra ns pl a nta ti on a nd detecti ng hepa ti c a rtery thrombos i s a fter tra ns pl a nta ti on
Detecti ng unus ua l va s cul a r s tructures (eg, ca vernous tra ns forma ti on of the porta l vei n)
As s es s i ng tumor va s cul a ri ty before s urgery
CT: CT i s commonl y us ed to i denti fy hepa ti c ma s s es , pa rti cul a rl y s ma l l meta s ta s es , wi th a n a ccura cy of a bout 80%. It i s cons i dered the mos t
a ccura te i ma gi ng techni que. CT wi th IV contra s t i s a ccura te for di a gnos i ng ca vernous hema ngi oma s of the l i ver a s wel l a s di fferenti a ti ng them
from other a bdomi na l ma s s es . Nei ther obes i ty nor i ntes ti na l ga s obs cures CT i ma ges . CT ca n detect fa tty l i ver a nd the i ncrea s ed hepa ti c dens i ty
tha t occurs wi th i ron overl oa d. CT i s l es s hel pful tha n ul tra s onogra phy i n i denti fyi ng bi l i a ry obs tructi on but often provi des the bes t a s s es s ment of
the pa ncrea s .
Cholescintigraphy: After pa ti ents fa s t, a n IV techneti um-l a bel ed i mi nodi a ceti c compound (eg, hydroxy or di i s opropyl i mi nodi a ceti c a ci d [HIDA or
DISIDA]) i s i njected; thes e s ubs ta nces a re ta ken up by the l i ver a nd excreted i n bi l e, then enter the ga l l bl a dder.
In a cute ca l cul ous chol ecys ti ti s , whi ch i s us ua l l y ca us ed by i mpa cti on of a s tone i n the cys ti c duct, the ga l l bl a dder does not a ppea r on a
s ci nti gra phi c s ca n beca us e the ra di onucl i de ca nnot enter the ga l l bl a dder. Such nonvi s ua l i za ti on i s di a gnos ti ca l l y qui te a ccura te (except for fa l s epos i ti ve res ul ts i n s ome cri ti ca l l y i l l pa ti ents ). However, chol es ci nti gra phy i s ra rel y needed cl i ni ca l l y to di a gnos e a cute chol ecys ti ti s .
If a ca l cul ous chol ecys ti ti s i s s us pected, the ga l l bl a dder i s s ca nned before a nd a fter a dmi ni s tra ti on of chol ecys toki ni n (us ed to i ni ti a te
ga l l bl a dder contra cti on). The decrea s e i n s ci nti gra phi c counts i ndi ca tes the ga l l bl a dder ejecti on fra cti on. Reduced emptyi ng, mea s ured a s the
ejecti on fra cti on, s ugges ts a ca l cul ous chol ecys ti ti s .
Chol es ci nti gra phy a l s o detects bi l e l ea ks (eg, a fter s urgery or tra uma ) a nd a na tomi c a bnorma l i ti es (eg, congeni ta l chol edocha l cys ts ,
chol edochoenteri c a na s tomos es ). After chol ecys tectomy, chol es ci nti gra phy ca n qua nti ta te bi l i a ry dra i na ge; bi l i a ry dra i na ge hel ps i denti fy
s phi ncter of Oddi dys functi on.
Radionuclide liver scanning: Ul tra s onogra phy a nd CT ha ve l a rgel y s uppl a nted ra di onucl i de s ca nni ng, whi ch ha d been us ed to di a gnos e di ffus e l i ver
di s orders a nd ma s s l es i ons of the l i ver. Ra di onucl i de s ca nni ng s hows the di s tri buti on of a n i njected ra di oa cti ve tra cer, us ua l l y techneti um ( 99mTc
s ul fur col l oi d), whi ch di s tri butes uni forml y wi thi n the norma l l i ver. Spa ce-occupyi ng l es i ons > 4 cm, s uch a s l i ver cys ts , a bs ces s es , meta s ta s es , a nd
tumors , a ppea r a s defects . Di ffus e l i ver di s orders (eg, ci rrhos i s , hepa ti ti s ) decrea s e l i ver upta ke of the tra cer, wi th more a ppea ri ng i n the s pl een
a nd bone ma rrow. In hepa ti c vei n obs tructi on (Budd-Chi a ri s yndrome), l i ver upta ke i s decrea s ed except i n the ca uda te l obe beca us e i ts dra i na ge
i nto the i nferi or vena ca va i s pres erved.
Plain x-ray of the abdomen: Pl a i n x-ra ys a re not us ua l l y us eful for di a gnos i s of hepa tobi l i a ry di s orders . They a re i ns ens i ti ve for ga l l s tones unl es s
the ga l l s tones a re ca l ci fi ed a nd l a rge. Pl a i n x-ra ys ca n detect a ca l ci fi ed (porcel a i n) ga l l bl a dder. Ra rel y, i n gra vel y i l l pa ti ents , x-ra ys s how a i r i n
the bi l i a ry tree, whi ch s ugges ts emphys ema tous chol a ngi ti s .
MRI: MRI i ma ges bl ood ves s el s (wi thout us i ng contra s t), ducts , a nd hepa ti c ti s s ues . Its cl i ni ca l us es a re s ti l l evol vi ng. MRI i s s uperi or to CT a nd
ul tra s onogra phy for di a gnos i ng di ffus e l i ver di s orders (eg, fa tty l i ver, hemochroma tos i s ) a nd for cl a ri fyi ng s ome foca l defects (eg, hema ngi oma s ).
MRI a l s o s hows bl ood fl ow a nd therefore compl ements Doppl er ul tra s onogra phy a nd CT a ngi ogra phy i n the di a gnos i s of va s cul a r a bnorma l i ti es
a nd i n va s cul a r ma ppi ng before l i ver tra ns pl a nta ti on.
Ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP) i s more s ens i ti ve tha n CT or ul tra s onogra phy i n di a gnos i ng common bi l e duct
a bnorma l i ti es , pa rti cul a rl y s tones . Its i ma ges of the bi l i a ry s ys tem a nd pa ncrea ti c ducts a re compa ra bl e to thos e obta i ned wi th ERCP a nd
percuta neous tra ns hepa ti c chol a ngi ogra phy, whi ch a re more i nva s i ve. Thus , MRCP i s a us eful s creeni ng tool when bi l i a ry obs tructi on i s s us pected
a nd before thera peuti c ERCP (eg, for s i mul ta neous i ma gi ng a nd s tone remova l ) i s done.
ERCP: ERCP combi nes endos copy through the s econd porti on of the duodenum wi th contra s t i ma gi ng of the bi l i a ry a nd pa ncrea ti c ducts . The pa pi l l a
of Va ter i s ca nnul a ted through a n endos cope pl a ced i n the des cendi ng duodenum, a nd the pa ncrea ti c a nd bi l i a ry ducts a re then i njected wi th a
contra s t a gent.
ERCP provi des deta i l ed i ma ges of much of the upper GI tra ct a nd the peri a mpul l a ry a rea , bi l i a ry tra ct, a nd pa ncrea s . ERCP ca n a l s o be us ed to
obta i n ti s s ue for bi ops y. ERCP i s the bes t tes t for di a gnos i s of a mpul l a ry ca ncers . ERCP i s a s a ccura te a s endos copi c ul tra s onogra phy for di a gnos i s
of common duct s tones . Beca us e i t i s i nva s i ve, ERCP i s us ed more for trea tment (i ncl udi ng s i mul ta neous di a gnos i s a nd trea tment) tha n for
di a gnos i s a l one. ERCP i s the procedure of choi ce for trea ti ng bi l i a ry a nd pa ncrea ti c obs tructi ng l es i ons , a s for
Remova l of bi l e duct s tones
Stenti ng of s tri ctures (i nfl a mma tory or ma l i gna nt)
Sphi ncterotomy (eg, for s phi ncter of Oddi dys functi on)
Morbi di ty from a di a gnos ti c ERCP wi th onl y i njecti on of contra s t ma teri a l i s a bout 1%. Addi ng s phi ncterotomy ra i s es morbi di ty to 4 to 9% (ma i nl y
due to pa ncrea ti ti s a nd bl eedi ng). ERCP wi th ma nometry to mea s ure s phi ncter of Oddi pres s ure ca us es pa ncrea ti ti s i n up to 25% of pa ti ents .
Percutaneous transhepatic cholangiography (PTC): Wi th fl uoros copi c or ul tra s ound gui da nce, the l i ver i s punctured wi th a needl e, the peri phera l
i ntra hepa ti c bi l e duct s ys tem i s ca nnul a ted a bove the common hepa ti c duct, a nd a contra s t a gent i s i njected.
PTC i s hi ghl y a ccura te i n di a gnos i ng bi l i a ry di s orders a nd ca n be thera peuti c (eg, decompres s i on of the bi l i a ry s ys tem, i ns erti on of a n
endopros thes i s ). However, ERCP i s us ua l l y preferred beca us e PTC ca us es more compl i ca ti ons (eg, s eps i s , bl eedi ng, bi l e l ea ks ).
Operative cholangiography: A contra s t a gent i s di rectl y i njected duri ng l a pa rotomy to i ma ge the bi l e duct s ys tem.
Opera ti ve chol a ngi ogra phy i s i ndi ca ted when ja undi ce occurs a nd noni nva s i ve procedures a re equi voca l , s ugges ti ng common duct s tones . The
procedure ca n be fol l owed by common duct expl ora ti on for remova l of bi l i a ry s tones . Techni ca l di ffi cul ti es ha ve l i mi ted i ts us e, pa rti cul a rl y duri ng
l a pa ros copi c chol ecys tectomy.
Liver Biopsy
Li ver bi ops y provi des hi s tol ogi c i nforma ti on a bout l i ver s tructure a nd evi dence of l i ver i njury (type a nd degree, a ny fi bros i s ); thi s i nforma ti on ca n
be es s enti a l not onl y to di a gnos i s but a l s o to s ta gi ng, prognos i s , a nd ma na gement. Al though onl y a s ma l l core of ti s s ue i s obta i ned, i t i s us ua l l y
repres enta ti ve, even for foca l l es i ons .
Li ver bi ops y i s us ua l l y done percuta neous l y a t the beds i de or wi th ul tra s ound gui da nce. Ul tra s ound gui da nce i s preferred beca us e i ts
compl i ca ti on ra te i s s l i ghtl y l ower a nd i t provi des opportuni ty to vi s ua l i ze the l i ver a nd ta rget foca l l es i ons .
Indications: Genera l l y, bi ops y i s i ndi ca ted for s us pected l i ver a bnorma l i ti es tha t a re not i denti fi ed by l es s i nva s i ve methods or tha t requi re
hi s topa thol ogy for s ta gi ng (s ee
Ta bl e 24-2). Bi ops y i s es peci a l l y va l ua bl e
[Table 24-2. Indi ca ti ons for Li ver Bi ops y*]
for detecti ng TB or other gra nul oma tous i nfi l tra ti ons a nd for cl a ri fyi ng gra ft probl ems (i s chemi c i njury, rejecti on, bi l i a ry tra ct di s orders , vi ra l
hepa ti ti s ) a fter l i ver tra ns pl a nta ti on. Seri a l bi ops i es , commonl y done over yea rs , ma y be neces s a ry to moni tor di s ea s e progres s i on.
Gros s exa mi na ti on a nd hi s topa thol ogy a re often defi ni ti ve. Cytol ogy (fi ne-needl e a s pi ra ti on), frozen s ecti on, a nd cul ture ma y be us eful for
s el ected pa ti ents . Meta l content (eg, copper i n s us pected Wi l s on's di s ea s e, i ron i n hemochroma tos i s ) ca n be mea s ured i n the bi ops y s peci men.
Li mi ta ti ons of l i ver bi ops y i ncl ude
Sa mpl i ng error
Occa s i ona l errors or uncerta i nty i n ca s es of chol es ta s i s
Need for a s ki l l ed hi s topa thol ogi s t (s ome pa thol ogi s ts ha ve l i ttl e experi ence wi th needl e s peci mens )
Contraindications: Abs ol ute contra i ndi ca ti ons to l i ver bi ops y i ncl ude
Pa ti ent's i na bi l i ty to rema i n s ti l l a nd to ma i nta i n bri ef expi ra ti on for the procedure
Sus pected va s cul a r l es i on (eg, hema ngi oma )
Bl eedi ng tendency (eg, INR > 1.2 des pi te recei vi ng vi ta mi n K, bl eedi ng ti me > 10 mi n)
Severe thrombocytopeni a (< 50,000/mL)
Rel a ti ve contra i ndi ca ti ons i ncl ude profound a nemi a , peri toni ti s , ma rked a s ci tes , hi gh-gra de bi l i a ry obs tructi on, a nd a s ubphreni c or ri ght pl eura l
i nfecti on or effus i on. Nonethel es s , percuta neous l i ver bi ops y i s s uffi ci entl y s a fe to be done on a n outpa ti ent ba s i s . Morta l i ty i s 0.01%. Ma jor
compl i ca ti ons (eg, i ntra -a bdomi na l hemorrha ge, bi l e peri toni ti s , l a cera ted l i ver) devel op i n a bout 2% of pa ti ents . Compl i ca ti ons us ua l l y become
evi dent wi thi n 3 to 4 hthe recommended peri od for moni tori ng pa ti ents .
Other routes: Tra ns jugul a r venous bi ops y of the l i ver i s more i nva s i ve tha n the percuta neous route; i t i s res erved for pa ti ents wi th a s evere
coa gul opa thy. The procedure i nvol ves ca nnul a ti ng the ri ght i nterna l jugul a r vei n a nd pa s s i ng a ca theter through the i nferi or vena ca va i nto the
hepa ti c vei n. A fi ne needl e i s then a dva nced through the hepa ti c vei n i nto the l i ver. Bi ops y i s s ucces s ful i n > 95% of pa ti ents . Compl i ca ti on ra te i s
l ow; 0.2% bl eed from puncture of the l i ver ca ps ul e.
Occa s i ona l l y, l i ver bi ops y i s done duri ng s urgery (eg, l a pa ros copy); a l a rger, more ta rgeted ti s s ue s a mpl e ca n then be obta i ned.
Chapter 25. Drugs and the Liver

Introduction
Intera cti on between drugs a nd the l i ver ca n be ca tegori zed a s fol l ows :
Effects of l i ver di s ea s e on drug meta bol i s m
Li ver i njury ca us ed by drugs
Effects of hepa ti c drug meta bol i s m (eg, i nducti on of hepa ti c enzymes , s ee p. 3177)
The number of pos s i bl e i ntera cti ons i s va s t.
Effects of Liver Disease on Drug Metabolism
Li ver di s ea s e ma y ha ve compl ex effects on drug cl ea ra nce, bi otra ns forma ti on, a nd pha rma coki neti cs . Pa thogeneti c fa ctors i ncl ude a l tera ti ons i n
i ntes ti na l a bs orpti on, pl a s ma protei n bi ndi ng, hepa ti c extra cti on ra ti o, l i ver bl ood fl ow, porta l -s ys temi c s hunti ng, bi l i a ry excreti on, enterohepa ti c
ci rcul a ti on, a nd rena l cl ea ra nce. Someti mes a l tera ti ons i ncrea s e l evel s of bi oa va i l a bl e drug, ca us i ng norma l drug dos es to ha ve toxi c effects .
However, l evel s a nd effects for a n i ndi vi dua l drug a re unpredi cta bl e a nd do not correl a te wel l wi th the type of l i ver i njury, i ts s everi ty, or l i ver
functi on tes t res ul ts . Thus , no genera l rul es a re a va i l a bl e for modi fyi ng drug dos a ge i n pa ti ents wi th l i ver di s ea s e.
Cl i ni ca l effects ca n va ry i ndependent of drug bi oa va i l a bi l i ty, es peci a l l y i n chroni c l i ver di s ea s e; eg, cerebra l s ens i ti vi ty to opi oi ds a nd s eda ti ves i s
often enha nced i n pa ti ents wi th chroni c l i ver di s ea s e. Thus , s eemi ngl y s ma l l dos es of thes e drugs gi ven to ci rrhoti c pa ti ents ma y preci pi ta te
encepha l opa thy. The mecha ni s m of thi s effect proba bl y i nvol ves a l tera ti ons i n cerebra l drug receptors .
Advers e drug rea cti ons do not a ppea r to be more l i kel y i n pa ti ents wi th a dva nced l i ver di s ea s e; however, s uch pa ti ents ma y tol era te a ny hepa ti c
a dvers e effects of drugs l es s wel l .
Liver Injury Caused by Drugs
Ma ny drugs (eg, s ta ti ns ) commonl y ca us e a s ymptoma ti c el eva ti on of hepa ti c enzymes (ALT, AST, a l ka l i ne phos pha ta s e). However, cl i ni ca l l y
s i gni fi ca nt l i ver i njury (eg, wi th ja undi ce, a bdomi na l pa i n, or pruri tus ) or i mpa i red l i ver functi oni e, res ul ti ng i n defi ci ent protei n s ynthes i s (eg,
wi th prol onged PT or wi th hypoa l bumi nemi a )i s ra re.
The term drug-i nduced l i ver i njury (DILI) ma y be us ed to mea n cl i ni ca l l y s i gni fi ca nt l i ver i njury or a l l (i ncl udi ng a s ymptoma ti c) l i ver i njury. DILI
i ncl udes i njury ca us ed by medi ci na l herbs , pl a nts , a nd nutri ti ona l s uppl ements a s wel l a s drugs .
Pathophysiology
The pa thophys i ol ogy of DILI va ri es dependi ng on the drug (or other hepa totoxi n) a nd, i n ma ny ca s es , i s not enti rel y unders tood. Drug-i nduced
i njury mecha ni s ms i ncl ude cova l ent bi ndi ng of the drug to cel l ul a r protei ns res ul ti ng i n i mmune i njury, i nhi bi ti on of cel l meta bol i c pa thwa ys ,
bl ocka ge of cel l ul a r tra ns port pumps , i nducti on of a poptos i s , a nd i nterference wi th mi tochondri a l functi on.
In genera l , the fol l owi ng a re thought to i ncrea s e ri s k of DILI:
Age 18 yr
Obes i ty
Pregna ncy
Concomi ta nt a l cohol cons umpti on
Geneti c pol ymorphi s ms (i ncrea s i ngl y recogni zed)
Patterns of liver injury: DILI ca n be predi cta bl e (when i njury us ua l l y occurs s hortl y a fter expos ure a nd i s dos e-rel a ted) or unpredi cta bl e (when i njury
devel ops a fter a peri od of l a tency a nd ha s no rel a ti on to dos e). Predi cta bl e DILI (commonl y, a ceta mi nophen-i nduced) i s a common ca us e of a cute
ja undi ce a nd a cute l i ver fa i l ure i n the US. Unpredi cta bl e DILI i s a ra re ca us e of s evere l i ver di s ea s e. Subcl i ni ca l DILI ma y be underreported.
Bi ochemi ca l l y, 3 types of l i ver i njury a re genera l l y noted (s ee
Ta bl e 25-1):
Hepatocellular: Hepa tocel l ul a r hepa totoxi ci ty genera l l y ma ni fes ts a s ma l a i s e a nd
[Table 25-1. Potenti a l l y Hepa totoxi c Drugs ]
ri ght upper qua dra nt a bdomi na l pa i n, a s s oci a ted wi th ma rked el eva ti on i n a mi notra ns fera s e l evel s (ALT, AST, or both), whi ch ma y be fol l owed
by hyperbi l i rubi nemi a i n s evere ca s es . Hyperbi l i rubi nemi a i n thi s s etti ng i s known a s hepa tocel l ul a r ja undi ce a nd, a ccordi ng to Hy's l a w, i s
a s s oci a ted wi th morta l i ty ra tes a s hi gh a s 50%. If hepa tocel l ul a r l i ver i njury i s a ccompa ni ed by ja undi ce, i mpa i red hepa ti c s ynthes i s , a nd
encepha l opa thy, cha nce of s ponta neous recovery i s l ow, a nd l i ver tra ns pl a nta ti on s houl d be cons i dered. Thi s type of i njury ca n res ul t from
drugs s uch a s a ceta mi nophen a nd i s oni a zi d.
Cholestatic: Chol es ta ti c hepa totoxi ci ty i s cha ra cteri zed by devel opment of pruri tus a nd ja undi ce a ccompa ni ed by ma rked el eva ti on of s erum
a l ka l i ne phos pha ta s e l evel s . Us ua l l y, thi s type of i njury i s l es s s eri ous tha n s evere hepa tocel l ul a r s yndromes , but recovery ma y be protra cted.
Subs ta nces known to l ea d to thi s type of i njury i ncl ude a moxi ci l l i n/cl a vul a na te a nd chl orproma zi ne. Ra rel y, chol es ta ti c hepa totoxi ci ty l ea ds to
chroni c l i ver di s ea s e a nd va ni s hi ng bi l e duct s yndrome (progres s i ve des tructi on of i ntra hepa ti c bi l e ducts ).
Mixed: In thes e cl i ni ca l s yndromes , nei ther a mi notra ns fera s e nor a l ka l i ne phos pha ta s e el eva ti ons a re cl ea rl y predomi na nt. Symptoms ma y a l s o
be mi xed. Drugs s uch a s phenytoi n ca n ca us e thi s type of i njury.
Diagnosis
Identi fi ca ti on of cha ra cteri s ti c pa tterns of l a bora tory a bnorma l i ti es
Excl us i on of other ca us es
Pres enta ti on va ri es wi del y, ra ngi ng from a bs ent or nons peci fi c s ymptoms (eg, ma l a i s e, na us ea , a norexi a ) to ja undi ce, i mpa i red hepa ti c s ynthes i s ,
a nd encepha l opa thy. Ea rl y recogni ti on of DILI i mproves prognos i s .
Identi fi ca ti on of a potenti a l hepa totoxi n a nd a pa ttern of l i ver tes t a bnorma l i ti es tha t i s cha ra cteri s ti c of the s ubs ta nce (i ts s i gna ture) ma ke the
di a gnos i s l i kel y.
Beca us e there i s no confi rma tory di a gnos ti c tes t, other ca us es of l i ver di s ea s e, es peci a l l y vi ra l , bi l i a ry, a l cohol i c, a utoi mmune, a nd meta bol i c
ca us es , need to be excl uded. Drug recha l l enge, a l though i t ca n s trengthen evi dence for the di a gnos i s , s houl d us ua l l y be a voi ded. Sus pected ca s es
of DILI s houl d be reported to MedWa tch (the FDA's a dvers e drug rea cti on moni tori ng progra m).
Treatment
Ea rl y drug wi thdra wa l
Ma na gement empha s i zes drug wi thdra wa l , whi ch, i f done ea rl y, us ua l l y res ul ts i n recovery. In s evere ca s es , cons ul ta ti on wi th a s peci a l i s t i s
i ndi ca ted, es peci a l l y i f pa ti ents ha ve hepa tocel l ul a r ja undi ce a nd i mpa i red l i ver functi on, beca us e l i ver tra ns pl a nta ti on ma y be requi red.
Anti dotes for DILI a re a va i l a bl e for onl y a few hepa totoxi ns ; s uch a nti dotes i ncl ude N-a cetyl cys tei ne for a ceta mi nophen toxi ci ty a nd s i l yma ri n or
peni ci l l i n for Amanita phalloides toxi ci ty.
Prevention
Efforts to a voi d DILI begi n duri ng the drug devel opment proces s , a l though a ppa rent s a fety i n s ma l l precl i ni ca l tri a l s does not ens ure eventua l
s a fety of the drug a fter i t i s i n wi des prea d us e. Pos tma rketi ng s urvei l l a nce, a l though often vol unta ry i n the US, ca n ca l l a ttenti on to potenti a l l y
hepa totoxi c drugs . Routi ne moni tori ng of l i ver enzymes ha s not been s hown to decrea s e the i nci dence of hepa totoxi ci ty. Us e of
pha rma cogenomi cs ma y a l l ow ta i l ori ng of drug us e a nd a voi da nce of potenti a l toxi ci ti es i n s us cepti bl e pa ti ents .
Chapter 26. Alcoholic Liver Disease

Al cohol cons umpti on i s hi gh i n mos t Wes tern countri es . In the US, > 10% of peopl e a bus e or a re dependent on a l cohol . The ma l e:fema l e ra ti o i s
a bout 2:1. Di s orders tha t occur i n a l cohol a bus ers , often i n s equence, i ncl ude
Fa tty l i ver (i n > 90%)
Al cohol i c hepa ti ti s (i n 10 to 35%)
Ci rrhos i s (i n 10 to 20%)
Hepa tocel l ul a r ca rci noma ma y a l s o devel op, es peci a l l y i n a s s oci a ti on wi th i ron a ccumul a ti on.
Risk Factors
The ma i n ca us a ti ve fa ctors i n a l cohol i c l i ver di s ea s e a re
Qua nti ty a nd dura ti on of a l cohol us e (us ua l l y > 8 yr)
Sex
Geneti c a nd meta bol i c tra i ts
Nutri ti ona l s ta tus
Quantity of alcohol: Among s us cepti bl e peopl e, a l i nea r correl a ti on genera l l y exi s ts between the a mount a nd dura ti on of a l cohol us e a nd the
devel opment of l i ver di s ea s e.
Al cohol content i s es ti ma ted to be the bevera ge vol ume (i n mL) mul ti pl i ed by i ts percenta ge of a l cohol . For exa mpl e, the a l cohol content of 40 mL
of a n 80-proof (40% a l cohol ) bevera ge i s 16 mL by vol ume. Ea ch mL conta i ns a bout 0.79 g of a l cohol . Al though va l ues ca n va ry, the percenta ge of
a l cohol a vera ges 2 to 7% for mos t beers a nd 10 to 15% for mos t wi nes . Thus , a 12-oz gl a s s of beer conta i ns a bout 3 to 10 g of a l cohol , a nd a n 8-oz
gl a s s of wi ne conta i ns a bout 10 to 15 g.
Ri s k i ncrea s es ma rkedl y for men who dri nk > 40 g, pa rti cul a rl y > 80 g, of a l cohol /da y for > 10 yr (eg, 3 to 6 ca ns of beer, 3 to 6 s hots of ha rd l i quor, 4
to 8 gl a s s es of wi ne). For ci rrhos i s to devel op, cons umpti on mus t us ua l l y be > 80 g/da y for > 10 yr. If cons umpti on exceeds 230 g/da y for 20 yr, ri s k of
ci rrhos i s i s a bout 50%. But onl y s ome chroni c a l cohol a bus ers devel op l i ver di s ea s e. Thus , va ri a ti ons i n a l cohol i nta ke do not ful l y expl a i n
va ri a ti ons i n s us cepti bi l i ty, i ndi ca ti ng tha t other fa ctors a re i nvol ved.
Sex: Women a re more s us cepti bl e to a l cohol i c l i ver di s ea s e, even a fter a djus tment for body s i ze. Women requi re onl y 20 to 40 g of a l cohol to be a t
ri s kha l f of tha t for men. Ri s k i n women ma y be i ncrea s ed beca us e they ha ve l es s a l cohol dehydrogena s e i n thei r ga s tri c mucos a ; thus , fi rs t-pa s s
oxi da ti on of a l cohol i s decrea s ed.
Genetic factors: Al cohol i c l i ver di s ea s e often runs i n fa mi l i es , s ugges ti ng geneti c fa ctors (eg, defi ci ency of cytopl a s mi c enzymes tha t el i mi na te
a l cohol ).
Nutritional status: Undernutri ti on, pa rti cul a rl y protei n-energy undernutri ti on, i ncrea s es s us cepti bi l i ty, a s does a di et hi gh i n uns a tura ted fa t a nd
obes i ty.
Other factors: Other ri s k fa ctors i ncl ude i ron a ccumul a ti on i n the l i ver (not neces s a ri l y rel a ted to i ron i nta ke) a nd concomi ta nt hepa ti ti s C.
Pathophysiology
Alcohol absorption and metabolism: Al cohol (etha nol ) i s rea di l y a bs orbed from the s toma ch, but mos t i s a bs orbed from the s ma l l i ntes ti ne. Al cohol
ca nnot be s tored. A s ma l l a mount i s degra ded i n tra ns i t through the ga s tri c mucos a , but mos t i s ca ta bol i zed i n the l i ver, pri ma ri l y by a l cohol
dehydrogena s e (ADH) but a l s o by cytochrome P-450 2E1 (CYP2E1) a nd the mi cros oma l enzyme oxi da ti on s ys tem (MEOS).
Meta bol i s m vi a the ADH pa thwa y i nvol ves the fol l owi ng:
ADH, a cytopl a s mi c enzyme, oxi di zes a l cohol i nto a ceta l dehyde. Geneti c pol ymorphi s ms i n ADH a ccount for s ome i ndi vi dua l di fferences i n bl ood
a l cohol l evel s a fter the s a me a l cohol i nta ke but not i n s us cepti bi l i ty to a l cohol i c l i ver di s ea s e.
Aceta l dehyde dehydrogena s e (ALDH), a mi tochondri a l enzyme, then oxi di zes a ceta l dehyde to a ceta te. Chroni c a l cohol cons umpti on enha nces
a ceta te forma ti on. As i a ns , who ha ve l ower l evel s of ALDH, a re more s us cepti bl e to toxi c a ceta l dehyde effects (eg, fl us hi ng); the effects a re
s i mi l a r to thos e of di s ul fi ra m, whi ch i nhi bi ts ALDH.
Thes e oxi da ti ve rea cti ons genera te hydrogen, whi ch converts ni coti na mi de-a deni ne di nucl eoti de (NAD) to i ts reduced form (NADH), i ncrea s i ng
the redox potenti a l (NADH/NAD) i n the l i ver.
The i ncrea s ed redox potenti a l i nhi bi ts fa tty a ci d oxi da ti on a nd gl uconeogenes i s , promoti ng fa t a ccumul a ti on i n the l i ver.
Chroni c a l cohol i s m i nduces the MEOS (ma i nl y i n endopl a s mi c reti cul um), i ncrea s i ng i ts a cti vi ty. The ma i n enzyme i nvol ved i s CYP2E1. When
i nduced, the MEOS pa thwa y ca n a ccount for 20% of a l cohol meta bol i s m. Thi s pa thwa y genera tes ha rmful rea cti ve O2 s peci es , i ncrea s i ng oxi da ti ve
s tres s a nd forma ti on of O2 -free ra di ca l s .
Hepatic fat accumulation: Fa t (tri gl yceri des ) a ccumul a tes throughout the hepa tocytes for the fol l owi ng rea s ons :
Export of fa t from the l i ver i s decrea s ed beca us e hepa ti c fa tty a ci d oxi da ti on a nd l i poprotei n producti on decrea s e.
Input of fa t i s i ncrea s ed beca us e the decrea s e i n hepa ti c fa t export i ncrea s es peri phera l l i pol ys i s a nd tri gl yceri de s ynthes i s , res ul ti ng i n
hyperl i pi demi a .
Hepa ti c fa t a ccumul a ti on ma y predi s pos e to s ubs equent oxi da ti ve da ma ge.
Endotoxins in the gut: Al cohol cha nges gut permea bi l i ty, i ncrea s i ng a bs orpti on of endotoxi ns rel ea s ed by ba cteri a i n the gut. In res pons e to the
endotoxi ns (whi ch the i mpa i red l i ver ca n no l onger detoxi fy), l i ver ma cropha ges (Kupffer cel l s ) rel ea s e free ra di ca l s , i ncrea s i ng oxi da ti ve da ma ge.
Oxidative damage: Oxi da ti ve s tres s i s i ncrea s ed by
Li ver hypermeta bol i s m, ca us ed by a l cohol cons umpti on
Free ra di ca l -i nduced l i pi d peroxi da ti ve da ma ge
Reducti on i n protecti ve a nti oxi da nts (eg, gl uta thi one, vi ta mi ns A a nd E), ca us ed by a l cohol -rel a ted undernutri ti on
Bi ndi ng of a l cohol oxi da ti on products , s uch a s a ceta l dehyde, to l i ver cel l protei ns , formi ng neoa nti gens a nd res ul ti ng i n i nfl a mma ti on
Accumul a ti on of neutrophi l s a nd other WBCs , whi ch a re a ttra cted by l i pi d peroxi da ti ve da ma ge a nd neoa nti gens
Infl a mma tory cytoki nes s ecreted by WBCs
Accumul a ti on of hepa ti c i ron, i f pres ent, a ggra va tes oxi da ti ve da ma ge. Iron ca n a ccumul a te i n a l cohol i c l i ver di s ea s e through i nges ti on of i ronconta i ni ng forti fi ed wi nes ; mos t often, the i ron a ccumul a ti on i s modes t. Thi s condi ti on mus t be di fferenti a ted from heredi ta ry hemochroma tos i s .
Resultant inflammation, cell death, and fibrosis: A vi ci ous ci rcl e of wors eni ng i nfl a mma ti on occurs : Cel l necros i s a nd a poptos i s res ul t i n hepa tocyte
l os s , a nd s ubs equent a ttempts a t regenera ti on res ul t i n fi bros i s . Stel l a te (Ito) cel l s , whi ch l i ne bl ood cha nnel s (s i nus oi ds ) i n the l i ver, prol i fera te
a nd tra ns form i nto myofi brobl a s ts , produci ng a n exces s of type I col l a gen a nd extra cel l ul a r ma tri x. As a res ul t, the s i nus oi ds na rrow, l i mi ti ng
bl ood fl ow. Fi bros i s na rrows the termi na l hepa ti c venul es , compromi s i ng hepa ti c perfus i on a nd thus contri buti ng to porta l hypertens i on.
Extens i ve fi bros i s i s a s s oci a ted wi th a n a ttempt a t regenera ti on, res ul ti ng i n l i ver nodul es . Thi s proces s cul mi na tes i n ci rrhos i s .
Pathology
Fa tty l i ver, a l cohol i c hepa ti ti s , a nd ci rrhos i s a re often cons i dered s epa ra te, progres s i ve ma ni fes ta ti ons of a l cohol i c l i ver di s ea s e. However, thei r
fea tures often overl a p.
Fatty liver (s tea tos i s ) i s the i ni ti a l a nd mos t common cons equence of exces s i ve a l cohol cons umpti on. Fa tty l i ver i s potenti a l l y revers i bl e.
Ma croves i cul a r fa t a ccumul a tes a s l a rge dropl ets of tri gl yceri de a nd di s pl a ces the hepa tocyte nucl eus , mos t ma rkedl y i n peri venul a r hepa tocytes .
The l i ver enl a rges .
Alcoholic hepatitis (s tea tohepa ti ti s ) i s a combi na ti on of fa tty l i ver, di ffus e l i ver i nfl a mma ti on, a nd l i ver necros i s (often foca l )a l l i n va ri ous
degrees of s everi ty. The da ma ged hepa tocytes a re s wol l en wi th a gra nul a r cytopl a s m (ba l l oon degenera ti on) or conta i n fi bri l l a r protei n i n the
cytopl a s m (Ma l l ory or a l cohol i c hya l i ne bodi es ). Severel y da ma ged hepa tocytes become necroti c. Si nus oi ds a nd termi na l hepa ti c venul es a re
na rrowed. Ci rrhos i s ma y a l s o be pres ent.
Alcoholic cirrhosis i s a dva nced l i ver di s ea s e cha ra cteri zed by extens i ve fi bros i s tha t di s rupts the norma l l i ver a rchi tecture. The a mount of fa t pres ent
va ri es . Al cohol i c hepa ti ti s ma y coexi s t. The feebl e compens a tory a ttempt a t hepa ti c regenera ti on produces rel a ti vel y s ma l l nodul es (mi cronodul a r
ci rrhos i s ). As a res ul t, the l i ver us ua l l y s hri nks . In ti me, even wi th a bs ti nence, fi bros i s forms broa d ba nds , s epa ra ti ng l i ver ti s s ue i nto l a rge
nodul es (ma cronodul a r ci rrhos i s s ee p. 241).
Symptoms and Signs
Symptoms us ua l l y become a ppa rent i n pa ti ents duri ng thei r 30s or 40s ; s evere probl ems a ppea r a bout a deca de l a ter.
Fatty liver i s often a s ymptoma ti c. In one thi rd of pa ti ents , the l i ver i s enl a rged a nd s mooth, but i t i s not us ua l l y tender.
Alcoholic hepatitis ra nges from mi l d a nd revers i bl e to l i fe threa teni ng. Mos t pa ti ents wi th modera te di s ea s e a re undernouri s hed a nd pres ent wi th
fa ti gue, fever, ja undi ce, ri ght upper qua dra nt pa i n, tender hepa tomega l y, a nd s ometi mes a hepa ti c brui t. About 40% deteri ora te s oon a fter
hos pi ta l i za ti on, wi th cons equences ra ngi ng from mi l d (eg, i ncrea s i ng ja undi ce) to s evere (eg, a s ci tes , porta l -s ys temi c encepha l opa thy, va ri cea l
bl eedi ng, l i ver fa i l ure wi th hypogl ycemi a , coa gul opa thy). Other ma ni fes ta ti ons of ci rrhos i s ma y be pres ent.
Cirrhosis, i f compens a ted, ma y be a s ymptoma ti c. The l i ver i s us ua l l y s ma l l ; when the l i ver i s enl a rged, fa tty l i ver or hepa toma s houl d be
cons i dered. Symptoms ra nge from thos e of a l cohol i c hepa ti ti s to the compl i ca ti ons of end-s ta ge l i ver di s ea s e, s uch a s porta l hypertens i on (often
wi th es opha gea l va ri ces a nd upper GI bl eedi ng, s pl enomega l y, a s ci tes , a nd porta l -s ys temi c encepha l opa thy). Porta l hypertens i on ma y l ea d to
i ntra pul mona ry a rteri ovenous s hunti ng wi th hypoxemi a (hepa topul mona ry s yndrome), whi ch ma y ca us e cya nos i s a nd na i l cl ubbi ng. Acute rena l
fa i l ure s econda ry to progres s i vel y decrea s i ng rena l bl ood fl ow (hepa torena l s yndrome) ma y devel op. Hepa tocel l ul a r ca rci noma devel ops i n 10 to
15% of pa ti ents wi th a l cohol i c ci rrhos i s .
Chronic alcoholism, ra ther tha n l i ver di s ea s e, ca us es Dupuytren's contra cture of the pa l ma r fa s ci a , va s cul a r s pi ders , a nd peri phera l neuropa thy. In
men, chroni c a l cohol i s m ca us es s i gns of hypogona di s m a nd femi ni za ti on (eg, s mooth s ki n, l a ck of ma l e-pa ttern ba l dnes s , gynecoma s ti a ,
tes ti cul a r a trophy, cha nges i n pubi c ha i r). Undernutri ti on ma y l ea d to mul ti pl e vi ta mi n defi ci enci es (eg, of fol a te a nd thi a mi n), enl a rged pa roti d
gl a nds , a nd whi te na i l s . In a l cohol i cs , Werni cke's encepha l opa thy a nd Kors a koff's ps ychos i s res ul t ma i nl y from thi a mi n defi ci ency. Hepa ti ti s C
occurs i n > 25% of a l cohol i cs ; thi s combi na ti on ma rkedl y wors ens the progres s i on of l i ver di s ea s e.
Ra rel y, pa ti ents wi th fa tty l i ver or ci rrhos i s pres ent wi th Zi eve's s yndrome (hyperl i pi demi a , hemol yti c a nemi a , a nd ja undi ce).
Diagnosis
Confi rmed hi s tory of a l cohol us e
Li ver functi on tes ts a nd CBC
Someti mes l i ver bi ops y
Al cohol i s s us pected a s the ca us e of l i ver di s ea s e i n a ny pa ti ent who chroni ca l l y cons umes exces s a l cohol , pa rti cul a rl y > 80 g/da y. Hi s tory s houl d
be confi rmed by fa mi l y members . Pa ti ents ca n be s creened for a l cohol i s m us i ng the CAGE ques ti onna i re (need to Cut down, Annoyed by cri ti ci s m,
Gui l ty a bout dri nki ng, a nd need for a morni ng Eye-opener). There i s no s peci fi c tes t for a l cohol i c l i ver di s ea s e, but i f the di a gnos i s i s s us pected,
l i ver functi on tes ts (PT; s erum bi l i rubi n, a mi notra ns fera s e, a nd a l bumi n l evel s ) a nd CBC a re done to detect s i gns of l i ver i njury a nd a nemi a .
El eva ti ons of a mi notra ns fera s es a re modera te (< 300 IU/L) a nd do not refl ect the extent of l i ver da ma ge. The ra ti o of AST to ALT i s 2. The ba s i s for
l ow ALT i s a di eta ry defi ci ency of pyri doxa l phos pha te (vi ta mi n B 6 ), whi ch i s needed for ALT to functi on. Its effect on AST i s l es s pronounced. Serum
-gl uta myl tra ns pepti da s e (GGT) i ncrea s es , more beca us e etha nol i nduces thi s enzyme tha n beca us e pa ti ents ha ve chol es ta s i s or l i ver i njury or
us e other drugs . Serum a l bumi n ma y be l ow, us ua l l y refl ecti ng undernutri ti on but occa s i ona l l y refl ecti ng otherwi s e obvi ous l i ver fa i l ure wi th
defi ci ent s ynthes i s . Ma crocytos i s wi th a n MCV > 100 fL refl ects the di rect effect of a l cohol on bone ma rrow a s wel l a s ma crocyti c a nemi a res ul ti ng
from fol a te defi ci ency, whi ch i s common a mong undernouri s hed a l cohol i cs . Indexes of the s everi ty of l i ver di s ea s e a re
Serum bi l i rubi n, whi ch repres ents s ecretory functi on
PT or INR, whi ch refl ects s yntheti c a bi l i ty
Thrombocytopeni a ca n res ul t from the di rect toxi c effects of a l cohol on bone ma rrow or from s pl enomega l y, whi ch a ccompa ni es porta l
hypertens i on. Neutrophi l i c l eukocytos i s ma y res ul t from a l cohol i c hepa ti ti s , a l though coexi s ti ng i nfecti on (pa rti cul a rl y pneumoni a a nd
s ponta neous ba cteri a l peri toni ti s ) s houl d a l s o be s us pected.
Ima gi ng tes ts a re not routi nel y needed for di a gnos i s . If done for other rea s ons , a bdomi na l ul tra s onogra phy or CT ma y s ugges t fa tty l i ver or s how
evi dence of s pl enomega l y, porta l hypertens i on, or a s ci tes . Ul tra s ound el a s trogra phy mea s ures l i ver s ti ffnes s a nd thus detects a dva nced fi bros i s .
Thi s va l ua bl e a djunct ca n obvi a te the need for l i ver bi ops y to check for ci rrhos i s a nd hel p a s s es s prognos i s . Its exa ct rol e i s under s tudy.
If a bnorma l i ti es s ugges t a l cohol i c l i ver di s ea s e, s creeni ng tes ts for other trea ta bl e forms of l i ver di s ea s e, es peci a l l y vi ra l hepa ti ti s , s houl d be
done. Beca us e fea tures of fa tty l i ver, a l cohol i c hepa ti ti s , a nd ci rrhos i s overl a p, des cri bi ng the preci s e fi ndi ngs i s more us eful tha n a s s i gni ng
pa ti ents to a s peci fi c ca tegory, whi ch ca n onl y be determi ned by l i ver bi ops y.
Not a l l experts a gree on the i ndi ca ti ons for l i ver bi ops y. Propos ed i ndi ca ti ons i ncl ude the fol l owi ng:
Uncl ea r cl i ni ca l di a gnos i s (eg, equi voca l cl i ni ca l a nd l a bora tory fi ndi ngs , unexpl a i ned pers i s tent el eva ti ons of a mi notra ns fera s e l evel s )
Cl i ni ca l s us pi ci on of > 1 ca us e of l i ver di s ea s e (eg, a l cohol pl us vi ra l hepa ti ti s )
Des i re for a preci s e predi cti on of prognos i s
Li ver bi ops y confi rms l i ver di s ea s e, hel ps i denti fy exces s i ve a l cohol us e a s the l i kel y ca us e, a nd es ta bl i s hes the s ta ge of l i ver i njury. If i ron
a ccumul a ti on i s obs erved, mea s urement of the i ron content a nd geneti c tes ti ng ca n el i mi na te heredi ta ry hemochroma tos i s (s ee p. 1032) a s the
ca us e.
For s ta bl e pa ti ents wi th ci rrhos i s , -fetoprotei n mea s urement a nd l i ver ul tra s onogra phy s houl d be done to s creen for hepa tocel l ul a r ca rci noma
(s ee p. 265).
Prognosis
Prognos i s i s determi ned by the degree of hepa ti c fi bros i s a nd i nfl a mma ti on. Fa tty l i ver a nd a l cohol i c hepa ti ti s wi thout fi bros i s a re revers i bl e i f
a l cohol i s a voi ded. Wi th a bs ti nence, fa tty l i ver compl etel y res ol ves wi thi n 6 wk. Fi bros i s a nd ci rrhos i s a re i rrevers i bl e.
Certa i n bi ops y fi ndi ngs (eg, neutrophi l s , peri venul a r fi bros i s ) i ndi ca te a wors e prognos i s . Propos ed qua nti ta ti ve i ndexes to predi ct s everi ty a nd
morta l i ty us e pri ma ri l y l a bora tory fea tures of l i ver fa i l ure s uch a s prothrombi n ti me, crea ti ni ne (for hepa torena l s yndrome) a nd bi l i rubi n l evel s .
The Ma ddrey di s cri mi na nt functi on i s ca l cul a ted from the formul a :
4.6 (PT - control PT)
+
s erum bi l i rubi n
For thi s formul a , bi l i rubi n l evel i s mea s ured i n mg/dL (converted from bi l i rubi n i n mol /L by di vi di ng by 17). A va l ue of > 32 i s a s s oci a ted wi th a
hi gh s hort-term morta l i ty ra te (eg, a fter 1 mo, 35% wi thout encepha l opa thy a nd 45% wi th encepha l opa thy). Other i ndexes i ncl ude the Model for
End-Sta ge Li ver Di s ea s e (MELD), Gl a s gow a l cohol i c hepa ti ti s s core, a nd Li l l e model .
Once ci rrhos i s a nd i ts compl i ca ti ons (eg, a s ci tes , bl eedi ng) devel op, the 5-yr s urvi va l ra te i s a bout 50%; s urvi va l i s hi gher i n pa ti ents who a bs ta i n
a nd l ower i n pa ti ents who conti nue dri nki ng.
Coexi s ti ng i ron a ccumul a ti on or chroni c hepa ti ti s C i ncrea s es ri s k of hepa tocel l ul a r ca rci noma .
Treatment
Abs ti nence
Supporti ve ca re
Corti cos teroi ds a nd entera l nutri ti on for s evere a l cohol i c hepa ti ti s
Someti mes tra ns pl a nta ti on
Restricting alcohol intake: Abs ti nence i s the ma i ns ta y of trea tment; i t prevents further da ma ge from a l cohol i c l i ver di s ea s e a nd thus prol ongs l i fe.
Beca us e compl i a nce i s probl ema ti c, a compa s s i ona te tea m a pproa ch i s es s enti a l . Beha vi ora l a nd ps ychos oci a l i nterventi ons ca n hel p moti va ted
pa ti ents ; they i ncl ude reha bi l i ta ti on progra ms a nd s upport groups (s ee p. 1521), bri ef i nterventi ons by pri ma ry ca re phys i ci a ns , a nd thera pi es tha t
expl ore a nd cl a ri fy the moti va ti on to a bs ta i n (moti va ti ona l enha ncement thera py).
Drugs , i f us ed, s houl d onl y s uppl ement other i nterventi ons . Opi oi d a nta goni s ts (na l trexone or na l mefene) a nd drugs tha t modul a te a mi nobutyri c a ci d receptors (ba cl ofen or a ca mpros a te) a ppea r to ha ve a s hort-term benefi t by reduci ng the cra vi ng a nd wi thdra wa l s ymptoms .
Di s ul fi ra m i nhi bi ts a l dehyde dehydrogena s e, a l l owi ng a ceta l dehyde to a ccumul a te; thus , dri nki ng a l cohol wi thi n 12 h of ta ki ng di s ul fi ra m ca us es
fl us hi ng a nd ha s other unpl ea s a nt effects . However, di s ul fi ra m ha s not been s hown to promote a bs ti nence a nd cons equentl y i s recommended
onl y for certa i n pa ti ents .
Supportive care: Genera l ma na gement empha s i zes s upporti ve ca re. A nutri ti ous di et a nd vi ta mi n s uppl ements (es peci a l l y B vi ta mi ns ) a re
i mporta nt duri ng the fi rs t few da ys of a bs ti nence. Al cohol wi thdra wa l requi res us e of benzodi a zepi nes (eg, di a zepa m). In pa ti ents wi th a dva nced
a l cohol i c l i ver di s ea s e, exces s i ve s eda ti on ca n preci pi ta te hepa ti c encepha l opa thy a nd thus mus t be a voi ded.
Severe a cute a l cohol i c hepa ti ti s commonl y requi res hos pi ta l i za ti on, often i n a n i ntens i ve ca re uni t, to fa ci l i ta te entera l feedi ng (whi ch ca n hel p
ma na ge nutri ti ona l defi ci enci es ) a nd to ma na ge s peci fi c compl i ca ti ons (eg, i nfecti on, bl eedi ng from es opha gea l va ri ces , s peci fi c nutri ti ona l
defi ci enci es , Werni cke's encepha l opa thy, Kors a koff's ps ychos i s , el ectrol yte a bnorma l i ti es , porta l hypertens i on, a s ci tes , porta l -s ys temi c
encepha l opa thys ee el s ewhere i n THE MANUAL).
Specific treatment: Corti cos teroi ds (eg, predni s ol one 40 mg/da y po for 4 wk, fol l owed by ta pered dos es i mprove outcome i n pa ti ents who ha ve
s evere a cute a l cohol i c hepa ti ti s a nd who do not ha ve i nfecti on, GI bl eedi ng, rena l fa i l ure, or pa ncrea ti ti s .
Other tha n corti cos teroi ds a nd entera l feedi ng, few s peci fi c trea tments a re cl ea rl y es ta bl i s hed. Anti oxi da nts (eg, S-a denos yl -L-methi oni ne,
phos pha ti dyl chol i ne, meta doxi ne) s how promi s e i n a mel i ora ti ng l i ver i njury duri ng ea rl y ci rrhos i s but requi re further s tudy. Thera pi es di rected a t
cytoki nes , pa rti cul a rl y tumor necros i s fa ctor- (TNF-), a nd a i mi ng to reduce i nfl a mma ti on ha ve ha d mi xed res ul ts i n s ma l l tri a l s . Pentoxi fyl l i ne, a
phos phodi es tera s e i nhi bi tor tha t i nhi bi ts TNF- s ynthes i s , ha s s ome benefi t. In contra s t, when bi ol ogi c a gents tha t i nhi bi t TNF- (eg, i nfl i xi ma b,
eta nercept) a re us ed, ri s k of i nfecti on outwei ghs benefi t. Drugs gi ven to decrea s e fi bros i s (eg, col chi ci ne, peni ci l l a mi ne) a nd drugs gi ven to
norma l i ze the hypermeta bol i c s ta te of the a l cohol i c l i ver (eg, propyl thi oura ci l ) ha ve no proven benefi t. Anti oxi da nt remedi es , s uch a s s i l yma ri n
(mi l k thi s tl e) a nd vi ta mi ns A a nd E, a re i neffecti ve.
Liver transplantation ca n be cons i dered i f di s ea s e i s s evere. Wi th tra ns pl a nta ti on, 5-yr s urvi va l ra tes a re compa ra bl e to thos e for nona l cohol i c l i ver
di s ea s ea s hi gh a s 80% i n pa ti ents wi thout a cti ve l i ver di s ea s e a nd 50% i n thos e wi th a cute a l cohol i c hepa ti ti s . Beca us e up to 50% of pa ti ents
res ume dri nki ng a fter tra ns pl a nta ti on, mos t progra ms requi re 6 mo of a bs ti nence before tra ns pl a nta ti on i s done.
Chapter 27. Fibrosis and Cirrhosis

Introduction
In hepa ti c fi bros i s , exces s i ve connecti ve ti s s ue a ccumul a tes i n the l i ver; thi s ti s s ue repres ents s ca rri ng i n res pons e to chroni c, repea ted l i ver cel l
i njury. Commonl y, fi bros i s progres s es , di s rupti ng hepa ti c a rchi tecture a nd eventua l l y functi on, a s regenera ti ng hepa tocytes a ttempt to repl a ce a nd
repa i r da ma ged ti s s ue. When s uch di s rupti on i s wi des prea d, ci rrhos i s i s di a gnos ed. To devel op, ci rrhos i s us ua l l y requi res > 6 mo of l i ver di s ea s e
but ca n occur more ra pi dl y (eg, duri ng i nfa ncy wi th bi l i a ry a tres i a , a fter l i ver tra ns pl a nta ti on for s evere l i ver di s ea s e s econda ry to chroni c hepa ti ti s
B or C).
Fibrosis
Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded
deficiently, or both. The trigger is chronic injury, especially if there is an inflammatory component. Fibrosis itself causes no symptoms but can lead to portal
hypertension (the scarring distorts blood flow through the liver) or cirrhosis (the scarring results in disruption of normal hepatic architecture and liver dysfunction).
Diagnosis is based on liver biopsy. Treatment involves correcting the underlying condition when possible.
Va ri ous types of chroni c l i ver i njury ca n ca us e fi bros i s (s ee
Ta bl e 27-1). Sel f-l i mi ted, a cute l i ver i njury (eg, a cute vi ra l hepa ti ti s A), even when ful mi na nt, does not neces s a ri l y di s tort the s ca ffol di ng
a rchi tecture a nd hence does not ca us e fi bros i s , des pi te l os s of hepa tocytes . In i ts i ni ti a l s ta ges , hepa ti c fi bros i s ca n regres s i f the ca us e i s
revers i bl e (eg, wi th vi ra l cl ea ra nce). After months or yea rs of chroni c or repea ted i njury, fi bros i s becomes perma nent. Fi bros i s devel ops even more
ra pi dl y i n mecha ni ca l bi l i a ry obs tructi on.
Pathophysiology
Acti va ti on of the hepa ti c peri va s cul a r s tel l a te cel l s (Ito cel l s , whi ch s tore fa t) i ni ti a tes fi bros i s . Thes e a nd a dja cent cel l s prol i fera te, becomi ng
contra cti l e cel l s termed myofi brobl a s ts . Thes e cel l s produce exces s i ve a mounts of a bnorma l ma tri x (cons i s ti ng of col l a gen, other gl ycoprotei ns ,
a nd gl yca ns ) a nd ma tri cel l ul a r protei ns . Kupffer cel l s (res i dent ma cropha ges ), i njured hepa tocytes , pl a tel ets , a nd l eukocytes a ggrega te. As a
res ul t, rea cti ve O2 s peci es a nd i nfl a mma tory medi a tors (eg, pl a tel et-deri ved growth fa ctor, tra ns formi ng growth fa ctors , a nd connecti ve ti s s ue
growth fa ctor) a re rel ea s ed. Thus , s tel l a te cel l a cti va ti on res ul ts i n a bnorma l extra cel l ul a r ma tri x, both i n qua nti ty a nd compos i ti on.
Myofi brobl a s ts , s ti mul a ted by endothel i n-1, contri bute to i ncrea s ed porta l vei n res i s ta nce a nd i ncrea s e the dens i ty of the a bnorma l ma tri x.
Fi brous tra cts joi n bra nches of a fferent porta l vei ns a nd efferent hepa ti c vei ns , bypa s s i ng the hepa tocytes a nd l i mi ti ng thei r bl ood s uppl y. Hence,
fi bros i s contri butes both to hepa tocyte i s chemi a (ca us i ng hepa tocel l ul a r dys functi on) a nd porta l hypertens i on. The
[Table 27-1. Di s orders a nd Drugs tha t Ca n Ca us e Hepa ti c Fi bros i s ]
extent of the i s chemi a a nd porta l hypertens i on determi nes how the l i ver i s a ffected. For exa mpl e, congeni ta l hepa ti c fi bros i s a ffects porta l vei n
bra nches , l a rgel y s pa ri ng the pa renchyma . The res ul t i s porta l hypertens i on wi th s pa ri ng of hepa tocel l ul a r functi on.
Symptoms and Signs
Hepa ti c fi bros i s i ts el f does not ca us e s ymptoms . Symptoms ma y devel op s econda ry to the pri ma ry di s order or to porta l hypertens i on. Porta l
hypertens i on wi th s pl enomega l y i s often a s ymptoma ti c unl es s compl i ca ti ons , s uch a s va ri cea l GI bl eedi ng, a s ci tes , or porta l -s ys temi c
encepha l opa thy, devel op. Eventua l l y, ci rrhos i s s upervenes .
Diagnosis
Bi ops y
Hepa ti c fi bros i s i s s us pected i n pa ti ents who ha ve a n underl yi ng di s order or ta ke a drug tha t coul d ca us e fi bros i s or who ha ve unexpl a i ned
a bnorma l i ti es i n l i ver functi on or enzymes . Noni nva s i ve tes ts (eg, s erol ogi c ma rkers ) a re under s tudy but a re not yet rea dy for routi ne cl i ni ca l us e.
Ima gi ng tes ts s uch a s ul tra s onogra phy, CT, a nd MRI ma y detect fi ndi ngs a s s oci a ted wi th fi bros i s (eg, porta l hypertens i on, s pl enomega l y, ci rrhos i s )
but a re not s ens i ti ve to pa renchyma l fi bros i s i ts el f. Li ver bi ops y i s currentl y the onl y mea ns of detecti ng hepa ti c fi bros i s . Bi ops y i s i ndi ca ted to
cl a ri fy the di a gnos i s (eg, nona l cohol i c s tea tohepa ti ti s , pri ma ry bi l i a ry ci rrhos i s ) a nd s ta ge i ts progres s (eg, i n chroni c hepa ti ti s C to determi ne
whether fi bros i s i s pres ent or whether i t ha s progres s ed to ci rrhos i s ).
Treatment
Trea tment of ca us e
Beca us e fi bros i s repres ents a res pons e to hepa ti c da ma ge, pri ma ry trea tment s houl d focus on the ca us e (removi ng the ba s i s of the l i ver i njury).
Such trea tment ma y i ncl ude el i mi na ti ng HBC or HCV i n chroni c vi ra l hepa ti ti s , a bs ta i ni ng from a l cohol i n a l cohol i c l i ver di s ea s e, removi ng hea vy
meta l s s uch a s i ron i n hemochroma tos i s or copper i n Wi l s on's di s ea s e, a nd decompres s i ng bi l e ducts i n bi l i a ry obs tructi on.
Trea tments a i med a t revers i ng the fi bros i s a re us ua l l y too toxi c for l ong-term us e (eg, corti cos teroi ds , peni ci l l a mi ne) or ha ve no proven effi ca cy
(eg, col chi ci ne). Other a nti fi broti c trea tments a re under s tudy. Si mul ta neous us e of mul ti pl e a nti fi broti c drugs ma y eventua l l y prove mos t
benefi ci a l .
Cirrhosis
Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative
nodules surrounded by dense fibrotic tissue. Symptoms may not develop for years and are often nonspecific (eg, anorexia, fatigue, weight loss). Late
manifestations include portal hypertension, ascites, and, when decompensation occurs, liver failure. Diagnosis often requires liver biopsy. Cirrhosis is usually
considered irreversible. Treatment is supportive.
Ci rrhos i s i s a l ea di ng ca us e of dea th worl dwi de. The ca us es of ci rrhos i s a re the s a me a s thos e of fi bros i s (s ee Ta bl e 27-1). In devel oped
countri es , mos t ca s es res ul t from chroni c a l cohol a bus e or chroni c hepa ti ti s C. In pa rts of As i a a nd Afri ca , ci rrhos i s often res ul ts from chroni c
hepa ti ti s B. Ci rrhos i s of unknown eti ol ogy (cryptogeni c ci rrhos i s ) i s becomi ng l es s common a s ma ny s peci fi c ca us es (eg, chroni c hepa ti ti s C,
s tea tohepa ti ti s ) a re i denti fi ed. Injury to the bi l e ducts a l s o ca n res ul t i n ci rrhos i s , a s occurs i n mecha ni ca l bi l e duct obs tructi on, pri ma ry bi l i a ry
ci rrhos i s (s ee p. 244), a nd pri ma ry s cl eros i ng chol a ngi ti s (s ee p. 278).
Pathophysiology
There a re 2 pri ma ry fa ctors :
Hepa ti c fi bros i s
Regenera ti ng l i ver cel l s
In res pons e to i njury a nd l os s , growth regul a tors i nduce hepa tocel l ul a r hyperpl a s i a (produci ng regenera ti ng nodul es ) a nd a rteri a l growth
(a ngi ogenes i s ). Among the growth regul a tors a re cytoki nes a nd hepa ti c growth fa ctors (eg, epi thel i a l growth fa ctor, hepa tocyte growth fa ctor,
tra ns formi ng growth fa ctor-, tumor necros i s fa ctor). Ins ul i n, gl uca gon, a nd pa tterns of i ntra hepa ti c bl ood fl ow determi ne how a nd where nodul es
devel op.
Angi ogenes i s produces new ves s el s wi thi n the fi brous s hea th tha t s urrounds nodul es . Thes e ves s el s connect the hepa ti c a rtery a nd porta l vei n to
hepa ti c venul es , res tori ng the i ntra hepa ti c ci rcul a tory pa thwa ys . Such i nterconnecti ng ves s el s provi de rel a ti vel y l ow-vol ume, hi gh-pres s ure venous
dra i na ge tha t ca nnot a ccommoda te a s much bl ood vol ume a s norma l . As a res ul t, porta l vei n pres s ure i ncrea s es . Such di s torti ons i n bl ood fl ow
contri bute to porta l hypertens i on, whi ch i ncrea s es beca us e the regenera ti ng nodul es compres s hepa ti c venul es .
The progres s i on ra te from fi bros i s to ci rrhos i s a nd the morphol ogy of ci rrhos i s va ry from pers on to pers on. Pres uma bl y, the rea s on for s uch
va ri a ti on i s the extent of expos ure to the i njuri ous s ti mul us a nd the i ndi vi dua l 's res pons e.
Complications: Porta l hypertens i on (s ee p. 218) i s the mos t common s eri ous compl i ca ti on; i t ca n ma ni fes t a s GI bl eedi ng from es opha gea l , ga s tri c,
or recta l va ri ces or porta l hypertens i ve ga s tropa thy. Porta l hypertens i on ca n be ma s s i ve. Ci rrhos i s ca n ca us e other ca rdi ova s cul a r compl i ca ti ons .
Va s odi l a ti on a nd i ntra pul mona ry ri ght-to-l eft s hunti ng a nd venti l a ti on/perfus i on mi s ma tch ca n res ul t i n hypoxi a (hepa topul mona ry s yndrome). A
ca rdi a c myopa thy ca n a l s o a ccompa ny ci rrhos i s .
As ci tes ca n devel op, wi th a ri s k of s ponta neous ba cteri a l peri toni ti s . Spl eni c conges ti on wi th hypers pl eni s m ma y occur, res ul ti ng i n
s pl enomega l y, pl a tel et s eques tra ti on, a nd cons equent cytopeni a .
Progres s i ve l os s of hepa ti c a rchi tecture i mpa i rs functi on, l ea di ng to hepa ti c i ns uffi ci ency; i t ma ni fes ts a s coa gul opa thy, rena l fa i l ure (hepa torena l
s yndromes ee p. 223), a nd hepa ti c encepha l opa thy. Hepa tocytes s ecrete l es s bi l e, contri buti ng to chol es ta s i s a nd ja undi ce. Les s bi l e i n the
i ntes ti ne ca us es ma l a bs orpti on of di eta ry fa t (tri gl yceri des ) a nd fa t-s ol ubl e vi ta mi ns . Ma l a bs orpti on of vi ta mi n D ma y contri bute to os teoporos i s .
Undernutri ti on i s common. It ma y res ul t from a norexi a wi th reduced food i nta ke or, i n pa ti ents wi th a l cohol i c l i ver di s ea s e, from ma l a bs orpti on
due to pa ncrea ti c i ns uffi ci ency.
Bl ood di s orders a re common. Anemi a res ul ts from hypers pl eni s m, chroni c GI bl eedi ng, fol a te defi ci ency (pa rti cul a rl y i n pa ti ents wi th a l cohol i s m),
a nd hemol ys i s . Cl otti ng ma y be i mpa i red beca us e of coa gul opa thy or thrombocytopeni a . Coa gul opa thy res ul ts from i mpa i red hepa ti c s ynthes i s of
the fa ctors neces s a ry for cl otti ng, ma l a bs orpti on of vi ta mi n K due to i mpa i red bi l e s ecreti on i nto the duodenum, or both. Thrombocytopeni a ma y
be ca us ed by hypers pl eni s m (pl a tel et s eques tra ti on), a l cohol exces s (di rectl y i nhi bi ti ng the bone ma rrow), or both. Pa ncytopeni a a l s o occurs wi th
a l cohol i s m.
Hepa tocel l ul a r ca rci noma frequentl y compl i ca tes ci rrhos i s , pa rti cul a rl y ci rrhos i s res ul ti ng from chroni c hepa ti ti s B a nd C vi rus es ,
hemochroma tos i s , a l cohol -rel a ted l i ver di s ea s e, 1 a nti tryps i n defi ci ency, or gl ycogen s tora ge di s ea s e.
Histopathology: Ci rrhos i s i s cha ra cteri zed by regenera ti ng nodul es a nd fi bros i s . Incompl etel y formed l i ver nodul es , nodul es wi thout fi bros i s
(nodul a r regenera ti ve hyperpl a s i a ), a nd congeni ta l hepa ti c fi bros i s (i e, wi des prea d fi bros i s wi thout regenera ti ng nodul es ) a re not true ci rrhos i s .
Ci rrhos i s ca n be mi cronodul a r or ma cronodul a r. Mi cronodul a r ci rrhos i s i s cha ra cteri zed by uni forml y s ma l l nodul es (< 3 mm i n di a meter) a nd thi ck
regul a r ba nds of connecti ve ti s s ue. Typi ca l l y, nodul es l a ck l obul a r orga ni za ti on; termi na l (centra l ) hepa ti c venul es a nd porta l tri a ds a re di s torted.
Wi th ti me, ma cronodul a r ci rrhos i s often devel ops . The nodul es va ry i n s i ze (3 mm to 5 cm i n di a meter) a nd ha ve s ome ra ther norma l l obul a r
orga ni za ti on of porta l tri a ds a nd termi na l hepa ti c venul es . Broa d fi brous ba nds of va ryi ng thi cknes s s urround the l a rge nodul es . Col l a ps e of the
norma l hepa ti c a rchi tecture i s s ugges ted by the concentra ti on of porta l tri a ds wi thi n the fi brous s ca rs . Mi xed ci rrhos i s (i ncompl ete s epta l
ci rrhos i s ) combi nes el ements of mi cronodul a r a nd ma cronodul a r ci rrhos i s . Di fferenti a ti on between thes e morphol ogi c types of ci rrhos i s ha s
l i mi ted cl i ni ca l va l ue.
Symptoms and Signs
Ci rrhos i s ma y be a s ymptoma ti c for yea rs . One thi rd of pa ti ents never devel op s ymptoms . Often, the fi rs t s ymptoms a re nons peci fi c; they i ncl ude
genera l i zed fa ti gue (due to cytoki ne rel ea s e), a norexi a , ma l a i s e, a nd wei ght l os s (s ee
Ta bl e 27-2). The l i ver i s typi ca l l y pa l pa bl e a nd fi rm, wi th a bl unt edge, but i s s ometi mes s ma l l a nd di ffi cul t to pa l pa te. Nodul es us ua l l y a re not
pa l pa bl e.
Cl i ni ca l s i gns tha t s ugges t a chroni c l i ver di s order or chroni c a l cohol us e but a re not s peci fi c for ci rrhos i s i ncl ude mus cl e wa s ti ng, pa l ma r
erythema , pa roti d gl a nd enl a rgement, whi te na i l s , cl ubbi ng, Dupuytren's contra cture, s pi der a ngi oma s (< 10 ma y be norma l ), gynecoma s ti a ,
a xi l l a ry ha i r l os s , tes ti cul a r a trophy, a nd peri phera l neuropa thy.
Once compl i ca ti ons of ci rrhos i s devel op, decompens a ti on i nexora bl y ens ues .
Diagnosis
Li ver functi on tes ts , coa gul a ti on tes ts , CBC, a nd s erol ogi c tes ts for vi ra l ca us e
Someti mes bi ops y
Identi fi ca ti on of ca us e ba s ed on cl i ni ca l eva l ua ti on a nd s el ecti ve tes ti ng
General approach: Ci rrhos i s i s s us pected i n pa ti ents wi th ma ni fes ta ti ons of a ny of i ts compl i ca ti ons (s ee Ta bl e 27-2), pa rti cul a rl y porta l
hypertens i on or a s ci tes . Ea rl y ci rrhos i s s houl d be cons i dered i n pa ti ents wi th nons peci fi c
[Table 27-2. Common Symptoms a nd Si gns Due to Compl i ca ti ons of Ci rrhos i s ]
s ymptoms or cha ra cteri s ti c l a bora tory a bnorma l i ti es detected i nci denta l l y duri ng l a bora tory tes ti ng, pa rti cul a rl y i n pa ti ents who ha ve a di s order
or ta ke a drug tha t mi ght ca us e fi bros i s .
Tes ti ng s eeks to detect ci rrhos i s a nd a ny compl i ca ti ons a nd to determi ne i ts ca us e.
Laboratory tests: Di a gnos ti c tes ti ng begi ns wi th l i ver functi on tes ts , coa gul a ti on tes ts , CBC, a nd s erol ogi c tes ts for vi ra l ca us es (eg, hepa ti ti s B a nd
C). La bora tory tes ts a l one ma y i ncrea s e s us pi ci on for ci rrhos i s but ca nnot confi rm or excl ude i t. Li ver bi ops y becomes neces s a ry i f a cl ea r di a gnos i s
woul d l ea d to better ma na gement a nd outcome.
Tes t res ul ts ma y be norma l or ma y i ndi ca te nons peci fi c a bnorma l i ti es due to compl i ca ti ons of ci rrhos i s or a l cohol i s m. ALT a nd AST l evel s a re
often modes tl y el eva ted. Al ka l i ne phos pha ta s e a nd -gl uta myl tra ns pepti da s e (GGT) a re often norma l ; el eva ted l evel s i ndi ca te chol es ta s i s or
bi l i a ry obs tructi on. Bi l i rubi n i s us ua l l y norma l but i ncrea s es when ci rrhos i s progres s es , pa rti cul a rl y i n pri ma ry bi l i a ry ci rrhos i s (s ee p. 244).
Decrea s ed s erum a l bumi n a nd a prol onged PT di rectl y refl ect i mpa i red hepa ti c s ynthes i s us ua l l y a n end-s ta ge event. Al bumi n ca n a l s o be l ow
when nutri ti on i s poor. Serum gl obul i n i ncrea s es i n ci rrhos i s a nd i n mos t l i ver di s orders wi th a n i nfl a mma tory component. Anemi a i s common a nd
us ua l l y normocyti c wi th a hi gh RBC di s tri buti on wi dth. Anemi a i s often mul ti fa ctori a l ; contri buti ng fa ctors ma y i ncl ude chroni c GI bl eedi ng (us ua l l y
ca us i ng mi crocyti c a nemi a ), fol a te nutri ti ona l defi ci ency (ca us i ng ma crocyti c a nemi a , es peci a l l y i n a l cohol a bus e), hemol ys i s , a nd hypers pl eni s m.
CBC ma y detect l eukopeni a , thrombocytopeni a , or pa ncytopeni a .
Diagnostic imaging: Ima gi ng tes ts a re not hi ghl y s ens i ti ve or s peci fi c for the di a gnos i s of ci rrhos i s by thems el ves , but they ca n often detect i ts
compl i ca ti ons . In a dva nced ci rrhos i s , ul tra s onogra phy s hows a s ma l l , nodul a r l i ver. Ul tra s onogra phy a l s o detects porta l hypertens i on a nd a s ci tes .
CT ca n detect a nodul a r texture, but i t ha s no a dva nta ge over ul tra s onogra phy. Ra di onucl i de l i ver s ca ns us i ng techneti um-99m s ul fur col l oi d ma y
s how i rregul a r l i ver upta ke a nd i ncrea s ed s pl een a nd bone ma rrow upta ke. MRI i s more expens i ve tha n other i ma gi ng tes ts a nd ha s l i ttl e
a dva nta ge.
Identification of the cause: Determi ni ng the s peci fi c ca us e of ci rrhos i s requi res key cl i ni ca l i nforma ti on from the hi s tory a nd exa mi na ti on, a s wel l a s
s el ecti ve tes ti ng. Al cohol i s the l i kel y ca us e i n pa ti ents wi th a documented hi s tory of a l cohol i s m a nd cl i ni ca l fi ndi ngs s uch a s gynecoma s ti a ,
s pi der a ngi oma s (tel a ngi ecta s i a ), a nd tes ti cul a r a trophy pl us l a bora tory confi rma ti on of l i ver da ma ge (AST el eva ted more tha n ALT) a nd l i ver
enzyme i nducti on (a grea tl y i ncrea s ed GGT). Fever, tender hepa tomega l y, a nd ja undi ce s ugges t the pres ence of a l cohol i c hepa ti ti s .
Detecti ng hepa ti ti s B s urfa ce a nti gen (HBs Ag) a nd IgG a nti bodi es to hepa ti ti s B (IgG a nti -HBc) confi rms chroni c hepa ti ti s B. Identi fyi ng s erum
a nti body to hepa ti ti s C (a nti -HCV) a nd HCV-RNA poi nts to hepa ti ti s C.
If common ca us es s uch a s a l cohol or vi ra l hepa ti ti s a re not confi rmed, other l es s common ca us es a re s ought:
Pres ence of a nti mi tochondri a l a nti bodi es (i n 95%) s ugges ts pri ma ry bi l i a ry ci rrhos i s .
Stri ctures a nd di l a ti ons of the i ntra hepa ti c a nd extra hepa ti c bi l e ducts s een on ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP) s ugges t
pri ma ry s cl eros i ng chol a ngi ti s .
Increa s ed s erum Fe a nd tra ns ferri n a nd pos s i bl y res ul ts of geneti c tes ti ng s ugges t hemochroma tos i s .
Decrea s ed s erum cerul opl a s mi n a nd cha ra cteri s ti c copper tes t res ul ts s ugges t Wi l s on's di s ea s e.
Hyperga mma gl obul i nemi a a nd pres ence of a utoa nti bodi es (eg, a nti nucl ea r or a nti -s mooth mus cl e a nti bodi es ) i ndi ca te a utoi mmune hepa ti ti s .
Liver biopsy: If cl i ni ca l cri teri a a nd noni nva s i ve tes ti ng a re i nconcl us i ve, l i ver bi ops y i s us ua l l y done. Its s ens i ti vi ty a pproa ches 100%. Nona l cohol i c
s tea tohepa ti ti s (NASH), often a s s oci a ted wi th obes i ty, di a betes , or the meta bol i c s yndrome, ma y be evi dent on ul tra s ound s ca ns but requi res l i ver
bi ops y for confi rma ti on. In obvi ous ca s es of ci rrhos i s wi th a ma rked coa gul opa thy, porta l hypertens i on, a s ci tes , a nd l i ver fa i l ure, bi ops y i s not
requi red when res ul ts woul d not cha nge ma na gement.
Monitoring: Pa ti ents wi th ci rrhos i s , pa rti cul a rl y i f due to chroni c vi ra l hepa ti ti s B or C or hemochroma tos i s , s houl d be s creened for hepa tocel l ul a r
ca rci noma (eg, mea s uri ng -fetoprotei n l evel s a nd ul tra s onogra phy every 6 to 12 mos ee p. 266).
Prognosis
Prognos i s i s often unpredi cta bl e. It depends on fa ctors s uch a s eti ol ogy, s everi ty, pres ence of compl i ca ti ons , comorbi d condi ti ons , hos t fa ctors ,
a nd effecti venes s of thera py. Pa ti ents who conti nue to dri nk a l cohol , even s ma l l a mounts , ha ve a very poor prognos i s . The Chi l d-Turcotte-Pugh
s cori ng s ys tem us es cl i ni ca l a nd l a bora tory i nforma ti on to s tra ti fy di s ea s e s everi ty, s urgi ca l ri s k, a nd overa l l prognos i s (s ee
Ta bl es 27-3 a nd
27-4).
Treatment
Supporti ve ca re
In genera l , trea tment i s s upporti ve a nd i ncl udes s toppi ng i njuri ous drugs , provi di ng nutri ti on (i ncl udi ng s uppl ementa l vi ta mi ns ), a nd trea ti ng the
underl yi ng di s orders a nd compl i ca ti ons . Dos es of drugs meta bol i zed i n the l i ver s houl d be reduced. Al l a l cohol a nd hepa totoxi c s ubs ta nces mus t
be a voi ded. Wi thdra wa l s ymptoms duri ng hos pi ta l i za ti on s houl d be a nti ci pa ted i n pa ti ents who ha ve ci rrhos i s a nd ha ve conti nued to a bus e
a l cohol .
Pa ti ents wi th va ri ces need thera py to prevent bl eedi ng (s ee p.
219). Li ver tra ns pl a nta ti on i s i ndi ca ted for end-s ta ge l i ver fa i l ure i n s ui ta bl e ca ndi da tes .
Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis,
cirrhosis, and liver failure. Patients usually are asymptomatic at presentation but may experience fatigue or have symptoms of cholestasis (eg, pruritus,
steatorrhea) or cirrhosis (eg, portal hypertension, ascites). Laboratory tests reveal cholestasis, increased IgM, and, characteristically, antimitochondrial antibodies
in the serum. Liver biopsy may be necessary for diagnosis and staging. Treatment includes ursodeoxycholic acid, cholestyramine (for pruritus),
[Table 27-3. Chi l d-Turcotte-Pugh Scori ng Sys tem]
[Table 27-4. Interpreta ti on of the Chi l d-Turcotte-Pugh Scori ng Sys tem]
supplementary fat-soluble vitamins, and, ultimately for advanced disease, liver transplantation.
Etiology
PBC i s the mos t common l i ver di s ea s e a s s oci a ted wi th chroni c chol es ta s i s i n a dul ts . Mos t (95%) ca s es occur i n women a ged 35 to 70. PBC a l s o
cl us ters i n fa mi l i es . A geneti c predi s pos i ti on, perha ps i nvol vi ng the X chromos ome, proba bl y contri butes . There ma y be a n i nheri ted a bnorma l i ty
of i mmune regul a ti on. An a utoi mmune mecha ni s m ha s been i mpl i ca ted; a nti bodi es to a nti gens l oca ted on the i nner mi tochondri a l membra nes
occur i n > 95% of ca s es . Thes e a nti mi tochondri a l a nti bodi es (AMAs ), the s erol ogi c ha l l ma rks of PBC, a re not cytotoxi c a nd a re not i nvol ved i n bi l e
duct da ma ge. PBC i s a s s oci a ted wi th other a utoi mmune di s orders , s uch a s RA, s ys temi c s cl eros i s , Sjogren's s yndrome, CREST s yndrome,
a utoi mmune thyroi di ti s , a nd rena l tubul a r a ci dos i s .
T cel l s a tta ck the s ma l l bi l e ducts . CD4 a nd CD8 T l ymphocytes di rectl y ta rget bi l i a ry epi thel i a l cel l s . The tri gger for the i mmunol ogi c a tta ck on bi l e
ducts i s unknown. Expos ure to forei gn a nti gens , s uch a s a n i nfecti ous (ba cteri a l or vi ra l ) or toxi c a gent, ma y be the i ns ti ga ti ng event. Thes e forei gn
a nti gens mi ght be s tructura l l y s i mi l a r to endogenous protei ns (mol ecul a r mi mi cry); then the s ubs equent i mmunol ogi c rea cti on woul d be
a utoi mmune a nd s el f-perpetua ti ng. Des tructi on a nd l os s of bi l e ducts l ea d to i mpa i red bi l e forma ti on a nd s ecreti on (chol es ta s i s ). Reta i ned toxi c
ma teri a l s s uch a s bi l e a ci ds then ca us e further da ma ge, pa rti cul a rl y to hepa tocytes . Chroni c chol es ta s i s thus l ea ds to l i ver cel l i nfl a mma ti on a nd
s ca rri ng i n the peri porta l a rea s . Eventua l l y, hepa ti c i nfl a mma ti on decrea s es a s hepa ti c fi bros i s progres s es to ci rrhos i s .
Autoi mmune chol a ngi ti s i s s ometi mes cons i dered to be a s epa ra te di s order. It i s cha ra cteri zed by a utoa nti bodi es , s uch a s a nti nucl ea r a nti bodi es
(ANAs ), a nti -s mooth mus cl e a nti bodi es , or both a nd ha s a cl i ni ca l cours e a nd res pons e to trea tment tha t a re s i mi l a r to PBC. However, i n
a utoi mmune chol a ngi ti s , AMAs a re a bs ent.
Symptoms and Signs
About ha l f of pa ti ents pres ent wi thout s ymptoms . Symptoms or s i gns ma y devel op duri ng a ny s ta ge of the di s ea s e a nd ma y i ncl ude fa ti gue or
refl ect chol es ta s i s (a nd the res ul ti ng fa t ma l a bs orpti on, whi ch ma y l ea d to vi ta mi n defi ci enci es a nd os teoporos i s ), hepa tocel l ul a r dys functi on, or
ci rrhos i s .
Symptoms us ua l l y devel op i ns i di ous l y. Pruri tus , fa ti gue, a nd dry mouth a nd eyes a re the i ni ti a l s ymptoms i n > 50% of pa ti ents a nd ca n precede
other s ymptoms by months or yea rs . Other i ni ti a l ma ni fes ta ti ons i ncl ude ri ght upper qua dra nt di s comfort (10%); a n enl a rged, fi rm, nontender l i ver
(25%); s pl enomega l y (15%); hyperpi gmenta ti on (25%); xa nthel a s ma s (10%); a nd ja undi ce (10%). Eventua l l y, a l l the fea tures a nd compl i ca ti ons of
ci rrhos i s occur. Peri phera l neuropa thy a nd other a utoi mmune di s orders a s s oci a ted wi th PBC ma y a l s o devel op.
Diagnosis
Li ver functi on tes ts
Anti mi tochondri a l a nti bodi es
Ul tra s onogra phy a nd often MRCP
Li ver bi ops y
In a s ymptoma ti c pa ti ents , PBC i s detected i nci denta l l y when l i ver functi on tes ts detect a bnorma l i ti es , typi ca l l y el eva ted l evel s of a l ka l i ne
phos pha ta s e a nd -gl uta myl tra ns pepti da s e (GGT). PBC i s s us pected i n mi ddl e-a ged women wi th cl a s s i c s ymptoms (eg, unexpl a i ned pruri tus ,
fa ti gue, ri ght upper qua dra nt di s comfort, ja undi ce) or l a bora tory res ul ts s ugges ti ng chol es ta ti c l i ver di s ea s e: el eva ted a l ka l i ne phos pha ta s e a nd
GGT but mi ni ma l l y a bnorma l a mi notra ns fera s es (ALT, AST). Serum bi l i rubi n i s us ua l l y norma l i n the ea rl y s ta ges ; el eva ti on i ndi ca tes di s ea s e
progres s i on a nd a wors eni ng prognos i s .
If PBC i s s us pected, l i ver functi on tes ts a nd tes ts to mea s ure s erum IgM (i ncrea s ed i n PBC) a nd AMA s houl d be done. ELISA tes ts a re 95% s ens i ti ve
a nd 98% s peci fi c for PBC; fa l s e-pos i ti ve res ul ts ca n occur i n a utoi mmune hepa ti ti s (type 1). Other a utoa nti bodi es (eg, ANAs , a nti -s mooth mus cl e
a nti bodi es , rheuma toi d fa ctor) ma y be pres ent. Extra hepa ti c bi l i a ry obs tructi on s houl d be rul ed out. Ul tra s onogra phy i s often done fi rs t, but
ul ti ma tel y MRCP a nd s ometi mes ERCP a re neces s a ry. Unl es s l i fe expecta ncy i s s hort or there i s a contra i ndi ca ti on, l i ver bi ops y i s us ua l l y done.
Li ver bi ops y confi rms the di a gnos i s ; i t ma y detect pa thognomoni c bi l e duct l es i ons , even i n ea rl y s ta ges . As PBC progres s es , i t becomes
morphol ogi ca l l y i ndi s ti ngui s ha bl e from other forms of ci rrhos i s . Li ver bi ops y a l s o hel ps s ta ge PBC, whi ch ha s 4 hi s tol ogi c s ta ges :
Sta ge 1: Infl a mma ti on, a bnorma l connecti ve ti s s ue, or both, confi ned to the porta l a rea s
Sta ge 2: Infl a mma ti on, fi bros i s , or both, confi ned to the porta l a nd peri porta l a rea s
Sta ge 3: Bri dgi ng fi bros i s
Sta ge 4: Ci rrhos i s
Autoi mmune chol a ngi ti s i s di a gnos ed when AMAs a re a bs ent i n a pa ti ent who otherwi s e woul d be di a gnos ed wi th PBC.
Prognosis
Us ua l l y, PBC progres s es to termi na l s ta ges over 15 to 20 yr, a l though the ra te of progres s i on va ri es . PBC ma y not di mi ni s h qua l i ty of l i fe for ma ny
yea rs . Pa ti ents who pres ent wi thout s ymptoms tend to devel op s ymptoms over 2 to 7 yr but ma y not do s o for 10 to 15 yr. Once s ymptoms devel op,
medi a n l i fe expecta ncy i s 10 yr. Predi ctors of ra pi d progres s i on i ncl ude the fol l owi ng:
Ra pi d wors eni ng of s ymptoms
Adva nced hi s tol ogi c cha nges
Ol der pa ti ent a ge
Pres ence of edema
Pres ence of a s s oci a ted a utoi mmune di s orders
Abnorma l i ti es i n bi l i rubi n, a l bumi n, PT, or INR
The prognos i s i s omi nous when pruri tus di s a ppea rs , xa nthoma s s hri nk, ja undi ce devel ops , a nd s erum chol es terol decrea s es .
Treatment
Arres ti ng or revers i ng l i ver da ma ge
Trea ti ng compl i ca ti ons (chroni c chol es ta s i s a nd l i ver fa i l ure)
Eventua l l y, doi ng l i ver tra ns pl a nta ti on
Al l a l cohol us e a nd hepa totoxi c drugs s houl d be s topped. Urs odeoxychol i c a ci d (15 mg/kg po once/da y) decrea s es l i ver da ma ge, prol ongs s urvi va l ,
a nd del a ys the need for l i ver tra ns pl a nta ti on. About 20% of pa ti ents do not ha ve bi ochemi ca l i mprovement a fter 4 mo; they ma y ha ve a dva nced
di s ea s e a nd requi re l i ver tra ns pl a nta ti on i n a few yea rs . Other drugs propos ed to decrea s e l i ver da ma ge ha ve not i mproved overa l l cl i ni ca l
outcomes or a re controvers i a l .
Pruri tus ma y be control l ed wi th chol es tyra mi ne 6 to 8 g po bi d. Thi s a ni oni c-bi ndi ng drug bi nds bi l e s a l ts a nd thus ma y a ggra va te fa t
ma l a bs orpti on. If chol es tyra mi ne i s ta ken l ong-term, s uppl ements of fa t-s ol ubl e vi ta mi ns s houl d be cons i dered. Chol es tyra mi ne ca n decrea s e
a bs orpti on of urs odeoxychol i c a ci d, s o thes e drugs s houl d not be gi ven s i mul ta neous l y.
Some pa ti ents wi th pruri tus res pond to urs odeoxychol i c a ci d a nd ul tra vi ol et l i ght; others ma y wa rra nt a tri a l of ri fa mpi n or a n opi oi d a nta goni s t,
s uch a s na l trexone. Pa ti ents wi th fa t ma l a bs orpti on due to bi l e s a l t defi ci ency s houl d be trea ted wi th vi ta mi ns A, D, E, a nd K. For os teoporos i s ,
wei ght-bea ri ng exerci s es , bi s phos phona tes , or ra l oxi fene ma y be needed i n a ddi ti on to Ca a nd vi ta mi n D s uppl ements . In l a ter s ta ges , porta l
hypertens i on (s ee p. 218) or compl i ca ti ons of ci rrhos i s (s ee p. 241) requi re trea tment.
Li ver tra ns pl a nta ti on ha s excel l ent res ul ts . The genera l i ndi ca ti on i s decompens a ted l i ver di s ea s e (uncontrol l ed va ri cea l bl eedi ng, refra ctory
a s ci tes , i ntra cta bl e pruri tus , a nd hepa ti c encepha l opa thy). Survi va l ra tes a fter l i ver tra ns pl a nta ti on a re > 90% a t 1 yr, > 80% a t 5 yr, a nd > 65% a t 10
yr. AMAs tend to pers i s t a fter tra ns pl a nta ti on. PBC recurs i n 15% of pa ti ents i n the fi rs t few yea rs a nd i n > 30% by 10 yr. So fa r, recurrent PBC a fter
l i ver tra ns pl a nta ti on ha s a beni gn cours e. Ci rrhos i s ra rel y occurs .
Chapter 28. Hepatitis

Introduction
Hepa ti ti s i s a n i nfl a mma ti on of the l i ver cha ra cteri zed by di ffus e or pa tchy necros i s . Ma jor ca us es a re s peci fi c hepa ti ti s vi rus es , a l cohol , a nd
drugs . Les s common ca us es i ncl ude other vi ra l i nfecti ons (eg, i nfecti ous mononucl eos i s , yel l ow fever, cytomega l ovi rus i nfecti on) a nd
l eptos pi ros i s . Pa ra s i ti c i nfecti ons (eg, s chi s tos omi a s i s , ma l a ri a , a mebi a s i s ), pyogeni c i nfecti ons , a nd a bs ces s es tha t a ffect the l i ver a re not
cons i dered hepa ti ti s . Li ver i nvol vement wi th TB a nd other gra nul oma tous i nfi l tra ti ons i s s ometi mes ca l l ed gra nul oma tous hepa ti ti s , but the
cl i ni ca l , bi ochemi ca l , a nd hi s tol ogi c fea tures di ffer from thos e of di ffus e hepa ti ti s .
Va ri ous s ys temi c i nfecti ons a nd other i l l nes s es ma y produce s ma l l foca l a rea s of hepa ti c i nfl a mma ti on or necros i s . Thi s nons peci fi c rea cti ve
hepa ti ti s ca n ca us e mi nor l i ver functi on a bnorma l i ti es but i s us ua l l y a s ymptoma ti c.
Some types of i nfecti ous a nd noni nfecti ous l i ver i nfl a mma ti on a re s umma ri zed (s ee
Ta bl e 28-1).
Acute Viral Hepatitis
Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A
nonspecific viral prodrome is followed by anorexia, nausea, and often fever or right upper quadrant pain. Jaundice often develops, typically as other symptoms
begin to resolve. Most cases resolve spontaneously, but some progress to chronic hepatitis. Occasionally, acute viral hepatitis progresses to acute hepatic failure
(fulminant hepatitis). Diagnosis is by liver function tests and serologic tests to identify the virus. Good hygiene can prevent acute viral hepatitis. Depending on
the specific virus, preexposure and postexposure prophylaxis may be possible using vaccines or serum globulins. Treatment is usually supportive.
(See a l s o Neona ta l Hepa ti ti s B Vi rus Infecti on on p. 2825.)
Acute vi ra l hepa ti ti s i s a common, worl dwi de di s ea s e tha t ha s di fferent ca us es ; ea ch type s ha res cl i ni ca l , bi ochemi ca l , a nd morphol ogi c fea tures .
Li ver i nfecti ons ca us ed by nonhepa ti ti s vi rus es (eg, Eps tei n-Ba rr vi rus , yel l ow fever vi rus , cytomega l ovi rus ) genera l l y a re not termed a cute vi ra l
hepa ti ti s .
Etiology
At l ea s t 5 s peci fi c vi rus es a ppea r to be res pons i bl e (s ee
Ta bl e 28-2). Other uni denti fi ed vi rus es proba bl y a l s o ca us e a cute vi ra l hepa ti ti s .
Hepatitis A virus (HAV): HAV i s a s i ngl e-s tra nded RNA pi corna vi rus . It i s the mos t common ca us e of a cute vi ra l hepa ti ti s a nd i s pa rti cul a rl y common
a mong chi l dren a nd young a dul ts . In s ome countri es , > 75% of a dul ts ha ve been expos ed. HAV s prea ds pri ma ri l y by feca l -ora l conta ct a nd thus ma y
occur i n a rea s of poor hygi ene. Wa terborne a nd food-borne epi demi cs occur, es peci a l l y i n underdevel oped countri es . Ea ti ng conta mi na ted ra w
s hel l fi s h i s s ometi mes res pons i bl e. Spora di c ca s es a re a l s o common, us ua l l y a s a res ul t of pers on-to-pers on conta ct. Feca l s heddi ng of the vi rus
occurs before s ymptoms devel op a nd us ua l l y cea s es a few da ys a fter s ymptoms begi n; thus , i nfecti vi ty often ha s a l rea dy cea s ed when hepa ti ti s
becomes cl i ni ca l l y evi dent. HAV ha s no known chroni c ca rri er s ta te a nd does not ca us e chroni c hepa ti ti s or ci rrhos i s .
Hepatitis B virus (HBV): HBV i s the mos t thoroughl y cha ra cteri zed a nd compl ex hepa ti ti s vi rus . The i nfecti ve pa rti cl e cons i s ts of a vi ra l core pl us a n
outer s urfa ce coa t. The core conta i ns ci rcul a r doubl e-s tra nded DNA a nd DNA pol ymera s e, a nd i t repl i ca tes wi thi n the nucl ei of i nfected
hepa tocytes . A s urfa ce coa t i s a dded i n the cytopl a s m a nd, for unknown rea s ons , i s produced i n grea t exces s .
HBV i s the 2nd mos t common ca us e of a cute vi ra l hepa ti ti s . Pri or unrecogni zed i nfecti on i s common but i s much l es s wi des prea d tha n tha t wi th
HAV. HBV i s often tra ns mi tted pa rentera l l y, typi ca l l y by conta mi na ted bl ood or bl ood products . Routi ne s creeni ng of donor bl ood for hepa ti ti s B
s urfa ce a nti gen (HBs Ag) ha s nea rl y el i mi na ted the previ ous l y common pos ttra ns fus i on tra ns mi s s i on, but tra ns mi s s i on through needl es s ha red by
drug us ers rema i ns common. Ri s k of HBV i s i ncrea s ed for pa ti ents i n rena l di a l ys i s a nd oncol ogy uni ts a nd for hos pi ta l pers onnel i n conta ct wi th
bl ood. The vi rus ma y be s prea d through conta ct wi th other body fl ui ds (eg, between s ex pa rtners , both heteros exua l a nd homos exua l ; i n cl os ed
i ns ti tuti ons , s uch a s menta l hea l th i ns ti tuti ons a nd pri s ons ), but i nfecti vi ty i s fa r l ower tha n tha t of HAV, a nd the mea ns of tra ns mi s s i on i s often
unknown. The rol e of i ns ect bi tes i n tra ns mi s s i on i s uncl ea r. Ma ny ca s es of a cute hepa ti ti s B occur s pora di ca l l y wi thout a known s ource.
HBV, for unknown rea s ons , i s s ometi mes a s s oci a ted wi th s evera l pri ma ri l y extra hepa ti c di s orders , i ncl udi ng pol ya rteri ti s nodos a , other
connecti ve ti s s ue di s ea s es , membra nous gl omerul onephri ti s , a nd es s enti a l mi xed cryogl obul i nemi a . The pa thogeni c rol e of HBV i n thes e
di s orders i s uncl ea r, but a utoi mmune mecha ni s ms a re s ugges ted.
Chroni c HBV ca rri ers provi de a worl dwi de res ervoi r of i nfecti on. Preva l ence va ri es wi del y a ccordi ng to s evera l fa ctors , i ncl udi ng geogra phy (eg, <
0.5% i n North Ameri ca a nd northern Europe, > 10% i n s ome regi ons of the Fa r Ea s t). Verti ca l tra ns mi s s i on from mother to i nfa nt i s common (s ee p.
2644).
[Table 28-1. Sel ected Di s ea s es or Orga ni s ms As s oci a ted wi th Li ver Infl a mma ti on]
Hepatitis C virus (HCV): HCV i s a s i ngl e-s tra nded RNA fl a vi vi rus . Si x ma jor HCV s ubtypes exi s t wi th va ryi ng a mi no a ci d s equences (genotypes ); thes e
s ubtypes va ry geogra phi ca l l y a nd i n vi rul ence a nd res pons e to thera py. HCV ca n a l s o a l ter i ts a mi no a ci d pa ttern over ti me i n a n i nfected pers on,
produci ng qua s i s peci es .
Infecti on i s mos t commonl y tra ns mi tted through bl ood, pri ma ri l y when pa rentera l drug us ers s ha re needl es , but a l s o through ta ttoos or body
pi erci ng. Sexua l tra ns mi s s i on a nd verti ca l tra ns mi s s i on from mother to i nfa nt a re rel a ti vel y ra re. Tra ns mi s s i on through bl ood tra ns fus i on ha s
become very ra re s i nce the a dvent of s creeni ng tes ts for dona ted bl ood. Some s pora di c ca s es occur i n pa ti ents wi thout a ppa rent ri s k fa ctors . HCV
preva l ence va ri es wi th geogra phy a nd other ri s k fa ctors .
HCV i nfecti on s ometi mes occurs s i mul ta neous l y wi th s peci fi c s ys temi c di s orders , i ncl udi ng es s enti a l mi xed cryogl obul i nemi a , porphyri a cuta nea
ta rda (a bout 60 to 80% of porphyri a pa ti ents ha ve HCV i nfecti on, but onl y a few pa ti ents i nfected wi th HCV devel op porphyri a ), a nd
gl omerul onephri ti s ; the mecha ni s ms a re uncerta i n. In a ddi ti on, up to 20% of pa ti ents wi th a l cohol i c l i ver di s ea s e ha rbor HCV. The rea s ons for thi s
hi gh a s s oci a ti on a re uncl ea r beca us e concomi ta nt a l cohol a nd drug us e a ccounts for onl y a porti on of ca s es . In thes e pa ti ents , HCV a nd a l cohol
a ct s ynergi s ti ca l l y to exa cerba te l i ver da ma ge.
Hepatitis D virus (HDV): HDV, or del ta a gent, i s a defecti ve RNA vi rus tha t ca n repl i ca te onl y i n the pres ence of HBV. It occurs uncommonl y a s a coi nfecti on wi th a cute hepa ti ti s B or a s a s uperi nfecti on i n chroni c hepa ti ti s B. Infected hepa tocytes conta i n del ta pa rti cl es coa ted wi th HBs Ag.
Preva l ence of HDV va ri es wi del y geogra phi ca l l y, wi th endemi c pockets i n s evera l countri es . Pa rentera l drug us ers a re a t rel a ti vel y hi gh ri s k, but
HDV (unl i ke HBV) ha s not wi del y permea ted the homos exua l communi ty.
Hepatitis E virus (HEV): HEV i s a n enteri ca l l y tra ns mi tted RNA vi rus . Outbrea ks of a cute HEV i nfecti on, often wa terborne a nd l i nked to feca l
conta mi na ti on of the wa ter s uppl y, ha ve occurred i n Chi na , Indi a , Mexi co, Pa ki s ta n, Peru, Rus s i a , a nd centra l a nd northern Afri ca . Thes e outbrea ks
ha ve epi demi ol ogi c cha ra cteri s ti cs s i mi l a r to HAV epi demi cs . Spora di c ca s es a l s o occur. No outbrea ks ha ve occurred i n the US or i n Wes tern
Europe. Li ke HAV, HEV does not ca us e chroni c hepa ti ti s or ci rrhos i s , a nd there i s no chroni c ca rri er s ta te.
Symptoms and Signs
General: Acute i nfecti on tends to devel op i n predi cta bl e pha s es . Infecti on begi ns wi th a n i ncuba ti on peri od (s ee Ta bl e 28-2), duri ng whi ch the
vi rus mul ti pl i es a nd s prea ds wi thout s ymptoms . The prodroma l , or pre-i cteri c, pha s e fol l ows , ca us i ng nons peci fi c s ymptoms , s uch a s profound
a norexi a , ma l a i s e, na us ea a nd vomi ti ng, a nd often fever or ri ght upper qua dra nt a bdomi na l pa i n. Urti ca ri a a nd a rthra l gi a s occa s i ona l l y occur,
es peci a l l y i n HBV i nfecti on. After 3 to 10 da ys , the uri ne da rkens , fol l owed by ja undi ce (the i cteri c pha s e). Sys temi c s ymptoms often regres s , a nd
the pa ti ent feel s better des pi te wors eni ng ja undi ce. Duri ng the i cteri c pha s e, the l i ver i s us ua l l y enl a rged a nd tender, but the edge of the l i ver
rema i ns s oft a nd s mooth. Mi l d s pl enomega l y occurs i n 15 to 20% of pa ti ents . Ja undi ce us ua l l y pea ks wi thi n 1 to 2 wk a nd then fa des duri ng a 2- to
4-wk recovery pha s e. Appeti te us ua l l y returns a fter the fi rs t week. Acute vi ra l hepa ti ti s us ua l l y res ol ves s ponta neous l y 4 to 8 wk a fter s ymptom
ons et.
Someti mes a ni cteri c hepa ti ti s , a mi nor fl ul i ke i l l nes s wi thout ja undi ce, i s the onl y ma ni fes ta ti on. It occurs more often tha n i cteri c hepa ti ti s i n
pa ti ents wi th HCV i nfecti on a nd i n chi l dren wi th HAV i nfecti on.
Recrudes cent hepa ti ti s occurs i n a few pa ti ents a nd i s cha ra cteri zed by recurrent ma ni fes ta ti ons duri ng the recovery pha s e. Ma ni fes ta ti ons of
chol es ta s i s ma y devel op duri ng the i cteri c pha s e (ca l l ed chol es ta ti c hepa ti ti s ) but us ua l l y res ol ve. When they pers i s t, they ca us e prol onged
ja undi ce, el eva ted a l ka l i ne phos pha ta s e, a nd pruri tus , des pi te genera l regres s i on of i nfl a mma ti on.
Virus-specific: HAV often does not ca us e ja undi ce a nd ma y not ca us e a ny s ymptoms . It a l mos t i nva ri a bl y res ol ves a fter the a cute i nfecti on, a l though
there ca n be ea rl y recrudes cence.
HBV ca us es a wi de s pectrum of l i ver di s ea s es , from a s ubcl i ni ca l ca rri er s ta te to s evere or ful mi na nt a cute hepa ti ti s , pa rti cul a rl y i n the el derl y, i n
whom morta l i ty ca n rea ch 10 to 15%. Fi ve to 10% of a l l pa ti ents wi th HBV devel op chroni c hepa ti ti s or become i na cti ve ca rri ers . Ci rrhos i s ca n
devel op. Hepa tocel l ul a r ca rci noma ca n ul ti ma tel y devel op i n chroni c HBV i nfecti on, even wi thout bei ng preceded by ci rrhos i s .
HCV ma y be a s ymptoma ti c duri ng the a cute i nfecti on. Its s everi ty often fl uctua tes , s ometi mes wi th recrudes cent hepa ti ti s a nd
[Table 28-2. Cha ra cteri s ti cs of Hepa ti ti s Vi rus es ]
rol l er-coa s ter a mi notra ns fera s e l evel s for ma ny yea rs or even deca des . HCV ha s the hi ghes t ra te of chroni ci ty (a bout 75%). The res ul ta nt chroni c
hepa ti ti s i s us ua l l y a s ymptoma ti c or beni gn but progres s es to ci rrhos i s i n 20 to 30% of pa ti ents ; ci rrhos i s often ta kes deca des to a ppea r.
Hepa tocel l ul a r ca rci noma ca n res ul t from HCV-i nduced ci rrhos i s but res ul ts onl y ra rel y from chroni c i nfecti on wi thout ci rrhos i s (unl i ke i n HBV
i nfecti on).
Acute HDV i nfecti on typi ca l l y ma ni fes ts a s unus ua l l y s evere a cute HBV i nfecti on (co-i nfecti on), a n a cute exa cerba ti on i n chroni c HBV ca rri ers
(s uperi nfecti on), or a rel a ti vel y a ggres s i ve cours e of chroni c HBV i nfecti on.
HEV ma y be s evere, es peci a l l y i n pregna nt women.
Diagnosis
Li ver functi on tes ts (AST a nd ALT el eva ted out of proporti on to a l ka l i ne phos pha ta s e, us ua l l y wi th hyperbi l i rubi nemi a )
Vi ra l s erol ogi c tes ti ng
PT mea s urement
Initial diagnosis: Acute hepa ti ti s mus t fi rs t be di fferenti a ted from other di s orders tha t ca us e s i mi l a r s ymptoms . In the prodroma l pha s e, hepa ti ti s
mi mi cs va ri ous nons peci fi c vi ra l i l l nes s es a nd i s di ffi cul t to di a gnos e. Ani cteri c pa ti ents s us pected of ha vi ng hepa ti ti s ba s ed on ri s k fa ctors a re
tes ted i ni ti a l l y wi th nons peci fi c l i ver functi on tes ts , i ncl udi ng a mi notra ns fera s es , bi l i rubi n, a nd a l ka l i ne phos pha ta s e. Us ua l l y, a cute hepa ti ti s i s
s us pected onl y duri ng the i cteri c pha s e. Thus , a cute hepa ti ti s s houl d be di fferenti a ted from other di s orders ca us i ng ja undi ce (s ee
Fi g. 28-1 a nd p. 212).
Acute hepa ti ti s ca n us ua l l y be di fferenti a ted from other ca us es of ja undi ce by i ts ma rked el eva ti ons of AST a nd ALT (typi ca l l y 400 IU/L). ALT i s
typi ca l l y hi gher tha n AST, but a bs ol ute l evel s correl a te poorl y wi th cl i ni ca l s everi ty. Va l ues i ncrea s e ea rl y i n the prodroma l pha s e, pea k before
ja undi ce i s ma xi ma l , a nd fa l l s l owl y duri ng the recovery pha s e. Uri na ry bi l i rubi n us ua l l y precedes ja undi ce. Hyperbi l i rubi nemi a i n a cute vi ra l
hepa ti ti s va ri es i n s everi ty, a nd fra cti ona ti on ha s no cl i ni ca l va l ue. Al ka l i ne phos pha ta s e i s us ua l l y onl y modera tel y el eva ted; ma rked el eva ti on
s ugges ts extra hepa ti c chol es ta s i s a nd prompts i ma gi ng tes ts (eg, ul tra s onogra phy). Li ver bi ops y genera l l y i s not needed unl es s the di a gnos i s i s
uncerta i n. If l a bora tory res ul ts s ugges t a cute hepa ti ti s , pa rti cul a rl y i f ALT a nd AST a re > 1000 IU/L, PT i s mea s ured. Ma ni fes ta ti ons of porta l s ys temi c encepha l opa thy, bl eedi ng di a thes i s , or prol onga ti on of INR s ugges t ful mi na nt hepa ti ti s (s ee p. 254).
If a cute hepa ti ti s i s s us pected, efforts a re next di rected towa rd i denti fyi ng i ts ca us e. A hi s tory of expos ure ma y provi de the onl y cl ue of drugi nduced or toxi c hepa ti ti s . The hi s tory s houl d a l s o el i ci t ri s k fa ctors for vi ra l hepa ti ti s . Prodroma l s ore throa t a nd di ffus e a denopa thy s ugges t
i nfecti ous mononucl eos i s ra ther tha n vi ra l hepa ti ti s . Al cohol i c hepa ti ti s i s s ugges ted by a hi s tory of dri nki ng, more gra dua l ons et of s ymptoms ,
a nd pres ence of va s cul a r s pi ders or s i gns of chroni c a l cohol us e or chroni c l i ver di s ea s e (s ee a l s o p. 235); a mi notra ns fera s e l evel s ra rel y exceed
300 IU/L, even i n s evere ca s es . Al s o, unl i ke i n vi ra l hepa ti ti s , AST i s typi ca l l y hi gher tha n ALT, a l though thi s di fference by i ts el f does not rel i a bl y
di fferenti a te the two. In uncerta i n ca s es , l i ver bi ops y us ua l l y di s ti ngui s hes a l cohol i c from vi ra l hepa ti ti s .
Serology: In pa ti ents wi th fi ndi ngs s ugges ti ng a cute vi ra l hepa ti ti s , the fol l owi ng s tudi es a re done to s creen for hepa ti ti s vi rus es A, B, a nd C:
IgM a nti body to HAV (IgM a nti -HAV)
HBs Ag
IgM a nti body to hepa ti ti s B core (IgM a nti -HBc)
Anti body to HCV (a nti -HCV)
If a ny a re pos i ti ve, further s erol ogi c tes ti ng ma y be neces s a ry to di fferenti a te a cute from pa s t or chroni c i nfecti on (s ee
Ta bl es 28-3,
28-4, a nd
28-5). If s erol ogy s ugges ts hepa ti ti s B, tes ti ng for hepa ti ti s B e a nti gen (HBeAg) a nd a nti body to hepa ti ti s B e a nti gen (a nti -HBe) i s us ua l l y done to
hel p determi ne the prognos i s a nd to gui de a nti vi ra l thera py. If s erol ogi ca l l y confi rmed HBV i s s evere, a nti -HDV i s mea s ured. If the pa ti ent ha s
recentl y tra vel ed to a n endemi c a rea , IgM a nti -HEV s houl d be mea s ured i f the tes t i s a va i l a bl e.
HAV i s pres ent i n s erum onl y duri ng a cute i nfecti on a nd ca nnot be detected by cl i ni ca l l y a va i l a bl e tes ts . IgM a nti body typi ca l l y devel ops ea rl y i n
the i nfecti on a nd pea ks a bout 1 to 2 wk a fter the devel opment of ja undi ce. It di mi ni s hes wi thi n s evera l weeks , fol l owed by the devel opment of
protecti ve IgG a nti body (IgG a nti -HAV), whi ch pers i s ts us ua l l y for l i fe. Thus , IgM a nti body i s a ma rker of a cute i nfecti on, wherea s IgG a nti -HAV
i ndi ca tes onl y previ ous expos ure to HAV a nd i mmuni ty to recurrent i nfecti on.
HBV ha s a t l ea s t 3 di s ti nct a nti gen-a nti body s ys tems tha t ca n be tes ted: HBs Ag, hepa ti ti s B core a nti gen (HBcAg), a nd HBeAg. HBV-DNA ca n a l s o be
tes ted. HBV s urfa ce coa t ca n be detected i n s erum a s HBs Ag. HBs Ag cha ra cteri s ti ca l l y a ppea rs duri ng the i ncuba ti on peri od, us ua l l y 1 to 6 wk
before cl i ni ca l or bi ochemi ca l
[Fig. 28-1. Si mpl i fi ed di a gnos ti c a pproa ch to pos s i bl e a cute vi ra l hepa ti ti s .]
i l l nes s devel ops , a nd i mpl i es i nfecti vi ty of the bl ood. It di s a ppea rs duri ng conva l es cence. However, HBs Ag i s occa s i ona l l y tra ns i ent. The
corres pondi ng protecti ve a nti body (a nti -HBs ) a ppea rs weeks or months l a ter, a fter cl i ni ca l recovery, a nd us ua l l y pers i s ts for l i fe; thus , i ts
detecti on i ndi ca tes pa s t HBV i nfecti on a nd rel a ti ve i mmuni ty. In 5 to 10% of pa ti ents , HBs Ag pers i s ts a nd a nti bodi es do not devel op; thes e
pa ti ents become a s ymptoma ti c ca rri ers of the vi rus or devel op chroni c hepa ti ti s .
HBcAg refl ects the vi ra l core. It i s detecta bl e i n i nfected l i ver cel l s but not i n s erum except by s peci a l techni ques . Anti body to HBcAg (a nti -HBc)
genera l l y a ppea rs a t the ons et of cl i ni ca l i l l nes s ; therea fter, ti ters gra dua l l y di mi ni s h, us ua l l y over yea rs or l i fe. Its pres ence wi th a nti -HBs
i ndi ca tes recovery from previ ous HBV i nfecti on. Anti -HBc i s a l s o pres ent i n chroni c HBs Ag ca rri ers , who do not mount a n a nti -HBs res pons e. In
a cute i nfecti on, a nti -HBc i s ma i nl y of the IgM cl a s s , wherea s i n chroni c i nfecti on, IgG a nti -HBc predomi na tes . IgM a nti -HBc i s a s ens i ti ve ma rker of
a cute HBV i nfecti on a nd occa s i ona l l y i s the onl y ma rker of recent i nfecti on, refl ecti ng a wi ndow between di s a ppea ra nce of HBs Ag a nd a ppea ra nce
of a nti -HBs .
HBeAg i s a protei n deri ved from the vi ra l core (not to be confus ed wi th hepa ti ti s E vi rus ).
[Table 28-3. Hepa ti ti s A Serol ogy]
Pres ent onl y i n HBs Ag-pos i ti ve s erum, HBeAg tends to s ugges t more a cti ve vi ra l repl i ca ti on a nd grea ter i nfecti vi ty. In contra s t, pres ence of the
corres pondi ng a nti body (a nti -HBe) s ugges ts l ower i nfecti vi ty. Thus , e a nti gen ma rkers a re more hel pful i n prognos i s tha n i n di a gnos i s . Chroni c
l i ver di s ea s e devel ops more often a mong pa ti ents wi th HBeAg a nd l es s often a mong pa ti ents wi th a nti -HBe.
In pa ti ents wi th a cti ve HBV i nfecti on, HBV-DNA ca n be detected i n the s erum wi th s peci a l tes ti ng, a l though thi s tes ti ng i s not routi nel y a va i l a bl e.
In HCV, s erum a nti body to HCV (a nti -HCV) a l mos t a l wa ys i mpl i es a cti ve i nfecti on; i t i s not protecti ve. Anti -HCV us ua l l y a ppea rs wi thi n 2 wk of a cute
i nfecti on but i s s ometi mes del a yed; however, HCV-RNA i s pos i ti ve. In a s ma l l proporti on of pa ti ents , a nti -HCV merel y refl ects pri or expos ure wi th
cl ea ra nce of the vi rus ra ther tha n a cti ve i nfecti on. In s uch ca s es , ALT a nd AST l evel s a re us ua l l y norma l . In uncl ea r ca s es , HCV-RNA i s mea s ured.
[Table 28-4. Hepa ti ti s B Serol ogy*]
[Table 28-5. Hepa ti ti s C Serol ogy]
In HDV, a nti -HDV i mpl i es a cti ve i nfecti on. It ma y not be detecta bl e unti l weeks a fter the a cute i l l nes s .
In HEV, the tes t for IgM a nti -HEV i s not routi nel y a va i l a bl e. In a pa ti ent wi th endemi c expos ure a nd compa ti bl e cl i ni ca l fi ndi ngs , a nti -HEV s ugges ts
a cute HEV i nfecti on.
Biopsy: Bi ops y i s us ua l l y unneces s a ry but, i f done, us ua l l y revea l s s i mi l a r hi s topa thol ogy rega rdl es s of the s peci fi c vi rus : pa tchy cel l dropout,
a ci dophi l i c hepa tocel l ul a r necros i s , mononucl ea r i nfl a mma tory i nfi l tra te, hi s tol ogi c evi dence of regenera ti on, a nd pres erva ti on of the reti cul i n
fra mework. HBV ca n occa s i ona l l y be di a gnos ed ba s ed on the pres ence of ground-gl a s s hepa tocytes (ca us ed by HBs Ag-pa cked cytopl a s m) a nd
us i ng s peci a l i mmunol ogi c s ta i ns for the vi ra l components . However, thes e fi ndi ngs a re unus ua l i n a cute HBV a nd a re much more common i n
chroni c HBV i nfecti on. HCV ca us a ti on ca n s ometi mes be i nferred from s ubtl e morphol ogi c cl ues . Li ver bi ops y ma y hel p predi ct prognos i s i n a cute
hepa ti ti s but i s ra rel y done s ol el y for thi s purpos e. Compl ete hi s tol ogi c recovery occurs unl es s extens i ve necros i s bri dges enti re a ci ni (bri dgi ng
necros i s ). Mos t pa ti ents wi th bri dgi ng necros i s recover ful l y. However, s ome ca s es progres s to chroni c hepa ti ti s .
Treatment
Supporti ve ca re
Occa s i ona l l y pos texpos ure prophyl a xi s
No trea tments a ttenua te a cute vi ra l hepa ti ti s except, occa s i ona l l y, pos texpos ure i mmunoprophyl a xi s . Al cohol s houl d be a voi ded beca us e i t ca n
i ncrea s e l i ver da ma ge. Res tri cti ons on di et or a cti vi ty, i ncl udi ng commonl y pres cri bed bed res t, ha ve no s ci enti fi c ba s i s . Mos t pa ti ents ma y s a fel y
return to work a fter ja undi ce res ol ves , even i f AST or ALT l evel s a re s l i ghtl y el eva ted. For chol es ta ti c hepa ti ti s , chol es tyra mi ne 8 g po once/da y or
bi d ca n rel i eve i tchi ng. Vi ra l hepa ti ti s s houl d be reported to the l oca l or s ta te hea l th depa rtment.
Prevention
Beca us e trea tments ha ve l i mi ted effi ca cy, preventi on of vi ra l hepa ti ti s i s very i mporta nt. Good pers ona l hygi ene hel ps prevent tra ns mi s s i on,
pa rti cul a rl y feca l -ora l tra ns mi s s i on, a s occurs wi th HAV a nd HEV. Bl ood a nd other body fl ui ds (eg, s a l i va , s emen) of pa ti ents wi th a cute HBV a nd
HCV a nd s tool of pa ti ents wi th HAV a re cons i dered i nfecti ous . Ba rri er protecti on i s recommended, but i s ol a ti on of pa ti ents does l i ttl e to prevent
s prea d of HAV a nd i s of no va l ue i n HBV or HCV i nfecti on. Pos ttra ns fus i on i nfecti on i s mi ni mi zed by a voi di ng unneces s a ry tra ns fus i ons a nd
s creeni ng a l l donors for HBs Ag a nd a nti -HCV. Screeni ng ha s decrea s ed the i nci dence of pos ttra ns fus i on hepa ti ti s , proba bl y to a bout 1/100,000
uni ts of bl ood component tra ns fus ed.
Immunoprophyl a xi s ca n i nvol ve a cti ve i mmuni za ti on us i ng va cci nes a nd pa s s i ve i mmuni za ti on.
HAV: Preexpos ure HAV prophyl a xi s s houl d be provi ded for tra vel ers to hi ghl y endemi c a rea s . It s houl d a l s o be cons i dered for mi l i ta ry pers onnel ,
da y-ca re center empl oyees , di a gnos ti c l a bora tory workers , a nd, beca us e they ha ve a n i ncrea s ed ri s k of ful mi na nt hepa ti ti s from HAV, pa ti ents
wi th chroni c l i ver di s orders (i ncl udi ng chroni c hepa ti ti s C). Severa l va cci nes a ga i ns t HAV a re a va i l a bl e, ea ch wi th di fferent dos es a nd s chedul es ;
they a re s a fe, provi de protecti on wi thi n a bout 4 wk, a nd provi de prol onged protecti on (proba bl y for > 20 yr).
Sta nda rd i mmune gl obul i n, formerl y i mmune s erum gl obul i n, prevents or decrea s es the s everi ty of HAV i nfecti on a nd s houl d be gi ven to fa mi l y
members a nd cl os e conta cts of pa ti ents for pos texpos ure prophyl a xi s ; 0.02 mL/kg IM i s genera l l y recommended, but s ome experts a dvi s e 0.06
mL/kg (3 to 5 mL for a dul ts ).
HBV: Va cci na ti on i n endemi c a rea s ha s dra ma ti ca l l y reduced l oca l preva l ence. Pre-expos ure i mmuni za ti on ha s l ong been recommended for
peopl e a t hi gh ri s k. However, s el ecti ve va cci na ti on of hi gh-ri s k groups i n the US a nd other nonendemi c a rea s ha s not s ubs ta nti a l l y decrea s ed the
i nci dence of HBV; thus , va cci na ti on i s now recommended for a l l US res i dents < 18 begi nni ng a t bi rth. Uni vers a l worl dwi de va cci na ti on i s des i ra bl e
but i s too expens i ve to be fea s i bl e.
Two recombi na nt va cci nes a re a va i l a bl e; both a re s a fe, even duri ng pregna ncy. Three IM del toi d i njecti ons a re gi ven: a t ba s el i ne, a t 1 mo, a nd a t 6
mo. Chi l dren a re gi ven l ower dos es , a nd i mmunos uppres s ed pa ti ents a nd pa ti ents recei vi ng hemodi a l ys i s a re gi ven hi gher dos es .
After va cci na ti on, l evel s of a nti -HBs rema i n protecti ve for 5 yr i n 80 to 90% of i mmunocompetent reci pi ents a nd for 10 yr i n 60 to 80%. Boos ter dos es
of va cci ne a re recommended for pa ti ents recei vi ng hemodi a l ys i s a nd i mmunos uppres s ed pa ti ents whos e a nti -HBs i s < 10 mIU/mL.
HBV pos texpos ure i mmunoprophyl a xi s combi nes va cci na ti on wi th hepa ti ti s B i mmune gl obul i n (HBIG), a product wi th hi gh ti ters of a nti -HBs . HBIG
proba bl y does not prevent i nfecti on but prevents or a ttenua tes cl i ni ca l i l l nes s . For i nfa nts born to HBs Ag-pos i ti ve mothers , a n i ni ti a l dos e of
va cci ne pl us 0.5 mL of HBIG i s gi ven IM i n the thi gh i mmedi a tel y a fter bi rth. For a nyone ha vi ng s exua l conta ct wi th a n HBs Ag-pos i ti ve pers on or
percuta neous or mucous membra ne expos ure to HBs Ag-pos i ti ve bl ood, 0.06 mL/kg of HBIG i s gi ven IM wi thi n da ys , a l ong wi th va cci ne. Any
previ ous l y va cci na ted pa ti ent s us ta i ni ng a percuta neous HBs Ag-pos i ti ve expos ure i s tes ted for a nti -HBs ; i f ti ters a re < 10 mIU/mL, a boos ter dos e
of va cci ne i s gi ven.
HCV, HDV, and HEV: A va cci ne i s now a va i l a bl e for hepa ti ti s E; i t a ppea rs to ha ve a bout 95% effi ca cy i n preventi ng s ymptoma ti c i nfecti on i n ma l es
a nd i s s a fe. Effi ca cy i n other groups , dura ti on of protecti on, a nd effi ca cy i n preventi ng a s ymptoma ti c i nfecti on a re unknown. No product exi s ts for
i mmunoprophyl a xi s of HCV or HDV. However, preventi on of HBV prevents HDV. The propens i ty of HCV for cha ngi ng i ts genome ha mpers va cci ne
devel opment.
Fulminant Hepatitis
Fulminant hepatitis is a rare syndrome of massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy) that usually occurs after
infection with certain hepatitis viruses, exposure to toxic agents, or drug-induced injury.
HBV i s s ometi mes res pons i bl e, a nd up to 50% of ca s es of ful mi na nt hepa ti ti s B i nvol ve HDV coi nfecti on. Ful mi na nt hepa ti ti s wi th HAV i s ra re but
ma y be more l i kel y i n peopl e wi th preexi s ti ng l i ver di s orders . The rol e of HCV rema i ns uncerta i n.
Pa ti ents ra pi dl y deteri ora te beca us e porta l -s ys temi c encepha l opa thy devel ops , often fol l owed by coma wi thi n hours or a few da ys , s ometi mes
wi th cerebra l edema . Bl eedi ng commonl y res ul ts from hepa ti c fa i l ure or di s s emi na ted i ntra va s cul a r coa gul a ti on, a nd functi ona l rena l fa i l ure
(hepa torena l s yndromes ee p. 223) ma y devel op. Increa s i ng PT, porta l -s ys temi c encepha l opa thy, a nd pa rti cul a rl y rena l fa i l ure a re omi nous .
Meti cul ous nurs i ng ca re a nd a ggres s i ve trea tment of compl i ca ti ons i mprove the outcome. However, emergency l i ver tra ns pl a nta ti on provi des the
bes t hope for s urvi va l . Survi va l i n a dul ts i s uncommon wi thout tra ns pl a nta ti on; chi l dren tend to do better. Pa ti ents who s urvi ve us ua l l y recover
ful l y.
Chronic Hepatitis
Chronic hepatitis is hepatitis that lasts > 6 mo. Common causes include hepatitis B and C viruses, autoimmune mechanisms (autoimmune hepatitis), and drugs.
Many patients have no history of acute hepatitis, and the first indication is discovery of asymptomatic aminotransferase elevations. Some patients present with
cirrhosis or its complications (eg, portal hypertension). Biopsy is necessary to confirm the diagnosis and to grade and stage the disease. Treatment is directed
toward complications and the underlying condition (eg, corticosteroids for autoimmune hepatitis, antiviral therapy for viral hepatitis). Liver transplantation is
often indicated for end-stage disease.
Etiology
Hepa ti ti s l a s ti ng > 6 mo i s genera l l y defi ned a s chroni c, a l though thi s dura ti on i s a rbi tra ry. Hepa ti ti s B vi rus (HBV) a nd hepa ti ti s C vi rus (HCV) a re
frequent ca us es of chroni c hepa ti ti s ; 5 to 10% of ca s es of HBV i nfecti on, wi th or wi thout hepa ti ti s D vi rus (HDV) co-i nfecti on, a nd a bout 75% of
ca s es of HCV i nfecti on become chroni c. Hepa ti ti s A a nd E vi rus es a re not ca us es . Al though the mecha ni s m of chroni ci ty i s uncerta i n, l i ver i njury i s
mos tl y determi ned by the pa ti ent's i mmune rea cti on to the i nfecti on.
Ma ny ca s es a re i di opa thi c. A hi gh proporti on of i di opa thi c ca s es ha ve promi nent fea tures of i mmune-medi a ted hepa tocel l ul a r i njury
(a utoi mmune hepa ti ti s ), i ncl udi ng the fol l owi ng:
The pres ence of s erol ogi c i mmune ma rkers
An a s s oci a ti on wi th hi s tocompa ti bi l i ty ha pl otypes common i n a utoi mmune di s orders (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4)
A predomi na nce of T l ymphocytes a nd pl a s ma cel l s i n l i ver hi s tol ogi c l es i ons
Compl ex i n vi tro defects i n cel l ul a r i mmuni ty a nd i mmunoregul a tory functi ons
An a s s oci a ti on wi th other a utoi mmune di s orders (eg, RA, a utoi mmune hemol yti c a nemi a , prol i fera ti ve gl omerul onephri ti s )
A res pons e to thera py wi th corti cos teroi ds or i mmunos uppres s a nts
Someti mes chroni c hepa ti ti s ha s fea tures of both a utoi mmune hepa ti ti s a nd a nother chroni c l i ver di s order (eg, pri ma ry bi l i a ry ci rrhos i s , chroni c
vi ra l hepa ti ti s ). Thes e condi ti ons a re ca l l ed overl a p s yndromes .
Ma ny drugs , i ncl udi ng i s oni a zi d, methyl dopa , ni trofura ntoi n, a nd, ra rel y, a ceta mi nophen, ca n ca us e chroni c hepa ti ti s . The mecha ni s m va ri es wi th
the drug a nd ma y i nvol ve a l tered i mmune res pons es , cytotoxi c i ntermedi a te meta bol i tes , or geneti ca l l y determi ned meta bol i c defects .
Other ca us es of chroni c hepa ti ti s i ncl ude a l cohol i c hepa ti ti s a nd nona l cohol i c s tea tohepa ti ti s . Les s often, chroni c hepa ti ti s res ul ts from 1 a nti tryps i n defi ci ency or Wi l s on's di s ea s e.
Ca s es were once cl a s s i fi ed hi s tol ogi ca l l y a s chroni c pers i s tent, chroni c l obul a r, or chroni c a cti ve hepa ti ti s . A more us eful recent cl a s s i fi ca ti on
s ys tem s peci fi es the eti ol ogy, the i ntens i ty of hi s tol ogi c i nfl a mma ti on a nd necros i s (gra de), a nd the degree of hi s tol ogi c fi bros i s (s ta ge).
Infl a mma ti on a nd necros i s a re potenti a l l y revers i bl e; fi bros i s genera l l y i s not.
Symptoms and Signs
Cl i ni ca l fea tures va ry wi del y. About one thi rd of ca s es devel op a fter a cute hepa ti ti s , but mos t devel op i ns i di ous l y de novo. Ma ny pa ti ents a re
a s ymptoma ti c, es peci a l l y i n chroni c HCV i nfecti on. However, ma l a i s e, a norexi a , a nd fa ti gue a re common, s ometi mes wi th l ow-gra de fever a nd
nons peci fi c upper a bdomi na l di s comfort. Ja undi ce i s us ua l l y a bs ent. Often, pa rti cul a rl y wi th HCV, the fi rs t fi ndi ngs a re s i gns of chroni c l i ver
di s ea s e (eg, s pl enomega l y, s pi der nevi , pa l ma r erythema ). A few pa ti ents wi th chroni c hepa ti ti s devel op ma ni fes ta ti ons of chol es ta s i s . In the
a utoi mmune va ri a nt, es peci a l l y i n young women, ma ni fes ta ti ons ma y i nvol ve vi rtua l l y a ny body s ys tem a nd ca n i ncl ude a cne, a menorrhea ,
a rthra l gi a , ul cera ti ve col i ti s , pul mona ry fi bros i s , thyroi di ti s , nephri ti s , a nd hemol yti c a nemi a .
Chroni c HCV i s occa s i ona l l y a s s oci a ted wi th l i chen pl a nus , mucocuta neous va s cul i ti s , gl omerul onephri ti s , porphyri a cuta nea ta rda , a nd perha ps
non-Hodgki n B-cel l l ymphoma . About 1% of pa ti ents devel op s ymptoma ti c cryogl obul i nemi a wi th fa ti gue, mya l gi a s , a rthra l gi a s , neuropa thy,
gl omerul onephri ti s , a nd s ki n ra s hes (urti ca ri a , purpura , or l eukocytocl a s ti c va s cul i ti s ); a s ymptoma ti c cryogl obul i nemi a i s more common.
Diagnosis
Li ver functi on tes t res ul ts compa ti bl e wi th hepa ti ti s
Vi ra l s erol ogi c tes ts
Pos s i bl y a utoa nti bodi es , i mmunogl obul i ns , 1 -a nti tryps i n l evel , a nd other tes ts
Us ua l l y bi ops y
Serum a l bumi n a nd PT
The di a gnos i s i s s us pected i n pa ti ents wi th s ugges ti ve s ymptoms a nd s i gns , i nci denta l l y noted el eva ti ons i n a mi notra ns fera s e l evel s , or
previ ous l y di a gnos ed a cute hepa ti ti s . Li ver functi on tes ts a re needed i f not previ ous l y done a nd i ncl ude s erum ALT, AST, a l ka l i ne phos pha ta s e,
a nd bi l i rubi n. Ami notra ns fera s e el eva ti ons a re the mos t cha ra cteri s ti c l a bora tory a bnorma l i ti es . Al though l evel s ca n va ry, they a re typi ca l l y 100 to
500 IU/L. ALT i s us ua l l y hi gher tha n AST. Ami no-tra ns fera s e l evel s ca n be norma l duri ng chroni c hepa ti ti s i f the di s ea s e i s qui es cent, pa rti cul a rl y
wi th HCV. Al ka l i ne phos pha ta s e i s us ua l l y norma l or onl y s l i ghtl y el eva ted but i s occa s i ona l l y ma rkedl y hi gh. Bi l i rubi n i s us ua l l y norma l unl es s
the di s ea s e i s s evere or a dva nced. However, a bnorma l i ti es i n thes e l a bora tory tes ts a re not s peci fi c a nd ca n res ul t from other di s orders , s uch a s
a l cohol i c l i ver di s ea s e, recrudes cent a cute vi ra l hepa ti ti s , a nd pri ma ry bi l i a ry ci rrhos i s .
If l a bora tory res ul ts a re compa ti bl e wi th hepa ti ti s , vi ra l s erol ogi c tes ts a re done to excl ude HBV a nd HCV (s ee Ta bl es 28-4 a nd 28-5). Unl es s thes e
tes ts i ndi ca te vi ra l eti ol ogy, further tes ti ng i s requi red. The fi rs t tes ts done i ncl ude a utoa nti bodi es , i mmunogl obul i ns , a nd 1 -a nti tryps i n l evel .
Chi l dren a nd young a dul ts a re s creened for Wi l s on's di s ea s e wi th a cerul opl a s mi n l evel . Ma rked el eva ti ons i n s erum i mmunogl obul i ns s ugges t
chroni c a utoi mmune hepa ti ti s but a re not concl us i ve. Autoi mmune hepa ti ti s i s norma l l y di a gnos ed ba s ed on the pres ence of a nti nucl ea r (ANA),
a nti -s mooth mus cl e, or a nti -l i ver/ki dney mi cros oma l type 1 (a nti -LKM1) a nti bodi es a t ti ters of 1:80 (i n a dul ts ) or 1:20 (i n chi l dren).
Unl i ke i n a cute hepa ti ti s , bi ops y i s neces s a ry. Mi l d ca s es ma y ha ve onl y mi nor hepa tocel l ul a r necros i s a nd i nfl a mma tory cel l i nfi l tra ti on, us ua l l y
i n porta l regi ons , wi th norma l a ci na r a rchi tecture a nd l i ttl e or no fi bros i s . Such ca s es ra rel y devel op i nto cl i ni ca l l y i mporta nt l i ver di s ea s e or
ci rrhos i s . In more s evere ca s es , bi ops y typi ca l l y s hows peri porta l necros i s wi th mononucl ea r cel l i nfi l tra tes (pi ecemea l necros i s ) a ccompa ni ed by
va ri a bl e peri porta l fi bros i s a nd bi l e duct prol i fera ti on. The a ci na r a rchi tecture ma y be di s torted by zones of col l a ps e a nd fi bros i s , a nd fra nk
ci rrhos i s s ometi mes coexi s ts wi th s i gns of ongoi ng hepa ti ti s . Bi ops y i s a l s o us ed to gra de a nd s ta ge the di s ea s e.
In mos t ca s es , the s peci fi c ca us e of chroni c hepa ti ti s ca nnot be di s cerned vi a bi ops y a l one, a l though ca s es ca us ed by HBV ca n be di s ti ngui s hed by
the pres ence of ground-gl a s s hepa tocytes a nd s peci a l s ta i ns for HBV components . Autoi mmune ca s es us ua l l y ha ve a more pronounced i nfi l tra ti on
by l ymphocytes a nd pl a s ma cel l s . In pa ti ents wi th hi s tol ogi c but not s erol ogi c cri teri a for chroni c a utoi mmune hepa ti ti s , va ri a nt a utoi mmune
hepa ti ti s i s di a gnos ed; ma ny ha ve overl a p s yndromes .
Serum a l bumi n a nd PT s houl d be mea s ured to determi ne s everi ty; hepa ti c i ns uffi ci ency i s s ugges ted by l ow s erum a l bumi n or prol onged PT. If
s ymptoms or s i gns of cryogl obul i nemi a devel op duri ng chroni c hepa ti ti s , pa rti cul a rl y wi th HCV, cryogl obul i n l evel s a nd rheuma toi d fa ctor s houl d
be mea s ured; hi gh l evel s of rheuma toi d fa ctor a nd l ow l evel s of compl ement s ugges t cryogl obul i nemi a .
Pa ti ents wi th chroni c HBV i nfecti on s houl d be s creened a nnua l l y for hepa tocel l ul a r ca ncer wi th ul tra s onogra phy a nd s erum -fetoprotei n
mea s urement, a l though the cos t-effecti venes s of thi s pra cti ce i s deba ted. Pa ti ents wi th chroni c HCV i nfecti on s houl d be s i mi l a rl y s creened onl y i f
ci rrhos i s i s pres ent.
Prognosis
Prognos i s i s hi ghl y va ri a bl e. Chroni c hepa ti ti s ca us ed by a drug often regres s es compl etel y when the offendi ng drug i s wi thdra wn. Wi thout
trea tment, ca s es ca us ed by HBV ca n res ol ve (uncommon), progres s ra pi dl y, or progres s s l owl y to ci rrhos i s over deca des . Res ol uti on often begi ns
wi th a tra ns i ent i ncrea s e i n di s ea s e s everi ty a nd res ul ts i n s eroconvers i on from hepa ti ti s B e a nti gen (HBeAg) to a nti body to hepa ti ti s B e a nti gen
(a nti -HBe). Co-i nfecti on wi th HDV ca us es the mos t s evere form of chroni c HBV i nfecti on; wi thout trea tment, ci rrhos i s devel ops i n up to 70% of
pa ti ents . Untrea ted chroni c hepa ti ti s due to HCV produces ci rrhos i s i n 20 to 30% of pa ti ents , a l though devel opment ma y ta ke deca des . Chroni c
a utoi mmune hepa ti ti s us ua l l y res ponds to thera py but s ometi mes ca us es progres s i ve fi bros i s a nd eventua l ci rrhos i s .
Chroni c HBV i nfecti on i ncrea s es the ri s k of hepa tocel l ul a r ca ncer. The ri s k i s a l s o i ncrea s ed i n chroni c HCV i nfecti on, but onl y i f ci rrhos i s ha s
a l rea dy devel oped (s ee p. 265).
Treatment
Supporti ve ca re
Trea tment of ca us e (eg, corti cos teroi ds for a utoi mmune hepa ti ti s , a nti vi ra l s for HBV, i nterferons for HCV)
Trea tment goa l s i ncl ude ma na gement of compl i ca ti ons (eg, a s ci tes , encepha l opa thy) a nd trea tment of the ca us e. Drugs tha t ca us e hepa ti ti s
s houl d be s topped. Underl yi ng di s orders , s uch a s Wi l s on's di s ea s e, s houl d be trea ted. In chroni c hepa ti ti s due to HBV, prophyl a xi s for conta cts of
pa ti ents ma y be hel pful (s ee p. 254); corti cos teroi ds a nd i mmunos uppres s i ve drugs s houl d be a voi ded beca us e they enha nce vi ra l repl i ca ti on. No
prophyl a cti c mea s ures a re requi red for conta cts of pa ti ents wi th HCV i nfecti on.
Autoimmune hepatitis: Corti cos teroi ds , wi th or wi thout a za thi opri ne, prol ong s urvi va l . Predni s one i s us ua l l y s ta rted a t 30 to 40 mg po once/da y, then
ta pered to the l owes t dos e tha t ma i nta i ns a mi notra ns fera s es a t norma l or nea r-norma l l evel s . Some experts gi ve concomi ta nt a za thi opri ne 1 to
1.5 mg/kg po once/da y; others a dd a za thi opri ne onl y i f l ow-dos e predni s one fa i l s to ma i nta i n s uppres s i on. Mos t pa ti ents requi re l ong-term, l owdos e ma i ntena nce trea tment. Li ver tra ns pl a nta ti on ma y be requi red for end-s ta ge di s ea s e.
HBV: Anti vi ra l trea tment i s i ndi ca ted for pa ti ents wi th el eva ted a mi notra ns fera s e l evel s , cl i ni ca l or bi ops y evi dence of progres s i ve di s ea s e, or
both. The goa l i s to el i mi na te HBV-DNA. Trea tment ma y need to be conti nued i ndefi ni tel y a nd thus ma y be very expens i ve; s toppi ng trea tment
prema turel y ca n l ea d to rel a ps e, whi ch ma y be s evere. However, trea tment ma y be s topped i f HBeAg converts to a nti -HBe or i f tes ts for HBs Ag
become nega ti ve. Drug res i s ta nce i s a l s o a concern. Si x a nti vi ra l drugs enteca vi r, a defovi r, l a mi vudi ne, i nterferon- (INF-), pegyl a ted INF-2a
(pegi nterferon-2a ), a nd tel bi vudi nea re a va i l a bl e (s ee
Ta bl e 28-6).
Fi rs t-l i ne trea tment i s us ua l l y wi th a n ora l a nti vi ra l drug, s uch a s enteca vi r (a nucl eos i de a na l ogue) or a defovi r (a nucl eoti de a na l ogue).
Combi na ti on thera py ha s not proved s uperi or to monothera py.
Enteca vi r a ppea rs to ha ve hi gher a nti vi ra l potency tha n other commonl y us ed drugs . Res i s ta nce to enteca vi r i s uncommon, but the drug ha s not
been i n wi des prea d cl i ni ca l us e for very l ong. Dos a ge i s 0.5 mg po once/da y; however, pa ti ents who ha ve previ ous l y ta ken
[Table 28-6. Compa ri s on of Drugs Commonl y Us ed to Trea t Chroni c Vi ra l Hepa ti ti s B*]
a nucl eos i de a na l ogue s houl d ta ke 1 mg po once/da y. Dos e reducti on i s requi red i n pa ti ents wi th rena l i ns uffi ci ency. Seri ous a dvers e effects
a ppea r to be uncommon s o fa r, a l though the drug ca n i nduce tumors i n a ni ma l s .
Adefovi r i s a l s o rel a ti vel y potent. Dos a ge i s 10 mg po once/da y. Adefovi r ma y ca us e rena l dys functi on, s o s erum crea ti ni ne l evel mus t be
mea s ured peri odi ca l l y a nd the dos e reduced i f neces s a ry.
Al terna ti vel y, l a mi vudi ne (a nucl eos i de a na l ogue) 100 mg po once/da y i s gi ven. It ha s few a dvers e effects , whi ch i s one of i ts a dva nta ges over
other a nti vi ra l drugs us ed to trea t chroni c HBV i nfecti on. INF- (us ua l l y IFN-2b), formerl y fi rs t-l i ne trea tment, ca n be us ed. Dos a ge i s 5 mi l l i on IU
s c once/da y or 10 mi l l i on IU s c 3 ti mes /wk for 4 mo. In a bout 40% of pa ti ents , thi s regi men el i mi na tes HBV-DNA a nd ca us es s eroconvers i on to a nti HBe; a s ucces s ful res pons e i s us ua l l y pres a ged by a tempora ry i ncrea s e i n a mi notra ns fera s e l evel s . The drug mus t be gi ven by i njecti on a nd i s
often poorl y tol era ted. The fi rs t 1 or 2 dos es ca us e a n i nfl uenza -l i ke s yndrome. La ter, fa ti gue, ma l a i s e, depres s i on, bone ma rrow s uppres s i on,
a nd, ra rel y, ba cteri a l i nfecti ons or a utoi mmune di s orders ca n occur. In pa ti ents wi th a dva nced ci rrhos i s , IFN- ca n preci pi ta te hepa ti c fa i l ure a nd
i s therefore contra i ndi ca ted. Other contra i ndi ca ti ons i ncl ude rena l fa i l ure, i mmunos uppres s i on, s ol i d orga n tra ns pl a nta ti on, cytopeni a , a nd
s ubs ta nce a bus e. In a few pa ti ents , trea tment mus t be s topped beca us e of i ntol era bl e a dvers e effects . The drug s houl d be gi ven ca uti ous l y or not
a t a l l to pa ti ents wi th ongoi ng s ubs ta nce a bus e or a ma jor ps ychi a tri c di s order.
Pegyl a ted IFN-2 ca n a l s o be gi ven. Dos a ge i s 180 g s c once/wk. Advers e effects a re s i mi l a r to thos e of INF- but ma y be l es s s evere.
Tel bi vudi ne i s a new drug tha t ha s grea ter effi ca cy tha n l a mi vudi ne but ha s hi gh ra tes of res i s ta nce.
Li ver tra ns pl a nta ti on s houl d be cons i dered for end-s ta ge l i ver di s ea s e ca us ed by HBV, but the i nfecti on a ggres s i vel y a tta cks the gra ft, a nd
prognos i s i s l es s fa vora bl e tha n when l i ver tra ns pl a nta ti on i s done for other i ndi ca ti ons . Long-term pos ttra ns pl a nta ti on thera py wi th l a mi vudi ne
i mproves the outcome.
HCV: For chroni c hepa ti ti s due to HCV, trea tment i s i ndi ca ted i f a mi notra ns fera s e l evel s a re el eva ted a nd bi ops y s hows a cti ve i nfl a mma tory
di s ea s e wi th evol vi ng fi bros i s . Trea tment a i ms to perma nentl y el i mi na te HCV-RNA (s us ta i ned res pons e), whi ch i s a s s oci a ted wi th perma nent
norma l i za ti on of a mi notra ns fera s e a nd ces s a ti on of hi s tol ogi c progres s i on.
Combi na ti on thera py wi th pegyl a ted IFN- pl us ri ba vi ri n ha s the bes t res ul ts . Pegyl a ted IFN-2b 1.5 g/kg s c once/wk a nd pegyl a ted IFN-2a 180 g
s c once/wk ha ve compa ra bl e res ul ts . Ri ba vi ri n 500 to 600 mg po bi d i s us ua l l y gi ven, a l though 400 mg bi d ma y be s uffi ci ent for vi ra l genotypes 2
a nd 3.
HCV genotype a nd vi ra l l oa d a re determi ned before trea tment beca us e res ul ts i nfl uence trea tment. Genotype 1 i s the mos t common type but i s
rel a ti vel y res i s ta nt to trea tment. Combi na ti on thera py i s gi ven for 1 yr; a s us ta i ned res pons e ra te of a bout 45 to 50% overa l l occurs . Res ul ts a re
more fa vora bl e i n pa ti ents wi th ea rl y di s ea s e a nd l es s fa vora bl e i n thos e who a l rea dy ha ve ci rrhos i s . HCV vi ra l l oa d s houl d be mea s ured a t 3 mo
a nd trea tment s topped i f RNA ha s not decl i ned by a t l ea s t 2 l og l evel s compa red wi th pretrea tment va l ues .
Les s common genotypes 2 a nd 3 res pond more fa vora bl y. Combi na ti on thera py i s requi red for onl y 6 mo a nd gi ves a n overa l l s us ta i ned res pons e
ra te of a bout 75%. Longer trea tment does not i mprove the res ul ts .
Advers e effects of pegyl a ted IFN a re s i mi l a r to thos e of IFN- but ma y be l es s s evere; contra i ndi ca ti ons a re a l s o s i mi l a r (s ee a bove).
Ri ba vi ri n i s us ua l l y wel l tol era ted but commonl y ca us es a nemi a due to hemol ys i s ; dos a ge s houl d be decrea s ed i f hemogl obi n fa l l s to < 10 g/dL.
Ri ba vi ri n i s tera togeni c for both men a nd women, neces s i ta ti ng contra cepti on unti l 6 mo a fter compl eti on of trea tment. Pa ti ents who ca nnot
tol era te ri ba vi ri n s houl d be gi ven pegyl a ted IFN-, but res ul ts a re not a s good a s wi th combi na ti on trea tment. Ri ba vi ri n monothera py i s of no
va l ue.
In mos t a dul t tra ns pl a nta ti on centers , a dva nced ci rrhos i s due to HCV i s now the mos t common i ndi ca ti on for l i ver tra ns pl a nta ti on. Al though HCV
recurs i n the gra ft, the cours e i s us ua l l y i ndol ent, a nd l ong-term s urvi va l ra tes a re rel a ti vel y hi gh.
Chapter 29. Vascular Disorders of the Liver

Introduction
The l i ver ha s a dua l bl ood s uppl y. The porta l vei n (whi ch i s ri ch i n nutri ents a nd rel a ti vel y hi gh i n O2 ) provi des two thi rds of bl ood fl ow to the l i ver.
The hepa ti c a rtery (whi ch i s O2 -ri ch) s uppl i es the res t. The hepa ti c vei ns dra i n the l i ver i nto the i nferi or vena ca va . When porta l vei n bl ood fl ow
i ncrea s es , hepa ti c a rtery fl ow decrea s es a nd vi ce vers a (the hepa ti c a rteri a l buffer res pons e). Thi s dua l , reci proca l l y compens a tory bl ood s uppl y
provi des s ome protecti on from hepa ti c i s chemi a i n hea l thy peopl e.
Des pi te i ts dua l bl ood s uppl y, the l i ver, a meta bol i ca l l y a cti ve orga n, ca n be i njured by
Ischemia: Is chemi a res ul ts from reduced bl ood fl ow, reduced O2 del i very, i ncrea s ed meta bol i c a cti vi ty, or a l l three.
Insufficient venous drainage: The ca us e ma y be foca l or di ffus e obs tructi on. Ma ni fes ta ti ons of foca l venous obs tructi on depend on the l oca ti on.
Di ffus e venous conges ti on ca us es conges ti ve hepa topa thy. Reduced venous outfl ow from the l i ver (ori gi na ti ng i n the hepa ti c vei ns or wi thi n
the l i ver i ts el f, us ua l l y from ci rrhos i s ) res ul ts i n porta l hypertens i on.
Specific vascular lesions: The hepa ti c a rtery, hepa ti c vei n, or porta l vei n ma y be i nvol ved. In pel i os i s hepa ti s , the va s cul a r l es i on occurs i n the
s i nus oi ds (mi crova s cul a r a na s tomos es between the porta l a nd hepa ti c vei ns ).
Hepatic Ischemia
Di ffus e i s chemi a ca n ca us e i s chemi c hepa ti ti s ; foca l i s chemi a ca n ca us e hepa ti c i nfa rcti on or i s chemi c chol a ngi opa thy. Hepa ti c i nfa rcti on res ul ts
from hepa ti c a rtery di s orders .
Ischemic Hepatitis
(Acute Hepa ti c Infa rcti on; Hypoxi c Hepa ti ti s ; Shock Li ver)
Ischemic hepatitis is diffuse liver damage due to an inadequate blood or O2 supply.
Ca us es a re mos t often s ys temi c:
Impa i red hepa ti c perfus i on (eg, due to hea rt fa i l ure or a cute hypotens i on)
Hypoxemi a (eg, due to res pi ra tory fa i l ure or ca rbon monoxi de toxi ci ty)
Increa s ed meta bol i c dema nd (eg, due to s eps i s )
Foca l l es i ons of the hepa ti c va s cul a ture a re l es s common ca us es . Is chemi c hepa ti ti s ma y devel op when hepa ti c a rtery thrombos i s occurs duri ng
l i ver tra ns pl a nta ti on or when a s i ckl e cel l cri s i s i s a s s oci a ted wi th porta l vei n thrombos i s (thus compromi s i ng the dua l bl ood s uppl y to the l i ver).
Centri zona l necros i s devel ops wi thout l i ver i nfl a mma ti on (i e, not a true hepa ti ti s ).
Symptoms ma y i ncl ude na us ea , vomi ti ng, a nd tender hepa tomega l y.
Diagnosis
Cl i ni ca l eva l ua ti on a nd l i ver functi on tes ts
Doppl er ul tra s onogra phy, MRI, or a rteri ogra phy
Is chemi c hepa ti ti s i s s us pected i n pa ti ents who ha ve ri s k fa ctors a nd l a bora tory a bnorma l i ti es :
Serum a mi notra ns fera s e i ncrea s es dra ma ti ca l l y (eg, to 1000 to 3000 IU/L).
LDH i ncrea s es wi thi n hours of i s chemi a (unl i ke a cute vi ra l hepa ti ti s ).
Serum bi l i rubi n i ncrea s es modes tl y, onl y to 4 ti mes i ts norma l l evel .
PT/INR i ncrea s es .
Di a gnos ti c i ma gi ng hel ps defi ne the ca us e: Doppl er ul tra s onogra phy, MRI, or a rteri ogra phy ca n i denti fy a n obs tructed hepa ti c a rtery or porta l vei n
thrombos i s .
Treatment
Hepa ti c reperfus i on
Trea tment i s di rected a t the ca us e, a i mi ng to res tore hepa ti c perfus i on, pa rti cul a rl y by i mprovi ng ca rdi a c output a nd revers i ng a ny hemodyna mi c
i ns ta bi l i ty.
If perfus i on i s res tored, a mi notra ns fera s e decrea s es over 1 to 2 wk. In mos t ca s es , l i ver functi on i s ful l y res tored. Ful mi na nt l i ver fa i l ure, a l though
uncommon, ca n occur i n pa ti ents wi th preexi s ti ng ci rrhos i s .
Ischemic Cholangiopathy
Ischemic cholangiopathy is focal damage to the biliary tree due to disrupted flow from the hepatic artery via the peribiliary arterial plexus.
Common ca us es of i s chemi c chol a ngi opa thy i ncl ude va s cul a r i njury duri ng orthotopi c l i ver tra ns pl a nta ti on or l a pa ros copi c chol ecys tectomy, gra ftrejecti on i njury, chemoembol i za ti on, ra di a ti on thera py, a nd thrombos i s res ul ti ng from hypercoa gul a bi l i ty di s orders . Bi l e duct i njury (i s chemi c
necros i s ) res ul ts , ca us i ng chol es ta s i s , chol a ngi ti s , or bi l i a ry s tri ctures (often mul ti pl e).
Symptoms (eg, pruri tus , da rk uri ne, pa l e s tool s ), l a bora tory tes ts , a nd i ma gi ng s tudi es i ndi ca te chol es ta s i s .
The di a gnos i s i s s us pected when chol es ta s i s i s evi dent i n pa ti ents a t ri s k, pa rti cul a rl y a fter l i ver tra ns pl a nta ti on. Ul tra s onogra phy i s the 1s t-l i ne
di a gnos ti c i ma gi ng tes t for chol es ta s i s , but mos t pa ti ents requi re ma gneti c res ona nce chol a ngi opa ncrea togra phy, ERCP, or both to rul e out other
ca us es s uch a s chol el i thi a s i s or chol a ngi oca rci noma .
Trea tment i s di rected a t the ca us e. After l i ver tra ns pl a nta ti on, s uch trea tment i ncl udes a nti rejecti on thera py a nd pos s i bl e retra ns pl a nta ti on.
Bi l i a ry s tri ctures wa rra nt endos copi c ba l l oon di l a ti on a nd s tenti ng.
Congestive Hepatopathy
(Pa s s i ve Hepa ti c Conges ti on)
Congestive hepatopathy is diffuse venous congestion within the liver that results from right-sided heart failure (usually due to a cardiomyopathy, tricuspid
regurgitation, mitral insufficiency, cor pulmonale, or constrictive pericarditis).
Modera te or s evere ri ght-s i ded hea rt fa i l ure i ncrea s es centra l venous pres s ure, whi ch i s tra ns mi tted to the l i ver vi a the i nferi or vena ca va a nd
hepa ti c vei ns . Chroni c conges ti on l ea ds to a trophy of hepa tocytes , di s tenti on of s i nus oi ds , a nd centri zona l fi bros i s , whi ch, i f s evere, progres s es to
ci rrhos i s (ca rdi a c ci rrhos i s ). The ba s i s for l i ver cel l dea th i s proba bl y s i nus oi da l thrombos i s tha t propa ga tes to the centra l vei ns a nd bra nches of
the porta l vei n, ca us i ng i s chemi a .
Mos t pa ti ents a re a s ymptoma ti c. However, modera te conges ti on ca us es ri ght upper qua dra nt di s comfort (due to s tretchi ng of the l i ver ca ps ul e)
a nd tender hepa tomega l y. Severe conges ti on l ea ds to ma s s i ve hepa tomega l y a nd ja undi ce. As ci tes ma y res ul t from the tra ns mi tted centra l
venous hypertens i on; i nfrequentl y, s pl enomega l y res ul ts . Wi th tra ns mi tted centra l venous hypertens i on, the hepa tojugul a r refl ex i s pres ent,
unl i ke i n hepa ti c conges ti on due to Budd-Chi a ri s yndrome.
Diagnosis
Conges ti ve hepa topa thy i s s us pected i n pa ti ents who ha ve ri ght-s i ded hea rt fa i l ure, ja undi ce, a nd tender hepa tomega l y. Li ver bi ochemi s tri es a re
modes tl y a bnorma l : unconjuga ted hyperbi l i rubi nemi a (tota l bi l i rubi n < 3 mg/dL), el eva ted (us ua l l y < 2 to 3 fol d) a mi notra ns fera s es , a nd
prol onged PT/INR. Any a s ci ti c fl ui d ha s a hi gh a l bumi n content (> 25 g/L) a nd s erum a s ci tes /a l bumi n gra di ent. ( 1.1). Beca us e the l a bora tory
a bnorma l i ti es a re nons peci fi c, recogni ti on of conges ti ve hepa topa thy i s ul ti ma tel y cl i ni ca l . The l i ver di s order i s more i mporta nt a s a n i ndex of the
s everi ty of hea rt fa i l ure tha n a s a di a gnos i s by i ts el f.
Treatment
Trea tment i s di rected a t the underl yi ng hea rt fa i l ure.
Hepatic Artery Disorders
The hepa ti c a rtery ma y be occl uded. Uncommonl y, a neurys ms devel op.
Hepatic Artery Occlusion
Ca us es of hepa ti c a rtery occl us i on i ncl ude thrombos i s (eg, due to hypercoa gul a bi l i ty di s orders , s evere a rteri os cl eros i s , or va s cul i ti s ), embol i (eg,
due to endoca rdi ti s , tumors , thera peuti c embol i za ti on, or chemoembol i za ti on), i a trogeni c ca us es (eg, l i ga ti on duri ng s urgery), va s cul i ti s (vi a
nonthromboti c mecha ni s ms ), s tructura l a rteri a l a bnorma l i ti es (eg, hepa ti c a rtery a neurys m), ecl a mps i a , coca i ne us e, a nd s i ckl e cel l cri s i s .
Us ua l l y, the res ul t i s a n hepa ti c i nfa rct. In pa ti ents wi th a l i ver tra ns pl a nt or preexi s ti ng porta l vei n thrombos i s , hepa ti c a rtery thrombos i s ca us es
i s chemi c hepa ti ti s (s ee p. 259). Beca us e of the l i ver's dua l bl ood s uppl y, the l i ver i s s omewha t res i s ta nt to i s chemi c hepa ti ti s a nd i nfa rcti on.
Hepa ti c a rtery occl us i on does not el i ci t s ymptoms wi thout hepa ti c i nfa rcti on or i s chemi c hepa ti ti s . Hepa ti c i nfa rcti on ma y be a s ymptoma ti c or
ca us e ri ght upper qua dra nt pa i n, fever, na us ea , vomi ti ng, a nd ja undi ce. Leukocytos i s a nd a hi gh a mi notra ns fera s e l evel a re common.
Diagnosis
Va s cul a r i ma gi ng
Di a gnos i s of hepa ti c a rtery occl us i on i s confi rmed by i ma gi ng wi th Doppl er ul tra s onogra phy, us ua l l y fol l owed by a ngi ogra phy. The choi ce between
CT a ngi ogra phy, ma gneti c res ona nce a ngi ogra phy, a nd cel i a c a rteri ogra phy l a rgel y depends on a va i l a bi l i ty a nd experti s e. CT ma y detect a wedges ha ped a rea of l ow a ttenua ti on.
Treatment
Trea tment i s di rected a t the ca us e.
Aneurysms
Aneurys ms of the hepa ti c a rtery a re uncommon. They tend to be s a ccul a r a nd mul ti pl e. Ca us es i ncl ude i nfecti on, a rteri os cl eros i s , tra uma , a nd
va s cul i ti s . Untrea ted a neurys ms ma y ca us e dea th by rupturi ng i nto the common bi l e duct (ca us i ng hemobi l i a ), peri toneum (ca us i ng peri toni ti s ), or
a dja cent hol l ow vi s cera . Hemobi l i a ma y ca us e ja undi ce, upper GI bl eedi ng, a nd a bdomi na l pa i n i n the ri ght upper qua dra nt.
Di a gnos i s i s s us pected i f typi ca l s ymptoms occur or i f i ma gi ng tes ts detect a n a neurys m. Doppl er ul tra s onogra phy, fol l owed by contra s t CT, i s
requi red for confi rma ti on.
Trea tment i s embol i za ti on or s urgi ca l l i ga ti on.
Hepatic Vein Disorders
Obs tructi on of hepa ti c venous outfl ow ca n occur i n extra hepa ti c ves s el s (Budd-Chi a ri s yndrome) or i ntra hepa ti c ves s el s (veno-occl us i ve di s ea s e)
but often occurs i n both. Obs tructi on res ul ts i n conges ti on of the s i nus oi ds , hepa tomega l y, porta l hypertens i on, reduced porta l bl ood fl ow,
a s ci tes , a nd s pl enomega l y.
Budd-Chiari Syndrome
Budd-Chiari syndrome is obstruction of hepatic venous outflow that originates anywhere from the small hepatic veins inside the liver to the inferior vena cava
and right atrium. Manifestations range from no symptoms to fulminant liver failure. Diagnosis is based on ultrasonography. Treatment includes supportive
medical therapy and measures to establish and maintain venous patency, such as thrombolysis, decompression with shunts, and long-term anticoagulation.
Etiology
In the Wes tern worl d, the mos t common ca us e i s a cl ot obs tructi ng the hepa ti c vei ns a nd the a dja cent i nferi or vena ca va . Cl ots commonl y res ul t
from the fol l owi ng:
Thromboti c condi ti ons (eg, protei n C or S defi ci ency, a nti phos phol i pi d s yndrome, a nti thrombi n III defi ci ency, fa ctor V Lei den muta ti on, pregna ncy,
ora l contra cepti ve us e)
Hema tol ogi c di s orders (eg, myel oprol i fera ti ve di s orders s uch a s pol ycythemi a a nd pa roxys ma l nocturna l hemogl obi nopa thy)
Infl a mma tory bowel di s ea s e
Connecti ve ti s s ue di s orders
Tra uma
Infecti on (eg, hyda ti d cys t, a mebi a s i s )
Tumor i nva s i on of the hepa ti c vei n (eg, hepa tocel l ul a r or rena l cel l ca rci noma )
Someti mes Budd-Chi a ri s yndrome begi ns duri ng pregna ncy a nd unma s ks a previ ous l y a s ymptoma ti c hypercoa gul a bi l i ty di s order.
The ca us e of obs tructi on i s often unknown. In As i a a nd South Afri ca , the ba s i c defect i s often a membra nous obs tructi on (webs ) of the i nferi or
vena ca va a bove the l i ver, l i kel y repres enti ng reca na l i za ti on of a pri or thrombus i n a dul ts or a devel opmenta l fl a w (eg, venous s tenos i s ) i n
chi l dren. Thi s type of obs tructi on i s ca l l ed obl i tera ti ve hepa toca vopa thy.
Budd-Chi a ri s yndrome us ua l l y devel ops over weeks or months . When i t does , ci rrhos i s a nd porta l hypertens i on tend to devel op.
Symptoms and Signs
Ma ni fes ta ti ons ra nge from none (a s ymptoma ti c) to ful mi na nt l i ver fa i l ure or ci rrhos i s . Symptoms va ry dependi ng on whether the obs tructi on
occurs a cutel y or over ti me.
Acute obs tructi on (i n a bout 20%) ca us es fa ti gue, ri ght upper qua dra nt pa i n, na us ea , vomi ti ng, mi l d ja undi ce, tender hepa tomega l y, a nd a s ci tes . It
typi ca l l y occurs duri ng pregna ncy. Ful mi na nt l i ver fa i l ure wi th encepha l opa thy i s ra re. Ami notra ns fera s e l evel s a re qui te hi gh
Chroni c outfl ow obs tructi on (devel opi ng over weeks to months ) ma y be ra ther a s ymptoma ti c i n s ome pa ti ents unti l i t progres s es or ma y ca us e
fa ti gue, a bdomi na l pa i n, a nd hepa tomega l y. Lower-extremi ty edema a nd a s ci tes ma y res ul t from venous obs tructi on, even i n the a bs ence of
ci rrhos i s . Ci rrhos i s ma y devel op, l ea di ng to va ri cea l bl eedi ng, ma s s i ve a s ci tes , s pl enomega l y, hepa topul mona ry s yndrome (s ee p. 1988), or a
combi na ti on. Compl ete obs tructi on of the i nferi or vena ca va ca us es edema of the a bdomi na l wa l l a nd l egs pl us vi s i bl y tortuous s uperfi ci a l
a bdomi na l vei ns from the pel vi s to the cos ta l ma rgi n.
Diagnosis
Va s cul a r i ma gi ng
Budd-Chi a ri s yndrome i s s us pected i n pa ti ents wi th
Hepa tomega l y, a s ci tes , l i ver fa i l ure, or ci rrhos i s when there i s no obvi ous ca us e (eg, a l cohol a bus e, hepa ti ti s ) or when the ca us e i s unexpl a i ned
Abnorma l l i ver functi on tes t res ul ts a nd ri s k fa ctors for thrombos i s

Li ver functi on tes ts a re us ua l l y a bnorma l ; the pa ttern i s va ri a bl e a nd nons peci fi c. Ima gi ng us ua l l y begi ns wi th a bdomi na l Doppl er
ul tra s onogra phy, whi ch ca n s how the di recti on of bl ood fl ow a nd the s i te of obs tructi on. Ma gneti c res ona nce a ngi ogra phy a nd CT a re us eful i f
ul tra s onogra phy i s not di a gnos ti c. Conventi ona l a ngi ogra phy (venogra phy wi th pres s ure mea s urements a nd a rteri ogra phy) i s neces s a ry i f
thera peuti c or s urgi ca l i nterventi on i s pl a nned. Li ver bi ops y i s done occa s i ona l l y to di a gnos e the a cute s ta ges a nd determi ne whether ci rrhos i s
ha s devel oped.
Prognosis
Wi thout trea tment, mos t pa ti ents wi th compl ete venous obs tructi on di e of l i ver fa i l ure wi thi n 3 yr. For pa ti ents wi th i ncompl ete obs tructi on, the
cours e va ri es .
Treatment
Supporti ve ca re
Res tora ti on a nd ma i ntena nce of a dequa te venous outfl ow
Trea tment va ri es a ccordi ng to i ts ons et (a cute vs chroni c) a nd s everi ty (ful mi na nt l i ver fa i l ure vs decompens a ted ci rrhos i s vs s ta bl e or
a s ymptoma ti c). The corners tones of ma na gement a re
Gi vi ng s upporti ve thera py di rected a t compl i ca ti ons (eg, a s ci tes , l i ver fa i l ure, es opha gea l va ri ces )
Decompres s i ng the conges ted l i ver (i e, ma i nta i ni ng venous outfl ow)
Preventi ng propa ga ti on of the cl ot
Aggres s i ve i nterventi ons (eg, thrombol ys i s , s tents ) a re us ed when the di s ea s e i s a cute (eg, wi thi n 4 wk a nd i n the a bs ence of ci rrhos i s ).
Thrombol ys i s ca n di s s ol ve a cute cl ots , a l l owi ng reca na l i za ti on a nd s o rel i evi ng hepa ti c conges ti on. Ra di ol ogi c procedures ha ve a ma jor rol e us i ng
a ngi opl a s ty, s tenti ng, a nd portos ytemi c s hunts . For ca va l webs or hepa ti c venous s tenos i s , decompres s i on vi a percuta neous tra ns l umi na l ba l l oon
a ngi opl a s ty wi th i ntra l umi na l s tents ca n ma i nta i n hepa ti c outfl ow. When di l a ti on of a hepa ti c outfl ow na rrowi ng i s not techni ca l l y fea s i bl e,
tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) a nd va ri ous s urgi ca l s hunts ca n provi de decompres s i on by di vers i on i nto the s ys temi c
ci rcul a ti on. Portos ys temi c s hunts a re genera l l y not us ed i f hepa ti c encepha l opa thy i s pres ent; s uch s hunts wors en l i ver functi on. Further, s hunts
tend to thrombos e, es peci a l l y when a s s oci a ted wi th hema tol ogi c di s orders .
Long-term a nti coa gul a ti on i s often neces s a ry to prevent recurrence. Li ver tra ns pl a nta ti on ma y be l i fes a vi ng i n pa ti ents wi th ful mi na nt di s ea s e or
decompens a ted ci rrhos i s .
Veno-Occlusive Disease
(Si nus oi da l Obs tructi on Syndrome)
Hepatic veno-occlusive disease is caused by endothelial injury, leading to nonthrombotic occlusion of the terminal hepatic venules and hepatic sinusoids, rather
than of the hepatic veins or inferior vena cava (as in Budd-Chiari syndrome).
Venous conges ti on ca us es porta l hypertens i on a nd i s chemi c necros i s (whi ch l ea ds to ci rrhos i s ).
Common ca us es i ncl ude
Irra di a ti on
Gra ft-vs -hos t di s ea s e res ul ti ng from bone ma rrow or hema topoi eti c cel l tra ns pl a nta ti on
Pyrrol i zi di ne a l ka l oi ds i n crota l a ri a a nd s eneci o pl a nts (eg, medi ci na l bus h tea s ) a nd other herbs (eg, comfrey)
Other hepa totoxi ns (eg, di methyl ni tros a mi ne, a fl a toxi n, a za thi opri ne, s ome a nti ca ncer drugs )
Ini ti a l ma ni fes ta ti ons i ncl ude s udden ja undi ce, a s ci tes , a nd tender, s mooth hepa tomega l y. Ons et i s wi thi n the fi rs t 3 wk of tra ns pl a nta ti on i n
bone ma rrow or hema topoi eti c cel l reci pi ents , who ei ther recover s ponta neous l y wi thi n a few weeks (or s ometi mes , wi th mi l d ca s es , a fter a n
i ncrea s e i n i mmunos uppres s a nt thera py) or di e of ful mi na nt l i ver fa i l ure. Other pa ti ents ha ve recurrent a s ci tes , porta l hypertens i on,
s pl enomega l y, a nd, eventua l l y, ci rrhos i s .
Diagnosis
Ul tra s onogra phy
Someti mes i nva s i ve tes ts (eg, l i ver bi ops y, mea s urement of porta l -hepa ti c venous pres s ure gra di ent)
The di a gnos i s i s s us pected i n pa ti ents wi th unexpl a i ned cl i ni ca l or l a bora tory evi dence of l i ver di s ea s e, pa rti cul a rl y i n thos e wi th known ri s k
fa ctors , s uch a s bone ma rrow or hema topoi eti c cel l tra ns pl a nta ti on. La bora tory res ul ts a re nons peci fi c: el eva ted a mi notra ns fera s e a nd
conjuga ted bi l i rubi n l evel s . PT/INR becomes a bnorma l when di s ea s e i s s evere. Ul tra s onogra phy s hows retrogra de fl ow i n the porta l vei n. If the
di a gnos i s i s uncl ea r, i nva s i ve tes ts become neces s a ryeg, l i ver bi ops y or mea s urement of the porta l -hepa ti c venous pres s ure gra di ent (a
pres s ure gra di ent > 10 mm Hg s ugges ts veno-occl us i ve di s ea s e). Mea s uri ng the pres s ure a cros s the l i ver enta i l s i ns erti ng a ca theter
percuta neous l y i nto a hepa ti c vei n a nd then wedgi ng i t i nto the l i ver. Thi s wedged pres s ure refl ects porta l vei n pres s ure. (An excepti on i s porta l
vei n thrombos i s ; i n thi s ca s e, the pres s ure i s norma l des pi te porta l hypertens i on.)
Treatment
Supporti ve ca re
For progres s i ve di s ea s e, tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng or tra ns pl a nta ti on
Urs odeoxychol i c a ci d hel ps prevent gra ft-vs -hos t di s ea s e i n bone ma rrow or hema topoi eti c cel l tra ns pl a nt reci pi ents . Ma na gement i ncl udes
wi thdra wi ng the ca us a ti ve a gent (s uch a s herba l tea s ) a nd provi di ng s upporti ve thera py. Mos t pa ti ents ha ve mi l d to modera te di s ea s e a nd do
qui te wel l . Thos e tha t progres s ma y requi re tra ns jugul a r i ntra hepa ti c portos ys temi c s hunti ng (TIPS) for rel i ef of porta l hypertens i on. However, i n
25%, veno-occl us i ve di s ea s e i s s evere, a ccompa ni ed by ful mi na nt l i ver fa i l ure. Li ver tra ns pl a nta ti on i s a l a s t res ort.
Portal Vein Disorders
Nea rl y a l l porta l vei n di s orders obs truct porta l vei n bl ood fl ow a nd ca us e porta l hypertens i on (s ee p. 218). Obs tructi on ca n be
Extra hepa ti cporta l vei n thrombos i s due to a hypercoa gul a bl e s ta te, ves s el wa l l l es i on (eg, pyl ephl ebi ti s , ompha l i ti s ), a n a dja cent l es i on (eg,
pa ncrea ti ti s , tumor), or congeni ta l a tres i a of the porta l vei n
Intra hepa ti c (eg, mi crova s cul a r porta l vei n obs tructi on a s i n s chi s tos omi a s i s , pri ma ry bi l i a ry ci rrhos i s , s a rcoi dos i s , nonci rrhoti c porta l
hypertens i on)
Portal Vein Thrombosis
Portal vein thrombosis causes portal hypertension and consequent GI bleeding from varices, usually in the lower esophagus or stomach. Diagnosis is based on
ultrasonography. Treatment involves control of variceal bleeding (usually with endoscopic banding, IV octreotide, or both), prevention of recurrence using blockers and sometimes surgical shunts and thrombolysis for acute thrombosis.
Etiology
Common ca us es va ry by a ge group (s ee
Ta bl e 29-1).
Symptoms and Signs
Acute porta l vei n thrombos i s i s commonl y a s ymptoma ti c unl es s a s s oci a ted wi th a nother event, s uch a s pa ncrea ti ti s (the ca us e), or a nother
compl i ca ti on, s uch a s mes enteri c venous thrombos i s . Mos t often, cl i ni ca l fea tures s pl enomega l y (es peci a l l y i n chi l dren) a nd va ri cea l
hemorrha gedevel op chroni ca l l y s econda ry to porta l hypertens i on. As ci tes i s uncommon (10%) i n pos ts i nus oi da l porta l hypertens i on. As ci tes ma y
be preci pi ta ted when ci rrhos i s i s a l s o pres ent or when s erum a l bumi n (a nd thus oncoti c pres s ure) decea s es a fter hi gh-vol ume fl ui d res us ci ta ti on
for a ma jor GI bl eed.
Diagnosis
Doppl er ul tra s onogra phy
Porta l vei n thrombos i s i s s us pected i n pa ti ents wi th the fol l owi ng:
Ma ni fes ta ti ons of porta l hypertens i on wi thout ci rrhos i s
Mi l d a bnorma l i ti es i n l i ver functi on or enzymes pl us ri s k fa ctors s uch a s neona ta l umbi l i ca l i nfecti on, chi l dhood a ppendi ci ti s , or a
hypercoa gul a bi l i ty di s order
Doppl er ul tra s onogra phy i s us ua l l y di a gnos ti c, s howi ng di mi ni s hed or a bs ent porta l vei n fl ow a nd s ometi mes the thrombus . Di ffi cul t ca s es ma y
requi re MRI or CT wi th contra s t. Angi ogra phy ma y be requi red to gui de s hunt s urgery.
[Table 29-1. Common Ca us es of Porta l Vei n Thrombos i s *]
Treatment
For s ome a cute ca s es , thrombol ys i s
Long-term a nti coa gul a ti on
Ma na gement of porta l hypertens i on a nd i ts compl i ca ti ons
In a cute ca s es , thrombol ys i s i s s ometi mes s ucces s ful , bes t res erved for recent occl us i on, pa rti cul a rl y i n hypercoa gul a bl e s ta tes . Anti coa gul a ti on
does not l ys e cl ots but ha s s ome va l ue for l ong-term preventi on i n hypercoa gul a bl e s ta tes des pi te the ri s k of va ri cea l bl eedi ng. In neona tes a nd
chi l dren, trea tment i s di rected a t the ca us e (eg, ompha l i ti s , a ppendi ci ti s ). Otherwi s e, ma na gement i s di rected a t the porta l hypertens i on a nd i ts
compl i ca ti ons (s ee p. 218); trea tment ca n i ncl ude octreoti de IV (a s yntheti c a na l og of s oma tos ta ti n) a nd endos copi c ba ndi ng to control va ri cea l
bl eedi ng a nd nons el ecti ve -bl ockers to prevent rebl eedi ng. Thes e thera pi es ha ve decrea s ed the us e of s urgi ca l s hunts (eg, mes oca va l ,
s pl enorena l ), whi ch ca n become occl uded a nd ha ve a n opera ti ve morta l i ty ra te of 5 to 50%. Tra ns jugul a r i ntra hepa ti c portos ytemi c s hunti ng (TIPS)
i s not recommended. TIPS requi res moni tori ng (i ncl udi ng frequent a ngi ogra phy) to a s s es s pa tency, ma y become bl ocked, a nd ma y not a dequa tel y
decompres s the l i ver.
Peliosis Hepatis
Peliosis hepatis is typically an asymptomatic disorder in which multiple blood-filled cystic spaces develop randomly in the liver.
Mea s uri ng a few mi l l i meters to a bout 3 cm i n di a meter, the cys ts of pel i os i s hepa ti s often l a ck a cel l l i ni ng a nd a re s urrounded by hepa tocytes .
Some ha ve a n endothel i a l cel l l i ni ng, a ccompa ni ed by di l a ted hepa ti c s i nus oi ds . The ca us e i s proba bl y da ma ge to the s i nus oi da l l i ni ng cel l s .
Pel i os i s hepa ti s i s a s s oci a ted wi th us e of hormones (eg, a na bol i c s teroi ds , ora l contra cepti ves , gl ucocorti coi ds ), ta moxi fen, vi nyl chl ori de, vi ta mi n
A, a nd, pa rti cul a rl y i n ki dney tra ns pl a nt reci pi ents , a za thi opri ne.
Pel i os i s hepa ti s i s us ua l l y a s ymptoma ti c, but occa s i ona l l y cys ts rupture, res ul ti ng i n hemorrha ge a nd s ometi mes ca us i ng dea th. Some pa ti ents
devel op overt l i ver di s ea s e, cha ra cteri zed by ja undi ce, hepa tomega l y, a nd l i ver fa i l ure.
Mi l d ca s es ma y be detected i nci denta l l y duri ng i ma gi ng tes ts done beca us e l i ver functi on tes t res ul ts a re s l i ghtl y a bnorma l or for other rea s ons .
Ul tra s onogra phy or CT ca n detect cys ts .
Chapter 30. Liver Masses and Granulomas

Introduction
Li ver ma s s es i ncl ude cys ts , beni gn tumors , pri ma ry l i ver ca ncers , a nd meta s ta ti c l i ver ca ncer. Certa i n drugs a nd di s orders ca n res ul t i n gra nul oma
forma ti on i n the l i ver.
Hepatic Cysts
Is ol a ted cys ts a re commonl y detected i nci denta l l y on a bdomi na l ul tra s onogra phy or CT. Thes e cys ts a re us ua l l y a s ymptoma ti c a nd ha ve no cl i ni ca l
s i gni fi ca nce. The ra re congeni ta l pol ycys ti c l i ver i s commonl y a s s oci a ted wi th pol ycys ti c di s ea s e of the ki dneys (s ee p. 2385) a nd other orga ns . It
ca us es progres s i ve nodul a r hepa tomega l y (s ometi mes ma s s i ve) i n a dul ts . Neverthel es s , hepa tocel l ul a r functi on i s rema rka bl y wel l pres erved,
a nd porta l hypertens i on ra rel y devel ops .
Other hepa ti c cys ts i ncl ude the fol l owi ng:
Hyda ti d (echi nococca l ) cys ts (s ee p. 1362)
Ca rol i 's di s ea s e, whi ch i s ra re, a utos oma l reces s i ve, a nd cha ra cteri zed by s egmenta l cys ti c di l a ti on of i ntra hepa ti c bi l e ducts (often becomi ng
s ymptoma ti c i n a dul thood, wi th s tone forma ti on, chol a ngi ti s , a nd s ometi mes chol a ngi oca rci noma )
True cys ti c tumors (ra re)
Benign Liver Tumors
Beni gn l i ver tumors a re rel a ti vel y common. Mos t a re a s ymptoma ti c, but s ome ca us e hepa tomega l y, ri ght upper qua dra nt di s comfort, or
i ntra peri tonea l hemorrha ge. Mos t a re detected i nci denta l l y on ul tra s ound or other s ca ns . Li ver functi on tes ts a re us ua l l y norma l or onl y s l i ghtl y
a bnorma l . Di a gnos i s i s us ua l l y pos s i bl e wi th i ma gi ng tes ts but ma y requi re bi ops y. Trea tment i s needed onl y i n a few s peci fi c ci rcums ta nces .
Hepatocellular adenoma: Hepa tocel l ul a r a denoma i s the mos t i mporta nt beni gn tumor to recogni ze. It occurs pri ma ri l y i n women of chi l dbea ri ng
a ge, pa rti cul a rl y thos e ta ki ng ora l contra cepti ves , pos s i bl y vi a es trogen's effects . Mos t a denoma s a re a s ymptoma ti c, but l a rge ones ma y ca us e
ri ght upper qua dra nt di s comfort. Ra rel y, a denoma s ma ni fes t a s peri toni ti s a nd s hock due to rupture a nd i ntra peri tonea l hemorrha ge. Ra rel y, they
become ma l i gna nt.
Di a gnos i s i s often s us pected ba s ed on ul tra s ound or CT res ul ts , but bi ops y i s s ometi mes needed for confi rma ti on.
Adenoma s due to contra cepti ve us e often regres s i f the contra cepti ve i s s topped. If the a denoma does not regres s or i f i t i s s ubca ps ul a r or > 5 cm,
s urgi ca l res ecti on i s often recommended.
Focal nodular hyperplasia: Thi s l oca l i zed ha ma rtoma ma y res embl e ma cronodul a r ci rrhos i s hi s tol ogi ca l l y. Di a gnos i s i s us ua l l y ba s ed on MRI or CT
wi th contra s t, but bi ops y ma y be neces s a ry. Trea tment i s ra rel y needed.
Hemangiomas: Hema ngi oma s a re us ua l l y s ma l l a nd a s ymptoma ti c; they occur i n 1 to 5% of a dul ts . Thes e tumors often ha ve a cha ra cteri s ti c hi ghl y
va s cul a r a ppea ra nce. Rupture i s ra re, even when tumors a re l a rge. Hema ngi oma s a re found i nci denta l l y duri ng ul tra s onogra phy, CT, or MRI.
Trea tment i s us ua l l y not i ndi ca ted.
In i nfa nts , hema ngi oma s often regres s s ponta neous l y by a ge 2 yr. However, l a rge hema ngi oma s occa s i ona l l y ca us e a rteri ovenous s hunti ng
s uffi ci ent to ca us e hea rt fa i l ure a nd s ometi mes cons umpti on coa gul opa thy. In thes e ca s es , trea tment ma y i ncl ude hi gh-dos e corti cos teroi ds ,
s ometi mes di ureti cs a nd di goxi n to i mprove hea rt functi on, i nterferon- (gi ven s c), s urgi ca l remova l , s el ecti ve hepa ti c a rtery embol i za ti on, a nd,
ra rel y, l i ver tra ns pl a nta ti on.
Other benign tumors: Li poma s (us ua l l y a s ymptoma ti c) a nd l oca l i zed fi brous tumors (eg, fi broma s ) ra rel y occur i n the l i ver.
Beni gn bi l e duct a denoma s a re ra re, i ncons equenti a l , a nd us ua l l y detected i nci denta l l y. They a re s ometi mes mi s ta ken for meta s ta ti c ca ncer.
Primary Liver Cancer
Pri ma ry l i ver ca ncer i s us ua l l y hepa tocel l ul a r ca rci noma . The fi rs t ma ni fes ta ti ons of l i ver ca ncer a re us ua l l y nons peci fi c, del a yi ng the di a gnos i s .
Prognos i s i s us ua l l y poor.
Hepatocellular Carcinoma
Hepatocellular carcinoma (hepatoma) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent.
Symptoms and signs are usually nonspecific. Diagnosis is based on -fetoprotein (AFP) levels, imaging tests, and sometimes liver biopsy. Screening with periodic
AFP measurement and ultrasonography is sometimes recommended for high-risk patients. Prognosis is poor when cancer is advanced, but for small tumors that
are confined to the liver, ablative therapies are palliative and surgical resection or liver transplantation is sometimes curative.
Hepa tocel l ul a r ca rci noma i s the mos t common type of pri ma ry l i ver ca ncer a nd res ul ts i n a bout 14,000 dea ths a nnua l l y i n the US. However, i t i s
more common outs i de the US, pa rti cul a rl y i n Ea s t As i a a nd s ub-Sa ha ra n Afri ca ; i nci dence genera l l y pa ra l l el s geogra phi c preva l ence of chroni c
hepa ti ti s B vi rus (HBV) i nfecti on.
Etiology
Hepa tocel l ul a r ca rci noma i s us ua l l y a compl i ca ti on of ci rrhos i s .
The pres ence of HBV i ncrea s es ri s k of hepa tocel l ul a r ca rci noma by > 100-fol d a mong HBV ca rri ers . Incorpora ti on of HBV-DNA i nto the hos t's
genome ma y i ni ti a te ma l i gna nt tra ns forma ti on, even i n the a bs ence of chroni c hepa ti ti s or ci rrhos i s .
Other di s orders tha t ca us e hepa tocel l ul a r ca rci noma i ncl ude ci rrhos i s due to chroni c hepa ti ti s C vi rus (HCV) i nfecti on, hemochroma tos i s , a nd
a l cohol i c ci rrhos i s . Pa ti ents wi th ci rrhos i s due to other condi ti ons a re a l s o a t i ncrea s ed ri s k.
Envi ronmenta l ca rci nogens ma y pl a y a rol e; eg, i nges ti on of food conta mi na ted wi th funga l a fl a toxi ns i s bel i eved to contri bute to the hi gh
i nci dence of hepa tocel l ul a r ca rci noma i n s ubtropi ca l regi ons .
Symptoms and Signs
Mos t commonl y, previ ous l y s ta bl e pa ti ents wi th ci rrhos i s pres ent wi th a bdomi na l pa i n, wei ght l os s , ri ght upper qua dra nt ma s s , a nd unexpl a i ned
deteri ora ti on. Fever ma y occur. In a few pa ti ents , the fi rs t ma ni fes ta ti on of hepa tocel l ul a r ca rci noma i s bl oody a s ci tes , s hock, or peri toni ti s ,
ca us ed by hemorrha ge of the tumor. Occa s i ona l l y, a hepa ti c fri cti on rub or brui t devel ops .
Occa s i ona l l y, s ys temi c meta bol i c compl i ca ti ons , i ncl udi ng hypogl ycemi a , erythrocytos i s , hyperca l cemi a , a nd hyperl i pi demi a , occur. Thes e
compl i ca ti ons ma y ma ni fes t cl i ni ca l l y.
Diagnosis
-Fetoprotei n (AFP) mea s urement
Ima gi ng (CT, ul tra s onogra phy, or MRI)
Di a gnos i s i s ba s ed on AFP mea s urement a nd a n i ma gi ng tes t. In a dul ts , AFP s i gni fi es dedi fferenti a ti on of hepa tocytes , whi ch mos t often
i ndi ca tes hepa tocel l ul a r ca rci noma ; 40 to 65% of pa ti ents wi th the ca ncer ha ve hi gh AFP l evel s (> 400 g/L). Hi gh l evel s a re otherwi s e ra re, except
i n tera toca rci noma of the tes ti s , a much l es s common tumor. Lower va l ues a re l es s s peci fi c a nd ca n occur wi th hepa tocel l ul a r regenera ti on (eg, i n
hepa ti ti s ). Other bl ood tes ts , s uch a s AFP-L3 (a n AFP i s oform) a nd des --ca rboxyprothrombi n, a re bei ng s tudi ed a s ma rkers to be us ed for ea rl y
detecti on of hepa tocel l ul a r ca rci noma .
Dependi ng on l oca l preferences a nd ca pa bi l i ti es , the fi rs t i ma gi ng tes t ma y be contra s t-enha nced CT, ul tra s onogra phy, or MRI. Hepa ti c
a rteri ogra phy i s occa s i ona l l y hel pful i n equi voca l ca s es a nd ca n be us ed to outl i ne the va s cul a r a na tomy when a bl a ti on or s urgery i s pl a nned.
If i ma gi ng s hows cha ra cteri s ti c fi ndi ngs a nd AFP i s el eva ted, the di a gnos i s i s cl ea r. Li ver bi ops y, often gui ded by ul tra s onogra phy or CT, i s
s ometi mes i ndi ca ted for defi ni ti ve di a gnos i s .
Staging: If a hepa tocel l ul a r ca rci noma i s di a gnos ed, eva l ua ti on us ua l l y i ncl udes ches t CT wi thout contra s t, i ma gi ng of the porta l vei n (i f not
a l rea dy done) by MRI or CT wi th contra s t to excl ude thrombos i s , a nd s ometi mes bone s ca nni ng.
Hepa tocel l ul a r ca rci noma i s s ta ged ba s ed on the fol l owi ng (Ameri ca n Ca ncer Soci ety cl a s s i fi ca ti on s ys tems ee
Ta bl e 30-1):
T: How ma ny pri ma ry tumors , how bi g they a re, a nd whether the ca ncer ha s s prea d to a dja cent orga ns
N: Whether the ca ncer ha s s prea d to nea rby l ymph nodes
M: Whether the ca ncer ha s meta s ta s i zed to other orga ns of the body
Numbers (0 to 4) a re a dded a fter T, N, a nd M to i ndi ca te i ncrea s i ng s everi ty. The l etter X mea ns no a s s es s ment i s pos s i bl e.
Screening: An i ncrea s i ng number of hepa tocel l ul a r ca rci noma s a re bei ng detected through s creeni ng progra ms . Screeni ng pa ti ents wi th ci rrhos i s i s
rea s ona bl e, a l though thi s mea s ure i s controvers i a l a nd ha s not been s hown to reduce morta l i ty. One common s creeni ng method i s AFP
mea s urement a nd ul tra s onogra phy every 6 or 12 mo. Ma ny experts a dvi s e s creeni ng pa ti ents wi th l ongs ta ndi ng hepa ti ti s B even when ci rrhos i s i s
a bs ent.
Treatment
Tra ns pl a nta ti on i f tumors a re s ma l l a nd few
[Table 30-1. Sta gi ng Hepa tocel l ul a r Ca rci noma *]
For s i ngl e tumors < 5 cm or 3 tumors 3 cm tha t a re l i mi ted to the l i ver, l i ver tra ns pl a nta ti on res ul ts i n a s good a prognos i s a s l i ver
tra ns pl a nta ti on done for nonca ncerous di s orders . Al terna ti vel y, s urgi ca l res ecti on ma y be done; however, the ca ncer us ua l l y recurs .
Abl a ti ve trea tments (eg, hepa ti c a rteri a l chemoembol i za ti on, i ntra tumora l etha nol i njecti on, cryoa bl a ti on, ra di ofrequency a bl a ti on) provi de
pa l l i a ti on a nd s l ow tumor growth; they a re us ed when pa ti ents a re a wa i ti ng l i ver tra ns pl a nta ti on.
If the tumor i s l a rge (> 5 cm), i s mul ti foca l , ha s i nva ded the porta l vei n, or i s meta s ta ti c (i e, s ta ge III or hi gher), prognos i s i s much l es s fa vora bl e
(eg, 5-yr s urvi va l ra tes of a bout 5% or l es s ). Ra di a ti on thera py i s us ua l l y i neffecti ve. Some newer chemothera peuti c regi mens a re promi s i ng.
Prevention
Us e of va cci ne a ga i ns t HBV eventua l l y decrea s es the i nci dence, es peci a l l y i n endemi c a rea s . Preventi ng the devel opment of ci rrhos i s of a ny ca us e
(eg, vi a trea tment of chroni c hepa ti ti s C, ea rl y detecti on of hemochroma tos i s , ma na gement of a l cohol i s m) ca n a l s o ha ve a s i gni fi ca nt effect.
Other Primary Liver Cancers

Other pri ma ry l i ver ca ncers a re uncommon or ra re. Di a gnos i s us ua l l y requi res bi ops y. Prognos i s i s typi ca l l y poor. Some ca ncers , i f l oca l i zed, ca n be
res ected. Wi th res ecti on or l i ver tra ns pl a nta ti on, s urvi va l ma y be prol onged.
Fibrolamellar carcinoma: Thi s di s ti nct va ri a nt of hepa tocel l ul a r ca rci noma ha s a cha ra cteri s ti c morphol ogy of ma l i gna nt hepa tocytes enmes hed i n
l a mel l a r fi brous ti s s ue. It us ua l l y occurs i n young a dul ts a nd ha s no a s s oci a ti on wi th preexi s ti ng ci rrhos i s , HBV, HCV, or other known ri s k fa ctors .
AFP l evel s a re ra rel y el eva ted. Prognos i s i s better tha n tha t for hepa tocel l ul a r ca rci noma , a nd ma ny pa ti ents s urvi ve s evera l yea rs a fter tumor
res ecti on.
Cholangiocarcinoma: Thi s tumor ori gi na tes i n the bi l i a ry epi thel i um. It i s common i n Chi na , where underl yi ng i nfes ta ti on wi th l i ver fl ukes i s
bel i eved to contri bute. El s ewhere, i t i s l es s common tha n hepa tocel l ul a r ca rci noma ; hi s tol ogi ca l l y, the two ma y overl a p. Pri ma ry s cl eros i ng
chol a ngi ti s grea tl y i ncrea s es ri s k of chol a ngi oca rci noma .
Hepatoblastoma: Al though ra re, hepa tobl a s toma i s one of the mos t common pri ma ry l i ver ca ncers i n i nfa nts , pa rti cul a rl y thos e wi th a fa mi l y hi s tory
of fa mi l i a l a denoma tous pol ypos i s (s ee p. 192). It ca n a l s o devel op i n chi l dren. Some pa ti ents wi th hepa tobl a s toma pres ent wi th precoci ous
puberty ca us ed by ectopi c gona dotropi n producti on, but the ca ncer i s us ua l l y detected beca us e of deteri ora ti ng genera l hea l th a nd a ri ght upper
qua dra nt ma s s . An el eva ted AFP l evel a nd a bnorma l i ma gi ng tes t res ul ts ma y hel p i n the di a gnos i s .
Angiosarcoma: Thi s ra re ca ncer i s a s s oci a ted wi th s peci fi c chemi ca l ca rci nogens , i ncl udi ng i ndus tri a l vi nyl chl ori de.
Metastatic Liver Cancer
Liver metastases are common in many types of cancer, especially those of the GI tract, breast, lung, and pancreas. The first symptoms of metastases are usually
nonspecific (eg, weight loss, right upper quadrant discomfort); they are sometimes the first symptoms of the primary cancer. Liver metastases are suspected in
patients with weight loss and hepatomegaly or with primary tumors likely to spread to the liver. Diagnosis is usually supported by an imaging test, most often
ultrasonography, spiral CT with contrast, or MRI with contrast. Treatment usually involves palliative chemotherapy.
Meta s ta ti c l i ver ca ncer i s more common tha n pri ma ry l i ver ca ncer a nd i s s ometi mes the i ni ti a l cl i ni ca l ma ni fes ta ti on of ca ncer ori gi na ti ng i n the
GI tra ct, brea s t, l ung, or pa ncrea s .
Symptoms and Signs
Ea rl y l i ver meta s ta s es ma y be a s ymptoma ti c. Nons peci fi c s ymptoms of ca ncer (eg, wei ght l os s , a norexi a , fever) often devel op fi rs t. The l i ver ma y be
enl a rged, ha rd, or tender; ma s s i ve hepa tomega l y wi th ea s i l y pa l pa bl e nodul es s i gni fi es a dva nced di s ea s e. Hepa ti c brui ts a nd pl euri ti c-type pa i n
wi th a n overl yi ng fri cti on rub a re uncommon but cha ra cteri s ti c. Spl enomega l y i s occa s i ona l l y pres ent, es peci a l l y when the pri ma ry ca ncer i s
pa ncrea ti c. Concomi ta nt peri tonea l tumor s eedi ng ma y produce a s ci tes , but ja undi ce i s us ua l l y a bs ent or mi l d i ni ti a l l y unl es s a tumor ca us es
bi l i a ry obs tructi on.
In the termi na l s ta ges , progres s i ve ja undi ce a nd hepa ti c encepha l opa thy pres a ge dea th.
Diagnosis
CT wi th contra s t or MRI wi th contra s t
Someti mes bi ops y
Li ver meta s ta s es a re s us pected i n pa ti ents wi th wei ght l os s a nd hepa tomega l y or wi th pri ma ry tumors l i kel y to s prea d to the l i ver. If meta s ta s es
a re s us pected, l i ver functi on tes ts a re often done, but res ul ts a re us ua l l y not s peci fi c for the di a gnos i s . Al ka l i ne phos pha ta s e, -gl uta myl
tra ns pepti da s e, a nd s ometi mes LDH typi ca l l y i ncrea s e ea rl i er or to a grea ter degree tha n do other tes t res ul ts ; a mi notra ns fera s e l evel s va ry.
Ima gi ng tes ts ha ve good s ens i ti vi ty a nd s peci fi ci ty. Ul tra s onogra phy i s us ua l l y hel pful , but CT wi th contra s t or MRI wi th contra s t i s often more
a ccura te.
Li ver bi ops y gui ded by i ma gi ng provi des the defi ni ti ve di a gnos i s a nd i s done i f other tes ts a re equi voca l or i f hi s tol ogi c i nforma ti on (eg, cel l type
of the l i ver meta s ta s i s ) ma y hel p determi ne the trea tment pl a n.
Treatment
Trea tment depends on the extent of meta s ta s i s . Wi th s ol i ta ry or very few meta s ta s es due to col orecta l ca ncer, s urgi ca l res ecti on ma y prol ong
s urvi va l . Dependi ng on cha ra cteri s ti cs of the pri ma ry tumor, s ys temi c chemothera py ma y s hri nk tumors a nd prol ong l i fe but i s not cura ti ve; hepa ti c
i ntra -a rteri a l chemothera py s ometi mes ha s the s a me effect but wi th fewer or mi l der s ys temi c a dvers e effects .
Ra di a ti on thera py to the l i ver occa s i ona l l y a l l evi a tes s evere pa i n due to a dva nced meta s ta s es but does not prol ong l i fe. Extens i ve di s ea s e i s
fa ta l a nd i s bes t ma na ged by pa l l i a ti on for the pa ti ent a nd s upport for the fa mi l y (s ee p. 3480).
Hematologic Cancers and the Liver
The l i ver i s commonl y i nvol ved i n a dva nced l eukemi a a nd rel a ted bl ood di s orders . Li ver bi ops y i s not needed. In hepa ti c l ymphoma , es peci a l l y
Hodgki n l ymphoma , the extent of l i ver i nvol vement determi nes s ta gi ng a nd trea tment but ma y be di ffi cul t to a s s es s . Hepa tomega l y a nd a bnorma l
l i ver functi on tes ts ma y refl ect a s ys temi c rea cti on to Hodgki n l ymphoma ra ther tha n s prea d to the l i ver, a nd bi ops y often s hows nons peci fi c foca l
mononucl ea r i nfi l tra tes or gra nul oma s of uncerta i n s i gni fi ca nce. Trea tment i s di rected a t the hema tol ogi c ca ncer.
Hepatic Granulomas
Hepatic granulomas have numerous causes and are usually asymptomatic. However, the underlying disorder may cause extrahepatic manifestations, hepatic
inflammation, fibrosis, portal hypertension, or a combination. Diagnosis is based on liver biopsy, but biopsy is necessary only if a treatable underlying disorder
(eg, infection) is suspected or if other liver disorders need to be ruled out. Treatment depends on the underlying disorder.
Hepa ti c gra nul oma s , a l though s ometi mes i ns i gni fi ca nt, more often refl ect cl i ni ca l l y rel eva nt di s ea s e. The term gra nul oma tous hepa ti ti s i s often
us ed to des cri be the condi ti on, but the di s order i s not true hepa ti ti s , a nd the pres ence of gra nul oma s does not i mpl y hepa tocel l ul a r
i nfl a mma ti on.
Etiology
Hepa ti c gra nul oma s ha ve ma ny ca us es (s ee
Ta bl e 30-2.); drugs a nd s ys temi c di s orders (often i nfecti ons ) a re more common ca us es tha n pri ma ry l i ver di s orders . Infecti ons mus t be i denti fi ed
beca us e they requi re s peci fi c trea tments . TB a nd s chi s tos omi a s i s a re the mos t common i nfecti ous ca us es worl dwi de; funga l a nd vi ra l ca us es a re
l es s common. Sa rcoi dos i s i s the mos t common noni nfecti ous ca us e; the l i ver i s i nvol ved i n a bout two thi rds of pa ti ents , a nd occa s i ona l l y, cl i ni ca l
ma ni fes ta ti ons of s a rcoi dos i s a re predomi na ntl y hepa ti c.
Gra nul oma s a re much l es s common i n pri ma ry l i ver di s orders ; pri ma ry bi l i a ry ci rrhos i s i s the onl y i mporta nt ca us e. Sma l l gra nul oma s occa s i ona l l y
occur i n other l i ver di s orders but a re not cl i ni ca l l y s i gni fi ca nt.
Idiopathic granulomatous hepatitis i s a ra re s yndrome of hepa ti c gra nul oma s wi th recurrent fever, mya l gi a s , fa ti gue, a nd other s ys temi c s ymptoms ,
whi ch often occur i ntermi ttentl y for yea rs . Some experts bel i eve i t i s a va ri a nt of s a rcoi dos i s .
Pathophysiology
A gra nul oma i s a l oca l i zed col l ecti on of chroni c i nfl a mma tory cel l s wi th epi thel i oi d cel l s a nd gi a nt mul ti nucl ea ted cel l s . Ca s ea ti on necros i s or
forei gn body ti s s ue (eg, s chi s tos ome eggs ) ma y be pres ent. Mos t gra nul oma s occur i n the pa renchyma , but i n pri ma ry bi l i a ry ci rrhos i s , gra nul oma s
ma y occur i n the hepa ti c tri a ds .
Gra nul oma forma ti on i s i ncompl etel y unders tood. Gra nul oma s ma y devel op i n res pons e to poorl y s ol ubl e exogenous or endogenous i rri ta nts .
Immunol ogi c mecha ni s ms a re i nvol ved.
Hepa ti c gra nul oma s ra rel y a ffect hepa tocel l ul a r functi on. However, when gra nul oma s a re pa rt of a broa der i nfl a mma tory rea cti on i nvol vi ng the
l i ver (eg, drug rea cti ons , i nfecti ous mononucl eos i s ), hepa tocel l ul a r dys functi on i s pres ent. Someti mes i nfl a mma ti on ca us es progres s i ve hepa ti c
fi bros i s a nd porta l hypertens i on, typi ca l l y wi th s chi s tos omi a s i s a nd occa s i ona l l y wi th extens i ve s a rcoi da l i nfi l tra ti on.
Symptoms and Signs
Gra nul oma s thems el ves a re typi ca l l y a s ymptoma ti c; even extens i ve i nfi l tra ti on us ua l l y ca us es onl y mi nor hepa tomega l y a nd l i ttl e or no ja undi ce.
Symptoms , i f they occur, refl ect the underl yi ng condi ti on (eg, cons ti tuti ona l s ymptoms i n i nfecti ons , hepa tos pl enomega l y i n s chi s tos omi a s i s ).
[Table 30-2. Ca us es of Hepa ti c Gra nul oma s ]
Diagnosis
Ima gi ng
Bi ops y
Hepa ti c gra nul oma s a re s us pected i n pa ti ents wi th
Condi ti ons tha t commonl y ca us e gra nul oma s
Unexpl a i ned hepa ti c ma s s es found duri ng i ma gi ng tes ts
Occa s i ona l l y, when a n i ma gi ng tes t i s done to eva l ua te a s ymptoma ti c el eva ti ons i n l i ver enzymes , pa rti cul a rl y a l ka l i ne phos pha ta s e
When gra nul oma s a re s us pected, l i ver functi on tes ts a re us ua l l y done, but res ul ts a re nons peci fi c a nd a re ra rel y hel pful i n di a gnos i s . Al ka l i ne
phos pha ta s e (a nd -gl uta myl tra ns fera s e) i s often mi l dl y el eva ted but occa s i ona l l y ma y be ma rkedl y el eva ted. Other tes t res ul ts ma y be norma l or
a bnorma l , refl ecti ng a ddi ti ona l hepa ti c da ma ge (eg, wi des prea d hepa ti c i nfl a mma ti on due to a drug rea cti on). Us ua l l y, i ma gi ng tes ts , s uch a s
ul tra s onogra phy, CT, or MRI, a re not di a gnos ti c; they ma y s how ca l ci fi ca ti on (i f gra nul oma s a re l ong-s ta ndi ng) or fi l l i ng defects , pa rti cul a rl y wi th
confl uent l es i ons .
Di a gnos i s i s ba s ed on l i ver bi ops y. However, bi ops y i s us ua l l y i ndi ca ted onl y to di a gnos e trea ta bl e ca us es (eg, i nfecti ons ) or to rul e out
nongra nul oma tous di s orders (eg, chroni c vi ra l hepa ti ti s ). Bi ops y s ometi mes detects evi dence of the s peci fi c ca us e (eg, s chi s tos ome eggs ,
ca s ea ti on of TB, funga l orga ni s ms ). However, other tes ts (eg, cul tures , s ki n tes ts , l a bora tory tes ts , i ma gi ng tes ts , other ti s s ue s peci mens ) a re often
needed.
In pa ti ents wi th cons ti tuti ona l or other s ymptoms s ugges ti ng i nfecti on (eg, FUO), s peci fi c mea s ures a re ta ken to i ncrea s e the di a gnos ti c
s ens i ti vi ty of bi ops y for i nfecti ons ; eg, a porti on of the fres h bi ops y s peci men i s s ent for cul ture, or s peci a l s ta i ns for a ci d-fa s t ba ci l l i , fungi , a nd
other orga ni s ms a re us ed. Often, ca us e ca nnot be es ta bl i s hed.
Prognosis
Hepa ti c gra nul oma s ca us ed by drugs or i nfecti on regres s compl etel y a fter trea tment. Sa rcoi d gra nul oma s ma y di s a ppea r s ponta neous l y or pers i s t
for yea rs , us ua l l y wi thout ca us i ng cl i ni ca l l y i mporta nt l i ver di s ea s e. Progres s i ve fi bros i s a nd porta l hypertens i on (s a rcoi da l ci rrhos i s ) ra rel y
devel op.
In s chi s tos omi a s i s , progres s i ve porta l s ca rri ng (pi pes tem fi bros i s ) i s typi ca l ; l i ver functi on i s us ua l l y pres erved, but ma rked s pl enomega l y a nd
va ri cea l hemorrha ge ca n occur.
Treatment
Trea tment i s di rected a t the underl yi ng di s order. When the ca us e i s unknown, trea tment i s us ua l l y wi thhel d, a nd fol l ow-up wi th peri odi c l i ver
functi on tes ts i s i ns ti tuted. However, i f s ymptoms of TB (eg, prol onged fever) a nd deteri ora ti ng hea l th occur, empi ri c a nti tubercul ous thera py ma y
be jus ti fi ed.
Corti cos teroi ds ma y benefi t pa ti ents wi th progres s i ve hepa ti c s a rcoi dos i s , a l though whether thes e drugs prevent hepa ti c fi bros i s i s uncl ea r.
However, corti cos teroi ds a re not i ndi ca ted for mos t pa ti ents wi th s a rcoi dos i s a nd a re wa rra nted onl y i f TB a nd other i nfecti ons ca n be excl uded
confi dentl y.
Chapter 31. Gallbladder and Bile Duct Disorders

Introduction
The l i ver produces a bout 500 to 600 mL of bi l e ea ch da y. Bi l e i s i s os moti c wi th pl a s ma a nd cons i s ts pri ma ri l y of wa ter a nd el ectrol ytes but a l s o
orga ni c compounds : bi l e s a l ts , phos phol i pi ds (mos tl y l eci thi n), chol es terol , bi l i rubi n, a nd other endogenous l y produced or i nges ted compounds ,
s uch a s protei ns tha t regul a te GI functi on a nd drugs or thei r meta bol i tes . Bi l i rubi n i s a degra da ti on product of heme compounds from worn-out
RBCs a nd i s the pi gment tha t gi ves bi l e i ts yel l ow-green col or.
Bi l e s a l ts (bi l e a ci ds ) a re the ma jor orga ni c component i n bi l e. The l i ver us es a cti ve tra ns port to s ecrete bi l e s a l ts i nto the ca na l i cul us , the cl eft
between a dja cent hepa tocytes . Ca na l i cul a r tra ns port i s the ra te-l i mi ti ng s tep i n bi l e forma ti on. Once s ecreted, bi l e s a l ts dra w other bi l e
components (pa rti cul a rl y Na + a nd wa ter) i nto the ca na l i cul us by os mos i s . Bi l e s a l ts a re a l s o bi ol ogi c detergents tha t ena bl e the body to excrete
chol es terol a nd potenti a l l y toxi c compounds (eg, bi l i rubi n, drug meta bol i tes ). The functi on of bi l e s a l ts i n the duodenum i s to s ol ubi l i ze i nges ted
fa t a nd fa t-s ol ubl e vi ta mi ns , fa ci l i ta ti ng thei r di ges ti on a nd a bs orpti on. From the l i ver, bi l e fl ows from the i ntra hepa ti c col l ecti ng s ys tem i nto the
ri ght or l eft hepa ti c duct, then i nto the common hepa ti c duct.
Duri ng fa s ti ng, a bout 75% of the bi l e s ecreted pa s s es from the common hepa ti c duct i nto the ga l l bl a dder vi a the cys ti c duct. The res t fl ows di rectl y
i nto the common bi l e duct (formed by the juncti on of the common hepa ti c a nd cys ti c ducts ) i nto the duodenum. Duri ng fa s ti ng, the ga l l bl a dder
a bs orbs up to 90% of bi l e wa ter, concentra ti ng a nd s tori ng bi l e.
Bi l e empti es from the ga l l bl a dder i nto the common bi l e duct. The common bi l e duct joi ns wi th the pa ncrea ti c duct to form the a mpul l a of Va ter,
whi ch empti es i nto the duodenum. Before joi ni ng the pa ncrea ti c duct, the common bi l e duct ta pers to a di a meter of 0.6 cm.
The s phi ncter of Oddi , whi ch s urrounds both the pa ncrea ti c duct a nd the common bi l e duct, i ncl udes a s phi ncter for ea ch duct. Bi l e does not
norma l l y fl ow retrogra de i nto the pa ncrea ti c duct. Thes e s phi ncters a re hi ghl y s ens i ti ve to chol ecys toki ni n a nd other gut hormones (eg, ga s tri nrel ea s i ng pepti de) a nd to a l tera ti ons i n chol i nergi c tone (eg, by a nti chol i nergi c drugs ).
Ea ti ng rel ea s es gut hormones a nd s ti mul a tes chol i nergi c nerves , ca us i ng the ga l l bl a dder to contra ct a nd the s phi ncter of Oddi to rel a x. As a res ul t,
the ga l l bl a dder empti es 50 to 75% of i ts contents i nto the duodenum. Convers el y, duri ng fa s ti ng, a n i ncrea s e i n s phi ncter tone fa ci l i ta tes
ga l l bl a dder fi l l i ng.
Bi l e s a l ts a re poorl y a bs orbed by pa s s i ve di ffus i on i n the proxi ma l s ma l l bowel ; mos t i ntes ti na l bi l e s a l ts rea ch the termi na l i l eum, whi ch
a cti vel y a bs orbs 90% i nto the porta l venous ci rcul a ti on. Returned to the l i ver, bi l e s a l ts a re effi ci entl y extra cted, promptl y modi fi ed (eg, conjuga ted
i f they a rri ve i n the free form), a nd s ecreted ba ck i nto bi l e. Bi l e s a l ts ci rcul a te through thi s pa thwa y from l i ver to gut to l i verthe enterohepa ti c
ci rcul a ti on10 to 12 ti mes /da y.
Cholelithiasis
Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. In developed countries, about 10% of adults and 20% of people > 65 yr have
gallstones. Gallstones tend to be asymptomatic. The most common symptom is biliary colic; gallstones do not cause dyspepsia or fatty food intolerance. More
serious complications include cholecystitis; biliary tract obstruction (from stones in the bile ducts or choledocholithiasis), sometimes with infection (cholangitis);
and gallstone pancreatitis. Diagnosis is usually by ultrasonography. If cholelithiasis causes symptoms or complications, cholecystectomy is necessary.
Ri s k fa ctors for ga l l s tones i ncl ude fema l e s ex, obes i ty, i ncrea s ed a ge, Ameri ca n Indi a n ethni ci ty, a Wes tern di et, a nd a fa mi l y hi s tory. Mos t
di s orders of the bi l i a ry tra ct res ul t from ga l l s tones .
Pathophysiology
Biliary sludge i s often a precurs or of ga l l s tones . It cons i s ts of Ca bi l i rubi na te (a pol ymer of bi l i rubi n), chol es terol mi crocrys ta l s , a nd muci n. Sl udge
devel ops duri ng ga l l bl a dder s ta s i s , a s occurs duri ng pregna ncy or us e of TPN. Mos t s l udge i s a s ymptoma ti c a nd di s a ppea rs when the pri ma ry
condi ti on res ol ves . Al terna ti vel y, s l udge ca n evol ve i nto ga l l s tones or mi gra te i nto the bi l i a ry tra ct, obs tructi ng the ducts a nd l ea di ng to bi l i a ry
col i c, chol a ngi ti s , or pa ncrea ti ti s .
There a re s evera l types of ga l l s tones .
Cholesterol stones a ccount for > 85% of ga l l s tones i n the Wes tern worl d. For chol es terol ga l l s tones to form, the fol l owi ng i s requi red:
Bi l e mus t be s upers a tura ted wi th chol es terol . Norma l l y, wa ter-i ns ol ubl e chol es terol i s ma de wa ter s ol ubl e by combi ni ng wi th bi l e s a l ts a nd
l eci thi n to form mi xed mi cel l es . Supers a tura ti on of bi l e wi th chol es terol mos t commonl y res ul ts from exces s i ve chol es terol s ecreti on (a s occurs
i n obes i ty or di a betes ) but ma y res ul t from a decrea s e i n bi l e s a l t s ecreti on (eg, i n cys ti c fi bros i s beca us e of bi l e s a l t ma l a bs orpti on) or i n
l eci thi n s ecreti on (eg, i n a ra re geneti c di s order tha t ca us es a form of progres s i ve i ntra hepa ti c fa mi l i a l chol es ta s i s ).
The exces s chol es terol mus t preci pi ta te from s ol uti on a s s ol i d mi crocrys ta l s . Such preci pi ta ti on i n the ga l l bl a dder i s a ccel era ted by muci n, a
gl ycoprotei n, or other protei ns i n bi l e.
The mi crocrys ta l s mus t a ggrega te a nd grow. Thi s proces s i s fa ci l i ta ted by the bi ndi ng effect of muci n formi ng a s ca ffol d a nd by retenti on of
mi crocrys ta l s i n the ga l l bl a dder wi th i mpa i red contra cti l i ty due to exces s chol es terol i n bi l e.
Black pigment stones a re s ma l l , ha rd ga l l s tones compos ed of Ca bi l i rubi na te a nd i norga ni c Ca s a l ts (eg, Ca ca rbona te, Ca phos pha te). Fa ctors tha t
a ccel era te s tone devel opment i ncl ude a l cohol i c l i ver di s ea s e, chroni c hemol ys i s , a nd ol der a ge.
Brown pigment stones a re s oft a nd grea s y, cons i s ti ng of bi l i rubi na te a nd fa tty a ci ds (Ca pa l mi ta te or s tea ra te). They form duri ng i nfecti on,
i nfl a mma ti on, a nd pa ra s i ti c i nfes ta ti on (eg, l i ver fl ukes i n As i a ).
Ga l l s tones grow a t a bout 1 to 2 mm/yr, ta ki ng 5 to 20 yr before becomi ng l a rge enough to ca us e probl ems . Mos t ga l l s tones form wi thi n the
ga l l bl a dder, but brown pi gment s tones form i n the ducts . Ga l l s tones ma y mi gra te to the bi l e duct a fter chol ecys tectomy or, pa rti cul a rl y i n the ca s e
of brown pi gment s tones , devel op behi nd s tri ctures a s a res ul t of s ta s i s a nd i nfecti on.
Symptoms and Signs
About 80% of peopl e wi th ga l l s tones a re a s ymptoma ti c. The rema i nder ha ve s ymptoms ra ngi ng from bi l i a ry-type pa i n (bi l i a ry col i c) to chol ecys ti ti s
to l i fe-threa teni ng chol a ngi ti s . Bi l i a ry col i c i s the mos t common s ymptom.
Stones occa s i ona l l y tra vers e the cys ti c duct wi thout ca us i ng s ymptoms . However, mos t ga l l s tone mi gra ti on l ea ds to cys ti c duct obs tructi on, whi ch,
even i f tra ns i ent, ca us es bi l i a ry col i c. Bi l i a ry col i c cha ra cteri s ti ca l l y begi ns i n the ri ght upper qua dra nt but ma y occur el s ewhere i n the a bdomen. It
i s often poorl y l oca l i zed, pa rti cul a rl y i n di a beti cs a nd the el derl y. The pa i n ma y ra di a te i nto the ba ck or down the a rm. Epi s odes begi n s uddenl y,
become i ntens e wi thi n 15 mi n to 1 h, rema i n a t a s tea dy i ntens i ty (not col i cky) for up to 12 h (us ua l l y < 6 h), a nd then gra dua l l y di s a ppea r over 30
to 90 mi n, l ea vi ng a dul l a che. The pa i n i s us ua l l y s evere enough to s end pa ti ents to the emergency depa rtment for rel i ef. Na us ea a nd s ome
vomi ti ng a re common, but fever a nd chi l l s do not occur unl es s chol ecys ti ti s ha s devel oped. Mi l d ri ght upper qua dra nt or epi ga s tri c tendernes s ma y
be pres ent; peri tonea l fi ndi ngs a re a bs ent. Between epi s odes , pa ti ents feel wel l .
Al though bi l i a ry-type pa i n ca n fol l ow a hea vy mea l , fa tty food i s not a s peci fi c preci pi ta ti ng fa ctor. Nons peci fi c GI s ymptoms , s uch a s ga s , bl oa ti ng,
a nd na us ea , ha ve been i na ccura tel y a s cri bed to ga l l bl a dder di s ea s e. Thes e s ymptoms a re common, ha vi ng a bout equa l preva l ence i n
chol el i thi a s i s , pepti c ul cer di s ea s e, a nd functi ona l GI di s orders .
Li ttl e correl a ti on exi s ts between the s everi ty a nd frequency of bi l i a ry col i c a nd pa thol ogi c cha nges i n the ga l l bl a dder. Bi l i a ry col i c ca n occur i n the
a bs ence of chol ecys ti ti s . If col i c l a s ts > 12 h, pa rti cul a rl y i f i t i s a ccompa ni ed by vomi ti ng or fever, a cute chol ecys ti ti s or pa ncrea ti ti s i s l i kel y.
Diagnosis
Ul tra s onogra phy
Ga l l s tones a re s us pected i n pa ti ents wi th bi l i a ry col i c. Abdomi na l ul tra s onogra phy i s the method of choi ce for detecti ng ga l l bl a dder s tones ;
s ens i ti vi ty a nd s peci fi ci ty a re 95%. Ul tra s onogra phy a l s o a ccura tel y detects s l udge. CT, MRI (s ee p. 230), a nd ora l chol ecys togra phy (ra rel y a va i l a bl e
now, a l though qui te a ccura te) a re a l terna ti ves . Endos copi c ul tra s onogra phy a ccura tel y detects s ma l l ga l l s tones (< 3 mm) a nd ma y be needed i f
other tes ts a re equi voca l . La bora tory tes ts us ua l l y a re not hel pful ; typi ca l l y, res ul ts a re norma l unl es s compl i ca ti ons devel op. As ymptoma ti c
ga l l s tones a nd bi l i a ry s l udge a re often detected i nci denta l l y when i ma gi ng, us ua l l y ul tra s onogra phy, i s done for other rea s ons . About 10 to 15% of
ga l l s tones a re ca l ci fi ed a nd vi s i bl e on pl a i n x-ra ys .
Prognosis
Pa ti ents wi th a s ymptoma ti c ga l l s tones become s ymptoma ti c a t a ra te of a bout 2%/yr. The s ymptom tha t devel ops mos t commonl y i s bi l i a ry col i c
ra ther tha n a ma jor bi l i a ry compl i ca ti on. Once bi l i a ry s ymptoms begi n, they a re l i kel y to recur; pa i n returns i n 20 to 40% of pa ti ents /yr, a nd a bout 1
to 2% of pa ti ents /yr devel op compl i ca ti ons s uch a s chol ecys ti ti s , chol edochol i thi a s i s , chol a ngi ti s , a nd ga l l s tone pa ncrea ti ti s .
Treatment
La pa ros copi c chol ecys tectomy for s ymptoma ti c s tones
Expecta nt for a s ymptoma ti c s tones ; s ometi mes s tone di s s ol uti on
Mos t a s ymptoma ti c pa ti ents deci de tha t the di s comfort, expens e, a nd ri s k of el ecti ve s urgery a re not worth removi ng a n orga n tha t ma y never
ca us e cl i ni ca l i l l nes s . However, i f s ymptoms occur, ga l l bl a dder remova l (chol ecys tectomy) i s i ndi ca ted beca us e pa i n i s l i kel y to recur a nd s eri ous
compl i ca ti ons ca n devel op.
Surgery: Surgery ca n be done wi th a n open or l a pa ros copi c techni que.
Open chol ecys tectomy, whi ch i nvol ves a l a rge a bdomi na l i nci s i on a nd di rect expl ora ti on, i s s a fe a nd effecti ve. Its overa l l morta l i ty ra te i s a bout
0.1% when done el ecti vel y duri ng a peri od free of compl i ca ti ons .
La pa ros copi c chol ecys tectomy i s the trea tment of choi ce. Us i ng vi deo endos copy a nd i ns trumenta ti on through s ma l l a bdomi na l i nci s i ons , the
procedure i s l es s i nva s i ve tha n open chol ecys tectomy. The res ul t i s a much s horter conva l es cence, decrea s ed pos topera ti ve di s comfort, i mproved
cos meti c res ul ts , yet no i ncrea s e i n morbi di ty or morta l i ty. La pa ros copi c chol ecys tectomy i s converted to a n open procedure i n 2 to 5% of pa ti ents ,
us ua l l y beca us e bi l i a ry a na tomy ca nnot be i denti fi ed or a compl i ca ti on ca nnot be ma na ged. Ol der a ge typi ca l l y i ncrea s es the ri s ks of a ny type of
s urgery.
Chol ecys tectomy effecti vel y prevents future bi l i a ry col i c but i s l es s effecti ve for preventi ng a typi ca l s ymptoms s uch a s dys peps i a . Chol ecys tectomy
does not res ul t i n nutri ti ona l probl ems or a need for di eta ry l i mi ta ti ons . Some pa ti ents devel op di a rrhea , often beca us e bi l e s a l t ma l a bs orpti on
i n the i l eum i s unma s ked. Prophyl a cti c chol ecys tectomy i s wa rra nted i n a s ymptoma ti c pa ti ents wi th chol el i thi a s i s onl y i f they ha ve l a rge
ga l l s tones (> 3 cm) or a ca l ci fi ed ga l l bl a dder (porcel a i n ga l l bl a dder); thes e condi ti ons i ncrea s e the ri s k of ga l l bl a dder ca rci noma .
Stone dissolution: For pa ti ents who decl i ne s urgery or who a re a t hi gh s urgi ca l ri s k (eg, beca us e of concomi ta nt medi ca l di s orders or a dva nced a ge),
ga l l bl a dder s tones ca n s ometi mes be di s s ol ved by i nges ti ng bi l e a ci ds ora l l y for ma ny months . The bes t ca ndi da tes for thi s trea tment a re thos e
wi th s ma l l , ra di ol ucent s tones (more l i kel y to be compos ed of chol es terol ) i n a functi oni ng nonobs tructed ga l l bl a dder (i ndi ca ted by norma l fi l l i ng
detected duri ng chol es ci nti gra phy or ora l chol ecys togra phy or by a bs ence of s tones i n the neck).
Urs odeoxychol i c a ci d 8 to 10 mg/kg/da y po di s s ol ves 80% of ti ny s tones < 0.5 cm i n di a meter wi thi n 6 mo. For l a rger s tones (the ma jori ty), the
s ucces s ra te i s much l ower, even wi th hi gher dos es of urs odeoxychol i c a ci d. Further, a fter s ucces s ful di s s ol uti on, s tones recur i n 50% wi thi n 5 yr.
Mos t pa ti ents a re thus not ca ndi da tes a nd prefer l a pa ros copi c chol ecys tectomy. However, urs odeoxychol i c a ci d ca n hel p prevent s tone forma ti on
i n morbi dl y obes e pa ti ents who a re l os i ng wei ght ra pi dl y a fter ba ri a tri c s urgery or whi l e on a very l ow ca l ori e di et.
Stone fra gmenta ti on (extra corporea l s hock wa ve l i thotri ps y) to a s s i s t s tone di s s ol uti on a nd cl ea ra nce i s now una va i l a bl e.
Cholecystitis
Chol ecys ti ti s , whi ch i s i nfl a mma ti on of the ga l l bl a dder, ca n be a cute or chroni c.
Acute Cholecystitis
Acute cholecystitis is inflammation of the gallbladder that develops over hours, usually because a gallstone obstructs the cystic duct. Symptoms include right
upper quadrant pain and tenderness, sometimes accompanied by fever, chills, nausea, and vomiting. Abdominal ultrasonography detects the gallstone and
sometimes the associated inflammation. Treatment usually involves antibiotics and cholecystectomy.
Acute chol ecys ti ti s i s the mos t common compl i ca ti on of chol el i thi a s i s . Convers el y, 95% of pa ti ents wi th a cute chol ecys ti ti s ha ve chol el i thi a s i s .
When a s tone becomes i mpa cted i n the cys ti c duct a nd pers i s tentl y obs tructs i t, a cute i nfl a mma ti on res ul ts . Bi l e s ta s i s tri ggers rel ea s e of
i nfl a mma tory enzymes (eg, phos phol i pa s e A, whi ch converts l eci thi n to l ys ol eci thi n, whi ch then ma y medi a te i nfl a mma ti on). The da ma ged
mucos a s ecretes more fl ui d i nto the ga l l bl a dder l umen tha n i t a bs orbs . The res ul ti ng di s tenti on further rel ea s es i nfl a mma tory medi a tors (eg,
pros ta gl a ndi ns ), wors eni ng mucos a l da ma ge a nd ca us i ng i s chemi a , a l l of whi ch perpetua te i nfl a mma ti on. Ba cteri a l i nfecti on ca n s upervene. The
vi ci ous ci rcl e of fl ui d s ecreti on a nd i nfl a mma ti on, when unchecked, l ea ds to necros i s a nd perfora ti on. If a cute i nfl a mma ti on res ol ves , the
ga l l bl a dder becomes fi broti c a nd contra cted a nd does not concentra te bi l e or empty norma l l yfea tures of chroni c chol ecys ti ti s .
Acute acalculous cholecystitis: Aca l cul ous chol ecys ti ti s i s chol ecys ti ti s wi thout s tones . It a ccounts for 5 to 10% of chol ecys tectomi es done for a cute
chol ecys ti ti s . Ri s k fa ctors i ncl ude the fol l owi ng:
Cri ti ca l i l l nes s (eg, ma jor s urgery, burns , s eps i s , or tra uma )
Prol onged fa s ti ng or TPN (both predi s pos e to bi l e s ta s i s )
Shock
Immune defi ci ency
Va s cul i ti s (eg, SLE, pol ya rteri ti s nodos a )
The mecha ni s m proba bl y i nvol ves i nfl a mma tory medi a tors rel ea s ed beca us e of i s chemi a , i nfecti on, or bi l e s ta s i s . Someti mes a n i nfecti ng
orga ni s m ca n be i denti fi ed (eg, Salmonella s p or cytomega l ovi rus i n i mmunodefi ci ent pa ti ents ). In young chi l dren, a cute a ca l cul ous chol ecys ti ti s
tends to fol l ow a febri l e i l l nes s wi thout a n i denti fi a bl e i nfecti ng orga ni s m.
Symptoms and Signs
Mos t pa ti ents ha ve ha d pri or a tta cks of bi l i a ry col i c or a cute chol ecys ti ti s . The pa i n of chol ecys ti ti s i s s i mi l a r i n qua l i ty a nd l oca ti on to bi l i a ry col i c
but l a s ts l onger (i e, > 6 h) a nd i s more s evere. Vomi ti ng i s common, a s i s ri ght s ubcos ta l tendernes s . Wi thi n a few hours , Murphy's s i gn (deep
i ns pi ra ti on exa cerba tes the pa i n duri ng pa l pa ti on of the ri ght upper qua dra nt a nd ha l ts i ns pi ra ti on) devel ops a l ong wi th i nvol unta ry gua rdi ng of
upper a bdomi na l mus cl es on the ri ght s i de. Fever, us ua l l y l ow gra de, i s common.
In the el derl y, the fi rs t or onl y s ymptoms ma y be s ys temi c a nd nons peci fi c (eg, a norexi a , vomi ti ng, ma l a i s e, wea knes s , fever). Someti mes fever
does not devel op.
Acute chol ecys ti ti s begi ns to s ubs i de i n 2 to 3 da ys a nd res ol ves wi thi n 1 wk i n 85% of pa ti ents .
Complications: Wi thout trea tment, 10% of pa ti ents devel op l oca l i zed perfora ti on, a nd 1% devel op free perfora ti on a nd peri toni ti s . Increa s i ng
a bdomi na l pa i n, hi gh fever, a nd ri gors wi th rebound tendernes s or i l eus s ugges t empyema (pus i n the ga l l bl a dder), ga ngrene, or perfora ti on.
When a cute chol ecys ti ti s i s a ccompa ni ed by ja undi ce or chol es ta s i s , pa rti a l common duct obs tructi on i s l i kel y, us ua l l y due to s tones or
i nfl a mma ti on. Other compl i ca ti ons i ncl ude the fol l owi ng:
Mi ri zzi 's s yndrome: Ra rel y, a ga l l s tone becomes i mpa cted i n the cys ti c duct or Ha rtma n's pouch a nd compres s es a nd obs tructs the common bi l e
duct, ca us i ng chol es ta s i s .
Ga l l s tone pa ncrea ti ti s : Ga l l s tones pa s s from the ga l l bl a dder i nto the bi l i a ry tra ct a nd bl ock the pa ncrea ti c duct.
Chol ecys toenteri c fi s tul a : Infrequentl y, a l a rge s tone erodes the ga l l bl a dder wa l l , crea ti ng a fi s tul a i nto the s ma l l bowel (or el s ewhere i n the
a bdomi na l ca vi ty); the s tone ma y pa s s freel y or obs truct the s ma l l bowel (ga l l s tone i l eus ).
Acute acalculous cholecystitis: The s ymptoms a re s i mi l a r to thos e of a cute chol ecys ti ti s wi th ga l l s tones but ma y be di ffi cul t to i denti fy beca us e
pa ti ents tend to be s everel y i l l (eg, ICU s etti ng) a nd ma y be una bl e to communi ca te cl ea rl y. Abdomi na l di s tenti on or unexpl a i ned fever ma y be the
onl y cl ue. Untrea ted, the di s ea s e ca n ra pi dl y progres s to ga l l bl a dder ga ngrene a nd perfora ti on, l ea di ng to s eps i s , s hock, a nd peri toni ti s ; morta l i ty
a pproa ches 65%.
Diagnosis
Ul tra s onogra phy
Chol es ci nti gra phy i f ul tra s onogra phy res ul ts a re equi voca l or i f a ca l cul ous chol ecys ti ti s i s s us pected
Acute chol ecys ti ti s i s s us pected ba s ed on s ymptoms a nd s i gns .

Tra ns a bdomi na l ul tra s onogra phy i s the bes t tes t to detect ga l l s tones . The tes t ma y a l s o el i ci t l oca l a bdomi na l tendernes s over the ga l l bl a dder
(ul tra s onogra phi c Murphy's s i gn). Peri chol ecys ti c fl ui d or thi ckeni ng of the ga l l bl a dder wa l l i ndi ca tes a cute i nfl a mma ti on.
Chol es ci nti gra phy i s us eful when res ul ts a re equi voca l ; fa i l ure of the ra di onucl i de to fi l l the ga l l bl a dder s ugges ts a n obs tructed cys ti c duct (i e, a n
i mpa cted s tone). Fa l s e-pos i ti ve res ul ts ma y be due to the fol l owi ng:
A cri ti ca l i l l nes s
Recei vi ng TPN a nd no ora l foods (beca us e ga l l bl a dder s ta s i s prevents fi l l i ng)
Severe l i ver di s ea s e (beca us e the l i ver does not s ecrete the ra di onucl i de)
Previ ous s phi ncterotomy (whi ch fa ci l i ta tes exi t i nto the duodenum ra ther tha n the ga l l bl a dder)
Morphi ne provoca ti on, whi ch i ncrea s es tone i n the s phi ncter of Oddi a nd enha nces fi l l i ng, hel ps el i mi na te fa l s e-pos i ti ve res ul ts .
Abdomi na l CT i denti fi es compl i ca ti ons s uch a s ga l l bl a dder perfora ti on or pa ncrea ti ti s .
La bora tory tes ts a re done but a re not di a gnos ti c. Leukocytos i s wi th a l eft s hi ft i s common. In uncompl i ca ted a cute chol ecys ti ti s , l i ver functi on tes ts
a re norma l or onl y s l i ghtl y el eva ted. Mi l d chol es ta ti c a bnorma l i ti es (bi l i rubi n up to 4 mg/dL a nd mi l dl y el eva ted a l ka l i ne phos pha ta s e) a re
common, proba bl y i ndi ca ti ng i nfl a mma tory medi a tors a ffecti ng the l i ver ra ther tha n mecha ni ca l obs tructi on. More ma rked i ncrea s es , es peci a l l y i f
l i pa s e (a myl a s e i s l es s s peci fi c) i s el eva ted > 2-fol d, s ugges t bi l e duct obs tructi on. Pa s s a ge of a s tone through the bi l i a ry tra ct i ncrea s es
a mi notra ns fera s es (ALT, AST).
Acute acalculous cholecystitis: Acute a ca l cul ous chol ecys ti ti s i s s ugges ted i f a pa ti ent ha s no ga l l s tones but ha s ul tra s onogra phi c Murphy's s i gn or a
thi ckened ga l l bl a dder wa l l a nd peri chol ecys ti c fl ui d. A di s tended ga l l bl a dder, bi l i a ry s l udge, a nd a thi ckened ga l l bl a dder wa l l wi thout
peri chol ecys ti c fl ui d (due to l ow a l bumi n or a s ci tes ) ma y res ul t s i mpl y from a cri ti ca l i l l nes s . CT i denti fi es extra bi l i a ry a bnorma l i ti es .
Chol es ci nti gra phy i s more hel pful ; fa i l ure of a ra di onucl i de to fi l l ma y i ndi ca te edema tous cys ti c duct obs tructi on. Gi vi ng morphi ne hel ps
el i mi na te a fa l s e-pos i ti ve res ul t due to ga l l bl a dder s ta s i s .
Treatment
Supporti ve ca re (hydra ti on, a na l ges i cs , a nti bi oti cs )
Chol ecys tectomy
Ma na gement i ncl udes hos pi ta l a dmi s s i on, IV fl ui ds , a nd a na l ges i a wi th a n NSAID (ketorol a c) or a n opi oi d. Nothi ng i s gi ven ora l l y, a nd
na s oga s tri c s ucti on i s i ns ti tuted i f vomi ti ng or a n i l eus i s pres ent. Pa rentera l a nti bi oti cs a re us ua l l y i ni ti a ted to trea t pos s i bl e i nfecti on, but
evi dence of benefi t i s l a cki ng. Empi ri c covera ge, di rected a t gra m-nega ti ve enteri c orga ni s ms , i nvol ves IV regi mens s uch a s ceftri a xone 2 g q 24 h
pl us metroni da zol e 500 mg q 8 h, pi pera ci l l i n/ta zoba cta m 4 g q 6 h, or ti ca rci l l i n/cl a vul a na te 4 g q 6 h.
Chol ecys tectomy cures a cute chol ecys ti ti s a nd rel i eves bi l i a ry pa i n. Ea rl y chol ecys tectomy i s genera l l y preferred, bes t done duri ng the fi rs t 24 to 48
h i n the fol l owi ng s i tua ti ons :
The di a gnos i s i s cl ea r a nd pa ti ents a re a t l ow s urgi ca l ri s k.
Pa ti ents a re el derl y or ha ve di a betes a nd a re thus a t hi gher ri s k of i nfecti ous compl i ca ti ons .
Pa ti ents ha ve empyema , ga ngrene, perfora ti on, or a ca l cul ous chol ecys ti ti s .
Surgery ma y be del a yed when pa ti ents ha ve a n underl yi ng s evere chroni c di s order (eg, ca rdi opul mona ry) tha t i ncrea s es the s urgi ca l ri s ks . In s uch
pa ti ents , chol ecys tectomy i s deferred unti l medi ca l thera py s ta bi l i zes the comorbi d di s orders or unti l chol ecys ti ti s res ol ves . If chol ecys ti ti s
res ol ves , chol ecys tectomy ma y be done 6 wk l a ter. Del a yed s urgery ca rri es the ri s k of recurrent bi l i a ry compl i ca ti ons . Percuta neous
chol ecys tos tomy i s a n a l terna ti ve to chol ecys tectomy for pa ti ents a t very hi gh s urgi ca l ri s k, s uch a s the el derl y, thos e wi th a ca l cul ous chol ecys ti ti s ,
a nd thos e i n a n ICU beca us e of burns , tra uma , or res pi ra tory fa i l ure.
Chronic Cholecystitis
Chronic cholecystitis is long-standing gallbladder inflammation almost always due to gallstones.
Chroni c chol ecys ti ti s a l mos t a l wa ys res ul ts from ga l l s tones a nd pri or epi s odes of a cute chol ecys ti ti s (even i f mi l d). Da ma ge ra nges from a modes t
i nfi l tra te of chroni c i nfl a mma tory cel l s to a fi broti c, s hrunken ga l l bl a dder. Extens i ve ca l ci fi ca ti on due to fi bros i s i s ca l l ed porcel a i n ga l l bl a dder.
Symptoms and Signs
Ga l l s tones i ntermi ttentl y obs truct the cys ti c duct a nd s o ca us e recurrent bi l i a ry col i c. Such epi s odes of pa i n a re not neces s a ri l y a ccompa ni ed by
overt ga l l bl a dder i nfl a mma ti on; the extent of i nfl a mma ti on does not correl a te wi th the i ntens i ty or frequency of bi l i a ry col i c. Upper a bdomi na l
tendernes s ma y be pres ent, but us ua l l y fever i s not. Fever s ugges ts a cute chol ecys ti ti s . Once epi s odes begi n, they a re l i kel y to recur.
Diagnosis
Ul tra s onogra phy

Chroni c chol ecys ti ti s i s s us pected i n pa ti ents wi th recurrent bi l i a ry col i c pl us ga l l s tones . Ul tra s onogra phy or a nother i ma gi ng tes t us ua l l y s hows
ga l l s tones a nd s ometi mes a s hrunken, fi broti c ga l l bl a dder. The di a gnos i s i s ma de i n pa ti ents wi th a hi s tory of recurrent bi l i a ry col i c a nd evi dence
of ga l l s tones on ul tra s onogra phy. Chol es ci nti gra phy ma y s how nonvi s ua l i za ti on of the ga l l bl a dder but i s l es s a ccura te.
Treatment
La pa ros copi c chol ecys tectomy i s i ndi ca ted to prevent s ymptom recurrence a nd further bi l i a ry compl i ca ti ons . Thi s procedure i s pa rti cul a rl y va l i d for
the porcel a i n ga l l bl a dder a s s oci a ted wi th ga l l bl a dder ca rci noma .
Acalculous Biliary Pain
Acalculous biliary pain is biliary colic without gallstones, resulting from structural or functional disorders; it is sometimes treated with laparoscopic
cholecystectomy.
Bi l i a ry col i c ca n occur i n the a bs ence of ga l l s tones , pa rti cul a rl y i n young women. Aca l cul ous bi l i a ry pa i n a ccounts for up to 15% of l a pa ros copi c
chol ecys tectomi es . Common ca us es of s uch bi l i a ry pa i n i ncl ude the fol l owi ng:
Mi cros copi c s tones not detected by routi ne a bdomi na l ul tra s onogra phy
Abnorma l ga l l bl a dder emptyi ng
An overl y s ens i ti ve bi l i a ry tra ct
Sphi ncter of Oddi dys functi on
Hypers ens i ti vi ty of the a dja cent duodenum
Pos s i bl y ga l l s tones tha t ha ve s ponta neous l y pa s s ed
Some pa ti ents eventua l l y devel op other functi ona l GI di s orders .
Diagnosis
Aca l cul ous bi l i a ry pa i n i s s us pected i n pa ti ents wi th bi l i a ry col i c when di a gnos ti c i ma gi ng ca nnot detect ga l l s tones . Ima gi ng s houl d i ncl ude
ul tra s onogra phy a nd, where a va i l a bl e, endos copi c ul tra s onogra phy (for s ma l l s tones < 1 cm). Abnorma l l a bora tory tes ts ma y revea l evi dence of a
bi l i a ry tra ct a bnorma l i ty (eg, el eva ted a l ka l i ne phos pha ta s e, bi l i rubi n, ALT, or AST) or a pa ncrea ti c a bnorma l i ty (eg, el eva ted l i pa s e) duri ng a n
epi s ode of a cute pa i n. Chol es ci nti gra phy wi th chol ecys toki ni n i nfus i on mea s ures ga l l bl a dder emptyi ng (ejecti on fra cti on); potenti a l l y i nterferi ng
drugs s uch a s Ca cha nnel bl ockers , opi oi ds , a nd a nti chol i nergi cs s houl d not be us ed. ERCP wi th bi l i a ry ma nometry detects s phi ncter of Oddi
dys functi on. The bes t di a gnos ti c a pproa ch rema i ns probl ema ti c.
Treatment
La pa ros copi c chol ecys tectomy i mproves outcomes for pa ti ents wi th mi cros copi c s tones a nd pos s i bl y a bnorma l ga l l bl a dder moti l i ty. The rol e of
l a pa ros copi c chol ecys tectomy or endos copi c s phi ncterotomy rema i ns probl ema ti c. Drug thera pi es ha ve no proven benefi t.
Postcholecystectomy Syndrome
Postcholecystectomy syndrome is occurrence of abdominal symptoms after cholecystectomy.
Pos tchol ecys tectomy s yndrome occurs i n 5 to 40% of pa ti ents . It refers to pres umed ga l l bl a dder s ymptoms tha t conti nue or tha t devel op a fter
chol ecys tectomy or to other s ymptoms tha t res ul t from chol ecys tectomy. Remova l of the ga l l bl a dder, the s tora ge orga n for bi l e, norma l l y ha s few
cons equences on bi l i a ry tra ct functi on or pres s ures . In a bout 10%, bi l i a ry col i c a ppea rs to res ul t from functi ona l or s tructura l a bnorma l i ti es of the
s phi ncter of Oddi , res ul ti ng i n a l tered bi l i a ry pres s ures or hei ghtened s ens i ti vi ty.
The mos t common s ymptoms a re dys peps i a or otherwi s e nons peci fi c s ymptoms ra ther tha n true bi l i a ry col i c. Pa pi l l a ry s tenos i s , whi ch i s ra re, i s
fi broti c na rrowi ng a round the s phi ncter, perha ps ca us ed by tra uma a nd i nfl a mma ti on due to pa ncrea ti ti s , i ns trumenta ti on (eg, ERCP), or pri or
pa s s a ge of a s tone. Other ca us es i ncl ude a reta i ned bi l e duct s tone, pa ncrea ti ti s , a nd ga s troes opha gea l refl ux.
Diagnosis
ERCP wi th bi l i a ry ma nometry or bi l i a ry nucl ea r s ca nni ng
Excl us i on of extra bi l i a ry pa i n
Pa ti ents wi th pos tchol ecys tectomy pa i n s houl d be eva l ua ted a s i ndi ca ted for extra -bi l i a ry a s wel l a s bi l i a ry ca us es . If the pa i n s ugges ts bi l i a ry
col i c, a l ka l i ne phos pha ta s e, bi l i rubi n, ALT, a myl a s e, a nd l i pa s e s houl d be mea s ured, a nd ERCP wi th bi l i a ry ma nometry or bi l i a ry nucl ea r s ca nni ng
s houl d be done. El eva ted l i ver enzymes s ugges t s phi ncter of Oddi dys functi on; el eva ted a myl a s e a nd l i pa s e s ugges t dys functi on of the s phi ncter's
pa ncrea ti c porti on.
Dys functi on i s bes t detected by bi l i a ry ma nometry done duri ng ERCP, a l though ERCP ha s a ri s k of i nduci ng pa ncrea ti ti s . Ma nometry s hows
i ncrea s ed pres s ure i n the bi l i a ry tra ct when pa i n i s reproduced. A s l owed hepa ti c hi l um-duodena l tra ns i t ti me on a s ca n a l s o s ugges ts s phi ncter
of Oddi dys functi on. Di a gnos i s of pa pi l l a ry s tenos i s i s ba s ed on a cl ea r-cut hi s tory of recurrent epi s odes of bi l i a ry pa i n a nd a bnorma l l i ver (or
pa ncrea ti c) enzyme tes ts .

Treatment
Endos copi c s phi ncterotomy ca n rel i eve recurrent pa i n due to s phi ncter of Oddi dys functi on, es peci a l l y i f due to pa pi l l a ry s tenos i s . It i s
controvers i a l for pa ti ents who ha ve pos tchol ecys tectomy pa i n a nd no objecti ve a bnorma l i ti es .
Choledocholithiasis and Cholangitis
Choledocholithiasis is the presence of stones in bile ducts; the stones can form in the gallbladder or in the ducts themselves. These stones cause biliary colic,
biliary obstruction, gallstone pancreatitis, or cholangitis (bile duct infection and inflammation). Cholangitis, in turn, can lead to strictures, stasis, and
choledocholithiasis. Diagnosis usually requires visualization by magnetic resonance cholangiopancreatography or ERCP. Early endoscopic or surgical
decompression is indicated.
Stones ma y be des cri bed a s
Pri ma ry s tones (us ua l l y brown pi gment s tones ), whi ch form i n the bi l e ducts
Seconda ry s tones (us ua l l y chol es terol ), whi ch form i n the ga l l bl a dder but mi gra te to the bi l e ducts
Res i dua l s tones , whi ch a re mi s s ed a t the ti me of chol ecys tectomy (evi dent < 3 yr l a ter)
Recurrent s tones , whi ch devel op i n the ducts > 3 yr a fter s urgery
In devel oped countri es , > 85% of common duct s tones a re s econda ry; a ffected pa ti ents ha ve a ddi ti ona l s tones l oca ted i n the ga l l bl a dder. Up to
10% of pa ti ents wi th s ymptoma ti c ga l l s tones a l s o ha ve a s s oci a ted common bi l e duct s tones . After chol ecys tectomy, brown pi gment s tones ma y
res ul t from s ta s i s (eg, due to a pos topera ti ve s tri cture) a nd the s ubs equent i nfecti on. The proporti on of ducta l s tones tha t a re pi gmented
i ncrea s es wi th ti me a fter chol ecys tectomy.
Bi l e duct s tones ma y pa s s i nto the duodenum a s ymptoma ti ca l l y. Bi l i a ry col i c occurs when the ducts become pa rti a l l y obs tructed. More compl ete
obs tructi on ca us es duct di l a ti on, ja undi ce, a nd, eventua l l y, chol a ngi ti s (a ba cteri a l i nfecti on). Stones tha t obs truct the
[
Table 31-1. Ca us es of Bi l e Duct Obs tructi on]
a mpul l a of Va ter ca n ca us e ga l l s tone pa ncrea ti ti s . Some pa ti ents (us ua l l y the el derl y) pres ent wi th bi l i a ry obs tructi on due to s tones tha t ha ve
ca us ed no s ymptoms previ ous l y.
In acute cholangitis, bi l e duct obs tructi on a l l ows ba cteri a to a s cend from the duodenum. Mos t (85%) ca s es res ul t from common bi l e duct s tones , but
bi l e duct obs tructi on ca n res ul t from tumors or other condi ti ons (s ee Ta bl e 31-1). Common i nfecti ng orga ni s ms i ncl ude gra m-nega ti ve ba cteri a (eg,
Escherichia coli, Klebsiella s p, Enterobacter s p); l es s common a re gra m-pos i ti ve ba cteri a (eg, Enterococcus s p) a nd mi xed a na erobes (eg, Bacteroides s p,
Clostridia s p). Symptoms i ncl ude a bdomi na l pa i n, ja undi ce, a nd fever or chi l l s (Cha rcot's tri a d). The a bdomen i s tender, a nd often the l i ver i s tender
a nd enl a rged (often conta i ni ng a bs ces s es ). Confus i on a nd hypotens i on predi ct a bout a 50% morta l i ty ra te a nd hi gh morbi di ty.
Recurrent pyogenic cholangitis (Ori enta l chol a ngi ohepa ti ti s , hepa tol i thi a s i s ) i s cha ra cteri zed by i ntra hepa ti c brown pi gment s tone forma ti on. Thi s
di s order occurs i n Southea s t As i a . It cons i s ts of s l udge a nd ba cteri a l debri s i n the bi l e ducts . Undernutri ti on a nd pa ra s i ti c i nfes ta ti on (eg,
Clonorchis sinensis, Opisthorchis viverrini) i ncrea s e s us cepti bi l i ty. Pa ra s i ti c i nfes ta ti on ca n ca us e obs tructi ve ja undi ce wi th i ntra hepa ti c ducta l
i nfl a mma ti on, proxi ma l s ta s i s , s tone forma ti on, a nd chol a ngi ti s . Repea ti ng cycl es of obs tructi on, i nfecti on, a nd i nfl a mma ti on l ea d to bi l e duct
s tri ctures a nd bi l i a ry ci rrhos i s . The extra hepa ti c ducts tend to be di l a ted, but the i ntra hepa ti c ducts a ppea r s tra i ght beca us e of peri ducta l fi bros i s .
In AIDS-rel a ted chol a ngi opa thy or chol a ngi ti s , di rect chol a ngi ogra phy ma y s how a bnorma l i ti es s i mi l a r to thos e i n pri ma ry s cl eros i ng chol a ngi ti s
or pa pi l l a ry s tenos i s (i e, mul ti pl e s tri ctures a nd di l a ti ons i nvol vi ng the i ntra hepa ti c a nd extra hepa ti c bi l e ducts ). Eti ol ogy i s proba bl y i nfecti on,
mos t l i kel y wi th cytomega l ovi rus , Cryptosporidium s p, or mi cros pori di a .
Diagnosis
Ul tra s onogra phy
Common duct s tones s houl d be s us pected i n pa ti ents wi th ja undi ce a nd bi l i a ry col i c. Fever a nd l eukocytos i s further s ugges t a cute chol a ngi ti s .
El eva ted l evel s of bi l i rubi n, a l ka l i ne phos pha ta s e, ALT, a nd -gl uta myl tra ns fera s e a re cons i s tent wi th extra hepa ti c obs tructi on, s ugges ti ng s tones ,
pa rti cul a rl y i n pa ti ents wi th fea tures of a cute chol ecys ti ti s or chol a ngi ti s .
Ul tra s onogra phy ma y s how s tones i n the ga l l bl a dder a nd occa s i ona l l y i n the common duct (l es s a ccura te). The common duct i s di l a ted (> 6 mm i n
di a meter i f the ga l l bl a dder i s i nta ct; > 10 mm a fter a chol ecys tectomy). If the ducts a re not di l a ted ea rl y i n the pres enta ti on (eg, fi rs t da y), s tones
ha ve proba bl y pa s s ed. If doubt exi s ts , ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP) i s hi ghl y a ccura te for reta i ned s tones . ERCP i s done i f
MRCP i s equi voca l ; i t ca n be thera peuti c a s wel l a s di a gnos ti c. CT, though l es s a ccura te tha n ul tra s onogra phy, ca n detect l i ver a bs ces s es .
For s us pected a cute chol a ngi ti s , CBC a nd bl ood cul tures a re es s enti a l . Leukocytos i s i s common, a nd a mi notra ns fera s es ma y rea ch 1000 IU/L,
s ugges ti ng a cute hepa ti c necros i s , often due to mi croa bs ces s es . Bl ood cul tures gui de a nti bi oti c choi ce.
Treatment
ERCP a nd s phi ncterotomy

If bi l i a ry obs tructi on i s s us pected, ERCP a nd s phi ncterotomy a re neces s a ry to remove the s tone. Succes s ra te exceeds 90%; up to 7% of pa ti ents
ha ve compl i ca ti ons (eg, bl eedi ng pa ncrea ti ti s , i nfecti on wi th fi bros i s a nd s ubs equent duct s tri cture). La pa ros copi c chol ecys tectomy, whi ch i s not
a s wel l s ui ted for opera ti ve chol a ngi ogra phy or common duct expl ora ti on, ca n be done el ecti vel y fol l owi ng ERCP a nd s phi ncterotomy. Morta l i ty a nd
morbi di ty a fter open chol ecys tectomy wi th common duct expl ora ti on a re hi gher. In pa ti ents a t hi gh ri s k of compl i ca ti ons wi th chol ecys tectomy (eg,
the el derl y), s phi ncterotomy a l one i s a n a l terna ti ve.
Acute chol a ngi ti s i s a n emergency requi ri ng a ggres s i ve s upporti ve ca re a nd urgent remova l of the s tones , endos copi ca l l y or s urgi ca l l y. Anti bi oti cs
a re gi ven, s i mi l a r to thos e us ed for a cute chol ecys ti ti s (s ee p. 274) An a l terna ti ve regi men for very i l l pa ti ents i s i mi penem a nd ci profl oxa ci n, pl us
metroni da zol e to cover a na erobes .
For recurrent pyogeni c chol a ngi ti s , ma na gement a i ms to provi de s upporti ve ca re (eg, broa d-s pectrum a nti bi oti cs ), era di ca te a ny pa ra s i tes , a nd
mecha ni ca l l y cl ea r the ducts of s tones a nd debri s endos copi ca l l y (vi a ERCP) or s urgi ca l l y.
Sclerosing Cholangitis
Sclerosing cholangitis refers to chronic cholestatic syndromes characterized by patchy inflammation, fibrosis, and strictures of the intrahepatic and extrahepatic
bile ducts. Progression obliterates the bile ducts and leads to cirrhosis, liver failure, and sometimes cholangiocarcinoma.
Scl eros i ng chol a ngi ti s ma y be pri ma ry (wi th no known ca us e) or s econda ry due to i mmune defi ci enci es (congeni ta l i n chi l dren, a cqui red i n a dul ts
a s AIDS chol a ngi opa thy) often a s s oci a ted wi th s uperi mpos ed i nfecti ons (eg, cytomega l ovi rus , Cryptosporidium), hi s ti ocytos i s X, or us e of drugs (eg,
i ntra a rteri a l fl oxuri di ne). Both pri ma ry a nd s econda ry s cl eros i ng chol a ngi ti s ca us e s i mi l a r i nfl a mma tory a nd fi bros i ng l es i ons s ca rri ng the bi l e
ducts . Other ca us es of bi l e duct s tri ctures a re chol edochol i thi a s i s , pos topera ti ve bi l i a ry s tri cture, i s chemi c bi l e duct i njury (duri ng l i ver
tra ns pl a nta ti on), congeni ta l bi l i a ry a bnorma l i ti es , chol a ngi oca rci noma , a nd pa ra s i ti c i nfes ta ti ons .
Di a gnos i s of bi l i a ry s tri ctures a nd di l a ti ons requi res i ma gi ng techni ques s uch a s ul tra s onogra phy a nd chol a ngi ogra phy. Trea tment focus es on
rel i evi ng bi l i a ry obs tructi on (eg, di l a ti ng a nd s tenti ng s tri ctures ) a nd, when pos s i bl e, era di ca ti ng res pons i bl e orga ni s ms or trea ti ng the ca us e (eg,
HIV).
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC), the most common form of sclerosing cholangitis, has no known cause. However, 80% of patients have inflammatory bowel
disease, most often ulcerative colitis. Other associated conditions include connective tissue disorders, alloimmune disorders, and immunodeficiency syndromes,
sometimes complicated by opportunistic infections. Fatigue and pruritus develop insidiously and progressively. Diagnosis is by cholangiography (magnetic
resonance cholangiopancreatography or ERCP). Liver transplantation is indicated for advanced disease.
Mos t (70%) pa ti ents wi th PSC a re men. Mea n a ge a t di a gnos i s i s 40 yr.
Etiology
Al though the ca us e i s unknown, PSC i s a s s oci a ted wi th i nfl a mma tory bowel di s ea s e, whi ch i s pres ent i n 80% of pa ti ents . About 5% of pa ti ents
wi th ul cera ti ve col i ti s a nd a bout 1% wi th Crohn's di s ea s e devel op PSC. Thi s a s s oci a ti on a nd the pres ence of s evera l a utoa nti bodi es (eg, a nti s mooth mus cl e a nd peri nucl ea r a nti neutrophi l i c a nti bodi es [pANCA]) s ugges t i mmune-medi a ted mecha ni s ms . T cel l s a ppea r to be i nvol ved i n the
des tructi on of the bi l e ducts , i mpl yi ng di s ordered cel l ul a r i mmuni ty. A geneti c predi s pos i ti on i s s ugges ted by a tendency for the di s order to
devel op i n mul ti pl e fa mi l y members a nd a hi gher frequency i n peopl e wi th HLAB8 a nd HLADR3, whi ch a re often correl a ted wi th a utoi mmune
di s orders . An unknown tri gger (eg, ba cteri a l i nfecti on, i s chemi c duct i njury) proba bl y ca us es PSC to devel op i n geneti ca l l y predi s pos ed peopl e.
Symptoms and Signs
Ons et i s us ua l l y i ns i di ous , wi th progres s i ve fa ti gue a nd then pruri tus . Ja undi ce tends to devel op l a ter. About 10 to 15% of pa ti ents pres ent wi th
repea ted epi s odes of ri ght upper qua dra nt pa i n a nd fever, pos s i bl y due to a s cendi ng ba cteri a l chol a ngi ti s . Stea torrhea a nd defi ci enci es of fa ts ol ubl e vi ta mi ns ca n devel op. Pers i s tent ja undi ce ha rbi ngers a dva nced di s ea s e. Symptoma ti c ga l l s tones a nd chol edochol i thi a s i s tend to devel op
i n a bout 75% of pa ti ents . Some pa ti ents , a s ymptoma ti c unti l l a te i n the cours e, fi rs t pres ent wi th hepa tos pl enomega l y or ci rrhos i s . PSC tends to
s l owl y a nd i nexora bl y progres s . The termi na l pha s e i nvol ves decompens a ted ci rrhos i s , porta l hypertens i on, a s ci tes , a nd l i ver fa i l ure. The ti me
from di a gnos i s to l i ver fa i l ure i s a bout 12 yr.
Des pi te the a s s oci a ti on between PSC a nd i nfl a mma tory bowel di s ea s e, the two di s ea s es tend to run s epa ra te cours es . Ul cera ti ve col i ti s ma y
a ppea r yea rs before PSC yet tends to ha ve a mi l der cours e when a s s oci a ted wi th PSC. Si mi l a rl y, tota l col ectomy does not cha nge the cours e of PSC.
The pres ence of both di s ea s es i ncrea s es the ri s k of col orecta l ca rci noma , rega rdl es s of whether a l i ver tra ns pl a nta ti on ha s been done for PSC.
Chol a ngi oca rci noma devel ops i n 10 to 15% of pa ti ents .
Diagnosis
Ma gneti c res ona nce chol a ngi opa ncrea togra phy (MRCP)
PSC i s s us pected i n pa ti ents wi th unexpl a i ned a bnorma l i ti es i n l i ver bi ochemi ca l tes ts , pa rti cul a rl y i n thos e wi th i nfl a mma tory bowel di s ea s e. A
chol es ta ti c pa ttern i s typi ca l : el eva ted a l ka l i ne phos pha ta s e a nd -gl uta myl tra ns fera s e (GGT) ra ther tha n a mi notra ns fera s es . Ga mma gl obul i n
a nd IgM l evel s tend to be i ncrea s ed. Anti -s mooth mus cl e a nti bodi es a nd pANCA a re us ua l l y pos i ti ve. Anti mi tochondri a l a nti body, pos i ti ve i n
pri ma ry bi l i a ry ci rrhos i s , i s cha ra cteri s ti ca l l y nega ti ve.
Ima gi ng of the hepa tobi l i a ry s ys tem begi ns wi th ul tra s onogra phy to excl ude extra hepa ti c bi l i a ry obs tructi on. Al though ul tra s onogra phy or CT ca n
s how ducta l di l a ti on, di a gnos i s requi res chol a ngi ogra phy to s how mul ti pl e s tri ctures a nd di l a ti ons i n the i ntra hepa ti c a nd extra hepa ti c bi l e
ducts . Ima gi ng s houl d begi n wi th MRCP. ERCP i s us ua l l y a 2nd choi ce beca us e i t i s i nva s i ve. Li ver bi ops y i s genera l l y not requi red for di a gnos i s ;
when done, i t s hows bi l e duct prol i fera ti on, peri ducta l fi bros i s , i nfl a mma ti on, a nd l os s of bi l e ducts . Wi th di s ea s e progres s i on, peri ducta l
fi bros i s extends from the porta l regi ons a nd eventua l l y l ea ds to s econda ry bi l i a ry ci rrhos i s .
Mea s urement of s erum tumor ma rkers a nd ERCP s urvei l l a nce wi th brus h cytol ogy s houl d be done regul a rl y to check for chol a ngi oca rci noma .
Treatment
Supporti ve ca re
ERCP di l a ti on for ma jor (domi na nt) s tri ctures
Tra ns pl a nta ti on for recurrent ba cteri a l chol a ngi ti s or compl i ca ti ons of end-s ta ge l i ver di s ea s e
As ymptoma ti c pa ti ents us ua l l y requi re onl y moni tori ng (eg, phys i ca l exa mi na ti on a nd l i ver bi ochemi ca l tes ts twi ce/yr). Urs odeoxychol i c a ci d (up to
15 mg/kg/da y reduces i tchi ng a nd i mprove bi ochemi ca l ma rkers but not s urvi va l . Chroni c chol es ta s i s (s ee p. 212) a nd ci rrhos i s requi re s upporti ve
trea tment. Epi s odes of ba cteri a l chol a ngi ti s wa rra nt a nti bi oti cs a nd thera peuti c ERCP, a s needed. If a s i ngl e s tri cture a ppea rs to be the ma jor
ca us e of obs tructi on (a domi na nt s tri cture, found i n a bout 20% of pa ti ents ), ERCP di l a ti on (wi th brus h cytol ogy to check for tumors ) a nd s tenti ng ca n
rel i eve s ymptoms .
Li ver tra ns pl a nta ti on i s the onl y trea tment tha t i mproves l i fe expecta ncy i n pa ti ents wi th PSC a nd offers a cure. Recurrent ba cteri a l chol a ngi ti s or
compl i ca ti ons of end-s ta ge l i ver di s ea s e (eg, i ntra cta bl e a s ci tes , porta l -s ys temi c encepha l opa thy, bl eedi ng es opha gea l va ri ces ) a re rea s ona bl e
i ndi ca ti ons for l i ver tra ns pl a nta ti on.
AIDS Cholangiopathy
AIDS cholangiopathy is biliary obstruction secondary to biliary tract strictures caused by various opportunistic infections.
Before the a dvent of hi ghl y a cti ve a nti retrovi ra l thera py, chol a ngi opa thy occurred i n 25% of pa ti ents wi th AIDS, es peci a l l y i n thos e wi th a l ow CD4
count (< 100/L). The mos t common pa thogen i s Cryptosporidium parvum. Others i ncl ude cytomega l ovi rus , mi cros pori di a , a nd Cyclospora s p. Pa pi l l a ry
s tenos i s or i ntra hepa ti c or extra hepa ti c s cl eros i ng chol a ngi ti s devel ops i n mos t pa ti ents . Over ha l f ha ve both.
Common s ymptoms i ncl ude ri ght upper qua dra nt a nd epi ga s tri c pa i n a nd di a rrhea . A few pa ti ents ha ve fever a nd ja undi ce. Severe pa i n us ua l l y
i ndi ca tes pa pi l l a ry s tenos i s . Mi l der pa i n s ugges ts s cl eros i ng chol a ngi ti s . The di a rrhea refl ects s ma l l -bowel i nfecti on, often cryptos pori di os i s .
Diagnosis
Us ua l l y ERCP a nd ul tra s onogra phy
ERCP provi des the di a gnos i s , i denti fi ca ti on of the ca us a l orga ni s m by s ma l l -bowel bi ops y, a nd a thera peuti c opportuni ty to rel i eve s tri ctures .
Ul tra s onogra phy i s noni nva s i ve a nd very a ccura te (> 95%). CT a nd ma gneti c res ona nce chol a ngi opa ncrea togra phy l i kel y ha ve s upporti ve rol es .
Li ver bi ochemi s try i s cons i s tent wi th chol es ta s i s , es peci a l l y a hi gh a l ka l i ne phos pha ta s e l evel .
Treatment
Endos copi c procedures
Endos copi c s phi ncterotomy ca n ma rkedl y rel i eve pa i n, ja undi ce, a nd chol a ngi ti s i n pa ti ents wi th pa pi l l a ry s tenos i s . Is ol a ted or domi na nt
s tri ctures ca n be s tented endos copi ca l l y. Al though the ca us e i s a n i nfecti ous a gent, a nti mi crobi a l thera py a l one does not rel i eve the bi l i a ry tra ct
da ma ge or i ts s equel a e. Beca us e of i ts us e i n pri ma ry s cl eros i ng chol a ngi ti s , urs odeoxychol i c a ci d ma y ha ve a rol e i n trea ti ng i ntra hepa ti c ducta l
s cl eros i s a nd chol es ta s i s .
Tumors of the Gallbladder and Bile Ducts
Gallbladder and bile duct tumors can cause extrahepatic biliary obstruction. Symptoms may be absent but often are constitutional or reflect biliary obstruction.
Diagnosis is based on ultrasonography plus CT cholangiography or magnetic resonance cholangiopancreatography. Prognosis is grim. Mechanical bile drainage can
often relieve pruritus, recurrent sepsis, and pain due to biliary obstruction.
Cholangiocarcinomas a nd other bi l e duct tumors a re ra re (1 to 2/100,000 peopl e) but a re us ua l l y ma l i gna nt. Chol a ngi oca rci noma s occur
predomi na ntl y i n the extra hepa ti c bi l e ducts : 60 to 70% i n the peri hi l a r regi on (Kl a ts ki n tumors ), a bout 25% i n the di s ta l ducts , a nd the res t i n the
l i ver. Ri s k fa ctors i ncl ude pri ma ry s cl eros i ng chol a ngi ti s , ol der a ge, i nfes ta ti on wi th l i ver fl ukes , a nd a chol edocha l cys t.
Gallbladder carcinoma i s uncommon (2.5/100,000). It i s more common a mong Ameri ca n Indi a ns , pa ti ents wi th l a rge ga l l s tones (> 3 cm), a nd thos e
wi th extens i ve ga l l bl a dder ca l ci fi ca ti on due to chroni c chol ecys ti ti s (porcel a i n ga l l bl a dder). Nea rl y a l l (70 to 90%) pa ti ents a l s o ha ve ga l l s tones .
Medi a n s urvi va l i s 3 mo. Cure i s pos s i bl e when ca ncer i s found ea rl y (eg, i nci denta l l y a t chol ecys tectomy).
Gallbladder polyps a re us ua l l y a s ymptoma ti c beni gn mucos a l projecti ons tha t devel op i n the l umen of the ga l l bl a dder. Mos t a re < 10 mm i n
di a meter a nd compos ed of chol es terol es ter a nd tri gl yceri des ; the pres ence of s uch pol yps i s ca l l ed chol es terol os i s . They a re found i n a bout 5%
of peopl e duri ng ul tra s onogra phy. Other, much l es s common beni gn pol yps i ncl ude a denoma s (ca us i ng a denomyoma tos i s ) a nd i nfl a mma tory
pol yps . Sma l l ga l l bl a dder pol yps a re i nci denta l fi ndi ngs tha t do not requi re trea tment.
Symptoms and Signs
Mos t pa ti ents wi th chol a ngi oca rci noma s pres ent wi th pruri tus a nd pa i nl es s obs tructi ve ja undi ce, typi ca l l y a t a ge 50 to 70 yr. Ea rl y peri hi l a r tumors
ma y ca us e onl y va gue a bdomi na l pa i n, a norexi a , a nd wei ght l os s . Other fea tures i ncl ude a chol i c s tool , a pa l pa bl e ma s s , hepa tomega l y, or a
di s tended ga l l bl a dder (Courvoi s i er's s i gn, wi th di s ta l chol a ngi oca rci noma ). Pa i n ma y res embl e tha t of bi l i a ry col i c (refl ecti ng bi l i a ry obs tructi on)
or ma y be cons ta nt a nd progres s i ve. Seps i s (a cute chol a ngi ti s ), though unus ua l , ma y be i nduced by ERCP.
Ma ni fes ta ti ons of ga l l bl a dder ca rci noma ma y ra nge from i nci denta l fi ndi ngs a t chol ecys tectomy done for bi l i a ry pa i n to chol el i thi a s i s to a dva nced
di s ea s e wi th cons ta nt pa i n, wei ght l os s , a nd a n a bdomi na l ma s s or obs tructi ve ja undi ce.
Mos t ga l l bl a dder pol yps ca us e no s ymptoms .
Diagnosis
Chol a ngi oca rci noma s a re s us pected when extra hepa ti c bi l i a ry obs tructi on i s unexpl a i ned. La bora tory tes t res ul ts refl ect the degree of chol es ta s i s .
In pa ti ents wi th pri ma ry s cl eros i ng chol a ngi ti s , s erum ca rci noembryoni c a nti gen (CEA) a nd ca ncer a nti gen (CA) 19-9 l evel s a re us ed for s urvei l l a nce
to detect the devel opment of chol a ngi oca rci noma . Di a gnos i s i s ba s ed on ul tra s onogra phy (or endos copi c ul tra s onogra phy) a nd CT
chol a ngi ogra phy or ma gneti c res ona nce chol a ngi opa ncrea togra phy. When thes e methods a re i nconcl us i ve, ERCP wi th percuta neous tra ns hepa ti c
chol a ngi ogra phy (PTC) becomes neces s a ry. ERCP not onl y detects the tumor but a l s o, wi th brus hi ngs , ca n provi de a ti s s ue di a gnos i s , s ometi mes
ma ki ng ul tra s onogra phy- or CT-gui ded needl e bi ops y unneces s a ry. Contra s t-enha nced CT a s s i s ts i n s ta gi ng.
Ga l l bl a dder ca rci noma s a re better defi ned by CT tha n by ul tra s onogra phy. Open l a pa rotomy i s neces s a ry to determi ne di s ea s e extent, whi ch
gui des trea tment.
Treatment
For chol a ngi oca rci noma s , s tenti ng (or a nother bypa s s procedure) or occa s i ona l l y res ecti on
For chol a ngi oca rci noma , s tenti ng or s urgi ca l l y bypa s s i ng the obs tructi on rel i eves pruri tus , ja undi ce, a nd perha ps fa ti gue.
Hi l a r chol a ngi oca rci noma s wi th CT evi dence of s prea d a re s tented vi a PTC or ERCP. Di s ta l duct chol a ngi oca rci noma s a re s tented endos copi ca l l y
wi th ERCP. If chol a ngi oca rci noma a ppea rs l oca l i zed, s urgi ca l expl ora ti on determi nes res ecta bi l i ty by hi l a r res ecti on or pa ncrea ti coduodenectomy.
However, s ucces s ful res ecti on i s uncommon.
Li ver tra ns pl a nta ti on i s not i ndi ca ted beca us e of the hi gh recurrence ra te. Effecti venes s of a djuva nt chemothera py a nd ra di a ti on thera py for
chol a ngi oca rci noma s i s unproved a s yet.
Ma ny ga l l bl a dder ca rci noma s a re trea ted s ymptoma ti ca l l y.
4 - Musculoskeletal and Connective Tissue Disorders

Chapter 32. Approach to the Patient With Joint Disease
Introduction
Some mus cul os kel eta l di s orders a ffect pri ma ri l y the joi nts , ca us i ng a rthri ti s . Others a ffect pri ma ri l y the bones (eg, fra ctures , Pa get's di s ea s e,
tumors ), mus cl es or other extra -a rti cul a r s oft ti s s ues (eg, fi bromya l gi a ), or peri a rti cul a r s oft ti s s ues (eg, pol ymya l gi a rheuma ti ca , burs i ti s ,
tendi ni ti s , s pra i n). Arthri ti s ha s myri a d pos s i bl e ca us es , i ncl udi ng i nfecti on, a utoi mmune di s orders , crys ta l -i nduced i nfl a mma ti on, a nd
noni nfl a mma tory ti s s ue degenera ti on (eg, os teoa rthri ti s ). Arthri ti s ma y a ffect s i ngl e joi nts (mona rthri ti s ) or mul ti pl e joi nts (pol ya rthri ti s ) i n a
s ymmetri c or a s ymmetri c ma nner. Joi nts ma y s uffer fra ctures or s pra i ns (s ee el s ewhere i n THE MANUAL).
History
The cl i ni ci a n s houl d focus on s ys temi c a nd extra -a rti cul a r s ymptoms a s wel l a s joi nt s ymptoms . Ma ny s ymptoms , i ncl udi ng fever, chi l l s , ma l a i s e,
wei ght l os s , Ra yna ud's s yndrome, mucocuta neous s ymptoms (eg, ra s h, eye i rri ta ti on or pa i n, photos ens i ti vi ty), a nd GI or ca rdi opul mona ry
s ymptoms , ca n be a s s oci a ted wi th va ri ous joi nt di s orders .
Pa i n i s the mos t common s ymptom of joi nt di s orders . The hi s tory s houl d a ddres s the cha ra cter, l oca ti on, s everi ty, fa ctors tha t a ggra va te or rel i eve
pa i n, a nd ti me fra me (new-ons et or recurrent). The cl i ni ci a n mus t determi ne whether pa i n i s wors e when fi rs t movi ng a joi nt or a fter prol onged
us e a nd whether i t i s pres ent upon wa ki ng or devel ops duri ng the da y. Us ua l l y, pa i n ori gi na ti ng from s uperfi ci a l s tructures i s better l oca l i zed tha n
pa i n ori gi na ti ng from deeper s tructures . Pa i n ori gi na ti ng i n s ma l l di s ta l joi nts tends to be better l oca l i zed tha n pa i n ori gi na ti ng i n l a rge proxi ma l
joi nts . Joi nt pa i n ca n be referred from extra -a rti cul a r s tructures or from other joi nts . Arthri ti s often ca us es a chi ng pa i n, wherea s neuropa thi es
often ca us e burni ng pa i n.
Sti ffnes s ma y mea n wea knes s , fa ti gue, or fi xed l i mi ta ti on of moti on to pa ti ents . The cl i ni ci a n mus t s epa ra te the i na bi l i ty to move a joi nt from
rel ucta nce to move a joi nt beca us e of pa i n. Cha ra cteri s ti cs of s ti ffnes s ma y s ugges t a ca us e, a s i n the fol l owi ng:
Di s comfort tha t occurs wi th moti on when a ttempti ng to move a joi nt a fter a peri od of res t occurs i n rheuma ti c di s ea s e. Dura ti on of s ti ffnes s a fter
begi nni ng joi nt moti on refl ects i ts s everi ty.
The thea ter s i gn (s ti ffnes s upon s ta ndi ng tha t neces s i ta tes wa l ki ng s l owl y a fter s i tti ng for s evera l hours ) i s common i n os teoa rthri ti s .
Sti ffnes s i s more s evere a nd prol onged i n i nfl a mma tory joi nt di s orders .
Morni ng s ti ffnes s i n peri phera l joi nts tha t l a s ts > 1 h ca n be a n i mporta nt ea rl y s ymptom of RA (s ee
Ta bl e 32-1).
In the l ow ba ck, morni ng s ti ffnes s tha t l a s ts > 1 h ma y refl ect s pondyl i ti s .
Fa ti gue i s a des i re to res t tha t refl ects exha us ti on. It di ffers from wea knes s , i na bi l i ty to move, a nd rel ucta nce to move due to pa i n wi th movement.
Ins ta bi l i ty (buckl i ng of a joi nt) ma y s ugges t wea knes s of the l i ga ments or other s tructures tha t s ta bi l i ze the joi nt, whi ch a re a s s es s ed by s tres s
tes ti ng. Buckl i ng occurs mos t often i n the knee a nd mos t often res ul ts from a n i nterna l joi nt dera ngement.
Physical Examination
Ea ch i nvol ved joi nt s houl d be i ns pected a nd pa l pa ted, a nd the ra nge of moti on s houl d be es ti ma ted. Wi th pol ya rti cul a r di s ea s e, certa i n
nona rti cul a r s i gns (eg, fever, wa s ti ng, ra s h) ma y refl ect s ys temi c di s orders .
The res t pos i ti on of joi nts i s noted, a l ong wi th a ny erythema , s wel l i ng, deformi ty, a nd s ki n a bra s i ons or punctures . Invol ved joi nts a re compa red
wi th thei r uni nvol ved oppos i tes or wi th thos e of the exa mi ner.
Joi nts a re gentl y pa l pa ted, noti ng the pres ence a nd l oca ti on of tendernes s , wa rmth, a nd s wel l i ng. Determi ni ng whether tendernes s i s pres ent
a l ong the joi nt l i ne or over tendon i ns erti ons or burs a e i s pa rti cul a rl y i mporta nt. Soft ma s s es , bul ges , or ti s s ues tha t fi l l norma l conca vi ti es or
s pa ces (repres enti ng joi nt effus i on or s ynovi a l prol i fera ti on) a re noted. Pa l pa ti on of
[Table 32-1. Di s ti ngui s hi ng Infl a mma tory vs Noni nfl a mma tory Fea tures i n Joi nt Di s ea s e by Fea tures ]
s wol l en joi nts ca n s ometi mes di fferenti a te a mong joi nt effus i on, s ynovi a l thi ckeni ng, a nd ca ps ul a r or bony enl a rgement. Sma l l joi nts (eg, the
a cromi ocl a vi cul a r, ti bi ofi bul a r, ra di oul na r) ca n be the s ource of pa i n tha t wa s i ni ti a l l y bel i eved to a ri s e from a nea rby ma jor joi nt. Bony
enl a rgement (often due to os teophytes ) i s noted.
Acti ve ra nge of moti on (the ma xi mum ra nge through whi ch the pa ti ent ca n move the joi nt) i s mea s ured fi rs t, us i ng a goni ometer; l i mi ta ti on ma y
refl ect wea knes s , pa i n, or s ti ffnes s a s wel l a s mecha ni ca l a bnorma l i ti es . Then pa s s i ve ra nge of moti on (the ma xi mum ra nge through whi ch the
exa mi ner ca n move the joi nt) i s a s s es s ed; pa s s i ve l i mi ta ti on genera l l y refl ects mecha ni ca l a bnorma l i ti es (eg, s ca rri ng, s wel l i ng, deformi ti es )
ra ther tha n wea knes s or pa i n. Acti ve a nd pa s s i ve movement of a n i nfl a med joi nt (eg, due to i nfecti on or gout) ma y be very pa i nful .
Pa tterns of joi nt i nvol vement s houl d be noted. Symmetri c i nvol vement of mul ti pl e joi nts i s common i n s ys temi c di s ea s es (eg, RA); mona rti cul a r
(i nvol vi ng one joi nt) or a s ymmetri c ol i goa rti cul a r (i nvol vi ng 4) joi nt i nvol vement i s more common i n os teoa rthri ti s a nd ps ori a ti c a rthri ti s . Sma l l
peri phera l joi nts a re commonl y a ffected i n RA, a nd the l a rger joi nts a nd s pi ne a re a ffected more i n s pondyl oa rthropa thi es . However, a pa ttern of
i nvol vement ma y not be a ppa rent i n ea rl y di s ea s e.
Crepi tus , a pa l pa bl e or a udi bl e gri ndi ng produced by moti on, i s noted. It ma y be ca us ed by roughened a rti cul a r ca rti l a ge or by tendons ; crepi tus ca us i ng moti ons s houl d be determi ned a nd ma y s ugges t whi ch s tructures a re i nvol ved.
Speci fi c fea tures s houl d be s ought a t ea ch joi nt.

Elbow: Synovi a l s wel l i ng a nd thi ckeni ng ca us ed by joi nt di s ea s e occur i n the l a tera l a s pect between the ra di a l hea d a nd ol ecra non, ca us i ng a
bul ge. Ful l 180 extens i on of the joi nt s houl d be a ttempted. Al though ful l extens i on i s pos s i bl e wi th nona rthri ti c or extra -a rti cul a r probl ems s uch
a s tendi ni ti s , i ts l os s i s a n ea rl y cha nge i n a rthri ti s . The a rea a round the joi nt i s exa mi ned for s wel l i ngs . Rheuma toi d nodul es a re fi rm, occurri ng
es peci a l l y a l ong the extens or s urfa ce of the forea rm. Tophi a re s ometi mes vi s i bl e under the s ki n a s crea m-col ored a ggrega tes a nd i ndi ca te gout.
Swel l i ng of the ol ecra non burs a occurs over the ti p of the ol ecra non, i s cys ti c, a nd does not l i mi t joi nt moti on; i nfecti on, tra uma , gout, a nd RA a re
pos s i bl e ca us es . Epi trochl ea r nodes occur a bove the medi a l epi condyl e; they ca n res ul t from i nfl a mma ti on i n the ha nd but ca n a l s o s ugges t
s a rcoi dos i s or l ymphoma .
Shoulder: Beca us e pa i n ca n be referred to a rea s a round the s houl der, s houl der pa l pa ti on s houl d i ncl ude the gl enohumera l , a cromi ocl a vi cul a r, a nd
s ternocl a vi cul a r joi nts , the cora coi d proces s , cl a vi cl e, a cromi on proces s , s uba cromi a l burs a , bi ceps tendon, a nd grea ter a nd l es s er tuberos i ti es of
the humerus , a s wel l a s the neck. Gl enohumera l joi nt effus i ons ma y ca us e a bul ge between the cora coi d proces s a nd the humera l hea d. Pos s i bl e
ca us es i ncl ude RA, os teoa rthri ti s , s epti c a rthri ti s , Mi l wa ukee s houl der (s ee p. 355), a nd other a rthropa thi es .
Li mi ted moti on, wea knes s , pa i n, a nd other di s turba nces of mobi l i ty ca us ed by rota tor cuff i mpa i rment ca n be qui ckl y i denti fi ed by ha vi ng the
pa ti ent a ttempt to a bduct a nd ra i s e both a rms a bove the hea d a nd then to s l owl y l ower them. Mus cl e a trophy a nd neurol ogi c a bnorma l i ti es
s houl d be s ought.
Knee: At the knee, gros s deformi ti es s uch a s s wel l i ng (eg, joi nt effus i on, popl i tea l cys ts ), qua dri ceps mus cl e a trophy, a nd joi nt i ns ta bi l i ty ma y be
obvi ous when the pa ti ent s ta nds a nd wa l ks . Wi th the pa ti ent s upi ne, the exa mi ner s houl d pa l pa te the knee, i denti fyi ng the pa tel l a , femora l
condyl es , ti bi a l tuberos i ty, ti bi a l pl a tea u, fi bul a r hea d, medi a l a nd l a tera l joi nt l i nes , popl i tea l fos s a , a nd qua dri ceps a nd pa tel l a r tendons . The
medi a l a nd l a tera l joi nt l i nes corres pond to l oca ti ons of the medi a l a nd l a tera l meni s ci a nd ca n be l oca ted by pa l pa ti on whi l e s l owl y fl exi ng a nd
extendi ng the knee. Tender extra -a rti cul a r burs a e s uch a s the a ns eri ne burs a bel ow the medi a l joi nt l i ne s houl d be di fferenti a ted from true i ntra a rti cul a r di s turba nces .
Detecti on of s ma l l knee effus i ons i s often di ffi cul t a nd i s bes t a ccompl i s hed us i ng the bul ge s i gn. The knee i s ful l y extended a nd the l eg s l i ghtl y
externa l l y rota ted whi l e the pa ti ent i s s upi ne wi th mus cl es rel a xed. The medi a l a s pect of the knee i s s troked to expres s a ny fl ui d a wa y from thi s
a rea . Pl a cement of one ha nd on the s upra pa tel l a r pouch a nd gentl e s troki ng or pres s i ng on the l a tera l a s pect of the knee ca n crea te a fl ui d wa ve
or bul ge, vi s i bl e medi a l l y when a n effus i on i s pres ent. La rger effus i ons ca n be i denti fi ed vi s ua l l y or by ba l l oti ng the pa tel l a . Joi nt effus i on ca n
res ul t from ma ny joi nt di s ea s es , i ncl udi ng RA, os teoa rthri ti s , gout, a nd tra uma .
Ful l 180 extens i on of the knee i s a ttempted to detect fl exi on contra ctures . The pa tel l a i s tes ted for free, pa i nl es s moti on.
Hip: Exa mi na ti on begi ns wi th ga i t eva l ua ti on. A l i mp i s common i n pa ti ents wi th s i gni fi ca nt hi p a rthri ti s . It ma y be ca us ed by pa i n, l eg s horteni ng,
fl exi on contra cture, mus cl e wea knes s , or knee probl ems . Los s of i nterna l rota ti on (often the ea rl i es t cha nge i n hi p os teoa rthri ti s or a ny hi p
s ynovi ti s ), fl exi on, extens i on, or a bducti on ca n us ua l l y be demons tra ted. Pl a cement of one ha nd on the pa ti ent's i l i a c cres t detects pel vi c
movement tha t mi ght be mi s ta ken for hi p movement. Fl exi on contra cture ca n be i denti fi ed by a ttempti ng l eg extens i on wi th the oppos i te hi p
ma xi ma l l y fl exed to s ta bi l i ze the pel vi s . Tendernes s over the femora l grea ter trocha nter s ugges ts burs i ti s (whi ch i s extra -a rti cul a r) ra ther tha n a n
i ntra -a rti cul a r di s order. Pa i n wi th pa s s i ve ra nge of moti on (a s s es s ed by i nterna l a nd externa l rota ti on wi th the pa ti ent s upi ne a nd the hi p a nd
knee fl exed to 90) s ugges ts i ntra -a rti cul a r ori gi n. However, pa ti ents ma y ha ve s i mul ta neous i ntra -a rti cul a r a nd extra -a rti cul a r di s orders .
Other: Ha nd exa mi na ti on i s di s cus s ed el s ewhere (s ee p. 385 a nd Pol ya rti cul a r Joi nt Pa i n on p. 292). Foot a nd a nkl e exa mi na ti on i s di s cus s ed i n Ch.
44. Exa mi na ti on of the neck a nd ba ck i s di s cus s ed on p. 379.
Testing
La bora tory tes ti ng a nd i ma gi ng s tudi es often provi de l es s i nforma ti on tha n do the hi s tory a nd phys i ca l exa mi na ti on. Whi l e s ome tes ti ng ma y be
wa rra nted i n s ome pa ti ents , extens i ve tes ti ng i s often not.
Blood tests: Some tes ts , a l though not s peci fi c, ca n be hel pful i n s upporti ng the pos s i bi l i ty of certa i n s ys temi c rheuma ti c di s ea s es , a s for the
fol l owi ng:
Anti nucl ea r a nti bodi es (ANA) a nd compl ement i n SLE
Rheuma toi d fa ctor a nd a nti ci trul l i na ted pepti de (CCP) i n RA
HLA-B27 i n s pondyl oa rthropa thy (occa s i ona l l y us eful )
Anti neutrophi l cytopl a s mi c a nti bodi es (ANCA) i n certa i n va s cul i ti des (occa s i ona l l y us eful )
Tes ts s uch a s WBC count, ESR, a nd C-rea cti ve protei n ma y hel p determi ne the l i kel i hood tha t a rthri ti s i s i nfl a mma tory due to i nfecti ous or other
s ys temi c di s orders , but thes e tes ts a re not hi ghl y s peci fi c or s ens i ti ve. For exa mpl e, a n el eva ted ESR or C-rea cti ve protei n l evel s ugges ts
i nfl a mma ti on or ma y be due to a gi ng or a l a rge number of nona rti cul a r i nfl a mma tory condi ti ons (eg, i nfecti on, ca ncer). Al s o, s uch ma rkers ma y not
be el eva ted i n a l l i nfl a mma tory di s orders .
Imaging studies: Ima gi ng s tudi es a re often unneces s a ry. Pl a i n x-ra ys i n pa rti cul a r revea l ma i nl y bony a bnorma l i ti es , a nd mos t joi nt di s orders do not
a ffect bone pri ma ri l y. However, i ma gi ng ma y hel p i n the i ni ti a l eva l ua ti on of rel a ti vel y l oca l i zed, unexpl a i ned pers i s tent or s evere joi nt a nd
pa rti cul a rl y s pi ne a bnorma l i ti es ; they ma y revea l pri ma ry or meta s ta ti c tumors , os teomyel i ti s , bone i nfa rcti ons , peri a rti cul a r ca l ci fi ca ti ons (a s i n
ca l ci fi c tendi ni ti s ), or other cha nges i n deep s tructures tha t ma y es ca pe phys i ca l exa mi na ti on. If chroni c RA, gout, or os teoa rthri ti s i s s us pected,
eros i ons , cys ts , a nd joi nt s pa ce na rrowi ng wi th os teophytes ma y be vi s i bl e. In ps eudogout, Ca pyrophos pha te depos i ti on ma y be vi s i bl e i n i ntra a rti cul a r ca rti l a ge.
For mus cul os kel eta l i ma gi ng, pl a i n x-ra ys ma y be obta i ned fi rs t, but they a re often l es s s ens i ti ve, pa rti cul a rl y duri ng ea rl y di s ea s e, tha n MRI, CT,
or ul tra s onogra phy. MRI i s the mos t a ccura te s tudy for fra ctures not vi s i bl e on pl a i n x-ra ys , pa rti cul a rl y i n the hi p a nd pel vi s , a nd for s oft ti s s ues
a nd i nterna l dera ngements of the knee. CT i s us eful i f MRI i s contra i ndi ca ted or una va i l a bl e. Ul tra s onogra phy, a rthrogra phy, a nd bone s ca nni ng
ma y hel p i n certa i n condi ti ons , a s ca n bi ops y of bone, s ynovi um, or other ti s s ues .
Arthrocentesis: Arthrocentes i s i s the proces s of puncturi ng the joi nt wi th a needl e to wi thdra w fl ui d. If there i s a n effus i on a nd a rthrocentes i s i s
done correctl y, fl ui d ca n genera l l y be wi thdra wn. Exa mi na ti on of s ynovi a l fl ui d i s the mos t a ccura te wa y to excl ude i nfecti on, di a gnos e crys ta l i nduced a rthri ti s , a nd otherwi s e determi ne the ca us e of joi nt effus i ons . It i s i ndi ca ted i n a l l pa ti ents wi th s evere or unexpl a i ned mona rti cul a r
joi nt effus i ons a nd i n pa ti ents wi th unexpl a i ned pol ya rti cul a r effus i ons .
Arthrocentes i s i s done us i ng s tri ctl y s teri l e techni que. Infecti on or other ra s h over the s i te us ed to enter the joi nt i s a contra i ndi ca ti on.
Prepa ra ti ons for col l ecti ng s a mpl es s houl d be ma de before doi ng the procedure. Loca l a nes thes i a , wi th l i doca i ne or di fl uoroetha ne s pra y, i s
often us ed. Ma ny joi nts a re punctured on the extens or s urfa ce to a voi d nerves , a rteri es , a nd vei ns , whi ch a re us ua l l y on the joi nt's fl exor s urfa ce. A
20-ga uge needl e ca n be us ed for mos t l a rger joi nts . Sma l l er joi nts of the upper a nd l ower extremi ti es a re proba bl y ea s i er to a cces s us i ng a 22- or
23-ga ge needl e. As much fl ui d a s i s pos s i bl e s houl d be removed. Speci fi c a na tomi c l a ndma rks a re us ed (s ee
Fi gs . 32-1,
32-2, a nd
32-3).
Meta ca rpopha l a ngea l joi nts , meta ta rs opha l a ngea l joi nts , a nd i nterpha l a ngea l joi nts of the ha nds a nd feet a re punctured s i mi l a rl y to ea ch other,
us i ng a 22- or 23-ga uge needl e. The needl e i s i ns erted dors a l l y, to ei ther s i de of the extens or tendon. Di s tra cti on of the joi nt i s s ometi mes us eful
to open the joi nt s pa ce a nd a l l ow ea s i er a cces s .
[Fig. 32-1. Arthrocentes i s of the s houl der.]
Synovial fluid examination: At the beds i de, gros s cha ra cteri s ti cs of the fl ui d a re a s s es s ed, s uch a s i ts col or, turbi di ty, a nd vi s cos i ty. Vi s cos i ty ca n be
a s s es s ed us i ng the s tri ng s i gn. The l ength of a vi s cous s tri ng of joi nt fl ui d dropped from the s yri nge i s norma l l y > 3 cm. Infl a mma ti on decrea s es
vi s cos i ty, s horteni ng the l ength of the s tri ng.
Gros s cha ra cteri s ti cs a l l ow ma ny effus i ons to be tenta ti vel y cl a s s i fi ed a s noni nfl a mma tory, i nfl a mma tory, or i nfecti ous (s ee
Ta bl e 32-2). Effus i ons ca n a l s o be hemorrha gi c. Ea ch type of effus i on s ugges ts certa i n joi nt di s ea s es (s ee
Ta bl e 32-3). So-ca l l ed noni nfl a mma tory effus i ons a re a ctua l l y mi l dl y i nfl a mma tory but tend to s ugges t di s ea s es s uch a s os teoa rthri ti s , i n whi ch
i nfl a mma ti on i s not s evere.
La bora tory tes ts commonl y done on joi nt fl ui d i ncl ude cel l count, l eukocyte di fferenti a l , Gra m s ta i n a nd cul ture (i f i nfecti on i s a concerns ee p.
365), a nd wet drop exa mi na ti on for cel l s a nd crys ta l s . However, the exa ct tes ts often depend on whi ch di a gnos es a re s us pected.
Mi cros copi c exa mi na ti on of a wet drop prepa ra ti on of s ynovi a l fl ui d for crys ta l s (onl y a s i ngl e drop of fl ui d from a joi nt i s needed), us i ng pol a ri zed
l i ght, i s es s enti a l for defi ni ti ve di a gnos i s of gout, ps eudogout, a nd other crys ta l -i nduced a rthri ti des (s ee p. 349). A pol a ri zer over the l i ght s ource
a nd a nother pol a ri zer between the s peci men a nd the exa mi ner's eye a l l ow vi s ua l i za ti on of crys ta l s wi th a s hi ny whi te bi refri ngence.
Compens a ted pol a ri zed l i ght i s provi ded by i ns erti ng a fi rs t-order red pl a te, a s i s found i n commerci a l l y a va i l a bl e mi cros copes . The effects of a
compens a tor ca n be reproduced by pl a ci ng 2 s tri ps of cl ea r a dhes i ve ta pe on a gl a s s s l i de a nd pl a ci ng thi s s l i de over the l ower pol a ri zer. Such a
homema de s ys tem s houl d be tes ted a ga i ns t a commerci a l pol a ri zi ng mi cros cope. The mos t common crys ta l s s een a re thos e di a gnos ti c of gout
(monos odi um ura te, nega ti vel y bi refri ngent needl e-s ha ped crys ta l s ) a nd ps eudogout (Ca pyrophos pha te, pos i ti vel y bi refri ngent s qua re-ended
crys ta l s ). If crys ta l s a ppea r a typi ca l i n a wet drop, s evera l l es s common crys ta l s (chol es terol , l i qui d l i pi d crys ta l s , oxa l a te, cryogl obul i ns ) or
a rti fa cts (eg, depot corti cos teroi d crys ta l s ) s houl d be cons i dered.
Other s ynovi a l fl ui d fi ndi ngs tha t occa s i ona l l y ma ke or s ugges t a s peci fi c di a gnos i s i ncl ude the fol l owi ng:
Speci fi c orga ni s ms (i denti fi a bl e by Gra m or a ci d-fa s t s ta i n)
Ma rrow s pi cul es or fa t gl obul es (ca us ed by fra cture)
Rei ter's cel l s (monocytes on Wri ght's -s ta i ned s mea rs tha t ha ve pha gocyti zed PMNs ), whi ch a ppea r mos t often i n rea cti ve a rthri ti s
Amyl oi d fra gments (i denti fi a bl e by Congo red s ta i n)
Si ckl ed RBCs (ca us ed by s i ckl e cel l hemogl obi nopa thi es )
[Fig. 32-2. Arthrocentes i s of the el bow.]
[Table 32-2. Cl a s s i fi ca ti on of Synovi a l Effus i ons ]
Monarticular Joint Pain
Mona rti cul a r pa i n ma y ori gi na te from the joi nt i ts el f or s urroundi ng s tructures . There ma y be pa i n (a rthra l gi a ) or a l s o i nfl a mma ti on (a rthri ti s ) wi th
rednes s , wa rmth, a nd s wel l i ng. Pa i n ma y occur onl y wi th us e, s ugges ti ng a mecha ni ca l probl em (eg, os teoa rthri ti s , tendi ni ti s ), or a l s o a t res t,
s ugges ti ng i nfl a mma ti on (eg, crys ta l di s ea s e, s epti c a rthri ti s ). There ma y or ma y not be fl ui d wi thi n the joi nt (effus i on). Prompt a s s es s ment i s
es s enti a l to excl ude i nfecti on. It i s i mporta nt to remember tha t a cute mona rti cul a r a rthri ti s i s s ometi mes the i ni ti a l ma ni fes ta ti on of s ome types
of pol ya rti cul a r a rthri ti s (eg, ps ori a ti c a rthri ti s , RA).
Pathophysiology
Mona rti cul a r pa i n ma y ori gi na te
Wi thi n a joi nt (i ntra -a rti cul a r)

Around a joi nt (peri a rti cul a r)
Intra -a rti cul a r di s orders ma y be i nfl a mma tory (eg, i nfecti ous , rheuma toi d, crys ta l depos i ti on a rthri ti s ) or noni nfl a mma tory (eg, os teoa rthri ti s ,
i nterna l dera ngement).
Peri a rti cul a r di s orders i ncl ude burs i ti s a nd tendi ni ti s .
Crys ta l -i nduced a rthri ti s i s us ua l l y ca us ed by monos odi um ura te crys ta l s (gout) or Ca pyrophos pha te di hydra te crys ta l s (ps eudogout).
Etiology
At a l l a ges , i njury i s the mos t common ca us e of a cute mona rti cul a r joi nt pa i n; hi s tory of tra uma i s us ua l l y obvi ous .
[Fig. 32-3. Arthrocentes i s of the knee.]
[Table 32-3. Di fferenti a l Di a gnos i s Ba s ed on Synovi a l Fl ui d Cl a s s i fi ca ti on* ]
Among young a dul ts , the mos t common nontra uma ti c ca us es a re the fol l owi ng:
Di s s emi na ted gonococca l i nfecti on
Peri a rti cul a r s yndromes
Among ol der a dul ts , the mos t common nontra uma ti c ca us es a re the fol l owi ng:
Os teoa rthri ti s
Crys ta l -i nduced di s ea s e (gout or ps eudogout)
Peri a rti cul a r s yndromes
The mos t da ngerous ca us e a t a ny a ge i s a cute i nfecti ous a rthri ti s , beca us e i t requi res a cute opera ti ve i nterventi on (s a l i ne wa s hout of the joi nt)
a nd a nti bi oti cs to mi ni mi ze perma nent da ma ge to the joi nt a nd to prevent s eps i s a nd dea th.
At a l l a ges , ra re ca us es i ncl ude a dja cent os teomyel i ti s , a va s cul a r necros i s , pi gmented vi l l onodul a r s ynovi ti s , hema rthros i s (eg, i n hemophi l i a or
coa gul opa thi es ), a nd tumors (s ee
Ta bl e 32-4).
Evaluation
Acute mona rti cul a r joi nt pa i n requi res es peci a l l y ra pi d di a gnos i s beca us e s ome of i ts ca us es , pa rti cul a rl y i nfecti ous (s epti c) a rthri ti s a nd crys ta l i nduced a rthri ti s , requi re ra pi d trea tment.
[Table 32-4. Some Ca us es of Mona rti cul a r Joi nt Pa i n]
Eva l ua ti on s houl d determi ne whether the joi nt or peri a rti cul a r s tructures a re the ca us e of s ymptoms a nd whether there i s i nfl a mma ti on. If
i nfl a mma ti on i s pres ent or the di a gnos i s i s uncl ea r, s ymptoms a nd s i gns of pol ya rti cul a r a nd s ys temi c di s orders s houl d be s ought a nd a l l joi nts
s houl d be exa mi ned.
History: History of present illness s houl d focus on the a cui ty of ons et (eg, a brupt, gra dua l ), whether the probl em i s new or recurrent, a nd whether
other joi nts ha ve ca us ed pa i n i n the pa s t. Al s o, tempora l pa tterns (eg, di urna l va ri a ti on, pers i s tent vs i ntermi ttent), exa cerba ti ng a nd mi ti ga ti ng
fa ctors (eg, col d wea ther, a cti vi ty), a nd a ny recent or pa s t tra uma to the joi nt s houl d be noted. Pa ti ents s houl d be s peci fi ca l l y a s ked a bout
unprotected s exua l conta ct (pos s i bl e gonococca l i nfecti on), ti ck bi tes , a nd res i dence i n or tra vel to a n a rea where Lyme di s ea s e i s endemi c.
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng fever (i nfecti on), urethri ti s (gonococca l a rthri ti s ), a nd previ ous
unexpl a i ned i l l nes s wi th ra s h (Lyme a rthri ti s ).
Past medical history s houl d i denti fy known joi nt di s orders (pa rti cul a rl y gout, os teoa rthri ti s ) a nd a ny known condi ti ons tha t ma y ca us e mona rti cul a r
joi nt pa i n (eg, coa gul opa thy, burs i ti s , tendi ni ti s , hemogl obi nopa thy). Drug hi s tory s houl d be revi ewed for a ny us e of a nti coa gul a nts or di ureti cs
a nd for chroni c corti cos teroi d us e. A fa mi l y hi s tory s houl d a l s o be obta i ned.
Physical examination: Vi ta l s i gns a re revi ewed for fever. Exa mi na ti on of the hea d, neck, a nd s ki n s houl d note a ny s i gns of conjuncti vi ti s , ps ori a ti c
pl a ques , mucos a l l es i ons , ecchymos es , or ma l a r ra s h. Geni ta l exa mi na ti on s houl d note a ny di s cha rge or other fi ndi ngs cons i s tent wi th s exua l l y
tra ns mi tted di s ea s es .
Joi nts a re i ns pected for deformi ti es , erythema , a nd s wel l i ng. Ra nge of moti on i s a s s a yed, fi rs t a cti vel y a nd then pa s s i vel y; a ny crepi tus on joi nt
moti on i s noted.
Pa l pa ti on i s done to detect wa rmth, i denti fy a ny effus i on, a nd l oca l i ze the a rea of tendernes s . Of pa rti cul a r i mporta nce i s whether the tendernes s
i s di rectl y over the joi nt l i ne or a dja cent to i t (hel pi ng to di fferenti a te a n i ntra -a rti cul a r from a peri a rti cul a r di s order). Someti mes , compres s i on of
the joi nt wi thout fl exi ng or extendi ng i t (eg, pus hi ng on the end of the grea t toe for pa ti ents wi th pa i n i n the 1s t meta ta rs opha l a ngea l joi nt),
s ometi mes wi th s l i ght rota ti on, a l s o hel ps di fferenti a te i ntra -a rti cul a r from peri a rti cul a r di s orders ; thi s ma neuver i s not pa rti cul a rl y pa i nful for
pa ti ents wi th tendi ni ti s or burs i ti s but i s qui te pa i nful for thos e wi th a rthri ti s . If the pa ti ent ca n tol era te i t, the joi nt i s s tres s ed wi th va ri ous
ma neuvers to i denti fy di s rupti on of ca rti l a ge or l i ga ments (eg, i n the knee, va l gus a nd va rus tes ts , a nteri or a nd pos teri or dra wer tes ts , La chma n's
tes t, a nd McMurra y's tes t). Compa ri s on wi th the contra l a tera l una ffected joi nt often hel ps detect more s ubtl e cha nges .
La rge effus i ons i n the knee a re typi ca l l y rea di l y a ppa rent. The exa mi ner ca n check for mi nor knee effus i ons by pus hi ng the s upra pa tel l a r pouch
i nferi orl y a nd then pres s i ng medi a l l y on the l a tera l s i de of the pa tel l a on a n extended knee. Thi s ma neuver ca us es s wel l i ng to a ppea r on the
medi a l s i de.
Peri a rti cul a r s tructures a l s o s houl d be exa mi ned to l ook for di s crete s oft s wel l i ng a t the s i te of a burs a (burs i ti s ), poi nt tendernes s a t the
i ns erti on of a tendon (tendi ni ti s ), a nd poi nt tendernes s over a tendon wi th fi ne crepi tus (tenos ynovi ti s ).
Erythema , wa rmth, effus i on, a nd decrea s ed ra nge of moti on
Fever
Acute-ons et joi nt pa i n i n a s exua l l y a cti ve young a dul t
Ski n brea ks wi th cel l ul i ti s a dja cent to the a ffected joi nt
Underl yi ng bl eedi ng di s order, hemogl obi nopa thy, or a nti coa gul a ti on
Extra -a rti cul a r or s ys temi c s ymptoms
Interpretation of findings: Antecedent tra uma s ugges ts a fra cture, meni s ca l tea r, or hema rthros i s . In the a bs ence of tra uma , hi s tory a nd phys i ca l
exa mi na ti on ma y s ugges t a ca us e, but tes ti ng i s often neces s a ry to rul e out s eri ous ca us es .
Acutenes s of ons et i s a very i mporta nt fea ture. Severe joi nt pa i n tha t devel ops over hours s ugges ts crys ta l -i nduced a rthri ti s or, l es s often,
i nfecti ous a rthri ti s . A previ ous a tta ck of crys ta l -i nduced a rthri ti s wi th devel opment of s i mi l a r s ymptoms s ugges ts recurrence. Gra dua l ons et of
pa i n i s typi ca l of RA or noni nfecti ous a rthri ti s but ca n res ul t from certa i n i nfecti ous a rthri ti des (eg, mycoba cteri a l , funga l ).
Pa i n duri ng res t a nd on i ni ti a ti ng a cti vi ty s ugges ts i nfl a mma tory a rthri ti s , wherea s pa i n wors ened by movement a nd rel i eved by res t s ugges ts
mecha ni ca l di s orders (eg, os teoa rthri ti s ).
Pa i n wors e wi th a cti ve tha n wi th pa s s i ve joi nt moti on ma y i ndi ca te tendi ni ti s or burs i ti s ; i ntra -a rti cul a r i nfl a mma ti on genera l l y res tri cts a cti ve
a nd pa s s i ve ra nge of joi nt moti on s everel y.
Increa s ed wa rmth a nd erythema s ugges t i nfl a mma ti on, but erythema i s often a bs ent duri ng i nfl a mma ti on. Tendernes s or s wel l i ng a t onl y one
s i de of a joi nt, or a wa y from the joi nt l i ne, s ugges ts a n extra -a rti cul a r ori gi n (eg, i n l i ga ments , tendons , or burs a e); fi ndi ngs on s evera l a s pects of
the joi nt s ugges t a n i ntra -a rti cul a r ca us e.
Al though gout ca n i nvol ve ma ny di fferent s i ngl e joi nts or combi na ti ons of joi nts , a cute, pa i nful mona rti cul a r a rthri ti s of the meta ta rs opha l a ngea l
joi nt of a grea t toe (poda gra ) i s es peci a l l y s ugges ti ve.
The pres ence of s ys temi c fi ndi ngs ca n hel p na rrow the di a gnos i s . Urethri ti s ca n s ugges t gonococca l i nfecti on (a l though gonococca l a rthri ti s often
devel ops i n pa ti ents wi thout s ymptoms of urethri ti s ). Fever i s i ndi ca ti ve of s epti c joi nt, crys ta l -i nduced a rthropa thy, or os teomyel i ti s . Symptoms
i ndi ca ti ng derma tol ogi c, ca rdi a c, or pul mona ry i nvol vement s ugges t di s ea s es tha t a re more commonl y a s s oci a ted wi th pol ya rti cul a r joi nt pa i n.
Testing: Joi nt a s pi ra ti on (a rthrocentes i s ) s houl d be done i n pa ti ents wi th a n effus i on or other s i gns of i nfl a mma ti on (eg, erythema , wa rmth, fever).
Studi es of the joi nt fl ui d s houl d i ncl ude WBC count wi th di fferenti a l (to determi ne whether the effus i on i s bl oody or i nfl a mma tory), Gra m s ta i n
a nd cul tures , a nd mi cros copi c exa mi na ti on for crys ta l s . Fi ndi ng crys ta l s i n s ynovi a l fl ui d confi rms crys ta l -i nduced a rthri ti s but does not rul e out
coexi s ti ng i nfecti on. A noni nfl a mma tory s ynovi a l fl ui d (eg, < 2000/L WBCs or < 75% neutrophi l s ) s houl d l ea d to cons i dera ti on of os teoa rthri ti s ,
s oft-ti s s ue i njury, or vi ra l i nfecti on.
X-ra ys us ua l l y a re done unl es s the ca us e i s cl ea rl y a fl a re-up of a known di s order (eg, gout) or i s a cl i ni ca l l y obvi ous burs i ti s or tendi ni ti s , whi ch
ca n often be di a gnos ed wi thout further tes ti ng.
Other i ma gi ng tes ts (eg, CT, MRI, bone s ca n) a re a djuncti ve a nd a re done dependi ng on wha t di a gnos es a re bei ng cons i dered (s ee Ta bl e 32-4).
Bl ood tes ts (eg, ESR, a nti nucl ea r a nti bodi es , rheuma toi d fa ctor, a nti cycl i c ci trul l i na ted pepti de [CCP] a nti body, HLA-B27 tes ti ng) ma y hel p s upport
a n ea rl y di a gnos i s of a noni nfecti ous i nfl a mma tory a rthri ti s .
Treatment
Overa l l trea tment i s di rected a t the underl yi ng di s order.
Joi nt i nfl a mma ti on i s us ua l l y trea ted s ymptoma ti ca l l y wi th NSAIDs . Pa i n wi thout i nfl a mma ti on i s us ua l l y more s a fel y trea ted wi th
a ceta mi nophen. Joi nt i mmobi l i za ti on wi th a s pl i nt or s l i ng ca n s ometi mes rel i eve pa i n. Hea t thera py ma y rel i eve mus cl e s pa s m a round joi nts .
Col d thera py ma y be a na l ges i c i n i nfl a mma tory joi nt di s ea s es .
Phys i ca l thera py a fter the a cute s ymptoms ha ve l es s ened i s us eful to ma i nta i n ra nge of moti on a nd s trengthen s urroundi ng mus cl es .
Key Points
Atra uma ti c joi nt pa i n s houl d prompt cons i dera ti on of degenera ti ve di s ea s e, crys ta l -i nduced a rthropa thy, i nfecti on, or ca ncer.
Arthrocentes i s i s ma nda tory to rul e out i nfecti on i n a joi nt tha t i s red, wa rm, a nd s wol l en.
Di s s emi na ted gonococca l i nfecti on i s the mos t common ca us e of a cute nontra uma ti c mona rthri ti s i n young a dul ts , wherea s os teoa rthri ti s i s the
mos t common ca us e i n ol der a dul ts .
Crys ta l s i n s ynovi a l fl ui d confi rm crys ta l -i nduced a rthri ti s but do not rul e out coexi s ti ng i nfecti on.
Joi nt pa i n tha t i s s ti l l unexpl a i ned a fter a rthrocentes i s a nd x-ra y s houl d be eva l ua ted wi th MRI to rul e out uncommon eti ol ogi es (eg, occul t
fra cture, a va s cul a r necros i s , pi gmented vi l l onodul a r s ynovi ti s ).
Polyarticular Joint Pain
Joi nts ma y s i mpl y be pa i nful (a rthra l gi a ) or a l s o i nfl a med (a rthri ti s ), wi th rednes s , wa rmth, a nd s wel l i ng. Pa i n ma y occur onl y wi th us e or a l s o a t
res t, a nd there ma y or ma y not be fl ui d wi thi n the joi nt (effus i on).
A us eful i ni ti a l di s ti ncti on i s whether pa i n i s pres ent i n one joi nt (mona rti cul a r) or mul ti pl e joi nts (pol ya rti cul a r). When mul ti pl e joi nts a re
a ffected, di fferent terms ca n be us ed:
Arthri ti s i nvol vi ng 4 joi nts , pa rti cul a rl y when i t occurs i n a n a s ymmetri c fa s hi on, i s ol i goa rti cul a r or pa uci a rti cul a r a rthri ti s .
Arthri ti s i nvol vi ng > 4 joi nts , us ua l l y i n a s ymmetri c fa s hi on, i s pol ya rti cul a r a rthri ti s .
Pathophysiology
Pol ya rti cul a r a rthra l gi a ca n ori gi na te from a rthri ti s or from extra -a rti cul a r di s orders (eg, pol ymya l gi a rheuma ti ca , fi bromya l gi a ). Pa i n ca us ed by
i ntra -a rti cul a r di s orders ma y be s econda ry to a n i nfl a mma tory a rthri ti s (eg, i nfecti on, RA, crys ta l depos i ti on) or a noni nfl a mma tory proces s (eg,
os teoa rthri ti s ).
Infl a mma tory a rthri ti s ma y i nvol ve peri phera l joi nts onl y (eg, ha nds , knees , feet) or both peri phera l a nd a xi a l joi nts (eg, s a croi l i a c, a pophys ea l ,
di s covertebra l , cos tovertebra l ).
Etiology
Peri phera l ol i goa rti cul a r a nd pol ya rti cul a r a rthri ti s ha ve s peci fi c, l i kel y ca us es (s ee
Ta bl e 32-5); the pres ence or a bs ence of a xi a l i nvol vement hel ps l i mi t pos s i bi l i ti es . However, i n ma ny pa ti ents , a rthri ti s i s often tra ns i ent a nd
res ol ves wi thout di a gnos i s or ma y not ful fi l l the cri teri a for a ny defi ned rheuma ti c di s ea s e.
Acute pol ya rti cul a r a rthri ti s i s mos t often due to the fol l owi ng:
Infecti on (us ua l l y vi ra l )
Fl a re of a rheuma ti c di s ea s e
[Table 32-5. Some Ca us es of Pol ya rti cul a r Joi nt Pa i n]
Chroni c pol ya rti cul a r a rthri ti s i n a dul ts i s mos t often due to the fol l owi ng:
RA (i nfl a mma tory)
Os teoa rthri ti s (noni nfl a mma tory)
Chroni c pol ya rti cul a r a rthri ti s i n chi l dren i s mos t often due to the fol l owi ng:
Juveni l e i di opa thi c a rthri ti s
Evaluation
Eva l ua ti on s houl d determi ne whether the joi nts or peri a rti cul a r s tructures a re the ca us e of s ymptoms a nd whether there i s i nfl a mma ti on or
effus i on. If i nfl a mma ti on i s pres ent or the di a gnos i s i s uncl ea r, s ymptoms a nd s i gns of s ys temi c di s orders s houl d be s ought.
History: History of present illness s houl d i denti fy the a cui ty of ons et (eg, a brupt, gra dua l ), tempora l pa tterns (eg, di urna l va ri a ti on, pers i s tent vs
i ntermi ttent), chroni ci ty (eg, a cute vs l ongs ta ndi ng), a nd exa cerba ti ng fa ctors (eg, col d wea ther, a cti vi ty). Pa ti ents s houl d be s peci fi ca l l y a s ked
a bout unprotected s exua l conta ct (pos s i bl e gonococca l i nfecti on) a nd ti ck bi tes or res i dence i n a Lyme-endemi c a rea .
Review of systems s houl d s eek s ymptoms a nd s i gns of ca us a ti ve di s orders (s ee Ta bl es 32-5 a nd
32-6).
[Table 32-6. Some Sugges ti ve Fi ndi ngs i n Pol ya rti cul a r Joi nt Pa i n]
Past medical history a nd fa mi l y hi s tory s houl d i denti fy known rheuma ti c di s orders a nd other condi ti ons ca pa bl e of ca us i ng joi nt s ymptoms (s ee
Ta bl e 32-5).
Physical examination: Vi ta l s i gns a re revi ewed for fever.
Exa mi na ti on of the hea d, neck, a nd s ki n s houl d note a ny s i gns of conjuncti vi ti s , i ri ti s , mucos a l l es i ons , s i nona s a l a bnorma l i ti es ,
l ympha denopa thy, ecchymos es , s ki n ul cers , ps ori a ti c pl a ques , purpura , or ma l a r ra s h.
Ca rdi opul mona ry exa mi na ti on s houl d note a ny s i gns of a cute i nfl a mma tory di s ea s e or s eros i ti s (eg, murmur, peri ca rdi a l rub, muffl ed hea rt
s ounds , bi ba s i l a r dul l nes s cons i s tent wi th pl eura l effus i on).
Geni ta l exa mi na ti on s houl d note a ny di s cha rge, ul cers , or other fi ndi ngs cons i s tent wi th s exua l l y tra ns mi tted di s ea s es .
Mus cul os kel eta l exa mi na ti on s houl d note mus cul a r poi nt tendernes s a s s oci a ted wi th fi bromya l gi a . Joi nt exa mi na ti on begi ns wi th i ns pecti on for
deformi ti es , erythema , s wel l i ng, or effus i on a nd then proceeds to pa l pa ti on a nd es ti ma ti on of pa i n a nd crepi tus wi th a cti ve a nd pa s s i ve ra nge of
moti on. Compa ri s on wi th the contra l a tera l una ffected joi nt often hel ps detect more s ubtl e cha nges . Exa mi na ti on s houl d note whether the
di s tri buti on of a ffected joi nts i s s ymmetri c.
Peri a rti cul a r s tructures a l s o s houl d be exa mi ned for di s crete, s oft s wel l i ng a t the s i te of a burs a (burs i ti s ), poi nt tendernes s a t the i ns erti on of a
tendon (tendi ni ti s ), a nd poi nt tendernes s over a tendon wi th fi ne crepi tus (tenos ynovi ti s ).
Hot, s wol l en, red joi nts
Any extra -a rti cul a r s ymptoms (eg, fever, ra s h, pl a ques , ul cers , conjuncti vi ti s , i ri ti s , murmur, purpura )
Interpretation of findings: An i mporta nt i ni ti a l el ement i s whether pa i n ori gi na tes i n the joi nts , s pi ne, or both or i n other s tructures s uch a s bones ,
tendons , burs a e, mus cl es , other s oft-ti s s ue s tructures , or nerves . Pa i n tha t wors ens wi th a cti ve ra ther tha n pa s s i ve joi nt moti on ma y i ndi ca te
tendi ni ti s or burs i ti s ; i ntra -a rti cul a r i nfl a mma ti on genera l l y res tri cts a cti ve a nd pa s s i ve ra nge of joi nt moti on s everel y. Tendernes s or s wel l i ng a t
onl y one s i de of a joi nt, or a wa y from the joi nt l i ne, s ugges ts a n extra -a rti cul a r ori gi n (eg, i n l i ga ments , tendons , or burs a e); fi ndi ngs on s evera l
a s pects of the joi nt s ugges t a n i ntra -a rti cul a r ca us e. Pa i n tha t i s di ffus e a nd des cri bed i ncons i s tentl y or va guel y ma y res ul t from fi bromya l gi a or
functi ona l di s orders .
If the joi nts , s pi ne, or both a re i nvol ved, di fferenti a ti ng i nfl a mma tory from noni nfl a mma tory di s orders ma y hel p. Cl i ni ca l fi ndi ngs of promi nent
morni ng s ti ffnes s , nontra uma ti c joi nt s wel l i ng, a nd fever or wei ght l os s a re s ugges ti ve of a n i nfl a mma tory di s order, but tes ti ng i s often hel pful .
Exa mi na ti on of the ha nd joi nts ma y yi el d other cl ues (s ee Ta bl e 32-6) a nd ma y hel p di fferenti a te os teoa rthri ti s from RA (s ee
Ta bl e 32-7).
Ba ck pa i n wi th a rthri ti s s ugges ts a nkyl os i ng s pondyl i ti s a rea cti ve or ps ori a ti c a rthri ti s , or fi bromya l gi a .
[Table 32-7. Di fferenti a l Fea tures of the Ha nd i n RA a nd Os teoa rthri ti s ]
Testing: The fol l owi ng tes ts a re of pa rti cul a r i mporta nce:
Arthrocentes i s
Serol ogi c tes ti ng
Us ua l l y ESR
Arthrocentes i s i s ma nda tory i n mos t pa ti ents wi th a new effus i on a nd ca n hel p rul e out i nfecti on a nd crys ta l a rthropa thy a s wel l a s di s ti ngui s h
between a n i nfl a mma tory a nd noni nfl a mma tory proces s . Other tes ts ma y be needed to i denti fy s peci fi c di s orders (s ee Ta bl e 32-5).
If the s peci fi c di a gnos i s ca nnot be es ta bl i s hed cl i ni ca l l y a nd i f determi ni ng whether a rthri ti s i s i nfl a mma tory ma y hel p determi ne the di a gnos i s ,
ESR a nd C-rea cti ve protei n ma y be done. A l ow ESR ma kes i nfl a mma tory ca us es (eg, rheuma ti c di s ea s e, gout, i nfecti on, va s cul i ti s ) l es s l i kel y but
does not rul e them out. El eva ted res ul ts a rgue more s trongl y for i nfl a mma ti on, but they a re very nons peci fi c, pa rti cul a rl y i n ol der a dul ts .
Once a di a gnos i s of a s ys temi c di s ea s e i s thought to be mos t l i kel y, s upporti ve s erol ogi c tes ti ng for a nti nucl ea r a nti bodi es , doubl e-s tra nded DNA,
rheuma toi d fa ctor, a nti cycl i c ci trul l i na ted pepti de, a nd a nti neutrophi l cytopl a s mi c a nti bodi es ma y a s s i s t i n ma ki ng the di a gnos i s .
Treatment
The underl yi ng di s order i s trea ted. Sys temi c di s ea s es ma y requi re ei ther i mmunos uppres s i on or a nti bi oti cs a s determi ned by the di a gnos i s . Joi nt
i nfl a mma ti on i s us ua l l y trea ted s ymptoma ti ca l l y wi th NSAIDs . Pa i n wi thout i nfl a mma ti on i s us ua l l y more s a fel y trea ted wi th a ceta mi nophen.
Joi nt i mmobi l i za ti on wi th a s pl i nt or s l i ng ca n s ometi mes rel i eve pa i n. Hea t thera py ma y rel i eve mus cl e s pa s m a round joi nts , a nd col d thera py
ma y be a na l ges i c i n i nfl a mma tory joi nt di s ea s es . For ca s es of chroni c a rthri ti s , conti nued phys i ca l a cti vi ty i s encoura ged.
Os teoa rthri ti s i s by fa r the mos t common ca us e of a rthri ti s i n ol der peopl e. RA mos t commonl y begi ns between a ges 30 a nd 40, but i n up to one
thi rd of pa ti ents , i t devel ops a fter the a ge of 60. Beca us e pa ra neopl a s ti c phenomena a l s o ca n ca us e i nfl a mma tory pol ya rthri ti s , ca ncer s houl d be
cons i dered i n ol der a dul ts i n whom new-ons et RA i s s us pected.
Key Points
The di fferenti a l di a gnos i s of pol ya rti cul a r joi nt pa i n ca n be na rrowed by cons i deri ng how ma ny joi nts a re a ffected, whether i nfl a mma ti on i s
pres ent, a nd whether a ny extra -a rti cul a r s i gns a re pres ent.
Chroni c a rthri ti s i s mos t often ca us ed by juveni l e i di opa thi c a rthri ti s i n chi l dren a nd os teoa rthri ti s a nd RA i n a dul ts .
Acute pol ya rti cul a r a rthri ti s i s mos t often due to i nfecti on, gout, or a fl a re of rheuma ti c di s ea s e.
Arthrocentes i s i s ma nda tory i n mos t ca s es of a new effus i on a nd ca n hel p rul e out i nfecti on a nd crys ta l -i nduced a rthropa thy a s wel l a s
di s ti ngui s h between a n i nfl a mma tory a nd noni nfl a mma tory proces s .
Chapter 33. Autoimmune Rheumatic Disorders

Introduction
Autoi mmune rheuma ti c di s orders i ncl ude eos i nophi l i c fa s ci i ti s , mi xed connecti ve ti s s ue di s ea s e, pol ymyos i ti s a nd derma tomyos i ti s , rel a ps i ng
pol ychondri ti s , Sjogren's s yndrome, SLE, a nd s ys temi c s cl eros i s . RA a nd the s pondyl oa rthropa thi es a nd thei r va ri a nts (s ee Ch. 35) a re a l s o i mmune
medi a ted. The tri ggers a nd preci s e pa thophys i ol ogy rema i n unknown for a l l thes e di s orders , a l though ma ny a s pects of pa thogenes i s a re
becomi ng cl ea rer. Pa ti ents wi th mos t a utoi mmune rheuma ti c di s orders a re a t i ncrea s ed ri s k of a theros cl eros i s .
Eosinophilic Fasciitis
Eosinophilic fasciitis (EF) is an uncommon disorder characterized by symmetric and painful inflammation, swelling, and induration of the arms and legs. Diagnosis
is by biopsy of skin and fascia. Treatment is with corticosteroids.
The ca us e of EF i s unknown. The di s order occurs mos tl y i n mi ddl e-a ged men but ca n occur i n women a nd chi l dren.
Symptoms and Signs
The di s ea s e often begi ns a fter s trenuous phys i ca l a cti vi ty (eg, choppi ng wood). The i ni ti a l fea tures a re pa i n, s wel l i ng, a nd i nfl a mma ti on of the
s ki n a nd s ubcuta neous ti s s ues , fol l owed by i ndura ti on, crea ti ng a cha ra cteri s ti c ora nge-peel confi gura ti on mos t evi dent over the a nteri or s urfa ces
of the extremi ti es . The fa ce a nd trunk a re occa s i ona l l y i nvol ved. Res tri cti on of a rm a nd l eg movement us ua l l y devel ops i ns i di ous l y. Contra ctures
commonl y evol ve, s econda ry to i ndura ti on a nd thi ckeni ng of the fa s ci a , but the proces s ma y a l s o i nvol ve tendons , s ynovi a l membra nes , a nd
mus cl e. Typi ca l l y, EF does not i nvol ve the fi ngers a nd toes (a cra l a rea s ). Mus cl e s trength i s uni mpa i red, but mya l gi a a nd a rthri ti s ma y occur. Ca rpa l
tunnel s yndrome ma y a l s o occur.
Fa ti gue a nd wei ght l os s a re common. Ra rel y, a pl a s ti c a nemi a , thrombocytopeni a , a nd l ymphoprol i fera ti ve proces s es devel op.
Diagnosis
Bi ops y
EF s houl d be s us pected i n pa ti ents wi th typi ca l s ymptoms . The cuta neous ma ni fes ta ti ons ma y s ugges t s ys temi c s cl eros i s ; however, pa ti ents wi th
s ys temi c s cl eros i s us ua l l y a l s o ha ve Ra yna ud's s yndrome, a cra l i nvol vement, tel a ngi ecta s i a , a nd vi s cera l cha nges (eg, es opha gea l dys moti l i ty). Al l
of thes e a re a bs ent i n EF.
Di a gnos i s i s confi rmed by en bl oc bi ops y, whi ch s houl d be deep enough to i ncl ude fa s ci a a nd a dja cent mus cl e fi bers . Cha ra cteri s ti c fi ndi ngs a re
i nfl a mma ti on of the fa s ci a , wi th or wi thout eos i nophi l s .
Bl ood tes ts a re not di a gnos ti c, but CBC s hows eos i nophi l i a (i n ea rl y a cti ve di s ea s e), a nd s erum protei n el ectrophores i s s hows pol ycl ona l
hyperga mma gl obul i nemi a . CBC s houl d be done i n a l l pa ti ents beca us e the pres ence of eos i nophi l i a hel ps i n the di a gnos i s . Autoa nti bodi es a re
us ua l l y a bs ent. MRI, a l though not s peci fi c, ca n s how thi ckened fa s ci a , the i ncrea s ed s i gna l i ntens i ty i n the s uperfi ci a l mus cl e fi bers correl a ti ng
wi th the i nfl a mma ti on.
Prognosis
Al though the l ong-term outcome va ri es , EF i s often s el f-l i mi ted a nd uncompl i ca ted.
Treatment
Ora l predni s one
Mos t pa ti ents res pond ra pi dl y to hi gh dos es of predni s one (40 to 60 mg po once/da y fol l owed by gra dua l reducti on to 5 to 10 mg/da y a s s oon a s
the fa s ci ti s res ol ves ). Conti nued l ow dos es ma y be requi red for 2 to 5 yr. Some pa ti ents requi re l onger cours es a nd pos s i bl y other drugs (eg,
hydroxychl oroqui ne, cycl os pori ne). NSAIDs a nd H 2 bl ockers (eg, ci meti di ne) a l s o ha ve been us ed to trea t EF.
Moni tori ng wi th CBCs i s a dvi s ed beca us e of the occa s i ona l hema tol ogi c compl i ca ti ons .
Mixed Connective Tissue Disease
Mixed connective tissue disease (MCTD) is an uncommon, specifically defined, overlap syndrome characterized by clinical features of SLE, systemic sclerosis, and
polymyositis with very high titers of circulating antinuclear antibody to a ribonucleoprotein antigen. Hand swelling, Raynaud's syndrome, polyarthralgia,
inflammatory myopathy, esophageal hypomotility, and pulmonary dysfunction are common. Diagnosis is by the combination of clinical features, antibodies to
ribonucleoprotein, and absence of antibodies specific for other autoimmune diseases. Treatment varies with disease severity and organ involvement but usually
includes corticosteroids and sometimes additional immunosuppressants.
MCTD occurs worl dwi de a nd i n a l l ra ces , wi th a pea k i nci dence i n the teens a nd 20s . About 80% of peopl e who ha ve thi s di s ea s e a re women. The
ca us e i s unknown. In s ome pa ti ents , the di s order evol ves i nto cl a s s i c s ys temi c s cl eros i s or SLE.
Symptoms and Signs
Ra yna ud's s yndrome ma y precede other ma ni fes ta ti ons by yea rs . Frequentl y, the fi rs t ma ni fes ta ti ons res embl e ea rl y SLE, s ys temi c s cl eros i s ,
pol ymyos i ti s , derma tomyos i ti s , or even RA. Wha tever the i ni ti a l ma ni fes ta ti on, l i mi ted di s ea s e tends to progres s a nd become wi des prea d, a nd
the cl i ni ca l pa ttern cha nges over ti me.
The mos t frequent fi ndi ng i s s wel l i ng of the ha nds tha t eventua l l y ca us es a s a us a ge-l i ke a ppea ra nce of the fi ngers . Ski n fi ndi ngs i ncl ude l upus or
derma tomyos i ti s -l i ke ra s hes . Di ffus e s ys temi c s cl eros i s -l i ke s ki n cha nges a nd i s chemi c necros i s or ul cera ti on of the fi ngerti ps ma y occa s i ona l l y
devel op.
Al mos t a l l pa ti ents ha ve pol ya rthra l gi a s , a nd 75% ha ve fra nk a rthri ti s . Often the a rthri ti s i s nondeformi ng, but eros i ve cha nges a nd deformi ti es
s i mi l a r to thos e i n RA (eg, boutonni ere a nd s wa n-neck deformi ti es ) ma y be pres ent. Proxi ma l mus cl e wea knes s wi th or wi thout tendernes s i s
common.
Rena l di s ea s e occurs i n a bout 10% a nd i s often mi l d but occa s i ona l l y ca us es morbi di ty or morta l i ty. Someti mes pul mona ry i nvol vement i s the
mos t s eri ous compl i ca ti on. Hea rt fa i l ure ca n occur. Sjogren's s yndrome ma y devel op. A tri gemi na l s ens ory neuropa thy devel ops more frequentl y i n
MCTD tha n i n other s ys temi c a utoi mmune di s ea s es . It ma y be the pres enti ng fea ture a nd i s cons i dered the mos t frequent CNS ma ni fes ta ti on.
Diagnosis
Tes ti ng for a nti nucl ea r a nti bodi es (ANA), extra cta bl e nucl ea r a nti gen (ENA), a nd ri bonucl eoprotei n (RNP)
Orga n i nvol vement determi ned a s cl i ni ca l l y i ndi ca ted
MCTD s houl d be s us pected when a ddi ti ona l overl a ppi ng fea tures a re pres ent i n pa ti ents a ppea ri ng to ha ve SLE, s ys temi c s cl eros i s , pol ymyos i ti s ,
or RA.
Tes ts for ANA a nd a nti body to ENA a nd RNP a nti gen a re done fi rs t. If res ul ts of thes e tes ts a re compa ti bl e wi th MCTD (eg, RNP a nti bodi es very hi gh,
pos i ti ve ANA), tes ts for rheuma toi d fa ctors , a nti Jo-1 (a nti -hi s ti dyl t-RNA s yntheta s e), a nti bodi es to the ri bonucl ea s e-res i s ta nt Smi th (Sm)
component of ENA, a nd doubl e-s tra nded DNA a re done to excl ude other pos s i bl e di a gnos es .
Further eva l ua ti on depends on s ymptoms a nd s i gns ; ma ni fes ta ti ons of myos i ti s , rena l i nvol vement, or pul mona ry i nvol vement prompt tes ts of
thos e orga ns (eg, CK, MRI, el ectromyogra m, or mus cl e bi ops y for di a gnos i s of myos i ti s ).
Al mos t a l l pa ti ents ha ve hi gh ti ters (often > 1:1000) of fl uores cent ANA tha t produce a s peckl ed pa ttern. Anti bodi es to ENA a re us ua l l y pres ent a t
very hi gh ti ters (> 1:100,000). Anti body to RNP i s pres ent, wherea s a nti body to the ri bonucl ea s e-res i s ta nt Sm component of ENA i s a bs ent.
Rheuma toi d fa ctors a re frequentl y pos i ti ve, a nd ti ters a re often hi gh. The ESR i s frequentl y el eva ted.
Prognosis
The overa l l 10-yr s urvi va l ra te i s 80%, but prognos i s depends l a rgel y on whi ch ma ni fes ta ti ons predomi na te. Pa ti ents wi th fea tures of s ys temi c
s cl eros i s a nd pol ymyos i ti s ha ve a wors e prognos i s . Pa ti ents a re a t i ncrea s ed ri s k of a theros cl eros i s . Ca us es of dea th i ncl ude pul mona ry
hypertens i on, rena l fa i l ure, MI, col oni c perfora ti on, di s s emi na ted i nfecti on, a nd cerebra l hemorrha ge. Some pa ti ents ha ve s us ta i ned remi s s i ons
for ma ny yea rs wi thout trea tment.
Treatment
NSAIDs or a nti ma l a ri a l s for mi l d di s ea s e
Corti cos teroi ds for modera te to s evere di s ea s e
Someti mes other i mmunos uppres s a nts
Genera l ma na gement a nd i ni ti a l drug thera py a re ta i l ored to the s peci fi c cl i ni ca l probl em a nd a re s i mi l a r to thos e of SLE. Mos t pa ti ents wi th
modera te or s evere di s ea s e res pond to corti cos teroi ds , pa rti cul a rl y i f trea ted ea rl y. Mi l d di s ea s e i s often control l ed by NSAIDs , a nti ma l a ri a l s , or
s ometi mes l ow-dos e corti cos teroi ds . Severe ma jor orga n i nvol vement us ua l l y requi res hi gher dos es of corti cos teroi ds (eg, predni s one 1 mg/kg po
once/da y) a nd a ddi ti ona l i mmunos uppres s a nts . If pa ti ents devel op fea tures of myos i ti s or s ys temi c s cl eros i s , trea tment i s a s for thos e di s ea s es .
Al l pa ti ents s houl d be cl os el y moni tored for a theros cl eros i s . Pa ti ents on l ong-term corti cos teroi d thera py s houl d recei ve os teoporos i s
prophyl a xi s .
Polymyositis and Dermatomyositis
Polymyositis and dermatomyositis are uncommon systemic rheumatic disorders characterized by inflammatory and degenerative changes in the muscles
(polymyositis) or in the skin and muscles (dermatomyositis). The most specific skin signs are Gottron's papules over the knuckles and a periorbital heliotropic
rash. Manifestations include symmetric weakness, some tenderness, and later atrophy, principally of the proximal limb girdle muscles. Complications can include
visceral involvement and cancer. Diagnosis is by clinical findings and abnormalities on muscle tests, which may include muscle enzymes, MRI, electromyography,
and muscle biopsy. Treatment is with corticosteroids, sometimes combined with immunosuppressants or IV immune globulin.
The fema l e:ma l e ra ti o i s 2:1. Thes e di s orders ma y a ppea r a t a ny a ge but occur mos t commonl y from a ge 40 to 60 or, i n chi l dren, from a ge 5 to 15.
Etiology
The ca us e s eems to be a n a utoi mmune rea cti on to mus cl e ti s s ue i n geneti ca l l y s us cepti bl e peopl e. Fa mi l i a l cl us teri ng occurs , a nd HLA s ubtypes
DR3, DR52, DR6 s eem to be the geneti c predi s pos i ti on. Pos s i bl e i nci ti ng events i ncl ude vi ra l myos i ti s a nd underl yi ng ca ncer. Pi corna vi rus -l i ke
s tructures ha ve been found i n mus cl e cel l s , but thei r s i gni fi ca nce i s not known, a nd vi rus es ca n tri gger s i mi l a r di s orders i n a ni ma l s . The
a s s oci a ti on of ca ncer wi th derma tomyos i ti s (much l es s s o wi th pol ymyos i ti s ) s ugges ts tha t a tumor ma y i nci te myos i ti s a s the res ul t of a n
a utoi mmune rea cti on a ga i ns t a common a nti gen i n mus cl e a nd tumor.
Pathophysiology
Pa thol ogi c cha nges i n both di s orders i ncl ude cel l ul a r da ma ge a nd a trophy, wi th va ri a bl e degrees of i nfl a mma ti on. Mus cl es i n the ha nds , feet,
a nd fa ce a re a ffected l es s tha n other s kel eta l mus cl es . Invol vement of vi s cera l mus cl es i n the pha rynx a nd upper es opha gus a nd occa s i ona l l y the
hea rt, s toma ch, or i ntes ti nes ca n i mpa i r the functi ons of thos e orga ns . Hi gh bl ood l evel s of myogl obi n from rha bdomyol ys i s ca n da ma ge the
ki dneys . Infl a mma ti on ma y occur i n joi nts a nd l ungs , es peci a l l y i n pa ti ents wi th a nti s yntheta s e a nti bodi es .
Derma tomyos i ti s i s cha ra cteri zed by i mmune compl ex depos i ti on i n the ves s el s a nd i s cons i dered a compl ement-medi a ted va s cul opa thy. In
contra s t, the ma i n pa thophys i ol ogi c a bnorma l i ty i n pol ymyos i ti s i s di rect T cel l -medi a ted mus cl e i njury.
Classification
Myos i ti s ha s been di vi ded i nto s evera l s ubtypes :
Pri ma ry i di opa thi c pol ymyos i ti s ca n occur a t a ny a ge a nd does not i nvol ve the s ki n.
Pri ma ry i di opa thi c derma tomyos i ti s i s s i mi l a r to pri ma ry i di opa thi c pol ymyos i ti s but a l s o i nvol ves the s ki n.
Pol ymyos i ti s or derma tomyos i ti s a s s oci a ted wi th ca ncer ca n occur a t a ny a ge but i s mos t common a mong ol der a dul ts ; the ca ncer ca n devel op up
to 2 yr before or a fter the myos i ti s .
Chi l dhood derma tomyos i ti s ca n be a s s oci a ted wi th s ys temi c va s cul i ti s .
Pol ymyos i ti s or derma tomyos i ti s ca n occur wi th a n a s s oci a ted di s order s uch a s progres s i ve s ys temi c s cl eros i s , mi xed connecti ve ti s s ue di s ea s e,
RA, SLE, or s a rcoi dos i s .
Incl us i on body myos i ti s i s a s epa ra te di s order tha t ha s cl i ni ca l ma ni fes ta ti ons s i mi l a r to chroni c i di opa thi c pol ymyos i ti s ; however, i t devel ops a t
a n ol der a ge, frequentl y i nvol ves di s ta l mus cl es (eg, ha nd a nd feet mus cl es ), ha s a l onger dura ti on, res ponds poorl y to thera py, a nd ha s a
di fferent hi s tol ogi c a ppea ra nce.
Symptoms and Signs
Ons et of pol ymyos i ti s ma y be a cute (pa rti cul a rl y i n chi l dren) or i ns i di ous (pa rti cul a rl y i n a dul ts ). Pol ya rthra l gi a s , Ra yna ud's s yndrome, dys pha gi a ,
pul mona ry s ymptoms , a nd cons ti tuti ona l compl a i nts (nota bl y fever, fa ti gue, a nd wei ght l os s ) ma y a l s o occur.
Muscle weakness ma y progres s over weeks to months . However, i t ta kes des tructi on of 50% of mus cl e fi bers to ca us e s ymptoma ti c wea knes s (i e,
mus cl e wea knes s i ndi ca tes a dva nced myos i ti s ). Pa ti ents ma y ha ve di ffi cul ty ra i s i ng thei r a rms a bove thei r s houl ders , cl i mbi ng s teps , or ri s i ng
from a s i tti ng pos i ti on. Pa ti ents ma y become wheel cha i r-bound or bedri dden beca us e of wea knes s of pel vi c a nd s houl der gi rdl e mus cl es . The
fl exors of the neck ma y be s everel y a ffected, ca us i ng a n i na bi l i ty to ra i s e the hea d from the pi l l ow. Invol vement of pha ryngea l a nd upper
es opha gea l mus cl es ma y i mpa i r s wa l l owi ng a nd predi s pos e to a s pi ra ti on. Mus cl es of the ha nds , feet, a nd fa ce es ca pe i nvol vement. Li mb
contra ctures ma y eventua l l y devel op.
Joint manifestations i ncl ude pol ya rthra l gi a or pol ya rthri ti s , often wi th s wel l i ng, effus i ons , a nd other cha ra cteri s ti cs of nondeformi ng a rthri ti s , whi ch
occur i n a bout 30% of pa ti ents . However, joi nt ma ni fes ta ti ons tend to be mi l d. They occur more often i n a s ubs et wi th Jo-1 or other a nti s yntheta s e
a nti bodi es .
Visceral involvement (except tha t of the pha rynx a nd upper es opha gus ) i s l es s common i n pol ymyos i ti s tha n i n s ome other rheuma ti c di s orders (eg,
SLE, s ys temi c s cl eros i s ). Occa s i ona l l y, a nd es peci a l l y i n pa ti ents wi th a nti s yntheta s e a nti bodi es , i nters ti ti a l pneumoni ti s (ma ni fes ted by dys pnea
a nd cough) i s the mos t promi nent ma ni fes ta ti on. Ca rdi a c a rrhythmi a s (i ncl udi ng conducti on di s turba nces a nd a bnorma l s ys tol i c ti me i nterva l s )
ca n occur but a re often a s ymptoma ti c. GI s ymptoms , more common a mong chi l dren wi th a s s oci a ted va s cul i ti s , ma y i ncl ude hema temes i s , mel ena ,
a nd i s chemi c bowel perfora ti on.
Skin changes, whi ch occur i n derma tomyos i ti s , tend to be dus ky a nd erythema tous . Peri orbi ta l edema wi th a purpl i s h a ppea ra nce (hel i otrope ra s h)
i s s peci fi c for derma tomyos i ti s . The ra s h ma y be s l i ghtl y el eva ted a nd s mooth or s ca l y; i t ma y a ppea r on the forehea d, V of the neck a nd
s houl ders , ches t a nd ba ck, forea rms a nd l ower l egs , el bows a nd knees , medi a l ma l l eol i , a nd ra di odors a l a s pects of the proxi ma l i nterpha l a ngea l
a nd meta ca rpopha l a ngea l joi nts (Gottron's pa pul es a l s o a rel a ti vel y s peci fi c fi ndi ng). The ba s e a nd s i des of the fi ngerna i l s ma y be hyperemi c or
thi ckened. Des qua ma ti ng derma ti ti s wi th s pl i tti ng of the s ki n ma y evol ve over the ra di a l a s pects of the fi ngers . The pri ma ry s ki n l es i ons
frequentl y fa de compl etel y but ma y be fol l owed by s econda ry cha nges (eg, browni s h pi gmenta ti on, a trophy, s ca rri ng, vi ti l i go). Subcuta neous
ca l ci fi ca ti on ma y occur, pa rti cul a rl y i n chi l dren.
Diagnosis
Cl i ni ca l cri teri a
Mus cl e bi ops y (defi ni ti ve)
Pol ymyos i ti s s houl d be s us pected i n pa ti ents wi th proxi ma l mus cl e wea knes s wi th or wi thout mus cl e tendernes s . Derma tomyos i ti s s houl d be
s us pected i n pa ti ents wi th a hel i otropi c ra s h or Gottron's pa pul es , even wi thout pol ymyos i ti s , a nd i n pa ti ents wi th s ymptoms of pol ymyos i ti s a nd
a ny s ki n fi ndi ngs compa ti bl e wi th derma tomyos i ti s . Pol ymyos i ti s a nd derma tomyos i ti s s ha re certa i n cl i ni ca l fi ndi ngs wi th s ys temi c s cl eros i s or,
l es s frequentl y, wi th SLE or va s cul i ti s . Es ta bl i s hi ng the di a gnos i s requi res a s ma ny a s pos s i bl e of the fol l owi ng 5 cri teri a :
Proxi ma l mus cl e wea knes s
Cha ra cteri s ti c ra s h
El eva ted s erum mus cl e enzymes (CK, or i f thi s i s not el eva ted, a mi notra ns fera s es or a l dol a s e)
Cha ra cteri s ti c el ectromyogra phi c or MRI a bnorma l i ti es
Mus cl e bi ops y cha nges (the defi ni ti ve tes t)
Muscle biopsy excl udes s ome s i mi l a r condi ti ons s uch a s i ncl us i on body myos i ti s a nd pos tvi ra l rha bdomyol ys i s . Bi ops y fi ndi ngs ca n be va ri a bl e, but
chroni c i nfl a mma ti on a nd mus cl e degenera ti on a nd regenera ti on a re typi ca l . A defi ni te di a gnos i s ma de by mus cl e bi ops y i s recommended before
trea tment of pol ymyos i ti s to excl ude other mus cl e di s orders . To i ncrea s e the s ens i ti vi ty of the bi ops y res ul ts , the bi ops y s a mpl e s houl d be
obta i ned from a mus cl e tha t ha s one or more of the fol l owi ng cha ra cteri s ti cs :
Wea knes s on cl i ni ca l exa mi na ti on
Infl a mma ti on i denti fi ed on MRI
Contra l a tera l pa i r of a mus cl e s hown to be a bnorma l on el ectromyogra phy
Laboratory studies ca n i ncrea s e or decrea s e s us pi ci on for the di s order, a s s es s i ts s everi ty, i denti fy overl a ps , a nd hel p detect compl i ca ti ons .
Autoa nti bodi es s houl d be tes ted. Anti nucl ea r a nti bodi es a re pos i ti ve i n up to 80% of pa ti ents . Deta i l ed tes ti ng of the a nti nucl ea r a nti bodi es
(ANA), when pres ent, i s i mporta nt i n i denti fyi ng other overl a p s yndromes , mos t often thos e wi th a nother a utoi mmune di s order. About 30% of
pa ti ents ha ve myos i ti s -s peci fi c a utoa nti bodi es : a nti bodi es to a mi noa cyl -tRNA s yntheta s es (a nti -s yntheta s e a nti bodi es ), i ncl udi ng a nti -Jo-1;
a nti bodi es to s i gna l recogni ti on pa rti cl e (SRPa nti -SRP a nti bodi es ); a nd a nti bodi es to Mi -2, a nucl ea r hel i ca s e. The rel a ti ons hi p between thes e
a utoa nti bodi es a nd di s ea s e pa thogenes i s rema i ns uncl ea r, a l though a nti body to Jo-1 i s a s i gni fi ca nt ma rker for fi bros i ng a l veol i ti s , pul mona ry
fi bros i s , a rthri ti s , a nd Ra yna ud's s yndrome.
Peri odi c mea s urement of CK i s hel pful i n moni tori ng trea tment. However, i n pa ti ents wi th wi des prea d mus cl e a trophy, l evel s a re occa s i ona l l y
norma l des pi te chroni c, a cti ve myos i ti s . Mus cl e bi ops y, MRI, or hi gh CK l evel s ca n often di fferenti a te a rel a ps e of pol ymyos i ti s from corti cos teroi di nduced myopa thy. Al dol a s e i s a l es s s peci fi c ma rker for mus cl e i njury tha n CK.
Cancer screening i s recommended by s ome a uthori ti es for a ny a dul t who ha s derma tomyos i ti s or for pa ti ents 60 yr who ha ve pol ymyos i ti s beca us e
thes e pa ti ents often ha ve uns us pected ca ncers . Screeni ng s houl d i ncl ude a phys i ca l exa mi na ti on tha t i ncl udes brea s t, pel vi s , a nd rectum (wi th
occul t bl ood tes ti ng); CBC; bi ochemi ca l profi l e; ma mmogra m; ca rci noembryoni c a nti gen; uri na l ys i s ; ches t x-ra y; a nd a ny other tes ts a ppropri a te
ba s ed on pa ti ent's a ge. Addi ti ona l i nves ti ga ti on s houl d be ba s ed on hi s tory a nd phys i ca l exa mi na ti on fi ndi ngs . Some a uthori ti es recommend CT
of the ches t, a bdomen, a nd pel vi s . Younger pa ti ents wi thout s ymptoms of ca ncer need not undergo s creeni ng.
Prognosis
Long remi s s i ons (even a ppa rent recovery) occur i n up to 50% of trea ted pa ti ents wi thi n 5 yr, more often i n chi l dren. Rel a ps e, however, ma y s ti l l
occur a t a ny ti me. Overa l l 5-yr s urvi va l ra te i s 75% a nd i s hi gher i n chi l dren. Dea th i n a dul ts i s preceded by s evere a nd progres s i ve mus cl e
wea knes s , dys pha gi a , undernutri ti on, a s pi ra ti on pneumoni a , or res pi ra tory fa i l ure wi th s uperi mpos ed pul mona ry i nfecti on. Pol ymyos i ti s tends to
be more s evere a nd res i s ta nt to trea tment i n pa ti ents wi th ca rdi a c or pul mona ry i nvol vement. Dea th i n chi l dren ma y be a res ul t of bowel
va s cul i ti s . Ca ncer, i f pres ent, genera l l y determi nes the overa l l prognos i s .
Treatment
Corti cos teroi ds
Someti mes i mmunos uppres s a nts (eg, methotrexa te, a za thi opri ne, cycl os pori ne, IV i mmune gl obul i n)
Phys i ca l a cti vi ti es s houl d be modes tl y curta i l ed unti l the i nfl a mma ti on s ubs i des . Corti cos teroi ds a re the drugs of choi ce i ni ti a l l y. For a cute
di s ea s e, a dul ts recei ve predni s one 40 to 60 mg po once/da y. Seri a l mea s urements of CK provi de the bes t ea rl y gui de of thera peuti c
effecti venes s , fa l l i ng towa rd or rea chi ng norma l i n mos t pa ti ents i n 6 to 12 wk, fol l owed by i mproved mus cl e s trength. Once enzyme l evel s ha ve
returned to norma l , predni s one ca n be gra dua l l y reduced. If mus cl e enzyme l evel s ri s e, the dos e i s i ncrea s ed. Pa ti ents who s eem to recover ca n
ha ve trea tment gra dua l l y wi thdra wn wi th cl os e moni tori ng, but mos t a dul ts requi re chroni c ma i ntena nce wi th predni s one (up to 10 to 15 mg/da y).
Chi l dren requi re i ni ti a l dos es of predni s one of 30 to 60 mg/m 2 once/da y. In chi l dren, i t ma y be pos s i bl e to s top predni s one a fter 1 yr of
remi s s i on.
Occa s i ona l l y, pa ti ents trea ted chroni ca l l y wi th hi gh-dos e corti cos teroi ds become i ncrea s i ngl y wea k beca us e of a s uperi mpos ed corti cos teroi d
myopa thy.
If a pa ti ent does not to res pond to corti cos teroi ds , depends on a hi gh to modera te dos e of corti cos teroi ds , or devel ops a corti cos teroi d myopa thy
or a nother compl i ca ti on tha t neces s i ta tes s toppi ng or decrea s i ng predni s one, i mmunos uppres s a nts (eg, methotrexa te, a za thi opri ne, cycl os pori ne,
IV i mmune gl obul i n) s houl d be tri ed. Some pa ti ents ha ve recei ved onl y methotrexa te (genera l l y i n hi gher dos es tha n us ed for RA) for 5 yr. IV
i mmune gl obul i ns ca n be effecti ve i n s ome pa ti ents refra ctory to drug trea tment, but the prohi bi ti ve cos t ha s precl uded compa ra ti ve tri a l s . Some
cl i ni ci a ns combi ne predni s one wi th a n i mmunos uppres s a nt. Other pos s i bl e emergi ng thera pi es i ncl ude a nti -tumor necros i s fa ctor (TNF) a gents
a nd ri tuxi ma b.
Myos i ti s a s s oci a ted wi th tumors , meta s ta ti c di s ea s e, or i ncl us i on body myos i ti s us ua l l y i s more refra ctory to corti cos teroi ds . Ca ncer-a s s oci a ted
myos i ti s ma y remi t i f the tumor i s removed.
Peopl e wi th a n a utoi mmune di s order a re a t hi gher ri s k of a theros cl eros i s a nd s houl d be cl os el y moni tored. Pa ti ents on l ong-term corti cos teroi d
thera py s houl d recei ve os teoporos i s prophyl a xi s .
Relapsing Polychondritis
Relapsing polychondritis is an episodic, inflammatory, and destructive disorder involving primarily cartilage of the ear and nose but also potentially affecting the
eyes, tracheobronchial tree, heart valves, kidneys, joints, skin, and blood vessels. Diagnosis is by a combination of clinical, laboratory, imaging, and sometimes
biopsy findings. Treatment usually requires prednisone and other immunosuppressants.
Rel a ps i ng pol ychondri ti s a ffects men a nd women equa l l y; ons et typi ca l l y i s i n mi ddl e a ge. An a s s oci a ti on wi th RA, s ys temi c va s cul i ti s , SLE, a nd
other connecti ve ti s s ue di s orders s ugges ts a n a utoi mmune eti ol ogy.
Symptoms and Signs
Acute pa i n, erythema , a nd s wel l i ng mos t commonl y a ffect the pi nna ca rti l a ge. Na s a l ca rti l a ge i nfl a mma ti on i s the next mos t common, fol l owed by
a rthri ti s tha t va ri es from a rthra l gi a s to s ymmetri c or a s ymmetri c nondeformi ng a rthri ti s i nvol vi ng l a rge a nd s ma l l joi nts , wi th a predi l ecti on for the
cos tochondra l joi nts . The next mos t common ma ni fes ta ti ons , i n decrea s i ng order of frequency, a re i nfl a mma ti on of the eye (eg, conjuncti vi ti s ,
s cl eri ti s , i ri ti s , kera ti ti s , chori oreti ni ti s ); ca rti l a gi nous ti s s ue of the l a rynx, tra chea , or bronchi (ca us i ng hoa rs enes s , cough, a nd tendernes s over
the l a ryngea l ca rti l a ge); i nterna l ea r; ca rdi ova s cul a r s ys tem (eg, a orti c regurgi ta ti on, mi tra l regurgi ta ti on, peri ca rdi ti s , myoca rdi ti s , a orti c
a neurys ms , a orti ti s ); ki dney; a nd s ki n. Bouts of a cute i nfl a mma ti on hea l over weeks to months , wi th recurrences over s evera l yea rs . Va ri ous
ra s hes ca n devel op.
Adva nced di s ea s e ca n l ea d to des tructi on of s upporti ng ca rti l a ge, ca us i ng fl oppy ea rs ; s a ddl e nos e; pectus exca va tum; a nd vi s ua l , a udi tory, a nd
ves ti bul a r a bnorma l i ti es . Tra chea l na rrowi ng ca n l ea d to dys pnea , pneumoni a , or even tra chea l col l a ps e. Coexi s ti ng s ys temi c va s cul i ti s
(l eukocytocl a s ti c va s cul i ti s or pol ya rteri ti s nodos a ), myel odys pl a s ti c s yndrome, or ca ncer i s pos s i bl e.
Diagnosis
Someti mes bi ops y
Di a gnos i s i s es ta bl i s hed i f the pa ti ent devel ops a t l ea s t 3 of the fol l owi ng:
Bi l a tera l chondri ti s of the externa l ea rs
Infl a mma tory pol ya rthri ti s
Na s a l chondri ti s
Ocul a r i nfl a mma ti on
Res pi ra tory tra ct chondri ti s
Audi tory or ves ti bul a r dys functi on
Bi ops y of i nvol ved ca rti l a ge, mos t often the pi nna , i s hel pful i f cl i ni ca l di a gnos i s i s not cl ea r-cut.
La bora tory tes ts a re done. They a re not s peci fi c but ma y hel p to excl ude other di s orders . Synovi a l fl ui d a na l ys i s revea l s mi l d i nfl a mma tory
cha nges tha t a re nons peci fi c but hel p to rul e out a n i nfecti ous proces s . Bl ood tes ts ma y s how normocyti c-normochromi c a nemi a , l eukocytos i s ,
el eva ted ESR or -gl obul i n l evel s , a nd occa s i ona l l y pos i ti ve rheuma toi d fa ctor, a nti nucl ea r a nti bodi es (ANA), or, i n up to 25%, a nti neutrophi l
cytopl a s mi c a nti bodi es (ANCA). Abnorma l rena l functi on ma y i ndi ca te a n a s s oci a ted va s cul i ti s . A pos i ti ve c-ANCA tes t (ANCA tha t a re rea cti ve
ma i nl y to protei na s e-3) s ugges ts Wegener's gra nul oma tos i s , whi ch ca n ca us e s i mi l a r fi ndi ngs (s ee p. 329).
The upper a nd l ower a i rwa ys s houl d be eva l ua ted, i ncl udi ng compl ete s pi rometri c tes ti ng a nd ches t CT, when the di a gnos i s i s ma de.
Prognosis
Morta l i ty a fter 5 yr i s 30%, from col l a ps e of l a ryngea l a nd tra chea l s tructures or from ca rdi ova s cul a r compl i ca ti ons s uch a s l a rge-ves s el a neurys m,
ca rdi a c va l vul a r i ns uffi ci ency, or s ys temi c va s cul i ti s .
Treatment
NSAIDs or da ps one for mi l d ea r di s ea s e
Corti cos teroi ds
Someti mes methotrexa te or other i mmunos uppres s a nts (eg, cycl os pori ne, cycl ophos pha mi de, a za thi opri ne)
Mi l d recurrent ea r di s ea s e ma y res pond to NSAIDs i n a nti -i nfl a mma tory dos es , or da ps one (50 to 100 mg po once/da y). However, mos t pa ti ents a re
trea ted wi th predni s one 30 to 60 mg po once/da y, wi th ta peri ng of the dos e a s s oon a s there i s a cl i ni ca l res pons e. Some pa ti ents requi re chroni c
us e. In s uch pa ti ents , methotrexa te 7.5 to 20 mg po once/wk ca n reduce the requi rement for corti cos teroi ds . Very s evere ca s es ma y requi re other
i mmunos uppres s a nts , s uch a s cycl os pori ne, cycl ophos pha mi de, or a za thi opri ne (s ee p. 337). None of thes e thera pi es ha s been tes ted i n
control l ed tri a l s or ha s been s hown to decrea s e morta l i ty. If tra chea l na rrowi ng ca us es s tri dor, a tra cheos tomy or s tent ma y be needed. More
extens i ve tra cheobronchi a l col l a ps e ma y requi re tra chea l recons tructi on. Eye di s ea s e ma y s ometi mes be reca l ci tra nt to trea tment, es peci a l l y
when i nvol vi ng the s cl era , a nd ca rri es a poor prognos i s .
Al l pa ti ents s houl d be cl os el y moni tored for a theros cl eros i s gi ven the ri s k of prema ture a theros cl eros i s i n s ys temi c va s cul i ti des . Pa ti ents on l ong-
term corti cos teroi d thera py s houl d recei ve os teoporos i s prophyl a xi s .

Sjogren's Syndrome
Sjogren's syndrome (SS) is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the
mouth, eyes, and other mucous membranes due to lymphocytic infiltration of the exocrine gland and secondary gland dysfunction. Sjogren's syndrome can affect
various exocrine glands or other organs. Diagnosis is by specific criteria relating to eye, mouth, and salivary gland involvement, autoantibodies, and (occasionally)
histopathology. Treatment is symptomatic.
SS occurs mos t frequentl y a mong mi ddl e-a ged women. SS i s cl a s s i fi ed a s pri ma ry when there i s no other a s s oci a ted di s ea s e. In a bout 30% of
pa ti ents wi th a utoi mmune di s orders s uch a s RA, SLE, s ys temi c s cl eros i s , mi xed connecti ve ti s s ue di s ea s e, Ha s hi moto's thyroi di ti s , pri ma ry bi l i a ry
ci rrhos i s , or chroni c a utoi mmune hepa ti ti s , SS devel ops a nd, i n s uch ca s es , i s cl a s s i fi ed a s s econda ry. Geneti c a s s oci a ti ons ha ve been found (eg,
HLADR3 a nti gens i n whi tes wi th pri ma ry SS).
Pathophysiology
Sa l i va ry, l a cri ma l , a nd other exocri ne gl a nds become i nfi l tra ted wi th CD4+ T cel l s a nd wi th s ome B cel l s . The T cel l s produce i nfl a mma tory
cytoki nes (eg, IL-2, i nterferon-). Sa l i va ry duct cel l s a l s o produce cytoki nes , eventua l l y da ma gi ng the s ecretory ducts . Atrophy of the s ecretory
epi thel i um of the l a cri ma l gl a nds ca us es des i cca ti on of the cornea a nd conjuncti va (kera toconjuncti vi ti s s i cca s ee p. 592). Lymphocyti c i nfi l tra ti on
a nd i ntra ducta l cel l ul a r prol i fera ti on i n the pa roti d gl a nd ca us e l umi na l na rrowi ng a nd i n s ome ca s es forma ti on of compa ct cel l ul a r s tructures
termed myoepi thel i a l i s l a nds ; a trophy of the gl a nd ca n res ul t. Drynes s a nd GI mucos a l or s ubmucos a l a trophy a nd di ffus e i nfi l tra ti on by pl a s ma
cel l s a nd l ymphocytes ma y ca us e s ymptoms (eg, dys pha gi a ).
Symptoms and Signs
Glandular manifestations: SS often a ffects the eyes or mouth i ni ti a l l y a nd s ometi mes excl us i vel y. Dry eyes ca n ca us e i rri ta ti on a nd photos ens i ti vi ty.
In a dva nced ca s es , the cornea i s s everel y da ma ged, epi thel i a l s tra nds ha ng from the cornea l s urfa ce (kera ti ti s fi l i formi s ), a nd vi s i on ca n be
i mpa i red. Di mi ni s hed s a l i va (xeros tomi a ) res ul ts i n di ffi cul ty chewi ng a nd s wa l l owi ng, s econda ry Candida i nfecti on, tooth deca y, a nd ca l cul i i n the
s a l i va ry ducts . Ta s te a nd s mel l ma y be di mi ni s hed. Drynes s ma y a l s o devel op i n the s ki n a nd i n mucous membra nes of the nos e, throa t, l a rynx,
bronchi , vul va , a nd va gi na . Drynes s of the res pi ra tory tra ct ma y ca us e cough. Al opeci a ma y occur. Pa roti d gl a nds enl a rge i n 33% of pa ti ents a nd a re
us ua l l y fi rm, s mooth, a nd mi l dl y tender. Chroni c s a l i va ry gl a nd enl a rgement i s ra rel y pa i nful unl es s there i s obs tructi on or i nfecti on.
Extraglandular manifestations: Joi nt di s ea s e i n SS i s typi ca l l y noneros i ve a nd nondeformi ng. Arthra l gi a s occur i n a bout 50% of pa ti ents . Arthri ti s
occurs i n a bout 33% of pa ti ents a nd i s s i mi l a r i n di s tri buti on to RA but i s not eros i ve.
Other common extra gl a ndul a r ma ni fes ta ti ons i ncl ude genera l i zed l ympha denopa thy, Ra yna ud's s yndrome, pa renchyma l l ung i nvol vement (whi ch
i s common but i nfrequentl y s eri ous ), a nd va s cul i ti s . Va s cul i ti s ca n occa s i ona l l y a ffect the peri phera l nerves (ca us i ng peri phera l pol yneuropa thy or
mononeuri ti s mul ti pl ex) or CNS or ca us e ra s hes (i ncl udi ng purpura ) a nd gl omerul onephri ti s . Ki dney i nvol vement ca n ca us e rena l tubul a r a ci dos i s ,
i mpa i red concentra ti ng a bi l i ty, ki dney s tones , or i nters ti ti a l nephri ti s . Ps eudol ymphoma , ma l i gna nt l ymphoma , or Wa l dens trom's
ma crogl obul i nemi a ca n devel op; pa ti ents devel op non-Hodgki n l ymphoma a t 40 ti mes the norma l ra te. Chroni c hepa tobi l i a ry di s ea s e a nd
pa ncrea ti ti s (exocri ne pa ncrea ti c ti s s ue i s s i mi l a r to tha t of s a l i va ry gl a nds ) ma y a l s o occur.
Diagnosis
Eye s ymptoms , ora l s ymptoms , a nd eye a nd s a l i va ry gl a nd tes ti ng
Autoa nti bodi es
Someti mes s a l i va ry gl a nd bi ops y
SS s houl d be s us pected i n pa ti ents wi th gri tty or dry eyes or dry mouth, enl a rged s a l i va ry gl a nds , peri phera l neuropa thy, purpura , or unexpl a i ned
rena l tubul a r a ci dos i s . Such pa ti ents s houl d recei ve di a gnos ti c tes ts tha t ca n i ncl ude eva l ua ti on of the eyes a nd s a l i va ry gl a nds a nd s erol ogi c
tes ts . Di fferent cri teri a ha ve been propos ed for cl a s s i fi ca ti on of SS. The l a tes t modi fi ca ti ons to the Ameri ca n-Europea n cl a s s i fi ca ti on cri teri a for SS
were propos ed i n 2002. Thes e cri teri a were not devel oped for us e i n routi ne cl i ni ca l pra cti ce, a nd not every pa ti ent who recei ves a cl i ni ca l
di a gnos i s of SS ful fi l l s the propos ed cri teri a (us ua l l y > 3 of 6 ma ni fes ta ti ons ). The 6 ma ni fes ta ti ons a re eye s ymptoms , ora l s ymptoms , pos i ti ve
eye tes ts , s a l i va ry gl a nd i nvol vement, a utoa nti bodi es , a nd hi s topa thol ogy.
Eye symptoms a re 3 mo of ei ther dry eyes or us e of tea r s ubs ti tutes 3 ti mes /da y; s l i t-l a mp exa mi na ti on ma y a l s o confi rm dry eyes .
Oral symptoms a re > 3 mo of da i l y dry mouth s ens a ti on, da i l y us e of l i qui ds to a i d i n s wa l l owi ng, or s wol l en s a l i va ry gl a nds .
Eye signs i ncl ude eva l ua ti on by Schi rmer's tes t, whi ch mea s ures the qua nti ty of tea rs s ecreted i n 5 mi n a fter i rri ta ti on from a fi l ter pa per s tri p
pl a ced under ea ch l ower eyel i d. A young pers on norma l l y moi s tens 15 mm of ea ch pa per s tri p. Mos t peopl e wi th SS moi s ten < 5 mm, a l though
a bout 15% of tes t res ul ts a re fa l s e-pos i ti ve a nd 15% a re fa l s e-nega ti ve. Ocul a r s ta i ni ng wi th a n eyedrop of ros e benga l or l i s s a mi ne green
s ol uti on i s hi ghl y s peci fi c. Sl i t-l a mp exa mi na ti on s howi ng a fl uores cei n tea r brea kup i n < 10 s ec i s a l s o s ugges ti ve.
Salivary gland involvement ca n be confi rmed by a bnorma l l y l ow s a l i va producti on ( 1.5 mL/15 mi n) a s mea s ured by s a l i va ry fl ow, s i a l ogra phy, or
s a l i va ry s ci nti s ca nni ng, a l though thes e tes ts a re us ed l es s often.
Autoantibodies (s erol ogi c cri teri a ) ha ve l i mi ted s ens i ti vi ty a nd s peci fi ci ty. They i ncl ude a nti bodi es to Ro (SS-A a utoa nti bodi es s ee Sys temi c Lupus
Erythema tos us on p. 305) or to nucl ea r a nti gens (termed La or SS-B a utoa nti bodi es ), a nti nucl ea r a nti bodi es , or a n el eva ted l evel of a nti bodi es
a ga i ns t -gl obul i n. Rheuma toi d fa ctor i s pres ent i n > 70% of pa ti ents . ESR i s el eva ted i n 70%, 33% ha ve a nemi a , a nd up to 25% ha ve l eukopeni a .
Histopathology i s a s s es s ed by bi ops y of mi nor s a l i va ry gl a nds i n the bucca l mucos a . Sa l i va ry gl a nd bi ops y i s us ua l l y res erved for pa ti ents i n whom
the di a gnos i s ca nnot be es ta bl i s hed by a utoa nti body tes ti ng or when a ma jor orga n i s i nvol ved. Hi s topa thol ogi c i nvol vement i s confi rmed i f
l a bi a l mi nor s a l i va ry gl a nds s how mul ti pl e l a rge foci of l ymphocytes wi th a trophy of a ci na r ti s s ue.
Mos t common ca us es of dry eyes a nd dry mouth (s i cca s ymptoms ) a re a gi ng a nd drugs , but when pa roti d enl a rgement occurs i n a ddi ti on to s i cca
s ymptoms , di s ea s es s uch a s hepa ti ti s C, HIV, bul i mi a , a nd s a rcoi dos i s s houl d be di fferenti a ted from SS.
Prognosis
SS i s chroni c, a nd dea th ma y occa s i ona l l y res ul t from pul mona ry i nfecti on a nd, ra rel y, from rena l fa i l ure or l ymphoma . As s oci a ted s ys temi c
a utoi mmune di s orders ma y di cta te prognos i s .
Treatment
Symptoma ti c trea tment for s i cca s ymptoms
Avoi da nce of a ggra va ti ng fa ctors
Occa s i ona l l y ora l corti cos teroi ds or cycl ophos pha mi de
SS s houl d be i ni ti a l l y ma na ged by topi ca l thera py of dry eyes a nd dry mouth. Other s ys temi c ma ni fes ta ti ons of SS s houl d be trea ted dependi ng on
the s everi ty a nd the i nvol ved orga n. Recogni ti on of thera pi es for other condi ti ons tha t ca n exa cerba te drynes s compl a i nts i s cruci a l .
Hydroxychl oroqui ne 200 to 400 mg po once/da y i s us ua l l y gi ven to ha l t the progres s i on of the di s ea s e a nd for the trea tment of a rthra l gi a s .
Dry eyes s houl d be trea ted wi th l ubri ca ti ng eye prepa ra ti ons (i ni ti a l l y drops s uch a s hypromel l os e or methyl cel l ul os e a nd a n OTC oi ntment a t
bedti me). Other trea tments i ncl ude dra i na ge (puncta l ) duct cl os ure a nd topi ca l cycl os pori ne. Ski n a nd va gi na l drynes s ca n be trea ted wi th
l ubri ca nts .
Mouth drynes s ma y be a voi ded by s i ppi ng fl ui ds throughout the da y, chewi ng s uga rl es s gum, a nd us i ng a s a l i va s ubs ti tute conta i ni ng
ca rboxymethyl cel l ul os e a s a mouthwa s h. Drugs tha t decrea s e s a l i va ry s ecreti on (eg, a nti hi s ta mi nes , a nti depres s a nts , other a nti chol i nergi cs )
s houl d be a voi ded. Fa s ti di ous ora l hygi ene a nd regul a r denta l vi s i ts a re es s enti a l . Stones mus t be promptl y removed, pres ervi ng vi a bl e s a l i va ry
ti s s ue. The pa i n of s uddenl y enl a rged s a l i va ry gl a nds i s genera l l y bes t trea ted wi th wa rm compres s es a nd a na l ges i cs . Pi l oca rpi ne 5 mg po ti d to
qi d or cevi mel i ne HCl 30 mg po ti d ca n s ti mul a te s a l i va ry producti on but s houl d be a voi ded i n pa ti ents wi th bronchos pa s m a nd cl os ed-a ngl e
gl a ucoma .
Aggres s i ve s ys temi c trea tment i s occa s i ona l l y i ndi ca ted. It i s us ua l l y res erved for pa ti ents wi th a s s oci a ted di s ea s es (eg, s evere va s cul i ti s or
vi s cera l i nvol vement); corti cos teroi ds (eg, predni s one 1 mg/kg po once/da y) or cycl ophos pha mi de 5 mg/kg po once/da y ma y be us ed.
Systemic Lupus Erythematosus
(Di s s emi na ted Lupus Erythema tos us )
Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women.
Common manifestations may include arthralgias and arthritis; malar and other skin rashes; pleuritis or pericarditis; renal or CNS involvement; and hematologic
cytopenias. Diagnosis requires clinical and serologic criteria. Treatment of severe ongoing active disease requires corticosteroids, often hydroxychloroquine, and
sometimes immunosuppressants.
Of a l l ca s es , 70 to 90% occur i n women (us ua l l y of chi l d-bea ri ng a ge). SLE i s more common a mong bl a cks a nd As i a ns tha n whi tes . It ca n a ffect
pa ti ents of a ny a ge, i ncl udi ng neona tes . Increa s ed a wa renes s of mi l d forms ha s res ul ted i n a worl dwi de ri s e i n reported ca s es . In s ome
countri es , the preva l ence of SLE ri va l s tha t of RA. SLE ma y be preci pi ta ted by currentl y unknown envi ronmenta l tri ggers tha t ca us e a utoi mmune
rea cti ons i n geneti ca l l y predi s pos ed peopl e. Some drugs (eg, hydra l a zi ne, proca i na mi de, i s oni a zi d) ca us e a revers i bl e l upus -l i ke s yndrome.
Symptoms and Signs
Cl i ni ca l fi ndi ngs va ry grea tl y. SLE ma y devel op a bruptl y wi th fever or i ns i di ous l y over months or yea rs wi th epi s odes of a rthra l gi a s a nd ma l a i s e.
Va s cul a r hea da ches , epi l eps y, or ps ychos es ma y be i ni ti a l fi ndi ngs . Ma ni fes ta ti ons refera bl e to a ny orga n s ys tem ma y a ppea r. Peri odi c
exa cerba ti ons (fl a res ) ma y occur.
Joint manifestations: Joi nt s ymptoms , ra ngi ng from i ntermi ttent a rthra l gi a s to a cute pol ya rthri ti s , occur i n a bout 90% of pa ti ents a nd ma y precede
other ma ni fes ta ti ons by yea rs . Mos t l upus pol ya rthri ti s i s nondes tructi ve a nd nondeformi ng. However, i n l ong-s ta ndi ng di s ea s e, deformi ti es
wi thout bone eros i ons ma y devel op (eg, the meta ca rpopha l a ngea l a nd i nterpha l a ngea l joi nts ma y ra rel y devel op ul na r dri ft or s wa n-neck
deformi ti es wi thout bony or ca rti l a gi nous eros i ons [Ja ccoud's a rthri ti s ]).
Skin and mucous membrane manifestations (s ee a l s o p. 309): Ski n l es i ons i ncl ude ma l a r butterfl y erythema (fl a t or ra i s ed) tha t genera l l y s pa res the
na s ol a bi a l fol ds . The a bs ence of pa pul es a nd pus tul es hel ps di s ti ngui s h SLE from ros a cea . A va ri ety of other erythema tous , fi rm, ma cul opa pul a r
l es i ons ca n occur el s ewhere, i ncl udi ng expos ed a rea s of the fa ce a nd neck, upper ches t, a nd el bows . Ski n bl i s teri ng a nd ul cera ti on a re ra re,
a l though recurrent ul cers on mucous membra nes (pa rti cul a rl y the centra l porti on of the ha rd pa l a te nea r the juncti on of the ha rd a nd s oft pa l a te,
the bucca l a nd gum mucos a , a nd the a nteri or na s a l s eptum) a re common. Genera l i zed or foca l a l opeci a i s common duri ng a cti ve pha s es of SLE.
Pa nni cul i ti s ca n ca us e s ubcuta neous nodul a r l es i ons . Va s cul i ti c s ki n l es i ons ma y i ncl ude mottl ed erythema on the pa l ms a nd fi ngers , peri ungua l
erythema , na i l -fol d i nfa rcts , urti ca ri a , a nd pa l pa bl e purpura . Petechi a e ma y devel op s econda ry to thrombocytopeni a . Photos ens i ti vi ty occurs i n
mos t pa ti ents .
Cardiopulmonary manifestations: Ca rdi opul mona ry s ymptoms commonl y i ncl ude recurrent pl euri s y, wi th or wi thout pl eura l effus i on. Pneumoni ti s i s
ra re, a l though mi nor i mpa i rments i n pul mona ry functi on a re common. Severe pul mona ry hemorrha ge occa s i ona l l y occurs . Prognos i s ha s
tra di ti ona l l y been poor but s eems to be i mprovi ng, pos s i bl y beca us e of better ea rl y, a ggres s i ve, cri ti ca l ca re. Other compl i ca ti ons i ncl ude
pul mona ry embol i , pul mona ry hypertens i on, a nd s hri nki ng l ung s yndrome. Ca rdi a c compl i ca ti ons i ncl ude peri ca rdi ti s (mos t commonl y),
peri ca rdi a l effus i on, a nd myoca rdi ti s . Seri ous , ra re compl i ca ti ons a re corona ry a rtery va s cul i ti s , va l vul a r i nvol vement, a nd Li bma n-Sa cks
endoca rdi ti s . Accel era ted a theros cl eros i s i s a n i ncrea s i ng ca us e of morbi di ty a nd morta l i ty. Congeni ta l hea rt bl ock ca n devel op i n neona tes .
Adenopathy and splenic manifestations: Genera l i zed a denopa thy i s common, pa rti cul a rl y a mong chi l dren, young a dul ts , a nd bl a cks . Spl enomega l y
occurs i n 10% of pa ti ents . The s pl een ma y devel op peri a rteri a l fi bros i s .
Neurologic manifestations: Neurol ogi c s ymptoms ca n res ul t from i nvol vement of a ny pa rt of the centra l or peri phera l nervous s ys tem or meni nges .
Mi l d cogni ti ve i mpa i rment i s common. There ma y a l s o be hea da ches , pers ona l i ty cha nges , i s chemi c s troke, s uba ra chnoi d hemorrha ge, s ei zures ,
ps ychos es , orga ni c bra i n s yndrome, a s epti c meni ngi ti s , peri phera l neuropa thi es , tra ns vers e myel i ti s , or cerebel l a r dys functi on.
Renal manifestations: Rena l i nvol vement ca n devel op a t a ny ti me a nd ma y be the onl y ma ni fes ta ti on of SLE. It ma y be beni gn a nd a s ymptoma ti c or
progres s i ve a nd fa ta l . Rena l l es i ons ca n ra nge i n s everi ty from a foca l , us ua l l y beni gn, gl omerul i ti s to a di ffus e, potenti a l l y fa ta l ,
membra noprol i fera ti ve gl omerul onephri ti s . Common ma ni fes ta ti ons i ncl ude protei nuri a (mos t often), a n a bnorma l uri na ry s edi ment ma ni fes ted
by RBC ca s ts a nd l eukocytes , hypertens i on, a nd edema .
Obstetric manifestations: Obs tetri c ma ni fes ta ti ons i ncl ude ea rl y a nd l a te feta l l os s . In pa ti ents wi th a nti phos phol i pi d a nti bodi es , the ri s k of
recurrent mi s ca rri a ges i s i ncrea s ed. Pregna ncy ca n be s ucces s ful (s ee p. 2636), pa rti cul a rl y a fter 6 to 12 mo of remi s s i on, but SLE fl a res a re common
duri ng pregna ncy. Pregna ncy s houl d be ti med for when di s ea s e i s i n remi s s i on. Duri ng pregna ncy, the pa ti ent s houl d be moni tored cl os el y for a ny
di s ea s e fl a re or thromboti c events by a mul ti di s ci pl i na ry tea m tha t i ncl udes a rheuma tol ogi s t, a n obs tetri ci a n who s peci a l i zes i n hi gh-ri s k
pregna nci es , a nd a hema tol ogi s t.
Hematologic manifestations: Hema tol ogi c ma ni fes ta ti ons i ncl ude a nemi a (often a utoi mmune hemol yti c), l eukopeni a (us ua l l y l ymphopeni a , wi th <
1500 cel l s /L,), a nd thrombocytopeni a (s ometi mes l i fe-threa teni ng a utoi mmune thrombocytopeni a ). Recurrent a rteri a l or venous thrombos i s ,
thrombocytopeni a , a nd a hi gh proba bi l i ty of obs tetri c compl i ca ti ons occur i n pa ti ents wi th a nti phos phol i pi d a nti bodi es . Thrombos es proba bl y
a ccount for ma ny of the compl i ca ti ons of SLE, i ncl udi ng obs tetri c compl i ca ti ons .
GI manifestations: GI ma ni fes ta ti ons ca n res ul t from bowel va s cul i ti s or i mpa i red bowel moti l i ty. In a ddi ti on, pa ncrea ti ti s ca n res ul t from SLE or
from i ts trea tment wi th corti cos teroi ds or a za thi opri ne. Ma ni fes ta ti ons ma y i ncl ude a bdomi na l pa i n from s eros i ti s , na us ea , vomi ti ng,
ma ni fes ta ti ons of bowel perfora ti on, a nd ps eudo-obs tructi on. SLE ra rel y ca us es pa renchyma l l i ver di s ea s e.
Diagnosis
Cytopeni a s
Autoa nti bodi es
SLE s houl d be s us pected i n pa ti ents , pa rti cul a rl y young women, wi th a ny of the s ymptoms a nd s i gns . However, ea rl y-s ta ge SLE ca n mi mi c other
connecti ve (or nonconnecti ve) ti s s ue di s orders , i ncl udi ng RA i f a rthri ti c s ymptoms predomi na te. Mi xed connecti ve ti s s ue di s ea s e ca n mi mi c SLE but
a l s o ma y i nvol ve fea tures of s ys temi c s cl eros i s , rheuma toi d-l i ke pol ya rthri ti s , a nd pol ymyos i ti s or derma tomyos i ti s . Infecti ons (eg, ba cteri a l
endoca rdi ti s , hi s topl a s mos i s ) ca n mi mi c SLE a nd ma y devel op a s a res ul t of trea tment-ca us ed i mmunos uppres s i on. Di s orders s uch a s s a rcoi dos i s
a nd pa ra neopl a s ti c s yndromes ca n a l s o mi mi c SLE.
La bora tory tes ti ng di fferenti a tes SLE from other connecti ve ti s s ue di s orders . Routi ne tes ti ng s houl d i ncl ude the fol l owi ng:
Anti nucl ea r a nti bodi es (ANA)
CBC
Uri na l ys i s
Chemi s try profi l e i ncl udi ng rena l a nd l i ver enzymes
The di a gnos i s i s es peci a l l y l i kel y i f 4 of the cri teri a i n
Ta bl e 33-1 a re pres ent a t a ny ti me but i s s ti l l pos s i bl e i f < 4 cri teri a a re pres ent. If the di a gnos i s i s s us pected but not es ta bl i s hed, a ddi ti ona l
tes ti ng for a utoa nti bodi es ca n be us eful . Es ta bl i s hi ng the di a gnos i s ma y requi re repea ted eva l ua ti ons over months or yea rs .
Fluorescent ANA: The fl uores cent tes t for ANA i s the bes t s creen for SLE; pos i ti ve ANA tes ts (us ua l l y i n hi gh ti ter: > 1:80) occur i n > 98%. However,
pos i ti ve ANA tes ts ca n a l s o occur i n RA, other connecti ve ti s s ue di s orders , ca ncers , a nd even i n the genera l popul a ti on. The fa l s e-pos i ti ve ra te
va ri es from a bout 3% for ANA ti ters of 1:320 to a bout 30% for ANA ti ters of 1:40 a mong hea l thy control s . Drugs s uch a s hydra l a zi ne, proca i na mi de,
a nd tumor necros i s fa ctor (TNF)- a nta goni s ts ca n produce pos i ti ve ANA res ul ts a s wel l a s a l upus -l i ke s yndrome; the ANA eventua l l y becomes
nega ti ve i f the drug i s s topped. Pos i ti ve ANA s houl d prompt more s peci fi c tes ti ng s uch a s a nti -doubl e-s tra nded DNA a nti bodi es ; hi gh ti ters a re
hi ghl y s peci fi c for SLE but occur i n onl y 25 to 30% of peopl e wi th SLE.
Other ANA and anticytoplasmic antibodies: The ANA tes t i s very s ens i ti ve, but i t i s not s peci fi c for SLE; thus , evi dence of other a utoa nti bodi es i s
needed to es ta bl i s h the di a gnos i s . They i ncl ude Ro [SSA], La [SSB], Smi th [Sm], ri bonucl eoprotei n [RNP], a nd doubl e-s tra nded DNA. Ro i s
predomi na ntl y cytopl a s mi c; a nti -Ro a nti bodi es a re occa s i ona l l y pres ent i n ANA-nega ti ve SLE pa ti ents pres enti ng wi th chroni c cuta neous l upus .
Anti -Ro i s the ca us a l a nti body for neona ta l l upus a nd congeni ta l hea rt bl ock. Anti -Sm i s hi ghl y s peci fi c for SLE but, l i ke a nti -doubl e-s tra nded DNA,
i s not s ens i ti ve. Anti -RNP occurs i n pa ti ents wi th SLE, mi xed connecti ve ti s s ue di s ea s e, a nd occa s i ona l l y other s ys temi c a utoi mmune di s orders a nd
s ys temi c s cl eros i s .
[Table 33-1. Cri teri a for the Cl a s s i fi ca ti on of SLE*]
Other blood tests: Leukopeni a (us ua l l y l ymphopeni a ) i s common. Hemol yti c a nemi a ma y occur. Thrombocytopeni a i n SLE ma y be di ffi cul t or
i mpos s i bl e to di fferenti a te from i di opa thi c thrombocytopeni c purpura except tha t pa ti ents ha ve other fea tures of SLE. Fa l s e-pos i ti ve s erol ogi c
tes ts for s yphi l i s occur i n 5 to 10% of SLE pa ti ents . Thes e tes t res ul ts ma y be a s s oci a ted wi th the l upus a nti coa gul a nt a nd a prol onged PTT.
Abnorma l va l ues i n one or more of thes e a s s a ys s ugges t the pres ence of a nti phos phol i pi d a nti bodi es (eg, a nti ca rdi ol i pi n a nti bodi es ), whi ch
s houl d then be mea s ured di rectl y by enzyme-l i nked i mmunos orbent a s s a y (ELISA). Anti phos phol i pi d a nti bodi es a re a s s oci a ted wi th a rteri a l or
venous thrombos i s , thrombocytopeni a , a nd, duri ng pregna ncy, s ponta neous a borti on or l a te feta l dea th but ma y be pres ent i n a s ymptoma ti c
pa ti ents .
Other tes ts hel p moni tor di s ea s e s everi ty a nd determi ne the need for trea tment. Serum compl ement l evel s (C3, C4) a re often depres s ed i n a cti ve
di s ea s e a nd a re us ua l l y l owes t i n pa ti ents wi th a cti ve nephri ti s . ESR i s el eva ted frequentl y duri ng a cti ve di s ea s e. C-rea cti ve protei n l evel s a re not
neces s a ri l y el eva ted.
Renal involvement: Screeni ng for rena l i nvol vement begi ns wi th uri na l ys i s . RBC a nd WBC ca s ts s ugges t a cti ve nephri ti s . Uri na l ys i s s houl d be done
a t regul a r i nterva l s , even for pa ti ents i n a ppa rent remi s s i on, beca us e ki dney di s ea s e ma y be a s ymptoma ti c. Rena l bi ops y i s us ua l l y not neces s a ry
for di a gnos i s of SLE or to confi rm rena l i nvol vement but i s hel pful i n eva l ua ti ng the s ta tus of rena l di s ea s e (i e, a cti ve i nfl a mma ti on vs
pos ti nfl a mma tory s ca rri ng) a nd gui de thera py. Pa ti ents wi th chroni c rena l i ns uffi ci ency a nd mos tl y s cl eroti c gl omerul i a re not l i kel y to benefi t
from a ggres s i ve i mmunos uppres s i ve thera py.
Prognosis
The cours e i s us ua l l y chroni c, rel a ps i ng, a nd unpredi cta bl e. Remi s s i ons ma y l a s t for yea rs . If the i ni ti a l a cute pha s e i s control l ed, even i f very
s evere (eg, wi th cerebra l thrombos i s or s evere nephri ti s ), the l ong-term prognos i s i s us ua l l y good. The 10-yr s urvi va l i n mos t devel oped countri es
i s > 95%. Improved prognos i s i s i n pa rt due to ea rl i er di a gnos i s a nd more effecti ve thera pi es . More s evere di s ea s e requi res more toxi c thera pi es ,
whi ch i ncrea s e ri s k of morta l i ty. Exa mpl es of s uch compl i ca ti ons i ncl ude i nfecti on from i mmunos uppres s i on or os teoporos i s from l ong-term
corti cos teroi d us e. Increa s ed ri s k of corona ry a rtery di s ea s e ca n contri bute to prema ture dea th.
Treatment
NSAIDs a nd often a nti ma l a ri a l s for mi l d di s ea s e
Corti cos teroi ds a nd often i mmunos uppres s a nts for s evere di s ea s e
To s i mpl i fy thera py, SLE s houl d be cl a s s i fi ed a s mi l d (eg, fever, a rthri ti s , pl euri s y, peri ca rdi ti s , hea da che, ra s h) or s evere (eg, hemol yti c a nemi a ,
thrombocytopeni c purpura , ma s s i ve pl eura l a nd peri ca rdi a l i nvol vement, s i gni fi ca nt rena l da ma ge, a cute va s cul i ti s of the extremi ti es or GI tra ct,
fl ori d CNS i nvol vement).
Mild or remittent disease: Li ttl e or no thera py ma y be needed. Arthra l gi a s a re us ua l l y control l ed wi th NSAIDs . Anti ma l a ri a l s hel p, pa rti cul a rl y when
joi nt a nd s ki n ma ni fes ta ti ons a re promi nent. Hydroxychl oroqui ne 200 mg po once/da y or bi d reduces the frequency of SLE fl a res . Al terna ti ves
i ncl ude chl oroqui ne 250 mg po once/da y a nd qui na cri ne 50 to 100 mg po once/da y. Hydroxychl oroqui ne ca n ra rel y ca us e reti na l toxi ci ty. The eyes
s houl d be exa mi ned a t 12-mo i nterva l s .
Severe disease: Corti cos teroi ds a re fi rs t-l i ne thera py. A combi na ti on of predni s one a nd i mmunos uppres s a nts i s recommended i n a cti ve, s eri ous
CNS l upus , va s cul i ti s es peci a l l y a ffecti ng vi s cera or nerves , or a cti ve l upus nephri ti s . Predni s one i s us ua l l y gi ven i n dos es of 40 to 60 mg po
once/da y, but the dos e ma y va ry a ccordi ng to the ma ni fes ta ti on of SLE. Ora l a za thi opri ne 1 to 2.5 mg/kg once/da y or ora l cycl ophos pha mi de 1 to 4
mg/kg once/da y ca n be us ed a s a n i mmunos uppres s a nt. For rena l i nvol vement, cycl ophos pha mi de i s us ua l l y gi ven i n i ntermi ttent IV pul s es
i ns tea d of da i l y ora l dos es ; eg, a bout 500 mg to 1 g/m 2 IV (together wi th mes na a nd fl ui d l oa di ng to protect the bl a dder) monthl y for 6 mo a nd then
once q 3 mo for 18 mo (l es s frequentl y i f there i s rena l or hema tol ogi c toxi ci tys ee
Ta bl e 33-2).
In CNS l upus or other cri ti ca l cri s es , methyl predni s ol one 1 g by s l ow (1-h) IV i nfus i on on 3 s ucces s i ve da ys i s often the i ni ti a l trea tment, fol l owed
by IV cycl ophos pha mi de, a s menti oned previ ous l y. Mycophenol a te mofeti l i s a n a l terna ti ve to cycl ophos pha mi de thera py for pa ti ents wi th a cti ve
ki dney di s ea s e who ha ve pres erved ki dney functi on. IgG 400 mg/kg IV once/da y for 5 cons ecuti ve da ys ma y be us eful for refra ctory
thrombocytopeni a . Pa ti ents
[Table 33-2. Protocol for Chemothera py wi th Cycl ophos pha mi de a nd IV Mes na ]
wi th end-s ta ge rena l di s ea s e ca n undergo ki dney tra ns pl a nta ti on, a s a n a l terna ti ve to di a l ys i s , wi th a s ucces s ful outcome, es peci a l l y i f thei r
di s ea s e ha s been i n remi s s i on.
Improvement of s evere SLE often ta kes 4 to 12 wk. Thrombos i s or embol i s m of cerebra l , pul mona ry, or pl a centa l ves s el s requi res s hort-term
trea tment wi th hepa ri n a nd l onger trea tment wi th wa rfa ri n, i f the di a gnos i s of a nti phos phol i pi d s yndrome i s confi rmed. The ta rget INR i s us ua l l y
3.
Suppressive therapy: For mos t pa ti ents , the ri s k of fl a res ca n be decrea s ed wi thout prol onged hi gh-dos e corti cos teroi ds . Chroni c di s ea s e s houl d be
trea ted wi th the l owes t dos e of corti cos teroi ds a nd other drugs tha t control i nfl a mma ti on (eg, a nti ma l a ri a l s , l ow-dos e i mmunos uppres s a nts ).
Trea tment s houl d be gui ded by cl i ni ca l fea tures pri ma ri l y, a l though a nti -doubl e-s tra nded DNA a nti body ti ters or s erum compl ement l evel s ma y be
fol l owed. Other perti nent bl ood a nd uri ne tes ts ma y be us ed to a s s es s s peci fi c orga n i nvol vement. Anti -doubl e-s tra nded DNA a nti body ti ters or
s erum compl ement l evel s ma y not pa ra l l el nonrena l di s ea s e fl a res . If a pa ti ent needs l ong-term hi gh-dos e corti cos teroi ds , a l terna ti ve ora l
i mmunos uppres s a nts s houl d be cons i dered. Ca , vi ta mi n D, a nd bi s phos phona te thera py s houl d be cons i dered i n pa ti ents ta ki ng corti cos teroi ds
l ong term.
Focal complications and coexisting medical conditions: Al l pa ti ents s houl d be cl os el y moni tored for a theros cl eros i s . Long-term a nti coa gul a ti on i s vi ta l
i n pa ti ents wi th a nti phos phol i pi d a nti bodi es a nd recurrent thrombos i s (s ee p. 2228).
If a pregna nt pa ti ent ha s a nti phos phol i pi d a nti bodi es , thromboti c compl i ca ti ons ca n be l i mi ted wi th corti cos teroi ds (predni s one 30 mg po
once/da y), l ow-dos e a s pi ri n, or a nti coa gul a ti on wi th hepa ri n. Da i l y hepa ri n gi ven s ubcuta neous l y wi th or wi thout one ba by a s pi ri n throughout the
2nd a nd 3rd tri mes ters ma y be the mos t s ucces s ful prophyl a cti c mea s ure.
Variant Forms of Lupus
Discoid lupus erythematosus (DLE): DLE, a l s o s ometi mes ca l l ed chroni c cuta neous l upus erythema tos us , i s a s et of s ki n cha nges tha t ca n occur a s
pa rt of l upus , wi th or wi thout s ys temi c i nvol vement. Ski n l es i ons begi n a s erythema tous pl a ques a nd progres s to a trophi c s ca rs . They cl us ter i n
l i ght-expos ed a rea s of the s ki n, s uch a s the fa ce, s ca l p, a nd ea rs . Untrea ted, l es i ons extend a nd devel op centra l a trophy a nd s ca rri ng. There ma y
be wi des prea d s ca rri ng a l opeci a . Mucous membra ne i nvol vement ma y be promi nent, es peci a l l y i n the mouth.
Pa ti ents pres enti ng wi th typi ca l di s coi d l es i ons s houl d be eva l ua ted for SLE. Anti bodi es a ga i ns t doubl e-s tra nded DNA a re a l mos t i nva ri a bl y
a bs ent i n DLE. Al though i t does not di fferenti a te DLE from SLE, bi ops y ca n rul e out other di s orders (eg, l ymphoma or s a rcoi dos i s ). Bi ops y s houl d be
done from the a cti ve ma rgi n of a s ki n l es i on.
Ea rl y trea tment ca n prevent perma nent a trophy. Expos ure to s unl i ght or ul tra vi ol et l i ght s houl d be mi ni mi zed (eg, us i ng potent s uns creens when
outdoors ). Topi ca l corti cos teroi d oi ntments (pa rti cul a rl y for dry s ki n) or crea ms (l es s grea s y tha n oi ntments ) ti d to qi d (eg, tri a mci nol one
a cetoni de 0.1 or 0.5%, fl uoci nol one 0.025 or 0.2%, fl ura ndrenol i de 0.05%, beta metha s one va l era te 0.1%, a nd, pa rti cul a rl y beta metha s one
di propi ona te 0.05%) us ua l l y ca us e i nvol uti on of s ma l l l es i ons ; they s houl d not be us ed exces s i vel y or on the fa ce (where they ca us e s ki n a trophy).
Res i s ta nt l es i ons ca n be covered wi th pl a s ti c ta pe coa ted wi th fl ura ndrenol i de. Al terna ti vel y, i ntra derma l i njecti on wi th tri a mci nol one a cetoni de
0.1% s us pens i on (< 0.1 mL per s i te) ma y res ol ve l es i ons , but s econda ry a trophy frequentl y fol l ows . Anti ma l a ri a l s (eg, hydroxychl oroqui ne 200 mg po
once/da y or bi d) ca n hel p, i ncl udi ng for fa ci a l l es i ons . In res i s ta nt ca s es , combi na ti ons (eg, hydroxychl oroqui ne 200 mg/da y pl us qui na cri ne 50 to
100 mg po once/da y) ma y be requi red for months to yea rs .
Subacute cutaneous lupus erythematosus (SCLE): SCLE i s a va ri a nt form of SLE i n whi ch s ki n i nvol vement i s promi nent. Pa ti ents wi th SCLE devel op
extens i ve recurri ng ra s hes . Annul a r or pa pul os qua mous l es i ons ma y devel op on the fa ce, a rms , a nd trunk. Les i ons a re us ua l l y photos ens i ti ve a nd
ca n devel op hypopi gmenta ti on but ra rel y s ca r. Arthri ti s a nd fa ti gue a re common i n SCLE, but neurol ogi c a nd rena l ma ni fes ta ti ons a re not. Pa ti ents
ma y be ANA-pos i ti ve or ANA-nega ti ve. Mos t ha ve a nti bodi es to Ro (SSA). Infa nts whos e mothers ha ve Ro a nti bodi es ma y ha ve congeni ta l SCLE or
congeni ta l hea rt bl ock. SCLE s houl d be trea ted s i mi l a rl y to SLE.
Systemic Sclerosis
(Scl eroderma )
Systemic sclerosis (SSc) is a rare chronic disease of unknown cause characterized by diffuse fibrosis, degenerative changes, and vascular abnormalities in the
skin, joints, and internal organs (especially the esophagus, lower GI tract, lungs, heart, and kidneys). Common symptoms include Raynaud's syndrome,
polyarthralgia, dysphagia, heartburn, and swelling and eventually skin tightening and contractures of the fingers. Lung, heart, and kidney involvement accounts
for most deaths. Diagnosis is clinical, but laboratory tests help with confirmation. Specific treatment is difficult, and emphasis is often on treatment of
complications.
SSc i s a bout 4 ti mes more common a mong women tha n men. It i s mos t common a mong peopl e a ged 20 to 50 a nd i s ra re i n chi l dren. SSc ca n
devel op a s pa rt of mi xed connecti ve ti s s ue di s ea s e.
Etiology
Immunol ogi c mecha ni s ms a nd heredi ty (certa i n HLA s ubtypes ) pl a y a rol e i n eti ol ogy. SSc-l i ke s yndromes ca n res ul t from expos ure to vi nyl
chl ori de, bl eomyci n, penta zoci ne, epoxy a nd a roma ti c hydroca rbons , conta mi na ted ra pes eed oi l , or L-tryptopha n.
Pathophysiology
Pa thophys i ol ogy i nvol ves va s cul a r da ma ge a nd a cti va ti on of fi brobl a s ts ; col l a gen a nd other extra cel l ul a r protei ns i n va ri ous ti s s ues a re
overproduced.
In SSc, the s ki n devel ops more compa ct col l a gen fi bers i n the reti cul a r dermi s , epi derma l thi nni ng, l os s of rete pegs , a nd a trophy of derma l
a ppenda ges . T cel l s ma y a ccumul a te, a nd extens i ve fi bros i s i n the derma l a nd s ubcuta neous l a yers devel ops . In the na i l fol ds , ca pi l l a ry l oops
di l a te a nd s ome mi crova s cul a r l oops a re l os t. In the extremi ti es , chroni c i nfl a mma ti on a nd fi bros i s of the s ynovi a l membra ne a nd s urfa ces a nd
peri a rti cul a r s oft ti s s ues occur.
Es opha gea l moti l i ty becomes i mpa i red, a nd the l ower es opha gea l s phi ncter becomes i ncompetent; ga s troes opha gea l refl ux a nd s econda ry
s tri ctures ca n devel op. The i ntes ti na l mus cul a ri s mucos a degenera tes , l ea di ng to ps eudodi verti cul a i n the col on a nd i l eum. Inters ti ti a l a nd
peri bronchi a l fi bros i s or i nti ma l hyperpl a s i a of s ma l l pul mona ry a rteri es ca n devel op; i f l ong-s ta ndi ng, pul mona ry hypertens i on ca n res ul t.
Di ffus e myoca rdi a l fi bros i s or ca rdi a c conducti on a bnorma l i ti es occur. Inti ma l hyperpl a s i a of i nterl obul a r a nd a rcua te a rteri es ca n devel op wi thi n
the ki dneys , ca us i ng rena l i s chemi a a nd hypertens i on.
SSc va ri es i n s everi ty a nd progres s i on, ra ngi ng from genera l i zed s ki n thi ckeni ng wi th ra pi dl y progres s i ve a nd often fa ta l vi s cera l i nvol vement (SSc
wi th di ffus e s cl eroderma ) to i s ol a ted s ki n i nvol vement (often jus t the fi ngers a nd fa ce) a nd s l ow progres s i on (often s evera l deca des ) before
vi s cera l di s ea s e devel ops . The l a tter form i s termed l i mi ted cuta neous s cl eroderma or CREST s yndrome (ca l ci nos i s cuti s , Ra yna ud's s yndrome,
es opha gea l dys moti l i ty, s cl eroda ctyl y, tel a ngi ecta s i a s ). In a ddi ti on, SSc ca n overl a p wi th other a utoi mmune rheuma ti c di s orders eg,
s cl eroderma tomyos i ti s (ti ght s ki n a nd mus cl e wea knes s i ndi s ti ngui s ha bl e from pol ymyos i ti s ) a nd mi xed connecti ve ti s s ue di s ea s e.
Symptoms and Signs
The mos t common i ni ti a l s ymptoms a nd s i gns a re Ra yna ud's s yndrome a nd i ns i di ous s wel l i ng of the di s ta l extremi ti es wi th gra dua l thi ckeni ng of
the s ki n of the fi ngers . Pol ya rthra l gi a i s a l s o promi nent. GI di s turba nces (eg, hea rtburn, dys pha gi a ) or res pi ra tory compl a i nts (eg, dys pnea ) a re
occa s i ona l l y the fi rs t ma ni fes ta ti ons .
Skin and nail manifestations: Swel l i ng of the s ki n i s us ua l l y s ymmetri c a nd progres s es to i ndura ti on. It ma y be confi ned to the fi ngers (s cl eroda ctyl y)
a nd ha nds , or i t ma y a ffect mos t or a l l of the body. The s ki n eventua l l y becomes ta ut, s hi ny, a nd hypopi gmented or hyperpi gmented; the fa ce
becomes ma s kl i ke; a nd tel a ngi ecta s es ma y a ppea r on the fi ngers , ches t, fa ce, l i ps , a nd tongue. Subcuta neous ca l ci fi ca ti ons ma y devel op, us ua l l y
on the fi ngerti ps (pul ps ) a nd over bony emi nences . Trophi c ul cers a re common, es peci a l l y on the fi ngerti ps , overl yi ng the fi nger joi nts , or over
ca l ci noti c nodul es . Abnorma l ca pi l l a ry a nd mi crova s cul a r l oops i n the na i l s ca n be s een wi th a n ophtha l mos cope or di s s ecti ng mi cros cope.
Joint manifestations: Pol ya rthra l gi a s or mi l d a rthri ti s ca n be promi nent. Fl exi on contra ctures ma y devel op i n the fi ngers , wri s ts , a nd el bows . Fri cti on
rubs ma y devel op over the joi nts , tendon s hea ths , a nd l a rge burs a e.
GI manifestations: Es opha gea l dys functi on i s the mos t frequent vi s cera l di s turba nce a nd occurs i n mos t pa ti ents . Dys pha gi a (us ua l l y retros terna l )
us ua l l y devel ops fi rs t. Aci d refl ux ca n ca us e hea rtburn a nd s tri cture. Ba rrett's es opha gus occurs i n one thi rd of pa ti ents a nd predi s pos es to
compl i ca ti ons (eg, s tri cture, a denoca rci noma ). Hypomoti l i ty of the s ma l l bowel ca us es a na erobi c ba cteri a l overgrowth tha t ca n l ea d to
ma l a bs orpti on. Ai r ma y penetra te the da ma ged bowel wa l l a nd be vi s i bl e on x-ra ys (pneuma tos i s i ntes ti na l i s ). Lea ka ge of bowel contents i nto
the peri tonea l ca vi ty ca n ca us e peri toni ti s . Di s ti ncti ve wi de-mouthed di verti cul a ca n devel op i n the col on. Bi l i a ry ci rrhos i s ma y devel op i n
pa ti ents wi th CREST s yndrome.
Cardiopulmonary manifestations: Lung i nvol vement genera l l y progres s es i ndol entl y, wi th s ubs ta nti a l i ndi vi dua l va ri a bi l i ty, but i s a common ca us e of
dea th. Lung fi bros i s ca n i mpa i r ga s excha nge, l ea di ng to exerti ona l dys pnea a nd res tri cti ve di s ea s e wi th eventua l res pi ra tory fa i l ure. Acute
a l veol i ti s (potenti a l l y res pons i ve to thera py) ca n devel op. Es opha gea l dys functi on ca n l ea d to a s pi ra ti on pneumoni a . Pul mona ry hypertens i on
ma y devel op, a s ca n hea rt fa i l ure, both of whi ch a re poor prognos ti c fi ndi ngs . Peri ca rdi ti s wi th effus i on or pl euri s y ca n occur. Ca rdi a c a rrhythmi a s
a re common.
Renal manifestations: Severe, often s udden rena l di s ea s e (rena l cri s i s ) ma y occur, mos t commonl y i n the fi rs t 4 to 5 yr a nd i n pa ti ents wi th di ffus e
s cl eroderma . It i s us ua l l y hera l ded by s udden, s evere hypertens i on.
Diagnosis
Us ua l l y a nti nucl ea r a nti bodi es (ANA), Scl -70 (topoi s omera s e I), a nd a nti centromere a nti bodi es
SSc s houl d be cons i dered i n pa ti ents wi th Ra yna ud's s yndrome, typi ca l mus cul os kel eta l or s ki n ma ni fes ta ti ons , or unexpl a i ned dys pha gi a ,
ma l a bs orpti on, pul mona ry fi bros i s , pul mona ry hypertens i on, ca rdi omyopa thi es , or conducti on di s turba nces . Di a gnos i s ca n be obvi ous i n pa ti ents
wi th combi na ti ons of cl a s s i c ma ni fes ta ti ons , s uch a s Ra yna ud's s yndrome, dys pha gi a , a nd ti ght s ki n. However, i n s ome pa ti ents , the di a gnos i s
ca nnot be ma de cl i ni ca l l y, a nd confi rma tory l a bora tory tes ts ca n i ncrea s e the proba bi l i ty of di s ea s e but do not rul e i t out.
Serum ANA a nd Scl -70 a nti body s houl d be obta i ned. ANA a re pres ent i n 90%, often wi th a n a nti nucl eol a r pa ttern. Anti body to centromeri c protei n
(a nti centromere a nti body) occurs i n the s erum of a hi gh proporti on of pa ti ents wi th CREST s yndrome a nd i s detecta bl e on the ANA. Scl -70 a nti gen
i s a DNA-bi ndi ng protei n s ens i ti ve to nucl ea s es . Pa ti ents wi th di ffus e s cl eroderma a re more l i kel y tha n thos e wi th CREST to ha ve a nti -Scl -70
a nti bodi es . Rheuma toi d fa ctor a l s o i s pos i ti ve i n one thi rd of pa ti ents .
If l ung i nvol vement i s s us pected, pul mona ry functi on tes ti ng, ches t CT, a nd echoca rdi ogra phy ca n begi n to defi ne i ts s everi ty. Acute a l veol i ti s i s
often detected by hi gh-res ol uti on ches t CT.
Prognosis
The cours e depends on the type of SSc but i s often unpredi cta bl e. Typi ca l l y, progres s i on i s s l ow. Overa l l 10-yr s urvi va l i s a bout 65%. Mos t pa ti ents
wi th di ffus e s ki n di s ea s e eventua l l y devel op vi s cera l compl i ca ti ons , whi ch a re the us ua l ca us es of dea th. Prognos i s i s poor i f ca rdi a c, pul mona ry,
or rena l ma ni fes ta ti ons a re pres ent ea rl y. Hea rt fa i l ure ma y be i ntra cta bl e. Ventri cul a r ectopy, even i f a s ymptoma ti c, i ncrea s es the ri s k of s udden
dea th. Acute rena l i ns uffi ci ency, i f untrea ted, progres s es ra pi dl y a nd ca us es dea th wi thi n months . Pa ti ents wi th CREST s yndrome ma y ha ve
di s ea s e tha t i s l i mi ted a nd nonprogres s i ve for l ong peri ods ; vi s cera l cha nges (eg, pul mona ry hypertens i on ca us ed by va s cul a r di s ea s e of the l ung,
a pecul i a r form of bi l i a ry ci rrhos i s ) eventua l l y devel op, but the cours e i s often rema rka bl y beni gn.
Treatment
Trea tment di rected a t s ymptoms a nd dys functi ona l orga ns
No drug s i gni fi ca ntl y i nfl uences the na tura l cours e of SSc overa l l , but va ri ous drugs a re of va l ue i n trea ti ng s peci fi c s ymptoms or orga n s ys tems .
NSAIDs ca n hel p a rthri ti s . Corti cos teroi ds ma y be hel pful i f there i s overt myos i ti s or mi xed connecti ve ti s s ue di s ea s e but ma y predi s pos e to rena l
cri s i s . Peni ci l l a mi ne, l ong us ed for trea tment of s ki n thi ckeni ng, ha s not s hown cl ea r effi ca cy i n recent tri a l s .
Va ri ous i mmunos uppres s a nts , i ncl udi ng methotrexa te, a za thi opri ne, a nd cycl ophos pha mi de, ma y hel p pul mona ry a l veol i ti s . Succes s ful l ung
tra ns pl a nta ti on ha s been reported. Epopros tenol (pros ta cycl i n) a nd bos enta n ma y be hel pful for pul mona ry hypertens i on. Ca cha nnel bl ockers ,
s uch a s ni fedi pi ne 20 mg po ti d or a s a n extended-rel ea s e formul a ti on, or a ngi otens i n receptor bl ockers , s uch a s l os a rta n 50 mg po once/da y, ma y
hel p Ra yna ud's s yndrome. Pa ti ents s houl d dres s wa rml y. IV i nfus i ons of pros ta gl a ndi n E1 (a l pros ta di l ) or epopros tenol or s ympa theti c bl ockers
ca n be us ed for di gi ta l i s chemi a . Refl ux es opha gi ti s i s rel i eved by frequent s ma l l feedi ngs , hi gh-dos e proton pump i nhi bi tors , a nd s l eepi ng wi th
the hea d of the bed el eva ted. Es opha gea l s tri ctures ma y requi re peri odi c di l a ti on; ga s troes opha gea l refl ux ma y pos s i bl y requi re ga s tropl a s ty.
Tetra cycl i ne 500 mg po bi d or a nother broa d-s pectrum a nti bi oti c ca n s uppres s overgrowth of i ntes ti na l fl ora a nd ma y a l l evi a te ma l a bs orpti on
s ymptoms . Phys i othera py ma y hel p pres erve mus cl e s trength but i s i neffecti ve i n preventi ng joi nt contra ctures . No trea tment a ffects ca l ci nos i s .
For a cute rena l cri s i s , prompt trea tment wi th a n ACE i nhi bi tor ca n dra ma ti ca l l y prol ong s urvi va l . Bl ood pres s ure i s us ua l l y, but not a l wa ys ,
control l ed. The morta l i ty ra te of rena l cri s i s rema i ns hi gh. If end-s ta ge rena l di s ea s e devel ops , i t ma y be revers i bl e, but di a l ys i s a nd
tra ns pl a nta ti on ma y be neces s a ry.
Chapter 34. Vasculitis

Introduction
Va s cul i ti s i s i nfl a mma ti on of bl ood ves s el s , often wi th i s chemi a , necros i s , a nd occl us i ve cha nges . It ca n a ffect a ny bl ood ves s el a rteri es ,
a rteri ol es , vei ns , venul es , or ca pi l l a ri es . Mos t da ma ge res ul ts when i nfl a mma ti on na rrows ves s el s a nd ca us es ti s s ue necros i s . Cl i ni ca l
ma ni fes ta ti ons of s peci fi c va s cul i ti c di s orders a re di vers e a nd depend on the s i ze of the i nvol ved ves s el s a nd the orga ns a ffected by i s chemi a .
Etiology
Va s cul i ti s ma y be pri ma ry or s econda ry. Pri ma ry va s cul i ti s res ul ts from a n i nfl a mma tory res pons e tha t ta rgets the ves s el wa l l s a nd ha s no known
ca us e. Seconda ry va s cul i ti s ma y be tri ggered by a n i nfecti on, a drug, or a toxi n or ma y occur a s pa rt of a nother i nfl a mma tory di s order or ca ncer.
Pathophysiology
Hi s tol ogi c des cri pti on of a n a ffected ves s el s houl d i ncl ude the fol l owi ng:
A des cri pti on of ves s el wa l l da ma ge
The na ture of the i nfl a mma tory i nfi l tra te i n the ves s el wa l l (eg, gra nul oma tous , nongra nul oma tous , l eukocytocl a s ti c va s cul i ti s )
A des cri pti on of hea l i ng res pons es (eg, i nti ma l hypertrophy, fi bros i s )
Certa i n fea tures (eg, predomi na nt i nfl a mma tory cel l s , l oca ti on of i nfl a mma ti on) s ugges t pa rti cul a r va s cul i ti c proces s es a nd ma y a i d i n the
di a gnos i s (s ee
Ta bl e 34-1). For exa mpl e, i n ma ny a cute l es i ons , the predomi na nt i nfl a mma tory cel l s a re PMNs ; i n chroni c l es i ons , l ymphocytes predomi na te.
Infl a mma ti on ma y be s egmenta l or i nvol ve the enti re ves s el . At s i tes of i nfl a mma ti on, va ryi ng degrees of cel l ul a r i nfl a mma ti on a nd necros i s or
s ca rri ng occur i n one or more l a yers
[Table 34-1. Hi s tol ogi c Cl ues to Di a gnos i s of Va s cul i ti c Di s orders ]
[
Table 34-2. Cl a s s i fi ca ti on of Va s cul i ti c Di s orders ]
of the ves s el wa l l . Infl a mma ti on i n the medi a of a mus cul a r a rtery tends to des troy the i nterna l el a s ti c l a mi na .
Leukocytocl a s ti c va s cul i ti s i s a hi s topa thol ogi c term us ed to des cri be fi ndi ngs i n s ma l l -ves s el va s cul i ti s . It refers to brea kdown of i nfl a mma tory
cel l s tha t l ea ves s ma l l nucl ea r fra gments (nucl ea r debri s ) i n a nd a round the ves s el s . Infl a mma ti on i s tra ns mura l , ra rel y necroti zi ng, a nd
nongra nul oma tous . PMNs predomi na te ea rl y; l a ter, l ymphocytes predomi na te. Res ol uti on of the i nfl a mma ti on tends to res ul t i n fi bros i s a nd
i nti ma l hypertrophy. Inti ma l hypertrophy or s econda ry cl ot forma ti on ca n na rrow the a rteri a l l umen a nd a ccounts for ti s s ue i s chemi a or necros i s .
Classification
Va s cul i ti c di s orders ca n be cl a s s i fi ed a ccordi ng to the s i ze of the predomi na nt ves s el a ffected (s ee Ta bl e 34-2). However, there i s often
s ubs ta nti a l overl a p.
Symptoms and Signs
Si ze of the a ffected ves s el s hel ps determi ne cl i ni ca l pres enta ti on (s ee Ta bl e 34-2).
Rega rdl es s of the s i ze of the ves s el s i nvol ved, pa ti ents ca n pres ent wi th s ymptoms a nd s i gns of s ys temi c i nfl a mma ti on (eg, fever, ni ght s wea ts ,
fa ti gue, a norexi a , wei ght l os s , a rthra l gi a s , a rthri ti s ). Some ma ni fes ta ti ons a re l i fe- or orga n-threa teni ng a nd requi re i mmedi a te trea tment. They
i ncl ude a l veol a r hemorrha ge, ra pi dl y progres s i ve gl omerul onephri ti s , mes enteri c i s chemi a , orbi ta l ps eudotumor threa teni ng the opti c nerve (i n
Wegener's gra nul oma tos i s ), a nd vi s i on l os s i n pa ti ents wi th gi a nt cel l a rteri ti s .
Diagnosis
Anti neutrophi l cytopl a s mi c a nti bodi es (ANCA) tes ts
Bi ops y
Angi ogra phy
Sys temi c va s cul i ti s i s s us pected i n pa ti ents wi th the fol l owi ng:
Symptoms or s i gns cha ra cteri s ti c of va s cul i ti s (eg, mononeuri ti s mul ti pl ex, l eukocytocl a s ti c va s cul i ti s )
Is chemi c ma ni fes ta ti ons (eg, i s chemi c s troke, l i mb cl a udi ca ti on, mes enteri c i s chemi a ) out of proporti on to a pa ti ent's ri s k fa ctors for
a theros cl eros i s
Unexpl a i ned combi na ti ons of s ymptoms i n more tha n one orga n s ys tem tha t a re compa ti bl e wi th va s cul i ti s (eg, hypertens i on, mya l gi a s ),
pa rti cul a rl y when s ymptoms of a s ys temi c i l l nes s a re pres ent
Pri ma ry va s cul i ti c di s orders a re di a gnos ed ba s ed on the pres ence of cha ra cteri s ti c s ymptoms , phys i ca l fi ndi ngs , compa ti bl e l a bora tory tes t
res ul ts , a nd excl us i on of other ca us es (i e, s econda ry va s cul i ti s ). Hi s tol ogi c exa mi na ti on i s done whenever pos s i bl e a nd ma y poi nt to a pa rti cul a r
va s cul i ti c di s order (s ee Ta bl e 34-1).
Routi ne l a bora tory tes ts a re done. Mos t res ul ts a re nons peci fi c but ca n hel p s upport the di a gnos i s . Tes ts us ua l l y i ncl ude CBC, ESR or C-rea cti ve
protei n, s erum a l bumi n a nd tota l protei n, a nd tes ts for ANCA. Often, pa ti ents pres ent wi th el eva ted ESR or C-rea cti ve protei n, a nemi a due to
chroni c i nfl a mma ti on, el eva ted pl a tel ets , a nd l ow s erum a l bumi n a nd tota l protei n. Fres hl y voi ded uri ne mus t be tes ted for RBCs , RBC ca s ts , a nd
protei n to i denti fy rena l i nvol vement. Serum crea ti ni ne l evel s s houl d be checked a nd moni tored. Leukopeni a a nd thrombocytopeni a a re
uncommon.
Detecti on of ANCA ma y s upport the di a gnos i s of Wegener's gra nul oma tos i s , Churg-Stra us s s yndrome, or mi cros copi c pol ya ngi i ti s . Sta nda rdi zed
tes ts for ANCA i ncl ude i mmunofl uores cence s ta i ni ng a nd enzyme-l i nked i mmunos orbent a s s a y (ELISA). Immunofl uores cence s ta i ni ng of etha nol fi xed neutrophi l s ca n detect the cytopl a s mi c pa ttern of cANCA or the peri nucl ea r pa ttern of pANCA. Then s ol i d-pha s e ELISA i s us ed to check for
a nti bodi es s peci fi c for the ma jor a utoa nti gens : protei na s e-3 (PR3), whi ch correl a tes wi th the cANCA s ta i ni ng pa ttern, or myel operoxi da s e (MPO),
whi ch correl a tes wi th the pANCA s ta i ni ng pa ttern. Beca us e fa l s e-pos i ti ves occur, ANCA s houl d be mea s ured onl y when one of thes e va s cul i ti c
di s orders i s cl i ni ca l l y s us pected.
Other us eful l a bora tory tes ts i ncl ude hepa ti ti s B a nd C s erol ogi c tes ti ng, tes ti ng for the pres ence of cryogl obul i ns , a nd compl ement l evel s to
di a gnos e vi ra l or cryogl obul i nemi c va s cul i ti s . Further tes ti ng i s determi ned by cl i ni ca l fi ndi ngs . A ches t x-ra y s houl d be done to check for
i nfi l tra tes , but hi gh-res ol uti on noncontra s t CT of the ches t ma y be needed to check for s ubtl e fi ndi ngs , s uch a s s ma l l nodul es or ca vi ti es . Bi l a tera l
di ffus e i nfi l tra tes s ugges t pos s i bl e a l veol a r hemorrha ge, whi ch requi res i mmedi a te di a gnos i s a nd trea tment. Other i ma gi ng tes ts ma y be
requi red. For exa mpl e, ma gneti c res ona nce a ngi ogra phy of l a rge bl ood ves s el s a nd the a orta i s us eful for di a gnos i s a nd moni tori ng when s uch
ves s el s a ppea r a ffected. If s ymptoms s ugges t mononeuri ti s mul ti pl ex, el ectromyogra phy i s done.
Beca us e va s cul i ti c di s orders a re ra re a nd trea tment ma y ha ve s evere a dvers e effects , ti s s ue bi ops y i s done to confi rm the di a gnos i s whenever
pos s i bl e. Us ua l l y, cl i ni ca l fi ndi ngs s ugges t the bes t s i te for bi ops y. For exa mpl e, i f cl i ni ca l a nd el ectromyogra phi c fi ndi ngs s ugges t mononeuri ti s
mul ti pl ex wi th dys functi on of a s peci fi c peri phera l nerve, ti s s ue a round a rteri es s uppl yi ng the nerve i s bi ops i ed. Us ua l l y, bi ops i es of una ffected
ti s s ue a re much l es s l i kel y to provi de pos i ti ve res ul ts .
Beca us e va s cul i ti s i s often s egmenta l or foca l , bi ops y ma y not s how i nfl a mma ti on even when a ves s el i s a ffected. Sa mpl i ng from mul ti pl e a rea s
or l ong s egments of a ves s el ma y i ncrea s e di a gnos ti c s ens i ti vi ty.
Treatment
Corti cos teroi ds a nd cycl ophos pha mi de to i nduce remi s s i on of l i fe- or orga n-threa teni ng di s orders
Ta peri ng or el i mi na ti on of corti cos teroi ds a nd s ubs ti tuti on of methotrexa te or a za thi opri ne to ma i nta i n remi s s i on
Trea tment depends on the eti ol ogy a nd extent a nd s everi ty of di s ea s e. For s econda ry va s cul i ti c di s orders , removi ng the ca us e (eg, i nfecti on, drug,
ca ncer) ca n hel p.
For pri ma ry va s cul i ti c di s orders , trea tment a i ms to i nduce a nd ma i nta i n remi s s i on. Remi s s i on i s i nduced by us i ng cytotoxi c i mmunos uppres s a nts
a nd hi gh-dos e corti cos teroi ds , us ua l l y for 3 to 6 mo, unti l remi s s i on occurs or di s ea s e a cti vi ty i s a ccepta bl y reduced. Adjus ti ng trea tment to
ma i nta i n remi s s i on us ua l l y ta kes l onger, on a vera ge > 1 or 2 yr. Duri ng thi s peri od, the goa l i s to el i mi na te corti cos teroi ds or reduce thei r dos e
a nd to us e l es s potent i mmunos uppres s a nts a s l ong a s needed.
Induction of remission: For l es s s evere forms of va s cul i ti s , l ow dos es of corti cos teroi ds a nd l es s potent i mmunos uppres s a nts (eg, methotrexa te,
a za thi opri ne, mycophenol a te mofeti l ) ma y be us ed.
Severe, ra pi dl y progres s i ve a nd l i fe- or orga n-threa teni ng va s cul i ti s (eg, ca us i ng a l veol a r hemorrha ge, ra pi dl y progres s i ve gl omerul onephri ti s , or
mes enteri c i s chemi a ) i s a medi ca l emergency requi ri ng hos pi ta l a dmi s s i on a nd i mmedi a te trea tment. Trea tment cons i s ts of the fol l owi ng:
Corticosteroids: Hi gh-dos e corti cos teroi ds (a l s o ca l l ed pul s e corti cos teroi ds ) a re often pres cri bed. Methyl predni s ol one 15 mg/kg or 1 g IV once/da y
for 3 da ys ma y be us ed. Ora l predni s one i s gi ven concurrentl y. A dos e of 1 mg/kg once/da y i s gi ven for a bout 4 wk unti l pa ti ents i mprove. The
dos e i s then ta pered s l owl y, a s tol era ted, us ua l l y by 10 mg every week to 40 mg/da y, by 5 mg every 2 wk to 20 mg/da y, by 2.5 mg every 2 wk to 10
mg/da y, a nd by 1 mg every month from there on unti l the drug i s s topped. Cha nges i n thi s ta peri ng s chedul e ma y be neces s a ry i f the pa ti ent
fa i l s to i mprove or rel a ps es .
Cyclophosphamide: A dos e of 2 mg/kg po once/da y i s us ua l l y recommended for a t l ea s t 3 mo or unti l remi s s i on occurs . The WBC count mus t be
cl os el y moni tored, a nd the dos e mus t be a djus ted to a voi d l eukopeni a . (WBC count s houl d be ma i nta i ned a t > 3500/L.) If pa ti ents ca nnot
tol era te ora l cycl ophos pha mi de, a re unl i kel y to ta ke ora l drugs a s di rected, or ha ve a hi gh ri s k of bl a dder ca ncer, IV cycl ophos pha mi de ma y be
us ed. The recommended cumul a ti ve dos e of cycl ophos pha mi de i s 0.75 to 1 g/m 2 monthl y. The dos e s houl d be reduced i n pa ti ents wi th
s i gni fi ca nt rena l i ns uffi ci ency. Pa ti ents ta ki ng cycl ophos pha mi de s houl d a l s o be gi ven prophyl a cti c trea tment a ga i ns t Pneumocystis jirovecii.
Acrol ei n, a product of cycl ophos pha mi de degra da ti on, i s toxi c to the bl a dder epi thel i um a nd ca n l ea d to hemorrha gi c cys ti ti s . For pa ti ents who
ha ve ta ken cycl ophos pha mi de l ong term, ri s k of cys ti ti s i s i ncrea s ed, a nd s ome devel op tra ns i ti ona l cel l ca rci noma of the bl a dder. Duri ng
cycl ophos pha mi de thera py, ca reful hydra ti on i s needed to reduce the ri s k of bl a dder hemorrha ge, cys ti ti s , a nd bl a dder ca ncer. Mes na bi nds
a crol ei n a nd i s mi xed together wi th the IV cycl ophos pha mi de i nfus i on. One mi l l i gra m of mes na i s a dded for ea ch mi l l i gra m of cycl ophos pha mi de.
Recurrence of hema turi a , es peci a l l y wi thout ca s ts a nd dys morphi c red cel l s , s houl d prompt a referra l for urol ogi c eva l ua ti on. Cys tos copy a nd rena l
i ma gi ng s houl d be done to excl ude ca ncer.
Remission maintenance: Corti cos teroi ds a re ta pered to zero or to the l owes t dos e tha t ca n ma i nta i n remi s s i on. Us ua l l y, methotrexa te (wi th fol a te)
or a za thi opri ne i s pres cri bed to repl a ce cycl ophos pha mi de beca us e thes e drugs ha ve a better a dvers e effects profi l e. The dura ti on of thi s
trea tment va ri es , from one yea r to s evera l yea rs . Pa ti ents wi th frequent rel a ps es ma y need to ta ke i mmunos uppres s a nts i ndefi ni tel y.
Long-term us e of corti cos teroi ds ca n ha ve s i gni fi ca nt a dvers e effects . Pa ti ents who a re ta ki ng s uch thera py s houl d be gi ven Ca a nd vi ta mi n D
s uppl ements a nd bi s phos phona tes to hel p prevent or mi ni mi ze os teoporos i s ; bone dens i ty s houl d be moni tored yea rl y.
Behcet's Syndrome
Behcet's syndrome is a multisystem, relapsing, chronic vasculitic disorder with prominent mucosal inflammation. Common manifestations include recurrent oral
ulcers, ocular inflammation, genital ulcers, and skin lesions. The most serious manifestations are blindness, neurologic or GI manifestations, venous thromboses,
and arterial aneurysms. Diagnosis is clinical, using international criteria. Treatment is mainly symptomatic but may involve corticosteroids for acute severe ocular
or neurologic manifestations or immunosuppressants for severe chronic lesions.
Behcet's s yndrome i nvol ves s ma l l a nd l a rge a rteri es a nd vei ns . Arteri a l thrombos i s a nd s uperfi ci a l a nd deep venous thrombos i s often occur.
The s yndrome occurs nea rl y equa l l y i n men a nd women, typi ca l l y begi nni ng duri ng thei r 20s . Occa s i ona l l y, the s yndrome devel ops i n chi l dren.
Inci dence va ri es by l oca ti on. Behcet's s yndrome i s mos t common a l ong the s i l k route from the Medi terra nea n to Chi na ; i t i s uncommon i n the US.
The ca us e i s unknown. Immunol ogi c (i ncl udi ng a utoi mmune) a nd vi ra l or ba cteri a l tri ggers ha ve been s ugges ted, a nd HLA-B51 i s a s s oci a ted wi th
ca s es from Turkey, Ira n, Chi na , Korea , a nd Ja pa n.
Neutrophi l i nfi l tra ti on i s detected i n bi ops y s peci mens from ora l a phthous ul cers a nd erythema nodos um a nd pa thergy l es i ons , but no hi s tol ogi c
cha nges a re pa thognomoni c.
Symptoms and Signs
Mucocutaneous: Al mos t a l l pa ti ents ha ve recurrent pa i nful ora l ul cers res embl i ng thos e of a phthous s toma ti ti s ; i n mos t, thes e ul cers a re the fi rs t
ma ni fes ta ti ons . The ul cers a re round or ova l , 2 to 10 mm i n di a meter, a nd s ha l l ow or deep wi th a centra l yel l owi s h necroti c center; they ca n occur
a nywhere i n the ora l ca vi ty, often i n cl us ters . Ul cers l a s t 1 to 2 wk. Si mi l a r ul cers occur on the peni s a nd s crotum, on the vul va where they a re
pa i nful , or i n the va gi na where they ma y ca us e l i ttl e or no pa i n.
Cuta neous l es i ons a re common a nd ma y i ncl ude a cnei form l es i ons , nodul es , erythema nodos um, s uperfi ci a l thrombophl ebi ti s , pyoderma
ga ngrenos um-type l es i ons , a nd pa l pa bl e purpura .
Pa thergy (a n erythema tous pa pul a r or pus tul a r res pons e to l oca l s ki n i njury) i s defi ned a s a pa pul e > 2 mm tha t a ppea rs 24 to 48 h a fter obl i que
i ns erti on of a 20- to 25-ga uge needl e i nto the s ki n. Pa thergy ha s occurred i n ma ny pa rts of the worl d but i s l es s common a mong North Ameri ca n
a nd northern Europea n pa ti ents tha n a mong Mi ddl e Ea s tern a nd As i a n pa ti ents .
Ocular: The eyes a re a ffected i n 25 to 75% of pa ti ents . The fol l owi ng ma y occur:
Rel a ps i ng uvei ti s or i ri docycl i ti s (mos t common) often ma ni fes ts a s pa i n, photophobi a , a nd red eye.
Hypopyon (a l a yer of pus vi s i bl e i n the a nteri or cha mber) ma y occur.
Uvei ti s i s typi ca l l y bi l a tera l a nd epi s odi c, often i nvol ves the enti re uvea l tra ct (pa nuvei ti s ), a nd ma y not res ol ve compl etel y between epi s odes .
Choroi di ti s , reti na l va s cul i ti s , va s cul a r occl us i on, a nd opti c neuri ti s ma y i rrevers i bl y i mpa i r vi s i on a nd even progres s to bl i ndnes s .
Musculoskeletal: Rel a ti vel y mi l d, s el f-l i mi ti ng, a nd nondes tructi ve a rthra l gi a s or fra nk a rthri ti s , es peci a l l y i n the knees a nd other l a rge joi nts , occur
i n 50% of pa ti ents . Sa croi l i a c i nfl a mma ti on ca n occur.
Vascular: Superfi ci a l a nd deep venous thrombos es a re common. La rge ves s el s a re a ffected i n a bout one thi rd of pa ti ents . Peri va s cul a r a nd
endova s cul a r i nfl a mma ti on ma y l ea d to hemorrha ge, s tenos i s , a neurys ms , a nd thrombos i s i n a rteri es a nd vei ns . Superi or a nd i nferi or vena ca va
occl us i on, Budd-Chi a ri s yndrome, a nd other venous obs tructi ve l es i ons ca n a l s o occur.
Di s ea s e of the a orta a nd l a rge bl ood ves s el s ma y be l i fe threa teni ng. Hemoptys i s ma y occur i f fi s tul a s between the pul mona ry a rtery a nd
bronchus devel op.
Neurologic and psychiatric: CNS i nvol vement i s l es s common but i s s eri ous . Ons et ma y be s udden or gra dua l . The fi rs t ma ni fes ta ti ons ma y be
pa renchyma l i nvol vement wi th pyra mi da l s i gns , s ma l l -ves s el di s ea s e wi th a mul ti pl e s cl eros i s -l i ke pa ttern, a s epti c meni ngi ti s or
meni ngoencepha l i ti s , or dura l s i nus thrombos i s .
Ps ychi a tri c di s orders i ncl udi ng pers ona l i ty cha nges a nd dementi a ma y devel op yea rs l a ter. Peri phera l neuropa thy, common i n other va s cul i ti c
di s orders , i s uncommon i n Behcet's s yndrome.
GI: Abdomi na l di s comfort, a bdomi na l pa i n, a nd di a rrhea wi th i ntes ti na l ul cers , occurri ng pri ma ri l y i n the i l eum a nd col on a nd cl os el y res embl i ng
Crohn's di s ea s e, ma y occur.
Diagnosis
Behcet's s yndrome s houl d be s us pected i n young a dul ts wi th recurrent ora l a phthous ul cers , unexpl a i ned ocul a r fi ndi ngs , or geni ta l ul cers .
Di a gnos i s i s cl i ni ca l a nd ma y requi re months beca us e ma ny of the ma ni fes ta ti ons a re nons peci fi c a nd ca n be i ns i di ous .
International criteria for di a gnos i s i ncl ude recurrent ora l ul cers (3 ti mes i n 1 yr) a nd 2 of the fol l owi ng:
Recurrent geni ta l ul cers
Eye l es i ons
Ski n l es i ons
Pos i ti ve pa thergy tes t wi th no other cl i ni ca l expl a na ti on
La bora tory tes ts (eg, CBC, ESR or C-rea cti ve protei n, s erum a l bumi n a nd tota l protei n l evel s ) a re done. Res ul ts a re nons peci fi c but cha ra cteri s ti c of
i nfl a mma tory di s ea s e (el eva ted ESR, C-rea cti ve protei n, a nd 2 - a nd -gl obul i ns ; mi l d l eukocytos i s ).
Di fferenti a l di a gnos i s i ncl udes rea cti ve a rthri ti s , SLE, Crohn's di s ea s e, ul cera ti ve col i ti s , a nkyl os i ng s pondyl i ti s , a nd herpes s i mpl ex i nfecti on.
Behcet's s yndrome ha s no s i ngl e pa thognomoni c fi ndi ng but ma y be di s ti ngui s hed by i ts combi na ti ons of rel a ps i ng s ymptoms wi th s ponta neous
remi s s i ons a nd mul ti pl e orga n i nvol vement, pa rti cul a rl y i n pa ti ents wi th recurrent, deep mucos a l ul cers .
Prognosis
Behcet's s yndrome typi ca l l y ha s a wa xi ng a nd wa ni ng cours e cha ra cteri zed by exa cerba ti ons a nd remi s s i ons . Mucocuta neous a nd ocul a r l es i ons
a nd a rthra l gi a s a re often wors e ea rl y i n the di s ea s e. CNS a nd l a rge-ves s el ma ni fes ta ti ons , i f they devel op, typi ca l l y occur l a ter. Occa s i ona l l y, the
s yndrome res ul ts i n dea th, us ua l l y due to neurol ogi c, va s cul a r (eg, a neurys ms ), or GI ma ni fes ta ti ons . Ma ny pa ti ents eventua l l y go i nto remi s s i on.
Treatment
Col chi ci ne, tha l i domi de, eta nercept, a nd i nterferon for mucos a l di s ea s e
Aza thi opri ne or cycl os pori ne for eye di s ea s e
Cycl ophos pha mi de a nd chl ora mbuci l for refra ctory or l i fe-threa teni ng di s ea s e
Trea tment depends on the cl i ni ca l ma ni fes ta ti ons .
Mucos a l di s ea s e ca n be ma na ged s ymptoma ti ca l l y. Col chi ci ne 0.6 mg po bi d ma y decrea s e the frequency a nd s everi ty of ora l or geni ta l ul cers a nd
ma y be effecti ve for erythema nodos um a nd a rthra l gi a s . Tha l i domi de 100 to 300 mg po once/da y ma y be us ed to trea t ora l , geni ta l , a nd s ki n
l es i ons , but l es i ons ma y recur when trea tment i s s topped. Eta nercept 50 mg s c once/wk or 25 mg s c twi ce/wk ma y s uppres s mucocuta neous
l es i ons . Eta nercept ca n be gi ven i f col chi ci ne i s i neffecti ve. Interferon a l fa -2a 6 mi l l i on uni ts s c 3 ti mes /wk ca n a l s o be gi ven i f col chi ci ne i s
i neffecti ve.
Aza thi opri ne 2.5 mg/kg po once/da y hel ps pres erve vi s ua l a cui ty a nd prevent new eye l es i ons . Aza thi opri ne i s a l s o us eful for mucocuta neous
l es i ons a nd a rthra l gi a . Cycl os pori ne 5 to 10 mg/kg po once/da y ma y be res erved for pa ti ents wi th s evere ocul a r ma ni fes ta ti ons a nd ma y be us ed
wi th a za thi opri ne to trea t refra ctory uvei ti s . Interferon a l fa -2a 6 mi l l i on uni ts s c 3 ti mes /wk a nd i nfl i xi ma b (a tumor necros i s fa ctor i nhi bi tor) 3 to
10 mg/kg IV a t 0, 2, 4, a nd then every 8 wk s how promi s e for pa ti ents wi th ocul a r ma ni fes ta ti ons .
Cycl ophos pha mi de a nd chl ora mbuci l a re us ed i n pa ti ents wi th refra ctory di s ea s e, l i fe-threa teni ng condi ti ons (eg, pul mona ry a neurys ms ), or CNS
ma ni fes ta ti ons .
The effi ca cy of corti cos teroi ds i s uns ubs ta nti a ted, des pi te thei r wi de us e. Topi ca l corti cos teroi ds ma y tempora ri l y rel i eve ocul a r ma ni fes ta ti ons
a nd mos t ora l l es i ons . However, topi ca l or s ys temi c corti cos teroi ds do not a l ter the frequency of rel a ps es . A few pa ti ents wi th s evere uvei ti s or
CNS ma ni fes ta ti ons res pond to hi gh-dos e s ys temi c corti cos teroi ds (eg, predni s one 60 to 80 mg po once/da y).
Whether i mmunos uppres s a nts s houl d be a dded to a nti coa gul a ti on thera py when pa ti ents ha ve thrombos es ha s not been es ta bl i s hed.
Churg-Strauss Syndrome
(Al l ergi c Angi i ti s a nd Gra nul oma tos i s )
Churg-Strauss syndrome is a pulmonary and systemic small-vessel necrotizing vasculitis, characterized by extravascular granulomas, eosinophilia, and tissue
infiltration by eosinophils. It tends to occur in people with adult-onset asthma, allergic rhinitis, nasal polyposis, or a combination. Diagnosis is best confirmed by
biopsy. Treatment is primarily with corticosteroids and, for severe disease, addition of other immunosuppressants.
Churg-Stra us s s yndrome occurs i n a bout 3 peopl e/mi l l i on. Mea n a ge a t ons et i s 48.
Churg-Stra us s s yndrome i s cha ra cteri zed by extra va s cul a r necroti zi ng gra nul oma s (us ua l l y conta i ni ng eos i nophi l i c i nfi l tra tes ), eos i nophi l i a , a nd
ti s s ue i nfi l tra ti on by eos i nophi l s . However, thes e a bnorma l i ti es ra rel y coexi s t. The va s cul i ti s typi ca l l y a ffects pul mona ry a nd s ys temi c a rteri es
a nd vei ns . Any orga n ca n be a ffected, but the l ungs , s ki n, ca rdi ova s cul a r s ys tem (eg, a s corona ry a rtery va s cul i ti s ), ki dneys , peri phera l nervous
s ys tem, s i nus es , joi nts , a nd GI tra ct a re mos t commonl y a ffected. Occa s i ona l l y, pul mona ry ca pi l l a ri ti s ma y ca us e a l veol a r hemorrha ge.
Etiology
The ca us e i s unknown. However, a n a l l ergi c mecha ni s m, wi th ti s s ue di rectl y i njured by eos i nophi l s a nd neutrophi l degra nul a ti on products , ma y
be i nvol ved. Acti va ti on of T l ymphocytes s eems to hel p ma i nta i n eos i nophi l i c i nfl a mma ti on. The s yndrome occurs i n pa ti ents who ha ve a dul tons et a s thma , a l l ergi c rhi ni ti s , na s a l pol ypos i s , or a combi na ti on. Anti neutrophi l cytopl a s mi c a utoa nti bodi es (ANCA) a re s ometi mes pres ent.
Symptoms and Signs

The s yndrome ha s 3 pha s es , whi ch ma y overl a p:
Prodroma l : Thi s pha s e ma y pers i s t for yea rs . Pa ti ents ha ve a l l ergi c rhi ni ti s , na s a l pol ypos i s , a s thma , or a combi na ti on.
2nd pha s e: Peri phera l bl ood a nd ti s s ue eos i nophi l i a i s typi ca l . Cl i ni ca l pres enta ti on, whi ch ma y res embl e Loffl er's s yndrome, i ncl udes chroni c
eos i nophi l i c pneumoni a a nd eos i nophi l i c ga s troenteri ti s .
3rd pha s e: Potenti a l l y l i fe-threa teni ng va s cul i ti s devel ops . Sys temi c s ymptoms (eg, fever, ma l a i s e, wei ght l os s , fa ti gue) a re common.
However, the pha s es do not neces s a ri l y fol l ow one a nother cons ecuti vel y, a nd the ti me i nterva l between them va ri es grea tl y.
Va ri ous orga ns a nd s ys tems ma y be a ffected:
Respiratory: As thma , often wi th ons et duri ng a dul thood, occurs i n mos t pa ti ents . Si nus i ti s i s common, typi ca l l y wi thout s evere necroti zi ng
i nfl a mma ti on. Si nus i ti s ca us es fa ci a l pa i n a nd i ncrea s es na s a l di s cha rge. Pa ti ents ma y be s hort of brea th. Cough a nd hemoptys i s , due to
a l veol a r hemorrha ge, ma y be pres ent. Tra ns i ent pa tchy pul mona ry i nfi l tra tes a re common.
Neurologic: Neurol ogi c ma ni fes ta ti ons a re common. Mononeuri ti s mul ti pl ex occurs i n up to three fourths of pa ti ents . CNS i nvol vement i s ra re but
ca n i ncl ude confus i on, s ei zures , a nd coma , wi th or wi thout cra ni a l nerve pa l s i es or evi dence of cerebra l i nfa rcti on.
Cutaneous: The s ki n i s a ffected i n a bout one ha l f of pa ti ents . Nodul es a nd pa pul es a ppea r on extens or s urfa ces of extremi ti es . They a re ca us ed
by extra va s cul a r pa l i s a di ng gra nul oma tous l es i ons wi th centra l necros i s . Purpura or erythema tous pa pul es , due to l eukocytocl a s ti c va s cul i ti s
wi th or wi thout promi nent eos i nophi l i c i nfi l tra ti on, ma y devel op.
Musculoskeletal: Occa s i ona l l y, a rthra l gi a s , mya l gi a s , or even a rthri ti s ca n occur, us ua l l y duri ng the va s cul i ti c pha s e.
Cardiac: Hea rt fa i l ure, MI, corona ry a rtery va s cul i ti s (pos s i bl y wi th MI), va l vul a r di s orders , or peri ca rdi ti s ma y devel op. The predomi na nt
hi s topa thol ogi c fi ndi ng i s eos i nophi l i c myoca rdi ti s .
GI: Up to one thi rd of pa ti ents pres ent wi th GI s ymptoms (eg, a bdomi na l pa i n, di a rrhea , bl eedi ng) due to eos i nophi l i c ga s troenteri ti s or
mes enteri c i s chemi a due to va s cul i ti s .
Renal: The ki dneys a re a ffected l es s often tha n i n other va s cul i ti c di s orders a s s oci a ted wi th ANCA. Typi ca l l y, pa uci -i mmune (few i f a ny i mmune
compl exes ), foca l s egmenta l necroti zi ng gl omerul onephri ti s wi th cres cent forma ti on i s pres ent; eos i nophi l i c or gra nul oma tous i nfl a mma ti on
of the ki dneys i s ra re.
Rena l , ca rdi a c, or neurol ogi c i nvol vement i ndi ca tes a wors e prognos i s .
Diagnosis
Routi ne l a bora tory tes ts
Bi ops y
Cri teri a for cl a s s i fi ca ti on from the Ameri ca n Col l ege of Rheuma tol ogy cons i s t of the fol l owi ng:
As thma
Eos i nophi l i a of > 10% i n peri phera l bl ood
Pa ra na s a l s i nus i ti s
Pul mona ry i nfi l tra tes , s ometi mes tra ns i ent
Hi s tol ogi c evi dence of va s cul i ti s wi th extra va s cul a r eos i nophi l s
Mononeuri ti s mul ti pl ex or pol yneuropa thy
If 4 cri teri a a re pres ent, s ens i ti vi ty i s 85%, a nd s peci fi ci ty i s 99.7%.
Tes ti ng a i ms to es ta bl i s h the di a gnos i s a nd the extent of orga n i nvol vement a nd to di s ti ngui s h Churg-Stra us s s yndrome from other eos i nophi l i c
di s orders (eg, pa ra s i ti c i nfecti ons , drug rea cti ons , a cute a nd chroni c eos i nophi l i c pneumoni a , a l l ergi c bronchopul mona ry a s pergi l l os i s , i di opa thi c
hypereos i nophi l i c s yndrome). Di a gnos i s i s s ugges ted by cl i ni ca l fi ndi ngs a nd res ul ts of routi ne l a bora tory tes ts but s houl d us ua l l y be confi rmed
by bi ops y of l ung or other a ffected ti s s ue.
Bl ood tes ts a nd ches t x-ra ys a re done, but res ul ts a re not di a gnos ti c. CBC wi th di fferenti a l i s done to check for eos i nophi l i a . Peri phera l bl ood
eos i nophi l i a i s a l s o a ma rker of di s ea s e a cti vi ty. IgE a nd C-rea cti ve protei n l evel s a nd ESR a re determi ned peri odi ca l l y to eva l ua te i nfl a mma tory
a cti vi ty. El ectrol yte l evel s a re mea s ured a nd uri na l ys i s i s done to check for evi dence of rena l i nvol vement a nd to fol l ow i ts s everi ty.
Serol ogi c tes ti ng i s done. It detects ANCA i n up to 50%; i f ANCA i s detected, enzyme-l i nked i mmunos orbent a s s a y (ELISA) i s done to check for
s peci fi c a nti bodi es . Peri nucl ea r ANCA (p-ANCA) wi th a nti bodi es a ga i ns t myel operoxi da s e i s the mos t common res ul t, but ANCA i s not s peci fi c for
Churg-Stra us s s yndrome.
Ches t x-ra y often s hows tra ns i ent pa tchy pul mona ry i nfi l tra tes .
Bi ops y of the mos t a cces s i bl e a ffected ti s s ue s houl d be done i f pos s i bl e.
Treatment
Corti cos teroi ds
Sys temi c corti cos teroi ds a re the ma i ns ta y of trea tment. When to a dd other i mmunos uppres s a nts i s not cl ea r, but Churg-Stra us s s yndrome i s
genera l l y trea ted the s a me wa y a s Wegener's gra nul oma tos i s (s ee p. 329) or mi cros copi c pol ya ngi i ti s (s ee p. 322). Recombi na nt i nterferon a l fa -2a
3 mi l l i on uni ts s c da i l y ha s been us ed when the s yndrome i s refra ctory to other drugs or when eos i nophi l i c i nfl a mma ti on i s di ffi cul t to control .
Cutaneous Vasculitis
Cutaneous vasculitis affects small or medium-sized vessels in the skin and subcutaneous tissue. This disorder may be limited to the skin or be part of systemic
vasculitis. Purpura, ulcers, livedo reticularis, or nodules may develop. Diagnosis requires biopsy. Treatment depends on etiology and extent of disease.
Common ca us es i ncl ude s erum s i cknes s , i nfecti ons (eg, hepa ti ti s C), ca ncers , rheuma tol ogi c or other a utoi mmune di s orders , a nd hypers ens i ti vi ty
to drugs .
Ves s el i nfl a mma ti on often res ul ts from i mmune compl ex depos i ti on, but other pa thogeneti c mecha ni s ms ma y be i nvol ved. Predomi na ntl y
cuta neous va s cul i ti s i s a l eukocytocl a s ti c va s cul i ti s , s o-ca l l ed beca us e i nfl a mma ti on di s rupts l eukocytes , res ul ti ng i n depos i ti on of nucl ea r
debri s (l eukocytocl a s i s ) i n the ves s el wa l l .
Symptoms and Signs
Pa ti ents ma y pres ent wi th s ki n s ymptoms s uch a s l es i ons , i ncl udi ng pa l pa bl e purpura , urti ca ri a , ul cers , l i vedo reti cul a ri s , a nd nodul es . If
cuta neous va s cul i ti s occurs a s pa rt of a s ys temi c va s cul i ti s , s ymptoms ma y a l s o i ncl ude fever, a rthra l gi a s , other orga n i nvol vement, or a
combi na ti on.
Diagnosis
Excl us i on of s ys temi c va s cul i ti s cl i ni ca l l y a nd by routi ne tes ts (eg, CBC, ESR, uri na l ys i s , ches t x-ra y, s erum crea ti ni ne)
Bi ops y
Tes ts for the ca us e of va s cul i ti s (eg, cryogl obul i ns , a nti neutrophi l cytopl a s mi c a nti bodi es [ANCA], hepa ti ti s B a nd C a nti bodi es , compl ement
l evel s )
A di a gnos i s of va s cul i ti s l i mi ted to the s ki n requi res a compl ete hi s tory a nd phys i ca l exa mi na ti on, focus i ng on excl udi ng ma ni fes ta ti ons of
i nfl a mma ti on or va s cul i ti s i n other orga ns , a s i n the fol l owi ng:
Lungs : Shortnes s of brea th, cough, hemoptys i s , a nd s i gns of cons ol i da ti on
Ki dneys : New-ons et hypertens i on or edema
Nerves : New-ons et a s ymmetri c wea knes s or pa res thes i a s
Intes ti ne: New-ons et a bdomi na l pa i n, di a rrhea , a nd bl oody s tool s
Uri na l ys i s s houl d excl ude bl ood, protei n, a nd RBC ca s ts . A ches t x-ra y i s needed to check for i nfi l tra tes (s ugges ti ng a l veol a r hemorrha ge). CBC a nd
other bl ood tes ts a re needed to check for a nemi a , to determi ne pl a tel et count a nd s erum crea ti ni ne l evel , a nd to check for el eva ted l evel s of
a cute-pha s e rea cta nts (eg, ESR, C-rea cti ve protei n).
A s ki n bi ops y i s done, opti ma l l y wi thi n 24 to 48 h a fter va s cul i ti c l es i ons a ppea r. Di a gnos ti c yi el d depends on the depth of the bi ops y. Genera l l y,
punch bi ops y or exci s i on bi ops y i nto the s ubcuti s i s preferred; thes e bi ops i es ca n s a mpl e s ma l l a nd medi um-s i zed ves s el s . Sha ve bi ops y i s
us ua l l y i na dequa te.
If hi s tol ogi c exa mi na ti on detects the fol l owi ng, cuta neous va s cul i ti s i s confi rmed:
Infi l tra ti on of the ves s el wa l l by i nfl a mma tory cel l s , res ul ti ng i n di s rupti on a nd des tructi on of the ves s el wa l l
Intra mura l a nd i ntra l umi na l fi bri n depos i ti on (fi bri noi d necros i s )
Extra va s a ti on of RBCs
Nucl ea r debri s (l eukocytocl a s i s )
Di rect i mmunofl uores cence s ta i ni ng i s needed to check for IgA, IgM, a nd IgG a nd compl ement depos i ti on i n a nd a round the ves s el wa l l , whi ch
s ugges ts a n i mmune compl ex-medi a ted proces s a nd s upports the di a gnos i s . Further tes ti ng to es ta bl i s h the ca us e of va s cul i ti s i ncl udes checki ng
for cryogl obul i ns , ANCA, a nd hepa ti ti s B a nd C a nti bodi es , mea s uri ng compl ement l evel s , a nd tes ts for a ny cl i ni ca l l y s us pected di s orders tha t ca n
ca us e va s cul i ti s .
Treatment
Anti hi s ta mi nes a nd s ometi mes l ow-dos e corti cos teroi ds to trea t s ki n l es i ons
Tri a l of col chi ci ne, hydroxychl oroqui ne, or da ps one to prevent recurrences
Trea tment i s fi rs t di rected a t a ny i denti fi ed ca us e. If no ca us e i s i denti fi ed a nd va s cul i ti s i s l i mi ted to the s ki n, trea tment i s mi ni ma l a nd
cons erva ti ve. Support hos e a nd a nti hi s ta mi nes ma y be s uffi ci ent. If thi s trea tment i s i neffecti ve, l ow-dos e corti cos teroi ds ca n be tri ed.
If l es i ons recur, col chi ci ne, hydroxychl oroqui ne, or da ps one ma y prevent further recurrences . Ra rel y, s tronger i mmunos uppres s a nts (eg,
a za thi opri ne, methotrexa te) a re us ed, pa rti cul a rl y i f l es i ons ul cera te.
Giant Cell Arteritis
(Tempora l Arteri ti s ; Cra ni a l Arteri ti s ; Horton's Di s ea s e)
Giant cell arteritis involves predominantly the thoracic aorta, large arteries emerging from the aorta in the neck, and extracranial branches of the carotid arteries.
Simultaneous polymyalgia rheumatica is common. Focal symptoms and signs may include headaches, visual disturbances, temporal artery tenderness, and pain
in the jaw muscles during chewing. Fever, weight loss, malaise, and fatigue are also common. ESR and C-reactive protein are typically elevated. Diagnosis is
clinical and confirmed by temporal artery biopsy. Treatment with high-dose corticosteroids and aspirin is usually effective and prevents vision loss.
Gi a nt cel l a rteri ti s i s a rel a ti vel y common form of va s cul i ti s i n the US a nd Europe. Inci dence va ri es dependi ng on ethni c ba ckground. Autops y
s tudi es s ugges t tha t the di s order ma y be more common tha n i s cl i ni ca l l y a ppa rent. Women a re a ffected more often. Mea n a ge a t ons et i s a bout
70, wi th a ra nge of 50 to > 90. About 40 to 60% of pa ti ents wi th gi a nt cel l a rteri ti s ha ve pol ymya l gi a rheuma ti ca . The i ntra cra ni a l ves s el s a re us ua l l y
not a ffected.
Pathophysiology
Va s cul i ti s ma y be l oca l i zed, mul ti foca l , or wi des prea d. The di s order tends to a ffect a rteri es conta i ni ng el a s ti c ti s s ue, mos t often the tempora l ,
cra ni a l , or other ca roti d s ys tem a rteri es . The a orti c a rch bra nches , corona ry a rteri es , a nd peri phera l a rteri es ca n a l s o be a ffected. Mononucl ea r
cel l i nfi l tra tes i n the a dventi ti a form gra nul oma s conta i ni ng a cti va ted T cel l s a nd ma cropha ges . Mul ti nucl ea ted gi a nt cel l s , when pres ent, cl us ter
nea r the di s rupted el a s ti c l a mi na . The i nti ma l l a yer i s ma rkedl y thi ckened, wi th concentri c na rrowi ng a nd occl us i on of the l umen.
Symptoms and Signs
Symptoms ma y begi n gra dua l l y over s evera l weeks or a bruptl y.
Pa ti ents ma y pres ent wi th s ys temi c s ymptoms s uch a s fever (us ua l l y l ow-gra de), fa ti gue, ma l a i s e, unexpl a i ned wei ght l os s , a nd s wea ts . Some
pa ti ents a re i ni ti a l l y di a gnos ed a s ha vi ng FUO. Eventua l l y, mos t pa ti ents devel op s ymptoms rel a ted to the a ffected a rteri es .
Severe, s ometi mes throbbi ng hea da che (tempora l , occi pi ta l , fronta l , or di ffus e) i s the mos t common s ymptom. It ma y be a ccompa ni ed by s ca l p
pa i n el i ci ted by touchi ng the s ca l p or combi ng the ha i r.
Vi s ua l di s turba nces i ncl ude di pl opi a , s cotoma s , ptos i s , bl urred vi s i on, a nd l os s of vi s i on (whi ch i s a n omi nous s i gn). Bri ef peri ods of pa rti a l or
compl ete vi s i on l os s (a ma uros i s fuga x) i n one eye ma y be ra pi dl y fol l owed by perma nent i rrevers i bl e l os s of vi s i on. If untrea ted, the other eye
ma y a l s o be a ffected. However, compl ete bi l a tera l bl i ndnes s i s uncommon. Vi s i on l os s i s ca us ed by a rteri ti s of bra nches of the ophtha l mi c a rtery
or pos teri or ci l i a ry a rteri es , whi ch l ea ds to i s chemi a of the opti c nerve. Fundus copi c fi ndi ngs ma y i ncl ude i s chemi c opti c neuri ti s wi th pa l l or a nd
edema of the opti c di s k, s ca ttered cotton-wool pa tches , a nd s ma l l hemorrha ges . La ter, the opti c nerve a trophi es . Ra rel y, centra l bl i ndnes s res ul ts
from i nfa rcti on i n the occi pi ta l cortex ca us ed by a rteri a l l es i ons i n the di s ta l cervi ca l regi on or ba s e of the bra i n.
Intermi ttent cl a udi ca ti on (i s chemi c mus cl e pa i n) ma y occur i n ja w mus cl es a nd mus cl es of the tongue or extremi ti es . Ja w cl a udi ca ti on i s noted
es peci a l l y when fi rm foods a re chewed.
Neurol ogi c ma ni fes ta ti ons , s uch a s s trokes a nd tra ns i ent i s chemi c a tta cks , ca n res ul t when the ca roti d or vertebroba s i l a r a rteri es or bra nches a re
na rrowed or occl uded.
Thora ci c a orti c a neurys ms a nd di s s ecti on of the a orta a re s eri ous , often l a te, compl i ca ti ons .
Diagnosis
ESR, C-rea cti ve protei n, a nd CBC
Bi ops y, us ua l l y of the tempora l a rtery
Gi a nt cel l a rteri ti s i s s us pected i n pa ti ents > 55 i f a ny of the fol l owi ng devel ops , es peci a l l y i f they a l s o ha ve s ymptoms of s ys temi c i nfl a mma ti on:
A new type of hea da che
Any new s ymptom or s i gn compa ti bl e wi th i s chemi a of a n a rtery a bove the neck
Ja w pa i n duri ng chewi ng
Tempora l a rtery tendernes s

Unexpl a i ned s uba cute fever or a nemi a
The di a gnos i s i s more l i kel y i f pa ti ents a l s o ha ve s ymptoms of pol ymya l gi a rheuma ti ca .
Phys i ca l exa mi na ti on ma y detect s wel l i ng a nd tendernes s , wi th or wi thout nodul a ri ty or erythema , over the tempora l a rteri es . Tempora l a rteri es
ca n become promi nent. A tempora l a rtery tha t rol l s under the exa mi ner's fi ngers , ra ther tha n col l a ps es , i s a bnorma l . The l a rge a rteri es of the neck
a nd l i mbs a nd the a orta s houl d be eva l ua ted for brui ts .
If the di a gnos i s i s s us pected, ESR, C-rea cti ve protei n, a nd CBC a re determi ned. In mos t pa ti ents , ESR a nd C-rea cti ve protei n a re el eva ted; a nemi a of
chroni c di s ea s e i s common. Occa s i ona l l y, pl a tel ets a re el eva ted, a nd s erum a l bumi n a nd tota l protei n, mea s ured for other rea s ons , a re l ow. Mi l d
l eukocytos i s i s commonl y detected but i s nons peci fi c.
If the di a gnos i s i s s us pected, bi ops y of a n a rtery i s recommended. Beca us e i nfl a med s egments often a l terna te wi th norma l s egments , a s egment
tha t a ppea rs a bnorma l s houl d be s a mpl ed i f pos s i bl e. Us ua l l y, the tempora l a rtery i s bi ops i ed, but the occi pi ta l a rtery ca n a l s o be bi ops i ed i f i t
a ppea rs a bnorma l . The opti ma l l ength of the tempora l a rtery to remove i s uncl ea r, but 5 cm i s recommended i f pos s i bl e. Trea tment s houl d not be
del a yed to do the bi ops y. Bi ops y ca n be done up to 2 wk or perha ps more a fter trea tment i s s ta rted beca us e the i nfl a mma tory i nfi l tra te i s s l ow to
res ol ve.
If pa ti ents ha ve pul s e defi ci ts , the a orta a nd i ts bra nches a re i ma ged (s ee
Ta bl e 34-3 on p. 328).
Treatment
Corti cos teroi ds
Low-dos e a s pi ri n
Trea tment s houl d be s ta rted a s s oon a s gi a nt cel l a rteri ti s i s s us pected, even i f bi ops y i s goi ng to be del a yed for s evera l da ys .
Corti cos teroi ds a re the corners tone of trea tment. Corti cos teroi ds ra pi dl y reduce s ymptoms a nd prevent vi s i on l os s i n mos t pa ti ents . The opti ma l
i ni ti a l dos e, ta peri ng s chedul e, a nd tota l l ength of trea tment a re deba ted. For mos t pa ti ents , a n i ni ti a l dos e of predni s one 40 to 60 mg po
once/da y (or equi va l ent) for 4 wk, fol l owed by gra dua l ta peri ng, i s effecti ve. If pa ti ents ha ve vi s ua l di s turba nces , a n i ni ti a l dos e of IV
methyl predni s ol one 500 to 1000 mg once/da y for 3 to 5 da ys ca n be tri ed i n a n a ttempt to hel p prevent further decl i ne i n vi s i on, pa rti cul a rl y i n the
contra l a tera l eye.
If s ymptoms l es s en, predni s one ca n be ta pered gra dua l l y from dos es of up to 60 mg/da y ba s ed on the pa ti ent's res pons e, us ua l l y a s fol l ows : by 5
to 10 mg/da y every week to 40 mg/da y, by 2 to 5 mg/da y every week to 10 to 20 mg/da y, then by 1 mg/da y every month therea fter unti l the drug i s
s topped. ESR a l one s houl d not be us ed a l one to eva l ua te pa ti ent res pons e (a nd di s ea s e a cti vi ty). Cl i ni ca l s ymptoms mus t a l s o be us ed.
Mos t pa ti ents requi re a t l ea s t 2 yr of trea tment wi th corti cos teroi ds . Long-term us e of corti cos teroi ds ca n ha ve s i gni fi ca nt a dvers e effects a nd thus
s houl d be l i mi ted i f pos s i bl e. More tha n one ha l f of pa ti ents ta ki ng thes e drugs ha ve drug-rel a ted compl i ca ti ons . Cons equentl y, a l terna ti ve
thera pi es a re bei ng s tudi ed. If pa ti ents ca nnot tol era te corti cos teroi ds or i f s ymptoms return when the dos e i s ta pered, methotrexa te 0.3
mg/kg/wk ma y be us eful .
Tumor necros i s fa ctor i nhi bi tors ha ve not been s hown to be effecti ve.
Low-dos e a s pi ri n (100 mg po once/da y) ma y hel p prevent i s chemi c events a nd s houl d be pres cri bed for a l l pa ti ents unl es s contra i ndi ca ted.
Henoch-Schonlein Purpura
Henoch-Schonlein purpura is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations include palpable purpura,
arthralgias, GI symptoms and signs, and glomerulonephritis. Diagnosis is clinical in children but usually warrants biopsy in adults. Disease is usually self-limited.
Corticosteroids can relieve arthralgias and GI symptoms but do not alter the course of the disease. Progressive glomerulonephritis may require high-dose
corticosteroids and cyclophosphamide.
In Henoch-Schonl ei n purpura , IgA-conta i ni ng i mmune compl exes a re depos i ted i n s ma l l ves s el s of the s ki n a nd other s i tes , wi th cons equent
a cti va ti on of compl ement. Pos s i bl e i nci ti ng a nti gens i ncl ude vi rus es tha t ca us e URIs , s treptococca l i nfecti on, drugs , foods , i ns ect bi tes , a nd
i mmuni za ti ons . Foca l , s egmenta l prol i fera ti ve gl omerul onephri ti s i s typi ca l but mi l d.
Symptoms and Signs
The di s ea s e begi ns wi th a s udden pa l pa bl e purpuri c ra s h typi ca l l y occurri ng on the feet, l egs , a nd a rms a nd a s a s tri p a cros s the buttocks . The
purpura ma y s ta rt a s s ma l l a rea s of urti ca ri a tha t become i ndura ted a nd pa l pa bl e. Crops of new l es i ons ma y a ppea r over da ys to s evera l weeks .
Ma ny pa ti ents a l s o ha ve fever a nd pol ya rthra l gi a wi th peri a rti cul a r tendernes s a nd s wel l i ng of the a nkl es , knees , hi ps , wri s ts , a nd el bows .
GI s ymptoms a re common a nd i ncl ude col i cky a bdomi na l pa i n, a bdomi na l tendernes s , a nd mel ena . Intus s us cepti on occa s i ona l l y devel ops i n
chi l dren. Stool ma y tes t pos i ti ve for occul t bl ood.
Symptoms us ua l l y remi t a fter a bout 4 wk but often recur a t l ea s t once a fter a di s ea s e-free i nterva l of s evera l weeks . In mos t pa ti ents , the di s order
s ubs i des wi thout s eri ous s equel a e; however, s ome pa ti ents devel op chroni c rena l fa i l ure.
Diagnosis
Bi ops y of s ki n l es i ons
The di a gnos i s i s s us pected i n pa ti ents , pa rti cul a rl y chi l dren, wi th typi ca l s ki n fi ndi ngs . It i s confi rmed by bi ops y of s ki n l es i ons when
l eukocytocl a s ti c va s cul i ti s wi th IgA i n the ves s el wa l l s i s i denti fi ed. Bi ops y i s unneces s a ry i f cl i ni ca l di a gnos i s i s cl ea r i n chi l dren. Uri na l ys i s i s
done; hema turi a , protei nuri a , a nd RBC ca s ts i ndi ca te rena l i nvol vement. CBC a nd rena l functi on tes ts a re done.
If rena l functi on i s deteri ora ti ng, rena l bi ops y ma y hel p defi ne the prognos i s . Di ffus e gl omerul a r i nvol vement or cres cent forma ti on i n mos t
gl omerul i predi cts progres s i ve rena l fa i l ure.
Treatment
Pri ma ri l y corti cos teroi ds a nd s ymptoma ti c mea s ures
If the ca us e i s a drug, i t ha s to be s topped. Otherwi s e, trea tment i s pri ma ri l y s ymptoma ti c. Corti cos teroi ds (eg, predni s one 2 mg/kg up to a tota l of
50 mg po once/da y) ma y hel p control a bdomi na l pa i n a nd a re occa s i ona l l y needed to trea t s evere joi nt pa i n or rena l di s ea s e. Pul s e IV
methyl predni s ol one fol l owed by ora l predni s one a nd cycl ophos pha mi de ca n be gi ven to a ttempt to control i nfl a mma ti on when the ki dneys a re
s everel y a ffected. However, the effects of corti cos teroi ds on rena l ma ni fes ta ti ons a re not cl ea r.
Microscopic Polyangiitis
Microscopic polyangiitis is a systemic pauci-immune necrotizing vasculitis that affects mainly small vessels. It may begin as a pulmonary-renal syndrome with
rapidly progressing glomerulonephritis and alveolar hemorrhage, but the pattern of disease depends on the organs affected. Diagnosis is by biopsy. Treatment,
which depends on disease severity, includes corticosteroids and immunosuppressants.
Mi cros copi c pol ya ngi i ti s i s ra re (a bout 13 to 19 ca s es /mi l l i on). Pa thogenes i s i s unknown. Li ke i mmune compl ex-a s s oci a ted va s cul i ti s (eg, SLE,
cryogl obul i nemi a , s erum s i cknes s , Henoch-Schonl ei n purpura ), mi cros copi c pol ya ngi i ti s a ffects s ma l l ves s el s . Pol ya rteri ti s nodos a ca n ca us e
s ome ma ni fes ta ti ons s i mi l a r to the s ma l l ves s el va s cul i ti des , s uch a s mononeuri ti s mul ti pl ex a nd bowel i s chemi a . Mi cros copi c pol ya ngi i ti s ca n
be di s ti ngui s hed from i mmune compl ex-a s s oci a ted va s cul i ti s a nd pol ya rteri ti s nodos a by the fol l owi ng:
Mi cros copi c pol ya ngi i ti s a ffects predomi na ntl y s ma l l ves s el s , unl i ke pol ya rteri ti s nodos a , whi ch a ffects medi um-s i zed mus cul a r a rteri es .
Mi cros copi c pol ya ngi i ti s , unl i ke pol ya rteri ti s nodos a , ma y ca us e gl omerul onephri ti s a nd ma y a ffect the l ungs a nd ca us e a l veol a r hemorrha ge.
Immune compl ex depos i ts a re s ca rce or a bs ent (i e, pa uci -i mmune) i n contra s t to i mmune compl ex-a s s oci a ted va s cul i ti s .
Cl i ni ca l ma ni fes ta ti ons res embl e thos e of Wegener's gra nul oma tos i s except tha t gra nul oma tous des tructi ve l es i ons a re a bs ent a nd the upper
res pi ra tory tra ct i s us ua l l y not s everel y a ffected. In both di s orders , a nti neutrophi l cytopl a s mi c a nti bodi es (ANCA) ma y be pres ent. Mi cros copi c
pol ya ngi i ti s ca n occur i n pa ti ents wi th vi ra l hepa ti ti s B or C.
Symptoms and Signs
Us ua l l y, a prodroma l i l l nes s wi th s ys temi c s ymptoms of fever, wei ght l os s , mya l gi a , a nd a rthra l gi a occurs . Other s ymptoms depend on whi ch
orga ns a nd s ys tems a re a ffected:
Renal: The ki dneys a re a ffected i n up to 90% of pa ti ents . Hema turi a , protei nuri a (s ometi mes > 3 g/24 h), a nd RBC ca s ts a re pres ent. Wi thout
prompt di a gnos i s a nd trea tment, rena l fa i l ure ma y fol l ow ra pi dl y.
Cutaneous: About one thi rd of pa ti ents ha ve a purpuri c ra s h a t the ti me of the di a gnos i s . Na i l bed i nfa rcts a nd s pl i nter hemorrha ges ma y occur;
di gi ta l i s chemi a occurs ra rel y.
Respiratory: If the l ungs a re a ffected, a l veol a r hemorrha ge ma y occur, fol l owed by pul mona ry fi bros i s . Ra pi d-ons et dys pnea a nd a nemi a , wi th or
wi thout hemoptys i s a nd bi l a tera l pa tchy i nfi l tra tes (s een on ches t x-ra y) ma y be due to a l veol a r hemorrha ge, a medi ca l emergency tha t
requi res i mmedi a te trea tment. Mi l d s ymptoms of rhi ni ti s , epi s ta xi s , a nd s i nus i ti s ma y occur; however, i f the upper res pi ra tory tra ct i s s everel y
a ffected, the ca us e i s more l i kel y to be Wegener's gra nul oma tos i s .
GI: GI s ymptoms i ncl ude a bdomi na l pa i n, na us ea , vomi ti ng, di a rrhea , a nd bl oody s tool s .
Neurologic: If the nervous s ys tem i s a ffected, mononeuri ti s mul ti pl ex tha t a ffects peri phera l or cra ni a l nerves us ua l l y occurs . Cerebra l
hemorrha ge, i nfa rcti on, s ei zures , or hea da che ra rel y res ul ts from cerebra l va s cul i ti s .
Cardiac: Ra rel y, the hea rt i s a ffected.
Ocular: If the eyes a re a ffected, epi s cl eri ti s us ua l l y res ul ts .
Diagnosis
Cl i ni ca l fi ndi ngs
Tes ts for ANCA a nd C-rea cti ve protei n a nd routi ne l a bora tory tes ts
Bi ops y
Mi cros copi c pol ya ngi i ti s ma y mi mi c ma ny other di s orders beca us e i ts ma ni fes ta ti ons va ry. The di s order s houl d be s us pected i n pa ti ents who ha ve
unexpl a i ned combi na ti ons of GI s ymptoms or s i gns , a l veol a r hemorrha ge, epi s cl eri ti s , a nd peri phera l neuropa thy. La bora tory tes ts a nd
s ometi mes x-ra ys a re done, but the di a gnos i s i s us ua l l y confi rmed by bi ops y.
Tes ts i ncl ude CBC, ESR, C-rea cti ve protei n, uri na l ys i s , s erum crea ti ni ne, a nd tes ts for ANCA. ESR, C-rea cti ve protei n l evel s , a nd WBC a nd pl a tel et
counts a re el eva ted, refl ecti ng s ys temi c i nfl a mma ti on. Anemi a of chroni c di s ea s e i s common. An a cute drop i n Hct s ugges ts a l veol a r hemorrha ge
or hemorrha ge i n the GI tra ct. Uri na l ys i s (to check for hema turi a , protei nuri a , a nd cel l ul a r ca s ts ) s houl d be done, a nd s erum crea ti ni ne s houl d be
mea s ured peri odi ca l l y to check for rena l i nvol vement.
Immunofl uores cence s ta i ni ng ca n detect ANCA; thi s tes t i s fol l owed by enzyme-l i nked i mmunos orbent a s s a y (ELISA) to check for s peci fi c
a nti bodi es . At l ea s t 60% of pa ti ents ha ve ANCA, us ua l l y peri nucl ea r ANCA (p-ANCA) wi th a nti bodi es a ga i ns t myel operoxi da s e.
Bi ops y of the mos t a cces s i bl e i nvol ved ti s s ue s houl d be done to confi rm va s cul i ti s . Rena l bi ops y ma y detect foca l s egmenta l pa uci -i mmune
necroti zi ng gl omerul onephri ti s wi th fi bri noi d necros i s of the gl omerul a r ca pi l l a ry wa l l , l ea di ng to forma ti on of cel l ul a r cres cents .
In pa ti ents wi th res pi ra tory s ymptoms , ches t x-ra y i s done to check for i nfi l tra tes . Bi l a tera l pa tchy i nfi l tra tes s ugges t a l veol a r hemorrha ge even i n
pa ti ents wi thout hemoptys i s .
If pa ti ents ha ve dys pnea a nd bi l a tera l i nfi l tra tes , bronchos copy s houl d be done i mmedi a tel y to check for a l veol a r hemorrha ges . Bl ood comi ng
from both l ungs a nd a l l bronchi , wi th more bl ood comi ng a s the bronchos cope goes deeper i n the a i rwa ys , i ndi ca tes a cti ve a l veol a r hemorrha ge.
Hemos i deri n-l a den ma cropha ges a ppea r wi thi n 24 to 72 h a fter ons et of hemorrha ge a nd ma y pers i s t for up to 2 mo.
Treatment
When vi ta l orga ns a re a ffected, corti cos teroi ds pl us cycl ophos pha mi de
For l es s s evere ca s es , corti cos teroi ds pl us a za thi opri ne or methotrexa te
Trea tment i s s i mi l a r to tha t of Wegener's gra nul oma tos i s . Cycl ophos pha mi de gi ven da i l y pl us corti cos teroi ds i mproves s urvi va l when vi ta l orga ns
a re a ffected. However, i nducti on a nd ma i ntena nce regi mens va ry, a nd a djuncti ve thera pi es s uch a s pl a s ma excha nge a nd pul s e IV
methyl predni s ol one ma y or ma y not be us ed.
Les s s evere ca s es ma y be ma na ged wi th corti cos teroi ds pl us a za thi opri ne or methotrexa te.
Polyarteritis Nodosa
(Pol ya rteri ti s ; Peri a rteri ti s Nodos a )
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular
arteries, resulting in secondary tissue ischemia. The kidneys, skin, joints, muscles, peripheral nerves, and GI tract are most commonly affected, but any organ can
be. However, the lungs are usually spared. Patients typically present with systemic symptoms (eg, fever, fatigue). Diagnosis requires a biopsy or arteriography.
Treatment with corticosteroids and immunosuppressants is often effective.
PAN i s ra re (a bout 2 to 33 ca s es /mi l l i on). It a ffects ma i nl y mi ddl e-a ged a dul ts , a nd i nci dence i ncrea s es wi th a gi ng, pea ki ng i n peopl e i n thei r 50s .
Etiology
Mos t ca s es a re i di opa thi c. About 20% of pa ti ents ha ve hepa ti ti s B or C.
The ca us e i s unknown, but i mmune mecha ni s ms a ppea r to be i nvol ved. The va ri ety of cl i ni ca l a nd pa thol ogi c fea tures s ugges ts mul ti pl e
pa thogeni c mecha ni s ms . Drugs ma y be a ca us e. Us ua l l y, no predi s pos i ng a nti gen i s i denti fi ed. Pa ti ents wi th certa i n l ymphoma s a nd l eukemi a s ,
RA, or Sjogren's s yndrome ma y devel op a s ys temi c va s cul i ti s s i mi l a r to PAN.
Pathophysiology
PAN i s cha ra cteri zed by s egmenta l , tra ns mura l necroti zi ng i nfl a mma ti on of mus cul a r a rteri es , mos t commonl y a t poi nts of bi furca ti on. Unl i ke other
va s cul i ti c di s orders , PAN does not i nvol ve pos tca pi l l a ry venul es or vei ns . Les i ons i n a l l s ta ges of devel opment a nd hea l i ng a re us ua l l y pres ent.
Ea rl y l es i ons conta i n PMNs a nd occa s i ona l l y eos i nophi l s ; l a ter l es i ons conta i n l ymphocytes a nd pl a s ma cel l s . Gra nul oma tous i nfl a mma ti on does
not occur. Inti ma l prol i fera ti on wi th s econda ry thrombos i s a nd occl us i on l ea ds to orga n a nd ti s s ue i nfa rcti on. Wea keni ng of the mus cul a r a rteri a l
wa l l ma y ca us e s ma l l a neurys ms a nd a rteri a l di s s ecti on. Hea l i ng ca n res ul t i n nodul a r fi bros i s of the a dventi ti a .
Mos tl y commonl y a ffected a re the ki dneys , s ki n, peri phera l nerves , joi nts , mus cl es , a nd GI tra ct. Often a ffected a re the l i ver a nd hea rt. Rena l
i s chemi a a nd i nfa rcti on occur, but gl omerul onephri ti s i s not a fea ture of PAN. Purpura i s not a cha ra cteri s ti c of PAN.
Symptoms and Signs
PAN mi mi cs ma ny di s orders . The cours e ma y be a cute a nd prol onged, s uba cute a nd fa ta l a fter s evera l months , or i ns i di ous , chroni c, a nd
debi l i ta ti ng. Symptoms depend ma i nl y on l oca ti on a nd s everi ty of the a rteri ti s a nd extent of s econda ry i s chemi a . Onl y one orga n or orga n s ys tem
ma y be a ffected.
Pa ti ents typi ca l l y pres ent wi th fever, fa ti gue, ni ght s wea ts , l os s of a ppeti te, wei ght l os s , a nd genera l i zed wea knes s . Mya l gi a s wi th a rea s of foca l
i s chemi c myos i ti s a nd a rthra l gi a s a re common. Affected mus cl es a re tender a nd wea k. Arthri ti s ma y occur.
Symptoms a nd s i gns va ry, dependi ng on orga n or orga n s ys tem predomi na ntl y a ffected:
Peripheral nervous system: Pa ti ents us ua l l y pres ent wi th a s ymmetri c peri phera l neuropa thy, s uch a s mononeuri ti s mul ti pl ex wi th s i gns of motor
a nd s ens ory i nvol vement of the peronea l , medi a n, or ul na r nerves . As a ddi ti ona l nerve bra nches a re a ffected, pa ti ents ma y a ppea r to ha ve a
di s ta l s ymmetri c pol yneuropa thy.
CNS: Hea da che a nd s ei zures ca n res ul t. In a few pa ti ents , i s chemi c s troke a nd cerebra l hemorrha ge occur, s ometi mes res ul ti ng from
hypertens i on.
Renal: If s ma l l a nd medi um-s i zed a rteri es i n the ki dneys a re a ffected, pa ti ents ma y ha ve hypertens i on, ol i guri a , uremi a , a nd a nons peci fi c
uri na ry s edi ment wi th hema turi a , protei nuri a , a nd no cel l ul a r ca s ts . Hypertens i on ma y wors en ra pi dl y. Rupture of rena l a rteri a l a neurys ms ca n
ca us e peri rena l hema toma s . In s evere ca s es , mul ti pl e rena l i nfa rcts wi th l umba r pa i n a nd gros s hema turi a ma y occur. Rena l i s chemi a a nd
i nfa rcti on ca n l ea d to rena l fa i l ure.
GI: Va s cul i ti s of the l i ver or ga l l bl a dder ca us es ri ght upper qua dra nt pa i n. Perfora ti on of the ga l l bl a dder wi th a cute a bdomen ma y occur.
Va s cul i ti s of medi um-s i zed mes enteri c a rteri es ca us es a bdomi na l pa i n, na us ea , vomi ti ng (wi th or wi thout bl oody di a rrhea ), ma l a bs orpti on,
i ntes ti na l perfora ti on, a nd a cute a bdomen. Aneurys ms ma y devel op i n hepa ti c or cel i a c a rteri es .
Cardiac: Some pa ti ents ha ve corona ry a rtery di s ea s e, whi ch i s us ua l l y a s ymptoma ti c, but ma y ca us e a ngi na . Hea rt fa i l ure ma y res ul t from
i s chemi c or hypertens i ve ca rdi omyopa thy
Cutaneous: Li vedo reti cul a ri s , s ki n ul cers , tender erythema tous nodul es , bul l ous or ves i cul a r erupti ons , i nfa rcti on a nd ga ngrene of fi ngers or toes ,
or a combi na ti on ma y occur. The nodul es i n PAN res embl e erythema nodos um (i nfl a mma ti on of s ubcuta neous fa t), but i n PAN, necroti zi ng
va s cul i ti s occurs wi thi n the wa l l s of medi um-s i zed a rteri es , us ua l l y l oca ted i n the deep dermi s a nd s ubcuta neous fa t.
Genital: Orchi ti s wi th tes ti cul a r pa i n a nd tendernes s ca n occur.
Diagnosis
Bi ops y
Arteri ogra phy i f no cl i ni ca l l y i nvol ved ti s s ue i s a va i l a bl e for bi ops y
PAN ma y be s us pected i n pa ti ents wi th unexpl a i ned fever, a bdomi na l pa i n, rena l fa i l ure, hypertens i on, a rthra l gi a , mus cl e tendernes s or
wea knes s , s ubcuta neous nodul es , s ki n ul cers , pa i n i n the a bdomen or extremi ti es , or ra pi dl y devel opi ng hypertens i on. If pa ti ents ha ve i ns i di ous ,
nons peci fi c s ymptoms , di a gnos i s i s much more di ffi cul t. The di a gnos i s i s further cl a ri fi ed when cl i ni ca l fi ndi ngs a re combi ned wi th certa i n
l a bora tory res ul ts a nd other ca us es a re excl uded. PAN i s a l s o s us pected i n pa ti ents wi th s ys temi c s ymptoms or s i gns a nd peri phera l (us ua l l y
mul ti pl e) neuri ti s i nvol vi ng ma jor nerve trunks (eg, ra di a l , peronea l , s ci a ti c) i n a bi l a tera l l y s ymmetri c or a s ymmetri c fa s hi on (mononeuri ti s
mul ti pl ex).
Di a gnos i s i s confi rmed by bi ops y s howi ng necroti zi ng a rteri ti s or by a rteri ogra phy s howi ng the typi ca l a neurys ms i n medi um-s i zed a rteri es .
Ma gneti c res ona nce a ngi ogra phy ma y s how mi croa neurys ms , but s ome a bnorma l i ti es ma y be too s ma l l for i t to detect. Thus , ma gneti c res ona nce
a ngi ogra phy i s not the tes t us ed pri ma ri l y for di a gnos i s . Bi ops y of cl i ni ca l l y uni nvol ved ti s s ue i s us ua l l y us el es s beca us e the di s ea s e i s foca l ;
bi ops y s houl d ta rget s i tes s ugges ted by cl i ni ca l eva l ua ti on. Sa mpl es of s ubcuta neous ti s s ue, s ura l nerve, a nd mus cl e, i f thought to be i nvol ved,
a re preferred to s a mpl es from the ki dneys or l i ver. If cl i ni ca l fi ndi ngs a re a bs ent or mi ni ma l , el ectromyogra phy a nd nerve conducti on s tudi es ma y
hel p s el ect the s i te of mus cl e or nerve bi ops y. If s ki n l es i ons a re pres ent, s urgi ca l s ki n bi ops i es tha t i ncl ude deeper dermi s a nd s ubcuta neous fa t
s houl d be done. (Punch bi ops i es of the s ki n tha t s a mpl e the epi dermi s a nd s uperfi ci a l dermi s mi s s the l es i ons of PAN.) Even though mi cros copi c
l es i ons i n the tes tes a re common, tes ti cul a r bi ops y s houl d not be done i f tes ti cul a r s ymptoms a re a bs ent a nd i f other pos s i bl e s i tes a re
a cces s i bl e beca us e the yi el d i s l ow. Al s o, men ma y be rel ucta nt to ha ve tes ti cul a r bi ops y.
La bora tory tes ts a re nons peci fi c. Leukocytos i s up to 20,000 to 40,000/L, protei nuri a , a nd mi cros copi c hema turi a a re the mos t common
a bnorma l i ti es . Pa ti ents ma y ha ve thrombocytos i s , ma rkedl y el eva ted ESR, a nemi a ca us ed by bl ood l os s or rena l fa i l ure, hypoa l bumi nemi a , a nd
el eva ted s erum i mmunogl obul i ns . AST a nd ALT a re often mi l dl y el eva ted. Tes ti ng for hepa ti ti s B a nd C s houl d be done. Other tes ti ng (eg,
a nti neutrophi l cytopl a s mi c a nti bodi es [ANCA], rheuma toi d fa ctor, a nti cycl i c ci trul l i na ted pepti des [CCP], a nti nucl ea r a nti bodi es [ANA], C3 a nd C4
compl ement l evel s , cryogl obul i n l evel s , nucl ea r a nti gens a nd a nti bodi es to extra cta bl e nucl ea r a nti gens s uch a s a nti -Smi th, a nti -Ro/SSA, a nti La /SSB, a nd a nti -RNP) i s done i f the cl i ni ca l pres enta ti on s ugges ts other di a gnos es , s uch a s RA, SLE, or Sjogren's s yndrome.
Prognosis
Wi thout trea tment, 5-yr s urvi va l i s < 15%. Wi th trea tment, 5-yr s urvi va l i s > 80% but ma y be l ower for pa ti ents wi th hepa ti ti s B. Prognos i s i s better i f
di s ea s e remi s s i on i s a chi eved wi thi n 18 mo a fter di a gnos i s .
The fol l owi ng fi ndi ngs a re a s s oci a ted wi th a poor prognos i s :
GI i nvol vement
Neurol ogi c i nvol vement
Treatment
Corti cos teroi ds a l one or wi th cycl ophos pha mi de, methotrexa te, or a za thi opri ne, dependi ng on di s ea s e s everi ty
Addi ti on of l a mi vudi ne a nd pl a s ma excha nge for pa ti ents wi th hepa ti ti s B

Trea tment depends on the s everi ty of the di s ea s e. For s ys temi c s ymptoms but no s eri ous neurol ogi c, rena l , GI, or ca rdi a c ma ni fes ta ti ons ,
corti cos teroi ds ma y be s uffi ci ent, a t l ea s t i ni ti a l l y. For s evere di s ea s e wi th neurol ogi c, rena l , GI, or ca rdi a c ma ni fes ta ti ons , cycl ophos pha mi de
pl us corti cos teroi ds ma y i mprove outcome. For modera te di s ea s e, corti cos teroi ds pl us methotrexa te or a za thi opri ne ca n be us ed. Hypertens i on
s houl d be trea ted a ggres s i vel y; ACE i nhi bi tors a re effecti ve.
Hepatitis B-related PAN: Trea tment a i ms a t ra pi dl y s uppres s i ng i nfl a mma ti on, then el i mi na ti ng the vi rus a nd i nduci ng s eroconvers i on vi a pl a s ma
excha nge. A s hort cours e of corti cos teroi ds i s us ed for a few weeks . La mi vudi ne 100 mg po once/da y i s gi ven for a ma xi mum of 6 mo. A l ower dos e
i s us ed i n pa ti ents wi th rena l i ns uffi ci ency. Pl a s ma excha nges a re s chedul ed a s fol l ows : 3 ti mes /wk for 3 wk, 2 ti mes /wk for 2 wk a nd once/wk
unti l hepa ti ti s B e a nti gen (HBeAg) converts to hepa ti ti s B e a nti body (a nti -HBe) or unti l cl i ni ca l recovery i s s us ta i ned for 2 to 3 mo. Al though thi s
a pproa ch ha s not been proved to i mprove s urvi va l when compa red wi th i mmunos uppres s i ve thera py onl y, i t ma y reduce the ri s k of l ong-term
compl i ca ti ons of hepa ti ti s B a nd s uppres s the s i de effects of l ong-term trea tment wi th corti cos teroi ds a nd i mmunos uppres s a nts .
Tra di ti ona l trea tment wi th corti cos teroi ds , s ometi mes wi th cytotoxi c i mmunos uppres s a nts (ma i nl y cycl ophos pha mi de), wa s often effecti ve i n the
s hort term but di d not prevent rel a ps es a nd compl i ca ti ons (eg, chroni c hepa ti ti s , ci rrhos i s ) due to pers i s tence of the hepa ti ti s B vi rus .
Polymyalgia Rheumatica
Polymyalgia rheumatica is a syndrome closely associated with giant cell (temporal) arteritis. It affects adults > 55. It typically causes severe pain and stiffness in
proximal muscles, without weakness or atrophy, and nonspecific systemic symptoms. ESR is markedly elevated. Diagnosis is clinical. Treatment with low-dose
corticosteroids is effective.
Pol ymya l gi a rheuma ti ca a ffects a dul ts > 55; the fema l e:ma l e ra ti o i s 2:1.
Beca us e pol ymya l gi a rheuma ti ca i s cl os el y a s s oci a ted wi th gi a nt cel l a rteri ti s (s ee p. 319), s ome a uthori ti es cons i der the two di s orders to be
di fferent pha s es of the s a me proces s . Pol ymya l gi a rheuma ti ca a ppea rs to be more common. A few pa ti ents wi th pol ymya l gi a rheuma ti ca devel op
gi a nt cel l a rteri ti s , but 40 to 60% of pa ti ents wi th gi a nt cel l a rteri ti s ha ve pol ymya l gi a rheuma ti ca . Pol ymya l gi a rheuma ti ca ma y precede or occur
s i mul ta neous l y wi th gi a nt cel l a rteri ti s .
Eti ol ogy a nd pa thogenes i s a re unknown. Whether s ymptoms res ul t from va s cul i ti s i s uncl ea r; they proba bl y res ul t from l ow-gra de a xi a l s ynovi ti s
a nd burs i ti s .
Symptoms and Signs
Pol ymya l gi a rheuma ti ca i s cha ra cteri zed by bi l a tera l proxi ma l a chi ng of the s houl der a nd hi p gi rdl e mus cl es a nd the ba ck (upper a nd l ower) a nd
neck mus cl es . Sti ffnes s i n the morni ng i s typi ca l . Shoul der s ymptoms ma y refl ect proxi ma l burs i ti s (eg, s ubdel toi d, s uba cromi a l ) a nd l es s often
bi ci pi ta l tenos ynovi ti s or joi nt s ynovi ti s . Di s comfort i s wors e i n the morni ng a nd i s occa s i ona l l y s evere enough to prevent pa ti ents from getti ng out
of bed a nd from doi ng s i mpl e a cti vi ti es . The pa i n ma y ma ke pa ti ents feel wea k, but objecti ve mus cl e wea knes s i s not a fea ture of the di s order.
Diagnosis
Pol ymya l gi a rheuma ti ca i s s us pected i n el derl y pa ti ents wi th typi ca l s ymptoms , but other pos s i bl e ca us es mus t be excl uded. Tes ts i ncl ude ESR,
CBC, thyroi d-s ti mul a ti ng hormone l evel s , a nd CK. In > 80 % of pa ti ents , ESR i s ma rkedl y el eva ted, often > 100 mm/h, us ua l l y > 50 mm/h (Wes tergren
method). El ectromyogra phy, bi ops y, a nd other tes ts (eg, rheuma toi d fa ctor), whi ch a re norma l i n pol ymya l gi a rheuma ti ca , a re s ometi mes done to
rul e out other cl i ni ca l l y s us pected di a gnos es .
The fol l owi ng fi ndi ngs i n pol ymya l gi a rheuma ti ca di s ti ngui s h i t:
From RA: Chroni c s ma l l joi nt s ynovi ti s (a l though s ome joi nt s wel l i ng ma y be pres ent), eros i ve or des tructi ve l es i ons , rheuma toi d nodul es , a nd
rheuma toi d fa ctor a re a bs ent.
From pol ymyos i ti s : Pa i n ra ther tha n wea knes s predomi na tes ; mus cl e enzyme l evel s a nd el ectromyogra phy a nd mus cl e bi ops y res ul ts a re norma l .
From hypothyroi di s m: Thyroi d functi on tes t res ul ts a nd mus cl e enzyme l evel s a re norma l .
From mul ti pl e myel oma : Monocl ona l ga mmopa thy i s a bs ent.
From fi bromya l gi a : Symptoms a re more l oca l i zed, a nd ESR i s typi ca l l y el eva ted.
Treatment
Predni s one
Predni s one s ta rted a t 15 to 20 mg po once/da y res ul ts i n dra ma ti c i mprovement. If gi a nt cel l a rteri ti s i s thought to be pres ent, the dos e s houl d be
hi gher, a nd tempora l a rtery bi ops y s houl d be done. As s ymptoms s ubs i de, corti cos teroi ds a re ta pered to the l owes t cl i ni ca l l y effecti ve dos e,
rega rdl es s of ESR. Some pa ti ents a re a bl e to s top corti cos teroi ds i n 1 yr; others requi re s ma l l dos es for yea rs . NSAIDs a re ra rel y s uffi ci ent.
In el derl y pa ti ents , phys i ci a ns s houl d wa tch for a nd trea t compl i ca ti ons of corti cos teroi d us e (eg, di a betes , hypertens i on). Pa ti ents ta ki ng
predni s one l ong term s houl d be gi ven a bi s phos phona te to prevent os teoporos i s .
Beca us e pa ti ents ma y devel op gi a nt cel l a rteri ti s , they s houl d be i ns tructed to i mmedi a tel y report hea da che, mus cl e pa i n duri ng chewi ng, a nd,
pa rti cul a rl y, vi s ua l di s turba nces to thei r phys i ci a n.
Takayasu's Arteritis
(Pul s el es s Di s ea s e; Occl us i ve Thromboa ortopa thy; Aorti c Arch Syndrome)
Takayasu's arteritis is an inflammatory disease affecting the aorta, its branches, and pulmonary arteries. It occurs predominantly in young women. Etiology is
unknown. Vascular inflammation may cause arterial stenosis, occlusion, dilation, or aneurysms. It causes asymmetric pulses and symptoms and signs of arterial
obstruction. Diagnosis is by aortic arteriography or magnetic resonance angiography. Treatment is with corticosteroids and, for organ-threatening ischemia,
vascular interventions such as bypass surgery.
Ta ka ya s u's a rteri ti s i s ra re. It i s more common a mong As i a ns but occurs worl dwi de. Fema l e:ma l e ra ti o i s 8:1, a nd a ge a t ons et i s typi ca l l y 15 to 30.
In North Ameri ca , a nnua l i nci dence i s es ti ma ted to be 2.6 ca s es /mi l l i on.
Etiology
The ca us e i s unknown. Cel l -medi a ted i mmune mecha ni s ms ma y be i nvol ved a nd ma y be s i mi l a r to thos e i n gi a nt cel l a rteri ti s .
Pathophysiology
Ta ka ya s u's a rteri ti s a ffects pri ma ri l y l a rge el a s ti c a rteri es . The mos t commonl y a ffected a re the i nnomi na te a nd s ubcl a vi a n a rteri es , a orta (ma i nl y
the a s cendi ng a orta a nd the a rch), common ca roti d a rteri es , a nd rena l a rteri es . Mos t pa ti ents ha ve s tenos es or occl us i ons . Aneurys ms occur i n
a bout one thi rd of pa ti ents . Us ua l l y, the wa l l of the a orta or i ts bra nches thi ckens i rregul a rl y, wi th i nti ma l wri nkl i ng. When the a orti c a rch i s
a ffected, ori fi ces of the ma jor a rteri es emergi ng from the a orta ma y be ma rkedl y na rrowed or even obl i tera ted by i nti ma l thi ckeni ng. In one ha l f of
pa ti ents , pul mona ry a rteri es a re a l s o a ffected.
Hi s tol ogi ca l l y, ea rl y cha nges cons i s t of a dventi ti a l mononucl ea r i nfi l tra te wi th peri va s cul a r cuffi ng of the va s a va s orum. La ter, i ntens e
mononucl ea r i nfl a mma ti on of the medi a ma y occur, s ometi mes a ccompa ni ed by gra nul oma tous cha nges , gi a nt cel l s , a nd pa tchy necros i s of the
medi a . Morphol ogi c cha nges ma y be i ndi s ti ngui s ha bl e from thos e of gi a nt cel l a rteri ti s . Pa na rteri ti c i nfl a mma tory i nfi l tra tes ca us e ma rked
thi ckeni ng of the a ffected a rtery a nd s ubs equent l umi na l na rrowi ng a nd occl us i on.
Symptoms and Signs
Mos t pa ti ents pres ent wi th onl y foca l s ymptoms tha t refl ect hypoperfus i on of the a ffected orga n or l i mb. Ta ka ya s u's a rteri ti s ma y ha ve 3 s ta ges :
Sys temi c di s ea s e, us ua l l y wi th s ys temi c, nons peci fi c s ymptoms (eg, fever, ma l a i s e, ni ght s wea ts , wei ght l os s , a rthra l gi a s , fa ti gue)
Va s cul a r i nfl a mma tory pha s e, wi th i s chemi c ma ni fes ta ti ons tha t ma y wa x a nd wa ne
Ina cti ve (burned-out) di s ea s e, s ometi mes wi th a cute or progres s i ve occl us i on (i ncl udi ng thrombos i s )
Onl y one thi rd of pa ti ents ha ve s ys temi c s ymptoms a t pres enta ti on or reca l l ha vi ng ha d s uch s ymptoms .
Repeti ti ve a rm movements a nd s us ta i ned a rm el eva ti on ma y ca us e pa i n a nd fa ti gue. Arteri a l pul s es i n a rms a nd l egs ma y be di mi ni s hed a nd
a s ymmetri c. Brui ts a re often a udi bl e over the s ubcl a vi a n a rteri es , bra chi a l a rteri es , ca roti d a rteri es , a bdomi na l a orta , or femora l a rteri es .
Reduced BP i n one or both a rms i s common.
When the ca roti d a nd vertebra l a rteri es a re a ffected, cerebra l bl ood fl ow decrea s es , l ea di ng to di zzi nes s , s yncope, orthos ta ti c hypotens i on,
hea da ches , tra ns i ent vi s ua l di s turba nces , tra ns i ent i s chemi c a tta cks , or s trokes . Stenoti c l es i ons i n a s ubcl a vi a n a rtery nea r the ori gi n of a pa tent
vertebra l a rtery ca n ca us e pos teri or ci rcul a ti on neurol ogi c s ymptoms or s yncope when the a rm i s us ed (ca l l ed s ubcl a vi a n s tea l s yndrome).
Retrogra de fl ow through the vertebra l a rtery s uppl i es the s ubcl a vi a n a rtery di s ta l to the s tenos i s , a nd va s odi l a ti on of the a rteri a l bed i n the upper
l i mb duri ng exerci s e compromi s es pos teri or cerebra l bl ood fl ow.
Angi na pectori s or MI ma y res ul t from na rrowi ng of the corona ry a rtery ori fi ce due to a orti ti s or corona ry a rteri ti s . Aorti c regurgi ta ti on ma y occur i f
the a s cendi ng a orta i s ma rkedl y di l a ted. Hea rt fa i l ure ca n devel op.
Obs tructi on of the des cendi ng thora ci c a orta s ometi mes ca us es s i gns of a orti c coa rcta ti on (eg, hypertens i on, hea da che, l eg cl a udi ca ti on).
Renova s cul a r hypertens i on ma y devel op i f the a bdomi na l a orta or rena l a rteri es a re na rrowed.
Pul mona ry a rteri es a re often a ffected, s ometi mes ca us i ng pul mona ry hypertens i on. Beca us e Ta ka ya s u's a rteri ti s i s chroni c, col l a tera l ci rcul a ti on
ca n devel op. Thus , i s chemi c ul cera ti ons or ga ngrene due to obs tructi on of the a rteri es to the extremi ti es i s ra re.
Diagnosis
Aorti c a rteri ogra phy or ma gneti c res ona nce a ngi ogra phy
Moni tori ng of di s ea s e a cti vi ty
The di a gnos i s i s s us pected when s ymptoms s ugges t i s chemi a of orga ns s uppl i ed by the a orta or i ts bra nches or when peri phera l pul s es a re
decrea s ed or a bs ent i n pa ti ents a t l ow ri s k of a theros cl eros i s a nd other a orti c di s orders , es peci a l l y i n young women. In thes e pa ti ents , a rteri a l
brui ts a nd ri ght-l eft or upper extremi ty-l ower extremi ty di s crepa nci es i n pul s es or i n BP a l s o s ugges t the di a gnos i s . Confi rma ti on of the di a gnos i s
requi res a orti c a rteri ogra phy or ma gneti c res ona nce a ngi ogra phy to eva l ua te a l l bra nches of the a orta . Cha ra cteri s ti c fi ndi ngs i ncl ude s tenos i s ,
occl us i on, i rregul a ri ti es i n a rteri a l l umens , pos ts tenoti c di l a ti on, col l a tera l a rteri es a round obs tructed ves s el s , a nd a neurys ms .
BP i s mea s ured i n both a rms . However, mea s urement ca n be di ffi cul t. If both s ubcl a vi a n a rteri es a re s everel y a ffected, s ys temi c BP ca n be
a ccura tel y mea s ured onl y i n the l egs . If the di s order a ffects both s ubcl a vi a n a rteri es i n pa ti ents wi th coa rcta ti on of the des cendi ng a orta or
i nvol vement of both i l i a c or femora l a rteri es , BP ca nnot be a ccura tel y mea s ured. Then, centra l a rteri a l pres s ure mus t be mea s ured vi a a ngi ogra phy
to detect occul t hypertens i on, whi ch ca n ca us e compl i ca ti ons .
La bora tory tes ts a re nons peci fi c a nd not hel pful i n di a gnos i s . Common fi ndi ngs i ncl ude a nemi a of chroni c di s ea s e, el eva ted pl a tel et l evel s ,
occa s i ona l l y el eva ted WBC counts , a nd el eva ted ESR a nd C-rea cti ve protei n.
Once Ta ka ya s u's a rteri ti s i s di a gnos ed, di s ea s e a cti vi ty mus t be moni tored to l ook for the fol l owi ng:
New s ys temi c s ymptoms , whi ch ma y refl ect a cti ve a rthri ti s or i nfecti on (s econda ry to i mmunos uppres s i on thera py)
Evi dence of i nfl a mma ti on detected by bl ood tes ts (a l though ma rkers of i nfl a mma ti on ma y mi s s a cti ve a rteri ti s )
Devel opment of s tenos i s , a neurys ms , or i s chemi c s ymptoms i n previ ous l y una ffected a rteri es , a s a s s es s ed wi th peri odi c i ma gi ng (us ua l l y
ma gneti c res ona nce a ngi ogra phy)
Peri odi c i ma gi ng of the a orta a nd l a rge a rteri es i s i mporta nt (s ee Ta bl e 34-3) beca us e the di s order ma y progres s s i l entl y, wi thout cl i ni ca l
s ymptoms or evi dence of i nfl a mma ti on i n bl ood. Once the di s order i s di a gnos ed, BP s houl d be mea s ured peri odi ca l l y i n a n una ffected l i mb
beca us e hypertens i on mus t be control l ed.
Di s orders tha t mi mi c Ta ka ya s u's a rteri ti s mus t be excl uded. They i ncl ude i nheri ted connecti ve ti s s ue di s orders (eg, Ehl ers -Da nl os or Ma rfa n
s yndrome), va s cul a r i nfecti ons (tubercul ous , funga l , or s yphi l i ti c), fi bromus cul a r
[Table 34-3. Ima gi ng Tes ts Us ed i n Ta ka ya s u's Arteri ti s ]
dys pl a s i a s , di s orders ca us i ng a rteri a l thrombos i s (eg, hypercoa gul a bl e s ta tes ), a nd i di opa thi c i nfl a mma tory condi ti ons (eg, a nkyl os i ng
s pondyl i ti s wi th a orti ti s , Coga n's or Behcet's s yndrome, Ka wa s a ki di s ea s e, s a rcoi dos i s ); a l l ca n a ffect l a rge ves s el s .
Prognosis
For 20% of pa ti ents , the cours e i s monopha s i c. For the res t, the cours e i s rel a ps i ng a nd remi tti ng or chroni c a nd progres s i ve. Even when s ymptoms
a nd l a bora tory a bnorma l i ti es s ugges t qui es cence, new l es i ons occur a nd a re evi dent on i ma gi ng s tudi es . A progres s i ve cours e a nd the pres ence
of compl i ca ti ons (eg, hypertens i on, a orti c regurgi ta ti on, hea rt fa i l ure, a neurys ms ) predi ct a l es s fa vora bl e prognos i s .
Treatment
Corti cos teroi ds
Someti mes i mmunos uppres s a nts
Anti hypertens i ves
Va s cul a r i nterventi ons
Drugs: Corti cos teroi ds a re the corners tone of trea tment. The opti ma l dos e, ta peri ng s chedul e, a nd l ength of trea tment ha ve not been determi ned.
Trea tment wi th corti cos teroi ds a l one i nduces remi s s i on i n mos t pa ti ents . Predni s one i s us ua l l y us ed. The s ta rti ng dos e i s 1 mg/kg po once/da y for
1 to 3 mo; the dos e i s then ta pered s l owl y over s evera l months . Lower s ta rti ng dos es ma y a l s o i nduce remi s s i on. About one ha l f of pa ti ents
rel a ps e when the drug i s ta pered or s topped, des pi te i ni ti a l res pons e.
Methotrexa te, cycl ophos pha mi de, a za thi opri ne, mycophenol a te mofeti l , a nd tumor necros i s fa ctor i nhi bi tors (eg, eta nercept, i nfl i xi ma b) ha ve
been us ed i n s ome pa ti ents . They ca n be tri ed i f corti cos teroi ds a re i ns uffi ci entl y effecti ve or ca nnot be ta pered. Methotrexa te i s gi ven wi th a
corti cos teroi d. Often, the s ta rti ng dos e i s 0.3 mg/kg once/wk, whi ch i s i ncrea s ed up to 25 mg/wk. Mycophenol a te mofeti l ca n a l s o be tri ed.
Cycl ophos pha mi de s houl d be cons i dered i n pa ti ents wi th corona ry va s cul i ti s or other s eri ous compl i ca ti ons thought to be due to a cti ve a rteri ti s .
An a nti pl a tel et drug (eg, a s pi ri n 325 mg po once/da y) i s frequentl y us ed beca us e pl a tel et-medi a ted occl us i on ca nnot be excl uded. Hypertens i on
s houl d be trea ted a ggres s i vel y; ACE i nhi bi tors ma y be effecti ve.
Procedures: Va s cul a r i nterventi on, us ua l l y a bypa s s procedure, ma y be needed to rees ta bl i s h bl ood fl ow to i s chemi c ti s s ues i f drug thera py i s
i neffecti ve. Indi ca ti ons i ncl ude the fol l owi ng:
Severe hypertens i on tha t i s refra ctory to medi ca l ma na gement beca us e rena l a rtery s tenos i s i s pres ent (a l though reoccl us i on a nd thrombos i s of
gra fts i s common)
Is chemi a i n the extremi ti es tha t i nterferes wi th da i l y a cti vi ti es
Is chemi a of cerebra l a rteri es
New York Hea rt As s oci a ti on (NYHA) cl a s s II hea rt fa i l ure s econda ry to a di s crete corona ry a rtery s tenos i s or occl us i on
Ca rdi a c i s chemi a ca us ed by s tenos i s of the corona ry a rteri es
Coa rcta ti on of the a orta

Di s s ecti on or enl a rgement of a n a orti c a neurys m
Bypa s s gra fti ng prefera bl y wi th a n a utol ogous gra ft ha s the bes t pa tency ra tes . The a na s tomos i s s houl d be ma de a t di s ea s e-free s i tes of the
a ffected a rteri es to hel p prevent a neurys m forma ti on a nd occl us i on.
Percuta neous tra ns l umi na l corona ry a ngi opl a s ty (PTCA) ha s few ri s ks a nd ma y be effecti ve for s hort l es i ons . But l ong-term res tenos i s ra tes s eem
much hi gher tha n thos e wi th bypa s s gra fti ng. Va s cul a r s tenti ng i s us ua l l y not recommended beca us e the res tenos i s ra te i s hi gh.
For a orti c regurgi ta ti on, va l vul a r s urgery wi th a orti c root repl a cement ma y be neces s a ry.
Wegener's Granulomatosis
Wegener's granulomatosis is characterized by necrotizing granulomatous inflammation, small and medium-sized vessel vasculitis, and focal necrotizing
glomerulonephritis, often with crescent formation. Typically, the upper and lower respiratory tract and the kidneys are affected, but any organ may be.
Symptoms vary depending on the organs and systems affected. Patients may present with upper and lower respiratory tract symptoms (eg, recurrent nasal
discharge or epistaxis, cough), followed by hypertension and edema, or with symptoms reflecting multiorgan involvement. Diagnosis usually requires biopsy.
Treatment is with corticosteroids plus an immunosuppressant. Remission is usually possible, although relapses are common.
Wegener's gra nul oma tos i s occurs i n a bout 1/25,000 peopl e; i t i s mos t common a mong whi tes but ca n occur i n a l l ethni c groups a nd a t a ny a ge.
Mea n a ge a t ons et i s 40.
The ca us e i s unknown, a l though i mmunol ogi c mecha ni s ms pl a y a rol e. Mos t pa ti ents wi th a cti ve genera l i zed di s ea s e ha ve a nti neutrophi l
cytopl a s mi c a nti bodi es (ANCA).
Pathophysiology
Cha ra cteri s ti ca l l y, gra nul oma s form wi th hi s ti ocyti c epi thel i oi d cel l s a nd often wi th gi a nt cel l s . Pl a s ma cel l s , l ymphocytes , neutrophi l s , a nd
eos i nophi l s a re pres ent. Infl a mma ti on a ffects ti s s ues a s wel l a s ves s el s ; va s cul i ti s ma y be a s ma l l or l a rge component of the di s ea s e.
Mi cronecros i s , us ua l l y wi th neutrophi l s (mi croa bs ces s es ), occurs ea rl y. Mi cronecros i s progres s es to ma cronecros i s . A centra l a rea of necros i s
(ca l l ed geogra phi c necros i s ) i s ri mmed by l ymphocytes , pl a s ma cel l s , ma cropha ges , a nd gi a nt cel l s . A zone of fi brobl a s ti c prol i fera ti on wi th
pa l i s a di ng hi s ti ocytes ma y s urround the a rea .
Nons peci fi c chroni c i nfl a mma ti on a nd ti s s ue necros i s occurs i n the nos e. The l ungs a re mos t l i kel y to di s pl a y the ful l s pectrum of hi s topa thol ogi c
a bnorma l i ti es . In the ki dneys , the mos t common fi ndi ng i s a prol i fera ti ve cres centi c foca l gl omerul onephri ti s wi th necros i s a nd thrombos i s of
i ndi vi dua l l oops or l a rger s egments of the gl omerul us . Va s cul i ti c l es i ons a nd di s s emi na ted gra nul oma s occur onl y occa s i ona l l y.
Symptoms and Signs
Ons et ma y be i ns i di ous or a cute; the ful l s pectrum of the di s ea s e ma y ta ke yea rs to evol ve. Some pa ti ents pres ent i ni ti a l l y wi th upper a nd l ower
res pi ra tory tra ct s ymptoms ; a t s ome poi nt l a ter, the ki dneys a re a ffected. In other pa ti ents , ons et of s ys temi c ma ni fes ta ti ons i s rel a ti vel y a cute;
s evera l orga ns a nd s ys tems , s uch a s the upper res pi ra tory tra ct, peri phera l nervous s ys tem (ca us i ng mononeuri ti s mul ti pl ex), ki dneys (ca us i ng
gl omerul onephri ti s ), a nd l ower res pi ra tory tra ct (ca us i ng hemorrha ge, l ung nodul es , ca vi ti es , or a combi na ti on), a re s i mul ta neous l y a ffected.
Upper respiratory tract: Si nus pa i n, s eros a ngui neous or purul ent di s cha rge, a nd epi s ta xi s ma y occur. The mucos a a ppea rs gra nul a r (l i ke
cobbl es tones ) a nd i s fri a bl e; ul cers , thi ck da rk crus ts , a nd s epta l perfora ti on a re common. Na s a l chondri ti s ca n occur wi th s wel l i ng, pa i n, a nd
col l a ps e of the na s a l bri dge (s a ddl e nos e). Pa ti ents ma y report recurrent s i nus i ti s tha t ha s res ponded i na dequa tel y to mul ti pl e a nti bi oti c
regi mens a nd ha s requi red one or more s i nus opera ti ons before di a gnos i s . Seconda ry i nfecti ons (eg, due to Staphylococcus aureus) ma y devel op.
Subgl otti c s tenos i s ma y devel op, ca us i ng s ymptoms s uch a s pa i n i n the l a rynx, hoa rs enes s , dys pnea , wheezi ng, a nd s tri dor.
Ears: Oti ti s , s ens ori neura l hea ri ng l os s , verti go, a nd chondri ti s ma y occur. The mi ddl e ea r, i nner ea r, a nd ma s toi ds a re often a ffected.
Eyes: Eyes ma y a ppea r red a nd s wol l en. Na s ol a cri ma l duct i nfl a mma ti on a nd obs tructi on ma y a ffect the eye; conjuncti vi ti s , s cl eri ti s , uvei ti s , or
reti na l va s cul i ti s ma y a l s o occur. Infl a mma tory i nfi l tra tes i n the retro-orbi ta l s pa ce (orbi ta l ps eudotumor) ca n ca us e proptos i s , compres s i on of
the opti c nerve, a nd bl i ndnes s . Extens i on i nto the extra ocul a r mus cl es l ea ds to di pl opi a . If s eri ous eye s ymptoms devel op, eva l ua ti on a nd
trea tment a re requi red i mmedi a tel y to prevent perma nent vi s i on l os s .
Lower respiratory tract: Res pi ra tory ma ni fes ta ti ons a re common. Infl a mma ti on of the ma jor bronchi a nd bra nches ca n ca us e l oca l i zed wheezi ng,
pos tobs tructi ve pneumoni a , a nd a tel ecta s i s . Si ngl e or mul ti pl e pul mona ry nodul es , wi th or wi thout ca vi ta ti on, a nd pa renchyma l i nfi l tra tes ,
s ometi mes ca us e s ymptoms , s uch a s ches t pa i n, s hortnes s of brea th, a nd producti ve cough. Dys pnea wi th bi l a tera l i nfi l tra tes , wi th or wi thout
hemoptys i s , ma y i ndi ca te a l veol a r hemorrha ge, a nd mus t be eva l ua ted i mmedi a tel y.
Heart: Corona ry a rtery di s ea s e ma y occur, but ra rel y.
Musculoskeletal system: Pa ti ents ma y pres ent wi th mya l gi a s , a rthra l gi a s , or noneros i ve i nfl a mma tory a rthri ti s .
Skin: Leukocytocl a s ti c va s cul i ti s , tender s ubcuta neous nodul es , pa pul es , l i vedo reti cul a ri s , or pyoderma ga ngrenos um ma y devel op.
Nervous system: Va s cul i ti s ma y ca us e i s chemi c peri phera l neuropa thy, bra i n l es i ons , or extens i on of l es i ons from conti guous s i tes . Les i ons tha t
ori gi na te i n the s i nus es or mi ddl e ea r ma y extend di rectl y to the retropha ryngea l a rea a nd ba s e of the s kul l , l ea di ng to cra ni a l neuropa thy,
proptos i s , di a betes i ns i pi dus , or meni ngi ti s .
Kidneys: Symptoms a nd s i gns of gl omerul onephri ti s devel op. Uri na ry s edi ment ma y be a bnorma l , a nd s erum crea ti ni ne ma y i ncrea s e ra pi dl y.
Edema a nd hypertens i on ma y res ul t. Ra pi dl y progres s i ve gl omerul onephri ti s , whi ch i s l i fe threa teni ng, ca n devel op.
Other organs: Occa s i ona l l y, a n i nfl a mma tory ma s s occurs i n the brea s ts , ki dneys , pros ta te, or other orga ns .
Diagnosis
Routi ne l a bora tory tes ts , i ncl udi ng uri na l ys i s
Tes ts for ANCA
Bi ops y for defi ni ti ve di a gnos i s
Wegener's gra nul oma tos i s s houl d be s us pected i n pa ti ents wi th chroni c, unexpl a i ned res pi ra tory s ymptoms a nd s i gns (i ncl udi ng oti ti s medi a i n
a dul ts ), pa rti cul a rl y i f ma ni fes ta ti ons i n other orga n s ys tems , es peci a l l y the ki dneys , a l s o s ugges t the di s order. Routi ne l a bora tory tes ts a re done,
but ANCA tes ti ng a nd bi ops y yi el d the mos t s peci fi c fi ndi ngs .
Routi ne l a bora tory tes ts i ncl ude ESR or C-rea cti ve protei n, CBC wi th di fferenti a l , s erum a l bumi n a nd tota l protei n, s erum crea ti ni ne, uri na l ys i s , 24h uri ne protei n, a nd ches t x-ra y. In mos t pa ti ents wi th a cti ve di s ea s e, ESR a nd C-rea cti ve protei n a re el eva ted, a nd s erum a l bumi n a nd tota l
protei n a re decrea s ed; a nemi a , thrombocytos i s , a nd mi l d to modera te eos i nophi l i a a re detected. Dys morphi c RBCs a nd RBC ca s ts , detected duri ng
uri na l ys i s , i ndi ca te gl omerul a r i nvol vement. Protei nuri a ma y be detected. Serum crea ti ni ne ma y be i ncrea s ed.
Serol ogi c tes ti ng to detect ANCA i s fol l owed by enzyme-l i nked i mmunos orbent a s s a y (ELISA) to check for s peci fi c a nti bodi es . Mos t pa ti ents wi th
a cti ve di s ea s e ha ve cytopl a s mi c ANCA (cANCA), wi th a nti bodi es a ga i ns t protei na s e-3 (PR3); thes e fi ndi ngs pl us cha ra cteri s ti c cl i ni ca l fi ndi ngs
s ugges t Wegener's gra nul oma tos i s .
Some pa ti ents wi th other di s orders (eg, ba cteri a l endoca rdi ti s , TB) tes t pos i ti ve for ANCA. If cha ra cteri s ti c cl i ni ca l fi ndi ngs a re a bs ent, a pos i ti ve
ANCA res ul t does not confi rm Wegener's gra nul oma tos i s . ANCA tes ti ng s houl d not be us ed to gui de trea tment. Duri ng a ppa rent remi s s i on, ANCA
ma y i ncrea s e or ANCA tes t res ul ts ma y cha nge from nega ti ve to pos i ti ve. In s ome of thes e pa ti ents , s ymptoms do not recur; i n others , s ymptoms
recur or wors en s oon a fter the tes t i s done or duri ng the next few weeks , months , or s ometi mes yea rs .
Bi ops y s houl d be done i f pos s i bl e to confi rm the di a gnos i s . Cl i ni ca l l y a bnorma l s i tes ma y be bi ops i ed fi rs t, but l ung bi ops y i s mos t l i kel y to
detect cha ra cteri s ti c fi ndi ngs . Open thora cotomy provi des the bes t a cces s to a ffected ti s s ue. Bi ops i es of l ung or s i nus ti s s ue a re cul tured to
excl ude i nfecti on. Rena l bi ops y ma y be neces s a ry to confi rm the di a gnos i s a nd to excl ude other ca us es , es peci a l l y i f s erum crea ti ni ne i s el eva ted.
Bi ops y res ul ts ma y a l s o provi de hi s tol ogi c i nforma ti on tha t ca n hel p gui de trea tment (eg, rena l fi bros i s , whi ch i s i rrevers i bl e wi th
i mmunos uppres s i ve trea tment).
Di fferenti a l di a gnos i s i ncl udes other va s cul i ti c di s orders tha t a ffect s ma l l a nd medi um-s i zed ves s el s . Pol ya rteri ti s nodos a i s unl i kel y i f l ung
i nvol vement i s promi nent a nd gl omerul onephri ti s i s pres ent. Infecti ons , es peci a l l y due to s l ow-growi ng fungi or a ci d-fa s t orga ni s ms s houl d be
rul ed out by s ta i ni ng a nd by cul ture of the s a mpl ed ti s s ues . RA s houl d not be di a gnos ed ba s ed onl y on the pres ence of rheuma toi d fa ctor, whi ch
i s pres ent i n one ha l f of pa ti ents wi th Wegener's gra nul oma tos i s .
Prognosis
Prognos i s depends on the extent of the di s orderwhether i t i s l i mi ted to na s a l a nd pul mona ry l es i ons , wi th l i ttl e or no s ys temi c i nvol vement, or
i t a ffects ma ny orga ns , ca us i ng s evere s ys temi c va s cul i ti s .
Us e of i mmunos uppres s a nts for s evere di s ea s e ha s dra ma ti ca l l y i mproved prognos i s . Wi th trea tment, compl ete remi s s i on i s pos s i bl e for a bout
70% of pa ti ents , but a bout one ha l f of them eventua l l y rel a ps e; rel a ps e ma y occur when trea tment i s s topped or ma ny yea rs a fter i t i s s topped.
Res umi ng or i ncrea s i ng trea tment ca n us ua l l y control the di s order. However, the di s ea s e or trea tment ca us es s i gni fi ca nt morbi di ty i n 90% of
pa ti ents .
Treatment
Emergency trea tment wi th corti cos teroi ds a nd cycl ophos pha mi de for s evere di s ea s e
Corti cos teroi ds a nd methotrexa te for l es s s evere di s ea s e
Ki dney tra ns pl a nta ti on i f neces s a ry
Trea tment depends on the s everi ty of di s ea s e. A mul ti di s ci pl i na ry a pproa ch i s requi red for mul ti orga n di s ea s e; a rheuma tol ogi s t, a n
otorhi nol a ryngol ogi s t, a pul monol ogi s t, a nd s ometi mes a nephrol ogi s t ma y be i ncl uded.
Pa ti ents who ha ve s evere l i fe- or orga n-threa teni ng ma ni fes ta ti ons (eg, a l veol a r hemorrha ge, ra pi dl y progres s i ve gl omerul onephri ti s ,
mononeuri ti s mul ti pl ex wi th motor i nvol vement) requi re i mmedi a te trea tment a nd hos pi ta l a dmi s s i on. Thes e pa ti ents requi re hi gh-dos e
corti cos teroi ds a nd cycl ophos pha mi de (s ee p. 314). The rol e of ri tuxi ma b i n s evere or refra ctory di s ea s e i s under s tudy.
For l es s s evere di s ea s e, corti cos teroi ds a nd methotrexa te a re us ed. Methotrexa te or a za thi opri ne i s us ed to ma i nta i n remi s s i on.
Irri ga ti on of s i nus es wi th s a l i ne, wi th or wi thout mupi roci n 2% na s a l oi ntment, hel ps mi ni mi ze crus ti ng a nd s econda ry s ta phyl ococca l i nfecti ons .
Trea tment of s ubgl otti c s tenos i s i s di ffi cul t. Sys temi c i mmunos uppres s a nts ma y not be effecti ve. Intra l es i ona l i njecti on of l ong-a cti ng
corti cos teroi ds , wi th gentl e progres s i ve di l a ti on, ma rkedl y i mproves outcomes a nd hel ps prevent unneces s a ry tra cheos tomi es .
Pa ti ents s houl d be ta ught a bout the di s order s o tha t rel a ps es ca n be detected ea rl y. Pa ti ents s houl d l ea rn how to tes t thei r uri ne for bl ood a nd
protei n a nd be i ns tructed to noti fy thei r phys i ci a n a t the fi rs t s i gn of hema turi a .

Ki dney tra ns pl a nta ti on ha s been s ucces s ful ; the ri s k of rel a ps e a fter tra ns pl a nta ti on i s reduced compa red wi th ma i ntena nce di a l ys i s trea tment
(pos s i bl y i n pa rt due to us e of i mmunos uppres s a nts to prevent rejecti on).
Chapter 35. Joint Disorders

Introduction
Joi nt di s orders ma y be i nfl a mma tory (RA, s pondyl oa rthropa thi es , crys ta l -i nduced a rthri ti s ) or rel a ti vel y l es s i nfl a mma tory (os teoa rthri ti s ,
neurogeni c a rthropa thy). Crys ta l -i nduced a rthri ti s a nd i nfecti ous a rthri ti s a re di s cus s ed el s ewhere i n THE MANUAL.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily involves the joints. RA causes damage mediated by cytokines, chemokines,
and metalloproteases. Characteristically, peripheral joints (eg, wrists, metacarpophalangeal joints) are symmetrically inflamed, leading to progressive destruction
of articular structures, usually accompanied by systemic symptoms. Diagnosis is based on specific clinical, laboratory, and imaging features. Treatment involves
drugs, physical measures, and sometimes surgery. Disease-modifying antirheumatic drugs help control symptoms and slow disease progression.
RA a ffects a bout 1% of the popul a ti on. Women a re a ffected 2 to 3 ti mes more often tha n men. Ons et ma y be a t a ny a ge, mos t often between 35 yr
a nd 50 yr, but ca n be duri ng chi l dhood (s ee Juveni l e Idi opa thi c Arthri ti s on p. 339) or ol d a ge.
Etiology
Al though RA i nvol ves a utoi mmune rea cti ons , the preci s e ca us e i s unknown; ma ny fa ctors ma y contri bute. A geneti c predi s pos i ti on ha s been
i denti fi ed a nd, i n whi te popul a ti ons , l oca l i zed to a s ha red epi tope i n the HLA-DR 1 l ocus of cl a s s II hi s tocompa ti bi l i ty a nti gens . Unknown
envi ronmenta l fa ctors (eg, vi ra l i nfecti ons ) a re thought to pl a y a rol e.
Pathophysiology
Promi nent i mmunol ogi c a bnorma l i ti es i ncl ude i mmune compl exes produced by s ynovi a l l i ni ng cel l s a nd i n i nfl a med bl ood ves s el s . Pl a s ma cel l s
produce a nti bodi es (eg, rheuma toi d fa ctor [RF]) tha t contri bute to thes e compl exes , but des tructi ve a rthri ti s ca n occur i n the a bs ence of RF.
Ma cropha ges a l s o mi gra te to di s ea s ed s ynovi um i n ea rl y di s ea s e; i ncrea s ed ma cropha ge-deri ved l i ni ng cel l s a re promi nent a l ong wi th ves s el
i nfl a mma ti on. Lymphocytes tha t i nfi l tra te the s ynovi a l ti s s ue a re pri ma ri l y CD4+ T cel l s . Ma cropha ges a nd l ymphocytes produce pro-i nfl a mma tory
cytoki nes a nd chemoki nes (eg, tumor necros i s fa ctors [TNF], gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor [GM-CSF], va ri ous ILs , i nterferon-)
i n the s ynovi um. Rel ea s e of i nfl a mma tory medi a tors proba bl y contri butes to the s ys temi c a nd joi nt ma ni fes ta ti ons of RA.
In chroni ca l l y a ffected joi nts , the norma l l y thi n s ynovi um thi ckens a nd devel ops ma ny vi l l ous fol ds . The s ynovi a l l i ni ng cel l s produce va ri ous
ma teri a l s , i ncl udi ng col l a gena s e a nd s tromel ys i n, whi ch contri bute to ca rti l a ge des tructi on, a nd IL-1 a nd TNF-, whi ch s ti mul a te ca rti l a ge
des tructi on, os teocl a s t-medi a ted bone a bs orpti on, s ynovi a l i nfl a mma ti on, a nd pros ta gl a ndi ns (whi ch potenti a te i nfl a mma ti on). Fi bri n
depos i ti on, fi bros i s , a nd necros i s a re a l s o pres ent. Hyperpl a s ti c s ynovi a l ti s s ue (pa nnus ) rel ea s es thes e i nfl a mma tory medi a tors , whi ch erode
ca rti l a ge, s ubchondra l bone, a rti cul a r ca ps ul e, a nd l i ga ments . PMNs on a vera ge ma ke up a bout 60% of WBCs i n the s ynovi a l fl ui d.
Rheuma toi d nodul es devel op i n a bout 30% of pa ti ents wi th RA. They a re gra nul oma s cons i s ti ng of a centra l necroti c a rea s urrounded by pa l i s a ded
hi s ti ocyti c ma cropha ges , a l l envel oped by l ymphocytes , pl a s ma cel l s , a nd fi brobl a s ts . Nodul es a nd va s cul i ti s ca n a l s o devel op i n vi s cera l orga ns .
Symptoms and Signs
Ons et i s us ua l l y i ns i di ous , often begi nni ng wi th s ys temi c a nd joi nt s ymptoms . Sys temi c s ymptoms i ncl ude ea rl y morni ng s ti ffnes s of a ffected
joi nts , genera l i zed a fternoon fa ti gue a nd ma l a i s e, a norexi a , genera l i zed wea knes s , a nd occa s i ona l l y l ow-gra de fever. Joi nt s ymptoms i ncl ude
pa i n, s wel l i ng, a nd s ti ffnes s .
The di s ea s e progres s es mos t ra pi dl y duri ng the fi rs t 6 yr, pa rti cul a rl y the fi rs t yea r; 80% of pa ti ents devel op s ome perma nent joi nt a bnorma l i ti es
wi thi n 10 yr. The cours e i s unpredi cta bl e i n i ndi vi dua l pa ti ents .
Joi nt s ymptoms a re cha ra cteri s ti ca l l y s ymmetri c. Typi ca l l y, s ti ffnes s l a s ts > 60 mi n a fter ri s i ng i n the morni ng but ma y occur a fter a ny prol onged
i na cti vi ty. Invol ved joi nts become tender, wi th erythema , wa rmth, s wel l i ng, a nd l i mi ta ti on of moti on. The joi nts i nvol ved i ncl ude the fol l owi ng:
Wri s ts a nd the i ndex a nd mi ddl e meta ca rpopha l a ngea l joi nts (mos t commonl y i nvol ved)
Proxi ma l i nterpha l a ngea l joi nts
Meta ta rs opha l a ngea l joi nts
Shoul ders
El bows
Hi ps
Knees
Ankl es
However, vi rtua l l y a ny joi nt except uncommonl y the di s ta l i nterpha l a ngea l (DIP) joi nts ma y be i nvol ved. The a xi a l s kel eton i s ra rel y i nvol ved except
for the upper cervi ca l s pi ne. Synovi a l thi ckeni ng i s detecta bl e. Joi nts a re often hel d i n fl exi on to mi ni mi ze pa i n, whi ch res ul ts from joi nt ca ps ul a r
di s tenti on.
Fi xed deformi ti es , pa rti cul a rl y fl exi on contra ctures , ma y devel op ra pi dl y; ul na r devi a ti on of the fi ngers wi th a n ul na r s l i ppa ge of the extens or
tendons off the meta ca rpopha l a ngea l joi nts i s typi ca l , a s a re s wa n-neck a nd boutonni ere deformi ti es (s ee
Fi g. 43-2 on p. 387). Joi nt i ns ta bi l i ty ca n a l s o occur. Ca rpa l tunnel s yndrome ca n res ul t from wri s t s ynovi ti s compres s i ng the medi a n nerve. Popl i tea l
(Ba ker's ) cys ts ca n devel op, ca us i ng ca l f s wel l i ng a nd tendernes s s ugges ti ve of deep venous thrombos i s .
Extra-articular manifestations: Subcuta neous rheuma toi d nodul es a re not us ua l l y a n ea rl y s i gn but eventua l l y devel op i n up to 30% of pa ti ents ,
us ua l l y a t s i tes of pres s ure a nd chroni c i rri ta ti on (eg, the extens or s urfa ce of the forea rm, meta ca rpopha l a ngea l joi nts , occi put). Vi s cera l nodul es ,
us ua l l y a s ymptoma ti c, a re common i n s evere RA. Other extra -a rti cul a r s i gns i ncl ude va s cul i ti s ca us i ng l eg ul cers or mononeuri ti s mul ti pl ex,
pl eura l or peri ca rdi a l effus i ons , pul mona ry nodul es , pul mona ry i nfi l tra tes or fi bros i s , peri ca rdi ti s , myoca rdi ti s , l ympha denopa thy, Fel ty's
s yndrome, Sjogren's s yndrome, s cl eroma l a ci a , a nd epi s cl eri ti s . Invol vement of the cervi ca l s pi ne ca n ca us e a tl a ntoa xi a l s ubl uxa ti on (s ee p. 385)
a nd s pi na l cord compres s i on (s ee p. 1810); i t ma y wors en wi th extens i on of the neck (eg, duri ng endotra chea l i ntuba ti on).
Diagnosis
Serum rheuma toi d fa ctor (RF) or a nti cycl i c ci trul l i na ted pepti de a nti body (a nti -CCP)
X-ra ys
RA s houl d be s us pected i n pa ti ents wi th pol ya rti cul a r, s ymmetri c a rthri ti s , pa rti cul a rl y i f the wri s ts a nd 2nd a nd 3rd meta ca rpopha l a ngea l joi nts
a re i nvol ved. Cri teri a for the di a gnos i s of RA a re l i s ted i n
Ta bl e 35-1. The pres ence of 4 cri teri a s ugges ts the di a gnos i s . Other ca us es of s ymmetri c pol ya rthri ti s , pa rti cul a rl y hepa ti ti s C, mus t be excl uded.
Pa ti ents s houl d ha ve a s erum RF tes t, ha nd a nd wri s t x-ra ys , a nd ba s el i ne x-ra ys of a ffected joi nts to document future eros i ve cha nges .
[Table 35-1. Di a gnos i ng Rheuma toi d Arthri ti s *]
RFs , a nti bodi es to huma n -gl obul i n, a re pres ent i n a bout 70% of pa ti ents wi th RA. However, RF, often i n l ow ti ters , occurs i n pa ti ents wi th other
di s ea s es , i ncl udi ng other connecti ve ti s s ue di s ea s es (eg, SLE), gra nul oma tous di s ea s es , chroni c i nfecti ons (eg, vi ra l hepa ti ti s , s uba cute ba cteri a l
endoca rdi ti s , TB), a nd ca ncers . Low RF ti ters ca n a l s o occur i n 3% of the genera l popul a ti on a nd 20% of the el derl y. An RF ti ter mea s ured by l a tex
a ggl uti na ti on of > 1:80 or a pos i ti ve a nti -CCP tes t s upports the di a gnos i s of RA.
Anti -CCP a nti bodi es ha ve hi gh s peci fi ci ty (90%) a nd s ens i ti vi ty (96%) for RA a nd, l i ke RF, predi ct a wors e prognos i s .
X-ra ys s how onl y s oft-ti s s ue s wel l i ng duri ng the fi rs t months of di s ea s e. Subs equentl y, peri a rti cul a r os teoporos i s , joi nt s pa ce (a rti cul a r ca rti l a ge)
na rrowi ng, a nd ma rgi na l eros i ons ma y become vi s i bl e. Eros i ons often devel op wi thi n the fi rs t yea r but ma y occur a ny ti me. MRI s eems to be more
s ens i ti ve a nd detects ea rl i er a rti cul a r i nfl a mma ti on a nd eros i ons . In a ddi ti on, a bnorma l s ubchondra l bone s i gna l s (eg, bone ma rrow l es i ons ,
bone ma rrow edema ) a round the knee s ugges t progres s i ve di s ea s e.
If RA i s di a gnos ed, a ddi ti ona l tes ts hel p detect compl i ca ti ons a nd unexpected a bnorma l i ti es . CBC wi th di fferenti a l s houl d be obta i ned. A
normochromi c (or s l i ghtl y hypochromi c)-normocyti c a nemi a occurs i n 80%; Hb i s us ua l l y > 10 g/dL. If Hb i s 10 g/dL, s uperi mpos ed i ron defi ci ency or
other ca us es of a nemi a s houl d be cons i dered. Neutropeni a occurs i n 1 to 2% of ca s es , often wi th s pl enomega l y (Fel ty's s yndrome). Acute-pha s e
rea cta nts (eg, thrombocytos i s , el eva ted ESR, el eva ted C-rea cti ve protei n) refl ect di s ea s e a cti vi ty. A mi l d pol ycl ona l hyperga mma gl obul i nemi a often
occurs . ESR i s el eva ted i n 90% of pa ti ents wi th a cti ve di s ea s e.
Synovi a l fl ui d exa mi na ti on i s neces s a ry wi th a ny new-ons et effus i on to rul e out other di s orders a nd di fferenti a te RA from other i nfl a mma tory
a rthri ti des (eg, s epti c a nd crys ta l -i nduced a rthri ti s ). In RA, duri ng a cti ve joi nt i nfl a mma ti on, s ynovi a l fl ui d i s turbi d, yel l ow, a nd s teri l e, wi th
reduced vi s cos i ty a nd us ua l l y 10,000 to 50,000 WBCs /L; PMNs typi ca l l y predomi na te, but > 50% ma y be l ymphocytes a nd other mononucl ea r cel l s .
Crys ta l s a re a bs ent.
Differential diagnosis: Ma ny di s orders ca n s i mul a te RA:
Crys ta l -i nduced a rthri ti s
Os teoa rthri ti s
SLE
Sa rcoi dos i s
Rea cti ve a rthri ti s
Ps ori a ti c a rthri ti s
Ankyl os i ng s pondyl i ti s
RF ca n be nons peci fi c a nd i s often pres ent i n s evera l a utoi mmune di s ea s es ; the pres ence of a nti -CCP a nti bodi es i s more s peci fi c for RA.
Some pa ti ents wi th crys ta l -i nduced a rthri ti s ma y meet cri teri a for RA; however, s ynovi a l fl ui d exa mi na ti on s houl d cl a ri fy the di a gnos i s . The
pres ence of crys ta l s ma kes RA unl i kel y. Joi nt i nvol vement a nd s ubcuta neous nodul es ca n res ul t from gout, chol es terol , a nd a myl oi dos i s a s wel l
a s RA; a s pi ra ti on or bi ops y of the nodul es ma y occa s i ona l l y be needed.
SLE us ua l l y ca n be di s ti ngui s hed i f there a re s ki n l es i ons on l i ght-expos ed a rea s , ha i r l os s , ora l a nd na s a l mucos a l l es i ons , a bs ence of joi nt
eros i ons i n even l ong-s ta ndi ng a rthri ti s , joi nt fl ui d tha t often ha s < 2000 WBCs /L (predomi na ntl y mononucl ea r cel l s ), a nti bodi es to doubl es tra nded DNA, rena l di s ea s e, a nd l ow s erum compl ement l evel s . In contra s t to RA, deformi ti es i n SLE a re us ua l l y reduci bl e beca us e of the l a ck of
eros i ons a nd bone or ca rti l a ge da ma ge. Arthri ti s s i mi l a r to RA ca n a l s o occur i n other rheuma ti c di s orders (eg, pol ya rteri ti s , s ys temi c s cl eros i s ,
derma tomyos i ti s , or pol ymyos i ti s ) or there ca n be fea tures of more tha n one di s ea s e, whi ch s ugges ts a n overl a p s yndrome or mi xed connecti ve
ti s s ue di s ea s e.
Sa rcoi dos i s , Whi ppl e's di s ea s e, mul ti centri c reti cul ohi s ti ocytos i s , a nd other s ys temi c di s ea s es ma y i nvol ve joi nts ; other cl i ni ca l fea tures a nd
ti s s ue bi ops y s ometi mes hel p di fferenti a te thes e condi ti ons . Acute rheuma ti c fever ha s a mi gra tory pa ttern of joi nt i nvol vement a nd evi dence of
a ntecedent s treptococca l i nfecti on (cul ture or cha ngi ng a nti s treptol ys i n-O ti ter); i n contra s t, RA ha s a n a ddi ti ve a rthri ti s .
Rea cti ve a rthri ti s (s ee p. 343) ca n be di fferenti a ted by a ntecedent GI or GU s ymptoms ; a s ymmetri c i nvol vement a nd pa i n a t the Achi l l es i ns erti on
of the heel , s a croi l i a c joi nts , a nd l a rge joi nts of the l eg; conjuncti vi ti s ; i ri ti s ; pa i nl es s bucca l ul cers ; ba l a ni ti s ci rci na ta ; or kera toderma
bl ennorrha gi cum on the s ol es a nd el s ewhere.
Ps ori a ti c a rthri ti s (s ee p. 344) tends to be a s ymmetri c a nd i s not us ua l l y a s s oci a ted wi th RF, but di fferenti a ti on ma y be di ffi cul t i n the a bs ence of
na i l or s ki n l es i ons . DIP joi nt i nvol vement a nd s everel y muti l a ti ng a rthri ti s (a rthri ti s muti l a ns ) i s s trongl y s ugges ti ve, a s i s the pres ence of a
di ffus el y s wol l en (s a us a ge) di gi t. Ankyl os i ng s pondyl i ti s (s ee p. 341) ma y be di fferenti a ted by s pi na l a nd a xi a l joi nt i nvol vement, a bs ence of
s ubcuta neous nodul es , a nd nega ti ve RF tes t.
Os teoa rthri ti s (s ee p. 345) ca n be di fferenti a ted by the joi nts i nvol ved; the a bs ence of rheuma toi d nodul es , s ys temi c ma ni fes ta ti ons , or s i gni fi ca nt
a mounts of RF; a nd s ynovi a l fl ui d WBC counts < 2000/L. Os teoa rthri ti s of the ha nds mos t typi ca l l y i nvol ves the DIP a nd proxi ma l i nterpha l a ngea l
joi nts . RA does not a ffect the DIP joi nts .
Prognosis
RA decrea s es l i fe expecta ncy by 3 to 7 yr, wi th hea rt di s ea s e, i nfecti on, a nd GI bl eedi ng a ccounti ng for mos t exces s morta l i ty; drug trea tment,
ca ncer, a s wel l a s the underl yi ng di s ea s e ma y be res pons i bl e.
At l ea s t 10% of pa ti ents eventua l l y a re s everel y di s a bl ed des pi te ful l trea tment. Whi tes a nd women ha ve a poorer prognos i s , a s do pa ti ents wi th
s ubcuta neous nodul es , a dva nced a ge a t di s ea s e ons et, i nfl a mma ti on i n 20 joi nts , ea rl y eros i ons , ci ga rette s moki ng, hi gh ESR, a nd hi gh l evel s of
RF or a nti -CCP.
Treatment
Supporti ve mea s ures (eg, nutri ti on, res t, phys i ca l mea s ures , a na l ges i cs )
NSAIDs
Drugs tha t modi fy di s ea s e progres s i on
Trea tment i nvol ves a ba l a nce of res t a nd exerci s e, a dequa te nutri ti on, phys i ca l mea s ures , drugs , a nd s ometi mes s urgery.
Rest and nutrition: Compl ete bed res t i s ra rel y i ndi ca ted, even for a s hort ti me; however, a progra m i ncl udi ng judi ci ous res t s houl d be pres cri bed. An
ordi na ry nutri ti ous di et i s genera l l y s uffi ci ent. Ra rel y, pa ti ents ha ve food-a s s oci a ted exa cerba ti ons ; no s peci fi c foods ha ve been noted to
exa cerba te RA. Food a nd di et qua ckery i s common a nd s houl d be di s coura ged. Subs ti tuti ng -3 fa tty a ci ds (i n fi s h oi l s ) for di eta ry -6 fa tty a ci ds
(i n mea ts ) ma y pa rti a l l y rel i eve s ymptoms by tra ns i entl y decrea s i ng producti on of i nfl a mma tory pros ta gl a ndi ns .
Physical measures: Joi nt s pl i nti ng reduces l oca l i nfl a mma ti on a nd ma y rel i eve s evere s ymptoms . Col d ma y be a ppl i ed to reduce pa i n from
tempora ry wors eni ng i n one joi nt. Orthopedi c or a thl eti c s hoes wi th good heel a nd a rch s upport a re frequentl y hel pful ; meta ta rs a l s upports
pl a ced pos teri orl y to pa i nful meta ta rs opha l a ngea l joi nts decrea s e the pa i n of wei ght bea ri ng. Mol ded s hoes ma y be needed for s evere
deformi ti es . Sel f-hel p devi ces ena bl e ma ny pa ti ents wi th debi l i ta ti ng RA to perform a cti vi ti es of da i l y l i vi ng.
Exerci s e s houl d proceed a s tol era ted. Duri ng a cute i nfl a mma ti on, pa s s i ve ra nge-of-moti on exerci s e hel ps prevent fl exi on contra ctures . Hea t
thera py ca n be hel pful . Ra nge-of-moti on exerci s es done i n wa rm wa ter a re hel pful beca us e hea t i mproves mus cl e functi on by reduci ng s ti ffnes s
a nd mus cl e s pa s m. However, contra ctures ca n be prevented a nd mus cl e s trength ca n be res tored more s ucces s ful l y a fter i nfl a mma ti on begi ns to
s ubs i de; a cti ve exerci s e (i ncl udi ng wa l ki ng a nd s peci fi c exerci s es for i nvol ved joi nts ) to res tore mus cl e ma s s a nd pres erve ra nge of joi nt moti on
s houl d not be fa ti gui ng. Fl exi on contra ctures ma y requi re i ntens i ve exerci s e, ca s ti ng, or i mmobi l i za ti on (eg, s pl i nti ng) i n progres s i vel y more
s tretched-open pos i ti ons . Pa ra ffi n ba ths ca n wa rm di gi ts a nd fa ci l i ta te fi nger exerci s e. Ma s s a ge by tra i ned thera pi s ts , tra cti on, a nd deep hea t
trea tment wi th di a thermy or ul tra s onogra phy ma y be us eful .
Surgery: Surgery mus t a l wa ys be cons i dered i n terms of the tota l di s ea s e a nd pa ti ent expecta ti ons . For exa mpl e, deformed ha nds a nd a rms l i mi t
crutch us e duri ng reha bi l i ta ti on; s eri ous l y a ffected knees a nd feet l i mi t benefi t from hi p s urgery. Rea s ona bl e objecti ves for ea ch pa ti ent mus t be
determi ned, a nd functi on mus t be cons i dered. Surgery ma y be done whi l e the di s ea s e i s a cti ve.
Arthropl a s ty wi th pros theti c joi nt repl a cement i s i ndi ca ted i f da ma ge s everel y l i mi ts functi on; tota l hi p a nd knee repl a cements a re mos t
cons i s tentl y s ucces s ful . Pros theti c hi ps a nd knees ca nnot tol era te vi gorous a cti vi ty (eg, competi ti ve a thl eti cs ). Exci s i on of s ubl uxed pa i nful
meta ta rs opha l a ngea l joi nts ma y grea tl y a i d wa l ki ng. Thumb fus i ons ma y provi de s ta bi l i ty for pi nch. Neck fus i on ma y be needed for C1-2
s ubl uxa ti on wi th s evere pa i n or potenti a l for s pi na l cord compres s i on. Arthros copi c or open s ynovectomy ca n rel i eve joi nt i nfl a mma ti on but onl y
tempora ri l y unl es s di s ea s e a cti vi ty ca n be control l ed.
Drugs for RA
The goa l i s to reduce i nfl a mma ti on a s a mea ns of preventi ng eros i ons a nd progres s i ve deformi ty. Di s ea s e-modi fyi ng a nti rheuma ti c drugs
(DMARDs ) a re us ed ea rl y, often i n combi na ti on. Other drug cl a s s es , i ncl udi ng bi ol ogi c a gents , TNF- a nta goni s ts , a nd IL-1 receptor a nta goni s ts ,
s eem to s l ow the progres s i on of RA. NSAIDs a re of s ome hel p for the pa i n of RA but do not prevent eros i ons or di s ea s e progres s i on. Someti mes
l ow-dos e s ys temi c corti cos teroi ds (predni s one < 10 mg da i l y) a re a dded to control s evere pol ya rti cul a r s ymptoms , us ua l l y wi th the objecti ve of
repl a cement wi th a DMARD. Intra -a rti cul a r depot corti cos teroi ds ca n control s evere mona rti cul a r or even ol i goa rti cul a r s ymptoms . The opti ma l
combi na ti ons of drugs a re not yet cl ea r. However, s ome da ta s ugges t tha t certa i n combi na ti ons of drugs from di fferent cl a s s es (eg, methotrexa te
pl us other DMARDs , a ra pi dl y ta pered corti cos teroi d pl us a DMARD, methotrexa te pl us a TNF- a nta goni s t or a n IL-1 receptor a nta goni s t, a TNF-
a nta goni s t or a n IL-1 receptor a nta goni s t pl us a DMARD) a re more effecti ve tha n us i ng DMARDs a l one s equenti a l l y or i n combi na ti on.
NSAIDs: As pi ri n i s no l onger us ed for RA, a s effecti ve dos es a re often toxi c. Onl y one NSAID s houl d be gi ven a t a ti me (s ee
Ta bl e 35-2), a l though pa ti ents ma y a l s o ta ke a s pi ri n a t 325 mg/da y for i ts a nti pl a tel et ca rdi oprotecti ve effect. Beca us e the ma xi ma l res pons e for
NSAIDs ca n ta ke up to 2 wk, dos es s houl d be i ncrea s ed no more frequentl y tha n thi s . Dos es of drugs wi th fl exi bl e dos i ng ca n be i ncrea s ed unti l
res pons e i s ma xi ma l or ma xi mum dos a ge i s rea ched. Al l NSAIDs trea t the s ymptoms of RA a nd decrea s e i nfl a mma ti on but do not a l ter the cours e
of the di s ea s e.
NSAIDs i nhi bi t cycl ooxygena s e (COX) enzymes a nd thus decrea s e producti on of pros ta gl a ndi ns . Some pros ta gl a ndi ns under COX-1 control ha ve
i mporta nt effects i n
[Table 35-2. NSAID Trea tment of Rheuma toi d Arthri ti s ]
ma ny pa rts of the body (i e, they protect ga s tri c mucos a a nd i nhi bi t pl a tel et a dhes i venes s ). Other pros ta gl a ndi ns a re i nduced by i nfl a mma ti on a nd
a re produced by COX-2. Sel ecti ve COX-2 i nhi bi tors , a l s o ca l l ed coxi bs (eg, cel ecoxi b), s eem to ha ve effi ca cy compa ra bl e to nons el ecti ve NSAIDs a nd
a re l es s l i kel y to ca us e GI toxi ci ty; however, they do not s eem l es s l i kel y to ca us e rena l toxi ci ty.
NSAIDs other tha n coxi bs s houl d be a voi ded i n pa ti ents wi th previ ous pepti c ul cer di s ea s e or dys peps i a . Other pos s i bl e a dvers e effects of a l l
NSAIDs i ncl ude hea da che, confus i on a nd other CNS s ymptoms , i ncrea s ed BP, wors eni ng of hypertens i on, edema , a nd decrea s ed pl a tel et functi on.
The effect of NSAIDs on ca rdi ova s cul a r ri s k i s s ti l l uncl ea r. Crea ti ni ne l evel s ca n ri s e revers i bl y beca us e of i nhi bi ted rena l pros ta gl a ndi ns ; l es s
frequentl y, i nters ti ti a l nephri ti s ca n occur. Pa ti ents wi th urti ca ri a , rhi ni ti s , or a s thma from a s pi ri n ca n ha ve the s a me probl ems wi th thes e other
NSAIDs .
Traditional DMARDs: (See
Ta bl e 35-3 for s peci fi c dos a ge i nforma ti on a nd a dvers e effects of other drugs us ed to trea t RA.)
Thes e drugs s eem to s l ow the progres s i on of RA a nd a re i ndi ca ted i n nea rl y a l l pa ti ents wi th RA. They di ffer from ea ch other chemi ca l l y a nd
pha rma col ogi ca l l y. Ma ny ta ke weeks or months to ha ve a n effect. About two thi rds of pa ti ents i mprove overa l l , but compl ete remi s s i ons a re
uncommon. Ma ny res ul t i n evi dence of decrea s ed da ma ge on i ma gi ng s tudi es , pres uma bl y refl ecti ng decrea s ed di s ea s e a cti vi ty. They ha ve
mi ni ma l i mmedi a te a na l ges i c effects , s o NSAIDs or l ow-dos e corti cos teroi ds mus t often be conti nued. Pa ti ents s houl d be ful l y a ppri s ed of the
ri s ks of DMARDs a nd moni tored ca reful l y for evi dence of toxi ci ty.
Combi na ti ons of DMARDs ma y be more effecti ve tha n s i ngl e drugs . For exa mpl e, hydroxychl oroqui ne, s ul fa s a l a zi ne, a nd methotrexa te together a re
more effecti ve tha n methotrexa te a l one or the other two together. Al s o, combi ni ng a DMARD wi th a nother drug, s uch a s methotrexa te pl us a TNF-
a nta goni s t or a n IL-1 receptor a nta goni s t or a ra pi dl y ta pered corti cos teroi d, ma y be more effecti ve tha n us i ng DMARDs a l one.
Methotrexate i s a fol a te a nta goni s t wi th i mmunos uppres s i ve effects a t hi gh dos e. It i s a nti -i nfl a mma tory a t dos es us ed i n RA. It i s very effecti ve
a nd ha s a rel a ti vel y ra pi d ons et (cl i ni ca l benefi t often wi thi n 3 to 4 wk). Methotrexa te s houl d be us ed wi th ca uti on, i f a t a l l , i n pa ti ents wi th
hepa ti c dys functi on or rena l fa i l ure. Al cohol s houl d be a voi ded. Suppl ementa l fol a te, 1 mg po once/da y, reduces the l i kel i hood of a dvers e effects .
CBC, AST, ALT, a nd a l bumi n a nd crea ti ni ne l evel s s houl d be determi ned a bout every 8 wk. Ra rel y, a l i ver bi ops y i s needed i f l i ver functi on tes t
fi ndi ngs a re pers i s tentl y twi ce the upper l i mi t of norma l or more a nd the pa ti ent needs to conti nue to us e methotrexa te. Severe rel a ps es of
a rthri ti s ca n occur a fter wi thdra wa l of methotrexa te. Pa ra doxi ca l l y, rheuma toi d nodul es ma y enl a rge wi th methotrexa te thera py.
Hydroxychloroquine ca n a l s o control s ymptoms of mi l d RA. Fundus copi c exa mi na ti on s houl d be done a nd vi s ua l fi el ds s houl d be a s s es s ed before
a nd every 12 mo duri ng trea tment. The drug s houl d be s topped i f no i mprovement occurs a fter 9 mo.
Sulfasalazine ca n a l l evi a te s ymptoms a nd s l ow devel opment of joi nt da ma ge. It i s us ua l l y gi ven a s enteri c-coa ted ta bl ets . Benefi t s houl d occur
wi thi n 3 mo. Enteri c coa ti ng or dos e reducti on ma y i ncrea s e tol era bi l i ty. CBCs s houl d be obta i ned a fter 1 to 2 wk a nd then a bout every 12 wk duri ng
thera py. AST a nd ALT s houl d be obta i ned a t a bout 6-mo i nterva l s a nd whenever the dos e i s i ncrea s ed.
Leflunomide i nterferes wi th a n enzyme i nvol ved wi th pyri mi di ne meta bol i s m. It i s a bout a s effecti ve a s methotrexa te but i s l es s l i kel y to s uppres s
bone ma rrow, ca us e a bnorma l l i ver functi on, or ca us e pneumoni ti s .
Pa rentera l gold compounds a re not commonl y us ed a nymore.
Corticosteroids: Sys temi c corti cos teroi ds decrea s e i nfl a mma ti on a nd other s ymptoms more ra pi dl y a nd to a grea ter degree tha n other drugs . They
a l s o s eem to s l ow bone eros i on. However, they do not prevent joi nt des tructi on, a nd thei r cl i ni ca l benefi t often di mi ni s hes wi th ti me.
Furthermore, rebound often fol l ows the wi thdra wa l of corti cos teroi ds i n a cti ve di s ea s e. Beca us e of thei r l ong-term a dvers e effects , ma ny doctors
recommend tha t corti cos teroi ds a re gi ven to ma i nta i n functi on onl y unti l a nother DMARD ha s ta ken effect.
Corti cos teroi ds ma y be us ed for s evere joi nt or s ys temi c ma ni fes ta ti ons of RA (eg, va s cul i ti s , pl euri s y, peri ca rdi ti s ). Rel a ti ve contra i ndi ca ti ons
i ncl ude pepti c ul cer di s ea s e, hypertens i on, untrea ted i nfecti ons , di a betes mel l i tus , a nd gl a ucoma . The ri s k of l a tent TB s houl d be cons i dered
before corti cos teroi d thera py i s begun.
Intra-articular injections of depot corti cos teroi ds ma y tempora ri l y hel p control pa i n a nd s wel l i ng i n pa rti cul a rl y pa i nful joi nts . Tri a mci nol one
hexa cetoni de ma y s uppres s i nfl a mma ti on for the l onges t ti me. Tri a mci nol one a cetoni de a nd methyl predni s ol one a ceta te a re a l s o effecti ve. No
s i ngl e joi nt s houl d be i njected wi th a corti cos teroi d more tha n 3 to 4 ti mes a yea r, a s too-frequent i njecti ons ma y a ccel era te joi nt des tructi on
(a l though there a re no s peci fi c da ta from huma ns to s upport thi s effect). Beca us e i njecta bl e corti cos teroi d es ters a re crys ta l l i ne, l oca l
i nfl a mma ti on tra ns i entl y i ncrea s es wi thi n a few hours i n < 2% of i njecti ons . Al though i nfecti on occurs i n onl y < 1:40,000, i t mus t be cons i dered i f
pa i n occurs > 24 h a fter i njecti on.
Immunomodulatory, cytotoxic, and immunosuppressive drugs: Trea tment wi th a za thi opri ne, cycl os pori ne (a n i mmunomodul a tory drug), or
cycl ophos pha mi de provi des effi ca cy s i mi l a r to DMARDs . However, thes e drugs a re more toxi c, pa rti cul a rl y cycl ophos pha mi de. Thus , they a re us ed
onl y for pa ti ents i n whom trea tment wi th DMARDs ha s fa i l ed or to decrea s e the need for corti cos teroi ds . They a re us ed i nfrequentl y unl es s there
a re extra -a rti cul a r compl i ca ti ons . For ma i ntena nce thera py wi th a za thi opri ne, the l owes t effecti ve dos e s houl d be us ed. Low-dos e cycl os pori ne
ma y be effecti ve a l one or when combi ned wi th methotrexa te. It ma y be l es s toxi c tha n a za thi opri ne a nd cycl ophos pha mi de.
Biologic agents: Bi ol ogi c res pons e modi fi ers other tha n TNF- a nta goni s ts ca n be us ed to ta rget B cel l s or T cel l s .
Rituximab i s a n a nti -CD 20 a nti body tha t depl etes B cel l s . It ca n be us ed i n refra ctory pa ti ents . Res pons e i s often del a yed but ma y l a s t 6 mo. The
cours e ca n be repea ted i n 6 mo. Mi l d a dvers e effects a re common, a nd a na l ges i a , corti cos teroi ds , di phenhydra mi ne, or a combi na ti on ma y need
to be gi ven concomi ta ntl y. Ri tuxi ma b i s gi ven onl y to pa ti ents who ha ve not i mproved a fter us i ng a TNF i nhi bi tor a nd methotrexa te.
Abatacept, a s ol ubl e fus i on cytotoxi c T l ymphocyte-a s s oci a ted a nti gen 4 (CTLA-4) Ig, i s i ndi ca ted for pa ti ents wi th RA wi th a n i na dequa te res pons e
to other DMARDs .
[Table 35-3. Other Drugs Us ed to Trea t RA]
Other agents: Anakinra i s a recombi na nt IL-1 receptor a nta goni s t. IL-1 i s hea vi l y i nvol ved i n the pa thogenes i s of RA. Infecti on a nd l eukopeni a ca n be
a probl em, pa rti cul a rl y when gi ven i n combi na ti on wi th a TNF a nta goni s t.
TNF- antagonists (eg, a da l i muma b, eta nercept, a nd i nfl i xi ma b) reduce the progres s i on of eros i ons a nd reduce the number of new eros i ons .
Al though not a l l pa ti ents res pond, ma ny ha ve a prompt, dra ma ti c feel i ng of wel l bei ng, s ometi mes wi th the fi rs t i njecti on. Infl a mma ti on i s often
dra ma ti ca l l y reduced.
Al though there a re s ome di fferences a mong a gents , the mos t s eri ous probl em i s i nfecti on, pa rti cul a rl y wi th rea cti va ted TB. Pa ti ents s houl d be
s creened for TB wi th PPD. Eta nercept, i nfl i xi ma b, a nd a da l i muma b ca n a nd proba bl y s houl d be us ed wi th methotrexa te. Hi gh-dos e i nfl i xi ma b
s houl d not be us ed i n pa ti ents wi th s evere hea rt fa i l ure.
Juvenile Idiopathic Arthritis
Juvenile idiopathic arthritis (JIA) is a group of rheumatic diseases that begins at or before age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and
iridocyclitis are typical of some forms. Diagnosis is clinical. Treatment involves NSAIDs and disease-modifying antirheumatic drugs.
JIA i s uncommon. The ca us e i s unknown, but there s eems to be a geneti c predi s pos i ti on a nd a n a utoi mmune pa thophys i ol ogy. JIA ma y be s i mi l a r
to a dul t RA (s ee p. 332), but mos t forms a re s l i ghtl y di fferent.
Symptoms and Signs
Pa ti ents wi th JIA ca n ha ve joi nt s ti ffnes s , s wel l i ng, effus i on, pa i n, a nd tendernes s . JIA ma y i nterfere wi th growth a nd devel opment. Mi crogna thi a
(receded chi n) due to ea rl y cl os ure of ma ndi bul a r epi phys es ma y occur. Iri docycl i ti s ma y devel op, whi ch ma y ca us e conjuncti va l i njecti on, pa i n,
a nd photophobi a but ca n be a s ymptoma ti c; s ca rri ng a nd gl a ucoma wi th ba nd kera topa thy ca n res ul t. The i ni ti a l s ymptoms a nd s i gns of JIA tend to
fa l l i nto 3 pos s i bl e pa tterns .
Systemic onset (Sti l l 's di s ea s e) occurs i n a bout 20% of pa ti ents . Hi gh fever, ra s h, s pl enomega l y, genera l i zed a denopa thy, a nd s eros i ti s wi th
peri ca rdi ti s or pl euri ti s a re common. Thes e s ymptoms ma y precede the devel opment of a rthri ti s . Fever (quoti di a n) i s often hi ghes t i n the
a fternoon or eveni ng a nd ma y pers i s t for up to 2 wk. A typi ca l tra ns i ent ra s h often a ppea rs wi th the fever or ma y be di ffus e a nd mi gra tory, wi th
urti ca ri a l or ma cul a r l es i ons .
Pauciarticular onset i s cha ra cteri zed by i nvol vement of 4 joi nts . It occurs i n a bout 40% of pa ti ents , us ua l l y young gi rl s . Iri docycl i ti s i s mos t common
i n pa uci a rti cul a r JIA, devel opi ng i n nea rl y 20%. Ma ny a ffected ol der boys ha ve the HLA-B27 a l l el e. Mos t of thes e boys s ubs equentl y devel op cl a s s i c
fea tures of one of the s pondyl oa rthropa thi es (eg, a nkyl os i ng s pondyl i ti s , ps ori a ti c a rthri ti s , rea cti ve a rthri ti s ).
Polyarticular onset i nvol ves 5 joi nts , often 20. It occurs i n the rema i ni ng 40% of pa ti ents a nd i s often s i mi l a r to a dul t RA. Arthri ti s tends to be
s ymmetri c a nd devel op s l owl y.
Diagnosis
Rheuma toi d fa ctor (RF) a nd a nti nucl ea r a nti bodi es (ANA)
JIA s houl d be s us pected i n chi l dren wi th s ymptoms of a rthri ti s , s i gns of i ri docycl i ti s , genera l i zed a denopa thy, s pl enomega l y, or unexpl a i ned ra s h
or fever l a s ti ng more tha n a few da ys . Di a gnos i s i s pri ma ri l y cl i ni ca l . Pa ti ents s us pected of ha vi ng JIA s houl d be tes ted for RF, ANA, a nd ESR
beca us e thes e tes ts ma y be hel pful i n di a gnos i ng JIA a nd di s ti ngui s hi ng i ts s ubtypes . In Sti l l 's di s ea s e, RF a nd ANA a re a bs ent. In pa uci a rti cul a rons et JIA, ANA a re pres ent i n up to 75% a nd RF i s a bs ent. In pol ya rti cul a r-ons et JIA, RF us ua l l y i s nega ti ve, but i n s ome pa ti ents , mos tl y a dol es cent
gi rl s , i t ca n be pos i ti ve.
To di a gnos e i ri docycl i ti s , s l i t-l a mp exa mi na ti on s houl d be done, even i n the a bs ence of ocul a r s ymptoms . A recentl y di a gnos ed pa ti ent wi th
pa uci a rti cul a r ons et s houl d ha ve a n eye exa mi na ti on every 3 to 4 mo, a nd a pa ti ent wi th pol ya rti cul a r ons et s houl d ha ve a n eye exa mi na ti on
a bout every 6 mo.
Prognosis
Compl ete remi s s i ons occur i n 50 to 75% of trea ted pa ti ents . Pa ti ents wi th pol ya rti cul a r ons et a nd a pos i ti ve RF ha ve a l es s fa vora bl e prognos i s .
Treatment
Drugs tha t s l ow di s ea s e progres s i on
Us ua l l y NSAIDs
Si mi l a r to the thera py of pa ti ents wi th a dul t RA, di s ea s e-modi fyi ng a nti rheuma ti c drugs (DMARDs ), pa rti cul a rl y the bi ol ogi c a gents , ha ve
dra ma ti ca l l y cha nged the thera peuti c a pproa ch.
Symptoms ma y be reduced wi th NSAIDs . Na proxen 5 to 10 mg/kg po bi d, i buprofen 5 to 10 mg/kg po qi d, a nd i ndometha ci n 0.5 to 1.0 mg/kg po ti d
a re a mong the mos t us eful . Sa l i cyl a tes a re ra rel y us ed beca us e of thei r pos s i bl e rol e i n ca us i ng Reye's s yndrome (s ee p. 2937).
Except for s evere s ys temi c di s ea s e, s ys temi c corti cos teroi ds ca n us ua l l y be a voi ded. When neces s a ry, the l owes t pos s i bl e dos e i s us ed (eg, ora l
predni s one, 0.0125 to 0.5 mg/kg qi d, or the s a me da i l y dos e gi ven once or twi ce da i l y). Growth reta rda ti on, os teoporos i s , a nd os teonecros i s a re the
ma jor ha za rds of prol onged corti cos teroi d us e i n chi l dren. Intra -a rti cul a r depot corti cos teroi ds ca n be gi ven. The dos a ge for chi l dren i s a djus ted
ba s ed on wei ght. Chi l dren ma y need to be s eda ted for i ntra -a rti cul a r i njecti on.
Methotrexa te i s us eful for pa uci a rti cul a r a nd pol ya rti cul a r di s ea s e. Advers e effects a re moni tored a s i n a dul ts . Bone ma rrow depres s i on a nd
hepa ti c toxi ci ty a re moni tored wi th CBC, AST, ALT, a nd a l bumi n. Occa s i ona l l y, s ul fa s a l a zi ne i s us ed, es peci a l l y i n ca s es of s us pected
s pondyl oa rthropa thy. IM gol d a nd peni ci l l a mi ne a re ra rel y us ed.
Eta nercept, us ed a s i n a dul ts , bl ocks tumor necros i s fa ctor- (TNF-) a nd i s often effecti ve; 0.4 mg/kg s c (up to a ma xi mum of 25 mg) i s gi ven
twi ce/wk. Ana ki nra i s pa rti cul a rl y effecti ve i n s ome pa ti ents wi th s ys temi c-ons et di s ea s e.
Phys i ca l thera py, exerci s es , s pl i nts , a nd other s upporti ve mea s ures hel p prevent fl exi on contra ctures . Ada pti ve devi ces ca n i mprove functi on a nd
mi ni mi ze unneces s a ry s tres s es on i nfl a med joi nts . Iri docycl i ti s i s trea ted wi th ophtha l mi c corti cos teroi d drops a nd mydri a ti cs (s ee p. 609).
Seronegative Spondyloarthropathies
(Seronega ti ve Spondyl oa rthri ti des )
Seronega ti ve s pondyl oa rthropa thi es s ha re certa i n cl i ni ca l cha ra cteri s ti cs (eg, ba ck pa i n, uvei ti s , GI s ymptoms , ra s hes ). Some a re s trongl y
a s s oci a ted wi th the HLA-B27 a l l el e. Cl i ni ca l a nd geneti c s i mi l a ri ti es s ugges t tha t they a l s o s ha re s i mi l a r ca us es or pa thophys i ol ogi es .
Rheuma toi d fa ctor (RF) i s nega ti ve i n the s pondyl oa rthropa thi es (hence, why they a re ca l l ed s eronega ti ve s pondyl oa rthropa thi es ). They i ncl ude
a nkyl os i ng s pondyl i ti s , rea cti ve a rthri ti s , ps ori a ti c a rthri ti s , a nd other di s orders .
Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back pain;
back stiffness; accentuated kyphosis; constitutional symptoms; aortitis; cardiac conduction abnormalities; and anterior uveitis. Diagnosis requires showing
sacroiliitis on x-ray. Treatment is with NSAIDs or tumor necrosis factor antagonists and physical measures that maintain joint flexibility.
AS i s 3 ti mes more frequent i n men tha n i n women a nd begi ns mos t often between a ges 20 a nd 40. It i s 10 to 20 ti mes more common a mong 1s tdegree rel a ti ves of AS pa ti ents tha n i n the genera l popul a ti on. The ri s k of AS i n 1s t-degree rel a ti ves wi th the HLA-B27 a l l el e i s a bout 20%.
Increa s ed preva l ence of HLA-B27 i n whi tes or HLA-B7 i n bl a cks s upports a geneti c predi s pos i ti on. However, the concorda nce ra te i n i denti ca l twi ns
i s onl y a bout 50%, s ugges ti ng tha t envi ronmenta l fa ctors contri bute. The pa thophys i ol ogy proba bl y i nvol ves i mmune-medi a ted i nfl a mma ti on.
Symptoms and Signs
The mos t frequent ma ni fes ta ti on i s ba ck pa i n, but di s ea s e ca n begi n i n peri phera l joi nts , es peci a l l y i n chi l dren a nd women, a nd ra rel y wi th a cute
i ri docycl i ti s (i ri ti s or a nteri or uvei ti s ). Other ea rl y s ymptoms a nd s i gns a re di mi ni s hed ches t expa ns i on from di ffus e cos tovertebra l i nvol vement,
l ow-gra de fever, fa ti gue, a norexi a , wei ght l os s , a nd a nemi a .
Ba ck pa i noften nocturna l a nd of va ryi ng i ntens i tyeventua l l y becomes recurrent. Morni ng s ti ffnes s , typi ca l l y rel i eved by a cti vi ty, a nd pa ra s pi na l
mus cl e s pa s m devel op. A fl exed or bent-over pos ture ea s es ba ck pa i n a nd pa ra s pi na l mus cl e s pa s m; thus , kyphos i s i s common i n untrea ted
pa ti ents . Severe hi p a rthri ti s ca n eventua l l y devel op. In l a te s ta ges , the pa ti ent ha s a ccentua ted kyphos i s , l os s of l umba r l ordos i s , a nd fi xed bentforwa rd pos turi ng, wi th compromi s ed pul mona ry functi on a nd i na bi l i ty to l i e fl a t. There ma y be peri phera l potenti a l l y deformi ng joi nt
i nvol vement, s ometi mes i nvol vi ng the di gi ts (da ctyl i ti s ). Achi l l es tendi ni ti s ca n occur.
Sys temi c ma ni fes ta ti ons occur i n one thi rd of pa ti ents . Recurrent, a cute a nteri or uvei ti s i s common but us ua l l y s el f-l i mi ted; uncommonl y i t
becomes protra cted a nd s evere enough to i mpa i r vi s i on. Neurol ogi c s i gns occa s i ona l l y res ul t from compres s i on ra di cul i ti s or s ci a ti ca , vertebra l
fra cture or s ubl uxa ti on, or ca uda equi na s yndrome (s ee p.
1806). Ca rdi ova s cul a r ma ni fes ta ti ons ca n i ncl ude a orti c i ns uffi ci ency, a orti ti s , a ngi na , peri ca rdi ti s , a nd ca rdi a c conducti on a bnorma l i ti es (whi ch
ma y be a s ymptoma ti c). Dys pnea , cough, or hemoptys i s ca n res ul t from nontubercul ous fi bros i s or ca vi ta ti on of a n upper l obe of the l ung;
s econda ry i nfecti on wi th Aspergillus ca n devel op. Ra rel y, AS res ul ts i n s econda ry a myl oi dos i s . Subcuta neous nodul es do not devel op.
Diagnosis
Lumbos a cra l s pi ne i ma gi ng
Bl ood tes ts (ESR, C-rea cti ve protei n, a nd CBC) or expl i ci t cl i ni ca l cri teri a (modi fi ed New York cri teri a )
AS s houl d be s us pected i n pa ti ents , pa rti cul a rl y young men, wi th nocturna l ba ck pa i n a nd kyphos i s , di mi ni s hed ches t expa ns i on, Achi l l es
tendi ni ti s , or unexpl a i ned a nteri or uvei ti s . A 1s t-degree rel a ti ve wi th AS s houl d hei ghten s us pi ci on. Pa ti ents s houl d genera l l y be tes ted wi th ESR,
C-rea cti ve protei n, a nd CBC. IgM, RF, a nd a nti nucl ea r a nti bodi es a re needed onl y i f peri phera l a rthri ti s s ugges ts other di a gnos es . No l a bora tory
tes t i s di a gnos ti c, but res ul ts ca n i ncrea s e s us pi ci on for the di s order or rul e out other di s orders tha n ca n s i mul a te AS. If, a fter thes e tes ts , AS i s
s ti l l s us pected, pa ti ents s houl d undergo i ma gi ng of the l umbos a cra l s pi ne; demons tra ti on of s a croi l i i ti s on x-ra y s trongl y s upports the di a gnos i s .
Al terna ti vel y, AS ca n be di a gnos ed by the modi fi ed New York cri teri a . Us i ng thes e cri teri a , the pa ti ent mus t ha ve i ma gi ng s tudy evi dence of
s a croi l i i ti s a nd one of the fol l owi ng:
Res tri cti on of l umba r s pi na l moti on i n both the s a gi tta l (l ooki ng from the s i de) a nd fronta l (l ooki ng from the ba ck) pl a nes
Res tri cti on of ches t expa ns i on, a djus ted for a ge
A hi s tory of i nfl a mma tory ba ck pa i n
Hi s tori ca l fea tures tha t di s ti ngui s h i nfl a mma tory ba ck pa i n from noni nfl a mma tory ba ck pa i n i ncl ude ons et a t 40 yr, gra dua l ons et, morni ng
s ti ffnes s , i mprovement wi th a cti vi ty, a nd dura ti on 3 mo before s eeki ng medi ca l a ttenti on.
ESR a nd other a cute-pha s e rea cta nts (eg, C-rea cti ve protei n) a re i ncons i s tentl y el eva ted i n pa ti ents wi th a cti ve AS. Tes ts for RF a nd a nti nucl ea r
a nti bodi es a re nega ti ve. The HLA-B27 geneti c ma rker i s not of di a gnos ti c va l ue.
The ea rl i es t x-ra y a bnorma l i ti es a re ps eudowi deni ng from s ubchondra l eros i ons , fol l owed by s cl eros i s or l a ter na rrowi ng a nd eventua l l y fus i on i n
the s a croi l i a c joi nts . Cha nges a re s ymmetri c. Ea rl y cha nges i n the s pi ne a re upper l umba r vertebra l s qua ri ng wi th s cl eros i s a t the corners ; s potty
l i ga mentous ca l ci fi ca ti on; a nd one or two evol vi ng s yndes mophytes . La te cha nges res ul t i n a "ba mboo s pi ne" a ppea ra nce, res ul ti ng from
promi nent s yndes mophytes , di ffus e pa ra s pi na l l i ga mentous ca l ci fi ca ti on, a nd os teoporos i s ; thes e cha nges devel op i n s ome pa ti ents on a vera ge
over 10 yr.
Cha nges typi ca l of AS ma y not become vi s i bl e on pl a i n x-ra ys for yea rs . CT a nd MRI s how cha nges ea rl i er, but there i s no cons ens us rega rdi ng thei r
rol e i n routi ne di a gnos i s .
A herni a ted i ntervertebra l di s k ca n ca us e ba ck pa i n a nd ra di cul opa thy s i mi l a r to AS, but the pa i n i s l i mi ted to the s pi ne, us ua l l y ca us es more
s udden s ymptoms , a nd ca us es no s ys temi c ma ni fes ta ti ons or l a bora tory tes t a bnorma l i ti es . If neces s a ry, CT or MRI ca n di fferenti a te i t from AS.
Invol vement of a s i ngl e s a croi l i a c joi nt s ugges ts a di fferent s pondyl oa rthropa thy, pos s i bl y i nfecti on. Tubercul ous s pondyl i ti s ca n s i mul a te AS (s ee
p. 1313).
Diffuse idiopathic skeletal hyperostosis (DISH) occurs pri ma ri l y i n men > 50 yr a nd ma y res embl e AS cl i ni ca l l y a nd on x-ra y. Pa ti ents uncommonl y ha ve
s pi na l pa i n, s ti ffnes s , a nd i ns i di ous l os s of moti on. X-ra y fi ndi ngs i n DISH i ncl ude l a rge os s i fi ca ti ons a nteri or to s pi na l l i ga ments (the
ca l ci fi ca ti on a ppea rs a s i f s omeone poured ca ndl e wa x i n front a nd on the s i des of the vertebra e), bri dgi ng s evera l vertebra e a nd us ua l l y s ta rti ng
a t the l ower thora ci c s pi ne, eventua l l y a ffecti ng the cervi ca l a nd l umba r s pi ne. There i s often s ubperi os tea l bone growth a l ong the pel vi c bri m a nd
a t i ns erti on of tendons (s uch a s the Achi l l es tendon i ns erti on). However, the a nteri or s pi na l l i ga ment i s i nta ct a nd frequentl y bul gi ng, a nd
s a croi l i a c a nd s pi na l a pophys ea l joi nts a re not eroded. Addi ti ona l di fferenti a ti ng fea tures a re s ti ffnes s tha t i s not a ccentua ted i n the morni ng
a nd a norma l ESR.
Prognosis
AS i s cha ra cteri zed by mi l d or modera te fl a res of a cti ve i nfl a mma ti on a l terna ti ng wi th peri ods of l i ttl e or no i nfl a mma ti on. Proper trea tment i n
mos t pa ti ents res ul ts i n mi ni ma l or no di s a bi l i ty a nd i n a ful l , producti ve l i fe des pi te ba ck s ti ffnes s . Occa s i ona l l y, the cours e i s s evere a nd
progres s i ve, res ul ti ng i n pronounced i nca pa ci ta ti ng deformi ti es .
Treatment
NSAIDs
Sul fa s a l a zi ne, methotrexa te, or tumor necros i s fa ctor (TNF) a nta goni s ts
Exerci s es a nd s upporti ve mea s ures
The goa l s of trea tment a re rel i evi ng pa i n, ma i nta i ni ng joi nt ra nge of moti on, a nd preventi ng end-orga n da ma ge. Beca us e the condi ti on ma y ca us e
l ung fi bros i s , ci ga rette s moki ng i s di s coura ged.
NSAIDs reduce pa i n a nd s uppres s joi nt i nfl a mma ti on a nd mus cl e s pa s m, thereby i ncrea s i ng ra nge of moti on, whi ch fa ci l i ta tes exerci s e a nd
prevents contra ctures . Mos t NSAIDs work i n AS, a nd tol era nce a nd toxi ci ty di cta te drug choi ce. The da i l y dos e of NSAIDs s houl d be a s l ow a s
pos s i bl e, but ma xi mum dos es ma y be needed wi th a cti ve di s ea s e. Drug wi thdra wa l s houl d be a ttempted onl y s l owl y, a fter s ys temi c a nd joi nt
s i gns of a cti ve di s ea s e ha ve been s uppres s ed for s evera l months .
Sul fa s a l a zi ne ma y hel p reduce peri phera l joi nt s ymptoms a nd l a bora tory ma rkers of i nfl a mma ti on. Dos a ge s houl d be s ta rted a t 500 mg/da y a nd
i ncrea s ed by 500 mg/da y a t 1-wk i nterva l s to 1 to 1.5 g bi d ma i ntena nce. Peri phera l joi nt s ymptoms ma y a l s o a ba te wi th methotrexa te (s ee p. 337).
Sys temi c corti cos teroi ds , i mmunos uppres s a nts , a nd mos t di s ea s e-modi fyi ng a nti rheuma ti c drugs ha ve no proven benefi t a nd s houl d genera l l y not
be us ed. TNF- a nta goni s ts (eg, eta nercept, i nfl i xi ma b, a da l i muma b) a re effecti ve trea tments for i nfl a mma tory ba ck pa i n.
For proper pos ture a nd joi nt moti on, da i l y exerci s e a nd other s upporti ve mea s ures (eg, pos tura l tra i ni ng, thera peuti c exerci s e) a re vi ta l to
s trengthen mus cl e groups tha t oppos e the di recti on of potenti a l deformi ti es (i e, the extens or ra ther tha n fl exor mus cl es ). Rea di ng whi l e l yi ng
prone a nd pus hi ng up on the el bows or pi l l ows a nd thus extendi ng the ba ck ma y hel p keep the ba ck fl exi bl e. Beca us e ches t wa l l moti on ca n be
res tri cted, whi ch i mpa i rs l ung functi on, ci ga rette s moki ng, whi ch a l s o i mpa i rs l ung functi on, i s s trongl y di s coura ged.
Intra -a rti cul a r depot corti cos teroi ds ma y be benefi ci a l , pa rti cul a rl y when one or two peri phera l joi nts a re more s everel y i nfl a med tha n others ,
thereby compromi s i ng exerci s e a nd reha bi l i ta ti on. They ma y a l s o hel p i f s ys temi c drugs a re i neffecti ve. Corti cos teroi ds i njected i nto the s a croi l i a c
joi nts ma y occa s i ona l l y hel p s evere s a croi l i i ti s .
For a cute uvei ti s , topi ca l corti cos teroi ds a nd mydri a ti cs a re us ua l l y a dequa te. If s evere hi p a rthri ti s devel ops , tota l hi p a rthropl a s ty ma y l es s en
pa i n a nd i mprove fl exi bi l i ty dra ma ti ca l l y.
Reactive Arthritis
Reactive arthritis is an acute spondyloarthropathy that often seems precipitated by an infection, usually GU or GI. Common manifestations include asymmetric
arthritis of variable severity that tends to affect the lower extremities, sausage-shaped deformities of fingers or toes or both, constitutional symptoms,
enthesitis, tendinitis, and mucocutaneous ulcers, including hyperkeratotic or crusted vesicular lesions (keratoderma blennorrhagicum). Diagnosis is clinical.
Treatment involves NSAIDs and sometimes sulfasalazine or immunosuppressants.
Spondyl oa rthropa thy a s s oci a ted wi th urethri ti s or cervi ci ti s , conjuncti vi ti s , a nd mucocuta neous l es i ons (previ ous l y ca l l ed Rei ter's s yndrome) i s
one type of rea cti ve a rthri ti s .
Etiology
Two forms of rea cti ve a rthri ti s a re common: s exua l l y tra ns mi tted a nd dys enteri c. The s exua l l y tra ns mi tted form occurs pri ma ri l y i n men a ged 20 to
40. Geni ta l i nfecti ons wi th Chlamydia trachomatis a re mos t often i mpl i ca ted. Men or women ca n a cqui re the dys enteri c form a fter enteri c i nfecti ons ,
pri ma ri l y Shigella, Salmonella, Yersinia, or Campylobacter. Rea cti ve a rthri ti s proba bl y res ul ts from joi nt i nfecti on or pos ti nfecti ous i nfl a mma ti on.
Al though there i s evi dence of mi crobi a l a nti gens i n the s ynovi um, orga ni s ms ca nnot be cul tured from joi nt fl ui d.
Epidemiology: The preva l ence of the HLA-B27 a l l el e i n pa ti ents i s 63 to 96% vs 6 to 15% i n hea l thy whi te control s , thus s upporti ng a geneti c
predi s pos i ti on.
Symptoms and Signs
Rea cti ve a rthri ti s ca n ra nge from tra ns i ent mona rti cul a r a rthri ti s to a s evere, mul ti s ys tem di s order. Cons ti tuti ona l s ymptoms ma y i ncl ude fever,
fa ti gue, a nd wei ght l os s . Arthri ti s ma y be mi l d or s evere. Joi nt i nvol vement i s genera l l y a s ymmetri c a nd ol i goa rti cul a r or pol ya rti cul a r, occurri ng
predomi na ntl y i n the l a rge joi nts of the l ower extremi ti es a nd i n the toes . Ba ck pa i n ma y occur, us ua l l y wi th s evere di s ea s e. Enthes opa thy
(i nfl a mma ti on a t tendi nous i ns erti on i nto boneeg, pl a nta r fa s ci i ti s , di gi ta l peri os ti ti s , Achi l l es tendi ni ti s ) i s common a nd cha ra cteri s ti c.
Mucocuta neous l es i ons s ma l l , tra ns i ent, rel a ti vel y pa i nl es s , s uperfi ci a l ul cers commonl y occur on the ora l mucos a , tongue, a nd gl a ns peni s
(ba l a ni ti s ci rci na ta ). Pa rti cul a rl y cha ra cteri s ti c a re ves i cl es (s ometi mes i denti ca l to pus tul a r ps ori a s i s ) of the pa l ms a nd s ol es a nd a round the
na i l s tha t become hyperkera toti c a nd form crus ts (kera toderma bl ennorrha gi cum). Ra rel y, ca rdi ova s cul a r compl i ca ti ons (eg, a orti ti s , a orti c
i ns uffi ci ency, ca rdi a c conducti on defects ), pl euri ti s , a nd CNS or peri phera l nervous s ys tem s ymptoms devel op.
Urethri ti s ma y devel op 7 to 14 da ys a fter s exua l conta ct (or occa s i ona l l y a fter dys entery); l ow-gra de fever, conjuncti vi ti s , a nd a rthri ti s devel op over
the next few weeks . Not a l l fea tures ma y occur, s o i ncompl ete forms need to be cons i dered. In men, the urethri ti s i s l es s pa i nful a nd producti ve of
purul ent di s cha rge tha n a cute gonococca l urethri ti s a nd ma y be a s s oci a ted wi th hemorrha gi c cys ti ti s or pros ta ti ti s . In women, urethri ti s a nd
cervi ci ti s ma y be mi l d (wi th dys uri a or s l i ght va gi na l di s cha rge) or a s ymptoma ti c. Conjuncti vi ti s i s the mos t common eye l es i on. It us ua l l y ca us es
eye rednes s a nd gri tti nes s , but kera ti ti s a nd a nteri or uvei ti s ca n devel op a l s o, ca us i ng eye pa i n, photophobi a , a nd tea ri ng.
Diagnosis
Typi ca l a rthri ti s
Symptoms of GI or GU i nfecti on
One other extra -a rti cul a r fea ture
Rea cti ve a rthri ti s s houl d be s us pected i n pa ti ents wi th a cute, a s ymmetri c a rthri ti s a ffecti ng the l a rge joi nts of the l ower extremi ti es or toes ,
pa rti cul a rl y i f there i s tendi ni ti s or a hi s tory of a n a ntecedent di a rrhea or dys uri a . Di a gnos i s i s ul ti ma tel y cl i ni ca l a nd requi res the typi ca l
peri phera l a rthri ti s wi th s ymptoms of GU or GI i nfecti on or one of the other extra -a rti cul a r fea tures . Beca us e thes e fea tures ma y ma ni fes t a t
di fferent ti mes , defi ni ti ve di a gnos i s ma y requi re s evera l months . Serum a nd s ynovi a l fl ui d compl ement l evel s a re hi gh, but thes e fi ndi ngs a re not
us ua l l y di a gnos ti c a nd need not be mea s ured.
Di s s emi na ted gonococca l i nfecti on ca n cl os el y s i mul a te rea cti ve a rthri ti s (s ee p. 1472). Arthrocentes i s ma y fa i l to di fferenti a te them, owi ng to
i nfl a mma tory cha ra cteri s ti cs of s ynovi a l fl ui d i n both di s orders a nd the di ffi cul ty of cul turi ng gonococci from thi s fl ui d. Cl i ni ca l cha ra cteri s ti cs ma y
hel p; di s s emi na ted gonococca l i nfecti on tends to i nvol ve upper a nd l ower extremi ti es equa l l y, be more mi gra tory, a nd not produce ba ck pa i n, a nd
ves i cl es tend not to be hyperkera toti c. A pos i ti ve gonococca l cul ture from bl ood or s ki n l es i ons hel ps di fferenti a te the two di s orders , but a
pos i ti ve cul ture from the urethra or cervi x does not. If di fferenti a ti on i s s ti l l di ffi cul t, ceftri a xone ma y be requi red for s i mul ta neous di a gnos i s a nd
trea tment.
Ps ori a ti c a rthri ti s ca n s i mul a te rea cti ve a rthri ti s , ca us i ng s i mi l a r s ki n l es i ons , uvei ti s , a nd a s ymmetri c a rthri ti s . However, ps ori a ti c a rthri ti s often
a ffects mos tl y the upper extremi ti es a nd es peci a l l y the di s ta l i nterpha l a ngea l joi nts , ma y be a brupt i n ons et but ma y a l s o devel op gra dua l l y,
ca us es l es s enthes opa thy, a nd tends not to ca us e mouth ul cers or s ymptoms of GU or GI i nfecti on.
Prognosis
Rea cti ve a rthri ti s often res ol ves i n 3 to 4 mo, but up to 50% of pa ti ents experi ence recurrent or prol onged s ymptoms over s evera l yea rs . Joi nt,
s pi na l , or s a croi l i a c i nfl a mma ti on or deformi ty ma y occur wi th chroni c or recurrent di s ea s e. Some pa ti ents a re di s a bl ed.
Treatment
NSAIDs
Someti mes s ul fa s a l a zi ne, doxycycl i ne, a za thi opri ne or methotrexa te, or a combi na ti on
NSAIDs (eg, i ndometha ci n 25 to 50 mg po ti d) us ua l l y hel p rel i eve s ymptoms . If i nduced by i nfecti on wi th C. trachomatis, doxycycl i ne 100 mg po bi d
for up to 3 mo ma y a ccel era te recovery, but thi s i s controvers i a l . Sul fa s a l a zi ne a s us ed to trea t RA ma y a l s o be hel pful (s ee p. 337). If s ymptoms a re
s evere des pi te NSAIDs a nd s ul fa s a l a zi ne, a za thi opri ne or methotrexa te ma y be cons i dered. Sys temi c corti cos teroi ds ha ve no proven va l ue.
Loca l i njecti on of depot corti cos teroi ds for enthes opa thy or res i s ta nt ol i goa rthri ti s ma y rel i eve s ymptoms . Phys i ca l thera py a i med a t ma i nta i ni ng
joi nt mobi l i ty i s hel pful duri ng the recovery pha s e. Anteri or uvei ti s i s trea ted a s us ua l , wi th corti cos teroi d a nd mydri a ti c eye drops to prevent
s ca rri ng. Conjuncti vi ti s a nd mucocuta neous l es i ons requi re onl y s ymptoma ti c trea tment.
Psoriatic Arthritis
Psoriatic arthritis is a chronic inflammatory arthritis that occurs in people with psoriasis of the skin or nails. The arthritis is often asymmetric, and some forms
involve the distal interphalangeal joints. Diagnosis is clinical. Treatment is usually similar to that of RA but can also involve phototherapy.
Ps ori a ti c a rthri ti s devel ops i n 5 to 40% of pa ti ents wi th ps ori a s i s . Preva l ence i s i ncrea s ed i n pa ti ents wi th AIDS. Ri s k of s ome i nvol vement i s
i ncrea s ed i n pa ti ents wi th HLA-B27 or s ome other s peci fi c a l l el es a nd i n fa mi l y members . Eti ol ogy a nd pa thophys i ol ogy a re unknown.
Symptoms and Signs
Ps ori a s i s of the s ki n or na i l s ma y precede or fol l ow joi nt i nvol vement. Ski n l es i ons ma y be hi dden i n the s ca l p, gl utea l fol ds , or umbi l i cus a nd go
unrecogni zed by the pa ti ent.
The di s ta l i nterpha l a ngea l (DIP) joi nts of fi ngers a nd toes a re es peci a l l y a ffected. As ymmetri c i nvol vement of l a rge a nd s ma l l joi nts , i ncl udi ng the
s a croi l i a cs a nd s pi ne, i s common. Joi nt a nd s ki n s ymptoms ma y l es s en or wors en s i mul ta neous l y. Infl a mma ti on of the fi ngers , toes , or both ma y
l ea d to s a us a ge-s ha ped deformi ti es . Rheuma toi d nodul es a re a bs ent. Arthri ti c remi s s i ons tend to be more frequent, ra pi d, a nd compl ete tha n i n
RA, but progres s i on to chroni c a rthri ti s a nd cri ppl i ng ma y occur. There ma y be a rthri ti s muti l a ns (des tructi on of mul ti pl e ha nd joi nts wi th
tel es copi ng of the di gi ts ).
Ba ck pa i n ma y be pres ent. It i s often a ccompa ni ed by a s ymmetri c s yndes mophytes of the s pi ne.
Diagnosis
RF
Ps ori a ti c a rthri ti s s houl d be s us pected i n pa ti ents wi th both ps ori a s i s a nd a rthri ti s . Beca us e ps ori a s i s ma y be overl ooked or hi dden or devel op
onl y a fter a rthri ti s occurs , ps ori a ti c a rthri ti s s houl d be cons i dered i n a ny pa ti ent wi th s eronega ti ve i nfl a mma tory a rthri ti s ; thes e pa ti ents s houl d
be exa mi ned for ps ori a s i s a nd na i l pi tti ng a nd s houl d be ques ti oned a bout a fa mi l y hi s tory of ps ori a s i s . Pa ti ents s us pected of ha vi ng ps ori a ti c
a rthri ti s s houl d be tes ted for rheuma toi d fa ctor, whi ch ca n coexi s t. Ps ori a ti c a rthri ti s i s di a gnos ed cl i ni ca l l y a nd by excl udi ng other di s orders tha t
ca n ca us e s uch s i mi l a r ma ni fes ta ti ons . X-ra y fi ndi ngs common i n ps ori a ti c a rthri ti s i ncl ude DIP i nvol vement; res orpti on of termi na l pha l a nges ;
a rthri ti s muti l a ns ; a nd extens i ve des tructi on, prol i fera ti ve bone rea cti on, a nd di s l oca ti on of l a rge a nd s ma l l joi nts .
Treatment
Arthri ti s trea ted genera l l y s i mi l a rl y to RA
Photothera py
Trea tment i s di rected a t control of s ki n l es i ons (s ee p. 677) a nd a t joi nt i nfl a mma ti on. Drug thera py i s s i mi l a r to tha t for RA, pa rti cul a rl y
methotrexa te. Hydroxychl oroqui ne i s i ncons i s tentl y of benefi t a nd ma y ca us e exfol i a ti ve derma ti ti s or a ggra va te underl yi ng ps ori a s i s . Benefi t ma y
be ga i ned from NSAIDs , cycl os pori ne, a nd TNF a nta goni s ts (s ee p. 335 under Drugs for RA); TNF a nta goni s ts ha ve been pa rti cul a rl y effecti ve.
Photothera py us i ng l ong-wa ve ps ora l en pl us ul tra vi ol et A (PUVA) combi ned wi th ora l methoxs a l en 600 g/kg po 2 h before PUVA twi ce/wk s eems to
be hi ghl y effecti ve for ps ori a ti c l es i ons a nd s omewha t effecti ve for peri phera l a rthri ti s , but not for s pi ne i nvol vement.
Other Spondyloarthropathies
Spondyl oa rthropa thy ca n devel op i n a s s oci a ti on wi th GI condi ti ons (s ometi mes ca l l ed enteropa thi c a rthri ti s ) s uch a s i nfl a mma tory bowel
di s ea s e, i ntes ti na l bypa s s s urgery, or Whi ppl e's di s ea s e.
Juveni l e-ons et s pondyl oa rthropa thy i s a n a s ymmetri c, mos tl y l ower extremi ty s pondyl oa rthropa thy tha t begi ns mos t commonl y i n boys a ged 7 to
16.
Spondyl oa rthropa thy ca n a l s o devel op i n peopl e wi thout cha ra cteri s ti cs of other s peci fi c s pondyl oa rthropa thy (undi fferenti a ted
s pondyl oa rthropa thy). Trea tment of the a rthri ti s of thes e other s pondyl oa rthropa thi es i s s i mi l a r to tha t of trea tment of rea cti ve a rthri ti s (s ee p.
344).
Osteoarthritis
(Degenera ti ve Joi nt Di s ea s e; Os teoa rthros i s ; Hypertrophi c Os teoa rthri ti s )
Osteoarthritis (OA) is a chronic arthropathy characterized by disruption and potential loss of joint cartilage along with other joint changes, including bone
hypertrophy (osteophyte formation). Symptoms include gradually developing pain aggravated or triggered by activity, stiffness lasting < 30 min on awakening
and after inactivity, and occasional joint swelling. Diagnosis is confirmed by x-rays. Treatment includes physical measures (including rehabilitation), patient
education, and drugs.
OA, the mos t common joi nt di s order, often becomes s ymptoma ti c i n the 40s a nd 50s a nd i s nea rl y uni vers a l (a l though not a l wa ys s ymptoma ti c) by
a ge 80. Onl y ha l f of pa ti ents wi th pa thol ogi c cha nges of OA ha ve s ymptoms . Bel ow a ge 40, mos t OA i s i n men a nd res ul ts from tra uma . Women
predomi na te from a ge 40 to 70, a fter whi ch men a nd women a re equa l l y a ffected.
Classification
OA i s cl a s s i fi ed a s pri ma ry (i di opa thi c) or s econda ry to s ome known ca us e.
Pri ma ry OA ma y be l oca l i zed to certa i n joi nts (eg, chondroma l a ci a pa tel l a e i s a mi l d OA tha t occurs i n young peopl e). Pri ma ry OA i s us ua l l y
s ubdi vi ded by the s i te of i nvol vement (eg, ha nds a nd feet, knee, hi p). If pri ma ry OA i nvol ves mul ti pl e joi nts , i t i s cl a s s i fi ed a s pri ma ry genera l i zed
OA.
Seconda ry OA res ul ts from condi ti ons tha t cha nge the mi croenvi ronment of the ca rti l a ge. Thes e condi ti ons i ncl ude s i gni fi ca nt tra uma , congeni ta l
joi nt a bnorma l i ti es , meta bol i c defects (eg, hemochroma tos i s , Wi l s on's di s ea s e), i nfecti ons (ca us i ng pos ti nfecti ous a rthri ti s ), endocri ne a nd
neuropa thi c di s ea s es , a nd di s orders tha t a l ter the norma l s tructure a nd functi on of hya l i ne ca rti l a ge (eg, RA, gout, chondroca l ci nos i s ).
Pathophysiology
Norma l joi nts ha ve l i ttl e fri cti on wi th movement a nd do not wea r out wi th typi ca l us e, overus e, or tra uma . Hya l i ne ca rti l a ge i s a va s cul a r, a neura l ,
a nd a l ympha ti c. It i s 95% wa ter a nd extra cel l ul a r ca rti l a ge ma tri x a nd onl y 5% chondrocytes . Chondrocytes ha ve the l onges t cel l cycl e i n the body
(s i mi l a r to CNS a nd mus cl e cel l s ). Ca rti l a ge hea l th a nd functi on depend on compres s i on a nd rel ea s e of wei ght bea ri ng a nd us e (i e, compres s i on
pumps fl ui d from the ca rti l a ge i nto the joi nt s pa ce a nd i nto ca pi l l a ri es a nd venul es , wherea s rel ea s e a l l ows the ca rti l a ge to reexpa nd,
hyperhydra te, a nd a bs orb neces s a ry el ectrol ytes a nd nutri ents ).
OA begi ns wi th ti s s ue da ma ge from mecha ni ca l i njury (eg, torn meni s cus ), tra ns mi s s i on of i nfl a mma tory medi a tors from the s ynovi um i nto
ca rti l a ge, or defects i n ca rti l a ge meta bol i s m. The ti s s ue da ma ge s ti mul a tes chondrocytes to a ttempt repa i r, whi ch i ncrea s es producti on of
proteogl yca ns a nd col l a gen. However, efforts a t repa i r a l s o s ti mul a te the enzymes tha t degra de ca rti l a ge, a s wel l a s i nfl a mma tory cytoki nes ,
whi ch a re norma l l y pres ent i n s ma l l a mounts . Infl a mma tory medi a tors tri gger a n i nfl a mma tory cycl e tha t further s ti mul a tes the chondrocytes a nd
s ynovi a l l i ni ng cel l s , eventua l l y brea ki ng down the ca rti l a ge. Chondrocytes undergo progra mmed cel l dea th (a poptos i s ). Once ca rti l a ge i s
des troyed, expos ed bone becomes eburna ted a nd s cl eroti c.
Al l a rti cul a r a nd s ome peri a rti cul a r ti s s ues become i nvol ved i n OA. Subchondra l bone s ti ffens , then undergoes i nfa rcti on, a nd devel ops
s ubchondra l cys ts . Attempts a t bony repa i r ca us e s ubchondra l s cl eros i s a nd os teophytes a t the joi nt ma rgi ns . The os teophytes s eem to devel op i n
a n a ttempt to s ta bi l i ze the joi nt. The s ynovi um becomes i nfl a med a nd thi ckened a nd produces s ynovi a l fl ui d wi th l es s vi s cos i ty a nd grea ter
vol ume. Peri a rti cul a r tendons a nd l i ga ments become s tres s ed, res ul ti ng i n tendi ni ti s a nd contra ctures . As the joi nt becomes l es s mobi l e,
s urroundi ng mus cl es thi n a nd become l es s s upporti ve. Meni s ci fi s s ure a nd ma y fra gment.
OA of the s pi ne ca n, a t the di s k l evel , ca us e ma rked thi ckeni ng a nd prol i fera ti on of the pos teri or l ongi tudi na l l i ga ments , whi ch a re pos teri or to
the vertebra l body but a nteri or to the s pi na l cord. The res ul t ca n be tra ns vers e ba rs tha t encroa ch on the a nteri or s pi na l cord. Hypertrophy a nd
hyperpl a s i a of the l i ga menta fl a va , whi ch a re pos teri or to the s pi na l cord, often compres s the pos teri or ca na l , ca us i ng l umba r s pi na l s tenos i s . In
contra s t, the a nteri or a nd pos teri or nerve roots , ga ngl i a , a nd common s pi na l nerve a re rel a ti vel y wel l protected i n the i ntervertebra l fora mi na ,
where they occupy onl y 25% of the a va i l a bl e a nd wel l -cus hi oned s pa ce.
Symptoms and Signs
Ons et i s mos t often gra dua l , us ua l l y begi nni ng wi th one or a few joi nts . Pa i n i s the ea rl i es t s ymptom, s ometi mes des cri bed a s a deep a che. Pa i n
i s us ua l l y wors ened by wei ght bea ri ng a nd rel i eved by res t but ca n eventua l l y become cons ta nt. Sti ffnes s fol l ows a wa keni ng or i na cti vi ty but l a s ts
< 30 mi n a nd l es s ens wi th movement. As OA progres s es , joi nt moti on becomes res tri cted, a nd tendernes s a nd crepi tus or gra ti ng s ens a ti ons
devel op. Prol i fera ti on of ca rti l a ge, bone, l i ga ment, tendon, ca ps ul es , a nd s ynovi um, a l ong wi th va ryi ng a mounts of joi nt effus i on, ul ti ma tel y ca us e
the joi nt enl a rgement cha ra cteri s ti c of OA. Fl exi on contra ctures ma y eventua l l y devel op. Acute a nd s evere s ynovi ti s i s uncommon.
Tendernes s on pa l pa ti on a nd pa i n on pa s s i ve moti on a re rel a ti vel y l a te s i gns . Mus cl e s pa s m a nd contra cture a dd to the pa i n. Mecha ni ca l bl ock
by i ntra -a rti cul a r l oos e bodi es or a bnorma l l y pl a ced meni s ci ca n occur a nd ca us e l ocki ng or ca tchi ng. Deformi ty a nd s ubl uxa ti ons ca n a l s o
devel op.
The joi nts mos t often a ffected i n genera l i zed OA i ncl ude the fol l owi ng:
Di s ta l i nterpha l a ngea l (DIP) a nd proxi ma l i nterpha l a ngea l (PIP) joi nts (ca us i ng Heberden's a nd Boucha rd's nodes )
Thumb ca rpometa ca rpa l joi nt
Intervertebra l di s ks a nd zyga pophys ea l joi nts i n the cervi ca l a nd l umba r vertebra e
Fi rs t meta ta rs opha l a ngea l joi nt
Hi p
Knee
Cervical and lumbar spinal OA ma y l ea d to myel opa thy or ra di cul opa thy. However, the cl i ni ca l s i gns of myel opa thy a re us ua l l y mi l d. Lumba r s pi na l
s tenos i s ma y ca us e l ower ba ck or l eg pa i n tha t i s wors ened by wa l ki ng or ba ck extens i on. Ra di cul opa thy ca n be promi nent but i s l es s common
beca us e the nerve roots a nd ga ngl i a a re wel l protected. Ins uffi ci ency of the vertebra l a rteri es , i nfa rcti on of the s pi na l cord, a nd dys pha gi a due to
es opha gea l i mpi ngement by os teophytes occa s i ona l l y occur. Symptoms a nd s i gns from OA i n genera l ma y a l s o deri ve from s ubchondra l bone,
l i ga mentous s tructures , s ynovi um, peri a rti cul a r burs a e, ca ps ul es , mus cl es , tendons , di s ks , a nd peri os teum, a l l of whi ch a re pa i n s ens i ti ve.
Venous pres s ure ma y i ncrea s e wi thi n the s ubchondra l bone ma rrow a nd ca us e pa i n (s ometi mes ca l l ed bone a ngi na ).
Hip OA ca us es gra dua l l os s of ra nge of moti on. Pa i n ma y be fel t i n the i ngui na l a rea or grea ter trocha nter or referred to the knee.
Knee OA ca us es ca rti l a ge to be l os t (medi a l l os s occurs i n 70% of ca s es ). The l i ga ments become l a x a nd the joi nt becomes l es s s ta bl e, wi th l oca l
pa i n a ri s i ng from the l i ga ments a nd tendons .
Erosive OA ca us es s ynovi ti s a nd cys ts i n the ha nd. It pri ma ri l y a ffects the DIP or PIP joi nts . The thumb ca rpometa ca rpa l joi nts a re i nvol ved i n 20% of
ha nd OA, but the meta ca rpopha l a ngea l joi nts a nd wri s ts a re us ua l l y s pa red. At thi s ti me, i t i s uncerta i n whether eros i ve i nterpha l a ngea l OA i s a
va ri a nt of ha nd OA or whether i t repres ents a s epa ra te enti ty.
OA i s us ua l l y s pora di ca l l y progres s i ve but occa s i ona l l y, wi th no predi cta bi l i ty, s tops or revers es .
Diagnosis
X-ra ys
OA s houl d be s us pected i n pa ti ents wi th gra dua l ons et of s ymptoms a nd s i gns , pa rti cul a rl y i n ol der a dul ts . If OA i s s us pected, pl a i n x-ra ys s houl d
be ta ken of the mos t s ymptoma ti c joi nts . X-ra ys genera l l y revea l ma rgi na l os teophytes , na rrowi ng of the joi nt s pa ce, i ncrea s ed dens i ty of the
s ubchondra l bone, s ubchondra l cys t forma ti on, bony remodel i ng, a nd joi nt effus i ons . Sta ndi ng x-ra ys of knees a re more s ens i ti ve i n detecti ng joi nt
s pa ce na rrowi ng.
La bora tory s tudi es a re norma l i n OA but ma y be requi red to rul e out other di s orders (eg, RA) or to di a gnos e a n underl yi ng di s order ca us i ng
s econda ry OA. If OA ca us es joi nt effus i ons , s ynovi a l fl ui d a na l ys i s ca n hel p di fferenti a te i t from i nfl a mma tory a rthri ti des ; i n OA, s ynovi a l fl ui d i s
us ua l l y cl ea r, vi s cous , a nd ha s 2000 WBC/L.
OA i nvol vement outs i de the us ua l joi nts s ugges ts s econda ry OA; further eva l ua ti on ma y be requi red to determi ne the underl yi ng pri ma ry di s order
(eg, endocri ne, meta bol i c, neopl a s ti c, bi omecha ni ca l di s orders ).
Treatment
Reha bi l i ta ti ve a nd s upporti ve mea s ures
Adjuncti ve drug thera py
Trea tment goa l s a re rel i evi ng pa i n, ma i nta i ni ng joi nt fl exi bi l i ty, a nd opti mi zi ng joi nt a nd overa l l functi on. Pri ma ry trea tments i ncl ude phys i ca l
mea s ures tha t i nvol ve reha bi l i ta ti on; s upport devi ces ; exerci s e for s trength, fl exi bi l i ty, a nd endura nce; pa ti ent educa ti on; a nd modi fi ca ti ons i n
a cti vi ti es of da i l y l i vi ng. Adjuncti ve thera pi es i ncl ude drug trea tment a nd s urgery.
Physical measures: Reha bi l i ta ti on techni ques a re bes t begun before di s a bi l i ty devel ops . Exerci s es (ra nge of moti on, i s ometri c, i s otoni c, i s oki neti c,
pos tura l , s trengtheni ngs ee p. 3453) ma i nta i n ra nge of moti on a nd i ncrea s e the ca pa ci ty for tendons a nd mus cl es to a bs orb s tres s duri ng joi nt
moti on. Exerci s e ca n s ometi mes a rres t or even revers e hi p a nd knee OA. Stretchi ng exerci s es s houl d be done da i l y. Immobi l i za ti on for a ny
prol onged peri od of ti me ca n promote contra ctures a nd wors en the cl i ni ca l cours e. However, a few mi nutes of res t (every 4 to 6 h i n the da yti me)
ca n hel p i f ba l a nced wi th exerci s e a nd us e.
Modi fyi ng a cti vi ti es of da i l y l i vi ng ca n hel p. For exa mpl e, a pa ti ent wi th l umba r s pi ne, hi p, or knee OA s houl d a voi d s oft deep cha i rs a nd recl i ners
i n whi ch pos ture i s poor a nd from whi ch ri s i ng i s di ffi cul t. The regul a r us e of pi l l ows under the knees whi l e recl i ni ng encoura ges contra ctures a nd
s houl d a l s o be a voi ded. Pa ti ents s houl d s i t i n s tra i ght-ba ck cha i rs wi thout s l umpi ng, s l eep on a fi rm bed, perha ps wi th a bed boa rd, us e a ca r
s ea t s hi fted forwa rd a nd des i gned for comfort, do pos tura l exerci s es , wea r wel l -s upported s hoes or a thl eti c s hoes , a nd conti nue empl oyment a nd
phys i ca l a cti vi ty.
In OA of the s pi ne, knee, or thumb ca rpometa ca rpa l joi nt, va ri ous s upports ca n rel i eve pa i n a nd i ncrea s e functi on, but to pres erve fl exi bi l i ty, they
s houl d be a ccompa ni ed by s peci fi c exerci s e progra ms . In eros i ve OA, ra nge-of-moti on exerci s es done i n wa rm wa ter ca n hel p prevent contra ctures .
Drugs: Drug thera py i s a n a djunct to the phys i ca l progra m. Aceta mi nophen i n dos es of up to 1 g po qi d ma y rel i eve pa i n a nd i s s a fe. More potent
a na l ges i a ma y be requi red.
NSAIDs , i ncl udi ng cycl ooxygena s e-2 (COX-2) i nhi bi tors or coxi bs , ma y be cons i dered i f pa ti ents ha ve refra ctory pa i n or s i gns of i nfl a mma ti on (eg,
rednes s , wa rmth). NSAIDs ma y be us ed s i mul ta neous l y wi th other a na l ges i cs (eg, tra ma dol , opi oi ds ) to provi de better rel i ef of s ymptoms .
Mus cl e rel a xa nts (us ua l l y i n l ow dos es ) occa s i ona l l y rel i eve pa i n tha t a ri s es from mus cl es s tra i ned by a ttempti ng to s upport OA joi nts . In the
el derl y, however, they ma y ca us e more a dvers e effects tha n rel i ef.
Ora l corti cos teroi ds ha ve no rol e. However, i ntra -a rti cul a r depot corti cos teroi ds hel p rel i eve pa i n a nd i ncrea s e joi nt fl exi bi l i ty.
Syntheti c hya l urona ns (s i mi l a r to hya l uroni c a ci d, a norma l component of the joi nt) ca n be i njected i nto the knee, wi th pa i n rel i ef for prol onged
peri ods of ti me (up to a yea r). However, the effect s eems to be s ma l l . The trea tment i s a s eri es of 3 to 5 weekl y i njecti ons .
Gl ucos a mi ne s ul fa te 1500 mg po once/da y ha s been s ugges ted to rel i eve pa i n a nd s l ow joi nt deteri ora ti on; chondroi ti n s ul fa te 1200 mg once/da y
ha s a l s o been s ugges ted for pa i n rel i ef. Studi es to da te ha ve s hown mi xed res ul ts i n terms of pa i n rel i ef.
Other adjunctive and experimental therapies: Other a djuncti ve mea s ures ca n rel i eve pa i n, i ncl udi ng ma s s a ge, hea ti ng pa ds , wei ght l os s , a cupuncture,
tra ns cuta neous el ectri ca l nerve s ti mul a ti on, a nd l oca l rubs (eg, wi th ca ps a i ci n). La mi nectomy, os teotomy, a nd tota l joi nt repl a cement s houl d be
cons i dered i f a l l nons urgi ca l a pproa ches fa i l . (See a l s o the Agency for Hea l thca re Res ea rch a nd Qua l i ty's Evi dence-Ba s ed Pra cti ce Progra m's
evi dence report.)
Experi menta l thera pi es tha t ma y pres erve ca rti l a ge or a l l ow chondrocyte gra fti ng a re bei ng s tudi ed. It i s not cl ea r whether us i ng a l i doca i ne 5%
pa tch rel i eves pa i n. Fl a vocoxi d, a new drug, ca n be tri ed.
Neurogenic Arthropathy
(Neuropa thi c Arthropa thy; Cha rcot's Joi nts )
Neurogenic arthropathy is a rapidly destructive arthropathy due to impaired pain perception and position sense, which can result from various underlying
disorders, most commonly diabetes and stroke. Common manifestations include joint swelling, effusion, deformity, and instability. Pain may be
disproportionately mild due to the underlying neuropathy. Diagnosis requires x-ray confirmation. Treatment consists of joint immobilization, which slows disease
progression, and sometimes surgery if the disease is advanced.
Pathophysiology
Ma ny condi ti ons predi s pos e to neurogeni c a rthropa thy (s ee
Ta bl e 35-4). Impa i red deep pa i n s ens a ti on or propri ocepti on a ffects the joi nt's norma l protecti ve refl exes , often a l l owi ng tra uma (es peci a l l y
repea ted mi nor epi s odes ) a nd s ma l l peri a rti cul a r fra ctures to go unrecogni zed. Increa s ed bl ood fl ow to bone from refl ex va s odi l a ti on, res ul ti ng i n
a cti ve bone res orpti on, contri butes to bone a nd joi nt da ma ge. Ea ch new i njury s us ta i ned by the joi nt ca us es more di s torti on a s i t hea l s .
Hemorrha gi c joi nt effus i ons a nd mul ti pl e s ma l l fra ctures ca n occur, a ccel era ti ng di s ea s e progres s i on. Li ga mentous l a xi ty, mus cul a r hypotoni a ,
a nd ra pi d des tructi on of joi nt ca rti l a ge a re common, predi s pos i ng to joi nt di s l oca ti ons , whi ch a l s o a ccel era te di s ea s e progres s i on. Adva nced
neurogeni c a rthropa thy ca n ca us e hypertrophi c cha nges , des tructi ve cha nges , or both.
[Table 35-4. Condi ti ons Underl yi ng Neurogeni c Arthropa thy]
Symptoms and Signs
Arthropa thy does not us ua l l y devel op unti l yea rs a fter ons et of the neurol ogi c condi ti on but ca n then progres s ra pi dl y a nd l ea d to compl ete joi nt
di s orga ni za ti on i n a few months . Pa i n i s a common ea rl y s ymptom. However, beca us e the a bi l i ty to s ens e pa i n i s commonl y i mpa i red, the degree
of pa i n i s often unexpectedl y mi l d for the degree of joi nt da ma ge. A promi nent, often hemorrha gi c, effus i on a nd s ubl uxa ti on a nd i ns ta bi l i ty of the
joi nt a re us ua l l y pres ent duri ng ea rl y s ta ges . Acute joi nt di s l oca ti on s ometi mes occurs a l s o.
Duri ng l a ter s ta ges , pa i n ma y be more s evere i f the di s ea s e ha s ca us ed ra pi d joi nt des tructi on (eg, peri a rti cul a r fra ctures or tens e hema toma s ).
Duri ng a dva nced s ta ges , the joi nt i s s wol l en from bony overgrowth a nd ma s s i ve s ynovi a l effus i on. Deformi ty res ul ts from di s l oca ti ons a nd
di s pl a ced fra ctures . Fra ctures a nd bony hea l i ng ma y produce ma ny l oos e pi eces of ca rti l a ge or bone tha t ca n s l ough i nto the joi nt, ca us i ng a
coa rs e, gra ti ng, often a udi bl e crepi tus us ua l l y more unpl ea s a nt for the obs erver tha n for the pa ti ent. The joi nt ma y feel l i ke a "ba g of bones ."
Al though ma ny joi nts ca n be i nvol ved, the knee a nd the a nkl e a re mos t often a ffected. Di s tri buti on depends l a rgel y on the underl yi ng di s ea s e.
Thus , ta bes dors a l i s a ffects the knee a nd hi p, a nd di a betes mel l i tus a ffects the foot a nd a nkl e. Syri ngomyel i a commonl y a ffects the s pi ne a nd
upper l i mb joi nts , es peci a l l y the el bow a nd s houl der. Frequentl y, onl y one joi nt i s a ffected a nd us ua l l y no more tha n two or three (except for the
s ma l l joi nts of the feet), i n a n a s ymmetri c di s tri buti on.
Infecti ous a rthri ti s ma y devel op wi th or wi thout s ys temi c s ymptoms (eg, fever, ma l a i s e), pa rti cul a rl y wi th di a betes . Structures s uch a s bl ood
ves s el s , nerves , a nd the s pi na l cord ca n become compres s ed due to the ti s s ue overgrowth.
Diagnosis
X-ra ys
The di a gnos i s s houl d be cons i dered i n a pa ti ent wi th a predi s pos i ng neurol ogi c di s order who devel ops a des tructi ve but unexpectedl y pa i nl es s
a rthropa thy, us ua l l y s evera l yea rs a fter the ons et of the underl yi ng neurol ogi c condi ti on. If neurogeni c a rthropa thy i s s us pected, x-ra ys s houl d be
ta ken. Di a gnos i s i s es ta bl i s hed by cha ra cteri s ti c x-ra y a bnorma l i ti es i n a pa ti ent wi th a predi s pos i ng condi ti on a nd typi ca l s ymptoms a nd s i gns .
X-ra y a bnorma l i ti es i n ea rl y neurogeni c a rthropa thy a re often s i mi l a r to thos e i n os teoa rthri ti s (OA). The ca rdi na l s i gns a re bone fra gmenta ti on,
bone des tructi on, new bone growth, a nd l os s of joi nt s pa ce. There ma y a l s o be s ynovi a l effus i on a nd joi nt s ubl uxa ti on. La ter, the bones a re
deformed, a nd new bone forms a dja cent to the cortex, s ta rti ng wi thi n the joi nt ca ps ul e a nd often extendi ng up the s ha ft, pa rti cul a rl y i n l ong
bones . Ra rel y, ca l ci fi ca ti on a nd os s i fi ca ti on occur i n the s oft ti s s ues . La rge, bi za rrel y s ha ped os teophytes ma y be pres ent a t the joi nt ma rgi ns or
wi thi n joi nts . La rge curved (pa rrot's bea k) os teophytes frequentl y devel op i n the s pi ne i n the a bs ence of cl i ni ca l s pi na l di s ea s e.
In i ts ea rl y s ta ges , neurogeni c a rthropa thy ca n s i mul a te OA. However, neurogeni c a rthropa thy progres s es more ra pi dl y tha n OA a nd frequentl y
ca us es proporti ona tel y l es s pa i n.
Treatment
Someti mes s urgery
Ea rl y di a gnos i s of a s ymptoma ti c or mi ni ma l l y s ymptoma ti c fra ctures fa ci l i ta tes ea rl y trea tment; i mmobi l i za ti on (wi th s pl i nts , s peci a l boots , or
ca l i pers ) protects the joi nt from further i njury, pos s i bl y s toppi ng di s ea s e evol uti on. Preventi on of neurogeni c a rthropa thy ma y even be pos s i bl e i n
a pa ti ent a t ri s k.
Trea tment of the underl yi ng neurol ogi c condi ti on ma y s l ow progres s i on of the a rthropa thy a nd, i f joi nt des tructi on i s s ti l l i n the ea rl y s ta ges ,
pa rti a l l y revers e the proces s . For a gros s l y di s orga ni zed joi nt, a rthrodes i s us i ng i nterna l fi xa ti on, compres s i on, a nd a n a dequa te bone gra ft ma y
be s ucces s ful . For gros s l y di s orga ni zed hi p a nd knee joi nts , i f neurogeni c a rthropa thy i s not expected to be progres s i ve, good res ul ts ca n be
obta i ned wi th tota l hi p a nd knee repl a cements . However, l oos eni ng a nd di s l oca ti on of the pros thes i s a re ma jor ha za rds .
Chapter 36. Crystal-Induced Arthritides

Introduction
Arthri ti s ca n res ul t from i ntra -a rti cul a r depos i ti on of crys ta l s : monos odi um ura te, Ca pyrophos pha te di hydra te, ba s i c Ca phos pha te (a pa ti te), a nd,
ra rel y, others s uch a s Ca oxa l a te crys ta l s . Di a gnos i s requi res s ynovi a l fl ui d a na l ys i s (s ee p. 287). Pol a ri zed l i ght mi cros copy i s us ed to s peci fi ca l l y
i denti fy mos t crys ta l s ; ba s i c Ca phos pha te crys ta l s a re of ul tra mi cros copi c s i ze a nd requi re other methods . Crys ta l s ma y be engul fed i n WBCs or
ma y be extra cel l ul a r. The pres ence of crys ta l s does not excl ude the pos s i bi l i ty of s i mul ta neous i nfecti ous or other i nfl a mma tory forms of a rthri ti s .
Gout
Gout is precipitation of monosodium urate crystals into tissue, usually in and around joints, most often causing recurrent acute or chronic arthritis. Acute arthritis
is initially monarticular and often involves the 1st metatarsophalangeal joint. Symptoms include acute pain, tenderness, warmth, redness, and swelling. Diagnosis
requires identification of crystals in synovial fluid. Treatment of acute attacks is with anti-inflammatory drugs. The frequency of attacks can be reduced by
regular use of NSAIDs, colchicine, or both and by treating hyperuricemia with allopurinol or uricosuric drugs.
Gout i s more common a mong men tha n women. Us ua l l y, gout devel ops duri ng mi ddl e a ge i n men a nd a fter menopa us e i n women. Gout i s ra re i n
younger peopl e but i s often more s evere i n peopl e who devel op the di s order before a ge 30. Gout often runs i n fa mi l i es .
Pathophysiology
The grea ter the degree a nd dura ti on of hyperuri cemi a , the grea ter i s the l i kel i hood of gout a nd the more s evere a re the s ymptoms . Ura te l evel s
ca n be el eva ted beca us e of
Decrea s ed excreti on
Increa s ed producti on
Increa s ed puri ne i nta ke
Why onl y s ome peopl e wi th el eva ted s erum uri c a ci d (ura te) l evel s devel op gout i s not known.
Decreased renal excretion i s by fa r the mos t common ca us e of hyperuri cemi a . It ma y be heredi ta ry a nd a l s o occurs i n pa ti ents recei vi ng di ureti cs a nd
i n thos e wi th di s ea s es tha t decrea s e GFR. Etha nol i ncrea s es puri ne ca ta bol i s m i n the l i ver a nd i ncrea s es the forma ti on of l a cti c a ci d, whi ch
bl ocks ura te s ecreti on by the rena l tubul es . Lea d poi s oni ng a nd cycl os pori ne, us ua l l y gi ven to tra ns pl a nt pa ti ents , i rrevers i bl y da ma ge rena l
tubul es , l ea di ng to ura te retenti on.
Increased production of ura te ma y be ca us ed by i ncrea s ed nucl eoprotei n turnover i n hema tol ogi c condi ti ons (eg, l ymphoma , l eukemi a , hemol yti c
a nemi a ) a nd i n condi ti ons wi th i ncrea s ed ra tes of cel l ul a r prol i fera ti on a nd cel l dea th (eg, ps ori a s i s , cytotoxi c ca ncer thera py, ra di a ti on thera py).
Increa s ed ura te producti on ma y a l s o occur a s a pri ma ry heredi ta ry a bnorma l i ty a nd i n obes i ty, beca us e ura te producti on correl a tes wi th body
s urfa ce a rea . In mos t ca s es , the ca us e i s unknown, but a few ca s es a re a ttri buta bl e to enzyme a bnorma l i ti es ; defi ci ency of hypoxa nthi ne-gua ni ne
phos phori bos yl tra ns fera s e (compl ete defi ci ency i s Les ch-Nyha n s yndrome) i s a pos s i bl e ca us e, a s i s overa cti vi ty of phos phori bos yl pyrophos pha te
s yntheta s e.
Increased intake of puri ne-ri ch foods (eg, l i ver, ki dney, a nchovi es , a s pa ra gus , cons omme, herri ng, mea t gra vi es a nd broths , mus hrooms , mus s el s ,
s a rdi nes , s weetbrea ds ) ca n contri bute to hyperuri cemi a . However, a s tri ct l ow-puri ne di et l owers s erum ura te by onl y a bout 1 mg/dL.
Ura te preci pi ta tes a s needl e-s ha ped monos odi um ura te (MSU) crys ta l s , whi ch a re depos i ted extra cel l ul a rl y i n a va s cul a r ti s s ues (eg, ca rti l a ge) or
i n rel a ti vel y a va s cul a r ti s s ues (eg, tendons , tendon s hea ths , l i ga ments , wa l l s of burs a e) a nd s ki n a round cool er di s ta l joi nts a nd ti s s ues (eg,
ea rs ). In s evere, l ongs ta ndi ng hyperuri cemi a , MSU crys ta l s ma y be depos i ted i n l a rger centra l joi nts a nd i n the pa renchyma of orga ns s uch a s the
ki dney. At the a ci d pH of uri ne, ura te preci pi ta tes rea di l y a s s ma l l pl a tel i ke or i rregul a r crys ta l s tha t ma y a ggrega te to form gra vel or s tones , whi ch
ma y ca us e obs tructi on. Tophi a re MSU crys ta l a ggrega tes tha t mos t often devel op i n joi nt a nd cuta neous ti s s ue.
Acute gouty a rthri ti s ma y be tri ggered by tra uma , medi ca l s tres s (eg, pneumoni a or other i nfecti on), a nd es peci a l l y va s cul a r occl us i ons (eg, s troke
or MI), or by s urgery, us e of thi a zi de di ureti cs or drugs wi th uri cos uri c a cti vi ty (eg, a l l opuri nol ), or i ndul gence i n puri ne-ri ch food or a l cohol . Atta cks
a re often preci pi ta ted by a s udden i ncrea s e or, more commonl y, a s udden decrea s e i n s erum ura te l evel s . Why a cute a tta cks fol l ow s ome of thes e
preci pi ta ti ng condi ti ons i s unknown. Tophi i n a nd a round joi nts ca n l i mi t moti on a nd ca us e deformi ti es , ca l l ed chroni c topha ceous gouty a rthri ti s .
Symptoms and Signs
Acute gouty a rthri ti s us ua l l y begi ns wi th s udden ons et of pa i n (often nocturna l ). The meta ta rs opha l a ngea l joi nt of a grea t toe i s mos t often
i nvol ved (poda gra ), but the i ns tep, a nkl e, knee, wri s t, a nd el bow a re a l s o common s i tes . Ra rel y, the hi p, s houl der, s a croi l i a c, s ternocl a vi cul a r, or
cervi ca l s pi ne joi nts a re i nvol ved. The pa i n becomes progres s i vel y more s evere, us ua l l y over a few hours , a nd i s often excruci a ti ng. Swel l i ng,
wa rmth, rednes s , a nd exqui s i te tendernes s ma y s ugges t i nfecti on. The overl yi ng s ki n ma y become tens e, wa rm, s hi ny, a nd red or purpl i s h. Fever,
ta chyca rdi a , chi l l s , a nd ma l a i s e s ometi mes occur. Coexi s ti ng hypertens i on, hyperl i pi demi a , a nd obes i ty a re common.
Course: The fi rs t few a tta cks us ua l l y a ffect onl y a s i ngl e joi nt a nd l a s t onl y a few da ys . La ter a tta cks ma y a ffect s evera l joi nts s i mul ta neous l y or
s equenti a l l y a nd pers i s t up to 3 wk i f untrea ted. Subs equent a tta cks devel op a fter progres s i vel y s horter s ymptom-free i nterva l s . Eventua l l y,
s evera l a tta cks ma y occur ea ch yea r.
Tophi: Tophi devel op mos t often i n pa ti ents wi th chroni c gout, but they ca n occur i n pa ti ents who ha ve never ha d a cute gouty a rthri ti s . They a re
us ua l l y fi rm yel l ow or whi te pa pul es or nodul es , s i ngl e or mul ti pl e. They ca n devel op i n va ri ous l oca ti ons , commonl y the fi ngers , ha nds , feet, a nd
a round the ol ecra non or Achi l l es tendon. Tophi ca n a l s o devel op i n the ki dneys a nd other orga ns a nd under the s ki n on the ea rs . Pa ti ents wi th
os teoa rthri ti c Heberden's nodes ma y devel op tophi i n the nodes . Thi s devel opment occurs mos t often i n el derl y women ta ki ng di ureti cs . Norma l l y
pa i nl es s , tophi , es peci a l l y i n the ol ecra non burs a e, ca n become a cutel y i nfl a med a nd pa i nful . Tophi ma y even erupt through the s ki n, di s cha rgi ng
cha l ky ma s s es of ura te crys ta l s . Tophi ma y eventua l l y ca us e deformi ti es .

Chronic gout: Chroni c gouty a rthri ti s ca n ca us e pa i n, deformi ty, a nd l i mi ted joi nt moti on. Infl a mma ti on ca n be fl a ri ng i n s ome joi nts whi l e s ubs i di ng
i n others . About 20% of pa ti ents wi th gout devel op urol i thi a s i s wi th uri c a ci d s tones or Ca oxa l a te s tones . Compl i ca ti ons i ncl ude obs tructi on a nd
i nfecti on, wi th s econda ry tubul oi nters ti ti a l di s ea s e. Untrea ted progres s i ve rena l dys functi on, mos t often rel a ted to coexi s ti ng hypertens i on or,
l es s often, s ome other ca us e of nephropa thy, further i mpa i rs excreti on of ura te, a ccel era ti ng crys ta l depos i ti on i n ti s s ues .
Ca rdi ova s cul a r di s ea s e a nd the meta bol i c s yndrome a re common a mong pa ti ents wi th gout.
Diagnosis
Synovi a l fl ui d a na l ys i s
Gout s houl d be s us pected i n pa ti ents wi th a cute mona rti cul a r or ol i goa rthri ti s , pa rti cul a rl y ol der a dul ts or thos e wi th other ri s k fa ctors . Poda gra
a nd recurrent i ns tep i nfl a mma ti on a re pa rti cul a rl y s ugges ti ve. Si mi l a r s ymptoms ca n res ul t from
Ca pyrophos pha te di hydra te (CPPD) crys ta l depos i ti on di s ea s e (s ee p. 354) (however, CPPD genera l l y a tta cks l a rger joi nts a nd i ts cl i ni ca l cours e i s
us ua l l y mi l der)
Acute rheuma ti c fever wi th joi nt i nvol vement a nd juveni l e RA (however, thes e di s orders occur mos tl y i n young peopl e, who ra rel y get gout)
RA (however, i n RA, a l l a ffected joi nts fl a re a nd s ubs i de together, wherea s i n gout, i nfl a mma ti on i s us ua l l y fl a ri ng i n s ome joi nts whi l e
s ubs i di ng i n others )
Acute fra cture i n pa ti ents una bl e to provi de a hi s tory of i njury
Infecti ous a rthri ti s (s ee pp. 365 a nd 369; di fferenti a ti on ma y requi re s ynovi a l fl ui d a na l ys i s )
Pa l i ndromi c rheuma ti s m
Pa l i ndromi c rheuma ti s m i s cha ra cteri zed by a cute, recurrent a tta cks of i nfl a mma ti on i n or nea r one or occa s i ona l l y s evera l joi nts wi th
s ponta neous res ol uti on; pa i n a nd erythema ca n be a s s evere a s i n gout. Atta cks s ubs i de s ponta neous l y a nd compl etel y i n 1 to 3 da ys . Such
a tta cks ma y hera l d the ons et of RA, a nd rheuma toi d fa ctor tes ts ca n hel p i n di fferenti a ti on; they a re pos i ti ve i n a bout 50% of pa ti ents (thes e tes ts
a re pos i ti ve i n 10% of gouty pa ti ents a l s o).
Synovial fluid analysis: If a cute gouty a rthri ti s i s s us pected, a rthrocentes i s a nd s ynovi a l fl ui d a na l ys i s s houl d be done a t the i ni ti a l pres enta ti on. A
typi ca l recurrence i n a pa ti ent wi th known gout does not ma nda te a rthrocentes i s , but i t s houl d be done i f there i s a ny ques ti on of the di a gnos i s
or i f the pa ti ent's ri s k fa ctors or a ny cl i ni ca l cha ra cteri s ti cs s ugges t i nfecti ous a rthri ti s . Synovi a l fl ui d a na l ys i s ca n confi rm the di a gnos i s by
i denti fyi ng needl e-s ha ped, s trongl y nega ti vel y bi refri ngent ura te crys ta l s tha t a re free i n the fl ui d or engul fed by pha gocytes . Synovi a l fl ui d duri ng
a tta cks ha s i nfl a mma tory cha ra cteri s ti cs (s ee
Ta bl e 36-1), us ua l l y 2,000 to 100,000 WBCs /L, wi th > 80% pol ymorphonucl ea r WBCs . Thes e fi ndi ngs overl a p cons i dera bl y wi th i nfecti ous a rthri ti s ,
whi ch mus t be excl uded by Gra m s ta i n a nd cul ture.
Serum urate level: An el eva ted s erum ura te l evel s upports the di a gnos i s of gout but i s nei ther s peci fi c nor s ens i ti ve; a t l ea s t 30% of pa ti ents ha ve a
norma l s erum ura te l evel duri ng a n a cute a tta ck. However, the s erum ura te l evel refl ects the s i ze of the extra cel l ul a r mi s ci bl e ura te pool . The
l evel s houl d be mea s ured on 2 or 3 occa s i ons i n pa ti ents wi th newl y proven gout to es ta bl i s h a ba s el i ne; i f el eva ted (> 7 mg/dL [> 0.41 mmol /L]),
24-h uri na ry ura te excreti on ca n a l s o be mea s ured. Norma l 24-h excreti on i n peopl e ea ti ng a regul a r di et i s a bout 600 to 900 mg. Qua nti fi ca ti on of
uri na ry uri c a ci d ca n i ndi ca te whether hyperuri cemi a res ul ts from i mpa i red excreti on or i ncrea s ed producti on a nd hel p gui de a ny s erum ura tel oweri ng thera py. Pa ti ents wi th el eva ted uri ne excreti on of ura te a re a t i ncrea s ed ri s k of urol i thi a s i s .
X-rays: X-ra ys of the a ffected joi nt ma y be ta ken to l ook for bony tophi but a re proba bl y unneces s a ry i f the di a gnos i s ha s been es ta bl i s hed by
s ynovi a l fl ui d a na l ys i s . In CPPD, ra di opa que depos i ts a re pres ent i n fi broca rti l a ge, hya l i ne a rti cul a r ca rti l a ge (pa rti cul a rl y the knee), or both.
Diagnosis of chronic gouty arthritis: Chroni c gouty a rthri ti s s houl d be s us pected i n pa ti ents wi th pers i s tent joi nt di s ea s e or s ubcuta neous
[Table 36-1. Mi cros copi c Exa mi na ti on of Crys ta l s i n Joi nts ]
or bony tophi . Pl a i n x-ra ys of the 1s t meta ta rs opha l a ngea l joi nt or other a ffected joi nt ma y be us eful . Thes e x-ra ys ma y s how punched-out l es i ons
of s ubchondra l bone wi th overha ngi ng bony ma rgi ns , mos t commonl y i n the 1s t meta ta rs opha l a ngea l joi nt; l es i ons mus t be 5 mm i n di a meter to
be vi s i bl e on x-ra y.
Bone l es i ons a re not s peci fi c or di a gnos ti c but nea rl y a l wa ys precede the a ppea ra nce of s ubcuta neous tophi .
Prognosis
Wi th ea rl y di a gnos i s , thera py ena bl es mos t pa ti ents to l i ve a norma l l i fe. For ma ny pa ti ents wi th a dva nced di s ea s e, a ggres s i ve l oweri ng of the
s erum ura te l evel ca n res ol ve tophi a nd i mprove joi nt functi on. Gout i s genera l l y more s evere i n pa ti ents whos e i ni ti a l s ymptoms a ppea r before
a ge 30. The meta bol i c s yndrome a nd ca rdi ova s cul a r di s ea s e proba bl y i ncrea s e morta l i ty i n pa ti ents wi th gout.
Some pa ti ents do not i mprove s uffi ci entl y wi th trea tment. The us ua l rea s ons i ncl ude nona dherence, a l cohol i s m, a nd undertrea tment by
phys i ci a ns .
Treatment
Termi na ti on of a n a cute a tta ck wi th NSAIDs or corti cos teroi ds
Preventi on of recurrent a cute a tta cks wi th da i l y col chi ci ne or a n NSAID
Preventi on of further depos i ti on of MSU crys ta l s a nd res ol uti on of exi s ti ng tophi by l oweri ng the s erum ura te l evel
Trea tment of coexi s ti ng hypertens i on, hyperl i pi demi a , a nd obes i ty
Treatment of acute attacks: NSAIDs a re effecti ve i n trea ti ng a cute a tta cks a nd a re genera l l y wel l tol era ted. However, they ca n s ti l l ca us e a dvers e
effects , i ncl udi ng GI ups et, hyperka l emi a , i ncrea s es i n crea ti ni ne, a nd fl ui d retenti on. El derl y a nd dehydra ted pa ti ents a re a t pa rti cul a r ri s k,
es peci a l l y i f there i s a hi s tory of rena l di s ea s e. Vi rtua l l y a ny NSAID us ed i n a nti -i nfl a mma tory (hi gh) dos es i s effecti ve a nd i s l i kel y to exert a n
a na l ges i c effect i n a few hours (s ee
Ta bl e 35-2 on p. 336). Trea tment s houl d be conti nued for s evera l da ys a fter the pa i n a nd s i gns of i nfl a mma ti on ha ve res ol ved to prevent rel a ps e.
Oral colchicine, a tra di ti ona l thera py, often produces a dra ma ti c res pons e i f begun s oon a fter the ons et of s ymptoms . Joi nt pa i n genera l l y begi ns to
s ubs i de a fter 12 to 24 h of trea tment a nd cea s es wi thi n 3 to 7 da ys . One regi men i s col chi ci ne 0.6 mg po q 1 h unti l s ymptoms a ba te to a ma xi mum
tota l dos e of 4 to 5 mg or unti l di a rrhea or vomi ti ng occurs . However, di a rrhea , s ometi mes s evere, devel ops i n up to 80% of pa ti ents gi ven thi s
regi men of ora l col chi ci ne for a n a cute a tta ck. If trea tment i s s ta rted very ea rl y, regi mens s uch a s 0.6 to 1.2 mg bi d to ti d for 1 to 2 da ys a re better
tol era ted a nd ma y be effecti ve. If col chi ci ne i s tol era ted, 0.6 to 1.2 mg once/da y ca n be conti nued a s the a tta ck s ubs i des .
IV colchicine i s much l es s l i kel y to ca us e GI s ymptoms a nd provi des a n a l terna ti ve, pa rti cul a rl y for pos topera ti ve pa ti ents . Col chi ci ne 1 mg i s
di l uted wi th 0.9% s a l i ne to 20 mL a nd i njected s l owl y (over 2 to 5 mi n); a s econd 1-mg dos e ca n be gi ven i n 12 h i f needed; no more tha n 2 mg i s
gi ven i n 24 h (a nd no more tha n 4 mg over 7 da ys ). IV colchicine should not be given to patients with renal or liver disease or those receiving prophylactic oral
colchicine, because severe bone marrow suppression, shock, and death may occur. IV col chi ci ne i s a l s o l oca l l y i rri ta ti ng, pa rti cul a rl y i f extra va s a ted.
Al though effecti ve a nd perha ps the opti on of choi ce i n certa i n s peci fi c s i tua ti ons , IV col chi ci ne s houl d onl y be us ed wi th ca reful a dherence to
pres cri bi ng i ndi ca ti ons a nd contra i ndi ca ti ons .
Corticosteroids a re s ometi mes us ed to trea t a cute a tta cks ; however, thi s us e i s controvers i a l beca us e i nfl a mma ti on ma y conti nue whi l e s ymptoms
a re ma s ked. As pi ra ti on of a ffected joi nts , fol l owed by i ns ti l l a ti on of corti cos teroi d es ter crys ta l s us pens i on, i s very effecti ve, pa rti cul a rl y for
mona rti cul a r s ymptoms ; predni s ol one tebuta te 4 to 40 mg or predni s ol one a ceta te 5 to 25 mg ca n be us ed, wi th dos e dependi ng on the s i ze of the
a ffected joi nt. Ora l predni s one (a bout 40 mg once/da y), IM or IV corti cos teroi ds , or s i ngl e-dos e ACTH 80 U IM i s a l s o very effecti ve, pa rti cul a rl y i f
mul ti pl e joi nts a re i nvol ved. As wi th NSAID thera py, corti cos teroi ds s houl d be conti nued unti l a fter the a tta ck ful l y res ol ves to prevent rel a ps e.
In a ddi ti on to NSAIDs or corti cos teroi ds , s uppl ementa ry a na l ges i cs , res t, i ce a ppl i ca ti on, a nd s pl i nti ng of the i nfl a med joi nt ma y be hel pful .
Beca us e l oweri ng the s erum ura te l evel duri ng a n a tta ck prol ongs the a tta ck or predi s pos es to recurrence, drugs tha t l ower the s erum ura te l evel
s houl d not be i ni ti a ted unti l a cute s ymptoms ha ve been compl etel y control l ed.
Prevention of recurrent attacks: The frequency of a cute a tta cks i s reduced by ta ki ng one to two 0.6-mg ta bl ets of col chi ci ne da i l y (dependi ng on
tol era nce a nd s everi ty). An extra two or three 0.6-mg ta bl ets of col chi ci ne ta ken a t the fi rs t s ugges ti on of a n a tta ck ma y a bort fl a res . A (revers i bl e)
neuropa thy or myopa thy ca n devel op duri ng chroni c col chi ci ne i nges ti on. Thi s condi ti on ma y occur i n pa ti ents wi th rena l i ns uffi ci ency, i n pa ti ents
a l s o recei vi ng a s ta ti n or ma crol i de, or i n pa ti ents wi th none of thes e ri s k fa ctors . Atta ck frequency ca n a l s o be decrea s ed wi th da i l y l ow-dos e
NSAIDs .
Lowering the serum urate level: Col chi ci ne, NSAIDs , a nd corti cos teroi ds do not reta rd the progres s i ve joi nt da ma ge ca us ed by tophi . Such da ma ge ca n
be prevented a nd, i f pres ent, revers ed wi th ura te-l oweri ng drugs . Topha ceous depos i ts a re res orbed by l oweri ng s erum ura te. Loweri ng s erum
ura te ma y a l s o decrea s e the frequency of a cute a rthri ti c a tta cks . Thi s decrea s e i s a ccompl i s hed by
Bl ocki ng ura te producti on wi th a l l opuri nol
Increa s i ng ura te excreti on wi th a uri cos uri c drug
Us i ng both types of drugs together i n s evere topha ceous gout
Uri ca s e ca n a l s o be gi ven but i s not yet routi nel y us ed. Uri ca s e i s a n enzyme tha t converts ura te to a l l a ntoi n, whi ch i s more s ol ubl e. IV uri ca s e
tra ns i entl y l owers s erum ura te by a l a rge a mount.
Hypouri cemi c thera py i s i ndi ca ted for pa ti ents wi th
Topha ceous depos i ts
Frequent or di s a bl i ng a tta cks of gouty a rthri ti s (eg, more tha n 2 a tta cks /yr or very s evere a tta cks ) des pi te prophyl a cti c col chi ci ne, a n NSAID, or
both
Gout wi th pers i s tent s erum ura te 9 mg/dL
Urol i thi a s i s
Mul ti pl e comorbi di ti es (eg, pepti c ul cer di s ea s e, chroni c ki dney di s ea s e) tha t a re rel a ti ve contra i ndi ca ti ons to the drugs us ed to trea t a cute
a tta cks (NSAIDs or corti cos teroi ds )
Hyperuri cemi a i s not us ua l l y trea ted i n the a bs ence of gout.
If the goa l of hypouri cemi c thera py i s to di s s ol ve tophi , the s erum ura te l evel s houl d be l owered to 4.5 mg/dL (0.26 mmol /L), the s a tura ti on l evel a t
the norma l tempera ture (31 C) of the buni on joi nt, or even l ower. If tophi do not need to be di s s ol ved, a l evel of 5 to 6 mg/dL (0.30 to 0.36 mmol /L),
whi ch i s bel ow the l evel of s a tura ti on (> 7.0 mg/dL [> 0.41 mmol /L] a t norma l core body tempera ture a nd pH), i s a ccepta bl e. Thes e ta rget l evel s
s houl d be ma i nta i ned i ndefi ni tel y. Low l evel s a re often di ffi cul t to ma i nta i n.
Drugs a re effecti ve i n l oweri ng s erum ura te; di eta ry res tri cti on of puri nes i s l es s effecti ve, but hi gh i nta ke of hi gh-puri ne food a nd a l cohol (beer i n
pa rti cul a r) s houl d be a voi ded. Ca rbohydra te res tri cti on a nd wei ght l os s ca n l ower s erum ura te i n pa ti ents wi th i ns ul i n res i s ta nce beca us e hi gh
i ns ul i n l evel s s uppres s ura te excreti on. Beca us e a cute a tta cks tend to devel op duri ng the fi rs t months of hypouri cemi c thera py, s uch thera py
s houl d be s ta rted i n conjuncti on wi th once or twi ce da i l y col chi ci ne or NSAIDs a nd duri ng a s ymptom-free peri od. Res ol uti on of tophi ma y ta ke
ma ny months even wi th ma i ntena nce of s erum ura te a t l ow l evel s . Serum ura te s houl d be mea s ured peri odi ca l l y, us ua l l y monthl y whi l e
determi ni ng requi red drug dos a ge a nd then yea rl y to confi rm the effecti venes s of thera py.
Allopurinol, whi ch i nhi bi ts ura te s ynthes i s , i s the mos t commonl y pres cri bed hypouri cemi c thera py. It i s es peci a l l y hel pful i n trea ti ng pa ti ents who
repea tedl y pa s s uri c a ci d or Ca oxa l a te s tones or who ha ve s evere rena l dys functi on. Uri c a ci d s tones or gra vel ma y di s s ol ve duri ng a l l opuri nol
trea tment. Trea tment begi ns wi th 100 mg po once/da y a nd ca n be i ncrea s ed up to 800 mg po once/da y, or even hi gher, to a chi eve ta rget ura te
l evel s ; however, the dos e mus t be decrea s ed i n pa ti ents wi th rena l i ns uffi ci ency. The mos t common da i l y dos e i s 300 mg. Advers e effects i ncl ude
mi l d GI di s tres s a nd s ki n ra s h, whi ch ca n be a ha rbi nger of Stevens -Johns on s yndrome, l i fe-threa teni ng hepa ti ti s , va s cul i ti s , or l eukopeni a .
Advers e effects a re more common a mong pa ti ents wi th rena l dys functi on.
Uricosuric therapy i s preferred to a l l opuri nol a s i ni ti a l thera py for pa ti ents 60 yr wi th norma l rena l functi on, no hi s tory of urol i thi a s i s , a nd
decrea s ed rena l ura te excreti on. Probeneci d or s ul fi npyra zone ca n be us ed. Probeneci d trea tment begi ns wi th 250 mg po bi d, wi th dos es i ncrea s ed
a s needed, to a ma xi mum of 1 g po ti d. Sul fi npyra zone trea tment begi ns wi th 50 to 100 mg po bi d, wi th dos es i ncrea s ed a s needed, to a ma xi mum
of 100 mg po qi d. Sul fi npyra zone i s more potent tha n probeneci d but i s more toxi c. Sa l i cyl a tes a t l ow dos es a nta goni ze both drugs a nd ca n
i ncrea s e ura te l evel s . Low dos es ma y wors en hyperuri cemi a , but a thera peuti c tri a l of a ca rdi oprotecti ve dos e whi l e moni tori ng ura te l evel s ma y
be i ndi ca ted for pa ti ents a t hi gh ri s k of ca rdi ova s cul a r di s ea s e. Aceta mi nophen provi des compa ra bl e a na l ges i a wi thout i nterferi ng wi th drug
effi ca cy.
Other treatments: Fl ui d i nta ke 3 L/da y i s des i ra bl e for a l l pa ti ents , es peci a l l y thos e who chroni ca l l y pa s s ura te gra vel or s tones . Al ka l i ni za ti on of
uri ne (wi th K ci tra te 20 to 40 mEq po bi d or a ceta zol a mi de 500 mg po a t bedti me) i s a l s o occa s i ona l l y effecti ve for pa ti ents wi th pers i s tent uri c a ci d
urol i thi a s i s des pi te hypouri cemi c thera py a nd a dequa te hydra ti on. However, exces s i ve uri ne a l ka l i ni za ti on ma y ca us e depos i ti on of Ca oxa l a te
crys ta l s . Extra corporea l s hock wa ve l i thotri ps y ma y be needed to di s i ntegra te rena l s tones . La rge tophi i n a rea s wi th hea l thy s ki n ma y be removed
s urgi ca l l y; a l l others s houl d s l owl y res ol ve under a dequa te hypouri cemi c thera py. Los a rta n, whi ch ha s uri cos uri c effects , ca n be cons i dered a s a n
a l terna ti ve to thi a zi de di ureti cs .
Asymptomatic Hyperuricemia
As ymptoma ti c hyperuri cemi a i s el eva ti on of s erum ura te > 7 mg/dL (> 0.42 mmol /L) i n the a bs ence of cl i ni ca l gout. Genera l l y, trea tment i s not
requi red. However, pa ti ents wi th overexcreti on of ura te who a re a t ri s k of urol i thi a s i s ma y recei ve a l l opuri nol .
Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
(Ps eudogout)
Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease involves intra-articular and/or extra-articular deposition of CPPD crystals. Manifestations are
protean and may be minimal or include intermittent attacks of acute arthritis and a degenerative arthropathy that is often severe. Diagnosis requires
identification of CPPD crystals in synovial fluid. Treatment is with intra-articular corticosteroids or oral NSAIDs or colchicine.
CPPD crys ta l depos i ti on (chondroca l ci nos i s ), whether s ymptoma ti c a nd a s ymptoma ti c, becomes more common wi th a ge.
The i nci dence of ra di ol ogi c (us ua l l y a s ymptoma ti c) chondroca l ci nos i s i n pa ti ents a ged 70 i s a bout 3%, rea chi ng nea rl y 50% i n pa ti ents a ged 90.
As ymptoma ti c chondroca l ci nos i s i s common i n the knee, hi p, a nul us fi bros us , a nd s ymphys i s pubi s . Men a nd women a re a ffected equa l l y.
Etiology
The ca us e i s unknown. Frequent a s s oci a ti on wi th other condi ti ons , s uch a s tra uma (i ncl udi ng s urgery), a myl oi dos i s , myxedema , hypoma gnes emi a ,
hyperpa ra thyroi di s m, gout, hemochroma tos i s , a nd ol d a ge, s ugges ts tha t CPPD crys ta l depos i ts a re s econda ry to degenera ti ve or meta bol i c
cha nges i n the a ffected ti s s ues . Some ca s es a re fa mi l i a l , us ua l l y tra ns mi tted i n a n a utos oma l domi na nt pa ttern, wi th compl ete penetra ti on by
a ge 40.
Symptoms and Signs
Acute, s uba cute, or chroni c a rthri ti s ca n occur, us ua l l y i n the knee or other l a rge peri phera l joi nts , whi ch ca n mi mi c ma ny other forms of a rthri ti s .
Atta cks a re s ometi mes s i mi l a r to gout but a re us ua l l y l es s s evere. There ma y be no s ymptoms between a tta cks or conti nuous l ow-gra de s ymptoms
i n mul ti pl e joi nts , s i mi l a r to RA or os teoa rthri ti s . Thes e pa tterns tend to pers i s t for l i fe.
Diagnosis
Synovi a l fl ui d a na l ys i s
Identi fi ca ti on of crys ta l s mi cros copi ca l l y
CPPD crys ta l depos i ti on di s ea s e s houl d be s us pected i n ol der pa ti ents wi th a rthri ti s , pa rti cul a rl y i nfl a mma tory a rthri ti s . Di a gnos i s i s es ta bl i s hed
by i denti fyi ng rhomboi d or rod-s ha ped, wea kl y pos i ti vel y bi refri ngent crys ta l s on pol a ri zed l i ght mi cros copy of s ynovi a l fl ui d (s ee Ta bl e 36-1).
Coi nci dent i nfecti ous a rthri ti s mus t be rul ed out by Gra m s ta i n a nd cul ture. X-ra ys a re i ndi ca ted i f s ynovi a l fl ui d ca nnot be obta i ned for a na l ys i s ;
fi ndi ngs of mul ti pl e l i nea r or puncta te ca l ci fi ca ti on i n a rti cul a r ca rti l a ge, es peci a l l y fi broca rti l a ges , s upport the di a gnos i s but do not excl ude gout
or i nfecti on.
Prognosis
The prognos i s for i ndi vi dua l a tta cks i s us ua l l y excel l ent. However, chroni c a rthri ti s ca n occur, a nd s evere des tructi ve a rthropa thy res embl i ng
neuropa thi c (Cha rcot's ) joi nts occa s i ona l l y occurs .
Treatment
Intra -a rti cul a r corti cos teroi ds
NSAIDs
Col chi ci ne ma i ntena nce
Symptoms of a cute s ynovi a l effus i on a ba te wi th s ynovi a l fl ui d dra i na ge a nd i ns ti l l a ti on of a mi crocrys ta l l i ne corti cos teroi d es ter s us pens i on i nto
the joi nt s pa ce (eg, 40 mg predni s ol one a ceta te or predni s ol one terti a ry butyl a ceta te i nto a knee). Indometha ci n, na proxen, or a nother NSAID
gi ven a t a nti -i nfl a mma tory dos es (s ee Ta bl e 35-2 on p. 336) often s tops a cute a tta cks promptl y. Col chi ci ne 0.6 mg po once/da y or bi d ma y decrea s e
the number of a cute a tta cks .
Basic Calcium Phosphate and Calcium Oxalate Crystal Deposition Diseases
Ba s i c Ca phos pha te (a pa ti te) a nd Ca oxa l a te crys ta l di s orders tend to ca us e cl i ni ca l ma ni fes ta ti ons s i mi l a r to other crys ta l -i nduced a rthri ti des .
Basic Ca phosphate crystal deposition disease: Mos t pa thol ogi c ca l ci fi ca ti ons throughout the body conta i n mi xtures of ca rbona te-s ubs ti tuted
hydroxya pa ti te a nd octa ca l ci um phos pha te. Beca us e thes e ul tra mi cros copi c crys ta l s a re nona ci di c Ca phos pha tes , the term ba s i c Ca phos pha te
(BCP) i s much more preci s e tha n a pa ti te. Thes e ul tra mi cros copi c crys ta l s occur i n s nowba l l -l i ke cl umps i n rheuma ti c condi ti ons (eg, ca l ci fi c
tendi ni ti s , ca l ci fi c peri a rthri ti s , s ome ca s es of progres s i ve s ys temi c s cl eros i s a nd derma tomyos i ti s ). They a l s o occur i n joi nt fl ui ds of pa ti ents wi th
a l l degenera ti ve a rthropa thi es s uffi ci entl y a dva nced to ca us e joi nt s pa ce na rrowi ng on x-ra y.
BCP crys ta l s ca n des troy joi nts a nd ca n ca us e s evere i ntra -a rti cul a r or peri a rti cul a r i nfl a mma ti on. Mi l wa ukee s houl der s yndrome i s one exa mpl e, a
profoundl y des tructi ve a rthropa thy a ffecti ng predomi na ntl y el derl y women tha t us ua l l y devel ops i n the s houl ders a nd (often) knees .
Acute poda gra due to peri a rti cul a r BCP depos i ti on ca n mi mi c gout; i t occurs a s a di s crete s yndrome i n young women (l es s often i n young men) a nd
i s trea ted the s a me a s a cute gout.
Bes i des s ynovi a l fl ui d a na l ys i s , x-ra ys s houl d be ta ken of s ymptoma ti c joi nts . On x-ra y, BCP crys ta l s ma y be vi s i bl e a s peri a rti cul a r cl oudl i ke
opa ci ti es . Defi ni ti ve a s s a y for BCP crys ta l s i n s ynovi a l fl ui d i s not rea di l y a va i l a bl e. Cl umped crys ta l s ca n be i denti fi ed onl y wi th tra ns mi s s i on
el ectron mi cros copy. The cl umps a re not bi refri ngent under pol a ri zed l i ght.
Trea tment wi th ora l or IV col chi ci ne, a n NSAID, or, i f a l a rge joi nt i s i nvol ved, i ntra -a rti cul a r corti cos teroi d es ter crys ta l s us pens i on i s hel pful .
Trea tment i s the s a me a s tha t for a cute gout (s ee p. 352).
Ca oxalate crystal deposition disease: Ca oxa l a te crys ta l depos i ti on i s ra re. It occurs mos t often i n a zotemi c pa ti ents recei vi ng hemodi a l ys i s or
peri tonea l di a l ys i s , pa rti cul a rl y thos e trea ted wi th a s corbi c a ci d (vi ta mi n C), whi ch i s meta bol i zed to oxa l a te. Crys ta l s ma y depos i t i n bl ood ves s el
wa l l s a nd s ki n, a s wel l a s joi nts . The crys ta l s a ppea r a s bi refri ngent bi pyra mi da l s tructures (s ee Ta bl e 36-1). Synovi a l fl ui d ma y ha ve > 2000
WBC/L. On x-ra y, Ca oxa l a te crys ta l s a re i ndi s ti ngui s ha bl e from BCP peri a rti cul a r ca l ci fi ca ti ons or Ca pyrophos pha te di hydra te (CPPD) crys ta l
depos i ts i n ca rti l a ge. Trea tment i s the s a me a s tha t for CPPD crys ta l s (s ee a bove).
Chapter 37. Osteoporosis

Introduction
Osteoporosis is a progressive metabolic bone disease that decreases bone density (bone mass per unit volume), with deterioration of bone structure. Skeletal
weakness leads to fractures with minor or inapparent trauma, particularly in the thoracic and lumbar spine, wrist, and hip. Acute or chronic back pain is common.
Diagnosis is by dual-energy x-ray absorptiometry. Prevention and treatment involve Ca and vitamin D supplements, exercises to maximize bone and muscle
strength and minimize the risk of falls, and drug therapy to preserve bone mass or stimulate new bone formation.
Pathophysiology
Norma l l y, bone forma ti on a nd res orpti on a re cl os el y coupl ed. Os teobl a s ts (cel l s tha t ma ke the orga ni c ma tri x of bone a nd then mi nera l i ze bone)
a nd os teocl a s ts (cel l s tha t res orb bone) a re regul a ted by pa ra thyroi d hormone (PTH), ca l ci toni n, es trogen, vi ta mi n D, va ri ous cytoki nes , a nd other
l oca l fa ctors s uch a s pros ta gl a ndi ns .
Pea k bone ma s s i n men a nd women occurs by the mi d 20s . Bl a cks rea ch hi gher bone ma s s tha n whi tes a nd As i a ns , wherea s Hi s pa ni cs ha ve
i ntermedi a te va l ues . Men ha ve hi gher bone ma s s tha n women. Bone ma s s pl a tea us for a bout 10 yr, duri ng whi ch ti me bone forma ti on
a pproxi ma tel y equa l s bone res orpti on. After thi s , bone l os s occurs a t a ra te of a bout 0.3 to 0.5%/yr. Begi nni ng wi th menopa us e, bone l os s
a ccel era tes i n women to a bout 3 to 5%/yr for a bout 5 to 7 yr.
Os teoporoti c bone l os s a ffects corti ca l a nd tra becul a r (ca ncel l ous ) bone. Corti ca l thi cknes s a nd the number a nd s i ze of tra becul a e decrea s e,
res ul ti ng i n i ncrea s ed poros i ty. Tra becul a e ma y be di s rupted or enti rel y a bs ent.
Classification
Os teoporos i s ca n devel op a s a pri ma ry di s order or s econda ri l y due to s ome other fa ctor.
Primary osteoporosis: More tha n 95% of os teoporos i s i n women a nd proba bl y a bout 80% i n men i s pri ma ry. Mos t ca s es occur i n pos tmenopa us a l
women a nd ol der men. The terms pos tmenopa us a l , i nvol uti ona l , s eni l e, a nd a ge-rel a ted os teoporos i s ha ve been us ed to des cri be pri ma ry
os teoporos i s i n el derl y pa ti ents . Es trogen defi ci ency i s a n i mporta nt fa ctor i n men a s wel l a s women. Other contri buti ng fa ctors ma y i ncl ude
decrea s ed Ca i nta ke, l ow vi ta mi n D l evel s , a nd s econda ry hyperpa ra thyroi di s m.
The ma jor mecha ni s m i s i ncrea s ed bone res orpti on, whi ch res ul ts i n decrea s ed bone ma s s a nd mi croa rchi tectura l deteri ora ti on, but other
mecha ni s ms a l s o contri bute not onl y i n pri ma ry os teoporos i s but a l s o i n the va ri ous s econda ry forms of os teoporos i s . The mecha ni s ms of bone
l os s ma y i nvol ve the fol l owi ng:
Loca l cha nges i n the producti on of bone-res orbi ng cytoki nes , s uch a s i ncrea s es i n cytoki nes tha t s ti mul a te bone res orpti on
Impa i red forma ti on res pons e duri ng bone remodel i ng (proba bl y ca us ed by a ge-rel a ted decl i ne i n the number a nd a cti vi ty of os teobl a s ts )
Other fa ctors s uch a s a decl i ne i n l oca l a nd s ys temi c growth fa ctors
Tra becul a r bone l os s occurs more ra pi dl y tha n corti ca l bone l os s beca us e tra becul a r bone i s more porous a nd bone turnover i s hi gh. However,
l os s of both types contri butes to s kel eta l fra gi l i ty.
The mos t common s i tes for fra gi l i ty fra ctures a re the di s ta l ra di us (dors a l l y di s pl a ced fra ctures ), s pi ne (vertebra l compres s i on fra ctures ), femora l
neck, a nd grea ter trocha nter. Other s i tes i ncl ude the proxi ma l humerus a nd pel vi s . Fra gi l i ty fra ctures ra rel y occur i n chi l dren or young a dul ts wi th
norma l gona da l functi on a nd no detecta bl e s econda ry ca us e. Thi s condi ti on i s ca l l ed i di opa thi c os teoporos i s .
Secondary osteoporosis: Seconda ry os teoporos i s a ccounts for < 5% of os teoporos i s ca s es i n women but proba bl y more i n men. The ca us es (s ee
Ta bl e 37-1) ma y a l s o a ggra va te bone l os s a nd i ncrea s e fra cture ri s k i n pa ti ents wi th pri ma ry os teoporos i s .
Risk Factors
Beca us e s tres s , i ncl udi ng wei ght bea ri ng, i s neces s a ry for bone growth, i mmobi l i za ti on or extended s edenta ry peri ods res ul t i n bone l os s . Bei ng
thi n predi s pos es to decrea s ed bone ma s s . Ins uffi ci ent di eta ry i nta ke of Ca , P, a nd vi ta mi n D predi s pos es to bone l os s , a s does endogenous
a ci dos i s (eg, hi gh-protei n di ets ). Ci ga rette s moki ng a nd exces s i ve ca ffei ne or a l cohol us e a l s o a dvers el y a ffect bone ma s s . Whi tes a nd As i a ns a re
a t hi gher ri s k. A fa mi l y hi s tory of os teoporos i s a l s o i ncrea s es ri s k. Other ri s k fa ctors (eg, decrea s i ng
[Table 37-1. Ca us es of Seconda ry Os teoporos i s ]
a mounts of s ex hormones ) predi s pos e to s peci fi c types of os teoporos i s . Pa ti ents who ha ve ha d one fra gi l i ty fra cture a re a t i ncrea s ed ri s k of
ha vi ng other cl i ni ca l (s ymptoma ti c) fra ctures a s wel l a s cl i ni ca l l y a s ymptoma ti c vertebra l compres s i on fra ctures .
Symptoms and Signs
Mos t of the chroni c pa i n typi ca l of os teoporos i s res ul ts from fra ctures , whi ch ma y devel op a fter mi ni ma l , i na ppa rent, or no tra uma . Pa ti ents ma y
be a s ymptoma ti c for yea rs , unti l fra ctures begi n to occur. Eventua l l y, pa ti ents often devel op pa i n i n the bones or mus cl es , pa rti cul a rl y of the ba ck.
Vertebra l compres s i on fra ctures a re common, us ua l l y i n wei ght-bea ri ng vertebra e (T6 a nd bel ow). The pa i n begi ns a cutel y, us ua l l y does not
ra di a te, i s a ggra va ted by wei ght bea ri ng, ma y ca us e l oca l tendernes s , a nd genera l l y begi ns to s ubs i de i n 1 wk. However, res i dua l pa i n ma y l a s t for
months or be cons ta nt.
Mul ti pl e thora ci c compres s i on fra ctures eventua l l y ca us e dors a l kyphos i s , wi th exa ggera ted cervi ca l l ordos i s (dowa ger's hump). Abnorma l s tres s
on the s pi na l mus cl es a nd l i ga ments ma y ca us e chroni c, dul l , a chi ng pa i n, pa rti cul a rl y i n the l ower ba ck. Fra ctures ca n devel op a t other s i tes ,
commonl y the hi p or wri s t, us ua l l y from fa l l s .
Diagnosis
Dua l -energy x-ra y a bs orpti ometry (DEXA)
Os teoporos i s s houl d be s us pected i n pa ti ents who s us ta i n fra ctures a fter onl y mi l d or tri vi a l tra uma ; ol der a dul ts , pa rti cul a rl y thos e wi th ri s k
fa ctors a nd unexpl a i ned ba ck pa i n; pa ti ents wi th decrea s ed bone dens i ty tha t i s i nci denta l l y noted on i ma gi ng s tudi es ; a nd pa ti ents a t ri s k of
s econda ry os teoporos i s . If i ma gi ng s tudi es ha ve been done or a re neces s a ry to eva l ua te s ymptoms (eg, ba ck pa i n), os teoporos i s ma y be obvi ous .
However, i ma gi ng s tudi es a re often equi voca l , a nd the di a gnos i s s houl d be es ta bl i s hed by bone dens i ty mea s urement.
Plain x-rays: Bones s how decrea s ed ra di odens i ty a nd l os s of tra becul a r s tructure, but not unti l a bout 30% of bone ha s been l os t. A l os s of
hori zonta l l y ori ented tra becul a e i ncrea s es the promi nence of the corti ca l end pl a tes a nd of verti ca l l y ori ented, wei ght-bea ri ng tra becul a e. Los s of
hei ght a nd i ncrea s ed bi conca vi ty cha ra cteri ze vertebra l compres s i on fra ctures . Thora ci c vertebra l fra ctures ma y ca us e a nteri or wedgi ng. In l ong
bones , a l though the corti ces ma y be thi n, the peri os tea l s urfa ce rema i ns s mooth. Vertebra l fra ctures a t T4 or a bove s ugges t ca ncer ra ther tha n
os teoporos i s .
Corti cos teroi d-i nduced os teoporos i s i s l i kel y to ca us e ri b fra ctures a nd exubera nt ca l l us forma ti on a t s i tes of hea l i ng fra ctures . Os teoma l a ci a ma y
ca us e a bnorma l i ti es on i ma gi ng tes ts s i mi l a r to thos e of os teoporos i s (s ee Si deba r 37-1). Hyperpa ra thyroi di s m ca n be di fferenti a ted when i t
ca us es s ubperi os tea l res orpti on or cys ti c bone l es i ons , but thes e a re uncommon.
Bone density measurement: DEXA i s us ed to mea s ure bone dens i ty. DEXA i s di a gnos ti c for os teoporos i s , predi cts the ri s k of fra cture, a nd ca n be us ed
to fol l ow trea tment res pons e. Bone dens i ty of the l umba r s pi ne, hi p, di s ta l ra di us or ul na , or the enti re body ca n be mea s ured. (Qua nti ta ti ve CT
s ca nni ng ca n produce s i mi l a r mea s urements i n the s pi ne or hi p.) Us ua l l y, the l umba r s pi ne, tota l proxi ma l femur, or femora l neck i s mea s ured.
DEXA res ul ts a re reported a s T s cores . A T s core corres ponds to the number of s ta nda rd devi a ti ons by whi ch bone dens i ty di ffers from a hea l thy,
young pers on of the s a me s ex a nd ra ce. A DEXA res ul t of > 1 i s defi ned a s os teopeni a a nd s ugges ts a n i ncrea s ed ri s k of os teoporos i s ; > 2.5 i s
di a gnos ti c for os teoporos i s .
If DEXA s ca nni ng of the centra l s kel eton i s una va i l a bl e, porta bl e, l es s expens i ve s ys tems s uch a s peri phera l DEXA or qua nti ta ti ve ul tra s onogra phy
of the heel ca n be us ed. However, moni tori ng the res pons e to trea tment wi th s eri a l mea s urements of bone dens i ty s houl d be done onl y wi th
centra l DEXA s ca nni ng.
Sidebar 37-1 Osteopenia: Differentiating Osteoporosis and Osteomalacia

Os teopeni a i s decrea s ed bone ma s s . Two meta bol i c bone di s ea s es decrea s e bone ma s s : os teoporos i s a nd os teoma l a ci a . In os teoporos i s , bone
ma s s decrea s es , but the ra ti o of bone mi nera l to bone ma tri x i s norma l . In os teoma l a ci a , the ra ti o of bone mi nera l to bone ma tri x i s l ow.
Os teoporos i s res ul ts from a combi na ti on of l ow pea k bone ma s s , i ncrea s ed bone res orpti on, a nd i mpa i red bone forma ti on. Os teoma l a ci a i s due
to i mpa i red mi nera l i za ti on, us ua l l y beca us e of s evere vi ta mi n D defi ci ency or a bnorma l vi ta mi n D meta bol i s m (s ee p. 41). Os teoporos i s i s much
more common tha n os teoma l a ci a i n the US. The 2 di s orders ma y coexi s t, a nd thei r cl i ni ca l expres s i on i s s i mi l a r; moreover, mi l d to modera te
vi ta mi n D defi ci ency ca n occur i n os teoporos i s .
Current centra l DEXA s ys tems ca n a l s o a s s es s vertebra l deformi ti es i n the l ower thora ci c a nd l umba r s pi ne, a procedure termed vertebra l fra cture
a na l ys i s (VFA). Vertebra l deformi ti es , even thos e cl i ni ca l l y s i l ent, ma y i ndi ca te i ncrea s ed ri s k of future fra ctures . VFA i s more l i kel y to be us eful i n
pa ti ents wi th l os s of 3 cm i n hei ght.
Other testing: Once os teoporos i s i s di a gnos ed, pa ti ents s houl d be checked for ca us es of s econda ry os teoporos i s . Serum Ca s houl d be mea s ured to
rul e out a s ymptoma ti c hyperpa ra thyroi di s m. PTH l evel s ma y be i ncrea s ed i n pa ti ents wi th decrea s ed Ca a bs orpti on or hyperca l ci uri a . Other tes ts
s uch a s thyroi d-s ti mul a ti ng hormone or free thyroxi ne to check for hyperthyroi di s m, vi ta mi n D l evel s , mea s urements of uri na ry free corti s ol , a nd
bl ood counts a nd other tes ts to rul e out ca ncer, es peci a l l y myel oma (eg, s erum protei n el ectrophores i s ), s houl d be cons i dered dependi ng on the
cl i ni ca l fi ndi ngs . Serum a l ka l i ne phos pha ta s e i s us ua l l y norma l but ma y be el eva ted by recent fra cture.
Pa ti ents wi th wei ght l os s s houl d be s creened for GI di s orders a s wel l a s ca ncer. Bone bi ops y i s res erved for unus ua l ca s es (eg, young pa ti ents
wi th pa thol ogi c fra ctures a nd no a ppa rent ca us e). Level s of s erum or uri ne N-tel opepti de cros s l i nks (NTX) or free deoxypyri di nol i ne (DPYR) ma y
refl ect i ncrea s ed brea kdown of col l a gen. Thes e tes ts a re not s uffi ci entl y a ccura te for routi ne cl i ni ca l us e but ma y be us ed to a s s es s the
effecti venes s of thera py.
Screening
DEXA s creeni ng i s recommended for a l l women > 65. Bone dens i ty s houl d a l s o be mea s ured i n women between 50 a nd 65 who ha ve ri s k fa ctors ,
i ncl udi ng a fa mi l y hi s tory of os teoporos i s , a hi s tory of fra gi l i ty fra ctures , a nd l ow body wei ght. Screeni ng i s a l s o recommended for both men a nd
women who ha ve ha d fra gi l i ty fra ctures , even a t younger a ges .
Treatment
Ri s k fa ctor modi fi ca ti on
Ca a nd vi ta mi n D s uppl ements
Bi s phos phona tes or s ometi mes other a nti res orpti ve drugs
The goa l s of trea tment a re to pres erve bone ma s s , prevent fra ctures , decrea s e pa i n, a nd ma i nta i n functi on.
Preserving bone mass: The ra te of bone l os s ca n be s l owed wi th drugs a nd, when pos s i bl e, modi fi ca ti on of ri s k fa ctors . Ca a nd vi ta mi n D i nta ke a nd
phys i ca l a cti vi ty mus t be a dequa te for drug trea tment to be effecti ve.
Ri s k fa ctor modi fi ca ti on ca n i ncl ude ma i nta i ni ng a dequa te body wei ght, i ncrea s i ng wei ght-bea ri ng exerci s e, mi ni mi zi ng ca ffei ne a nd a l cohol
i nta ke, a nd s toppi ng s moki ng. The opti ma l a mount of wei ght-bea ri ng exerci s e i s not es ta bl i s hed, but a n a vera ge of 30 mi n/da y i s recommended.
A phys i ca l thera pi s t ca n devel op a s a fe exerci s e progra m.
Al l men a nd women s houl d cons ume a t l ea s t 1000 mg of el ementa l Ca da i l y. An i nta ke of 1200 to 1500 mg/da y i s recommended for
pos tmenopa us a l women a nd ol der men a nd for peri ods of i ncrea s ed requi rements , s uch a s puberta l growth, pregna ncy, a nd l a cta ti on. Di et a l one
i s ra rel y a dequa te; Ca s uppl ements a re needed, mos t commonl y a s Ca ca rbona te or Ca ci tra te. Suppl ements di ffer i n thei r el ementa l Ca
concentra ti on. Ca ci tra te i s better a bs orbed i n pa ti ents wi th a chl orhydri a , but both a re wel l a bs orbed when ta ken wi th mea l s . Ca s houl d be ta ken
i n di vi ded dos es of 500 to 600 mg bi d or ti d.
Vi ta mi n D i n dos es of 800 U once/da y i s genera l l y recommended, but up to 2000 U/da y i s s a fe a nd ma y be hel pful i n os teoporoti c pa ti ents .
Pa ti ents wi th vi ta mi n D defi ci ency ma y need even hi gher dos es . Suppl ementa l vi ta mi n D i s us ua l l y gi ven a s chol eca l ci ferol , the na tura l form of
vi ta mi n D, a l though ergoca l ci ferol , the s yntheti c pl a nt deri ved form, i s proba bl y a l s o a ccepta bl e.
Bi s phos phona tes a re fi rs t-l i ne drug thera py. By i nhi bi ti ng bone res orpti on, bi s phos phona tes pres erve bone ma s s a nd ca n decrea s e vertebra l a nd
hi p fra ctures by 50%. To trea t os teoporos i s , bi s phos phona tes ca n be gi ven ora l l y. Al endrona te ca n be gi ven a t dos es of 10 mg po once/da y or 70 mg
po once/wk, i ba ndrona te 2.5 mg po once/da y or 150 mg once/mo, or ri s edrona te a t 5 mg po once/da y or 35 mg once/wk. Al l i ncrea s e bone mi nera l
dens i ty a nd decrea s e ri s k of a t l ea s t vertebra l fra ctures . Ora l bi s phos phona tes mus t be ta ken on a n empty s toma ch wi th a ful l gl a s s of wa ter, a nd
the pa ti ent mus t rema i n upri ght for 30 mi n. They ca n ca us e es opha gea l i rri ta ti on. Es opha gea l di s orders tha t del a y tra ns i t ti me a nd s ymptoms of
upper GI di s orders a re rel a ti ve contra i ndi ca ti ons to ora l bi s phos phona tes . Weekl y or monthl y thera py i s genera l l y preferred for i ts grea ter
conveni ence a nd proba bl y fewer a dvers e effects .
Pa rentera l zol endrona te i s a n a l terna ti ve to ora l bi s phos phona tes . Dos es of 5 mg IV once/yea r i ncrea s e bone ma s s a nd decrea s e ri s k of vertebra l
a nd nonvertebra l fra ctures . Pa mi drona te ca n a l s o be gi ven IV but ha s not yet been s hown to prevent fra ctures .
Os teonecros i s of the ja w ha s been a s s oci a ted wi th us e of bi s phos phona tes ; however, thi s condi ti on i s ra re i n pa ti ents ta ki ng ora l
bi s phos phona tes . Ri s k fa ctors i ncl ude IV bi s phos phona te us e a nd ca ncer. Bi s phos phona tes ma y a l s o be a s s oci a ted wi th a tri a l fi bri l l a ti on, but
the mecha ni s m i s not cl ea r a nd there ha s been no a s s oci a ti on wi th i ncrea s ed ca rdi ova s cul a r morta l i ty.
Sa l mon ca l ci toni n i s l es s effecti ve tha n bi s phos phona tes for trea ti ng os teoporos i s . The s ubcuta neous dos e i s 100 IU/da y or every other da y; the
na s a l s pra y dos e i s 200 U/da y i n a l terna ti ng nos tri l s (1 s pra y). Sa l mon ca l ci toni n ma y provi de s hort-term a na l ges i a a fter a n a cute fra cture.
Es trogen ca n pres erve bone dens i ty a nd prevent fra ctures . Mos t effecti ve i f s ta rted wi thi n 4 to 6 yr of menopa us e, es trogen ma y s l ow bone l os s
a nd pos s i bl y reduce fra ctures even when s ta rted much l a ter. It i s us ua l l y gi ven a s conjuga ted es trogen 0.625 to 1.25 mg po once/da y. However, 0.3
mg po once/da y ma y be a s effecti ve. Us e of es trogen i ncrea s es the ri s k of thromboembol i s m a nd endometri a l ca ncer a nd ma y i ncrea s e the ri s k of
brea s t ca ncer. The ri s k of endometri a l ca ncer ca n be reduced i n women wi th a n i nta ct uterus by ta ki ng a proges ti n wi th es trogen (s ee p. 2519).
However, ta ki ng a combi na ti on of a proges ti n a nd es trogen i ncrea s es the ri s k of brea s t ca ncer, corona ry a rtery di s ea s e, s troke, a nd bi l i a ry
di s ea s e.
Ra l oxi fene i s a s el ecti ve es trogen receptor modul a tor (SERM) tha t ma y be a ppropri a te for trea tment of os teoporos i s i n women who ca nnot ta ke
bi s phos phona tes . It reduces vertebra l fra ctures by a bout 50% but ha s not been s hown to reduce nonvertebra l fra ctures . Ra l oxi fene does not
s ti mul a te the uterus a nd a nta goni zes es trogen effects i n the brea s t, proba bl y reduci ng the ri s k of brea s t ca ncer.
PTH, whi ch s ti mul a tes new bone forma ti on, i s genera l l y res erved for pa ti ents who ha ve the fol l owi ng cha ra cteri s ti cs :
Ca nnot tol era te a nti res orpti ve drugs or ha ve contra i ndi ca ti ons to thei r us e
Fa i l to res pond to a nti res orpti ve drugs , a s wel l a s Ca , vi ta mi n D, a nd exerci s e, devel opi ng new fra ctures a nd l os s of bone mi nera l dens i ty
Pos s i bl y ha ve s evere os teoporos i s (eg, T s core < 3.5)
When gi ven da i l y by i njecti on for a n a vera ge of 20 mo, s yntheti c PTH (PTH 1-34; teri pa ra ti de) i ncrea s es bone ma s s a nd reduces ri s k of fra ctures .
Preventing fractures: Ma ny el derl y pa ti ents a re a t ri s k of fa l l s beca us e of poor coordi na ti on, poor vi s i on, mus cl e wea knes s , confus i on, a nd us e of
drugs tha t ca us e pos tura l hypotens i on or a l ter the s ens ori um. Educa ti ng pa ti ents a bout the ri s ks of fa l l s a nd fra ctures a nd devel opi ng
i ndi vi dua l i zed progra ms to i ncrea s e phys i ca l s ta bi l i ty a nd a ttenua te ri s k ca n hel p. Strengtheni ng exerci s es ma y i ncrea s e s ta bi l i ty. Hi p pa ds ca n
reduce the i nci dence of hi p fra cture des pi te conti nued fa l l s .
Treating pain and maintaining function: Acute ba ck pa i n from a vertebra l compres s i on fra cture s houl d be trea ted wi th orthopedi c s upport, a na l ges i cs ,
a nd (when mus cl e s pa s m i s promi nent) hea t a nd ma s s a ge (s ee p.
3459). Chroni c ba cka che ma y be rel i eved by a n orthopedi c ga rment a nd exerci s es to s trengthen pa ra vertebra l mus cl es . Avoi di ng hea vy l i fti ng ca n
hel p. Bed res t s houl d be mi ni mi zed, a nd cons i s tent, ca reful l y des i gned wei ght-bea ri ng exerci s e s houl d be encoura ged.
In s ome ca s es , vertebropl a s ty, s ometi mes preceded by kyphopl a s ty, ca n rel i eve s evere pa i n. In vertebropl a s ty, methyl metha cryl a te i s i njected i nto
the vertebra l body. In kyphopl a s ty, the vertebra l body i s expa nded wi th a ba l l oon. Thes e procedures ma y reduce deformi ty i n the i njected
vertebra e but do not reduce a nd ma y even i ncrea s e the ri s k of fra ctures i n a dja cent vertebra e. Other ri s ks ma y i ncl ude ri b fra ctures , cement
l ea ka ge, a nd pul mona ry edema or MI.
Prevention
The goa l s of preventi on a re to pres erve bone ma s s a nd prevent fra ctures . Preventi ve mea s ures a re i ndi ca ted i n pos tmenopa us a l women a nd ol der
men, pa ti ents ta ki ng l ong-term s ys temi c corti cos teroi ds , a nd pa ti ents a t hi gh ri s k (eg, os teopeni a wi th mul ti pl e ri s k fa ctors or s econda ry ca us es ).
Preventi ve mea s ures a re s i mi l a r to trea tment mea s ures , i ncl udi ng thos e a i med a t pres ervi ng bone ma s s . Bi s phos phona tes a nd other drugs ca n be
gi ven a s for trea tment of os teoporos i s , but a l endrona te i s gi ven a t a reduced dos e (5 mg po once/da y or 35 mg once/wk). Mea s ures to prevent
fra ctures a re a l s o i ndi ca ted.
Chapter 38. Paget's Disease of Bone

Introduction
(Os tei ti s Deforma ns )
Paget's disease of bone is a chronic disorder of the adult skeleton in which bone turnover is accelerated in localized areas. Normal matrix is replaced with
softened and enlarged bone. The disease may be asymptomatic or cause gradual onset of bone pain or deformity. Diagnosis is by x-ray. Treatment includes
symptomatic measures and often drugs, usually bisphosphonates.
About 1% of a dul ts i n the US > 40 ha ve Pa get's di s ea s e, wi th a 3:2 ma l e predomi na nce. Preva l ence i ncrea s es wi th a gi ng. However, overa l l
preva l ence s eems to be decrea s i ng. The di s ea s e i s mos t common i n Europe (except Sca ndi na vi a ), Aus tra l i a , a nd New Zea l a nd. It i s pa rti cul a rl y
common i n Engl a nd.
Etiology
Severa l geneti c a bnorma l i ti es , ma ny a ffecti ng os teocl a s t genera ti on a nd a cti vi ty, ha ve been i denti fi ed. Muta ti ons of the Sequestrum 1 gene from
chromos ome 6 a re commonl y rel a ted to Pa get's di s ea s e. Appea ra nce of i nvol ved bone on el ectron mi cros copy s ugges ts a vi ra l i nfecti on, but a vi ra l
ca us e ha s not been es ta bl i s hed.
Pathophysiology
Any bone ca n be i nvol ved. The bones mos t commonl y a ffected a re, i n decrea s i ng order, the pel vi s , femur, s kul l , ti bi a , vertebra e, cl a vi cl e, a nd
humerus .
Bone turnover i s a ccel era ted a t i nvol ved s i tes . Pa geti c l es i ons a re meta bol i ca l l y a cti ve a nd hi ghl y va s cul a r. Exces s i vel y a cti ve os teocl a s ts a re often
l a rge a nd conta i n ma ny nucl ei . Os teobl a s ti c repa i r i s a l s o hypera cti ve, ca us i ng coa rs el y woven, thi ckened l a mel l a e a nd tra becul a e. Thi s a bnorma l
s tructure wea kens the bone, des pi te bone enl a rgement a nd hea vy ca l ci fi ca ti on.
Complications: Overgrown bone ma y compres s nerves a nd other s tructures pa s s i ng through s ma l l fora mi na . Spi na l s tenos i s or s pi na l cord
compres s i on ma y devel op. Os teoa rthri ti s ma y devel op i n joi nts a dja cent to i nvol ved bone.
In a bout 10 to 15% of pa ti ents , i ncrea s ed bone forma ti on a nd Ca requi rement l ea ds to s econda ry hyperpa ra thyroi di s m; i f thi s need i s not ma tched
by a n i ncrea s e i n Ca i nta ke, hypoca l cemi a ma y occur. Hyperca l cemi a (s ee p. 843) occa s i ona l l y devel ops i n pa ti ents who a re i mmobi l e. It a l s o
occurs i n pa ti ents wi th Pa get's di s ea s e who devel op s econda ry hyperpa ra thyroi di s m.
La rge or numerous l es i ons ma y l ea d to hi gh-output hea rt fa i l ure.
Symptoms and Signs
There a re us ua l l y no s ymptoms for a prol onged peri od. If s ymptoms occur, they devel op i ns i di ous l y, wi th pa i n, s ti ffnes s , fa ti gue, a nd bone
deformi ty. Bone pa i n i s a chi ng, deep, a nd occa s i ona l l y s evere, s ometi mes wors e a t ni ght. Pa i n a l s o ma y a ri s e from compres s i on neuropa thy or
os teoa rthri ti s . If the s kul l i s i nvol ved, there ma y be hea da ches a nd hea ri ng i mpa i rment.
Si gns ma y i ncl ude s kul l enl a rgement bi tempora l l y a nd fronta l l y (fronta l bos s i ng); di l a ted s ca l p vei ns ; nerve dea fnes s i n one or both ea rs ; a ngi oi d
s trea ks i n the fundus of the eye; a s hort kyphoti c trunk wi th s i mi a n a ppea ra nce; hobbl i ng ga i t; a nd a nterol a tera l a ngul a ti on (bowi ng) of the thi gh
or l eg, often wi th wa rmth a nd tendernes s . Deformi ti es ma y devel op from bowi ng of the l ong bones or os teoa rthri ti s . Pa thol ogi c fra ctures ma y be
the pres enti ng ma ni fes ta ti on. Sa rcoma tous degenera ti on devel ops i n < 1% a nd i s often s ugges ted by i ncrea s i ngl y s evere pa i n.
Diagnosis
Pl a i n x-ra ys
Serum a l ka l i ne phos pha ta s e, Ca , a nd PO4
Bone s ca n a fter the di a gnos i s i s es ta bl i s hed
Pa get's di s ea s e s houl d be s us pected i n pa ti ents wi th the fol l owi ng:
Unexpl a i ned bone pa i n or deformi ty
Sugges ti ve fi ndi ngs on x-ra y
Unexpl a i ned el eva ti on of s erum a l ka l i ne phos pha ta s e on l a bora tory tes ts done for other rea s ons , pa rti cul a rl y i f -gl uta myl -tra ns pepti da s e
(GGT) i s norma l
Hyperca l cemi a tha t devel ops duri ng bed res t, pa rti cul a rl y a mong el derl y pa ti ents
Bone s a rcoma i n el derl y pa ti ents
If Pa get's di s ea s e i s s us pected, pl a i n x-ra ys a nd s erum a l ka l i ne phos pha ta s e, Ca , a nd PO4 l evel s s houl d be obta i ned. Confi rma ti on on x-ra y i s
requi red to es ta bl i s h the di a gnos i s . Cha ra cteri s ti c x-ra y fi ndi ngs i ncl ude the fol l owi ng:
Increa s ed bone s cl eros i s
Abnorma l a rchi tecture wi th coa rs e corti ca l tra becul a ti on or corti ca l thi ckeni ng
Bowi ng
Bone enl a rgement
There ma y be s tres s mi crofra ctures of the ti bi a or femur.
Cha ra cteri s ti c l a bora tory fi ndi ngs i ncl ude el eva ted s erum a l ka l i ne phos pha ta s e (i ncrea s ed a na bol i c a cti vi ty of bone) but us ua l l y norma l GGT a nd
s erum PO4 l evel s . Serum Ca i s us ua l l y norma l but ca n i ncrea s e beca us e of i mmobi l i za ti on or hyperpa ra thyroi di s m or decrea s e (often tra ns i entl y)
beca us e of i ncrea s ed bone s ynthes i s . If a l ka l i ne phos pha ta s e i s not el eva ted or i t i s uncl ea r whether the i ncrea s ed s erum a l ka l i ne phos pha ta s e
i s of bony ori gi n (i e, i f GGT i s i ncrea s ed i n proporti on to a l ka l i ne phos pha ta s e), a bone-s peci fi c fra cti on ca n be mea s ured.
Occa s i ona l l y, i ncrea s ed ca ta bol i c a cti vi ty of bone, a s demons tra ted by el eva ted uri ne ma rkers of bone col l a gen turnover (eg, pyri di nol i ne
cros s l i nks ), s uppl ements the fi ndi ngs .
Ra di onucl i de bone s ca n us i ng techneti um-l a bel ed phos phona tes s houl d be done a t ba s el i ne to determi ne the extent of bone i nvol vement.
Treatment
Supporti ve ca re for s ymptoms a nd compl i ca ti ons
Bi s phos phona tes
Loca l i zed, a s ymptoma ti c di s ea s e requi res no trea tment. Symptoma ti c trea tment i ncl udes
[
Table 38-1. Drug Thera py for Pa get's Di s ea s e]
a na l ges i cs or NSAIDs for pa i n. Orthoti cs hel p correct a bnorma l ga i t ca us ed by bowed l ower extremi ti es . Some pa ti ents requi re orthopedi c s urgery
(eg, hi p or knee repl a cement, decompres s i on of the s pi na l cord). Wei ght bea ri ng s houl d be encoura ged, a nd bed res t s houl d be a voi ded.
Drug therapy: Drug thera py s uppres s es os teocl a s t a cti vi ty. It i s i ndi ca ted for the fol l owi ng:
To prevent or reduce bl eedi ng duri ng orthopedi c s urgery
To prevent or reta rd progres s i on of compl i ca ti ons (eg, hea ri ng l os s , deformi ty, os teoa rthri ti s , pa ra pa res i s or pa ra pl egi a rel a ted to vertebra l
Pa get's di s ea s e, or other neurol ogi c defi ci ts , pa rti cul a rl y i n a poor s urgi ca l ca ndi da te)
To trea t pa i n cl ea rl y rel a ted to the pa geti c proces s a nd not to a nother s ource (eg, os teoa rthri ti s )
When s erum a l ka l i ne phos pha ta s e (of bony ori gi n) i s > 2 ti mes the norma l l evel , even i n the a bs ence of s ymptoms
Al though di s ea s e progres s i on ca n be reta rded, exi s ti ng defi ci ts (eg, deformi ty, os teoa rthri ti s , hea ri ng l os s , neura l i mpi ngement) a re not revers ed.
Severa l bi s phos phona tes a re a va i l a bl e a nd a re the drugs of choi ce (s ee Ta bl e 38-1 on p. 361). Syntheti c s a l mon ca l ci toni n i s a n a l terna ti ve to
bi s phos phona tes for pa ti ents i ntol era nt of or res i s ta nt to them. The newer bi s phos phona tes (a mi no-conta i ni ng bi s phos phona tes , eg,
zol endrona te) s eem to provi de more prol onged res pons e.
Chapter 39. Osteonecrosis

Introduction
(Ava s cul a r Necros i s ; As epti c Necros i s ; Is chemi c Necros i s of Bone)
Osteonecrosis (ON) is a focal infarct of bone that may be caused by specific etiologic factors or may be idiopathic. It can cause pain, limitation of motion, joint
collapse, and osteoarthritis. Diagnosis is by x-rays and MRI. In early stages, surgical procedures may slow or prevent progression. In later stages, joint
replacement may be required for relief of pain and maintenance of function.
In the US, ON a ffects a bout 20,000 new pa ti ents a nnua l l y. The hi p (femora l hea d) i s mos t commonl y a ffected, fol l owed by the knee a nd s houl der
(humera l hea d). The wri s t a nd a nkl e a re l es s often i nvol ved. It i s unus ua l for ON to i nvol ve the s houl der or other l es s commonl y a ffected s i tes
wi thout the hi p a l s o bei ng i nvol ved.
Etiology
The mos t common ca us e of ON i s tra uma . Nontra uma ti c ON a ffects men more often tha n women, i s bi l a tera l i n > 60% of ca s es , a nd occurs pri ma ri l y
i n pa ti ents between a ges 30 a nd 50.
Traumatic ON: The mos t common ca us e of tra uma ti c ON i s a di s pl a ced s ubca pi ta l fra cture of the hi p (s ee p. 3211); ON i s uncommon a fter
i ntertrocha nteri c fra ctures . The i nci dence of ON a fter hi p di s l oca ti on i s hi gh wi thout prompt reducti on; the s ooner reducti on occurs , the l ower the
i nci dence. Fra cture or di s l oca ti on ma y ca us e ON by gros s l y di s rupti ng or compres s i ng nea rby bl ood ves s el s .
Sponta neous ON of the knee (SPONK) i s l oca l i zed ON of the femora l condyl e or ti bi a l pl a tea u i n el derl y women (occa s i ona l l y men). SPONK i s
thought to be ca us ed by a n i ns uffi ci ency fra cture (a type of fra gi l i ty fra cture ca us ed by norma l wea r a nd tea r on os teoporoti c bone tha t occurs
wi thout di rect tra uma ).
Nontraumatic ON: Fa ctors ca us i ng or contri buti ng to nontra uma ti c ON a re l i s ted i n
Ta bl e 39-1. The mos t common fa ctors a re the fol l owi ng:
Chroni c corti cos teroi d us e
Exces s i ve a l cohol cons umpti on
The ri s k of ON i s i ncrea s ed when the dos e of predni s one or a n equi va l ent corti cos teroi d i s > 25 mg/da y for s evera l weeks or months , res ul ti ng i n a
cumul a ti ve dos e us ua l l y > 3000 mg. The ri s k of ON a l s o i s i ncrea s ed when > 3 dri nks /da y (> 500 mL etha nol /wk) a re cons umed for s evera l yea rs .
Some geneti c fa ctors i ncrea s e s us cepti bi l i ty to ON. Subtl e cl otti ng a bnorma l i ti es due to defi ci enci es i n protei n C, protei n S, or a nti thrombi n III or
to a nti ca rdi ol i pi n a nti bodi es (s ee Ch. 110) ca n be detected i n a hi gh percenta ge of pa ti ents wi th ON. Some di s orders tha t a re thems el ves
a s s oci a ted wi th ON a re trea ted wi th corti cos teroi ds (eg, SLE), s o i t i s not cl ea r whether ri s k i s i ncrea s ed beca us e of corti cos teroi d us e or the
di s order. About 20% of ca s es a re i di opa thi c.
[Table 39-1. Nontra uma ti c Ri s k Fa ctors for Os teonecros i s ]
ON of the ja w ha s recentl y been reported i n s evera l pa ti ents who ha ve recei ved hi gh-dos e IV bi s phos phona te thera py (s ee Si deba r 39-1).
Nontra uma ti c ON of the hi p i s bi l a tera l i n 60% of pa ti ents .
Pathophysiology
ON i nvol ves the dea th of os teocytes a nd bone ma rrow. Mecha ni s ms of nontra uma ti c ON ma y i ncl ude embol i za ti on by bl ood cl ots or l i pi d dropl ets ,
i ntra va s cul a r thrombos i s , a nd extra va s cul a r compres s i on. After the va s cul a r i ns ul t, the repa i r proces s es a ttempt to remove necroti c bone a nd
ma rrow a nd repl a ce them wi th vi a bl e ti s s ue. If the i nfa rct i s s ma l l , pa rti cul a rl y i f i t i s not s ubject to ma jor wei ght bea ri ng, thi s proces s ma y
s ucceed. However, i n a bout 80% of pa ti ents , the proces s i s not s ucces s ful a nd the i nfa rct gra dua l l y col l a ps es . The overl yi ng a rti cul a r s urfa ce
becomes fl a ttened a nd i rregul a r, ca us i ng i ncrea s ed pa i n a nd eventua l l y l ea di ng to os teoa rthri ti s .
Symptoms and Signs
General symptoms: Affected a rea s ma y rema i n a s ymptoma ti c for weeks to months a fter the va s cul a r i ns ul t. Us ua l l y pa i n then devel ops gra dua l l y,
a l though i t ma y be a cute. Wi th progres s i ve col l a ps e of the joi nt, pa i n i ncrea s es a nd i s exa cerba ted by moti on a nd wei ght bea ri ng a nd i s rel i eved
by res t.
Joint-specific symptoms: ON of the hi p ca us es groi n pa i n tha t ma y ra di a te down the thi gh or i nto the buttock. Moti on becomes l i mi ted, a nd a l i mp
us ua l l y devel ops . SPONK us ua l l y ca us es s udden knee pa i n wi thout precedi ng tra uma . Thi s pa i n i s mos t often on the medi a l s i de of the femora l
condyl e or ti bi a l pl a tea u a nd ma ni fes ts wi th tendernes s , joi nt effus i on, pa i nful moti on, a nd a l i mp. ON of the humera l hea d often ca us es l es s
pa i n a nd di s a bi l i ty tha n hi p a nd knee i nvol vement. Wi th a dva nced di s ea s e, pa ti ents ha ve pa i n a nd decrea s ed moti on, a l though pa s s i ve ra nge of
moti on i s l es s a ffected tha n a cti ve ra nge of moti on.
Sidebar 39-1 Osteonecrosis of the Jaw

Os teonecros i s of the ja w (ONJ) ha s no una ni mous l y a ccepted defi ni ti on but i s genera l l y hel d to be a n ora l l es i on i nvol vi ng ba re ma ndi bul a r or
ma xi l l a ry bone, whi ch us ua l l y ma ni fes ts wi th pa i n a nd purul ent di s cha rge, a l though i t ma y be a s ymptoma ti c. ONJ ma y occur s ponta neous l y or
a fter denta l extra cti on or tra uma , ra di a ti on thera py to the hea d a nd neck (os teora di onecros i s ), or hi gh-dos e IV bi s phos phona te thera py (eg, for
ca ncer trea tment). It i s not cl ea r whether routi ne us e of ora l bi s phos phona tes for trea tment or preventi on of os teoporos i s i ncrea s es ri s k of ONJ.
Currentl y, otherwi s e a ppropri a te bi s phos phona te us e s houl d not be di s coura ged. However, i t s eems rea s ona bl e to do a ny neces s a ry ora l s urgery
before begi nni ng bi s phos phona te thera py a nd to encoura ge good ora l hygi ene whi l e pa ti ents a re ta ki ng bi s phos phona tes .
Once es ta bl i s hed, ONJ i s cha l l engi ng to trea t a nd s houl d be ma na ged by a n ora l s urgeon wi th experi ence trea ti ng ONJ. Trea tment typi ca l l y
i nvol ves l i mi ted debri dement, a nti bi oti cs , a nd ora l ri ns es . Surgi ca l res ecti on of the a ffected a rea ma y wors en the condi ti on a nd s houl d not be the
i ni ti a l trea tment.
Diagnosis
X-ra ys
MRI
ON s houl d be s us pected i n pa ti ents wi th the fol l owi ng:
Fra ctures a s s oci a ted wi th a n i ncrea s ed i nci dence of ON, pa rti cul a rl y i f pa i n pers i s ts or wors ens
Pers i s tent s ponta neous hi p, knee, or s houl der pa i n, pa rti cul a rl y i f ri s k fa ctors for ON a re pres ent
Pl a i n x-ra ys s houl d be done i ni ti a l l y. They ma y s how no a bnorma l i ti es for months . The ea rl i es t fi ndi ngs a re l oca l i zed a rea s of s cl eros i s a nd
l ucency. La ter, a s ubchondra l cres cent s i gn ma y a ppea r. Then, gros s col l a ps e a nd fl a tteni ng of the a rti cul a r s urfa ce i s s een, fol l owed by a dva nced
degenera ti ve cha nges .
When x-ra ys a re norma l or nondi a gnos ti c, a n MRI, whi ch i s much more s ens i ti ve a nd more s peci fi c, s houl d be done. Both hi ps s houl d be i ma ged.
Bone s ca ns a re l es s s ens i ti ve a nd l es s s peci fi c tha n MRI. CT i s ra rel y needed, a l though i t ma y occa s i ona l l y be of va l ue to detect joi nt col l a ps e,
whi ch does not a ppea r on pl a i n x-ra ys .
La bora tory s tudi es a re us ua l l y norma l a nd of l i ttl e va l ue i n detecti ng ON. However, they mi ght hel p detect a n underl yi ng di s order (eg, coa gul a ti on
defects , hemogl obi nopa thi es , l i pi d a bnorma l i ti es ).
Treatment
Symptoma ti c mea s ures (eg, res t, phys i ca l thera py, NSAIDs )
Surgi ca l decompres s i on or other procedures to s ti mul a te hea l i ng
Hi p repl a cement
Nonsurgical treatments: Sma l l , a s ymptoma ti c l es i ons ma y hea l s ponta neous l y a nd ma y not need trea tment.
La rger l es i ons , both s ymptoma ti c a nd a s ymptoma ti c, ha ve a poor prognos i s i f untrea ted, es peci a l l y when i n the femora l hea d. Therefore, ea rl y
trea tment to s l ow or prevent progres s i on a nd s a ve the joi nt i s des i ra bl e. No compl etel y effecti ve trea tment i s yet a va i l a bl e. Nons urgi ca l
trea tments i ncl ude drugs (eg, bi s phos phona tes ) a nd phys i ca l moda l i ti es (eg, el ectroma gneti c fi el ds a nd a cous ti c wa ves ). Drug thera py a nd
phys i ca l moda l i ti es ha ve s hown promi s e i n l i mi ted s tudi es but a re not currentl y i n genera l us e.
Surgical treatments: Surgi ca l trea tments a re mos t effecti ve when done before joi nt col l a ps e. They ha ve been us ed mos t often i n trea ti ng ON of the
hi p when the prognos i s wi thout trea tment i s wors e tha n tha t for other regi ons . Core decompres s i on i s the procedure mos t frequentl y done; one or
more cores of bone a re removed from the necroti c regi on or mul ti pl e s ma l l tra cks or perfora ti ons a re ma de i n a n a ttempt to decrea s e
i ntra os s eous pres s ure a nd s ti mul a te repa i r. Core decompres s i on i s techni ca l l y s i mpl e, a nd the compl i ca ti on ra te i s very l ow i f the procedure i s
done correctl y. Protected wei ght bea ri ng i s needed for a bout 6 wk. Mos t reports i ndi ca te s a ti s fa ctory or good res ul ts i n 65% of pa ti ents , i ncl udi ng
thos e whos e hi ps ha ve s ome degree of col l a ps e, a nd i n 80% of pa ti ents whos e hi ps ha ve s ma l l , ea rl y l es i ons . Other es ta bl i s hed procedures
i ncl ude va ri ous proxi ma l femora l os teotomi es a nd bone gra fti ng, both va s cul a ri zed a nd nonva s cul a ri zed. Thes e procedures a re techni ca l l y
dema ndi ng, requi re protected wei ght bea ri ng for up to 6 mo, a nd ha ve not been done often i n the US. Reports va ry a s to thei r i ndi ca ti ons a nd
effecti venes s . They s houl d be done pri ma ri l y a t s el ected centers tha t ha ve the s urgi ca l experi ence a nd fa ci l i ti es to a chi eve opti ma l res ul ts . An
a pproa ch currentl y bei ng eva l ua ted i s i njecti on of a utol ogous ma rrow i nto the necroti c l es i on.
If extens i ve col l a ps e of the femora l hea d a nd degenera ti ve cha nges i n the a ceta bul um ca us e s uffi ci ent pa i n a nd di s a bi l i ty, a n a rthropl a s ty
us ua l l y i s the onl y wa y to effecti vel y rel i eve pa i n a nd i ncrea s e ra nge of moti on. The conventi ona l a pproa ch i s tota l hi p repl a cement. Good to
excel l ent res ul ts a re a chi eved i n 95% of tota l hi p a nd tota l knee repl a cements , compl i ca ti on ra tes a re l ow, a nd pa ti ents res ume mos t a cti vi ti es of
da i l y l i vi ng wi thi n 3 mo. Mos t pros theti c hi ps a nd knees l a s t > 15 to 20 yr.
Two a l terna ti ves under i nves ti ga ti on i ncl ude s urfa ce repl a cement a rthropl a s ty (SRA) a nd hemi -SRA. SRA, whi ch ca n be done i ns tea d of tota l hi p
repl a cement, i nvol ves the i ns erti on of 2 meta l ca ps , one i nto the a ceta bul um a nd one onto the femora l hea d, produci ng a meta l -on-meta l
a rti cul a ti on. Hemi -SRA i nvol ves pl a cement of a meta l ca p onto onl y the femora l hea d. It i s done onl y i f di s ea s e i s l i mi ted to the femora l hea d a nd
i s cons i dered a tempori zi ng procedure.
ON of the knee a nd s houl der ca n be ma na ged nons urgi ca l l y more often tha n ON of the hi p. Li mi ted experi ence wi th core decompres s i on ha s been
promi s i ng. In a dva nced s ta ges , pa rti a l or tota l joi nt repl a cement ma y be i ndi ca ted.
Prevention
Ri s k of ON ca us ed by corti cos teroi ds ca n be mi ni mi zed by us i ng them onl y when es s enti a l a nd by gi vi ng them i n a s l ow a dos e a s needed a nd for
a s s hort a dura ti on a s pos s i bl e. To prevent ON ca us ed by decompres s i on s i cknes s , peopl e s houl d fol l ow a ccepted rul es for decompres s i on when
di vi ng a nd when worki ng i n pres s uri zed envi ronments . Exces s i ve a l cohol us e a nd s moki ng s houl d be di s coura ged. Va ri ous drugs (eg,
a nti coa gul a nts , va s odi l a tors , l i pi d-l oweri ng drugs ) a re bei ng eva l ua ted for preventi on of ON i n pa ti ents a t hi gh ri s k.
Chapter 40. Infections of Joints and Bones

Acute Infectious Arthritis
Acute infectious arthritis is a joint infection that evolves over hours or days. The infection resides in synovial or periarticular tissues and is usually bacterialin
younger adults, frequently Neisseria gonorrhoeae. However, nongonococcal bacterial infections can also occur and can rapidly destroy joint structures. Symptoms
include rapid onset of pain, effusion, and restriction of both active and passive range of motion, usually within a single joint. Diagnosis requires synovial fluid
analysis and culture. Treatment is IV antibiotics and drainage of pus from joints.
Acute i nfecti ous a rthri ti s ma y occur i n chi l dren. About 50% of chi l dren wi th joi nt i nfecti on a re < 3 yr. However, routi ne chi l dhood va cci na ti on for
Haemophilus influenzae a nd Streptococcus pneumoniae i s decrea s i ng the i nci dence i n thi s a ge group.
Ri s k fa ctors a re l i s ted i n
Ta bl e 40-1. Ri s k i s s ubs ta nti a l l y i ncrea s ed i n pa ti ents wi th RA a nd other di s orders ca us i ng chroni c joi nt da ma ge, a pa s t hi s tory of joi nt i nfecti on,
IV drug a bus e, or a pros theti c joi nt (s ee p. 370). RA pa ti ents a re a t pa rti cul a r ri s k of ba cteri a l a rthri ti s (preva l ence 0.3 to 3.0%; a nnua l i nci dence
0.5%). Mos t chi l dren who devel op i nfecti ous a rthri ti s do not ha ve i denti fi ed ri s k fa ctors .
Etiology
Infecti ous orga ni s ms rea ch joi nts by di rect penetra ti on (eg, tra uma , s urgery, a rthrocentes i s , bi tes ), extens i on from a n a dja cent i nfecti on (eg,
os teomyel i ti s , a s oft-ti s s ue a bs ces s , a n i nfected wound), or hema togenous s prea d from a remote s i te of i nfecti on.
[Table 40-1. Ri s k Fa ctors for Infecti ous Arthri ti s ]
Common orga ni s ms a re l i s ted i n
Ta bl e 40-2. In a dul ts , mos t ca s es res ul t from ba cteri a a nd a re cl a s s i fi ed a s gonococca l or nongonococca l . In a dul ts overa l l , Staphylococcus aureus
tends to be the mos t frequent ca us e of i nfecti ous a rthri ti s . Methi ci l l i n res i s ta nce ha s become more common a mong communi ty i s ol a tes of S.
aureus. In young a dul ts a nd a dol es cents , Neisseria gonorrhoeae i s the mos t common ca us e a nd res ul ts when N. gonorrhoeae
[Table 40-2. Orga ni s ms tha t Commonl y Ca us e Acute Infecti ous Arthri ti s ]
s prea ds from i nfected mucos a l s urfa ces (cervi x, urethra , rectum, pha rynx) vi a the bl oods trea m. Affected pa ti ents often ha ve s i mul ta neous geni ta l
i nfecti ons wi th Chlamydia trachomatis (s ee p. 1468). Streptococcus s peci es a re a l s o frequent ca us es , pa rti cul a rl y i n pa ti ents wi th pol ya rti cul a r
i nfecti ons .
Pathophysiology
Infecti ng orga ni s ms mul ti pl y i n the s ynovi a l fl ui d a nd s ynovi a l l i ni ng. Some ba cteri a (eg, S. aureus) produce vi rul ence fa ctors (a dhes i ns ), whi ch
a l l ow ba cteri a to penetra te, rema i n wi thi n, a nd i nfect joi nt ti s s ues . Other ba cteri a l products (eg, endotoxi n from gra m-nega ti ve orga ni s ms , cel l
wa l l fra gments , exotoxi ns from gra m-pos i ti ve orga ni s ms , i mmune compl exes formed by ba cteri a l a nti gens a nd hos t a nti bodi es ) a ugment the
i nfl a mma tory rea cti on.
PMNs mi gra te i nto the joi nt a nd pha gocytos e the i nfecti ng orga ni s ms . Pha gocytos i s of ba cteri a a l s o res ul ts i n PMN a utol ys i s wi th rel ea s e of
l ys os oma l enzymes i nto the joi nt, whi ch da ma ge s ynovi a , l i ga ments , a nd ca rti l a ge. Therefore, PMNs a re both the ma jor hos t defens e s ys tem a nd
the ca us e of joi nt da ma ge. Arti cul a r ca rti l a ge ca n be des troyed wi thi n hours or da ys . Infl a mma tory s ynovi ti s ma y occa s i ona l l y pers i s t even a fter
the i nfecti on ha s been era di ca ted by a nti bi oti cs . Pa rti cul a rl y i n gonococca l ca s es , pers i s tent a nti gen debri s from ba cteri a or i nfecti on ma y a l ter
ca rti l a ge, ca us i ng i t to become a nti geni c, a ndtogether wi th the a djuva nt effects of ba cteri a l components i mmune-medi a ted, "s teri l e" chroni c
i nfl a mma tory s ynovi ti s res ul ts .
Symptoms and Signs
Over a few hours to a few da ys , pa ti ents devel op modera te to s evere joi nt pa i n, wa rmth, tendernes s , effus i on, res tri cted a cti ve a nd pa s s i ve
moti on, a nd s ometi mes rednes s . Sys temi c s ymptoms ma y be mi ni ma l or a bs ent. Infa nts a nd chi l dren ma y pres ent wi th l i mi ted s ponta neous
movement of a l i mb (ps eudopa ra l ys i s ), i rri ta bi l i ty, feedi ng di s turba nces , a nd a hi gh, l ow-gra de, or no fever.
Gonococcal arthritis: Gonococca l a rthri ti s ca n ca us e a di s ti ncti ve derma ti ti s -pol ya rthri ti s tenos ynovi ti s s yndrome. Cl a s s i c ma ni fes ta ti ons a re fever
(for 5 to 7 da ys ); s ha ki ng chi l l s ; mul ti pl e s ki n l es i ons (petechi a e, pa pul es , pus tul es , hemorrha gi c ves i cl es or bul l a e, necroti c l es i ons ) on mucos a l
s urfa ces a nd on the s ki n of the trunk, ha nds , or l ower extremi ti es ; a nd mi gra tory a rthra l gi a s , a rthri ti s , a nd tenos ynovi ti s , whi ch evol ves i nto
pers i s tent i nfl a mma tory a rthri ti s i n one or more joi nts , mos t often the s ma l l joi nts of the ha nds , wri s ts , el bows , knees , a nd a nkl es , a nd ra rel y the
a xi a l s kel eta l joi nts . Symptoms of the ori gi na l mucos a l i nfecti on (eg, urethri ti s , cervi ci ti s ) ma y not be pres ent.
Nongonococcal bacterial arthritis: Nongonococca l ba cteri a l a rthri ti s ca us es progres s i ve modera te to s evere joi nt pa i n tha t i s ma rkedl y wors ened by
movement or pa l pa ti on. Mos t i nfected joi nts a re s wol l en, red, a nd wa rm. Fever i s a bs ent or l ow gra de i n up to 50% of pa ti ents ; 20% of pa ti ents
report a s ha ki ng chi l l . Vi rul ent orga ni s ms (eg, S. aureus, Pseudomonas aeruginosa) genera l l y ca us e a more ful mi na nt a rthri ti s , wherea s l es s vi rul ent
orga ni s ms (eg, coa gul a s e-nega ti ve s ta phyl ococci , Propionibacterium acnes) ca us e a l es s ful mi na nt a rthri ti s . In 80% of a dul ts , nongonococca l
ba cteri a l a rthri ti s i s mona rti cul a r a nd us ua l l y occurs i n a peri phera l joi nt: knee, hi p, s houl der, wri s t, a nkl e, or el bow. In chi l dren, 90% i s
mona rti cul a r: knee (39%), hi p (26%), a nd a nkl e (13%). Pol ya rti cul a r i nvol vement i s s omewha t more common a mong pa ti ents who a re
i mmunos uppres s ed or ha ve a n underl yi ng chroni c a rthri ti s (eg, RA, os teoa rthri ti s ). In IV drug us ers a nd pa ti ents wi th i ndwel l i ng va s cul a r
ca theters , a xi a l joi nts (eg, s ternocl a vi cul a r, cos tochondra l , hi p, s houl der, vertebra l , s ymphys i s pubi s , s a croi l i a c) a re often i nvol ved.
Infectious arthritis secondary to bite wounds: Infecti on due to huma n, dog, or ca t bi tes us ua l l y devel ops wi thi n 48 h. Ra t bi tes ca us e s ys temi c
s ymptoms s uch a s fever, ra s h, a nd joi nt pa i n or true a rthri ti s wi th regi ona l a denopa thy wi thi n a bout 2 to 10 da ys .
Viral infectious arthritis: Vi ra l i nfecti ous a rthri ti s s ometi mes ca us es s ymptoms s i mi l a r to a cute nongonococca l ba cteri a l a rthri ti s a nd i s more l i kel y
to be pol ya rti cul a r tha n ba cteri a l a rthri ti s .
Borrelia burgdorferi arthritis: Pa ti ents wi th B. burgdorferi a rthri ti s ma y ha ve other s ymptoms of Lyme di s ea s e (s ee p. 1269) or pres ent onl y wi th a cute
mona rthri ti s or ol i goa rthri ti s .
Diagnosis
Arthrocentes i s wi th s ynovi a l fl ui d exa mi na ti on a nd cul ture
Bl ood cul ture
Someti mes i ma gi ng s tudi es
Often CBC a nd ESR (or C-rea cti ve protei n)
Infecti ous a rthri ti s i s s us pected i n pa ti ents wi th a cute mona rti cul a r a rthri ti s a nd i n pa ti ents wi th other combi na ti ons of s ymptoms cha ra cteri s ti c
of pa rti cul a r i nfecti ous a rthri ti s s yndromes (eg, mi gra tory pol ya rthri ti s , tenos ynovi ti s a nd s ki n l es i ons typi ca l of di s s emi na ted gonococca l
i nfecti on; erythema mi gra ns or other s ymptoms a nd s i gns of Lyme di s ea s es ee p. 1269). Even mi l d mona rti cul a r joi nt s ymptoms s houl d a rous e
s us pi ci on i n pa ti ents wi th ri s k fa ctors (eg, RA), a pros theti c joi nt, or a n extra -a rti cul a r i nfecti on ca pa bl e of s prea di ng to a joi nt (eg, geni ta l
gonococca l i nfecti on, ba cteremi a , a ny a na erobi c i nfecti on).
General arthritis: Synovial fluid examination i s the corners tone of di a gnos i s . Fl ui d i s exa mi ned gros s l y a nd s ent for cel l count a nd di fferenti a l , Gra m
s ta i n, a erobi c a nd a na erobi c cul ture, a nd crys ta l s . Foul -s mel l i ng s ynovi a l fl ui d s ugges ts a na erobi c i nfecti on. Fl ui d from a n a cutel y i nfected joi nt
us ua l l y revea l s a WBC count > 20,000/L (often > 100,000/L) cons i s ti ng of > 95% PMNs . WBC counts tend to be hi gher i n nongonococca l ba cteri a l
tha n i n gonococca l i nfecti ous a rthri ti s . WBC counts ma y a l s o be l ower i n ea rl y or pa rti a l l y trea ted i nfecti ons . Gra m s ta i n revea l s orga ni s ms i n onl y
50 to 75% of joi nts wi th a cute ba cteri a l a rthri ti s , mos t often wi th s ta phyl ococci . If pos i ti ve, Gra m s ta i n i s us ua l l y rel a ti vel y s peci fi c, but cul tures a re
defi ni ti ve. The pres ence of crys ta l s does not excl ude i nfecti ous a rthri ti s . Someti mes s ynovi a l fl ui d a na l ys i s ca nnot di fferenti a te between
i nfecti ous a nd other i nfl a mma tory s ynovi a l fl ui d. If di fferenti a ti on i s i mpos s i bl e by cl i ni ca l mea ns or s ynovi a l fl ui d exa mi na ti on, i nfecti ous
a rthri ti s i s a s s umed, pendi ng cul ture res ul ts .
Blood tests, s uch a s bl ood cul tures , CBC, a nd ESR (or C-rea cti ve protei n), a re us ua l l y obta i ned. However, norma l res ul ts do not excl ude i nfecti on.
Li kewi s e, WBC count, ESR, or C-rea cti ve protei n ma y be i ncrea s ed i n noni nfecti ous a s wel l a s i nfecti ous joi nt i nfl a mma ti on.
Plain x-rays of the i nvol ved joi nt a re not di a gnos ti c of a cute i nfecti on but ca n excl ude other condi ti ons under cons i dera ti on (eg, fra ctures ).
Abnorma l i ti es i n ea rl y a cute ba cteri a l a rthri ti s a re l i mi ted to s oft-ti s s ue s wel l i ng a nd s i gns of s ynovi a l effus i ons . After 10 to 14 da ys of untrea ted
ba cteri a l i nfecti on, des tructi ve cha nges of joi nt s pa ce na rrowi ng (refl ecti ng ca rti l a ge des tructi on) a nd eros i ons or foci of s ubchondra l
os teomyel i ti s ma y a ppea r. Ga s vi s i bl e wi thi n the joi nts s ugges ts i nfecti on wi th Escherichia coli or a na erobes .
MRI i s cons i dered i f the joi nt i s not ea s i l y a cces s i bl e for exa mi na ti on a nd a s pi ra ti on (eg, a n a xi a l joi nt). MRI or ul tra s onogra phy ca n i denti fy s i tes
of effus i on or a bs ces s tha t ca n be a s pi ra ted or dra i ned for both di a gnos i s a nd thera py. MRI ca n provi de ea rl y s ugges ti on of a s s oci a ted
os teomyel i ti s . Bone s ca ns us i ng techneti um-99m ca n be fa l s el y nega ti ve i n i nfecti ous a rthri ti s . Al s o, beca us e they s how i ncrea s ed upta ke wi th
i ncrea s ed bl ood fl ow i n i nfl a med s ynovi a l membra nes a nd i n meta bol i ca l l y a cti ve bone, they ca n be fa l s el y pos i ti ve i n noni nfecti ous
i nfl a mma tory a rthri ti s . Nucl ea r i ma gi ng a nd MRI do not di s ti ngui s h i nfecti on from crys ta l -i nduced a rthri ti s .
Gonococcal arthritis: If gonococca l a rthri ti s i s s us pected, bl ood a nd s ynovi a l fl ui d s a mpl es s houl d be immediately pl a ted on nons el ecti ve chocol a te
a ga r, a nd s peci mens from the urethra , endocervi x, rectum, a nd pha rynx s houl d be pl a ted on s el ecti ve Tha yer-Ma rti n medi um. Geni ta l chl a mydi a l
cul tures a re a l s o done. Bl ood cul tures a re pos i ti ve i n 60 to 75% of ca s es duri ng the fi rs t week a nd ma y be the onl y method by whi ch to i denti fy the
orga ni s m; cul tures from joi nts wi th ea rl y tenos ynovi ti s or a rthri ti s a re often nega ti ve. Synovi a l fl ui d cul tures from joi nts wi th fra nk purul ent
a rthri ti s a re us ua l l y pos i ti ve, a nd fl ui d from s ki n l es i ons ma y be pos i ti ve. If di s s emi na ted gonococca l i nfecti on i s s us pected ba s ed on cl i ni ca l
cri teri a , i t i s a s s umed to be pres ent even i f a l l gonococca l cul tures a re nega ti ve. Cl i ni ca l res pons e to a nti bi oti cs (a nti ci pa ted wi thi n 5 to 7 da ys )
ca n hel p confi rm the di a gnos i s .
Prognosis
Acute nongonococca l ba cteri a l a rthri ti s ca n des troy a rti cul a r ca rti l a ge, perma nentl y da ma gi ng the joi nt wi thi n hours or da ys . Gonococca l a rthri ti s
does not us ua l l y da ma ge joi nts perma nentl y. Fa ctors tha t i ncrea s e s us cepti bi l i ty to i nfecti ous a rthri ti s ma y a l s o i ncrea s e di s ea s e s everi ty. In
pa ti ents wi th RA, functi ona l outcome i s pa rti cul a rl y poor, a nd the morta l i ty ra te i s i ncrea s ed.
Treatment
IV a nti bi oti cs
Dra i na ge of pus from i nfected joi nts (for a cute nongonococca l ba cteri a l a rthri ti s or a ny s epti c a rthri ti s wi th pers i s tent effus i on
Antibiotic therapy: Ini ti a l a nti bi oti c s el ecti on i s di rected a t the mos t l i kel y pa thogens . The regi men i s a djus ted ba s ed on the res ul ts of cul ture a nd
s us cepti bi l i ty tes ti ng.
Gonococca l a rthri ti s i s trea ted wi th ceftri a xone 1 g IV once/da y unti l a t l ea s t 24 h a fter s ymptoms a nd s i gns res ol ve, fol l owed by cefi xi me 400 mg
po bi d for 7 da ys . Joi nt dra i na ge a nd debri dement ma y be unneces s a ry. Coexi s ti ng geni ta l i nfecti on wi th C. trachomatis i s a l s o trea ted, often wi th
doxycycl i ne 100 mg po bi d for 7 da ys , a nd s exua l conta cts of the pa ti ent a re trea ted a s neces s a ry (s ee p. 1470).
If nongonococca l gra m-pos i ti ve i nfecti on i s s us pected by Gra m s ta i n i n a n a dul t, the empi ri c choi ce i s one of the fol l owi ng: a s emi s yntheti c
peni ci l l i n (eg, na fci l l i n 2 g IV q 4 h), a cepha l os pori n (eg, cefa zol i n 2 g IV q 8 h), or va ncomyci n 1 g IV q 12 h (i f methi ci l l i n res i s ta nce i s common
a mong l oca l communi ty i s ol a tes of S. aureus). If gra m-nega ti ve i nfecti on i s s us pected, empi ri c trea tment i ncl udes a pa rentera l 3rd-genera ti on
cepha l os pori n wi th a nti ps eudomona l a cti vi ty (eg, cefta zi di me 2 g IV q 8 h) a nd, i f i nfecti on i s s evere, a n a mi nogl ycos i de.
Pa rentera l a nti bi oti cs a re conti nued unti l cl i ni ca l i mprovement i s cl ea r (us ua l l y 2 to 4 wk), a nd ora l a nti bi oti cs s houl d be gi ven a t hi gh dos es for
a nother 2 to 6 wk a ccordi ng to the cl i ni ca l res pons e. Infecti ons ca us ed by s treptococci a nd Haemophilus a re us ua l l y era di ca ted a fter 2 wk of ora l
a nti bi oti cs a fter IV trea tment. Sta phyl ococca l i nfecti ons requi re a t l ea s t 3 wk a nd often 6 wk or l onger, es peci a l l y i n pa ti ents wi th pri or a rthri ti s .
Other therapies: In a ddi ti on to a nti bi oti cs , a cute nongonococca l ba cteri a l a rthri ti s requi res l a rge-bore needl e a s pi ra ti on of i ntra -a rti cul a r pus a t
l ea s t once/da y, or ti da l i rri ga ti on l a va ge, a rthros copi c l a va ge, or a rthrotomy for debri dement. Infected RA joi nts s houl d genera l l y undergo even
ea rl i er a nd more a ggres s i ve s urgi ca l debri dement a nd dra i na ge. For gonococca l a rthri ti s wi th pers i s tent effus i on, pus i s a s pi ra ted a nd dra i na ge
ma y need to be repea ted a s neces s a ry. Acute ba cteri a l a rthri ti s requi res joi nt s pl i nti ng for the fi rs t few da ys to reduce pa i n, fol l owed by pa s s i ve
a nd a cti ve ra nge-of-moti on exerci s es to l i mi t contra ctures , wi th mus cl e s trengtheni ng a s s oon a s tol era ted. NSAIDs ca n hel p decrea s e pa i n a nd
i nfl a mma ti on.
Viral arthritis and arthritis secondary to bite wounds: Vi ra l a rthri ti s i s trea ted s upporti vel y. Bi te wounds a re trea ted wi th a nti bi oti cs a nd s urgi ca l
dra i na ge a s neces s a ry (s ee p. 3307).
Chronic Infectious Arthritis
Chronic infectious arthritis develops over weeks and is usually caused by mycobacteria, fungi, or bacteria with low pathogenicity.
Chroni c i nfecti ous a rthri ti s a ccounts for 5% of i nfecti ous a rthri ti s . It ca n devel op i n hea l thy peopl e, but pa ti ents a t i ncrea s ed ri s k i ncl ude thos e
wi th
RA
HIV i nfecti on
Immunos uppres s i on (eg, hema tol ogi c or other ca ncers , i mmunos uppres s i ve drug us e)
Pros theti c joi nts (s ee p. 370)
Exa mpl es of pos s i bl e ca us es a re Mycobacterium tuberculosis, M. marinum, M. kansasii, Candida s p, Coccidioides immitis, Histoplasma capsulatum,
Cryptococcus neoformans, Blastomyces dermatitidis, Sporothrix schenckii, Aspergillus fumigatus, Actinomyces israelii, a nd Brucella s p. The a rthri ti s of Lyme
di s ea s e i s us ua l l y a cute but ma y be chroni c a nd recurrent. Unus ua l opportuni s ti c orga ni s ms a re pos s i bl e i n pa ti ents wi th hema tol ogi c ca ncers or
HIV i nfecti on or who a re ta ki ng i mmunos uppres s i ve drugs . In chroni c i nfecti ous a rthri ti s , the s ynovi a l membra ne ca n prol i fera te a nd ca n erode
a rti cul a r ca rti l a ge a nd s ubchondra l bone.
Ons et i s often i ndol ent, wi th gra dua l s wel l i ng, mi l d wa rmth, mi ni ma l or no rednes s of the joi nt a rea , a nd a chi ng pa i n tha t ma y be mi l d. Us ua l l y a
s i ngl e joi nt i s i nvol ved. A prol onged dura ti on a nd l a ck of res pons e to conventi ona l a nti bi oti cs s ugges t a mycoba cteri a l or funga l ca us e.
Pa ti ents s houl d ha ve funga l a nd mycoba cteri a l cul tures ta ken of s ynovi a l fl ui d or s ynovi a l ti s s ue, a s wel l a s routi ne s tudi es . Pl a i n x-ra y fi ndi ngs
ma y di ffer from thos e of a cute i nfecti ous a rthri ti s i n tha t joi nt s pa ce i s pres erved l onger, a nd ma rgi na l eros i ons a nd bony s cl eros i s ma y occur.
Mycoba cteri a l a nd funga l joi nt i nfecti ons requi re prol onged trea tment. Mycoba cteri a l i nfecti ons a re often trea ted wi th mul ti pl e a nti bi oti cs ,
gui ded by s ens i ti vi ty tes ti ng res ul ts .
Prosthetic Joint Infectious Arthritis
Prosthetic joints are at risk of acute and chronic infection, which can cause sepsis, morbidity, or mortality.
Etiology
Infecti ons a re more common i n pros theti c joi nts . They a re frequentl y ca us ed by peri opera ti ve i nocul a ti ons of ba cteri a i nto the joi nt or by
pos topera ti ve ba cteremi a res ul ti ng from s ki n i nfecti on, pneumoni a , denta l procedures , i nva s i ve i ns trumenta ti on, UTI, or pos s i bl y fa l l s . They
devel op wi thi n 1 yr of s urgery i n two thi rds of ca s es . Duri ng the fi rs t few months a fter s urgery, the ca us es a re Staphylococcus aureus i n 50% of ca s es ,
mi xed fl ora i n 35%, gra m-nega ti ve orga ni s ms i n 10%, a nd a na erobes i n 5%.
Symptoms and Signs
There i s a hi s tory of a fa l l wi thi n 2 wk of s ymptom ons et i n a bout 25% of pa ti ents a nd of pri or s urgi ca l revi s i ons i n a bout 20%. Some pa ti ents ha ve
ha d a pos topera ti ve wound i nfecti on tha t a ppea red to res ol ve, s a ti s fa ctory pos topera ti ve recovery for ma ny months , a nd then devel opment of
pers i s tent joi nt pa i n a t res t a nd duri ng wei ght bea ri ng. Symptoms a nd s i gns ma y i ncl ude pa i n, s wel l i ng, a nd l i mi ted moti on; tempera ture ma y be
norma l .
Diagnosis
Cl i ni ca l , mi crobi ol ogi c, pa thol ogi c, a nd ra di ogra phi c cri teri a
The di a gnos i s often us es a combi na ti on of cl i ni ca l , mi crobi ol ogi c, pa thol ogi c, a nd ra di ogra phi c cri teri a . Communi ca ti on between a s i nus tra ct a nd
the pros thes i s ma y a l s o be cons i dered di a gnos ti c of i nfecti on. Synovi a l fl ui d s houl d be s a mpl ed for cel l count a nd cul ture. X-ra ys ma y s how
l oos eni ng of the pros thes i s or peri os tea l rea cti on but a re not di a gnos ti c. Techneti um-99m bone s ca nni ng a nd i ndi um-l a bel ed WBC s ca nni ng a re
more s ens i ti ve tha n pl a i n x-ra ys but ma y l a ck s peci fi ci ty i n the i mmedi a te pos topera ti ve peri od. Ul ti ma tel y, peri pros theti c ti s s ue col l ected a t the
ti me of s urgery ma y be s ent for cul ture a nd hi s tol ogi c a na l ys i s .
Treatment
Arthrotomy wi th debri dement

Long-term s ys temi c a nti bi oti c thera py
Trea tment mus t be prol onged a nd us ua l l y i nvol ves a rthrotomy for pros thes i s remova l wi th meti cul ous debri dement of a l l cement, a bs ces s es , a nd
devi ta l i zed ti s s ues . Debri dement i s fol l owed by i mmedi a te pros thes i s revi s i on or pl a cement of a n a nti bi oti c-i mpregna ted s pa cer a nd then
del a yed (2 to 4 mo) i mpl a nta ti on of a new pros thes i s us i ng a nti bi oti c-i mpregna ted cement. Long-term s ys temi c a nti bi oti c thera py i s us ed i n ei ther
ca s e; empi ri c thera py i s i ni ti a ted a fter i ntra opera ti ve cul ture i s done a nd us ua l l y combi nes covera ge for methi ci l l i n-res i s ta nt gra m-pos i ti ve
orga ni s ms (eg, va ncomyci n 1 g IV q 12 h) a nd a erobi c gra m-nega ti ve orga ni s ms (eg, pi pera ci l l i n/ta zoba cta m 3.375 g IV q 6 h or cefta zi di me 2 g IV q 8
h) a nd i s revi s ed ba s ed on res ul ts of cul ture a nd s ens i ti vi ty tes ti ng. Infecti on devel ops i n 38% of new i mpl a nts , whether repl a ced i mmedi a tel y or
a fter del a y.
If pa ti ents ca nnot tol era te s urgery, l ong-term a nti bi oti c thera py a l one ca n be tri ed. Exci s i on a rthropl a s ty wi th or wi thout fus i on us ua l l y i s res erved
for pa ti ents wi th uncontrol l ed i nfecti on a nd i ns uffi ci ent bone s tock.
Prevention
In the a bs ence of other i ndi ca ti ons (eg, va l vul a r hea rt di s ea s e), pa ti ents wi th pros theti c joi nts do not need prophyl a cti c a nti bi oti cs before
procedures s uch a s denta l work a nd urol ogi c i ns trumenta ti on. Deta i l ed recommenda ti ons a re a va i l a bl e a t www.a a os .org.
Osteomyelitis
Osteomyelitis is inflammation and destruction of bone caused by bacteria, mycobacteria, or fungi. Common symptoms are localized bone pain and tenderness
with constitutional symptoms (in acute osteomyelitis) or without constitutional symptoms (in chronic osteomyelitis). Diagnosis is by imaging studies and
cultures. Treatment is with antibiotics and sometimes surgery.
Etiology
Os teomyel i ti s i s ca us ed by
Conti guous s prea d (from i nfected ti s s ue or a n i nfected pros theti c joi nt)
Bl oodborne orga ni s ms (hema togenous os teomyel i ti s )
Open wounds (from conta mi na ted open fra ctures or bone s urgery)
Tra uma , i s chemi a , a nd forei gn bodi es predi s pos e to os teomyel i ti s . Os teomyel i ti s ma y form under deep decubi tus ul cers .
About 80% of os teomyel i ti s res ul ts from conti guous s prea d or from open wounds ; i t i s often pol ymi crobi a l . Staphylococcus aureus (i ncl udi ng both
methi ci l l i n-s ens i ti ve a nd methi ci l l i n-res i s ta nt s tra i ns ) i s pres ent i n 50%; other common ba cteri a i ncl ude s treptococci , gra m-nega ti ve enteri c
orga ni s ms , a nd a na erobi c ba cteri a . Os teomyel i ti s tha t res ul ts from conti guous s prea d i s common i n the feet (i n pa ti ents wi th di a betes or
peri phera l va s cul a r di s ea s e), a t s i tes where bone wa s penetra ted duri ng tra uma or s urgery, a t s i tes da ma ged by ra di a ti on thera py, a nd i n bones
conti guous to decubi tus ul cers , s uch a s the hi ps a nd s a crum. A s i nus , gum, or tooth i nfecti on ma y s prea d to the s kul l .
Hema togenous l y s prea d os teomyel i ti s us ua l l y res ul ts from a s i ngl e orga ni s m. In chi l dren, gra m-pos i ti ve ba cteri a a re mos t common, us ua l l y
a ffecti ng the meta phys es of the ti bi a , femur, or humerus . Hema togenous l y s prea d os teomyel i ti s i n a dul ts us ua l l y a ffects the vertebra e. Ri s k
fa ctors i n a dul ts a re ol der a ge, debi l i ta ti on, hemodi a l ys i s , s i ckl e cel l di s ea s e, a nd IV drug us e. Common i nfecti ng orga ni s ms i ncl ude S. aureus
(methi ci l l i n-res i s ta nt S. aureus [MRSA] i s common) a nd enteri c gra m-nega ti ve ba cteri a (i n a dul ts who a re ol der, debi l i ta ted, or recei vi ng
hemodi a l ys i s ); S. aureus, Pseudomonas aeruginosa, a nd Serratia s p (i n IV drug us ers ); a nd Salmonella s p (i n pa ti ents wi th s i ckl e cel l di s ea s e). Fungi
a nd mycoba cteri a ca n ca us e hema togenous os teomyel i ti s , us ua l l y i n i mmunocompromi s ed pa ti ents or i n a rea s of endemi c i nfecti on wi th
hi s topl a s mos i s , bl a s tomycos i s , or cocci di oi domycos i s . The vertebra e a re often i nvol ved.
Pathophysiology
Os teomyel i ti s tends to occl ude l oca l bl ood ves s el s , whi ch ca us es bone necros i s a nd l oca l s prea d of i nfecti on. Infecti on ma y expa nd through the
bone cortex a nd s prea d under the peri os teum, wi th forma ti on of s ubcuta neous a bs ces s es tha t ma y dra i n s ponta neous l y through the s ki n. In
vertebra l os teomyel i ti s , pa ra vertebra l or epi dura l a bs ces s ca n devel op.
If trea tment of a cute os teomyel i ti s i s onl y pa rti a l l y s ucces s ful , l ow-gra de chroni c os teomyel i ti s devel ops .
Symptoms and Signs
Pa ti ents wi th a cute os teomyel i ti s of peri phera l bones us ua l l y experi ence wei ght l os s , fa ti gue, fever, a nd l oca l i zed wa rmth, s wel l i ng, erythema ,
a nd tendernes s .
Vertebra l os teomyel i ti s ca us es l oca l i zed ba ck pa i n a nd tendernes s wi th pa ra vertebra l mus cl e s pa s m tha t i s unres pons i ve to cons erva ti ve
trea tment. Pa ti ents a re us ua l l y a febri l e.
Chroni c os teomyel i ti s ca us es i ntermi ttent (months to ma ny yea rs ) bone pa i n, tendernes s , a nd dra i ni ng s i nus es .
Diagnosis
ESR or C-rea cti ve protei n
X-ra ys , MRI, or ra di oi s otopi c bone s ca nni ng

Cul ture of bone, a bs ces s , or both
Acute os teomyel i ti s i s s us pected i n pa ti ents wi th l oca l i zed peri phera l bone pa i n, fever, a nd ma l a i s e or wi th l oca l i zed refra ctory vertebra l pa i n,
pa rti cul a rl y i n pa ti ents wi th recent ri s k fa ctors for ba cteremi a . Chroni c os teomyel i ti s i s s us pected i n pa ti ents wi th pers i s tent l oca l i zed bone pa i n,
pa rti cul a rl y i f they ha ve ri s k fa ctors .
If os teomyel i ti s i s s us pected, CBC a nd ESR or C-rea cti ve protei n, a s wel l a s pl a i n x-ra ys of the a ffected bone, a re obta i ned. The WBC count ma y not
be el eva ted, but the ESR a nd C-rea cti ve protei n us ua l l y a re. X-ra ys become a bnorma l a fter 2 to 4 wk, s howi ng peri os tea l el eva ti on, bone
des tructi on, s oft-ti s s ue s wel l i ng, a nd, i n the vertebra e, l os s of vertebra l body hei ght or na rrowi ng of the a dja cent i nfected i ntervertebra l di s k
s pa ce a nd des tructi on of the end pl a tes a bove a nd bel ow the di s k.
If x-ra ys a re equi voca l or s ymptoms a re a cute, CT a nd MRI a re the current i ma gi ng techni ques of choi ce to defi ne a bnorma l i ti es a nd revea l
a bs ces s es (eg, pa ra vertebra l or epi dura l a bs ces s es ). Al terna ti vel y, a ra di oi s otope bone s ca n wi th techneti um-99m ca n be done. The bone s ca n
s hows a bnorma l i ti es ea rl i er tha n pl a i n x-ra ys but does not di s ti ngui s h a mong i nfecti on, fra ctures , a nd tumors . A whi te bl ood cel l s ca n us i ng
i ndi um-111-l a bel ed cel l s ma y hel p to better i denti fy a rea s of i nfecti on s een on bone s ca n. Ba cteri ol ogi c di a gnos i s i s neces s a ry for opti ma l
thera py of os teomyel i ti s ; bone bi ops y wi th a needl e or s urgi ca l exci s i on a nd a s pi ra ti on or debri dement of a bs ces s es provi des ti s s ue for cul ture
a nd a nti bi oti c s ens i ti vi ty tes ti ng. Cul ture of s i nus dra i na ge does not neces s a ri l y revea l the bone pa thogen. Bi ops y a nd cul ture s houl d precede
a nti bi oti c thera py unl es s the pa ti ent i s i n s hock or ha s neurol ogi c dys functi on.
Treatment
Anti bi oti cs
Surgery for a bs ces s , cons ti tuti ona l s ymptoms , potenti a l s pi na l i ns ta bi l i ty, or much necroti c bone
Anti bi oti cs effecti ve a ga i ns t both gra m-pos i ti ve a nd gra m-nega ti ve orga ni s ms a re gi ven unti l cul ture res ul ts a nd s ens i ti vi ti es a re a va i l a bl e. Ini ti a l
a nti bi oti c trea tment for a cute hema togenous os teomyel i ti s s houl d i ncl ude a peni ci l l i na s e-res i s ta nt s emi s yntheti c peni ci l l i n (eg, na fci l l i n or
oxa ci l l i n 2 g IV q 4 h) or va ncomyci n 1 g IV q 12 h (when MRSA i s preva l ent i n a communi ty) a nd a 3rd- or 4th-genera ti on cepha l os pori n (s uch a s
cefta zi di me 2 g IV q 8 h or cefepi me 2 g IV q 12 h). Empi ri c trea tment of chroni c os teomyel i ti s a ri s i ng from a conti guous s oft-ti s s ue focus ,
pa rti cul a rl y i n pa ti ents wi th di a betes , mus t be effecti ve a ga i ns t a na erobi c orga ni s ms i n a ddi ti on to gra m-pos i ti ve a nd gra m-nega ti ve a erobes .
Ampi ci l l i n/s ul ba cta m 3 g IV q 6 h or pi pera ci l l i n/ta zoba cta m 3.375 g IV q 6 h i s commonl y us ed; va ncomyci n 1 g IV q 12 h i s a dded when i nfecti on i s
s evere or MRSA i s preva l ent. Anti bi oti cs mus t be gi ven pa rentera l l y for 4 to 8 wk a nd ta i l ored to res ul ts of a ppropri a te cul tures . If a ny
cons ti tuti ona l fi ndi ngs (eg, fever, ma l a i s e, wei ght l os s ) pers i s t or i f l a rge a rea s of bone a re des troyed, necroti c ti s s ue i s debri ded s urgi ca l l y.
Surgery ma y a l s o be needed to dra i n coexi s ti ng pa ra vertebra l or epi dura l a bs ces s es or to s ta bi l i ze the s pi ne to prevent i njury. Ski n or pedi cl e
gra fts ma y be needed to cl os e l a rge s urgi ca l defects . Broa d-s pectrum a nti bi oti cs s houl d be conti nued for > 3 wk a fter s urgery. In chroni c
os teomyel i ti s , l ong-term a nti bi oti c thera py ma y be needed.
Chapter 41. Bursa, Muscle, and Tendon Disorders

Introduction
Often, mus cl es , burs a e, a nd tendons a re i njured duri ng s ports a cti vi ti es . Injury, overus e, i nfecti on, a nd occa s i ona l l y di s ea s e ca n tempora ri l y or
perma nentl y da ma ge thes e s tructures . Da ma ge ca n ca us e pa i n, l i mi t control of movement, a nd reduce ra nge of moti on.
Bursitis
Bursitis is acute or chronic inflammation of a bursa. The cause is usually unknown, but trauma, repetitive or acute, may contribute, as may infection and crystalinduced disease. Symptoms include pain (particularly with motion or pressure), swelling, and tenderness. Diagnosis is usually clinical; however, ultrasonography
may be needed to evaluate deep bursae. Diagnosis of infection and crystal-induced disease requires analysis of bursal fluid. Treatment includes splinting, NSAIDs,
sometimes corticosteroid injections, and treatment of the cause.
Burs a e a re fl ui d-fi l l ed s a c-l i ke ca vi ti es or potenti a l ca vi ti es tha t a re l oca ted where fri cti on occurs (eg, where tendons or mus cl es pa s s over bony
promi nences ). Burs a e mi ni mi ze fri cti on between movi ng pa rts a nd fa ci l i ta te movement. Some communi ca te wi th joi nts .
Burs i ti s ma y occur i n the s houl der (s uba cromi a l or s ubdel toi d burs i ti s ), pa rti cul a rl y i n pa ti ents wi th rota tor cuff tendi ni ti s , whi ch i s us ua l l y the
pri ma ry l es i on i n the s houl der. Other commonl y a ffected burs a e i ncl ude ol ecra non (mi ners ' or ba rfl y's el bow), prepa tel l a r (hous ema i d's knee),
s upra pa tel l a r, retroca l ca nea l , i l i opecti nea l (i l i ops oa s ), i s chi a l (ta i l or's or wea ver's bottom), grea ter trocha nteri c, pes a ns eri ne, a nd fi rs t
meta ta rs a l hea d (buni on) burs a e. Occa s i ona l l y, burs i ti s ca us es i nfl a mma ti on i n a communi ca ti ng joi nt.
Etiology
Burs i ti s ma y be ca us ed by the fol l owi ng:
Injury
Chroni c overus e
Infl a mma tory a rthri ti s (eg, gout, RA)
Acute or chroni c i nfecti on (eg, pyogeni c orga ni s ms , pa rti cul a rl y Staphylococcus aureus)
Idi opa thi c a nd tra uma ti c ca us es a re by fa r the mos t common. Acute burs i ti s ma y fol l ow unus ua l exerci s e or s tra i n a nd us ua l l y ca us es burs a l
effus i on. Infecti on mos t often a ffects ol ecra non a nd prepa tel l a r burs a e.
Chroni c burs i ti s ma y devel op a fter previ ous a tta cks of burs i ti s or repea ted tra uma . The burs a l wa l l i s thi ckened, wi th prol i fera ti on of i ts s ynovi a l
l i ni ng; burs a l a dhes i ons , vi l l us forma ti on, ta gs , a nd cha l ky depos i ts ma y devel op.
Symptoms and Signs
Acute burs i ti s ca us es pa i n, pa rti cul a rl y when the burs a i s compres s ed or s tretched duri ng moti on. Swel l i ng, s ometi mes wi th other s i gns of
i nfl a mma ti on, i s common i f the burs a i s s uperfi ci a l (eg, prepa tel l a r, ol ecra non). Swel l i ng ma y be more promi nent tha n pa i n i n ol ecra non burs i ti s .
Crys ta l - or ba cteri a l -i nduced burs i ti s i s us ua l l y a ccompa ni ed by erythema , pi tti ng edema , pa i n, a nd wa rmth i n the a rea over the burs a .
Chroni c burs i ti s ma y l a s t for s evera l months a nd ma y recur frequentl y. Bouts ma y l a s t a few da ys to s evera l weeks . If i nfl a mma ti on pers i s ts nea r a
joi nt, the joi nt's ra nge of moti on ma y be l i mi ted. Li mi ted moti on ma y l ea d to mus cl e a trophy.
Diagnosis
Ul tra s onogra phy or MRI for deep burs i ti s
As pi ra ti on for s us pected i nfecti on or crys ta l -i nduced burs i ti s
Superfi ci a l burs i ti s s houl d be s us pected i n pa ti ents wi th s wel l i ng or s i gns of i nfl a mma ti on over burs a e. Deep burs i ti s i s s us pected i n pa ti ents
wi th unexpl a i ned pa i n wors ened by moti on i n a l oca ti on compa ti bl e wi th burs i ti s . Us ua l l y, burs i ti s ca n be di a gnos ed cl i ni ca l l y. Ul tra s onogra phy
or MRI ca n hel p confi rm the di a gnos i s when deep burs a e a re not rea di l y a cces s i bl e for i ns pecti on, pa l pa ti on, or a s pi ra ti on. Thes e tes ts a re done
to confi rm or excl ude a s us pected di a gnos i s . Thes e i ma gi ng techni ques i ncrea s e the a ccura cy of i denti fyi ng the i nvol ved s tructures .
If burs a l s wel l i ng i s pa rti cul a rl y pa i nful , red, or wa rm or i f the ol ecra non or prepa tel l a r burs a i s a ffected, i nfecti on a nd crys ta l -i nduced di s ea s e
s houl d be excl uded by burs a l a s pi ra ti on. After a l oca l a nes theti c i s i njected, fl ui d i s wi thdra wn from the burs a us i ng s teri l e techni ques ; a na l ys i s
i ncl udes cel l count, Gra m s ta i n a nd cul ture, a nd mi cros copi c s ea rch for crys ta l s . Gra m s ta i n, a l though hel pful , ma y not be s peci fi c, a nd WBC counts
i n i nfected burs a e a re us ua l l y l ower tha n thos e i n s epti c joi nts . Ura te crys ta l s a re ea s i l y s een wi th pol a ri zed l i ght, but the a pa ti te crys ta l s typi ca l
of ca l ci fi c tendi ni ti s a ppea r onl y a s s hi ny chunks tha t a re not bi refri ngent. X-ra ys s houl d be ta ken i f burs i ti s i s pers i s tent or i f ca l ci fi ca ti on i s
s us pected.
Acute burs i ti s s houl d be di s ti ngui s hed from hemorrha ge i nto a burs a , whi ch ca n ca us e s i mi l a r ma ni fes ta ti ons beca us e bl ood i s i nfl a mma tory.
Fl ui d i n tra uma ti c burs i ti s i s s eros a ngui neous . Cel l ul i ti s ca n ca us e s i gns of i nfl a mma ti on but does not norma l l y ca us e burs a l effus i on; cel l ul i ti s
overl yi ng the burs a i s a rel a ti ve contra i ndi ca ti on to burs a l puncture through the cel l ul i ti s , but i f s epti c burs i ti s i s s trongl y s us pected, a s pi ra ti on
mus t occa s i ona l l y be done.
Treatment
Res t
Hi gh-dos e NSAIDs
Trea tment of crys ta l -i nduced di s ea s e or i nfecti on
Crys ta l -i nduced di s ea s e (s ee p. 349) or i nfecti on s houl d be trea ted i f pres ent. For i nfecti on, choi ce of a nti bi oti c i s determi ned by res ul ts of Gra m
s ta i n a nd cul ture. Empi ri c a nti bi oti cs effecti ve a ga i ns t S. aureus s houl d be gi ven. Infecti ous burs i ti s requi res dra i na ge or exci s i on i n a ddi ti on to
a nti bi oti cs .
Acute nons epti c burs i ti s i s trea ted wi th tempora ry res t or i mmobi l i za ti on a nd hi gh-dos e NSAIDs a nd s ometi mes wi th other a na l ges i cs . Vol unta ry
movement s houl d be i ncrea s ed a s pa i n s ubs i des . Pendul um exerci s es a re hel pful for the s houl der joi nt.
If ora l drugs a nd res t a re i na dequa te, a s pi ra ti on a nd i ntra burs a l i njecti on of depot corti cos teroi ds 0.5 to 1 mL (eg, tri a mci nol one a cetoni de 40
mg/mL) a re the trea tment of choi ce. About 1 mL of l oca l a nes theti c (eg, 2% l i doca i ne) ca n be i njected before the corti cos teroi d i njecti on. The s a me
needl e i s us ed; i t i s kept i n pl a ce a nd the s yri nges a re cha nged. Dos e a nd vol ume of the corti cos teroi d ma y va ry a ccordi ng to the s i ze of the burs a .
Infrequentl y, a fl a re-up occurs wi thi n s evera l hours of i njecti on of a depot corti cos teroi d; the fl a re-up i s proba bl y a form of crys ta l -i nduced
s ynovi ti s . It us ua l l y l a s ts 24 h a nd res ponds to col d compres s es pl us a na l ges i cs . Ora l corti cos teroi ds (eg, predni s one) ca n be us ed i f a l oca l
i njecti on i s not fea s i bl e.
Chroni c burs i ti s i s trea ted the s a me a s a cute burs i ti s , except tha t s pl i nti ng a nd res t a re l es s l i kel y to hel p a nd ra nge-of-moti on exerci s es a re
es peci a l l y i mporta nt. Ra rel y, the burs a needs to be exci s ed.
Tendinitis and Tenosynovitis
Tendinitis is inflammation of a tendon, often developing after degeneration (tendinopathy); tenosynovitis is tendinitis with inflammation of the tendon sheath
lining. Symptoms usually include pain with motion and tenderness with palpation. Chronic deterioration or inflammation can cause scars that restrict motion.
Diagnosis is clinical, sometimes supplemented with imaging. Treatment includes rest, NSAIDs, and sometimes corticosteroid injections.
Tendi nopa thy us ua l l y res ul ts from repea ted s ma l l tea rs or degenera ti ve cha nges (s ometi mes wi th Ca depos i t) tha t occur over yea rs i n the tendon.
Tendi ni ti s a nd tenos ynovi ti s mos t commonl y a ffect tendons a s s oci a ted wi th the s houl der (rota tor cuff), the tendon of the l ong hea d of the bi ceps
mus cl e (bi ci pi ta l tendon), fl exor ca rpi ra di a l i s or ul na ri s , fl exor di gi torum (for i nfecti ous fl exor tenos ynovi ti s , s ee p. 390), popl i teus tendon,
Achi l l es tendon (s ee p. 3304), a nd the a bductor pol l i ci s l ongus a nd extens or pol l i ci s brevi s , whi ch s ha re a common fi brous s hea th (the res ul ti ng
di s order i s de Querva i n's s yndromes ee p. 393).
Etiology
The ca us e of tendi ni ti s i s often unknown. It us ua l l y occurs i n peopl e who a re mi ddl e-a ged or ol der a s the va s cul a ri ty of tendons decrea s es ;
repeti ti ve mi crotra uma ma y contri bute. Repea ted or extreme tra uma (s hort of rupture), s tra i n, a nd exces s i ve or una ccus tomed exerci s e proba bl y
a l s o contri bute. Some qui nol one a nti bi oti cs ma y i ncrea s e the ri s k of tendi nopa thy a nd tendon rupture.
Ri s k of tendi ni ti s ma y be i ncrea s ed by certa i n s ys temi c di s orders mos t commonl y RA, s ys temi c s cl eros i s , gout, rea cti ve a rthri ti s , a nd di a betes or,
very ra rel y, a myl oi dos i s or ma rkedl y el eva ted bl ood chol es terol l evel s . In younger a dul ts , pa rti cul a rl y women, di s s emi na ted gonococca l i nfecti on
ma y ca us e a cute mi gra tory tenos ynovi ti s .
Symptoms and Signs
Affected tendons a re us ua l l y pa i nful when moved. Occa s i ona l l y, tendon s hea ths become s wol l en a nd fl ui d a ccumul a tes , us ua l l y when pa ti ents
ha ve i nfecti on, RA, or gout. Swel l i ng ma y be vi s i bl e or onl y pa l pa bl e. Al ong the tendon, pa l pa ti on el i ci ts l oca l i zed tendernes s of va ryi ng s everi ty.
In s ys temi c s cl eros i s , the tendon s hea th ma y rema i n dry, but movement of the tendon i n i ts s hea th ca us es fri cti on, whi ch ca n be fel t, or hea rd wi th
a s tethos cope.
Diagnosis
Someti mes i ma gi ng
Us ua l l y, the di a gnos i s ca n be ba s ed on s ymptoms a nd phys i ca l exa mi na ti on, i ncl udi ng pa l pa ti on or s peci fi c ma neuvers to a s s es s pa i n. MRI or
ul tra s onogra phy ma y be done to confi rm the di a gnos i s or rul e out other di s orders . MRI ca n detect tendon tea rs a nd i nfl a mma ti on (a s ca n
ul tra s onogra phy).
Rotator cuff tendinitis: Thi s di s order i s the mos t common ca us e of s houl der pa i n. Acti ve a bducti on i n a n a rc of 40 to 120 a nd i nterna l rota ti on
ca us e pa i n (s ee p. 3298). Pa s s i ve a bducti on ca us es l es s pa i n. Ca depos i ts i n the tendon jus t bel ow the a cromi on a re s ometi mes vi s i bl e on xra y. Ul tra s onogra phy or MRI ma y hel p wi th further eva l ua ti on a nd wi th trea tment deci s i ons .
Bicipital tendinitis: Pa i n i n the bi ceps tendon i s a ggra va ted by s houl der fl exi on or res i s ted s upi na ti on of the forea rm. Exa mi ners ca n el i ci t
tendernes s proxi ma l l y over the bi ci pi ta l groove of the humerus by rol l i ng (fl i ppi ng) the bi ci pi ta l tendon under thei r thumb.
Volar flexor tenosynovitis (di gi ta l tendi ni ti s ): Thi s common mus cul os kel eta l di s order i s often overl ooked (s ee p. 393). Pa i n occurs i n the pa l m on
the vol a r a s pect of the thumb or other di gi ts a nd ma y ra di a te di s ta l l y. Pa l pa ti on of the tendon a nd s hea th el i ci ts tendernes s ; s wel l i ng a nd
s ometi mes a nodul e a re pres ent. In l a ter s ta ges , the di gi t ma y l ock when i t i s fl exed, then extend s uddenl y wi th a s na p (tri gger fi nger).
Gluteus medius tendinitis: Pa ti ents wi th trocha nteri c burs i ti s a l mos t a l wa ys ha ve gl uteus medi us tendi ni ti s . In pa ti ents wi th trocha nteri c burs i ti s ,
pa l pa ti on over the l a tera l promi nence of the grea ter trocha nter el i ci ts tendernes s . Pa ti ents often ha ve a hi s tory of chroni c pres s ure on the
joi nt, tra uma , a cha nge i n ga i t (eg, due to os teoa rthri ti s , s troke, or l eg-l ength di s crepa ncy), or i nfl a mma ti on a t thi s s i te (eg, i n RA).
Treatment
Res t or i mmobi l i za ti on, hea t or col d, fol l owed by exerci s e
Hi gh-dos e NSAIDs
Someti mes corti cos teroi d i njecti on
Symptoms a re rel i eved by res t or i mmobi l i za ti on (s pl i nt or s l i ng) of the tendon, a ppl i ca ti on of hea t (us ua l l y for chroni c i nfl a mma ti on) or col d
(us ua l l y for a cute i nfl a mma ti on), a nd hi gh-dos e NSAIDs (s ee
Ta bl e 35-2 on p. 336) for 7 to 10 da ys . Indometha ci n or col chi ci ne ma y be hel pful i f gout i s the ca us e (s ee p. 349). After i nfl a mma ti on i s control l ed,
exerci s es tha t gra dua l l y i ncrea s e ra nge of moti on s houl d be done s evera l ti mes a da y, es peci a l l y for the s houl der, whi ch ca n devel op contra ctures
ra pi dl y.
Injecti ng a s us ta i ned-rel ea s e corti cos teroi d (eg, beta metha s one 6 mg/mL, tri a mci nol one 40 mg/mL, methyl predni s ol one 20 to 40 mg/mL) i n the
tendon s hea th ma y hel p; i njecti on i s us ua l l y i ndi ca ted i f pa i n i s s evere or i f the probl em ha s been chroni c. Injecti on vol ume ma y ra nge from 0.3 mL
to 1 mL, dependi ng on the s i te. An i njecti on through the s a me needl e of a n equa l or doubl e vol ume of l oca l a nes theti c (eg, 1 to 2% l i doca i ne)
confi rms the di a gnos i s i f pa i n i s rel i eved i mmedi a tel y. Cl i ni ci a ns s houl d be ca reful not to i nject the tendon (whi ch ca n be recogni zed by ma rked
res i s ta nce to i njecti on); doi ng s o ma y wea ken i t, i ncrea s i ng ri s k of rupture. Pa ti ents a re a dvi s ed to res t the i njected joi nt to reduce the s l i ght ri s k
of rupture. Infrequentl y, s ymptoms ca n wors en for up to 24 h a fter the i njecti on.
Repea t i njecti ons a nd s ymptoma ti c trea tment ma y be requi red. Ra rel y, for pers i s tent ca s es , pa rti cul a rl y rota tor cuff tendi ni ti s , s urgi ca l expl ora ti on
wi th remova l of Ca depos i ts or tendon repa i r, fol l owed by gra ded phys i ca l thera py, i s needed. Occa s i ona l l y, pa ti ents requi re s urgery to rel ea s e
s ca rs tha t l i mi t functi on or tenos ynovectomy to rel i eve chroni c i nfl a mma ti on.
Fibromyalgia
(Myofa s ci a l Pa i n Syndrome; Fi bros i ti s ; Fi bromyos i ti s )
Fibromyalgia is a common nonarticular disorder of unknown cause characterized by generalized aching (sometimes severe); widespread tenderness of muscles,
areas around tendon insertions, and adjacent soft tissues; muscle stiffness; fatigue; and poor sleep. Diagnosis is clinical. Treatment includes exercise, local heat,
stress management, drugs to improve sleep, and analgesics.
In fi bromya l gi a , a ny fi bromus cul a r ti s s ues ma y be i nvol ved, es peci a l l y thos e of the occi put, neck, s houl ders , thora x, l ow ba ck, a nd thi ghs . There i s
no s peci fi c hi s tol ogi c a bnorma l i ty. Symptoms a nd s i gns a re genera l i zed, i n contra s t to l oca l i zed s oft-ti s s ue pa i n a nd tendernes s (myofa s ci a l pa i n
s yndromes ee a l s o p. 533), whi ch i s often rel a ted to overus e or mi crotra uma .
Fi bromya l gi a i s common; i t i s a bout 7 ti mes more common a mong women, us ua l l y young or mi ddl e-a ged women, but ca n occur i n men, chi l dren,
a nd a dol es cents . Beca us e of the s ex di fference, i t i s s ometi mes overl ooked i n men. It s ometi mes occurs i n pa ti ents wi th s ys temi c rheuma ti c
di s orders .
The ca us e i s unknown, but di s rupti on of s ta ge 4 s l eep ma y contri bute, a s ca n emoti ona l s tres s . Pa ti ents ma y tend to be perfecti oni s ts .
Fi bromya l gi a ma y be preci pi ta ted by a vi ra l or other s ys temi c i nfecti on (eg, Lyme di s ea s e) or a tra uma ti c event.
Symptoms and Signs
Sti ffnes s a nd pa i n frequentl y begi n gra dua l l y a nd di ffus el y a nd ha ve a n a chy qua l i ty. Symptoms ca n be exa cerba ted by envi ronmenta l or
emoti ona l s tres s , poor s l eep, tra uma , or expos ure to da mpnes s or col d or by a phys i ci a n who i mpl i es tha t the di s order i s "a l l i n the hea d."
Pa ti ents tend to be s tres s ed, tens e, a nxi ous , fa ti gued, a mbi ti ous , a nd s ometi mes depres s ed. Ma ny pa ti ents a l s o ha ve i rri ta bl e bowel s yndrome
s ymptoms or mi gra i ne or tens i on hea da ches . Pa i n ma y wors en wi th fa ti gue, mus cl e s tra i n, or overus e. Speci fi c, di s crete a rea s of mus cl e (tender
poi nts ) ma y be tender when pa l pa ted.
Diagnosis
Fi bromya l gi a i s s us pected i n pa ti ents wi th the fol l owi ng:
Genera l i zed pa i n a nd tendernes s , es peci a l l y i f di s proporti ona te to phys i ca l fi ndi ngs
Nega ti ve l a bora tory res ul ts des pi te wi des prea d s ymptoms
Fa ti gue a s the predomi na nt s ymptom
Tes ts s houl d i ncl ude ESR or C-rea cti ve protei n, CK, a nd proba bl y tes ts for hypothyroi di s m a nd hepa ti ti s C (whi ch ca n ca us e fa ti gue a nd genera l i zed
mya l gi a s ). The di a gnos i s i s ba s ed on cl i ni ca l cri teri a , i ncl udi ng tendernes s a t s ome of the 18 s peci fi ed tender poi nts (s ee
Fi g. 41-1). Mos t experts no l onger requi re a s peci fi c number of tender poi nts to ma ke the di a gnos i s , a s ori gi na l l y propos ed ( 11 of 18). Pa ti ents
wi th onl y s ome of the s peci fi ed fea tures ma y s ti l l ha ve fi bromya l gi a .

[Fig. 41-1. Di a gnos i ng fi bromya l gi a .]
To a voi d potenti a l pi tfa l l s , cl i ni ci a ns s houl d cons i der the fol l owi ng:
Fi bromya l gi a i s often overl ooked i n men, chi l dren, a nd a dol es cents .
Chroni c fa ti gue s yndrome (s ee p. 3442) ca n ca us e s i mi l a r genera l i zed mya l gi a s a nd fa ti gue a nd typi ca l l y produces norma l l a bora tory tes t res ul ts .
Pol ymya l gi a rheuma ti ca (s ee p. 325) ca n ca us e genera l i zed mya l gi a s , pa rti cul a rl y i n ol der a dul ts ; i t ca n be di s ti ngui s hed beca us e i t tends to
a ffect proxi ma l mus cl es s el ecti vel y a nd ESR i s hi gh.
In pa ti ents wi th s ys temi c rheuma ti c di s orders , di a gnos i ng fi bromya l gi a ma y be di ffi cul t. For exa mpl e, fi bromya l gi a ma y be mi s i nterpreted a s a n
exa cerba ti on of RA or SLE.
Prognosis
Fi bromya l gi a tends to be chroni c but ma y remi t s ponta neous l y i f s tres s decrea s es . It ca n a l s o recur a t frequent i nterva l s . Functi ona l prognos i s i s
us ua l l y fa vora bl e for pa ti ents bei ng trea ted wi th a comprehens i ve, s upporti ve progra m, a l though s ymptoms tend to pers i s t to s ome degree.
Treatment
Stretchi ng a nd a erobi c exerci s e, l oca l hea t, a nd ma s s a ge
Stres s ma na gement
Tri cycl i c a nti depres s a nts or cycl obenza pri ne to i mprove s l eep
Ana l ges i cs
Stretchi ng exerci s es , a erobi c exerci s es , s uffi ci ent s ound s l eep, l oca l a ppl i ca ti ons of hea t, a nd gentl e ma s s a ge ma y provi de rel i ef. Overa l l s tres s
ma na gement (eg, deep brea thi ng exerci s es , medi ta ti on, ps ychol ogi c s upport, couns el i ng i f neces s a ry) i s i mporta nt.
Exerci s es to gentl y s tretch the a ffected mus cl es s houl d be done da i l y; s tretches s houl d be hel d for a bout 30 s ec a nd repea ted a bout 5 ti mes .
Aerobi c exerci s e (eg, fa s t wa l ki ng, s wi mmi ng, exerci s e bi cycl e) ca n l es s en s ymptoms .
Improvi ng s l eep i s cri ti ca l . Low-dos e ora l tri cycl i c a nti depres s a nts a t bedti me (eg, a mi tri ptyl i ne 10 to 50 mg, tra zodone 50 to 150 mg, doxepi n 10 to
25 mg) or the pha rma col ogi ca l l y s i mi l a r cycl obenza pri ne 10 to 40 mg ma y promote deeper s l eep a nd decrea s e mus cl e pa i n. The l owes t effecti ve
dos e s houl d be us ed. Drows i nes s , dry mouth, a nd other a dvers e effects ma y ma ke s ome or a l l of thes e drugs i ntol era bl e, pa rti cul a rl y for the
el derl y.
Nonopi oi d a na l ges i cs (eg, tra ma dol , propoxyphene, a ceta mi nophen, NSAIDs ) ma y hel p s ome pa ti ents but on a vera ge a re not effecti ve. Opi oi ds
s houl d be a voi ded. Prega ba l i n, us ed a s a n a djunct to exerci s e, mea s ures to i mprove s l eep, a nd s tres s ma na gement, ma y hel p reduce pa i n.
Ra rel y, i njecti ons of 0.5% bupi va ca i ne or 1% l i doca i ne 1 to 5 mL a re us ed to trea t i nca pa ci ta ti ng a rea s of foca l tendernes s , but s uch i njecti ons
s houl d not be rel i ed on a s pri ma ry trea tment.
Drugs ta ken by the pa ti ent s houl d be revi ewed to i denti fy thos e tha t ma y a ggra va te s l eep probl ems . Such drugs s houl d be s topped, a nd future us e
s houl d be a voi ded. Anxi ety or depres s i on, i f pres ent, ma y requi re trea tment.
Muscle Cramps
A muscle cramp is a sudden, brief, painful contraction of a muscle or group of muscles.
Cra mps (cha rl ey hors es ) ca n occur i n hea l thy peopl e (us ua l l y mi ddl e-a ged a nd el derl y peopl e), s ometi mes duri ng res t, but pa rti cul a rl y duri ng or
a fter exerci s e. Leg cra mps ca n occur duri ng s l eep, ca us i ng pa i n a nd pl a nta r fl exi on of the foot a nd toes .
Ti ght ca l f mus cl es (eg, from l a ck of s tretchi ng, i na cti vi ty, or s ometi mes chroni c l ower l eg edema ) a re a common ca us e of l eg cra mps . Cra mps ma y
a l s o be ca us ed by el ectrol yte a bnorma l i ti es (eg, hypoka l emi a ). Exerti ona l mus cl e pa i n from i s chemi a due to peri phera l a rteri a l di s ea s e
(cl a udi ca ti on) ma y ca us e s i mi l a r ca l f pa i n, but thi s pa i n i s due to i na dequa te bl ood fl ow to mus cl es a nd not to a mus cl e contra cti on a s wi th a
cra mp.
Treatment
Stretchi ng
If a cra mp occurs , s tretchi ng the a ffected mus cl e often rel i eves the cra mp. For exa mpl e, for a ca l f cra mp, the pers on coul d us e a ha nd to pul l the
foot a nd toes upwa rd (dors i fl exi on) or do the runner's s tretch.
Prevention
Mea s ures to prevent cra mps i ncl ude the fol l owi ng:
Not exerci s i ng i mmedi a tel y a fter ea ti ng

Gentl y s tretchi ng the mus cl es before exerci s i ng or goi ng to bed
Dri nki ng pl enty of fl ui ds (pa rti cul a rl y bevera ges tha t conta i n pota s s i um) a fter exerci s e
Not cons umi ng s ti mul a nts (eg, ca ffei ne, ni coti ne, ephedri ne, ps eudoephedri ne)
The runner's s tretch i s mos t us eful . A pers on s ta nds wi th one l eg forwa rd a nd bent a t the knee a nd the other l eg behi nd a nd the knee s tra i ghta
l unge pos i ti on. The ha nds ca n be pl a ced on the wa l l for ba l a nce. Both heel s rema i n on the fl oor. The knee of the front l eg i s bent further unti l a
s tretch i s fel t a l ong the ba ck of the other l eg. The grea ter the di s ta nce between the two feet a nd the more the front knee i s bent, the grea ter the
s tretch. The s tretch i s hel d for 30 s ec a nd repea ted 5 ti mes . The s et of s tretches i s repea ted on the other s i de.
Mos t of the drugs pres cri bed to prevent cra mps (eg, qui ni ne, ma gnes i um, benzodi a zepi nes ) ha ve no demons tra ted effi ca cy a nd a re not
recommended. Mexi l eti ne s ometi mes hel ps , but whether us i ng i t i s worth the ri s k of a dvers e effects i s uncl ea r. Thes e a dvers e effects i ncl ude
na us ea , vomi ti ng, hea rtburn, di zzi nes s , a nd tremor. Ca s uppl ements a re s a fe a nd ha ve few a dvers e effects but ha ve not proved effecti ve.
Chapter 42. Neck and Back Pain

Introduction
Neck pa i n a nd ba ck pa i n a re a mong the mos t common rea s ons for phys i ci a n vi s i ts . Thi s di s cus s i on covers neck pa i n i nvol vi ng the pos teri or neck
(not pa i n l i mi ted to the a nteri or neck) a nd does not cover mos t ma jor tra uma ti c i njuri es (eg, fra ctures , di s l oca ti ons , s ubl uxa ti ons ).
Pathophysiology
Dependi ng on the ca us e, neck or ba ck pa i n ma y be a ccompa ni ed by neurol ogi c s ymptoms .
If a nerve root i s a ffected, pa i n ma y ra di a te di s ta l l y a l ong the di s tri buti on of tha t root (ca l l ed ra di cul a r pa i n or, i n the l ow ba ck, s ci a ti ca ). Strength,
s ens a ti on, a nd refl exes of the a rea i nnerva ted by tha t root ma y be i mpa i red.
If the s pi na l cord i s a ffected, s trength, s ens a ti on, a nd refl exes ma y be i mpa i red a t the a ffected s pi na l cord l evel a nd a l l l evel s bel ow (ca l l ed
s egmenta l neurol ogi c defi ci ts ).
If the ca uda equi na i s a ffected, s egmenta l defi ci ts devel op i n the l umbos a cra l regi on, typi ca l l y wi th l os s of bowel a nd bl a dder functi on, l os s of
peri a na l s ens a ti on, erecti l e dys functi on, uri na ry retenti on, a nd l os s of recta l tone a nd s phi ncter (eg, bul boca vernos us , a na l wi nk) refl exes .
Any pa i nful di s order of the s pi ne ma y a l s o ca us e refl ex ti ghteni ng (s pa s m) of pa ra s pi na l mus cl es , whi ch ca n be excruci a ti ng.
Etiology
Mos t neck a nd ba ck pa i n i s ca us ed by di s orders of the s pi ne. Fi bromya l gi a i s a l s o a common ca us e. Occa s i ona l l y, pa i n i s referred from extra s pi na l
di s orders (pa rti cul a rl y va s cul a r, GI, or GU di s orders ). Some uncommon ca us es s pi na l a nd extra s pi na l a re s eri ous .
Mos t s pi na l di s orders a re mecha ni ca l . Onl y a few i nvol ve i nfecti on, i nfl a mma ti on, or ca ncer (cons i dered nonmecha ni ca l ).
Common causes: Mos t mecha ni ca l s pi ne di s orders tha t ca us e neck or ba ck pa i n i nvol ve a nons peci fi c mecha ni ca l dera ngement:
Mus cl e s tra i n, l i ga ment s pra i n, s pa s m, or a combi na ti on
Onl y a bout 15% i nvol ve s peci fi c s tructura l l es i ons tha t cl ea rl y ca us e the s ymptoms , pri ma ri l y the fol l owi ng:
Di s k herni a ti on
Compres s i on fra cture
Lumba r s pi na l s tenos i s
Os teoa rthri ti s
Spondyl ol i s thes i s
In the other mecha ni ca l di s orders , there a re no s peci fi c l es i ons , or the fi ndi ngs (eg, di s k bul gi ng or degenera ti on, os teophytes , s pondyl ol ys i s ,
congeni ta l fa cet a bnorma l i ti es ) a re common a mong peopl e wi thout neck or ba ck pa i n, a nd thus a re ques ti ona bl e a s the eti ol ogy of pa i n.
However, eti ol ogy of ba ck pa i n, pa rti cul a rl y i f mecha ni ca l , i s often mul ti fa ctori a l , wi th a n underl yi ng di s order exa cerba ted by fa ti gue, phys i ca l
decondi ti oni ng, a nd s ometi mes ps ychos oci a l s tres s or ps ychi a tri c a bnorma l i ty. Thus , i denti fyi ng a s i ngl e ca us e i s often di ffi cul t or i mpos s i bl e.
Serious uncommon causes: Seri ous ca us es ma y requi re ti mel y trea tment to prevent di s a bi l i ty or dea th.
Seri ous extraspinal di s orders i ncl ude the fol l owi ng:
Abdomi na l a orti c a neurys m
Aorti c di s s ecti on
Ca roti d or vertebra l a rtery di s s ecti on
Acute meni ngi ti s
Angi na or MI
Certa i n GI di s orders (eg, chol ecys ti ti s , di verti cul i ti s , di verti cul a r a bs ces s , pa ncrea ti ti s , penetra ti ng pepti c ul cer, retroceca l a ppendi ci ti s )
Certa i n pel vi c di s orders (eg, ectopi c pregna ncy, ova ri a n ca ncer, s a l pi ngi ti s )
Certa i n pul mona ry di s orders (eg, pl euri ti s , pneumoni a )
Certa i n uri na ry tra ct di s orders (eg, pros ta ti ti s , pyel onephri ti s )
Seri ous spinal di s orders i ncl ude the fol l owi ng:
Infecti ons (eg, di s ki ti s , epi dura l a bs ces s , os teomyel i ti s )
Pri ma ry tumors (of s pi na l cord or vertebra e)

Meta s ta ti c vertebra l tumors (mos t often from brea s ts , l ungs , or pros ta te)
Mecha ni ca l s pi ne di s orders ca n be s eri ous i f they compres s the s pi na l nerve roots or, pa rti cul a rl y, the s pi na l cord. Spi na l cord compres s i on ma y
res ul t from di s orders s uch a s tumors a nd s pi na l epi dura l a bs ces s or hema toma .
Other uncommon causes: Neck or ba ck pa i n ca n res ul t from ma ny other di s orders , s uch a s Pa get's di s ea s e of bone, torti col l i s , thora ci c outl et
s yndrome, temporoma ndi bul a r joi nt s yndrome, herpes zos ter, a nd s pondyl oa rthropa thi es (a nkyl os i ng s pondyl i ti s mos t often, but a l s o
enteropa thi c a rthri ti s , ps ori a ti c a rthri ti s , rea cti ve a rthri ti s , a nd undi fferenti a ted s pondyl oa rthropa thy).
Evaluation
General: Beca us e the ca us e i s often mul ti fa ctori a l , a defi ni ti ve di a gnos i s ca nnot be es ta bl i s hed i n ma ny pa ti ents . However, cl i ni ci a ns s houl d
determi ne the fol l owi ng i f pos s i bl e:
Whether pa i n ha s a s pi na l or extra s pi na l ca us e
Whether the ca us e i s a s eri ous di s order
History: History of present illness s houl d i ncl ude qua l i ty, ons et, dura ti on, s everi ty, l oca ti on, ra di a ti on, a nd ti me cours e of pa i n, a s wel l a s modi fyi ng
fa ctors s uch a s res t, a cti vi ty, cha nges i n pos i ti on, wei ght bea ri ng, a nd ti me of da y (eg, a t ni ght, when a wa keni ng). Accompa nyi ng s ymptoms to note
i ncl ude s ti ffnes s , numbnes s , pa res thes i a s , wea knes s , uri na ry retenti on, a nd i nconti nence.
Review of systems s houl d note s ymptoms s ugges ti ng a ca us e, i ncl udi ng fever a nd chi l l s (i nfecti on); wei ght l os s a nd poor a ppeti te (i nfecti on or
ca ncer); fa ti gue, depres s i ve s ymptoms , a nd hea da ches (mul ti fa ctori a l mecha ni ca l ba ck pa i n); wors eni ng of neck pa i n duri ng s wa l l owi ng
(es opha gea l di s orders ); a norexi a , na us ea , vomi ti ng, a nd cha nge i n bowel functi on or s tool (GI di s orders ); uri na ry s ymptoms a nd fl a nk pa i n
(uri na ry tra ct di s orders ); cough, dys pnea , a nd wors eni ng duri ng i ns pi ra ti on (pul mona ry di s orders ); va gi na l bl eedi ng or di s cha rge a nd pa i n rel a ted
to mens trua l cycl e pha s e (pel vi c di s orders ).
Past medical history i ncl udes known neck or ba ck di s orders (i ncl udi ng os teoporos i s , os teoa rthri ti s , di s k di s orders , recent or remote i njury) a nd
s urgery, ri s k fa ctors for ba ck di s orders (eg, ca ncer, os teoporos i s ), ri s k fa ctors for a neurys m (eg, s moki ng, hypertens i on), a nd ri s k fa ctors for
i nfecti on (eg, i mmunos uppres s i on; IV drug us e; recent s urgery, penetra ti ng tra uma , or ba cteri a l i nfecti on).
Physical examination: Tempera ture a nd genera l a ppea ra nce a re noted. When pos s i bl e, pa ti ents s houl d be unobtrus i vel y obs erved a s they move
i nto the exa mi na ti on room, undres s , a nd cl i mb onto the ta bl e. If s ymptoms a re exa cerba ted by ps ychol ogi c i s s ues , true functi ona l l evel ca n be
a s s es s ed more a ccura tel y when pa ti ents a re not a wa re they a re bei ng eva l ua ted.
The exa mi na ti on focus es on the s pi ne a nd the neurol ogi c exa mi na ti on. If no mecha ni ca l s pi na l s ource of pa i n i s obvi ous , pa ti ents a re checked for
s ources of referred pa i n.
In the s pi na l exa mi na ti on, the ba ck a nd neck a re i ns pected for a ny vi s i bl e deformi ty, a rea of erythema , or ves i cul a r ra s h. The s pi ne a nd
pa ra vertebra l mus cl es a re pa l pa ted for tendernes s a nd mus cl e s pa s m. Gros s ra nge of moti on i s tes ted.
In the neurol ogi c exa mi na ti on, s trength a nd deep tendon refl exes a re tes ted. In pa ti ents wi th neurol ogi c s ymptoms , s ens a ti on a nd s a cra l nerve
functi on (eg, recta l tone, a na l wi nk refl ex, bul boca vernos us refl ex) a re tes ted. Thes e tes ts a re a mong the mos t rel i a bl e phys i ca l tes ts for
confi rmi ng norma l s pi na l cord functi on. Corti cos pi na l tra ct dys functi on i s i ndi ca ted by the extens or pl a nta r res pons e a nd Hoffma n's s i gn. To tes t
for Hoffma n's s i gn, cl i ni ci a ns ta p the na i l or fl i ck the vol a r s urfa ce of the 3rd fi nger; i f the di s ta l pha l a nx of the thumb fl exes , the tes t i s pos i ti ve,
us ua l l y i ndi ca ti ng corti cos pi na l tra ct dys functi on ca us ed by s tenos i s of the cervi ca l cord. Sens ory fi ndi ngs a re s ubjecti ve a nd ma y be unrel i a bl e.
The s tra i ght l eg ra i s e tes t hel ps confi rm s ci a ti ca . The pa ti ent i s s upi ne wi th both knees extended a nd the a nkl es dors i fl exed. The cl i ni ci a n ra i s es
the a ffected l eg, keepi ng the knee extended. If s ci a ti ca i s pres ent, 10 to 60 of el eva ti on typi ca l l y ca us es s ymptoms . For the cros s ed s tra i ght l eg
ra i s e tes t, the una ffected l eg i s ra i s ed; the tes t i s pos i ti ve i f s ci a ti ca occurs i n the a ffected l eg. A pos i ti ve s tra i ght l eg tes t i s s ens i ti ve but not
s peci fi c for herni a ted di s k; the cros s ed s tra i ght l eg ra i s e tes t i s l es s s ens i ti ve but 90% s peci fi c. The s ea ted s tra i ght l eg ra i s e tes t i s done whi l e
pa ti ents a re s ea ted wi th the hi p joi nt fl exed a t 90; the l ower l eg i s s l owl y ra i s ed unti l the knee i s ful l y extended. If s ci a ti ca i s pres ent, the pa i n
occurs a s the l eg i s extended.
In the genera l exa mi na ti on, the l ungs a re a us cul ta ted. The a bdomen i s checked for tendernes s , ma s s es , a nd, pa rti cul a rl y i n pa ti ents > 55, a
pul s a ti l e ma s s (whi ch s ugges ts a bdomi na l a orti c a neurys m). Wi th a fi s t, cl i ni ci a ns percus s the cos tovertebra l a ngl e for tendernes s , s ugges ti ng
pyel onephri ti s .
Recta l exa mi na ti on, i ncl udi ng s tool tes ti ng for occul t bl ood a nd, i n men, pros ta te exa mi na ti on, i s done. In women wi th s ymptoms s ugges ti ng a
pel vi c di s order or wi th unexpl a i ned fever, pel vi c exa mi na ti on i s done.
Lower-extremi ty pul s es a re checked.
Abdomi na l a orta tha t i s > 5 cm (pa rti cul a rl y i f tender) or l ower-extremi ty pul s e defi ci ts
Acute, tea ri ng mi d-ba ck pa i n
Ca ncer, di a gnos ed or s us pected
Dura ti on of pa i n > 6 wk
Neurol ogi c defi ci t
Fever
GI fi ndi ngs s uch a s l oca l i zed a bdomi na l tendernes s , peri toni ti s , mel ena , or hema tochezi a
Infecti on ri s k fa ctors (eg, i mmunos uppres s i on; IV drug us e; recent s urgery, penetra ti ng tra uma , or ba cteri a l i nfecti on)
Meni ngi s mus
Severe nocturna l or di s a bl i ng pa i n
Unexpl a i ned pa i n a fter a ge 55
Unexpl a i ned wei ght l os s
Interpretation of findings: Al though s eri ous extra s pi na l di s orders (eg, ca ncers , a orti c a neurys ms , epi dura l a bs ces s es , os teomyel i ti s ) a re uncommon
ca us es of ba ck pa i n, they a re not ra re, pa rti cul a rl y i n hi gh-ri s k groups .
A s pi na l ca us e i s more l i kel y (but not defi ni ti ve) tha n referred pa i n from a n extra s pi na l ca us e when
Pa i n i s wors ened by movement or wei ght bea ri ng a nd i s rel i eved by res t or recumbency
Vertebra l or pa ra vertebra l tendernes s i s pres ent
Red fl a g fi ndi ngs s houl d hei ghten s us pi ci on of a s eri ous ca us e (s ee
Ta bl e 42-1).
Other fi ndi ngs a re a l s o hel pful . Erythema a nd tendernes s over the s pi ne s ugges ts i nfecti on, pa rti cul a rl y i n pa ti ents wi th ri s k fa ctors . Wors eni ng of
pa i n wi th fl exi on i s cons i s tent wi th i ntervertebra l di s k di s ea s e; wors eni ng wi th extens i on s ugges ts s pi na l s tenos i s , a rthri ti s a ffecti ng the fa cet
joi nts , or retroperi tonea l i nfl a mma ti on or i nfi l tra ti on (eg, pa ncrea ti c or ki dney i nfl a mma ti on or tumor). Tendernes s over certa i n s peci fi c tri gger
poi nts s ugges ts fi bromya l gi a . Deformi ti es of the proxi ma l i nterpha l a ngea l (PIP) a nd di s ta l i nterpha l a ngea l (DIP) fi nger joi nts a nd s ti ffnes s tha t
l es s ens wi thi n 30 mi n a fter a wa keni ng s ugges t os teoa rthri ti s . Neck pa i n tha t i s unrel a ted to s wa l l owi ng a nd i s exerti ona l ma y i ndi ca te a ngi na .
Testing: Us ua l l y, i f dura ti on of pa i n i s s hort (< 4 to 6 wk), no tes ti ng i s requi red unl es s red fl a g fi ndi ngs a re pres ent, pa ti ents ha ve ha d a s eri ous
i njury (eg, vehi cul a r cra s h, fa l l from a hei ght, penetra ti ng tra uma ), or eva l ua ti on s ugges ts a s peci fi c nonmecha ni ca l ca us e (eg, pyel onephri ti s ).
Pl a i n x-ra ys ca n i denti fy mos t os teoporoti c fra ctures a nd os teoa rthri ti s . However, they do not i denti fy a bnorma l i ti es i n s oft ti s s ue (the mos t
common ca us e of ba ck a nd neck pa i n) or nerve ti s s ue (a s occurs i n ma ny s eri ous di s orders ). Thus , x-ra ys a re us ua l l y unneces s a ry a nd do not
cha nge ma na gement. Someti mes
[Table 42-1. Interpreta ti on of Red Fl a g Fi ndi ngs i n Pa ti ents wi th Ba ck Pa i n]
x-ra ys a re done to i denti fy obvi ous bone a bnorma l i ti es (eg, thos e due to i nfecti on or tumors ) a nd to a voi d MRI a nd CT, whi ch a re ha rder to obta i n
but whi ch a re much more a ccura te a nd us ua l l y neces s a ry.
Tes ti ng i s gui ded by fi ndi ngs a nd s us pected ca us e:
Neurol ogi c defi ci ts , pa rti cul a rl y thos e cons i s tent wi th s pi na l cord compres s i on: MRI or CT myel ogra phy, done a s s oon a s pos s i bl e
Pos s i bl e i nfecti on: WBC count, ESR, i ma gi ng (us ua l l y MRI or CT), a nd cul ture of i nfected ti s s ue
Pos s i bl e ca ncer: CT or MRI a nd pos s i bl y bi ops y
Pos s i bl e a neurys m: CT, a ngi ogra phy, or s ometi mes ul tra s onogra phy
Pos s i bl e a orti c di s s ecti on: Angi ogra phy, CT, or MRI
Symptoms tha t a re di s a bl i ng or tha t pers i s t > 6 wk: Ima gi ng (us ua l l y MRI or CT) a nd, i f i nfecti on i s s us pected, WBC count a nd ESR
Other extra s pi na l di s orders : Tes ti ng a s a ppropri a te (eg, ches t x-ra y for pul mona ry di s orders , uri na l ys i s for uri na ry tra ct di s orders )
Treatment
Underl yi ng di s orders a re trea ted.
Acute mus cul os kel eta l pa i n (wi th or wi thout ra di cul opa thy) i s trea ted wi th
Ana l ges i cs
Hea t a nd col d
Ea rl y mobi l i za ti on fol l owed by s ta bi l i za ti on exerci s es

Aceta mi nophen or NSAIDs a re the i ni ti a l choi ce of a na l ges i cs , but opi oi ds ma y be neces s a ry for s evere pa i n. Adequa te a na l ges i a i s i mporta nt
i mmedi a tel y a fter a cute i njury to hel p l i mi t the cycl e of pa i n a nd s pa s m.
Acute mus cl e s pa s ms ma y a l s o be rel i eved by col d or hea t. Col d i s us ua l l y preferred to hea t duri ng the fi rs t 2 da ys a fter a n i njury. Ice a nd col d
pa cks s houl d not be a ppl i ed di rectl y to the s ki n. They s houl d be encl os ed (eg, i n pl a s ti c) a nd pl a ced over a towel or cl oth. The i ce i s removed a fter
20 mi n, then l a ter rea ppl i ed for 20 mi n over a peri od of 60 to 90 mi n. Thi s proces s ca n be repea ted s evera l ti mes duri ng the fi rs t 24 h. Hea t, us i ng a
hea ti ng pa d, ca n be a ppl i ed for the s a me peri ods of ti me. Beca us e the s ki n on the ba ck ma y be i ns ens i ti ve to hea t, hea ti ng pa ds mus t be us ed
ca uti ous l y to prevent burns . Pa ti ents a re a dvi s ed not to us e a hea ti ng pa d a t bedti me to a voi d prol onged expos ure due to fa l l i ng a s l eep wi th the
pa d s ti l l on thei r ba ck. Di a thermy ma y hel p reduce mus cl e s pa s m a nd pa i n a fter the a cute s ta ge.
Ora l mus cl e rel a xa nts (eg, cycl obenza pri ne, methoca rba mol , meta xa l one) a re controvers i a l . Benefi ts of thes e drugs s houl d be wei ghed a ga i ns t
thei r CNS a nd other a dvers e effects , pa rti cul a rl y i n el derl y pa ti ents , who ma y ha ve more s evere a dvers e effects .
Al though a bri ef i ni ti a l peri od (eg, 1 to 2 da ys ) of decrea s ed a cti vi ty i s s ometi mes needed for comfort, prol onged bed res t, s pi na l tra cti on, a nd
cors ets a re not benefi ci a l . Pa ti ents wi th s evere torti col l i s ma y benefi t from a cervi ca l col l a r a nd contour pi l l ow unti l pa i n i s rel i eved a nd they ca n
pa rti ci pa te i n a s ta bi l i za ti on progra m.
Spi na l ma ni pul a ti on ma y hel p rel i eve pa i n ca us ed by mus cl e s pa s m or a n a cute neck or ba ck i njury; however, s ome forms of ma ni pul a ti on ma y
ha ve ri s ks for pa ti ents wi th di s k di s orders or os teoporos i s .
When a cute pa i n decrea s es enough tha t moti on i s pos s i bl e, a l umba r s ta bi l i za ti on progra m i s begun. Thi s progra m i ncl udes exerci s es tha t
s trengthen a bdomi na l a nd l ow ba ck mus cl es pl us i ns tructi on i n work pos ture; the a i m i s to s trengthen the s upporti ng s tructures of the ba ck a nd
reduce the l i kel i hood of the condi ti on becomi ng chroni c or recurrent.
Cl i ni ci a ns s houl d rea s s ure pa ti ents wi th a cute nons peci fi c mus cul os kel eta l ba ck pa i n tha t the prognos i s i s good a nd tha t a cti vi ty a nd exerci s e a re
s a fe even when they ca us e s ome di s comfort. Cl i ni ci a ns s houl d be thorough, ki nd, fi rm, a nd nonjudgmenta l . If depres s i on or s econda ry ga i n
pers i s ts for s evera l months , ps ychol ogi c eva l ua ti on s houl d be cons i dered.
Low ba ck pa i n a ffects 50% of a dul ts > 60.
Abdomi na l a orti c a neurys m (a nd CT or ul tra s onogra phy to detect i t) s houl d be cons i dered i n el derl y pa ti ents wi th a tra uma ti c l ow ba ck pa i n, even
i f no phys i ca l fi ndi ngs s ugges t thi s di a gnos i s .
Ima gi ng of the s pi ne ma y be a ppropri a te for el derl y pa ti ents (eg, to rul e out ca ncer) even when the ca us e a ppea rs to be uncompl i ca ted
mus cul os kel eta l ba ck pa i n.
Ora l mus cl e rel a xa nts (eg, cycl obenza pri ne, methoca rba mol , meta xa l one) a re controvers i a l ; a nti chol i nergi c, CNS, a nd other a dvers e effects ma y
outwei gh potenti a l benefi ts i n el derl y pa ti ents .
Key Points
Mos t neck a nd ba ck pa i n i s ca us ed by mecha ni ca l s pi na l di s orders , us ua l l y nons peci fi c, s el f-l i mi ted mus cul os kel eta l dera ngements .
Mos t mecha ni ca l di s orders a re trea ted wi th a na l ges i cs , ea rl y mobi l i za ti on, a nd exerci s es ; prol onged bed res t a nd i mmobi l i za ti on a re a voi ded.
Ba ck pa i n i s often mul ti fa ctori a l , ma ki ng di a gnos i s di ffi cul t.
Seri ous s pi na l or extra s pi na l di s orders a re unus ua l ca us es .
Red fl a g fi ndi ngs often i ndi ca te a s eri ous di s order a nd the need for tes ti ng.
Pa ti ents wi th s egmenta l neurol ogi c defi ci ts s ugges ti ng s pi na l cord compres s i on requi re MRI or CT myel ogra phy a s s oon a s pos s i bl e.
Norma l s pi na l cord functi on duri ng phys i ca l exa mi na ti on i s bes t confi rmed by tes ts of s a cra l nerve functi on (eg, recta l tone, a na l wi nk refl ex,
bul boca vernos us refl ex).
Pa i n not wors ened by movement i s often extra s pi na l , pa rti cul a rl y i f no vertebra l or pa ra vertebra l tendernes s i s detected.
Abdomi na l a orti c a neurys m s houl d be cons i dered i n a ny el derl y pa ti ent wi th l ow ba ck pa i n, even i f no phys i ca l fi ndi ngs s ugges t thi s di a gnos i s .
Spasmodic Torticollis
Spasmodic torticollis is characterized by involuntary tonic contractions or intermittent spasms of neck muscles. The cause is unknown. Diagnosis is clinical.
Treatment can include physical therapy, drugs, and selective denervation of neck muscles with surgery or locally injected botulinum toxin.
In torti col l i s , contra cti on of the neck mus cl es ca us es the neck to turn from i ts us ua l pos i ti on. It i s the mos t common dys toni a (s ee p.
1760).
Spa s modi c (or a dul t-ons et) torti col l i s i s us ua l l y i di opa thi c. About 5% of pa ti ents wi th s pa s modi c torti col l i s ha ve a fa mi l y hi s tory. One thi rd of
thes e pa ti ents ha ve other dys toni a s (eg, eyel i ds , fa ce, ja w, ha nd). Torti col l i s ca n a l s o be congeni ta l or s econda ry to other condi ti ons s uch a s
l es i ons of the bra i n s tem a nd ba s a l ga ngl i a .
Symptoms and Signs
Symptoms ma y begi n a t a ny a ge but us ua l l y begi n between a ge 20 a nd 60, wi th a pea k between a ge 30 a nd 50.
Symptoms us ua l l y begi n gra dua l l y but ma y begi n s uddenl y. Pa i nful toni c contra cti ons or i ntermi ttent s pa s ms of the s ternocl ei doma s toi d,
tra pezi us , a nd other neck mus cl es occur, us ua l l y uni l a tera l l y, a nd res ul t i n a bnorma l hea d pos i ti on. Sternocl ei doma s toi d mus cl e contra cti on
ca us es the hea d to rota te to the oppos i te s i de a nd the neck to fl ex l a tera l l y to the s a me s i de. Rota ti on ma y i nvol ve a ny pl a ne but a l mos t a l wa ys
ha s a hori zonta l component. Bes i des rota ti ona l ti l ti ng (torti col l i s ), the hea d ca n ti l t l a tera l l y (l a terocol l i s ), forwa rd (a nterocol l i s ), or ba ckwa rd
(retrocol l i s ). Duri ng s l eep, mus cl e s pa s ms di s a ppea r.
Spa s modi c torti col l i s ra nges from mi l d to s evere. Us ua l l y, i t progres s es s l owl y for 1 to 5 yr, then pl a tea us . About 10 to 20% of pa ti ents recover
s ponta neous l y wi thi n 5 yr of ons et (us ua l l y i n mi l der ca s es wi th younger a ge ons et). However, i t ma y pers i s t for l i fe a nd ca n res ul t i n res tri cted
movement a nd pos tura l deformi ty.
Diagnosis
The di a gnos i s i s ba s ed on cha ra cteri s ti c s ymptoms a nd s i gns a nd excl us i on of a l terna ti ve di a gnos es , s uch a s the fol l owi ng:
Ta rdi ve dys ki nes i a ca n ca us e torti col l i s but ca n us ua l l y be di s ti ngui s hed by a hi s tory of chroni c a nti ps ychoti c us e a nd i nvol unta ry movements i n
mus cl es outs i de of the neck.
Ba s a l ga ngl i a di s ea s e a nd occa s i ona l l y CNS i nfecti ons ca n ca us e movement di s orders but us ua l l y a l s o i nvol ve other mus cl es . Al s o, CNS
i nfecti ons a re us ua l l y a cute a nd ca us e other s ymptoms .
Neck i nfecti ons or tumors a re us ua l l y di fferenti a ted by fea tures of the pri ma ry proces s .
Anti ps ychoti cs a nd other drugs ca n ca us e a cute torti col l i s , but the s ymptoms us ua l l y devel op i n hours a nd res ol ve wi thi n da ys .
Treatment
Phys i ca l mea s ures
Someti mes botul i num toxi n or ora l drugs
Spa s ms ca n s ometi mes be tempora ri l y i nhi bi ted by phys i ca l thera py a nd ma s s a ge, i ncl udi ng s ens ory bi ofeedba ck techni ques (s l i ght ta cti l e
pres s ure to the ja w on the s a me s i de a s hea d rota ti on) a nd a ny l i ght touch.
Injecti ons of botul i num toxi n type A i nto the dys toni c mus cl es ca n reduce pa i nful s pa s ms for 1 to 3 mo i n a bout 70% of pa ti ents , res tori ng a more
neutra l pos i ti on of the hea d. However, thi s trea tment ca n l os e effecti venes s wi th repea ted i njecti ons beca us e a nti bodi es devel op a ga i ns t the
toxi n. Drugs ca n us ua l l y rel i eve pa i n, but they s uppres s dys toni c movements i n onl y a bout 25 to 33% of pa ti ents . Anti chol i nergi cs s uch a s
tri hexypheni dyl 10 to 25 mg po once/da y or bi d ma y hel p, but a dvers e effects ma y l i mi t thei r us e; benzodi a zepi nes (pa rti cul a rl y cl ona zepa m 0.5 mg
po bi d) a nd ba cl ofen a nd ca rba ma zepi ne ma y hel p. Al l drugs s houl d be s ta rted i n l ow dos es . Dos es s houl d be i ncrea s ed unti l s ymptoms a re
control l ed or i ntol era bl e a dvers e effects (pa rti cul a rl y l i kel y i n the el derl y) devel op.
Surgery i s controvers i a l . The mos t s ucces s ful s urgi ca l a pproa ch s el ecti vel y s evers nerves to a ffected neck mus cl es , perma nentl y wea keni ng or
pa ra l yzi ng them. Res ul ts a re fa vora bl e when the procedure i s done a t centers wi th extens i ve experi ence.
Ra rel y, a n emoti ona l probl em contri butes to s pa s modi c torti col l i s ; ps ychi a tri c trea tment i s i ndi ca ted. Ps ychi a tri c prognos i s i s bes t i f s ymptom
ons et coi nci ded wi th exogenous s tres s .
Sciatica
Sciatica is pain along the sciatic nerve. It usually results from compression of nerve roots in the lower back. Common causes include intervertebral disk herniation,
osteophytes, and narrowing of the spinal canal (spinal stenosis). Symptoms include pain radiating from the buttocks down the leg. Diagnosis sometimes involves
MRI or CT. Electromyography and nerve conduction studies can identify the affected level. Treatment includes symptomatic measures and sometimes surgery,
particularly if there is a neurologic deficit.
Etiology
Sci a ti ca i s typi ca l l y ca us ed by nerve root compres s i on, us ua l l y due to i ntervertebra l di s k herni a ti on (s ee p. 1810), bony i rregul a ri ti es (eg,
os teoa rthri ti c os teophytes , s pondyl ol i s thes i s ), or, much l es s often, i ntra s pi na l tumor or a bs ces s . Compres s i on ma y occur wi thi n the s pi na l ca na l
or i ntervertebra l fora men. The nerves ca n a l s o be compres s ed outs i de the vertebra l col umn, i n the pel vi s or buttocks . L5-S1, L4-L5, a nd L3-L4 nerve
roots a re mos t often a ffected (s ee
Ta bl e 186-1 on p. 1805).
Symptoms and Signs
Pa i n ra di a tes a l ong the cours e of the s ci a ti c nerve, mos t often down the buttocks a nd pos teri or a s pect of the l eg to bel ow the knee. The pa i n i s
typi ca l l y burni ng, l a nci na ti ng, or s ta bbi ng. It ma y occur wi th or wi thout l ow ba ck pa i n. The Va l s a l va ma neuver or coughi ng ma y wors en pa i n due to
di s k herni a ti on. Pa ti ents ma y compl a i n of numbnes s a nd s ometi mes wea knes s i n the a ffected l eg.
Nerve root compres s i on ca n ca us e s ens ory, motor, or, the mos t objecti ve fi ndi ng, refl ex defi ci ts s ee p. 1810). L5-S1 di s k herni a ti on ma y a ffect the
a nkl e jerk refl ex; L3-L4 herni a ti on ma y a ffect the knee jerk. Stra i ght l eg ra i s i ng ma y ca us e pa i n tha t ra di a tes down the l eg when the l eg i s ra i s ed
a bove 60 a nd s ometi mes l es s . Thi s fi ndi ng i s s ens i ti ve for s ci a ti ca ; pa i n ra di a ti ng down the a ffected l eg when the contra l a tera l l eg i s l i fted
(cros s ed s tra i ght l eg ra i s i ng) i s more s peci fi c for s ci a ti ca .
Diagnosis
Someti mes MRI, el ectrodi a gnos ti c s tudi es , or both
Sci a ti ca i s s us pected ba s ed on the cha ra cteri s ti c pa i n. If i t i s s us pected, s trength, refl exes , a nd s ens a ti on s houl d be tes ted. If there a re neurol ogi c
defi ci ts or i f s ymptoms pers i s t for > 6 wk, i ma gi ng a nd el ectrodi a gnos ti c s tudi es s houl d be done. Structura l a bnorma l i ti es ca us i ng s ci a ti ca
(i ncl udi ng s pi na l s tenos i s ) a re mos t a ccura tel y di a gnos ed by MRI or CT. El ectrodi a gnos ti c s tudi es ca n confi rm the pres ence a nd degree of nerve
root compres s i on a nd ca n excl ude condi ti ons tha t ma y mi mi c s ci a ti ca , s uch a s pol yneuropa thy. Thes e s tudi es ma y hel p determi ne whether the
l es i on i nvol ves s i ngl e or mul ti pl e nerve l evel s a nd whether the cl i ni ca l fi ndi ngs correl a te wi th MRI a bnorma l i ti es (es peci a l l y va l ua bl e before
s urgery). However, a bnorma l i ti es ma y not be evi dent on el ectrodi a gnos ti c s tudi es for up to a few weeks a fter s ymptoms begi n.
Treatment
Bed res t (bri ef), a na l ges i cs , a nd s ometi mes drugs tha t rel i eve neuropa thi c pa i n
Surgery for s evere ca s es
Acute pa i n rel i ef ca n come from 24 to 48 h of bed res t i n a recumbent pos i ti on wi th the hea d of the bed el eva ted a bout 30 (s emi -Fowl er's
pos i ti on). Mea s ures us ed to trea t l ow ba ck pa i n, i ncl udi ng nonopi oi d a na l ges i cs (eg, NSAIDs , a ceta mi nophen), ca n be tri ed for up to 6 wk. Drugs
tha t decrea s e neuropa thi c pa i n (s ee p. 1633), s uch a s ga ba penti n or other a nti convul s a nts or l ow-dos e tri cycl i c a nti depres s a nts (no tri cycl i c i s
s uperi or to a nother), ma y rel i eve s ymptoms . Ga ba penti n 100 to 300 mg po a t bedti me i s us ed i ni ti a l l y, but dos es typi ca l l y ha ve to be much hi gher,
up to 3600 mg/da y. As wi th a l l s eda ti ng drugs , ca re s houl d be ta ken i n the el derl y, pa ti ents a t ri s k of fa l l s , a nd thos e wi th a rrhythmi a s .
Mus cl e s pa s m ma y be rel i eved wi th thera peuti c hea t or col d (s ee p.
3459), a nd phys i ca l thera py ma y be us eful . Whether corti cos teroi ds s houl d be us ed to trea t a cute ra di cul a r pa i n i s controvers i a l . Gi ven epi dura l l y,
corti cos teroi ds ma y a ccel era te pa i n rel i ef, but they proba bl y s houl d not be us ed unl es s pa i n i s s evere or pers i s tent.
Surgery i s i ndi ca ted onl y for unequi voca l di s k herni a ti on pl us one of the fol l owi ng:
Mus cul a r wea knes s
Progres s i ve neurol ogi c defi ci t
Intol era bl e, i ntra cta bl e pa i n tha t i nterferes wi th job or pers ona l functi ons i n a n emoti ona l l y s ta bl e pa ti ent a nd tha t ha s not l es s ened a fter 6 wk
of cons erva ti ve trea tment
Some of thes e pa ti ents benefi t from epi dura l corti cos teroi ds i ns tea d of s urgery.
Cl a s s i c di s kectomy wi th l i mi ted l a mi notomy for i ntervertebra l di s k herni a ti on i s the s ta nda rd procedure. If herni a ti on i s l oca l i zed,
mi crodi s kectomy ma y be done; wi th i t, the s ki n i nci s i on a nd l a mi notomy ca n be s ma l l er. Chemonucl eol ys i s , us i ng i ntra di s ka l i njecti on of
chymopa pa i n, i s no l onger us ed.
Predi ctors of poor s urgi ca l outcome i ncl ude
Promi nent ps ychi a tri c fa ctors
Pers i s tence of s ymptoms for > 6 mo
Hea vy ma nua l l a bor
Promi nence of ba ck pa i n (nonra di cul a r)
Seconda ry ga i n (i e, l i ti ga ti on a nd compens a bi l i ty)
Lumbar Spinal Stenosis
Lumbar spinal stenosis (LSS) is narrowing of the lumbar spinal canal, which puts pressure on the sciatic nerve roots (or sometimes the cord) before their exit from
the foramina. It causes positional back pain, symptoms of nerve root compression, and lower-extremity pain during walking or weight bearing.
Spi na l s tenos i s ca n be congeni ta l or a cqui red. It ma y i nvol ve the cervi ca l or l umba r s pi ne. Acqui red LSS i s a common ca us e of s ci a ti ca i n mi ddl ea ged or el derl y pa ti ents . The mos t common ca us es of LSS a re os teoa rthri ti s , degenera ti ve di s k di s orders , a nd s pondyl ol i s thes i s wi th compres s i on
of the ca uda equi na . Other ca us es i ncl ude Pa get's di s ea s e of bone, RA, a nd a nkyl os i ng s pondyl i ti s .
Symptoms and Signs
Pa i n occurs i n the buttocks , thi ghs , or ca l ves duri ng wa l ki ng, runni ng, cl i mbi ng s ta i rs , or even s ta ndi ng. The pa i n i s not rel i eved by s ta ndi ng s ti l l
but by fl exi ng the ba ck or by s i tti ng (a l though pa res thes i a s ma y conti nue). Wa l ki ng up hi l l s i s l es s pa i nful tha n wa l ki ng down beca us e the ba ck i s
s l i ghtl y fl exed. Pa ti ents ma y ha ve pa i n, pa res thes i a s , wea knes s , a nd di mi ni s hed refl exes i n the a ffected nerve root di s tri buti on. Ra rel y, s pi na l
cord compres s i on ma y ca us e ca uda equi na s yndrome (s ee p.
1806).
Diagnosis
Someti mes MRI, el ectrodi a gnos ti c s tudi es , or both
Spi na l s tenos i s i s s us pected ba s ed on cha ra cteri s ti c s ymptoms . Di a gnos ti c tes ts a re the s a me a s for s ci a ti ca (s ee p. 383). Ca l f s ymptoms ma y
s i mul a te thos e of i ntermi ttent cl a udi ca ti on. Cl a udi ca ti on ca n be di fferenti a ted by rel i ef wi th res t (not pos i ti on cha nge), s ki n a trophy, a nd
a bnorma l i ti es i n pul s es , ca pi l l a ry refi l l , a nd va s cul a r tes ts .
Treatment
Bed res t (bri ef), a na l ges i cs , a nd s ometi mes drugs tha t rel i eve neuropa thi c pa i n
Surgery for s evere ca s es
Cons erva ti ve trea tments a nd i ndi ca ti ons for s urgery a re s i mi l a r to thos e for s ci a ti ca . For a dva nced s pi na l s tenos i s , s urgery i nvol ves
decompres s i on of nerve root entra pment by vertebra l ca na l a nd fora mi na l encroa chments , whi ch s ometi mes requi res l a mi nectomy a t 2 or 3 l evel s
pl us fora mi notomi es .
Spi na l s ta bi l i ty mus t be pres erved. Spi na l fus i on i s i ndi ca ted i f there i s i ns ta bi l i ty or s evere, wel l -l oca l i zed a rthri ti c cha nges i n 1 or 2 vertebra l
i nters pa ces .
Nontraumatic Subluxation
Spi na l di s l oca ti on a nd s ubl uxa ti on (pa rti a l di s l oca ti on) a re us ua l l y due to tra uma . For exa mpl e, a tl a ntoa xi a l s ubl uxa ti on a nd s pondyl ol i s thes i s
ca n res ul t from obvi ous ma jor tra uma , s uch a s a hi gh-s peed decel era ti on i njury. However, thes e di s orders ca n occur wi th mi ni ma l , unrecogni zed,
or no tra uma . Ra rel y, cervi ca l di s k di s orders ca n ca us e nontra uma ti c s pi na l s ubl uxa ti on.
Atlantoaxial Subluxation
(C1-C2 Subl uxa ti on)
Atlantoaxial subluxation is misalignment of the 1st and 2nd cervical vertebrae, which may occur only with neck flexion.
Atl a ntoa xi a l s ubl uxa ti on ca n res ul t from ma jor tra uma or ca n occur wi thout tra uma i n pa ti ents wi th RA, juveni l e RA, or a nkyl os i ng s pondyl i ti s .
Atl a ntoa xi a l s ubl uxa ti on i s us ua l l y a s ymptoma ti c but ma y ca us e va gue neck pa i n, occi pi ta l hea da che, or occa s i ona l l y i ntermi ttent (a nd potenti a l l y
fa ta l ) cervi ca l s pi na l cord compres s i on.
Diagnosis
Pl a i n x-ra ys
MRI i f cord compres s i on s us pected
It i s us ua l l y di a gnos ed wi th pl a i n cervi ca l x-ra ys ; however, fl exi on vi ews ma y be requi red to s how i ntermi ttent s ubl uxa ti on. Vi ews duri ng fl exi on,
done by the pa ti ent, s how dyna mi c i ns ta bi l i ty of the enti re cervi ca l s pi ne. If x-ra ys a re norma l a nd s ubl uxa ti on i s s ti l l s us pected, MRI, whi ch i s
more s ens i ti ve, s houl d be done. MRI a l s o provi des the mos t s ens i ti ve eva l ua ti on of s pi na l cord compres s i on a nd i s done i mmedi a tel y i f cord
compres s i on i s s us pected.
Treatment
Indi ca ti ons for trea tment i ncl ude pa i n, neurol ogi c defi ci ts , a nd potenti a l s pi na l i ns ta bi l i ty. Trea tment i ncl udes s ymptoma ti c mea s ures a nd
cervi ca l i mmobi l i za ti on, us ua l l y begi nni ng wi th a ri gi d cervi ca l col l a r. Surgery ma y be needed to s ta bi l i ze the s pi ne.
Spondylolisthesis
Spondylolisthesis is subluxation of lumbar vertebrae, usually occurring during adolescence. It usually results from a congenital defect in the pars interarticularis
(spondylolysis).
Spondyl ol i s thes i s i s us ua l l y fi xed. It us ua l l y i nvol ves the L3-L4, L4-L5, or L5-S1 vertebra e. Spondyl ol i s thes i s often occurs i n a dol es cents or young
a dul ts who a re a thl etes a nd who ha ve ha d onl y mi ni ma l tra uma ; the ca us e i s a l umba r vertebra wea kened by a congeni ta l defect i n the pa rs
i ntera rti cul a ri s . Thi s defect i s ea s i l y fra ctured; s epa ra ti on of the fra cture fra gments ca us es the s ubl uxa ti on. Spondyl ol i s thes i s ca n a l s o occur wi th
mi ni ma l tra uma i n pa ti ents who a re > 60 a nd ha ve os teoa rthri ti s . If mi l d to modera te (s ubl uxa ti on of 50%), s pondyl ol i s thes i s , pa rti cul a rl y i n the
young, ma y ca us e l i ttl e or no pa i n. Spondyl ol i s thes i s ca n predi s pos e to l a ter devel opment of s pi na l s tenos i s . If due to ma jor tra uma ,
s pondyl ol i s thes i s ca n ca us e s pi na l cord compres s i on or other neurol ogi c defi ci ts (s ee p. 1810); thes e defi ci ts ra rel y occur.
Spondyl ol i s thes i s i s s ta ged a ccordi ng to the degree of s ubl uxa ti on of a dja cent vertebra l bodi es :
Sta ge I: 0 to 25%
Sta ge II: 25 to 50%
Sta ge III: 50 to 75%
Sta ge IV: 75 to 100%
Spondyl ol i s thes i s i s evi dent on pl a i n l umba r x-ra ys . The l a tera l vi ew i s us ua l l y us ed for s ta gi ng.
Trea tment i s us ua l l y s ymptoma ti c.
Chapter 43. Hand Disorders

Introduction
Common ha nd di s orders i ncl ude a va ri ety of deformi ti es , ga ngl i a , i nfecti ons , Ki enbock's di s ea s e, nerve compres s i on s yndromes , noni nfecti ous
tenos ynovi ti s , a nd os teoa rthri ti s . Compl ex regi ona l pa i n s yndrome (refl ex s ympa theti c dys trophy) i s di s cus s ed on p. 1633, a nd ha nd i njuri es a re
di s cus s ed i n Ch. 323.
Evaluation
Hi s tory a nd phys i ca l exa mi na ti on fi ndi ngs a re often di a gnos ti c i n ha nd di s orders .
History: The hi s tory s houl d i ncl ude i nforma ti on a bout the tra uma or other events tha t ma y be a s s oci a ted wi th s ymptoms . The pres ence a nd
dura ti on of deformi ty a nd di ffi cul ty wi th moti on a re noted. The pres ence, dura ti on, s everi ty, a nd fa ctors tha t exa cerba te or rel i eve pa i n a re
el i ci ted. As s oci a ted s ymptoms , s uch a s fever, s wel l i ng, ra s hes , Ra yna ud's s yndrome (s ee p. 2221), pa res thes i a s , a nd wea knes s , a re a l s o recorded.
Physical examination: Exa mi na ti on s houl d i ncl ude i ns pecti on for rednes s , s wel l i ng, or deformi ty a nd pa l pa ti on for tendernes s . Acti ve ra nge of
moti on s houl d be tes ted for a ny pos s i bl e tendon i njury. Pa s s i ve ra nge of moti on ca n a s s es s whether s peci fi c moti ons a ggra va te pa i n. Sens a ti on i s
tes ted mos t a ccura tel y by 2-poi nt di s cri mi na ti on, us i ng 2 ends of a pa per cl i p. Motor functi on tes ti ng i nvol ves mus cl es i nnerva ted by the ra di a l ,
medi a n, a nd ul na r nerves . Va s cul a r exa mi na ti on s houl d i ncl ude eva l ua ti on of ca pi l l a ry refi l l , ra di a l a nd ul na r pul s es , a nd Al l en's tes t (s ee p.
1856). Stres s tes ti ng i s hel pful when s peci fi c l i ga ment i njuri es a re s us pected (eg, ul na r col l a tera l l i ga ment i n ga mekeeper's thumbs ee p. 3216).
Provoca ti ve tes ti ng ca n a i d i n the di a gnos i s of tenos ynovi ti s a nd nerve compres s i on s yndromes .
Laboratory testing: La bora tory tes ti ng ha s a l i mi ted rol e. Pl a i n x-ra ys a nd MRI a re hel pful for i njuri es , a rthri ti s , a nd Ki enbock's di s ea s e or to rul e out
hi dden forei gn bodi es tha t coul d be s ources of i nfecti ons . Nerve conducti on tes ti ng ca n hel p di a gnos e nerve compres s i on s yndromes . Bone s ca ns
ma y a s s i s t i n di a gnos i ng occul t fra ctures a nd refl ex s ympa theti c dys trophy.
Deformities
Deformi ti es ca n res ul t from genera l i zed di s orders (eg, a rthri ti s ) or di s l oca ti ons , fra ctures , a nd other l oca l i zed di s orders . Mos t nontra uma ti c
l oca l i zed di s orders ca n be di a gnos ed by phys i ca l exa mi na ti on. Once a ha nd deformi ty becomes fi rml y es ta bl i s hed, i t ca nnot be s i gni fi ca ntl y
a l tered by s pl i nti ng, exerci s e, or other nons urgi ca l trea tment.
Mallet Finger
Mallet finger is a flexion deformity of the distal interphalangeal joint preventing extension (see
Fig. 43-1).
Thi s deformi ty res ul ts from a n extens or tendon rupture or a n a vul s i on fra cture of the di s ta l pha l a nx. The deformi ty ma y not be obvi ous
i mmedi a tel y a fter i njury, but on exa mi na ti on, pa ti ents ca nnot ful l y extend the di s ta l i nterpha l a ngea l (DIP) joi nt. Cl os ed i njuri es ma y be trea ted
wi th s pl i nti ng tha t hol ds the DIP joi nt i n extens i on a nd l ea ves the proxi ma l i nterpha l a ngea l (PIP) joi nt free. Avul s i on fra ctures a re us ua l l y uni ted
a fter 6 wk, but pure tendon i njuri es requi re a n a ddi ti ona l 2 to 4 wk of ni ghtti me s pl i nti ng. Surgery ma y be requi red i f there i s a fra cture tha t
i nvol ves a l a rge proporti on of the a rti cul a r s urfa ce or i f the joi nt i s s ubl uxa ted.
Swan-Neck Deformity
A swan-neck deformity consists of hyperextension of the PIP joint, flexion of the DIP joint, and sometimes flexion of the metacarpophalangeal joint (see
Fig. 43-2).
Al though cha ra cteri s ti c i n RA, s wa n-neck deformi ty ha s s evera l ca us es , i ncl udi ng untrea ted ma l l et fi nger, l a xi ty of the l i ga ments of the vol a r
a s pect of the PIP joi nt, s pa s ti ci ty of i ntri ns i c ha nd mus cl es , rupture of the fl exor tendon of the PIP joi nt, a nd ma l uni on of a fra cture of the mi ddl e or
proxi ma l pha l a nx. The i na bi l i ty to correct or compens a te for hyperextens i on of the PIP joi nt ma kes fi nger cl os ure i mpos s i bl e a nd ca n ca us e s evere
di s a bi l i ty. Trea tment i s a i med a t correcti ng the underl yi ng di s order when pos s i bl e (eg, correcti ng the ma l l et fi nger or a ny bony ma l a l i gnment,
rel ea s i ng s pa s ti c i ntri ns i c mus cl es ). Mi l d deformi ti es i n pa ti ents wi th RA ma y be trea ted wi th a functi ona l ri ng s pl i nt.
True s wa n-neck deformi ty does not a ffect the thumb, whi ch ha s onl y one i nterpha l a ngea l
[Fig. 43-1. Ma l l et fi nger.]
[Fig. 43-2. Boutonni ere a nd s wa n-neck deformi ti es .]
joi nt. However, s evere hyperextens i on of the i nterpha l a ngea l joi nt of the thumb wi th fl exi on of the meta ca rpopha l a ngea l (MCP) joi nt ca n occur;
thi s i s ca l l ed a duck bi l l , Z (zi gza g) type, or 90-a ngl e deformi ty. Wi th s i mul ta neous thumb i ns ta bi l i ty, pi nch i s grea tl y i mpa i red. Thi s deformi ty ca n
us ua l l y be corrected by i nterpha l a ngea l a rthrodes i s a l ong wi th tendon recons tructi on a t the MCP joi nt.
Boutonniere Deformity
(Buttonhol e Deformi ty)
A boutonniere deformity consists of flexion of the PIP joint accompanied by hyperextension of the DIP joint (see Fig. 43-2).
Thi s deformi ty ca n res ul t from tendon l a cera ti on, di s l oca ti on, fra cture, os teoa rthri ti s , or RA. Cl a s s i ca l l y, the deformi ty i s ca us ed by di s rupti on of
the centra l s l i p a tta chment of the extens or tendon to the ba s e of the mi ddl e pha l a nx, a l l owi ng the proxi ma l pha l a nx to protrude ("buttonhol e")
between the l a tera l ba nds of the extens or tendon. Ini ti a l trea tment cons i s ts of s pl i nti ng, but i t mus t occur before s ca rri ng a nd fi xed deformi ti es
devel op. Surgi ca l recons tructi on often ca nnot res tore norma l moti on but ma y decrea s e the deformi ty a nd i mprove ha nd functi on.
Dupuytren's Contracture
(Pa l ma r Fi broma tos i s )
Dupuytren's contracture is progressive contracture of the palmar fascial bands, causing flexion deformities of the fingers.
Dupuytren's contra cture i s one of the more common ha nd deformi ti es ; the i nci dence i s hi gher a mong men a nd i ncrea s es a fter a ge 45. Thi s
a utos oma l domi na nt condi ti on wi th va ri a bl e penetra nce ma y occur more commonl y a mong pa ti ents wi th di a betes , a l cohol i s m, or epi l eps y.
However, the s peci fi c fa ctor tha t ca us es the pa l ma r fa s ci a to thi cken a nd contra ct i s unknown.
Symptoms and Signs
The ea rl i es t ma ni fes ta ti on i s us ua l l y a tender nodul e i n the pa l m, mos t often nea r the mi ddl e or ri ng fi nger; i t gra dua l l y becomes pa i nl es s . Next,
a s uperfi ci a l cord forms a nd contra cts the MCP joi nts a nd i nterpha l a ngea l joi nts of the fi ngers . The ha nd eventua l l y becomes a rched. The di s ea s e
i s occa s i ona l l y a s s oci a ted wi th fi brous thi ckeni ng of the dors um of the PIP joi nts (Ga rrod's pa ds ), Peyroni e's di s ea s e (peni l e fi broma tos i s ) i n
a bout 7 to 10% of pa ti ents , a nd ra rel y nodul es on the pl a nta r s urfa ce of the feet (pl a nta r fi broma tos i s ). Other types of fl exi on deformi ti es of the
fi ngers ca n a l s o occur i n di a betes , s ys temi c s cl eros i s , a nd chroni c refl ex s ympa theti c dys trophy, whi ch need to be di fferenti a ted.
Treatment
Corti cos teroi d i njecti on (before contra ctures devel op)
Surgery for di s a bl i ng contra ctures
Injecti on of a corti cos teroi d s us pens i on i nto the nodul e ca n rel i eve l oca l tendernes s i f begun before contra ctures devel op. If the ha nd ca nnot be
pl a ced fl a t on a ta bl e or, es peci a l l y, when s i gni fi ca nt contra cture devel ops a t the PIP joi nts , s urgery i s us ua l l y i ndi ca ted. Exci s i on of the di s ea s ed
fa s ci a mus t be meti cul ous beca us e i t s urrounds neurova s cul a r bundl es a nd tendons . Incompl ete exci s i on or new di s ea s e res ul ts i n recurrent
contra cture, es peci a l l y i n pa ti ents who a re young a t di s ea s e ons et or who ha ve a fa mi l y hi s tory, Ga rrod's pa ds , Peyroni e's di s ea s e, or pl a nta r foot
i nvol vement. Injecta bl e col l a gena s e ma y revers e s ome contra ctures , a l though thi s trea tment i s not yet i n wi des prea d cl i ni ca l us e.
Ganglia
(Ga ngl i on Cys ts )
Ganglia are cystic swellings occurring usually on the hands, especially on the dorsal aspect of the wrists. Aspiration or excision is indicated for symptomatic
ganglia.
Ga ngl i a cons ti tute a bout 60% of chroni c s oft-ti s s ue s wel l i ngs a ffecti ng the ha nd a nd wri s t. They us ua l l y devel op s ponta neous l y i n a dul ts a ged 20
to 50, wi th a fema l e:ma l e prepondera nce of 3:1.
Etiology
The ca us e of mos t ga ngl i a i s unknown. The cys ti c s tructures a re nea r or a tta ched (often by a pedi cl e) to tendon s hea ths a nd joi nt ca ps ul es . The
wa l l of the ga ngl i on i s s mooth, fi brous , a nd of va ri a bl e thi cknes s . The cys t i s fi l l ed wi th cl ea r gel a ti nous , s ti cky, or mucoi d fl ui d of hi gh vi s cos i ty.
The fl ui d i n the cys t i s s ometi mes a l mos t pure hya l uroni c a ci d.
Mos t ga ngl i a a re i s ol a ted a bnorma l i ti es . The dors a l wri s t ga ngl i on a ri s es from the s ca phol una te joi nt a nd cons ti tutes a bout 65% of ga ngl i a of the
wri s t a nd ha nd. The vol a r wri s t ga ngl i on a ri s es over the di s ta l a s pect of the ra di us a nd cons ti tutes a bout 20 to 25% of ga ngl i a . Fl exor tendon
s hea th ga ngl i a a nd mucous cys ts (a ri s i ng from dors a l di s ta l i nterpha l a ngea l joi nt) ma ke up the rema i ni ng 10 to 15%. Ga ngl i a ma y s ponta neous l y
regres s .
Diagnosis
Exa mi na ti on
Ga ngl i a a re evi dent on exa mi na ti on. Another type of ga ngl i on on the dors a l wri s t occurs i n pa ti ents wi th RA; i t i s ea s i l y di fferenti a ted by i ts s oft
i rregul a r a ppea ra nce a nd a s s oci a ti on wi th prol i fera ti ve rheuma toi d extens or tenos ynovi ti s .
Treatment
As pi ra ti on or exci s i on i f troubl es ome
Mos t ga ngl i a do not requi re trea tment. However, i f the pa ti ent i s di s turbed by i ts a ppea ra nce or i f the ga ngl i on i s pa i nful or tender, a s i ngl e
a s pi ra ti on wi th a l a rge-bore needl e i s effecti ve i n a bout 50% of pa ti ents . Attempti ng to rupture the ga ngl i on by hi tti ng i t wi th a ha rd object ri s ks
l oca l i njury wi thout l i kel y benefi t. Nons urgi ca l trea tment fa i l s i n a bout 40 to 70% of pa ti ents , neces s i ta ti ng s urgi ca l exci s i on. Recurrence ra tes
a fter s urgi ca l remova l a re a bout 5 to 15%.
Infections
Common ba cteri a l ha nd i nfecti ons i ncl ude pa ronychi a (s ee p. 735), i nfected bi te wounds , fel on, pa l m a bs ces s , a nd i nfecti ous fl exor tenos ynovi ti s .
Herpeti c whi tl ow i s a vi ra l ha nd i nfecti on. Infecti ons often begi n wi th cons ta nt, i ntens e, throbbi ng pa i n a nd a re us ua l l y di a gnos ed by phys i ca l
exa mi na ti on. X-ra ys a re ta ken i n s ome i nfecti ons (eg, bi te wounds , i nfecti ous fl exor tenos ynovi ti s ) to detect occul t forei gn bodi es but ma y not
detect s ma l l or ra di ol ucent objects .
Treatment
Surgi ca l mea s ures a nd a nti bi oti cs
The i ncrea s ed i nci dence of communi ty-a cqui red a nd nos ocomi a l methi ci l l i n-res i s ta nt Staphylococcus aureus (MRSA) s houl d be ta ken i nto
cons i dera ti on. Uncompl i ca ted MRSA i nfecti ons a re bes t trea ted wi th i nci s i on a nd dra i na ge. If there i s a hi gh i nci dence of MRSA a nd the i nfecti on
i s s evere, hos pi ta l i za ti on a nd va ncomyci n or da ptomyci n (for IV thera py) a re recommended, a s i s cons ul ta ti on wi th a n i nfecti ous di s ea s e
s peci a l i s t. For outpa ti ents , tri methopri m/s ul fa methoxa zol e, cl i nda myci n, doxycycl i ne, or l i nezol i d (for ora l thera py) ca n be gi ven. Once cul ture a nd
s ens i ti vi ty res ul ts rul e out MRSA, na fci l l i n, cl oxa ci l l i n, di cl oxa ci l l i n, or a 1s t- or 2nd-genera ti on cepha l os pori n ca n be gi ven.
Infected Bite Wounds
A s ma l l puncture wound, pa rti cul a rl y from a huma n or ca t bi te, ma y i nvol ve s i gni fi ca nt i njury to the tendon, joi nt ca ps ul e, or a rti cul a r ca rti l a ge. The
mos t common ca us e of huma n bi tes i s a tooth-i nduced i njury to the meta ca r-popha l a ngea l
[
Fig. 43-3. Spl i nt i n the functi ona l pos i ti on (20 wri s t extens i on, 60 meta ca rpopha l a ngea l joi nt fl exi on, s l i ght i nterpha l a ngea l joi nt fl exi on).]
joi nt a s a res ul t of a punch to the mouth (cl enched fi s t i njury). The ora l fl ora of huma ns i ncl udes Eikenella corrodens, s ta phyl ococci , s treptococci , a nd
a na erobes . Pa ti ents wi th cl enched fi s t i njuri es tend to wa i t hours or da ys a fter the wound occurs before s eeki ng medi ca l a ttenti on, whi ch
i ncrea s es the s everi ty of the i nfecti on. Ani ma l bi tes us ua l l y conta i n mul ti pl e potenti a l pa thogens , i ncl udi ng Pasteurella multocida (pa rti cul a rl y i n
ca t bi tes ), s ta phyl ococci , s treptococci , a nd a na erobes . Seri ous compl i ca ti ons i ncl ude i nfecti ous a rthri ti s a nd os teomyel i ti s .
Diagnosis
X-ra ys
Erythema a nd pa i n l oca l i zed to the bi te s ugges t i nfecti on. Tendernes s a l ong the cours e of a tendon s ugges ts s prea d to the tendon s hea th. Pa i n
wors eni ng s i gni fi ca ntl y wi th moti on s ugges ts i nfecti on of a joi nt or tendon s hea th.
The di a gnos i s i s cl i ni ca l , but i f the s ki n i s broken, x-ra ys s houl d be ta ken to detect fra cture or teeth or other forei gn bodi es tha t coul d be a ni dus
of conti nui ng i nfecti on.
Treatment
Debri dement
Anti bi oti cs
Trea tment i ncl udes s urgi ca l debri dement, wi th the wound l eft open, a nd a nti bi oti cs . For outpa ti ent trea tment, empi ri c a nti bi oti cs us ua l l y i ncl ude
monothera py wi th a moxi ci l l i n/cl a vul a na te 500 mg po ti d or combi ned thera py wi th a peni ci l l i n 500 mg po qi d (for E. corrodens, P. multocida,
s treptococci , a nd a na erobes ) pl us a cepha l os pori n (eg, cepha l exi n 500 mg po qi d) or s emi s yntheti c peni ci l l i n (eg, di cl oxa ci l l i n 500 mg po qi d) for
s ta phyl ococci . In a rea s where MRSA i s preva l ent, tri methopri m/s ul fa methoxa zol e, cl i nda myci n, doxycycl i ne, or l i nezol i d s houl d be us ed i ns tea d of
a cepha l os pori n. If the pa ti ent i s a l l ergi c to peni ci l l i n, cl i nda myci n 300 mg po q 6 h ca n be us ed. The ha nd s houl d be s pl i nted i n the functi ona l
pos i ti on a nd el eva ted (s ee Fi g. 43-3).
Noni nfected bi tes ma y requi re s urgi ca l debri dement a nd prophyl a xi s wi th 50% of the dos e of a nti bi oti c us ed to trea t i nfected wounds .
Felon
A felon is an infection of the pulp space of the fingertip, usually with staphylococci and streptococci.
The mos t common s i te i s the di s ta l pul p, whi ch ma y be i nvol ved centra l l y, l a tera l l y, or a pi ca l l y. The s epta between pul p s pa ces ordi na ri l y l i mi t the
s prea d of i nfecti on, res ul ti ng i n a n a bs ces s , whi ch crea tes pres s ure a nd necros i s of a dja cent ti s s ues . The underl yi ng bone, joi nt, or fl exor tendons
ma y become i nfected. There i s i ntens e throbbi ng pa i n a nd a s wol l en, wa rm, extremel y tender pul p. Trea tment i nvol ves prompt i nci s i on a nd
dra i na ge (us i ng a mi d-l a tera l i nci s i on tha t a dequa tel y di vi des the fi brous s epta ) a nd ora l a nti bi oti c thera py. Empi ri c trea tment wi th a
cepha l os pori n i s a dequa te. In a rea s where MRSA i s preva l ent, tri methopri m/s ul fa methoxa zol e, cl i nda myci n, doxycycl i ne, or l i nezol i d s houl d be
us ed i ns tea d of a cepha l os pori n.
Palm Abscess
A palm abscess is a purulent infection of deep spaces in the palm, typically with staphylococci or streptococci.
Pa l m a bs ces s es ca n i ncl ude col l a r-button a bs ces s es , thena r s pa ce a bs ces s es , a nd mi dpa l ma r s pa ce a bs ces s es . An a bs ces s ca n occur i n a ny of the
deep pa l ma r compa rtments a nd s prea d between the meta ca rpa l s , from the mi dpa l ma r s pa ce to the dors um, ma ni fes ti ng a s a n i nfecti on on the
dors um of the ha nd. Intens e throbbi ng pa i n occurs wi th s wel l i ng a nd s evere tendernes s on pa l pa ti on. X-ra ys s houl d be ta ken to detect occul t
forei gn bodi es . Inci s i on a nd dra i na ge i n the opera ti ng room (wi th cul tures ), wi th ca re to a voi d the ma ny i mporta nt a na tomi c s tructures , a nd
a nti bi oti cs (eg, a cepha l os pori n) a re requi red. In a rea s where MRSA i s preva l ent, tri methopri m/s ul fa methoxa zol e, cl i nda myci n, doxycycl i ne, or
l i nezol i d s houl d be us ed i ns tea d of a cepha l os pori n.
Infectious Flexor Tenosynovitis
Infectious flexor tenosynovitis is an acute infection within the flexor tendon sheath.
The us ua l ca us e i s a penetra ti on a nd ba cteri a l i nocul a ti on of the s hea th.
Diagnosis
Ka na vel 's s i gns
X-ra ys
Infecti ous fl exor tenos ynovi ti s ca us es Ka na vel 's s i gns :
Fl exed res ti ng pos i ti on of the di gi t
Fus i form s wel l i ng
Tendernes s a l ong the fl exor tendon s hea th
Pa i n wi th pa s s i ve extens i on of the di gi t
X-ra ys s houl d be ta ken to detect occul t forei gn bodi es . Acute ca l ci fi c tendi ni ti s a nd RA ca n res tri ct moti on a nd ca us e pa i n i n the tendon s hea th but
ca n us ua l l y be di fferenti a ted from i nfecti ous fl exor tenos ynovi ti s by a more gra dua l ons et a nd the a bs ence of s ome of Ka na vel 's s i gns .
Di s s emi na ted gonococca l i nfecti on ca n ca us e tenos ynovi ti s but often i nvol ves mul ti pl e joi nts (pa rti cul a rl y thos e of the wri s ts , fi ngers , a nkl es , a nd
toes ), a nd pa ti ents often ha ve recent fever, ra s h, pol ya rthra l gi a s , a nd often ri s k fa ctors for a n STD. Infecti on of the tendon s hea th ma y i nvol ve
a typi ca l mycoba cteri a , but thes e i nfecti ons a re us ua l l y i ndol ent a nd chroni c.
Treatment
Surgi ca l dra i na ge a nd a nti bi oti cs
Trea tment i s s urgi ca l dra i na ge (eg, i rri ga ti on of the tendon s hea th by i ns erti ng a ca nnul a i nto one end a nd a l l owi ng the i rri ga ti ng fl ui d to pa s s
a l ong the tendon s hea th to the other end). Anti bi oti c thera py (begi nni ng empi ri ca l l y wi th a cepha l os pori n) a nd cul tures a re a l s o requi red. In
a rea s where MRSA i s preva l ent, tri methopri m/s ul fa methoxa zol e, cl i nda myci n, doxycycl i ne, or l i nezol i d s houl d be us ed i ns tea d of a cepha l os pori n.
Herpetic Whitlow
Herpetic whitlow is a cutaneous infection of the distal aspect of the finger caused by herpes simplex virus.
Herpeti c whi tl ow ma y ca us e i ntens e pa i n. The di gi ta l pul p i s not very tens e. Ves i cl es devel op on the vol a r or dors a l di s ta l pha l a nx but often not
unti l 2 to 3 da ys a fter pa i n begi ns . The i ntens e pa i n ca n s i mul a te a fel on, but herpeti c whi tl ow ca n us ua l l y be di fferenti a ted by the a bs ence of
tens enes s i n the pul p or the pres ence of ves i cl es . The condi ti on i s s el f-l i mi ted but ma y recur. Inci s i on a nd dra i na ge a re contra i ndi ca ted. Topi ca l
a cycl ovi r 5% ca n s horten the dura ti on of a fi rs t epi s ode. Ora l a cycl ovi r (800 mg po bi d) ma y prevent recurrences i f gi ven i mmedi a tel y a fter ons et of
recurrent s ymptoms . Open or dra i ni ng ves i cl es s houl d be covered to prevent tra ns mi s s i on.
Kienbock's Disease
Kienbock's disease is avascular necrosis of the lunate bone.
Ki enbock's di s ea s e occurs mos t commonl y i n the domi na nt ha nd of men a ged 20 to 45, us ua l l y i n workers doi ng hea vy ma nua l l a bor. Overa l l ,
Ki enbock's di s ea s e i s rel a ti vel y ra re. Its ca us e i s unknown. The l una te ca n eventua l l y col l a ps e a nd ca us e fi xed rota ti on of the s ca phoi d a nd
s ubs equent degenera ti on of the ca rpa l joi nts .
Symptoms and Signs
Symptoms genera l l y s ta rt wi th i ns i di ous ons et of wri s t pa i n, l oca l i zed to the regi on of the l una te ca rpa l bone; pa ti ents ha ve no recol l ecti on of
tra uma . Ki enbock's di s ea s e i s bi l a tera l i n 10% of ca s es . There i s l oca l i zed tendernes s i n the l una te bone.
Diagnosis
Ima gi ng
MRI a nd CT a re the mos t s ens i ti ve; pl a i n x-ra ys s how a bnorma l i ti es l a ter, us ua l l y begi nni ng wi th a s cl eroti c l una te, then l a ter cys ti c cha nges ,
fra gmenta ti on, a nd col l a ps e.
Treatment
Surgi ca l procedures
Trea tment i s a i med a t rel i evi ng pres s ure on the l una te by s urgi ca l l y s horteni ng the ra di us or l engtheni ng the ul na . Al terna ti ve trea tments a ttempt
to reva s cul a ri ze the l una te (eg, i mpl a nti ng a bl ood ves s el or bone gra ft on a va s cul a r pedi cl e). Sa l va ge procedures (eg, proxi ma l row ca rpectomy or
i nterca rpa l fus i ons ) ma y hel p pres erve s ome wri s t functi on i f the ca rpa l joi nts ha ve degenera ted. Tota l wri s t a rthrodes i s ca n be done a s a l a s t
res ort to rel i eve pa i n. Nons urgi ca l trea tments a re not effecti ve.
Nerve Compression Syndromes

Common nerve compres s i on s yndromes i ncl ude ca rpa l tunnel s yndrome, cubi ta l tunnel s yndrome, a nd ra di a l tunnel s yndrome. Compres s i on of
nerves often ca us es pa res thes i a s ; thes e pa res thes i a s ca n often be reproduced by ta ppi ng the compres s ed nerve, us ua l l y wi th the exa mi ner's
fi ngerti p (Ti nel 's s i gn). Sus pected nerve compres s i on ca n be confi rmed by tes ti ng nerve conducti on vel oci ty a nd di s ta l l a tenci es , whi ch a ccura tel y
mea s ure motor a nd s ens ory nerve conducti on. Ini ti a l trea tment i s us ua l l y cons erva ti ve, but s urgi ca l decompres s i on ma y be neces s a ry i f
cons erva ti ve mea s ures fa i l or i f there a re s i gni fi ca nt motor or s ens ory defi ci ts .
Carpal Tunnel Syndrome
Carpal tunnel syndrome is compression of the median nerve as it passes through the carpal tunnel in the wrist. Symptoms include pain and paresthesias in the
median nerve distribution. Diagnosis is suggested by symptoms and signs and is confirmed by nerve conduction velocity testing. Treatments include ergonomic
improvements, analgesia, splinting, and sometimes corticosteroid injection or surgery.
Ca rpa l tunnel s yndrome i s very common a nd mos t often occurs i n women a ged 30 to 50. Ri s k fa ctors i ncl ude RA or other wri s t a rthri ti s (s ometi mes
the pres enti ng ma ni fes ta ti on), di a betes mel l i tus , hypothyroi di s m, a cromega l y, a myl oi dos i s , hemodi a l ys i s , a nd pregna ncy-i nduced edema i n the
ca rpa l tunnel . Acti vi ti es or jobs tha t requi re repeti ti ve fl exi on a nd extens i on of the wri s t ma y contri bute, but ra rel y. Mos t ca s es a re i di opa thi c.
Symptoms and Signs
Symptoms i ncl ude pa i n of the ha nd a nd wri s t a s s oci a ted wi th ti ngl i ng a nd numbnes s , cl a s s i ca l l y di s tri buted a l ong the medi a n nerve (the pa l ma r
s i de of the thumb, the i ndex a nd mi ddl e fi ngers , a nd the ra di a l ha l f of the ri ng fi nger) but pos s i bl y i nvol vi ng the enti re ha nd. Typi ca l l y, the pa ti ent
wa kes a t ni ght wi th burni ng or a chi ng pa i n a nd wi th numbnes s a nd ti ngl i ng a nd s ha kes the ha nd to obta i n rel i ef a nd res tore s ens a ti on. Thena r
a trophy a nd wea knes s of thumb oppos i ti on a nd a bducti on ma y devel op l a te.
Diagnosis
Nerve conducti on tes ti ng
The di a gnos i s i s s trongl y s ugges ted by Ti nel 's s i gn, i n whi ch medi a n nerve pa res thes i a s a re reproduced by ta ppi ng a t the vol a r s urfa ce of the wri s t
over the s i te of the medi a n nerve i n the ca rpa l tunnel . Reproducti on of ti ngl i ng wi th wri s t fl exi on (Pha l en's s i gn) i s a l s o s ugges ti ve. However,
cl i ni ca l di fferenti a ti on from other types of peri phera l neuropa thy ma y s ometi mes be di ffi cul t. If s ymptoms a re s evere or the di a gnos i s i s
uncerta i n, nerve conducti on tes ti ng s houl d be done on the a ffected a rm for di a gnos i s a nd to excl ude a more proxi ma l neuropa thy.
Treatment
Spl i nti ng
Someti mes corti cos teroi d/a nes theti c i njecti on
Someti mes s urgi ca l decompres s i on
Cha ngi ng the pos i ti on of computer keyboa rds a nd ma ki ng other ergonomi c correcti ons ma y occa s i ona l l y provi de rel i ef. Otherwi s e, trea tment
i ncl udes wea ri ng a l i ghtwei ght neutra l wri s t s pl i nt (s ee
Fi g. 43-4), es peci a l l y a t ni ght, a nd ta ki ng mi l d a na l ges i cs (eg, a ceta mi nophen, NSAIDs ). If thes e mea s ures do not control s ymptoms , a mi xture of a
corti cos teroi d a nd a n a nes theti c (eg, 1.5 mL of a 4-mg/mL dexa metha s one s ol uti on mi xed wi th 1.5 mL of 1% l i doca i ne) s houl d be i njected i nto the
ca rpa l tunnel a t a s i te jus t ul na r to the pa l ma ri s l ongus tendon a nd proxi ma l to the di s ta l crea s e a t the wri s t. If bothers ome s ymptoms pers i s t or
recur or i f ha nd wea knes s a nd thena r wa s ti ng devel op, the ca rpa l tunnel ca n be s urgi ca l l y decompres s ed by us i ng a n open or endos copi c
techni que.
[Fig. 43-4. Neutra l wri s t s pl i nt.]
Cubital Tunnel Syndrome
(Ul na r Neuropa thy)
Cubital tunnel syndrome is compression or traction of the ulnar nerve at the elbow.
The ul na r nerve i s commonl y i rri ta ted a t the el bow or, ra rel y, the wri s t. Cubi ta l tunnel s yndrome i s mos t often ca us ed by l ea ni ng on the el bow or
by prol onged a nd exces s i ve el bow fl exi on. It i s l es s common tha n ca rpa l tunnel s yndrome. Ba s eba l l pi tchi ng (pa rti cul a rl y s l i ders ), whi ch ca n
i njure the medi a l el bow l i ga ments , confers ri s k.
Symptoms and Signs
Symptoms i ncl ude numbnes s a nd pa res thes i a a l ong the ul na r nerve di s tri buti on (i n the ri ng a nd l i ttl e fi ngers a nd the ul na r a s pect of the ha nd)
a nd el bow pa i n. In a dva nced s ta ges , wea knes s of the i ntri ns i c mus cl es of the ha nd a nd the fl exors of the ri ng a nd l i ttl e fi ngers ma y devel op.
Wea knes s i nterferes wi th pi nch between the thumb a nd i ndex fi nger a nd wi th ha nd gri p.
Diagnosis
Someti mes nerve conducti on s tudi es

Di a gnos i s i s often pos s i bl e cl i ni ca l l y. However, i f cl i ni ca l di a gnos i s i s equi voca l a nd when s urgery i s bei ng cons i dered, nerve conducti on s tudi es
a re done. Cubi ta l tunnel s yndrome i s di fferenti a ted from ul na r nerve entra pment a t the wri s t (i n Guyon's ca na l ) by the pres ence of s ens ory defi ci ts
(on s ens ory tes ti ng or wi th Ti nel 's s i gn) over the ul na r dors a l ha nd a nd by the pres ence of ul na r nerve defi ci ts proxi ma l to the wri s t on mus cl e
tes ti ng or nerve conducti on vel oci ty tes ti ng.
Treatment
Trea tment i nvol ves s pl i nti ng a t ni ght, wi th the el bow extended a t 45, a nd us e of a n el bow pa d duri ng the da y. Surgi ca l decompres s i on ca n hel p i f
cons erva ti ve trea tment fa i l s .
Radial Tunnel Syndrome
(Pos teri or Interos s eous Nerve Syndrome)
Radial tunnel syndrome is compression of the radial nerve in the proximal forearm.
Compres s i on a t the el bow ca n res ul t from tra uma , ga ngl i a , l i poma s , bone tumors , or ra di oca pi tel l a r (el bow) s ynovi ti s .
Symptoms and Signs
Symptoms i ncl ude l a nci na ti ng pa i n i n the dors um of the forea rm a nd l a tera l el bow. Pa i n i s preci pi ta ted by a ttempted extens i on of the wri s t a nd
fi ngers a nd forea rm s upi na ti on. Sens ory l os s i s ra re beca us e the ra di a l nerve i s pri nci pa l l y a motor nerve a t thi s l evel . Thi s di s order i s s ometi mes
confus ed wi th ba ckha nd tenni s el bow (l a tera l epi condyl i ti s ). When wea knes s of the extens or mus cl es i s the pri ma ry fi ndi ng, the condi ti on i s
referred to a s pos teri or i nteros s eus nerve pa l s y.
Diagnosis
La tera l epi condyl i ti s ca n ca us e s i mi l a r tendernes s a round the l a tera l epi condyl e but does not ca us e Ti nel 's s i gn or tendernes s a l ong the cours e
of the ra di a l nerve.
Treatment
Spl i nti ng
Spl i nti ng a l l ows a voi da nce of the forceful or repea ted moti on of s upi na ti on or wri s t dors i fl exi on, reduci ng pres s ure on the nerve. If wri s tdrop or
wea kened di gi ta l extens i on devel ops , or cons erva ti ve trea tment fa i l s to provi de rel i ef a fter 3 mo, s urgi ca l decompres s i on ma y be needed.
Noninfectious Tenosynovitis
(See a l s o p. 374.)
Al though the di gi ta l fl exor tendons a nd extens or pol l i ci s brevi s a re commonl y a ffected, tenos ynovi ti s ma y i nvol ve a ny of the tendons i n or a round
the ha nd.
Digital Flexor Tendinitis and Tenosynovitis
(Tri gger Fi nger)
Digital flexor tendinitis and tenosynovitis are inflammation, sometimes with subsequent fibrosis, of tendons and tendon sheaths of the digits.
Thes e condi ti ons a re i di opa thi c but a re common a mong pa ti ents wi th RA or di a betes mel l i tus . Repeti ti ve us e of the ha nds (a s ma y occur when
us i ng hea vy ga rdeni ng s hea rs ) ma y contri bute. In di a betes , they often coexi s t wi th ca rpa l tunnel s yndrome a nd occa s i ona l l y wi th fi bros i s of the
pa l ma r fa s ci a . Pa thol ogi c cha nges begi n wi th a thi ckeni ng or nodul e wi thi n the tendon; when l oca ted a t the s i te of the ti ght fi rs t a nnul a r pul l ey,
the thi ckeni ng or nodul e bl ocks s mooth extens i on or fl exi on of the fi nger. The fi nger ma y l ock i n fl exi on, or "tri gger," s uddenl y extendi ng wi th a
s na p.
Treatment
Cons erva ti ve mea s ures
Someti mes corti cos teroi d i njecti on
Trea tment of a cute i nfl a mma ti on a nd pa i n i ncl udes s pl i nti ng, moi s t hea t, a nd a nti -i nfl a mma tory dos es of NSAIDs (s ee p. 335). If thes e mea s ures
fa i l , i njecti on of a corti cos teroi d s us pens i on i nto the fl exor tendon s hea th, a l ong wi th s pl i nti ng, ma y provi de s a fe, ra pi d rel i ef of pa i n a nd
tri ggeri ng. Opera ti ve rel ea s e ca n be done i f corti cos teroi d thera py fa i l s .
De Quervain's Syndrome
(Wa s herwoma n's Spra i n)
De Quervain's syndrome is stenosing tenosynovitis of the short extensor (extensor pollicis brevis) and long abductor tendon (abductor pollicis longus) of the
thumb within the first extensor compartment.
De Querva i n's s yndrome us ua l l y occurs a fter repeti ti ve us e (es peci a l l y wri ngi ng) of the wri s t, a l though i t occa s i ona l l y occurs i n a s s oci a ti on wi th
RA. The ma jor s ymptom i s a chi ng pa i n a t the wri s t a nd thumb, a ggra va ted by moti on. Tendernes s ca n be el i ci ted jus t proxi ma l to the ra di a l s tyl oi d
proces s over the s i te of the i nvol ved tendon s hea ths . Di a gnos i s i s hi ghl y s ugges ted by the Fi nkel s tei n tes t. The pa ti ent a dducts the i nvol ved
thumb i nto the pa l m a nd wra ps the fi ngers over the thumb. The tes t i s pos i ti ve i f gentl e pa s s i ve ul na r devi a ti on of the wri s t provokes s evere pa i n
a t the a ffected tendon s hea ths .
Treatment
Corti cos teroi d i njecti on
Thumb s pi ca s pl i nt
Res t, wa rm s oa ks , a nd NSAIDs ma y hel p i n very mi l d ca s es . Loca l corti cos teroi d i njecti ons a nd a thumb s pi ca s pl i nt hel p 70 to 80% of ca s es .
Tendon rupture i s a ra re compl i ca ti on of i njecti on a nd ca n be prevented by confi ni ng i nfi l tra ti on to the tendon s hea th a nd a voi di ng i njecti on of
the corti cos teroi d i nto the tendon. Intra tendi nous l oca ti on of the needl e i s l i kel y i f i njecti on i s met wi th modera te or s evere res i s ta nce. Surgi ca l
rel ea s e of the fi rs t extens or compa rtment i s very effecti ve when cons erva ti ve thera py fa i l s .
Osteoarthritis of the Hand
Hand involvement is extremely common in osteoarthritis.
Os teoa rthri ti s a ffecti ng the ha nd ma y be a s ymptoma ti c enl a rgement of nodul es a t the proxi ma l i nterpha l a ngea l joi nt (Boucha rd's nodul es ) or
di s ta l i nterpha l a ngea l joi nt (Heberden's nodes ) or a ngul a ti on a t thes e joi nts . Pa i n a nd s ti ffnes s of thes e joi nts a nd the ba s e of the thumb a re
a l s o common. The wri s t us ua l l y i s s pa red, a nd there i s us ua l l y mi ni ma l or no meta ca rpopha l a ngea l joi nt i nvol vement unl es s the pa ti ent a l s o ha s
a meta bol i c di s order (eg, hemochroma tos i s ). Di fferenti a ti on of ha nd cha nges i n os teoa rthri ti s from thos e i n RA i s di s cus s ed i n
Ta bl e 32-7 on p. 296.
Treatment
Cons erva ti ve mea s ures
Occa s i ona l l y corti cos teroi d i njecti on or s urgery
Trea tment i s s ymptoma ti c wi th a na l ges i cs , a ppropri a te res t, s pl i nti ng, a nd occa s i ona l l y corti cos teroi d i njecti on a s needed. Surgi ca l procedures
ca n hel p rel i eve pa i n a nd correct deformi ty for s evere cha nges a t the ba s e of the thumb a nd, l es s commonl y, for a dva nced degenera ti on of the
i nterpha l a ngea l joi nts .
Chapter 44. Foot and Ankle Disorders

Introduction
Mos t foot probl ems res ul t from a na tomi c di s orders or a bnorma l functi on of a rti cul a r or extra -a rti cul a r s tructures (s ee
Fi g. 44-1). Les s commonl y, foot probl ems refl ect a s ys temi c di s order (s ee
Ta bl e 44-1).
In peopl e wi th di a betes a nd peopl e wi th peri phera l va s cul a r di s ea s e, ca reful exa mi na ti on of the feet, wi th eva l ua ti on of va s cul a r s uffi ci ency a nd
neurol ogi c i ntegri ty, s houl d be done a t l ea s t twi ce/yr. Peopl e wi th thes e di s ea s es s houl d exa mi ne thei r own feet a t l ea s t once/da y.
The feet a re a l s o common s i tes for corns a nd ca l l us es (s ee p. 660) a nd i nfecti ons by fungus (s ee Ti nea Pedi s on p. 708), ba cteri a (s ee p. 694), a nd
vi rus es (s ee Wa rts on p. 715).
Ta bl e 44-2 l i s ts foot a nd a nkl e di s orders a ccordi ng to a na tomi c s i te.
Ta bl e 44-3 l i s ts common ca us es of heel pa i n a ccordi ng to l oca ti on.
Tibialis Posterior Tendinosis
Tibialis posterior tendinosis, degeneration of the tibialis posterior tendon, is the most common cause of pain behind the medial malleolus.
The pos teri or ti bi a l tendon l i es i mmedi a tel y behi nd the medi a l ma l l eol us . Degenera ti on res ul ts from l ong-s ta ndi ng bi omecha ni ca l probl ems ,
s uch a s exces s i ve prona ti on often i n obes e peopl e. The tendon ca n a l s o be i nvol ved by pri ma ry i nfl a mma tory di s orders , s uch a s RA or gout.
Symptoms and Signs
Ea rl y on, pa ti ents experi ence occa s i ona l pa i n behi nd the medi a l ma l l eol us . Over ti me, the pa i n becomes s evere, wi th pa i nful s wel l i ng behi nd the
medi a l ma l l eol us . Norma l s ta ndi ng, wa l ki ng, a nd s ta ndi ng on the toes become di ffi cul t.
[Fig. 44-1. Bones of the foot.]
[Table 44-1. Foot Ma ni fes ta ti ons of Sys temi c Di s orders ]
Diagnosis
MRI
Cl i ni ca l fi ndi ngs s ugges t the di a gnos i s . Pa l pa ti on of the tendon i n a n i nverted-pl a nta r fl exed pos i ti on us ua l l y el i ci ts pa i n. Sta ndi ng on the toes i s
us ua l l y pa i nful a nd ma y not be pos s i bl e i f the tendon i s ruptured. Pa i n a nd s wel l i ng behi nd the medi a l ma l l eol us , es peci a l l y wi th ti bi a l i s
pos teri or tendon pa i n on
[Table 44-2. Common Foot a nd Ankl e Di s orders by Ana tomi c Si te]
pa l pa ti on, a re hi ghl y s ugges ti ve. MRI or ul tra s onogra phy ca n confi rm i njury to the tendon a nd i ts extent.
Treatment
Orthoti cs a nd bra ces or s urgery
Compl ete rupture requi res s urgery i f norma l functi on i s the goa l . Surgery i s es peci a l l y i mporta nt i n young a cti ve pa ti ents wi th a cute tea rs .
Cons erva ti ve thera py cons i s ts of mecha ni ca l l y off-l oa di ng the tendon by us i ng orthoti cs a nd a nkl e bra ces . Corti cos teroi d i njecti ons exa cerba te the
degenera ti ve proces s (s ee Si deba r 44-1). If the tendon i s i nfl a med, res t a nd a ggres s i ve a nti -i nfl a mma tory thera py a re wa rra nted.
Tarsal Tunnel Syndrome
(Pos teri or Ti bi a l Nerve Neura l gi a )
Tarsal tunnel syndrome is pain along the course of the posterior tibial nerve, usually resulting from nerve compression within the tarsal tunnel.
At the l evel of the a nkl e, the pos teri or ti bi a l nerve pa s s es through a fi bro-os s eous ca na l a nd di vi des i nto the medi a l a nd l a tera l pl a nta r nerves .
Ta rs a l tunnel s yndrome refers to compres s i on of the nerve wi thi n thi s ca na l , but the term ha s been l oos el y a ppl i ed to neura l gi a of the pos teri or
ti bi a l nerve res ul ti ng from a ny ca us e. Synovi ti s of the fl exor tendons of the a nkl e ca us ed by a bnorma l foot functi on, i nfl a mma tory a rthri ti s (eg, RA),
fra cture, a nd a nkl e venous s ta s i s edema a re contri buti ng fa ctors . Pa ti ents wi th hypothyroi di s m ma y devel op ta rs a l tunnel -l i ke s ymptoms a s a
res ul t of peri neura l muci n depos i ti on.
Symptoms and Signs
Pa i n (occa s i ona l l y burni ng a nd ti ngl i ng) i s us ua l l y retroma l l eol a r a nd s ometi mes i n the pl a nta r medi a l heel a nd ma y extend a l ong the pl a nta r
s urfa ce a s fa r a s the toes . Al though the pa i n i s wors e duri ng s ta ndi ng a nd wa l ki ng, pa i n a t res t ma y occur a s the di s order progres s es .
Diagnosis
Exa mi na ti on a nd el ectrodi a gnos ti c tes ti ng
Ta ppi ng or pa l pa ti ng the pos teri or ti bi a l nerve bel ow the medi a l ma l l eol us a t a s i te of compres s i on or i njury often ca us es di s ta l ti ngl i ng (Ti nel 's
s i gn). Whi l e fa l s e-nega ti ve res ul ts on el ectrodi a gnos ti c tes ts a re s omewha t common, a pos i ti ve hi s tory combi ned wi th s upporti ve phys i ca l
fi ndi ngs a nd pos i ti ve el ectrodi a gnos ti c res ul ts ma kes the di a gnos i s of ta rs a l tunnel s yndrome hi ghl y l i kel y. The ca us e of a ny s wel l i ng nea r the
nerve s houl d be determi ned.
Treatment
Foot i nvers i on, i njecti on, s urgery, or a combi na ti on
Stra ppi ng the foot i n a neutra l or s l i ghtl y i nverted pos i ti on or wea ri ng a n orthoti c tha t keeps the foot i nverted reduces nerve tens i on. Loca l
i nfi l tra ti on of a mi xture of a n i ns ol ubl e corti cos teroi d a nd a n a nes theti c ma y be effecti ve i f the ca us e i s i nfl a mma ti on or fi bros i s . Surgi ca l
decompres s i on ma y be neces s a ry to rel i eve s us pected fi bro-os s eus compres s i on wi th reca l ci tra nt s ymptoms .
[Table 44-3. Di s orders As s oci a ted wi th Heel Pa i n Accordi ng to Loca ti on]
Metatarsalgia
Metatarsalgia is a general term for pain in the area of the metatarsophalangeal joints (ball of the foot). Most common causes include Freiberg's disease,
interdigital nerve pain (Morton's neuroma), metatarsophalangeal joint pain, and sesamoiditis.
Freiberg's Disease
Freiberg's disease is avascular necrosis of the metatarsal head.
Frei berg's di s ea s e i s ca us ed by mi crotra uma a t the meta phys i s a nd growth pl a te. Ava s cul a r necros i s fl a ttens the meta ta rs a l hea d. The 2nd
meta ta rs a l hea d i s mos t often a ffected. Frei berg's di s ea s e occurs more frequentl y a mong puberta l fema l es a nd a mong peopl e who ha ve a s hort
1s t meta ta rs a l bone, whi ch i ncrea s es s tres s on the 2nd meta ta rs a l hea d a nd joi nt.
Symptoms and Signs
The pa i n i s mos t pronounced i n the forefoot a t the meta ta rs a l hea d wi th wei ght bea ri ng, pa rti cul a rl y when pus hi ng off or when wea ri ng hi ghheel ed footwea r. The meta ta rs opha l a ngea l joi nt ma y a l s o be s wol l en a nd ha ve l i mi ted a nd pa i nful pa s s i ve ra nge of moti on.
Diagnosis
X-ra ys
The di a gnos i s i s confi rmed wi th x-ra ys . Typi ca l l y, the hea d of the 2nd meta ta rs a l i s wi dened a nd fl a ttened, a nd the meta ta rs a l joi nt i s s cl eroti c
a nd i rregul a r.
Sidebar 44-1 Considerations for Using Corticosteroid Injections

Corti cos teroi d i njecti ons s houl d be us ed judi ci ous l y to a voi d a dvers e effects . Injecta bl e corti cos teroi ds s houl d be res erved for i nfl a mma ti on,
whi ch i s not pres ent i n mos t foot di s orders . Beca us e the ta rs us , a nkl e, retroca l ca nea l s pa ce, a nd dors um of the toes ha ve l i ttl e connecti ve ti s s ue
between the s ki n a nd underl yi ng bone, i njecti on of i ns ol ubl e corti cos teroi ds i nto thes e s tructures ma y ca us e depi gmenta ti on, a trophy, or
ul cera ti on, es peci a l l y i n el derl y pa ti ents wi th peri phera l a rteri a l di s ea s e.
Ins ol ubl e corti cos teroi ds ca n be gi ven deepl y ra ther tha n s uperfi ci a l l y wi th grea ter s a fety (eg, i n the heel pa d, ta rs a l ca na l , or meta ta rs a l
i nters pa ces ). The foot s houl d be i mmobi l i zed for a few da ys a fter tendon s hea ths a re i njected. Unus ua l res i s ta nce to i njecti on s ugges ts i njecti on
i nto a tendon. Repea ted i njecti on i nto a tendon s houl d be a voi ded beca us e the tendon ma y wea ken (pa rti a l l y tea r), predi s pos i ng to s ubs equent
rupture.
Treatment
Immobi l i za ti on a nd wei ght unl oa di ng i f a cute, then modi fi ca ti on of footwea r
Corti cos teroi d i njecti ons a nd i mmobi l i za ti on ma y hel p to a l l evi a te a cutel y pa i nful fl a re-ups . Long-term ma na gement ma y requi re orthos es wi th
meta ta rs a l ba rs a nd l ow-heel ed footwea r to reduce s tres s on the 2nd meta ta rs a l hea d a nd joi nt. Corti cos teroi d i njecti ons ca n be tri ed, a nd, ra rel y,
s urgi ca l exci s i on of the meta ta rs a l hea d ma y be neces s a ry to rel i eve reca l ci tra nt pa i n.
Interdigital Nerve Pain
(Morton's Neuroma /Neura l gi a )
Interdigital nerve irritation (neuralgia) or persistent benign enlargement of the perineurium (neuroma) can cause pain, which may be nonspecific, burning, or
lancinating, or a foreign body sensation. Diagnosis is usually clinical. Treatment may involve correction of footwear, local injection, or sometimes surgical
excision.
The i nterdi gi ta l nerves of the foot tra vel benea th a nd between the meta ta rs a l s , extendi ng di s ta l l y to i nnerva te the toes . Neura l gi a of the
i nterdi gi ta l nerve a l ong i ts di s ta l i nnerva ti on nea r the ba l l of the foot devel ops pri ma ri l y a s a res ul t of i mproper or cons tri cti ve footwea r or, l es s
commonl y, nerve tra cti on res ul ti ng from a bnorma l foot s tructure. As a res ul t of chroni c repeti ti ve tra uma , a beni gn thi ckeni ng of the nerve
devel ops (Morton's neuroma ).
Symptoms and Signs

Interdi gi ta l neura l gi a i s cha ra cteri zed by pa i n a round the meta ta rs a l hea ds or the toes . Ea rl y i nterdi gi ta l neura l gi a often ca us es a n occa s i ona l
mi l d a che or di s comfort i n the ba l l of the foot, us ua l l y when wea ri ng a s peci fi c s hoe, s uch a s thos e tha t a re too na rrow a t the front. Neura l gi a i s
us ua l l y uni l a tera l . As the condi ti on progres s es , the nerve thi ckens . The pa i n becomes wors e, often wi th a burni ng or l a nci na ti ng qua l i ty or
pa res thes i a s . In ti me, pa ti ents a re una bl e to wea r mos t s hoes . Whi l e wa l ki ng, pa ti ents often fa l s el y s ens e a pebbl e i n thei r s hoes , whi ch they
ta ke off for rel i ef. Neuroma mos t frequentl y a ffects the 3rd i nters pa ce. Onl y s l i ghtl y l es s common i s i nvol vement of the 2nd i nters pa ce. Someti mes
both i nters pa ces or feet a re i nvol ved s i mul ta neous l y.
Diagnosis
The s ymptoms a re often s peci fi c, a nd the di a gnos i s i s confi rmed by tendernes s on pl a nta r pa l pa ti on of the i nterdi gi ta l s pa ce a nd reproducti on of
the ra di a ti ng burni ng pa i n by s queezi ng the s pa ce. Al though MRI does not us ua l l y confi rm neuroma , i t ma y be us eful to rul e out other i nters pa ce
l es i ons or a rthri ti s ca us i ng s i mi l a r s ymptoms .
Treatment
Modi fi ca ti on of footwea r a nd i njecti on
Neura l gi a of recent ons et us ua l l y res ol ves qui ckl y wi th properl y fi tti ng s hoes a nd i ns ol es or wi th l oca l a nes theti c i njecti on. In contra s t, neuroma s
ma y requi re one or more peri neura l i nfi l tra ti ons of l ong-a cti ng corti cos teroi ds wi th a l oca l a nes theti c. Injecti on i s a t a 45 a ngl e to the foot, i nto
the i nters pa ce a t the l evel of the dors a l a s pect of the meta ta rs opha l a ngea l joi nts . An a ppropri a te orthoti c often rel i eves s ymptoms . If
cons erva ti ve thera py i s i neffecti ve, exci s i on often bri ngs compl ete rel i ef. However, a nother neuroma occa s i ona l l y devel ops a t the s i te of nerve
exci s i on (a mputa ti on or s tump neuroma ).
Metatarsophalangeal Joint Pain
Metatarsophalangeal joint pain usually results from tissue changes due to aberrant foot biomechanics. Symptoms and signs include pain with walking and
tenderness. Diagnosis is clinical; however, infection or systemic rheumatic diseases (eg, RA) may need to be excluded by testing. Treatment includes orthotics,
sometimes local injection, and occasionally surgery.
Meta ta rs opha l a ngea l joi nt pa i n mos t commonl y res ul ts from mi s a l i gnment of the joi nt s urfa ces wi th a l tered foot bi omecha ni cs , ca us i ng joi nt
s ubl uxa ti ons , ca ps ul a r i mpi ngement, a nd joi nt ca rti l a ge des tructi on (os teoa rthros i s ). Mi s a l i gned joi nts ma y ca us e s ynovi a l i mpi ngement, wi th
mi ni ma l i f a ny hea t a nd s wel l i ng (os teoa rthri ti c s ynovi ti s ).
Meta ta rs opha l a ngea l joi nt s ubl uxa ti ons a l s o occur a s a res ul t of i nfl a mma tory a rthropa thy, pa rti cul a rl y RA. Infl a mma tory s ynovi ti s a nd
i nteros s eous mus cl e a trophy i n RA l ea d to s ubl uxa ti ons of the l es s er meta ta rs opha l a ngea l joi nts a s wel l , res ul ti ng i n ha mmer toe deformi ti es .
Cons equentl y, the meta ta rs a l fa t pa d, whi ch us ua l l y cus hi ons the s tres s between the meta ta rs a l s a nd i nterdi gi ta l nerves duri ng wa l ki ng, moves
di s ta l l y under the toes ; i nterdi gi ta l neura l gi a or Morton's neuroma ma y res ul t. To compens a te for the l os s of cus hi oni ng, a dventi ti a l ca l l us es a nd
burs a e ma y devel op.
Meta ta rs opha l a ngea l joi nt pa i n ma y a l s o res ul t from functi ona l ha l l ux l i mi tus , whi ch l i mi ts pa s s i ve a nd a cti ve joi nt moti on a nd us ua l l y occurs a t
the 1s t meta ta rs opha l a ngea l joi nt. Pa ti ents us ua l l y ha ve foot prona ti on di s orders tha t res ul t i n el eva ti on of the 1s t ra y wi th l oweri ng of the
medi a l l ongi tudi na l a rch duri ng wei ght bea ri ng. As a res ul t of the 1s t ra y el eva ti on, the proxi ma l pha l a nx of the grea t toe ca nnot freel y extend on
the 1s t meta ta rs a l hea d; the res ul t i s ja mmi ng a t the dors a l joi nt l ea di ng to os teoa rthri ti c cha nges a nd l os s of joi nt moti on. Over ti me, pa i n ma y
devel op, a nd the joi nt ma y become l es s mobi l e wi th a n a rthros i s (ha l l ux ri gi dus ), whi ch ca n be debi l i ta ti ng.
Symptoms and Signs
Symptoms i ncl ude pa i n on wa l ki ng. Dors a l a nd pl a nta r joi nt tendernes s i s us ua l l y pres ent on pa l pa ti on a nd duri ng pa s s i ve ra nge of moti on. Mi l d
s wel l i ng wi th mi ni ma l hea t occurs i n os teoa rthri ti c s ynovi ti s . Si gni fi ca nt wa rmth, s wel l i ng, or rednes s s ugges ts i nfl a mma tory a rthropa thi es or
i nfecti on.
Diagnosis
Ma i nl y cl i ni ca l eva l ua ti on
Excl us i on of i nfecti on or a rthropa thy i f s i gns of i nfl a mma ti on
Meta ta rs opha l a ngea l joi nt pa i n ca n us ua l l y be di fferenti a ted from neura l gi a or neuroma of the i nterdi gi ta l nerves by the a bs ence of burni ng,
numbnes s , a nd ti ngl i ng a nd i nters pa ce pa i n, a l though thes e s ymptoms ma y devel op from joi nt i nfl a mma ti on; i f s o, pa l pa ti on ca n hel p wi th
di fferenti a ti on.
Mona rti cul a r hea t, rednes s , a nd s wel l i ng i ndi ca te i nfecti on unti l proven otherwi s e, a l though gout i s more l i kel y. When wa rmth, rednes s , a nd
s wel l i ng i nvol ve mul ti pl e joi nts , eva l ua ti on for a s ys temi c ca us e of joi nt i nfl a mma ti on (eg, gout, RA, vi ra l -a s s oci a ted a rthri ti s , enteropa thi c
a rthri ti s ) wi th a rheuma ti c di s ea s e a s s es s ment (eg, a nti nucl ea r a nti bodi es , rheuma toi d fa ctor, ESR) i s i ndi ca ted.
Treatment
Orthos es
Foot orthos es ma y hel p to redi s tri bute a nd rel i eve pres s ure from the noni nfl a med joi nts . Wi th exces s s ubta l a r evers i on or when the feet a re
hi ghl y a rched, a n orthoti c tha t corrects thes e a bnorma l moti ons s houl d be pres cri bed. For functi ona l ha l l ux l i mi tus , orthos i s modi fi ca ti ons ma y
further hel p to pl a nta rfl ex the 1s t ra y to i mprove meta ta rs opha l a ngea l joi nt moti on a nd reduce pa i n. For more s evere l i mi ta ti on of 1s t
meta ta rs opha l a ngea l moti on or pa i n, the us e of ri gi d orthos es , ca rbon fi ber pl a tes , or externa l s hoe ba rs or rocker s ol es ma y be neces s a ry to
reduce moti on a t the joi nt. Surgery ma y be needed i f cons erva ti ve thera pi es a re i neffecti ve. If i nfl a mma ti on (s ynovi ti s ) i s pres ent, i njecti on of a
l oca l corti cos teroi d/a nes theti c mi xture ma y be us eful .
Sesamoiditis
Sesamoiditis is pain at the sesamoid bones beneath the head of the 1st metatarsal, with or without inflammation or fracture. Diagnosis is usually clinical.
Treatment is usually modification of footwear.
The 2 s emi l una r-s ha ped s es a moi d bones a i d the foot i n l ocomoti on. The medi a l bone i s the ti bi a l s es a moi d, a nd the l a tera l bone i s the fi bul a r
s es a moi d. Di rect tra uma or pos i ti ona l cha nge of the s es a moi ds due to a l tera ti ons i n foot s tructure (eg, l a tera l di s pl a cement of a s es a moi d due to
l a tera l devi a ti on of the grea t toe) ca n ma ke the s es a moi ds pa i nful . Ses a moi di ti s i s pa rti cul a rl y common a mong da ncers , joggers , a nd thos e who
ha ve hi gh-a rched feet or wea r hi gh heel s . Ma ny peopl e wi th s es a moi di ti s ha ve buni ons .
Symptoms and Signs
The pa i n of s es a moi di ti s i s benea th the hea d of the 1s t meta ta rs a l ; the pa i n i s us ua l l y ma de wors e by wa l ki ng a nd ma y be wors e when wea ri ng
certa i n s hoes . Occa s i ona l l y, i nfl a mma ti on occurs , ca us i ng mi l d wa rmth a nd s wel l i ng or occa s i ona l l y rednes s tha t ma y extend medi a l l y a nd a ppea r
to i nvol ve the 1s t meta ta rs opha l a ngea l joi nt. Ses a moi d fra cture ca n a l s o ca us e pa i n, modera te s wel l i ng, a nd pos s i bl y i nfl a mma ti on.
Diagnosis
Ima gi ng i f fra cture, i nfecti on, or gout i s s us pected
Wi th the foot a nd 1s t (bi g) toe dors i fl exed, the exa mi ner i ns pects the meta ta rs a l hea d a nd pa l pa tes ea ch s es a moi d. Tendernes s i s l oca l i zed to a
s es a moi d, us ua l l y the ti bi a l s es a moi d. Hyperkera toti c ti s s ue ma y i ndi ca te tha t a wa rt or corn i s ca us i ng pa i n. If i nfl a mma ti on ca us es s wel l i ng
a round the 1s t meta ta rs opha l a ngea l joi nt, a rthrocentes i s i s us ua l l y i ndi ca ted to excl ude gout a nd i nfecti ous a rthri ti s . If fra cture, os teoa rthri ti s , or
di s pl a cement i s s us pected, x-ra ys a re ta ken. Ses a moi ds s epa ra ted by ca rti l a ge or fi brous ti s s ue (bi pa rti te s es a moi ds ) ma y a ppea r fra ctured on xra ys . If pl a i n x-ra ys a re equi voca l , MRI ma y be ordered.
Treatment
New s hoes , orthoti cs , or both
Si mpl y not wea ri ng the s hoes tha t ca us e pa i n ma y be s uffi ci ent. If s ymptoms pers i s t, s hoes wi th a thi ck s ol e a nd orthoti cs a re pres cri bed a nd hel p
by reduci ng s es a moi d pres s ure. If fra cture wi thout di s pl a cement i s pres ent, cons erva ti ve thera py ma y be s uffi ci ent a nd ma y a l s o i nvol ve
i mmobi l i za ti on of the joi nt wi th the us e of a fl a t, ri gi d, s urgi ca l s hoe. NSAIDs a nd i njecti ons of a corti cos teroi d/l oca l a nes theti c s ol uti on ca n be
hel pful . Al though s urgery ma y hel p i n reca l ci tra nt ca s es , i t i s controvers i a l beca us e of the potenti a l for di s turbi ng bi omecha ni cs a nd l ocomoti on
of the foot. If i nfl a mma ti on i s pres ent, trea tment i ncl udes cons erva ti ve mea s ures pl us l oca l i nfi l tra ti on of a corti cos teroi d/a nes theti c s ol uti on to
hel p reduce s ymptoms .
Plantar Fasciosis
(Pl a nta r Fa s ci i ti s )
Plantar fasciosis is pain at the site of the attachment of the plantar fascia and the calcaneus, with or without accompanying pain along the medial band of the
plantar fascia. Diagnosis is mainly clinical. Treatment involves calf muscle and plantar soft-tissue foot-stretching exercises, night splints, and orthotics.
Syndromes of pa i n i n the pl a nta r fa s ci a ha ve been ca l l ed pl a nta r fa s ci i ti s ; however, beca us e there i s us ua l l y no i nfl a mma ti on, pl a nta r fa s ci os i s i s
more correct. Other terms us ed i ncl ude ca l ca nea l enthes opa thy pa i n or ca l ca nea l s pur s yndrome; however, there ma y be no bone s purs on the
ca l ca neus . Pl a nta r fa s ci os i s ma y i nvol ve a cute or chroni c s tretchi ng, tea ri ng, a nd degenera ti on of the fa s ci a a t i ts a tta chment s i te.
Etiology
Recogni zed ca us es i ncl ude s horteni ng or contra cture of the ca l f mus cl es a nd pl a nta r fa s ci a . Ri s k fa ctors for s uch s horteni ng i ncl ude a s edenta ry
l i fes tyl e, occupa ti ons requi ri ng s i tti ng, very hi gh or l ow a rches i n the feet, a nd wea ri ng hi gh-heel s hoes . The di s order i s a l s o common a mong
runners a nd da ncers a nd ma y occur i n peopl e whos e occupa ti ons i nvol ve s ta ndi ng or wa l ki ng on ha rd s urfa ces for prol onged peri ods . Di s orders
tha t ma y be a s s oci a ted wi th pl a nta r fa s ci os i s a re obes i ty, RA, rea cti ve a rthri ti s , a nd ps ori a ti c a rthri ti s . Mul ti pl e i njecti ons of corti cos teroi ds ma y
contri bute by ca us i ng degenera ti ve cha nges of the fa s ci a a nd pos s i bl e l os s of the cus hi oni ng s ubca l ca nea l fa t pa d.
Symptoms and Signs
Pl a nta r fa s ci os i s i s cha ra cteri zed by pa i n a t the bottom of the heel on wei ght bea ri ng, pa rti cul a rl y when fi rs t a ri s i ng i n the morni ng; pa i n us ua l l y
i mproves wi thi n 5 to 10 mi n, onl y to return l a ter i n the da y. It i s often wors e when pus hi ng off of the heel (the propul s i ve pha s e of ga i t). Acute
s evere heel pa i n, es peci a l l y wi th mi l d l oca l puffi nes s , ma y i ndi ca te a n a cute tea r. Some pa ti ents des cri be burni ng or s ti cki ng pa i n a l ong the
pl a nta r medi a l border of the foot when wa l ki ng.
Diagnosis
Pa i n reproduced by ca l ca nea l pres s ure duri ng dors i fl exi on
Other di s orders ca us i ng heel pa i n ca n mi mi c pl a nta r fa s ci os i s :

Throbbi ng heel pa i n, pa rti cul a rl y when the s hoes a re removed or when mi l d hea t a nd puffi nes s a re pres ent, i s more s ugges ti ve of ca l ca nea l
burs i ti s (s ee p. 401).
Acute s evere retroca l ca nea l pa i n, wi th rednes s a nd hea t, ma y i ndi ca te gout.
Pa i n tha t ra di a tes from the l ow ba ck to the heel ma y be a n S1 ra di cul opa thy due to a n L5 di s k herni a ti on.
Pl a nta r fa s ci os i s i s confi rmed i f fi rm thumb pres s ure a ppl i ed to the ca l ca neus when the foot i s dors i fl exed el i ci ts pa i n. Fa s ci a l pa i n a l ong the
pl a nta r medi a l border of the fa s ci a ma y a l s o be pres ent. If fi ndi ngs a re equi voca l , demons tra ti on of a heel s pur on x-ra y ma y s upport the
di a gnos i s ; however, a bs ence does not rul e out the di a gnos i s , a nd vi s i bl e s purs a re not genera l l y the ca us e of s ymptoms . Al s o, i nfrequentl y,
ca l ca nea l s purs a ppea r i l l defi ned on x-ra y, exhi bi ti ng fl uffy new bone forma ti on, s ugges ti ng s pondyl oa rthropa thy (eg, a nkyl os i ng s pondyl i ti s ,
rea cti ve a rthri ti s ). If a n a cute fa s ci a l tea r i s s us pected, MRI i s done.
Treatment
Spl i nti ng, s tretchi ng, a nd cus hi oni ng or orthoti cs
To a l l evi a te the s tres s a nd pa i n on the fa s ci a , the pers on ca n ta ke s horter s teps a nd a voi d wa l ki ng ba refoot. Acti vi ti es tha t i nvol ve foot i mpa ct,
s uch a s joggi ng, s houl d be a voi ded. The mos t effecti ve trea tments i ncl ude the us e of i n-s hoe heel a nd a rch cus hi oni ng wi th ca l f-s tretchi ng
exerci s es a nd ni ght s pl i nti ng devi ces tha t s tretch the ca l f a nd pl a nta r fa s ci a whi l e the pa ti ent s l eeps . Prefa bri ca ted or cus tom-ma de foot orthoti cs
ma y a l s o a l l evi a te fa s ci a l tens i on a nd s ymptoms . Other trea tments ma y i ncl ude a cti vi ty modi fi ca ti ons , NSAIDs , wei ght l os s i n obes e pa ti ents , col d
a nd i ce ma s s a ge thera py, a nd occa s i ona l corti cos teroi d i njecti ons . However, beca us e corti cos teroi d i njecti ons ca n predi s pos e to pl a nta r fa s ci os i s ,
ma ny cl i ni ci a ns l i mi t thes e i njecti ons . For reca l ci tra nt ca s es , phys i ca l medi ci ne, ora l corti cos teroi ds , a nd ca s t i mmobi l i za ti on s houl d be us ed
before s urgi ca l i nterventi on i s cons i dered.
Inferior Calcaneal Bursitis
Burs i ti s ca n devel op a t the i nferi or ca l ca neus , nea r the i ns erti on of the pl a nta r fa s ci a . Symptoms a nd s i gns i ncl ude throbbi ng heel pa i n,
pa rti cul a rl y when the s hoes a re removed; mi l d wa rmth; a nd s wel l i ng. The pa i n i s mos t pronounced when the heel fi rs t conta cts the ground duri ng
wa l ki ng or runni ng a cti vi ty. Trea tment i s i njecti on of a l oca l a nes theti c/corti cos teroi d mi xture a nd s oft-s ol ed s hoes wi th a dded protecti ve heel
cus hi on pa ddi ng.
Achilles Tendon Enthesopathy
Achilles tendon enthesopathy is pain at the insertion of the Achilles tendon at the posterosuperior aspect of the calcaneus.
The ca us e i s chroni c tra cti on of the Achi l l es tendon on the ca l ca neus . Contra cted or s hortened ca l f mus cl es (res ul ti ng from a s edenta ry l i fes tyl e
a nd obes i ty) a nd a thl eti c overus e a re fa ctors . Enthes opa thy ma y be ca us ed by a s pondyl oa rthropa thy.
Pa i n a t the pos teri or heel bel ow the top of the s hoe counter duri ng a mbul a ti on i s cha ra cteri s ti c. Pa i n on pa l pa ti on of the tendon a t i ts i ns erti on i s
di a gnos ti c. Ma nua l dors i fl exi on of the a nkl e duri ng pa l pa ti on us ua l l y exa cerba tes the pa i n. Recurrent a nd es peci a l l y mul ti foca l enthes i ti s s houl d
prompt eva l ua ti on (hi s tory a nd exa mi na ti on) for a s pondyl oa rthropa thy.
Treatment
Stretchi ng, s pl i nti ng, a nd heel l i fts
Phys i ca l thera py a i med a t ca l f mus cl e s tretchi ng s houl d be done 10 mi n three ti mes /da y. The pa ti ent ca n exert pres s ure pos teri orl y to s tretch the
ca l f mus cl e whi l e fa ci ng a wa l l a t a rms ' l ength, wi th knees extended a nd foot dors i fl exed. To mi ni mi ze s tres s to the Achi l l es tendon wi th wei ght
bea ri ng, the pa ti ent s houl d move the foot a nd a nkl e a cti vel y through thei r ra nge of moti on for a bout 1 mi n when ri s i ng a fter extended peri ods of
res t. Ni ght s pl i nts ma y a l s o be pres cri bed to provi de pa s s i ve s tretch duri ng s l eep a nd hel p prevent contra ctures . Heel l i fts s houl d be us ed
tempora ri l y to decrea s e tendon s tres s duri ng wei ght bea ri ng a nd rel i eve pa i n. Heel l i fts s houl d be us ed bi l a tera l l y to prevent ga i t di s turba nce
even i f pa i n i s onl y i n one heel .
Anterior Achilles Tendon Bursitis
(Al bert's Di s ea s e; Retroma l l eol a r Burs i ti s )
Anterior Achilles tendon bursitis is inflammation of the retromalleolar (retrocalcaneal) bursa, located anterior (deep) to the attachment of the Achilles tendon to
the calcaneus.
Burs i ti s i s due to tra uma (eg, from ri gi d or poorl y fi tti ng s hoes ) or i nfl a mma tory a rthri ti s (eg, RA, gout). On occa s i on, s ma l l ca l ca nea l eros i ons ma y
devel op from s evere i nfl a mma ti on.
Symptoms and Signs
Symptoms a nd s i gns ca us ed by tra uma or gout devel op ra pi dl y; thos e ca us ed by a nother s ys temi c di s order devel op gra dua l l y. Pa i n, s wel l i ng, a nd
wa rmth a round the heel a re common, a s a re di ffi cul ty wa l ki ng a nd wea ri ng s hoes . The burs a i s tender. Ini ti a l l y, the s wel l i ng i s l oca l i zed a nteri or
to the Achi l l es tendon but i n ti me extends medi a l l y a nd l a tera l l y.
Us i ng the thumb a nd i ndex fi nger, s i de-to-s i de compres s i on a nteri or to the Achi l l es tendon ca us es pa i n.
Diagnosis
Cl i ni ca l eva l ua ti on a nd x-ra ys
Fra cture of the pos terol a tera l ta l a r tubercl e a l s o ca us es tendernes s a nteri or to the i ns erti on of the Achi l l es tendon. Burs i ti s i s often
di fferenti a ted from the fra cture by the l oca l i za ti on of wa rmth a nd s wel l i ng conti guous to the tendon a nd pa i n l oca l i zed pri ma ri l y i n the s oft
ti s s ue. Al s o, x-ra ys a re ta ken to rul e out fra cture a s wel l a s eros i ve ca l ca nea l cha nges cha ra cteri s ti c of chroni c RA or other rheuma ti c di s orders .
Treatment
Intra burs a l i njecti on of a s ol ubl e corti cos teroi d/a nes theti c s ol uti on
A corti cos teroi d/a nes theti c i njecti on, NSAIDs , a nd wa rm or col d compres s es ma y be effecti ve. Ca re mus t be ta ken to i nject onl y the burs a l s a c a nd
not the tendon proper beca us e tendon i njecti on ma y l ea d to tendon wea keni ng or tea ri ng, predi s pos i ng to s ubs equent rupture.
Posterior Achilles Tendon Bursitis
Posterior Achilles tendon bursitis is inflammation of a bursa that forms in response to shoe pressure and is located at the top edge of the posterior shoe counter
between the skin and Achilles tendon.
Thi s di s order occurs ma i nl y i n young women. Wea ri ng hi gh-heel ed s hoes i s a ri s k fa ctor. Ma ny pa ti ents ha ve a bony promi nence (Ha gl und's
deformi ty) on the ca l ca neus .
Symptoms and Signs
Symptoms a nd s i gns devel op a t the top edge of the pos teri or s hoe counter. Ea rl y s ymptoms ma y be l i mi ted to rednes s , pa i n, a nd wa rmth. La ter,
s uperfi ci a l s ki n eros i on ma y occur. After months or l onger, a fl uctua nt, tender, cys ti c nodul e 1- to 3-cm i n di a meter devel ops . It i s red or fl es hcol ored. In chroni c ca s es , the burs a becomes fi broti c.
Diagnosis
Symptoms a nd a s ma l l , tender, fl es h-col ored or red nodul e
The pres ence of the s ma l l , tender, fl es h-col ored or red nodul e i n a pa ti ent wi th compa ti bl e s ymptoms i s di a gnos ti c. Ra rel y, a n Achi l l es tendon
xa nthoma devel ops a t the top edge of the pos teri or s hoe counter but tends to be pi nk a nd a s ymptoma ti c. Achi l l es tendon enthes opa thy ca us es
pa i n ma i nl y a t the tendon's i ns erti on but ma y a l s o ca us e pa i n a t the top edge of the pos teri or s hoe counter. Enthes opa thy i s di fferenti a ted by the
a bs ence of a s oft-ti s s ue l es i on.
Treatment
Modi fi ca ti on of footwea r
Properl y fi tti ng s hoes wi th l ow heel s a re es s enti a l . A foa m rubber or fel t heel pa d ma y be needed to l i ft the heel hi gh enough s o tha t the burs a
does not hi t the s hoe counter. Pa ddi ng a round the burs a or the wea ri ng of a ba ckl es s s hoe unti l i nfl a mma ti on s ubs i des i s i ndi ca ted. Foot
orthoti cs ma y enha nce rea r foot s ta bi l i ty a nd hel p reduce i rri ta ti ng moti on on the pos teri or ca l ca neus whi l e wa l ki ng. Wa rm or cool compres s es ,
NSAIDs , a nd i ntra burs a l i njecti on of a l oca l a nes theti c/corti cos teroi d s ol uti on offer tempora ry rel i ef; the Achi l l es tendon i ts el f mus t not be
i njected. Surgi ca l remova l of a porti on of the underl yi ng bone ma y ra rel y be neces s a ry to reduce s oft-ti s s ue i mpi ngement.
Epiphysitis of the Calcaneus
(Sever's Di s ea s e)
Epiphysitis of the calcaneus is painful disruption between the calcaneal apophysis and the body of the heel that occurs before calcaneal ossification is complete.
The ca l ca neus devel ops from two centers of os s i fi ca ti on: one begi ns a t bi rth, the other us ua l l y a fter a ge 8. Os s i fi ca ti on i s us ua l l y compl ete by a ge
15. The ca rti l a gi nous di s rupti on i n ca l ca nea l epi phys i ti s ma y res ul t from a n exces s i ve pul l on the a pophys i s by contra cted or s hortened ca l f
mus cl es . Bone growth s purts wi thout a da pti ve ca l f mus cl e l engtheni ng ma y pl a y a rol e.
Pa i n devel ops i n a pa ti ent (us ua l l y a ged 9 to 14) wi th a hi s tory of a thl eti c a cti vi ty; i t a ffects the s i des or ma rgi ns of the heel a nd i s a ggra va ted by
s ta ndi ng on ti p toes or runni ng. Wa rmth a nd s wel l i ng a re occa s i ona l l y pres ent.
The di a gnos i s i s cl i ni ca l . X-ra ys a re not hel pful .
Treatment
Heel pa ds a nd s pl i nti ng or ca s ti ng
Heel pa ds rel i eve s ymptoms by reduci ng the pul l of the Achi l l es tendon on the heel . Ni ght s pl i nts ma y be us ed to pa s s i vel y s tretch the ca l f
mus cl es , hel pi ng ma i nta i n fl exi bi l i ty. In more s evere or reca l ci tra nt ca s es , ca s t i mmobi l i za ti on ma y be us ed to rel i eve pa i n a nd s tretch the ca l f
mus cl es . Rea s s ura nce i s i mporta nt beca us e s ymptoms ma y l a s t s evera l months .
Medial Plantar Nerve Entrapment
Medial plantar nerve entrapment is symptomatic compression of the medial branch of the posterior tibial nerve at the medial heel.
Symptoms i ncl ude a l mos t cons ta nt pa i n, wi th a nd wi thout wei ght bea ri ng. Si mpl e s ta ndi ng i s often di ffi cul t. Burni ng, numbnes s , a nd
pa res thes i a s a re us ua l l y a bs ent.
Diagnosis
Medi a l pl a nta r nerve entra pment ma y be confus ed wi th pl a nta r fa s ci os i s a nd heel s pur pa i n a s wel l a s ta rs a l tunnel s yndrome. In medi a l pl a nta r
nerve entra pment, the fol l owi ng a re pres ent:
Tendernes s i s a t the medi a l heel .
Other s i gns of ta rs a l tunnel s yndrome a re a bs ent.
Symptoms ca n be reproduced by pa l pa ti on over the proxi ma l a s pect of the a bductor ha l -l uci s , the ori gi n of the pl a nta r fa s ci a , or both a t the
medi a l tubercl e of the ca l ca neus .
Treatment
Orthos es , i mmobi l i za ti on, a nd phys i ca l thera py
Immobi l i za ti on a nd foot orthos es to prevent i rri ta ti ng moti on a nd pres s ure ma y be hel pful , a s ma y phys i ca l thera py a nd cryothera py. If thes e
trea tments a re i neffecti ve, i njecti on wi th a s cl eros i ng a gent tha t conta i ns a l cohol or ca reful s urgi ca l decompres s i on of the nerve ma y hel p rel i eve
pa i n.
Plantar Fibromatosis
Plantar fibromatosis is a benign proliferative neoplasia of the plantar fascia.
In pl a nta r fi broma tos i s , nodul es a re di s pl a yed mos t ea s i l y when the foot i s dors i fl exed a ga i ns t the l eg. Mos t pa ti ents a l s o ha ve pa l ma r nodul es ,
us ua l l y l oca ted a t the 4th meta ca rpopha l a ngea l joi nt. Reported a s s oci a ti ons wi th di a betes , epi l eps y, a nd a l cohol i s m ma y be a necdota l .
Trea tment i s us ua l l y not i ndi ca ted unl es s the nodul es become l a rge enough to ca us e pres s ure-rel a ted pa i n wi th wei ght bea ri ng. If s o, orthos es
ca n hel p redi s tri bute pres s ure a wa y from the fi broti c nodul a r l es i ons . Surgery us ua l l y res ul ts i n recurrence a nd ma y a l s o res ul t i n uni ntenti ona l
i ns ta bi l i ty of the foot when fa s ci a l remova l i s exces s i ve.
Hammer Toe Deformity
Hammer toe is a C-shaped deformity caused by dorsal subluxation at the metatarsophalangeal joint.
[
Fig. 44-2. Ha mmer toe.]
The us ua l ca us e i s mi s a l i gnment of the joi nt s urfa ces due to a geneti c predi s pos i ti on towa rd a berra nt foot bi omecha ni cs a nd tendon
contra ctures . RA a nd neurol ogi c di s orders s uch a s Cha rcot-Ma ri e-Tooth di s ea s e a re other ca us es . The 2nd toe i s the mos t common di gi t to devel op
a ha mmer toe deformi ty (s ee Fi g. 44-2). Second toe ha mmer toes commonl y res ul t from a n el onga ted 2nd meta ta rs a l a nd from pres s ure due to a n
exces s i vel y a bducted grea t toe (ha l l ux va l gus deformi ty) ca us i ng a buni on (s ee bel ow). Pa i nful corns (s ee p. 660) often devel op i n ha mmer toe
deformi ty, pa rti cul a rl y of the 5th toe. Rea cti ve a dventi ti a l burs a s often devel op benea th corns , whi ch ma y become i nfl a med.
Symptoms i ncl ude pa i n whi l e wea ri ng s hoes , es peci a l l y s hoes wi th l ow a nd na rrow toe boxes , a nd s ometi mes meta ta rs a l gi a . Di a gnos i s i s
cl i ni ca l . Joi nts a re exa mi ned for coexi s tent a rthri ti s (eg, RA).
Treatment
Wi de toe box, toe pa ds , orthoti cs , or a combi na ti on
Shoes s houl d ha ve a wi de toe box. Toe pa ds s ol d i n pha rma ci es a l s o hel p by s hi el di ng the a ffected toes from the overl yi ng s hoe. If thes e
mea s ures a re i neffecti ve, s urgi ca l correcti on of the deformi ty often rel i eves s ymptoms . If there i s a ccompa nyi ng meta ta rs a l gi a , OTC or pres cri pti on
orthoti c devi ces wi th meta ta rs a l pa ds a nd cus hi oni ng ma y hel p a l l evi a te the pa i n.
Bunion
Bunion is a prominence of the medial portion of the head of the 1st metatarsal bone. The cause is often variations in position of the 1st metatarsal bone or great
toe, such as lateral angulation of the great toe (hallux valgus). Secondary osteoarthritis and spur formation are common. Symptoms may include pain and
redness, bursitis medial to the joint, and mild synovitis. Diagnosis is usually clinical. Treatment is usually a shoe with a wide toe box, protective pads, and
orthotics. For bursitis or synovitis, corticosteroid injection may be helpful.
Contri buti ng fa ctors ma y i ncl ude exces s i ve turni ng i n (prona ti on) of the a nkl es , wea ri ng ti ght a nd poi nted-toe s hoes , a nd occa s i ona l l y tra uma .
Joi nt mi s a l i gnment ca us es os teoa rthri ti s wi th ca rti l a ge eros i on a nd exos tos i s forma ti on, res ul ti ng i n joi nt moti on bei ng l i mi ted (ha l l ux l i mi tus ) or
el i mi na ted (ha l l ux ri gi dus ). In l a te s ta ges , s ynovi ti s occurs , ca us i ng joi nt s wel l i ng. In rea cti on to pres s ure from ti ght s hoes , a n a dventi ti ous burs a
ca n devel op medi a l to the joi nt promi nence, whi ch ca n become pa i nful , s wol l en, a nd i nfl a med (s ee
Fi g. 44-3).
Symptoms and Signs

The i ni ti a l s ymptom ma y be pa i n a t the joi nt promi nence when wea ri ng certa i n s hoes . The joi nt ca ps ul e ma y be tender a t a ny s ta ge. La ter
s ymptoms ma y i ncl ude a pa i nful , wa rm, red, cys ti c, mova bl e, fl uctua nt s wel l i ng l oca ted medi a l l y (a dventi ti a l burs i ti s ) a nd s wel l i ngs a nd mi l d
i nfl a mma ti on a ffecti ng the enti re joi nt (os teoa rthri ti c s ynovi ti s ), whi ch i s more ci rcumferenti a l . Wi th ha l l ux l i mi tus or ri gi dus , there i s res tri cti on
of pa s s i ve joi nt moti on, tendernes s of the l a tera l a s pect of the joi nt, a nd i ncrea s ed dors i fl exi on of the di s ta l pha l a nx.
[Fig. 44-3. Buni on.]
Diagnosis
Cl i ni ca l fi ndi ngs a re us ua l l y s peci fi c. Acute ci rcumferenti a l i ntens e pa i n, wa rmth, s wel l i ng, a nd rednes s s ugges t gouty a rthri ti s or i nfecti ous
a rthri ti s , ma nda ti ng exa mi na ti on of s ynovi a l fl ui d. If mul ti pl e joi nts a re a ffected, gout or a nother s ys temi c rheuma ti c di s ea s e s houl d be
cons i dered. If cl i ni ca l di a gnos i s of os teoa rthri ti c s ynovi ti s i s equi voca l , x-ra ys a re ta ken. Sugges ti ve fi ndi ngs i ncl ude joi nt s pa ce na rrowi ng a nd
bony s purs extendi ng from the meta ta rs a l hea d or s ometi mes from the ba s e of the proxi ma l pha l a nx. Peri a rti cul a r eros i ons (Ma rtel 's s i gn) s een
on i ma gi ng s tudi es s ugges t gout.
Treatment
Wi de toe box, buni on pa ds , orthoti cs , or a combi na ti on
Trea tment of compl i ca ti ons
Mi l d di s comfort ma y l es s en by wea ri ng a s hoe wi th a wi de toe box. If not, buni on pa ds purcha s ed i n mos t pha rma ci es ca n s hi el d the pa i nful a rea .
Orthoti cs ca n a l s o be pres cri bed to redi s tri bute a nd rel i eve pres s ure from the a ffected a rti cul a ti on. If cons erva ti ve thera py fa i l s or i f the pa ti ent i s
unwi l l i ng to wea r l a rge, wi de s hoes a nd orthoti cs beca us e they a re una ttra cti ve, s urgery a i med a t correcti ng a bnorma l bony a l i gnments a nd
res tori ng joi nt mobi l i ty s houl d be s trongl y cons i dered. For burs i ti s , burs a l a s pi ra ti on a nd i njecti on of a corti cos teroi d a re i ndi ca ted. For
os teoa rthri ti c s ynovi ti s , ora l NSAIDs or a n i ntra -a rti cul a r i njecti on of a corti cos teroi d/a nes theti c s ol uti on reduces s ymptoms . For ha l l ux l i mi tus or
ha l l ux ri gi dus , trea tment a i ms to pres erve joi nt mobi l i ty by us i ng pa s s i ve s tretchi ng exerci s es , whi ch occa s i ona l l y requi re i njecti on of a l oca l
a nes theti c to rel i eve mus cl e s pa s m. Someti mes s urgi ca l rel ea s e of contra ctures i s neces s a ry.
Chapter 45. Tumors of Bones and Joints

Introduction
Bone tumors ma y be pri ma ry or meta s ta ti c a nd beni gn or ma l i gna nt.
In chi l dren, mos t bone tumors a re pri ma ry a nd beni gn; s ome a re ma l i gna nt pri ma ry tumors (eg, os teos a rcoma , Ewi ng's s a rcoma ). Very few a re
meta s ta ti c tumors (eg, neurobl a s toma , Wi l ms ' tumor). Bone a l s o ca n be a ffected by chi l dhood l eukemi a a nd l ymphoma s .
In a dul ts , es peci a l l y thos e over a ge 40, meta s ta ti c tumors a re a bout 100 ti mes more common tha n pri ma ry ma l i gna nt tumors . Excl udi ng ma rrow
cel l tumors (eg, mul ti pl e myel oma ), there a re onl y a bout 2500 ca s es of pri ma ry ma l i gna nt bone tumors i n the US ea ch yea r a mong chi l dren a nd
a dul ts .
Synovi a l tumors a re extremel y ra re i n both chi l dren a nd a dul ts . Pi gmented vi l l onodul a r s ynovi ti s i s a beni gn but a t ti mes des tructi ve tumor of
s ynovi a l cel l s . Synovi a l s a rcoma (often wi th both s pi ndl e cel l a nd gl a ndul a r-l i ke components ) i s a ma l i gna nt s oft-ti s s ue tumor not of s ynovi a l
ori gi n, whi ch s el dom occurs i ns i de of a joi nt.
Symptoms and Signs
Bone tumors typi ca l l y ca us e unexpl a i ned, progres s i ve pa i n a nd s wel l i ng. Pa i n ca n occur wi thout wei ght bea ri ng or bone s tres s a nd ca n occur a t
res t a nd a t ni ght.
Diagnosis
Pl a i n x-ra ys
MRI us ua l l y a nd s ometi mes CT
Bone s ca n i f mul ti centri c or meta s ta ti c tumors a re s us pected
Bi ops y unl es s i ma gi ng s tudi es cl ea rl y s how beni gn cha ra cteri s ti cs
The mos t common rea s on tha t di a gnos i s of bone tumors i s del a yed i s tha t phys i ci a ns fa i l to s us pect the tumor a nd order a ppropri a te i ma gi ng
s tudi es . Pers i s tent or progres s i ve unexpl a i ned pa i n of the trunk or extremi ti es , pa rti cul a rl y i f a s s oci a ted wi th a ma s s , i s s ugges ti ve. Pl a i n x-ra ys
a re the fi rs t tes t. Tumors s houl d a l s o be s us pected i f a ra di ogra phi c s tudy s hows a n unexpl a i ned a bnorma l i ty cons i s tent wi th a tumor. Les i ons
s ugges ti ve of tumors us ua l l y requi re further a s s es s ment, often wi th a ddi ti ona l i ma gi ng s tudi es a nd a bi ops y.
Characteristic findings: Some tumors (eg, Pa get's di s ea s e, nonos s i fyi ng fi broma , fi brous dys pl a s i a , enchondroma s ) ma y ha ve cha ra cteri s ti c
ra di ogra phi c fi ndi ngs a nd ca n be di a gnos ed wi thout bi ops y.
Ra di ogra phi c fi ndi ngs tha t s ugges t ca ncer i ncl ude the fol l owi ng:
A l yti c, des tructi ve, or permea ti ve a ppea ra nce
Irregul a r tumor borders
Area s , es peci a l l y mul ti pl e a rea s , of bone des tructi on (moth-ea ten a ppea ra nce)
Corti ca l des tructi on
Soft-ti s s ue extens i on
Pa thol ogi c fra cture
A l yti c a ppea ra nce i s cha ra cteri zed by cl ea r a rea s of bone des tructi on tha t a re s ha rpl y dema rca ted. A permea ti ve a ppea ra nce i s cha ra cteri zed by a
fa i nt, gra dua l l os s of bone or a n i nfi l tra ti ng pa ttern wi thout cl ea r borders . Certa i n tumors ha ve a cha ra cteri s ti c a ppea ra nce (eg, Ewi ng's s a rcoma
typi ca l l y s hows permea ti ve-type bone des tructi on, i ncl udi ng a l a rge s oft-ti s s ue ma s s wi th peri os tea l oni on-s ki n rea cti ve bone often before there
i s a n extens i ve, l yti c, des tructi ve a ppea ra nce; gi a nt cel l tumor ha s a cys ti c a ppea ra nce wi thout a s cl eroti c i nterfa ce between the tumor a nd norma l
bone). The tumor's l oca ti on ma y na rrow di a gnos ti c pos s i bi l i ti es (eg, Ewi ng's s a rcoma commonl y a ppea rs i n the s ha ft of a l ong bone;
os teos a rcoma us ua l l y a ppea rs i n the meta phys ea l -di a phys ea l regi on towa rd the end of a l ong bone; gi a nt cel l tumor us ua l l y occurs i n the
epi phys i s ).
Some beni gn condi ti ons , however, ca n mi mi c a ma l i gna nt tumor:
Heterotopi c os s i fi ca ti on (myos i ti s os s i fi ca ns ) a nd exubera nt ca l l us forma ti on a fter fra cture ca n ca us e mi nera l i za ti on a round bony corti ces a nd
i n a dja cent s oft ti s s ues , mi mi cki ng ma l i gna nt tumors .
La ngerha ns ' cel l hi s ti ocytos i s (hi s ti ocytos i s X, Letterer-Si we di s ea s e, Ha nd-Schul l er-Chri s ti a n di s ea s e, eos i nophi l i c gra nul oma ) ca n ca us e
s ol i ta ry or mul ti pl e bone l es i ons tha t a re us ua l l y di s ti ngui s ha bl e on x-ra y. In s ol i ta ry l es i ons , there ma y be peri os tea l new bone forma ti on,
s ugges ti ng a ma l i gna nt bone tumor.
Os teopoi ki l os i s (s potted bones ) i s a n a s ymptoma ti c condi ti on of no cl i ni ca l cons equence but ca n s i mul a te os teobl a s ti c bone meta s ta s es of
brea s t ca ncer. It i s cha ra cteri zed by mul ti pl e s ma l l , round, or ova l foci of bony s cl eros i s , us ua l l y i n the ta rs a l , ca rpa l , or pel vi c bones or the
meta phys ea l -epi phys ea l regi ons of tubul a r bones .
Other testing: CT a nd MRI ma y hel p defi ne the l oca ti on a nd extent of a bone tumor a nd s ometi mes s ugges t a s peci fi c di a gnos i s . MRI i s us ua l l y
done i f ca ncer i s s us pected. If tumors a re s us pected of bei ng meta s ta ti c or i nvol vi ng mul ti pl e foci (mul ti centri c), then ra di oi s otopi c techneti um
bone s ca nni ng s houl d be done to s ea rch for a l l tumors .
Bi ops y i s us ua l l y es s enti a l for di a gnos i s of ma l i gna nt tumors , unl es s the i ma gi ng s tudi es ha ve a cl a s s i ca l l y beni gn a ppea ra nce. The pa thol ogi s t
s houl d be gi ven perti nent deta i l s of the cl i ni ca l hi s tory a nd s houl d revi ew i ma gi ng s tudi es . Hi s topa thol ogi c di a gnos i s ma y be di ffi cul t a nd
requi res s uffi ci ent vi a bl e ti s s ue from a repres enta ti ve porti on of the tumor (us ua l l y the s oft porti on). The bes t res ul ts a re obta i ned i n centers wi th
extens i ve experi ence i n bone bi ops i es . Immedi a te, a ccura te, defi ni ti ve di a gnos i s i s pos s i bl e i n > 90% of ca s es . If a ma l i gna nt di a gnos i s i s
s us pected on frozen s ecti on hi s tol ogy, often the s urgeon wi l l wa i t upon perma nent hi s tol ogy before trea ti ng defi ni ti vel y. Mi s ta kes occur more
frequentl y i n hos pi ta l s tha t i nfrequentl y encounter pa ti ents wi th ma l i gna nt pri ma ry tumors .
Benign Bone Tumors
Osteochondroma: Os teochondroma s (os teoca rti l a gi nous exos tos es ), the mos t common beni gn bone tumors , ma y a ri s e from a ny bone but tend to
occur nea r the ends of l ong bones . Thes e tumors ma ni fes t mos t often i n peopl e a ged 10 to 20 a nd ma y be s i ngl e or mul ti pl e. Mul ti pl e
os teochondroma s tend to run i n fa mi l i es . Seconda ry ma l i gna nt chondros a rcoma devel ops i n a bout 10% of pa ti ents wi th mul ti pl e
os teochondroma s a nd i n wel l < 1% of thos e wi th s i ngl e os teochondroma s . Os teochondroma s ra rel y ca us e the bone to fra cture.
On i ma gi ng s tudi es , the l es i on a ppea rs a s a bony promi nence wi th a ca rti l a ge ca p (< 2 cm) off the s urfa ce of the bone wi th no underl yi ng cortex
under the promi nence.
Exci s i on i s needed i f the tumor i s compres s i ng a l a rge nerve; ca us es pa i n (es peci a l l y when i mpi ngi ng on mus cl e a nd crea ti ng a n i nfl a mma tory
burs a ); di s turbs growth; or on i ma gi ng s tudy ha s a des tructi ve a ppea ra nce, s oft-ti s s ue ma s s , or thi ckened ca rti l a gi nous ca p (> 2 cm) s ugges ti ng
tra ns forma ti on i nto ma l i gna nt chondros a rcoma .
Enchondroma: Enchondroma s ma y occur a t a ny a ge but tend to be recogni zed i n pa ti ents a ged 10 to 40. They a re us ua l l y l oca ted wi thi n the
medul l a ry bone meta phys ea l -di a phys ea l regi on. Thes e tumors a re us ua l l y a s ymptoma ti c but ma y enl a rge a nd become pa i nful . They a re often
found when x-ra ys a re ta ken for a nother rea s on.
On x-ra y, the tumor ma y a ppea r a s a l obul a ted ca l ci fi ed a rea wi thi n bone; s ome l es i ons a re l es s ca l ci fi ed, wi th a rea s of s ti ppl ed ca l ci fi ca ti on
ei ther on pl a i n fi l ms or CT. If a dja cent to the cortex, enchondroma s s how mi nor endos tea l s ca l l opi ng. Al mos t a l l enchondroma s ha ve i ncrea s ed
upta ke on a bone s ca n a nd thus crea te concern of ca ncer. X-ra y fi ndi ngs , i ncl udi ng MRI a nd CT, ma y be di a gnos ti c; i f they a re not, a nd es peci a l l y i f
the tumor (not the a s s oci a ted joi nt) i s pa i nful , the di a gnos i s s houl d be confi rmed by bi ops y. To hel p di fferenti a te bone pa i n from joi nt pa i n, the
joi nt ca n be i njected, us ua l l y wi th a l ong-l a s ti ng a nes theti c (eg, bupi va ca i ne); i f pa i n pers i s ts , i t ma y be ca us ed by the bone l es i on.
An a s ymptoma ti c enchondroma does not need bi ops y, exci s i on, or other trea tment (us ua l l y curetta ge); however, fol l ow-up i ma gi ng s tudi es a re
i ndi ca ted to rul e out di s ea s e progres s i on. Thes e a re done a t 6 mo a nd a ga i n a t 1 yr or whenever s ymptoms devel op.
Chondroblastoma: Chondrobl a s toma i s ra re a nd occurs mos t commonl y a mong peopl e a ged 10 to 20. Ari s i ng i n the epi phys i s , thi s tumor ma y
conti nue to grow a nd des troy bone a nd the joi nt. It a ppea rs on i ma gi ng s tudi es a s a s cl eroti c ma rgi na ted cys t conta i ni ng s pots of puncta te
ca l ci fi ca ti on. MRI ca n hel p di a gnos ti ca l l y by s howi ng cha ra cteri s ti c cha nges wel l a wa y from the l es i on.
The tumor mus t be s urgi ca l l y removed by curetta ge, a nd the ca vi ty mus t be bone gra fted. Loca l recurrence ra te i s a bout 10 to 20%, a nd recurrent
l es i ons often res ol ve wi th repea t bone curetta ge a nd bone gra fti ng.
Chondromyxofibroma: Chondromyxofi broma i s very ra re a nd us ua l l y occurs before a ge 30. The a ppea ra nce on i ma gi ng s tudi es (us ua l l y eccentri c,
s ha rpl y ci rcums cri bed, l yti c, a nd l oca ted nea r the end of l ong bones ) s ugges ts the di a gnos i s . Trea tment a fter bi ops y i s s urgi ca l exci s i on or
curetta ge.
Osteoid osteoma: Os teoi d os teoma , whi ch tends to a ffect young peopl e (commonl y a ged 10 to 35), ca n occur i n a ny bone but i s mos t common a mong
l ong bones . It ca n ca us e pa i n (us ua l l y wors e a t ni ght) tha t i s typi ca l l y rel i eved by mi l d a na l ges i cs , pa rti cul a rl y a s pi ri n or other NSAIDs . In growi ng
chi l dren, the i nfl a mma tory res pons e a nd a s s oci a ted hyperemi a , i f cl os e to the open growth pl a te, ma y ca us e overgrowth a nd l i mb l ength
di s crepa ncy. Phys i ca l exa mi na ti on ma y revea l a trophy of regi ona l mus cl es beca us e the pa i n ca us es mus cl e di s us e.
Cha ra cteri s ti c a ppea ra nce on i ma gi ng s tudi es i s a s ma l l ra di ol ucent zone s urrounded by a l a rger s cl eroti c zone. If a tumor i s s us pected, a
techneti um-99m bone s ca n s houl d be done; a n os teoi d os teoma a ppea rs a s a n a rea of i ncrea s ed upta ke. CT wi th fi ne i ma ge s equences i s a l s o
done a nd i s mos t hel pful i n di s ti ngui s hi ng the l es i on.
Remova l of the s ma l l ra di ol ucent zone wi th percuta neous ra di ofrequency a bl a ti on provi des perma nent rel i ef. Mos t os teoi d os teoma s a re trea ted
by a n i nterventi ona l mus cul os kel eta l ra di ol ogi s t us i ng percuta neous techni ques a nd a nes thes i a . Les s often, os teoi d os teoma s a re s urgi ca l l y
curetted or exci s ed.
Benign giant cell tumor: Thes e tumors , whi ch mos t commonl y a ffect peopl e i n thei r 20s a nd 30s , occur i n the epi phys es a nd ma y eventua l l y erode the
res t of the bone a nd extend i nto the s oft ti s s ues . They ma y ca us e pa i n. Gi a nt cel l tumors a re notori ous for thei r tendency to recur. Ra rel y, a gi a nt
cel l tumor ma y meta s ta s i ze to the l ung, even though i t rema i ns hi s tol ogi ca l l y beni gn.
Beni gn gi a nt cel l tumors a ppea r a s expa ns i l e l yti c l es i ons on i ma gi ng. On i ma gi ng s tudi es , there i s a ma rgi n wi thout a s cl eroti c ri m where the
tumor ends a nd norma l tra becul a r bone begi ns .
Mos t beni gn gi a nt cel l tumors a re trea ted by curetta ge a nd pa cki ng wi th methyl metha cryl a te or by bone gra ft. To reduce recurrence ra te, s urgeons
often prefer us i ng a n a djuva nt s uch a s therma l hea t (provi ded by the ha rdeni ng of methyl metha cryl a te) or chemi ca l l y by phenol or freezi ng wi th
l i qui d ni trogen. If a tumor i s very l a rge a nd des tructi ve to the joi nt, compl ete exci s i on wi th joi nt recons tructi on ma y be neces s a ry.
Primary Malignant Bone Tumors
(See a l s o Ch. 117.)

Multiple myeloma: Mul ti pl e myel oma i s the mos t common pri ma ry ma l i gna nt bone tumor but i s often cons i dered a ma rrow cel l tumor wi thi n the
bone ra ther tha n a bone tumor. It i s of hema topoi eti c deri va ti on (s ee a l s o p. 1029) a nd occurs mos tl y i n ol der a dul ts . The neopl a s ti c proces s i s
us ua l l y mul ti centri c a nd often i nvol ves the bone ma rrow s o di ffus el y tha t bone ma rrow a s pi ra ti on i s di a gnos ti c. Ima gi ng s tudi es us ua l l y s how
s ha rpl y ci rcums cri bed l yti c l es i ons or di ffus e demi nera l i za ti on. Ra rel y, the l es i on ca n a ppea r a s s cl eroti c or a s di ffus e os teopeni a , es peci a l l y i n a
vertebra l body. An i s ol a ted s i ngl e myel oma l es i on wi thout s ys temi c ma rrow i nvol vement i s ca l l ed a pl a s ma cytoma .
Osteosarcoma: Os teos a rcoma (os teogeni c s a rcoma ) i s the 2nd mos t common pri ma ry bone tumor a nd i s hi ghl y ma l i gna nt. It i s mos t common a mong
peopl e a ged 10 to 25, a l though i t ca n occur a t a ny a ge. Os teos a rcoma produces ma l i gna nt os teoi d (i mma ture bone) from tumor bone cel l s .
Os teos a rcoma us ua l l y devel ops a round the knee (di s ta l femur more often tha n proxi ma l ti bi a ) or i n other l ong bones , pa rti cul a rl y the
meta phys ea l -di a phys ea l a rea , a nd ma y meta s ta s i ze, us ua l l y to l ung or other bone. Pa i n a nd s wel l i ng a re the us ua l s ymptoms .
Fi ndi ngs on i ma gi ng s tudi es va ry a nd ma y i ncl ude s cl eroti c or l yti c fea tures . Di a gnos i s requi res bi ops y. Pa ti ents need a ches t x-ra y a nd CT to detect
l ung meta s ta s es a nd a bone s ca n to detect bone meta s ta s es .
Trea tment i s a combi na ti on of chemothera py a nd s urgery. Us e of a djuva nt chemothera py i ncrea s es s urvi va l from < 20% to > 65% a t 5 yr.
Chemothera py us ua l l y begi ns before a ny s urgery. Decrea s ed tumor s i ze on x-ra y, decrea s ed pa i n l evel , a nd decrea s ed s erum a l ka l i ne
phos pha ta s e i ndi ca te s ome res pons e, but the des i red res pons e i s for > 95% tumor necros i s on ma ppi ng of the res ected s peci men. After s evera l
cours es of chemothera py (over s evera l months ), l i mb-s pa ri ng s urgery a nd l i mb recons tructi on ca n proceed. In l i mb-s pa ri ng s urgery, the tumor i s
res ected en bl oc, i ncl udi ng a l l s urroundi ng rea cti ve ti s s ue a nd a ri m of s urroundi ng norma l ti s s ue; to a voi d mi cros copi c s pi l l a ge of tumor cel l s ,
the tumor i s not vi ol a ted. More tha n 80% of pa ti ents ca n be trea ted wi th l i mb-s pa ri ng s urgery wi thout decrea s i ng l ong-term s urvi va l ra te.
Conti nua ti on of chemothera py a fter s urgery i s us ua l l y neces s a ry. If there i s nea rl y compl ete tumor necros i s (a bout 99%) from preopera ti ve
chemothera py, 5-yr s urvi va l ra te i s > 90%.
Fibrosarcoma: Fi bros a rcoma s ha ve s i mi l a r cha ra cteri s ti cs to os teos a rcoma s but produce fi brous tumor cel l s (ra ther tha n bone tumor cel l s ), a ffect
the s a me a ge group, a nd pos e s i mi l a r probl ems .
Malignant fibrous histiocytoma: Thi s tumor i s cl i ni ca l l y s i mi l a r to os teos a rcoma a nd fi bros a rcoma , a l though ma l i gna nt fi brous hi s ti ocytoma s ha ve
been cl a s s i fi ed a s di fferent from the os teos a rcoma group beca us e of a di fferent hi s tol ogy (no tumor bone producti on). Ma l i gna nt fi brous
hi s ti ocytoma s tend to occur i n chi l dren a nd teena gers but ca n a l s o occur i n ol der a dul ts a s s econda ry l es i ons i n bone i nfa rcts a nd ra di a ti on
fi el ds . Trea tment i s s i mi l a r to tha t of os teos a rcoma .
Chondrosarcoma: Chondros a rcoma s a re ma l i gna nt tumors of ca rti l a ge. They di ffer from os teos a rcoma s cl i ni ca l l y, thera peuti ca l l y, a nd prognos ti ca l l y.
Of chondros a rcoma s , 90% a re pri ma ry tumors . Chondros a rcoma s a ri s e i n other pre-exi s ti ng condi ti ons , pa rti cul a rl y mul ti pl e os teochondroma s a nd
mul ti pl e enchondroma tos i s (eg, i n Ol l i er's di s ea s e a nd Ma ffucci 's s yndrome). Chondros a rcoma s tend to occur i n ol der a dul ts . They often devel op
i n fl a t bones (eg, pel vi s , s ca pul a ) but ca n devel op i n a ny porti on of a ny bone a nd ca n i mpl a nt i n s urroundi ng s oft ti s s ues .
X-ra ys often revea l puncta te ca l ci fi ca ti ons . Pri ma ry chondros a rcoma s often a l s o exhi bi t corti ca l bone des tructi on a nd l os s of norma l bone
tra becul a e. Seconda ry chondros a rcoma ma y be s ugges ted by the a ppea ra nce of puncta te ca l ci fi ca ti ons or a n i ncrea s e i n s i ze of a n
os teochondroma . Techneti um-99m bone s ci nti gra phy i s a hel pful s creeni ng s tudy; a l l ca rti l a gi nous l es i ons s how i ncrea s ed upta ke on the s ca n,
a l though chondros a rcoma s exhi bi t pa rti cul a rl y hi gh upta ke. Bi ops y i s requi red for di a gnos i s a nd ca n a l s o determi ne the tumor's gra de
(proba bi l i ty of meta s ta s i zi ng).
Low-gra de chondros a rcoma s (gra de 1/2 or gra de 1) a re often trea ted i ntra l es i ona l l y (wi de curetta ge) wi th a ddi ti on of a n a djuva nt (often freezi ng
l i qui d ni trogen; a rgon bea m; hea t of methyl metha cryl a te; ra di ofrequency; or phenol ). Other tumors a re trea ted wi th tota l s urgi ca l res ecti on. When
s urgi ca l res ecti on wi th ma i ntena nce of functi on i s i mpos s i bl e, a mputa ti on ma y be neces s a ry. Beca us e of the potenti a l to i mpl a nt the tumor,
meti cul ous ca re mus t be ta ken to a voi d s pi l l a ge of tumor cel l s i nto the s oft ti s s ues duri ng bi ops y or s urgery. Recurrence i s i nevi ta bl e i f tumor cel l s
s pi l l . If no s pi l l a ge occurs , the cure ra te depends on the tumor gra de. Low-gra de tumors a re nea rl y a l l cured wi th a dequa te trea tment. Beca us e
thes e tumors ha ve l i mi ted va s cul a ri ty, chemothera py a nd ra di a ti on thera py ha ve l i ttl e effi ca cy.
Ewing's sarcoma of bone: Ewi ng's s a rcoma i s a round-cel l bone tumor wi th a pea k i nci dence between 10 a nd 25 yr. Mos t devel op i n the extremi ti es ,
but a ny bone ma y be i nvol ved. Ewi ng's s a rcoma tends to be extens i ve, s ometi mes i nvol vi ng the enti re bone s ha ft, mos t often the di a phys ea l
regi on. About 15 to 20% occur a round the meta phys ea l regi on. Pa i n a nd s wel l i ng a re the mos t common s ymptoms .
Lyti c des tructi on, pa rti cul a rl y a permea ti ve i nfi l tra ti ng pa ttern wi thout cl ea r borders , i s the mos t common fi ndi ng on i ma gi ng, but mul ti pl e l a yers
of s ubperi os tea l rea cti ve new bone forma ti on ma y gi ve a n oni on-s ki n a ppea ra nce. X-ra ys do not us ua l l y revea l the ful l extent of bone
i nvol vement, a nd a l a rge s oft-ti s s ue ma s s us ua l l y s urrounds the a ffected bone. MRI better defi nes di s ea s e extent, whi ch ca n hel p gui de
trea tment. Ma ny other beni gn a nd ma l i gna nt tumors ca n a ppea r very s i mi l a r, s o di a gnos i s i s ma de by bi ops y. At ti mes thi s tumor ma y be confus ed
wi th a n i nfecti on. Accura te hi s tol ogi c di a gnos i s ca n be a ccompl i s hed wi th mol ecul a r ma rkers , i ncl udi ng eva l ua ti on for a typi ca l cl ona l
chromos oma l a bnorma l i ty.
Trea tment i ncl udes va ri ous combi na ti ons of s urgery, chemothera py, a nd ra di a ti on thera py. Currentl y, > 60% of pa ti ents wi th pri ma ry l oca l i zed
Ewi ng's s a rcoma ma y be cured by thi s mul ti moda l a pproa ch. Cure i s s ometi mes pos s i bl e even wi th meta s ta ti c di s ea s e. Chemothera py i n
conjuncti on wi th s urgi ca l en bl oc res ecti on, i f a ppl i ca bl e, often yi el ds better l ong-term res ul ts .
Lymphoma of bone: Lymphoma of bone (previ ous l y known a s reti cul um cel l s a rcoma ) a ffects a dul ts , us ua l l y i n thei r 40s a nd 50s . It ma y a ri s e i n a ny
bone. The tumor cons i s ts of s ma l l round cel l s , often wi th a mi xture of reti cul um cel l s , l ymphobl a s ts , a nd l ymphocytes . It ca n devel op a s a n
i s ol a ted pri ma ry bone tumor, i n a s s oci a ti on wi th s i mi l a r tumors i n other ti s s ues , or a s a meta s ta s i s from known s oft-ti s s ue l ymphoma tous
di s ea s e. Pa i n a nd s wel l i ng a re the us ua l s ymptoms . Pa thol ogi c fra cture i s common.
Ima gi ng s tudi es revea l bone des tructi on, whi ch ma y be i n a mottl ed or pa tchy or even i nfi l tra ti ng, permea ti ve pa ttern, often wi th a cl i ni ca l a nd
ra di ogra phi c l a rge s oft-ti s s ue ma s s . In a dva nced di s ea s e, the enti re outl i ne of the a ffected bone ma y be l os t.
In i s ol a ted pri ma ry bone l ymphoma , the 5-yr s urvi va l ra te i s 50%. Combi na ti on ra di a ti on thera py a nd chemothera py i s a s cura ti ve a s a mputa ti on
or other extens i ve a bl a ti ve s urgery. Sta bi l i za ti on of l ong bones i s often neces s a ry to prevent pa thol ogi c fra cture. Amputa ti on i s i ndi ca ted onl y
ra rel y, when functi on i s l os t beca us e of pa thol ogi c fra cture or extens i ve s oft-ti s s ue i nvol vement tha t ca nnot be ma na ged otherwi s e.
Malignant giant cell tumor: Ma l i gna nt gi a nt cel l tumor, whi ch i s ra re, i s us ua l l y l oca ted a t the extreme end of a l ong bone. X-ra y revea l s cl a s s i c
fea tures of ma l i gna nt des tructi on (predomi na ntl y l yti c des tructi on, corti ca l des tructi on, s oft-ti s s ue extens i on, a nd pa thol ogi c fra cture). A
ma l i gna nt gi a nt cel l tumor tha t devel ops i n a previ ous l y beni gn gi a nt cel l tumor i s cha ra cteri s ti ca l l y ra di ores i s ta nt. Trea tment i s s i mi l a r to tha t of
os teos a rcoma , but the cure ra te i s l ow.
Chordoma: Chordoma , whi ch i s ra re, devel ops from the remna nts of the pri mi ti ve notochord. It tends to occur a t the ends of the s pi na l col umn,
us ua l l y i n the mi ddl e of the s a crum or nea r the ba s e of the s kul l . A chordoma i n the s a crococcygea l regi on ca us es nea rl y cons ta nt pa i n. A
chordoma i n the ba s e of the s kul l ca n ca us e defi ci ts i n a cra ni a l nerve, mos t commonl y i n nerves to the eye.
Symptoms ma y exi s t for months to s evera l yea rs before di a gnos i s . A chordoma a ppea rs on i ma gi ng s tudi es a s a n expa ns i l e, des tructi ve bone
l es i on tha t ma y be a s s oci a ted wi th a s oft-ti s s ue ma s s . Meta s ta s i s i s unus ua l , but l oca l recurrence i s not. Chordoma s i n the s a crococcygea l regi on
ma y be cured by ra di ca l en bl oc exci s i on. Chordoma s i n the ba s e of the s kul l a re us ua l l y i na cces s i bl e to s urgery but ma y res pond to ra di a ti on
thera py.
Metastatic Bone Tumors
Any ca ncer ma y meta s ta s i ze to bone, but meta s ta s es from ca rci noma s a re the mos t common, pa rti cul a rl y thos e a ri s i ng i n the fol l owi ng a rea s :
Brea s t
Lung
Pros ta te
Ki dney
Thyroi d
Col on
Pros ta te ca ncer i n men a nd brea s t ca ncer i n women a re the mos t common types of ca ncers . Lung ca ncer i s the mos t common ca us e of ca ncer dea th
i n both s exes . Brea s t ca ncer i s the mos t common ca ncer to meta s ta s i ze to bone. Any bone ma y be i nvol ved wi th meta s ta s es . Meta s ta ti c di s ea s e
does not commonl y s prea d to bone bel ow the mi d forea rm or mi d ca l f, but when i t occurs i n thos e s i tes , i t res ul ts mos t often from l ung or
s ometi mes ki dney ca ncer.
Symptoms and Signs
Meta s ta s es ma ni fes t a s bone pa i n, a l though they ma y rema i n a s ymptoma ti c for s ome ti me. Bone meta s ta s es ma y ca us e s ymptoms before the
pri ma ry tumor i s s us pected or ma y a ppea r i n pa ti ents wi th a known di a gnos i s of ca ncer.
Diagnosis
X-ra y
Ra di onucl i de s ca nni ng to i denti fy a l l meta s ta s es
Cl i ni ca l eva l ua ti on a nd tes ti ng to di a gnos e the pri ma ry tumor (i f unknown)
Often bi ops y i f the pri ma ry tumor i s unknown a fter a s s es s ment
Meta s ta ti c bone tumors a re cons i dered i n a l l pa ti ents wi th unexpl a i ned bone pa i n, but pa rti cul a rl y i n pa ti ents who ha ve
Known ca ncer
Pa i n a t more tha n one s i te
Fi ndi ngs on i ma gi ng s tudi es tha t s ugges t meta s ta s es
Pros ta te ca ncer i s mos t often bl a s ti c, l ung ca ncer i s mos t often l yti c, a nd brea s t ca ncer ma y be bl a s ti c or l yti c.
CT a nd MRI a re hi ghl y s ens i ti ve for s peci fi c meta s ta s es . However, i f meta s ta s es a re s us pected, a ra di onucl i de whol e-body s ca n, whi ch i s not qui te
a s s ens i ti ve, i s us ua l l y done. Bone s ca n i s more s ens i ti ve for ea rl y a nd a s ymptoma ti c meta s ta s es tha n pl a i n x-ra ys a nd ca n be us ed to s ca n the
enti re body. Les i ons on the s ca n a re us ua l l y pres umed to be meta s ta s es i f the pa ti ent ha s a known pri ma ry ca ncer. Meta s ta s es s houl d be
s us pected i n pa ti ents who ha ve mul ti pl e l es i ons on bone s ca n. Al though meta s ta s es a re s us pected i n pa ti ents wi th known ca ncer a nd a s i ngl e
bone l es i on, the l es i on ma y not be a meta s ta s i s ; thus , a needl e bi ops y of the l es i on i s often done to confi rm the di a gnos i s of a meta s ta s i s . PET
for a l mos t whol e-body s ca nni ng i s now often us ed for s ome tumors .
If bone meta s ta s es a re s us pected beca us e mul ti pl e l yti c l es i ons a re found, a s s es s ment for the pri ma ry tumor ca n begi n wi th cl i ni ca l eva l ua ti on
for pri ma ry ca ncers (pa rti cul a rl y focus ed on the brea s t, pros ta te, a nd thyroi d), ches t x-ra y, ma mmogra phy, a nd mea s urement of pros ta te-s peci fi c
a nti gen l evel . Ini ti a l CT of the ches t, a bdomen, a nd pel vi s ma y a l s o revea l the pri ma ry tumor. However, bone bi ops y, es peci a l l y fi ne-needl e or core
bi ops y, i s neces s a ry i f meta s ta ti c tumor i s s us pected a nd the pri ma ry tumor ha s not been otherwi s e di a gnos ed. Bi ops y wi th us e of
i mmunohi s tol ogi c s ta i ns ma y gi ve cl ues to the pri ma ry tumor type.
Treatment
Us ua l l y ra di a ti on thera py
Surgery to s ta bi l i ze bone a t ri s k of pa thol ogi c fra cture
Kyphopl a s ty or vertebra pl a s ty for certa i n pa i nful vertebra l fra ctures
Trea tment depends on the type of ti s s ue i nvol ved (whi ch orga n ti s s ue type). Ra di a ti on thera py, combi ned wi th s el ected chemothera peuti c or
hormona l drugs , i s the mos t common trea tment moda l i ty. Ea rl y us e of ra di a ti on (30 Gy) a nd bi s phos phona tes (eg, zol edrona te, pa mi drona te)
s l ows bone des tructi on. Some tumors a re more l i kel y to hea l a fter ra di a ti on thera py; for exa mpl e, bl a s ti c l es i ons of pros ta te a nd brea s t ca ncer
a re more l i kel y to hea l tha n l yti c des tructi ve l es i ons of l ung ca ncer a nd rena l cel l ca rci noma .
If bone des tructi on i s extens i ve, res ul ti ng i n i mmi nent or a ctua l pa thol ogi c fra cture, s urgi ca l fi xa ti on or res ecti on a nd recons tructi on ma y be
requi red to provi de s ta bi l i za ti on a nd hel p mi ni mi ze morbi di ty. When the pri ma ry ca ncer ha s been removed a nd onl y a s i ngl e bone meta s ta s i s
rema i ns (es peci a l l y i f the meta s ta ti c l es i on a ppea rs 1 yr a fter the pri ma ry tumor), en bl oc exci s i on s ometi mes combi ned wi th ra di a ti on thera py,
chemothera py, or both ra rel y ma y be cura ti ve. Ins erti on of methyl metha cryl a te i nto the s pi ne (kyphopl a s ty or vertebra pl a s ty) rel i eves pa i n a nd
expa nds a nd s ta bi l i zes compres s i on fra ctures tha t do not ha ve epi dura l s oft-ti s s ue extens i on.
Other Bone Lesions
Ma ny nonneopl a s ti c condi ti ons of bone ma y cl i ni ca l l y or ra di ol ogi ca l l y mi mi c s ol i ta ry bone tumors .
Unicameral bone cyst: Si mpl e uni ca mera l bone cys ts occur i n the l ong bones s ta rti ng di s ta l to the epi phys ea l pl a te i n chi l dren. The cys t ca us es the
cortex to thi n a nd predi s pos es the a rea to a buckl e-l i ke pa thol ogi c fra cture, whi ch i s us ua l l y how the cys t i s recogni zed. Cys ts < 5 cm ma y hea l a nd
ma y di s a ppea r a s the fra cture hea l s . Cys ts > 5 cm, pa rti cul a rl y i n chi l dren, ma y requi re exci s i on or curetta ge a nd bone gra fti ng; however, ma ny
res pond to i njecti ons of corti cos teroi ds , demi nera l i zed bone ma tri x, or s yntheti c bone s ubs ti tutes . The res pons e ma y be va ri a bl e a nd ma y requi re
mul ti pl e i njecti ons . Rega rdl es s of trea tment, cys ts pers i s t i n a bout 10 to 15% of pa ti ents .
Fibrous dysplasia: Fi brous dys pl a s i a i nvol ves a bnorma l bone devel opment duri ng chi l dhood. It ma y a ffect one or s evera l bones . Cuta neous
pi gmenta ti on a nd endocri ne a bnorma l i ti es ma y be pres ent (Al bri ght's s yndrome). The a bnorma l bone l es i ons of fi brous dys pl a s i a commonl y s top
devel opi ng a t puberty. They ra rel y undergo ma l i gna nt degenera ti on. On x-ra y, the l es i ons ca n a ppea r cys ti c a nd ma y be extens i ve a nd deformi ng.
Ca l ci toni n ma y hel p rel i eve pa i n. Progres s i ve deformi ti es , fra ctures tha t do not hea l wi th i mmobi l i za ti on, or i ntra cta bl e pa i n ma y be effecti vel y
trea ted wi th orthopedi c s urgery.
Aneurysmal bone cyst: An a neurys ma l bone cys t i s a n i di opa thi c expa ns i l e l es i on tha t us ua l l y devel ops before a ge 25 yr. Thi s cys ti c l es i on us ua l l y
occurs i n the meta phys ea l regi on of the l ong bones , but a l mos t a ny bone ma y be a ffected. It tends to grow s l owl y. A peri os tea l new bone s hel l
forms a round the expa ns i l e l es i on a nd i s often wi der tha n the ori gi na l bone. Pa i n a nd s wel l i ng a re common. The l es i on ma y be pres ent for a few
weeks to a yea r before di a gnos i s . The a ppea ra nce on x-ra y i s often cha ra cteri s ti c: The ra refi ed a rea i s us ua l l y wel l ci rcums cri bed a nd eccentri c;
the peri os teum bul ges , extendi ng i nto the s oft ti s s ues , a nd ma y be s urrounded by new bone forma ti on.
Surgi ca l remova l of the enti re l es i on i s the mos t s ucces s ful trea tment; regres s i on a fter i ncompl ete remova l s ometi mes occurs . Ra di a ti on s houl d
be a voi ded when pos s i bl e beca us e s a rcoma s occa s i ona l l y devel op. However, ra di a ti on ma y be the trea tment of choi ce i n compl etel y s urgi ca l l y
i na cces s i bl e vertebra l l es i ons tha t a re compres s i ng the s pi na l cord.
Joint Tumors
Tumors ra rel y a ffect joi nts , unl es s by di rect extens i on of a n a dja cent bone or s oft-ti s s ue tumor. However, 2 condi ti ons s ynovi a l chondroma tos i s
a nd pi gmented vi l l onodul a r s ynovi ti s occur i n the l i ni ng (s ynovi um) of joi nts . Thes e condi ti ons a re beni gn but l oca l l y a ggres s i ve. Both us ua l l y
a ffect one joi nt, mos t often the knee a nd s econd mos t often the hi p, a nd ca n ca us e pa i n a nd effus i on. Both a re trea ted by s ynovectomy a nd
remova l of a ny i ntra -a rti cul a r bodi es .
Synovial chondromatosis: Synovi a l chondroma tos i s (previ ous l y ca l l ed s ynovi a l os teochondroma tos i s ) i s cons i dered meta pl a s ti c. It i s cha ra cteri zed
by numerous ca l ci fi ed ca rti l a gi nous bodi es i n the s ynovi um, whi ch often become l oos e. Ea ch body ma y be no l a rger tha n a gra i n of ri ce, i n a
s wol l en, pa i nful joi nt. Ma l i gna nt cha nge i s very ra re. Recurrence i s common.
Pigmented villonodular synovitis: Pi gmented vi l l onodul a r s ynovi ti s i s cons i dered neopl a s ti c. The s ynovi um becomes thi ckened a nd conta i ns
hemos i deri n, whi ch gi ves the ti s s ue i ts bl ood-s ta i ned a ppea ra nce a nd cha ra cteri s ti c a ppea ra nce on MRI. Thi s ti s s ue tends to i nva de a dja cent
bone, ca us i ng cys ti c des tructi on a nd da ma ge to the ca rti l a ge. Pi gmented vi l l onodul a r s ynovi ti s i s us ua l l y mona rti cul a r but ma y be pol ya rti cul a r.
La te ma na gement, es peci a l l y a fter recurrence, ma y requi re tota l joi nt repl a cement. On ra re occa s i ons a fter s evera l s ynovectomi es , ra di a ti on
thera py ca n be us ed.
5 - Ear, Nose, Throat, and Dental Disorders

Chapter 46. Approach to the Patient With Ear Problems
Introduction
Ea ra che, hea ri ng l os s , otorrhea , ti nni tus , a nd verti go a re the pri nci pa l s ymptoms of ea r probl ems . Hea ri ng l os s i s di s cus s ed i n Ch. 47.
In a ddi ti on to the ea rs , nos e, na s opha rynx, a nd pa ra na s a l s i nus es , the teeth, tongue, tons i l s , hypopha rynx, l a rynx, s a l i va ry gl a nds , a nd
temporoma ndi bul a r joi nt a re exa mi ned; pa i n a nd di s comfort ma y be referred from them to the ea rs . It i s i mporta nt to exa mi ne cra ni a l nerve
functi on (s ee pp. 1587 a nd 1745) a nd to perform tes ts of hea ri ng (s ee p. 431) a nd of the ves ti bul a r a ppa ra tus . The pa ti ent i s a l s o exa mi ned for
nys ta gmus (a rhythmi c movement of the eyes s ee Si deba r 46-1).
Testing
Pa ti ents wi th a bnorma l hea ri ng on hi s tory or phys i ca l exa mi na ti on or wi th ti nni tus or verti go undergo a n a udi ogra m (s ee p. 433). Pa ti ents wi th
nys ta gmus or a l tered ves ti bul a r functi on ma y benefi t from computeri zed el ectronys ta gmogra phy (ENG), whi ch qua nti fi es s ponta neous , ga ze, or
pos i ti ona l nys ta gmus tha t mi ght not be vi s ua l l y detecta bl e. Computeri zed ENG ca l ori c tes ti ng qua nti fi es the s trength of res pons e of the ves ti bul a r
s ys tem to cool a nd wa rm i rri ga ti ons i n ea ch ea r, ena bl i ng the phys i ci a n to di s cri mi na te uni l a tera l wea knes s . Di fferent components of the
ves ti bul a r s ys tem ca n be tes ted by va ryi ng hea d a nd body pos i ti on or by pres enti ng vi s ua l s ti mul i .
Sidebar 46-1 Nystagmus

Nys ta gmus i s a rhythmi c movement of the eyes tha t ca n ha ve va ri ous ca us es . Ves ti bul a r di s orders ca n res ul t i n nys ta gmus beca us e the ves ti bul a r
s ys tem a nd the ocul omotor nucl ei a re i nterconnected. The pres ence of ves ti bul a r nys ta gmus hel ps i denti fy ves ti bul a r di s orders a nd s ometi mes
di s ti ngui s hes centra l from peri phera l verti go. Ves ti bul a r nys ta gmus ha s a s l ow component ca us ed by the ves ti bul a r i nput a nd a qui ck, correcti ve
component tha t ca us es movement i n the oppos i te di recti on. The di recti on of the nys ta gmus i s defi ned by the di recti on of the qui ck component
beca us e i t i s ea s i er to s ee. Nys ta gmus ma y be rota ry, verti ca l , or hori zonta l a nd ma y occur s ponta neous l y, wi th ga ze, or wi th hea d moti on.
Ini ti a l i ns pecti on for nys ta gmus i s done wi th the pa ti ent l yi ng s upi ne wi th unfocus ed ga ze (+30 di opter or Frenzel l ens es ca n be us ed to prevent
ga ze fi xa ti on). The pa ti ent i s then s l owl y rota ted to a l eft a nd then to a ri ght l a tera l pos i ti on. The di recti on a nd dura ti on of nys ta gmus a re noted.
If nys ta gmus i s not detected, the Di x-Ha l l pi ke (or Ba ra ny) ma neuver i s done. In thi s ma neuver, the pa ti ent s i ts erect on a s tretcher s o tha t when
l yi ng ba ck, the hea d extends beyond the end. Wi th s upport, the pa ti ent i s ra pi dl y l owered to hori zonta l , a nd the hea d i s extended ba ck 45 bel ow
hori zonta l a nd rota ted 45 to the l eft. Di recti on a nd dura ti on of nys ta gmus a nd devel opment of verti go a re noted. The pa ti ent i s returned to a n
upri ght pos i ti on, a nd the ma neuver i s repea ted wi th rota ti on to the ri ght. Any pos i ti on or ma neuver tha t ca us es nys ta gmus s houl d be repea ted to
s ee whether i t fa ti gues .
Nys ta gmus s econda ry to peri phera l nervous s ys tem di s orders ha s a l a tency peri od of 3 to 10 s ec a nd fa ti gues ra pi dl y, wherea s nys ta gmus
s econda ry to CNS ha s no l a tency peri od a nd does not fa ti gue. Duri ng i nduced nys ta gmus , the pa ti ent i s i ns tructed to focus on a n object. Nys ta gmus
ca us ed by peri phera l di s orders i s i nhi bi ted by vi s ua l fi xa ti on. Beca us e Frenzel l ens es prevent vi s ua l fi xa ti on, they mus t be removed to a s s es s
vi s ua l fi xa ti on.
Ca l ori c s ti mul a ti on of the ea r ca na l i nduces nys ta gmus i n a pers on wi th a n i nta ct ves ti bul a r s ys tem. Fa i l ure to i nduce nys ta gmus or > 20%
di fference i n dura ti on between s i des s ugges ts a l es i on on the s i de of the decrea s ed res pons e. Qua nti fi ca ti on of ca l ori c res pons e i s bes t done
wi th forma l (computeri zed) el ectronys ta gmogra phy.
Abi l i ty of the ves ti bul a r s ys tem to res pond to peri phera l s ti mul a ti on ca n be a s s es s ed a t the beds i de. Ca re s houl d be ta ken not to i rri ga te a n ea r
wi th a known tympa ni c membra ne perfora ti on or chroni c i nfecti on. Wi th the pa ti ent s upi ne a nd the hea d el eva ted 30 , ea ch ea r i s i rri ga ted
s equenti a l l y wi th 3 mL of i ce wa ter. Al terna ti vel y, 240 mL of wa rm wa ter (40 to 44C) ma y be us ed, ta ki ng ca re not to burn the pa ti ent wi th overl y hot
wa ter. Col d wa ter ca us es nys ta gmus to the oppos i te s i de; wa rm wa ter ca us es nys ta gmus to the s a me s i de. A mnemoni c devi ce i s COWS (Col d to
the Oppos i te a nd Wa rm to the Sa me).
Pri ma ry i ma gi ng tes ts i ncl ude CT of the tempora l bone wi th or wi thout ra di opa que dye a nd ga dol i ni um-enha nced MRI of the bra i n, wi th a ttenti on
pa i d to the i nterna l a udi tory ca na l s to rul e out a n a cous ti c neuroma . Thes e tes ts ma y be i ndi ca ted i n ca s es of tra uma to the ea r, hea d, or both;
chroni c i nfecti on; hea ri ng l os s ; verti go; fa ci a l pa ra l ys i s ; a nd ota l gi a of obs cure ori gi n.
Earache
(Ota l gi a )
Ea ra che ma y occur i n i s ol a ti on or a l ong wi th di s cha rge or, ra rel y, hea ri ng l os s .
Pathophysiology
Pa i n ma y come from a proces s wi thi n the ea r i ts el f or ma y be referred to the ea r from a nea rby nonotol ogi c di s order.
Pain from the ear itself ma y res ul t from a pres s ure gra di ent between the mi ddl e ea r a nd outs i de a i r, from l oca l i nfl a mma ti on, or both. A mi ddl e ea r
pres s ure gra di ent us ua l l y i nvol ves eus ta chi a n tube obs tructi on, whi ch i nhi bi ts equi l i bra ti on between mi ddl e ea r pres s ure a nd a tmos pheri c
pres s ure a nd a l s o a l l ows fl ui d to a ccumul a te i n the mi ddl e ea r. Oti ti s medi a ca us es pa i nful i nfl a mma ti on of the tympa ni c membra ne (TM) a s
wel l a s pa i n from i ncrea s ed mi ddl e ea r pres s ure (ca us i ng bul gi ng of the TM).
Referred pain ca n res ul t from di s orders i n a rea s i nnerva ted by cra ni a l nerves res pons i bl e for s ens a ti on i n the externa l a nd mi ddl e ea r (5th, 9th,
a nd 10th). Speci fi c a rea s i ncl ude the nos e, pa ra na s a l s i nus es , na s opha rynx, teeth, gi ngi va , temporoma ndi bul a r joi nt (TMJ), ma ndi bl e, pa roti d
gl a nds , tongue, pa l a ti ne tons i l s , pha rynx, l a rynx, tra chea , a nd es opha gus . Di s orders i n thes e a rea s s ometi mes a l s o obs truct the eus ta chi a n tube,
ca us i ng pa i n from a mi ddl e ea r pres s ure gra di ent.
Etiology
Ea ra che res ul ts from otol ogi c ca us es (i nvol vi ng the mi ddl e ea r or externa l ea r) or from nonotol ogi c ca us es referred to the ea r from nea rby di s ea s e
proces s es (s ee
Ta bl e 46-1).
Wi th acute pain, the mos t common ca us es a re
Mi ddl e ea r i nfecti on
Externa l ea r i nfecti on
Wi th chronic pain (> 2 to 3 wk), the mos t common ca us es a re
TMJ dys functi on
Chroni c eus ta chi a n tube dys functi on
Chroni c oti ti s externa
Al s o wi th chroni c pa i n, a tumor mus t be cons i dered, pa rti cul a rl y i n el derl y pa ti ents a nd i f the pa i n i s a s s oci a ted wi th ea r dra i na ge. Peopl e wi th
di a betes or i n other i mmunocompromi s ed s ta tes ma y devel op a pa rti cul a rl y s evere form of externa l oti ti s termed ma l i gna nt or necroti zi ng
externa l oti ti s . In thi s s i tua ti on, i f a bnorma l s oft ti s s ue i s found on exa mi na ti on of the ea r ca na l , the ti s s ue mus t be bi ops i ed to rul e out ca ncer.
TMJ dys functi on i s a common ca us e of ea ra che i n pa ti ents wi th a norma l ea r exa mi na ti on.
Evaluation
History: History of present illness s houl d a s s es s the l oca ti on, dura ti on, a nd s everi ty of pa i n a nd whether i t i s cons ta nt or i ntermi ttent. If i ntermi ttent,
i t i s i mporta nt to determi ne whether i t i s ra ndom or occurs ma i nl y wi th s wa l l owi ng or ja w movement. Importa nt a s s oci a ted s ymptoms i ncl ude ea r
dra i na ge, hea ri ng l os s , a nd s ore throa t. The pa ti ent s houl d be a s ked a bout a ny a ttempts a t cl ea ni ng the ea r ca na l (eg, wi th cotton s wa b) or other
recent i ns trumenta ti on, forei gn bodi es , recent a i r tra vel or s cuba di vi ng, a nd s wi mmi ng or other recurrent wa ter expos ure to ea rs .
Review of systems s houl d a s k a bout s ymptoms of chroni c i l l nes s , s uch a s wei ght l os s a nd fevers .
Past medical history s houl d a s k a bout known di a betes or other i mmunocompromi s ed s ta te, previ ous ea r di s orders (pa rti cul a rl y i nfecti ons ), a nd
a mount a nd dura ti on of toba cco a nd a l cohol us e.
Physical examination: Vi ta l s i gns s houl d be checked for fever.
Exa mi na ti on focus es on the ea rs , nos e, a nd throa t.
The pi nna a nd a rea over the ma s toi d proces s s houl d be i ns pected for rednes s a nd s wel l i ng. The ea r ca na l s houl d be exa mi ned for rednes s ,
di s cha rge, cerumen or forei gn body, a nd a ny other l es i ons . The TM s houl d be exa mi ned for rednes s , perfora ti on, a nd s i gns of mi ddl e ea r fl ui d
col l ecti on (eg, bul gi ng, di s torti on, cha nge i n norma l l i ght refl ex). A bri ef beds i de tes t of hea ri ng (s ee p. 431) s houl d be conducted.
The throa t s houl d be exa mi ned for erythema , tons i l l a r exuda te, peri tons i l l a r s wel l i ng, a nd a ny mucos a l l es i ons s ugges ti ng ca ncer.
TMJ functi on s houl d be a s s es s ed by pa l pa ti on of the joi nts on openi ng a nd cl os i ng of the mouth, a nd nota ti on s houl d be ma de of tri s mus or
evi dence of bruxi s m.
The neck s houl d be pa l pa ted for l ympha denopa thy. In-offi ce fi beropti c exa mi na ti on of the pha rynx a nd l a rynx s houl d be cons i dered, pa rti cul a rl y i f
no ca us e for the pa i n i s i denti fi ed on routi ne exa mi na ti on a nd i f nonotol ogi c s ymptoms s uch a s hoa rs enes s , di ffi cul ty s wa l l owi ng, or na s a l
obs tructi on a re reported.
Di a betes or i mmunocompromi s ed s ta te
Rednes s a nd fl uctua nce over ma s toi d a nd protrus i on of a uri cl e
Severe s wel l i ng a t externa l a udi tory ca na l mea tus
Chroni c pa i n, es peci a l l y i f a s s oci a ted wi th other hea d/neck s ymptoms
Interpretation of findings: An i mporta nt di fferenti a tor i s whether the ea r exa mi na ti on
[Table 46-1. Some Ca us es of Ea ra che]
i s norma l ; mi ddl e a nd externa l ea r di s orders ca us e a bnorma l phys i ca l fi ndi ngs , whi ch, when combi ned wi th hi s tory, us ua l l y s ugges t a n eti ol ogy
(s ee Ta bl e 46-1). For exa mpl e, thos e wi th chroni c eus ta chi a n tube dys functi on ha ve a bnorma l i ti es of the TM, typi ca l l y a retra cti on pocket.
Thos e wi th a norma l ea r exa mi na ti on ma y ha ve a vi s i bl e oropha ryngea l ca us e, s uch a s tons i l l i ti s or peri tons i l l a r a bs ces s . Ea r pa i n due to
neura l gi a ha s a cl a s s i c ma ni fes ta ti on a s bri ef (us ua l l y s econds , a l wa ys < 2 mi n) epi s odes of extremel y s evere, s ha rp pa i n. Chroni c ea r pa i n
wi thout a bnorma l i ty on ea r exa mi na ti on mi ght be due to a TMJ di s order, but pa ti ents s houl d ha ve a thorough hea d a nd neck exa mi na ti on
(i ncl udi ng fi beropti c exa mi na ti on) to rul e out ca ncer.
Testing: Mos t ca s es a re cl ea r a fter hi s tory a nd phys i ca l exa mi na ti on. Dependi ng on cl i ni ca l fi ndi ngs , nonotol ogi c ca us es ma y requi re tes ti ng (s ee
Ta bl e 46-1). Thos e wi th a norma l ea r exa mi na ti on, pa rti cul a rl y wi th chroni c or recurrent pa i n, ma y wa rra nt eva l ua ti on wi th a n MRI to rul e out
ca ncer.
Treatment
Underl yi ng di s orders a re trea ted.
Pa i n i s trea ted wi th ora l a na l ges i cs ; us ua l l y a n NSAID or a ceta mi nophen i s a dequa te, but s ometi mes a bri ef cours e of a n ora l opi oi d i s neces s a ry,
pa rti cul a rl y for ca s es of s evere oti ti s externa . In ca s es of s evere oti ti s externa , effecti ve trea tment requi res s ucti on of debri s from the ea r ca na l
a nd i ns erti on of a wi ck to a l l ow for del i very of a nti bi oti c ea r drops to the i nfected ti s s ue. Topi ca l a na l ges i cs (eg, a nti pyri ne-benzoca i ne
combi na ti ons ) a re genera l l y not very effecti ve but ca n be us ed on a l i mi ted ba s i s .
Pa ti ents s houl d be i ns tructed to a voi d di ggi ng i n thei r ea rs wi th a ny objects (no ma tter how s oft the objects a re or how ca reful the pa ti ent cl a i ms
to be). Al s o, pa ti ents s houl d not i rri ga te thei r ea rs unl es s i ns tructed by a phys i ci a n to do s o, a nd then onl y gentl y. An ora l i rri ga tor s houl d never be
us ed to i rri ga te the ea r.
Key Points
Mos t ca s es a re due to i nfecti on of the mi ddl e or externa l ea r.
Hi s tory a nd phys i ca l exa mi na ti on a re us ua l l y a dequa te for di a gnos i s .
Nonotol ogi c ca us es s houl d be cons i dered when ea r exa mi na ti on i s norma l .
Otorrhea
Ea r di s cha rge (otorrhea ) i s dra i na ge exi ti ng the ea r. It ma y be s erous , s eros a ngui neous , or purul ent. As s oci a ted s ymptoms ma y i ncl ude ea r pa i n,
fever, pruri tus , verti go, ti nni tus , a nd hea ri ng l os s .
Etiology
Ca us es ma y ori gi na te from the ea r ca na l , the mi ddl e ea r, or the cra ni a l va ul t. Certa i n ca us es tend to ma ni fes t a cutel y beca us e of the s everi ty of
thei r s ymptoms or a s s oci a ted condi ti ons . Others us ua l l y ha ve a more i ndol ent, chroni c cours e but s ometi mes ma ni fes t a cutel y (s ee
Ta bl e 46-2).
Overa l l , the mos t common ca us es a re
Acute oti ti s medi a wi th perfora ti on
Chroni c oti ti s medi a (wi th a perfora ti on of the ea rdrum, chol es tea toma , or both)
Oti ti s externa
The mos t s eri ous ca us es a re necroti zi ng externa l oti ti s a nd ca ncer of the ea r.
Evaluation
History: History of present illness s houl d cover dura ti on of s ymptoms a nd whether s ymptoms ha ve been recurrent. Importa nt a s s oci a ted s ymptoms
i ncl ude pa i n, i tchi ng, decrea s ed hea ri ng, verti go, a nd ti nni tus . Pa ti ents a re ques ti oned a bout a cti vi ti es tha t ca n a ffect the ca na l or tympa ni c
membra ne (TMeg, s wi mmi ng; i ns erti on of objects , i ncl udi ng cotton s wa bs ; us e of ea r drops ). Hea d tra uma s uffi ci ent to ca us e a CSF l ea k i s
rea di l y a ppa rent.
Review of systems s houl d s eek s ymptoms of cra ni a l nerve defi ci t a nd s ys temi c s ymptoms s ugges ti ng Wegener's gra nul oma tos i s (eg, na s a l
di s cha rge, cough, joi nt pa i ns ).
Past medical history s houl d note a ny previ ous known ea r di s orders , ea r s urgery (pa rti cul a rl y tympa nos tomy tube pl a cement), a nd di a betes or
i mmunodefi ci ency.
Physical examination: Exa mi na ti on begi ns wi th a revi ew of vi ta l s i gns for fever.
Ea r a nd s urroundi ng ti s s ues (pa rti cul a rl y the a rea over the ma s toi d) a re i ns pected for erythema a nd edema . The pi nna i s pul l ed a nd the tra gus i s
pus hed gentl y to s ee whether pa i n i s wors ened. The ea r ca na l i s i ns pected wi th a n otos cope; the cha ra cter of di s cha rge a nd pres ence of ca na l
l es i ons , gra nul a ti on ti s s ue, or forei gn body a re noted. Edema a nd di s cha rge ma y bl ock vi s ua l i za ti on of a l l but the di s ta l ca na l (i rri ga ti on s houl d
not be us ed i n ca s e there i s a TM perfora ti on), but when
[Table 46-2. Some Ca us es of Ea r Di s cha rge]
pos s i bl e, the TM i s i ns pected for i nfl a mma ti on, perfora ti on, di s torti on, a nd s i gns of chol es tea toma (eg, ca na l debri s , pol ypoi d ma s s from TM).
When the ea r ca na l i s s everel y s wol l en a t the mea tus (eg, a s wi th s evere oti ti s externa ) or there i s copi ous dra i na ge, ca reful s ucti oni ng ca n
permi t a n a dequa te exa mi na ti on a nd a l s o a l l ow trea tment (eg, a ppl i ca ti on of drops , wi th or wi thout a wi ck).
The cra ni a l nerves a re tes ted. The na s a l mucos a i s exa mi ned for ra i s ed, gra nul a r l es i ons , a nd the s ki n i s i ns pected for va s cul i ti c l es i ons , both of
whi ch ma y s ugges t Wegener's gra nul oma tos i s .
Recent ma jor hea d tra uma
Any cra ni a l nerve dys functi on (i ncl udi ng s ens ori neura l hea ri ng l os s )
Fever
Erythema of ea r or peri a uri cul a r ti s s ue
Di a betes or i mmunodefi ci ency
Interpretation of findings: Otos copi c exa mi na ti on ca n us ua l l y di a gnos e perfora ted TM, externa l oti ti s medi a , forei gn body, or other uncompl i ca ted
s ources of otorrhea . Some fi ndi ngs a re hi ghl y s ugges ti ve (s ee Ta bl e 46-2). Other fi ndi ngs a re l es s s peci fi c but i ndi ca te a more s eri ous probl em
tha t i nvol ves more tha n a l oca l i zed externa l ea r or mi ddl e ea r di s order:
Verti go a nd ti nni tus (di s order of the i nner ea r)
Cra ni a l nerve defi ci ts (di s order i nvol vi ng the s kul l ba s e)
Erythema a nd tendernes s of ea r, s urroundi ng ti s s ues , or both (s i gni fi ca nt i nfecti on)
Testing: Ma ny ca s es a re cl ea r a fter cl i ni ca l eva l ua ti on.
If CSF l ea ka ge i s i n ques ti on, di s cha rge ca n be tes ted for gl ucos e or 2 -tra ns ferri n; thes e s ubs ta nces a re pres ent i n CSF but not i n other types of
di s cha rge.
Pa ti ents wi thout a n obvi ous eti ol ogy on exa mi na ti on requi re a udi ogra m a nd CT of the tempora l bone or ga dol i ni um-enha nced MRI. Bi ops y s houl d
be cons i dered when a udi tory ca na l gra nul a ti on ti s s ue i s pres ent.
Treatment
Trea tment i s di rected a t the ca us e. Mos t phys i ci a ns do not trea t a s us pected CSF l ea k wi th a nti bi oti cs wi thout a defi ni ti ve di a gnos i s beca us e
drugs mi ght ma s k the ons et of meni ngi ti s .
Key Points
Acute di s cha rge i n a pa ti ent wi thout chroni c ea r probl ems or i mmunodefi ci ency i s l i kel y the res ul t of oti ti s externa or perfora ted oti ti s medi a .
Severe oti ti s externa ma y requi re s peci a l ty referra l for more extens i ve cl ea ni ng a nd pos s i bl e wi ck pl a cement.
Thos e wi th recurrent ea r s ymptoms (di a gnos ed or undi a gnos ed), cra ni a l nerve fi ndi ngs , or s ys temi c s ymptoms s houl d ha ve s peci a l ty referra l .
Tinnitus
Ti nni tus i s a noi s e i n the ea rs . It i s experi enced by 10 to 15% of the popul a ti on.
Subjective tinnitus i s percepti on of s ound i n the a bs ence of a n a cous ti c s ti mul us a nd i s hea rd onl y by the pa ti ent. Mos t ti nni tus i s s ubjecti ve.
Objective tinnitus i s uncommon a nd res ul ts from noi s e genera ted by s tructures nea r the ea r. Someti mes the ti nni tus i s l oud enough to be hea rd by
the exa mi ner.
Characteristics: Ti nni tus ma y be des cri bed a s buzzi ng, ri ngi ng, roa ri ng, whi s tl i ng, or hi s s i ng a nd i s s ometi mes va ri a bl e a nd compl ex. Objecti ve
ti nni tus typi ca l l y i s pul s a ti l e (s ynchronous wi th the hea rtbea t) or i ntermi ttent. Ti nni tus i s mos t noti cea bl e i n qui et envi ronments a nd i n the
a bs ence of di s tra cti ng s ti mul i a nd, thus , frequentl y s eems wors e a t bedti me.
Ti nni tus ma y be i ntermi ttent or conti nuous . Conti nuous ti nni tus i s a t bes t a nnoyi ng a nd i s often qui te di s tres s i ng. Some pa ti ents a da pt to i ts
pres ence better tha n others ; depres s i on occa s i ona l l y res ul ts . Stres s genera l l y exa cerba tes ti nni tus .
Pathophysiology
Subjective tinnitus i s thought to be ca us ed by a bnorma l neurona l a cti vi ty i n the a udi tory cortex. Thi s a cti vi ty res ul ts when i nput from the a udi tory
pa thwa y (cochl ea , a udi tory nerve, bra i n s tem nucl ei , a udi tory cortex) i s di s rupted or a l tered i n s ome ma nner. Thi s di s rupti on ma y ca us e l os s of
s uppres s i on of i ntri ns i c corti ca l a cti vi ty a nd perha ps crea ti on of new neura l connecti ons . Some bel i eve the phenomenon i s s i mi l a r to the
devel opment of pha ntom l i mb pa i n a fter a mputa ti on. Conducti ve hea ri ng l os s (eg, ca us ed by cerumen i mpa cti on, oti ti s medi a , or eus ta chi a n tube
dys functi on) ma y a l s o be a s s oci a ted wi th s ubjecti ve ti nni tus , by a l teri ng s ound i nput to the centra l a udi tory s ys tem.
Objective tinnitus repres ents a ctua l noi s e genera ted by phys i ol ogi c phenomena occurri ng nea r the mi ddl e ea r. Us ua l l y the noi s e comes from bl ood
ves s el s , ei ther norma l ves s el s i n condi ti ons of i ncrea s ed or turbul ent fl ow (eg, ca us ed by a theros cl eros i s ) or a bnorma l ves s el s (eg, i n tumors or
va s cul a r ma l forma ti ons ). Someti mes mus cl e s pa s ms or myocl onus of pa l a ta l mus cl es or mus cl es i n the mi ddl e ea r (s ta pedi us , tens or tympa ni )
ca us e cl i cki ng s ounds .
Etiology
Ca us es ma y be cons i dered by whether they ca us e s ubjecti ve or objecti ve ti nni tus (s ee
Ta bl e 46-3).
Subjective tinnitus: Subjecti ve ti nni tus ma y occur wi th a l mos t a ny di s order a ffecti ng the a udi tory pa thwa ys .
The mos t common di s orders a re thos e tha t i nvol ve s ens ori neura l hea ri ng l os s , pa rti cul a rl y
Acous ti c tra uma (noi s e-i nduced s ens ori neura l hea ri ng l os s )
Agi ng (pres bycus i s )
Ototoxi c drugs
Meni ere's di s ea s e
Infecti ons a nd CNS l es i ons (eg, ca us ed by tumor, s troke, mul ti pl e s cl eros i s ) tha t a ffect a udi tory pa thwa ys a l s o ma y be res pons i bl e.
Di s orders ca us i ng conducti ve hea ri ng l os s a l s o ma y ca us e ti nni tus . Thes e i ncl ude obs tructi on of the ea r ca na l by cerumen, a forei gn body, or
externa l oti ti s . Oti ti s medi a , ba rotra uma , eus ta chi a n tube dys functi on, a nd otos cl eros i s ma y a l s o be a s s oci a ted wi th ti nni tus .
Temporoma ndi bul a r joi nt dys functi on ma y be a s s oci a ted wi th ti nni tus i n s ome pa ti ents .
Objective tinnitus: Objecti ve ti nni tus us ua l l y i nvol ves noi s e from va s cul a r fl ow, whi ch ca us es a n a udi bl e pul s a ti ng s ound s ynchronous wi th the
pul s e. Ca us es i ncl ude
Turbul ent fl ow through the ca roti d a rtery or jugul a r vei n
Hi ghl y va s cul a r mi ddl e ea r tumors
Dura l a rteri ovenous ma l forma ti ons (AVMs )
Mus cl e s pa s ms or myocl onus of pa l a ta l mus cl es or thos e of the mi ddl e ea r (s ta pedi us , tens or tympa ni ) ma y ca us e percepti bl e noi s e, typi ca l l y a
rhythmi c cl i cki ng. Such s pa s ms ma y be i di opa thi c or ca us ed by tumors , hea d tra uma , a nd i nfecti ous or demyel i na ti ng di s ea s es (eg, mul ti pl e
s cl eros i s ). Pa l a ta l myocl onus ca us es vi s i bl e movement of the pa l a te, tympa ni c membra ne, or both tha t coi nci des wi th ti nni tus .
Evaluation
History: History of present illness s houl d note dura ti on of ti nni tus , whether i t i s i n one or both ea rs , a nd whether i t i s a cons ta nt tone or i ntermi ttent.
If i ntermi ttent, the cl i ni ci a n s houl d determi ne whether i t i s regul a r a nd whether i t i s a bout the ra te of the pul s e or s pora di c. Any exa cerba ti ng or
rel i evi ng fa ctors (eg, s wa l l owi ng, hea d pos i ti on) s houl d be noted. Importa nt a s s oci a ted s ymptoms i ncl ude hea ri ng l os s , verti go, ea r pa i n, a nd ea r
di s cha rge.
Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng di pl opi a a nd di ffi cul ty s wa l l owi ng or s pea ki ng (l es i ons of the bra i n s tem)
a nd foca l wea knes s a nd s ens ory cha nges (peri phera l nervous s ys tem di s orders ). The i mpa ct of the ti nni tus on the pa ti ent a l s o s houl d be
a s s es s ed. Whether the ti nni tus i s s uffi ci entl y di s tres s i ng to ca us e s i gni fi ca nt a nxi ety, depres s i on, or s l eepl es s nes s s houl d be noted.
Past medical history s houl d a s k a bout ri s k fa ctors for ti nni tus , i ncl udi ng expos ure to l oud noi s e, s udden pres s ure cha nge (from di vi ng or a i r tra vel ),
hi s tory of ea r or CNS i nfecti ons or tra uma , ra di a ti on thera py to the hea d, a nd recent ma jor wei ght l os s (ri s k of eus ta chi a n dys functi on). Drug us e
s houl d be a s certa i ned, pa rti cul a rl y a ny s a l i cyl a tes , a mi nogl ycos i des , or l oop di ureti cs .
Physical examination: Phys i ca l exa mi na ti on focus es on the ea r a nd the nervous s ys tem.
The ea r ca na l s houl d be i ns pected for di s cha rge, forei gn body, a nd cerumen. The tympa ni c membra ne s houl d be i ns pected for s i gns of a cute
i nfecti on (eg, rednes s , bul gi ng), chroni c i nfecti on (eg, perfora ti on, chol es tea toma ), a nd tumor (red or bl ui s h ma s s ). A beds i de hea ri ng tes t s houl d
be done.
Cra ni a l nerves , pa rti cul a rl y ves ti bul a r functi on (s ee p. 423), a re tes ted a l ong wi th peri phera l s trength, s ens a ti on, a nd refl exes . A s tethos cope i s
us ed to l i s ten for va s cul a r noi s e over the cours e of the ca roti d a rteri es a nd jugul a r vei ns a nd over a nd a dja cent to the ea r.
Brui t, pa rti cul a rl y over the ea r or s kul l
Accompa nyi ng neurol ogi c s ymptoms or s i gns (other tha n hea ri ng l os s )
Uni l a tera l ti nni tus
Interpretation of findings: In s ome ca s es , ti nni tus ma y i ndi ca te retrocochl ea r pa thol ogy, s uch a s a n a cous ti c neuroma (beni gn but i nva s i ve tumor
ori gi na ti ng from the ves ti bul a r porti on of the 8th cra ni a l nerve i n the i nterna l a udi tory ca na l ).
It i s i mporta nt to note whether the ti nni tus i s uni l a tera l beca us e a cous ti c neuroma s ma y ma ni fes t onl y wi th uni l a tera l ti nni tus . Thi s di a gnos i s i s
more l i kel y i f there i s a l s o uni l a tera l s ens ori neura l hea ri ng l os s or a s ymmetri c hea ri ng l os s wi th wors e hea ri ng i n the ea r wi th ti nni tus .
It a l s o i s i mporta nt to di s ti ngui s h the uncommon ca s es of objecti ve ti nni tus from the more common ca s es of s ubjecti ve ti nni tus . Ti nni tus tha t i s
pul s a ti l e or i ntermi ttent i s a l mos t a l wa ys objecti ve (a l though not a l wa ys detecta bl e by the exa mi ner), a s i s tha t a s s oci a ted wi th a brui t. Pul s a ti l e
ti nni tus i s nea rl y a l wa ys beni gn. Conti nuous ti nni tus i s us ua l l y s ubjecti ve (except perha ps for tha t ca us ed by a venous hum, whi ch ma y be
i denti fi ed by pres ence of a brui t a nd often by a cha nge i n ti nni tus wi th hea d rota ti on or jugul a r vei n compres s i on).
Speci fi c ca us es ca n often be s us pected by fi ndi ngs on exa mi na ti on (s ee Ta bl e 46-3). In pa rti cul a r, expos ure to l oud noi s e, ba rotra uma , or certa i n
drugs before ons et s ugges ts thos e fa ctors a s the ca us e.
Testing: Al l pa ti ents wi th s i gni fi ca nt ti nni tus s houl d be referred for comprehens i ve a udi ol ogi c eva l ua ti on to determi ne the pres ence, degree, a nd
type of hea ri ng l os s .
In pa ti ents wi th uni l a tera l ti nni tus a nd hea ri ng l os s , a cous ti c neuroma s houl d be rul ed out by ga dol i ni um-enha nced MRI. In thos e wi th uni l a tera l
ti nni tus a nd norma l hea ri ng a nd phys i ca l exa mi na ti on, MRI i s not neces s a ry unl es s ti nni tus pers i s ts > 6 mo.
Other tes ti ng depends on pa ti ent pres enta ti on (s ee Ta bl e 46-3).
Thos e wi th vi s i bl e evi dence of a va s cul a r tumor i n the mi ddl e ea r requi re CT, ga dol i ni um-enha nced MRI, a nd referra l to a s ubs peci a l i s t i f the
di a gnos i s i s confi rmed.
Thos e wi th pul s a ti l e, objecti ve ti nni tus a nd no ea r a bnorma l i ti es on exa mi na ti on or a udi ol ogy requi re further i nves ti ga ti on of the va s cul a r s ys tem
(ca roti d, vertebra l , a nd i ntra cra ni a l ves s el s ). The us ua l tes t s equence i s to begi n wi th ma gneti c res ona nce a ngi ogra phy (MRA). However, beca us e
MRA i s not very s ens i ti ve for dura l AVMs , ma ny cl i ni ci a ns then cons i der doi ng a n a rteri ogra m. However, beca us e dura l AVMs a re ra re, the
s i gni fi ca nt ri s ks of a rteri ogra phy mus t be wei ghed a ga i ns t the potenti a l benefi t of di a gnos i s a nd trea tment (wi th embol i za ti on) of thi s va s cul a r
a noma l y.
Treatment
Trea tment of the underl yi ng di s order ma y l es s en ti nni tus . Correcti ng hea ri ng l os s (eg, wi th a hea ri ng a i d) rel i eves ti nni tus i n a bout 50% of
pa ti ents .
Beca us e s tres s a nd other menta l fa ctors (eg, depres s i on) ca n exa cerba te s ymptoms , efforts to recogni ze a nd trea t thes e fa ctors ma y hel p. Ma ny
pa ti ents a re rea s s ured by l ea rni ng tha t thei r ti nni tus does not repres ent a s eri ous medi ca l probl em. Ti nni tus a l s o ca n be wors ened by ca ffei ne
a nd other s ti mul a nts , s o pa ti ents s houl d try el i mi na ti ng us e of thes e s ubs ta nces .
Al though no s peci fi c medi ca l or s urgi ca l thera py i s a va i l a bl e, ma ny pa ti ents fi nd tha t ba ckground s ound ma s ks the ti nni tus a nd ma y hel p them
fa l l a s l eep. Some pa ti ents benefi t from a ti nni tus ma s ker, a devi ce worn l i ke a hea ri ng a i d tha t provi des a l ow-l evel s ound tha t ca n cover up the
ti nni tus . Ti nni tus retra i ni ng thera py, offered by progra ms tha t s peci a l i ze i n ti nni tus trea tment, a re hel pful for ma ny pa ti ents . El ectri ca l s ti mul a ti on
of the i nner ea r, a s wi th a cochl ea r i mpl a nt, occa s i ona l l y
[Table 46-3. Some Ca us es of Ti nni tus ]
reduces the ti nni tus but i s a ppropri a te onl y for pa ti ents who a re profoundl y dea f.
One out of 4 peopl e > 65 yr ha ve s i gni fi ca nt hea ri ng i mpa i rment. Beca us e ti nni tus i s common i n peopl e wi th s ens ori neura l hea ri ng l os s , ti nni tus
i s a common compl a i nt a mong the el derl y.
Key Points
Subjecti ve ti nni tus i s ca us ed by a n a bnorma l i ty s omewhere i n the a udi tory pa thwa y.
Objecti ve ti nni tus i s ca us ed by a n a ctua l noi s e produced i n a va s cul a r s tructure nea r the ea r.
Loud noi s e, a gi ng, Meni ere's di s ea s e, a nd drugs a re the mos t common ca us es of s ubjecti ve ti nni tus .
Uni l a tera l ti nni tus wi th hea ri ng l os s or di zzi nes s /dys equi l i bri um wa rra nts ga dol i ni um-enha nced MRI to rul e out a cous ti c neuroma .
Any ti nni tus a ccompa ni ed by a neurol ogi c defi ci t i s of concern.
Dizziness and Vertigo
Dizziness i s a n i mpreci s e term pa ti ents often us e to des cri be va ri ous rel a ted s ens a ti ons , i ncl udi ng
Fa i ntnes s (a feel i ng of i mpendi ng s yncope)
Li ght-hea dednes s
Feel i ng of i mba l a nce or uns tea di nes s

A va gue s pa ced-out or s wi mmy-hea ded feel i ng
Vertigo i s a fa l s e s ens a ti on of movement of the s el f or the envi ronment. Us ua l l y the percei ved movement i s rota rya s pi nni ng or wheel i ng
s ens a ti onbut s ome pa ti ents s i mpl y feel pul l ed to one s i de. Verti go i s not a di a gnos i s i t i s a des cri pti on of a s ens a ti on.
Both s ens a ti ons ma y be a ccompa ni ed by na us ea a nd vomi ti ng or di ffi cul ty wi th ba l a nce, ga i t, or both.
Perha ps beca us e thes e s ens a ti ons a re ha rd to des cri be i n words , pa ti ents often us e "di zzi nes s ," "verti go," a nd other terms i ntercha ngea bl y a nd
i ncons i s tentl y. Di fferent pa ti ents wi th the s a me underl yi ng di s order ma y des cri be thei r s ymptoms very di fferentl y. A pa ti ent ma y even gi ve
di fferent des cri pti ons of the s a me "di zzy" event duri ng a gi ven vi s i t dependi ng on how the ques ti on i s a s ked. Beca us e of thi s di s crepa ncy, even
though verti go s eems to be a cl ea rl y del i nea ted s ubs et of di zzi nes s , ma ny cl i ni ci a ns prefer to cons i der the two s ymptoms together.
However they a re des cri bed, di zzi nes s a nd verti go ma y be di s turbi ng a nd even i nca pa ci ta ti ng, pa rti cul a rl y when a ccompa ni ed by na us ea a nd
vomi ti ng. Symptoms ca us e pa rti cul a r probl ems for peopl e doi ng a n exa cti ng or da ngerous ta s k, s uch a s dri vi ng, fl yi ng, or opera ti ng hea vy
ma chi nery.
Di zzi nes s a ccounts for a bout 5 to 6% of phys i ci a n vi s i ts . It ma y occur a t a ny a ge but becomes more common wi th i ncrea s i ng a ge; i t a ffects a bout
40% of peopl e over 40 yr a t s ome ti me. Di zzi nes s ma y be tempora ry or chroni c. Chroni c di zzi nes s , defi ned a s l a s ti ng > 1 mo, i s more common a mong
el derl y peopl e.
Pathophysiology
The vestibular system i s the ma i n neurol ogi c s ys tem i nvol ved i n ba l a nce. Thi s s ys tem i ncl udes
The ves ti bul a r a ppa ra tus of the i nner ea r
The 8th (ves ti bul ocochl ea r) cra ni a l nerve, whi ch conducts s i gna l s from the ves ti bul a r a ppa ra tus to the centra l components of the s ys tem
The ves ti bul a r nucl ei i n the bra i n s tem a nd cerebel l um
Di s orders of the i nner ea r a nd 8th cra ni a l nerve a re cons i dered peri phera l di s orders . Thos e of the ves ti bul a r nucl ei a nd thei r pa thwa ys i n the
bra i n s tem a nd cerebel l um a re cons i dered centra l di s orders .
The s ens e of ba l a nce a l s o i ncorpora tes vi s ua l i nput from the eyes a nd propri ocepti ve i nput from the peri phera l nerves (vi a the s pi na l cord). The
cerebra l cortex recei ves output from the l ower centers a nd i ntegra tes the i nforma ti on to produce the percepti on of moti on.
Vestibular apparatus: Percepti on of s ta bi l i ty, moti on, a nd ori enta ti on to gra vi ty ori gi na tes i n the ves ti bul a r a ppa ra tus , whi ch cons i s ts of
The 3 s emi ci rcul a r ca na l s
The 2 otol i th orga ns the s a ccul e a nd utri cl e
Rota ry moti on ca us es fl ow of endol ymph i n the s emi ci rcul a r ca na l ori ented i n the pl a ne of moti on. Dependi ng on the di recti on of fl ow, endol ymph
movement ei ther s ti mul a tes or i nhi bi ts neurona l output from ha i r cel l s l i ni ng the ca na l . Si mi l a r ha i r cel l s i n the s a ccul e a nd utri cl e a re
embedded i n a ma tri x of Ca ca rbona te crys ta l s (otol i ths ). Defl ecti on of the otol i ths by gra vi ty s ti mul a tes or i nhi bi ts neurona l output from the
a tta ched ha i r cel l s .
Etiology
There a re numerous s tructura l (tra uma , tumors , degenera ti ve), va s cul a r, i nfecti ous , toxi c (i ncl udi ng drug-rel a ted), a nd i di opa thi c ca us es (s ee
Ta bl e 46-4), but onl y a bout 5% of ca s es a re ca us ed by a s eri ous di s order.
[Table 46-4. Some Ca us es of Di zzi nes s a nd Verti go]
The most common causes of dizziness with vertigo i nvol ve s ome component of the peri phera l ves ti bul a r s ys tem:
Beni gn pos i ti ona l verti go
Meni ere's di s ea s e
Ves ti bul a r neuroni ti s
La byri nthi ti s
Les s often, the ca us e i s a centra l ves ti bul a r di s order (mos t commonl y mi gra i ne), a di s order wi th a more gl oba l effect on cerebra l functi on, a
ps ychi a tri c di s order, or a di s order a ffecti ng vi s ua l or propri ocepti ve i nput. Someti mes , no ca us e ca n be found.
The most common causes of dizziness without vertigo a re l es s cl ea r cut, but they a re us ua l l y not otol ogi c a nd proba bl y a re
Drug effects
Mul ti fa ctori a l or i di opa thi c

Nonneurol ogi c di s orders wi th a more gl oba l effect on cerebra l functi on s ometi mes ma ni fes t a s di zzi nes s a nd ra rel y a s verti go. Thes e di s orders
typi ca l l y i nvol ve i na dequa te s ubs tra te (eg, O2 , gl ucos e) del i very ca us ed by hypotens i on, hypoxemi a , a nemi a , or hypogl ycemi a ; when s evere, s ome
of thes e di s orders ma y ma ni fes t a s s yncope. Addi ti ona l l y, certa i n hormona l cha nges (eg, a s wi th thyroi d di s ea s e, mens trua ti on, pregna ncy) ca n
ca us e di zzi nes s . Numerous CNS-a cti ve drugs ca n ca us e di zzi nes s i ndependent of a ny toxi c effect on the ves ti bul a r s ys tem.
Occa s i ona l l y, di zzi nes s a nd verti go ma y be ps ychogeni c. Pa ti ents wi th pa ni c di s order, hyperventi l a ti on s yndrome, a nxi ety, or depres s i on ma y
pres ent wi th compl a i nts of di zzi nes s .
In el derl y pa ti ents , di zzi nes s i s often mul ti fa ctori a l s econda ry to drug a dvers e effects a nd a ge-di mi ni s hed vi s ua l , ves ti bul a r, a nd propri ocepti ve
a bi l i ti es . Two of the mos t common s peci fi c ca us es a re di s orders of the i nner ea r: beni gn pa roxys ma l pos i ti ona l verti go a nd Meni ere's di s ea s e.
Evaluation
History: History of present illness s houl d cover the s ens a ti ons fel t; a n open-ended ques ti on i s bes t (eg, "Di fferent peopl e us e the word 'di zzi nes s '
di fferentl y. Ca n you pl ea s e des cri be a s thoroughl y a s you ca n wha t you feel ?"). Bri ef, s peci fi c ques ti oni ng a s to whether the feel i ng i s fa i ntnes s ,
l i ght-hea dednes s , l os s of ba l a nce, or verti gi nous ma y bri ng s ome cl a ri ty, but pers i s tent efforts to ca tegori ze a pa ti ent's s ens a ti ons a re
unneces s a ry. Other el ements a re more va l ua bl e a nd cl ea r-cut:
Severi ty of i ni ti a l epi s ode
Severi ty a nd cha ra cteri s ti cs of s ubs equent epi s odes
Symptoms conti nuous or epi s odi c
If epi s odi c, frequency a nd dura ti on
Tri ggers a nd rel i evers (i e, tri ggered by hea d/body pos i ti on cha nge)
As s oci a ted a ura l s ymptoms (eg, hea ri ng l os s , ea r ful l nes s , ti nni tus )
Severi ty a nd rel a ted di s a bi l i ty
Is the pa ti ent ha vi ng a s i ngl e, s udden, a cute event, or ha s di zzi nes s been chroni c a nd recurrent? Wa s the fi rs t epi s ode the mos t s evere (ves ti bul a r
cri s i s )? How l ong do epi s odes l a s t, a nd wha t s eems to tri gger a nd wors en them? The pa ti ent s houl d be a s ked s peci fi ca l l y a bout movement of the
hea d, a ri s i ng, bei ng i n a nxi ous or s tres s ful s i tua ti ons , a nd mens es . Importa nt a s s oci a ted s ymptoms i ncl ude hea da che, hea ri ng l os s , ti nni tus ,
na us ea a nd vomi ti ng, i mpa i red vi s i on, foca l wea knes s , a nd di ffi cul ty wa l ki ng. The s everi ty of i mpa ct on the pa ti ent's l i fe s houl d be es ti ma ted:
Ha s the pa ti ent fa l l en? Is the pa ti ent rel ucta nt to dri ve or l ea ve the hous e? Ha s the pa ti ent mi s s ed work da ys ?
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng URI s ymptoms (i nner ea r di s orders ); ches t pa i n, pa l pi ta ti ons , or both
(hea rt di s ea s e); dys pnea (l ung di s ea s e); da rk s tool s (a nemi a ca us ed by GI bl ood l os s ); a nd wei ght cha nge or hea t or col d i ntol era nce (thyroi d
di s ea s e).
Past medical history s houl d note pres ence of recent hea d tra uma (us ua l l y obvi ous ), mi gra i ne, di a betes , hea rt or l ung di s ea s e, a nd drug a nd a l cohol
a bus e. In a ddi ti on to i denti fyi ng a l l current drugs , drug hi s tory s houl d a s s es s recent cha nges i n drugs , dos es , or both.
Physical examination: Exa mi na ti on begi ns wi th a revi ew of vi ta l s i gns , i ncl udi ng pres ence of fever, ra pi d or i rregul a r pul s e, a nd s upi ne a nd s ta ndi ng
BP, noti ng a ny drop i n BP on s ta ndi ng up (orthos ta ti c hypotens i on) a nd whether s ta ndi ng provokes s ymptoms . If s ta ndi ng does provoke s ymptoms ,
pos tura l s ymptoms s houl d be di s ti ngui s hed from thos e tri ggered by hea d movement by returni ng the pa ti ent s upi ne unti l s ymptoms di s s i pa te a nd
then rota ti ng the hea d.
The ENT a nd neurol ogi c exa mi na ti ons a re funda menta l . Speci fi ca l l y, wi th the pa ti ent s upi ne, the eyes a re checked for pres ence, di recti on, a nd
dura ti on of s ponta neous nys ta gmus (for ful l des cri pti on of exa mi na ti on for nys ta gmus , s ee Si deba r 46-1). Di recti on a nd dura ti on of nys ta gmus a nd
devel opment of verti go a re noted.
A gros s beds i de hea ri ng tes t i s done, the ea r ca na l i s i ns pected for di s cha rge a nd forei gn body, a nd the tympa ni c membra ne i s checked for s i gns
of i nfecti on or perfora ti on.
Cerebel l a r functi on i s tes ted by a s s es s i ng ga i t a nd doi ng a fi nger-nos e tes t a nd Romberg's tes t. The rema i nder of the neurol ogi c exa mi na ti on i s
done, i ncl udi ng tes ti ng the res t of the cra ni a l nerves .
Hea d or neck pa i n
Ata xi a
Los s of cons ci ous nes s
Foca l neurol ogi c defi ci t
Interpretation of findings: Tra di ti ona l l y, di fferenti a l di a gnos i s ha s been ba s ed on the exa ct na ture of the chi ef compl a i nt (i e, di s ti ngui s hi ng
di zzi nes s from l i ght-hea dednes s from verti go). However, the i ncons i s tency of pa ti ents ' des cri pti ons a nd the poor s peci fi ci ty of s ymptoms ma ke
thi s unrel i a bl e. A better a pproa ch pl a ces more wei ght on the ons et a nd ti mi ng of s ymptoms , the tri ggers , a nd a s s oci a ted s ymptoms a nd fi ndi ngs ,
pa rti cul a rl y otol ogi c a nd neurol ogi c ones .
Some cons tel l a ti ons of fi ndi ngs a re hi ghl y s ugges ti ve (s ee Ta bl e 46-4), pa rti cul a rl y thos e tha t hel p di fferenti a te peri phera l from centra l ves ti bul a r
di s orders .
Peri phera l : Ea r s ymptoms (eg, ti nni tus , ful l nes s , hea ri ng l os s ) us ua l l y i ndi ca te a peri phera l di s order. They a re typi ca l l y a s s oci a ted wi th verti go
a nd not genera l i zed di zzi nes s (unl es s ca us ed by uncompens a ted peri phera l ves ti bul a r wea knes s ). Symptoms a re us ua l l y pa roxys ma l , s evere,
a nd epi s odi c; conti nuous di zzi nes s i s ra rel y due to peri phera l verti go. Los s of cons ci ous nes s i s not a s s oci a ted wi th di zzi nes s due to peri phera l
ves ti bul a r pa thol ogy.
Centra l : Ea r s ymptoms a re ra rel y pres ent, but ga i t/ba l a nce di s turba nce i s common. Nys ta gmus i s not i nhi bi ted by vi s ua l fi xa ti on.
Testing: Pa ti ents wi th a s udden, ongoi ng a tta ck s houl d ha ve pul s e oxi metry a nd fi nger-s ti ck gl ucos e tes t. Women s houl d ha ve a pregna ncy tes t.
Mos t cl i ni ci a ns a l s o do a n ECG. Other tes ts a re done ba s ed on fi ndi ngs (s ee Ta bl e 46-4), but genera l l y ga dol i ni um-enha nced MRI i s i ndi ca ted for
pa ti ents wi th a cute s ymptoms who ha ve hea da che, neurol ogi c a bnorma l i ti es , or a ny other fi ndi ngs s ugges ti ve of a CNS eti ol ogy.
Pa ti ents wi th chroni c s ymptoms s houl d ha ve ga dol i ni um-enha nced MRI to l ook for evi dence of s troke, mul ti pl e s cl eros i s , or other CNS l es i ons .
Pa ti ents for whom res ul ts of beds i de tes ts of hea ri ng a nd ves ti bul a r functi on a re a bnorma l or equi voca l s houl d undergo forma l tes ti ng wi th
a udi ometry a nd el ectronys ta gmogra phy.
La bora tory tes ts a re ra rel y hel pful , except for pa ti ents wi th chroni c verti go a nd bi l a tera l hea ri ng l os s , for whom s yphi l i s s erol ogy i s i ndi ca ted.
Treatment
Trea tment i s di rected a t the ca us e, i ncl udi ng s toppi ng, reduci ng, or s wi tchi ng a ny ca us a ti ve drugs .
If a ves ti bul a r di s order i s pres ent a nd thought to be s econda ry to a cti ve Meni ere's di s ea s e or ves ti bul a r neuroni ti s or l a byri nthi ti s , the mos t
effecti ve ves ti bul a r nerve s uppres s a nts a re di a zepa m (2 to 5 mg po q 6 to 8 h, wi th hi gher dos es gi ven under s upervi s i on for s evere verti go) or ora l
a nti hi s ta mi ne/a nti chol i nergi c drugs (eg, mecl i zi ne 25 to 50 mg ti d). Al l of thes e drugs ca n ca us e drows i nes s , thereby l i mi ti ng thei r us e for certa i n
pa ti ents . Na us ea ca n be trea ted wi th prochl orpera zi ne 10 mg IM qi d or 25 mg recta l l y bi d. Verti go a s s oci a ted wi th beni gn pa roxys ma l pos i ti ona l
verti go i s trea ted wi th the Epl ey ma neuver (otol i th repos i ti oni ng) done by a n experi enced pra cti ti oner (s ee
Fi g. 48-1 on p. 443). Meni ere's di s ea s e i s bes t ma na ged by a n otol a ryngol ogi s t wi th tra i ni ng i n ma na gement of thi s chroni c di s order, but i ni ti a l
ma na gement cons i s ts of a l ow-s a l t di et a nd a K-s pa ri ng di ureti c.
Pa ti ents wi th pers i s tent or recurrent verti go s econda ry to uni l a tera l ves ti bul a r wea knes s (s uch a s s econda ry to ves ti bul a r neuroni ti s ) us ua l l y
benefi t from ves ti bul a r reha bi l i ta ti on thera py done by a n experi enced phys i ca l thera pi s t. Mos t pa ti ents compens a te wel l , a l though s ome,
es peci a l l y the el derl y, ha ve more di ffi cul ty. Phys i ca l thera py ca n a l s o provi de i mporta nt s a fety i nforma ti on for el derl y or pa rti cul a rl y di s a bl ed
pa ti ents .
As peopl e a ge, orga ns i nvol ved i n ba l a nce functi on l es s wel l . For exa mpl e, s eei ng i n di m l i ght becomes more di ffi cul t, i nner ea r s tructures
deteri ora te, propri ocepti on becomes l es s s ens i ti ve, a nd mecha ni s ms tha t control BP become l es s res pons i ve (eg, to pos tura l cha nges ,
pos tpra ndi a l dema nds ). Ol der peopl e a l s o a re more l i kel y to ha ve ca rdi a c or cerebrova s cul a r di s orders tha t ca n contri bute to di zzi nes s . They a l s o
a re more l i kel y to be ta ki ng drugs tha t ca n ca us e di zzi nes s , i ncl udi ng thos e for hypertens i on, a ngi na , hea rt fa i l ure, s ei zures , a nd a nxi ety, a s wel l
a s certa i n a nti bi oti cs , a nti hi s ta mi nes , a nd s l eep a i ds . Thus , di zzi nes s i n el derl y pa ti ents us ua l l y ha s more tha n one ca us e.
Al though unpl ea s a nt a t a ny a ge, the cons equences of di zzi nes s a nd verti go a re a pa rti cul a r probl em for el derl y pa ti ents . Thos e wi th fra i l ty a re a t
s i gni fi ca nt ri s k of fa l l i ng wi th cons equent fra ctures ; thei r fea r of movi ng a nd fa l l i ng often s i gni fi ca ntl y decrea s es thei r a bi l i ty to do da i l y a cti vi ti es .
In a ddi ti on to trea tment of s peci fi c ca us es , el derl y pa ti ents wi th di zzi nes s or verti go ma y benefi t from phys i ca l thera py a nd exerci s es to
s trengthen mus cl es a nd hel p ma i nta i n i ndependent a mbul a ti on a s l ong a s pos s i bl e.
Key Points
Va gue or i ncons i s tentl y des cri bed s ymptoms ma y s ti l l be a s s oci a ted wi th a s eri ous condi ti on.
Cerebrova s cul a r di s ea s e a nd drug effects s houl d be s ought, pa rti cul a rl y i n el derl y pa ti ents .
Peri phera l ves ti bul a r s ys tem di s orders s houl d be di fferenti a ted from centra l ves ti bul a r s ys tem di s orders .
Immedi a te neuroi ma gi ng s houl d be done when s ymptoms a re a ccompa ni ed by hea da che, foca l neurol ogi c a bnorma l i ti es , or both.
Chapter 47. Hearing Loss

Introduction
Nea rl y 10% of peopl e i n the US ha ve s ome degree of hea ri ng l os s . About 1/800 to 1/1000 neona tes a re born wi th s evere to profound hea ri ng l os s .
Two to 3 ti mes a s ma ny a re born wi th l es s er hea ri ng l os s . Duri ng chi l dhood, a nother 2 to 3/1000 chi l dren a cqui re modera te to s evere hea ri ng l os s .
Adol es cents a re a t ri s k from exces s i ve expos ure to noi s e, hea d tra uma , or both. Ol der a dul ts typi ca l l y experi ence a progres s i ve decrea s e i n
hea ri ng (pres bycus i s s ee p. 438), whi ch i s proba bl y rel a ted to a gi ng a nd noi s e expos ure.
Hea ri ng defi ci ts i n ea rl y chi l dhood ca n res ul t i n l i fel ong i mpa i rments i n recepti ve a nd expres s i ve l a ngua ge s ki l l s . The s everi ty of the ha ndi ca p i s
determi ned by the a ge a t whi ch the hea ri ng l os s occurred; the na ture of the l os s (i ts dura ti on, the frequenci es a ffected, a nd the degree); a nd the
s us cepti bi l i ti es of the i ndi vi dua l chi l d (eg, coexi s ti ng vi s ua l i mpa i rment, i ntel l ectua l di s a bi l i ty, pri ma ry l a ngua ge defi ci ts , i na dequa te l i ngui s ti c
envi ronment). Chi l dren who ha ve other s ens ory, l i ngui s ti c, or cogni ti ve defi ci enci es a re a ffected mos t s everel y.
Pathophysiology
Hea ri ng l os s ca n be cl a s s i fi ed a s conducti ve, s ens ori neura l , or both (mi xed l os s ).
Conductive hearing loss occurs s econda ry to l es i ons i n the externa l a udi tory ca na l , tympa ni c membra ne (TM), or mi ddl e ea r. Thes e l es i ons prevent
s ound from bei ng effecti vel y conducted to the i nner ea r.
Sensorineural hearing loss i s ca us ed by l es i ons of ei ther the i nner ea r (s ens ory) or the a udi tory (8th) nerve (neura l s ee
Ta bl e 47-1). Thi s di s ti ncti on i s i mporta nt beca us e s ens ory
[Table 47-1. Di fferences Between Sens ory a nd Neura l Hea ri ng Los s es ]
hea ri ng l os s i s s ometi mes revers i bl e a nd i s s el dom l i fe threa teni ng. A neura l hea ri ng l os s i s ra rel y recovera bl e a nd ma y be due to a potenti a l l y
l i fe-threa teni ng bra i n tumorcommonl y a cerebel l oponti ne a ngl e tumor.
Mixed loss ma y be ca us ed by s evere hea d i njury wi th or wi thout fra cture of the s kul l or tempora l bone, by chroni c i nfecti on, or by one of ma ny
geneti c di s orders . It ma y a l s o occur when a tra ns i ent conducti ve hea ri ng l os s , commonl y due to oti ti s medi a , i s s uperi mpos ed on a s ens ori neura l
hea ri ng l os s .
Etiology
Hea ri ng l os s ca n be congeni ta l (s ee
Ta bl e 47-2) or a cqui red (s ee
Ta bl e 47-3), progres s i ve or s udden (s ee a l s o p. 438), tempora ry or perma nent, uni l a tera l or bi l a tera l , a nd mi l d or profound. Drug-i nduced
ototoxi ci ty i s di s cus s ed el s ewhere (s ee p. 443).
The most common causes overa l l a re the fol l owi ng:
Cerumen a ccumul a ti on
Noi s e
Agi ng
Infecti ons (pa rti cul a rl y a mong chi l dren a nd young a dul ts )
Cerumen (ea rwa x) a ccumul a ti on i s the mos t common ca us e of trea ta bl e hea ri ng l os s , es peci a l l y i n the el derl y. Forei gn bodi es obs tructi ng the
ca na l a re s ometi mes a probl em i n chi l dren, both beca us e of thei r pres ence a nd beca us e of a ny da ma ge i na dvertentl y ca us ed duri ng thei r
remova l .
Noise ca n ca us e s udden or gra dua l s ens ori neura l hea ri ng l os s . In a cous ti c tra uma , hea ri ng l os s res ul ts from expos ure to a s i ngl e, extreme noi s e
(eg, a nea rby guns hot or expl os i on); s ome pa ti ents ha ve ti nni tus a s wel l . The l os s i s us ua l l y tempora ry (unl es s there i s a l s o bl a s t da ma ge, whi ch
ma y des troy the TM, os s i cl es , or both). In noi s e-i nduced hea ri ng l os s , the l os s devel ops over ti me beca us e of chroni c expos ure to noi s e > 85
deci bel s (dBs ee Si deba r 47-1 on p. 434). Al though peopl e va ry s omewha t i n s us cepti bi l i ty to noi s e-i nduced hea ri ng l os s , nea rl y everyone l os es
s ome hea ri ng i f they a re expos ed to s uffi ci entl y i ntens e noi s e for a n a dequa te ti me. Repea ted expos ure to l oud noi s e ul ti ma tel y res ul ts i n l os s of
ha i r cel l s i n the orga n of Corti . Hea ri ng l os s typi ca l l y occurs fi rs t a t 4 kHz a nd gra dua l l y s prea ds to the l ower a nd hi gher frequenci es a s expos ure
conti nues . In contra s t to mos t other ca us es of s ens ori neura l hea ri ng l os s es , noi s e-i nduced hea ri ng l os s ma y be l es s s evere a t 8 kHz tha n a t 4 kHz.
[Table 47-2. Congeni ta l Ca us es of Hea ri ng Los s *]
Acute otitis media (AOMs ee p. 448) i s a common ca us e of tra ns i ent mi l d to modera te hea ri ng l os s (ma i nl y i n chi l dren). However, wi thout
trea tment, AOM s equel a e a nd chroni c oti ti s medi a (a nd the ra rer purul ent l a byri nthi ti s ) ca n ca us e perma nent l os s , pa rti cul a rl y i f a chol es tea toma
forms .
Secretory otitis media (SOMs ee p. 450) occurs i n s evera l wa ys . Al mos t a l l epi s odes of AOM a re fol l owed by a peri od of 2 to 4 wk of SOM. SOM ca n
a l s o be ca us ed by eus ta chi a n tube dys functi on (eg, res ul ti ng from cl eft pa l a te, beni gn or ma l i gna nt tumors of the na s opha rynx, or ra pi d cha nges
i n externa l a i r pres s ure a s occur duri ng des cent from hi gh a l ti tudes or ra pi d a s cent whi l e s cuba di vi ng).
Autoimmune disorders ca n ca us e s ens ori neura l hea ri ng l os s a t a l l a ges a nd ca n ca us e other s ymptoms a nd s i gns a s wel l .
Evaluation
Eva l ua ti on cons i s ts of detecti ng a nd qua nti fyi ng hea ri ng l os s a nd determi ni ng eti ol ogy (pa rti cul a rl y revers i bl e ca us es ).
Screening: Mos t a dul ts a nd ol der chi l dren noti ce a s udden hea ri ng l os s , a nd ca regi vers ma y s us pect tha t a neona te ha s a s evere hea ri ng l os s
wi thi n the fi rs t week of l i fe when the neona te does not res pond to voi ces or other s ounds . However, progres s i ve l os s es a nd nea rl y a l l l os s es i n
i nfa nts a nd young chi l dren mus t be detected by s creeni ng. Screeni ng s houl d begi n a t bi rth (s ee p. 2717) s o tha t l i ngui s ti c i nput ca n a l l ow opti ma l
l a ngua ge devel opment. Sus pected hea ri ng l os s a t a ny ti me s houl d prompt referra l to a s peci a l i s t. If s creeni ng i s not done, s evere bi l a tera l l os s es
ma y not be recogni zed unti l a ge 2 yr, a nd mi l d to modera te or s evere uni l a tera l l os s es a re often not recogni zed unti l chi l dren rea ch s chool a ge.
History: History of present illness s houl d note how l ong hea ri ng l os s ha s been percei ved, how i t bega n (eg, gra dua l , a cute), whether i t i s uni l a tera l or
bi l a tera l , a nd whether s ound i s di s torted (eg, mus i c i s offdul l or l i fel es s ) or there i s di ffi cul ty wi th s peech di s cri mi na ti on. The pa ti ent s houl d be
a s ked whether the l os s fol l owed a ny a cute event (eg, hea d i njury, ba rotra uma [pa rti cul a rl y a di vi ng i njury], s ta rti ng of a drug). Importa nt
a ccompa nyi ng s ymptoms i ncl ude other otol ogi c s ymptoms (eg, ea r pa i n, ti nni tus , ea r di s cha rge), ves ti bul a r s ymptoms (eg, di s ori enta ti on i n the
da rk, verti go), a nd other neurol ogi c s ymptoms (eg, hea da che, wea knes s or a s ymmetry of the fa ce, a n a bnorma l s ens e of ta s te, ful l nes s of the ea r).
In chi l dren, i mporta nt a s s oci a ted s ymptoms i ncl ude pres ence of del a ys i n s peech or l a ngua ge devel opment a nd del a yed motor devel opment.
Review of systems s houl d s eek to determi ne the i mpa ct of hea ri ng di ffi cul ty on the pa ti ent's l i fe.
Past medical history s houl d note previ ous pos s i bl y ca us a ti ve di s orders , i ncl udi ng CNS i nfecti on, repea ted ea r i nfecti ons , chroni c expos ure to l oud
noi s e, hea d tra uma , rheuma ti c di s orders (eg, RA, l upus ), a nd a fa mi l y hi s tory of hea ri ng l os s . Drug hi s tory s houl d s peci fi ca l l y query current or
previ ous us e of ototoxi c drugs (s ee Ta bl e 47-3).
Physical examination: The focus i s exa mi na ti on of the ea rs a nd hea ri ng a nd the neurol ogi c exa mi na ti on. The externa l ea r i s i ns pected for
obs tructi on, i nfecti on, congeni ta l ma l forma ti ons , a nd other l es i ons . The TM i s exa mi ned for perfora ti on, dra i na ge, oti ti s medi a , a nd
chol es tea toma . Duri ng the neurol ogi c exa mi na ti on, pa rti cul a r a ttenti on needs to be pa i d to the 2nd through 7th cra ni a l nerves a s wel l a s to
ves ti bul a r a nd cerebel l a r functi on beca us e a bnorma l i ti es i n thes e a rea s often occur wi th tumors of the bra i n s tem a nd cerebel l oponti ne a ngl e.
Weber's tes t a nd the Ri nne tes t requi re a tuni ng fork to di fferenti a te conducti ve from s ens ori neura l hea ri ng l os s .
In Weber's test, the s tem of a vi bra ti ng 512-Hz or 1024-Hz tuni ng fork i s pl a ced on the mi dl i ne of the hea d, a nd the pa ti ent i ndi ca tes i n whi ch ea r
the tone i s l ouder. In uni l a tera l conducti ve hea ri ng l os s , the tone i s l ouder i n the ea r wi th hea ri ng l os s . In uni l a tera l s ens ori neura l hea ri ng l os s ,
the tone i s l ouder i n the norma l ea r beca us e the tuni ng fork s ti mul a tes both i nner ea rs equa l l y a nd the pa ti ent percei ves the s ti mul us wi th the
una ffected ea r.
In the Rinne test, hea ri ng by bone a nd by a i r conducti on i s compa red. Bone conducti on bypa s s es the externa l a nd mi ddl e ea r a nd tes ts the i ntegri ty
of the i nner ea r, 8th cra ni a l nerve, a nd centra l a udi tory pa thwa ys . The s tem of a vi bra ti ng tuni ng fork i s hel d a ga i ns t the ma s toi d (for bone
conducti on); a s s oon a s the s ound i s no l onger percei ved, the fork i s removed from the ma s toi d, a nd the s ti l l -vi bra ti ng ti nes a re hel d cl os e to the
pi nna (for a i r conducti on). Norma l l y, the fork ca n once more be hea rd, i ndi ca ti ng tha t a i r conducti on i s better tha n bone conducti on. Wi th
conducti ve hea ri ng l os s , the rel a ti ons hi p i s revers ed; bone conducti on i s l ouder tha n a i r conducti on. Wi th s ens ori neura l hea ri ng l os s , both a i r
a nd bone conducti on a re reduced, but a i r conducti on rema i ns l ouder.
Red flags: Fi ndi ngs of pa rti cul a r concern a re
Uni l a tera l s ens ori neura l hea ri ng l os s
Abnorma l i ti es of cra ni a l nerves (other tha n hea ri ng l os s )
Interpretation of findings: Ma ny ca us es of hea ri ng l os s (eg, cerumen, i njury, s i gni fi ca nt noi s e expos ure, i nfecti ous s equel a e, drugs ) a re rea di l y
a ppa rent ba s ed on res ul ts of the exa mi na ti on (s ee Ta bl e 47-3).
As s oci a ted fi ndi ngs a re hel pful i n di a gnos i ng the rema i ni ng s ma l l number of pa ti ents i n
[Table 47-3. Some Ca us es of Acqui red Hea ri ng Los s ]
whom no cl ea r ca us e ca n be found. Thos e who ha ve foca l neurol ogi c a bnorma l i ti es a re of pa rti cul a r concern. The 5th or 7th cra ni a l nerve or both
a re often a ffected by tumors tha t i nvol ve the 8th nerve, s o l os s of fa ci a l s ens a ti on a nd wea k ja w cl ench (5th) a nd hemi fa ci a l wea knes s a nd ta s te
a bnorma l i ti es (7th) poi nt to a l es i on i n tha t a rea . Si gns of a utoi mmune di s orders , ma xi l l ofa ci a l ma l forma ti ons , a nd rena l dys functi on ma y
s ugges t thes e di s orders a s a ca us e.
Any chi l d wi th del a ys i n s peech or l a ngua ge devel opment or di ffi cul ty i n s chool s houl d be eva l ua ted for hea ri ng l os s . Intel l ectua l di s a bi l i ty,
a pha s i a , a nd a uti s m mus t a l s o be cons i dered. Del a yed motor devel opment ma y s i gna l ves ti bul a r defi ci t, whi ch i s often a s s oci a ted wi th a
s ens ori neura l hea ri ng l os s .
Testing: Tes ti ng i ncl udes
Audi ol ogi c tes ts
Someti mes MRI or CT
Audiologic tests a re requi red for a l l peopl e who ha ve hea ri ng l os s ; thes e tes ts us ua l l y i ncl ude
Mea s urement of pure-tone thres hol ds wi th a i r a nd bone conducti on
Speech recepti on thres hol d
Speech di s cri mi na ti on
Tympa nometry
Acous ti c refl ex tes ti ng
Informa ti on ga i ned from thes e tes ts hel ps determi ne whether more defi ni ti ve di fferenti a ti on of s ens ory from neura l hea ri ng l os s i s needed.
Pure-tone a udi ometry qua nti fi es hea ri ng l os s . An a udi ometer del i vers s ounds of s peci fi c frequenci es (pure tones ) a t di fferent i ntens i ti es to
determi ne the pa ti ent's hea ri ng thres hol d (how l oud a s ound mus t be to be percei ved) for ea ch frequency. Hea ri ng i n ea ch ea r i s tes ted from 125
or 250 to 8000 Hz by a i r conducti on (us i ng ea rphones ) a nd up to 4 kHz by bone conducti on (us i ng a n os ci l l a tor i n conta ct wi th the ma s toi d proces s
or forehea d). Tes t res ul ts a re pl otted on gra phs ca l l ed a udi ogra ms (s ee
Fi g. 47-1), whi ch s how the di fference between the pa ti ent's hea ri ng thres hol d a nd norma l hea ri ng a t ea ch frequency. The di fference i s mea s ured
i n dB (s ee Si deba r 47-1). The norma l thres hol d i s cons i dered 0 dB hea ri ng l evel (Hl ); hea ri ng l os s i s cons i dered pres ent i f the pa ti ent's thres hol d
i s > 25 dB Hl . When hea ri ng l os s i s s uch a s to requi re l oud tes t tones , i ntens e tones pres ented to one ea r ma y be hea rd i n the other ea r. In s uch
ca s es , a ma s ki ng s ound, us ua l l y na rrow ba nd noi s e, i s pres ented to the ea r not bei ng tes ted to i s ol a te i t.
Speech a udi ometry i ncl udes the s peech recepti on thres hol d (SRT) a nd the word recogni ti on s core. The SRT i s a mea s ure of the i ntens i ty a t whi ch
s peech i s recogni zed. To determi ne the SRT, the exa mi ner pres ents the pa ti ent wi th a l i s t of words a t s peci fi c s ound i ntens i ti es . Thes e words
us ua l l y ha ve 2 equa l l y a ccented s yl l a bl es (s pondees ), s uch a s ra i l roa d, s ta i rca s e, a nd ba s eba l l . The exa mi ner notes the i ntens i ty a t whi ch the
pa ti ent repea ts 50% of the words correctl y. The SRT a pproxi ma tes the a vera ge hea ri ng l evel a t s peech frequenci es (eg, 500 Hz, 1000 Hz, 2000 Hz).
Sidebar 47-1 Sound Levels

Sound i ntens i ty a nd pres s ure (the phys i ca l correl a tes of l oudnes s ) a re mea s ured i n deci bel s (dB). A dB i s a uni tl es s fi gure tha t compa res 2 va l ues
a nd i s defi ned a s the l oga ri thm of the ra ti o of a mea s ured va l ue to a reference va l ue, mul ti pl i ed by a cons ta nt:
dB = k l og (Vmeasured/Vref)
By conventi on, the reference va l ue for s ound pres s ure l evel (SPL) i s ta ken a s the qui etes t 1000-Hz s ound detecta bl e by young, hea l thy huma n
ea rs .* The s ound ma y be mea s ured i n terms of pres s ure (N/m 2 ) or i ntens i ty (wa tts /m 2 ).
Beca us e s ound i ntens i ty equa l s the s qua re of s ound pres s ure, the cons ta nt (k) for SPL i s 20; for s ound i ntens i ty, 10. Thus , ea ch 20-dB i ncrea s e
repres ents a 10-fol d i ncrea s e i n SPL but a 100-fol d i ncrea s e i n s ound i ntens i ty.
The dB va l ues i n the ta bl e bel ow gi ve onl y a rough i dea of the ri s k of hea ri ng l os s . Some of them a re dB SPL va l ues (referenced to N/m 2 ), wherea s
others repres ent pea k dB or dB on the A-s ca l e (a s ca l e tha t empha s i zes the frequenci es tha t a re mos t ha za rdous to huma n hea ri ng).
Db
0 Fa i ntes t s ound hea rd by huma n ea r
30 Whi s per, qui et l i bra ry
60 Norma l convers a ti on, s ewi ng ma chi ne, typewri ter
Example
90 La wnmower, s hop tool s , truck tra ffi c (8 h/da y i s the ma xi mum expos ure wi thout protecti on )
100 Cha i n s a w, pneuma ti c dri l l , s nowmobi l e (2 h/da y i s the ma xi mum expos ure wi thout protecti on)
115 Sa ndbl a s ti ng, l oud rock concert, a utomobi l e horn (15 mi n/da y i s the ma xi mum expos ure wi thout protecti on)
Gun muzzl e bl a s t, jet engi ne (noi s e ca us es pa i n a nd even bri ef expos ure i njures unprotected ea rs ; i njury ma y occur even wi th hea ri ng
140
protectors )
180 Rocket l a unchi ng pa d
*In a udi ometri c tes ti ng, beca us e huma n ea rs res pond di fferentl y a t di fferent frequenci es , the reference va l ue cha nges for ea ch frequency tes ted.
Thres hol d va l ues reported on a udi ogra ms ta ke thi s i nto a ccount; the norma l thres hol d i s a l wa ys 0 dB, rega rdl es s of the a ctua l SPL.
Ma nda tory federa l s ta nda rd, but protecti on i s recommended for more tha n bri ef expos ure to s ound l evel s > 85 db.
The word recogni ti on s core tes ts the a bi l i ty to di s cri mi na te a mong the va ri ous s peech s ounds or phonemes . It i s determi ned by pres enti ng 50
phoneti ca l l y ba l a nced one-s yl l a bl e words a t a n i ntens i ty of 35 to 40 dB a bove the pa ti ent's SRT. The word l i s t conta i ns phonemes i n the s a me
rel a ti ve frequency found i n convers a ti ona l Engl i s h. The s core i s the percenta ge of words correctl y repea ted by the pa ti ent a nd refl ects the a bi l i ty
to unders ta nd s peech
[Fig. 47-1. Audi ogra m of ri ght ea r i n a pa ti ent wi th norma l hea ri ng.]
under opti ma l l i s teni ng condi ti ons . A norma l s core ra nges from 90 to 100%. The word recogni ti on s core i s norma l wi th conducti ve hea ri ng l os s ,
a l bei t a t a hi gher i ntens i ty l evel , but ca n be reduced a t a l l i ntens i ty l evel s wi th s ens ori neura l hea ri ng l os s . Di s cri mi na ti on i s even poorer i n
neura l tha n i n s ens ory hea ri ng l os s .
Tympa nometry mea s ures the i mpeda nce of the mi ddl e ea r to a cous ti c energy a nd does not requi re pa ti ent pa rti ci pa ti on. It i s commonl y us ed to
s creen chi l dren for mi ddl e ea r effus i ons . A probe conta i ni ng a s ound s ource, mi crophone, a nd a i r pres s ure regul a tor i s pl a ced s nugl y wi th a n
a i rti ght s ea l i nto the ea r ca na l . The probe mi crophone records the refl ected s ound from the TM whi l e pres s ure i n the ca na l i s va ri ed. Norma l l y,
ma xi ma l compl i a nce of the mi ddl e ea r occurs when the pres s ure i n the ea r ca na l equa l s a tmos pheri c pres s ure. Abnorma l compl i a nce pa tterns
s ugges t s peci fi c a na tomi c di s rupti ons . In eus ta chi a n tube obs tructi on a nd mi ddl e ea r effus i on, ma xi ma l compl i a nce occurs wi th a nega ti ve
pres s ure i n the ea r ca na l . When the os s i cul a r cha i n i s di s rupted, a s i n necros i s or di s l oca ti on of the l ong proces s of the i ncus , the mi ddl e ea r i s
exces s i vel y compl i a nt. When the os s i cul a r cha i n i s fi xed, a s i n s ta pedi a l a nkyl os i s i n otos cl eros i s , compl i a nce ma y be norma l or reduced.
The a cous ti c refl ex i s contra cti on of the s ta pedi us mus cl e i n res pons e to l oud s ounds , whi ch cha nges the compl i a nce of the TM, protecti ng the
mi ddl e ea r from a cous ti c tra uma . The refl ex i s tes ted by pres enti ng a tone a nd mea s uri ng wha t i ntens i ty provokes a cha nge i n mi ddl e ea r
i mpeda nce a s noted by movement of the TM. An a bs ent refl ex coul d i ndi ca te mi ddl e ea r di s ea s e or a tumor of the a udi tory nerve.
Advanced testing i s s ometi mes needed. Ga dol i ni um-enha nced MRI of the hea d to detect l es i ons of the cerebel l oponti ne a ngl e ma y be needed i n
pa ti ents wi th a n a bnorma l neurol ogi c exa mi na ti on or thos e whos e a udi ol ogi c tes ti ng s hows poor word recogni ti on, a s ymmetri c s ens ori neura l
hea ri ng l os s , or a combi na ti on when the eti ol ogy i s not cl ea r.
CT i s done i f bony tumors or bony eros i on i s s us pected. Ma gneti c res ona nce a ngi ogra phy i s done i f va s cul a r a bnorma l i ti es s uch a s gl omus tumors
a re s us pected.
The a udi tory bra i n s tem res pons e us es s urfa ce el ectrodes to moni tor bra i n wa ve res pons e to a cous ti c s ti mul a ti on i n peopl e who ca nnot
otherwi s e res pond.
El ectrocochl eogra phy mea s ures the a cti vi ty of the cochl ea a nd the a udi tory nerve wi th a n el ectrode pl a ced on or through the ea rdrum. It ca n be
us ed to a s s es s a nd moni tor pa ti ents wi th di zzi nes s , ca n be us ed i n pa ti ents who a re a wa ke, a nd i s us eful i n i ntra opera ti ve moni tori ng.
Otoa cous ti c emi s s i ons tes ti ng mea s ures s ounds produced by outer ha i r cel l s of the cochl ea i n res pons e to a s ound s ti mul us us ua l l y pl a ced i n the
ea r ca na l . It i s us ed to s creen neona tes a nd i nfa nts for hea ri ng l os s a nd to moni tor the hea ri ng of pa ti ents who a re us i ng ototoxi c drugs (eg,
genta mi ci n, ci s pl a ti n).
Certa i n pa ti ents , s uch a s chi l dren wi th a rea di ng or other l ea rni ng probl em a nd el derl y peopl e who s eem to hea r but do not comprehend, s houl d
undergo a centra l a udi tory eva l ua ti on. It mea s ures di s cri mi na ti on of degra ded or di s torted s peech, di s cri mi na ti on i n the pres ence of a competi ng
mes s a ge i n the oppos i te ea r, the a bi l i ty to fus e i ncompl ete or pa rti a l mes s a ges del i vered to ea ch ea r i nto a mea ni ngful mes s a ge, a nd the
ca pa ci ty to l oca l i ze s ound i n s pa ce when a cous ti c s ti mul i a re del i vered s i mul ta neous l y to both ea rs .
Treatment
The ca us es of a hea ri ng l os s s houl d be determi ned a nd trea ted. Ototoxi c drugs s houl d be s topped or the dos e s houl d be l owered unl es s the
s everi ty of the di s ea s e bei ng trea ted (us ua l l y ca ncer or a s evere i nfecti on) requi res tha t the ri s k of a ddi ti ona l ototoxi c hea ri ng l os s be a ccepted.
Attenti on to pea k a nd trough drug l evel s ma y hel p mi ni mi ze ri s k.
Fl ui d from mi ddl e ea r effus i on ca n be dra i ned by myri ngotomy a nd prevented wi th the i ns erti on of a tympa nos tomy tube. Beni gn growths (eg,
enl a rged a denoi ds , na s a l pol yps ) a nd ma l i gna nt tumors (eg, na s opha ryngea l ca ncers , s i nus ca ncers ) bl ocki ng the eus ta chi a n tube or ea r ca na l
ca n be removed. Hea ri ng l os s ca us ed by a utoi mmune di s orders ma y res pond to corti cos teroi ds .
Da ma ge to the TM or os s i cl es or otos cl eros i s ma y requi re recons tructi ve s urgery. Bra i n tumors ca us i ng hea ri ng l os s ma y i n s ome ca s es be removed
a nd hea ri ng pres erved.
Ma ny ca us es of hea ri ng l os s ha ve no cure, a nd trea tment i nvol ves compens a ti ng for the hea ri ng l os s wi th hea ri ng a i ds a nd, for s evere to profound
l os s , a cochl ea r i mpl a nt. In a ddi ti on, va ri ous copi ng mecha ni s ms ma y hel p.
Hearing aids: Ampl i fi ca ti on of s ound wi th a hea ri ng a i d hel ps ma ny peopl e. Al though hea ri ng a i ds do not res tore hea ri ng to norma l , they ca n
s i gni fi ca ntl y i mprove communi ca ti on. Phys i ci a ns s houl d encoura ge hea ri ng a i d us e a nd hel p pa ti ents overcome a s ens e of s oci a l s ti gma tha t
conti nues to obs truct us e of thes e devi ces , perha ps by ma ki ng the a na l ogy tha t a hea ri ng a i d i s to hea ri ng a s eye gl a s s es a re to s eei ng.
Al l hea ri ng a i ds ha ve a mi crophone, a mpl i fi er, s pea ker, ea rpi ece, a nd vol ume control , a l though they di ffer i n the l oca ti on of thes e components .
An a udi ol ogi s t s houl d be i nvol ved i n s el ecti on a nd fi tti ng of a hea ri ng a i d.
The bes t model s a re a djus ted to a pers on's pa rti cul a r pa ttern of hea ri ng l os s . Peopl e wi th ma i nl y hi gh-frequency hea ri ng l os s do not benefi t from
s i mpl e a mpl i fi ca ti on, whi ch merel y ma kes the ga rbl ed s peech they hea r s ound l ouder. They us ua l l y need a hea ri ng a i d tha t s el ecti vel y a mpl i fi es
the hi gh frequenci es . Some hea ri ng a i ds conta i n vents i n the ea r mol d, whi ch fa ci l i ta te the pa s s a ge of hi gh-frequency s ound wa ves . Some us e
di gi ta l s ound proces s i ng wi th mul ti pl e frequency cha nnel s s o tha t a mpl i fi ca ti on more preci s el y ma tches hea ri ng l os s a s mea s ured on the
a udi ogra m.
Tel ephone us e ca n be di ffi cul t for peopl e wi th hea ri ng a i ds . Typi ca l hea ri ng a i ds ca us e s quea l i ng when the ea r i s pl a ced next to the phone
ha ndl e. Some hea ri ng a i ds ha ve a phone coi l wi th a s wi tch tha t turns the mi crophone off a nd l i nks the phone coi l el ectroma gneti ca l l y to the
s pea ker ma gnet i n the phone.
For modera te to s evere hea ri ng l os s , a pos ta uri cul a r (ea r-l evel ) a i d, whi ch fi ts behi nd the pi nna a nd i s coupl ed to the ea r mol d wi th fl exi bl e
tubi ng, i s a ppropri a te. An i n-the-ea r a i d i s conta i ned enti rel y wi thi n the ea r mol d a nd fi ts l es s cons pi cuous l y i nto the concha a nd ea r ca na l ; i t i s
a ppropri a te for mi l d to modera te hea ri ng l os s . Some peopl e wi th mi l d hea ri ng l os s l i mi ted to hi gh frequenci es a re mos t comforta bl y fi tted wi th
pos ta uri cul a r a i ds a nd compl etel y open ea r ca na l s . Ca na l a i ds a re conta i ned enti rel y wi thi n the ea r ca na l a nd a re cos meti ca l l y a ccepta bl e to
ma ny peopl e who woul d otherwi s e refus e to us e a hea ri ng a i d, but they a re di ffi cul t for s ome peopl e (es peci a l l y the el derl y) to ma ni pul a te. The
CROS a i d (contra l a tera l routi ng of s i gna l s ) i s occa s i ona l l y us ed for s evere uni l a tera l hea ri ng l os s ; a hea ri ng-a i d mi crophone i s pl a ced i n the
nonfuncti oni ng ea r, a nd s ound i s routed to the functi oni ng ea r through a wi re or ra di o tra ns mi tter. Thi s devi ce ena bl es the wea rer to hea r s ounds
from the nonfuncti oni ng s i de, a l l owi ng for s ome l i mi ted ca pa ci ty to l oca l i ze s ound. If the better ea r a l s o ha s s ome hea ri ng l os s , the s ound from
both s i des ca n be a mpl i fi ed wi th the bi na ura l CROS (Bi CROS) a i d. The body a i d type i s a ppropri a te for profound hea ri ng l os s . It i s worn i n a s hi rt
pocket or a body ha rnes s a nd connected by a wi re to the ea rpi ece (the recei ver), whi ch i s coupl ed to the ea r ca na l by a pl a s ti c i ns ert (ea r mol d).
A bone conducti on a i d ma y be us ed when a n ea r mol d or tube ca nnot be us ed, a s i n a tres i a of the ea r ca na l or pers i s tent otorrhea . An os ci l l a tor i s
hel d a ga i ns t the hea d, us ua l l y over the ma s toi d, wi th a s pri ng ba nd, a nd s ound i s conducted through the s kul l to the cochl ea . Bone conducti on
hea ri ng a i ds requi re more power, i ntroduce more di s torti on, a nd a re l es s comforta bl e to wea r tha n a i r conducti on hea ri ng a i ds . Some bone
conducti on a i ds (bone-a nchored hea ri ng a i ds or BAHAs ) a re s urgi ca l l y i mpl a nted i n the ma s toi d proces s , a voi di ng the di s comfort a nd promi nence
of the s pri ng ba nd.
Cochlear implants: Profoundl y dea f pa ti ents , i ncl udi ng thos e wi th s ome hea ri ng but who even wi th a hea ri ng a i d ca nnot unders ta nd s peech wi thout
the a s s i s ta nce of vi s i on (l i p-rea di ng or s peech-rea di ng), ma y benefi t from a cochl ea r i mpl a nt. Thi s devi ce provi des el ectri ca l s i gna l s di rectl y i nto
the a udi tory nerve vi a mul ti pl e el ectrodes i mpl a nted i n the cochl ea . An externa l mi crophone a nd proces s or convert s ound wa ves to el ectri ca l
i mpul s es , whi ch a re tra ns mi tted through the s ki n el ectroma gneti ca l l y from a n externa l i nducti on coi l to a n i nterna l coi l i mpl a nted i n the s kul l
a bove a nd behi nd the ea r. The i nterna l coi l connects to el ectrodes i ns erted i n the s ca l a tympa ni .
Cochl ea r i mpl a nts hel p wi th s peech-rea di ng by provi di ng i nforma ti on a bout the i ntona ti on of words a nd the rhythm of s peech. Ma ny i f not mos t
a dul ts wi th cochl ea r i mpl a nts ca n di s cri mi na te words wi thout vi s ua l cl ues , a l l owi ng them to ta l k on the tel ephone. Cochl ea r i mpl a nts ena bl e
dea f peopl e to hea r a nd di s ti ngui s h envi ronmenta l s ounds a nd wa rni ng s i gna l s . They a l s o hel p dea f peopl e modul a te thei r voi ce a nd ma ke thei r
s peech more i ntel l i gi bl e.
Brain stem implants: Pa ti ents who ha ve ha d both a cous ti c nerves des troyed (eg, by bi l a tera l tempora l bone fra ctures or neurofi broma tos i s ) ca n ha ve
s ome hea ri ng res tored by mea ns of bra i n s tem i mpl a nts tha t ha ve el ectrodes connected to s ound-detecti ng a nd s ound-proces s i ng devi ces s i mi l a r
to thos e us ed for cochl ea r i mpl a nts .
Coping mechanisms: Al erti ng s ys tems tha t us e l i ght l et peopl e know when the doorbel l i s ri ngi ng, a s moke detector i s s oundi ng, or a ba by i s cryi ng.
Speci a l s ound s ys tems tra ns mi tti ng i nfra red or FM ra di o s i gna l s hel p peopl e hea r i n thea ters , churches , or other pl a ces where competi ng noi s e
exi s ts . Ma ny tel evi s i on progra ms ca rry cl os ed ca pti oni ng. Tel ephone communi ca ti on devi ces a re a l s o a va i l a bl e.
Li p-rea di ng or s peech-rea di ng i s pa rti cul a rl y i mporta nt for peopl e who ca n hea r but ha ve troubl e di s cri mi na ti ng s ounds . Mos t peopl e get us eful
s peech i nforma ti on from l i p-rea di ng even wi thout forma l tra i ni ng. Even peopl e wi th norma l hea ri ng ca n better unders ta nd s peech i n a noi s y pl a ce
i f they ca n s ee the s pea ker. To us e thi s i nforma ti on the l i s tener mus t be a bl e to s ee the s pea ker's mouth. Hea l th ca re pers onnel s houl d be
s ens i ti ve to thi s i s s ue a nd a l wa ys pos i ti on thems el ves a ppropri a tel y when s pea ki ng to the hea ri ng-i mpa i red. Obs ervi ng the pos i ti on of a
s pea ker's l i ps a l l ows recogni ti on of the cons ona nt bei ng s poken, thereby i mprovi ng s peech comprehens i on i n pa ti ents wi th hi gh-frequency
hea ri ng l os s . Li p-rea di ng ma y be l ea rned i n a ura l reha bi l i ta ti on s es s i ons i n whi ch a group of a ge-ma tched peers meets regul a rl y for i ns tructi on
a nd s upervi s ed pra cti ce i n opti mi zi ng communi ca ti on.
Peopl e ca n ga i n control over thei r l i s teni ng envi ronment by modi fyi ng or a voi di ng di ffi cul t s i tua ti ons . For exa mpl e, peopl e ca n vi s i t a res ta ura nt
duri ng off-pea k hours , when i t i s qui eter. They ca n a s k for a booth, whi ch bl ocks out s ome extra neous s ounds . In di rect convers a ti ons , peopl e ma y
a s k the s pea ker to fa ce them. At the begi nni ng of a tel ephone convers a ti on, they ca n i denti fy thems el ves a s bei ng hea ri ng-i mpa i red. At a
conference, the s pea ker ca n be a s ked to us e a n a s s i s ti ve l i s teni ng s ys tem, whi ch ma kes us e of ei ther i nducti ve l oop, i nfra red, or FM technol ogy
tha t s ends s ound through the mi crophone to a pa ti ent's hea ri ng a i d.
Peopl e wi th profound hea ri ng l os s often communi ca te by us i ng s i gn l a ngua ge. Ameri ca n Si gn La ngua ge (ASL) i s the mos t common vers i on i n the
US. Other forms i ncl ude Si gned Engl i s h, Si gni ng Exa ct Engl i s h, a nd Cued Speech.
Treatment in Children
In a ddi ti on to trea tment of a ny ca us e a nd the provi s i on of hea ri ng a i ds , chi l dren wi th hea ri ng l os s requi re s upport of l a ngua ge devel opment wi th
a ppropri a te thera py. Beca us e chi l dren mus t hea r l a ngua ge to l ea rn i t s ponta neous l y, mos t dea f chi l dren devel op l a ngua ge onl y wi th s peci a l
tra i ni ng, i dea l l y begi nni ng a s s oon a s the hea ri ng l os s i s i denti fi ed (a n excepti on woul d be a dea f chi l d growi ng up wi th dea f pa rents who a re
fl uent s i gn l a ngua ge us ers ). Dea f i nfa nts mus t be provi ded wi th a form of l a ngua ge i nput. For exa mpl e, a vi s ua l l y ba s ed s i gn l a ngua ge ca n
provi de a founda ti on for l a ter devel opment of ora l l a ngua ge i f a cochl ea r i mpl a nt i s not a va i l a bl e.
If i nfa nts a s young a s 1 mo ha ve profound bi l a tera l hea ri ng l os s a nd ca nnot benefi t from hea ri ng a i ds , they ca n be a ca ndi da te for a cochl ea r
i mpl a nt. Al though cochl ea r i mpl a nts a l l ow a udi tory communi ca ti on i n ma ny chi l dren wi th ei ther congeni ta l or a cqui red dea fnes s , they a re, i n the
ma i n, more effecti ve i n chi l dren who a l rea dy ha ve devel oped l a ngua ge. Chi l dren who ha ve pos tmeni ngi ti c dea fnes s devel op a n os s i fi ed i nner
ea r; they s houl d recei ve cochl ea r i mpl a nts ea rl y to ma xi mi ze effecti venes s . Chi l dren whos e a cous ti c nerves ha ve been des troyed by tumors ma y be
hel ped by i mpl a nta ti on of bra i n s tem a udi tory-s ti mul a ti ng el ectrodes . Chi l dren wi th cochl ea r i mpl a nts ma y ha ve a s l i ghtl y grea ter ri s k of
meni ngi ti s tha n chi l dren wi thout cochl ea r i mpl a nts or a dul ts wi th cochl ea r i mpl a nts .
Chi l dren wi th uni l a tera l dea fnes s s houl d be a l l owed to us e a s peci a l s ys tem i n the cl a s s room, s uch a s a n FM a udi tory tra i ner. Wi th thes e
s ys tems , the tea cher s pea ks i nto a mi crophone tha t s ends s i gna l s to a hea ri ng a i d i n the chi l d's nona ffected ea r, i mprovi ng the chi l d's grea tl y
i mpa i red a bi l i ty to hea r s peech a ga i ns t a noi s y ba ckground.
El derl y peopl e typi ca l l y experi ence a progres s i ve decrea s e i n hea ri ng (pres bycus i s ). The preva l ence of hea ri ng i mpa i rment i s 30% i n peopl e > 65
a nd i s 40 to 50% i n thos e > 75. Nonethel es s , hea ri ng l os s i n the el derl y s houl d be eva l ua ted a nd not a s cri bed to a gi ng; el derl y pa ti ents ma y ha ve a
tumor, a neurol ogi c or a utoi mmune di s order, or a n ea s i l y correcti bl e conducti ve hea ri ng l os s . Al s o, hea ri ng l os s i n the el derl y fa ci l i ta tes dementi a
(whi ch ca n be mi ti ga ted by properl y correcti ng hea ri ng l os s ).
Presbycusis: Pres bycus i s i s s ens ori neura l hea ri ng l os s tha t proba bl y res ul ts from a combi na ti on of a ge-rel a ted deteri ora ti on a nd cel l dea th i n
va ri ous components of the hea ri ng s ys tem a nd the effects of chroni c noi s e expos ure.
Hea ri ng l os s us ua l l y a ffects the hi ghes t frequenci es (18 to 20 kHz) ea rl y on a nd gra dua l l y a ffects the l ower frequenci es ; i t us ua l l y becomes
cl i ni ca l l y s i gni fi ca nt when i t a ffects the cri ti ca l 2- to 4-kHz ra nge a t a bout a ge 55 to 65 (s ometi mes s ooner). The l os s of hi gh-frequency hea ri ng
s i gni fi ca ntl y a ffects s peech comprehens i on. Al though the l oudnes s of s peech s eems norma l , certa i n cons ona nt s ounds (eg, C, D, K, P, S, T) become
ha rd to hea r. Cons ona nt s ounds a re the mos t i mporta nt s ounds for s peech recogni ti on. For exa mpl e, when "s hoe," "bl ue," "true," "too," or "new" i s
s poken, ma ny peopl e wi th pres bycus i s ca n hea r the "oo" s ound, but mos t ha ve di ffi cul ty recogni zi ng whi ch word ha s been s poken beca us e they
ca nnot di s ti ngui s h the cons ona nts . Thi s i na bi l i ty to di s ti ngui s h cons ona nts ca us es a ffected peopl e to often thi nk the s pea ker i s mumbl i ng. A
s pea ker a ttempti ng to s pea k l ouder us ua l l y a ccentua tes vowel s ounds (whi ch a re l ow frequency), doi ng l i ttl e to i mprove s peech recogni ti on.
Speech comprehens i on i s pa rti cul a rl y di ffi cul t when ba ckground noi s e i s pres ent.
Screening: A s creeni ng tool i s often hel pful for el derl y peopl e beca us e ma ny do not compl a i n of hea ri ng l os s . One tool i s the Hea ri ng Ha ndi ca p
Inventory for the El derl y-Screeni ng Vers i on, whi ch a s ks
Does a hea ri ng probl em ca us e you to feel emba rra s s ed when you meet peopl e?
Does a hea ri ng probl em ca us e you to feel frus tra ted when ta l ki ng to a fa mi l y member?
Do you ha ve di ffi cul ty hea ri ng when s omeone whi s pers ?
Do you feel ha ndi ca pped by a hea ri ng probl em?
Does a hea ri ng probl em ca us e you di ffi cul ty when vi s i ti ng fri ends , rel a ti ves , or nei ghbors ?
Does a hea ri ng probl em ca us e you to a ttend rel i gi ous s ervi ces l es s often tha n you woul d l i ke?
Does a hea ri ng probl em ca us e you to ha ve a rguments wi th fa mi l y members ?
Does a hea ri ng probl em ca us e you di ffi cul ty when l i s teni ng to the tel evi s i on or ra di o?
Do you feel tha t a ny di ffi cul ty wi th your hea ri ng ha mpers your pers ona l or s oci a l l i fe?
Does a hea ri ng probl em ca us e you di ffi cul ty when i n a res ta ura nt wi th rel a ti ves or fri ends ?
Scori ng i s "no" = 0 poi nts , "s ometi mes " = 2 poi nts , a nd "yes " = 4 poi nts . Scores > 10 s ugges t s i gni fi ca nt hea ri ng i mpa i rment a nd neces s i ta te fol l owup.
Prevention
Preventi on of hea ri ng l os s cons i s ts ma i nl y of l i mi ti ng dura ti on a nd i ntens i ty of noi s e expos ure. Peopl e requi red to expos e thems el ves to l oud
noi s e mus t wea r ea r protectors (eg, pl a s ti c pl ugs i n the ea r ca na l s or gl yceri n-fi l l ed muffs over the ea rs ). The Occupa ti ona l Sa fety a nd Hea l th
Admi ni s tra ti on (OSHA) of the US Depa rtment of La bor a nd s i mi l a r a genci es i n ma ny other countri es ha ve s ta nda rds rega rdi ng the l ength of ti me
tha t a pers on ca n be expos ed to a noi s e. The l ouder the noi s e, the s horter the permi s s i bl e ti me of expos ure.
Key Points
Cerumen, geneti c di s orders , i nfecti ons , a gi ng, a nd noi s e expos ure a re the mos t common ca us es .
Al l pa ti ents wi th hea ri ng l os s s houl d ha ve a udi ol ogi c tes ti ng.
Cra ni a l nerve defi ci ts a nd other neurol ogi c defi ci ts s houl d ra i s e concern a nd wa rra nt i ma gi ng tes ts .
Sudden Deafness
Sudden dea fnes s i s s evere s ens ori neura l hea ri ng l os s tha t devel ops wi thi n a few hours or i s noti ced on a wa keni ng. It a ffects a bout 1/5000
peopl e ea ch yea r. Ini ti a l hea ri ng l os s i s typi ca l l y uni l a tera l (unl es s drug-i nduced) a nd ma y ra nge i n s everi ty from mi l d to profound. Ma ny a l s o
ha ve ti nni tus , a nd s ome ha ve di zzi nes s , verti go, or both.
Sudden dea fnes s ha s s ome ca us es tha t di ffer from chroni c hea ri ng l os s a nd mus t be a ddres s ed urgentl y.
Etiology
The fol l owi ng a re common cha ra cteri s ti cs of s udden dea fnes s :
Mos t ca s es (s ee
Ta bl e 47-4) a re i di opa thi c.
Some occur i n the cours e of a n obvi ous expl a na tory event.
A few repres ent the i ni ti a l ma ni fes ta ti on of a n occul t but i denti fi a bl e di s order.
Idiopathic: There a re numerous theori es for whi ch s ome evi dence (a l though confl i cti ng a nd i ncompl ete) exi s ts . The mos t promi s i ng pos s i bi l i ti es
i ncl ude vi ra l i nfecti ons (pa rti cul a rl y i nvol vi ng herpes s i mpl ex), a utoi mmune a tta cks , a nd a cute mi crova s cul a r occl us i on.
Obvious event: Some ca us es of s udden dea fnes s a re rea di l y a ppa rent.
Blunt head trauma wi th tempora l bone fra cture or s evere concus s i on i nvol vi ng the cochl ea ca n ca us e s udden hea ri ng l os s .
Large ambient pressure changes (eg, ca us ed by di vi ng) or s trenuous a cti vi ti es (eg, wei ghtl i fti ng) ca n i nduce a peri l ympha ti c fi s tul a between the
mi ddl e a nd i nner ea r, ca us i ng s udden, s evere s ymptoms . Peri l ympha ti c fi s tul a ca n a l s o be congeni ta l ; i t ca n s ponta neous l y ca us e a s udden l os s
or l os s ma y occur a fter tra uma or pres s ure cha nges .
[Table 47-4. Some Ca us es of Sudden Dea fnes s ]
Ototoxic drugs ca n res ul t i n hea ri ng l os s occurri ng s ometi mes wi thi n a da y, es peci a l l y wi th a n overdos e (s ys temi ca l l y or when a ppl i ed to a l a rge
wound a rea , s uch a s a burn). There i s a ra re geneti c mi tochondri a l -tra ns mi tted di s order tha t i ncrea s es the s us cepti bi l i ty to a mi nogl ycos i de
ototoxi ci ty.
A number of infections ca us e s udden dea fnes s duri ng or i mmedi a tel y a fter a cute i l l nes s . Common ca us es i ncl ude ba cteri a l meni ngi ti s , Lyme
di s ea s e, a nd ma ny vi ra l i nfecti ons tha t a ffect the cochl ea (a nd s ometi mes the ves ti bul a r a ppa ra tus ). The mos t common vi ra l ca us es i n the
devel oped worl d a re mumps a nd herpes . Mea s l es i s a very ra re ca us e beca us e mos t of the popul a ti on i s i mmuni zed.
Occult disorders: Sudden dea fnes s ra rel y ca n be a n i s ol a ted fi rs t ma ni fes ta ti on of s ome di s orders tha t us ua l l y ha ve other i ni ti a l s ymptoms . Sudden
dea fnes s ra rel y ma y be the fi rs t ma ni fes ta ti on of a n a cous ti c neuroma , mul ti pl e s cl eros i s , Meni ere's di s ea s e, or a s ma l l cerebel l a r s troke.
Syphi l i s rea cti va ti on i n HIV-i nfected pa ti ents ra rel y ca n ca us e s udden dea fnes s .
Coga n's s yndrome i s a ra re a utoi mmune rea cti on di rected a ga i ns t a n unknown common a utoa nti gen i n the cornea a nd i nner ea r; > 50% of pa ti ents
pres ent wi th ves ti bul oa udi tory s ymptoms . About 10 to 30% of pa ti ents a l s o ha ve a s evere s ys temi c va s cul i ti s , whi ch ma y i ncl ude l i fe-threa teni ng
a orti ti s .
Some va s cul i ti c di s orders ca n ca us e hea ri ng l os s , s ome of whi ch i s a cute. Hema tol ogi c di s orders , s uch a s Wa l dens trom's ma crogl obul i nemi a ,
s i ckl e cel l di s ea s e, a nd s ome forms of l eukemi a , ra rel y ca n ca us e s udden dea fnes s .
Evaluation
Eva l ua ti on cons i s ts of detecti ng a nd qua nti fyi ng hea ri ng l os s a nd determi ni ng eti ol ogy (pa rti cul a rl y revers i bl e ca us es ).
History: History of present illness s houl d veri fy tha t l os s i s s udden a nd not chroni c. The hi s tory s houl d a l s o note whether l os s i s uni l a tera l or
bi l a tera l a nd whether there i s a current a cute event (eg, hea d i njury, ba rotra uma [pa rti cul a rl y a di vi ng i njury], i nfecti ous i l l nes s ). Importa nt
a ccompa nyi ng s ymptoms i ncl ude other otol ogi c s ymptoms (eg, ti nni tus , ea r di s cha rge), ves ti bul a r s ymptoms (eg, di s ori enta ti on i n the da rk,
verti go), a nd other neurol ogi c s ymptoms (eg, hea da che, wea knes s or a s ymmetry of the fa ce, a bnorma l s ens e of ta s te).
Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng tra ns i ent, mi gra tory neurol ogi c defi ci ts (mul ti pl e s cl eros i s ) a nd eye
i rri ta ti on a nd rednes s (Coga n's s yndrome).
Past medical history s houl d a s k a bout known HIV or s yphi l i s i nfecti on a nd ri s k fa ctors for them (eg, mul ti pl e s ex pa rtners , unprotected i ntercours e).
Fa mi l y hi s tory s houl d note cl os e rel a ti ves wi th hea ri ng l os s (s ugges ti ng a congeni ta l fi s tul a ). Drug hi s tory s houl d s peci fi ca l l y query current or
previ ous us e of ototoxi c drugs (s ee Ta bl e 47-4) a nd whether the pa ti ent ha s known rena l i ns uffi ci ency or rena l fa i l ure.
Physical examination: The exa mi na ti on focus es on the ea rs a nd hea ri ng a nd on the neurol ogi c exa mi na ti on.
The tympa ni c membra ne i s i ns pected for perfora ti on, dra i na ge, or other l es i ons . Duri ng the neurol ogi c exa mi na ti on, a ttenti on s houl d be pa i d to
the cra ni a l nerves (pa rti cul a rl y the 5th, 7th, a nd 8th) a nd to ves ti bul a r a nd cerebel l a r functi on beca us e a bnorma l i ti es i n thes e a rea s often occur
wi th tumors of the bra i n s tem a nd cerebel l oponti ne a ngl e.
Weber's tes t a nd the Ri nne tes t requi re a tuni ng fork to di fferenti a te conducti ve from s ens ori neura l hea ri ng l os s (s ee p. 429).
Addi ti ona l l y, the eyes a re exa mi ned for rednes s a nd photophobi a (pos s i bl e Coga n's s yndrome), a nd the s ki n i s exa mi ned for ra s h (eg, vi ra l
i nfecti on, s yphi l i s ).
Abnorma l i ti es of cra ni a l nerves (other tha n hea ri ng l os s )
Interpretation of findings: Tra uma ti c, ototoxi c, a nd s ome i nfecti ous ca us es a re us ua l l y a ppa rent cl i ni ca l l y. A pa ti ent wi th peri l ympha ti c fi s tul a ma y
hea r a n expl os i ve s ound i n the a ffected ea r when the fi s tul a occurs a nd ma y a l s o ha ve s udden verti go, nys ta gmus , a nd ti nni tus .
Foca l neurol ogi c a bnorma l i ti es a re of pa rti cul a r concern. The 5th cra ni a l nerve, 7th cra ni a l nerve, or both a re often a ffected by tumors tha t i nvol ve
the 8th cra ni a l nerve, s o l os s of fa ci a l s ens a ti on a nd wea k ja w cl ench (5th) a nd hemi fa ci a l wea knes s a nd ta s te a bnorma l i ti es (7th) poi nt to a
l es i on i n tha t a rea .
Uni l a tera l hea ri ng l os s a ccompa ni ed by ti nni tus a nd verti go a l s o s ugges ts Meni ere's di s ea s e. Sys temi c s ymptoms s ugges ti ng i nfl a mma ti on (eg,
fevers , ra s h, joi nt pa i ns , mucos a l l es i ons ) s houl d ra i s e s us pi ci on of a n occul t i nfecti on or a utoi mmune di s order.
Testing: Typi ca l l y, pa ti ents s houl d ha ve a n a udi ogra m, a nd unl es s the di a gnos i s i s cl ea rl y a n a cute i nfecti on or drug toxi ci ty, mos t cl i ni ci a ns do
ga dol i ni um-enha nced MRI to di a gnos e i na ppa rent ca us es . Pa ti ents wi th a n a cute tra uma ti c ca us e a l s o s houl d ha ve MRI. If a peri l ympha ti c fi s tul a
i s s us pected cl i ni ca l l y, i t ma y be confi rmed by tympa nometry a nd el ectronys ta gmogra phy (ENG); CT i s us ua l l y done to s how the bony cha ra cteri s ti cs
of the i nner ea r.
Pa ti ents who ha ve ri s k fa ctors for or s ymptoms tha t s ugges t ca us es s houl d ha ve a ppropri a te tes ts (eg, s erol ogi c tes ts for pos s i bl e HIV i nfecti on or
s yphi l i s , CBC a nd coa gul a ti on profi l e for hema tol ogi c di s orders , ESR a nd a nti nucl ea r a nti bodi es for va s cul i ti s ).
Treatment
Trea tment focus es on the ca us a ti ve di s order when known. Fi s tul a s a re expl ored a nd repa i red s urgi ca l l y.
In vi ra l a nd i di opa thi c ca s es , hea ri ng returns to norma l i n a bout 50% of pa ti ents a nd i s pa rti a l l y recovered i n others .
In pa ti ents who recover thei r hea ri ng, i mprovement us ua l l y occurs wi thi n 10 to 14 da ys .
For pa ti ents wi th i di opa thi c l os s , ma ny cl i ni ci a ns empi ri ca l l y gi ve a s hort cours e of gl ucocorti coi ds a nd a nti vi ra l drugs effecti ve a ga i ns t herpes
s i mpl ex (eg, va l a cycl ovi r, fa mci cl ovi r). Gl ucocorti coi ds ca n be gi ven ora l l y or by tra ns tympa ni c i njecti on; i t i s uncl ea r whi ch route i s more effecti ve.
Key Points
Mos t ca s es a re i di opa thi c.
A few ca s es ha ve a n obvi ous ca us e (eg, ma jor tra uma , a cute i nfecti on, drugs ).
A very few ca s es repres ent unus ua l ma ni fes ta ti ons of trea ta bl e di s orders .
Chapter 48. Inner Ear Disorders

Introduction
(See a l s o Hea ri ng Los s on p. 429.)
The i nner ea r i s i n the petrous a rea of the tempora l bone. Wi thi n the bone i s the os s eous l a byri nth, whi ch enca s es the membra nous l a byri nth.
The os s eous l a byri nth i ncl udes the ves ti bul a r s ys tem (ma de up of the s emi ci rcul a r ca na l s a nd the ves ti bul e) a nd the cochl ea . The ves ti bul a r
s ys tem i s res pons i bl e for ba l a nce a nd pos ture; the cochl ea , for hea ri ng.
Acoustic Neuroma
(Acous ti c Neuri noma ; 8th Nerve Tumor; Ves ti bul a r Schwa nnoma )
An acoustic neuroma is a Schwann cell-derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology and
confirmed by MRI. Treatment is surgical removal, stereotactic radiation therapy, or both.
Acous ti c neuroma s a l mos t a l wa ys a ri s e from the ves ti bul a r di vi s i on of the 8th cra ni a l nerve a nd a ccount for a bout 7% of a l l i ntra cra ni a l tumors . As
the tumor expa nds , i t projects from the i nterna l a udi tory mea tus i nto the cerebel l oponti ne a ngl e a nd compres s es the cerebel l um a nd bra i n s tem.
The 5th cra ni a l nerve a nd l a ter the 7th cra ni a l nerve a re a ffected.
Bi l a tera l a cous ti c neuroma s a re common i n neurofi broma tos i s type 2.
Symptoms and Signs
Sl owl y progres s i ve uni l a tera l s ens ori neura l hea ri ng l os s i s the ha l l ma rk s ymptom. However, the ons et of hea ri ng l os s ma y be a brupt, a nd the
degree of i mpa i rment ma y fl uctua te. Other ea rl y s ymptoms i ncl ude uni l a tera l ti nni tus , di zzi nes s a nd dys equi l i bri um, hea da che, s ens a ti on of
pres s ure or ful l nes s i n the ea r, ota l gi a , tri gemi na l neura l gi a , a nd numbnes s or wea knes s of the fa ci a l nerve.
Diagnosis
Audi ogra m
If pos i ti ve, ga dol i ni um-enha nced MRI
An a udi ogra m i s the fi rs t tes t done (s ee p. 433). It us ua l l y revea l s a n a s ymmetri c s ens ori neura l hea ri ng l os s a nd a grea ter i mpa i rment of s peech
di s cri mi na ti on tha n woul d be expected for the degree of hea ri ng l os s . Acous ti c refl ex deca y, the a bs ence of wa veforms , a nd i ncrea s ed l a tency of
the 5th wa veform i n a udi tory bra i n s tem res pons e tes ti ng a re further evi dence of a neura l l es i on. Al though not us ua l l y requi red i n the routi ne
eva l ua ti on of a pa ti ent wi th a s ymmetri c s ens ori neura l hea ri ng l os s , ca l ori c tes ti ng s hows ma rked ves ti bul a r hypoa cti vi ty (ca na l pa res i s ). Such
fi ndi ngs i ndi ca te the need for i ma gi ng tes ts , prefera bl y ga dol i ni um-enha nced MRI.
Treatment
Surgi ca l remova l
Someti mes s tereota cti c ra di a ti on thera py
Sma l l tumors ma y be removed wi th mi cros urgery tha t pres erves the fa ci a l nerve. A mi ddl e cra ni a l fos s a or retros i gmoi d a pproa ch ma y pres erve
rema i ni ng hea ri ng; a tra ns l a byri nthi ne route ma y be us ed i f no us eful hea ri ng rema i ns . La rge tumors a re removed wi th the tra ns l a byri nthi ne
a pproa ch rega rdl es s of the rema i ni ng hea ri ng. Stereota cti c ra di a ti on thera py a s the s ol e trea tment moda l i ty i s us ed predomi na ntl y i n the
ma na gement of s ma l l tumors i n ol der pa ti ents ; i ts l ong-term effi ca cy a nd a dvers e effects a re under s tudy.
Benign Paroxysmal Positional Vertigo
(Beni gn Pos tura l or Pos i ti ona l Verti go)
In benign paroxysmal positional vertigo (BPPV), short (< 60 sec) episodes of vertigo occur with certain head positions. Nausea and nystagmus develop. Diagnosis
is clinical. Treatment involves canalith repositioning maneuvers. Drugs and surgery are rarely, if ever, indicated.
BPPV i s the mos t common ca us e of rel a ps i ng otogeni c verti go. It a ffects peopl e i ncrea s i ngl y a s they a ge a nd ca n s everel y a ffect ba l a nce i n the
el derl y, l ea di ng to potenti a l l y i njuri ous fa l l s .
Etiology
The condi ti on i s thought to be ca us ed by di s pl a cement of otoconi a l crys ta l s (Ca ca rbona te crys ta l s norma l l y embedded i n the s a ccul e a nd utri cl e).
Thi s di s pl a ced ma teri a l s ti mul a tes ha i r cel l s i n the pos teri or s emi ci rcul a r ca na l , crea ti ng the i l l us i on of moti on. Eti ol ogi c fa ctors i ncl ude
s ponta neous degenera ti on of the utri cul a r otol i thi c membra nes , l a byri nthi ne concus s i on, oti ti s medi a , ea r s urgery, recent vi ra l i nfecti on (eg, vi ra l
neuroni ti s ), hea d tra uma , prol onged a nes thes i a or bed res t, previ ous ves ti bul a r di s orders (eg, Meni ere's di s ea s e), a nd occl us i on of the a nteri or
ves ti bul a r a rtery.
Symptoms and Signs
Verti go i s tri ggered when the pa ti ent's hea d moves (eg, when rol l i ng over i n bed or bendi ng over to pi ck up s omethi ng). Acute verti go l a s ts onl y a
few s econds to mi nutes ; epi s odes tend to pea k i n the morni ng a nd a ba te throughout the da y. Na us ea a nd vomi ti ng ma y occur, but hea ri ng l os s
a nd ti nni tus do not.
Diagnosis
Ga dol i ni um-enha nced MRI i f fi ndi ngs s ugges t CNS l es i on
Di a gnos i s i s ba s ed on cha ra cteri s ti c s ymptoms , on nys ta gmus a s determi ned by the Di x-Ha l l pi ke ma neuver (a provoca ti ve tes t for pos i ti ona l
nys ta gmus s ee Si deba r 46-1 on p. 414), a nd on a bs ence of other a bnorma l i ti es on neurol ogi c exa mi na ti on. Such pa ti ents requi re no further
tes ti ng. Pa ti ents wi th nys ta gmus s ugges ti ng a CNS l es i on undergo ga dol i ni um-enha nced MRI. Unl i ke the pos i ti ona l nys ta gmus of BPPV, the
pos i ti ona l nys ta gmus of CNS l es i ons l a cks l a tency, fa ti ga bi l i ty, a nd s evere s ubjecti ve s ens a ti on a nd ma y conti nue for a s l ong a s the pos i ti on i s
ma i nta i ned. Nys ta gmus ca us ed by a CNS l es i on ma y be verti ca l or cha nge di recti on a nd, i f rota ry, i s l i kel y to be i n the unexpected di recti on.
Treatment
Provoca ti ve ma neuvers to fa ti gue s ymptoms
Ca na l i th repos i ti oni ng ma neuvers
Drug trea tment typi ca l l y not recommended
BPPV us ua l l y s ubs i des s ponta neous l y i n s evera l weeks or months but ma y conti nue for months or yea rs . Beca us e the condi ti on ca n be l ongl a s ti ng, drug trea tment (l i ke tha t us ed i n Meni ere's di s ea s es ee p. 445) i s not recommended. Often, the a dvers e effects of drugs wors en
dys equi l i bri um.
Beca us e BPPV i s fa ti ga bl e, one thera py i s to ha ve the pa ti ent perform provoca ti ve ma neuvers ea rl y i n the da y i n a s a fe envi ronment. Symptoms a re
then mi ni ma l for the res t of the da y.
Ca na l i th repos i ti oni ng ma neuvers (Epl ey ma neuvers ee
Fi g. 48-1a nd Semont ma neuver) i nvol ve movi ng the hea d through a s eri es of s peci fi c pos i ti ons i ntended to return the erra nt ca na l i th to the
utri cl e. After performi ng thes e ma neuvers , the pa ti ent s houl d rema i n erect or s emi -erect for 1 to 2 da ys . Both ma neuvers ca n be repea ted a s
neces s a ry.
[Fig. 48-1. The Epl ey ma neuver.]
For the Semont ma neuver, the pa ti ent i s s ea ted upri ght i n the mi ddl e of a s tretcher. The pa ti ent's hea d i s rota ted towa rd the una ffected ea r; thi s
rota ti on i s ma i nta i ned throughout the ma neuver. Next, the tors o i s l owered l a tera l l y onto the s tretcher s o tha t the pa ti ent i s l yi ng on the s i de of
the a ffected ea r wi th the nos e poi nted up. After 3 mi n i n thi s pos i ti on, the pa ti ent i s qui ckl y moved through the upri ght pos i ti on wi thout
s tra i ghteni ng the hea d a nd i s l owered l a tera l l y to the other s i de now wi th the nos e poi nted down. After 3 mi n i n thi s pos i ti on, the pa ti ent i s
s l owl y returned to the upri ght pos i ti on, a nd the hea d i s rota ted ba ck to norma l .
Drug-Induced Ototoxicity
A wi de va ri ety of drugs ca n be ototoxi c (s ee
Ta bl e 48-1).
Fa ctors a ffecti ng ototoxi ci ty i ncl ude dos e, dura ti on of thera py, concurrent rena l fa i l ure,
[Table 48-1. Some Drugs tha t Ca us e Ototoxi ci ty]
i nfus i on ra te, l i feti me dos e, co-a dmi ni s tra ti on wi th other drugs ha vi ng ototoxi c potenti a l , a nd geneti c s us cepti bi l i ty. Ototoxi c drugs s houl d not be
us ed for oti c topi ca l a ppl i ca ti on when the tympa ni c membra ne i s perfora ted beca us e the drugs mi ght di ffus e i nto the i nner ea r.
Streptomyci n tends to ca us e more da ma ge to the ves ti bul a r porti on tha n to the a udi tory porti on of the i nner ea r. Al though verti go a nd di ffi cul ty
ma i nta i ni ng ba l a nce tend to be tempora ry, s evere l os s of ves ti bul a r s ens i ti vi ty ma y pers i s t, s ometi mes perma nentl y. Los s of ves ti bul a r s ens i ti vi ty
ca us es di ffi cul ty wa l ki ng, es peci a l l y i n the da rk, a nd os ci l l ops i a (a s ens a ti on of bounci ng of the envi ronment wi th ea ch s tep). About 4 to 15% of
pa ti ents who recei ve 1 g/da y for > 1 wk devel op mea s ura bl e hea ri ng l os s , whi ch us ua l l y occurs a fter a s hort l a tent peri od (7 to 10 da ys ) a nd s l owl y
wors ens i f trea tment i s conti nued. Compl ete, perma nent dea fnes s ma y fol l ow.
Neomyci n ha s the grea tes t cochl eotoxi c effect of a l l a nti bi oti cs . When l a rge dos es a re gi ven ora l l y or by col oni c i rri ga ti on for i ntes ti na l
s teri l i za ti on, enough ma y be a bs orbed to a ffect hea ri ng, pa rti cul a rl y i f mucos a l l es i ons a re pres ent. Neomyci n s houl d not be us ed for wound
i rri ga ti on or for i ntra pl eura l or i ntra peri tonea l i rri ga ti on, beca us e ma s s i ve a mounts of the drug ma y be reta i ned a nd a bs orbed, ca us i ng dea fnes s .
Ka na myci n a nd a mi ka ci n a re cl os e to neomyci n i n cochl eotoxi c potenti a l a nd a re both ca pa bl e of ca us i ng profound, perma nent hea ri ng l os s whi l e
s pa ri ng ba l a nce. Vi omyci n ha s both cochl ea r a nd ves ti bul a r toxi ci ty. Genta mi ci n a nd tobra myci n ha ve ves ti bul a r a nd cochl ea r toxi ci ty, ca us i ng
i mpa i rment i n ba l a nce a nd hea ri ng.
Va ncomyci n ca n ca us e hea ri ng l os s , es peci a l l y i n the pres ence of rena l i ns uffi ci ency.
Chemothera peuti c (a nti neopl a s ti c) drugs , pa rti cul a rl y thos e conta i ni ng pl a ti num (ci s pl a ti n a nd ca rbopl a ti n), ca n ca us e ti nni tus a nd hea ri ng l os s .
Hea ri ng l os s ca n be profound a nd perma nent, occurri ng i mmedi a tel y a fter the fi rs t dos e, or ca n be del a yed unti l s evera l months a fter compl eti on
of trea tment. Sens ori neura l hea ri ng l os s s tri kes bi l a tera l l y, progres s es decrementa l l y, a nd i s perma nent.
Etha cryni c a ci d a nd furos emi de gi ven IV ha ve ca us ed profound, perma nent hea ri ng l os s i n pa ti ents wi th rena l fa i l ure who ha d been recei vi ng
a mi nogl ycos i de a nti bi oti cs .
Sa l i cyl a tes i n hi gh dos es (> 12 325-mg ta bl ets of a s pi ri n per da y) ca us e tempora ry hea ri ng l os s a nd ti nni tus . Qui ni ne a nd i ts s yntheti c s ubs ti tutes
ca n a l s o ca us e tempora ry hea ri ng l os s .
Prevention
Ototoxi c a nti bi oti cs s houl d be a voi ded duri ng pregna ncy. The el derl y a nd peopl e wi th preexi s ti ng hea ri ng l os s s houl d not be trea ted wi th ototoxi c
drugs i f other effecti ve drugs a re a va i l a bl e. The l owes t effecti ve dos a ge of ototoxi c drugs s houl d be us ed a nd l evel s s houl d be cl os el y moni tored.
If pos s i bl e before trea tment wi th a n ototoxi c drug, hea ri ng s houl d be mea s ured a nd then moni tored duri ng trea tment; s ymptoms a re not rel i a bl e
wa rni ng s i gns .
Herpes Zoster Oticus
(Geni cul a te Herpes ; Ra ms a y Hunt Syndrome; Vi ra l Neuroni ti s )
Herpes zoster oticus is infection of the 8th cranial nerve ganglia and the geniculate ganglion of the facial nerve by the herpes zoster virus.
Ri s k fa ctors for herpes i nfecti on i ncl ude i mmunodefi ci ency s econda ry to ca ncer, chemothera py, ra di a ti on thera py, a nd HIV i nfecti on.
Symptoms and Signs
Symptoms i ncl ude s evere ea r pa i n, tra ns i ent or perma nent fa ci a l pa ra l ys i s (res embl i ng Bel l 's pa l s y), verti go l a s ti ng da ys to weeks , a nd hea ri ng
l os s (whi ch ma y be perma nent or whi ch ma y res ol ve pa rti a l l y or compl etel y). Ves i cl es occur on the pi nna a nd i n the externa l a udi tory ca na l a l ong
the di s tri buti on of the s ens ory bra nch of the fa ci a l nerve. Symptoms of meni ngoencepha l i ti s (eg, hea da che, confus i on, s ti ff neck) a re uncommon.
Someti mes other cra ni a l nerves a re i nvol ved.
Diagnosis
Di a gnos i s us ua l l y i s cl i ni ca l . If there i s a ny ques ti on a bout vi ra l eti ol ogy, ves i cul a r s cra pi ngs ma y be col l ected for di rect i mmunofl uores cence or
for vi ra l cul tures , a nd MRI i s done.
Treatment
Perha ps corti cos teroi ds , a nti vi ra l s , a nd s urgi ca l decompres s i on
Al though there i s no rel i a bl e evi dence tha t corti cos teroi ds , a nti vi ra l drugs , or s urgi ca l decompres s i on ma kes a di fference, they a re the onl y
pos s i bl y us eful trea tments . Corti cos teroi ds a re s ta rted wi th predni s one 60 mg po once/da y for 4 da ys , fol l owed by gra dua l ta peri ng of the dos e
over the next 2 wk. Acycl ovi r 800 mg po q 4 h 5 ti mes /da y or va l a cycl ovi r 1 g po bi d for 10 da ys ma y s horten the cl i ni ca l cours e. Verti go i s effecti vel y
s uppres s ed wi th di a zepa m 2 to 5 mg po q 4 to 6 h. Pa i n ma y requi re ora l opi oi ds . Pos therpeti c neura l gi a ma y be trea ted wi th a mi tri ptyl i ne.
Surgi ca l decompres s i on of the fa l l opi a n ca na l ma y be i ndi ca ted i f the fa ci a l pa l s y i s compl ete (no vi s i bl e fa ci a l movement). Before s urgery,
however, el ectroneurogra phy i s done a nd s houl d s how a > 90% decrement.
Meniere's Disease
(Endol ympha ti c Hydrops )
Meniere's disease is an inner ear disorder that causes vertigo, fluctuating sensorineural hearing loss, and tinnitus. There is no diagnostic test. Vertigo and nausea
are treated with anticholinergics or benzodiazepines. Diuretics and a low-salt diet may decrease frequency and severity of episodes. For severe cases, the
vestibular system can be ablated with topical gentamicin or surgery.
In Meni ere's di s ea s e, pres s ure a nd vol ume cha nges of the l a byri nthi ne endol ymph a ffect i nner ea r functi on. The eti ol ogy of endol ympha ti c fl ui d
bui l dup i s unknown. Ri s k fa ctors i ncl ude a fa mi l y hi s tory of Meni ere's di s ea s e, preexi s ti ng a utoi mmune di s orders , a l l ergi es , tra uma to the hea d
or ea r, a nd, ra rel y, s yphi l i s (even s evera l deca des previ ous l y). Pea k i nci dence i s between a ges 20 a nd 50.
Symptoms and Signs
Pa ti ents ha ve s udden a tta cks of verti go l a s ti ng up to 24 h, us ua l l y wi th na us ea a nd vomi ti ng. Accompa nyi ng s ymptoms i ncl ude di a phores i s ,
di a rrhea , a nd ga i t uns tea di nes s . Ti nni tus ma y be cons ta nt or i ntermi ttent, buzzi ng or roa ri ng; i t i s not rel a ted to pos i ti on or moti on. Hea ri ng
i mpa i rment, typi ca l l y a ffecti ng l ow frequenci es , ma y fol l ow. Before a n epi s ode, mos t pa ti ents s ens e ful l nes s or pres s ure i n the a ffected ea r. In
50% of pa ti ents , onl y one ea r i s a ffected.
Duri ng the ea rl y s ta ges , s ymptoms remi t between epi s odes ; s ymptom-free i nterl udes ma y l a s t > 1 yr. As the di s ea s e progres s es , however, hea ri ng
i mpa i rment pers i s ts a nd gra dua l l y wors ens , a nd ti nni tus ma y be cons ta nt.
Diagnosis
Audi ogra m a nd ga dol i ni um-enha nced MRI to rul e out other ca us es
The di a gnos i s , ma de cl i ni ca l l y, i s pri ma ri l y one of excl us i on. Si mi l a r s ymptoms ca n res ul t from vi ra l l a byri nthi ti s or neuri ti s , a cerebel l oponti ne
a ngl e tumor (eg, a cous ti c neuroma ), or a bra i n s tem s troke. Pa ti ents wi th s ugges ti ve s ymptoms s houl d ha ve a n a udi ogra m a nd a n MRI (wi th
ga dol i ni um enha ncement) of the CNS wi th a ttenti on to the i nterna l a udi tory ca na l s to excl ude other ca us es . Audi ogra m typi ca l l y s hows a l owfrequency s ens ori neura l hea ri ng l os s i n the a ffected ea r.
On exa mi na ti on duri ng a n a cute a tta ck, the pa ti ent ha s nys ta gmus a nd fa l l s to the a ffected s i de. Between a tta cks , the Fuka da s teppi ng tes t
(ma rchi ng i n pl a ce wi th eyes cl os ed) ca n be us ed; a pa ti ent wi th Meni ere's di s ea s e often turns a wa y from the a ffected ea r, cons i s tent wi th a
uni l a tera l l a byri nthi ne l es i on. Addi ti ona l l y, the Ri nne tes t a nd Weber's tes t ma y i ndi ca te s ens ori neura l hea ri ng l os s (s ee p. 431).
Treatment
Symptom rel i ef wi th a nti emeti cs , a nti hi s ta mi nes , or benzodi a zepi nes
Di ureti cs a nd l ow-s a l t di et
Ra rel y ves ti bul a r a bl a ti on by drugs or s urgery
Meni ere's di s ea s e tends to be s el f-l i mi ted. Trea tment of a n a cute a tta ck i s a i med a t s ymptom rel i ef. Anti chol i nergi cs (eg, prochl orpera zi ne or
prometha zi ne 25 mg recta l l y or 10 mg po q 6 to 8 h) ca n mi ni mi ze va ga l -medi a ted GI s ymptoms . Anti hi s ta mi nes (eg, di phenhydra mi ne, mecl i zi ne,
or cycl i zi ne 50 mg po q 6 h) or benzodi a zepi nes (eg, di a zepa m 5 mg po q 6 to 8 h) a re us ed to s eda te the ves ti bul a r s ys tem. Some phys i ci a ns a l s o
us e a corti cos teroi d burs t (eg, predni s one 60 mg once/da y for 1 wk, ta pered over a nother wk) for a n a cute epi s ode.
A l ow-s a l t (< 1.5 g/da y) di et, a voi da nce of a l cohol a nd ca ffei ne, a nd a di ureti c (eg, hydrochl orothi a zi de 25 mg po once/da y) ma y hel p prevent
verti go a nd a re us eful for ma ny pa ti ents .
Intra tympa ni c genta mi ci n (chemi ca l l a byri nthectomy) ma y be us ed when medi ca l ma na gement i s uns ucces s ful . Typi ca l dos e i s 1 mL (a t a 30 mg/mL
concentra ti on, ma de by di l uti ng the commerci a l 40 mg/mL prepa ra ti on wi th bi ca rbona te) i njected through the tympa ni c membra ne. Fol l ow-up wi th
s eri a l a udi ometry i s recommended to di s ti ngui s h hea ri ng l os s from cochl eotoxi ci ty. The i njecti on ca n be repea ted i n 4 wk i f verti go pers i s ts
wi thout hea ri ng l os s .
Surgery i s res erved for pa ti ents wi th frequent, s everel y debi l i ta ti ng epi s odes who a re unres pons i ve to other moda l i ti es . Endol ympha ti c s a c
decompres s i on rel i eves verti go i n s ome pa ti ents a nd pos es mi ni ma l ri s k of hea ri ng l os s . Ves ti bul a r neurectomy (a n i ntra cra ni a l procedure)
rel i eves verti go i n a bout 95% of pa ti ents a nd us ua l l y pres erves hea ri ng. A s urgi ca l l a byri nthectomy i s done onl y i f preexi s ti ng hea ri ng l os s i s
profound.
Unfortuna tel y, there i s no known wa y to prevent the na tura l progres s i on of hea ri ng l os s . Mos t pa ti ents s us ta i n modera te to s evere s ens ori neura l
hea ri ng l os s i n the a ffected ea r wi thi n 10 to 15 yr.
Purulent Labyrinthitis
Purulent (suppurative) labyrinthitis is bacterial infection of the inner ear, often causing deafness and loss of vestibular function.
Purul ent l a byri nthi ti s us ua l l y occurs when ba cteri a s prea d to the i nner ea r duri ng the cours e of s evere a cute oti ti s medi a , purul ent meni ngi ti s , or
a n enl a rgi ng chol es tea toma .
Symptoms i ncl ude s evere verti go a nd nys ta gmus , na us ea a nd vomi ti ng, ti nni tus , a nd va ryi ng degrees of hea ri ng l os s . Pa i n a nd fever a re common.
Purul ent l a byri nthi ti s i s s us pected i f verti go, nys ta gmus , s ens ori neura l hea ri ng l os s , or a combi na ti on occurs duri ng a n epi s ode of a cute oti ti s
medi a . CT of the tempora l bone i s done to i denti fy eros i on of the oti c ca ps ul e bone or other compl i ca ti ons of a cute oti ti s medi a , s uch a s
coa l es cent ma s toi di ti s . MRI ma y be i ndi ca ted i f s ymptoms of meni ngi ti s or bra i n a bs ces s , s uch a s a l tered menta l s ta tus , meni ngi s mus , or hi gh
fever, a re pres ent; i n s uch ca s es , a l umba r puncture a nd bl ood cul tures a l s o a re done.
Trea tment i s wi th IV a nti bi oti cs a ppropri a te for meni ngi ti s (eg, ceftri a xone 50 to 100 mg/kg IV once/da y to ma xi mum 2 g) a djus ted a ccordi ng to
res ul ts of cul ture a nd s ens i ti vi ty tes ti ng. A myri ngotomy (a nd s ometi mes tympa nos tomy tube pl a cement) i s done to dra i n the mi ddl e ea r.
Ma s toi dectomy ma y be requi red.
Vestibular Neuronitis
Vestibular neuronitis causes a self-limited episode of vertigo, presumably due to inflammation of the vestibular division of the 8th cranial nerve; some vestibular
dysfunction may persist.
Al though eti ol ogy i s uncl ea r, a vi ra l ca us e i s s us pected.
Symptoms and Signs
Symptoms i ncl ude a s i ngl e a tta ck of s evere verti go, wi th na us ea a nd vomi ti ng a nd pers i s tent nys ta gmus towa rd the a ffected s i de, whi ch l a s ts 7 to
10 da ys . The nys ta gmus i s uni di recti ona l , hori zonta l , a nd s ponta neous , wi th fa s t-bea t os ci l l a ti ons i n the di recti on of the una ffected ea r. The
a bs ence of concomi ta nt ti nni tus or hea ri ng l os s i s a ha l l ma rk of ves ti bul a r neuroni ti s . The condi ti on s l owl y s ubs i des a fter thi s i ni ti a l epi s ode.
Some pa ti ents ha ve res i dua l dys equi l i bri um, es peci a l l y wi th ra pi d hea d movements , proba bl y due to perma nent ves ti bul a r i njury.
Diagnosis
Audi ol ogy, el ectronys ta gmogra phy, a nd MRI
Pa ti ents undergo a n a udi ol ogi c a s s es s ment, el ectronys ta gmogra phy wi th ca l ori c tes ti ng, a nd ga dol i ni um-enha nced MRI of the hea d, wi th
a ttenti on to the i nterna l a udi tory ca na l s to excl ude other di a gnos es , s uch a s cerebel l oponti ne a ngl e tumor, bra i n s tem hemorrha ge, or i nfa rcti on.
MRI ma y s how enha ncement of the ves ti bul a r nerves , cons i s tent wi th i nfl a mma tory neuri ti s .
Treatment
Symptom rel i ef wi th a nti emeti cs , a nti hi s ta mi nes , or benzodi a zepi nes
Symptoms a re a ddres s ed a s i n Meni ere's di s ea s e (s ee p. 445), i e, wi th a nti chol i nergi cs , a nti emeti cs (eg, prochl orpera zi ne or prometha zi ne 25 mg
recta l l y or 10 mg po q 6 to 8 h), a nti hi s ta mi nes or benzodi a zepi nes , a nd a corti cos teroi d burs t wi th ra pi d ta per. If vomi ti ng i s prol onged, IV fl ui ds
a nd el ectrol ytes ma y be requi red. Ves ti bul a r reha bi l i ta ti on (us ua l l y gi ven by a phys i ca l thera pi s t) hel ps compens a te for a ny res i dua l ves ti bul a r
defi ci t.
Chapter 49. Middle Ear and Tympanic Membrane Disorders

Introduction
(See a l s o Oti c Tumors on p. 493)
Mi ddl e ea r di s orders ma y be s econda ry to i nfecti on, eus ta chi a n tube obs tructi on, or tra uma . Informa ti on a bout objects pl a ced i n the ea r a nd
s ymptoms s uch a s rhi norrhea , na s a l obs tructi on, s ore throa t, URI, a l l ergi es , hea da che, s ys temi c s ymptoms , a nd fever a i d di a gnos i s . The
a ppea ra nce of the externa l a udi tory ca na l a nd tympa ni c membra ne (s ee
Fi g. 49-1) often yi el ds a di a gnos i s . The nos e, na s opha rynx, a nd oropha rynx a re exa mi ned for s i gns of i nfecti on a nd a l l ergy a nd for evi dence of
tumors . Mi ddl e ea r functi on i s eva l ua ted wi th us e of pneuma ti c otos copy, Weber's tuni ng fork tes t a nd the Ri nne tuni ng fork tes t, tympa nometry,
a nd a udi ol ogi c tes ts (s ee p. 431).
Mastoiditis
Mastoiditis is a bacterial infection of the mastoid air cells, which typically occurs after acute otitis media. Symptoms include redness, tenderness, swelling, and
fluctuation over the mastoid process, with displacement of the pinna. Diagnosis is clinical. Treatment is with antibiotics, such as ceftriaxone, and mastoidectomy
if drug therapy is not effective.
In a cute purul ent oti ti s medi a , i nfl a mma ti on often extends i nto the ma s toi d a ntrum a nd a i r cel l s , res ul ti ng i n fl ui d a ccumul a ti on. In a few
pa ti ents , ba cteri a l i nfecti on devel ops i n the col l ected fl ui d, typi ca l l y wi th the s a me orga ni s m ca us i ng the oti ti s medi a ; pneumococcus i s mos t
common. Ma s toi d i nfecti on ca n ca us e os tei ti s of the s epta e, l ea di ng to coa l es cence of the a i r cel l s . The i nfecti on ma y decompres s through a
perfora ti on i n the tympa ni c membra ne or extend through the l a tera l ma s toi d cortex, formi ng a pos ta uri cul a r s ubperi os tea l a bs ces s . Ra rel y, i t
extends centra l l y, ca us i ng a tempora l l obe a bs ces s or a s epti c thrombos i s of the l a tera l s i nus . Occa s i ona l l y, the i nfecti on ma y erode through the
ti p of the ma s toi d a nd dra i n i nto the neck (ca l l ed a Bezol d a bs ces s ).
Symptoms and Signs
Symptoms begi n da ys to weeks a fter ons et of a cute oti ti s medi a a nd i ncl ude fever a nd pers i s tent, throbbi ng ota l gi a . Nea rl y a l l pa ti ents ha ve s i gns
of oti ti s medi a (s ee p. 448) a nd purul ent otorrhea . Rednes s , s wel l i ng,
[Fig. 49-1. Tympa ni c membra ne of ri ght ea r (A); tympa ni c ca vi ty wi th tympa ni c membra ne removed (B).]
tendernes s , a nd fl uctua ti on ma y devel op over the ma s toi d proces s ; the pi nna i s typi ca l l y di s pl a ced l a tera l l y a nd i nferi orl y.
Diagnosis
Ra rel y CT
Di a gnos i s i s cl i ni ca l . CT i s ra rel y neces s a ry but ca n confi rm the di a gnos i s a nd s how the extent of the i nfecti on. Any mi ddl e ea r dra i na ge i s s ent for
cul ture a nd s ens i ti vi ty. Tympa nocentes i s for cul ture purpos es ca n be done i f no s ponta neous dra i na ge occurs . CBC a nd ESR ma y be a bnorma l but
a re nei ther s ens i ti ve nor s peci fi c a nd a dd l i ttl e to the di a gnos i s .
Treatment
IV ceftri a xone
IV a nti bi oti c trea tment i s i ni ti a ted i mmedi a tel y wi th a drug tha t provi des CNS penetra ti on, s uch a s ceftri a xone 1 to 2 g (chi l dren, 50 to 75 mg/kg)
once/da y conti nued for 2 wk. Ora l trea tment wi th a qui nol one ma y be a ccepta bl e. Subs equent a nti bi oti c choi ce i s gui ded by cul ture a nd
s ens i ti vi ty tes t res ul ts .
A s ubperi os tea l a bs ces s us ua l l y requi res a s i mpl e ma s toi dectomy, i n whi ch the a bs ces s i s dra i ned, the i nfected ma s toi d cel l s a re removed, a nd
dra i na ge i s es ta bl i s hed from the a ntrum of the ma s toi d to the mi ddl e ea r ca vi ty.
Myringitis
(Bul l ous Myri ngi ti s )
Myringitis is a form of acute otitis media in which vesicles develop on the tympanic membrane.
Myri ngi ti s ca n devel op wi th vi ra l , ba cteri a l (pa rti cul a rl y Streptococcus pneumoniae), or mycopl a s ma l oti ti s medi a . Pa i n occurs s uddenl y a nd pers i s ts
for 24 to 48 h. Hea ri ng l os s a nd fever s ugges t a ba cteri a l ori gi n. Di a gnos i s i s ba s ed on otos copi c vi s ua l i za ti on of ves i cl es on the tympa ni c
membra ne.
Beca us e di fferenti a ti on a mong a vi ra l , ba cteri a l , a nd mycopl a s ma l ca us e i s di ffi cul t, a nti bi oti cs effecti ve a ga i ns t orga ni s ms ca us i ng oti ti s medi a
a re pres cri bed (s ee
Ta bl e 49-1). Severe, conti nued pa i n ma y be rel i eved by rupturi ng the ves i cl es wi th a myri ngotomy kni fe or by ora l a na l ges i cs (eg, oxycodone wi th
a ceta mi nophen). Topi ca l a na l ges i cs (eg, benzoca i ne, a nti pyri ne) ma y a l s o be benefi ci a l .
Acute Otitis Media
Acute otitis media (AOM) is a bacterial or viral infection of the middle ear, usually accompanying a URI. Symptoms include otalgia, often with systemic
symptoms (eg, fever, nausea, vomiting, diarrhea), especially in the very young. Diagnosis is based on otoscopy. Treatment is with analgesics and sometimes
antibiotics.
Al though AOM ca n occur a t a ny a ge, i t i s mos t common between a ges 3 mo a nd 3 yr. At thi s a ge, the eus ta chi a n tube i s s tructura l l y a nd functi ona l l y
i mma ture; the a ngl e of the eus ta chi a n tube i s more hori zonta l ; a nd the a ngl e of the tens or vel i pa l a ti ni mus cl e a nd the ca rti l a gi nous eus ta chi a n
tube renders the openi ng mecha ni s m l es s effi ci ent.
The eti ol ogy ma y be vi ra l or ba cteri a l . Vi ra l i nfecti ons a re often compl i ca ted by s econda ry ba cteri a l i nfecti on. In neona tes , gra m-nega ti ve enteri c
ba ci l l i , pa rti cul a rl y Escherichia coli, a nd Staphylococcus aureus ca us e AOM. In ol der i nfa nts a nd chi l dren < 14 yr, the mos t common orga ni s ms a re
Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, a nd nontypea bl e Haemophilus influenzae; l es s common ca us es a re group A -hemol yti c
s treptococci a nd S. aureus. In pa ti ents > 14 yr, S. pneumoniae, group A -hemol yti c s treptococci , a nd S. aureus a re mos t common, fol l owed by H.
influenzae.
In ra re ca s es , ba cteri a l mi ddl e ea r i nfecti on s prea ds l oca l l y, res ul ti ng i n a cute ma s toi di ti s , petros i ti s , or l a byri nthi ti s . Intra cra ni a l s prea d i s
extremel y ra re a nd us ua l l y ca us es meni ngi ti s , but bra i n a bs ces s , s ubdura l empyema , epi dura l a bs ces s , l a tera l s i nus thrombos i s , or oti ti c
hydrocepha l us ma y occur. Even wi th a nti bi oti c trea tment, i ntra cra ni a l compl i ca ti ons a re s l ow to res ol ve, es peci a l l y i n i mmunocompromi s ed
pa ti ents .
Symptoms and Signs
The us ua l i ni ti a l s ymptom i s ea ra che, often wi th hea ri ng l os s . Infa nts ma y s i mpl y be cra nky or ha ve di ffi cul ty s l eepi ng. Fever, na us ea , vomi ti ng,
a nd di a rrhea often occur i n young chi l dren. Otos copi c exa mi na ti on ca n s how a bul gi ng, erythema tous tympa ni c membra ne (TM) wi th i ndi s ti nct
l a ndma rks a nd di s pl a cement of the l i ght refl ex. Ai r i ns uffl a ti on (pneuma ti c otos copy) s hows poor mobi l i ty of the TM. Sponta neous perfora ti on of
the TM ca us es s eros a ngui neous or purul ent otorrhea .
Severe hea da che, confus i on, or foca l neurol ogi c s i gns ma y occur wi th i ntra cra ni a l s prea d of i nfecti on. Fa ci a l pa ra l ys i s or verti go s ugges ts l oca l
extens i on to the fa l l opi a n ca na l or l a byri nth.
[Table 49-1. Anti bi oti cs for Oti ti s Medi a ]
Diagnosis
Di a gnos i s us ua l l y i s cl i ni ca l . Except for fl ui d obta i ned duri ng myri ngotomy, cul tures a re not genera l l y done.
Treatment
Ana l ges i cs
Someti mes a nti bi oti cs
Ra rel y myri ngotomy
Al though 80% of ca s es res ol ve s ponta neous l y, i n the US, a nti bi oti cs a re often gi ven (s ee Ta bl e 49-1). Anti bi oti cs rel i eve s ymptoms qui cker
(a l though res ul ts a fter 1 to 2 wk a re s i mi l a r) a nd ma y reduce the cha nce of res i dua l hea ri ng l os s a nd l a byri nthi ne or i ntra cra ni a l s equel a e.
However, wi th the recent emergence of res i s ta nt orga ni s ms , pedi a tri c orga ni za ti ons ha ve s trongl y recommended i ni ti a l a nti bi oti cs onl y for thos e
a t hi ghes t ri s k (eg, thos e who a re younger or more s everel y i l l s ee
Ta bl e 49-2) or for thos e wi th recurrent AOM (eg, 4 epi s odes i n 6 mo). Others , provi ded there i s good fol l ow-up, ca n s a fel y
[Table 49-2. Gui del i nes for Us i ng Anti bi oti cs i n Acute Oti ti s Medi a ]
be obs erved for up to 72 h a nd gi ven a nti bi oti cs onl y i f no i mprovement i s s een; i f fol l ow-up by phone i s pl a nned, a pres cri pti on ca n be gi ven a t
the i ni ti a l vi s i t to s a ve ti me a nd expens e.
Al l pa ti ents recei ve a na l ges i cs (eg, a ceta mi nophen, i buprofen). In a dul ts , topi ca l i ntra na s a l va s ocons tri ctors , s uch a s phenyl ephri ne 0.25% 3 drops
q 3 h, i mprove eus ta chi a n tube functi on. To a voi d rebound conges ti on, thes e prepa ra ti ons s houl d not be us ed > 4 da ys . Sys temi c deconges ta nts
(eg, ps eudoephedri ne 30 to 60 mg po q 6 h prn) ma y be hel pful . Anti hi s ta mi nes (eg, chl orpheni ra mi ne 4 mg po q 4 to 6 h for 7 to 10 da ys ) ma y
i mprove eus ta chi a n tube functi on i n peopl e wi th a l l ergi es but s houl d be res erved for the trul y a l l ergi c. For chi l dren, nei ther va s ocons tri ctors nor
a nti hi s ta mi nes a re of benefi t.
Myri ngotomy ma y be done for a bul gi ng TM, pa rti cul a rl y i f s evere or pers i s tent pa i n, fever, vomi ti ng, or di a rrhea i s pres ent. The pa ti ent's hea ri ng,
tympa nometry, a nd TM a ppea ra nce a nd movement a re moni tored unti l norma l .
Prevention
Routi ne chi l dhood va cci na ti on a ga i ns t pneumococci (wi th pneumococca l conjuga te va cci ne), H. influenzae type B, a nd i nfl uenza decrea s es the
i nci dence of AOM. Infa nts s houl d not s l eep wi th a bottl e, a nd el i mi na ti on of hous ehol d s moki ng ma y decrea s e i nci dence.
Secretory Otitis Media
(Serous Oti ti s Medi a )
Secretory otitis media is an effusion in the middle ear resulting from incomplete resolution of acute otitis media or obstruction of the eustachian tube without
infection. Symptoms include hearing loss and a sense of fullness or pressure in the ear. Diagnosis is based on appearance of the tympanic membrane and
sometimes on tympanometry. Most cases resolve in 2 to 3 wk. If there is no improvement in 1 to 3 mo, some form of myringotomy is indicated, usually with
insertion of a tympanostomy tube. Antibiotics and decongestants are not effective.
Norma l l y, the mi ddl e ea r i s venti l a ted 3 to 4 ti mes /mi n a s the eus ta chi a n tube opens duri ng s wa l l owi ng, a nd O2 i s a bs orbed by bl ood i n the
ves s el s of the mi ddl e ea r mucous membra ne. If pa tency of the eus ta chi a n tube i s i mpa i red, a rel a ti ve nega ti ve pres s ure devel ops wi thi n the
mi ddl e ea r, whi ch ca n l ea d to fl ui d a ccumul a ti on. Thi s fl ui d ma y ca us e hea ri ng l os s .
Secretory oti ti s medi a i s a common s equel a to a cute oti ti s medi a i n chi l dren (often i denti fi ed on routi ne ea r recheck) a nd ma y pers i s t for weeks
to months . In other ca s es , eus ta chi a n tube obs tructi on ma y be s econda ry to i nfl a mma tory proces s es i n the na s opha rynx, a l l ergi es , hypertrophi c
a denoi ds or other obs tructi ve l ymphoi d a ggrega ti ons on the torus of the eus ta chi a n tube a nd i n Ros enmul l er's fos s a , or beni gn or ma l i gna nt
tumors . The effus i on ma y be s teri l e or (more commonl y) conta i n pa thogeni c ba cteri a s ometi mes a s a bi ofi l m, a l though i nfl a mma ti on i s not
obs erved.
Symptoms and Signs
Pa ti ents ma y report no s ymptoms , but s ome (or thei r fa mi l y members ) note hea ri ng l os s . Pa ti ents ma y experi ence a feel i ng of ful l nes s , pres s ure,
or poppi ng i n the ea r wi th s wa l l owi ng. Ota l gi a i s ra re.
Va ri ous pos s i bl e cha nges to the tympa ni c membra ne (TM) i ncl ude a n a mber or gra y col or, di s pl a cement of the l i ght refl ex, mi l d to s evere
retra cti on, a nd a ccentua ted l a ndma rks . On a i r i ns uffl a ti on, the TM ma y be i mmobi l e. An a i r-fl ui d l evel or bubbl es of a i r ma y be vi s i bl e through the
TM.
Diagnosis
Di a gnos i s i s cl i ni ca l . Tympa nometry ma y be done to confi rm mi ddl e ea r effus i on. Adul ts a nd a dol es cents mus t undergo na s opha ryngea l
exa mi na ti on to excl ude ma l i gna nt or beni gn tumors .
Treatment
Obs erva ti on
If unres ol ved, myri ngotomy wi th tympa nos tomy tube i ns erti on
If recurrent i n chi l dhood, s ometi mes a denoi dectomy
For mos t pa ti ents , wa tchful wa i ti ng i s a l l tha t i s requi red. Anti bi oti cs a nd deconges ta nts a re not hel pful . For pa ti ents i n whom a l l ergi es a re
cl ea rl y i nvol ved, a nti hi s ta mi nes a nd topi ca l corti cos teroi ds ma y be hel pful .
If no i mprovement occurs i n 1 to 3 mo, myri ngotomy ma y be done for a s pi ra ti on of fl ui d a nd i ns erti on of a tympa nos tomy tube, whi ch a l l ows
venti l a ti on of the mi ddl e ea r a nd tempora ri l y a mel i ora tes eus ta chi a n tube obs tructi on, rega rdl es s of ca us e. Tympa nos tomy tubes ma y be i ns erted
for pers i s tent conducti ve hea ri ng l os s or to hel p prevent recurrence of a cute oti ti s medi a .
Occa s i ona l l y, the mi ddl e ea r i s tempora ri l y venti l a ted wi th the Va l s a l va ma neuver or pol i tzeri za ti on. To do the Va l s a l va ma neuver, pa ti ents keep
thei r mouth cl os ed a nd try to forci bl y bl ow a i r out through thei r pi nched nos tri l s (i e, poppi ng the ea r). To do pol i tzeri za ti on, the phys i ci a n bl ows
a i r wi th a s peci a l s yri nge (mi ddl e ea r i nfl a tor) i nto one of the pa ti ent's nos tri l s a nd bl ocks the other whi l e the pa ti ent s wa l l ows . Thi s forces the
a i r i nto the eus ta chi a n tube a nd mi ddl e ea r. Nei ther procedure s houl d be done i f the pa ti ent ha s a col d a nd rhi norrhea .
Pers i s tent, recurrent s ecretory oti ti s medi a ma y requi re correcti on of underl yi ng na s opha ryngea l condi ti ons . Chi l dren ma y benefi t from
a denoi dectomy, i ncl udi ng the remova l of the centra l a denoi d ma s s a s wel l a s l ymphoi d a ggrega ti ons on the torus of the eus ta chi a n tube a nd i n
Ros enmul l er's fos s a . Anti bi oti cs s houl d be gi ven for ba cteri a l rhi ni ti s , s i nus i ti s , a nd na s opha ryngi ti s . Demons tra ted a l l ergens s houl d be
el i mi na ted from the pa ti ent's envi ronment a nd i mmunothera py s houl d be cons i dered.
Chronic Otitis Media
Chronic otitis media is a persistent, chronically draining (> 6 wk), suppurative perforation of the tympanic membrane. Symptoms include painless otorrhea with
conductive hearing loss. Complications include development of aural polyps, cholesteatoma, and other infections. Treatment requires complete cleaning of the ear
canal several times daily, careful removal of granulation tissue, and application of topical corticosteroids and antibiotics. Systemic antibiotics and surgery are
reserved for severe cases.
Chroni c oti ti s medi a ca n res ul t from a cute oti ti s medi a , eus ta chi a n tube obs tructi on, mecha ni ca l tra uma , therma l or chemi ca l burns , bl a s t i njuri es ,
or i a trogeni c ca us es (eg, a fter tympa nos tomy tube pl a cement). Further, pa ti ents wi th cra ni ofa ci a l a bnorma l i ti es (eg, Down s yndrome, cri du cha t
s yndrome, cl eft l i p a nd/or cl eft pa l a te, vel oca rdi ofa ci a l s yndrome [Shpri ntzen's s yndrome]) ha ve a n i ncrea s ed ri s k.
Chroni c oti ti s medi a ma y become exa cerba ted a fter a URI or when wa ter enters the mi ddl e ea r through a tympa ni c membra ne (TM) perfora ti on
duri ng ba thi ng or s wi mmi ng. Infecti ons often a re ca us ed by gra m-nega ti ve ba ci l l i or Staphylococcus aureus, res ul ti ng i n pa i nl es s , purul ent,
s ometi mes foul -s mel l i ng otorrhea . Pers i s tent chroni c oti ti s medi a ma y res ul t i n des tructi ve cha nges i n the mi ddl e ea r (s uch a s necros i s of the
l ong proces s of the i ncus ) or a ura l pol yps (gra nul a ti on ti s s ue prol a ps i ng i nto the ea r ca na l through the TM perfora ti on). Aura l pol yps a re a s eri ous
s i gn, a l mos t i nva ri a bl y s ugges ti ng chol es tea toma .
A chol es tea toma i s a n epi thel i a l cel l growth tha t forms i n the mi ddl e ea r, ma s toi d, or epi tympa num a fter chroni c oti ti s medi a (s ee
Pl a te 1). Lyti c enzymes , s uch a s col l a gena s es , produced by the chol es tea toma ca n des troy a dja cent bone a nd s oft ti s s ue. The chol es tea toma i s
a l s o a ni dus for i nfecti on; purul ent l a byri nthi ti s , fa ci a l pa ra l ys i s , or i ntra cra ni a l a bs ces s ma y devel op.
Symptoms and Signs
Chroni c oti ti s medi a us ua l l y ma ni fes ts wi th conducti ve hea ri ng l os s a nd otorrhea . Pa i n i s uncommon unl es s a n a s s oci a ted os tei ti s of the
tempora l bone occurs . The TM i s perfora ted a nd dra i ni ng, a nd the a udi tory ca na l i s ma cera ted a nd l i ttered wi th gra nul a ti on ti s s ue.
A pa ti ent wi th chol es tea toma ha s whi te debri s i n the mi ddl e ea r, a dra i ni ng pol ypoi d ma s s protrudi ng through the TM perfora ti on, a nd a n ea r
ca na l tha t a ppea rs cl ogged wi th mucopurul ent gra nul a ti on ti s s ue.
Diagnosis
Di a gnos i s i s us ua l l y cl i ni ca l . Dra i na ge i s cul tured. When chol es tea toma or other compl i ca ti ons a re s us pected (a s i n a febri l e pa ti ent or one wi th
verti go or ota l gi a ), CT or MRI i s done. Thes e tes ts ma y revea l i ntra tempora l or i ntra cra ni a l proces s es (eg, l a byri nthi ti s , os s i cul a r or tempora l
eros i on, a bs ces s es ).
Treatment
Irri ga ti on a nd topi ca l a nti bi oti c drops
Remova l of gra nul a ti on ti s s ue
The ea r ca na l i s i rri ga ted wi th a bul b s yri nge 3 ti mes /da y wi th a s l i ghtl y wa rmed s ol uti on of ha l f vi nega r a nd ha l f s teri l e wa ter. After the ea r
dra i ns , 10 drops topi ca l ofl oxa ci n s ol uti on a re i ns ti l l ed i n the a ffected ea r 2 ti mes /da y for 14 da ys .
When gra nul a ti on ti s s ue i s pres ent, i t i s removed wi th mi croi ns truments or ca uteri za ti on wi th s i l ver ni tra te s ti cks . Ci profl oxa ci n 0.3% a nd
dexa metha s one 0.1% i s then i ns ti l l ed i nto the ea r ca na l for 7 to 10 da ys .
Severe exa cerba ti ons requi re s ys temi c a nti bi oti c thera py wi th a moxi ci l l i n 250 to 500 mg po q 8 h for 10 da ys or a 3rd-genera ti on cepha l os pori n,
s ubs equentl y modi fi ed by cul ture res ul ts a nd res pons e to thera py.
Tympa nopl a s ty i s i ndi ca ted for pa ti ents wi th ma rgi na l or a tti c perfora ti ons a nd chroni c centra l TM perfora ti ons . A di s rupted os s i cul a r cha i n ma y
be repa i red duri ng tympa nopl a s ty a s wel l .
Chol es tea toma s mus t be removed s urgi ca l l y. Beca us e recurrence i s common, recons tructi on of the mi ddl e ea r i s us ua l l y deferred unti l a 2nd-l ook
opera ti on i s done 6 to 8 mo l a ter.
Otic Barotrauma
(Ba roti ti s Medi a or Aeroti ti s Medi a )
Otic barotrauma is ear pain or damage to the tympanic membrane caused by rapid changes in pressure.
To ma i nta i n equa l pres s ure on both s i des of the tympa ni c membra ne (TM), ga s mus t move freel y between the na s opha rynx a nd mi ddl e ea r. When
a URI, a l l ergy, or other mecha ni s m i nterferes wi th eus ta chi a n tube functi oni ng duri ng cha nges i n envi ronmenta l pres s ure, the pres s ure i n the
mi ddl e ea r ei ther fa l l s bel ow a mbi ent pres s ure, ca us i ng retra cti on of the TM, or ri s es a bove i t, ca us i ng bul gi ng. Wi th nega ti ve mi ddl e ea r
pres s ure, a tra ns uda te of fl ui d ma y form i n the mi ddl e ea r. As the pres s ure di fferenti a l i ncrea s es , ecchymos i s a nd s ubepi thel i a l hema toma ma y
devel op i n the mucous membra ne of the mi ddl e ea r a nd the TM. A very l a rge pres s ure di fferenti a l ma y ca us e bl eedi ng i nto the mi ddl e ea r, TM
rupture, a nd the devel opment of a peri l ymph fi s tul a through the ova l or round wi ndow.
Symptoms a re s evere pa i n, conducti ve hea ri ng l os s , a nd, i f there i s a peri l ymph fi s tul a , s ens ory neura l l os s . Symptoms us ua l l y wors en duri ng
ra pi d i ncrea s e i n externa l a i r pres s ures , s uch a s a ra pi d a s cent (eg, duri ng s cuba di vi ng) or des cent (eg, duri ng a i r tra vel ). Sens ori neura l hea ri ng
l os s or verti go duri ng des cent s ugges ts the devel opment of a peri l ymph fi s tul a ; the s a me s ymptoms duri ng a s cent from a deep-s ea di ve ca n
a ddi ti ona l l y s ugges t a n a i r bubbl e forma ti on i n the i nner ea r.
Treatment
Methods to equa l i ze pres s ure (eg, ya wni ng, s wa l l owi ng, chewi ng gum)
Routi ne s el f-trea tment of pa i n a s s oci a ted wi th cha ngi ng pres s ure i n a n a i rcra ft i ncl udes chewi ng gum, a ttempti ng to ya wn a nd s wa l l ow, bl owi ng
a ga i ns t cl os ed nos tri l s , a nd us i ng deconges ta nt na s a l s pra ys .
If hea ri ng l os s i s s ens ori neura l a nd verti go i s pres ent, a peri l ymph fi s tul a i s s us pected a nd mi ddl e ea r expl ora ti on to cl os e a fi s tul a i s
cons i dered. If pa i n i s s evere a nd hea ri ng l os s i s conducti ve, myri ngotomy i s hel pful .
Prevention
A pers on wi th na s a l conges ti on due to URI or a l l ergi es s houl d a voi d fl yi ng a nd di vi ng. When thes e a cti vi ti es a re una voi da bl e, a topi ca l na s a l
va s ocons tri ctor (eg, phenyl ephri ne 0.25 to 1.0%) i s a ppl i ed 30 to 60 mi n before des cent or a s cent.
Otosclerosis
Otosclerosis is a disease of the bone of the otic capsule that causes an abnormal accumulation of new bone within the oval window.
In otos cl eros i s , the new bone tra ps a nd res tri cts the movement of the s ta pes , ca us i ng conducti ve hea ri ng l os s (s ee p. 429). Otos cl eros i s a l s o ma y
ca us e a s ens ori neura l hea ri ng l os s , pa rti cul a rl y when the foci of otos cl eroti c bone a re a dja cent to the s ca l a medi a . Ha l f of a l l ca s es a re i nheri ted.
The mea s l es vi rus pl a ys a n i nci ti ng rol e i n pa ti ents wi th a geneti c predi s pos i ti on for otos cl eros i s .
Al though a bout 10% of whi te a dul ts ha ve s ome otos cl eros i s (compa red wi th 1% of bl a cks ), onl y a bout 10% of a ffected peopl e devel op conducti ve
hea ri ng l os s . Hea ri ng l os s ca us ed by otos cl eros i s ma y ma ni fes t a s ea rl y a s a ge 7 or 8, but mos t ca s es do not become evi dent unti l the l a te teen or
ea rl y a dul t yea rs , when s l owl y progres s i ve, a s ymmetri c hea ri ng l os s i s di a gnos ed. Fi xa ti on of the s ta pes ma y progres s ra pi dl y duri ng pregna ncy.
A hea ri ng a i d ma y res tore hea ri ng. Al terna ti vel y, mi cros urgery to remove s ome or a l l of the s ta pes a nd to repl a ce i t wi th a pros thes i s ma y be
benefi ci a l .
Traumatic Perforation of the Tympanic Membrane
Traumatic perforation of the tympanic membrane (TM) can cause pain, bleeding, hearing loss, tinnitus, and vertigo. Diagnosis is based on otoscopy. Treatment
often is unnecessary. Antibiotics may be needed for infection. Surgery may be needed for perforations persisting > 2 mo, disruption of the ossicular chain, or
injuries affecting the inner ear.
Tra uma ti c ca us es of TM perfora ti on i ncl ude
Ins erti on of objects i nto the ea r ca na l purpos el y (eg, cotton s wa bs ) or a cci denta l l y
Concus s i on ca us ed by a n expl os i on or open-ha nded s l a p a cros s the ea r
Hea d tra uma (wi th or wi thout ba s i l a r fra cture)
Sudden nega ti ve pres s ure (eg, s trong s ucti on a ppl i ed to the ea r ca na l )
Ba rotra uma (eg, duri ng a i r tra vel or s cuba di vi ng)
Ia trogeni c perfora ti on duri ng i rri ga ti on or forei gn body remova l
Penetra ti ng i njuri es of the TM ma y res ul t i n di s l oca ti ons of the os s i cul a r cha i n, fra cture of the s ta pedi a l footpl a te, di s pl a cement of fra gments of
the os s i cl es , bl eedi ng, a peri l ymph fi s tul a from the ova l or round wi ndow res ul ti ng i n l ea ka ge of peri l ymph i nto the mi ddl e ea r s pa ce, or fa ci a l
nerve i njury.
Symptoms and Signs
Tra uma ti c perfora ti on of the TM ca us es s udden s evere pa i n s ometi mes fol l owed by bl eedi ng from the ea r, hea ri ng l os s , a nd ti nni tus . Hea ri ng l os s
i s more s evere i f the os s i cul a r cha i n i s di s rupted or the i nner ea r i s i njured. Verti go s ugges ts i njury to the i nner ea r. Purul ent otorrhea ma y begi n
i n 24 to 48 h, pa rti cul a rl y i f wa ter enters the mi ddl e ea r.
Diagnosis
Otos copy
Audi ometry
Perfora ti on i s genera l l y evi dent on otos copy. Any bl ood obs curi ng the ea r ca na l i s ca reful l y s ucti oned. Irri ga ti on a nd pneuma ti c otos copy a re
a voi ded. Extremel y s ma l l perfora ti ons ma y requi re otomi cros copy or mi ddl e ea r i mpeda nce s tudi es for defi ni ti ve di a gnos i s . If pos s i bl e,
a udi ometri c s tudi es a re done before a nd a fter trea tment to a voi d confus i on between tra uma -i nduced a nd trea tment-i nduced hea ri ng l os s .
Pa ti ents wi th ma rked hea ri ng l os s or s evere verti go a re eva l ua ted by a n otol a ryngol ogi s t a s s oon a s pos s i bl e. Expl ora tory tympa notomy ma y be
needed to a s s es s a nd repa i r da ma ge. Pa ti ents wi th a l a rge TM defect s houl d a l s o be eva l ua ted, beca us e the di s pl a ced fl a ps ma y need to be
repos i ti oned.
Treatment
Ea r kept dry
Ora l or topi ca l a nti bi oti cs i f di rty i njury
Often, no s peci fi c trea tment i s needed. The ea r s houl d be kept dry; routi ne a nti bi oti c ea rdrops a re unneces s a ry. However, prophyl a xi s wi th ora l
broa d-s pectrum a nti bi oti cs or a nti bi oti c ea rdrops i s neces s a ry i f conta mi na nts ma y ha ve entered through the perfora ti on a s occurs i n di rty
i njuri es .
If the ea r becomes i nfected, a moxi ci l l i n 500 mg po q 8 h i s gi ven for 7 da ys .
Al though mos t perfora ti ons cl os e s ponta neous l y, s urgery i s i ndi ca ted for a perfora ti on pers i s ti ng > 2 mo. Pers i s tent conducti ve hea ri ng l os s
s ugges ts di s rupti on of the os s i cul a r cha i n, neces s i ta ti ng s urgi ca l expl ora ti on a nd repa i r.
Chapter 50. External Ear Disorders

Introduction
The externa l ea r (pi nna a nd externa l a udi tory ca na l ) ca n be a ffected by congeni ta l , derma tol ogi c, i nfecti ous , neopl a s ti c, obs tructi ve, a nd tra uma ti c
di s orders . Congeni ta l defects a re di s cus s ed on p.
2971. Ea r tra uma i s di s cus s ed on p. 3231.
Dermatitis
Dermatitis is inflammation of the ear canal involving itching and skin changes that are caused by exposure to allergens (contact dermatitis) or are spontaneous
occurrences (aural eczematoid dermatitis).
Common conta ct a l l ergens i ncl ude ni ckel -conta i ni ng ea rri ngs a nd numerous bea uty products (eg, ha i rs pra ys , l oti ons , ha i r dye). Aura l eczema toi d
derma ti ti s i s more common a mong peopl e wi th a predi s pos i ti on towa rd a topy a nd wi th other s i mi l a r derma ti ti des (eg, s eborrhea , ps ori a s i s ).
Both conta ct derma ti ti s a nd a ura l eczema toi d derma ti ti s ca us e i tchi ng, rednes s , di s cha rge, des qua ma ti on, hyperpi gmenta ti on, a nd, s ometi mes ,
fi s s uri ng. A s econda ry i nfecti on ca n occur.
Conta ct derma ti ti s requi res a voi da nce or wi thdra wa l of a l l ergi c tri ggers . Tri a l a nd error ma y be needed to i denti fy the offendi ng a gent. Topi ca l
corti cos teroi ds (eg, 1% hydrocorti s one crea m) ca n decrea s e i nfl a mma ti on a nd i tchi ng.
Aura l eczema toi d derma ti ti s ca n be trea ted wi th di l ute a l umi num a ceta te s ol uti on (Burow's s ol uti on), whi ch ca n be a ppl i ed a s often a s requi red
for comfort. Itchi ng a nd i nfl a mma ti on ca n be reduced wi th topi ca l corti cos teroi ds . If di ffus e externa l oti ti s ens ues , a nti bi oti c thera py ma y be
requi red (s ee p. 455).
External Otitis
External otitis is infection of the ear canal, typically by bacteria. Symptoms include itching, pain, and discharge. Diagnosis is based on inspection. Treatment is
with topical drugs, including antibiotics, corticosteroids, and acetic acid or a combination.
Externa l oti ti s ma y ma ni fes t a s a l oca l i zed furuncl e or a s a di ffus e i nfecti on of the enti re ca na l (genera l i zed or di ffus e externa l oti ti s ). Thi s
condi ti on i s often ca l l ed s wi mmer's ea r beca us e i t s ometi mes a ffl i cts peopl e who s wi m. Ma l i gna nt externa l oti ti s (s ee p. 455) i s a s evere
Pseudomonas i nfecti on of the tempora l bone a nd i s es peci a l l y da ngerous i n di a beti cs .
Etiology
Di ffus e externa l oti ti s i s us ua l l y ca us ed by ba cteri a , s uch a s Pseudomonas aeruginosa, Proteus vulgaris, Staphylococcus aureus, or Escherichia coli. Funga l
externa l oti ti s (otomycos i s ), typi ca l l y ca us ed by Aspergillus niger or Candida albicans, i s l es s common. Furuncl es us ua l l y a re due to S. aureus.
Predi s pos i ng condi ti ons i ncl ude a l l ergi es , ps ori a s i s , eczema , s eborrhei c derma ti ti s , decrea s ed ca na l a ci di ty (pos s i bl y due to the repea ted
pres ence of wa ter), i rri ta nts (eg, ha i r s pra y, ha i r dye), a nd i na dvertent i njury to the ca na l ca us ed by exces s i ve cl ea ni ng wi th cotton s wa bs or other
objects . Attempts to cl ea n the ea r ca na l ma y pus h debri s a nd cerumen deeper i nto the ca na l ; thes e a ccumul a ted s ubs ta nces tend to tra p wa ter,
res ul ti ng i n s ki n ma cera ti on tha t s ets the s ta ge for ba cteri a l i nfecti on.
Symptoms and Signs
Pa ti ents ha ve i tchi ng a nd pa i n. Someti mes , a foul -s mel l i ng di s cha rge a nd hea ri ng l os s occur i f the ca na l becomes s wol l en or fi l l ed wi th purul ent
debri s . Exqui s i te tendernes s a ccompa ni es tra cti on of the pi nna or pres s ure over the tra gus . Otos copi c exa mi na ti on i s pa i nful a nd di ffi cul t to
conduct. It s hows the ea r ca na l to be red, s wol l en, a nd l i ttered wi th moi s t, purul ent debri s . Otomycos i s ca us ed by A. niger us ua l l y ma ni fes ts wi th
gra yi s h bl a ck or yel l ow dots (funga l coni di ophores ) s urrounded by a cottonl i ke ma teri a l (funga l hypha e). Infecti on ca us ed by C. albicans does not
s how a ny vi s i bl e fungi but us ua l l y conta i ns a thi ckened, crea my whi te exuda te.
Furuncl es ca us e s evere pa i n a nd ma y dra i n s a ngui neous , purul ent ma teri a l . They a ppea r a s a foca l , erythema tous s wel l i ng.
Diagnosis
Di a gnos i s i s ba s ed on i ns pecti on. When di s cha rge i s copi ous , externa l oti ti s ca n be di ffi cul t to di fferenti a te from perfora ted oti ti s medi a ; pa i n
wi th pul l i ng on the pi nna ma y i ndi ca te a n externa l oti ti s . Funga l i nfecti on i s di a gnos ed by a ppea ra nce or cul ture.
Treatment
Topi ca l a ceti c a ci d a nd corti cos teroi ds
Someti mes topi ca l a nti bi oti cs
In di ffus e externa l oti ti s , topi ca l a nti bi oti cs a nd corti cos teroi ds a re effecti ve. Fi rs t, the i nfected debri s s houl d be gentl y a nd thoroughl y removed
from the ca na l wi th s ucti on or dry cotton wi pes . Mi l d externa l oti ti s ca n be trea ted by a l teri ng the ea r ca na l 's pH wi th 2% a ceti c a ci d a nd by
rel i evi ng i nfl a mma ti on wi th topi ca l hydrocorti s one; thes e a re gi ven a s 5 drops ti d for 7 da ys . Modera te externa l oti ti s requi res the a ddi ti on of a n
a nti ba cteri a l s ol uti on or s us pens i on, s uch a s neomyci n, pol ymyxi n, ci profl oxa ci n, or ofl oxa ci n. When i nfl a mma ti on of the ea r ca na l i s rel a ti vel y
s evere, a n ea r wi ck s houl d be pl a ced i nto the ea r ca na l a nd wetted wi th the neces s a ry drugs 4 ti mes /da y. The wi ck i s l eft i n pl a ce for 24 to 72 h,
a fter whi ch ti me the s wel l i ng ma y ha ve receded enough to a l l ow the i ns ti l l a ti on of drops di rectl y i nto the ca na l .
Severe externa l oti ti s or the pres ence of cel l ul i ti s extendi ng beyond the ea r ca na l ma y requi re s ys temi c a nti bi oti cs , s uch a s cepha l exi n 500 mg po
ti d for 10 da ys or ci profl oxa ci n 500 mg po bi d for 10 da ys . An a na l ges i c, s uch a s a n NSAID or even a n ora l opi oi d, ma y be neces s a ry for the fi rs t 24 to
48 h. Funga l externa l oti ti s requi res thorough cl ea ni ng of the ea r ca na l a nd a ppl i ca ti on of a n a nti mycoti c s ol uti on (eg, genti a n vi ol et, cres yl a te
a ceta te, nys ta ti n, cl otri ma zol e). Repea ted cl ea ni ngs a nd trea tments ma y be needed.
A furuncl e, i f obvi ous l y poi nti ng, s houl d be i nci s ed a nd dra i ned. Inci s i on i s of l i ttl e va l ue, however, i f the pa ti ent i s s een a t a n ea rl y s ta ge. Topi ca l
a nti bi oti cs a re i neffecti ve; ora l a nti s ta phyl ococca l a nti bi oti cs s houl d be gi ven. Ana l ges i cs , s uch a s oxycodone wi th a ceta mi nophen, ma y be
neces s a ry for pa i n rel i ef. Dry hea t ca n a l s o l es s en pa i n a nd ha s ten res ol uti on.
Prevention
Externa l oti ti s often ca n be prevented by i rri ga ti ng the ea rs wi th a 1:1 mi xture of rubbi ng a l cohol a nd vi nega r i mmedi a tel y a fter s wi mmi ng. The
a l cohol hel ps remove wa ter, a nd the vi nega r a l ters the pH of the ca na l .
Malignant External Otitis
Malignant external otitis is typically a Pseudomonas osteomyelitis of the temporal bone.
Soft ti s s ue, ca rti l a ge, a nd bone a re a l l a ffected. The os teomyel i ti s s prea ds a l ong the ba s e of the s kul l a nd ma y cros s the mi dl i ne.
Ma l i gna nt externa l oti ti s occurs ma i nl y i n el derl y pa ti ents wi th di a betes or i n i mmunocompromi s ed pa ti ents a nd i s often i ni ti a ted by
Pseudomonas externa l oti ti s . It i s cha ra cteri zed by pers i s tent a nd s evere ea ra che, foul -s mel l i ng purul ent otorrhea , a nd gra nul a ti on ti s s ue i n the
ea r ca na l (us ua l l y a t the juncti on of the bony a nd ca rti l a gi nous porti ons of the ca na l ). Va ryi ng degrees of conducti ve hea ri ng l os s ma y occur. In
s evere ca s es , fa ci a l nerve pa ra l ys i s ma y ens ue.
Di a gnos i s i s ba s ed on a CT s ca n of the tempora l bone, whi ch ma y s how i ncrea s ed ra di odens i ty i n the a i r-cel l s ys tem a nd mi ddl e ea r ra di ol ucency
(demi nera l i za ti on) i n s ome a rea s . Cul tures a re done, a nd the ea r ca na l i s bi ops i ed to di fferenti a te the gra nul a ti on ti s s ue of thi s di s order from a
ma l i gna nt tumor.
Trea tment i s wi th a 6-wk IV cours e of a fl uoroqui nol one or a n a mi nogl ycos i de-s emi s yntheti c peni ci l l i n combi na ti on. Extens i ve bone di s ea s e ma y
requi re more prol onged a nti bi oti c thera py. Ca reful control of di a betes i s es s enti a l . Surgery us ua l l y i s not neces s a ry.
Obstructions
The ear canal may be obstructed by cerumen (earwax), insertion of a foreign object, or an insect. Itching, pain, and temporary conductive hearing loss may result.
Most causes of obstruction are readily apparent during otoscopic examination. Treatment is manual removal.
Cerumen: Cerumen ma y get pus hed further i nto the ea r ca na l a nd a ccumul a te duri ng i l l -a dvi s ed a ttempts to cl ea n the ea r ca na l wi th cotton s wa bs ,
res ul ti ng i n obs tructi on. Cerumen s ol vents (hydrogen peroxi de, ca rba mi de peroxi de, gl yceri n, tri etha nol a mi ne) ma y be us ed to s often very ha rd
wa x before i rri ga ti on or di rect remova l . However, the prol onged us e of thes e a gents ma y l ea d to ca na l s ki n i rri ta ti on or a l l ergi c rea cti ons .
Al though cerumen ma y be removed by i rri ga ti on, rol l i ng the cerumen out of the ea r ca na l wi th a bl unt curet or l oop or removi ng i t wi th a s ucti on ti p
(eg, Ba ron, s i ze 7 French) i s qui cker, nea ter, s a fer, a nd more comforta bl e for the pa ti ent. Irri ga ti on i s contra i ndi ca ted i f the pa ti ent ha s a hi s tory of
otorrhea or perfora ti on of the tympa ni c membra ne; wa ter enteri ng the mi ddl e ea r through a perfora ti on ma y exa cerba te chroni c oti ti s medi a .
Foreign bodies: Forei gn bodi es a re common, pa rti cul a rl y a mong chi l dren, who often i ns ert objects , pa rti cul a rl y bea ds , era s ers , a nd bea ns , i nto the
ea r ca na l . Forei gn bodi es ma y rema i n unnoti ced unti l they provoke a n i nfl a mma tory res pons e, ca us i ng pa i n, i tchi ng, i nfecti on, a nd foul -s mel l i ng,
purul ent dra i na ge. A forei gn body i n the ea r ca na l i s bes t removed by rea chi ng behi nd i t a nd rol l i ng i t out wi th a bl unt hook. Forceps tend to pus h
s mooth objects deeper i nto the ca na l . Unfortuna tel y, a forei gn body l yi ng medi a l to the i s thmus (the bony ca rti l a gi nous juncti on of the externa l
a udi tory ca na l ) i s di ffi cul t to remove wi thout i njuri ng the tympa ni c membra ne a nd os s i cul a r cha i n. Meta l a nd gl a s s bea ds ca n s ometi mes be
removed by i rri ga ti on, but hygros copi c forei gn bodi es (eg, bea ns or other vegeta bl e ma tter) s wel l when wa ter i s a dded, compl i ca ti ng remova l . A
genera l a nes theti c ma y be needed when a chi l d ca nnot rema i n s ti l l or when remova l i s di ffi cul t, threa teni ng i njury to the tympa ni c membra ne or
os s i cl es . Further, i f ma ni pul a ti ng a pres umed forei gn object res ul ts i n bl eedi ng, i mmedi a te otol a ryngol ogi c cons ul ta ti on s houl d be s ought.
Bl eedi ng ma y i ndi ca te a mucos a l pol yp ori gi na ti ng i n the mi ddl e ea r, whi ch ma y be a tta ched to the os s i cl es or fa ci a l nerve.
Ins ects i n the ca na l a re mos t a nnoyi ng whi l e a l i ve. Fi l l i ng the ca na l wi th vi s cous l i doca i ne ki l l s the i ns ect, whi ch provi des i mmedi a te rel i ef a nd
a l l ows the i mmobi l i zed i ns ect to be removed wi th forceps .
Perichondritis
Perichondritis is infection of the perichondrium of the pinna in which pus accumulates between the cartilage and the perichondrium.
Ca us es of peri chondri ti s i ncl ude tra uma , i ns ect bi tes , body pi erci ngs , a nd i nci s i on of s uperfi ci a l i nfecti ons of the pi nna . Beca us e the ca rti l a ge's
bl ood s uppl y i s provi ded by the peri chondri um, s epa ra ti on of the peri chondri um from both s i des of the ca rti l a ge ma y l ea d to a va s cul a r necros i s
a nd a deformed pi nna . Septi c necros i s ma y a l s o ens ue, often wi th i nfecti on by gra m-nega ti ve ba ci l l i . Symptoms i ncl ude rednes s , pa i n, a nd
s wel l i ng. The cours e of peri chondri ti s tends to be i ndol ent, l ong-term, a nd des tructi ve.
The a ffected a rea i s i nci s ed, a nd a dra i n i s l eft i n pl a ce for 24 to 72 h. Sys temi c a nti bi oti cs a re i ni ti a ted wi th a n a mi nogl ycos i de a nd s emi s yntheti c
peni ci l l i n. Subs equent a nti bi oti c choi ce i s gui ded by cul ture a nd s ens i ti vi ty tes ts . Wa rm compres s es ma y hel p.
Chapter 51. Approach to the Patient With Nasal and Pharyngeal Symptoms
Introduction
The nos e a nd pha rynx (cons i s ti ng of the na s opha rynx, oropha rynx, a nd hypopha rynx) ma y be a ffected by i nfl a mma ti on, i nfecti on, tra uma , tumors ,
a nd s evera l mi s cel l a neous condi ti ons .
Anatomy
Throat: The uvul a ha ngs i n the mi dl i ne a t the fa r end of the s oft pa l a te. It va ri es grea tl y i n l ength. A l ong uvul a a nd l oos e or exces s vel opha ryngea l
ti s s ue ma y ca us e s nori ng a nd occa s i ona l l y contri bute to obs tructi ve s l eep a pnea .
Tons i l s a nd a denoi ds a re pa tches of l ymphoi d ti s s ue s urroundi ng the pos teri or pha rynx i n a n a rea termed Wa l deyer's ri ng. Thei r rol e i s to comba t
i nfecti on.
The l a rynx i s di s cus s ed i n Ch. 54.
Nose: The na s a l ca vi ty i s covered wi th a hi ghl y va s cul a r mucos a tha t wa rms a nd humi di fi es i ncomi ng a i r. Ea ch l a tera l wa l l of the ca vi ty ha s 3
turbi na tes , whi ch a re bony s hel ves tha t i ncrea s e the s urfa ce a rea , thereby a l l owi ng more effecti ve hea t a nd moi s ture excha nge. Na s a l mucus
tra ps i ncomi ng pa rti cul a te ma tter. The s pa ce between the mi ddl e a nd i nferi or turbi na te i s the mi ddl e mea tus , i nto whi ch the ma xi l l a ry a nd mos t
of the ethmoi d s i nus es dra i n. Pol yps ma y devel op between the turbi na tes , often i n a s s oci a ti on wi th a s thma , a l l ergy, a s pi ri n us e, a nd cys ti c
fi bros i s .
Sinuses: The pa ra na s a l s i nus es a re mucus -l i ned bony ca vi ti es tha t connect to the na s opha rynx. The 4 types a re ma xi l l a ry, fronta l , ethmoi d, a nd
s phenoi d s i nus es . They a re l oca ted i n the fa ci a l a nd cra ni a l bones (s ee
Fi g. 51-1). The phys i ol ogi c rol e of the s i nus es i s uncl ea r.
[Fig. 51-1. Pa ra na s a l s i nus es .]
Evaluation
Exa mi na ti on of the nos e a nd pha rynx i s pa rt of every genera l phys i ca l exa mi na ti on.
History: Genera l i nforma ti on i ncl udes us e of a l cohol or toba cco (both ma jor ri s k fa ctors for hea d a nd neck ca ncer) a nd s ys temi c s ymptoms , s uch a s
fever a nd wei ght l os s . Oropha ryngea l s ymptoms i ncl ude pa i n, ul cers , a nd di ffi cul ty s wa l l owi ng or s pea ki ng. Na s a l a nd s i nus s ymptoms i ncl ude
pres ence a nd dura ti on of conges ti on, di s cha rge, or bl eedi ng.
Physical examination: Mos t phys i ci a ns us e a hea d-mounted l i ght. However, beca us e the l i ght ca nnot be preci s el y a l i gned on the a xi s of vi s i on, i t i s
di ffi cul t to a voi d s ha dowi ng i n na rrow a rea s (eg, na s a l ca vi ty). Better i l l umi na ti on res ul ts wi th a hea d-mounted convex mi rror; the phys i ci a n l ooks
through a hol e i n the center of the mi rror, s o the i l l umi na ti on i s a l wa ys on-a xi s . The hea d mi rror refl ects l i ght from a s ource (a ny i nca ndes cent
l i ght) pl a ced behi nd the pa ti ent a nd s l i ghtl y to one s i de a nd requi res pra cti ce to us e effecti vel y.
The nos e i s exa mi ned us i ng a na s a l s pecul um, whi ch i s hel d s o tha t the 2 bl a des open i n a n a nteropos teri or (or s l i ghtl y obl i que) di recti on a nd do
not pres s a ga i ns t the s eptum. The phys i ci a n notes crus ti ng, di s cha rge, s epta l devi a ti on, or perfora ti on; whether mucos a i s erythema tous , boggy, or
s wol l en; a nd pres ence of pol yps . The s ki n over the fronta l a nd ma xi l l a ry s i nus es i s exa mi ned for erythema a nd tendernes s , s ugges ti ng s i nus
i nfl a mma ti on.
If neces s a ry, the na s opha rynx a nd hypopha rynx ca n be exa mi ned wi th mi rrors , whi ch s houl d be wa rmed before us e to a voi d foggi ng. A s ma l l mi rror
i s us ed for the na s opha rynx. It i s hel d jus t bel ow the uvul a , a ngl i ng upwa rd; the tongue i s pus hed down wi th a tongue bl a de. A l a rger mi rror i s
us ed for the hypopha rynx a nd l a rynx. The tongue i s retra cted by gra s pi ng i t wi th a ga uze pa d, a nd the mi rror i s pl a ced a ga i ns t the s oft pa l a te,
a ngl i ng downwa rd. If pa ti ents do not tol era te mi rror exa mi na ti on, a fl exi bl e fi beropti c na s opha ryngos cope i s hel pful . A topi ca l a nes theti c (eg,
l i doca i ne 4%) i s s pra yed i n the nos e a nd throa t, a nd the nos e i s a l s o s pra yed wi th a deconges ta nt (eg, phenyl ephri ne 0.5%). After s evera l mi nutes ,
the s cope i s gentl y pa s s ed through the na res , a nd the na s a l ca vi ty, hypopha rynx, a nd l a rynx a re i ns pected.
Neck exa mi na ti on cons i s ts of i ns pecti on a nd pa l pa ti on for ma s s es . If ma s s es a re found, the phys i ci a n notes whether they a re tender; fl uctua nt,
fi rm, or s tony ha rd; a nd mova bl e or fi xed. Ma s s es ca us ed by i nfecti on a re tender a nd mobi l e; ca ncers tend to be nontender, ha rd, a nd fi xed.
Pa rti cul a r a ttenti on i s pa i d to the cervi ca l l ymph nodes a nd thyroi d a nd pa roti d gl a nds .
Epistaxis
Epistaxis is nose bleeding. Bleeding can range from a trickle to a strong flow, and the consequences can range from a minor annoyance to life-threatening
hemorrhage. Swallowed blood is a gastric irritant, so patients also may describe vomiting blood.
Pathophysiology
Mos t na s a l bl eedi ng i s a nteri or, ori gi na ti ng from a pl exus of ves s el s i n the a nteroi nferi or s eptum (Ki es s el ba ch's a rea ).
Les s common but more s eri ous a re pos teri or nos ebl eeds , whi ch ori gi na te i n the pos teri or s eptum overl yi ng the vomer bone, or l a tera l l y on the
i nferi or or mi ddl e turbi na te. Pos teri or nos ebl eeds tend to occur i n pa ti ents who ha ve preexi s ti ng a theros cl eroti c ves s el s or bl eedi ng di s orders
a nd ha ve undergone na s a l or s i nus s urgery.
Etiology
The mos t common ca us es of epi s ta xi s a re
Loca l tra uma (eg, nos e bl owi ng a nd pi cki ng)

Dryi ng of the na s a l mucos a
There a re a number of l es s common ca us es (s ee
Ta bl e 51-1). Hypertens i on ma y contri bute to the pers i s tence of a nos ebl eed tha t ha s a l rea dy begun but i s unl i kel y to be the s ol e eti ol ogy.
Evaluation
History: History of present illness s houl d try to determi ne whi ch s i de bega n bl eedi ng fi rs t; a l though ma jor epi s ta xi s qui ckl y i nvol ves both na res , mos t
pa ti ents ca n l oca l i ze the i ni ti a l fl ow to one s i de, whi ch focus es the phys i ca l exa mi na ti on. Al s o, the dura ti on of bl eedi ng s houl d be es ta bl i s hed,
a s wel l a s a ny tri ggers (eg, s neezi ng, nos e bl owi ng, pi cki ng) a nd a ttempts by the pa ti ent to s top the bl eedi ng. Importa nt a s s oci a ted s ymptoms
pri or to ons et i ncl ude s ymptoms of a URI, s ens a ti on of na s a l obs tructi on, a nd na s a l or fa ci a l pa i n. The ti me a nd number of previ ous nos ebl eedi ng epi s odes a nd thei r res ol uti on s houl d be i denti fi ed.
[Table 51-1. Some Ca us es of Epi s ta xi s ]
Review of systems s houl d a s k a bout s ymptoms of exces s i ve bl eedi ng, i ncl udi ng ea s y brui s i ng; bl oody or ta rry s tool s ; hemoptys i s ; bl ood i n uri ne;
a nd exces s bl eedi ng wi th toothbrus hi ng, phl ebotomy, or mi nor tra uma .
Past medical history s houl d note pres ence of known bl eedi ng di s orders (i ncl udi ng a fa mi l y hi s tory) a nd condi ti ons a s s oci a ted wi th defects i n
pl a tel ets or coa gul a ti on, pa rti cul a rl y ca ncer, ci rrhos i s , HIV, a nd pregna ncy. Drug hi s tory s houl d s peci fi ca l l y query a bout us e of drugs tha t ma y
promote bl eedi ng, i ncl udi ng a s pi ri n a nd other NSAIDs , other a nti pl a tel et drugs (eg, cl opi dogrel ), hepa ri n, a nd wa rfa ri n.
Physical examination: Vi ta l s i gns s houl d be revi ewed for i ndi ca ti ons of i ntra va s cul a r vol ume depl eti on (ta chyca rdi a , hypotens i on) a nd ma rked
hypertens i on. Wi th a cti ve bl eedi ng, trea tment ta kes pl a ce s i mul ta neous l y wi th eva l ua ti on.
Duri ng a cti ve bl eedi ng, i ns pecti on i s di ffi cul t, s o a ttempts a re fi rs t ma de to s top the bl eedi ng a s des cri bed bel ow. The nos e i s then exa mi ned
us i ng a na s a l s pecul um a nd a bri ght hea d l a mp or hea d mi rror, whi ch l ea ves one ha nd free to ma ni pul a te s ucti on or a n i ns trument.
Anteri or bl eedi ng s i tes a re us ua l l y a ppa rent on di rect exa mi na ti on. If no s i te i s a ppa rent a nd there ha ve been onl y 1 or 2 mi nor nos ebl eeds ,
further exa mi na ti on i s not needed. If bl eedi ng i s s evere or recurrent a nd no s i te i s s een, fi beropti c endos copy ma y be neces s a ry.
The genera l exa mi na ti on s houl d l ook for s i gns of bl eedi ng di s orders , i ncl udi ng petechi a e, purpura , a nd peri ora l a nd ora l mucos a l tel a ngi ecta s i a s
a s wel l a s a ny i ntra na s a l ma s s es .
Si gns of hypovol emi a or hemorrha gi c s hock
Anti coa gul a nt drug us e
Cuta neous s i gns of a bl eedi ng di s order
Bl eedi ng not s topped by di rect pres s ure or va s ocons tri ctor-s oa ked pl edgets
Mul ti pl e recurrences , pa rti cul a rl y wi th no cl ea r ca us e
Interpretation of findings: Ma ny ca s es ha ve a cl ea r-cut tri gger (pa rti cul a rl y nos e bl owi ng or pi cki ng) a s s ugges ted by fi ndi ngs (s ee Ta bl e 51-1).
Testing: Routi ne l a bora tory tes ti ng i s not requi red. Pa ti ents wi th s ymptoms or s i gns of a bl eedi ng di s order a nd thos e wi th s evere or recurrent
epi s ta xi s s houl d ha ve CBC, PT, a nd PTT.
CT ma y be done i f a forei gn body, a tumor, or s i nus i ti s i s s us pected.
Treatment
Pres umpti ve trea tment for a cti vel y bl eedi ng pa ti ents i s tha t for a nteri or bl eedi ng. The need for bl ood repl a cement i s determi ned by the Hb l evel ,
s ymptoms of a nemi a , a nd vi ta l s i gns . Any i denti fi ed bl eedi ng di s orders a re trea ted.
Anterior epistaxis: Bl eedi ng ca n us ua l l y be control l ed by pi nchi ng the na s a l a l a e together for 10 mi n whi l e the pa ti ent s i ts upri ght (i f pos s i bl e). If
thi s ma neuver fa i l s , a cotton pl edget i mpregna ted wi th a va s ocons tri ctor (eg, phenyl ephri ne 0.25%) a nd a topi ca l a nes theti c (eg, l i doca i ne 2%) i s
i ns erted a nd the nos e pi nched for a nother 10 mi n. The bl eedi ng poi nt ma y then be ca uteri zed wi th el ectroca utery or s i l ver ni tra te on a n a ppl i ca tor
s ti ck. Ca uteri zi ng 4 qua dra nts i mmedi a tel y a dja cent to the bl eedi ng ves s el i s mos t effecti ve. Ca re mus t be ta ken to a voi d burni ng the mucous
membra ne too deepl y; therefore, s i l ver ni tra te i s the preferred method. Al terna ti vel y, a na s a l ta mpon of expa nda bl e foa m ma y be i ns erted.
Coa ti ng the ta mpon wi th a topi ca l oi ntment, s uch a s ba ci tra ci n or mupi roci n, ma y hel p. If thes e methods a re i neffecti ve, va ri ous commerci a l na s a l
ba l l oons ca n be us ed to compres s bl eedi ng s i tes . Al terna ti vel y, a n a nteri or na s a l pa ck cons i s ti ng of 1/2-i n petrol a tum ga uze ma y be i ns erted; up
to 72 i n of ga uze ma y be requi red. Thi s procedure i s pa i nful , a nd a na l ges i cs us ua l l y a re needed; i t s houl d be us ed onl y when other methods fa i l
or a re not a va i l a bl e.
Posterior epistaxis: Pos teri or bl eedi ng ma y be di ffi cul t to control . Commerci a l na s a l ba l l oons a re qui ck a nd conveni ent; a ga uze pos teri or pa ck i s
effecti ve but more di ffi cul t to pos i ti on. Both a re very uncomforta bl e; IV s eda ti on a nd a na l ges i a ma y be needed, a nd hos pi ta l i za ti on i s requi red.
Commerci a l ba l l oons a re i ns erted a ccordi ng to the i ns tructi ons a ccompa nyi ng the product.
The pos teri or ga uze pa ck cons i s ts of 4-i n ga uze s qua res fol ded, rol l ed, ti ed i nto a ti ght bundl e wi th 2 s tra nds of hea vy s i l k s uture, a nd coa ted wi th
a nti bi oti c oi ntment. The ends of one s uture a re ti ed to a ca theter tha t ha s been i ntroduced through the na s a l ca vi ty on the s i de of the bl eedi ng
a nd brought out through the mouth. As the ca theter i s wi thdra wn from the nos e, the pos tna s a l pa ck i s pul l ed i nto pl a ce a bove the s oft pa l a te i n
the na s opha rynx. The 2nd s uture ha ngs down the ba ck of the throa t a nd i s tri mmed bel ow the l evel of the s oft pa l a te s o tha t i t ca n be us ed to
remove the pa ck. The na s a l ca vi ty a nteri or to thi s pa ck i s fi rml y pa cked wi th 1/2-i n petrol a tum ga uze, a nd the 1s t s uture i s ti ed over a rol l of ga uze
a t the a nteri or na res to s ecure the pos tna s a l pa ck. The pa cki ng rema i ns i n pl a ce for 4 to 5 da ys . An a nti bi oti c (eg, a moxi ci l l i n/cl a vul a na te 875 mg
po bi d for 7 to 10 da ys ) i s gi ven to prevent s i nus i ti s a nd oti ti s medi a . Pos teri or na s a l pa cki ng l owers the a rteri a l PO2 , a nd s uppl ementa ry O2 i s
gi ven whi l e the pa cki ng i s i n pl a ce.
Ra rel y, the i nterna l ma xi l l a ry a rtery a nd i ts bra nches mus t be l i ga ted to control the bl eedi ng. The a rteri es ma y be l i ga ted wi th cl i ps us i ng
endos copi c or mi cros copi c gui da nce a nd a s urgi ca l a pproa ch through the ma xi l l a ry s i nus . Al terna ti vel y, a ngi ogra phi c embol i za ti on ma y be done by
a s ki l l ed ra di ol ogi s t.
Bleeding disorders: In Rendu-Os l er-Weber s yndrome, a s pl i t-thi cknes s s ki n gra ft (s epta l derma topl a s ty) reduces the number of nos ebl eeds a nd
a l l ows the a nemi a to be corrected. La s er (Nd:YAG) photocoa gul a ti on ca n be done i n the opera ti ng room. Sel ecti ve embol i za ti on a l s o i s very
effecti ve, pa rti cul a rl y i n pa ti ents who ca nnot tol era te genera l a nes thes i a or for whom s urgi ca l i nterventi on ha s not been s ucces s ful . New
endos copi c s i nus devi ces ha ve ma de tra ns na s a l s urgery more effecti ve.
Bl ood ma y be s wa l l owed i n l a rge a mounts a nd, i n pa ti ents wi th l i ver di s ea s e, s houl d be el i mi na ted promptl y wi th enema s a nd ca tha rti cs to
prevent hepa ti c encepha l opa thy. The GI tra ct s houl d be s teri l i zed wi th nona bs orba bl e a nti bi oti cs (eg, neomyci n 1 g po qi d) to prevent the
brea kdown of bl ood a nd the a bs orpti on of a mmoni a .
Key Points
Mos t nos ebl eeds a re a nteri or a nd s top wi th di rect pres s ure.
Screeni ng (by hi s tory a nd phys i ca l exa mi na ti on) for bl eedi ng di s orders i s i mporta nt.
Pa ti ents s houl d a l wa ys be a s ked a bout a s pi ri n or i buprofen us e.
Nasal Congestion and Rhinorrhea
Na s a l conges ti on a nd rhi norrhea (runny nos e) a re extremel y common probl ems tha t commonl y occur together but occa s i ona l l y occur a l one.
Etiology
The mos t common ca us es (s ee
Ta bl e 51-2) a re the fol l owi ng:
Vi ra l i nfecti ons
Al l ergi c rea cti ons
Dry a i r ma y provoke conges ti on. Acute s i nus i ti s i s s l i ghtl y l es s common, a nd a na s a l forei gn body i s unus ua l (a nd occurs predomi na ntl y i n
chi l dren).
Pa ti ents who us e topi ca l deconges ta nts for > 1 da y often experi ence s i gni fi ca nt rebound conges ti on when the effects of the drug wea r off, ca us i ng
them to conti nue us i ng the deconges ta nt i n a vi ci ous ci rcl e of pers i s tent, wors eni ng conges ti on. Thi s s i tua ti on (rhi ni ti s medi ca mentos a ) ma y
pers i s t for s ome ti me a nd ma y be mi s i nterpreted a s a conti nua ti on of the ori gi na l probl em ra ther tha n a cons equence of trea tment.
Evaluation
History: History of present illness s houl d determi ne the na ture of the di s cha rge (eg, wa tery, mucoi d, purul ent, bl oody) a nd whether di s cha rge i s
chroni c or recurrent. If recurrent, a ny rel a ti on to pa ti ent l oca ti on, s ea s on, or expos ure to potenti a l tri ggeri ng a l l ergens (numerous ) s houl d be
determi ned.
Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng fever a nd fa ci a l pa i n (s i nus i ti s ); wa tery, i tchy eyes (a l l ergi es ); a nd s ore
throa t, ma l a i s e, fever, a nd cough (vi ra l URI).
Past medical history s houl d s eek known a l l ergi es a nd exi s tence of di a betes or i mmunocompromi s e. Drug hi s tory s houl d a s k s peci fi ca l l y a bout
topi ca l deconges ta nt us e.
Exa mi na ti on focus es on the nos e a nd a rea over the s i nus es . The fa ce i s i ns pected for foca l erythema over the fronta l a nd ma xi l l a ry s i nus es ; thes e
a rea s a re a l s o pa l pa ted for tendernes s . Na s a l mucos a i s i ns pected for col or (eg, red or pa l e), s wel l i ng, col or a nd na ture of di s cha rge, a nd
(pa rti cul a rl y i n chi l dren) pres ence of a ny forei gn body.
Uni l a tera l di s cha rge, pa rti cul a rl y i f purul ent or bl oody
Fa ci a l pa i n, tendernes s , or both
Interpretation of findings: Symptoms a nd exa mi na ti on a re often enough to s ugges t a di a gnos i s (s ee Ta bl e 51-2).

In chi l dren, uni l a tera l foul -s mel l i ng di s cha rge s ugges ts a na s a l forei gn body. If no forei gn body i s s een, s i nus i ti s i s s us pected when purul ent
rhi norrhea pers i s ts for > 10 da ys a l ong wi th fa ti gue a nd cough.
Testing: Tes ti ng i s genera l l y not i ndi ca ted for a cute na s a l s ymptoms unl es s i nva s i ve s i nus i ti s i s s us pected i n a di a beti c or i mmunocompromi s ed
pa ti ent; thes e pa ti ents us ua l l y s houl d undergo CT.
[Table 51-2. Some Ca us es of Na s a l Conges ti on a nd Rhi norrhea ]
Treatment
Speci fi c condi ti ons a re trea ted. Symptoma ti c rel i ef of conges ti on ca n be a chi eved wi th topi ca l or ora l deconges ta nts . Topi ca l deconges ta nts
i ncl ude oxymeta zol i ne, 2 s pra ys ea ch nos tri l once/da y or bi d for 3 da ys . Ora l deconges ta nts i ncl ude ps eudoephedri ne 60 mg bi d. Prol onged us e
s houl d be a voi ded.
Vi ra l rhi norrhea ca n be trea ted wi th ora l a nti hi s ta mi nes (eg, di phenhydra mi ne 25 to 50 mg po bi d), whi ch a re recommended beca us e of thei r
a nti chol i nergi c properti es unrel a ted to thei r H 2 -bl ocki ng properti es .
Al l ergi c conges ti on a nd rhi norrhea ca n be trea ted wi th a nti hi s ta mi nes ; i n s uch ca s es , nona nti chol i nergi c a nti hi s ta mi nes (eg, fexofena di ne 60 mg
po bi d) a s needed provoke fewer a dvers e effects . Na s a l corti cos teroi ds (eg, mometa s one 2 s pra ys ea ch nos tri l da i l y) a l s o hel p a l l ergi c condi ti ons .
Anti hi s ta mi nes a nd deconges ta nts a re not recommended for chi l dren < 6 yr.
Anti hi s ta mi nes a nd ca n ha ve s eda ti ng a nd a nti chol i nergi c effects a nd s houl d be gi ven i n decrea s ed dos a ge i n the el derl y. Si mi l a rl y,
s ympa thomi meti cs s houl d be us ed wi th the l owes t dos a ge tha t i s cl i ni ca l l y effecti ve.
Key Points
Mos t na s a l conges ti on a nd rhi norrhea a re ca us ed by URI or a l l ergi es .
A forei gn body s houl d be cons i dered i n chi l dren.
Rebound from topi ca l deconges ta nt overus e s houl d a l s o be cons i dered.
Neck Mass
Pa ti ents or thei r fa mi l y members ma y noti ce a ma s s on the neck, or one ma y be di s covered duri ng routi ne exa mi na ti on. A neck ma s s ma y be
pa i nl es s or pa i nful dependi ng on the ca us e. When a neck ma s s i s pa i nl es s , much ti me ma y pa s s before pa ti ents s eek medi ca l ca re.
Etiology
There a re ma ny ca us es of neck ma s s , i ncl udi ng i nfecti ous , ca ncerous , a nd congeni ta l ca us es (s ee
Ta bl e 51-3).
The mos t common ca us es i n younger pa ti ents i ncl ude the fol l owi ng:
Rea cti ve a deni ti s
Pri ma ry ba cteri a l l ymph node i nfecti on
Sys temi c i nfecti ons
[Table 51-3. Some Ca us es of Neck Ma s s ]
Rea cti ve a deni ti s occurs i n res pons e to vi ra l or ba cteri a l i nfecti on s omewhere i n the oropha rynx. Some s ys temi c i nfecti ons (eg, mononucl eos i s ,
HIV, TB) ca us e cervi ca l l ymph node enl a rgementus ua l l y genera l i zed ra ther tha n i s ol a ted.
Congeni ta l di s orders ma y ca us e a neck ma s s , typi ca l l y l ongs ta ndi ng. The mos t common a re thyrogl os s a l duct cys ts , bra nchi a l cl eft cys ts , a nd
dermoi d or s eba ceous cys ts .
Ca ncerous ma s s es a re more common a mong ol der pa ti ents but ma y occur i n younger ones . Thes e ma s s es ma y repres ent a l oca l pri ma ry tumor or
l ymph node i nvol vement from a l oca l , regi ona l , or di s ta nt pri ma ry ca ncer. About 60% of s upra cl a vi cul a r tri a ngl e ma s s es a re meta s ta s es from
di s ta nt pri ma ry s i tes . El s ewhere i n the neck, 80% of ca ncerous cervi ca l a denopa thy ori gi na tes i n the upper res pi ra tory or a l i menta ry tra ct. Li kel y
s i tes of ori gi n a re the pos teri or-l a tera l border of the tongue a nd the fl oor of the mouth fol l owed by the na s opha rynx, pa l a ti ne tons i l , l a ryngea l
s urfa ce of the epi gl otti s , a nd hypopha rynx, i ncl udi ng the pyri form s i nus es .
The thyroi d gl a nd ma y enl a rge i n va ri ous di s orders , i ncl udi ng s i mpl e nontoxi c goi ter, s uba cute thyroi di ti s , a nd, l es s often, thyroi d ca ncer.
Evaluation
History: History of present illness s houl d note how l ong the ma s s ha s been pres ent a nd whether i t i s pa i nful . Importa nt a s s oci a ted a cute s ymptoms
i ncl ude s ore throa t, URI s ymptoms , a nd tootha che.
Review of systems s houl d a s k a bout di ffi cul ty s wa l l owi ng or s pea ki ng a nd s ymptoms of chroni c di s ea s e (eg, fever, wei ght l os s , ma l a i s e). Regi ona l
a nd di s ta nt ca ncers ca us i ng meta s ta s es to the neck occa s i ona l l y ca us e s ymptoms i n thei r s ys tem of ori gi n (eg, cough i n l ung ca ncer, s wa l l owi ng
di ffi cul ty i n es opha gea l ca ncer). Beca us e numerous ca ncers ca n meta s ta s i ze to the neck, a compl ete revi ew of s ys tems i s i mporta nt to hel p
i denti fy a s ource.
Past medical history s houl d i nqui re a bout known HIV or TB a nd ri s k fa ctors for them. Ri s k fa ctors for ca ncer a re a s s es s ed, i ncl udi ng cons umpti on of
a l cohol or us e of toba cco (pa rti cul a rl y s nuff or chewi ng toba cco), i l l -fi tti ng denta l a ppl i a nces , a nd chroni c ora l ca ndi di a s i s . Poor ora l hygi ene a l s o
ma y be a ri s k.
Physical examination: The neck ma s s i s pa l pa ted to determi ne cons i s tency (i e, whether s oft a nd fl uctua nt, rubbery, or ha rd) a nd pres ence a nd
degree of tendernes s . Whether the ma s s i s freel y mobi l e or a ppea rs fi xed to the s ki n or underl yi ng ti s s ue a l s o needs to be determi ned.
The s ca l p, ea rs , na s a l ca vi ti es , ora l ca vi ty, na s opha rynx, oropha rynx, hypopha rynx, a nd l a rynx a re cl os el y i ns pected for s i gns of i nfecti on a nd a ny
other vi s i bl e l es i ons . Teeth a re percus s ed to detect the exqui s i te tendernes s of root i nfecti on. The ba s e of the tongue, fl oor of the mouth, a nd the
thyroi d a nd s a l i va ry gl a nds a re pa l pa ted for ma s s es .
The brea s ts a nd pros ta te gl a nd a re pa l pa ted for ma s s es , a nd the s pl een i s pa l pa ted for enl a rgement. Stool i s checked for occul t bl ood, s ugges ti ve
of a GI ca ncer.
Other l ymph nodes a re pa l pa ted (eg, a xi l l a ry, i ngui na l ).
Ha rd, fi xed ma s s
Ol der pa ti ent
Pres ence of oropha ryngea l l es i ons (other tha n s i mpl e pha ryngi ti s or denta l i nfecti on)
A hi s tory of pers i s tent hoa rs enes s or dys pha gi a
Interpretation of findings: Importa nt di fferenti a ti ng fa ctors for a neck ma s s (s ee a l s o Ta bl e 51-3) i ncl ude a cui ty, pa i n a nd tendernes s , a nd
cons i s tency a nd mobi l i ty.
A new ma s s (i e, devel opi ng over onl y a few da ys ), pa rti cul a rl y a fter s ymptoms of a URI or pha ryngi ti s , s ugges ts beni gn rea cti ve l ympha denopa thy.
An a cute tender ma s s s ugges ts l ympha deni ti s or a n i nfected dermoi d cys t.
A chroni c ma s s i n younger pa ti ents s ugges ts a cys t. A non-mi dl i ne ma s s i n ol der pa ti ents , pa rti cul a rl y thos e wi th ri s k fa ctors , s houl d be
cons i dered ca ncer unti l proven otherwi s e; a mi dl i ne ma s s i s l i kel y of thyroi d ori gi n (beni gn or ma l i gna nt).
Pa i n, tendernes s , or both i n the ma s s s ugges t i nfl a mma ti on (pa rti cul a rl y i nfecti ous ), wherea s a pa i nl es s ma s s s ugges ts a cys t or tumor. A ha rd,
fi xed, nontender ma s s s ugges ts ca ncer, wherea s rubbery cons i s tency a nd mobi l i ty s ugges t otherwi s e.
Genera l i zed a denopa thy a nd s pl enomega l y s ugges t i nfecti ous mononucl eos i s or a l ymphoreti cul a r ca ncer. Genera l i zed a denopa thy a l one ma y
s ugges t HIV i nfecti on, pa rti cul a rl y i n thos e wi th ri s k fa ctors .
Red a nd whi te mucos a l pa tches (erythropl a ki a a nd l eukopl a ki a ) i n the oropha rynx ma y be ma l i gna nt l es i ons res pons i bl e for the neck ma s s .
Di ffi cul ty s wa l l owi ng ma y be noted wi th thyroi d enl a rgement or ca ncer ori gi na ti ng i n va ri ous s i tes i n the neck. Di ffi cul ty s pea ki ng s ugges ts a
ca ncer i nvol vi ng the l a rynx or recurrent l a ryngea l nerve.
Testing: If the na ture of the ma s s i s rea di l y a ppa rent (eg, l ympha denopa thy ca us ed by recent pha ryngi ti s ) or i s i n a hea l thy young pa ti ent wi th a
recent, tender s wel l i ng a nd no other fi ndi ngs , then no i mmedi a te tes ti ng i s requi red. However, the pa ti ent i s reexa mi ned regul a rl y; i f the ma s s
fa i l s to res ol ve, further eva l ua ti on i s needed.
Mos t other pa ti ents s houl d ha ve a CBC a nd ches t x-ra y. Thos e wi th fi ndi ngs s ugges ti ng s peci fi c ca us es s houl d a l s o ha ve tes ti ng for thos e
di s orders (s ee Ta bl e 51-3).
If exa mi na ti on revea l s a n ora l or na s opha ryngea l l es i on tha t fa i l s to begi n res ol vi ng wi thi n 2 wk, tes ti ng ma y i ncl ude CT or MRI a nd fi ne-needl e
bi ops y of tha t l es i on.
In young pa ti ents wi th no ri s k fa ctors for hea d a nd neck ca ncer a nd no other a ppa rent l es i ons , the neck ma s s ma y be bi ops i ed.
Ol der pa ti ents , pa rti cul a rl y thos e wi th ri s k fa ctors for ca ncer, s houl d fi rs t undergo further tes ti ng to i denti fy the pri ma ry s i te; bi ops y of the neck
ma s s ma y s i mpl y revea l undi fferenti a ted s qua mous cel l ca rci noma wi thout i l l umi na ti ng the s ource. Such pa ti ents s houl d ha ve di rect
l a ryngos copy, bronchos copy, a nd es opha gos copy wi th bi ops y of a l l s us pi ci ous a rea s . CT of the hea d, neck, a nd ches t a nd pos s i bl y a thyroi d s ca n
a re done. If a pri ma ry tumor i s not found, fi ne-needl e a s pi ra ti on bi ops y of the neck ma s s s houl d be done, whi ch i s prefera bl e to a n i nci s i ona l
bi ops y beca us e i t does not l ea ve a tra ns ected ma s s i n the neck. If the neck ma s s i s ca ncerous a nd a pri ma ry tumor ha s not been i denti fi ed,
ra ndom bi ops y of the na s opha rynx, pa l a ti ne tons i l s , a nd ba s e of the tongue s houl d be cons i dered.
Treatment
Trea tment i s di rected a t the ca us e.

Key Points
An a cute neck ma s s i n younger pa ti ents i s us ua l l y beni gn.
Neck ma s s i n a n el derl y pa ti ent ra i s es concern of ca ncer.
Thorough oropha ryngea l exa mi na ti on i s i mporta nt.
Pharyngitis
Pharyngitis (sore throat) is pain in the posterior pharynx that occurs with or without swallowing. Pain can be severe; many patients refuse oral intake.
Etiology
Sore throa t res ul ts from i nfecti on; the mos t common ca us e i s
Tons i l l opha ryngi ti s
Ra rel y, a n a bs ces s or epi gl otti ti s i s i nvol ved; a l though uncommon, thes e a re of pa rti cul a r concern beca us e they ma y compromi s e the a i rwa y.
Tonsillopharyngitis: Tons i l l opha ryngi ti s i s predomi na ntl y a vi ra l i nfecti on; a l es s er number of ca s es a re ca us ed by ba cteri a .
The res pi ra tory vi rus es (rhi novi rus , a denovi rus , i nfl uenza , corona vi rus , res pi ra tory s yncyti a l vi rus ) a re the mos t common vi ra l ca us es , but
occa s i ona l l y Eps tei n-Ba rr vi rus (the ca us e of mononucl eos i s ), herpes s i mpl ex, cytomega l ovi rus , or pri ma ry HIV i nfecti on i s i nvol ved.
The ma i n ba cteri a l ca us e i s group A -hemol yti c s treptococcus (GABHS), whi ch, a l though es ti ma tes va ry, ca us es perha ps 10% of ca s es i n a dul ts a nd
s l i ghtl y more i n chi l dren. GABHS i s a concern beca us e of the pos s i bi l i ty of the pos ts treptococca l s equel a e of rheuma ti c fever, gl omerul onephri ti s ,
a nd a bs ces s . Uncommon ba cteri a l ca us es i ncl ude gonorrhea , di phtheri a , mycopl a s ma , a nd chl a mydi a .
Abscess: An a bs ces s i n the pha ryngea l a rea (peri tons i l l a r, pa ra pha ryngea l , a nd, i n chi l dren, retropha ryngea l ) i s uncommon but ca us es s i gni fi ca nt
throa t pa i n. The us ua l ca us a ti ve orga ni s m i s GABHS.
Epiglottitis: Epi gl otti ti s , perha ps better termed s upra gl otti ti s , us ed to occur pri ma ri l y i n chi l dren a nd us ua l l y wa s ca us ed by Haemophilus influenzae
type B (Hi B). Now, beca us e of wi des prea d chi l dhood va cci na ti on a ga i ns t Hi B, s upra gl otti ti s /epi gl otti ti s ha s been a l mos t era di ca ted i n chi l dren
(more ca s es occur i n a dul ts ). Ca us a l orga ni s ms i n chi l dren a nd a dul ts i ncl ude Streptococcus pneumoniae, Staphylococcus aureus, nontypea bl e H.
influenzae, Haemophilus parainfluenzae, -hemol yti c s treptococci , Branhamella catarrhalis, a nd Klebsiella pneumoniae. Hi B i s s ti l l a ca us e i n a dul ts a nd
unva cci na ted chi l dren.
Evaluation
History: History of present illness s houl d note the dura ti on a nd s everi ty of s ore throa t.
Review of systems s houl d s eek i mporta nt a s s oci a ted s ymptoms , s uch a s runny nos e, cough, a nd di ffi cul ty s wa l l owi ng, s pea ki ng, or brea thi ng. The
pres ence a nd dura ti on of a ny precedi ng wea knes s a nd ma l a i s e (s ugges ti ng mononucl eos i s ) a re noted.
Past medical history s houl d s eek hi s tory of previ ous documented mononucl eos i s (recurrence i s hi ghl y unl i kel y). Soci a l hi s tory s houl d i nqui re a bout
cl os e conta ct wi th peopl e wi th documented GABHS i nfecti on, ri s k fa ctors for gonorrhea tra ns mi s s i on (eg, recent ora l -geni ta l s exua l conta ct), a nd
ri s k fa ctors for HIV a cqui s i ti on (eg, unprotected i ntercours e, mul ti pl e s ex pa rtners , IV drug a bus e).
Physical examination: Genera l exa mi na ti on s houl d note fever a nd s i gns of res pi ra tory di s tres s , s uch a s ta chypnea , dys pnea , s tri dor, a nd, i n chi l dren,
the tri pod pos i ti on (s i tti ng upri ght, l ea ni ng forwa rd wi th neck hyperextended a nd ja w thrus t forwa rd).
Pha ryngea l exa mi na ti on s houl d not be done i n chi l dren i f s upra gl otti ti s /epi gl otti ti s i s s us pected, beca us e i t ma y tri gger compl ete a i rwa y
obs tructi on. Adul ts wi th no res pi ra tory di s tres s ma y be exa mi ned but wi th ca re. Erythema , exuda tes , a nd a ny s i gns of s wel l i ng a round the tons i l s
or retropha ryngea l a rea s houl d be noted. Whether the uvul a i s i n the mi dl i ne or a ppea rs pus hed to one s i de s houl d a l s o be noted.
The neck i s exa mi ned for pres ence of enl a rged, tender l ymph nodes . The a bdomen i s pa l pa ted for pres ence of s pl enomega l y.
Stri dor or other s i gn of res pi ra tory di s tres s
Drool i ng
Muffl ed, "hot pota to" voi ce
Vi s i bl e bul ge i n pha rynx
Interpretation of findings: Supra gl otti ti s /epi gl otti ti s a nd pha ryngea l a bs ces s pos e a threa t to the a i rwa y a nd mus t be di fferenti a ted from s i mpl e
tons i l l opha ryngi ti s , whi ch i s uncomforta bl e but not a cutel y da ngerous . Cl i ni ca l fi ndi ngs hel p ma ke thi s di s ti ncti on.
Wi th s upra gl otti ti s /epi gl otti ti s , there i s a brupt ons et of s evere throa t pa i n a nd dys pha gi a , us ua l l y wi th no precedi ng URI s ymptoms . Chi l dren
often ha ve drool i ng a nd s i gns of toxi ci ty. Someti mes (more often i n chi l dren), there a re res pi ra tory ma ni fes ta ti ons , wi th ta chypnea , dys pnea ,
s tri dor, a nd s i tti ng i n the tri pod pos i ti on. If exa mi ned, the pha rynx a l mos t a l wa ys a ppea rs unrema rka bl e.
Pha ryngea l a bs ces s a nd tons i l l opha ryngi ti s both ma y ca us e pha ryngea l erythema , exuda te, or both. However, s ome fi ndi ngs a re more l i kel y i n one
condi ti on or a nother:
Pha ryngea l a bs ces s : Muffl ed, "hot pota to" voi ce (s pea ki ng a s i f a hot object i s bei ng hel d i n the mouth); vi s i bl e foca l s wel l i ng i n the pos teri or
pha ryngea l a rea (often wi th devi a ti on of the uvul a )
Tons i l l opha ryngi ti s : Accompa ni ed by URI s ymptoms (eg, runny nos e, cough)
Al though tons i l l opha ryngi ti s i s ea s i l y recogni zed cl i ni ca l l y, i ts ca us e i s not. Ma ni fes ta ti ons of vi ra l a nd GABHS i nfecti on overl a p s i gni fi ca ntl y,
a l though URI s ymptoms a re more common wi th a vi ra l ca us e. In a dul ts , cl i ni ca l cri teri a tha t i ncrea s e s us pi ci on of GABHS a s a ca us e i ncl ude
Tons i l l a r exuda te
Tender l ympha denopa thy
Fever (i ncl udi ng hi s tory)
Abs ence of cough
Thos e wi th 1 cri teri on rea s ona bl y ma y be pres umed to ha ve vi ra l i l l nes s . If 2 cri teri a a re pres ent, the l i kel i hood of GABHS i s hi gh enough to
wa rra nt tes ti ng but proba bl y not hi gh enough to wa rra nt a nti bi oti cs , but thi s deci s i on needs to be pa ti ent-s peci fi c (i e, thres hol d for tes ti ng a nd
trea tment ma y be l ower i n thos e a t ri s k beca us e of di a betes or i mmunocompromi s e). In chi l dren, tes ti ng us ua l l y i s done.
Rega rdi ng ra rer ca us es of tons i l l opha ryngi ti s , i nfecti ous mononucl eos i s s houl d be cons i dered when there i s pos teri or cervi ca l or genera l i zed
a denopa thy, hepa tos pl enomega l y, a nd fa ti gue a nd ma l a i s e for > 1 wk. Thos e wi th no URI s ymptoms but recent ora l -geni ta l conta ct ma y ha ve
pha ryngea l gonorrhea . A di rty-gra y, thi ck, tough membra ne on the pos teri or pha rynx tha t bl eeds i f peel ed a wa y i ndi ca tes di phtheri a (ra re i n the
US). HIV i nfecti on s houl d be cons i dered i n pa ti ents wi th ri s k fa ctors .
Testing: If s upra gl otti ti s /epi gl otti ti s i s cons i dered pos s i bl e a fter eva l ua ti on, tes ti ng i s requi red. Pa ti ents who do not a ppea r s eri ous l y i l l a nd ha ve
no res pi ra tory s ymptoms ma y ha ve pl a i n l a tera l neck x-ra ys to l ook for a n edema tous epi gl otti s . However, a chi l d who a ppea rs s eri ous l y i l l or ha s
s tri dor or a ny other res pi ra tory s ymptoms s houl d not be tra ns ported to the x-ra y s ui te. Such pa ti ents (a nd thos e wi th pos i ti ve or equi voca l x-ra y
fi ndi ngs ) us ua l l y s houl d ha ve fl exi bl e fi beropti c l a ryngos copy. (CAUTION: Examination of the pharynx and larynx may precipitate complete respiratory
obstruction in children, and the pharynx and larynx should not be directly examined except in the operating room, where the most advanced airway intervention is
available.)
Ma ny a bs ces s es a re ma na ged cl i ni ca l l y, but i f l oca ti on a nd extent a re uncl ea r, i mmedi a te CT of the neck s houl d be done.
In tons i l l opha ryngi ti s , throa t cul ture i s the onl y rel i a bl e wa y to di fferenti a te vi ra l i nfecti on from GABHS. To ba l a nce ti mel i nes s of di a gnos i s , cos t,
a nd a ccura cy, one s tra tegy i n chi l dren i s to do a ra pi d s trep s creen i n the offi ce, trea t i f pos i ti ve, a nd s end a forma l cul ture i f nega ti ve. In a dul ts ,
beca us e other ba cteri a l pa thogens ma y be i nvol ved, throa t cul ture for a l l ba cteri a l pa thogens i s a ppropri a te for thos e meeti ng cl i ni ca l cri teri a
des cri bed previ ous l y.
Tes ti ng for mononucl eos i s , gonorrhea , or HIV i s done onl y when cl i ni ca l l y s us pected.
Treatment
Speci fi c condi ti ons a re trea ted. Thos e wi th s evere s ymptoms of tons i l l opha ryngi ti s ma y be s ta rted on a broa d-s pectrum a nti bi oti c (eg,
a moxi ci l l i n/cl a vul a na te) pendi ng cul ture res ul ts .
Symptoma ti c trea tments s uch a s wa rm s a l twa ter ga rgl es a nd topi ca l a nes theti cs (eg, benzoca i ne, l i doca i ne, dycl oni ne) ma y hel p tempora ri l y
rel i eve pa i n i n tons i l l opha ryngi ti s . Pa ti ents i n s evere pa i n (even from tons i l l opha ryngi ti s ) ma y requi re s hort-term us e of opi oi ds .
Key Points
Mos t s ore throa ts a re ca us ed by vi ra l tons i l l opha ryngi ti s .
It i s di ffi cul t to cl i ni ca l l y di s ti ngui s h vi ra l from ba cteri a l ca us es of tons i l l opha ryngi ti s .
Abs ces s a nd epi gl otti ti s a re ra re but s eri ous ca us es .
Severe s ore throa t i n a pa ti ent wi th a norma l -a ppea ri ng pha rynx s houl d ra i s e s us pi ci on of epi gl otti ti s .
Smell and Taste Abnormalities
Beca us e di s ti nct fl a vors depend on a roma s to s ti mul a te the ol fa ctory chemoreceptors , s mel l a nd ta s te a re phys i ol ogi ca l l y i nterdependent.
Dys functi on of one often di s turbs the other. Di s orders of s mel l a nd ta s te a re ra rel y i nca pa ci ta ti ng or l i fe threa teni ng, s o they often do not recei ve
cl os e medi ca l a ttenti on, a l though thei r effect on qua l i ty of l i fe ca n be s evere.
Taste: Al though a bnorma l ta s te s ens a ti ons ma y be due to menta l di s orders , l oca l ca us es s houl d a l wa ys be s ought. Gl os s opha ryngea l a nd fa ci a l
nerve i ntegri ty ca n be determi ned by tes ti ng ta s te on both s i des of the dors um of the tongue wi th s uga r, s a l t, vi nega r (a ci d), a nd qui ni ne (bi tter).
Dryi ng of the ora l mucos a ca us ed by hea vy s moki ng, Sjogren's s yndrome, ra di a ti on thera py of the hea d a nd neck, or des qua ma ti on of the tongue
ca n i mpa i r ta s te, a nd va ri ous drugs (eg, thos e wi th a nti chol i nergi c properti es a nd vi ncri s ti ne) a l ter ta s te. In a l l i ns ta nces , the gus ta tory receptors
a re di ffus el y i nvol ved. When l i mi ted to one s i de of the tongue (eg, i n Bel l 's pa l s y), a geus i a (l os s of the s ens e of ta s te) i s ra rel y noti ced.
Smell: The i na bi l i ty to detect certa i n odors , s uch a s ga s or s moke, ma y be da ngerous , a nd s evera l s ys temi c a nd i ntra cra ni a l di s orders s houl d be
excl uded before di s mi s s i ng s ymptoms a s ha rml es s . Whether bra i n s tem di s ea s e (i nvol vement of the nucl eus s ol i ta ri us ) ca n ca us e di s orders of
s mel l a nd ta s te i s uncerta i n, beca us e other neurol ogi c ma ni fes ta ti ons us ua l l y ta ke precedence.
Anos mi a (l os s of the s ens e of s mel l ) i s proba bl y the mos t common a bnorma l i ty. Hyperos mi a (i ncrea s ed s ens i ti vi ty to odors ) us ua l l y refl ects a
neuroti c or hi s tri oni c pers ona l i ty but ca n occur i ntermi ttentl y wi th s ei zure di s orders . Dys os mi a (di s a greea bl e or di s torted s ens e of s mel l ) ma y
occur wi th i nfecti on of the na s a l s i nus es , pa rti a l da ma ge to the ol fa ctory bul bs , or menta l depres s i on. Some ca s es , a ccompa ni ed by a
di s a greea bl e ta s te, res ul t from poor denta l hygi ene. Unci na te epi l eps y ca n produce bri ef, vi vi d, unpl ea s a nt ol fa ctory ha l l uci na ti ons . Hypos mi a
(di mi ni s hed s ens e of s mel l ) a nd hypogeus i a (di mi ni s hed s ens e of ta s te) ca n fol l ow a cute i nfl uenza , us ua l l y tempora ri l y.
Ra rel y, i di opa thi c dys geus i a (di s torted s ens e of ta s te), hypogeus i a , a nd dys os mi a res pond to zi nc s uppl ementa ti on.
Anosmia
Anos mi a i s compl ete l os s of s mel l . Hypos mi a i s pa rti a l l os s of s mel l . Mos t pa ti ents wi th a nos mi a ha ve norma l percepti on of s a l ty, s weet, s our,
a nd bi tter s ubs ta nces but l a ck fl a vor di s cri mi na ti on, whi ch l a rgel y depends on ol fa cti on. Therefore, they often compl a i n of l os i ng the s ens e of
ta s te (a geus i a ) a nd of not enjoyi ng food. If uni l a tera l , a nos mi a i s often unrecogni zed.
Etiology
Anos mi a occurs when i ntra na s a l s wel l i ng or other obs tructi on prevents odors from ga i ni ng a cces s to the ol fa ctory a rea ; when the ol fa ctory
neuroepi thel i um i s des troyed; or when the ol fa ctory nerve fi l a , bul bs , tra cts , or centra l connecti ons a re des troyed (s ee
Ta bl e 51-4).
Ma jor ca us es i ncl ude
Hea d tra uma (young a dul ts )
Vi ra l i nfecti ons a nd Al zhei mer's di s ea s e (ol der a dul ts )
[Table 51-4. Some Ca us es of Anos mi a ]
Pri or URI, es peci a l l y i nfl uenza i nfecti on, i s i mpl i ca ted i n 14 to 26% of a l l pres enti ng ca s es of hypos mi a or a nos mi a .
Drugs ca n contri bute to a nos mi a i n s us cepti bl e pa ti ents . Other ca us es i ncl ude pri or hea d a nd neck ra di a ti on, recent na s a l or s i nus s urgery, na s a l
a nd bra i n tumors , a nd toxi ns . The rol e of toba cco i s uncerta i n.
Evaluation
History: History of present illness s houl d a s s es s the ti me cours e of s ymptoms a nd thei r rel a ti on to a ny URI or hea d i njury. Importa nt a s s oci a ted
s ymptoms a re na s a l conges ti on, rhi norrhea , or both. The na ture of rhi norrhea s houl d be a s s es s ed (eg, wa tery, mucoi d, purul ent, bl oody).
Review of systems s houl d a s s es s neurol ogi c s ymptoms , pa rti cul a rl y thos e i nvol vi ng menta l s ta tus (eg, di ffi cul ty wi th recent memory) a nd cra ni a l
nerves (eg, di pl opi a , di ffi cul ty s pea ki ng or s wa l l owi ng, ti nni tus , verti go).
Past medical history s houl d i ncl ude hi s tory of s i nus di s orders , cra ni a l tra uma or s urgery, a l l ergi es , drugs us ed, a nd expos ure to chemi ca l s or fumes .
Physical examination: The na s a l pa s s a ges s houl d be i ns pected for s wel l i ng, i nfl a mma ti on, di s cha rge, a nd pol yps . Ha vi ng the pa ti ent brea the
through ea ch nos tri l s equenti a l l y (whi l e the other i s ma nua l l y occl uded) ma y hel p i denti fy obs tructi on.
A compl ete neurol ogi c exa mi na ti on, pa rti cul a rl y of menta l s ta tus a nd cra ni a l nerves , i s done.
Previ ous hea d i njury
Neurol ogi c s ymptoms or s i gns
Sudden ons et
Interpretation of findings: Sudden ons et a fter s i gni fi ca nt hea d tra uma or toxi n expos ure s trongl y i mpl i ca tes tha t event a s the ca us e.
A hi s tory of chroni c rhi nos i nus i ti s i s s ugges ti ve, pa rti cul a rl y when s i gni fi ca nt conges ti on, pol yps , or both a re vi s i bl e on exa mi na ti on. However,
beca us e thes e fi ndi ngs a re common i n the popul a ti on, the phys i ci a n s houl d be wa ry of mi s s i ng a nother di s order. Progres s i ve confus i on a nd
recent memory l os s i n a n el derl y pa ti ent s ugges t Al zhei mer's di s ea s e a s a ca us e. Wa xi ng a nd wa ni ng neurol ogi c s ymptoms a ffecti ng mul ti pl e
a rea s s ugges t a neurodegenera ti ve di s ea s e s uch a s mul ti pl e s cl eros i s . Sl owl y progres s i ve a nos mi a i n a n el derl y pa ti ent wi th no other s ymptoms
or fi ndi ngs s ugges ts norma l a gi ng a s the ca us e.
Testing: An i n-offi ce tes t of ol fa cti on ca n hel p confi rm ol fa ctory dys functi on. Commonl y, one nos tri l i s pres s ed s hut, a nd a pungent odor s uch a s
from a vi a l conta i ni ng coffee, ci nna mon, or toba cco i s pl a ced under the open nos tri l ; i f the pa ti ent ca n i denti fy the s ubs ta nce, ol fa cti on i s
pres umed i nta ct. The tes t i s repea ted on the other nos tri l to determi ne whether the res pons e i s bi l a tera l . Unfortuna tel y, the tes t i s crude a nd
unrel i a bl e.
If a nos mi a i s pres ent a nd no ca us e i s rea di l y a ppa rent on cl i ni ca l eva l ua ti on (s ee Ta bl e 51-4), pa ti ents s houl d ha ve CT of the hea d (i ncl udi ng
s i nus es ) wi th contra s t to rul e out a tumor or uns us pected fra cture of the fl oor of the a nteri or cra ni a l fos s a . MRI i s a l s o us ed to eva l ua te
i ntra cra ni a l di s ea s e a nd ma y be needed a s wel l , pa rti cul a rl y i n thos e pa ti ents wi th no na s a l or s i nus pa thol ogy on CT.
A ps ychophys i ca l a s s es s ment of odor a nd ta s te i denti fi ca ti on a nd thres hol d detecti on i s done a s wel l . Thi s a s s es s ment commonl y i nvol ves us e of
one or s evera l commerci a l l y a va i l a bl e tes ti ng ki ts . One ki t us es a s cra tch-a nd-s ni ff ba ttery of odors , wherea s a nother ki t i nvol ves s equenti a l
di l uti ons of a n odorous chemi ca l .
Treatment
Speci fi c ca us es a re trea ted, a l though s mel l does not a l wa ys recover even a fter s ucces s ful trea tment of s i nus i ti s .
There a re no trea tments for a nos mi a . Pa ti ents who reta i n s ome s ens e of s mel l ma y fi nd a ddi ng concentra ted fl a vori ng a gents to food i mproves
thei r enjoyment of ea ti ng. Smoke a l a rms , i mporta nt i n a l l homes , a re even more es s enti a l for pa ti ents wi th a nos mi a . Pa ti ents s houl d be
ca uti oned a bout cons umpti on of s tored food a nd us e of na tura l ga s for cooki ng or hea ti ng, beca us e they ha ve di ffi cul ty detecti ng food s poi l a ge or
ga s l ea ks .
There i s a s i gni fi ca nt l os s of ol fa ctory receptor neurons wi th norma l a gi ng, l ea di ng to a ma rked di mi nuti on of the s ens e of s mel l . Cha nges a re
us ua l l y noti cea bl e by a ge 60 a nd ca n be ma rked a fter a ge 70.
Key Points
Anos mi a ma y be pa rt of norma l a gi ng.
Common ca us es i ncl ude URI, s i nus i ti s , a nd hea d tra uma .
Cra ni a l i ma gi ng i s typi ca l l y requi red unl es s the ca us e i s obvi ous .
Chapter 52. Oral and Pharyngeal Disorders

Introduction
Ora l a nd pha ryngea l di s orders i ncl ude a denoi d di s orders , epi gl otti ti s , pa ra pha ryngea l a bs ces s , peri tons i l l a r a bs ces s a nd cel l ul i ti s ,
retropha ryngea l a bs ces s , s a l i va ry s tones , s i a l a deni ti s , s ubma ndi bul a r s pa ce i nfecti on, tons i l l opha ryngi ti s , Tornwa l dt's cys t, a nd vel opha ryngea l
i ns uffi ci ency. Ora l , pha ryngea l , a nd s a l i va ry gl a nd tumors a re di s cus s ed i n Ch. 55.
Sialadenitis
Sialadenitis is bacterial infection of a salivary gland, usually due to an obstructing stone or gland hyposecretion. Symptoms are swelling, pain, redness, and
tenderness. Diagnosis is clinical. CT, ultrasound, and MRI may help identify the cause. Treatment is with antibiotics.
Etiology
Si a l a deni ti s us ua l l y occurs a fter hypos ecreti on or duct obs tructi on but ma y devel op wi thout a n obvi ous ca us e. The ma jor s a l i va ry gl a nds a re the
pa roti d, s ubma ndi bul a r, a nd s ubl i ngua l gl a nds . Si a l a deni ti s i s mos t common i n the pa roti d gl a nd a nd typi ca l l y occurs i n pa ti ents i n thei r 50s a nd
60s , i n chroni ca l l y i l l pa ti ents wi th xeros tomi a , i n thos e wi th Sjogren's s yndrome, a nd i n thos e who ha ve ha d ra di a ti on thera py to the ora l ca vi ty.
Teena gers a nd young a dul ts wi th a norexi a a re a l s o prone to thi s di s order. The mos t common ca us a ti ve orga ni s m i s Staphylococcus aureus; others
i ncl ude s treptococci , col i forms , a nd va ri ous a na erobi c ba cteri a .
Symptoms and Signs
Fever, chi l l s , a nd uni l a tera l pa i n a nd s wel l i ng devel op. The gl a nd i s fi rm a nd di ffus el y tender, wi th erythema a nd edema of the overl yi ng s ki n. Pus
ca n often be expres s ed from the duct by compres s i ng the a ffected gl a nd a nd s houl d be cul tured. Foca l enl a rgement ma y i ndi ca te a n a bs ces s .
Diagnosis
CT, ul tra s ound, a nd MRI ca n confi rm s i a l a deni ti s or a bs ces s tha t i s not obvi ous cl i ni ca l l y, a l though MRI ma y mi s s a n obs tructi ng s tone.
Treatment
Anti s ta phyl ococca l a nti bi oti cs
Loca l mea s ures (eg, s i a l a gogues , wa rm compres s es )
Ini ti a l trea tment i s wi th a nti bi oti cs a cti ve a ga i ns t S. aureus (eg, di cl oxa ci l l i n, 250 mg po qi d, a 1s t-genera ti on cepha l os pori n, or cl i nda myci n),
modi fi ed a ccordi ng to cul ture res ul ts . Wi th the i ncrea s i ng preva l ence of methi ci l l i n-res i s ta nt S. aureus, es peci a l l y a mong the el derl y l i vi ng i n
extended-ca re nurs i ng fa ci l i ti es , va ncomyci n i s often requi red. Hydra ti on, s i a l a gogues (eg, l emon jui ce, ha rd ca ndy, or s ome other s ubs ta nce tha t
tri ggers s a l i va fl ow), wa rm compres s es , gl a nd ma s s a ge, a nd good ora l hygi ene a re a l s o i mporta nt. Abs ces s es requi re dra i na ge. Occa s i ona l l y, a
s uperfi ci a l pa roti dectomy or s ubma ndi bul a r gl a nd exci s i on i s i ndi ca ted for pa ti ents wi th chroni c or rel a ps i ng s i a l a deni ti s .
Other Salivary Gland Infections
Mumps often ca us e pa roti d s wel l i ng (s ee
Ta bl e 155-1 on p. 1462). Pa ti ents wi th HIV i nfecti on often ha ve pa roti d enl a rgement s econda ry to one or more l ymphoepi thel i a l cys ts . Ca t-s cra tch
di s ea s e ca us ed by Bartonella i nfecti on often i nva des peri pa roti d l ymph nodes a nd ma y i nfect the pa roti d gl a nds by conti guous s prea d. Al though
ca t-s cra tch di s ea s e i s s el f-l i mi ted, a nti bi oti c thera py i s often provi ded, a nd i nci s i on a nd dra i na ge a re neces s a ry i f a n a bs ces s devel ops .
Atypi ca l mycoba cteri a l i nfecti ons i n the tons i l s or teeth ma y s prea d conti guous l y to the ma jor s a l i va ry gl a nds . The PPD ma y be nega ti ve, a nd the
di a gnos i s ma y requi re bi ops y a nd ti s s ue cul ture for a ci d-fa s t ba cteri a . Trea tment recommenda ti ons a re controvers i a l . Opti ons i ncl ude s urgi ca l
debri dement wi th curetta ge, compl ete exci s i on of the i nfected ti s s ue, a nd us e of a nti -TB drug thera py (ra rel y neces s a ry).
Salivary Stones
(Si a l ol i thi a s i s )
Stones composed of Ca salts often obstruct salivary glands, causing pain, swelling, and sometimes infection. Diagnosis is made clinically or with CT,
ultrasonography, or sialography. Treatment involves stone expression with saliva stimulants, manual manipulation, a probe, or surgery.
The ma jor s a l i va ry gl a nds a re the pa i red pa roti d, s ubma ndi bul a r, a nd s ubl i ngua l gl a nds . Stones i n the s a l i va ry gl a nds a re mos t common a mong
a dul ts . Ei ghty percent of s tones ori gi na te i n the s ubma ndi bul a r gl a nds a nd obs truct Wha rton's duct. Mos t of the res t ori gi na te i n the pa roti d
gl a nds a nd bl ock Stens en's duct. Onl y a bout 1% ori gi na te i n the s ubl i ngua l gl a nds . Mul ti pl e s tones occur i n a bout 25% of pa ti ents .
Etiology
Mos t s a l i va ry s tones a re compos ed of Ca phos pha te wi th s ma l l a mounts of Mg a nd ca rbona te. Pa ti ents wi th gout ma y ha ve uri c a ci d s tones . Stone
forma ti on requi res a ni dus on whi ch s a l ts ca n preci pi ta te duri ng s a l i va ry s ta s i s . Sta s i s occurs i n pa ti ents who a re debi l i ta ted, dehydra ted, ha ve
reduced food i nta ke, or ta ke a nti chol i nergi cs . Pers i s ti ng or recurrent s tones predi s pos e to i nfecti on of the i nvol ved gl a nd (s i a l a deni ti s s ee p.
469).
Symptoms and Signs
Obs tructi ng s tones ca us e gl a ndul a r s wel l i ng a nd pa i n, pa rti cul a rl y a fter ea ti ng, whi ch s ti mul a tes s a l i va fl ow. Symptoms ma y s ubs i de a fter a few
hours . Rel i ef ma y coi nci de wi th a gus h of s a l i va . Some s tones ca us e i ntermi ttent or no s ymptoms . If a s tone i s l odged di s ta l l y, i t ma y be vi s i bl e or
pa l pa bl e a t the duct's outl et.

Diagnosis
Someti mes i ma gi ng (eg, CT, ul tra s onogra phy, s i a l ogra phy)
If a s tone i s not a ppa rent on exa mi na ti on, the pa ti ent ca n be gi ven a s i a l a gogue (eg, l emon jui ce, ha rd ca ndy, or s ome other s ubs ta nce tha t
tri ggers s a l i va fl ow). Reproducti on of s ymptoms i s a l mos t a l wa ys di a gnos ti c of a s tone. CT, ul tra s onogra phy, a nd s i a l ogra phy a re hi ghl y s ens i ti ve
a nd a re us ed i f cl i ni ca l di a gnos i s i s equi voca l . Contra s t s i a l ogra phy ma y be done through a ca theter i ns erted i nto the duct a nd ca n di fferenti a te
between s tone, s tenos i s , a nd tumor. Thi s techni que i s occa s i ona l l y thera peuti c. Beca us e 90% of s ubma ndi bul a r ca l cul i a re ra di opa que a nd 90% of
pa roti d ca l cul i a re ra di ol ucent, pl a i n x-ra ys a re not a l wa ys a ccura te. MRI i s not i ndi ca ted.
Treatment
Loca l mea s ures (eg, s i a l a gogues , ma s s a ge)
Someti mes ma nua l expres s i on or s urgi ca l remova l
Ana l ges i cs , hydra ti on, a nd ma s s a ge ca n rel i eve s ymptoms . Anti s ta phyl ococca l a nti bi oti cs ca n be us ed to prevent a cute s i a l a deni ti s i f s ta rted
ea rl y. Stones ma y pa s s s ponta neous l y or when s a l i va ry fl ow i s s ti mul a ted by s i a l a gogues ; pa ti ents a re encoura ged to s uck a l emon wedge or s our
ca ndy every 2 to 3 h. Stones ri ght a t the duct ori fi ce ca n s ometi mes be expres s ed ma nua l l y by s queezi ng wi th the fi ngerti ps . Di l a ti on of the duct
wi th a s ma l l probe ma y fa ci l i ta te expul s i on. Surgi ca l remova l of s tones s ucceeds i f other methods fa i l . Stones a t or nea r the ori fi ce of the duct
ma y be removed tra ns ora l l y, wherea s thos e i n the hi l um of the gl a nd often requi re compl ete exci s i on of the s a l i va ry gl a nd.
Submandibular Space Infection
(Ludwi g's Angi na )
Submandibular space infection is acute cellulitis of the soft tissues below the mouth. Symptoms include pain, dysphagia, and potentially fatal airway obstruction.
Diagnosis usually is clinical. Treatment includes airway management, surgical drainage, and IV antibiotics.
Subma ndi bul a r s pa ce i nfecti on i s a ra pi dl y s prea di ng, bi l a tera l , i ndura ted cel l ul i ti s occurri ng i n the s upra hyoi d s oft ti s s ues , the fl oor of the
mouth, a nd both s ubl i ngua l a nd s ubma xi l l a ry s pa ces wi thout a bs ces s forma ti on. Al though not a true a bs ces s , i t res embl es one cl i ni ca l l y a nd i s
trea ted s i mi l a rl y.
The condi ti on us ua l l y devel ops from a n odontogeni c i nfecti on, es peci a l l y of the 2nd a nd 3rd ma ndi bul a r mol a rs , or a s a n extens i on of
peri tons i l l a r cel l ul i ti s . Contri buti ng fa ctors ma y i ncl ude poor denta l hygi ene, tooth extra cti ons , a nd tra uma (eg, fra ctures of the ma ndi bl e,
l a cera ti ons of the fl oor of the mouth).
Symptoms and Signs
Ea rl y ma ni fes ta ti ons a re pa i n i n a ny i nvol ved teeth, wi th s evere, tender, l oca l i zed s ubmenta l a nd s ubl i ngua l i ndura ti on. Boa rd-l i ke fi rmnes s of
the fl oor of the mouth a nd bra wny i ndura ti on of the s upra hyoi d s oft ti s s ues ma y devel op ra pi dl y. Drool i ng, tri s mus , dys pha gi a , s tri dor ca us ed by
l a ryngea l edema , a nd el eva ti on of the pos teri or tongue a ga i ns t the pa l a te ma y be pres ent. Fever, chi l l s , a nd ta chyca rdi a a re us ua l l y pres ent a s
wel l . The condi ti on ca n ca us e a i rwa y obs tructi on wi thi n hours a nd does s o more often tha n do other neck i nfecti ons .
Diagnosis
The di a gnos i s us ua l l y i s obvi ous . If not, CT i s done.
Treatment
Ma i ntena nce of a i rwa y pa tency
Surgi ca l i nci s i on a nd dra i na ge
Anti bi oti cs a cti ve a ga i ns t ora l fl ora
Ma i nta i ni ng a i rwa y pa tency i s of the hi ghes t pri ori ty. Beca us e s wel l i ng ma kes ora l endotra chea l i ntuba ti on di ffi cul t, fi beropti c na s otra chea l
i ntuba ti on done wi th topi ca l a nes thes i a i n the opera ti ng room or ICU wi th the pa ti ent a wa ke i s prefera bl e. Some pa ti ents requi re a tra cheotomy.
Pa ti ents wi thout i mmedi a te need for i ntuba ti on requi re i ntens e obs erva ti on a nd ma y benefi t tempora ri l y from a na s a l trumpet.
Inci s i on a nd dra i na ge wi th pl a cement of dra i ns deep i nto the myl ohyoi d mus cl es rel i eve the pres s ure. Anti bi oti cs s houl d be chos en to cover both
ora l a na erobes a nd a erobes (eg, cl i nda myci n, a mpi ci l l i n/s ul ba cta m, hi gh-dos e peni ci l l i n).
Adenoid Disorders
Hypertrophy or inflammation of the adenoids is common among children. Symptoms include nasal obstruction, sleep disturbances, and middle ear effusions with
hearing loss. Diagnosis is enhanced by flexible fiberoptic nasopharyngoscopy. Treatment often includes intranasal corticosteroids, antibiotics, and, for significant
nasal obstruction or persistent recurrent acute otitis media or middle ear effusion, adenoidectomy.
The a denoi ds a re a recta ngul a r ma s s of l ympha ti c ti s s ue i n the pos teri or na s opha rynx. They a re l a rges t i n chi l dren 2 to 6 yr. Enl a rgement ma y be
phys i ol ogi c or s econda ry to vi ra l or ba cteri a l i nfecti on, a l l ergy, i rri ta nts , a nd, pos s i bl y, ga s troes opha gea l refl ux. Other ri s k fa ctors i ncl ude ongoi ng
expos ure to ba cteri a l or vi ra l i nfecti on (eg, to mul ti pl e chi l dren a t a chi l d ca re center). Severe hypertrophy ca n obs truct the eus ta chi a n tubes
(ca us i ng oti ti s medi a ), pos teri or choa na e (ca us i ng s i nus i ti s ), or both.
Symptoms and Signs
Al though pa ti ents wi th a denoi d hypertrophy ma y not compl a i n of s ymptoms , they us ua l l y ha ve chroni c mouth brea thi ng, s nori ng, s l eep
di s turba nce, ha l i tos i s , recurrent a cute oti ti s medi a , conducti ve hea ri ng l os s (s econda ry to recurrent oti ti s medi a or pers i s tent mi ddl e ea r
effus i ons ), a nd a hypona s a l voi ce qua l i ty. Chroni c a denoi di ti s ca n a l s o ca us e chroni c or recurrent na s opha ryngi ti s , rhi nos i nus i ti s , epi s ta xi s ,
ha l i tos i s , a nd cough.
Diagnosis
Fl exi bl e na s opha ryngos copy
Adenoi d hypertrophy i s s us pected i n chi l dren a nd a dol es cents wi th cha ra cteri s ti c s ymptoms , pers i s tent mi ddl e ea r effus i ons , or recurrent a cute
oti ti s medi a or rhi nos i nus i ti s . Si mi l a r s ymptoms a nd s i gns i n a ma l e a dol es cent ma y res ul t from a n a ngi ofi broma . The gol d s ta nda rd for offi ce
a s s es s ment of the na s opha rynx i s fl exi bl e na s opha ryngos copy. X-ra y i ma gi ng a nd s l eep ta pe recordi ng, a l though a l s o often us ed, a re not a s
a ccura te. A s l eep s tudy ma y hel p defi ne the s everi ty of a ny s l eep di s turba nce due to chroni c obs tructi on.
Treatment
Someti mes a denoi dectomy
Underl yi ng a l l ergy i s trea ted wi th i ntra na s a l corti cos teroi ds , a nd underl yi ng ba cteri a l i nfecti on i s trea ted wi th a nti bi oti cs . In chi l dren wi th
pers i s tent mi ddl e ea r effus i ons or frequent oti ti s medi a , a denoi dectomy often l i mi ts recurrence. Chi l dren > 4 yr who requi re tympa nos tomy tubes
often undergo a denoi dectomy when tubes a re pl a ced. Surgery i s a l s o recommended for younger chi l dren wi th recurrent epi s ta xi s or s i gni fi ca nt
na s a l obs tructi on (eg, s l eep di s turba nce, voi ce cha nge). Al though i t requi res genera l a nes thes i a , a denoi dectomy us ua l l y ca n be done on a n
outpa ti ent ba s i s wi th recovery i n 48 to 72 h.
Retropharyngeal Abscess
Retropharyngeal abscesses, most common among young children, can cause sore throat, fever, neck stiffness, and stridor. Diagnosis requires lateral neck x-ray or
CT. Treatment is with endotracheal intubation, drainage, and antibiotics.
Retropha ryngea l a bs ces s es devel op i n the retropha ryngea l l ymph nodes a t the ba ck of the pha rynx, a dja cent to the vertebra e. They ca n be s eeded
by i nfecti on of the pha rynx, s i nus es , a denoi ds , or nos e. They occur ma i nl y i n chi l dren 1 to 8 yr, a s the retropha ryngea l l ymph nodes begi n to recede
by 4 to 5 yr. However, a dul ts ma y devel op i nfecti on a fter forei gn body i nges ti on or a fter i ns trumenta ti on. Common orga ni s ms i ncl ude a erobi c
(Streptococcus a nd Staphylococcus s p) a nd a na erobi c (Bacteroides a nd Fusobacterium) ba cteri a a nd, i ncrea s i ngl y i n a dul ts a nd chi l dren, HIV a nd TB.
The mos t s eri ous cons equences i ncl ude a i rwa y obs tructi on, s epti c s hock, rupture of the a bs ces s i nto the a i rwa y res ul ti ng i n a s pi ra ti on
pneumoni a or a s phyxi a , medi a s ti ni ti s , ca roti d rupture, a nd s uppura ti ve thrombophl ebi ti s of the i nterna l jugul a r vei ns (Lemi erre s yndrome).
Symptoms and Signs
Symptoms a nd s i gns a re us ua l l y preceded i n chi l dren by a n a cute URI a nd i n a dul ts by forei gn body i nges ti on or i ns trumenta ti on. Chi l dren ma y
ha ve odynopha gi a , dys pha gi a , fever, cervi ca l l ympha denopa thy, nucha l ri gi di ty, s tri dor, dys pnea , s nori ng or noi s y brea thi ng, a nd torti col l i s . Adul ts
ma y ha ve s evere neck pa i n but l es s often ha ve s tri dor. The pos teri or pha ryngea l wa l l ma y bul ge to one s i de.
Diagnosis
CT
Di a gnos i s i s s us pected i n pa ti ents wi th s evere, unexpl a i ned s ore throa t a nd neck s ti ffnes s ; s tri dor; or noi s y brea thi ng. La tera l s oft-ti s s ue x-ra ys of
the neck, ta ken i n the ma xi mum pos s i bl e hyperextens i on a nd duri ng i ns pi ra ti on, ma y s how foca l wi deni ng of the prevertebra l s oft ti s s ues ,
revers a l of norma l cervi ca l l ordos i s , a i r i n the prevertebra l s oft ti s s ues , or eros i on of the a dja cent vertebra l body. CT ca n hel p di a gnos e
ques ti ona bl e ca s es , hel p di fferenti a te cel l ul i ti s from a n a bs ces s , a nd a s s es s extent of the a bs ces s .
Treatment
Anti bi oti cs (eg, ceftri a xone, cl i nda myci n)
Us ua l l y s urgi ca l dra i na ge
Anti bi oti cs , s uch a s a broa d-s pectrum cepha l os pori n (eg, ceftri a xone 50 to 75 mg/kg IV once/da y) or cl i nda myci n, ma y occa s i ona l l y be s uffi ci ent for
chi l dren wi th s ma l l a bs ces s es . However, mos t pa ti ents a l s o requi re dra i na ge through a n i nci s i on i n the pos teri or pha ryngea l wa l l . Endotra chea l
i ntuba ti on i s done preopera ti vel y a nd ma i nta i ned for 24 to 48 h.
Tornwaldt's Cyst
(Pha ryngea l Burs a )
Tornwaldt's cyst is a rare cyst in the midline of the nasopharynx that may become infected.
Tornwa l dt's cys t i s a remna nt of the embryona l notochord s uperfi ci a l to the s uperi or cons tri ctor mus cl e of the pha rynx a nd i s covered by the
mucous membra ne of the na s opha rynx. It ma y become i nfected, ca us i ng pers i s tent purul ent dra i na ge wi th a foul ta s te a nd odor, eus ta chi a n tube
obs tructi on, a nd s ore throa t.
Purul ent exuda te ma y be s een a t the openi ng of the cys t. Di a gnos i s i s ba s ed on na s opha ryngos copy s uppl emented by CT or MRI when the
di a gnos i s i s i n doubt. Trea tment cons i s ts of ma rs upi a l i za ti on or exci s i on.
Velopharyngeal Insufficiency
Velopharyngeal insufficiency is incomplete closure of a sphincter between the oropharynx and nasopharynx, often resulting from anatomic abnormalities of the
palate and causing hypernasal speech. Treatment is with speech therapy and surgery.
Vel opha ryngea l i ns uffi ci ency i s i ncompl ete cl os ure of the vel opha ryngea l s phi ncter between the oropha rynx a nd the na s opha rynx. Cl os ure,
norma l l y a chi eved by the s phi ncteri c a cti on of the s oft pa l a te a nd the s uperi or cons tri ctor mus cl e, i s i mpa i red i n pa ti ents wi th cl eft pa l a te,
repa i red cl eft pa l a te, congeni ta l l y s hort pa l a te, s ubmucous cl eft pa l a te, pa l a ta l pa ra l ys i s , a nd, s ometi mes , enl a rged tons i l s . The condi ti on ma y
a l s o res ul t when a denoi dectomy or uvul opa l a topha ryngopl a s ty i s done i n a pa ti ent wi th a congeni ta l underdevel opment (s ubmucous cl eft) or
pa ra l ys i s of the pa l a te.
Symptoms and Signs
Speech i n a pa ti ent wi th vel opha ryngea l i ns uffi ci ency i s cha ra cteri zed by hyperna s a l res ona nt voi ce, na s a l emi s s i on of a i r, na s a l turbul ence, a nd
i na bi l i ty to produce s ounds requi ri ng ora l pres s ure (pl os i ves ). Severe vel opha ryngea l i ns uffi ci ency res ul ts i n regurgi ta ti on of s ol i d foods a nd
fl ui ds through the nos e. Ins pecti on of the pa l a te duri ng phona ti on ma y revea l pa l a ta l pa ra l ys i s .
Diagnosis
Di rect i ns pecti on wi th a fi beropti c na s oendos cope
The di a gnos i s i s s us pected i n pa ti ents wi th the typi ca l s peech a bnorma l i ti es . Pa l pa ti on of the mi dl i ne of the s oft pa l a te ma y revea l a n occul t
s ubmucous cl eft. Di rect i ns pecti on wi th a fi beropti c na s oendos cope i s the pri ma ry di a gnos ti c techni que. Mul ti vi ew vi deofl uoros copy duri ng
connected s peech a nd s wa l l owi ng (modi fi ed ba ri um s wa l l ow), done i n conjuncti on wi th a s peech pa thol ogi s t, ca n a l s o be us ed.
Treatment
Surgi ca l repa i r a nd s peech thera py
Trea tment cons i s ts of s peech thera py a nd s urgi ca l correcti on by a pa l a ta l el onga ti on pus hba ck procedure, pos teri or pha ryngea l wa l l i mpl a nt,
pha ryngea l fl a p, or pha ryngopl a s ty, dependi ng on the mobi l i ty of the l a tera l pha ryngea l wa l l s , the degree of vel a r el eva ti on, a nd the s i ze of the
defect.
Tonsillopharyngitis
(See a l s o p.
1232.)
Tonsillopharyngitis is acute infection of the pharynx, palatine tonsils, or both. Symptoms may include sore throat, dysphagia, cervical lymphadenopathy, and
fever. Diagnosis is clinical, supplemented by culture or rapid antigen test. Treatment depends on symptoms and, in the case of group A -hemolytic streptococcus,
involves antibiotics.
The tons i l s pa rti ci pa te i n s ys temi c i mmune s urvei l l a nce. In a ddi ti on, l oca l tons i l l a r defens es i ncl ude a l i ni ng of a nti gen-proces s i ng s qua mous
epi thel i um tha t i nvol ves B- a nd T-cel l res pons es .
Tons i l l opha ryngi ti s of a l l va ri eti es cons ti tutes a bout 15% of a l l offi ce vi s i ts to pri ma ry ca re phys i ci a ns .
Etiology
Tons i l l opha ryngi ti s i s us ua l l y vi ra l , mos t often ca us ed by the common col d vi rus es (a denovi rus , rhi novi rus , i nfl uenza , corona vi rus , res pi ra tory
s yncyti a l vi rus ), but occa s i ona l l y by Eps tei n-Ba rr vi rus , herpes s i mpl ex vi rus , cytomega l ovi rus , or HIV.
In a bout 30% of pa ti ents , the ca us e i s ba cteri a l . Group A -hemol yti c s treptococcus (GABHS) i s mos t common (s ee p. 1232), but Staphylococcus aureus,
Streptococcus pneumoniae, Mycoplasma pneumoniae, a nd Chlamydia pneumoniae a re s ometi mes i nvol ved. Ra re ca us es i ncl ude pertus s i s , Fusobacterium,
di phtheri a , s yphi l i s , a nd gonorrhea .
GABHS occurs mos t commonl y between a ges 5 a nd 15 a nd i s uncommon before a ge 3.
Symptoms and Signs
Pa i n wi th s wa l l owi ng i s the ha l l ma rk a nd i s often referred to the ea rs . Very young chi l dren who a re not a bl e to compl a i n of s ore throa t often
refus e to ea t. Hi gh fever, ma l a i s e, hea da che, a nd GI ups et a re common, a s a re ha l i tos i s a nd a muffl ed voi ce. A s ca rl a ti ni form or nons peci fi c ra s h
ma y a l s o be pres ent. The tons i l s a re s wol l en a nd red a nd often ha ve purul ent exuda tes . Tender cervi ca l l ympha denopa thy ma y be pres ent. Fever,
a denopa thy, pa l a ta l petechi a e, a nd exuda tes a re s omewha t more common wi th GABHS tha n wi th vi ra l tons i l l opha ryngi ti s , but there i s much
overl a p. GABHS us ua l l y res ol ves wi thi n 7 da ys . Untrea ted GABHS ma y l ea d to l oca l s uppura ti ve compl i ca ti ons (eg, peri tons i l l a r a bs ces s or
cel l ul i ti s ) a nd s ometi mes to rheuma ti c fever or gl omerul onephri ti s .

Diagnosis
GABHS rul ed out by ra pi d a nti gen tes t, cul ture, or both
Pha ryngi ti s i ts el f i s ea s i l y recogni zed cl i ni ca l l y. However, i ts ca us e i s not. Rhi norrhea a nd cough us ua l l y i ndi ca te a vi ra l ca us e. Infecti ous
mononucl eos i s i s s ugges ted by pos teri or cervi ca l or genera l i zed a denopa thy, hepa tos pl enomega l y, fa ti gue, a nd ma l a i s e for > 1 wk; a ful l neck
wi th petechi a e of the s oft pa l a te; a nd thi ck tons i l l a r exuda tes . A di rty gra y, thi ck, tough membra ne tha t bl eeds i f peel ed a wa y i ndi ca tes di phtheri a
(ra re i n the US).
Beca us e GABHS requi res a nti bi oti cs , i t mus t be di a gnos ed ea rl y. Cri teri a for tes ti ng a re controvers i a l . Ma ny a uthori ti es recommend tes ti ng wi th a
ra pi d a nti gen tes t or cul ture for a l l chi l dren. Ra pi d a nti gen tes ts a re s peci fi c but not s ens i ti ve a nd ma y need to be fol l owed by a cul ture, whi ch i s
a bout 90% s peci fi c a nd 90% s ens i ti ve. In a dul ts , ma ny a uthori ti es recommend us i ng the fol l owi ng 4 cri teri a :
Hi s tory of fever
Tons i l l a r exuda tes
Abs ence of cough
Tender a nteri or cervi ca l l ympha denopa thy
Pa ti ents who meet 1 or no cri teri a a re unl i kel y to ha ve GABHS a nd s houl d not be tes ted. Pa ti ents who meet 2 cri teri a ca n be tes ted. Pa ti ents who
meet 3 or 4 cri teri a ca n be tes ted or trea ted empi ri ca l l y for GABHS.
Treatment
Symptoma ti c trea tment
Anti bi oti cs for GABHS
Tons i l l ectomy cons i dered for recurrent GABHS
Supporti ve trea tments i ncl ude a na l ges i a , hydra ti on, a nd res t. Peni ci l l i n V i s us ua l l y cons i dered the drug of choi ce for GABHS tons i l l opha ryngi ti s ;
dos e i s 250 mg po bi d for 10 da ys for pa ti ents < 27 kg a nd 500 mg for thos e > 27 kg (s ee a l s o p. 1234). Amoxi ci l l i n i s effecti ve a nd more pa l a ta bl e i f
a l i qui d prepa ra ti on i s requi red. If a dherence i s a concern, a s i ngl e dos e of benza thi ne peni ci l l i n 1.2 mi l l i on uni ts IM (600,000 uni ts for chi l dren
27 kg) i s effecti ve. Other ora l drugs i ncl ude ma crol i des for pa ti ents a l l ergi c to peni ci l l i n, a 1s t-genera ti on cepha l os pori n, a nd cl i nda myci n.
Trea tment ma y be s ta rted i mmedi a tel y or del a yed unti l cul ture res ul ts a re known. If trea tment i s s ta rted pres umpti vel y, i t s houl d be s topped i f
cul tures a re nega ti ve. Fol l ow-up throa t cul tures a re not done routi nel y. They a re us eful i n pa ti ents wi th mul ti pl e GABHS recurrences or i f
pha ryngi ti s s prea ds to cl os e conta cts a t home or s chool .
Tonsillectomy: Tons i l l ectomy s houl d be cons i dered i f GABHS tons i l l i ti s recurs repea tedl y (> 6 epi s odes /yr, > 4 epi s odes /yr for 2 yr, > 3 epi s odes /yr
for 3 yr) or i f a cute i nfecti on i s s evere a nd pers i s tent des pi te a nti bi oti cs . Other cri teri a for tons i l l ectomy i ncl ude obs tructi ve s l eep di s order,
recurrent peri tons i l l a r a bs ces s , a nd s us pi ci on of ca ncer.
Numerous effecti ve s urgi ca l techni ques a re us ed to perform tons i l l ectomy, i ncl udi ng el ectroca utery, mi crodebri der, ra di ofrequency cobl a ti on, a nd
s ha rp di s s ecti on. Si gni fi ca nt i ntra opera ti ve or pos topera ti ve bl eedi ng occurs i n < 2% of pa ti ents , us ua l l y wi thi n 24 h of s urgery or a fter 7 da ys ,
when the es cha r deta ches . Pa ti ents wi th bl eedi ng s houl d go to the hos pi ta l . If bl eedi ng conti nues on a rri va l , pa ti ents genera l l y a re exa mi ned i n
the opera ti ng room, a nd hemos ta s i s i s obta i ned. Any cl ot pres ent i n the tons i l l a r fos s a i s removed, a nd pa ti ents a re obs erved for 24 h.
Pos topera ti ve IV rehydra ti on i s neces s a ry i n 3% of pa ti ents , pos s i bl y i n fewer pa ti ents wi th us e of opti ma l preopera ti ve hydra ti on, peri opera ti ve
a nti bi oti cs , a na l ges i cs , a nd corti cos teroi ds . Pos topera ti ve a i rwa y obs tructi on occurs mos t frequentl y i n chi l dren < 2 yr who ha ve preexi s ti ng s evere
obs tructi ve s l eep di s orders a nd i n pa ti ents who a re morbi dl y obes e or ha ve neurol ogi c di s orders , cra ni ofa ci a l a noma l i es , or s i gni fi ca nt
preopera ti ve obs tructi ve s l eep a pnea . Compl i ca ti ons a re genera l l y more common a nd s eri ous a mong a dul ts .
Peritonsillar Abscess and Cellulitis
Peritonsillar abscess and cellulitis are acute pharyngeal infections most common among adolescents and young adults. Symptoms are severe sore throat, trismus,
"hot potato" voice, and uvular deviation. Diagnosis requires needle aspiration. Treatment includes broad-spectrum antibiotics, drainage of any pus, hydration,
analgesics, and, occasionally, acute tonsillectomy.
Etiology
Abs ces s (qui ns y) a nd cel l ul i ti s proba bl y repres ent a s pectrum of the s a me proces s i n whi ch ba cteri a l i nfecti on of the tons i l s a nd pha rynx s prea ds
to the s oft ti s s ues . Infecti on i s vi rtua l l y a l wa ys uni l a tera l a nd i s l oca ted between the tons i l a nd the s uperi or pha ryngea l cons tri ctor mus cl e. It
us ua l l y i nvol ves mul ti pl e ba cteri a . Streptococcus a nd Staphylococcus a re the mos t frequent a erobi c pa thogens , wherea s Bacteroides s p i s the
predomi na nt a na erobi c pa thogen.
Symptoms and Signs
Symptoms i ncl ude gra dua l ons et of s evere uni l a tera l s ore throa t, dys pha gi a , fever, ota l gi a , a nd a s ymmetri c cervi ca l a denopa thy. Tri s mus , "hot
pota to" voi ce (s pea ki ng a s i f a hot object wa s i n the mouth), a toxi c a ppea ra nce (s ee Epi gl otti ti s on p. 475), drool i ng, s evere ha l i tos i s , tons i l l a r
erythema , a nd exuda tes a re common. Abs ces s a nd cel l ul i ti s both ha ve s wel l i ng a bove the a ffected tons i l , but wi th a bs ces s there i s more of a
di s crete bul ge, wi th devi a ti on of the s oft pa l a te a nd uvul a a nd pronounced tri s mus .
Diagnosis
Needl e a s pi ra ti on
Someti mes CT
Peri tons i l l a r cel l ul i ti s i s recogni zed i n pa ti ents wi th s evere s ore throa t who ha ve tri s mus , "hot pota to" voi ce, a nd uvul a r devi a ti on. Al l s uch
pa ti ents requi re needl e a s pi ra ti on of the tons i l l a r ma s s a nd cul tures . As pi ra ti on of pus di fferenti a tes a bs ces s from cel l ul i ti s . CT or ul tra s ound of
the neck ca n hel p confi rm the di a gnos i s when the phys i ca l exa mi na ti on i s di ffi cul t or the di a gnos i s i s i n doubt, pa rti cul a rl y when the condi ti on
mus t be di fferenti a ted from a pa ra pha ryngea l i nfecti on or other deep neck i nfecti on.
Treatment
Anti bi oti cs
Dra i na ge of a bs ces s
Cel l ul i ti s s ubs i des , us ua l l y wi thi n 48 h, wi th hydra ti on a nd hi gh-dos e peni ci l l i n (eg, 2 mi l l i on uni ts IV q 4 h or 1 g po qi d); a l terna ti ve drugs
i ncl ude a 1s t-genera ti on cepha l os pori n or cl i nda myci n. Cul ture-di rected a nti bi oti cs a re then pres cri bed for 10 da ys . Abs ces s es a re i nci s ed a nd
dra i ned i n the emergency depa rtment us i ng thorough l oca l a nes thes i a a nd s ometi mes procedura l s eda ti on; ma ny cl i ni ci a ns bel i eve needl e
a s pi ra ti on a l one provi des a dequa te dra i na ge. Al though mos t pa ti ents ca n be trea ted a s outpa ti ents , s ome need bri ef hos pi ta l i za ti on for
pa rentera l a nti bi oti cs , IV hydra ti on, a nd a i rwa y moni tori ng. Ra rel y, a n i mmedi a te tons i l l ectomy i s done, pa rti cul a rl y i n a young or uncoopera ti ve
pa ti ent who ha s other i ndi ca ti ons for el ecti ve tons i l l ectomy (eg, hi s tory of frequentl y recurrent tons i l l i ti s or obs tructi ve s l eep a pnea ). Otherwi s e,
el ecti ve tons i l l ectomy i s done 4 to 6 wk out to prevent a bs ces s recurrence.
Parapharyngeal Abscess
A parapharyngeal abscess is a deep neck abscess treated with antibiotics and surgical drainage.
The pa ra pha ryngea l (pha ryngoma xi l l a ry) s pa ce i s l a tera l to the s uperi or pha ryngea l cons tri ctor a nd medi a l to the ma s s eter mus cl e. Thi s s pa ce
connects to every other ma jor fa s ci a l neck s pa ce a nd i s di vi ded i nto a nteri or a nd pos teri or compa rtments by the s tyl oi d proces s . The pos teri or
compa rtment conta i ns the ca roti d a rtery, i nterna l jugul a r vei n, a nd numerous nerves . Infecti ons i n the pa ra pha ryngea l s pa ce us ua l l y ori gi na te i n
the tons i l s or pha rynx, a l though l oca l s prea d from odontogeni c s ources a nd l ymph nodes ma y occur.
Abs ces s s wel l i ng ca n compromi s e the a i rwa y. Pos teri or s pa ce a bs ces s ca n erode i nto the ca roti d a rtery or ca us e s epti c thrombophl ebi ti s of the
i nterna l jugul a r vei n (Lemi erre s yndrome).
Symptoms and Signs
Mos t pa ti ents ha ve fever, s ore throa t, odynopha gi a , a nd s wel l i ng i n the neck down to the hyoi d bone. Anteri or s pa ce a bs ces s es ca us e tri s mus a nd
i ndura ti on a l ong the a ngl e of the ma ndi bl e, wi th medi a l bul gi ng of the tons i l a nd l a tera l pha ryngea l wa l l . Pos teri or s pa ce a bs ces s es ca us e
s wel l i ng tha t i s more promi nent i n the pos teri or pha ryngea l wa l l . Tri s mus i s mi ni ma l . Pos teri or a bs ces s es ma y i nvol ve s tructures wi thi n the
ca roti d s hea th, pos s i bl y ca us i ng ri gors , hi gh fever, ba cteremi a , neurol ogi c defi ci ts , a nd ma s s i ve hemorrha ge ca us ed by ca roti d a rtery rupture.
Diagnosis
CT
Di a gnos i s i s s us pected i n pa ti ents wi th poorl y defi ned deep neck i nfecti on or other typi ca l s ymptoms a nd i s confi rmed by us i ng contra s tenha nced CT.
Treatment
Broa d-s pectrum a nti bi oti cs (eg, ceftri a xone, cl i nda myci n)
Surgi ca l dra i na ge
Trea tment ma y requi re a i rwa y control . Pa rentera l broa d-s pectrum a nti bi oti cs (eg, ceftri a xone, cl i nda myci n) a nd s urgi ca l dra i na ge a re genera l l y
needed. Pos teri or a bs ces s es a re dra i ned externa l l y through the s ubma xi l l a ry fos s a . Anteri or a bs ces s es ca n often be dra i ned through a n i ntra -ora l
i nci s i on. Severa l da ys of pa rentera l cul ture-determi ned a nti bi oti cs a re requi red a fter dra i na ge, fol l owed by 10 to 14 da ys of ora l a nti bi oti cs .
Occa s i ona l l y, s ma l l a bs ces s es ca n be trea ted wi th IV a nti bi oti cs a l one.
Epiglottitis
(Supra gl otti ti s )
Epiglottitis is a rapidly progressive bacterial infection of the epiglottis and surrounding tissues that may lead to sudden respiratory obstruction and death.
Symptoms include severe sore throat, dysphagia, high fever, drooling, and inspiratory stridor. Diagnosis requires direct visualization of the supraglottic structures,
which is not to be done until full respiratory support is available. Treatment includes airway protection and antibiotics.
Epi gl otti ti s us ed to be pri ma ri l y a di s ea s e of chi l dren a nd us ua l l y wa s ca us ed by Haemophilus influenzae type B. Now, beca us e of wi des prea d
va cci na ti on, i t ha s been a l mos t era di ca ted i n chi l dren (more ca s es occur i n a dul ts ). Ca us a l orga ni s ms i n chi l dren a nd a dul ts i ncl ude Streptococcus
pneumoniae, Staphylococcus aureus, nontypea bl e H. influenzae, Haemophilus parainfluenzae, -hemol yti c s treptococci , Branhamella catarrhalis, a nd
Klebsiella pneumoniae. H. influenzae type B i s s ti l l a ca us e i n a dul ts a nd unva cci na ted chi l dren.
Ba cteri a tha t ha ve col oni zed the na s opha rynx s prea d l oca l l y to ca us e s upra gl otti c cel l ul i ti s wi th ma rked i nfl a mma ti on of the epi gl otti s , va l l ecul a ,
a ryepi gl otti c fol ds , a rytenoi ds , a nd l a ryngea l ventri cl es . Wi th H. influenzae type B, i nfecti on ma y s prea d hema togenous l y.
The i nfl a med s upra gl otti c s tructures mecha ni ca l l y obs truct the a i rwa y, i ncrea s i ng the work of brea thi ng, ul ti ma tel y ca us i ng res pi ra tory fa i l ure.
Cl ea ra nce of i nfl a mma tory s ecreti ons i s a l s o i mpa i red.
Symptoms and Signs
In chi l dren, s ore throa t, odynopha gi a , a nd dys pha gi a devel op a bruptl y. Fa ta l a s phyxi a ma y occur wi thi n a few hours of ons et. Drool i ng i s very
common. Addi ti ona l l y, the chi l d ha s s i gns of toxi ci ty (poor or a bs ent eye conta ct, fa i l ure to recogni ze pa rents , cya nos i s , i rri ta bi l i ty, i na bi l i ty to be
cons ol ed or di s tra cted) a nd i s febri l e a nd a nxi ous . Dys pnea , ta chypnea , a nd i ns pi ra tory s tri dor ma y be pres ent, often ca us i ng the chi l d to s i t
upri ght, l ea n forwa rd, a nd hyperextend the neck wi th the ja w thrus t forwa rd a nd mouth open i n a n effort to enha nce a i r excha nge (tri pod pos i ti on).
Rel i nqui s hi ng thi s pos i ti on ma y hera l d res pi ra tory fa i l ure. Supra s terna l , s upra cl a vi cul a r, a nd s ubcos ta l i ns pi ra tory retra cti ons ma y be pres ent.
In a dul ts , s ymptoms a re s i mi l a r to thos e of chi l dren, i ncl udi ng s ore throa t, fever, dys pha gi a , a nd drool i ng, but pea k s ymptoms us ua l l y ta ke > 24 h
to devel op. Beca us e of the l a rger di a meter of the a dul t a i rwa y, obs tructi on i s l es s common a nd l es s ful mi na nt. Often, there i s no vi s i bl e
oropha ryngea l i nfl a mma ti on. However, s evere throa t pa i n wi th a norma l -a ppea ri ng pha rynx ra i s es s us pi ci on of epi gl otti ti s .
Diagnosis
Di rect i ns pecti on (typi ca l l y i n opera ti ng room)
X-ra y i n mi l der ca s es wi th l ow s us pi ci on
Epi gl otti ti s i s s us pected i n pa ti ents wi th s evere s ore throa t a nd no pha ryngi ti s a nd a l s o i n pa ti ents wi th s ore throa t a nd i ns pi ra tory s tri dor. Stri dor
i n chi l dren ma y a l s o res ul t from croup (vi ra l l a ryngotra chea l bronchi ti s s ee
Ta bl e 52-1 a nd p. 2879), ba cteri a l tra chei ti s , a nd a i rwa y forei gn body. The tri pod pos i ti on ma y a l s o occur wi th peri tons i l l a r or retropha ryngea l
a bs ces s .
The pa ti ent i s hos pi ta l i zed i f epi gl otti ti s i s s us pected. Di a gnos i s requi res di rect exa mi na ti on, us ua l l y wi th fl exi bl e fi beropti c l a ryngos copy.
(CAUTION: Examination of the pharynx and larynx may precipitate complete respiratory obstruction in children, and the pharynx and larynx should not be directly
examined except in the operating room, where the most advanced airway intervention is available.) Al though pl a i n x-ra ys ma y be hel pful , a chi l d wi th
s tri dor s houl d not be tra ns ported to the x-ra y s ui te. Di rect l a ryngos copy tha t revea l s a beefy-red, s ti ff, edema tous epi gl otti s i s di a gnos ti c. Cul tures
from the s upra gl otti c ti s s ues a nd bl ood ca n then be ta ken to s ea rch for the ca us a ti ve orga ni s m.
[Table 52-1. Di fferenti a ti ng Epi gl otti ti s from Croup]
Adul ts ma y, i n s ome ca s es , s a fel y undergo fl exi bl e fi beropti c l a ryngos copy.
Treatment
Adequa te a i rwa y ens ured
Anti bi oti cs (eg, ceftri a xone)
In chi l dren, the a i rwa y mus t be s ecured i mmedi a tel y, prefera bl y by na s otra chea l i ntuba ti on. Securi ng the a i rwa y ca n be qui te di ffi cul t a nd s houl d,
i f pos s i bl e, be done by experi enced pers onnel i n the opera ti ng room. An endotra chea l tube i s us ua l l y requi red unti l the pa ti ent ha s been
s ta bi l i zed for 24 to 48 h (us ua l tota l i ntuba ti on ti me i s < 60 h). Al terna ti vel y, a tra cheotomy i s done. If res pi ra tory a rres t occurs before a n a i rwa y i s
es ta bl i s hed, ba g-ma s k venti l a ti on ma y be a l i fe-s a vi ng tempora ry mea s ure. For emergency ca re of chi l dren wi th epi gl otti ti s , ea ch i ns ti tuti on
s houl d ha ve a protocol tha t i nvol ves cri ti ca l ca re, otol a ryngol ogy, a nes thes i a , a nd pedi a tri cs .
Adul ts whos e a i rwa y i s s everel y obs tructed ca n be endotra chea l l y i ntuba ted duri ng fl exi bl e fi beropti c l a ryngos copy. Other a dul ts ma y not requi re
i mmedi a te i ntuba ti on but s houl d be obs erved for a i rwa y compromi s e i n a n ICU wi th a n i ntuba ti on s et a nd cri cothyrotomy tra y a t the beds i de.
A -l a cta ma s e-res i s ta nt a nti bi oti c, s uch a s ceftri a xone 50 to 75 mg/kg IV once/da y (ma xi mum 2 g), s houl d be us ed empi ri ca l l y, pendi ng cul ture a nd
s ens i ti vi ty tes t res ul ts .
Epi gl otti ti s ca us ed by H. influenzae type B ca n be effecti vel y prevented wi th the H. influenzae type B (Hi b) conjuga te va cci ne.
Chapter 53. Nose and Paranasal Sinus Disorders

Introduction
(See Ch. 51 for a deta i l ed des cri pti on of the a na tomy of the nos e a nd s i nus es .)
Bacterial Infections
Nasal vestibulitis i s ba cteri a l i nfecti on of the na s a l ves ti bul e, typi ca l l y wi th Staphylococcus aureus. It ma y res ul t from nos e pi cki ng or exces s i ve nos e
bl owi ng a nd ca us es a nnoyi ng crus ts a nd bl eedi ng when the crus ts s l ough off. Ba ci tra ci n or mupi roci n oi ntment a ppl i ed topi ca l l y bi d for 14 da ys i s
effecti ve.
Furuncles of the na s a l ves ti bul e a re us ua l l y s ta phyl ococca l ; they ma y devel op i nto s prea di ng cel l ul i ti s of the ti p of the nos e. Sys temi c
a nti s ta phyl ococca l a nti bi oti cs (eg, cepha l exi n 500 mg po qi d) a re gi ven a nd wa rm compres s es a nd topi ca l mupi roci n a re a ppl i ed. Furuncl es a re
i nci s ed a nd dra i ned to prevent l oca l thrombophl ebi ti s a nd s ubs equent ca vernous s i nus thrombos i s .
Foreign Bodies
Na s a l forei gn bodi es a re found occa s i ona l l y i n young chi l dren, the i ntel l ectua l l y i mpa i red, a nd ps ychi a tri c pa ti ents . Common objects pus hed i nto
the nos e i ncl ude bea ds , bea ns , s eeds , nuts , i ns ects , a nd button ba tteri es (whi ch ma y ca us e chemi ca l burns ). When mi nera l s a l ts a re depos i ted
on a l ong-reta i ned forei gn body, the object i s ca l l ed a rhi nol i th.
A na s a l forei gn body i s s us pected i n a ny pa ti ent wi th a uni l a tera l , foul -s mel l i ng, bl oody, purul ent rhi norrhea . Di a gnos i s i s often ma de through
a nother pa rty's obs erva ti on of the i tem bei ng pus hed i nto the nos e or through vi s ua l i za ti on wi th a na s a l s pecul um.
Na s a l forei gn bodi es ca n s ometi mes be removed i n the offi ce wi th a na s a l s pecul um a nd Ha rtma nn's na s a l forceps . Pretrea tment wi th topi ca l
phenyl ephri ne ma y a i d vi s ua l i za ti on a nd remova l . To a voi d pus hi ng a s l i ppery, round object deeper, i t i s better to rea ch behi nd the object wi th the
bent ti p of a bl unt probe a nd pul l i t forwa rd. Someti mes , genera l a nes thes i a i s neces s a ry i f a rhi nol i th ha s formed or i f the forei gn body ma y be
di s pl a ced dors a l l y a nd then a s pi ra ted, res ul ti ng i n a i rwa y obs tructi on.
Nasal Polyps
Nasal polyps are fleshy outgrowths of the nasal mucosa that form at the site of dependent edema in the lamina propria of the mucous membrane, usually around
the ostia of the maxillary sinuses (see
Plate 2).
Al l ergi c rhi ni ti s , a cute a nd chroni c i nfecti ons , a nd cys ti c fi bros i s a l l predi s pos e to the forma ti on of na s a l pol yps . Bl eedi ng pol yps occur i n
rhi nos pori di os i s . Uni l a tera l pol yps occa s i ona l l y occur i n a s s oci a ti on wi th or repres ent beni gn or ma l i gna nt tumors of the nos e or pa ra na s a l
s i nus es . They ca n a l s o occur i n res pons e to a forei gn body. Na s a l pol yps a re s trongl y a s s oci a ted wi th a s pi ri n a l l ergy, s i nus i nfecti ons , a nd
a s thma .
Symptoms i ncl ude obs tructi on a nd pos tna s a l dra i na ge, conges ti on, s neezi ng, rhi norrhea , a nos mi a , hypos mi a , fa ci a l pa i n, a nd ocul a r i tchi ng.
Di a gnos i s genera l l y i s ba s ed on phys i ca l exa mi na ti on. A devel opi ng pol yp i s tea rdrop-s ha ped; when ma ture, i t res embl es a peel ed s eedl es s
gra pe.
Treatment
Topi ca l corti cos teroi d s pra y
Someti mes s urgi ca l remova l
Corti cos teroi ds (eg, mometa s one [30 g/s pra y], becl ometha s one [42 g/s pra y], fl uni s ol i de [25 g/s pra y] a eros ol s ), gi ven a s 1 or 2 s pra ys bi d i n
ea ch na s a l ca vi ty, ma y s hri nk or el i mi na te pol yps , a s ma y a 1-wk ta pered cours e of ora l corti cos teroi ds . Surgi ca l remova l i s s ti l l requi red i n ma ny
ca s es . Pol yps tha t obs truct the a i rwa y or promote s i nus i ti s a re removed, a s a re uni l a tera l pol yps tha t ma y be obs curi ng beni gn or ma l i gna nt
tumors . However, pol yps tend to recur unl es s the underl yi ng a l l ergy or i nfecti on i s control l ed. After remova l of na s a l pol yps , topi ca l
becl ometha s one or fl uni s ol i de thera py tends to reta rd recurrence. In s evere recurrent ca s es , ma xi l l a ry s i nus otomy or ethmoi dectomy ma y be
i ndi ca ted. Thes e procedures a re us ua l l y done endos copi ca l l y.
Rhinitis
(See a l s o Al l ergi c Rhi ni ti s on p. 1117.)
Rhinitis is inflammation of the nasal mucous membrane, with resultant nasal congestion, rhinorrhea, and variable associated symptoms depending on etiology
(eg, itching, sneezing, purulence, anosmia, ozena). The cause is usually viral, although irritants can cause it. Diagnosis is usually clinical. Treatment includes
humidification of room air, sympathomimetic amines, and antihistamines. Bacterial superinfection requires appropriate antibiotic treatment.
There a re s evera l forms of rhi ni ti s .
Acute rhinitis: Thi s form of rhi ni ti s , ma ni fes ti ng wi th edema a nd va s odi l a ti on of the na s a l mucous membra ne, rhi norrhea , a nd obs tructi on, i s
us ua l l y the res ul t of a common col d (s ee p. 1404); other ca us es i ncl ude s treptococca l , pneumococca l , a nd s ta phyl ococca l i nfecti ons .
Chronic rhinitis: Thi s form of rhi ni ti s i s genera l l y a prol onga ti on of s uba cute i nfl a mma tory or i nfecti ous vi ra l rhi ni ti s but ma y a l s o occur i n s yphi l i s ,
TB, rhi nos cl eroma , rhi nos pori di os i s , l ei s hma ni a s i s , bl a s tomycos i s , hi s topl a s mos i s , a nd l epros ya l l of whi ch a re cha ra cteri zed by gra nul oma
forma ti on a nd des tructi on of s oft ti s s ue, ca rti l a ge, a nd bone. Na s a l obs tructi on, purul ent rhi norrhea , a nd frequent bl eedi ng res ul t. Rhi nos cl eroma
ca us es progres s i ve na s a l obs tructi on from i ndura ted i nfl a mma tory ti s s ue i n the l a mi na propri a . Rhi nos pori di os i s i s cha ra cteri zed by bl eedi ng
pol yps . Both l ow humi di ty a nd a i rborne i rri ta nts ca n res ul t i n chroni c rhi ni ti s .
Atrophic rhinitis: Thi s form of rhi ni ti s res ul ts i n a trophy a nd s cl eros i s of mucous membra ne; the mucous membra ne cha nges from ci l i a ted
ps eudos tra ti fi ed col umna r epi thel i um to s tra ti fi ed s qua mous epi thel i um, a nd the l a mi na propri a i s reduced i n a mount a nd va s cul a ri ty. Atrophi c
rhi ni ti s i s a s s oci a ted wi th a dva nced a ge, Wegener's gra nul oma tos i s , a nd i a trogeni ca l l y i nduced exces s i ve na s a l ti s s ue exti rpa ti on. Al though the
exa ct eti ol ogy i s unknown, ba cteri a l i nfecti on frequentl y pl a ys a rol e. Na s a l mucos a l a trophy often occurs i n the el derl y.
Vasomotor rhinitis: Thi s form of rhi ni ti s i s a chroni c condi ti on i n whi ch i ntermi ttent va s cul a r engorgement of the na s a l mucous membra ne l ea ds to
wa tery rhi norrhea a nd s neezi ng. Eti ol ogy i s uncerta i n, a nd no a l l ergy ca n be i denti fi ed. A dry a tmos phere s eems to a ggra va te the condi ti on.
Symptoms and Signs
Acute rhi ni ti s res ul ts i n cough, l ow-gra de fever, na s a l conges ti on, rhi norrhea , a nd s neezi ng. Symptoms a nd s i gns of chroni c rhi ni ti s a re s i mi l a r but
ma y i ncl ude purul ent rhi norrhea a nd bl eedi ng.
Atrophi c rhi ni ti s res ul ts i n a bnorma l pa tency of the na s a l ca vi ti es , crus t forma ti on, a nos mi a , a nd epi s ta xi s tha t ma y be recurrent a nd s evere.
Va s omotor rhi ni ti s res ul ts i n s neezi ng a nd wa tery rhi norrhea . The turges cent mucous membra ne va ri es from bri ght red to purpl e. The condi ti on i s
ma rked by peri ods of remi s s i on a nd exa cerba ti on. Va s omotor rhi ni ti s i s di fferenti a ted from s peci fi c vi ra l a nd ba cteri a l i nfecti ons of the nos e by
the l a ck of purul ent exuda te a nd crus ti ng. It i s di fferenti a ted from a l l ergi c rhi ni ti s by the a bs ence of a n i denti fi a bl e a l l ergen.
Diagnosis
The di fferent forms of rhi ni ti s a re di a gnos ed cl i ni ca l l y. Tes ti ng i s unneces s a ry.
Treatment
For vi ra l rhi ni ti s , deconges ta nts , a nti hi s ta mi nes , or both
For a trophi c rhi ni ti s , topi ca l trea tment
For va s omotor rhi ni ti s , humi di fi ca ti on a nd s ometi mes topi ca l corti cos teroi ds a nd ora l ps eudoephedri ne
Vi ra l rhi ni ti s ma y be trea ted s ymptoma ti ca l l y wi th deconges ta nts (ei ther topi ca l va s ocons tri cti on wi th a s ympa thomi meti c a mi ne, s uch a s
oxymeta zol i ne q 8 to 12 h or phenyl ephri ne 0.25% q 3 to 4 h for not more tha n 7 da ys , or s ys temi c s ympa thomi meti c a mi nes , s uch a s
ps eudoephedri ne 30 mg po q 4 to 6 h). Anti hi s ta mi nes (s ee
Ta bl e 127-2 on p. 1111) ma y be hel pful . Thos e wi th a nti chol i nergi c properti es dry mucous membra nes a nd therefore ma y i ncrea s e i rri ta ti on.
Deconges ta nts a l s o ma y rel i eve s ymptoms of a cute ba cteri a l rhi ni ti s a nd chroni c rhi ni ti s , wherea s a n underl yi ng ba cteri a l i nfecti on requi res
cul ture or bi ops y, pa thogen i denti fi ca ti on, a nti bi oti c s ens i ti vi ti es , a nd a ppropri a te a nti mi crobi a l trea tment.
Trea tment of a trophi c rhi ni ti s i s di rected a t reduci ng the crus ti ng a nd el i mi na ti ng the odor wi th topi ca l a nti bi oti cs (eg, ba ci tra ci n), topi ca l or
s ys temi c es trogens , a nd vi ta mi ns A a nd D. Occl udi ng or reduci ng the pa tency of the na s a l ca vi ti es s urgi ca l l y decrea s es the crus ti ng ca us ed by the
dryi ng effect of a i r fl owi ng over the a trophi c mucous membra ne.
Trea tment of va s omotor rhi ni ti s i s by tri a l a nd error a nd i s not a l wa ys s a ti s fa ctory. Pa ti ents benefi t from humi di fi ed a i r, whi ch ma y be provi ded by
a humi di fi ed centra l hea ti ng s ys tem or a va pori zer i n the workroom or bedroom. Sys temi c s ympa thomi meti c a mi nes (eg, for a dul ts ,
ps eudoephedri ne 30 mg po q 4 to 6 h prn) rel i eve s ymptoms but a re not recommended for l ong-term us e. Topi ca l va s ocons tri ctors a re a voi ded
beca us e they ca us e the va s cul a ture of the na s a l mucous membra ne to l os e i ts s ens i ti vi ty to other va s ocons tri cti ve s ti mul i eg, the humi di ty a nd
tempera ture of i ns pi red a i r. Topi ca l corti cos teroi ds (eg, mometa s one 2 s pra ys bi d) ca n be of s ome benefi t.
Septal Deviation and Perforation
Deviations of the nasal septum due to devel opmenta l a bnorma l i ti es or tra uma a re common but often a re a s ymptoma ti c a nd requi re no trea tment.
Symptoma ti c s epta l devi a ti on ca us es na s a l obs tructi on a nd predi s pos es the pa ti ent to s i nus i ti s (pa rti cul a rl y i f the devi a ti on obs tructs the os ti um
of a pa ra na s a l s i nus ) a nd to epi s ta xi s due to dryi ng a i r currents . Other s ymptoms ma y i ncl ude fa ci a l pa i n, hea da ches , a nd noi s y ni ght brea thi ng.
Septa l devi a ti on i s us ua l l y evi dent on exa mi na ti on, a l though a fl a s hl i ght a nd exa mi na ti on of the a nteri or na s a l pa s s a ge ma y not be s uffi ci ent.
Trea tment cons i s ts of s eptopl a s ty (s epta l recons tructi on).
Septal ulcers and perforations ma y res ul t from na s a l s urgery; repea ted tra uma , s uch a s chroni c nos e pi cki ng; cos meti c pi erci ng; toxi c expos ures (eg,
a ci ds , chromi um, phos phorus , copper va por); chroni c coca i ne us e; chroni c na s a l s pra y us e (i ncl udi ng corti cos teroi ds a nd OTC phenyl ephri ne or
oxymeta zol i ne s pra ys ); tra ns na s a l O2 us e; or di s ea s es s uch a s TB, s yphi l i s , l epros y, SLE, a nd Wegener's gra nul oma tos i s . Crus ti ng a round the
ma rgi ns a nd repea ted epi s ta xi s , whi ch ca n be s evere, ma y res ul t. Sma l l perfora ti ons ma y whi s tl e. Anteri or rhi nos copy or fi beropti c endos copy ca n
be us ed to vi ew s epta l perfora ti ons . Topi ca l ba ci tra ci n or mupi roci n oi ntment reduces crus ti ng, a s ma y s a l i ne na s a l s pra y. Symptoma ti c s epta l
perfora ti ons a re occa s i ona l l y repa i red wi th bucca l or s epta l mucous membra ne fl a ps ; cl os i ng the perfora ti on wi th a s i l i cone s epta l button i s a
rel i a bl e opti on.
Sinusitis
Sinusitis is inflammation of the paranasal sinuses due to viral, bacterial, or fungal infections or allergic reactions. Symptoms include nasal obstruction and
congestion, purulent rhinorrhea, cough, facial pain, malaise, and sometimes fever. Treatment is with antibiotics, such as amoxicillin, penicillin, erythromycin, or
trimethoprim/sulfamethoxazole, given for 12 to 14 days for acute sinusitis and for up to 6 wk for chronic sinusitis. Decongestants and application of heat and
humidity may help relieve symptoms and improve sinus drainage. Recurrent sinusitis may require surgery to improve sinus drainage.
Si nus i ti s ma y be cl a s s i fi ed a s a cute (compl etel y res ol ved i n < 30 da ys ); s uba cute (compl etel y res ol ved i n 30 to 90 da ys ); recurrent (mul ti pl e
di s crete a cute epi s odes , ea ch compl etel y res ol ved i n < 30 da ys but recurri ng i n cycl es , wi th a t l ea s t 10 da ys between compl ete res ol uti on of
s ymptoms a nd i ni ti a ti on of a new epi s ode); a nd chroni c (l a s ti ng > 90 da ys ).
Etiology
Acute sinusitis i s us ua l l y preci pi ta ted by vi ra l URI, fol l owed by s econda ry ba cteri a l col oni za ti on wi th s treptococci , pneumococci , Haemophilus
influenzae, Moraxella catarrhalis, or s ta phyl ococci . In a URI, the s wol l en na s a l mucous membra ne obs tructs the os ti um of a pa ra na s a l s i nus , a nd the
O2 i n the s i nus i s a bs orbed i nto the bl ood ves s el s of the mucous membra ne. The res ul ti ng rel a ti ve nega ti ve pres s ure i n the s i nus (va cuum
s i nus i ti s ) i s pa i nful . If the va cuum i s ma i nta i ned, a tra ns uda te from the mucous membra ne devel ops a nd fi l l s the s i nus ; the tra ns uda te s erves a s
a medi um for ba cteri a tha t enter the s i nus through the os ti um or through a s prea di ng cel l ul i ti s or thrombophl ebi ti s i n the l a mi na propri a of the
mucous membra ne. An outpouri ng of s erum a nd l eukocytes to comba t the i nfecti on res ul ts , a nd pa i nful pos i ti ve pres s ure devel ops i n the
obs tructed s i nus . The mucous membra ne becomes hyperemi c a nd edema tous .
Chronic sinusitis ma y be exa cerba ted by gra m-nega ti ve ba ci l l i or a na erobi c mi cro-orga ni s ms . In a few ca s es , chroni c ma xi l l a ry s i nus i ti s i s s econda ry
to denta l i nfecti on or expos ure to envi ronmenta l pol l uti on. Funga l i nfecti ons (Aspergillus, Sporothrix, Pseudallescheria) tend to s tri ke the
i mmunocompromi s ed pa ti ent, wherea s hos pi ta l -a cqui red i nfecti ons compl i ca te cys ti c fi bros i s , na s oga s tri c a nd na s otra chea l i ntuba ti on, a nd
debi l i ta ted pa ti ents . Typi ca l orga ni s ms i ncl ude Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, a nd
Enterobacter.
Allergic fungal sinusitis i s cha ra cteri zed by di ffus e na s a l conges ti on, ma rkedl y vi s ci d na s a l s ecreti ons , a nd, often, na s a l pol yps . It i s a n a l l ergi c
res pons e to the pres ence of topi ca l fungi , often Aspergillus, a nd i s not ca us ed by a n i nva s i ve i nfecti on.
Symptoms and Signs
Acute a nd chroni c s i nus i ti s ca us e s i mi l a r s ymptoms a nd s i gns , i ncl udi ng purul ent rhi norrhea , pres s ure a nd pa i n i n the fa ce, na s a l conges ti on a nd
obs tructi on, hypos mi a , ha l i tos i s , a nd producti ve cough (es peci a l l y a t ni ght). Often the pa i n i s more s evere i n a cute s i nus i ti s . The a rea over the
a ffected s i nus ma y be tender, s wol l en, a nd erythema tous . Ma xi l l a ry s i nus i ti s ca us es pa i n i n the ma xi l l a ry a rea , tootha che, a nd fronta l hea da che.
Fronta l s i nus i ti s ca us es pa i n i n the fronta l a rea a nd fronta l hea da che. Ethmoi d s i nus i ti s ca us es pa i n behi nd a nd between the eyes , fronta l
hea da che often des cri bed a s s pl i tti ng, peri orbi ta l cel l ul i ti s , a nd tea ri ng. Pa i n ca us ed by s phenoi d s i nus i ti s i s l es s wel l l oca l i zed a nd i s referred
to the fronta l or occi pi ta l a rea . Ma l a i s e ma y be pres ent. Fever a nd chi l l s s ugges t a n extens i on of the i nfecti on beyond the s i nus es .
The na s a l mucous membra ne i s red a nd turges cent; yel l ow or green purul ent rhi norrhea ma y be pres ent. Seropurul ent or mucopurul ent exuda te
ma y be s een i n the mi ddl e mea tus wi th ma xi l l a ry, a nteri or ethmoi d, or fronta l s i nus i ti s a nd i n the a rea medi a l to the mi ddl e turbi na te wi th
pos teri or ethmoi d or s phenoi d s i nus i ti s .
Diagnosis
Someti mes CT
Si nus i nfecti ons a re us ua l l y di a gnos ed cl i ni ca l l y. Abs ence or dul l nes s of l i ght on tra ns i l l umi na ti on ma y s ugges t fl ui d-fi l l ed ma xi l l a ry or fronta l
s i nus es . In a cute a nd chroni c s i nus i ti s , the s wol l en mucous membra nes a nd reta i ned exuda te ca us e the a ffected s i nus to a ppea r opa que on 4vi ew x-ra ys . Pl a i n x-ra ys a re not a s va l ua bl e a s CT, whi ch provi des better defi ni ti on of the extent a nd degree of s i nus i ti s . X-ra ys of the a pi ces of the
teeth ma y be requi red i n chroni c ma xi l l a ry s i nus i ti s to excl ude a peri a pi ca l a bs ces s . When ques ti ons pers i s t (eg, rega rdi ng i ntra cra ni a l extens i on,
trea tment fa i l ure, or hos pi ta l -a cqui red ca us es of s i nus i ti s ), cul ture a nd s ens i ti vi ty tes ts ca n be done on s i nus s ecreti ons obta i ned through
endos copy or s i nus puncture a nd a s pi ra ti on.
Si nus i ti s i n chi l dren i s s us pected when purul ent rhi norrhea pers i s ts for > 10 da ys a l ong wi th fa ti gue a nd cough. Fever i s uncommon. Loca l fa ci a l
pa i n or di s comfort ma y be pres ent. Na s a l exa mi na ti on di s cl os es purul ent dra i na ge; CT i s confi rma tory. CT i s of l i mi ted cuts i n the corona l
projecti on to l i mi t ra di a ti on expos ure.
Treatment
Loca l mea s ures to enha nce dra i na ge (eg, s tea m, topi ca l va s ocons tri ctors )
Anti bi oti cs (eg, a moxi ci l l i n, erythromyci n, tri methopri m/s ul fa methoxa zol e)
In a cute s i nus i ti s , i mproved dra i na ge a nd control of i nfecti on a re the a i ms of thera py. Stea m i nha l a ti on; hot, wet towel s over the a ffected s i nus es ;
a nd hot bevera ges a l l evi a te na s a l va s ocons tri cti on a nd promote dra i na ge. Topi ca l va s ocons tri ctors , s uch a s phenyl ephri ne 0.25% s pra y q 3 h, a re
effecti ve but s houl d be us ed for a ma xi mum of 5 da ys or for a repea ti ng cycl e of 3 da ys on a nd 3 da ys off unti l the s i nus i ti s i s res ol ved. Sys temi c
va s ocons tri ctors , s uch a s ps eudoephedri ne 30 mg po (for a dul ts ) q 4 to 6 h, a re l es s effecti ve.
In a cute a nd chroni c s i nus i ti s , a nti bi oti cs a re gi ven for a t l ea s t 10 da ys a nd often for 14 da ys . In a cute s i nus i ti s , a moxi ci l l i n 500 mg po q 8 h wi th or
wi thout cl a vul a na te i s pri ma ry thera py. Erythromyci n 250 mg po q 6 h or tri methopri m/s ul fa methoxa zol e 80/400 mg q 6 h ca n be gi ven to pa ti ents
a l l ergi c to peni ci l l i n. Second-l i ne thera py i ncl udes cefuroxi me 500 mg q 12 h or moxi fl oxa ci n 400 mg once/da y. For chi l dren, s i mi l a r a nti bi oti cs a re
us ed, a djus ted for the chi l d's wei ght. Fl uoroqui nol ones , however, a re not us ed i n chi l dren beca us e of concerns of prema ture epi phys ea l growth
pl a te cl os ure.
In exa cerba ti ons of chroni c s i nus i ti s i n chi l dren or a dul ts , a broa d-s pectrum a nti bi oti c, s uch a s a moxi ci l l i n/cl a vul a na te 875 mg po q 12 h (12.5 to 25
mg/kg q 12 h i n chi l dren), cefuroxi me, or, i n a dul ts , moxi fl oxa ci n, i s us ed. In chroni c s i nus i ti s , prol onged a nti bi oti c thera py for 4 to 6 wk often
bri ngs compl ete res ol uti on. The s ens i ti vi ti es of pa thogens i s ol a ted from the s i nus exuda te a nd the pa ti ent's res pons e gui de s ubs equent thera py.
Si nus i ti s unres pons i ve to a nti bi oti c thera py ma y requi re s urgery (ma xi l l a ry s i nus otomy, ethmoi dectomy, or s phenoi d s i nus otomy) to i mprove
venti l a ti on a nd dra i na ge a nd to remove i ns pi s s a ted mucopurul ent ma teri a l , epi thel i a l debri s , a nd hypertrophi c mucous membra ne. Thes e
procedures us ua l l y a re done i ntra na s a l l y wi th the a i d of a n endos cope. Chroni c fronta l s i nus i ti s ma y be ma na ged ei ther wi th os teopl a s ti c
obl i tera ti on of the fronta l s i nus es or endos copi ca l l y i n s el ected pa ti ents . The us e of i ntra opera ti ve computer-a i ded s urgery to l oca l i ze di s ea s e
a nd prevent i njury to s urroundi ng conti guous s tructures (s uch a s the eye a nd bra i n) ha s become common.
Sinusitis in Immunocompromised Patients
Aggres s i ve a nd even fa ta l funga l or ba cteri a l s i nus i ti s ca n occur i n pa ti ents who a re i mmunocompromi s ed beca us e of poorl y control l ed di a betes ,
neutropeni a , or HIV i nfecti on.
Mucormycosis: Mucormycos i s (phycomycos i s )a mycos i s due to fungi of the order Mucora l es , i ncl udi ng s peci es of Mucor, Absidia, a nd Rhizopusma y
devel op i n pa ti ents wi th poorl y control l ed di a betes . It i s cha ra cteri zed by bl a ck, devi ta l i zed ti s s ue i n the na s a l ca vi ty a nd neurol ogi c s i gns
s econda ry to retrogra de thromboa rteri ti s i n the ca roti d a rteri a l s ys tem. Di a gnos i s i s ba s ed on hi s topa thol ogi c demons tra ti on of mycel i a i n the
a va s cul a ri zed ti s s ue. Trea tment requi res control of the underl yi ng condi ti on (s uch a s revers a l of ketoa ci dos i s i n di a betes ) a nd IV a mphoteri ci n B
thera py. Prompt bi ops y of i ntra na s a l ti s s ue for hi s tol ogy a nd cul ture i s wa rra nted.
Aspergillosis and candidiasis: Aspergillus a nd Candida s pp ma y i nfect the pa ra na s a l s i nus es of pa ti ents who a re i mmunocompromi s ed s econda ry to
thera py wi th cytotoxi c drugs or to i mmunos uppres s i ve di s ea s es , s uch a s l eukemi a , l ymphoma , mul ti pl e myel oma , a nd AIDS. Thes e i nfecti ons ca n
a ppea r a s pol ypoi d ti s s ue i n the nos e a s wel l a s thi ckened mucos a ; ti s s ue i s requi red for di a gnos i s . Aggres s i ve pa ra na s a l s i nus s urgery a nd IV
a mphoteri ci n B thera py a re us ed to control thes e often-fa ta l i nfecti ons .
Chapter 54. Laryngeal Disorders

Introduction
The l a rynx conta i ns the voca l cords a nd s erves a s the openi ng to the tra cheobronchi a l tree. La ryngea l di s orders i ncl ude va ri ous beni gn a nd
ma l i gna nt tumors , conta ct ul cers , gra nul oma s , l a ryngi ti s , l a ryngocel es , s pa s modi c dys phoni a , voca l cord pa ra l ys i s , a nd voca l cord pol yps a nd
nodul es . For a cute l a ryngotra cheobronchi ti s , s ee Croup on p. 2879.
La ryngea l ca ncer i s di s cus s ed on p. 489.
Mos t l a ryngea l di s orders ca us e dys phoni a , whi ch i s i mpa i rment of the voi ce (s ee Si deba r 54-1). A pers i s tent cha nge i n the voi ce (eg, > 3 wk)
requi res vi s ua l i za ti on of the voca l cords , i ncl udi ng thei r mobi l i ty. Al though the voi ce cha nges wi th a dva nci ng a ge, becomi ng brea thy a nd a peri odi c,
a cute or promi nent cha nges i n the el derl y s houl d not be pres umed to res ul t from a gi ng, a nd eva l ua ti on i s requi red.
The voi ce s houl d be a s s es s ed a nd recorded, pa rti cul a rl y i f s urgi ca l procedures a re pl a nned. Exa mi na ti on of the l a rynx i ncl udes externa l
i ns pecti on a nd pa l pa ti on of the neck a nd i nterna l vi s ua l i za ti on of the epi gl otti s , fa l s e cords , true cords , a rytenoi ds , pyri form s i nus es , a nd
s ubgl otti c regi on bel ow the cords . Interna l vi s ua l i za ti on i s a ccompl i s hed by ei ther i ndi rect mi rror exa mi na ti on (s ee
Fi g. 54-1) or di rect fl exi bl e fi beropti c l a ryngos copy i n a n outpa ti ent s etti ng wi th a topi ca l a nes theti c. Ri gi d l a ryngos copy wi th the pa ti ent under
genera l a nes thes i a a l l ows for bi ops y when neces s a ry or a s s es s ment of pa s s i ve mobi l i ty of the voca l cords when i mmobi l i zed by ei ther pa ra l ys i s
or fi xa ti on.
Sidebar 54-1 The Professional Voice

Peopl e who us e thei r voi ce profes s i ona l l y for publ i c s pea ki ng a nd s i ngi ng often experi ence voi ce di s orders ma ni fes ti ng a s hoa rs enes s or
brea thi nes s , l owered voca l pi tch, voca l fa ti gue, nonproducti ve cough, pers i s tent throa t cl ea ri ng, a nd/or throa t a che. Thes e s ymptoms often ha ve
beni gn ca us es , s uch a s voca l nodul es , voca l fol d edema , pol yps , or gra nul oma s . Such di s orders a re us ua l l y ca us ed by voca l fol d hyperfuncti on
(exces s i ve l a ryngea l mus cul a r tens i on when s pea ki ng) a nd pos s i bl y l a ryngopha ryngea l refl ux.
Trea tment i n mos t ca s es i ncl udes the fol l owi ng:
Voi ce eva l ua ti on by a s peech pa thol ogi s t or experi enced phys i ci a n, i ncl udi ng, when a va i l a bl e, us e of a computer-a s s i s ted progra m to a s s es s
pi tch a nd i ntens i ty a nd to determi ne pa ra meters of voca l a cous ti cs
Beha vi ora l trea tment (decrea s i ng mus cul os kel eta l l a ryngea l tens i on when s pea ki ng) us i ng the s a me computer progra m for vi s ua l a nd a udi tory
bi ofeedba ck
A voca l hygi ene progra m to el i mi na te voca l l y a bus i ve beha vi ors , s uch a s exces s i ve l oudnes s , l ong dura ti on, voca l tens i on, a nd ha bi tua l throa t
cl ea ri ng
An a nti refl ux regi men, when a ppropri a te
Adequa te hydra ti on to promote a n a dequa te gl otta l mucos a l wa ve
Di et modi fi ca ti on before voca l performa nces , whi ch ma y i ncl ude a voi da nce of da i ry products , ca ffei ne, a nd a mbi ent toba cco s moke a nd other
i nha l ed i rri ta nts
Benign Tumors
Beni gn l a ryngea l tumors i ncl ude juveni l e pa pi l l oma s hema ngi oma s , fi broma s , chondroma s , myxoma s , a nd neurofi broma s . They ma y a ppea r i n a ny
pa rt of the l a rynx. Symptoms i ncl ude hoa rs enes s , brea thy voi ce, dys pnea , a s pi ra ti on, dys pha gi a , pa i n, ota l gi a (pa i n referred to the ea r), a nd
hemoptys i s . Di a gnos i s i s ba s ed on di rect or i ndi rect vi s ua l i za ti on of the l a rynx, s uppl emented by CT. Remova l res tores the voi ce, the functi ona l
i ntegri ty of the l a ryngea l s phi ncter, a nd the a i rwa y. Sma l l er l es i ons ma y be exci s ed endos copi ca l l y by us i ng a CO2 l a s er a nd genera l a nes thes i a .
La rger l es i ons extendi ng beyond the l a ryngea l fra mework often requi re pha ryngotomy or l a ryngofi s s ure.
Ca ncerous tumors a re di s cus s ed i n Ch. 55.
Contact Ulcers
Contact ulcers are unilateral or bilateral erosions of the mucous membrane over the vocal process of the arytenoid cartilage.
Conta ct ul cers a re us ua l l y ca us ed by voi ce a bus e i n the form of repea ted s ha rp gl otta l a tta cks (a brupt l oudnes s a t the ons et of phona ti on), often
experi enced by s i ngers . They ma y a l s o occur a fter endotra chea l i ntuba ti on i f a n overs i zed tube erodes the mucos a overl yi ng the ca rti l a gi nous
voca l proces s es . Ga s troes opha gea l refl ux ma y a l s o ca us e or a ggra va te conta ct ul cers . Symptoms i ncl ude va ryi ng degrees of hoa rs enes s a nd mi l d
pa i n wi th phona ti on a nd s wa l l owi ng. Bi ops y to excl ude ca rci noma or TB i s i mporta nt. Prol onged ul cera ti on l ea ds to nons peci fi c gra nul oma s tha t
a l s o ca us e va ryi ng degrees of hoa rs enes s .
Trea tment cons i s ts of 6 wk of voi ce res t. Pa ti ents mus t recogni ze the l i mi ta ti ons of thei r voi ce a nd l ea rn to a djus t thei r pos trecovery voca l
a cti vi ti es to a voi d recurrence. Gra nul oma s tend to recur a fter s urgi ca l remova l . Ri s k of recurrence i s reduced through vi gorous trea tment of
ga s troes opha gea l refl ux (s ee p. 125). Suppres s i on of ba cteri a l fl ora by a nti bi oti cs duri ng pos topera ti ve hea l i ng i s a l s o recommended.
Laryngitis
Laryngitis is inflammation of the larynx, usually the result of a virus or overuse. The result is acute change in the voice, with decreased volume and hoarseness.
Diagnosis is based on clinical findings. Laryngoscopy is required for symptoms persisting > 3 wk. Viral laryngitis is self-limited. Other infectious or irritating
causes may require specific treatment.
The mos t common ca us e of a cute l a ryngi ti s i s a vi ra l URI. Coughi ng-i nduced l a ryngi ti s ma y a l s o occur i n bronchi ti s , pneumoni a , i nfl uenza ,
pertus s i s , mea s l es , a nd di phtheri a .
[Fig. 54-1. La ryngea l di s orders .]
Exces s i ve us e of the voi ce (es peci a l l y wi th l oud s pea ki ng or s i ngi ng), a l l ergi c rea cti ons , ga s troes opha gea l refl ux, bul i mi a , or i nha l a ti on of
i rri ta ti ng s ubs ta nces (eg, ci ga rette s moke or certa i n a eros ol i zed drugs ) ca n ca us e a cute or chroni c l a ryngi ti s . Ba cteri a l l a ryngi ti s i s extremel y ra re.
Smoki ng ca n ca us e Rei nke's edema , whi ch i s a wa tery s wel l i ng of both voca l cords .
Symptoms and Signs
An unna tura l cha nge of voi ce i s us ua l l y the mos t promi nent s ymptom. Vol ume i s typi ca l l y grea tl y decrea s ed; s ome pa ti ents ha ve a phoni a .
Hoa rs enes s , a s ens a ti on of ti ckl i ng, ra wnes s , a nd a cons ta nt urge to cl ea r the throa t ma y occur. Symptoms va ry wi th the s everi ty of the
i nfl a mma ti on. Fever, ma l a i s e, dys pha gi a , a nd throa t pa i n ma y occur i n more s evere i nfecti ons . La ryngea l edema , a l though ra re, ma y ca us e
dys pnea .
Diagnosis
Someti mes di rect or i ndi rect l a ryngos copy
Di a gnos i s i s ba s ed on s ymptoms . Indi rect or di rect fl exi bl e l a ryngos copy i s recommended for s ymptoms pers i s ti ng > 3 wk; fi ndi ngs i n l a ryngi ti s
i ncl ude mi l d to ma rked erythema of the mucous membra ne, whi ch ma y a l s o be edema tous . Wi th refl ux, there i s s wel l i ng of the i nner l i ni ng of the
l a rynx a nd rednes s of the voca l cords tha t extends a bove a nd bel ow the edges of the ba ck pa rt of the cords . If a ps eudomembra ne i s pres ent,
di phtheri a i s s us pected.
Treatment
Symptoma ti c trea tment (eg, cough s uppres s a nts , voi ce res t, s tea m i nha l a ti ons )
No s peci fi c trea tment i s a va i l a bl e for vi ra l l a ryngi ti s . Cough s uppres s a nts , voi ce res t, a nd s tea m i nha l a ti ons rel i eve s ymptoms a nd promote
res ol uti on of a cute l a ryngi ti s . Smoki ng ces s a ti on a nd trea tment of a cute or chroni c bronchi ti s ma y rel i eve l a ryngi ti s . Dependi ng on the pres umed
ca us e, s peci fi c trea tments to control ga s troes opha gea l refl ux, bul i mi a , or drug-i nduced l a ryngi ti s ma y be benefi ci a l .
Laryngoceles
Laryngoceles are evaginations of the mucous membrane of the laryngeal ventricle.
Interna l l a ryngocel es di s pl a ce a nd enl a rge the fa l s e voca l cords , res ul ti ng i n hoa rs enes s a nd a i rwa y obs tructi on. Externa l l a ryngocel es extend
through the thyrohyoi d membra ne, ca us i ng a ma s s i n the neck. La ryngocel es tend to occur i n mus i ci a ns who pl a y wi nd i ns truments . La ryngocel es
a re fi l l ed wi th a i r a nd ca n be expa nded by the Va l s a l va ma neuver. They a ppea r on CT a s s mooth, ovoi d, l ow-dens i ty ma s s es . La ryngocel es ma y
become i nfected (l a ryngopyocel e) or fi l l ed wi th mucoi d fl ui d. Trea tment i s exci s i on.
Spasmodic Dysphonia
Spasmodic dysphonia (vocal cord spasms) is intermittent spasm of laryngeal muscles that causes an abnormal voice.
Ca us e i s unknown. Pa ti ents often des cri be the ons et of s ymptoms fol l owi ng a URI, a peri od of exces s i ve voi ce us e, or occupa ti ona l or emoti ona l
s tres s . As a l oca l i zed form of movement di s order, s pa s modi c dys phoni a ha s a n ons et between a ges 30 a nd 50 yr, a nd a bout 60% of pa ti ents a re
women.
In the a dductor type of s pa s modi c dys phoni a , pa ti ents a ttempt to s pea k through the s pa s modi c cl os ure wi th a voi ce tha t s ounds s queezed,
effortful , or s tra i ned. Thes e s pa s modi c epi s odes us ua l l y occur when vowel s ounds a re bei ng formed, pa rti cul a rl y a t the begi nni ng of words . The
l es s common a bductor form res ul ts i n s udden i nterrupti ons of s ound ca us ed by momenta ry a bducti on of the voca l cords a ccompa ni ed by a udi bl e
es ca pe of a i r duri ng connected s peech.
Surgery ha s been more s ucces s ful tha n other a pproa ches for a dductor s pa s modi c dys phoni a . The us e of botul i num toxi n i njecti on ha s res tored a
norma l voi ce i n 70% of pa ti ents for up to 3 mo. Beca us e the effect i s tempora ry, i njecti ons ma y be repea ted. There i s no known tempora ry
a l l evi a ti on of the a bductor form of thi s di s order.
Vocal Cord Paralysis
Vocal cord paralysis has numerous causes and can affect speaking, breathing, and swallowing. The left vocal cord is affected twice as often as the right, and
females are affected more often than males (3:2). Diagnosis is based on direct visualization. An extensive assessment may be necessary to determine the cause.
Several direct surgical approaches are available if treating the cause is not curative.
Voca l cord pa ra l ys i s ma y res ul t from l es i ons a t the nucl eus a mbi guus , i ts s upra nucl ea r tra cts , the ma i n trunk of the va gus , or the recurrent
l a ryngea l nerves .
Pa ra l ys i s i s us ua l l y uni l a tera l . About one thi rd of uni l a tera l voca l cord pa ra l ys es a re neopl a s ti c i n ori gi n, one thi rd a re tra uma ti c, a nd one thi rd
a re i di opa thi c. Intra cra ni a l tumors , va s cul a r a cci dents , a nd demyel i na ti ng di s ea s es ca us e nucl eus a mbi guus pa ra l ys i s . Tumors a t the ba s e of the
s kul l a nd tra uma to the neck ca us e va gus pa ra l ys i s . Recurrent l a ryngea l nerve pa ra l ys i s i s ca us ed by neck or thora ci c l es i ons (eg, a orti c a neurys m;
mi tra l s tenos i s ; medi a s ti na l tubercul ous a deni ti s ; tumors of the thyroi d gl a nd, es opha gus , l ung, or medi a s ti na l s tructures ), tra uma ,
thyroi dectomy, neurotoxi ns (eg, l ea d, a rs eni c, mercury), neurotoxi c i nfecti ons (eg, di phtheri a ), cervi ca l s pi ne i njury or s urgery, Lyme di s ea s e, a nd
vi ra l i l l nes s . Vi ra l neuroni ti s proba bl y a ccounts for mos t i di opa thi c ca s es .
Bi l a tera l voca l cord pa ra l ys i s i s a l i fe-threa teni ng di s order ca us ed by thyroi d a nd cervi ca l s urgery, tra chea l i ntuba ti on, tra uma , a nd
neurodegenera ti ve a nd neuromus cul a r di s ea s es .
Symptoms and Signs
Voca l cord pa ra l ys i s res ul ts i n l os s of voca l cord a bducti on a nd a dducti on. Pa ra l ys i s ma y a ffect phona ti on, res pi ra ti on, a nd degl uti ti on, a nd food
a nd fl ui ds ma y be a s pi ra ted i nto the tra chea . The pa ra l yzed cord genera l l y l i es 2 to 3 mm l a tera l to the mi dl i ne. In recurrent l a ryngea l nerve
pa ra l ys i s , the cord ma y move wi th phona ti on but not wi th i ns pi ra ti on. In uni l a tera l pa ra l ys i s , the voi ce ma y be hoa rs e a nd brea thy, but the a i rwa y
i s us ua l l y not obs tructed beca us e the norma l cord a bducts s uffi ci entl y. In bi l a tera l pa ra l ys i s , both cords genera l l y l i e wi thi n 2 to 3 mm of the
mi dl i ne, a nd the voi ce i s of good qua l i ty but of l i mi ted i ntens i ty. The a i rwa y, however, i s i na dequa te, res ul ti ng i n s tri dor a nd dys pnea wi th
modera te exerti on a s ea ch cord i s dra wn to the mi dl i ne gl otti s by a n i ns pi ra tory Bernoul l i effect. As pi ra ti on i s a l s o a da nger.
Diagnosis
La ryngos copy
Va ri ous tes ts for pos s i bl e ca us es
Di a gnos i s i s ba s ed on l a ryngos copy. The ca us e mus t a l wa ys be s ought. Eva l ua ti on i s gui ded by a bnorma l i ti es i denti fi ed on hi s tory a nd phys i ca l
exa mi na ti on. Duri ng the hi s tory, the phys i ci a n a s ks a bout a l l pos s i bl e ca us es of peri phera l neuropa thy, i ncl udi ng chroni c hea vy meta l expos ure
(a rs eni c, l ea d, mercury), drug effects from phenytoi n a nd vi ncri s ti ne, a nd hi s tory of connecti ve ti s s ue di s orders , Lyme di s ea s e, s a rcoi dos i s ,
di a betes , a nd a l cohol i s m. Further eva l ua ti on ma y i ncl ude enha nced CT or MRI of the hea d, neck, a nd ches t; thyroi d s ca n; ba ri um s wa l l ow or
bronchos copy; a nd es opha gos copy. Cri coa rytenoi d a rthri ti s , whi ch ma y ca us e fi xa ti on of the cri coa rytenoi d joi nt, mus t be di fferenti a ted from a
neuromus cul a r eti ol ogy. Fi xa ti on i s bes t documented by a bs ence of pa s s i ve mobi l i ty duri ng ri gi d l a ryngos copy under genera l a nes thes i a .
Cri coa rytenoi d a rthri ti s ma y compl i ca te s uch condi ti ons a s RA, externa l bl unt tra uma , a nd prol onged endotra chea l i ntuba ti on.
Treatment
For uni l a tera l pa ra l ys i s , s urgi ca l procedures to move cords cl os er together
For bi l a tera l pa ra l ys i s , s urgi ca l procedures a nd mea s ures to ma i nta i n a i rwa y
In uni l a tera l pa ra l ys i s , trea tment i s di rected a t i mprovi ng voi ce qua l i ty through a ugmenta ti on, medi a l i za ti on, or rei nnerva ti on.
Augmenta ti on i nvol ves i njecti ng a pa s te of pl a s ti ci zed pa rti cl es , col l a gen, mi croni zed dermi s , or a utol ogous fa t i nto the pa ra l yzed cord, bri ngi ng
the cords cl os er together to i mprove the voi ce a nd prevent a s pi ra ti on.
Medi a l i za ti on i s s hi fti ng the voca l cord towa rd the mi dl i ne by i ns erti ng a n a djus ta bl e s pa cer l a tera l l y to the a ffected cord. Thi s ca n be done wi th a
l oca l a nes theti c, a l l owi ng the pos i ti on of the s pa cer to be "tuned" to the pa ti ent's voi ce. Unl i ke a ugmenta ti on wi th pl a s ti ci zed pa rti cl es , whi ch
perma nentl y fi xes the cord, the s pa cer i s both a djus ta bl e a nd remova bl e.
Rei nnerva ti on ha s onl y ra rel y been s ucces s ful .
In bi l a tera l pa ra l ys i s , a n a dequa te a i rwa y mus t be rees ta bl i s hed. Tra cheotomy ma y be needed perma nentl y or tempora ri l y duri ng a URI. An
a rytenoi dectomy wi th l a tera l i za ti on of the true voca l cord opens the gl otti s a nd i mproves the a i rwa y but ma y a dvers el y a ffect voi ce qua l i ty.
Pos teri or l a s er cordectomy opens the pos teri or gl otti s a nd ma y be preferred to endos copi c or open a rytenoi dectomy. Succes s ful l a s er
es ta bl i s hment of a pos teri or gl otti c a i rwa y us ua l l y obvi a tes the need for l ong-term tra cheotomy whi l e pres ervi ng a s ervi cea bl e voi ce qua l i ty.
Vocal Cord Polyps and Nodules
Acute trauma or chronic irritation causes changes in the vocal cords that can lead to polyps or nodules. Both cause hoarseness and a breathy voice. Persistence of
these symptoms for > 3 wk dictates visualization of the vocal cords. Diagnosis is based on laryngoscopy and on biopsy to rule out cancer. Surgical removal
restores the voice, and removal of the irritating source prevents recurrence.
Etiology
Pol yps a nd nodul es res ul t from i njury to the l a mi na propri a of the true voca l cords . Pol yps ma y occur a t the mi d thi rd of the membra nous cords a nd
a re more often uni l a tera l . They frequentl y res ul t from a n i ni ti a ti ng a cute phona tory i njury. Nodul es us ua l l y occur bi l a tera l l y a t the juncti on of the
a nteri or a nd mi ddl e thi rd of the cords . Thei r ma i n ca us e i s chroni c voi ce a bus eyel l i ng, s houti ng, s i ngi ng l oudl y, or us i ng a n unna tura l l y l ow
frequency. Pol yps ma y ha ve s evera l other ca us es , i ncl udi ng ga s tri c refl ux, untrea ted hypothyroi d s ta tes , chroni c l a ryngea l a l l ergi c rea cti ons , or
chroni c i nha l a ti on of i rri ta nts , s uch a s i ndus tri a l fumes or ci ga rette s moke. Pol yps tend to be l a rger a nd more protubera nt tha n nodul es a nd often
ha ve a domi na nt s urfa ce bl ood ves s el .
Symptoms and Signs
Both res ul t i n s l owl y devel opi ng hoa rs enes s a nd a brea thy voi ce.
Diagnosis
La ryngos copy
Someti mes bi ops y
Di a gnos i s i s ba s ed on di rect or i ndi rect vi s ua l i za ti on of the l a rynx wi th a mi rror or l a ryngos cope. Bi ops y of di s crete l es i ons to excl ude ca rci noma i s
done by mi crol a ryngos copy.
Treatment
Avoi da nce of ca us e
For pol yps , us ua l l y s urgi ca l remova l
Correcti on of the underl yi ng voi ce a bus e cures mos t nodul es a nd prevents recurrence. Remova l of the offendi ng i rri ta nts a l l ows hea l i ng, a nd voi ce
thera py wi th a s peech thera pi s t reduces the tra uma to the voca l cords ca us ed by i mproper s i ngi ng or protra cted l oud s pea ki ng. Nodul es us ua l l y
regres s wi th voi ce thera py a l one.
Mos t pol yps mus t be s urgi ca l l y removed to res tore a norma l voi ce. Col d-kni fe mi cros urgi ca l exci s i on duri ng di rect mi crol a ryngos copy i s prefera bl e
to l a s er exci s i on, whi ch i s more l i kel y to ca us e col l a tera l therma l i njury i f i mproperl y a ppl i ed.
In mi crol a ryngos copy, a n opera ti ng mi cros cope i s us ed to exa mi ne, bi ops y, a nd opera te on the l a rynx. Ima ges ca n be recorded on vi deo a s wel l .
The pa ti ent i s a nes theti zed, a nd the a i rwa y i s s ecured by hi gh-pres s ure jet venti l a ti on through the l a ryngos cope, endotra chea l i ntuba ti on, or, for
a n i na dequa te upper a i rwa y, tra cheotomy. Beca us e the mi cros cope a l l ows obs erva ti on wi th ma gni fi ca ti on, ti s s ue ca n be removed preci s el y a nd
a ccura tel y, mi ni mi zi ng da ma ge (pos s i bl y perma nent) to the voca l mecha ni s m. La s er s urgery ca n be done through the opti ca l s ys tem of the
mi cros cope to a l l ow for preci s e cuts . Mi crol a ryngos copy i s preferred for a l mos t a l l l a ryngea l bi ops i es , for procedures i nvol vi ng beni gn tumors , a nd
for ma ny forms of phonos urgery.
Chapter 55. Tumors of the Head and Neck

Introduction
The mos t common noncuta neous tumor of the hea d a nd neck i s s qua mous cel l ca rci noma of the l a rynx, fol l owed by s qua mous cel l ca rci noma s of
the tongue, pa l a ti ne tons i l , a nd fl oor of the mouth. Les s common a re tumors of the s a l i va ry gl a nds , ja w, nos e a nd pa ra na s a l s i nus es , a nd ea r.
Tumors of the thyroi d gl a nd, eye, a nd s ki n a re di s cus s ed el s ewhere i n THE MANUAL.
Excl udi ng the s ki n a nd thyroi d gl a nd, > 90% of hea d a nd neck ca ncers a re s qua mous cel l (epi dermoi d) ca rci noma s , a nd 5% a re mel a noma s ,
l ymphoma s , a nd s a rcoma s . Pa ti ents wi th s a rcoma s or ca rci noma s of the s a l i va ry gl a nds or pa ra na s a l s i nus es a re often younger tha n pa ti ents wi th
s qua mous cel l ca rci noma , who a re more commonl y i n thei r mi d-50s a nd ol der.
Etiology
The va s t ma jori ty of pa ti ents , 85% or more, wi th ca ncer of the hea d a nd neck ha ve a hi s tory of a l cohol us e, s moki ng, or both. Other s us pected
ca us es i ncl ude us e of s nuff or chewi ng toba cco, s unl i ght expos ure, previ ous x-ra ys of the hea d a nd neck, certa i n vi ra l i nfecti ons , i l l -fi tti ng denta l
a ppl i a nces , chroni c ca ndi di a s i s , a nd poor ora l hygi ene. In Indi a , ora l ca ncer i s extremel y common, proba bl y beca us e of chewi ng betel qui d (a
mi xture of s ubs ta nces , a l s o ca l l ed pa a n). Long-term expos ure to s unl i ght a nd the us e of toba cco products a re the pri ma ry ca us es of s qua mous cel l
ca rci noma of the l ower l i p.
Pa ti ents who i n the pa s t were trea ted wi th ra di a ti on for a cne, exces s fa ci a l ha i r, enl a rged thymus , or hypertrophi c tons i l s a nd a denoi ds a re
predi s pos ed to thyroi d a nd s a l i va ry gl a nd ca ncers a nd beni gn s a l i va ry tumors .
Eps tei n-Ba rr vi rus pl a ys a rol e i n the pa thogenes i s of na s opha ryngea l ca ncer, a nd s erum mea s ures of certa i n Eps tei n-Ba rr vi rus protei ns ma y be
bi oma rkers of recurrence. Huma n pa pi l l oma vi rus s eems to be a s s oci a ted wi th hea d a nd neck s qua mous cel l ca rci noma , pa rti cul a rl y
oropha ryngea l ca ncer. The mecha ni s m for vi ra l -medi a ted tumor genes i s ma y be di s ti nct from toba cco-rel a ted pa thwa ys a nd s eem to ha ve a
di fferent, better, prognos i s .
Symptoms and Signs
Mos t hea d a nd neck ca ncers fi rs t ma ni fes t a s a n a s ymptoma ti c neck ma s s , pa i nful mucos a l ul cera ti on, or vi s i bl e mucos a l l es i on (eg, l eukopl a ki a ,
erythropl a ki a ). Subs equent s ymptoms depend on l oca ti on a nd extent of the tumor a nd i ncl ude pa i n, pa res thes i a , nerve pa l s i es , tri s mus , a nd
ha l i tos i s . Ota l gi a i s a n often overl ooked s ymptom us ua l l y repres enti ng referred pa i n from the pri ma ry tumor. Wei ght l os s ca us ed by perturbed
ea ti ng a nd odynopha gi a i s a l s o common.
Diagnosis
Bi ops y
Ima gi ng tes ts a nd endos copy to eva l ua te extent of di s ea s e
Routi ne phys i ca l exa mi na ti on (i ncl udi ng a thorough ora l exa mi na ti on) i s the bes t wa y to detect ca ncers ea rl y before they become s ymptoma ti c.
Commerci a l l y a va i l a bl e brus h bi ops y ki ts hel p s creen for ora l ca ncers . Any hea d a nd neck s ymptom (eg, s ore throa t, hoa rs enes s , ota l gi a ) l a s ti ng >
2 to 3 wk s houl d prompt referra l to a hea d a nd neck s peci a l i s t.
Defi ni ti ve di a gnos i s us ua l l y requi res a bi ops y. Addi ti ona l i mporta nt i nforma ti on i s obta i ned from a combi na ti on of i ma gi ng tes ts (eg, CT, MRI,
PET/CT), endos copy, a nd fi ne-needl e a s pi ra ti on of a ny neck ma s s .
Staging
Hea d a nd neck ca ncers ma y rema i n l oca l i zed for months to yea rs . Loca l ti s s ue i nva s i on eventua l l y i s fol l owed by meta s ta s i s to regi ona l l ymph
nodes , rel a ted i n l a rge pa rt to tumor s i ze a nd extent, a nd reduces overa l l s urvi va l by nea rl y ha l f. Di s ta nt meta s ta s es tend to occur l a te, us ua l l y i n
pa ti ents wi th a dva nced tumor a nd noda l s ta ges . Meta s ta s es occur more commonl y a mong i mmunocompromi s ed pa ti ents . Common s i tes of
di s ta nt meta s ta s es a re the l ungs , l i ver, bone, a nd bra i n.
Hea d a nd neck ca ncers a re s ta ged (s ee
Ta bl e 55-1) a ccordi ng to s i ze a nd s i te of the pri ma ry tumor (T), number a nd s i ze of meta s ta s es to the cervi ca l l ymph nodes (N), a nd evi dence of
di s ta nt meta s ta s es (M). Sta gi ng us ua l l y requi res i ma gi ng wi th CT, MRI, or both, a nd often PET.
Prognosis
Prognos i s i s fa vora bl e i f di a gnos i s i s ea rl y a nd trea tment i s ti mel y a nd a ppropri a te. In genera l , the more poorl y di fferenti a ted the ca ncer, the
grea ter the cha nce of regi ona l a nd di s ta nt meta s ta s es . The pres ence of regi ona l noda l s prea d reduces overa l l s urvi va l by nea rl y ha l f. Di s ta nt
meta s ta s i s grea tl y reduces s urvi va l , ha vi ng onl y ra re cures . Loca l i nva s i on, a cri teri on for a dva nced T s ta ge, wi th i nva s i on of mus cl e, bone, or
ca rti l a ge, a l s o s i gni fi ca ntl y decrea s es cure ra te. Peri neura l s prea d, a s evi denced by pa i n, pa ra l ys i s , or numbnes s , i ndi ca tes a hi ghl y a ggres s i ve
tumor, i s a s s oci a ted wi th noda l meta s ta s i s , a nd ha s a l es s fa vora bl e prognos i s tha n a s i mi l a r l es i on wi thout peri neura l i nva s i on.
Wi th a ppropri a te trea tment, 5-yr s urvi va l ca n be a s hi gh a s 90% for s ta ge I, 75 to 80% for s ta ge II, 45 to 75% for s ta ge III, a nd up to 40% for s ta ge IV.
The s urvi va l ra tes va ry grea tl y dependi ng on the pri ma ry s i te. Sta ge I l a ryngea l ca ncers ha ve a n excel l ent s urvi va l ra te when compa red to other
s i tes .
Treatment
Surgery, ra di a ti on thera py, or both

Someti mes chemothera py
Ma ny s ta ge I tumors , rega rdl es s of l oca ti on, res pond s i mi l a rl y to s urgery a nd to ra di a ti on thera py, a l l owi ng other fa ctors (eg, pa ti ent preference)
to determi ne choi ce of thera py. Thus , the trea ti ng phys i ci a n s houl d ca reful l y revi ew ri s ks a nd benefi ts wi th the pa ti ent. However, a t certa i n
l oca ti ons , there i s cl ea r s uperi ori ty of one moda l i ty over a nother. For
[Table 55-1. Sta gi ng of Hea d a nd Neck Ca ncer]
exa mpl e, s urgery i s the better trea tment for ea rl y-s ta ge di s ea s e i nvol vi ng the ora l ca vi ty. In s el ect hea d a nd neck ca ncers , endos copi c s urgery ha s
cure ra tes s i mi l a r to thos e of open s urgery or ra di a ti on, a nd morbi di ty i s s i gni fi ca ntl y l es s . However, ma ny phys i ci a ns s ti l l recommend ra di a ti on
for ea rl y-s ta ge l a ryngea l ca ncer.
If ra di a ti on thera py i s chos en for pri ma ry thera py, i t i s del i vered to the pri ma ry s i te a nd s ometi mes bi l a tera l l y to the cervi ca l l ymph nodes . The
trea tment of l ympha ti cs , whether by ra di a ti on or s urgery, i s determi ned by the pri ma ry s i te, hi s tol ogi c cri teri a , a nd ri s k of noda l di s ea s e.
Adva nced-s ta ge di s ea s e (s ta ges III a nd IV) often requi res mul ti moda l i ty trea tment, i ncorpora ti ng s ome combi na ti on of chemothera py, ra di a ti on
thera py, a nd s urgery. Bone or ca rti l a ge i nva s i on requi res s urgi ca l res ecti on of the pri ma ry s i te a nd us ua l l y regi ona l l ymph nodes beca us e of the
hi gh ri s k of noda l s prea d. If the pri ma ry s i te i s trea ted s urgi ca l l y, then pos topera ti ve ra di a ti on to the cervi ca l l ymph nodes i s del i vered i f there a re
hi gh-ri s k fea tures , s uch a s mul ti pl e l ymph nodes wi th ca ncer or extra ca ps ul a r extens i on. Pos topera ti ve ra di a ti on us ua l l y i s preferred over
preopera ti ve ra di a ti on, beca us e ra di a ted ti s s ues hea l poorl y. Recent s tudi es ha ve s hown tha t a ddi ng chemothera py to a djuva nt ra di a ti on thera py
to the neck i mproves regi ona l control of the ca ncer a nd i mproves s urvi va l . There a re s i gni fi ca nt ri s ks to thi s a pproa ch, s o the deci s i on to a dd
chemothera py s houl d be ca reful l y cons i dered.
Adva nced s qua mous cel l ca rci noma wi thout bony i nva s i on often i s trea ted wi th concomi ta nt chemothera py a nd ra di a ti on thera py. Al though
a dvoca ted a s orga n-s pa ri ng, combi ni ng chemothera py wi th ra di a ti on thera py doubl es the ra te of a cute toxi ci ti es , pa rti cul a rl y s evere dys pha gi a .
Ra di a ti on ma y be us ed a l one for debi l i ta ted pa ti ents wi th a dva nced di s ea s e who ca nnot tol era te the s equel a e of chemothera py a nd a re too hi gh
a ri s k for genera l a nes thes i a .
Pri ma ry chemothera py i s res erved for chemos ens i ti ve tumors , s uch a s Burki tt's l ymphoma , or for pa ti ents who ha ve wi des prea d meta s ta s es (eg,
hepa ti c or pul mona ry i nvol vement). Severa l drugs ci s pl a ti n, fl uoroura ci l , bl eomyci n, a nd methotrexa teprovi de pa l l i a ti on for pa i n a nd s hri nk
the tumor i n pa ti ents who ca nnot be trea ted wi th other methods . Res pons e ma y be good i ni ti a l l y but i s not dura bl e, a nd the ca ncer wi l l return.
Tumor recurrence: Ma na gi ng recurrent tumors a fter thera py i s compl ex a nd ha s potenti a l compl i ca ti ons . A pa l pa bl e ma s s or ul cera ted l es i on wi th
edema or pa i n a t the pri ma ry s i te a fter thera py s trongl y s ugges ts a pers i s tent tumor. Such pa ti ents requi re CT (wi th thi n cuts ) or MRI. For l oca l
recurrence a fter s urgi ca l trea tment, a l l s ca r pl a nes a nd recons tructi ve fl a ps a re exci s ed a l ong wi th res i dua l ca ncer. Ra di a ti on thera py,
chemothera py, or both ma y be done but ha ve l i mi ted effecti venes s . Pa ti ents wi th recurrence a fter ra di a ti on thera py s houl d not recei ve a ddi ti ona l
ra di a ti on a nd a re bes t trea ted wi th s urgery.
Symptom control: Pa i n i s a common s ymptom i n pa ti ents wi th hea d a nd neck ca ncer a nd mus t be a dequa tel y a ddres s ed. Pa l l i a ti ve s urgery or
ra di a ti on ma y tempora ri l y a l l evi a te pa i n, a nd i n 30 to 50% of pa ti ents , chemothera py ca n produce i mprovement tha t l a s ts a mea n of 3 mo. A
s tepwi s e a pproa ch to pa i n ma na gement, a s recommended by the WHO, i s cri ti ca l to control l i ng pa i n. Severe pa i n i s bes t ma na ged i n a s s oci a ti on
wi th a pa i n a nd pa l l i a ti ve ca re s peci a l i s t.
Pa i n, di ffi cul ty ea ti ng, choki ng on s ecreti ons , a nd other probl ems ma ke a dequa te s ymptoma ti c trea tment es s enti a l . Pa ti ent di recti ves rega rdi ng
s uch ca re s houl d be cl a ri fi ed ea rl y (s ee p. 3471).
Adverse effects of treatment: Al l ca ncer trea tments ha ve potenti a l compl i ca ti ons a nd expected s equel a e. Beca us e ma ny trea tments ha ve s i mi l a r
cure ra tes , the choi ce of moda l i ty i s ba s ed l a rgel y on rea l , or percei ved, di fferences i n s equel a e.
Al though i t i s commonl y thought tha t s urgery requi res reha bi l i ta ti on for s wa l l owi ng a nd s pea ki ng, ma ny procedures do not requi re s uch
reha bi l i ta ti on. Increa s i ngl y compl ex recons tructi ve procedures a nd techni ques , i ncl udi ng pros thes es , gra fts , regi ona l pedi cl e fl a ps , a nd compl ex
free fl a ps , ca n res tore functi on a nd a ppea ra nce often to nea r norma l .
Toxi c effects of chemothera py i ncl ude ma l a i s e, s evere na us ea a nd vomi ti ng, mucos i ti s , tra ns i ent ha i r l os s , ga s troenteri ti s , hema topoi eti c a nd
i mmune s uppres s i on, a nd i nfecti on.
Thera peuti c ra di a ti on for hea d a nd neck ca ncers ha s s evera l a dvers e effects . The functi on of a ny s a l i va ry gl a nd wi thi n the bea m i s perma nentl y
des troyed by a dos e of a bout 40 Gy, res ul ti ng i n xeros tomi a , whi ch ma rkedl y i ncrea s es the ri s k of denta l ca ri es . Newer ra di a ti on techni ques , s uch
a s i ntens i ty-modul a ted ra di a ti on thera py, ca n mi ni mi ze or el i mi na te toxi c dos es to the pa roti d gl a nds i n certa i n pa ti ents . Ra di oprotecta nt drugs
(eg, a mi fos ti ne) a l s o ca n hel p protect s a l i va ry functi on. In a ddi ti on, the bl ood s uppl y of bone, pa rti cul a rl y i n the ma ndi bl e, i s compromi s ed by
dos es of > 60 Gy, a nd os teora di onecros i s ma y occur (s ee a l s o p. 505). In thi s condi ti on, tooth extra cti on s i tes brea k down, s l oughi ng bone a nd s oft
ti s s ue. Therefore, a ny needed denta l trea tment, i ncl udi ng s ca l i ng, fi l l i ngs , a nd extra cti ons , s houl d be done before ra di a ti on thera py. Any teeth i n
poor condi ti on tha t ca nnot be reha bi l i ta ted s houl d be extra cted. Ra di a ti on thera py ma y a l s o ca us e ora l mucos i ti s a nd derma ti ti s i n the overl yi ng
s ki n, whi ch ma y res ul t i n derma l fi bros i s . Los s of ta s te (a geus i a ) a nd i mpa i red s mel l (dys os mi a ) often occur but a re us ua l l y tra ns i ent.
Prevention
Removi ng ri s k fa ctors i s cri ti ca l , a nd a l l pa ti ents s houl d cea s e toba cco us e a nd l i mi t a l cohol cons umpti on. Removi ng ri s k fa ctors a l s o hel ps
prevent di s ea s e recurrence i n thos e trea ted for ca ncer. A new pri ma ry ca ncer devel ops i n a bout 5% of pa ti ents /yr (to a ma xi mum ri s k of a bout 20%);
ri s k i s l ower i n thos e who s top.
Ca ncer of the l ower l i p ma y be prevented by s uns creen us e a nd toba cco ces s a ti on. Beca us e 60% of hea d a nd neck ca ncers a re wel l a dva nced
(s ta ge III or IV) a t the ti me of di a gnos i s , the mos t promi s i ng s tra tegy for reduci ng morbi di ty a nd morta l i ty i s di l i gent routi ne exa mi na ti on of the
ora l ca vi ty.
Jaw Tumors
Numerous tumor types, both benign and malignant, originate in the jaw. Symptoms are swelling, pain, tenderness, and unexplained tooth mobility; some tumors
are discovered on routine dental x-rays, whereas others are found on routine examinations of the oral cavity and teeth. Treatment depends on location and tumor
type. Benign tumors may be observed and may not need surgical excision, although most tumors require resection with possible reconstruction.
If not i ni ti a l l y detected on x-ra y, ja w tumors a re di a gnos ed cl i ni ca l l y beca us e thei r growth ca us es s wel l i ng of the fa ce, pa l a te, or a l veol a r ri dge
(the pa rt of the ja w s upporti ng the teeth). They ca n a l s o ca us e bone tendernes s a nd s evere pa i n.
Bony outgrowths (torus pa l a ti nus , torus ma ndi bul a ri s ) ma y devel op on the pa l a te or ma ndi bl e. Thes e a re common growths a nd ma y prompt
concerns a bout ca ncer, a l though they a re beni gn a nd of concern onl y i f they i nterfere wi th denta l ca re or functi on of the s ubma ndi bul a r gl a nd.
When on the pa l a te, they a re i n the mi dl i ne a nd ha ve i nta ct, s mooth mucos a . Mul ti pl e os teoma s s een on denta l x-ra y ma y s ugges t Ga rdner's
s yndrome.
The mos t common tumor of the ma ndi bl e a nd ma xi l l a i s s qua mous cel l ca rci noma i nva di ng the bone through denta l s ockets . Thes e ca n i nvol ve
a ny porti on of the i ntra ora l ma ndi bl e or ma xi l l a .
Amel obl a s toma , the mos t common epi thel i a l odontogeni c tumor, us ua l l y a ri s es i n the pos teri or ma ndi bl e. It i s s l owl y i nva s i ve a nd ra rel y
meta s ta ti c. On x-ra y, i t typi ca l l y a ppea rs a s mul ti l ocul a ted or s oa p-bubbl e ra di ol ucency. Trea tment i s wi de s urgi ca l exci s i on a nd recons tructi on i f
a ppropri a te.
Odontoma , the mos t common odontogeni c tumor, a ffects the denta l fol l i cl e or the denta l ti s s ues a nd us ua l l y a ppea rs i n the ma ndi bl es of young
peopl e. Odontoma s i ncl ude fi brous odontoma s a nd cementoma s . A cl i ni ca l l y a bs ent mol a r tooth s ugges ts a compos i te odontoma . Typi ca l l y, no
trea tment i s i ndi ca ted. Thes e tumors ma y be exci s ed when the di a gnos i s i s i n doubt.
Os teos a rcoma , gi a nt cel l tumor, Ewi ng's tumor, mul ti pl e myel oma , a nd meta s ta ti c tumors ma y a ffect the ja w. Trea tment i s the s a me a s for thos e
tumors i n other bony s i tes .
Laryngeal Cancer
Ninety percent of laryngeal cancer is squamous cell carcinoma. Smoking, alcohol abuse, lower socioeconomic status, and being male and > 60 yr increase risk.
Early diagnosis is common with vocal cord tumors because vocal, swallowing, or respiratory symptoms develop early. However, supraglottic tumors (above the
vocal cords) and subglottic tumors (below the vocal cords) are often very large and at an advanced stage when diagnosed because they are asymptomatic until
obstructive symptoms develop. Diagnosis is based on laryngoscopy and biopsy. Treatment of early-stage tumors is with surgery or radiation. Advanced-stage
tumors are most often treated with chemotherapy and radiation therapy. Surgery is reserved for salvage treatment or lesions with significant extralaryngeal
extension or cartilage destruction. Reestablishment of speaking ability is needed if a total laryngectomy is done.
Squa mous cel l ca rci noma i s the mos t common ca ncer of the l a rynx. In the US, i t i s 4 ti mes more common a mong men a nd i s more common a mong
thos e of l ower s oci oeconomi c s ta tus . Over 95% of pa ti ents a re s mokers ; 15 pa ck-yea rs of s moki ng i ncrea s e the ri s k 30-fol d. The i nci dence of l a rynx
ca ncer i s decrea s i ng, pa rti cul a rl y a mong men, mos t l i kel y due to cha nges i n s moki ng ha bi ts .
Si xty percent of pa ti ents pres ent wi th l oca l i zed di s ea s e a l one; 25% pres ent wi th l oca l di s ea s e a nd regi ona l noda l meta s ta ti c di s ea s e; a nd 15%
pres ent wi th a dva nced di s ea s e, di s ta nt meta s ta s es , or both. Di s ta nt meta s ta s es occur mos t frequentl y i n the l ungs a nd l i ver.
Common s i tes of ori gi n a re the true voca l cords (gl otti s ) a nd the s upra gl otti c l a rynx. The l ea s t common s i te i s the s ubgl otti c l a rynx, where onl y 1%
of pri ma ry l a ryngea l ca ncers ori gi na te. Verrucous ca rci noma , a ra re va ri a nt of s qua mous cel l ca rci noma , us ua l l y a ri s es i n the gl otti c a rea a nd ha s a
better s urvi va l ra te tha n s ta nda rd s qua mous cel l ca rci noma .
Symptoms and Signs
Symptoms a nd s i gns di ffer ba s ed on the i nvol ved porti on of the l a rynx. Hoa rs enes s i s common ea rl y i n gl otti c ca ncers but i s a l a te s ymptom for
s upra gl otti c a nd s ubgl otti c ca ncers . Supra gl otti c ca ncer i s often a s ymptoma ti c unti l i t ma ni fes ts a s a ma s s l es i on (eg, wi th a i rwa y obs tructi on,
dys pha gi a , ota l gi a , or a "hot pota to" voi ce) or wi th wei ght l os s . Such pa ti ents s houl d be referred for i ndi rect l a ryngos copy wi thout del a y.
Diagnosis
La ryngos copy
Opera ti ve endos copy a nd bi ops y
Ima gi ng tes ts for s ta gi ng
Al l pa ti ents who ha ve hoa rs enes s for > 2 to 3 wk s houl d ha ve thei r l a rynx exa mi ned by a hea d a nd neck s peci a l i s t. Any l es i ons di s covered requi re
further eva l ua ti on, us ua l l y wi th opera ti ve endos copy a nd bi ops y, wi th concomi ta nt eva l ua ti on of the upper a i rwa y a nd GI tra ct for coexi s ti ng
ca ncers . The i nci dence of a s ynchronous s econd pri ma ry tumor ma y be a s hi gh a s 10%.
Pa ti ents wi th confi rmed ca rci noma typi ca l l y ha ve neck CT wi th contra s t a nd a ches t x-ra y or ches t CT. Mos t cl i ni ci a ns a l s o do PET of the neck a nd
ches t a t the ti me of di a gnos i s .
Treatment
Ea rl y-s ta ge: Surgery or ra di a ti on thera py

Adva nced: Ra di a ti on thera py a nd s ometi mes chemothera py
For ea rl y-s ta ge gl otti c ca rci noma , l a s er exci s i on, ra di a ti on thera py, or occa s i ona l l y open l a ryngea l s urgery res ul ts i n a 5-yr s urvi va l ra te of 85 to
95%. Endos copi c l a s er res ecti on a nd ra di a ti on thera py us ua l l y pres erve a norma l voi ce a nd pos t-trea tment functi on a nd ha ve s i mi l a r cure ra tes .
For a dva nced gl otti c ca rci noma , defi ned by a l a ck of voca l cord mobi l i ty, thyroi d ca rti l a ge i nva s i on, or extens i on i nto the tongue, mos t pa ti ents a re
trea ted wi th chemothera py a nd ra di a ti on thera py. Surgery (fol l owed by ra di a ti on thera py) i s res erved for s a l va ge s i tua ti ons ; mos t s uch ca s es
requi re tota l l a ryngectomy, a l though endos copi c or open pa rti a l l a ryngectomy ma y s ometi mes be us ed. Extens i ve l oca l i nva s i on, however, us ua l l y
requi res a n i ni ti a l tota l l a ryngectomy ra ther tha n nons urgi ca l thera py.
Ea rl y s upra gl otti c ca rci noma ca n be effecti vel y trea ted wi th ra di a ti on thera py or pa rti a l l a ryngectomy. La s er res ecti on ha s s hown cons i dera bl e
s ucces s on ea rl y-s ta ge s upra gl otti c s qua mous cel l ca rci noma s a nd mi ni mi zes functi ona l cha nges a fter s urgery. If the ca rci noma i s more a dva nced
but does not a ffect the true voca l cords , a s upra gl otti c pa rti a l l a ryngectomy ca n be done to pres erve the voi ce a nd gl otti c s phi ncter. If the true voca l
cords a l s o a re a ffected, a s upra cri coi d l a ryngectomy or a tota l l a ryngectomy i s requi red i f s urgery i s chos en. As wi th gl otti c ca rci noma , mos t
a dva nced-s ta ge s upra gl otti c ca ncers i ni ti a l l y a re trea ted wi th chemothera py a nd ra di a ti on thera py.
Trea tment of hypopha ryngea l ca rci noma s i s s i mi l a r to tha t of l a ryngea l ca ncer. Ea rl y-s ta ge l es i ons us ua l l y a re trea ted wi th ra di a ti on a l one,
a l though endos copi c res ecti on i s a n opti on. However, the ma jori ty of pa ti ents wi th hypopha ryngea l ca ncer ha ve a dva nced-s ta ge di s ea s e, beca us e
of the s i l ent na ture of the di s ea s e a nd frequent regi ona l l ympha ti c s prea d; s uch pa ti ents a re trea ted wi th chemothera py a nd ra di a ti on thera py
pri ma ri l y, wi th s urgi ca l s a l va ge.
Rehabilitation: Reha bi l i ta ti on ma y be requi red a fter ei ther s urgi ca l or nons urgi ca l trea tment. Si gni fi ca nt s wa l l owi ng probl ems a re common a fter
chemothera py a nd ra di a ti on thera py a nd ma y requi re es opha gea l di l a ti on, s wa l l owi ng thera py, or, i n s evere ca s es , s urgi ca l repl a cement of the
pha rynx or ga s tros tomy tube feedi ngs . Swa l l owi ng a l s o i s a ffected by s urgery a nd ma y requi re s wa l l owi ng thera py or di l a ti on a s wel l .
Speech, on the other ha nd, i s more s i gni fi ca ntl y a ffected by s urgery. After tota l l a ryngectomy, the pa ti ent requi res crea ti on of a new voi ce by wa y of
Es opha gea l s peech
A tra cheoes opha gea l puncture
An el ectrol a rynx
In a l l 3 techni ques , s ound i s a rti cul a ted i nto s peech by the pha rynx, pa l a te, tongue, teeth, a nd l i ps .
Es opha gea l s peech i nvol ves ta ki ng a i r i nto the es opha gus duri ng i ns pi ra ti on a nd gra dua l l y eructa ti ng the a i r through the pha ryngoes opha gea l
juncti on to produce a s ound.
A tra cheoes opha gea l puncture i nvol ves pl a cement of a one-wa y va l ve between the tra chea a nd es opha gus to fa ci l i ta te phona ti on. Thi s va l ve
forces a i r i nto the es opha gus duri ng expi ra ti on to produce a s ound. Pa ti ents recei ve phys i ca l reha bi l i ta ti on, s peech thera py, a nd a ppropri a te
tra i ni ng i n the ma i ntena nce a nd us e of thi s va l ve a nd mus t be ca uti oned a ga i ns t the pos s i bl e a s pi ra ti on of food, fl ui ds , a nd s ecreti ons .
An el ectrol a rynx i s a ba ttery-powered s ound s ource tha t i s hel d a ga i ns t the neck to produce s ound. Al though i t ca rri es a grea t dea l of s oci a l
s ti gma for ma ny pa ti ents , i t ha s the a dva nta ge of bei ng functi ona l i mmedi a tel y wi th l i ttl e or no tra i ni ng.
Nasopharyngeal Cancer
Nasopharyngeal cancers are rare in the US but common in the South China Sea region. Symptoms develop late, including unilateral bloody nasal discharge, nasal
obstruction, facial swelling, and numbness. Diagnosis is based on inspection and biopsy, with CT, MRI, or PET to evaluate extent. Treatment is with radiation,
chemotherapy, and, rarely, surgery.
Squa mous cel l ca rci noma i s the mos t common ma l i gna nt tumor of the na s opha rynx. It ca n occur i n a ny a ge group a nd i s ra re i n North Ameri ca . It i s
one of the mos t common ca ncers a mong peopl e of Chi nes e, es peci a l l y s outhern Chi nes e, a nd Southea s t As i a n a nces try, i ncl udi ng Chi nes e
i mmi gra nts to North Ameri ca . Over s evera l genera ti ons , the preva l ence a mong Chi nes e-Ameri ca ns gra dua l l y decrea s es to tha t a mong non-Chi nes e
Ameri ca ns , s ugges ti ng a n envi ronmenta l component to eti ol ogy. Di eta ry expos ure to ni tri tes a nd s a l ted fi s h a l s o i s thought to i ncrea s e ri s k.
Eps tei n-Ba rr vi rus i s a s i gni fi ca nt ri s k fa ctor, a nd there i s heredi ta ry predi s pos i ti on. Other na s opha ryngea l ca ncers i ncl ude a denoi d cys ti c a nd
mucoepi dermoi d ca rci noma s , ma l i gna nt mi xed tumors , a denoca rci noma s , l ymphoma s , fi bros a rcoma s , os teos a rcoma s , chondros a rcoma s , a nd
mel a noma s .
Symptoms and Signs
The fi rs t s ymptom i s often na s a l or eus ta chi a n tube obs tructi on ca us i ng hea ri ng l os s due to a mi ddl e ea r effus i on. Other s ymptoms i ncl ude
purul ent bl oody rhi norrhea , fra nk epi s ta xi s , cra ni a l nerve pa l s i es , a nd cervi ca l l ympha denopa thy. Cra ni a l nerve pa l s i es mos t often i nvol ve the 6th,
4th, a nd 3rd cra ni a l nerves due to thei r l oca ti on i n the ca vernous s i nus , i n cl os e proxi mi ty to the fora men l a cerum, whi ch i s the mos t common
route of i ntra cra ni a l s prea d for thes e tumors . Beca us e l ympha ti cs of the na s opha rynx communi ca te a cros s the mi dl i ne, bi l a tera l meta s ta s es a re
common.
Diagnosis
Na s opha ryngea l endos copy a nd bi ops y
Ima gi ng tes ts for s ta gi ng
Pa ti ents s us pected of ha vi ng na s opha ryngea l ca ncer mus t undergo exa mi na ti on wi th a na s opha ryngea l mi rror or endos cope, a nd l es i ons a re
bi ops i ed. Open cervi ca l node bi ops y s houl d not be done a s the i ni ti a l procedure (s ee Neck Ma s s on p. 461), a l though a needl e bi ops y i s
a ccepta bl e a nd often recommended. Ga dol i ni um-enha nced MRI (wi th fa t s uppres s i on) of the hea d wi th a ttenti on to the na s opha rynx a nd s kul l
ba s e i s done; the s kul l ba s e i s i nvol ved i n a bout 25% of pa ti ents . CT a l s o i s requi red to a ccura tel y a s s es s s kul l ba s e bony cha nges , whi ch a re l es s
vi s i bl e on MRI. A PET s ca n a l s o commonl y i s done to a s s es s the extent of di s ea s e a s wel l a s the cervi ca l l ympha ti cs .
Treatment
Chemothera py pl us ra di a ti on thera py
Beca us e of the l oca ti on a nd extent of i nvol vement, na s opha ryngea l ca ncers often a re not a mena bl e to s urgi ca l res ecti on. They a re typi ca l l y
trea ted wi th chemothera py a nd ra di a ti on thera py, whi ch a re often fol l owed by a djuva nt chemothera py.
Recurrent tumors ca n be trea ted wi th a nother cours e of ra di a ti on, commonl y wi th bra chythera py; ra di onecros i s of the s kul l ba s e i s a ri s k. An
a l terna ti ve to ra di a ti on i s s kul l ba s e res ecti on.
Oral Squamous Cell Carcinoma
Oral squamous cell carcinoma affects about 30,000 Americans each year. Over 95% smoke, drink alcohol, or both. Early, curable lesions are rarely symptomatic;
thus, preventing fatal disease requires early detection by screening. Treatment is with surgery, radiation, or both. The overall 5-yr survival rate (all sites and
stages combined) is > 50%.
In the US, 3% of ca ncers i n men a nd 2% i n women a re ora l s qua mous cel l ca rci noma s , mos t of whi ch occur a fter a ge 50. Squa mous cel l ca rci noma i s
the mos t common ora l or pha ryngea l ca ncer (a nd the mos t common a t hea d a nd neck s i tes i n genera l ).
The chi ef ri s k fa ctors for ora l s qua mous cel l ca rci noma a re s moki ng (es peci a l l y > 2 pa cks /da y) a nd a l cohol us e. Ri s k i ncrea s es dra ma ti ca l l y when
a l cohol us e exceeds 6 oz of di s ti l l ed l i quor, 6 oz of wi ne, or 12 oz of beer/da y. The combi na ti on of hea vy s moki ng a nd a l cohol a bus e i s es ti ma ted
to ra i s e the ri s k 100-fol d i n women a nd 38-fol d i n men. Squa mous cel l ca rci noma of the tongue ma y a l s o res ul t from a ny chroni c i rri ta ti on, s uch a s
denta l ca ri es , overus e of mouthwa s h, chewi ng toba cco, or the us e of betel qui d. Ora l huma n pa pi l l oma vi rus (HPV), typi ca l l y a cqui red vi a ora l geni ta l conta ct, ma y ha ve a rol e i n eti ol ogy.
About 40% of i ntra ora l s qua mous cel l ca rci noma s begi n on the fl oor of the mouth or on the l a tera l a nd ventra l s urfa ces of the tongue. About 38%
of a l l ora l s qua mous cel l ca rci noma s occur on the l ower l i p; thes e a re us ua l l y s ol a r-rel a ted ca ncers on the externa l s urfa ce. About 11% begi n i n
the pa l a te a nd tons i l l a r a rea . Squa mous cel l ca rci noma of the tons i l (a n oropha ryngea l ca ncer), 2nd i n frequency onl y to ca rci noma of the l a rynx
a mong ca ncers of the upper res pi ra tory tra ct, occurs predomi na ntl y i n ma l es .
Symptoms and Signs
Ora l l es i ons a re a s ymptoma ti c i ni ti a l l y, hi ghl i ghti ng the need for ora l s creeni ng. Mos t denta l profes s i ona l s ca reful l y exa mi ne the ora l ca vi ty a nd
oropha rynx duri ng routi ne ca re a nd ma y do a brus h bi ops y of a bnorma l a rea s . The l es i ons ma y a ppea r a s a rea s of erythropl a ki a or l eukopl a ki a
a nd ma y be exophyti c or ul cera ted. Ca ncers a re often i ndura ted a nd fi rm wi th a rol l ed border. Tons i l l a r ca rci noma us ua l l y ma ni fes ts a s a n
a s ymmetri c s wel l i ng a nd s ore throa t, wi th pa i n often ra di a ti ng to the i ps i l a tera l ea r. A meta s ta ti c ma s s i n the neck ma y be the fi rs t s ymptom,
pa rti cul a rl y i n tons i l l a r ca ncer.
Diagnosis
Bi ops y
Endos copy to detect s econd pri ma ry ca ncer
Ches t x-ra y a nd CT of hea d a nd neck
Bi ops y of s us pect a rea s i s done. Di rect l a ryngos copy, bronchos copy, a nd es opha gos copy a re done to excl ude a s i mul ta neous s econd pri ma ry
ca ncer. Hea d a nd neck CT us ua l l y i s done. Ches t x-ra y i s done; ches t CT i s done i f a n a dva nced s ta ge i s s us pected or confi rmed.
Prognosis
If ca rci noma of the tongue i s l oca l i zed (no l ymph node i nvol vement), 5-yr s urvi va l i s > 50%. For l oca l i zed ca rci noma of the fl oor of the mouth, 5-yr
s urvi va l i s 65%. Lymph node meta s ta s i s decrea s es s urvi va l ra te by a bout 50%. Meta s ta s es rea ch the regi ona l l ymph nodes fi rs t a nd l a ter the l ungs .
For l ower l i p l es i ons , 5-yr s urvi va l i s 90%, a nd meta s ta s es a re ra re. Ca rci noma of the upper l i p tends to be more a ggres s i ve a nd meta s ta ti c. For
ca rci noma of the pa l a te a nd tons i l l a r a rea , 5-yr s urvi va l i s 68% i f pa ti ents a re trea ted before l ymph node i nvol vement but onl y 17% a fter
i nvol vement. The prognos i s for tons i l l a r ca rci noma i s often better s ta ge for s ta ge tha n tha t for ora l ca ncers . Oropha ryngea l ca ncer a s s oci a ted wi th
HPV i nfecti on ma y ha ve a better prognos i s .
Treatment
Surgery or ra di a ti on thera py
Surgery a nd ra di a ti on thera py a re the trea tments of choi ce. Regi ona l or di s ta nt di s ea s e neces s i ta tes a more ra di ca l trea tment a pproa ch.
For tongue l es i ons , s urgery i s us ua l l y the i ni ti a l trea tment, pa rti cul a rl y for ea rl y-s ta ge di s ea s e. Sel ecti ve neck di s s ecti on i s i ndi ca ted i f the ri s k of
noda l di s ea s e exceeds 15 to 20%. Routi ne s urgi ca l recons tructi on i s the key to reduci ng pos topera ti ve ora l di s a bi l i ti es ; procedures ra nge from
l oca l ti s s ue fl a ps to free ti s s ue tra ns fers . Speech a nd s wa l l owi ng thera py ma y be requi red a fter s i gni fi ca nt res ecti ons . Ra di a ti on thera py i s a n
a l terna ti ve trea tment. Chemothera py i s not us ed routi nel y but i s recommended on a n i ndi vi dua l ba s i s ; ra re di s ta nt meta s ta s es a re pres ent i n
s i tes where chemothera py ma y be of s ome pa l l i a ti ve va l ue (eg, l ung, bone, hea rt, peri ca rdi um).
Trea tment of s qua mous cel l ca rci noma of the l i p i s s urgi ca l exci s i on wi th recons tructi on to ma xi mi ze pos topera ti ve functi on. When l a rge a rea s of
the l i p exhi bi t prema l i gna nt cha nge, the l i p ca n be s urgi ca l l y s ha ved, or a l a s er ca n remove a l l a ffected mucos a . Therea fter, a ppropri a te
s uns creen a ppl i ca ti on i s recommended.
Trea tment of tons i l l a r ca rci noma us ua l l y cons i s ts of concomi ta nt chemothera py a nd ra di a ti on thera py. Another opti on i ncl udes ra di ca l res ecti on
of the tons i l l a r fos s a , s ometi mes wi th pa rti a l ma ndi bul ectomy a nd neck di s s ecti on.
Otic Tumors
A number of malignant and benign otic tumors occur, usually manifesting with hearing loss. They may also manifest with dizziness, vertigo, or imbalance. These
tumors are rare and can be difficult to diagnose.
Malignant otic tumors: Ba s a l cel l a nd s qua mous cel l ca rci noma s ma y a ri s e i n the ea r ca na l . Pers i s tent i nfl a mma ti on ca us ed by chroni c oti ti s medi a
ma y predi s pos e to the devel opment of s qua mous cel l ca rci noma . Extens i ve res ecti on i s i ndi ca ted, fol l owed by ra di a ti on thera py. En bl oc res ecti on
of the ea r ca na l wi th s pa ri ng of the fa ci a l nerve i s done when l es i ons a re l i mi ted to the ca na l a nd ha ve not i nva ded the mi ddl e ea r. Deeper
i nva s i on requi res a more s i gni fi ca nt tempora l bone res ecti on.
Ra rel y, s qua mous cel l ca rci noma ori gi na tes i n the mi ddl e ea r. The pers i s tent otorrhea of chroni c oti ti s medi a ma y be a predi s pos i ng fa ctor.
Res ecti on of the tempora l bone a nd pos topera ti ve ra di a ti on thera py a re neces s a ry.
Nonchroma ffi n pa ra ga ngl i oma s (chemodectoma s ) a ri s e i n the tempora l bone from gl omus bodi es i n the jugul a r bul b (gl omus jugul a re tumors ) or
the medi a l wa l l of the mi ddl e ea r (gl omus tympa ni cum tumors ). They a ppea r a s a pul s a ti l e red ma s s i n the mi ddl e ea r. The fi rs t s ymptom often i s
ti nni tus tha t i s s ynchronous wi th the pul s e. Hea ri ng l os s devel ops , fol l owed by verti go. Cra ni a l nerve pa l s i es of the 9th, 10th, or 11th nerve ma y
a ccompa ny gl omus jugul a re tumors tha t extend through the jugul a r fora men. Exci s i on i s the trea tment of choi ce, a nd ra di a ti on i s us ed for
nons urgi ca l ca ndi da tes .
Benign otic tumors: Seba ceous cys ts , os teoma s , a nd kel oi ds ma y a ri s e i n a nd occl ude the ea r ca na l , ca us i ng retenti on of cerumen a nd conducti ve
hea ri ng l os s . Exci s i on i s the trea tment of choi ce for a l l beni gn oti c tumors .
Cerumi noma s occur i n the outer thi rd of the ea r ca na l . Thes e tumors a ppea r beni gn hi s tol ogi ca l l y a nd do not meta s ta s i ze regi ona l l y or di s ta ntl y
but they a re l oca l l y i nva s i ve a nd potenti a l l y des tructi ve a nd s houl d be exci s ed wi del y.
Salivary Gland Tumors
Most salivary gland tumors are benign and occur in the parotid glands. A painless salivary mass is the most common sign and is evaluated by fine-needle
aspiration biopsy. Imaging with CT and MRI can be helpful. For malignant tumors, treatment is with excision and radiation. Long-term results are related to the
grade of the cancer.
About 85% of s a l i va ry gl a nd tumors occur i n the pa roti d gl a nds , fol l owed by the s ubma ndi bul a r a nd mi nor s a l i va ry gl a nds , a nd a bout 1% occur i n
the s ubl i ngua l gl a nds . About 75 to 80% a re beni gn, s l ow-growi ng, mova bl e, pa i nl es s , us ua l l y s ol i ta ry nodul es benea th norma l s ki n or mucos a .
Occa s i ona l l y, when cys ti c, they a re s oft but mos t often they a re fi rm.
Benign tumors: The mos t common type i s a pl eomorphi c a denoma (mi xed tumor). Ma l i gna nt tra ns forma ti on i s pos s i bl e, res ul ti ng i n ca rci noma ex
mi xed tumor, but thi s us ua l l y occurs onl y a fter the beni gn tumor ha s been pres ent for 15 to 20 yr. If ma l i gna nt tra ns forma ti on occurs , the cure ra tes
a re very l ow, des pi te a dequa te s urgery a nd a djuva nt thera py.
Other beni gn tumors i ncl ude monomorphi c a denoma , oncocytoma , a nd pa pi l l a ry cys ta denoma l ymphoma tos um (previ ous l y known a s cyl i ndroma ).
Thes e tumors ra rel y recur a nd ra rel y become ma l i gna nt.
Malignant salivary gland tumors: Ma l i gna nt tumors a re l es s common a nd a re cha ra cteri zed by ra pi d growth or a s udden growth s purt. They a re fi rm,
nodul a r, a nd ca n be fi xed to a dja cent ti s s ue, often wi th a poorl y defi ned peri phery. Pa i n a nd neura l i nvol vement a re common. Eventua l l y, the
overl yi ng s ki n or mucos a ma y become ul cera ted or the a dja cent ti s s ues ma y become i nva ded. Surgery, fol l owed by ra di a ti on thera py, i s the
trea tment of choi ce for res ecta bl e di s ea s e. Currentl y, there i s no effecti ve chemothera py for s a l i va ry ca ncer.
Mucoepi dermoi d ca rci noma i s the mos t common s a l i va ry gl a nd ca ncer, typi ca l l y occurri ng i n peopl e i n thei r 20s to 50s . It ca n ma ni fes t i n a ny
s a l i va ry gl a nd, often i n a mi nor s a l i va ry gl a nd of the pa l a te, or i t ca n occur deep wi thi n the bone, s uch a s i n the wa l l of a denti gerous cys t.
Intermedi a te a nd hi gh-gra de mucoepi dermoi d ca rci noma s ma y meta s ta s i ze to the regi ona l l ympha ti cs , whi ch mus t be a ddres s ed wi th s urgi ca l
di s s ecti on or pos topera ti ve ra di a ti on thera py.
Adenoi d cys ti c ca rci noma i s the mos t common ma l i gna nt tumor of mi nor s a l i va ry gl a nds (a nd of the tra chea ). It i s a s l owl y growi ng ma l i gna nt
tra ns forma ti on of a much more common beni gn cyl i ndroma . Its pea k i nci dence i s between a ges 40 a nd 60, a nd s ymptoms i ncl ude s evere pa i n a nd,
often, fa ci a l nerve pa ra l ys i s . It ha s a propens i ty for peri neura l i nva s i on a nd s prea d, wi th di s ea s e potenti a l l y extendi ng ma ny centi meters from the
ma i n tumor ma s s . Lympha ti c s prea d i s not a common fea ture of thi s tumor, s o el ecti ve noda l trea tment i s l es s common. Al though the 5- a nd 10-yr
s urvi va l ra tes a re qui te good, the 15- a nd 20-yr ra tes a re qui te poor, wi th mos t pa ti ents devel opi ng di s ta nt meta s ta s es . Pul mona ry meta s ta s es a re
common, a l though pa ti ents ca n l i ve qui te l ong wi th them.
Aci ni c cel l ca rci noma , a common pa roti d tumor, occurs i n peopl e i n thei r 40s a nd 50s . Thi s ca rci noma ha s a more i ndol ent cours e, a s wel l a s a n
i nci dence of mul ti foca l i ty.
Ca rci noma ex mi xed tumor i s a denoca rci noma a ri s i ng i n a preexi s ti ng beni gn ca rci noma ex mi xed tumor. Onl y the ca rci noma tous el ement
meta s ta s i zes .
Symptoms and Signs
Mos t beni gn a nd ma l i gna nt tumors ma ni fes t a s a pa i nl es s ma s s . However, ma l i gna nt tumors ma y i nva de nerves , ca us i ng l oca l i zed or regi ona l
pa i n, numbnes s , pa res thes i a , ca us a l gi a , or a l os s of motor functi on.
Diagnosis
Bi ops y
CT a nd MRI for extent of di s ea s e
CT a nd MRI l oca te the tumor a nd des cri be i ts extent. Bi ops y confi rms the cel l type. A s ea rch for s prea d to regi ona l nodes or di s ta nt meta s ta s es i n
the l ung, l i ver, bone, or bra i n ma y be i ndi ca ted before trea tment i s s el ected.
Treatment
Surgery, s ometi mes pl us ra di a ti on thera py
Trea tment of beni gn tumors i s s urgery. The recurrence ra te i s hi gh when exci s i on i s i ncompl ete.
Trea tment of mucoepi dermoi d ca rci noma cons i s ts of wi de exci s i on a nd pos topera ti ve ra di a ti on. The 5-yr s urvi va l ra te i s 95% wi th the l ow-gra de
type, pri ma ri l y a ffecti ng mucus cel l s , a nd 50% wi th the hi gh-gra de type, pri ma ri l y a ffecti ng epi dermoi d cel l s . Trea tment of a denoi d cys ti c
ca rci noma i s wi de s urgi ca l exci s i on, but l oca l recurrence i s common. Lung meta s ta s es a nd dea th a re l i kel y, a l though ma ny yea rs , to a deca de or
more, a fter the i ni ti a l di a gnos i s a nd trea tment. The prognos i s for a ci ni c cel l ca rci noma i s fa vora bl e a fter wi de exci s i on. Al l s urgeri es a re des i gned
to s pa re the fa ci a l nerve, whi ch i s s a cri fi ced onl y i n ca s es of di rect tumor i nvol vement wi th the nerve.
Chapter 56. Approach to Dental and Oral Symptoms

Introduction
A phys i ci a n s houl d a l wa ys exa mi ne the mouth a nd be a bl e to recogni ze ma jor ora l di s orders , pa rti cul a rl y pos s i bl e ca ncers . However, cons ul ta ti on
wi th a denti s t i s needed to eva l ua te nonma l i gna nt cha nges a s wel l a s pa ti ents wi th tooth probl ems . Li kewi s e, pa ti ents wi th xeros tomi a or
unexpl a i ned s wel l i ng or pa i n i n the mouth, fa ce, or neck requi re a denta l cons ul ta ti on. Chi l dren wi th a bnorma l fa ci es (who a l s o ma y ha ve denta l
ma l forma ti ons requi ri ng correcti on) s houl d be eva l ua ted by a denti s t. In FUO or a s ys temi c i nfecti on of unknown ca us e, a denta l di s order s houl d
be cons i dered. A denta l cons ul ta ti on i s neces s a ry before hea d a nd neck ra di a ti on thera py a nd i s a dvi s a bl e before chemothera py.
Cl ues s ugges ti ng s ys temi c di s ea s e ma y be found i n the mouth a nd a dja cent s tructures (s ee
Ta bl e 56-1). A denti s t s houl d cons ul t a phys i ci a n when a s ys temi c di s order i s s us pected, when the pa ti ent i s ta ki ng certa i n drugs (eg, wa rfa ri n,
bi s phos phona tes ), a nd when a pa ti ent's a bi l i ty to wi ths ta nd genera l a nes thes i a or extens i ve ora l s urgery mus t be eva l ua ted. Pa ti ents wi th
certa i n hea rt va l ve a bnorma l i ti es ma y requi re a nti bi oti c prophyl a xi s to hel p prevent ba cteri a l endoca rdi ti s before undergoi ng certa i n denta l
procedures (s ee
Ta bl es 215-3 a nd
215-4 on pp. 2199 a nd 2200).
Common denta l di s orders a re di s cus s ed i n Ch. 57. Denta l emergenci es , i ncl udi ng tootha che, a re di s cus s ed i n Ch. 58.
Anatomy and Development
Teeth: The teeth a re ca tegori zed a s i nci s ors , ca ni nes , premol a rs , a nd mol a rs a nd conventi ona l l y a re numbered begi nni ng wi th the ma xi l l a ry ri ght
3rd mol a r (s ee
Fi g. 56-1).
Ea ch tooth ha s a crown a nd a root. The ca ni nes ha ve the l a rges t a nd s tronges t roots . An i nner pul p conta i ns bl ood ves s el s , l ympha ti cs , a nd nerves ,
s urrounded by the ha rd but porous denti n, a very ha rd ena mel coa ti ng tha t covers the crown. The bonel i ke cementum i s over the root, whi ch, when
hea l thy, i s covered by gi ngi va (s ee
Fi g. 56-2). Twenty deci duous
[Table 56-1. Ora l Fi ndi ngs i n Sys temi c Di s orders ]
teeth norma l l y begi n a ppea ri ng a t cl os e to a ge 6 mo a nd s houl d a l l be i n pl a ce by a ge 30 mo (s ee
Ta bl e 271-1 on p. 2757). Thes e teeth a re fol l owed by 32 perma nent teeth tha t begi n to a ppea r by a bout a ge 6. The peri od from a ge 6 to 11 i s ca l l ed
the mi xed denti ti on s ta ge, i n whi ch both deci duous a nd perma nent teeth a re pres ent. Ti mi ng of tooth erupti on i s one i ndi ca tor of s kel eta l a ge
a nd ma y i denti fy growth reta rda ti on or es ta bl i s h a ge for forens i c purpos es .
Supporting tissues: The gi ngi va s urrounds the teeth a t the ba s e of thei r crown. The a l veol a r ri dges a re tra becul a r bone conta i ni ng s ockets for the
teeth. The peri odonti um cons i s ts of the ti s s ues tha t s upport the teeththe gi ngi va , epi thel i a l a tta chment, connecti ve ti s s ue a tta chment,
peri odonta l l i ga ment, a nd a l veol a r bone. The ma ndi bl e a nd ma xi l l a s upport the a l veol a r ri dges a nd hous e the teeth. Sa l i va from the s a l i va ry
gl a nds ba thes a nd protects the teeth. The tongue di rects food between the gri ndi ng s urfa ces a nd hel ps cl ea n the teeth. The ma xi l l a recei ves
i nnerva ti on from the ma xi l l a ry nerve, the 2nd di vi s i on of the tri gemi na l nerve (the 5th cra ni a l nerve). The ma ndi bul a r nerve, whi ch i s the 3rd a nd
mos t i nferi or di vi s i on of the tri gemi na l nerve, i nnerva tes the ma ndi bl e.
In the el derl y, or i n s ome peri odonta l di s ea s es , gi ngi va l reces s i on expos es the denta l root a dja cent to the crown, ma ki ng root ca ri es common. If
tooth des tructi on res ul ts a nd the tooth mus t be removed, the mecha ni ca l s ti mul a ti on neces s a ry for ma i nta i ni ng bone i ntegri ty cea s es .
Cons equentl y, a trophy of the a l veol a r ri dge (s eni l e a trophy) begi ns when teeth a re a bs ent.
Mouth: Norma l l y, kera ti ni zed epi thel i um occurs on the fa ci a l a s pect of the l i ps , dors um of the tongue, ha rd pa l a te, a nd gi ngi va a round the teeth.
When hea l thy, the gi ngi va extends
[Fig. 56-1. Identi fyi ng the teeth.]
5 to 7 mm from the tooth. Nonkera ti ni zed mucos a occurs over a l veol a r bone further from the teeth, i ns i de the l i ps a nd cheeks , on the s i des a nd
unders urfa ce of the tongue, on the s oft pa l a te, a nd coveri ng the fl oor of the mouth. The s ki n a nd mucos a of the l i ps a re dema rca ted by the
vermi l i on border.
The bucca l mucos a , i ncl udi ng the ves ti bul e a nd nonkera ti ni zed a l veol a r mucos a , i s us ua l l y s mooth, moi s t, a nd more red tha n pi nk (a s compa red
to hea l thy gi ngi va ). Innocuous enti ti es i n thi s regi on i ncl ude l i nea a l ba (a thi n whi te l i ne, typi ca l l y bi l a tera l , on the l evel of the occl us a l pl a ne,
where the cheek i s bi tten), Fordyce's gra nul es (a berra nt s eba ceous gl a nds a ppea ri ng a s < 1 mm l i ght yel l ow s pots tha t a l s o ma y occur on the l i ps ),
a nd whi te s ponge nevus (bi l a tera l thi ck whi te fol ds over mos t of the bucca l mucos a ). Recogni zi ng thes e a voi ds needl es s bi ops y a nd
a pprehens i on. The ori fi ces of the pa roti d (Stens en's ) ducts a re oppos i te the ma xi l l a ry 1s t mol a r on the i ns i de of ea ch cheek a nd s houl d not be
mi s ta ken for a n a bnorma l i ty.
The dors a l s urfa ce of the tongue i s covered wi th numerous whi ti s h el eva ti ons ca l l ed the fi l i form pa pi l l a e. Inters pers ed a mong them a re i s ol a ted
reddi s h promi nences ca l l ed the fungi form pa pi l l a e, occurri ng mos tl y on the a nteri or pa rt of the tongue. The ci rcumva l l a te pa pi l l a e, numberi ng 8 to
12, a re cons i dera bl y l a rger a nd l i e pos teri orl y i n a V pa ttern. The ci rcumva l l a te pa pi l l a e do not project from the tongue but i ns tea d a re s urrounded
by a trench. The fol i a te pa pi l l a e a ppea r a s a s eri es of pa ra l l el , s l i tl i ke fol ds on the l a tera l borders of the tongue, nea r the a nteri or pi l l a rs of the
fa uces . They va ry i n l ength a nd ca n ea s i l y be confus ed wi th ma l i gna nt l es i ons , a s ma y the fora men cecum, medi a n rhomboi d gl os s i ti s , a nd, ra rel y,
a l i ngua l thyroi d nodul e. Li ngua l tons i l s a re components of Wa l deyer's ri ng, a re a t the ba ck of the tongue, a nd s houl d not be mi s ta ken for l es i ons .
If a n a ppa rent a bnorma l i ty i s bi l a tera l , i t i s a l mos t a l wa ys a norma l va ri a nt.
Innerva ti on i s s uppl i ed by the l i ngua l nerves (bra nches of the 5th cra ni a l nerves ), for genera l s ens ory i nnerva ti on, a nd the chorda tympa ni fi bers
(of the 7th cra ni a l nerve), whi ch i nnerva te the ta s te buds of the a nteri or two thi rds of the tongue. Behi nd the ci rcumva l l a te pa pi l l a e, the
gl os s opha ryngea l nerves (9th cra ni a l nerves ) provi de the s ens a ti ons of touch a nd ta s te. The tongue ha s ta s te receptors for s weet, s a l ty, s our,
bi tter, a nd uma mi (a s a vory
[Fig. 56-2. Secti on of a ca ni ne tooth.]
ta s te tri ggered by na tura l gl uta mi c a ci d a nd gl uta ma tes s uch a s the fl a vori ng a gent monos odi um gl uta ma te). Al though previ ous l y thought to be
i s ol a ted to pa rti cul a r porti ons of the tongue, thes e receptors a re now known to be di s tri buted over the s urfa ce of the tongue. The hypogl os s a l
nerves (12th cra ni a l nerves ) control movement of the tongue.
The ma jor s a l i va ry gl a nds a re the pa i red pa roti d, s ubma ndi bul a r, a nd s ubl i ngua l gl a nds . Mos t ora l mucos a l s urfa ces conta i n ma ny mi nor mucus s ecreti ng s a l i va ry gl a nds . Anteri orl y a nd nea r the mi dl i ne on ea ch s i de of the fl oor of the mouth a re the openi ngs of Wha rton's ducts , whi ch dra i n
the i ps i l a tera l s ubma ndi bul a r a nd s ubl i ngua l gl a nds . The pa roti d gl a nds dra i n i nto the cheeks vi a Stens en's ducts .
Evaluation
The fi rs t routi ne denta l exa mi na ti on s houl d ta ke pl a ce by a ge 1 yr or when the fi rs t tooth erupts . Subs equent eva l ua ti ons s houl d ta ke pl a ce a t 6mo i nterva l s or whenever s ymptoms devel op. Exa mi na ti on of the mouth i s pa rt of every genera l phys i ca l exa mi na ti on. Ora l fi ndi ngs i n ma ny
s ys temi c di s ea s es a re uni que, s ometi mes pa thognomoni c, a nd ma y be the fi rs t s i gn of di s ea s e. Ora l ca ncer ma y be detected a t a n ea rl y s ta ge.
History: Importa nt denta l s ymptoms i ncl ude bl eedi ng, pa i n, ma l occl us i on, new growths , numbnes s or pa res thes i a s , a nd chewi ng probl ems (whi ch
ma y l ea d to wei ght l os s s ee
Ta bl e 56-2). Genera l i nforma ti on i ncl udes us e of a l cohol or toba cco (both ma jor ri s k fa ctors for hea d a nd neck ca ncer) a nd s ys temi c s ymptoms ,
s uch a s fever a nd wei ght l os s .
Physical examination: A thorough i ns pecti on requi res good i l l umi na ti on, a tongue bl a de, gl oves , a nd a ga uze pa d. Compl ete or pa rti a l dentures a re
removed s o tha t underl yi ng s oft ti s s ues ca n be s een.
Mos t phys i ci a ns us e a hea d-mounted l i ght. However, beca us e the l i ght ca nnot be preci s el y a l i gned on the a xi s of vi s i on, i t i s di ffi cul t to a voi d
s ha dowi ng i n na rrow a rea s . Better i l l umi na ti on res ul ts wi th a hea d-mounted convex mi rror; the phys i ci a n l ooks through a hol e i n the center of the
mi rror, s o the i l l umi na ti on i s a l wa ys on-a xi s . The hea d mi rror refl ects l i ght from a s ource (a ny i nca ndes cent l i ght) pl a ced behi nd the pa ti ent a nd
s l i ghtl y to one s i de a nd requi res pra cti ce to us e effecti vel y.
The exa mi ner i ni ti a l l y l ooks a t the fa ce for a s ymmetry, ma s s es , a nd s ki n l es i ons . Sl i ght fa ci a l a s ymmetry i s uni vers a l , but more ma rked a s ymmetry
ma y i ndi ca te a n underl yi ng di s order, ei ther congeni ta l or a cqui red (s ee
Ta bl e 56-3).
Teeth a re i ns pected for s ha pe, a l i gnment, defects , mobi l i ty, col or, a nd pres ence of a dherent pl a que, ma teri a a l ba (dea d ba cteri a , food debri s ,
des qua ma ted epi thel i a l cel l s ), a nd ca l cul us (ta rta r).
Teeth a re gentl y ta pped wi th a tongue depres s or or mi rror ha ndl e to a s s es s tendernes s (percus s i on s ens i ti vi ty). Tendernes s to percus s i on
s ugges ts deep ca ri es tha t ha s ca us ed a necroti c pul p wi th peri a pi ca l a bs ces s or s evere peri odonta l di s ea s e. Percus s i on s ens i ti vi ty or pa i n on
bi ti ng a l s o ca n i ndi ca te a n i ncompl ete (green s ti ck) fra cture of a tooth. Percus s i on tendernes s i n mul ti pl e a dja cent ma xi l l a ry teeth ma y res ul t from
ma xi l l a ry s i nus i ti s . Tendernes s to pa l pa ti on a round the a pi ces of the teeth a l s o ma y i ndi ca te a n a bs ces s .
Loos e teeth us ua l l y i ndi ca te s evere peri odonta l di s ea s e but ca n be ca us ed by bruxi s m (cl enchi ng or gri ndi ng of teeths ee p. 506) or tra uma tha t
da ma ges peri odonta l ti s s ues . Ra rel y, teeth become l oos e when a l veol a r bone i s eroded by a n underl yi ng ma s s (eg, a mel obl a s toma , eos i nophi l i c
gra nul oma ). A tumor or s ys temi c ca us e of a l veol a r bone l os s (eg, di a betes mel l i tus , hyperpa ra thyroi di s m, os teoporos i s , Cus hi ng's s yndrome) i s
s us pected when teeth a re l oos e a nd hea vy pl a que a nd ca l cul us a re a bs ent.
Ca l cul us i s mi nera l i zed ba cteri a l pl a quea concreti on of ba cteri a , food res i due, s a l i va ,
[Table 56-2. Some Ora l Symptoms a nd Pos s i bl e Ca us es ]
a nd mucus wi th Ca a nd phos pha te s a l ts . After a tooth i s cl ea ned, a mucopol ys a ccha ri de coa ti ng (pel l i cl e) i s depos i ted a l mos t i mmedi a tel y. After
a bout 24 h, ba cteri a l col oni za ti on turns the pel l i cl e i nto pl a que. After a bout 72 h, the pl a que s ta rts ca l ci fyi ng, becomi ng ca l cul us . When pres ent,
ca l cul us i s depos i ted mos t hea vi l y on the l i ngua l (i nner, or tongue) s urfa ces of the ma ndi bul a r a nteri or teeth nea r the s ubma ndi bul a r a nd
s ubl i ngua l duct ori fi ces (Wha rton's ducts ) a nd on the bucca l (cheek) s urfa ces of the ma xi l l a ry mol a rs nea r the pa roti d duct ori fi ces (Stens en's
ducts ).
Ca ri es (tooth deca ys ee p. 516) fi rs t a ppea rs a s defects i n the tooth ena mel . Ca ri es then a ppea rs a s whi te s pots , l a ter becomi ng brown.
Attri ti on (wea ri ng of bi ti ng s urfa ces ) ca n res ul t from chewi ng a bra s i ve foods or toba cco or from the wea r tha t a ccompa ni es a gi ng, but i t us ua l l y
i ndi ca tes bruxi s m. Another common ca us e i s a bra s i on of a porcel a i n crown occl udi ng a ga i ns t oppos i ng ena mel , beca us e porcel a i n i s cons i dera bl y
ha rder tha n ena mel . Attri ti on ma kes chewi ng l es s effecti ve a nd ca us es nonca ri ous teeth to become
[Table 56-3. Some Di s orders of the Ora l Regi on by Predomi na nt Si te of Invol vement]
pa i nful when the erodi ng ena mel expos es the underl yi ng denti n. Denti n i s s ens i ti ve to touch a nd to tempera ture cha nges . A denti s t ca n
des ens i ti ze s uch teeth or res tore the denta l a na tomy by pl a ci ng crowns or onl a ys over ba dl y worn teeth. In mi nor ca s es of root s ens i ti vi ty, the
expos ed root ma y be des ens i ti zed by fl uori de a ppl i ca ti on or denti n-bondi ng a gents .
Deformed teeth ma y i ndi ca te a devel opmenta l or endocri ne di s order. In Down s yndrome, teeth a re s ma l l . In congeni ta l s yphi l i s , the i nci s ors ma y
be s ma l l a t the i nci s a l thi rd, ca us i ng a pegged or s crewdri ver s ha pe wi th a notch i n the center of the i nci s a l edge (Hutchi ns on's i nci s ors ), a nd the
1s t mol a r i s s ma l l , wi th a s ma l l occl us a l s urfa ce a nd roughened, l obul a ted, often hypopl a s ti c ena mel (mul berry mol a r). In ectoderma l dys pl a s i a ,
teeth a re a bs ent or coni ca l , s o tha t dentures a re needed from chi l dhood. Denti nogenes i s i mperfecta , a n a utos oma l domi na nt di s order, ca us es
a bnorma l denti n tha t i s dul l bl ui s h brown a nd opa l es cent a nd does not cus hi on the overl yi ng ena mel a dequa tel y. Such teeth ca nnot wi ths ta nd
occl us a l s tres s es a nd ra pi dl y become worn. Peopl e wi th pi tui ta ry dwa rfi s m or wi th congeni ta l hypopa ra thyroi di s m ha ve s ma l l denta l roots ;
peopl e wi th gi ga nti s m ha ve l a rge ones . Acromega l y ca us es exces s cementum i n the roots a s wel l a s enl a rgement of the ja ws , s o teeth ma y
become wi del y s pa ced. Acromega l y a l s o ca n ca us e a n open bi te to devel op i n a dul thood. Congeni ta l l y na rrow l a tera l i nci s ors occur i n the a bs ence
of s ys temi c di s ea s e. The mos t commonl y congeni ta l l y a bs ent teeth a re the 3rd mol a rs , fol l owed i n frequency by the ma xi l l a ry l a tera l i nci s ors a nd
2nd ma ndi bul a r premol a rs .
Defects i n tooth col or mus t be di fferenti a ted from the da rkeni ng or yel l owi ng tha t i s ca us ed by food pi gments , a gi ng, a nd, mos t promi nentl y,
s moki ng. A tooth ma y a ppea r gra y beca us e of pul pa l necros i s , us ua l l y due to extens i ve ca ri es penetra ti ng the pul p or beca us e of hemos i deri n
depos i ted i n the denti n a fter tra uma , wi th or wi thout pul pa l necros i s . Chi l dren's teeth da rken a ppreci a bl y a nd perma nentl y a fter even s hort-term
us e of tetra cycl i nes by the mother duri ng the 2nd ha l f of pregna ncy or by the chi l d duri ng odontogenes i s (tooth devel opment), s peci fi ca l l y
ca l ci fi ca ti on of the crowns , whi ch l a s ts unti l a ge 9. Tetra cycl i nes ra rel y ca us e perma nent di s col ora ti on of ful l y formed teeth i n a dul ts . However,
mi nocycl i ne da rkens bone, whi ch ca n be s een i n the mouth when the overl yi ng gi ngi va a nd mucos a a re thi n. Affected teeth fl uores ce wi th
di s ti ncti ve col ors under ul tra vi ol et l i ght corres pondi ng to the s peci fi c tetra cycl i ne ta ken. In congeni ta l porphyri a , both the deci duous a nd
perma nent teeth ma y ha ve red or browni s h di s col ora ti on but a l wa ys fl uores ce red from the pi gment depos i ted i n the denti n. Congeni ta l
hyperbi l i rubi nemi a ca us es a yel l owi s h tooth di s col ora ti on. Teeth ca n be whi tened (s ee
Ta bl e 56-4).
Defects i n tooth ena mel ma y be ca us ed by ri ckets , whi ch res ul ts i n a rough, i rregul a r ba nd i n the ena mel . Any prol onged febri l e i l l nes s duri ng
odontogenes i s ca n ca us e a perma nent na rrow zone of cha l ky, pi tted ena mel or s i mpl y whi te di s col ora ti on vi s i bl e a fter the tooth erupts . Thus , the
a ge a t whi ch the di s ea s e occurred a nd i ts dura ti on ca n be es ti ma ted from the l oca ti on a nd hei ght of the ba nd. Amel ogenes i s i mperfecta , a n
a utos oma l domi na nt di s ea s e, ca us es s evere ena mel hypopl a s i a . Chroni c vomi ti ng a nd es opha gea l refl ux ca n deca l ci fy the denta l crowns ,
pri ma ri l y the l i ngua l s urfa ces of the ma xi l l a ry a nteri or teeth. Chroni c s norti ng of coca i ne ca n res ul t i n wi des prea d deca l ci fi ca ti on of teeth,
beca us e the drug di s s oci a tes i n s a l i va i nto a ba s e a nd HCl . Chroni c us e of metha mpheta mi nes ma rkedl y i ncrea s es denta l ca ri es ("meth mouth").
Swi mmers who s pend a l ot of ti me i n over-chl ori na ted pool s ma y l os e ena mel from the outer fa ci a l /bucca l s i de of the teeth, es peci a l l y the
ma xi l l a ry i nci s ors , ca ni nes , a nd 1s t premol a rs . If Na ca rbona te ha s been a dded to the pool wa ter to correct pH, then brown ca l cul us devel ops but
ca n be removed by a denta l cl ea ni ng.
Fl uoros i s i s mottl ed ena mel tha t ma y devel op i n chi l dren who dri nk wa ter conta i ni ng > 1 ppm of fl uori de duri ng tooth devel opment. Fl uoros i s
depends on the a mount of fl uori de i nges ted. Ena mel cha nges ra nge from i rregul a r whi ti s h opa que a rea s to s evere brown di s col ora ti on of the
enti re crown wi th a roughened s urfa ce. Such teeth a re hi ghl y res i s ta nt to denta l ca ri es .
The l i ps a re pa l pa ted. Wi th the pa ti ent's mouth open, the bucca l mucos a a nd ves ti bul es a re exa mi ned wi th a tongue bl a de; then the ha rd a nd
s oft pa l a tes , uvul a , a nd oropha rynx a re vi ewed. The pa ti ent i s a s ked to extend the tongue a s fa r a s pos s i bl e, expos i ng the dors um, a nd to move
the extended tongue a s fa r a s pos s i bl e to ea ch s i de, s o tha t i ts pos terol a tera l s urfa ces ca n be s een. If a pa ti ent does not extend the tongue fa r
enough to expos e the ci rcumva l l a te pa pi l l a e, the exa mi ner gra s ps the ti p of the tongue wi th a ga uze pa d a nd extends i t. Then the tongue i s ra i s ed
to vi ew the ventra l s urfa ce a nd the fl oor of the mouth. The teeth a nd gi ngi va a re vi ewed. An a bnorma l di s tri buti on of kera ti ni zed or
nonkera ti ni zed ora l mucos a dema nds a ttenti on. Kera ti ni zed ti s s ue tha t occurs i n norma l l y nonkera ti ni zed a rea s a ppea rs whi te. Thi s a bnorma l
condi ti on, ca l l ed l eukopl a ki a , requi res a bi ops y beca us e i t ma y be ca ncerous or preca ncerous . More omi nous , however, a re thi nned a rea s of
mucos a . Thes e
[Table 56-4. Tooth Whi teni ng Procedures ]
red a rea s , ca l l ed erythropl a ki a , i f pres ent for a t l ea s t 2 wk, es peci a l l y on the ventra l tongue a nd fl oor of the mouth, s ugges t dys pl a s i a , ca rci noma
i n s i tu, or ca ncer.
Wi th gl oved ha nds , the exa mi ner pa l pa tes the ves ti bul es a nd the fl oor of the mouth, i ncl udi ng the s ubl i ngua l a nd s ubma ndi bul a r gl a nds . To
ma ke pa l pa ti on more comforta bl e, the exa mi ner a s ks the pa ti ent to rel a x the mouth, keepi ng i t open jus t wi de enough to a l l ow a cces s .
The temporoma ndi bul a r joi nt (TMJ) i s a s s es s ed by l ooki ng for ja w devi a ti on on openi ng a nd by pa l pa ti ng the hea d of the condyl e a nteri or to the
externa l a udi tory mea tus . Exa mi ners then pl a ce thei r l i ttl e fi ngers i nto the externa l ea r ca na l s wi th the pa ds of the fi ngerti ps l i ghtl y pus hi ng
a nteri orl y whi l e pa ti ents open wi del y a nd cl os e 3 ti mes . Pa ti ents a l s o s houl d be a bl e to comforta bl y open wi de enough to fi t 3 of thei r fi ngers
verti ca l l y between the i nci s ors (typi ca l l y 4 to 5 cm). Tri s mus , the i na bi l i ty to open the mouth, ma y i ndi ca te temporoma ndi bul a r di s ea s e (the mos t
common ca us e), peri coroni ti s , s cl eroderma , a rthri ti s , a nkyl os i s of the TMJ, di s l oca ti on of the temporoma ndi bul a r di s k, teta nus , or peri tons i l l a r
a bs ces s . Unus ua l l y wi de openi ng s ugges ts s ubl uxa ti on or type III Ehl ers -Da nl os s yndrome.
Testing: For a new pa ti ent or for s omeone who requi res extens i ve ca re, the denti s t ta kes a ful l mouth x-ra y s eri es . Thi s s eri es cons i s ts of 14 to 16
peri a pi ca l fi l ms to s how the roots a nd bone pl us 4 bi te-wi ng fi l ms to detect ea rl y ca ri es between pos teri or teeth. Modern techni ques reduce
ra di a ti on expos ure to a nea r-negl i gi bl e l evel . Pa ti ents a t hi gh ri s k of ca ri es (i e, thos e who ha ve ha d ca ri es detected duri ng the cl i ni ca l
exa mi na ti on, ha ve ma ny res tora ti ons , or ha ve recurrent ca ri es on teeth previ ous l y res tored) s houl d undergo bi te-wi ng x-ra ys every 12 mo.
Otherwi s e, bi te-wi ngs a re i ndi ca ted every 2 to 3 yr. A pa nora mi c x-ra y ca n yi el d us eful i nforma ti on a bout tooth devel opment, cys ts or tumors of the
ja ws , s upernumera ry or congeni ta l l y a bs ent teeth, 3rd mol a r i mpa cti on, Ea gl e's s yndrome (l es s frequentl y), a nd ca roti d pl a ques .
Wi th a gi ng, res ti ng s a l i va ry s ecreti on di mi ni s hes a nd ca n be further di mi ni s hed by drugs , a l though mea l -s ti mul a ted s a l i va ry fl ow i s us ua l l y
a dequa te. The fl a ttened cus ps of worn teeth a nd wea knes s of the ma s ti ca tory mus cl es ma y ma ke chewi ng ti res ome, i mpa i ri ng food i nta ke. Los s
of bone ma s s i n the ja ws (pa rti cul a rl y the a l veol a r porti on), drynes s of the mouth, thi nni ng of the ora l mucos a , a nd i mpa i red coordi na ti on of l i p,
cheek, a nd tongue movements ma y ma ke denture retenti on di ffi cul t. The ta s te buds become l es s s ens i ti ve, s o the el derl y ma y a dd a bunda nt
s ea s oni ngs , pa rti cul a rl y s a l t (whi ch i s ha rmful for s ome), or they ma y des i re very hot foods for more ta s te, s ometi mes burni ng the often a trophi c
ora l mucos a . Gi ngi va l reces s i on a nd xeros tomi a contri bute to devel opment of root ca ri es . Des pi te thes e cha nges , i mproved denta l hygi ene ha s
grea tl y decrea s ed the preva l ence of tooth l os s , a nd mos t ol der peopl e ca n expect to reta i n thei r teeth.
Poor ora l hea l th contri butes to poor nutri ti ona l i nta ke, whi ch i mpa i rs genera l hea l th. Denta l di s ea s e (pa rti cul a rl y peri odonti ti s ) i s a s s oci a ted
wi th a 2-fol d i ncrea s ed ri s k of corona ry a rtery di s ea s e. Edentul ous pa ti ents ca nnot ha ve peri odonti ti s (beca us e they do not ha ve a peri odonti um),
a l though peri odonti ti s ma y ha ve res ul ted i n thei r tooth l os s . As pi ra ti on pneumoni a i n pa ti ents wi th peri odonti ti s ca n i nvol ve a na erobi c
orga ni s ms a nd ha s a hi gh morta l i ty ra te. Severe ba cteremi a s s econda ry to a cute or chroni c denta l i nfecti on ma y contri bute to bra i n a bs ces s es ,
ca vernous s i nus thrombos i s , endoca rdi ti s , pros theti c joi nt i nfecti ons , a nd unexpl a i ned fevers .
Dental Care of Patients With Systemic Disorders
Certa i n medi ca l condi ti ons (a nd thei r trea tment) predi s pos e pa ti ents to denta l probl ems or a ffect denta l ca re.
Hematologic disorders: Peopl e who ha ve di s orders tha t i nterfere wi th coa gul a ti on (eg, hemophi l i a , a cute l eukemi a , thrombocytopeni a ) requi re
medi ca l cons ul ta ti on before undergoi ng denta l procedures tha t mi ght ca us e bl eedi ng (eg, extra cti on, ma ndi bul a r bl ock). Hemophi l i a cs s houl d
ha ve cl otti ng fa ctors gi ven before, duri ng, a nd a fter a n extra cti on. Such ora l s urgery s houl d be done i n the hos pi ta l i n cons ul ta ti on wi th a
hema tol ogi s t. Al l pa ti ents wi th bl eedi ng di s orders s houl d ma i nta i n a l i fel ong routi ne of regul a r denta l vi s i ts , whi ch i ncl udes cl ea ni ngs , fi l l i ngs ,
topi ca l fl uori de, a nd preventa ti ve s ea l a nts , to a voi d the need for extra cti ons .
Cardiovascular disorders: After a n MI, denta l procedures s houl d be a voi ded for 6 mo, i f pos s i bl e, to a l l ow da ma ged myoca rdi um to become l es s
el ectri ca l l y l a bi l e. Pa ti ents wi th pul mona ry or ca rdi a c di s ea s e who requi re i nha l a ti on a nes thes i a for denta l procedures s houl d be hos pi ta l i zed.
Endocarditis prophylaxis i s requi red before denta l procedures onl y i n pa ti ents wi th
Pros theti c ca rdi a c va l ves
Previ ous hi s tory of ba cteri a l endoca rdi ti s
Cya noti c congeni ta l defects of the hea rt or grea t ves s el s (i f unrepa i red, i f compl etel y repa i red duri ng fi rs t 6 mo a fter s urgery, or i f repa i red but
wi th res i dua l defects )
Ca rdi a c tra ns pl a nta ti on reci pi ents wi th a va l vul opa thy
The hea rt i s better protected a ga i ns t l ow-gra de ba cteremi a s , whi ch occur i n chroni c denta l condi ti ons , when denta l trea tment i s recei ved (wi th
prophyl a xi s ) tha n when i t i s not recei ved. Pa ti ents who a re to undergo ca rdi a c va l ve s urgery or repa i r of congeni ta l hea rt defects s houl d ha ve a ny
neces s a ry denta l trea tment compl eted before s urgery.
Al though proba bl y of ma rgi na l benefi t, a nti bi oti c prophyl a xi s i s s ometi mes recommended for pa ti ents wi th hemodi a l ys i s s hunts a nd wi thi n 2 yr of
recei pt of a ma jor pros theti c joi nt (hi p, knee, s houl der, el bow). The orga ni s ms ca us i ng i nfecti ons a t thes e s i tes a re a l mos t i nva ri a bl y of derma l
ra ther tha n ora l ori gi n.
Epi nephri ne a nd l evonordefri n a re a dded to l oca l a nes theti cs to i ncrea s e the dura ti on of a nes thes i a . In s ome ca rdi ova s cul a r pa ti ents , exces s
a mounts of thes e drugs ca us e a rrhythmi a s , myoca rdi a l i s chemi a , or hypertens i on. Pl a i n a nes theti c ca n be us ed for procedures requi ri ng < 45 mi n,
but i n l onger procedures or where hemos ta s i s i s needed, up to 0.04 mg epi nephri ne (2 denta l ca rtri dges wi th 1:100,000 epi nephri ne) i s cons i dered
s a fe. Genera l l y, no hea l thy pa ti ent s houl d recei ve > 0.2 mg epi nephri ne a t a ny one a ppoi ntment. Abs ol ute contra i ndi ca ti ons to epi nephri ne (a ny
dos e) a re uncontrol l ed hyperthyroi di s m; pheochromocytoma ; BP > 200 mm Hg s ys tol i c or > 115 mm Hg di a s tol i c; uncontrol l ed a rrhythmi a s des pi te
drug thera py; a nd uns ta bl e a ngi na , MI, or s troke wi thi n 6 mo.
Some el ectri ca l denta l equi pment, s uch a s a n el ectros urgi ca l ca utery, a pul p tes ter, or a n ul tra s oni c s ca l er, ca n i nterfere wi th ea rl y-genera ti on
pa cema kers .
Cancer: Extra cti ng a tooth a dja cent to a ca rci noma of the gi ngi va , pa l a te, or a ntrum fa ci l i ta tes i nva s i on of the a l veol us (tooth s ocket) by the tumor.
Therefore, a tooth s houl d be extra cted onl y duri ng the cours e of defi ni ti ve trea tment. In pa ti ents wi th l eukemi a or a gra nul ocytos i s , i nfecti on ma y
fol l ow a n extra cti on des pi te the us e of a nti bi oti cs .
Immunosuppression: Peopl e wi th i mpa i red i mmuni ty a re prone to s evere mucos a l a nd peri odonta l i nfecti ons by fungi , herpes a nd other vi rus es ,
a nd, l es s commonl y, ba cteri a . The i nfecti ons ma y ca us e hemorrha ge, del a yed hea l i ng, or s eps i s . Dys pl a s ti c or neopl a s ti c ora l l es i ons ma y
devel op a fter a few yea rs of i mmunos uppres s i on. Peopl e wi th AIDS ma y devel op Ka pos i 's s a rcoma , non-Hodgki n l ymphoma , ha i ry l eukopl a ki a ,
ca ndi di a s i s , a phthous ul cers , or a ra pi dl y progres s i ve form of peri odonta l di s ea s e.
Endocrine disorders: Denta l trea tment ma y be compl i ca ted by s ome endocri ne di s orders . For exa mpl e, peopl e wi th hyperthyroi di s m ma y devel op
ta chyca rdi a a nd exces s i ve a nxi ety a s wel l a s thyroi d s torm i f gi ven epi nephri ne. Ins ul i n requi rements ma y be reduced on el i mi na ti on of ora l
i nfecti on i n di a beti cs ; i ns ul i n dos e ma y requi re reducti on when food i nta ke i s l i mi ted beca us e of pa i n a fter ora l s urgery. In peopl e wi th di a betes ,
hypergl ycemi a wi th res ul ta nt pol yuri a ma y l ea d to dehydra ti on, res ul ti ng i n decrea s ed s a l i va ry fl ow (xeros tomi a ), whi ch, a l ong wi th el eva ted
s a l i va ry gl ucos e l evel s , contri butes to ca ri es .
Pa ti ents recei vi ng corti cos teroi ds a nd thos e wi th a drenocorti ca l i ns uffi ci ency ma y requi re s uppl ementa l corti cos teroi ds duri ng ma jor denta l
procedures . Pa ti ents wi th Cus hi ng's s yndrome or who a re ta ki ng corti cos teroi ds ma y ha ve a l veol a r bone l os s , del a yed wound hea l i ng, a nd
i ncrea s ed ca pi l l a ry fra gi l i ty.
Neurologic disorders: Pa ti ents wi th s ei zures who requi re denta l a ppl i a nces s houl d ha ve nonremova bl e a ppl i a nces tha t ca nnot be s wa l l owed or
a s pi ra ted. Pa ti ents una bl e to brus h or fl os s effecti vel y ma y us e chl orhexi di ne 12% ri ns es i n the morni ng a nd a t bedti me.
Obstructive sleep apnea: Pa ti ents wi th obs tructi ve s l eep a pnea who a re una bl e to tol era te trea tment wi th a pos i ti ve a i rwa y pres s ure (CPAP, bi PAP)
ma s k a re s ometi mes trea ted wi th a n i ntra ora l devi ce tha t expa nds the oropha rynx. Thi s trea tment i s not a s effecti ve a s CPAP, but more pa ti ents
tol era te us i ng i t.
Drugs: Certa i n drugs , s uch a s corti cos teroi ds , i mmunos uppres s a nts , a nd a nti neopl a s ti cs , compromi s e hea l i ng a nd hos t defens es . When pos s i bl e,
denta l procedures s houl d not be done whi l e thes e drugs a re bei ng gi ven.
Some a nti neopl a s ti cs (eg, doxorubi ci n, 5-fl uoroura ci l , bl eomyci n, da cti nomyci n, cytos i ne, a ra bi nos i de, methotrexa te) ca us e s toma ti ti s , whi ch i s
wors e i n pa ti ents wi th preexi s ti ng peri odonta l di s ea s e. Before s uch drugs a re pres cri bed, ora l prophyl a xi s s houl d be compl eted, a nd pa ti ents
s houl d be i ns tructed i n proper toothbrus hi ng a nd fl os s i ng.
Drugs tha t i nterfere wi th cl otti ng ma y need to be reduced or s topped before ora l s urgery. Pa ti ents ta ki ng a s pi ri n, NSAIDs , or cl opi dogrel s houl d
s top doi ng s o 4 da ys before undergoi ng denta l s urgery a nd ca n res ume ta ki ng thes e drugs a fter bl eedi ng s tops . Wa rfa ri n s houl d be s topped 2 to 3
da ys before ora l s urgery. PT i s obta i ned; INR of 1.5 i s cons i dered s a fe for s urgery. For peopl e recei vi ng hemodi a l ys i s , denta l procedures s houl d be
done the da y a fter di a l ys i s , when hepa ri ni za ti on ha s s ubs i ded.
Phenytoi n a nd Ca cha nnel bl ockers , pa rti cul a rl y ni fedi pi ne, contri bute to gi ngi va l hyperpl a s i a ; however, thi s hyperpl a s i a i s mi ni mi zed wi th
excel l ent ora l hygi ene a nd frequent ora l prophyl a xes (cl ea ni ngs ).
Bi s phos phona tes , pri ma ri l y when gi ven pa rentera l l y for trea tment of bone ca ncer, a nd to a much l es s er degree when us ed ora l l y to prevent
os teoporos i s , ca n res ul t i n os teonecros i s a fter a n extra cti on (s ee Si deba r 39-1 on p.
363).
Radiation therapy: (CAUTION: Extraction of teeth from irradiated tissues [particularly if the total dose was > 65 Gy, especially in the mandible] is commonly
followed by osteoradionecrosis of the jaw. This is a catastrophic complication in which extraction sites break down, frequently sloughing bone and soft tissue.)
Thus , i f pos s i bl e, pa ti ents s houl d ha ve a ny neces s a ry denta l trea tment compl eted before undergoi ng ra di a ti on thera py of the hea d a nd neck
regi on, wi th ti me a l l owed for hea l i ng. Teeth tha t ma y not s urvi ve s houl d be extra cted. Neces s a ry s ea l a nts a nd topi ca l fl uori de s houl d be a ppl i ed.
After ra di a ti on, extra cti on s houl d be a voi ded, i f pos s i bl e, by us i ng denta l res tora ti ons a nd root ca na l trea tment i ns tea d.
Hea d a nd neck ra di a ti on often da ma ges s a l i va ry gl a nds , ca us i ng xeros tomi a , whi ch promotes ca ri es . Pa ti ents mus t therefore pra cti ce l i fel ong
good ora l hygi ene. A fl uori de gel a nd fl uori de mouth ri ns e s houl d be us ed da i l y. Ri ns i ng wi th 0.12% chl orhexi di ne for 30 to 60 s ec, i f tol era ted, ca n
be done i n the morni ng a nd a t bedti me. Vi s cous l i doca i ne ma y ena bl e a pa ti ent wi th s ens i ti ve ora l ti s s ues to brus h a nd fl os s the teeth a nd ea t. A
denti s t mus t be s een a t 3-, 4-, or 6-mo i nterva l s , dependi ng on fi ndi ngs a t the l a s t exa mi na ti on. Irra di a ted ti s s ue under dentures i s l i kel y to brea k
down, s o dentures s houl d be checked a nd a djus ted whenever di s comfort i s noted. Ea rl y ca ri es ma y a l s o be revers ed by Ca phos phopepti des a nd
a morphous Ca phos pha te, whi ch ca n be a ppl i ed by a denti s t or pres cri bed to a pa ti ent for a t-home us e.
Pa ti ents who undergo ra di a ti on thera py ma y devel op ora l mucos a l i nfl a mma ti on a nd di mi ni s hed ta s te a s wel l a s tri s mus due to fi bros i s of the
ma s ti ca tory mus cl es . Tri s mus ma y be mi ni mi zed by s uch exerci s es a s openi ng a nd cl os i ng the mouth wi del y 20 ti mes 3 or 4 ti mes /da y. Extra cti ons
of teeth i n i rra di a ted bone s houl d be a voi ded (beca us e of pos s i bl e os teora di onecros i s ). Someti mes root ca na l thera py i s done, a nd the tooth i s
ground down to the gum l i ne. If extra cti on i s requi red a fter ra di a ti on, 10 to 20 trea tments i n a hyperba ri c O2 cha mber ma y fores ta l l or prevent
os teora di onecros i s .
Bruxism
Bruxi s m i s cl enchi ng or gri ndi ng of teeth. Bruxi s m ca n a bra de a nd eventua l l y wea r down denta l crowns a nd l oos en teeth. In ma ny peopl e,
hea da ches , ja w pa i n, or both a ctua l l y a re the res ul t of bruxi s m. The mos t s evere a nd extens i ve gri ndi ng a nd cl enchi ng occurs duri ng s l eep, s o the
pers on ma y be obl i vi ous to i t, but fa mi l y members mi ght noti ce.
Trea tment requi res tha t the pa ti ent cons ci ous l y try to reduce bruxi s m whi l e a wa ke. Pl a s ti c ora l a ppl i a nces (ni ght gua rds ) tha t prevent occl us a l
conta ct by fi tti ng between the teeth ca n be us ed whi l e s l eepi ng. When s ymptoms a re s evere, a gua rd ca n be us ed a l s o duri ng the da y. Us ua l l y,
s uch devi ces a re ma de by denti s ts . However, i f the onl y probl em i s tooth wea r, OTC hea t-mol da bl e devi ces , fi tted a t home, a re a va i l a bl e. Mi l d
a nxi ol yti cs , pa rti cul a rl y benzodi a zepi nes , ma y hel p unti l a ni ght gua rd i s a va i l a bl e but s houl d not be us ed for extended peri ods .
Halitosis
(Fetor Ori s ; Ora l Ma l odor)
Ha l i tos i s i s a frequent or pers i s tent unpl ea s a nt odor to the brea th.
Pathophysiology
Ha l i tos i s mos t often res ul ts from fermenta ti on of food pa rti cl es by a na erobi c gra m-nega ti ve ba cteri a i n the mouth, produci ng vol a ti l e s ul fur
compounds s uch a s hydrogen s ul fi de a nd methyl merca pta n. Ca us a ti ve ba cteri a ma y be pres ent i n a rea s of gi ngi va l or peri odonta l di s ea s e,
pa rti cul a rl y when ul cera ti on or necros i s i s pres ent. The ca us a ti ve orga ni s ms res i de deep i n peri odonta l pockets a round teeth. In pa ti ents wi th
hea l thy peri odonta l ti s s ue, thes e ba cteri a ma y depos i t on the dors a l pos teri or tongue.
Fa ctors contri buti ng to the overgrowth of ca us a ti ve ba cteri a i ncl ude decrea s ed s a l i va ry fl ow (eg, due to pa roti d di s ea s e, Sjogren's s yndrome, us e
of a nti chol i nergi cs s ee p. 513), s a l i va ry s ta gna ti on, a nd i ncrea s ed s a l i va ry pH.
Certa i n foods or s pi ces , a fter di ges ti on, rel ea s e the odor of tha t s ubs ta nce to the l ungs ; the exha l ed odor ma y be unpl ea s a nt to others . For
exa mpl e, the odor of ga rl i c i s noted on the brea th by others 2 or 3 h a fter cons umpti on, l ong a fter i t i s gone from the mouth.
Etiology
About 85% of ca s es res ul t from ora l condi ti ons . A va ri ety of s ys temi c a nd extra ora l condi ti ons a ccount for the rema i nder (s ee
Ta bl e 56-5).
The most common causes overa l l a re the fol l owi ng:

Gi ngi va l or peri odonta l di s ea s e
Smoki ng
Inges ted foods tha t ha ve a vol a ti l e component
GI di s orders ra rel y ca us e ha l i tos i s beca us e the es opha gus i s norma l l y col l a ps ed. It i s a fa l l a cy tha t brea th odor refl ects the s ta te of di ges ti on a nd
bowel functi on.
Other breath odors: Severa l s ys temi c di s ea s es produce vol a ti l e s ubs ta nces detecta bl e on the brea th, a l though not the pa rti cul a rl y foul , pungent
odors typi ca l l y cons i dered ha l i tos i s . Di a beti c ketoa ci dos i s produces a s weet or frui ty odor of a cetone; l i ver fa i l ure produces a mous y or
s ometi mes fa i ntl y s ul furous odor; a nd rena l fa i l ure produces a n odor of uri ne or a mmoni a .
Evaluation
History: History of present illness s houl d a s certa i n dura ti on a nd s everi ty of ha l i tos i s (i ncl udi ng whether other peopl e ha ve noti ced or compl a i ned),
a dequa cy of pa ti ent's ora l hygi ene, a nd the rel a ti ons hi p of ha l i tos i s to i nges ti on of ca us a ti ve foods (s ee Ta bl e 56-5).
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng na s a l di s cha rge a nd fa ce or hea d pa i n (s i nus i ti s , na s a l forei gn body);
producti ve cough a nd fevers (pul mona ry i nfecti on); a nd regurgi ta ti on of undi ges ted food when l yi ng down or bendi ng over (Zenker's di verti cul um).
Predi s pos i ng fa ctors s uch a s dry mouth, dry eyes , or both (Sjogren's s yndrome) s houl d be noted.
Past medical history s houl d a s k a bout dura ti on a nd a mount of us e of a l cohol a nd toba cco. Drug hi s tory s houl d s peci fi ca l l y a s k a bout us e of thos e
tha t ca n ca us e dry mouth.
[Table 56-5. Some Ca us es of Ha l i tos i s ]
Physical examination: Vi ta l s i gns a re revi ewed, pa rti cul a rl y for pres ence of fever.
The nos e i s exa mi ned for di s cha rge a nd forei gn body.
The mouth i s exa mi ned for s i gns of gum di s ea s e, denta l i nfecti on, a nd ca ncer. Si gns of a ppa rent drynes s a re noted (eg, whether the mucos a i s dry,
s ti cky, or moi s t; whether s a l i va i s foa my, s tri ngy, or norma l i n a ppea ra nce).
The pha rynx i s exa mi ned for s i gns of i nfecti on a nd ca ncer.
Sniff test: A s ni ff tes t of exha l ed a i r i s conducted. In genera l , ora l ca us es res ul t i n a putrefyi ng, pungent s mel l , wherea s s ys temi c condi ti ons res ul t
i n a more s ubtl e, a bnorma l odor. Idea l l y, for 48 h before the exa mi na ti on, the pa ti ent a voi ds ea ti ng ga rl i c or oni ons , a nd for 2 h before, the
pa ti ent a bs ta i ns from ea ti ng, chewi ng, dri nki ng, ga rgl i ng, ri ns i ng, or s moki ng. Duri ng the tes t, the pa ti ent exha l es 10 cm a wa y from the exa mi ner's
nos e, fi rs t through the mouth a nd then wi th the mouth cl os ed. A wors e odor through the mouth s ugges ts a n ora l eti ol ogy. A wors e odor through the
nos e s ugges ts a na s a l or s i nus eti ol ogy. Si mi l a r odor through both nos e a nd mouth s ugges ts a s ys temi c or pul mona ry ca us e. If s i te of ori gi n i s
uncl ea r, the pos teri or tongue i s s cra ped wi th a pl a s ti c s poon. After 5 s ec, the s poon i s s ni ffed 5 cm from the exa mi ner's nos e.
Fever
Purul ent na s a l di s cha rge or s putum
Vi s i bl e or pa l pa bl e ora l l es i ons
Interpretation of findings: Beca us e ora l ca us es a re by fa r the mos t common, a ny vi s i bl e ora l di s ea s e ma y be pres umed to be the ca us e i n pa ti ents
wi th no extra ora l s ymptoms or s i gns . When other di s orders a re i nvol ved, cl i ni ca l fi ndi ngs often s ugges t a di a gnos i s (s ee Ta bl e 56-5).
In pa ti ents whos e s ymptoms s eem to be rel a ted to i nta ke of certa i n s ubs ta nces a nd who ha ve no other fi ndi ngs , a tri a l of a voi da nce ma y cl a ri fy
the di a gnos i s .
Testing: Extens i ve di a gnos ti c eva l ua ti on s houl d not be underta ken unl es s the hi s tory a nd phys i ca l exa mi na ti on s ugges t a n underl yi ng di s ea s e
(s ee Ta bl e 56-5). Porta bl e s ul fur moni tors , ga s chroma togra phy, a nd chemi ca l tes ts of tongue s cra pi ngs a re a va i l a bl e but bes t l eft to res ea rch
protocol s or the occa s i ona l denta l offi ce tha t focus es on ha l i tos i s .
Treatment
Underl yi ng di s ea s es a re trea ted.
If the ca us e i s ora l , the pa ti ent s houl d s ee a denti s t for profes s i ona l cl ea ni ng a nd trea tment of gi ngi va l di s ea s e a nd ca ri es . Home trea tment
i nvol ves enha nced ora l hygi ene, i ncl udi ng thorough fl os s i ng, toothbrus hi ng, a nd brus hi ng of the tongue wi th the toothbrus h or a s cra per.
Mouthwa s hes a re of l i mi ted benefi t except to ma s k odor for a bout 20 mi n. Ps ychogeni c ha l i tos i s ma y requi re ps ychi a tri c cons ul ta ti on.
El derl y pa ti ents a re more l i kel y to ta ke drugs tha t ca us e dry mouth, whi ch l ea ds to di ffi cul ti es wi th ora l hygi ene a nd hence to ha l i tos i s , but a re
otherwi s e not more l i kel y to ha ve ha l i tos i s . Al s o, ora l ca ncers a re more common wi th a gi ng a nd a re more of a concern a mong el derl y tha n younger
pa ti ents .
Key Points
Mos t ha l i tos i s comes from fermenta ti on of food pa rti cl es by a na erobi c gra m-nega ti ve ba cteri a i n the mouth.
Extra ora l di s orders ma y ca us e ha l i tos i s but a re often a ccompa ni ed by s ugges ti ve fi ndi ngs .
It i s a fa l l a cy tha t brea th odor refl ects the s ta te of di ges ti on a nd bowel functi on.
Mouthwa s hes provi de onl y bri ef benefi t.
Malocclusion
Ma l occl us i on i s a bnorma l conta ct between the ma xi l l a ry a nd ma ndi bul a r teeth.
Norma l l y, ea ch denta l a rch cons i s ts of teeth i n s i de-by-s i de conta ct, formi ng a s mooth curve, wi th the ma xi l l a ry a nteri or teeth overl yi ng the upper
thi rd of the ma ndi bul a r a nteri or teeth. The bucca l (outer) cus ps of the ma xi l l a ry pos teri or teeth a re externa l to the corres pondi ng cus ps of the
ma ndi bul a r pos teri or teeth. On ea ch s i de of the mouth, the a nteri or bucca l cus p of the ma xi l l a ry 1s t perma nent mol a r fi ts i nto the a nteri or bucca l
groove of the ma ndi bul a r 1s t mol a r. Beca us e the outer pa rts of a l l ma xi l l a ry teeth a re norma l l y externa l to the ma ndi bul a r teeth, the l i ps a nd
cheeks a re di s pl a ced from between the teeth s o tha t they a re not bi tten. The l i ngua l (i nner) s urfa ces of the l ower teeth form a s ma l l er a rc tha n
thos e of the upper teeth, confi ni ng the tongue a nd mi ni mi zi ng the l i kel i hood of i ts bei ng bi tten. Al l the ma xi l l a ry teeth s houl d conta ct the
corres pondi ng ma ndi bul a r teeth, s o tha t the ma s ti ca tory forces (whi ch ma y be > 150 l b i n the mol a r regi on a nd 250 l b when cl enchi ng duri ng s l eep)
a re wi del y di s tri buted. If thes e forces a re a ppl i ed to onl y a few teeth, thos e teeth wi l l eventua l l y l oos en.
Etiology
Ma l occl us i on often res ul ts from ja w a nd tooth s i ze di s crepa nci es (i e, the ja w i s too s ma l l or the teeth a re too l a rge for the ja w to a ccommoda te
them i n proper a l i gnment) but ma y be ca us ed by a number of congeni ta l deformi ti es a nd di s orders or by tooth l os s . When perma nent teeth a re
l os t, a dja cent teeth s hi ft a nd oppos i ng teeth extrude, ca us i ng ma l occl us i on unl es s a bri dge, i mpl a nt, or pa rti a l denture i s worn to prevent thes e
movements . When chi l dren l os e deci duous teeth prema turel y, the teeth more pos teri or i n the a rch or the perma nent 1s t mol a rs often dri ft
forwa rd, l ea vi ng i ns uffi ci ent s pa ce for other perma nent teeth to erupt. Ma l occl us i on a fter fa ci a l tra uma ma y i ndi ca te tooth di s pl a cement or ja w
fra cture. In ectoderma l dys pl a s i a , ma l occl us i on res ul ts from ha vi ng too few teeth.
Evaluation
Occl us i on i s checked on both s i des of the mouth by retra cti ng ea ch cheek wi th a tongue depres s or whi l e tel l i ng the pa ti ent to cl os e on the ba ck
teeth. Ma l occl us i on s ometi mes i s i denti fi ed a s ea rl y a s the fi rs t denta l vi s i t. Ea rl y i denti fi ca ti on ma y ma ke l a ter trea tment ea s i er a nd more
effecti ve.
Treatment
Ma l occl us i ons a re corrected pri ma ri l y for a es theti c a nd ps ychol ogi c rea s ons . However, i n s ome ca s es , trea tment ma y i ncrea s e res i s ta nce to ca ri es
(i n s peci fi c teeth), to a nteri or tooth fra cture, a nd, pos s i bl y, to peri odonta l di s ea s e or s tri ppi ng of the gi ngi va on the pa l a te. Trea tment ma y
i mprove s peech a nd ma s ti ca ti on a s wel l . Occl us i on ca n be i mproved by a l i gni ng teeth properl y, by s el ecti vel y gri ndi ng teeth a nd res tora ti ons tha t
conta ct prema turel y, a nd by i ns erti ng crowns or onl a ys to bui l d up tooth s urfa ces tha t a re bel ow the pl a ne of occl us i on.
Orthodonti c a ppl i a nces (bra ces ) a ppl y a conti nuous mi l d force to teeth to gra dua l l y remodel the s urroundi ng a l veol a r bone. Extra cti on of one or
more perma nent teeth (us ua l l y a 1s t premol a r) ma y be needed to a l l ow other teeth to be repos i ti oned or to erupt i nto a s ta bl e a l i gnment. After
the teeth a re properl y a l i gned, the pa ti ent wea rs a pl a s ti c-a nd-wi re reta i ner 24 h/da y i ni ti a l l y, then onl y a t ni ght for 2 to 3 yr.
When orthodonti c trea tment a l one i s i ns uffi ci ent, s urgi ca l correcti on of ja w a bnorma l i ti es contri buti ng to ma l occl us i on (orthogna thi c s urgery) ma y
be i ndi ca ted.
Stomatitis
Ora l i nfl a mma ti on a nd ul cers , known a s s toma ti ti s , ma y be mi l d a nd l oca l i zed or s evere a nd wi des prea d. They a re i nva ri a bl y pa i nful . Stoma ti ti s
ma y i nvol ve s wel l i ng a nd rednes s of the ora l mucos a or di s crete, pa i nful ul cers (s i ngl e or mul ti pl e). Les s commonl y, whi ti s h l es i ons form, a nd,
ra rel y, the mouth a ppea rs norma l (burni ng mouth s yndrome) des pi te s i gni fi ca nt s ymptoms . Symptoms hi nder ea ti ng, s ometi mes l ea di ng to
dehydra ti on a nd ma l nutri ti on. Seconda ry i nfecti on occa s i ona l l y occurs . Some condi ti ons a re recurrent.
Etiology
Stoma ti ti s ma y be ca us ed by l oca l i nfecti on, s ys temi c di s ea s e, a phys i ca l or chemi ca l i rri ta nt, or a n a l l ergi c rea cti on (s ee
Ta bl e 56-6); ma ny ca s es a re i di opa thi c. Beca us e the norma l fl ow of s a l i va protects the mucos a a ga i ns t ma ny i ns ul ts , xeros tomi a predi s pos es the
mouth to s toma ti ti s of a ny ca us e.
The most common specific causes overa l l i ncl ude
Recurrent a phthous s toma ti ti s (RAS)a l s o ca l l ed recurrent a phthous ul cers (RAU)
Vi ra l i nfecti ons , pa rti cul a rl y herpes s i mpl ex a nd herpes zos ter
Other i nfecti ous a gents (Candida albicans a nd ba cteri a )

Tra uma
Toba cco
Chemothera py a nd ra di a ti on thera py
Evaluation
History: History of present illness s houl d a s certa i n the dura ti on of s ymptoms a nd whether the pa ti ent ever ha d them previ ous l y. Pres ence a nd
s everi ty of pa i n s houl d be noted. The rel a ti on of s ymptoms to food, drugs , a nd other s ubs ta nces (pa rti cul a rl y occupa ti ona l expos ure to chemi ca l s ,
meta l s , fumes , or dus t) i s s ought.
Review of systems s eeks s ymptoms of pos s i bl e ca us es , i ncl udi ng chroni c di a rrhea a nd wea knes s (i nfl a mma tory bowel di s ea s e, cel i a c s prue);
geni ta l l es i ons (Behcet's s yndrome, s yphi l i s ); eye i rri ta ti on (Behcet's s yndrome); a nd wei ght l os s , ma l a i s e, a nd fever (nons peci fi c chroni c i l l nes s ).
Past medical history s houl d a s certa i n known condi ti ons tha t ca us e ora l l es i ons , i ncl udi ng herpes s i mpl ex, Behcet's s yndrome, i nfl a mma tory bowel
di s ea s e, a nd ri s k fa ctors for ora l l es i ons , i ncl udi ng i mmunocompromi s ed s ta te (eg, ca ncer, di a betes , orga n tra ns pl a nt, us e of
i mmunos uppres s a nts , HIV i nfecti on). Whether chemothera py or ra di a ti on thera py ha s ever been us ed to ma na ge ca ncer needs to be determi ned.
Drug hi s tory s houl d note a l l recent drugs us ed. Hi s tory of toba cco us e s houl d be noted. Soci a l hi s tory s houl d i ncl ude s exua l conta ct, pa rti cul a rl y
ora l s ex, unprotected s ex, a nd s ex wi th mul ti pl e pa rtners .
Physical examination: Vi ta l s i gns a re revi ewed for fever. The pa ti ent's genera l a ppea ra nce i s noted for l etha rgy, di s comfort, or other s i gns of
s i gni fi ca nt s ys temi c i l l nes s .
The mouth i s i ns pected for the l oca ti on a nd na ture of a ny l es i ons .
The s ki n a nd other mucos a l s urfa ces (i ncl udi ng the geni ta l s ) a re i ns pected for a ny l es i ons ,
[Table 56-6. Some Ca us es of Stoma ti ti s ]
ra s h, petechi a e, or des qua ma ti on. Any bul l ous l es i ons a re rubbed for Ni kol s ky's s i gn (peel i ng of epi thel i um wi th l a tera l pres s ure).
Fever
Cuta neous bul l a e
Ocul a r i nfl a mma ti on
Immunocompromi s e
Interpretation of findings: Occa s i ona l l y, ca us es a re obvi ous i n the hi s tory (eg, cytotoxi c chemothera py; s i gni fi ca nt occupa ti ona l expos ure to
chemi ca l s , fumes , or dus t). Recurrent epi s odes of ora l l es i ons occur wi th RAS, herpes s i mpl ex, a nd Behcet's s yndrome. Hi s tory of di a betes , HIV
i nfecti on or other i mmunocompromi s e, or recent a nti bi oti c us e s houl d i ncrea s e s us pi ci on of Candida i nfecti on. Recent drug us e (pa rti cul a rl y s ul fa
drugs , other a nti bi oti cs , a nd a nti epi l epti cs ) s houl d i ncrea s e s us pi ci on of Stevens -Johns on s yndrome (SJS).
Some ca us es typi ca l l y ha ve extraoral, noncutaneous findings, s ome of whi ch s ugges t a ca us e. Recurrent GI s ymptoms s ugges t i nfl a mma tory bowel
di s ea s e or cel i a c s prue. Ocul a r s ymptoms ca n occur wi th Behcet's s yndrome a nd SJS. Geni ta l l es i ons ma y occur wi th Behcet's s yndrome a nd
pri ma ry s yphi l i s .
Some ca us es us ua l l y a l s o ha ve extraoral, cutaneous findings.
Cuta neous bul l a e s ugges t SJS, pemphi gus vul ga ri s , or bul l ous pemphi goi d. Prodrome of ma l a i s e, fever, conjuncti vi ti s , a nd genera l i zed ma cul a r
ta rget l es i ons s ugges ts SJS. Pemphi gus vul ga ri s s ta rts wi th ora l l es i ons , then progres s es to fl a cci d cuta neous bul l a e. Bul l ous pemphi goi d ha s
tens e bul l a e on norma l -a ppea ri ng s ki n. Ni kol s ky's s i gn i s us ua l l y pos i ti ve i n SJS a nd pemphi gus vul ga ri s .
Cuta neous ves i cl es a re typi ca l wi th chi ckenpox or herpes zos ter. Uni l a tera l l es i ons i n a ba nd a fter a derma tome s ugges t herpes zos ter. Di ffus e,
s ca ttered ves i cul a r a nd pus tul a r l es i ons i n di fferent s ta ges s ugges t chi ckenpox.
Ka wa s a ki di s ea s e us ua l l y ha s a ma cul a r ra s h, des qua ma ti on of ha nds a nd feet, a nd conjuncti vi ti s ; i t occurs i n chi l dren, us ua l l y thos e < 5 yr. Ora l
fi ndi ngs i ncl ude erythema of the l i ps a nd ora l mucos a .
Other cuta neous l es i ons ma y i mpl i ca te erythema mul ti forme, ha nd-foot-a nd-mouth di s ea s e (from coxs a cki evi rus ), or s econda ry s yphi l i s .
Some ca us es ha ve isolated oral findings, i ncl udi ng RAS, mos t vi ra l i nfecti ons , a cute necroti zi ng ul cera ti ve gi ngi vi ti s , pri ma ry s yphi l i s , gonorrhea , a nd
Candida.
Loca ti on of ora l l es i ons ma y hel p i denti fy the ca us e. Interdenta l ul cers occur wi th pri ma ry herpes s i mpl ex or a cute necroti zi ng ul cera ti ve gi ngi vi ti s .
Les i ons on kera ti ni zed s urfa ces s ugges t herpes s i mpl ex, RAS, or phys i ca l i njury. Phys i ca l i njury typi ca l l y ha s a n i rregul a r a ppea ra nce a nd occurs
nea r projecti ons of teeth, denta l a ppl i a nces , or where bi ti ng ca n i njure the mucos a . An a s pi ri n burn next to a tooth a nd pi zza burn on the pa l a te
a re common.
Pri ma ry herpes s i mpl ex i nfecti on ca us es mul ti pl e ves i cul a r l es i ons on the i ntra ora l mucos a on both kera ti ni zed a nd nonkera ti ni zed s urfa ces a nd
a l wa ys i ncl udes the gi ngi va . Thes e l es i ons ra pi dl y ul cera te. Cl i ni ca l ma ni fes ta ti on occurs mos t often i n chi l dren. Subs equent rea cti va ti ons
(s econda ry herpes s i mpl ex, col d s ore) us ua l l y a ppea r s ta rti ng i n puberty on the l i p a t the vermi l i on border a nd, ra rel y, on the ha rd pa l a te.
Acute necroti zi ng ul cera ti ve gi ngi vi ti s ca us es s evere i nfl a mma ti on a nd punched-out ul cers on the denta l pa pi l l a e a nd ma rgi na l gi ngi va e. A s evere
va ri a nt ca l l ed noma (ga ngrenous s toma ti ti s ) ca n ca us e ful l -thi cknes s ti s s ue des tructi on (s ometi mes i nvol vi ng the l i ps or cheek), typi ca l l y i n a
debi l i ta ted pa ti ent. It begi ns a s a gi ngi va l , bucca l , or pa l a ta l (mi dl i ne l etha l gra nul oma ) ul cer tha t becomes necroti c a nd s prea ds ra pi dl y. Ti s s ue
s l oughi ng ma y occur.
Is ol a ted ora l gonorrhea very ra rel y ca us es burni ng ul cers a nd erythema of the gi ngi va a nd tongue, a s wel l a s the more common pha ryngi ti s .
Pri ma ry s yphi l i s cha ncres ma y a ppea r i n the mouth. Terti a ry s yphi l i s ma y ca us e ora l gumma s or a genera l i zed gl os s i ti s a nd mucos a l a trophy. The
s i te of a gumma i s the onl y ti me tha t s qua mous cel l ca rci noma devel ops on the dors um of the tongue. A common s i gn of HIV becomi ng AIDS i s
ha i ry l eukopl a ki a (verti ca l whi te l i nes on the l a tera l border of the tongue).
C. albicans a nd rel a ted s peci es , whi ch a re norma l ora l fl ora , ca n overgrow i n peopl e who ha ve ta ken a nti bi oti cs or corti cos teroi ds or who a re
i mmunocompromi s ed, s uch a s pa ti ents wi th AIDS. C. albicans ca n ca us e whi ti s h, chees y pl a ques tha t l ea ve eros i ons when wi ped off. Someti mes
onl y fl a t, erythema tous a rea s a ppea r (eros i ve form of Candida).
Testing: Pa ti ents wi th a cute s toma ti ti s a nd no s ymptoms , s i gns , or ri s k fa ctors for s ys temi c i l l nes s proba bl y requi re no tes ti ng.
If s toma ti ti s i s recurrent, vi ra l a nd ba cteri a l cul tures , CBC, s erum i ron, ferri ti n, vi ta mi n B 12 , fol a te, zi nc, a nd endomys i a l a nti body (for s prue) a re
done. Bi ops y a t the peri phery of norma l a nd a bnorma l ti s s ue ca n be done for pers i s tent l es i ons tha t do not ha ve a n obvi ous eti ol ogy.
Sys tema ti ca l l y el i mi na ti ng foods from the di et ca n be us eful , a s ca n cha ngi ng bra nds of toothpa s te, chewi ng gum, or mouthwa s h.
Treatment
Speci fi c di s orders a re trea ted, a nd a ny ca us a ti ve s ubs ta nces or drugs a re a voi ded.
Meti cul ous ora l hygi ene (us i ng a s oft toothbrus h) ma y hel p prevent s econda ry i nfecti on. A s oft di et tha t does not i ncl ude a ci di c or s a l ty foods i s
fol l owed.
Topical measures: Numerous topi ca l trea tments , a l one or i n combi na ti on, a re us ed to ea s e s ymptoms . Thes e trea tments i ncl ude
Anes theti cs
Protecti ve coa ti ngs
Corti cos teroi ds
Anti bi oti cs
Phys i ca l mea s ures (eg, ca utery)
For topi ca l a nes thes i a of di s comfort tha t ma y i nterfere wi th ea ti ng a nd dri nki ng, the fol l owi ng ma y be effecti ve:
Li doca i ne ri ns e
Sucra l fa te pl us a l umi num-ma gnes i um a nta ci d ri ns e
A 2-mi n ri ns e i s done wi th 15 mL (1 tbs p) 2% vi s cous l i doca i ne q 3 h prn; pa ti ent expectora tes when done (no ri ns i ng wi th wa ter a nd no s wa l l owi ng
unl es s the pha rynx i s i nvol ved). A s oothi ng coa ti ng ma y be prepa red wi th s ucra l fa te (1-g pi l l di s s ol ved i n 15 mL wa ter) pl us 30 mL of a l umi numma gnes i um l i qui d a nta ci d; the pa ti ent s houl d ri ns e wi th or wi thout s wa l l owi ng. Ma ny i ns ti tuti ons a nd pha rma ci es ha ve thei r own va ri a ti on of
thi s formul a ti on (ma gi c mouthwa s h), whi ch s ometi mes a l s o conta i ns a n a nti hi s ta mi ne.
If the phys i ci a n i s certa i n the i nfl a mma ti on i s not ca us ed by a n i nfecti ous orga ni s m, the pa ti ent ca n
Ri ns e a nd expectora te a fter mea l s wi th dexa metha s one el i xi r 0.5 mg/5 mL (1 ts p)
Appl y a pa s te of 0.1% tri a mci nol one i n a n ora l emol l i ent
Wi pe a ml exa nox over the ul cera ted a rea wi th the ti p of a fi nger
Chemi ca l or phys i ca l ca utery ca n ea s e pa i n of l oca l i zed l es i ons . Si l ver ni tra te s ti cks a re not a s effecti ve a s l ow-power (2- to 3-wa tt), defocus ed,
pul s ed-mode CO2 l a s er trea tments , a fter whi ch pa i n rel i ef i s i mmedi a te a nd l es i ons tend not to recur l oca l l y.
Key Points
Is ol a ted s toma ti ti s i n pa ti ents wi th no other s ymptoms a nd s i gns or ri s k fa ctors for s ys temi c i l l nes s i s us ua l l y ca us ed by a vi ra l i nfecti on or RAS.
Extra ora l s ymptoms , s ki n ra s h, or both s ugges t more i mmedi a te need for di a gnos i s .
Recurrent Aphthous Stomatitis
Recurrent aphthous stomatitis is a common condition in which round or ovoid painful ulcers recur on the oral mucosa. Etiology is unclear. Diagnosis is clinical.
Treatment is symptomatic and usually includes topical corticosteroids.
Recurrent a phthous s toma ti ti s (RAS) a ffects 20 to 30% of a dul ts a nd a grea ter percenta ge of chi l dren a t s ome ti me i n thei r l i fe.
Etiology
Eti ol ogy i s uncl ea r, but RAS tends to run i n fa mi l i es . The da ma ge i s predomi na tel y cel l -medi a ted. Cytoki nes , s uch a s IL-2, IL-10, a nd, pa rti cul a rl y,
tumor necros i s fa ctor-, pl a y a rol e.
Predisposing factors i ncl ude
Ora l tra uma
Stres s
Foods , pa rti cul a rl y chocol a te, coffee, pea nuts , eggs , cerea l s , a l monds , s tra wberri es , chees e, a nd toma toes
Al l ergy does not s eem to be i nvol ved.
Fa ctors tha t ma y, for unknown rea s ons , be protective i ncl ude ora l contra cepti ves , pregna ncy, a nd toba cco, i ncl udi ng s mokel es s toba cco a nd
ni coti ne-conta i ni ng ta bl ets .
Symptoms and Signs
Symptoms a nd s i gns us ua l l y begi n i n chi l dhood (80% of pa ti ents a re < 30 yr) a nd decrea s e i n frequency a nd s everi ty wi th a gi ng. Symptoms ma y
i nvol ve a s few a s one ul cer 2 to 4 ti mes /yr or a l mos t conti nuous di s ea s e, wi th new ul cers formi ng a s ol d ones hea l . A prodrome of pa i n or burni ng
for 1 to 2 da ys precedes ul cers , but there a re no a ntecedent ves i cl es or bul l a e. Severe pa i n, di s proporti ona te to the s i ze of the l es i on, ca n l a s t
from 4 to 7 da ys .
Ul cers a re wel l -dema rca ted, s ha l l ow, ovoi d, or round a nd ha ve a necroti c center wi th a yel l ow-gra y ps eudomembra ne, a red ha l o, a nd s l i ghtl y
ra i s ed red ma rgi ns .
Minor aphthae (Mi kul i cz's di s ea s e) a ccount for 85% of ca s es . They occur on the fl oor of the mouth, l a tera l a nd ventra l tongue, bucca l mucos a , a nd
pha rynx; a re < 8 mm (typi ca l l y 2 to 3 mm); a nd hea l i n 10 da ys wi thout s ca rri ng.
Major aphthae (Sutton's di s ea s e, peri a deni ti s mucos a necroti ca recurrens ) cons ti tute 10% of ca s es . Appea ri ng a fter puberty, the prodrome i s more
i ntens e a nd the ul cers a re deeper, l a rger (> 1 cm), a nd l onger l a s ti ng (weeks to months ) tha n mi nor a phtha e. They a ppea r i n the l i ps , s oft pa l a te,
a nd throa t. Fever, dys pha gi a , ma l a i s e, a nd s ca rri ng ma y occur.
Herpetiform ulcers (morphol ogi ca l l y res embl i ng but unrel a ted to herpes vi rus ) a ccount for 5% of ca s es . They begi n a s mul ti pl e (up to 100) 1- to 3-mm
crops of s ma l l , pa i nful cl us ters of ul cers on a n erythema tous ba s e. They coa l es ce to form l a rger ul cers tha t l a s t 2 wk. They tend to occur i n women
a nd a t a l a ter a ge of ons et tha n do other forms of RAS.
Diagnosis
Eva l ua ti on proceeds a s des cri bed previ ous l y under s toma ti ti s (s ee p. 509). Di a gnos i s i s ba s ed on a ppea ra nce a nd on excl us i on, beca us e there a re
no defi ni ti ve hi s tol ogi c fea tures or l a bora tory tes ts .
Pri ma ry ora l herpes s i mpl ex ma y mi mi c RAS but us ua l l y occurs i n younger chi l dren, a l wa ys i nvol ves the gi ngi va a nd ma y a ffect a ny kera ti ni zed
mucos a (ha rd pa l a te, a tta ched gi ngi va , dors um of tongue), a nd i s a s s oci a ted wi th s ys temi c s ymptoms . Vi ra l cul ture ca n be done to i denti fy herpes
s i mpl ex. Recurrent herpeti c l es i ons a re us ua l l y uni l a tera l .
Si mi l a r recurrent epi s odes ca n occur wi th Behcet's s yndrome, i nfl a mma tory bowel di s ea s e, s prue, HIV i nfecti on, a nd nutri ti ona l defi ci enci es ;
thes e condi ti ons genera l l y ha ve s ys temi c s ymptoms a nd s i gns . Is ol a ted recurrent ora l ul cers ca n occur wi th herpes i nfecti on, HIV, a nd, ra rel y,
nutri ti ona l defi ci ency. Vi ra l tes ti ng a nd s erum hema tol ogi c tes ts ca n i denti fy thes e condi ti ons .
Drug rea cti ons ma y mi mi c RAS but a re us ua l l y tempora l l y rel a ted to i nges ti on. However, rea cti ons to foods or denta l products ma y be di ffi cul t to
i denti fy; s equenti a l el i mi na ti on ma y be neces s a ry.
Treatment
Topi ca l chl orhexi di ne a nd corti cos teroi ds
Genera l trea tments for s toma ti ti s (s ee p. 512) ma y hel p pa ti ents wi th RAS. Chl orhexi di ne gl ucona te mouthwa s hes a nd topi ca l corti cos teroi ds , the
ma i ns ta ys of thera py, s houl d be us ed duri ng the prodrome, i f pos s i bl e. The corti cos teroi d ca n be dexa metha s one 0.5 mg/5 mL ti d us ed a s a ri ns e
a nd then expectora ted or cl obeta s ol oi ntment 0.05% or fl uoci noni de oi ntment 0.05% i n ca rboxymethyl cel l ul os e mucos a l protecti ve pa s te (1:1)
a ppl i ed ti d. Pa ti ents us i ng thes e corti cos teroi ds s houl d be moni tored for ca ndi di a s i s . If topi ca l corti cos teroi ds a re i neffecti ve, predni s one (eg, 40
mg po once/da y) ma y be needed for 5 da ys . Conti nuous or pa rti cul a rl y s evere RAS i s bes t trea ted by a s peci a l i s t i n ora l medi ci ne. Trea tment ma y
requi re prol onged us e of s ys temi c corti cos teroi ds , a za thi opri ne or other i mmunos uppres s a nts , pentoxi fyl l i ne, or tha l i domi de. Intra l es i ona l
i njecti ons ca n be done wi th beta metha s one, dexa metha s one, or tri a mci nol one. Suppl ementa l B 1 , B 2 , B 6 , B 12 , fol a te, or i ron l es s ens RAS i n s ome
pa ti ents .
Xerostomia
Xeros tomi a i s dry mouth ca us ed by reduced or a bs ent fl ow of s a l i va . Thi s condi ti on ca n res ul t i n di s comfort, i nterfere wi th s peech a nd s wa l l owi ng,
ma ke wea ri ng dentures di ffi cul t, ca us e ha l i tos i s , a nd i mpa i r ora l hygi ene by ca us i ng a decrea s e i n ora l pH a nd a n i ncrea s e i n ba cteri a l growth.
Longs ta ndi ng xeros tomi a ca n res ul t i n s evere tooth deca y a nd ora l ca ndi di a s i s . Xeros tomi a i s a common compl a i nt a mong ol der a dul ts , a ffecti ng
a bout 20% of the el derl y.
Pathophysiology
Sti mul a ti on of the ora l mucos a s i gna l s the s a l i va tory nucl ei i n the medul l a , tri ggeri ng a n efferent res pons e. The efferent nerve i mpul s es rel ea s e
a cetyl chol i ne a t s a l i va ry gl a nd nerve termi na l s , a cti va ti ng mus ca ri ni c receptors (M3 ), whi ch i ncrea s e s a l i va producti on a nd fl ow. Medul l a ry s i gna l s
res pons i bl e for s a l i va ti on ma y a l s o be modul a ted by corti ca l i nputs from other s ti mul i (eg, ta s te, s mel l , a nxi ety).
Etiology
Xeros tomi a i s us ua l l y ca us ed by the fol l owi ng:
Drugs
Ra di a ti on to the hea d a nd neck (for ca ncer trea tment)
Sys temi c di s orders a re l es s commonl y the ca us e, but xeros tomi a i s common i n Sjogren's s yndrome a nd ma y occur i n HIV/AIDS, uncontrol l ed
di a betes , a nd certa i n other di s orders .
Drugs: Drugs a re the mos t common ca us e (s ee
Ta bl e 56-7); a bout 400 pres cri pti on drugs
[Table 56-7. Some Ca us es of Xeros tomi a ]
a nd ma ny OTC drugs ca us e decrea s ed s a l i va ti on. The mos t common i ncl ude the fol l owi ng:
Anti chol i nergi cs
Anti pa rki ns oni a ns
Anti neopl a s ti cs (chemothera py)
Chemothera py drugs ca us e s evere drynes s a nd s toma ti ti s whi l e they a re bei ng ta ken; thes e probl ems us ua l l y end a fter thera py i s s topped.
Other common drug cl a s s es tha t ca us e xeros tomi a i ncl ude a nti hypertens i ves , a nxi ol yti cs , a nd a nti depres s a nts (l es s s evere wi th SSRIs tha n wi th
tri cycl i cs ).
The ri s e of i l l i ci t metha mpheta mi ne us e ha s res ul ted i n a n i ncrea s i ng i nci dence of meth mouth, whi ch i s s evere tooth deca y ca us ed by
metha mpheta mi ne-i nduced xeros tomi a . The da ma ge i s exa cerba ted by the bruxi ng a nd cl enchi ng ca us ed by the drug. Thi s combi na ti on ca us es
very ra pi d des tructi on of teeth. Toba cco us e us ua l l y ca us es a decrea s e of s a l i va .
Radiation: Inci denta l ra di a ti on to the s a l i va ry gl a nds duri ng ra di a ti on thera py for hea d a nd neck ca ncer often ca us es s evere xeros tomi a (5200 cGy
ca us es s evere, perma nent drynes s , but even l ow dos es ca n ca us e tempora ry dryi ng).
Evaluation
History: History of present illness s houl d i ncl ude a cui ty of ons et, tempora l pa tterns (eg, cons ta nt vs i ntermi ttent, pres ence onl y on a wa keni ng),
provoki ng fa ctors , i ncl udi ng s i tua ti ona l or ps ychogeni c fa ctors (eg, whether xeros tomi a occurs onl y duri ng peri ods of ps ychol ogi c s tres s or certa i n
a cti vi ti es ), a s s es s ment of fl ui d s ta tus (eg, fl ui d i nta ke ha bi ts , recurrent vomi ti ng or di a rrhea ), a nd s l eepi ng ha bi ts . Us e of recrea ti ona l drugs
s houl d be s peci fi ca l l y el i ci ted.
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng dry eyes , dry s ki n, ra s hes , a nd joi nt pa i n (Sjogren's s yndrome).
Past medical history s houl d i nqui re a bout condi ti ons a s s oci a ted wi th xeros tomi a , i ncl udi ng Sjogren's s yndrome, hi s tory of ra di a ti on trea tment,
hea d a nd neck tra uma , a nd a di a gnos i s of or ri s k fa ctors for HIV i nfecti on. Drug profi l es s houl d be revi ewed for potenti a l offendi ng drugs (s ee
Ta bl e 56-7).
Physical examination: Phys i ca l exa mi na ti on i s focus ed on the ora l ca vi ty, s peci fi ca l l y a ny a ppa rent drynes s (eg, whether the mucos a i s dry, s ti cky, or
moi s t; whether s a l i va i s foa my, s tri ngy, or norma l i n a ppea ra nce), the pres ence of a ny l es i ons ca us ed by Candida albicans, a nd the condi ti on of the
teeth.
The pres ence a nd s everi ty of xeros tomi a ca n be a s s es s ed a t the beds i de i n s evera l wa ys . For exa mpl e, a tongue bl a de ca n be hel d a ga i ns t the
bucca l mucos a for 10 s ec. If the tongue bl a de fa l l s off i mmedi a tel y when rel ea s ed, s a l i va ry fl ow i s norma l . The more di ffi cul ty encountered
removi ng the tongue bl a de, the more s evere the xeros tomi a . In women, the l i ps ti ck s i gn, where l i ps ti ck a dheres to the front teeth, ma y be a us eful
i ndi ca tor of xeros tomi a .
If there a ppea rs to be drynes s , the s ubma ndi bul a r, s ubl i ngua l , a nd pa roti d gl a nds s houl d be pa l pa ted whi l e obs ervi ng the ducta l openi ngs for
s a l i va fl ow. The openi ngs a re a t the ba s e of the tongue a nteri orl y for the s ubma ndi bul a r gl a nds a nd on the mi ddl e of the i ns i de of the cheek for
the pa roti d gl a nds . Dryi ng the duct openi ngs wi th a ga uze s qua re before pa l pa ti on a i ds obs erva ti on. If a gra dua ted conta i ner i s a va i l a bl e, the
pa ti ent ca n expectora te once to empty the mouth a nd then expectora te a l l s a l i va i nto the conta i ner. Norma l producti on i s 0.3 to 0.4 mL/mi n.
Si gni fi ca nt xeros tomi a i s 0.1 mL/mi n.
Denta l ca ri es ma y be s ought a t the ma rgi ns of res tora ti ons or i n unus ua l pl a ces (eg, a t the neck or ti p of the tooth).
The mos t common ma ni fes ta ti on of C. albicans i nfecti on i s a rea s of erythema a nd a trophy (eg, on the dors um of the tongue). Les s common i s the
better-known whi te, chees y curd tha t bl eeds when wi ped off.
Extens i ve tooth deca y
Concomi ta nt dry eyes , dry s ki n, ra s h, or joi nt pa i n
Ri s k fa ctors for HIV
Interpretation of findings: Xeros tomi a i s di a gnos ed by s ymptoms , a ppea ra nce, a nd a bs ence of s a l i va ry fl ow when ma s s a gi ng the s a l i va ry gl a nds .
No further a s s es s ment i s requi red when xeros tomi a occurs a fter i ni ti a ti on of a new drug a nd s tops a fter ces s a ti on of tha t drug or when s ymptoms
a ppea r wi thi n s evera l weeks of i rra di a ti on of the hea d a nd neck. Xeros tomi a tha t occurs wi th a brupt ons et a fter hea d a nd neck tra uma i s ca us ed
by nerve da ma ge.
Concomi ta nt pres ence of dry eyes , dry s ki n, ra s h, or joi nt pa i n, pa rti cul a rl y i n a fema l e pa ti ent, s ugges ts a di a gnos i s of Sjogren's s yndrome. Severe
tooth deca y, out of proporti on to expected fi ndi ngs , ma y be i ndi ca ti ve of i l l i ci t drug us e, pa rti cul a rl y metha mpheta mi nes . Xeros tomi a tha t occurs
onl y duri ng ni ghtti me or tha t i s noted onl y on a wa keni ng ma y be i ndi ca ti ve of exces s i ve mouth brea thi ng i n a dry envi ronment.
Testing: For thos e i n whom the pres ence of xeros tomi a i s uncl ea r, s i a l ometry ca n be conducted by pl a ci ng col l ecti on devi ces over the ma jor duct
ori fi ces a nd then s ti mul a ti ng s a l i va ry producti on wi th ci tri c a ci d or by chewi ng pa ra ffi n. Norma l pa roti d fl ow i s 0.4 to 1.5 mL/mi n/gl a nd. Fl ow
moni tori ng ca n a l s o hel p determi ne res pons e to thera py.
The ca us e of xeros tomi a i s often a ppa rent, but i f the eti ol ogy i s uncl ea r a nd s ys temi c di s ea s e i s cons i dered pos s i bl e, further a s s es s ment s houl d
be purs ued wi th bi ops y of a mi nor s a l i va ry gl a nd (for detecti on of Sjogren's s yndrome, s a rcoi dos i s , a myl oi dos i s , TB, or ca ncer) a nd HIV tes ti ng.
Treatment
When pos s i bl e, the ca us e of xeros tomi a s houl d be a ddres s ed a nd trea ted.
For pa ti ents wi th drug-rel a ted xeros tomi a whos e thera py ca nnot be cha nged to a nother drug, drug s chedul es s houl d be modi fi ed to a chi eve
ma xi mum drug effect duri ng the da y, beca us e ni ghtti me xeros tomi a i s more l i kel y to ca us e ca ri es . For a l l drugs , ea s y-to-ta ke formul a ti ons , s uch a s
l i qui ds , s houl d be cons i dered, a nd s ubl i ngua l dos a ge forms s houl d be a voi ded. The mouth a nd throa t s houl d be l ubri ca ted wi th wa ter before
s wa l l owi ng ca ps ul es a nd ta bl ets or before us i ng s ubl i ngua l ni trogl yceri n. Pa ti ents s houl d a voi d deconges ta nts a nd a nti hi s ta mi nes .
Pa ti ents us i ng conti nuous pos i ti ve a i rwa y pres s ure for obs tructi ve s l eep a pnea ma y benefi t from humi di fyi ng the s ource a i r (room humi di fi er for
thos e us i ng ora l a ppl i a nce thera py).
Symptom control: Symptoma ti c trea tment cons i s ts of mea s ures tha t do the fol l owi ng:
Increa s e exi s ti ng s a l i va
Repl a ce l os t s ecreti ons
Control ca ri es
Drugs tha t a ugment s a l i va producti on i ncl ude cevi mel i ne a nd pi l oca rpi ne, both chol i nergi c a goni s ts . Cevi mel i ne (30 mg po ti d) ha s l es s M2
(ca rdi a c) receptor a cti vi ty tha n pi l oca rpi ne a nd a l onger ha l f-l i fe. The ma i n a dvers e effect i s na us ea . Pi l oca rpi ne (5 mg po ti d) ma y be gi ven a fter
ophtha l mol ogi c a nd ca rdi ores pi ra tory contra i ndi ca ti ons a re excl uded; a dvers e effects i ncl ude s wea ti ng, fl us hi ng, a nd pol yuri a .
Si ppi ng s uga rl es s fl ui ds frequentl y, chewi ng xyl i tol -conta i ni ng gum, a nd us i ng a n OTC s a l i va s ubs ti tute conta i ni ng ca rboxymethyl cel l ul os e or
hydroxyethyl cel l ul os e ma y hel p. Petrol eum jel l y ca n be a ppl i ed to the l i ps a nd under dentures to rel i eve dryi ng, cra cki ng, s orenes s , a nd mucos a l
tra uma . A col d-a i r humi di fi er ma y a i d mouth brea thers who typi ca l l y ha ve thei r wors t s ymptoms a t ni ght.
Meti cul ous ora l hygi ene i s es s enti a l . Pa ti ents s houl d brus h a nd fl os s regul a rl y a nd us e fl uori de ri ns es or gel s da i l y; us i ng newer toothpa s tes
wi th a dded Ca a nd phos phorous a l s o ma y hel p a voi d ra mpa nt ca ri es . An i ncrea s ed frequency of preventi ve denta l vi s i ts wi th pl a que remova l i s
a dvi s ed. The mos t effecti ve wa y to prevent ca ri es i s to s l eep wi th i ndi vi dua l l y fi tted ca rri ers conta i ni ng 1.1% Na fl uori de or 0.4% s ta nnous fl uori de.
If 2 ca rri ers ca nnot be worn a t once, then ea ch a rch s houl d be covered every other ni ght. In a ddi ti on, a denti s t ca n a ppl y a 5% Na fl uori de va rni s h 2
to 4 ti mes /yr.
Pa ti ents s houl d a voi d s uga ry or a ci di c foods a nd bevera ges a nd a ny i rri ta ti ng foods tha t a re dry, s pi cy, a s tri ngent, or exces s i vel y hot or col d.
Al though dry mouth becomes more common a mong the el derl y, thi s i s proba bl y due to the ma ny drugs typi ca l l y us ed by the el derl y ra ther tha n
a gi ng i ts el f.
Key Points
Drugs a re the mos t common ca us e, but s ys temi c di s ea s es (mos t commonl y Sjogren's s yndrome or HIV) a nd ra di a ti on thera py a l s o ca n ca us e
xeros tomi a .
Symptoma ti c trea tment i ncl udes i ncrea s i ng exi s ti ng s a l i va fl ow wi th s ti mul a nts or drugs , a nd a rti fi ci a l s a l i va repl a cement. Xyl i tol -conta i ni ng
gum a nd ca ndy ma y be us eful .
Pa ti ents wi th xeros tomi a a re a t hi gh ri s k of tooth deca y; meti cul ous ora l hygi ene a nd profes s i ona l l y a ppl i ed fl uori des a re es s enti a l .
Chapter 57. Common Dental Disorders

Introduction
Common denta l di s orders i ncl ude ca ri es , gi ngi vi ti s , peri odonti ti s , a nd pul pi ti s . Denta l emergenci es , s uch a s tootha che, fra ctured or a vul s ed teeth,
a nd pos textra cti on compl i ca ti ons , a re di s cus s ed i n Ch. 58.
Caries
Caries is tooth decay, commonly called cavities. The symptomstender, painful teethappear late. Diagnosis is based on inspection, probing of the enamel
surface with a fine metal instrument, and dental x-rays. Treatment involves removing affected tooth structure and restoring it with various materials. Fluoride,
diligent dental hygiene, sealants, and proper diet can prevent virtually all caries.
Etiology
Ca ri es i s ca us ed by a ci ds produced by ba cteri a i n denta l pl a que. Pl a que i s , a t fi rs t, a s oft, thi n fi l m of ba cteri a , muci n, dea d epi thel i a l cel l s , a nd
food debri s tha t devel ops on the tooth s urfa ce wi thi n a bout 24 h a fter the tooth i s cl ea ned. Mutans streptococci i s a group of rel a ted ba cteri a tha t
grow i n pl a que a nd ca n ca us e ca ri es . Some s tra i ns a re more ca ri ogeni c tha n others . Eventua l l y (commonl y, a fter 72 h), s oft pl a que mi nera l i zes ,
ma i nl y wi th Ca , phos pha te, a nd other mi nera l s , becomi ng ca l cul us (ha rd pl a que or ta rta r), whi ch ca nnot ea s i l y be removed wi th a toothbrus h.
Risk factors: There a re s evera l ri s k fa ctors for ca ri es :
Denta l defects
Hi gh-a ci d or l ow-fl uori de envi ronment
Reduced s a l i va ry fl ow
Ma ny teeth ha ve open ena mel pi ts , fi s s ures , a nd grooves , whi ch ma y extend from the s urfa ce to the denti n. Thes e defects ma y be wi de enough to
ha rbor ba cteri a but too na rrow to cl ea n effecti vel y. They predi s pos e teeth to ca ri es . La rge a mounts of s uga r i n the di et provi de nutri ents for
pl a que-formi ng ba cteri a .
A tooth s urfa ce i s more s us cepti bl e to ca ri es when i t i s poorl y ca l ci fi ed, ha s l ow fl uori de expos ure, or i s i n a n a ci di c envi ronment. Typi ca l l y,
deca l ci fi ca ti on begi ns when the pH a t the tooth fa l l s bel ow 5.5 (eg, when l a cti c a ci d-produci ng ba cteri a col oni ze the a rea or when peopl e dri nk
col a bevera ges , whi ch conta i n phos phori c a ci d).
Ra mpa nt ca ri es i n deci duous teeth s ugges ts prol onged conta ct wi th i nfa nt formul a , mi l k, or jui ce, typi ca l l y when a n i nfa nt goes to bed wi th a
bottl e (ba by or nurs i ng bottl e ca ri es ). Thus , bedti me bottl es s houl d conta i n onl y wa ter.
The el derl y often ta ke drugs tha t reduce s a l i va ry fl ow, predi s pos i ng to ca ri es . The el derl y a l s o ha ve a hi gher i nci dence of root ca ri es beca us e of
gi ngi va l reces s i on, expos ure of root s urfa ces , a nd decl i ni ng ma nua l dexteri ty.
Complications: Untrea ted ca ri es l ea ds to tooth des tructi on, i nfecti ons , a nd the need for extra cti ons a nd repl a cement pros thes es . Prema ture l os s of
deci duous teeth ma y s hi ft the a dja cent teeth, hi nderi ng erupti on of thei r perma nent s ucces s ors .
Symptoms and Signs
Ca ri es i ni ti a l l y i nvol ves onl y the ena mel a nd ca us es no s ymptoms . A ca vi ty tha t i nva des the denti n ca us es pa i n, fi rs t when hot, col d, or s weet
foods or bevera ges conta ct the i nvol ved tooth, a nd l a ter wi th chewi ng or percus s i on. Pa i n ca n be i ntens e a nd pers i s tent when the pul p i s s everel y
i nvol ved (s ee Pul pi ti s on p. 522).
Diagnosis
Di rect i ns pecti on
Someti mes us e of x-ra ys or s peci a l tes ti ng i ns truments
Routi ne, frequent (q 6 to 12 mo) cl i ni ca l eva l ua ti on i denti fi es ea rl y ca ri es a t a ti me when mi ni ma l i nterventi on prevents i ts progres s i on. A thi n
probe, s ometi mes s peci a l dyes , a nd tra ns i l l umi na ti on by fi beropti c l i ghts a re us ed, frequentl y s uppl emented by new devi ces tha t detect ca ri es by
cha nges i n el ectri ca l conducti vi ty or l a s er refl ecti vi ty. However, x-ra ys a re s ti l l i mporta nt for detecti ng ca ri es , determi ni ng the depth of
i nvol vement, a nd i denti fyi ng ca ri es under exi s ti ng res tora ti ons .
Treatment
Res tora ti ve thera py
Someti mes a root ca na l a nd crown
Inci pi ent ca ri es (whi ch i s confi ned to the ena mel ) s houl d be remi nera l i zed through i mproved home ca re (brus hi ng a nd fl os s i ng), cl ea ni ngs ,
pres cri pti ons for hi gh-fl uori de toothpa s tes , a nd mul ti pl e fl uori de a ppl i ca ti ons a t the denta l offi ce.
The pri ma ry trea tment of ca ri es tha t ha s entered denti n i s remova l by dri l l i ng, fol l owed by fi l l i ng of the res ul ta nt defect. For very deep ca vi ti es , a
tempora ry fi l l i ng ma y be l eft i n pl a ce 6 to 10 wk i n the hope tha t a tooth wi l l depos i t repa ra ti ve denti n, preventi ng expos ure of the pul p, whi ch
neces s i ta tes root ca na l trea tment.
Fi l l i ngs for occl us a l s urfa ces of pos teri or teeth, whi ch bea r the brunt of ma s ti ca ti on, mus t be compos ed of s trong ma teri a l s . The mos t common
ma teri a l ha s been s i l ver a ma l ga m, whi ch combi nes s i l ver, mercury, copper, ti n, a nd, occa s i ona l l y, zi nc, pa l l a di um, or i ndi um. Ama l ga m i s
i nexpens i ve a nd l a s ts a n a vera ge of 14 yr. However, i f ora l hygi ene i s good a nd i f a ma l ga m wa s pl a ced us i ng a rubber da m for i s ol a ti on from
s a l i va , ma ny a ma l ga m fi l l i ngs l a s t > 40 yr. Al though concern ha s been ra i s ed a bout mercury poi s oni ng, the number of a ma l ga m fi l l i ngs a pers on
ha s bea rs no rel a ti ons hi p to bl ood mercury l evel s . Repl a ci ng a ma l ga m i s not recommended beca us e i t i s expens i ve, da ma ges tooth s tructure, a nd
a ctua l l y i ncrea s es pa ti ent expos ure to mercury.
Compos i te res i ns , whi ch ha ve a more a ccepta bl e a ppea ra nce, ha ve l ong been us ed i n a nteri or teeth, where a es theti cs a re pri ma ry a nd the forces
of chewi ng a re mi ni ma l . Some pa ti ents reques t them i n pos teri or teeth a s wel l , a nd they a re becomi ng common there. However, compos i te res i ns
under hi gh occl us a l s tres s genera l l y l a s t l es s tha n ha l f a s l ong a s a ma l ga m a nd tend to devel op recurrent deca y beca us e the compos i te res i n
s hri nks when i t ha rdens a nd expa nds a nd contra cts wi th hea t a nd col d more tha n the tooth or other fi l l i ng ma teri a l s . The current genera ti on of
compos i tes a l s o cl os el y res embl e ena mel but do not a ppea r to ha ve the s a me i nci dence of recurrent ca ri es a s ea rl i er ma teri a l s a nd ma y a l s o l a s t
l onger. However, a l though l ong-term res ul ts wi th thes e newer a ma l ga m s ubs ti tutes a ppea r good, da ta equi va l ent i n numbers a nd dura ti on to
thos e wi th a ma l ga m a re not yet a va i l a bl e.
If deca y l ea ves too l i ttl e denti n to hol d a res tora ti on, a denti s t repl a ces the mi s s i ng denti n wi th cement, a ma l ga m, compos i te, or other ma teri a l s .
Someti mes a pos t mus t be i ns erted i nto one or more roots to s upport a gol d, s i l ver, or compos i te core, whi ch repl a ces the corona l denti n. Thi s
procedure neces s i ta tes a root ca na l fi l l i ng, i n whi ch a n openi ng i s ma de i n the tooth a nd the pul p i s removed. The root ca na l s ys tem i s thoroughl y
debri ded, s ha ped, a nd then fi l l ed wi th gutta -percha . The outer tooth s urfa ces (wha t woul d ha ve been the ena mel ) a re then reduced s o tha t a n
a rti fi ci a l crown, us ua l l y ma de of gol d, porcel a i n, or both, ca n be pl a ced. Crowns for a nteri or teeth cons i s t of, or a re covered wi th, porcel a i n.
Prevention
Regul a r brus hi ng a nd fl os s i ng
Fl uori de i n wa ter, toothpa s te, or both
Regul a r profes s i ona l cl ea ni ngs
Ra rel y chl orhexi di ne ri ns es a nd topi ca l fl uori de a ppl i ca ti ons
For mos t peopl e, ca ri es i s preventa bl e. Ca vi ti es fi rs t form on perma nent teeth i n the ea rl y teens to l a te 20s . Ca ri es -prone peopl e typi ca l l y ha ve
l ow expos ure to fl uori de a nd a rel a ti vel y ca ri ogeni c mi crofl ora a cqui red from thei r mothers a nd through s oci a l conta ct. Ma i nta i ni ng good ora l
hygi ene a nd mi ni mi zi ng s uga r i nta ke a re es peci a l l y i mporta nt.
Remova l of pl a que a t l ea s t q 24 h, us ua l l y by brus hi ng a nd fl os s i ng, hel ps prevent denta l ca ri es . The gi ngi va l thi rd of the tooth i s the mos t
i mporta nt a rea to cl ea n but i s the a rea mos t often negl ected. El ectri c a nd el ectroni c toothbrus hes a re excel l ent, but a ma nua l s oft toothbrus h,
us ed for a n a vera ge of 3 to 4 mi n, s uffi ces . Us i ng exces s toothpa s te, pa rti cul a rl y a n a bra s i ve type, ma y erode the teeth. Denta l fl os s i s pl a ced
between ea ch of the teeth, curved a ga i ns t the s i de of ea ch tooth, a nd moved up a nd down 3 ti mes , goi ng jus t benea th the gi ngi va l ma rgi n. Fl os s es
tha t a re very thi n (denta l ta pe) or coa ted wi th wa x or pol ytetra ethyl ene ca n be us ed for excepti ona l l y ti ght conta cts between teeth or rough fi l l i ng
ma rgi ns .
Teeth wi th fl uori de i ncorpora ted i nto thei r ena mel a re more res i s ta nt to a ci di c deca l ci fi ca ti on a nd more rea di l y reca l ci fy when pH i ncrea s es . If
dri nki ng wa ter i s not a dequa tel y fl uori da ted, fl uori de s uppl ements a re recommended for chi l dren from s hortl y a fter bi rth through a ge 8 yr a nd for
pregna nt women begi nni ng a t 3 mo ges ta ti on (when teeth a re formi ng i n the fetus ). The dos e mus t be s el ected a ccordi ng to the a mount of
fl uori de pres ent i n the dri nki ng wa ter a nd the a ge of the chi l d. The tota l dos e s houl d not be s o hi gh a s to ca us e denta l fl uoros i s (s ee p. 52).
Fl uori da ted toothpa s te s houl d a l s o be us ed by peopl e of a l l a ges .
Fl uori da ti on offers l es s protecti on a ga i ns t ca ri es i n pi ts a nd fi s s ures tha n a ga i ns t thos e on s mooth s urfa ces . Pi ts a nd fi s s ures requi re us e of
s ea l a nts (pl a s ti c ma teri a l s tha t a dhere ti ghtl y to the s urfa ce of the ena mel ) to prevent nutri ents from rea chi ng ba cteri a , reduci ng thei r growth a nd
a ci d producti on.
If thes e mea s ures do not decrea s e ca vi ty forma ti on, more i ntens i ve thera py i s a i med a t cha ngi ng the fl ora . After ca vi ti es a re trea ted, pi ts a nd
fi s s ures , whi ch ca n ha rbor M. streptococci, a re s ea l ed. Thi s trea tment i s fol l owed by 60-s ec mouth ri ns es us i ng 0.12% chl orhexi di ne bi d for 2 wk,
whi ch ma y reduce the ca ri ogeni c ba cteri a i n pl a que a nd a l l ow repopul a ti on wi th l es s ca ri ogeni c s tra i ns of M. streptococci. To encoura ge thi s
repopul a ti on, xyl i tol i n the form of ha rd ca ndy or chewi ng gum i s us ed for 5 mi n ti d. Addi ti ona l l y, topi ca l fl uori de ma y be a ppl i ed by a denti s t or
us ed a t ni ght i n a cus tom-ma de fl uori de ca rri er.
For pregna nt women wi th a hi s tory of s evere ca ri es , the a bove regi men ma y be us ed before the chi l d's teeth erupt. If thi s i s not fea s i bl e, the
mother ca n us e xyl i tol , a s menti oned a bove, from the ti me of the ba by's bi rth to the a ge a t whi ch the mother no l onger s a mpl es the chi l d's food
(the hypothes i zed mode of tra ns fer).
For preventi on of ca ri es i n deci duous teeth (once they ha ve erupted) i n i nfa nts , bedti me bottl es s houl d conta i n onl y wa ter.
Gingivitis
Gingivitis is inflammation of the gingivae, causing bleeding with swelling, redness, exudate, a change of normal contours, and, occasionally, discomfort.
Diagnosis is based on inspection. Treatment involves professional teeth cleaning and intensified home dental hygiene. Advanced cases may require antibiotics or
surgery.
Norma l l y, the gi ngi va e a re fi rm, ti ghtl y a da pted to the teeth, a nd contoured to a poi nt. Kera ti ni zed gi ngi va nea r the crowns i s pi nk s ti ppl ed ti s s ue.
Thi s ti s s ue s houl d fi l l the enti re s pa ce between the crowns . The gi ngi va fa rther from the crowns , ca l l ed a l veol a r mucos a , i s nonkera ti ni zed, hi ghl y
va s cul a r, red, mova bl e, a nd conti nuous wi th the bucca l mucos a . A tongue depres s or s houl d expres s no bl ood or pus from norma l gi ngi va .
Infl a mma ti on, or gi ngi vi ti s , the mos t common gi ngi va l probl em, ma y evol ve i nto peri odonti ti s (s ee p. 520).
Etiology
The mos t common ca us e of gi ngi vi ti s i s poor ora l hygi ene.
Poor ora l hygi ene a l l ows pl a que to a ccumul a te between the gi ngi va a nd the teeth; gi ngi vi ti s does not occur i n edentul ous a rea s . Irri ta ti on due to
pl a que deepens the norma l crevi ce between the tooth a nd gi ngi va , crea ti ng gi ngi va l pockets . Thes e pockets conta i n ba cteri a tha t ma y ca us e both
gi ngi vi ti s a nd root ca ri es . Other l oca l fa ctors , s uch a s ma l occl us i on, denta l ca l cul us , food i mpa cti on, fa ul ty denta l res tora ti ons , a nd xeros tomi a ,
pl a y a s econda ry rol e.
Systemic causes: Gi ngi vi ti s a l s o commonl y occurs a t puberty, duri ng mens trua ti on a nd pregna ncy, a nd a t menopa us e, pres uma bl y beca us e of
hormona l cha nges . Si mi l a rl y, ora l contra cepti ves ma y exa cerba te i nfl a mma ti on.
Gi ngi vi ti s ma y be a n ea rl y s i gn of a s ys temi c di s order, pa rti cul a rl y thos e tha t a ffect the res pons e to i nfecti on (eg, di a betes , AIDS, vi ta mi n
defi ci ency, l eukopeni a ), pa rti cul a rl y i f i t occurs i n pa ti ents wi th mi ni ma l denta l pl a que. Some pa ti ents wi th Crohn's di s ea s e ha ve a cobbl es tone
a rea of gra nul oma tous gi ngi va l hypertrophy when i ntes ti na l fl a re-ups occur. Expos ure to hea vy meta l s (eg, l ea d, bi s muth) ma y ca us e gi ngi vi ti s a nd
a da rk l i ne a t the gi ngi va l ma rgi n. Severe defi ci ency of ni a ci n or vi ta mi n C ca n ca us e gi ngi vi ti s .
Symptoms and Signs
Si mpl e gi ngi vi ti s fi rs t ca us es a deepeni ng of the s ul cus (gi ngi va l crevi ce) between the tooth a nd the gi ngi va , fol l owed by a ba nd of red, i nfl a med
gi ngi va a l ong one or more teeth, wi th s wel l i ng of the i nterdenta l pa pi l l a e a nd ea s y bl eedi ng. Pa i n i s us ua l l y a bs ent. It ma y res ol ve, rema i n
s uperfi ci a l for yea rs , or occa s i ona l l y progres s to peri odonti ti s .
Peri coroni ti s i s a cute, pa i nful i nfl a mma ti on of the gi ngi va l fl a p over a pa rtl y erupted tooth, us ua l l y a round ma ndi bul a r 3rd mol a rs (wi s dom teeth).
Infecti on i s common, a nd a n a bs ces s ma y devel op. Peri coroni ti s often recurs a s food gets tra pped benea th the fl a p. The gi ngi va l fl a p di s a ppea rs
when the tooth i s ful l y erupted.
Des qua ma ti ve gi ngi vi ti s ma y occur duri ng menopa us e. It i s cha ra cteri zed by deep red, pa i nful gi ngi va l ti s s ue tha t bl eeds ea s i l y. Ves i cl es ma y
precede des qua ma ti on. The gi ngi va e a re s oft beca us e the kera ti ni zed cel l s tha t res i s t a bra s i on by food pa rti cl es a re a bs ent. A s i mi l a r gi ngi va l
l es i on ma y be a s s oci a ted wi th pemphi gus vul ga ri s , bul l ous pemphi goi d, beni gn mucous membra ne pemphi goi d, or a trophi c l i chen pl a nus .
Duri ng pregna ncy, s wel l i ng, es peci a l l y of the i nterdenta l pa pi l l a e, i s l i kel y to occur. Peduncul a ted gi ngi va l growths often a ri s e i n the i nterdenta l
pa pi l l a e duri ng the 1s t tri mes ter, ma y pers i s t throughout pregna ncy, a nd ma y or ma y not s ubs i de a fter del i very. Pregna ncy tumors a re s oft reddi s h
ma s s es tha t a re, hi s tol ogi ca l l y, pyogeni c gra nul oma s . They devel op ra pi dl y a nd then rema i n s ta ti c. An underl yi ng i rri ta nt i s common, s uch a s
ca l cul us or a res tora ti on wi th a rough ma rgi n.
Uncontrol l ed di a betes ca n exa ggera te the effects of gi ngi va l i rri ta nts , ma ki ng s econda ry i nfecti ons a nd a cute gi ngi va l a bs ces s es common.
In l eukemi a , the gi ngi va e ma y become engorged wi th a l eukemi c i nfi l tra te, exhi bi ti ng cl i ni ca l s ymptoms of edema , pa i n, a nd ea s i l y i nduced
bl eedi ng.
In s curvy (vi ta mi n C defi ci ency), the gi ngi va e a re i nfl a med, hyperpl a s ti c, a nd engorged, bl eedi ng ea s i l y. Petechi a e a nd ecchymos es ma y a ppea r
throughout the mouth.
In pel l a gra (ni a ci n defi ci ency), the gi ngi va e a re i nfl a med, bl eed ea s i l y, a nd a re s us cepti bl e to s econda ry i nfecti on. Addi ti ona l l y, the l i ps a re
reddened a nd cra cked, the mouth feel s s ca l ded, the tongue i s s mooth a nd bri ght red, a nd the tongue a nd mucos a ma y ha ve ul cera ti ons .
Diagnosis
Fi ndi ng erythema tous , fri a bl e ti s s ue a t the gum l i nes confi rms the di a gnos i s . To detect ea rl y gi ngi va l di s ea s e, s ome denti s ts frequentl y mea s ure
the depth of the pocket a round ea ch tooth. Depths < 3 mm a re norma l ; deeper pockets a re a t hi gh ri s k of gi ngi vi ti s a nd peri odonti ti s .
Treatment
Regul a r ora l hygi ene a nd profes s i ona l cl ea ni ng
Si mpl e gi ngi vi ti s i s control l ed by proper ora l hygi ene wi th or wi thout a n a nti ba cteri a l mouth ri ns e. Thorough s ca l i ng (profes s i ona l cl ea ni ng wi th
ha nd or ul tra s oni c i ns truments ) s houl d be done. If a ppropri a te, poorl y contoured res tora ti ons a re res ha ped or repl a ced a nd l oca l i rri ta nts a re
removed. Exces s gi ngi va , i f pres ent, ca n be exci s ed. Drugs ca us i ng gi ngi va l hyperpl a s i a s houl d be s topped i f pos s i bl e; i f not, i mproved home ca re
a nd more frequent profes s i ona l cl ea ni ngs (a t l ea s t every 3 mo) us ua l l y reduce the hyperpl a s i a . Pregna ncy tumors a re exci s ed.
Trea tment of peri coroni ti s cons i s ts of
Remova l of debri s from under the gi ngi va l fl a p
Irri ga ti on wi th s a l i ne, 1.5% hydrogen peroxi de, or 0.12% chl orhexi di ne
Pa rti cul a rl y when epi s odes recur, extra cti on
If s evere i nfecti on devel ops , a nti bi oti cs ma y be gi ven for a da y before extra cti on a nd conti nued duri ng hea l i ng. A common regi men i s a moxi ci l l i n
500 mg po q 6 h for 10 da ys (or unti l 3 da ys a fter a l l i nfl a mma ti on ha s s ubs i ded). Abs ces s es a s s oci a ted wi th peri coroni ti s requi re l oca l i zed
i nci s i on a nd dra i na ge, a peri odonta l fl a p a nd root debri dement, or extra cti on.
In gi ngi vi ti s ca us ed by s ys temi c di s orders , trea tment i s di rected a t the ca us e. In des qua ma ti ve gi ngi vi ti s duri ng menopa us e, s equenti a l
a dmi ni s tra ti on of es trogens a nd proges ti ns ma y be benefi ci a l , but a dvers e effects of thi s thera py (s ee p. 2519) l i mi t recommenda ti ons for i ts us e.
Otherwi s e, denti s ts ma y pres cri be a corti cos teroi d ri ns e or a corti cos teroi d pa s te tha t i s a ppl i ed di rectl y to the gums . Gi ngi vi ti s ca us ed by
pemphi gus vul ga ri s (s ee p. 658) a nd s i mi l a r mucocuta neous condi ti ons ma y requi re s ys temi c corti cos teroi d thera py.
Prevention
Da i l y remova l of pl a que wi th denta l fl os s a nd a toothbrus h a nd routi ne cl ea ni ng by a denti s t or hygi eni s t a t 6-mo to 1-yr i nterva l s ca n hel p
mi ni mi ze gi ngi vi ti s . Pa ti ents wi th s ys temi c di s orders predi s pos i ng to gi ngi vi ti s requi re more frequent profes s i ona l cl ea ni ngs (from q 2 wk to 4
ti mes /yr).
Acute Necrotizing Ulcerative Gingivitis
(Fus os pi rochetos i s ; Trench Mouth; Vi ncent's Infecti on or Angi na )
Acute necrotizing ulcerative gingivitis is a painful infection of the gums. Symptoms are acute pain, bleeding, and foul breath. Diagnosis is based on clinical
findings. Treatment is gentle debridement, improved oral hygiene, mouth rinses, supportive care, and, if debridement must be delayed, antibiotics.
Acute necroti zi ng ul cera ti ve gi ngi vi ti s occurs mos t frequentl y i n s mokers a nd debi l i ta ted pa ti ents who a re under s tres s . Other ri s k fa ctors a re poor
ora l hygi ene, nutri ti ona l defi ci enci es , a nd s l eep depri va ti on.
Symptoms and Signs
The us ua l l y a brupt ons et ma y be a ccompa ni ed by ma l a i s e or fever. The chi ef ma ni fes ta ti ons a re a cutel y pa i nful , bl eedi ng gi ngi va e; exces s i ve
s a l i va ti on; a nd overwhel mi ngl y foul brea th (fetor ori s ). Ul cera ti ons , whi ch a re pa thognomoni c, a re pres ent on the denta l pa pi l l a e a nd ma rgi na l
gi ngi va ; thes e ha ve a cha ra cteri s ti ca l l y punched-out a ppea ra nce a nd a re covered by a gra y ps eudomembra ne. Si mi l a r l es i ons on the bucca l
mucos a a nd tons i l s a re ra re. Swa l l owi ng a nd ta l ki ng ma y be pa i nful . Regi ona l l ympha denopa thy often i s pres ent.
Diagnosis
Ra rel y, tons i l l a r or pha ryngea l ti s s ues a re a ffected, a nd di phtheri a or i nfecti on due to a gra nul ocytos i s mus t be rul ed out by throa t cul ture a nd CBC.
Treatment
Debri dement
Ri ns es (eg, hydrogen peroxi de, chl orhexi di ne)
Improved ora l hygi ene
Someti mes ora l a nti bi oti cs
Trea tment cons i s ts of gentl e debri dement wi th a ha nd s ca l er or ul tra s oni c devi ce. Debri dement i s done over s evera l da ys . The pa ti ent us es a s oft
toothbrus h to wi pe the teeth. Ri ns es a t hourl y i nterva l s wi th wa rm norma l s a l i ne or twi ce/da y wi th 1.5% hydrogen peroxi de or 0.12% chl orhexi di ne
ma y hel p duri ng the fi rs t few da ys a fter i ni ti a l debri dement. Es s enti a l s upporti ve mea s ures i ncl ude i mproved ora l hygi ene (done gentl y a t fi rs t),
a dequa te nutri ti on, hi gh fl ui d i nta ke, res t, a na l ges i cs a s needed, a nd a voi di ng i rri ta ti on (eg, ca us ed by s moki ng or hot or s pi cy foods ). Ma rked
i mprovement us ua l l y occurs wi thi n 24 to 48 h, a fter whi ch debri dement ca n be compl eted. If debri dement i s del a yed (eg, i f a denti s t or the
i ns truments neces s a ry for debri dement a re una va i l a bl e), ora l a nti bi oti cs (eg, a moxi ci l l i n 500 mg, erythromyci n 250 mg, or tetra cycl i ne 250 mg q 6 h)
provi de ra pi d rel i ef a nd ca n be conti nued unti l 72 h a fter s ymptoms res ol ve. If the gi ngi va l contour i nverts (i e, i f the ti ps of pa pi l l a e a re l os t)
duri ng the a cute pha s e, s urgery i s eventua l l y requi red to prevent s ubs equent peri odonti ti s .
Other Gingival Disorders
Hyperpl a s i a of gi ngi va l ti s s ues ma y occur wi thout i nfl a mma ti on i n res pons e to va ri ous drugs , pa rti cul a rl y phenytoi n, cycl os pori ne, a nd ni fedi pi ne
or, l es s commonl y, other Ca cha nnel bl ockers . Hyperpl a s i a i s cha ra cteri zed by di ffus e, rel a ti vel y a va s cul a r s mooth or nodul a r enl a rgement of the
gi ngi va , whi ch ma y a l mos t cover s ome teeth. The hypertrophi ed ti s s ue i s often exci s ed. If pos s i bl e, s ubs ti tuti ons a re ma de for the offendi ng
drugs . Scrupul ous ora l hygi ene ma y mi ni mi ze recurrence.
Ca rci noma ca n a l s o ori gi na te i n the gi ngi va a nd s prea d to regi ona l l ymph nodes .
Periodontitis
Periodontitis is an infection of the periodontiumcausing inflammation of the periodontal ligament, gingiva, cementum, and alveolar bone. It usually manifests
as a worsening of gingivitis. Symptoms are rare except with HIV or when abscesses develop, in which case pain and swelling are common. Diagnosis is based on
inspection, periodontal probing, and x-rays. Treatment involves dental cleaning that extends under the gums and a vigorous home hygiene program. Advanced
cases may require antibiotics and surgery.
Etiology
Peri odonti ti s us ua l l y devel ops when gi ngi vi ti s , us ua l l y wi th a bunda nt pl a que a nd ca l cul us benea th the gi ngi va l ma rgi n, ha s not been a dequa tel y
trea ted. In peri odonti ti s , the deep pockets ca n ha rbor a na erobi c orga ni s ms tha t do more da ma ge tha n thos e us ua l l y pres ent i n s i mpl e gi ngi vi ti s .
The gi ngi va progres s i vel y l os es i ts a tta chment to the teeth, peri odonta l pockets deepen, a nd bone l os s begi ns . Wi th progres s i ve bone l os s , teeth
ma y l oos en, a nd gi ngi va recedes . Tooth mi gra ti on i s common i n l a ter s ta ges .
Systemic causes: Sys temi c di s ea s es tha t predi s pos e pa ti ents to peri odonti ti s i ncl ude di a betes (es peci a l l y type 1); a cqui red, fa mi l i a l , a nd cycl i c
neutropeni a ; l eukemi a ; Down s yndrome; l eukocyte a dhes i on defi ci ency s yndromes ; Pa pi l l on-Lefevre s yndrome; Crohn's di s ea s e; hi s ti ocytos i s
s yndromes ; a gra nul ocytos i s ; l a zy l eukocyte s yndrome; hypoga mma gl obul i nemi a ; Chedi a k-Hi ga s hi s yndrome; gl ycogen s tora ge di s ea s e; i nfa nti l e
geneti c a gra nul ocytos i s ; Ehl ers -Da nl os s yndrome (types IV a nd VIII); vi ta mi n C defi ci ency (s curvy); a nd hypophos pha ta s i a . Fa ul ty occl us i on, ca us i ng
a n exces s i ve functi ona l l oa d on teeth, ma y contri bute to progres s i on of a pa rti cul a r type of peri odonti ti s cha ra cteri zed by a ngul a r bony defects .
Pathophysiology
Peri odonti ti s i s us ua l l y chroni c a nd cha ra cteri zed by peri ods of exa cerba ti on a nd remi s s i on. Chroni c peri odonti ti s (formerl y a dul t peri odonti ti s )
occurs i n l oca l i zed a nd genera l i zed forms , a nd peopl e wi th s i gni fi ca nt di s ea s e tend to be > 35 yr. About 85% of the popul a ti on i s a ffected to a mi l d
degree, but the mos t a dva nced ca s es a re s een i n l es s tha n 5% of the popul a ti on.
Aggressive periodontitis: Severa l more ra pi dl y progres s i ve s ubtypes of chroni c peri odonti ti s exi s t, col l ecti vel y known a s a ggres s i ve peri odonti ti s .
Aggres s i ve peri odonti ti s ma y devel op a s ea rl y a s chi l dhood, s ometi mes before a ge 3 yr. Pa ti ents ma y ha ve s evere bone l os s , even tooth l os s , by
a ge 20. Neutrophi l functi on ma y be defecti ve i n a ggres s i ve peri odonti ti s ; i ts cl i ni ca l s i gni fi ca nce i s unknown.
In one type of a ggres s i ve peri odonti ti s tha t occurs i n hea l thy a dol es cents (formerl y ca l l ed l oca l i zed juveni l e peri odonti ti s ), pa ti ents often ha ve
s i gni fi ca nt col oni za ti on of Actinobacillus actinomycetemcomitans. Typi ca l l y, the s i gns of i nfl a mma ti on a re mi nor. The di s ea s e i s detected by
peri odonta l probi ng or x-ra ys , whi ch s how l oca l i zed, deep (verti ca l ) bone l os s , commonl y l i mi ted to the 1s t mol a rs a nd i nci s ors . Bone l os s
progres s es fa s ter tha n i n a dul t peri odonti ti s , often a t a ra te of 3 to 4 m/da y.
An uncommon type of a ggres s i ve peri odonti ti s (formerl y ca l l ed prepuberta l peri odonti ti s ) a ffects deci duous teeth, us ua l l y s hortl y a fter erupti on.
Genera l i zed a cute prol i fera ti ve gi ngi vi ti s a nd ra pi d a l veol a r bone des tructi on a re i ts ha l l ma rks . Pa ti ents a l s o ha ve frequent bouts of oti ti s medi a
a nd a re us ua l l y di a gnos ed by a ge 4 yr. In s ome pa ti ents , the di s ea s e res ol ves before the perma nent teeth erupt. Trea tment regi mens a re under
s tudy.
Prototypi ca l a ggres s i ve peri odonti ti s (formerl y ca l l ed ra pi dl y progres s i ve peri odonti ti s ) occurs i n pa ti ents a ged 20 to 35 yr. It i s often a s s oci a ted
wi th A. actinomycetemcomitans, Porphyromonas gingivalis, Eikenella corrodens, a nd ma ny gra m-nega ti ve ba ci l l i , but ca us e a nd effect a re not cl ea r. Some
ca s es res ul t from undi a gnos ed l oca l i zed juveni l e peri odonti ti s or prepuberta l peri odonti ti s , but others a ppea r i ndependentl y.
HIV-a s s oci a ted peri odonti ti s i s a pa rti cul a rl y vi rul ent, ra pi dl y progres s i ng di s ea s e. Cl i ni ca l l y, i t res embl es a cute necroti zi ng ul cera ti ve gi ngi vi ti s
(s ee p. 520) combi ned wi th ra pi dl y progres s i ve peri odonti ti s . Pa ti ents ma y l os e 9 to 12 mm of a tta chment i n a s l i ttl e a s 6 mo.
Symptoms and Signs
Pa i n i s us ua l l y a bs ent unl es s a n a cute i nfecti on forms i n one or more peri odonta l pockets or i f HIV-a s s oci a ted peri odonti ti s i s pres ent. Impa cti on
of food i n the pockets ca n ca us e pa i n a t mea l s . Abunda nt pl a que a l ong wi th rednes s , s wel l i ng, a nd exuda te a re cha ra cteri s ti c. Gums ma y be
tender a nd bl eed ea s i l y, a nd brea th ma y be foul .
Diagnosis
Someti mes denta l x-ra ys
Ins pecti on of the teeth a nd gi ngi va combi ned wi th probi ng of the pockets a nd mea s urement of thei r depth a re us ua l l y s uffi ci ent for di a gnos i s .
Pockets deeper tha n 4 mm i ndi ca te peri odonti ti s . Denta l x-ra ys revea l a l veol a r bone l os s a dja cent to the peri odonta l pockets .
Treatment
Sca l i ng a nd root pl a ni ng
Someti mes ora l a nti bi oti cs , a nti bi oti c pa cks , or both
Surgery or extra cti on
For a l l forms of peri odonti ti s , the fi rs t pha s e of trea tment cons i s ts of thorough s ca l i ng a nd root pl a ni ng (i e, remova l of di s ea s ed or toxi n-a ffected
cementum a nd denti n fol l owed by s moothi ng of the root) to remove pl a que a nd ca l cul us depos i ts . Thorough home ora l hygi ene i s neces s a ry. The
pa ti ent i s reeva l ua ted a fter 3 wk. If pockets a re no deeper tha n 4 mm a t thi s poi nt, the onl y trea tment needed i s regul a r cl ea ni ngs .
If deeper pockets pers i s t, s ys temi c a nti bi oti cs ca n be us ed. A common regi men i s a moxi ci l l i n 500 mg po qi d for 10 da ys . In a ddi ti on, a gel
conta i ni ng doxycycl i ne or mi cros pheres of mi nocycl i ne ca n be pl a ced i nto i s ol a ted reca l ci tra nt pockets . Thes e a re res orbed i n 2 wk.
Another a pproa ch i s to s urgi ca l l y el i mi na te the pocket a nd recontour the bone s o tha t the pa ti ent ca n cl ea n the depth of the s ul cus (pocket
reducti on/el i mi na ti on s urgery). In s el ected s i tua ti ons , regenera ti ve s urgery a nd bone gra fti ng a re done to encoura ge a l veol a r bone growth.
Spl i nti ng of l oos e teeth a nd s el ecti ve res ha pi ng of tooth s urfa ces to el i mi na te tra uma ti c occl us i on ma y be neces s a ry. Extra cti ons a re often
neces s a ry i n a dva nced di s ea s e. Contri buti ng s ys temi c fa ctors s houl d be control l ed before i ni ti a ti ng peri odonta l thera py.
Ni nety percent of pa ti ents wi th HIV-a s s oci a ted peri odonti ti s res pond to i rri ga ti on of the s ul cus wi th povi done-i odi ne (whi ch the denti s t a ppl i es
wi th a s yri nge), regul a r us e of chl orhexi di ne mouth ri ns es , a nd s ys temi c a nti bi oti cs , us ua l l y metroni da zol e 250 mg po ti d for 14 da ys .
Loca l i zed juveni l e peri odonti ti s requi res peri odonta l s urgery pl us ora l a nti bi oti cs (eg, a moxi ci l l i n 500 mg qi d or metroni da zol e 250 mg ti d for 14
da ys ).
Pulpitis
Pulpitis is inflammation of the dental pulp resulting from untreated caries, trauma, or multiple restorations. Its principal symptom is pain. Diagnosis is based on
clinical findings and is confirmed by x-ray. Treatment involves removing decay, restoring the damaged tooth, and sometimes doing root canal therapy or
extracting the tooth.
Pul pi ti s ca n occur when
Ca ri es progres s es deepl y i nto the denti n
A tooth requi res mul ti pl e i nva s i ve procedures
Tra uma di s rupts the l ympha ti c a nd bl ood s uppl y to the pul p
Pul pi ti s begi ns a s a revers i bl e condi ti on i n whi ch the tooth ca n be s a ved by a s i mpl e fi l l i ng. It becomes i rrevers i bl e a s s wel l i ng i ns i de the ri gi d
enca s ement of the denti n compromi s es ci rcul a ti on, ma ki ng the pul p necroti c, whi ch predi s pos es to i nfecti on.
Complications: Infecti ous s equel a e of pul pi ti s i ncl ude a pi ca l peri odonti ti s , peri a pi ca l a bs ces s , cel l ul i ti s , a nd os teomyel i ti s of the ja w. Sprea d from
ma xi l l a ry teeth ma y ca us e purul ent s i nus i ti s , meni ngi ti s , bra i n a bs ces s , orbi ta l cel l ul i ti s , a nd ca vernous s i nus thrombos i s . Sprea d from
ma ndi bul a r teeth ma y ca us e Ludwi g's a ngi na , pa ra pha ryngea l a bs ces s , medi a s ti ni ti s , peri ca rdi ti s , empyema , a nd jugul a r thrombophl ebi ti s .
Symptoms and Signs
In revers i bl e pul pi ti s , pa i n occurs when a s ti mul us (us ua l l y col d or s weet) i s a ppl i ed to the tooth. When the s ti mul us i s removed, the pa i n cea s es
wi thi n 1 to 2 s ec.
In i rrevers i bl e pul pi ti s , pa i n occurs s ponta neous l y or l i ngers mi nutes a fter the s ti mul us i s removed. A pa ti ent ma y ha ve di ffi cul ty l oca ti ng the
tooth from whi ch the pa i n ori gi na tes , even confus i ng the ma xi l l a ry a nd ma ndi bul a r a rches (but not the l eft a nd ri ght s i des of the mouth). The pa i n
ma y then cea s e for s evera l da ys beca us e of pul pa l necros i s . As i nfecti on devel ops a nd extends through the a pi ca l fora men, the tooth becomes
exqui s i tel y s ens i ti ve to pres s ure a nd percus s i on. A peri a pi ca l (dentoa l veol a r) a bs ces s el eva tes the tooth from i ts s ocket a nd feel s "hi gh" when
the pa ti ent bi tes down.
Diagnosis
Someti mes denta l x-ra ys
Di a gnos i s i s ba s ed on the hi s tory a nd phys i ca l exa mi na ti on, whi ch ma kes us e of provoki ng s ti mul i (a ppl i ca ti on of hea t, col d, percus s i on). X-ra ys
hel p determi ne whether i nfl a mma ti on ha s extended beyond the tooth a pex a nd hel p excl ude other condi ti ons .
Treatment
Dri l l i ng a nd fi l l i ng for revers i bl e pul pi ti s
Root ca na l a nd crown or extra cti on for i rrevers i bl e pul pi ti s
Anti bi oti cs (eg, a moxi ci l l i n) for i nfecti on
In revers i bl e pul pi ti s , pul p vi ta l i ty ca n be ma i nta i ned i f the tooth i s trea ted, us ua l l y by ca ri es remova l , a nd then res tored.
Irrevers i bl e pul pi ti s a nd i ts s equel a e requi re endodonti c (root ca na l ) thera py or tooth extra cti on. In endodonti c thera py, a n openi ng i s ma de i n
the tooth a nd the pul p i s removed. The root ca na l s ys tem i s thoroughl y debri ded, s ha ped, a nd then fi l l ed wi th gutta -percha . After root ca na l
thera py, a dequa te hea l i ng i s ma ni fes ted cl i ni ca l l y by res ol uti on of s ymptoms a nd ra di ogra phi ca l l y by bone fi l l i ng i n the ra di ol ucent a rea a t the
root a pex over a peri od of months . If pa ti ents ha ve s ys temi c s i gns of i nfecti on (eg, fever), a n ora l a nti bi oti c i s pres cri bed (a moxi ci l l i n 500 mg q 8 h;
for pa ti ents a l l ergi c to peni ci l l i n, cl i nda myci n 150 mg or 300 mg q 6 h). If s ymptoms pers i s t or wors en, root ca na l thera py i s us ua l l y repea ted i n
ca s e a root ca na l wa s mi s s ed, but a l terna ti ve di a gnos es (eg, temporoma ndi bul a r di s order, occul t tooth fra cture, neurol ogi c di s order) s houl d be
cons i dered.
Very ra rel y, s ubcuta neous or medi a s ti na l emphys ema devel ops a fter compres s ed a i r or a hi gh-s peed a i r turbi ne denta l dri l l ha s been us ed duri ng
root ca na l thera py or extra cti on. Thes e devi ces ca n force a i r i nto the ti s s ues a round the tooth s ocket tha t di s s ects a l ong fa s ci a l pl a nes . Acute
ons et of ja w a nd cervi ca l s wel l i ng wi th cha ra cteri s ti c crepi tus of the s wol l en s ki n on pa l pa ti on i s di a gnos ti c. Trea tment us ua l l y i s not requi red,
a l though prophyl a cti c a nti bi oti cs a re s ometi mes gi ven.
Dental Appliances
Teeth ma y be l os t to denta l ca ri es , peri odonta l di s ea s e, or tra uma or ma y be removed when trea tment fa i l s . Mi s s i ng teeth ma y ca us e cos meti c,
phona ti on, a nd occl us a l probl ems a nd ma y a l l ow movement of rema i ni ng teeth.
Types: Denta l a ppl i a nces i ncl ude fi xed bri dges , remova bl e pa rti a l or compl ete dentures , a nd os s eo-i ntegra ted i mpl a nts .
A bridge (fi xed pa rti a l denture) i s compos ed of fa l s e teeth ca s t or s ol dered to ea ch other a nd, a t ea ch end, to a crown tha t i s cemented to na tura l
(a butment) teeth, whi ch bea r a l l s tres s of bi ti ng. A bri dge i s not removed. A bri dge i s s ma l l er tha n a remova bl e pa rti a l denture, but one or
mul ti pl e bri dges ca n be ma de to repl a ce ma ny of the teeth i n a denta l a rch.
A removable partial denture, typi ca l l y a n a ppl i a nce wi th cl a s ps tha t s na p over a butment teeth, ma y be removed for cl ea ni ng a nd duri ng s l eep. Pa rt of
the occl us a l s tres s ma y be borne by the s oft ti s s ues under the denture, often on both s i des of the ja w. Thi s a ppl i a nce commonl y i s us ed when
ma ny teeth ha ve to be repl a ced a nd bri dges or i mpl a nts a re not fea s i bl e or a fforda bl e.
Complete dentures a re remova bl e a ppl i a nces us ed when no teeth rema i n. They hel p a pa ti ent chew a nd i mprove s peech a nd a ppea ra nce but do not
provi de the effi ci ency or s ens a ti on of na tura l denti ti on. When teeth a re a bs ent, the ma ndi bl e s l owl y res orbs , res ul ti ng i n i l l -fi tti ng dentures tha t
requi re revi s i on (ca l l ed rel i ne or reba s e) or repl a cement. Al terna ti ves a re ora l s urgi ca l procedures to enl a rge the a l veol a r ri dge or denta l
i mpl a nts to repl a ce mi s s i ng teeth.
An implant i s typi ca l l y a ti ta ni um cyl i nder or s crew tha t repl a ces a tooth root. One or more i mpl a nts a re pl a ced i nto the a l veol a r bone, where they
a nkyl os e. After 4 to 6 mo, a rti fi ci a l teeth a re a tta ched to the i mpl a nts . Impl a nts a re not rea di l y remova bl e, a l though the pros thes es they s upport
ca n be. The potenti a l for i nfecti on a t thes e s i tes wa rra nts s crupul ous a ttenti on to ora l hygi ene.
Dental appliances and surgery: Genera l l y, a l l remova bl e denta l a ppl i a nces a re removed before genera l a nes thes i a , throa t s urgery, or convul s i ve
thera py to prevent thei r brea ka ge or a s pi ra ti on. They a re s tored i n wa ter to prevent cha nges i n s ha pe. However, s ome a nes thes i ol ogi s ts bel i eve
tha t l ea vi ng a ppl i a nces i n pl a ce a i ds the pa s s a ge of a n a i rwa y tube, keeps the fa ce i n a more norma l s ha pe s o tha t the a nes theti c ma s k fi ts
better, prevents na tura l teeth from i njuri ng the oppos i ng gi ngi va of a compl etel y edentul ous ja w, a nd does not i nterfere wi th l a ryngos copy.
Denture problems: Occa s i ona l l y, the mucos a benea th a denture becomes i nfl a med (denture s ore mouth, i nfl a mma tory pa pi l l a ry hyperpl a s i a ).
Contri buti ng fa ctors to thi s us ua l l y pa i nl es s condi ti on i ncl ude ca ndi da l i nfecti ons , poor denture fi t, poor hygi ene, exces s i ve movement of the
denture, a nd, mos t frequentl y, wea ri ng a denture 24 h/da y. The mucos a a ppea rs red a nd vel vety. Ca ndi da l overgrowth ma y be i ndi ca ted by
a dherent cottonl i ke pa tches or, more commonl y, eros i ve l es i ons on the mucos a . The pres ence of Candida ca n be confi rmed by the mi cros copi c
a ppea ra nce of typi ca l bra nchi ng hypha e. Wi thout Candida, i nfl a mma tory pa pi l l a ry hyperpl a s i a i s unl i kel y.
A new wel l -ma de denture a l mos t a l wa ys i mproves the s i tua ti on. Other trea tments cons i s t of i mprovi ng ora l a nd denture hygi ene, refi tti ng the
exi s ti ng denture, removi ng the denture for extended peri ods , a nd us i ng a nti -funga l thera py (nys ta ti n ri ns es for the mouth a nd overni ght nys ta ti n
s oa ks for the denture). Soa ki ng the denture i n a commerci a l cl ea ns er i s s ometi mes hel pful . Other opti ons a re a ppl yi ng nys ta ti n s us pens i on to the
ti s s ue s urfa ce of the denture a nd cl otri ma zol e troches 10 mg 5 ti mes /da y. Ketocona zol e 200 mg po once/da y ma y be requi red. If i nfl a mma ti on
pers i s ts , bi ops y i s i ndi ca ted, a nd s ys temi c condi ti ons s houl d be rul ed out.
Chapter 58. Dental Emergencies

Introduction
Emergency denta l trea tment by a phys i ci a n i s s ometi mes requi red when a denti s t i s una va i l a bl e.
Ora l a na l ges i cs effecti ve for mos t denta l probl ems i ncl ude a ceta mi nophen 650 to 1000 mg q 6 h a nd NSAIDs s uch a s i buprofen 400 to 800 mg q 6 h.
For s evere pa i n, thes e drugs ma y be combi ned wi th opi oi ds s uch a s codei ne 60 mg; hydrocodone 5 mg, 7.5 mg, or 10 mg; or oxycodone 5 mg.
Anti bi oti cs for denta l i nfecti ons i ncl ude peni ci l l i n VK 500 mg po q 6 h a nd cl i nda myci n 300 mg po q 8 h.
Prophylactic antibiotics: Current Ameri ca n Hea rt As s oci a ti on gui del i nes (2007) recommend fa r fewer peopl e us e prophyl a cti c a nti bi oti cs for
preventi on of i nfecti ve endoca rdi ti s (IEs ee p. 2199).
Covera ge for denta l procedures i s recommended onl y for pa ti ents wi th pros theti c ca rdi a c va l ves , previ ous IE, s peci fi c congeni ta l hea rt di s ea s es ,
a nd for ca rdi a c tra ns pl a nt reci pi ents wi th hea rt va l ve probl ems (va l vul opa thy). Denta l procedures requi ri ng prophyl a xi s a re thos e tha t requi re
ma ni pul a ti on or perfora ti on of gi ngi va l or ora l mucos a or tha t i nvol ve the root end a rea of the teeth (i e, thos e mos t l i kel y to ca us e ba cteremi a ).
The preferred drug i s a moxi ci l l i n 2 g po 30 to 60 mi n before the procedure. For thos e who ca nnot tol era te peni ci l l i ns , a l terna ti ves i ncl ude
cl i nda myci n 600 mg or cepha l exi n 2 g.
Fractured and Avulsed Teeth
Tooth fracture: Fra ctures a re di vi ded by depth i nto thos e tha t
Affect onl y the ena mel
Expos e the denti n
Expos e the pul p
If the fra cture i nvol ves onl y the ena mel , pa ti ents noti ce rough or s ha rp edges but a re a s ymptoma ti c. Denta l trea tment to s mooth the edges a nd
i mprove a ppea ra nce i s el ecti ve.
If denti n i s expos ed but not the denta l pul p, pa ti ents us ua l l y exhi bi t s ens i ti vi ty to col d a i r a nd wa ter. Trea tment i s a mi l d a na l ges i c a nd referra l
to a denti s t. Denta l trea tment cons i s ts of res tora ti on of the tooth by a compos i te (whi te fi l l i ng) or, i f the fra cture i s extens i ve, a denta l crown, to
cover the expos ed denti n.
If the pul p i s expos ed (i ndi ca ted by bl eedi ng from the tooth) or i f the tooth i s mobi l e, denta l referra l i s urgent. Denta l trea tment us ua l l y i nvol ves
a root ca na l .
Root fra ctures a nd a l veol a r fra ctures a re not vi s i bl e, but the tooth (or s evera l teeth) ma y be mobi l e. Denta l referra l i s a l s o urgent for s ta bi l i za ti on
by bondi ng a n orthodonti c a rch wi re or pol yethyl ene l i ne onto s evera l a dja cent teeth.
Tooth avulsion: Avul s ed pri ma ry teeth a re not repl a ced beca us e they typi ca l l y become necroti c, then i nfected. They ma y a l s o become a nkyl os ed a nd
do not exfol i a te, thereby i nterferi ng wi th the erupti on of the perma nent tooth.
If a s econda ry tooth i s a vul s ed, the pa ti ent s houl d repl a ce i t i n i ts s ocket i mmedi a tel y a nd s eek denta l ca re to s ta bi l i ze i t. If thi s ca nnot be done,
the tooth s houl d be kept i mmers ed i n mi l k or wra pped i n a moi s tened pa per towel a nd brought to a denti s t for repl a cement a nd s ta bi l i za ti on.
The tooth s houl d not be s crubbed, beca us e s crubbi ng ma y remove vi a bl e peri odonta l l i ga ment fi bers , whi ch a i d i n rea tta chment. A pa ti ent wi th
a n a vul s ed tooth s houl d ta ke a n a nti bi oti c for s evera l da ys . If the a vul s ed tooth ca nnot be found, i t ma y ha ve been a s pi ra ted, embedded i n s oft
ti s s ue, or s wa l l owed. A ches t x-ra y ma y be needed to rul e out a s pi ra ti on, but a s wa l l owed tooth i s ha rml es s .
A pa rti a l l y a vul s ed tooth tha t i s repos i ti oned a nd s ta bi l i zed qui ckl y us ua l l y i s perma nentl y reta i ned. A compl etel y a vul s ed tooth ma y be
perma nentl y reta i ned i f repl a ced i n the s ocket wi th mi ni ma l ha ndl i ng wi thi n 30 mi n to 1 h. Both pa rti a l a nd compl ete a vul s i ons us ua l l y ul ti ma tel y
requi re root ca na l thera py beca us e the pul p ti s s ue becomes necroti c. When repl a cement of the tooth i s del a yed, the l ong-term retenti on ra te
drops , a nd root res orpti on eventua l l y occurs . Neverthel es s , a pa ti ent ma y be a bl e to us e the tooth for s evera l yea rs .
Mandibular Dislocation
Sponta neous ma ndi bul a r di s l oca ti on us ua l l y occurs i n peopl e wi th a hi s tory of s uch di s l oca ti ons . Al though a di s l oca ted ma ndi bl e i s occa s i ona l l y
ca us ed by tra uma , the i ni ti a ti ng epi s ode i s typi ca l l y a wi de openi ng fol l owed by bi ti ng pres s ure (eg, bi ti ng i nto a l a rge
[
Fig. 58-1. Ma ndi bul a r reducti on.]
s a ndwi ch wi th ha rd brea d), a wi de ya wn, or a denta l procedure. Peopl e prone to di s l oca ti on ma y ha ve na tura l l y l oos e temporoma ndi bul a r joi nt
(TMJ) l i ga ments .
Pa ti ents pres ent wi th a wi de-open mouth tha t they a re una bl e to cl os e. Pa i n i s s econda ry to pa ti ents ' a ttempts to cl os e the mouth. If the
ma ndi bul a r mi dl i ne devi a tes to one s i de, the di s l oca ti on i s uni l a tera l . Al though ra rel y us ed, a l oca l a nes theti c (eg, 2% l i doca i ne 2 to 5 mL)
i njected i nto the i ps i l a tera l joi nt a nd i nto the a dja cent a rea of i ns erti on of the l a tera l pterygoi d mus cl e ma y a l l ow the ma ndi bl e to reduce
s ponta neous l y.
Ma nua l reducti on ma y be neces s a ry (s ee Fi g. 58-1). Premedi ca ti on ma y be us ed (eg, di a zepa m 5 to 10 mg IV a t 5 mg/mi n or mi da zol a m 3 to 5 mg IV
a t 2 mg/mi n a nd a n opi oi d s uch a s meperi di ne 25 mg IV or fenta nyl 0.5 to 1 g/kg IV) but i s us ua l l y unneces s a ry, es peci a l l y i f ti me wi l l be l os t
prepa ri ng the IV. The l onger the ma ndi bl e i s di s l oca ted, the more di ffi cul t i t i s to reduce a nd the grea ter the l i kel i hood tha t di s l oca ti on wi l l recur.
Ba rton's ba nda ge ma y be needed for 2 or 3 da ys . Mos t i mporta ntl y, the pa ti ent mus t a voi d openi ng the mouth wi de for a t l ea s t 6 wk. When
a nti ci pa ti ng a ya wn, the pa ti ent s houl d pl a ce a fi s t under the chi n to prevent wi de openi ng. Food mus t be cut i nto s ma l l pi eces . If the pa ti ent
s uffers from chroni c di s l oca ti ons a nd more cons erva ti ve trea tment moda l i ti es ha ve been exha us ted, a n ora l a nd ma xi l l ofa ci a l s urgeon ma y be
cons ul ted. As l a s t-res ort trea tments , the l i ga ments a round the TMJ ca n be s urgi ca l l y ti ghtened (s hortened) i n a n a ttempt to s ta bi l i ze the joi nt or
the a rti cul a r emi nence ca n be reduced (emi nectomy).
Postextraction Problems
Pain and swelling: Swel l i ng i s norma l a fter ora l s urgery a nd i s proporti ona l to the degree of ma ni pul a ti on a nd tra uma . If s wel l i ng does not begi n to
s ubs i de by the 3rd pos topera ti ve da y, i nfecti on i s l i kel y a nd a n a nti bi oti c ma y be gi ven (eg, peni ci l l i n VK 500 mg po q 6 h unti l 72 h a fter s ymptoms
s ubs i de).
Pos topera ti ve pa i n va ri es from modera te to s evere a nd i s trea ted wi th a na l ges i cs (s ee p. 1623).
Alveolitis and osteomyelitis: Pos textra cti on a l veol i ti s (dry s ocket) i s pa i n ema na ti ng from ba re bone i f the s ocket's cl ot l ys es . Al though a s s umed to
be due to ba cteri a l a cti on, i t i s much more common a mong s mokers a nd ora l contra cepti ve us ers . It i s pecul i a r to the remova l of ma ndi bul a r
mol a rs , us ua l l y wi s dom teeth. Typi ca l l y, the pa i n begi ns on the 2nd or 3rd pos topera ti ve da y, i s referred to the ea r, a nd l a s ts from a few da ys to
ma ny weeks . Al veol i ti s i s bes t trea ted wi th topi ca l a na l ges i cs : a 1- to 2-i n i odoform ga uze s tri p s a tura ted i n eugenol or coa ted wi th a n a nes theti c
oi ntment, s uch a s l i doca i ne 2.5% or tetra ca i ne 0.5%, i s pl a ced i n the s ocket. The ga uze i s cha nged every 1 to 3 da ys unti l s ymptoms do not return
a fter the ga uze i s l eft out for a few hours . Thi s procedure el i mi na tes the need for s ys temi c a na l ges i cs .
Os teomyel i ti s , whi ch i n ra re ca s es i s confus ed wi th a l veol i ti s , i s di fferenti a ted by fever, l oca l tendernes s , a nd s wel l i ng. If s ymptoms l a s t a month,
a s eques trum, whi ch i s di a gnos ti c of os teomyel i ti s , s houl d be s ought by x-ra y. Os teomyel i ti s requi res l ong-term trea tment wi th a nti bi oti cs
effecti ve a ga i ns t both gra m-pos i ti ve a nd gra m-nega ti ve orga ni s ms a nd referra l for defi ni ti ve ca re.
Osteonecrosis of the jaw (ONJ): ONJ (s ee a l s o Si deba r 39-1 on p. 363) i s a n ora l l es i on i nvol vi ng pers i s tent expos ure of ma ndi bul a r or ma xi l l a ry bone,
whi ch us ua l l y ma ni fes ts wi th pa i n, l oos eni ng of teeth, a nd purul ent di s cha rge. ONJ ma y occur a fter denta l extra cti on but a l s o ma y devel op a fter
tra uma or ra di a ti on thera py to the hea d a nd neck. Recentl y, a n a s s oci a ti on ha s been di s covered between IV bi s phos phona te (BP) us e a nd ONJ.
However, ora l BP thera py s eems to pos e very l ow ri s k of ONJ. Stoppi ng ora l BP thera py i s unl i kel y to reduce thi s a l rea dy l ow ra te of ONJ, a nd
ma i nta i ni ng good ora l hygi ene i s a more effecti ve preventa ti ve mea s ure tha n s toppi ng ora l BP before denta l procedures . Ma na gement of ONJ i s
cha l l engi ng a nd typi ca l l y i nvol ves l i mi ted debri dement, a nti bi oti cs , a nd ora l ri ns es .
Bleeding: Pos textra cti on bl eedi ng us ua l l y occurs i n the s ma l l ves s el s . Any cl ots extendi ng out of the s ocket a re removed wi th ga uze, a nd a 4-i n
ga uze pa d (fol ded) or a tea ba g i s pl a ced over the s ocket. Then the pa ti ent i s i ns tructed to a ppl y conti nuous pres s ure by bi ti ng for 1 h. The
procedure ma y ha ve to be repea ted 2 or 3 ti mes . Pa ti ents a re tol d to wa i t a t l ea s t 1 h before checki ng the s i te s o a s not to di s rupt cl ot forma ti on.
They a l s o a re i nformed tha t a few drops of bl ood di l uted i n a mouth ful l of s a l i va a ppea r to be more bl ood tha n i s a ctua l l y pres ent. If bl eedi ng
conti nues , the s i te ma y be a nes theti zed by nerve bl ock or l oca l i nfi l tra ti on wi th 2% l i doca i ne conta i ni ng 1:100,000 epi nephri ne. The s ocket i s then
curetted to remove the exi s ti ng cl ot a nd to fres hen the bone a nd i s i rri ga ted wi th norma l s a l i ne. Then the a rea i s s utured under gentl e tens i on.
Loca l hemos ta ti c a gents , s uch a s oxi di zed cel l ul os e, topi ca l thrombi n on a gel a ti n s ponge, or mi crofi bri l l a r col l a gen, ma y be pl a ced i n the s ocket
before s uturi ng.
If pos s i bl e, pa ti ents ta ki ng l ow-dos e a nti coa gul a nts (eg, a s pi ri n, cl opedi grol , wa rfa ri n) s houl d s top thera py 3 to 4 da ys before s urgery. Thera py ca n
be rei ns ta ted tha t eveni ng. If thes e mea s ures fa i l , a s ys temi c ca us e (eg, bl eedi ng di a thes i s ) i s s ought.
Toothache and Infection
Pa i n i n a nd a round the teeth i s a common probl em, pa rti cul a rl y a mong thos e wi th poor ora l hygi ene. Pa i n ma y be cons ta nt, fel t a fter s ti mul a ti on
(eg, hea t, col d, s weet food or dri nk, chewi ng, brus hi ng), or both.
Etiology
The mos t common ca us es of tootha che (s ee
Ta bl e 58-1) a re
Denta l ca ri es
Pul pi ti s
Tra uma
Erupti ng wi s dom tooth (ca us i ng peri coroni ti s )
Tootha che i s us ua l l y ca us ed by denta l ca ri es a nd i ts cons equences .
Ca ri es ca us es pa i n when the l es i on extends through the ena mel i nto denti n. Pa i n us ua l l y occurs a fter s ti mul a ti on from col d, hea t, s weet food or
dri nk, or brus hi ng; thes e s ti mul i ca us e fl ui d to move a l ong denti na l tubul es to the pul p. As l ong a s the di s comfort does not pers i s t a fter the
s ti mul us i s removed, the pul p i s l i kel y hea l thy enough to be ma i nta i ned. Thi s i s referred to a s norma l denti na l s ens i ti vi ty, revers i bl e pul pa l gi a , or
revers i bl e pul pi ti s .
Pul pi ti s i s i nfl a mma ti on of the pul p, typi ca l l y due to a dva nci ng ca ri es , cumul a ti ve mi nor pul p da ma ge from previ ous l a rge res tora ti ons , a defecti ve
res tora ti on, or tra uma . It ma y be revers i bl e or i rrevers i bl e. Pres s ure necros i s frequentl y res ul ts from pul pi ti s , beca us e the pul p i s enca s ed i n a
ri gi d compa rtment. Pa i n ma y be s ponta neous or i n res pons e to s ti mul a ti on. In both ca s es , pa i n l i ngers for a mi nute or l onger. Once the pul p
becomes necroti c, pa i n ends bri efl y (hours to weeks ). Subs equentl y, peri a pi ca l i nfl a mma ti on (a pi ca l peri odonti ti s ) or a n a bs ces s devel ops . The
tooth i s exqui s i tel y s ens i ti ve to percus s i on (ta pped wi th a meta l denta l probe or tongue bl a de) a nd chewi ng.
Peri a pi ca l a bs ces s ma y fol l ow untrea ted ca ri es or pul pi ti s . The a bs ces s ma y poi nt i ntra ora l l y a nd eventua l l y dra i n or ma y become a cel l ul i ti s .
Tooth tra uma ca n da ma ge the pul p. The da ma ge ma y ma ni fes t s oon a fter the i njury or up to deca des l a ter.
Peri coroni ti s i s i nfl a mma ti on a nd i nfecti on of the ti s s ue between the tooth a nd i ts overl yi ng fl a p of gi ngi va (opercul um). It us ua l l y occurs i n a n
erupti ng wi s dom tooth (a l mos t a l wa ys a l ower one).
Complications: Ra rel y, s i nus i ti s res ul ts from untrea ted ma xi l l a ry denta l i nfecti on. More commonl y, pa i n from a s i nus i nfecti on i s percei ved a s
ori gi na ti ng i n the (una ffected) teeth, mi s ta kenl y crea ti ng the i mpres s i on of a denta l ori gi n.
Ra rel y, ca vernous s i nus thrombos i s (s ee p. 624) or Ludwi g's a ngi na (s ubma ndi bul a r s pa ce i nfecti ons ee p. 470) devel ops ; thes e condi ti ons a re
l i fe threa teni ng a nd requi re i mmedi a te i nterventi on.
[Table 58-1. Some Ca us es of Tootha che]
Evaluation
History: History of present illness s houl d i denti fy the l oca ti on a nd dura ti on of the pa i n a nd whether i t i s cons ta nt or pres ent onl y a fter s ti mul a ti on.
Speci fi c tri ggeri ng fa ctors to revi ew i ncl ude hea t, col d, s weet food or dri nk, chewi ng, a nd brus hi ng. Any precedi ng tra uma or denta l work s houl d be
noted.
Review of systems s houl d s eek s ymptoms of compl i ca ti ons , i ncl udi ng fa ce pa i n, s wel l i ng, or both (denta l a bs ces s , s i nus i ti s ); pa i n bel ow the
tongue a nd di ffi cul ty s wa l l owi ng (s ubma ndi bul a r s pa ce i nfecti on); pa i n wi th bendi ng forwa rd (s i nus i ti s ); a nd retro-orbi ta l hea da che, fever, a nd
vi s i on s ymptoms (ca vernous s i nus thrombos i s ).
Past medical history s houl d note previ ous denta l probl ems a nd trea tment.
The exa mi na ti on focus es on the fa ce a nd mouth. The fa ce i s i ns pected for s wel l i ng a nd i s pa l pa ted for i ndura ti on a nd tendernes s .
The ora l exa mi na ti on i ncl udes i ns pecti on for gum i nfl a mma ti on a nd ca ri es a nd a ny l oca l i zed s wel l i ng a t the ba s e of a tooth tha t ma y repres ent a
poi nti ng a pi ca l a bs ces s . If no tooth i s cl ea rl y i nvol ved, teeth i n the a rea of pa i n a re percus s ed for tendernes s wi th a tongue depres s or. Al s o, a n
i ce cube ca n be a ppl i ed bri efl y to ea ch tooth, removi ng i t i mmedi a tel y once pa i n i s fel t. In hea l thy teeth, the pa i n s tops a l mos t i mmedi a tel y. Pa i n
l i ngeri ng more tha n a few s econds i ndi ca tes pul p da ma ge (eg, i rrevers i bl e pul pi ti s , necros i s ). The fl oor of the mouth i s pa l pa ted for i ndura ti on
a nd tendernes s , s ugges ti ng a deep s pa ce i nfecti on.
Neurol ogi c exa mi na ti on, concentra ti ng on the cra ni a l nerves , s houl d be done i n thos e wi th fever, hea da che, or fa ci a l s wel l i ng.
Hea da che
Fever
Swel l i ng or tendernes s of fl oor of the mouth
Cra ni a l nerve a bnorma l i ti es
Interpretation of findings: Red fl a g fi ndi ng of hea da che s ugges ts s i nus i ti s , pa rti cul a rl y i f mul ti pl e upper mol a r a nd premol a r (ba ck) teeth a re pa i nful .
However, pres ence of vi s i on s ymptoms or a bnorma l i ti es of the pupi l s or of ocul a r moti l i ty s ugges ts ca vernous s i nus thrombos i s .
Fever i s unus ua l wi th routi ne denta l i nfecti on unl es s there i s s i gni fi ca nt l oca l extens i on. Bi l a tera l tendernes s of the fl oor of the mouth s ugges ts
Ludwi g's a ngi na .
[
Table 58-2. Cha ra cteri s ti cs of Pa i n i n Tootha che]
Di ffi cul ty openi ng the mouth (tri s mus ) ca n occur wi th a ny l ower mol a r i nfecti on but i s common onl y wi th peri coroni ti s .
Isolated dental condition: Pa ti ents wi thout red fl a g fi ndi ngs or fa ci a l s wel l i ng l i kel y ha ve a n i s ol a ted denta l condi ti on, whi ch, a l though
uncomforta bl e, i s not s eri ous . Cl i ni ca l fi ndi ngs , pa rti cul a rl y the na ture of the pa i n, hel p s ugges t a ca us e (s ee Ta bl es 58-1 a nd 58-2). Beca us e of i ts
i nnerva ti on, the pul p ca n percei ve s ti mul i (eg, hea t, col d, s weets ) onl y a s pa i n. An i mporta nt di s ti ncti on i s whether there i s conti nuous pa i n or
pa i n onl y on s ti mul a ti on a nd, i f pa i n i s onl y on s ti mul a ti on, whether the pa i n l i ngers a fter the s ti mul us i s removed.
Swel l i ng a t the ba s e of a tooth, on the cheek, or both i ndi ca tes i nfecti on, ei ther cel l ul i ti s or a bs ces s . A tender, fl uctua nt a rea a t the ba s e of a
tooth s ugges ts a poi nti ng a bs ces s .
Testing: Denta l x-ra ys a re the ma i ns ta y of tes ti ng but ca n be deferred to a denti s t.
The ra re ca s es i n whi ch ca vernous s i nus thrombos i s or Ludwi g's a ngi na a re s us pected requi re i ma gi ng s tudi es , typi ca l l y CT or MRI.
Treatment
Analgesics (s ee p. 1623) a re gi ven pendi ng denta l eva l ua ti on a nd defi ni ti ve trea tment. A pa ti ent who i s s een frequentl y for emergenci es but who
never recei ves defi ni ti ve denta l trea tment des pi te a va i l a bi l i ty ma y be s eeki ng opi oi ds .
Antibiotics di rected a t ora l fl ora a re gi ven for mos t di s orders beyond i rrevers i bl e pul pi ti s (eg, necroti c pul p, a pi ca l peri odonti ti s , a bs ces s ,
cel l ul i ti s ). The pa ti ent wi th peri coroni ti s a l s o s houl d recei ve a n a nti bi oti c. However, a nti bi oti cs ca n be deferred i f the pa ti ent ca n be s een the
s a me da y by a denti s t, who ma y be a bl e to trea t the i nfecti on by removi ng the s ource (eg, by extra cti on, pul pectomy, or curetta ge). When
a nti bi oti cs a re us ed, peni ci l l i n i s preferred, wi th cl i nda myci n the a l terna ti ve.
An abscess a s s oci a ted wi th wel l -devel oped (s oft) fl uctua nce i s typi ca l l y dra i ned through a n i nci s i on wi th a #15 s ca l pel bl a de a t the mos t
dependent poi nt of the s wel l i ng. A rubber dra i n, hel d by a s uture, i s often pl a ced.
Pericoronitis or erupti ng 3rd mol a rs a re trea ted wi th chl orhexi di ne 0.12% ri ns es or hypertoni c s a l twa ter s oa ks (1 tbs p s a l t mi xed i n a gl a s s of hot
wa terno hotter tha n the coffee or tea a pa ti ent norma l l y dri nks ). The s a l t wa ter i s hel d i n the mouth on the a ffected s i de unti l i t cool s a nd then
i s expectora ted a nd i mmedi a tel y repl a ced wi th a nother mouthful . Three or 4 gl a s s es of s a l t wa ter a da y us ua l l y control i nfl a mma ti on a nd pa i n
pendi ng denta l eva l ua ti on.
Teething pain i n young chi l dren ma y be trea ted wi th wei ght-ba s ed dos es of a ceta mi nophen or i buprofen. Topi ca l trea tments ca n i ncl ude chewi ng
ha rd cra ckers (eg, bi s cotti ), a ppl yi ng 7.5% or 10% benzoca i ne gel qi d (provi ded there i s no fa mi l y hi s tory of methemogl obi nemi a ), a nd chewi ng on
a nythi ng col d (eg, gel -conta i ni ng teethi ng ri ngs ).
The ra re pa ti ent wi th ca vernous s i nus thrombos i s or Ludwi g's a ngi na requi res i mmedi a te hos pi ta l i za ti on, remova l of the i nfected tooth, a nd
cul ture-gui ded pa rentera l a nti bi oti cs .
The el derl y a re more prone to ca ri es of the root s urfa ces , us ua l l y beca us e of gi ngi va l reces s i on. Peri odonti ti s often begi ns i n young a dul thood; i f
untrea ted, tooth pa i n a nd l os s a re common i n ol d a ge.
Key Points
Mos t tootha che i nvol ves denta l ca ri es or i ts compl i ca ti ons (eg, pul pi ti s , a bs ces s ).
Symptoma ti c trea tment a nd denta l referra l a re us ua l l y a dequa te.
Anti bi oti cs a re gi ven i f s i gns of a necroti c pul p or more s evere condi ti ons a re pres ent.
Very ra re but s eri ous compl i ca ti ons i ncl ude extens i on of denta l i nfecti on to the fl oor of the mouth or to the ca vernous s i nus .
Denta l i nfecti ons ra rel y ca us e s i nus i ti s , but s i nus i nfecti on ma y ca us e pa i n percei ved a s ori gi na ti ng i n the teeth.
Chapter 59. Temporomandibular Disorders

Introduction
(See a l s o Ma ndi bul a r Di s l oca ti on on p. 524, Tempora l Bone Fra ctures on p. 3234, a nd Ja w Tumors on p. 489.)
The term temporoma ndi bul a r di s orders i s a n umbrel l a term for condi ti ons ca us i ng dys functi on of the ja w joi nt or pa i n i n the ja w a nd fa ce, often i n
or a round the temporoma ndi bul a r joi nt (TMJ), i ncl udi ng ma s ti ca tory a nd other mus cl es of the hea d a nd neck, the fa s ci a , or both. A pers on i s
cons i dered to ha ve a temporoma ndi bul a r di s order onl y i f pa i n or l i mi ta ti on of moti on i s s evere enough to requi re profes s i ona l ca re.
Temporoma ndi bul a r di s orders typi ca l l y a re mul ti fa ctori a l , but mos t a re rel a ted to probl ems wi th mus cl es or joi nts . Interna l dera ngements of the
TMJ ca us e di s turbed movement of the ma ndi bul a r condyl e i n the gl enoi d fos s a or a ga i ns t the ca rti l a gi nous a rti cul a r di s k (s ee
Fi g. 59-1). Thi s di s k, s ha ped l i ke a donut wi th a cl os ed hol e or l i ke a ma ture red bl ood cel l , s erves a s a cus hi on between joi nt s urfa ces . Ca us es for
thi s di s turbed movement i ncl ude cl enchi ng a nd gri ndi ng of the teeth, tra uma , a rthri ti s , a nd ma l occl us i on a nd mi s s i ng teeth. Even the tra uma of
pers i s tent gum chewi ng ca n be enough to da ma ge the joi nt.
Diagnosis
Di s orders of the TMJ mus t be di s ti ngui s hed from the ma ny condi ti ons tha t mi mi c them (s ee
Ta bl e 59-1). Pa i n exa cerba ted by fi nger pres s ure on the joi nt when the mouth i s opened i mpl i ca tes the TMJ.
Pa ti ents a re a s ked to des cri be the pa i n a nd des i gna te pa i nful a rea s . The cervi ca l a nd occi pi ta l mus cl es a nd ea ch of the ma jor mus cl e groups
i nvol ved i n ma s ti ca ti on a re pa l pa ted for genera l tendernes s a nd tri gger poi nts (s pots
[Fig. 59-1. The temporoma ndi bul a r joi nt.]
tha t ra di a te pa i n to a nother a rea ). Pa ti ents a re obs erved openi ng the mouth a s wi de a s i s comforta bl e. When pa ti ents open a nd cl os e thei r
mouth wi th the juncti on of the ma xi l l a ry a nd ma ndi bul a r centra l i nci s ors (norma l l y i n the mi dl i ne) l i ned up a ga i ns t a verti ca l s tra i ght edge, the
ma ndi bul a r mi dl i ne typi ca l l y devi a tes towa rd the pa i nful s i de. Pa l pa ti on a nd a us cul ta ti on of the joi nt duri ng openi ng a nd cl os i ng ma y revea l
tendernes s , ca tchi ng, cl i cki ng, or poppi ng. Condyl a r moti on ca n bes t be pa l pa ted by pl a ci ng the 5th fi ngers i nto the externa l ea r ca na l s a nd
exerti ng very gentl e forwa rd pres s ure a s pa ti ents move the ja w. The a vera ge-s i zed pa ti ent ca n open the mouth a t l ea s t 40 to 45 mm (mea s ured
between upper a nd l ower centra l i nci s ors ). To a ccount for di fferences i n pa ti ent s i ze, a pa ti ent s houl d be a bl e to fi t 3 fi ngers (i ndex, mi ddl e, ri ng)
i n the mouth on top of ea ch other.
Ankylosis of the Temporomandibular Joint
Ankylosis of the TMJ is immobility or fusion of the joint.
Ankyl os i s of the TMJ mos t often res ul ts from tra uma or i nfecti on, but i t ma y be congeni ta l or a res ul t of RA. Chroni c, pa i nl es s l i mi ta ti on of moti on
occurs . When a nkyl os i s l ea ds to a rres t of condyl a r growth, fa ci a l a s ymmetry i s common (s ee Condyl a r Hyperpl a s i a on p. 532). Intra -a rti cul a r (true)
a nkyl os i s mus t be di s ti ngui s hed from extra -a rti cul a r (fa l s e) a nkyl os i s , whi ch ma y be ca us ed by enl a rgement of the coronoi d proces s , depres s ed
fra cture of the zygoma ti c a rch, or s ca rri ng res ul ti ng from s urgery, i rra di a ti on, or i nfecti on. In mos t ca s es of true a nkyl os i s , x-ra ys of the joi nt s how
l os s of norma l bony a rchi tecture.
Trea tment ma y i ncl ude a condyl ectomy i f the a nkyl os i s i s i ntra -a rti cul a r or a n os tectomy of pa rt of the ra mus i f the coronoi d proces s a nd zygoma ti c
a rch a re a l s o a ffected. Ja w-openi ng exerci s es mus t be done for months to yea rs to ma i nta i n the s urgi ca l correcti on, but forced openi ng of the ja ws
wi thout s urgery i s genera l l y i neffecti ve beca us e of bony fus i on.
Arthritis of the Temporomandibular Joint
Infectious arthritis, traumatic arthritis, osteoarthritis, RA, and secondary degenerative arthritis can affect the TMJ.
Infectious arthritis: Infecti on of the TMJ ma y res ul t from di rect extens i on of a dja cent i nfecti on or hema togenous s prea d of bl ood-borne orga ni s ms
(s ee a l s o Acute Infecti ous Arthri ti s on p. 365). The a rea i s i nfl a med, a nd ja w movement i s l i mi ted. Loca l s i gns of i nfecti on a s s oci a ted wi th
evi dence of a s ys temi c di s ea s e or wi th a n a dja cent i nfecti on s ugges t the di a gnos i s . X-ra y res ul ts a re nega ti ve i n the ea rl y s ta ges but ma y s how
bone des tructi on l a ter. If s uppura ti ve a rthri ti s i s s us pected, the joi nt i s a s pi ra ted to confi rm the di a gnos i s a nd to i denti fy the ca us a ti ve orga ni s m.
Di a gnos i s mus t be ma de ra pi dl y to prevent perma nent joi nt da ma ge.
[Table 59-1. Some Condi ti ons tha t Mi mi c Temporoma ndi bul a r Di s orders ]
Trea tment i ncl udes a nti bi oti cs , proper hydra ti on, pa i n control , a nd moti on res tri cti on. Pa rentera l peni ci l l i n G i s the drug of choi ce unti l a s peci fi c
ba cteri ol ogi c di a gnos i s ca n be ma de on the ba s i s of cul ture a nd s ens i ti vi ty tes ti ng. Suppura ti ve i nfecti ons a re a s pi ra ted or i nci s ed. Once the
i nfecti on i s control l ed, ja w-openi ng exerci s es hel p prevent s ca rri ng a nd l i mi ta ti on of moti on.
Traumatic arthritis: Ra rel y, a cute i njury (eg, due to di ffi cul t tooth extra cti on or endotra chea l i ntuba ti on) ma y l ea d to a rthri ti s of the TMJ. Pa i n,
tendernes s , a nd l i mi ta ti on of moti on occur. Di a gnos i s i s ba s ed pri ma ri l y on hi s tory. X-ra y res ul ts a re nega ti ve except when i ntra -a rti cul a r edema
or hemorrha ge wi dens the joi nt s pa ce. Trea tment i ncl udes NSAIDs , a ppl i ca ti on of hea t, a s oft di et, a nd res tri cti on of ja w movement.
Osteoarthritis: The TMJ ma y be a ffected, us ua l l y i n peopl e > 50 yr. Occa s i ona l l y, pa ti ents compl a i n of s ti ffnes s , gra ti ng, or mi l d pa i n. Crepi tus res ul ts
from a hol e worn through the di s k, ca us i ng bone to gra te on bone. Joi nt i nvol vement i s genera l l y bi l a tera l . X-ra ys or CT ma y s how fl a tteni ng a nd
l i ppi ng of the condyl e, s ugges ti ve of dys functi ona l cha nge. Trea tment i s s ymptoma ti c.
Rheumatoid arthritis: The TMJ i s a ffected i n > 17% of a dul ts a nd chi l dren wi th RA, but i t i s us ua l l y a mong the l a s t joi nts i nvol ved. Pa i n, s wel l i ng, a nd
l i mi ted movement a re the mos t common fi ndi ngs . In chi l dren, des tructi on of the condyl e res ul ts i n ma ndi bul a r growth di s turba nce a nd fa ci a l
deformi ty. Ankyl os i s ma y fol l ow. X-ra ys of the TMJ a re us ua l l y nega ti ve i n ea rl y s ta ges but l a ter s how bone des tructi on, whi ch ma y res ul t i n a n
a nteri or open-bi te deformi ty. The di a gnos i s i s s ugges ted by TMJ i nfl a mma ti on a s s oci a ted wi th pol ya rthri ti s a nd i s confi rmed by other fi ndi ngs
typi ca l of the di s ea s e.
Trea tment i s s i mi l a r to tha t of RA i n other joi nts . In the a cute s ta ge, NSAIDs ma y be gi ven, a nd ja w functi on s houl d be res tri cted. A ni ght gua rd or
s pl i nt i s often hel pful . When s ymptoms s ubs i de, mi l d ja w exerci s es hel p prevent exces s i ve l os s of moti on. Surgery i s neces s a ry i f a nkyl os i s
devel ops but s houl d not be done unti l the condi ti on i s qui es cent.
Secondary degenerative arthritis: Thi s type of a rthri ti s us ua l l y devel ops i n peopl e a ged 20 to 40 a fter tra uma or i n peopl e wi th pers i s tent myofa s ci a l
pa i n s yndrome (s ee p. 533). It i s cha ra cteri zed by l i mi ted openi ng of the mouth, uni l a tera l pa i n duri ng ja w movement, joi nt tendernes s , a nd
crepi tus . When i t i s a s s oci a ted wi th the myofa s ci a l pa i n s yndrome, s ymptoms wa x a nd wa ne. Di a gnos i s i s ba s ed on x-ra ys , whi ch genera l l y s how
condyl a r fl a tteni ng, l i ppi ng, s purri ng, or eros i on. Uni l a tera l joi nt i nvol vement hel ps di s ti ngui s h s econda ry degenera ti ve a rthri ti s from
os teoa rthri ti s .
Trea tment i s cons erva ti ve, a s i t i s for myofa s ci a l pa i n s yndrome, a l though a rthropl a s ty or hi gh condyl ectomy ma y be neces s a ry. An occl us a l s pl i nt
(mouth gua rd) us ua l l y rel i eves s ymptoms . The s pl i nt i s worn cons ta ntl y, except duri ng mea l s , ora l hygi ene, a nd a ppl i a nce cl ea ni ng. When
s ymptoms res ol ve, the l ength of ti me tha t the s pl i nt i s worn ea ch da y i s gra dua l l y reduced. Intra -a rti cul a r i njecti on of corti cos teroi ds ma y rel i eve
s ymptoms but ma y ha rm the joi nt i f repea ted often.
Condylar Hyperplasia
Condylar hyperplasia is a disorder of unknown etiology characterized by persistent or accelerated growth of the condyle when growth should be slowing or ended.
Growth eventually stops without treatment.
Sl owl y progres s i ve uni l a tera l enl a rgement of the hea d a nd neck of the condyl e ca us es cros s bi te ma l occl us i on, fa ci a l a s ymmetry, a nd s hi fti ng of
the mi dpoi nt of the chi n to the una ffected s i de. The pa ti ent ma y a ppea r progna thi c. The l ower border of the ma ndi bl e i s often convex on the
a ffected s i de. Chondroma a nd os teochondroma ma y ca us e s i mi l a r s ymptoms a nd s i gns , but they grow more ra pi dl y a nd ma y ca us e even grea ter
a s ymmetri c condyl a r enl a rgement.
Diagnosis
Pl a i n x-ra ys
Us ua l l y CT
On x-ra y, the temporoma ndi bul a r joi nt ma y a ppea r norma l , or the condyl e ma y be proporti ona l l y enl a rged a nd the ma ndi bul a r neck el onga ted. CT
i s us ua l l y done to determi ne whether bone growth i s genera l i zed, whi ch confi rms the di a gnos i s , or l oca l i zed to pa rt of the condyl a r hea d. If
growth i s l oca l i zed, a bi ops y ma y be neces s a ry to di s ti ngui s h between tumor a nd hyperpl a s i a .
Treatment
Duri ng a cti ve growth, us ua l l y condyl ectomy
After growth ces s a ti on, orthodonti cs or s urgi ca l ma ndi bul a r repos i ti oni ng
Trea tment us ua l l y i ncl udes condyl ectomy duri ng the peri od of a cti ve growth. If growth ha s s topped, orthodonti cs a nd s urgi ca l ma ndi bul a r
repos i ti oni ng a re i ndi ca ted. If the hei ght of the ma ndi bul a r body i s grea tl y i ncrea s ed, fa ci a l s ymmetry ca n be further i mproved by reduci ng the
i nferi or border.
Condylar Hypoplasia
Condylar hypoplasia is facial deformity caused by a short mandibular ramus.
Thi s condi ti on us ua l l y res ul ts from tra uma , i nfecti on, or i rra di a ti on occurri ng duri ng the growth peri od but ma y be i di opa thi c. The deformi ty
i nvol ves ful l nes s of the fa ce, devi a ti on of the chi n to the a ffected s i de, a n el onga ted ma ndi bl e, a nd fl a tnes s of the fa ce on the una ffected s i de.
(The s i de to whi ch the ra mus i s s hort ca us es mus cl es to a ppea r ful l er; the mus cl es on the una ffected s i de a re s tretched s o tha t s i de a ppea rs
fl a tter.) Ma ndi bul a r devi a ti on ca us es ma l occl us i on.
Di a gnos i s i s ba s ed on a hi s tory of progres s i ve fa ci a l a s ymmetry duri ng the growth peri od, x-ra y evi dence of condyl a r deformi ty a nd a ntegoni a l
notchi ng (a depres s i on i n the i nferi or border of the ma ndi bl e jus t a nteri or to the a ngl e of the ma ndi bl e), a nd, frequentl y, a ca us a ti ve hi s tory.
Trea tment cons i s ts of s urgi ca l s horteni ng of the una ffected s i de of the ma ndi bl e or l engtheni ng of the a ffected s i de. Pres urgi ca l orthodonti c
thera py hel ps opti mi ze res ul ts .
Internal Joint Derangement
The most common form of internal joint derangement is anterior misalignment or displacement of the articular disk above the condyle. Symptoms are localized
joint pain and popping on jaw movement. Diagnosis is based on history and physical examination. Treatment is with analgesics, jaw rest, muscle relaxation,
physical therapy, and bite splinting. If these methods fail, surgery may be necessary. Early treatment greatly improves results.
The s uperi or hea d of the l a tera l pterygoi d mus cl e ma y pul l the a rti cul a r di s k out of pl a ce when a bnorma l ja w mecha ni cs pl a ce unus ua l s tres s on
the joi nt. Abnorma l ja w mecha ni cs ca n be due to congeni ta l or a cqui red a s ymmetri es or to the s equel a e of tra uma or a rthri ti s . If the di s k rema i ns
a nteri or, the dera ngement i s s a i d to be wi thout reducti on. Res tri cted ja w openi ng (l ocked ja w) a nd pa i n i n the ea r a nd a round the
temporoma ndi bul a r joi nt res ul t. If a t s ome poi nt i n the joi nt's excurs i on the di s k returns to the hea d of the condyl e, i t i s s a i d to be wi th reducti on.
Dera ngement wi th reducti on occurs i n a bout one thi rd of the popul a ti on a t s ome poi nt. Al l types of dera ngement ca n ca us e ca ps ul i ti s (or
s ynovi ti s ), whi ch i s i nfl a mma ti on of the ti s s ues s urroundi ng the joi nt (eg, tendons , l i ga ments , connecti ve ti s s ue, s ynovi um). Ca ps ul i ti s ca n a l s o
occur s ponta neous l y or res ul t from a rthri ti s , tra uma , or i nfecti on.
Symptoms and Signs
Dera ngement wi th reducti on often ca us es a cl i cki ng or poppi ng s ound when the mouth i s opened. Pa i n ma y be pres ent, pa rti cul a rl y when chewi ng
ha rd foods . Pa ti ents a re often emba rra s s ed beca us e they thi nk others ca n hea r noi s e when they chew. Indeed, a l though the s ound s eems l ouder
to the pa ti ent, others ca n s ometi mes hea r i t.
Dera ngement wi thout reducti on us ua l l y ca us es no s ound, but ma xi mum openi ng between the ti ps of the upper a nd l ower i nci s ors i s reduced from
the norma l 40 to 45 mm to 30 mm. Pa i n a nd a cha nge i n the pa ti ents ' percepti on of thei r bi te genera l l y res ul t.
Ca ps ul i ti s res ul ts i n l oca l i zed joi nt pa i n, tendernes s , a nd, s ometi mes , res tri cted openi ng.
Diagnosis
Di a gnos i s of dera ngement wi th reducti on requi res obs erva ti on of the ja w when the mouth i s opened. When the ja w i s opened > 10 mm (mea s ured
between upper a nd l ower i nci s ors ), a cl i ck or pop i s hea rd or a ca tch i s fel t a s the di s k pops ba ck over the hea d of the condyl e. The condyl e
rema i ns on the di s k duri ng further openi ng. Us ua l l y, a nother cl i ck i s hea rd duri ng cl os i ng when the condyl e s l i ps over the pos teri or ri m of the di s k
a nd the di s k s l i ps forwa rd (reci proca l cl i cki ng).
Di a gnos i s of dera ngement wi thout reducti on requi res tha t the pa ti ent open a s wi de a s pos s i bl e. The openi ng i s mea s ured, a nd gentl e pres s ure
i s then exerted to open the mouth a l i ttl e wi der. Norma l l y, the ja w opens a bout 45 to 50 mm; i f the di s k i s dera nged, i t wi l l open a bout 20 mm.
Cl os i ng or protrudi ng the ja w a ga i ns t res i s ta nce wors ens the pa i n.
MRI i s us ua l l y done to confi rm pres ence of dera ngement or to determi ne why a pa ti ent i s not res pondi ng to trea tment.
Ca ps ul i ti s i s often di a gnos ed ba s ed on a hi s tory of i njury or i nfecti on a l ong wi th exqui s i te tendernes s over the joi nt a nd by excl us i on when pa i n
rema i ns a fter trea tment for myofa s ci a l pa i n s yndrome, di s k dera ngement, a rthri ti s , a nd s tructura l a s ymmetri es . However, ca ps ul i ti s ma y be
pres ent wi th a ny of thes e condi ti ons .
Treatment
Ana l ges i cs a s needed
Someti mes repos i ti oni ng s pl i nt or s urgery
Someti mes corti cos teroi d i njecti on for ca ps ul i ti s
Dera ngement wi th reducti on does not requi re trea tment i f the pa ti ent ca n open rea s ona bl y wi de (a bout 40 mm or the wi dth of the i ndex, mi ddl e,
a nd ri ng fi ngers ) wi thout di s comfort. If pa i n occurs , mi l d a na l ges i cs , s uch a s NSAIDs (i buprofen 400 mg po q 6 h), ca n be us ed. If ons et i s < 6 mo, a n
a nteri or repos i ti oni ng s pl i nt ma y be us ed to pos i ti on the ma ndi bl e forwa rd a nd on the di s k. The s pl i nt i s a hors es hoe-s ha ped a ppl i a nce of ha rd,
tra ns pa rent a cryl i c (pl a s ti c) ma de to fi t s nugl y over the teeth of one a rch. Its chewi ng s urfa ce i s des i gned to hol d the ma ndi bl e forwa rd when the
pa ti ent cl os es on the s pl i nt. In thi s pos i ti on, the di s k i s a l wa ys on the hea d of the condyl e. The s pl i nt i s gra dua l l y a djus ted to a l l ow the ma ndi bl e
to move pos teri orl y. If the di s k s ta ys wi th the condyl e a s the s uperi or hea d of the externa l pterygoi d s tretches , the di s k i s s a i d to be ca ptured. The
l onger the di s k i s di s pl a ced, the more deformed i t becomes a nd the l es s l i kel y repos i ti oni ng wi l l s ucceed. Surgi ca l pl i ca ti on of the di s k ma y be
done, wi th va ri a bl e s ucces s .
Dera ngement wi thout reducti on ma y not requi re trea tment other tha n a na l ges i cs . Spl i nts ma y hel p i f the a rti cul a r di s k ha s not been s i gni fi ca ntl y
deformed, but l ong-term us e ma y res ul t i n i rrevers i bl e cha nges i n ora l a rchi tecture. In s ome ca s es , the pa ti ent i s i ns tructed to s l owl y s tretch the
di s k out of pos i ti on, whi ch a l l ows the ja w to open norma l l y. Va ri ous a rthros copi c a nd open s urgi ca l procedures a re a va i l a bl e when cons erva ti ve
trea tment fa i l s .
Ca ps ul i ti s i s i ni ti a l l y trea ted wi th NSAIDs , ja w res t, a nd mus cl e rel a xa ti on. If thes e trea tments a re uns ucces s ful , corti cos teroi ds ma y be i njected
i nto the joi nt, or a rthros copi c joi nt l a va ge a nd debri dement a re us ed.
Myofascial Pain Syndrome
Myofascial pain syndrome can occur in patients with a normal temporomandibular joint. It is caused by tension, fatigue, or spasm in the masticatory muscles
(medial or internal and lateral or external pterygoids, temporalis, and masseter). Symptoms include bruxism, pain and tenderness in and around the masticatory
apparatus or referred to other locations in the head and neck, and, often, abnormalities of jaw mobility. Diagnosis is based on history and physical examination.
Conservative treatment, including analgesics, muscle relaxation, habit modification, and bite splinting, usually is effective.
Thi s s yndrome i s the mos t common di s order a ffecti ng the temporoma ndi bul a r regi on. It i s more common a mong women a nd ha s a bi moda l a ge
di s tri buti on i n the ea rl y 20s a nd a round menopa us e. The mus cl e s pa s m ca us i ng the di s order us ua l l y i s the res ul t of nocturna l bruxi s m (cl enchi ng
or gri ndi ng of the teeth). Whether bruxi s m i s ca us ed by i rregul a r tooth conta cts , emoti ona l s tres s , or s l eep di s orders i s controvers i a l . Bruxi s m
us ua l l y ha s a mul ti fa ctori a l eti ol ogy. Myofa s ci a l pa i n s yndrome i s not l i mi ted to the mus cl es of ma s ti ca ti on. It ca n occur a nywhere i n the body,
mos t commonl y i nvol vi ng mus cl es i n the neck a nd ba ck.
Symptoms and Signs
Symptoms i ncl ude pa i n a nd tendernes s of the ma s ti ca tory mus cl es a nd often pa i n a nd l i mi ta ti on of ja w excurs i on. Nocturna l bruxi s m ma y l ea d to
hea da che tha t i s more s evere on a wa keni ng a nd tha t gra dua l l y s ubs i des duri ng the da y. Such pa i n s houl d be di s ti ngui s hed from tempora l
a rteri ti s . Da yti me s ymptoms , i ncl udi ng hea da che, ma y wors en i f bruxi s m conti nues throughout the da y.
The ja w devi a tes when the mouth opens but us ua l l y not a s s uddenl y or a l wa ys a t the s a me poi nt of openi ng a s i t does wi th i nterna l joi nt
dera ngement (s ee p. 532). Exerti ng gentl e pres s ure, the exa mi ner ca n open the pa ti ent's mouth a nother 1 to 3 mm beyond una i ded ma xi mum
openi ng.
Diagnosis
A s i mpl e tes t ma y a i d the di a gnos i s : Tongue bl a des of 2 or 3 thi cknes s es a re pl a ced between the rea r mol a rs on ea ch s i de, a nd the pa ti ent i s
a s ked to bi te down gentl y. The di s tra cti on produced i n the joi nt s pa ce ma y ea s e the s ymptoms . X-ra ys us ua l l y do not hel p except to rul e out
a rthri ti s . If tempora l a rteri ti s i s s us pected, ESR i s mea s ured.
Treatment
Mi l d a na l ges i cs
Spl i nt or mouth gua rd
An a nxi ol yti c a t bedti me cons i dered
Phys i ca l thera py moda l i ti es cons i dered
A pl a s ti c s pl i nt or mouth gua rd from the denti s t ca n keep teeth from conta cti ng ea ch other a nd prevent the da ma ges of bruxi s m. Comforta bl e,
hea t-mol da bl e s pl i nts a re a va i l a bl e from ma ny s porti ng goods s tores or drugs tores . Low dos es of a benzodi a zepi ne a t bedti me a re often effecti ve
for a cute exa cerba ti ons a nd tempora ry rel i ef of s ymptoms . Mi l d a na l ges i cs , s uch a s NSAIDs or a ceta mi nophen, a re i ndi ca ted. Cycl obenza pri ne ma y
hel p mus cl e rel a xa ti on i n s ome peopl e. Beca us e the condi ti on i s chroni c, opi oi ds s houl d not be us ed, except perha ps bri efl y for a cute
exa cerba ti ons . The pa ti ent mus t l ea rn to s top cl enchi ng the ja w a nd gri ndi ng the teeth. Ha rd-to-chew foods a nd chewi ng gum s houl d be a voi ded.
Phys i ca l thera py, bi ofeedba ck to encoura ge rel a xa ti on, a nd couns el i ng hel p s ome pa ti ents . Phys i ca l moda l i ti es i ncl ude tra ns cuta neous el ectri c
nerve s ti mul a ti on a nd "s pra y a nd s tretch," i n whi ch the ja w i s s tretched open a fter the s ki n over the pa i nful a rea ha s been chi l l ed wi th i ce or
s pra yed wi th a s ki n refri gera nt, s uch a s ethyl chl ori de. Botul i num toxi n ha s recentl y been us ed s ucces s ful l y to rel i eve mus cl e s pa s m i n myofa s ci a l
pa i n s yndrome. Mos t pa ti ents , even i f untrea ted, s top ha vi ng s i gni fi ca nt s ymptoms wi thi n 2 to 3 yr.
6 - Eye Disorders
Chapter 60. Approach to the Ophthalmologic Patient
Introduction
The eye ca n be exa mi ned wi th routi ne equi pment, i ncl udi ng a s ta nda rd ophtha l mos cope; thorough exa mi na ti on requi res s peci a l equi pment a nd
eva l ua ti on by a n ophtha l mol ogi s t. (See
Fi g. 60-1 for a cros s -s ecti on of the eye.)
History
Hi s tory i ncl udes l oca ti on, s peed of ons et, a nd dura ti on of current s ymptoms a nd hi s tory of previ ous ocul a r s ymptoms ; the pres ence a nd na ture of
pa i n, di s cha rge, or rednes s ; a nd cha nges i n vi s ua l a cui ty. Worri s ome s ymptoms bes i des vi s i on l os s a nd eye pa i n i ncl ude fl a s hi ng l i ghts , s howers
of fl oa ters (both of whi ch ma y be s ymptoms of reti na l deta chment), di pl opi a , a nd l os s of peri phera l vi s i on.
Visual acuity: The fi rs t s tep i s to record vi s ua l a cui ty. Ma ny pa ti ents do not gi ve a ful l effort. Provi di ng a dequa te ti me a nd coa xi ng pa ti ents tend to
yi el d more a ccura te res ul ts . Vi s ua l a cui ty i s mea s ured wi th a nd wi thout the pa ti ent's own gl a s s es . If pa ti ents do not ha ve thei r gl a s s es , a pi nhol e
refra ctor i s us ed. If a commerci a l pi nhol e refra ctor i s una va i l a bl e, one ca n be ma de a t the beds i de by poki ng hol es through a pi ece of ca rdboa rd
us i ng a n 18-ga uge needl e a nd va ryi ng the di a meter of ea ch hol e s l i ghtl y. Pa ti ents choos e the hol e tha t corrects vi s i on the mos t. If a cui ty corrects
wi th pi nhol e refra cti on, the probl em i s a refra cti ve error. Pi nhol e refra cti on i s a ra pi d, effi ci ent wa y to di a gnos e refra cti ve errors , whi ch a re the
mos t common ca us e of bl urred vi s i on. However, wi th pi nhol e refra cti on, bes t correcti on i s us ua l l y to onl y a bout 20/30, not 20/20.
[Fig. 60-1. Cros s -s ecti on of the eye.]
Vi s ua l a cui ty i n ea ch eye i s tes ted a s the oppos i te eye i s covered wi th a s ol i d object (not the pa ti ent's fi ngers , whi ch ma y s epa ra te duri ng tes ti ng).
Pa ti ents l ook a t a n eye cha rt 20 ft (6 m) a wa y. If thi s tes t ca nnot be done, a cui ty ca n be mea s ured us i ng a cha rt hel d a bout 36 cm (14 i n) from the
eye. Norma l a nd a bnorma l vi s i on i s qua nti fi ed by Snel l en nota ti on. A Snel l en nota ti on of 20/40 (6/12) i ndi ca tes tha t the s ma l l es t l etter tha t ca n
be rea d by s omeone wi th norma l vi s i on a t 40 ft (12 m) ha s to be brought to 20 ft (6 m) before i t i s recogni zed by the pa ti ent. Vi s i on i s recorded a s
the s ma l l es t l etter pa ti ents rea d correctl y, even i f pa ti ents feel tha t the l etter i s bl urry or they ha ve to gues s . If the pa ti ent ca nnot rea d the top
l i ne of the Snel l en cha rt a t 20 ft (6 m), a cui ty i s tes ted a t 10 ft (3 m). If nothi ng ca n be rea d from a cha rt even a t the cl os es t di s ta nce, the exa mi ner
hol ds up di fferent numbers of fi ngers to s ee whether the pa ti ent ca n a ccura tel y count them. If not, the exa mi ner tes ts whether the pa ti ent ca n
percei ve ha nd moti on. If not, a l i ght i s s hi ned i nto the eye to s ee whether l i ght i s percei ved.
Nea r vi s i on i s checked by a s ki ng pa ti ents to rea d a s ta nda rd nea r ca rd or news pri nt a t 14 i n (35 cm); pa ti ents > 40 yr who requi re correcti ve l ens es
(rea di ng gl a s s es ) s houl d wea r them duri ng nea r vi s i on tes ti ng.
Refra cti ve error ca n be es ti ma ted roughl y wi th a ha ndhel d ophtha l mos cope by noti ng the l ens neces s a ry for the exa mi ner to focus on the reti na ;
thi s procedure requi res exa mi ners to us e thei r own correcti ve l ens es a nd i s never a s ubs ti tute for a comprehens i ve a s s es s ment of refra cti on.
More commonl y, refra cti ve error i s mea s ured wi th a s ta nda rd phoropter or a n a utoma ted refra ctor (a devi ce tha t mea s ures cha nges i n l i ght
projected a nd refl ected by the pa ti ent's eye). Thes e devi ces a l s o mea s ure a s ti gma ti s m (s ee p. 571).
Eyelid and conjunctival examination: Eyel i d ma rgi ns a nd peri ocul a r cuta neous ti s s ues a re exa mi ned under a foca l l i ght a nd ma gni fi ca ti on (eg,
provi ded by l oupe, s l i t l a mp, or ophtha l mos cope focus ed a t the exa mi ner's worki ng di s ta nce). In ca s es of s us pected da cryocys ti ti s or ca na l i cul i ti s ,
the l a cri ma l s a cs a re pa l pa ted a nd a n a ttempt i s ma de to expres s a ny contents through the ca na l i cul i a nd puncta . After eyel i d evers i on, the
pa l pebra l a nd bul ba r conjuncti va e a nd the forni ces ca n be i ns pected for forei gn bodi es , s i gns of i nfl a mma ti on (eg, fol l i cul a r hypertrophy, exuda te,
hyperemi a , edema ), or other a bnorma l i ti es .
Corneal examination: Indi s ti nct or bl urred edges of the cornea l l i ght refl ex (refl ecti on of l i ght from the cornea when i l l umi na ted) s ugges t the cornea l
s urfa ce i s not i nta ct or i s roughened, a s occurs wi th a cornea l a bra s i on or kera ti ti s . Fl uores cei n s ta i ni ng revea l s a bra s i ons a nd ul cers . Before
s ta i ni ng, a drop of topi ca l a nes theti c (eg, propa ra ca i ne 0.5%, tetra ca i ne 0.5%) ma y be a dded to fa ci l i ta te exa mi na ti on i f the pa ti ent i s i n pa i n or i f
i t i s neces s a ry to touch the cornea or conjuncti va (eg, to remove a forei gn body or mea s ure i ntra ocul a r pres s ure). A s teri l e, i ndi vi dua l l y pa cka ged
fl uores cei n s tri p i s moi s tened wi th 1 drop of s teri l e s a l i ne or topi ca l a nes theti c a nd, wi th the pa ti ent's eye turned upwa rd, i s touched
momenta ri l y to the i ns i de of the l ower eyel i d. The pa ti ent bl i nks s evera l ti mes to s prea d the dye i nto the tea r fi l m, a nd then the eye i s exa mi ned
under ma gni fi ca ti on a nd coba l t bl ue i l l umi na ti on. Area s where cornea l or conjuncti va l epi thel i um i s a bs ent (a bra ded or ul cera ted) fl uores ce
green.
Pupil examination: The s i ze a nd s ha pe of the pupi l s a re noted, a nd pupi l l a ry rea cti on to l i ght i s tes ted i n ea ch eye, one a t a ti me, whi l e the pa ti ent
l ooks i n the di s ta nce. Then the s wi ngi ng fl a s hl i ght tes t i s done wi th a penl i ght to compa re di rect a nd cons ens ua l pupi l l a ry res pons e. There a re 3
s teps :
1. One pupi l i s ma xi ma l l y cons tri cted by bei ng expos ed to l i ght from the penl i ght for 1 to 3 s ec.
2. The penl i ght i s ra pi dl y moved to the other eye for 1 to 3 s ec.
3. The l i ght i s moved ba ck to the fi rs t eye.
Norma l l y, a pupi l cons tri cts s i mi l a rl y when l i ght i s s hone on i t (di rect res pons e) a nd when l i ght i s s hone on the other eye (cons ens ua l res pons e).
However, i f one eye ha s l es s l i ght percepti on tha n the other, a s ca us ed by dys functi on of the a fferent l i mb (from the opti c nerve to the opti c
chi a s m) or extens i ve reti na l di s ea s e, then the consensual res pons e i n the a ffected eye i s s tronger tha n the direct res pons e. Thus , on s tep 3 of the
s wi ngi ng l i ght tes t, when the l i ght i s s hi ned ba ck on the a ffected eye, i t pa ra doxi ca l l y a ppea rs to di l a te. Thi s fi ndi ng i ndi ca tes a rel a ti ve a fferent
pupi l l a ry defect (RAPD, or Ma rcus Gunn pupi l ).
Extraocular muscles: The exa mi ner gui des the pa ti ent to l ook i n 8 di recti ons (up, up a nd ri ght, ri ght, down a nd ri ght, down, down a nd l eft, l eft, l eft
a nd up) wi th a movi ng fi nger, penl i ght, or tra ns i l l umi na ti on l i ght, obs ervi ng for ga ze devi a ti on, l i mi ta ti on of movement, di s conjuga te ga ze, or a
combi na ti on cons i s tent wi th cra ni a l nerve pa l s y, orbi ta l di s ea s e, or other a bnorma l i ti es tha t res tri ct movement.
Ophthalmoscopy: Ophtha l mos copy ca n be done di rectl y by us i ng a ha ndhel d ophtha l mos cope or i ndi rectl y by us i ng a hea d-mounted
ophtha l mos cope wi th a ha ndhel d l ens . Wi th ha ndhel d ophtha l mos copy, the exa mi ner di a l s the ophtha l mos cope to zero di opters , then i ncrea s es
or decrea s es the s etti ng unti l the fundus comes i nto focus . The vi ew of the reti na i s l i mi ted wi th a ha ndhel d ophtha l mos cope, wherea s i ndi rect
ophtha l mos copy gi ves a 3-di mens i ona l vi ew a nd i s better for vi s ua l i zi ng the peri phera l reti na , where reti na l deta chment mos t commonl y occurs .
The vi ew of the fundus ca n be i mproved by di l a ti ng the pupi l s . Before di l a ti on, the a nteri or cha mber depth i s es ti ma ted beca us e mydri a s i s ca n
preci pi ta te a n a tta ck of a cute a ngl e-cl os ure gl a ucoma i f the a nteri or cha mber i s s ha l l ow. Depth ca n be es ti ma ted wi th a s l i t l a mp (s ee bel ow) or
l es s a ccura tel y wi th a penl i ght hel d a t the tempora l l i mbus pa ra l l el to the pl a ne of the i ri s a nd poi nted towa rd the nos e. If the medi a l i ri s i s i n
s ha dow, the cha mber i s s ha l l ow a nd di l a ti on s houl d be a voi ded. Other contra i ndi ca ti ons to di l a ti on i ncl ude hea d tra uma , s us pi ci on of a ruptured
gl obe, a na rrow a ngl e, a nd a ngl e-cl os ure gl a ucoma .
Pupi l s ca n be di l a ted us i ng 1 drop of tropi ca mi de 1%, phenyl ephri ne 2.5%, or both (repea ted i n 5 to 10 mi n i f neces s a ry); for l onger a cti on, a l a rger
di l a ted pupi l , or both, cycl opentol a te 1% ca n be s ubs ti tuted for tropi ca mi de.
Ophtha l mos copy ca n detect l ens or vi treous opa ci ti es , a s s es s the opti c cup-to-di s k ra ti o, a nd i denti fy reti na l a nd va s cul a r cha nges . The opti c cup
i s the centra l depres s i on, a nd the opti c di s k i s the enti re a rea of the opti c nerve hea d. The norma l ra ti o of the cup-to-nerve di a meters i s 0 to 0.4. A
ra ti o of 0.5 ma y s i gni fy l os s of ga ngl i on cel l s a nd ma y be a s i gn of gl a ucoma . Reti na l cha nges i ncl ude hemorrha ge, ma ni fes ted a s s ma l l or l a rge
a rea s of bl ood, a nd drus en (s ma l l s ubreti na l yel l ow-whi te s pots tha t ma y s i gni fy dry a ge-rel a ted ma cul a r degenera ti on). Va s cul a r cha nges
i ncl ude a rteri ovenous ni cki ng, a s i gn of chroni c hypertens i on i n whi ch reti na l vei ns a re compres s ed by a rteri es where the two cros s ; copper wi ri ng,
a s i gn of a rteri os cl eros i s i n whi ch thi ckened a rteri ol a r wa l l s i ncrea s e the thi cknes s of the l i ght refl ex; s i l ver wi ri ng, a s i gn of hypertens i on i n
whi ch thi n, fi broti c a rteri ol a r wa l l s decrea s e the thi cknes s of the l i ght refl ex; a nd l os s of venous pul s a ti ons , a s i gn of i ncrea s ed i ntra cra ni a l
pres s ure i n pa ti ents known to ha ve ha d pul s a ti ons .
Slit-lamp examination: A s l i t l a mp focus es the hei ght a nd wi dth of a bea m of l i ght for a preci s e s tereos copi c vi ew of the eyel i ds , conjuncti va , cornea ,
a nteri or cha mber, i ri s , l ens , a nd a nteri or vi treous . It i s es peci a l l y us eful for the fol l owi ng:
Identi fyi ng cornea l forei gn bodi es a nd a bra s i ons
Mea s uri ng depth of the a nteri or cha mber
Detecti ng cel l s (RBCs or WBCs ) a nd fl a re (evi dence of protei n) i n the a nteri or cha mber
Identi fyi ng ci l i a ry fl us h (di l a ti on of bl ood ves s el s l oca l i zed to the l i mba l regi on overl yi ng the ci l i a ry body), whi ch occurs wi th uvei ti s
Identi fyi ng s cl era l edema , whi ch i s s een a s a bowi ng forwa rd of the s l i t bea m when i t i s focus ed benea th the conjuncti va a nd whi ch i s us ua l l y a
s i gn of s cl eri ti s
Tonometry (s ee p. 540) a nd goni os copy, whi ch qua nti fi es the i ri docornea l a ngl e a nd requi res the us e of a s peci a l l ens , ma y be done.
Visual field testing: Vi s ua l fi el ds ma y be i mpa i red by l es i ons a nywhere i n the neura l vi s ua l pa thwa ys from the opti c nerves to the occi pi ta l l obes
(s ee
Ta bl e 60-1 a nd
Fi g. 69-1 on p. 620). Gl a ucoma ca us es l os s of peri phera l vi s i on. Fi el ds ca n be a s s es s ed gros s l y by di rect confronta ti on tes ti ng or by more preci s e,
deta i l ed tes ti ng.
In direct confrontation, pa ti ents ma i nta i n a fi xed ga ze a t the exa mi ner's eye or nos e. The exa mi ner bri ngs a s ma l l ta rget (eg, a ma tch or a fi nger)
from the pa ti ents ' vi s ua l peri phery i nto ea ch of the 4 vi s ua l qua dra nts a nd a s ks pa ti ents to i ndi ca te when they fi rs t s ee the object. Wi ggl i ng the
s ma l l ta rget hel ps pa ti ents s epa ra te a nd defi ne i t. Another method of di rect confronta ti on vi s ua l fi el d tes ti ng i s to hol d a number of fi ngers i n
ea ch qua dra nt a nd a s k pa ti ents how ma ny they s ee. For both methods , ea ch eye i s tes ted s epa ra tel y. Abnorma l i ti es i n ta rget detecti on s houl d
prompt deta i l ed tes ti ng wi th more preci s e i ns truments .
More deta i l ed methods i ncl ude us e of a ta ngent s creen, Gol dma nn peri meter, or computeri zed a utoma ted peri metry (i n whi ch the vi s ua l fi el d i s
ma pped out i n deta i l ba s ed on pa ti ent res pons e to a s eri es of fl a s hi ng l i ghts i n di fferent l oca ti ons control l ed by a s ta nda rdi zed computer
progra m). The Ams l er gri d i s us ed to tes t centra l vi s i on. Di s torti on of the gri d (meta morphops i a ) or a mi s s i ng a rea (centra l s cotoma ) ma y i ndi ca te
di s ea s e of the ma cul a (eg, choroi da l neova s cul a ri za ti on), a s occurs i n a ge-rel a ted ma cul a r degenera ti on.
Color vision testing: Twel ve to 24 Is hi ha ra col or pl a tes , whi ch ha ve col ored numbers or s ymbol s hi dden i n a fi el d of col ored dots , a re commonl y us ed
to tes t col or vi s i on. Col orbl i nd pa ti ents or pa ti ents wi th a cqui red col or defi ci ency (eg, i n opti c nerve di s ea s es ) ca nnot s ee s ome or a l l of the
hi dden numbers . Mos t
[Table 60-1. Types of Fi el d Defects ]
congeni ta l col or bl i ndnes s i s red-green; mos t a cqui red (eg, ca us ed by gl a ucoma or opti c nerve di s ea s e) i s bl ue-yel l ow.
Testing
Tonometry: Tonometry mea s ures i ntra ocul a r pres s ure by determi ni ng the a mount of force needed to i ndent the cornea . Ha ndhel d pen-type
tonometers a re us ed for s creeni ng. Thi s tes t requi res topi ca l a nes thes i a (eg, propa ra ca i ne 0.5%). Offi ce-ba s ed s creeni ng wi th nonconta ct a i r-puff
tonometry a l s o ca n be us ed; i t requi res l es s tra i ni ng beca us e i t ma kes no di rect cornea l conta ct. Gol dma nn a ppl a na ti on tonometry i s the mos t
a ccura te method but requi res more tra i ni ng a nd typi ca l l y i s us ed onl y by ophtha l mol ogi s ts . Mea s urement of i ntra ocul a r pres s ure a l one i s not
a dequa te s creeni ng for gl a ucoma ; the opti c nerve a l s o s houl d be exa mi ned.
Fluorescein angiography: After IV i njecti on of fl uores cei n s ol uti on, the reti na l , choroi da l , opti c di s k, or i ri s va s cul a ture i s photogra phed i n ra pi d
s equence. Fl uores cei n a ngi ogra phy i s us ed to i nves ti ga te underperfus i on a nd neova s cul a ri za ti on i n condi ti ons s uch a s di a betes , a ge-rel a ted
ma cul a r degenera ti on, reti na l va s cul a r occl us i on, a nd ocul a r hi s topl a s mos i s . It i s a l s o us eful i n preopera ti ve a s s es s ment for reti na l l a s er
procedures .
Electroretinography: El ectrodes a re pl a ced on ea ch cornea a nd on the s urroundi ng s ki n, a nd el ectri ca l a cti vi ty i n the reti na i s recorded. Thi s
techni que eva l ua tes reti na l functi on i n pa ti ents wi th reti na l degenera ti on. It does not eva l ua te vi s i on.
Ultrasonography: B-mode ul tra s onogra phy provi des 2-di mens i ona l s tructura l i nforma ti on even i n the pres ence of opa ci ti es of the cornea a nd l ens .
Exa mpl es of ophtha l mol ogi c a ppl i ca ti ons i ncl ude a s s es s ment of reti na l tumors , deta chments , a nd vi treous hemorrha ges ; l oca ti on of forei gn
bodi es ; detecti on of pos teri or s cl era l edema cha ra cteri s ti c of pos teri or s cl eri ti s ; a nd di s ti ncti on of choroi da l mel a noma from meta s ta ti c
ca rci noma a nd s ubreti na l hemorrha ge.
A-mode ul tra s onogra phy i s 1-di mens i ona l ul tra s onogra phy us ed to determi ne the a xi a l l ength of the eye, a mea s urement needed to ca l cul a te the
power of a n i ntra ocul a r l ens for i mpl a nta ti on a s a pa rt of ca ta ra ct s urgery.
Ul tra s oni c pa chymetry i s us e of ul tra s onogra phy to mea s ure the thi cknes s of the cornea before refra cti ve s urgery (eg, LASIK) a nd i n pa ti ents wi th
cornea l dys trophi es .
CT and MRI: Thes e i ma gi ng techni ques mos t often a re us ed for eva l ua ti on of ocul a r tra uma , pa rti cul a rl y i f a n i ntra ocul a r forei gn body i s s us pected,
a nd i n the eva l ua ti on of orbi ta l tumors , opti c neuri ti s , a nd opti c nerve tumors . MRI s houl d not be done when there i s s us pi ci on of a meta l l i c
i ntra ocul a r forei gn body.
Electronystagmography: See p. 414.
Acute Vision Loss
Los s of vi s i on i s us ua l l y cons i dered a cute i f i t devel ops wi thi n a few mi nutes to a coupl e of da ys . It ma y a ffect one or both eyes a nd a l l or pa rt of a
vi s ua l fi el d. Pa ti ents wi th s ma l l vi s ua l fi el d defects (eg, ca us ed by a s ma l l reti na l deta chment) ma y des cri be thei r s ymptoms a s bl urred vi s i on.
Pathophysiology
Acute l os s of vi s i on ha s 3 genera l ca us es :
Opa ci fi ca ti on of norma l l y tra ns pa rent s tructures through whi ch l i ght ra ys pa s s to rea ch the reti na (eg, cornea , vi treous )
Reti na l a bnorma l i ti es
Abnorma l i ti es a ffecti ng the opti c nerve or vi s ua l pa thwa ys
Etiology
The mos t common ca us es of a cute l os s of vi s i on a re
Va s cul a r occl us i ons of the reti na (centra l reti na l a rtery occl us i on, centra l reti na l vei n occl us i on)
Is chemi c opti c neuropa thy (often i n pa ti ents wi th tempora l a rteri ti s )
Vi treous hemorrha ge (ca us ed by di a beti c reti nopa thy or tra uma )
Tra uma
In a ddi ti on, s udden recogni ti on of l os s of vi s i on (ps eudo-s udden l os s of vi s i on) ma y ma ni fes t i ni ti a l l y a s s udden ons et. For exa mpl e, a pa ti ent
wi th l ong-s ta ndi ng reduced vi s i on i n one eye (pos s i bl y ca us ed by a dens e ca ta ra ct) s uddenl y i s a wa re of the reduced vi s i on i n the a ffected eye
when coveri ng the una ffected eye.
Pres ence or a bs ence of pa i n hel ps ca tegori ze l os s of vi s i on (s ee
Ta bl e 60-2).
Mos t di s orders tha t ca us e tota l l os s of vi s i on when they a ffect the enti re eye ma y a ffect onl y pa rt of the eye a nd ca us e onl y a vi s ua l fi el d defect
(eg, bra nch occl us i on of the reti na l a rtery or reti na l vei n, foca l reti na l deta chment).
Les s common ca us es of a cute l os s of vi s i on i ncl ude
Anteri or uvei ti s (a common di s order, but one tha t us ua l l y ca us es eye pa i n s evere enough to tri gger eva l ua ti on before vi s i on i s l os t)
Hi ghl y a ggres s i ve reti ni ti s
Certa i n drugs (eg, metha nol , s a l i cyl a tes , ergot a l ka l oi ds , qui ni ne)
Evaluation
History: History of present illness s houl d des cri be l os s of vi s i on i n terms of ons et, dura ti on, progres s i on, a nd l oca ti on (whether i t i s monocul a r or
bi nocul a r a nd whether i t i nvol ves the enti re vi s ua l fi el d or a s peci fi c pa rt a nd whi ch pa rt). Importa nt a s s oci a ted vi s ua l s ymptoms i ncl ude fl oa ters ,
fl a s hi ng l i ghts , ha l os a round l i ghts , di s torted col or vi s i on,
[Table 60-2. Some Di s orders tha t Ca us e Acute Vi s i on Los s ]
a nd ja gged or mos a i c pa tterns (s ci nti l l a ti ng s cotoma ta ). The pa ti ent s houl d be a s ked a bout eye pa i n a nd whether i t i s cons ta nt or occurs onl y wi th
eye movement.
Review of systems s houl d s eek extra ocul a r s ymptoms of pos s i bl e ca us es , i ncl udi ng ja w or tongue cl a udi ca ti on, tempora l hea da che, proxi ma l
mus cl e pa i n, a nd s ti ffnes s (gi a nt cel l a rteri ti s ); a nd hea da ches (ocul a r mi gra i ne).
Past medical history s houl d s eek known ri s k fa ctors for eye di s orders (eg, conta ct l ens us e, s evere myopi a , recent eye s urgery or i njury), ri s k fa ctors
for va s cul a r di s ea s e (eg, di a betes , hypertens i on), a nd hema tol ogi c di s orders (eg, s i ckl e cel l a nemi a or di s orders s uch a s Wa l dens trom's
ma crogl obul i nemi a or mul ti pl e myel oma tha t coul d ca us e a hypervi s cos i ty s yndrome).
Fa mi l y hi s tory s houl d note a ny fa mi l y hi s tory of mi gra i ne hea da ches .
Physical examination: Vi ta l s i gns , i ncl udi ng tempera ture, a re mea s ured.
If the di a gnos i s of a tra ns i ent i s chemi c a tta ck i s under cons i dera ti on, a compl ete neurol ogi c exa mi na ti on i s done. The fa ci a l s ki n i s i ns pected for
ves i cl es or ul cers i n the V1 di s tri buti on (ophtha l mi c di vi s i on of the tri gemi na l nerve), a nd the templ es a re pa l pa ted for pul s es , tendernes s , or
nodul a ri ty over the cours e of the tempora l a rtery. However, mos t of the exa mi na ti on focus es on the eye.
Eye exa mi na ti on i ncl udes the fol l owi ng:
Vi s ua l a cui ty i s mea s ured.
Peri phera l vi s ua l fi el ds a re a s s es s ed by confronta ti on.
Centra l vi s ua l fi el ds a re a s s es s ed by Ams l er gri d.
Di rect a nd cons ens ua l pupi l l a ry l i ght refl exes a re exa mi ned us i ng the s wi ngi ng fl a s hl i ght tes t.
Ocul a r moti l i ty i s a s s es s ed.
Col or vi s i on i s tes ted wi th col or pl a tes .
The eyel i ds , s cl era , a nd conjuncti va a re exa mi ned us i ng a s l i t l a mp i f pos s i bl e.
The cornea i s exa mi ned wi th fl uores cei n s ta i ni ng.
The a nteri or cha mber i s exa mi ned for cel l s a nd fl a re i n pa ti ents who ha ve eye pa i n or conjuncti va l i njecti on.
The l ens i s checked for ca ta ra cts us i ng a di rect ophtha l mos cope, s l i t l a mp, or both.
Intra ocul a r pres s ure i s mea s ured.
Ophtha l mos copy i s done, prefera bl y a fter di l a ti ng the pupi l wi th a drop of a s ympa thomi meti c (eg, 2.5% phenyl ephri ne), cycl opl egi c (eg, 1%
cycl opentol a te or 1% tropi ca mi de), or both; di l a ti on i s nea rl y ful l a fter a bout 20 mi n. The enti re fundus , i ncl udi ng the reti na , ma cul a , fovea ,
ves s el s , a nd opti c di s k a nd i ts ma rgi ns , i s exa mi ned.
If pupi l l a ry l i ght res pons es a re norma l a nd functi ona l l os s of vi s i on i s s us pected (ra rel y),
[
Fig. 60-2. Eva l ua ti on of a cute vi s i on l os s .]
optoki neti c nys ta gmus i s checked. If a n optoki neti c drum i s una va i l a bl e, a mi rror ca n be hel d nea r the pa ti ent's eye a nd s l owl y moved. If the
pa ti ent ca n s ee, the eyes us ua l l y tra ck movement of the mi rror.
Red flags: Acute l os s of vi s i on i s i ts el f a red fl a g; mos t ca us es a re s eri ous .
Interpretation of findings: Di a gnos i s ca n be begun s ys tema ti ca l l y. Fi g. 60-2 des cri bes a s i mpl i fi ed, genera l a pproa ch. Speci fi c pa tterns of vi s ua l fi el d
defi ci t hel p s ugges t a ca us e (s ee Ta bl e 60-1). Other cl i ni ca l fi ndi ngs a l s o hel p s ugges t a ca us e (s ee Ta bl e 60-2):
Di ffi cul ty s eei ng the red refl ex duri ng ophtha l mos copy s ugges ts opa ci fi ca ti on of tra ns pa rent s tructures (eg, ca us ed by cornea l ul cer, vi treous
hemorrha ge, or s evere endophtha l mi ti s ).
Reti na l a bnorma l i ti es tha t a re s evere enough to ca us e a cute l os s of vi s i on a re detecta bl e duri ng ophtha l mos copy, pa rti cul a rl y i f the pupi l s a re
di l a ted. Reti na l deta chment ma y s how reti na l fol ds ; reti na l vei n occl us i on ma y s how ma rked reti na l hemorrha ges ; a nd reti na l a rtery occl us i on
ma y s how a pa l e reti na wi th cherry-red fovea .
An a fferent pupi l l a ry defect (a bs ence of a di rect pupi l l a ry l i ght res pons e but a norma l cons ens ua l res pons e) wi th a n otherwi s e norma l
exa mi na ti on (except s ometi mes a n a bnorma l opti c di s k) s ugges ts a n a bnorma l i ty of the opti c nerve or reti na (i e, a nteri or to the chi a s m).
In a ddi ti on, the fol l owi ng fa cts ma y hel p:

Monocul a r s ymptoms s ugges t a l es i on a nteri or to the opti c chi a s m.
Bi l a tera l , s ymmetri c vi s ua l fi el d defects s ugges t a l es i on pos teri or to the chi a s m.
Cons ta nt eye pa i n s ugges ts a cornea l l es i on (ul cer or a bra s i on), a nteri or cha mber i nfl a mma ti on, or i ncrea s ed i ntra ocul a r pres s ure, wherea s eye
pa i n wi th movement s ugges ts opti c neuri ti s .
Tempora l hea da ches s ugges t gi a nt cel l a rteri ti s or mi gra i ne.
Testing: ESR i s done for a l l pa ti ents wi th s ymptoms (eg, tempora l hea da ches , ja w cl a udi ca ti on, proxi ma l mya l gi a s , s ti ffnes s ) or s i gns (eg, tempora l
a rtery tendernes s or i ndura ti on, pa l e reti na , pa pi l l edema ) s ugges ti ng opti c nerve or reti na l i s chemi a to excl ude gi a nt cel l a rteri ti s .
Other tes ti ng i s l i s ted i n Ta bl e 60-2. The fol l owi ng a re of pa rti cul a r i mporta nce:
Ul tra s onogra phy i s done to vi ew the reti na i f the reti na i s not cl ea rl y vi s i bl e wi th pupi l l a ry di l a ti on a nd i ndi rect ophtha l mos copy done by a n
ophtha l mol ogi s t.
Ga dol i ni um-enha nced MRI i s done for pa ti ents who ha ve eye pa i n wi th movement or a fferent pupi l l a ry defect, pa rti cul a rl y wi th opti c nerve
s wel l i ng on ophtha l mos copy, to di a gnos e mul ti pl e s cl eros i s .
Treatment
Ca us a ti ve di s orders a re trea ted. Trea tment s houl d us ua l l y commence i mmedi a tel y i f the ca us e i s trea ta bl e. In ma ny ca s es (eg, va s cul a r
di s orders ), trea tment i s unl i kel y to s a l va ge the a ffected eye but ca n decrea s e the ri s k of the s a me proces s occurri ng i n the contra l a tera l eye.
Key Points
Di a gnos i s a nd trea tment s houl d occur a s ra pi dl y a s pos s i bl e.
Acute monocul a r l os s of vi s i on wi th a n a fferent pupi l l a ry defect i ndi ca tes a l es i on of the eye or of the opti c nerve a nteri or to the opti c chi a s m.
Opti c nerve l es i on, pa rti cul a rl y i s chemi a , i s cons i dered i n pa ti ents wi th a cute monocul a r l os s of vi s i on or a fferent pupi l l a ry defect a nd i n thos e
wi th or wi thout opti c nerve a bnorma l i ti es on ophtha l mos copy but no other a bnorma l i ti es on eye exa mi na ti on.
Cornea l ul cer, a cute a ngl e-cl os ure gl a ucoma , endophtha l mi ti s , or s evere a nteri or uvei ti s i s cons i dered i n pa ti ents wi th a cute monocul a r l os s of
vi s i on, a fferent pupi l l a ry defect, eye pa i n, a nd conjuncti va l i njecti on.
Anisocoria
(Unequa l Pupi l s )
Ani s ocori a i s unequa l pupi l s i zes . Ani s ocori a i ts el f does not ca us e s ymptoms .
Etiology
The mos t common ca us e of a ni s ocori a i s
Phys i ol ogi c (pres ent i n a bout 20% of peopl e)
See
Ta bl e 60-3 for other ca us es of a ni s ocori a .
Ma ny di s orders a re a ccompa ni ed by a ni s ocori a due to i ri s or neurol ogi c dys functi on but us ua l l y ma ni fes t wi th other, more bothers ome s ymptoms
(eg, uvei ti s , opti c neuri ti s , s troke, s uba ra chnoi d hemorrha ge, a cute a ngl e-cl os ure gl a ucoma ).
Evaluation
The goa l of eva l ua ti on i s to el uci da te the phys i ol ogi c mecha ni s m of a ni s ocori a . By i denti fyi ng certa i n mecha ni s ms (eg, Horner's s yndrome, 3rd
cra ni a l nerve pa l s y), cl i ni ci a ns ca n di a gnos e the occa s i ona l s eri ous occul t di s order (eg, tumor, a neurys m) ma ni fes ti ng wi th a ni s ocori a .
History: History of present illness i ncl udes the pres ence, na ture, a nd dura ti on of s ymptoms . Any hi s tory of hea d or ocul a r tra uma i s noted.
Review of systems s eeks s ymptoms tha t ma y s ugges t a ca us e, s uch a s bi rth defects or chromos oma l a bnorma l i ti es (congeni ta l defects ); droopy
eyel i d, cough, ches t pa i n, or dys pnea (Horner's s yndrome); geni ta l l es i ons , a denopa thy, ra s hes , or fever (s yphi l i s ); a nd hea da ches or other
neurol ogi c s ymptoms (Horner's s yndrome or 3rd cra ni a l nerve pa l s y).
Past medical history i ncl udes known ocul a r di s orders a nd s urgeri es a nd expos ure to drugs .
[Table 60-3. Some Common Ca us es of Ani s ocori a ]
Physical examination: Pupi l l a ry s i ze a nd l i ght res pons es s houl d be exa mi ned i n l i ghted a nd da rk rooms . Accommoda ti on a nd extra ocul a r
movements s houl d be tes ted. Ocul a r s tructures a re i ns pected by us i ng a s l i t l a mp or other ma gni fi ca ti on to i denti fy s tructura l a bnorma l i ti es a nd
ptos i s . Other ocul a r s ymptoms a re eva l ua ted by eye exa mi na ti on a s cl i ni ca l l y i ndi ca ted. An ol d photogra ph of the pa ti ent or the pa ti ent's dri ver's
l i cens e s houl d be exa mi ned (under ma gni fi ca ti on i f pos s i bl e) to s ee whether a ni s ocori a wa s pres ent previ ous l y.
Testing: Tes ti ng i s us ua l l y unneces s a ry but i s i ndi ca ted for cl i ni ca l l y s us pected di s orders . Pa ti ents wi th Horner's s yndrome or 3rd cra ni a l nerve
pa l s y us ua l l y requi re bra i n MRI or CT.
Ptos i s
Anhi dros i s
Pupi l s tha t res pond more to a ccommoda ti on tha n l i ght
Impa i red extra ocul a r movements
Interpretation of findings: If the di fference i n s i ze i s grea ter i n the da rk, the s ma l l er pupi l i s a bnorma l . Common ca us es i ncl ude Horner's s yndrome
a nd phys i ol ogi c a ni s ocori a . An ophtha l mol ogi s t ca n di fferenti a te them beca us e the s ma l l pupi l i n Horner's s yndrome does not di l a te a fter
i ns ti l l a ti on of a n ocul a r di l a ti ng drop (eg, 10% coca i ne).
If the di fference i n pupi l l a ry s i zes i s grea ter i n l i ght, the l a rger pupi l i s a bnorma l . If extra ocul a r movements a re i mpa i red, pa rti cul a rl y wi th ptos i s ,
3rd cra ni a l nerve pa l s y i s l i kel y. If extra ocul a r movements a re i nta ct, a n ophtha l mol ogi s t ca n further di fferenti a te a mong ca us es by i ns ti l l i ng a
drop of a pupi l l a ry cons tri ctor (eg, 0.1% pi l oca rpi ne). If the l a rge pupi l cons tri cts , the ca us e i s proba bl y Adi e's toni c pupi l ; i f the l a rge pupi l does
not cons tri ct, the ca us e i s proba bl y drugs or s tructura l (eg, tra uma ti c, s urgi ca l ) da ma ge to the i ri s .
Treatment
Trea tment of a ni s ocori a i s unneces s a ry.
Key Points
Phys i ol ogi c a ni s ocori a i s very common a nd ca us es < 1 mm of di fference between the pupi l s i n s i ze.
Exa mi ni ng the pupi l s i n l i ght a nd da rk a nd i ns pecti ng a n ol d photogra ph or the dri ver's l i cens e of the pa ti ent provi de a grea t dea l of di a gnos ti c
i nforma ti on.
Seri ous di s orders s houl d be cons i dered i n pa ti ents wi th Horner's s yndrome or 3rd cra ni a l nerve pa l s y.
Blurred Vision
Bl urred vi s i on i s the mos t common vi s ua l s ymptom. It us ua l l y refers to decrea s ed vi s ua l a cui ty of gra dua l ons et. For s udden, compl ete l os s of
vi s i on i n one or both eyes (bl i ndnes s ), s ee p. 541. Pa ti ents wi th s ma l l vi s ua l fi el d defects (eg, ca us ed by a s ma l l reti na l deta chment) ma y des cri be
thei r s ymptoms a s bl urri ng.
Etiology
The mos t common ca us es of bl urred vi s i on (s ee
Ta bl e 60-4) i ncl ude
Refra cti ve errors (the mos t common ca us e overa l l )
Age-rel a ted ma cul a r degenera ti on
Ca ta ra cts
Di a beti c reti nopa thy
Gl a ucoma
Bl urred vi s i on ha s 4 genera l mecha ni s ms :
Opa ci fi ca ti on of norma l l y tra ns pa rent ocul a r s tructures (cornea , l ens , vi treous ) through whi ch l i ght ra ys mus t pa s s to rea ch the reti na
Di s orders a ffecti ng the reti na
Di s orders a ffecti ng the opti c nerve or i ts connecti ons
Refra cti ve errors
Certa i n di s orders ca n ha ve more tha n one mecha ni s m. For exa mpl e, refra cti on ca n be i mpa i red by ea rl y ca ta ra cts or the revers i bl e l ens s wel l i ng
ca us ed by poorl y control l ed di a betes .
Pa ti ents wi th certa i n di s orders tha t ca us e bl urred vi s i on (eg, a cute cornea l l es i ons [s uch a s a bra s i ons ], ul cers , herpes s i mpl ex kera ti ti s , herpes
zos ter ophtha l mi cus , a cute a ngl e-cl os ure gl a ucoma ) a re more l i kel y to pres ent wi th other s ymptoms s uch a s eye pa i n a nd red eye.
Ra re di s orders tha t ca n ca us e bl urred vi s i on i ncl ude heredi ta ry opti c neuropa thi es (eg, domi na nt opti c a trophy, Leber's heredi ta ry opti c
neuropa thy) a nd cornea l s ca rri ng due to vi ta mi n A defi ci ency or a mi oda rone toxi ci ty.
Evaluation
History: History of present illness s houl d a s certa i n the ons et, dura ti on, a nd progres s i on of s ymptoms , a s wel l a s whether they a re bi l a tera l or
uni l a tera l . The s ymptom s houl d be defi ned a s preci s el y a s pos s i bl e by a s ki ng a n open-ended ques ti on or reques t (eg, "Pl ea s e des cri be wha t you
mea n by bl urred vi s i on"). For exa mpl e, l os s of deta i l i s not the s a me a s l os s of contra s t. Al s o, vi s ua l fi el d defects ma y not be recogni zed a s s uch
by pa ti ents , who ma y i ns tea d des cri be s ymptoms s uch a s mi s s i ng s teps or the i na bi l i ty to s ee words when rea di ng. Importa nt a s s oci a ted
s ymptoms i ncl ude eye rednes s , photophobi a , fl oa ters , s ens a ti on of l i ghtni ng-l i ke fl a s hes of l i ght (photops i a s ), a nd pa i n a t res t or wi th eye
movement. The effects of da rknes s (ni ght vi s i on), bri ght l i ghts (i e, ca us i ng bl ur, s ta r burs ts , ha l os , photophobi a ), di s ta nce from a n object, a nd
correcti ve l ens es a nd whether centra l or peri phera l vi s i on s eems to be more a ffected s houl d be a s certa i ned.
Review of systems i ncl udes ques ti ons a bout s ymptoms of pos s i bl e ca us es , s uch a s i ncrea s ed thi rs t a nd pol yuri a (di a betes ).
Past medical history s houl d note previ ous eye i njury or other di a gnos ed eye di s orders a nd a s k a bout di s orders known to be ri s k fa ctors for eye
di s orders (eg, hypertens i on, di a betes , HIV/AIDS, SLE, s i ckl e cel l a nemi a , di s orders tha t coul d ca us e hypervi s cos i ty s yndrome s uch a s mul ti pl e
myel oma or Wa l dens trom's ma crogl obul i nemi a ). Drug hi s tory s houl d i ncl ude ques ti ons a bout us e of drugs tha t coul d a ffect vi s i on (eg,
a mi oda rone, corti cos teroi ds ) a nd trea tments for di s orders a ffecti ng vi s i on (eg, di a beti c reti nopa thy).
Physical examination: Nonvi s ua l s ymptoms a re eva l ua ted a s needed; however, exa mi na ti on of the eyes ma y be a l l tha t i s neces s a ry.
Tes ti ng visual acuity i s key. Ma ny pa ti ents do not gi ve a ful l effort. Provi di ng a dequa te ti me a nd coa xi ng pa ti ents tend to yi el d more a ccura te
res ul ts .
Acui ty i dea l l y i s mea s ured whi l e the pa ti ent s ta nds 6 m (a bout 20 ft) from a Snel l en cha rt pos ted on a wa l l . If thi s tes t ca nnot be done, a cui ty ca n
be mea s ured us i ng a cha rt hel d a bout 36 cm (14 i n) from the eye. Mea s urement of nea r vi s i on s houl d be done wi th rea di ng correcti on i n pl a ce for
pa ti ents > a ge 40. Ea ch eye i s mea s ured s epa ra tel y whi l e the other eye i s covered wi th a s ol i d object (not the pa ti ent's fi ngers , whi ch ma y
s epa ra te duri ng tes ti ng). If the pa ti ent ca nnot rea d the top l i ne of the Snel l en cha rt a t 6 m, a cui ty i s tes ted a t 3 m. If nothi ng ca n be rea d from a
cha rt even a t the cl os es t di s ta nce, the exa mi ner hol ds up di fferent numbers of fi ngers to s ee whether the pa ti ent ca n a ccura tel y count them. If not,
the exa mi ner tes ts whether the pa ti ent ca n percei ve ha nd moti on. If not, a l i ght i s s hi ned i nto the eye to s ee whether l i ght i s percei ved.
Vi s ua l a cui ty i s mea s ured wi th a nd wi thout the pa ti ents ' own gl a s s es . If a cui ty i s corrected
[Table 60-4. Some Ca us es of Bl urred Vi s i on]
wi th gl a s s es , the probl em i s a refra cti ve error. If pa ti ents do not ha ve thei r gl a s s es , a pi nhol e refra ctor i s us ed. If a commerci a l pi nhol e refra ctor
i s una va i l a bl e, one ca n be ma de a t the beds i de by poki ng hol es through a pi ece of ca rdboa rd us i ng a n 18-ga uge needl e a nd va ryi ng the di a meter
of ea ch hol e s l i ghtl y. Pa ti ents choos e the hol e tha t corrects vi s i on the mos t. If a cui ty corrects wi th pi nhol e refra cti on, the probl em i s a refra cti ve
error. Pi nhol e refra cti on i s a ra pi d, effi ci ent wa y to di a gnos e refra cti ve errors , whi ch a re the mos t common ca us e of bl urred vi s i on. However, wi th
pi nhol e refra cti on, bes t correcti on i s us ua l l y to onl y a bout 20/30, not 20/20.
Eye examination i s a l s o i mporta nt. Di rect a nd cons ens ua l pupi l l a ry l i ght res pons es a re exa mi ned us i ng the s wi ngi ng fl a s hl i ght tes t. Vi s ua l fi el ds
a re checked us i ng confronta ti on a nd a n Ams l er gri d.
The cornea i s exa mi ned for opa ci fi ca ti on, i dea l l y us i ng a s l i t l a mp. The a nteri or cha mber i s exa mi ned for cel l s a nd fl a re us i ng a s l i t l a mp i f
pos s i bl e, a l though res ul ts of thi s exa mi na ti on a re unl i kel y to expl a i n vi s ua l bl urri ng i n pa ti ents wi thout eye pa i n or rednes s .
The l ens i s exa mi ned for opa ci ti es us i ng a n ophtha l mos cope, s l i t l a mp, or both.
Ophtha l mos copy i s done us i ng a di rect ophtha l mos cope. More deta i l i s vi s i bl e i f the eyes a re di l a ted for ophtha l mos copy wi th a drop of a
s ympa thomi meti c (eg, 2.5% phenyl ephri ne), cycl opl egi c (eg, 1% tropi ca mi de or 1% cycl opentol a te), or both; di l a ti on i s nea rl y ful l a fter a bout 20
mi n. As much of the fundus a s i s vi s i bl e, i ncl udi ng the reti na , ma cul a , fovea , ves s el s , a nd opti c di s k a nd i ts ma rgi ns , i s exa mi ned. To s ee the
enti re fundus (i e, to s ee a peri phera l reti na l deta chment), the exa mi ner, us ua l l y a n ophtha l mol ogi s t, mus t us e a n i ndi rect ophtha l mos cope.
Intra ocul a r pres s ure i s mea s ured.
Sudden cha nge i n vi s i on
Eye pa i n (wi th or wi thout eye movement)
Vi s ua l fi el d defect (by hi s tory or exa mi na ti on)
Vi s i bl e a bnorma l i ty of the reti na or opti c di s k
HIV/AIDS or other i mmunos uppres s i ve di s order
A s ys temi c di s order tha t coul d ca us e reti nopa thy (eg, s i ckl e cel l a nemi a , pos s i bl e hypervi s cos i ty s yndrome, di a betes , hypertens i on)
Interpretation of findings: Symptoms a nd s i gns hel p s ugges t a ca us e (s ee Ta bl e 60-4).
If vi s ua l a cui ty i s corrected wi th gl a s s es or a pi nhol e refra ctor, s i mpl e refra cti ve error i s the ca us e of bl urri ng. Los s of contra s t or gl a re ma y s ti l l be
ca us ed by ca ta ra ct, whi ch s houl d be cons i dered.
However, red fl a g fi ndi ngs s ugges t a more s eri ous ophtha l mol ogi c di s order (s ee
Ta bl e 60-5) a nd need for a compl ete exa mi na ti on, i ncl udi ng s l i t-l a mp exa mi na ti on, tonometry, ophtha l mos copi c exa mi na ti on wi th pupi l l a ry
di l a ti on, a nd, dependi ng on fi ndi ngs , pos s i bl y i mmedi a te or urgent ophtha l mol ogi c referra l .
Speci fi c reti na l fi ndi ngs hel p s ugges t a ca us e (s ee
Ta bl e 60-6).
[Table 60-5. Interpreta ti on of Some Red Fl a g Fi ndi ngs ]
[Table 60-6. Interpreta ti on of Reti na l Fi ndi ngs ]
Testing: If a cui ty corrects a ppropri a tel y wi th refra cti on, pa ti ents a re referred to a n optometri s t or ophtha l mol ogi s t for routi ne forma l refra cti on. If
vi s ua l a cui ty i s not corrected wi th refra cti on but there a re no red fl a g fi ndi ngs , pa ti ents a re referred to a n ophtha l mol ogi s t for routi ne eva l ua ti on.
Wi th certa i n red fl a g fi ndi ngs , pa ti ents a re referred for i mmedi a te or urgent ophtha l mol ogi c eva l ua ti on.
Pa ti ents wi th s ymptoms or s i gns of s ys temi c di s orders s houl d ha ve a ppropri a te tes ti ng:
Di a betes : Fi ngers ti ck or ra ndom gl ucos e mea s urement
Poorl y control l ed hypertens i on a nd a cute hypertens i ve reti nopa thy (hemorrha ges , exuda tes , or pa pi l l edema ): Uri na l ys i s , rena l functi on tes ti ng,
BP moni tori ng, a nd pos s i bl y ECG
HIV/AIDS a nd reti na l a bnorma l i ti es : HIV s erol ogy a nd CD4+ count
SLE a nd reti na l a bnorma l i ty: Anti nucl ea r a nti bodi es , ESR, a nd CBC
Wa l dens trom's ma crogl obul i nemi a , mul ti pl e myel oma , or s i ckl e cel l a nemi a : CBC wi th di fferenti a l count a nd other tes ti ng (eg, s erum protei n
el ectrophores i s ) a s cl i ni ca l l y i ndi ca ted
Treatment
Underl yi ng di s orders a re trea ted. Correcti ve l ens es ma y be us ed to i mprove vi s ua l a cui ty, even when the di s order ca us i ng bl urri ng i s not purel y a
refra cti ve error (eg, ea rl y ca ta ra ct).
Al though s ome decrea s e i n vi s ua l a cui ty norma l l y occurs wi th a gi ng, a cui ty norma l l y i s correcta bl e to 20/20 wi th refra cti on, even i n very el derl y
pa ti ents .
Key Points
If vi s ua l a cui ty i s corrected wi th pi nhol e refra cti on, refra cti ve error i s the probl em.
Beca us e gl a ucoma i s common, i ntra ocul a r pres s ure s houl d be mea s ured.
If pi nhol e refra cti on does not correct a cui ty a nd there i s no obvi ous ca ta ra ct or cornea l a bnorma l i ty, ophtha l mos copy s houl d be done a fter
pupi l l a ry di l a ti on.
Ma ny a bnorma l i ti es on ophtha l mos copy, pa rti cul a rl y i f s ymptoms a re recentl y wors eni ng, requi re urgent or i mmedi a te ophtha l mol ogi c referra l .
Diplopia
(Doubl e Vi s i on)
Di pl opi a i s the percepti on of 2 i ma ges of a s i ngl e object. Di pl opi a ma y be monocul a r or bi nocul a r. Monocul a r di pl opi a i s pres ent when onl y one
eye i s open. Bi nocul a r di pl opi a di s a ppea rs when ei ther eye i s cl os ed.
Etiology
Monocular diplopia ca n occur when s omethi ng di s torts l i ght tra ns mi s s i on through the eye to the reti na . There ma y be > 2 i ma ges . One of the i ma ges
i s of norma l qua l i ty (eg, bri ghtnes s , contra s t, cl a ri ty); the res t a re of i nferi or qua l i ty. The mos t common ca us es of monocul a r di pl opi a a re
Ca ta ra ct
Cornea l s ha pe probl ems , s uch a s kera toconus or s urfa ce i rregul a ri ty
Uncorrected refra cti ve error, us ua l l y a s ti gma ti s m
Other ca us es i ncl ude cornea l s ca rri ng a nd di s l oca ted l ens . Compl a i nts a l s o ma y repres ent ma l i ngeri ng.
Binocular diplopia s ugges ts di s conjuga te a l i gnment of the eyes . There a re onl y 2 i ma ges , a nd they a re of equa l qua l i ty. There a re ma ny pos s i bl e
ca us es of bi nocul a r di pl opi a (s ee
Ta bl e 60-7). The mos t common a re
Cra ni a l nerve (3rd, 4th, or 6th) pa l s y
Mya s theni a gra vi s
Orbi ta l i nfi l tra ti on (eg, thyroi d i nfi l tra ti ve ophtha l mopa thy, orbi ta l ps eudotumor)
Mos t commonl y, the eyes a re mi s a l i gned beca us e of a di s order a ffecti ng the cra ni a l nerves i nnerva ti ng the extra ocul a r mus cl es (3rd, 4th, or 6th
cra ni a l nerves ). Thes e pa l s i es ma y be i s ol a ted a nd i di opa thi c or the res ul t of va ri ous di s orders i nvol vi ng the cra ni a l nerve nucl ei or the
i nfra nucl ea r nerve or nerves . Other ca us es i nvol ve mecha ni ca l i nterference wi th ocul a r moti on or a genera l i zed di s order of neuromus cul a r
tra ns mi s s i on.
Evaluation
History: History of present illness s houl d determi ne whether di pl opi a i nvol ves one or both eyes , whether di pl opi a i s i ntermi ttent or cons ta nt, a nd
whether the i ma ges a re s epa ra ted verti ca l l y, hori zonta l l y, or both. Any a s s oci a ted pa i n i s noted, a s wel l a s whether i t occurs wi th or wi thout eye
movement.
Review of systems s houl d s eek s ymptoms of other cra ni a l nerve dys functi on, s uch a s vi s i on a bnorma l i ti es (2nd cra ni a l nerve); numbnes s of
forehea d a nd cheek (5th cra ni a l nerve); fa ci a l wea knes s (7th cra ni a l nerve); di zzi nes s , hea ri ng l os s , or ga i t di ffi cul ti es (8th cra ni a l nerve); a nd
s wa l l owi ng or s peech di ffi cul ti es (9th a nd 12th cra ni a l nerves ). Other neurol ogi c s ymptoms , s uch a s wea knes s a nd s ens ory a bnorma l i ti es , s houl d
be s ought noti ng whether thes e a re i ntermi ttent or cons ta nt. Nonneurol ogi c s ymptoms of potenti a l ca us es a re a s certa i ned; they i ncl ude na us ea ,
vomi ti ng, a nd di a rrhea (botul i s m); pa l pi ta ti ons , hea t s ens i ti vi ty, a nd wei ght l os s (Gra ves ' di s ea s e); a nd di ffi cul ty wi th bl a dder control (mul ti pl e
s cl eros i s ).
Past medical history s houl d s eek pres ence of known hypertens i on, di a betes , or both; a theros cl eros i s , pa rti cul a rl y i ncl udi ng cerebrova s cul a r
di s ea s e; a nd a l cohol a bus e.
Physical examination: Exa mi na ti on begi ns wi th a revi ew of vi ta l s i gns for fever a nd genera l a ppea ra nce for s i gns of toxi ci ty (eg, pros tra ti on,
confus i on).
Eye exa mi na ti on begi ns wi th mea s uri ng vi s ua l a cui ty (wi th correcti on) i n ea ch eye a nd both together, whi ch a l s o hel ps determi ne whether
di pl opi a i s monocul a r or bi nocul a r. Eye exa mi na ti on s houl d note pres ence of bul gi ng of one or both eyes , eyel i d droop, pupi l l a ry a bnorma l i ti es ,
a nd di s conjuga te eye movement a nd nys ta gmus duri ng ocul a r moti l i ty tes ti ng. Ophtha l mos copy s houl d be done, pa rti cul a rl y noti ng a ny
a bnorma l i ti es of the l ens (eg, ca ta ra ct, di s pl a cement) a nd reti na (eg, deta chment).
Ocul a r moti l i ty i s tes ted by ha vi ng the pa ti ent hol d the hea d s tea dy a nd tra ck the exa mi ner's fi nger, whi ch i s moved to extreme ga ze to the ri ght,
l eft, upwa rd, downwa rd, di a gona l l y to ei ther s i de, a nd fi na l l y i nwa rd towa rd the pa ti ent's nos e (convergence). However, mi l d pa res i s of ocul a r
moti l i ty s uffi ci ent to ca us e di pl opi a ma y es ca pe detecti on by s uch exa mi na ti on.
If di pl opi a occurs i n one di recti on of ga ze, the eye tha t produces ea ch i ma ge ca n be determi ned by repea ti ng the exa mi na ti on wi th a red gl a s s
pl a ced over one of the pa ti ent's eyes . The i ma ge tha t i s more peri phera l ori gi na tes i n the pa reti c eye; i e, i f the more peri phera l i ma ge i s red, the
red gl a s s i s coveri ng the pa reti c eye. If a red gl a s s i s not a va i l a bl e, the pa reti c eye ca n s ometi mes be i denti fi ed by ha vi ng the pa ti ent cl os e ea ch
eye. The pa reti c eye i s the eye tha t when cl os ed el i mi na tes the more peri phera l i ma ge.
The other cra ni a l nerves a re tes ted, a nd the rema i nder of the neurol ogi c exa mi na ti on, i ncl udi ng s trength, s ens a ti on, refl exes , cerebel l a r functi on,
a nd obs erva ti on of ga i t, i s compl eted.
Rel eva nt nonneurophtha l mol ogi c components of the exa mi na ti on i ncl ude pa l pa ti on of the neck for goi ter a nd i ns pecti on of the s hi ns for preti bi a l
myxedema (Gra ves ' di s ea s e).
More tha n one cra ni a l nerve defi ci t
Pupi l l a ry i nvol vement of a ny degree
Any neurol ogi c s ymptoms or s i gns bes i des di pl opi a
Pa i n
Proptos i s
Interpretation of findings: Fi ndi ngs s ometi mes s ugges t whi ch nerve i s i nvol ved.
Nerve III: Eyel i d droop, eye devi a ted l a tera l l y a nd down, s ometi mes pupi l l a ry di l a ti on
[Table 60-7. Some Ca us es of Bi nocul a r Di pl opi a ]
Nerve IV: Verti ca l di pl opi a wors e on downwa rd ga ze (pa ti ent ti l ts hea d to i mprove vi s i on)
Nerve VI: Eye devi a ted medi a l l y, di pl opi a wors e on l a tera l ga ze (pa ti ent turns hea d to i mprove vi s i on)
Other fi ndi ngs hel p s ugges t a ca us e (s ee Ta bl e 60-7).

Intermi ttent di pl opi a s ugges ts a wa xi ng a nd wa ni ng neurol ogi c di s order, s uch a s mya s theni a gra vi s or mul ti pl e s cl eros i s , or unma s ki ng of a l a tent
phori a (eye devi a ti on). Pa ti ents wi th l a tent phori a do not ha ve a ny other neurol ogi c ma ni fes ta ti ons .
Internucl ea r ophtha l mopl egi a (INO) res ul ts from a bra i n s tem l es i on i n the medi a l l ongi tudi na l fa s ci cul us (MLF). INO ma ni fes ts on hori zonta l
ga ze tes ti ng wi th di pl opi a , wea k a dducti on on the a ffected s i de (us ua l l y ca nnot a dduct eye pa s t mi dl i ne), a nd nys ta gmus of the contra l a tera l eye.
However, the a ffected eye a dducts norma l l y on convergence tes ti ng (whi ch does not requi re a n i nta ct MLF).
Pa i n s ugges ts a compres s i ve l es i on or i nfl a mma tory di s order.
Testing: Pa ti ents wi th monocul a r di pl opi a a re referred to a n ophtha l mol ogi s t to eva l ua te for ocul a r pa thol ogy; no other tes ts a re requi red
beforeha nd.
For bi nocul a r di pl opi a , pa ti ents wi th a uni l a tera l , s i ngl e cra ni a l nerve pa l s y, a norma l pupi l l a ry l i ght res pons e, a nd no other s ymptoms or s i gns
ca n us ua l l y be obs erved wi thout tes ti ng for a few weeks . Ma ny ca s es res ol ve s ponta neous l y. Ophtha l mol ogi c eva l ua ti on ma y be done to moni tor
the pa ti ent a nd hel p further del i nea te the defi ci t.
Mos t other pa ti ents requi re neuroi ma gi ng wi th MRI to detect orbi ta l , cra ni a l , or CNS a bnorma l i ti es . CT ma y be s ubs ti tuted i f there i s concern a bout
a meta l l i c i ntra ocul a r forei gn body or i f MRI i s otherwi s e contra i ndi ca ted or una va i l a bl e. Ima gi ng s houl d be done i mmedi a tel y i f fi ndi ngs s ugges t
i nfecti on, a neurys m, or a cute (< 3 h) s troke.
Pa ti ents wi th ma ni fes ta ti ons of Gra ves ' di s ea s e s houl d ha ve thyroi d tes ts (s erum thyroxi ne [T4 ] a nd thyroi d-s ti mul a ti ng hormone [TSH] l evel s ).
Tes ti ng for mya s theni a gra vi s a nd mul ti pl e s cl eros i s s houl d be s trongl y cons i dered for thos e wi th i ntermi ttent di pl opi a .
Treatment
Trea tment i s ma na gement of the underl yi ng di s order.
Key Points
Is ol a ted, pupi l -s pa ri ng nerve pa l s y i n pa ti ents wi th no other s ymptoms ma y res ol ve s ponta neous l y.
Ima gi ng i s requi red for thos e wi th red fl a g fi ndi ngs .
Foca l wea knes s (i n a ny mus cl e) ma y i ndi ca te a di s order of neuromus cul a r tra ns mi s s i on.
Eyelid Swelling
Eyel i d s wel l i ng ca n be uni l a tera l or bi l a tera l . It ma y be a s ymptoma ti c or a ccompa ni ed by i tchi ng or pa i n.
Etiology
Eyel i d s wel l i ng ha s ma ny ca us es (s ee
Ta bl e 60-8). It us ua l l y res ul ts from a n eyel i d di s order but ma y res ul t from di s orders i n a nd a round the orbi t or from s ys temi c di s orders tha t ca us e
genera l i zed edema .
The mos t common ca us es a re a l l ergi c, i ncl udi ng
Loca l a l l ergy (conta ct s ens i ti vi ty)
Sys temi c a l l ergy (eg, a ngi oedema , s ys temi c a l l ergy a ccompa nyi ng a l l ergi c rhi ni ti s )
Foca l s wel l i ng of one eyel i d i s mos t often ca us ed by a cha l a zi on.
The mos t i mmedi a tel y da ngerous ca us es a re orbi ta l cel l ul i ti s a nd ca vernous s i nus thrombos i s (ra re).
[Table 60-8. Some Ca us es of Eyel i d Swel l i ng]
In a ddi ti on to the di s orders l i s ted i n Ta bl e 60-8, eyel i d s wel l i ng ma y res ul t from the fol l owi ng:
Di s orders tha t ma y i nvol ve the eyel i d but do not ca us e s wel l i ng unl es s very a dva nced (eg, eyel i d tumors , i ncl udi ng s qua mous cel l ca rci noma s
a nd mel a noma )
Di s orders (eg, da cryocys ti ti s , ca na l i cul i ti s ) tha t ca us e s wel l i ng tha t begi ns a nd i s us ua l l y mos t s evere i n s tructures nea r, but not pa rt of, the
eyel i ds
Di s orders i n whi ch s wel l i ng occurs but i s not the pres enti ng s ymptom (eg, ba s i l a r s kul l fra cture, burns , tra uma , pos ts urgery)
Evaluation
History: History of present illness s houl d a s certa i n how l ong s wel l i ng ha s been pres ent, whether i t i s uni l a tera l or bi l a tera l , a nd whether i t ha s been
preceded by a ny tra uma (i ncl udi ng i ns ect bi tes ). Importa nt a ccompa nyi ng s ymptoms to i denti fy i ncl ude i tchi ng, pa i n, hea da che, cha nge i n vi s i on,
fever, a nd eye di s cha rge.

Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng runny nos e, i tchi ng, ra s h, a nd wheezi ng (s ys temi c a l l ergi c rea cti on);
hea da che, na s a l conges ti on, a nd purul ent na s a l di s cha rge (s i nus i ti s ); tootha che (denta l i nfecti on); dys pnea , orthopnea , a nd pa roxys ma l
nocturna l dys pnea (hea rt fa i l ure); col d i ntol era nce a nd cha nges i n s ki n texture (hypothyroi di s m); a nd hea t i ntol era nce, a nxi ety, a nd wei ght l os s
(hyperthyroi di s m).
Past medical history s houl d i ncl ude recent eye i njury or s urgery; known hea rt, l i ver, rena l , or thyroi d di s ea s e; a nd a l l ergi es a nd expos ure to pos s i bl e
a l l ergens . Drug hi s tory s houl d s peci fi ca l l y i ncl ude us e of ACE i nhi bi tors .
Physical examination: Vi ta l s i gns s houl d be a s s es s ed for fever a nd ta chyca rdi a .
Eye i ns pecti on s houl d a s s es s the l oca ti on a nd col or of s wel l i ng (erythema tous or pa l e), i ncl udi ng whether i t i s pres ent on one eyel i d, both
eyel i ds , or both eyes a nd whether i t i s tender, wa rm, or both. The exa mi ner s houl d obs erve whether the fi ndi ng repres ents edema of the eyel i ds ,
protrus i on of the gl obe (proptos i s ), or both. Eye exa mi na ti on s houl d pa rti cul a rl y note vi s ua l a cui ty a nd ra nge of extra ocul a r moti on (ful l or
l i mi ted). Thi s exa mi na ti on ca n be di ffi cul t when s wel l i ng i s ma rked but i s i mporta nt beca us e defi ci ts s ugges t a n orbi ta l or retro-orbi ta l di s order
ra ther tha n a n eyel i d di s order; a n a s s i s ta nt ma y be requi red to hol d the eyel i ds open. Conjuncti va e a re exa mi ned for i njecti on a nd di s cha rge. Any
eyel i d or eye l es i ons a re eva l ua ted us i ng a s l i t l a mp.
Genera l exa mi na ti on s houl d a s s es s s i gns of toxi ci ty, s ugges ti ng a s eri ous i nfecti on, a nd s i gns of a ca us a ti ve di s order. Fa ci a l s ki n i s i ns pected for
drynes s a nd s ca l es (whi ch ma y s ugges t hypothyroi di s m) a nd grea s y s ca l es or other s i gns of s eborrhei c derma ti ti s . Extremi ti es a nd the pres a cra l
a rea a re exa mi ned for edema , whi ch s ugges ts a s ys temi c ca us e. If a s ys temi c ca us e i s s us pected, s ee p. 2031 for further di s cus s i on of the
eva l ua ti on.
Fever
Los s of vi s ua l a cui ty
Impa i red extra ocul a r movements
Proptos i s
Interpretation of findings: Some fi ndi ngs hel p di s ti ngui s h a mong ca tegori es of di s orders . The fi rs t i mporta nt di s ti ncti on i s between i nfl a mma ti on or
i nfecti on a nd a l l ergy or fl ui d overl oa d. Pa i n, rednes s , wa rmth, a nd tendernes s s ugges t i nfl a mma ti on or i nfecti on. Pa i nl es s , pa l e s wel l i ng s ugges ts
a ngi oedema . Itchi ng s ugges ts a l l ergi c rea cti on, a nd a bs ence of i tchi ng s ugges ts ca rdi a c or rena l dys functi on.
Swel l i ng l oca l i zed to one eyel i d i n the a bs ence of other s i gns i s ra rel y ca us ed by a da ngerous di s order. Ma s s i ve s wel l i ng of the eyel i ds of one or
both eyes s houl d ra i s e s us pi ci on of a s eri ous probl em. Si gns of i nfl a mma ti on, proptos i s , l os s of vi s i on, a nd i mpa i red extra ocul a r movements
s ugges t a n orbi ta l di s order (eg, orbi ta l cel l ul i ti s , ca vernous s i nus thrombos i s ) tha t ma y be pus hi ng the gl obe forwa rd or a ffecti ng the nerves or
mus cl es . Other s ugges ti ve a nd s peci fi c fi ndi ngs a re l i s ted i n Ta bl e 60-8.
Testing: In mos t ca s es , di a gnos i s ca n be es ta bl i s hed cl i ni ca l l y a nd no tes ti ng i s neces s a ry. If orbi ta l cel l ul i ti s or ca vernous s i nus thrombos i s i s
s us pected, di a gnos i s a nd trea tment s houl d proceed a s ra pi dl y a s pos s i bl e. Immedi a te i ma gi ng wi th CT or MRI s houl d be done. If ca rdi a c, l i ver,
rena l , or thyroi d dys functi on i s s us pected, orga n functi on i s eva l ua ted wi th l a bora tory tes ts a nd i ma gi ng a s a ppropri a te for tha t s ys tem.
Treatment
Trea tment i s di rected a t the underl yi ng di s order. There i s no s peci fi c trea tment for the s wel l i ng.
Key Points
Proptos i s wi th i mpa i red vi s i on or extra ocul a r movements s ugges ts orbi ta l cel l ul i ti s or ca vernous s i nus thrombos i s , a nd di a gnos i s a nd trea tment
s houl d proceed a s ra pi dl y a s pos s i bl e.
Eyel i d di s orders s houl d be di fferenti a ted from orbi ta l a nd s ys temi c ca us es of s wel l i ng.
Eye Pain
Eye pa i n ma y be des cri bed a s s ha rp, a chi ng, or throbbi ng a nd s houl d be di s ti ngui s hed from s uperfi ci a l i rri ta ti on or a forei gn body s ens a ti on. In
s ome di s orders , pa i n i s wors ened by bri ght l i ght. Eye pa i n ma y be ca us ed by a s eri ous di s order a nd requi res prompt eva l ua ti on. Ma ny ca us es of
eye pa i n a l s o ca us e a red eye.
Pathophysiology
The cornea i s ri chl y i nnerva ted a nd hi ghl y s ens i ti ve to pa i n. Ma ny di s orders tha t a ffect the cornea or a nteri or cha mber (eg, uvei ti s ) a l s o ca us e pa i n
vi a ci l i a ry mus cl e s pa s m; when s uch s pa s m i s pres ent, bri ght l i ght ca us es mus cl e contra cti on, wors eni ng pa i n.
Etiology
Di s orders tha t ca us e eye pa i n ca n be di vi ded i nto thos e tha t a ffect pri ma ri l y the cornea , other ocul a r di s orders , a nd di s orders tha t ca us e pa i n
referred to the eye (s ee
Ta bl e 60-9).
The mos t common ca us es overa l l a re

Cornea l a bra s i on
Forei gn bodi es
However, mos t cornea l di s orders ca n ca us e eye pa i n.
A feel i ng of s cra tchi nes s or of a forei gn body ma y be ca us ed by ei ther a conjuncti va l or a cornea l di s order.
Evaluation
History: History of present illness s houl d a ddres s the ons et, qua l i ty, a nd s everi ty of pa i n a nd a ny hi s tory of pri or epi s odes (eg, da i l y epi s odes i n
cl us ters ). Importa nt a s s oci a ted s ymptoms i ncl ude true photophobi a (s hi ni ng a l i ght i nto the una ffected eye ca us es pa i n i n the a ffected eye when
the a ffected eye i s s hut), decrea s ed vi s ua l a cui ty, forei gn body s ens a ti on a nd pa i n when bl i nki ng, a nd pa i n when movi ng the eye.
Review of systems s houl d s eek s ymptoms s ugges ti ng a ca us e, i ncl udi ng pres ence of a n a ura (mi gra i ne); fever a nd chi l l s (i nfecti on); a nd pa i n when
movi ng the hea d, purul ent rhi norrhea , producti ve or nocturna l cough, a nd ha l i tos i s (s i nus i ti s ).
Past medical history s houl d i ncl ude known di s orders tha t a re ri s k fa ctors for eye pa i n, i ncl udi ng a utoi mmune di s orders , mul ti pl e s cl eros i s ,
mi gra i ne, a nd s i nus i nfecti ons . Addi ti ona l ri s k fa ctors to a s s es s i ncl ude us e (a nd overus e) of conta ct l ens es (conta ct l ens kera ti ti s ), expos ure to
exces s i ve s unl i ght or to wel di ng (UV kera ti ti s ), ha mmeri ng or dri l l i ng meta l (forei gn body), a nd recent eye i njury or s urgery (endophtha l mi ti s ).
Physical examination: Vi ta l s i gns a re checked for the pres ence of fever. The nos e i s i ns pected for purul ent rhi norrhea , a nd the fa ce i s pa l pa ted for
tendernes s . If the eye i s red, the prea uri cul a r regi on i s checked for a denopa thy. Hygi ene duri ng exa mi na ti on mus t be s crupul ous when exa mi ni ng
pa ti ents who ha ve chemos i s , prea uri cul a r a denopa thy, puncta te cornea l s ta i ni ng, or a combi na ti on; thes e fi ndi ngs s ugges t epi demi c
kera toconjuncti vi ti s , whi ch i s hi ghl y conta gi ous .
Eye exa mi na ti on s houl d be a s compl ete a s pos s i bl e for pa ti ents wi th eye pa i n. Bes t corrected vi s ua l a cui ty i s checked. Vi s ua l fi el ds a re typi ca l l y
tes ted by confronta ti on i n pa ti ents wi th eye pa i n, but thi s tes t ca n be i ns ens i ti ve (pa rti cul a rl y for s ma l l defects ) a nd unrel i a bl e beca us e of poor
pa ti ent coopera ti on. A l i ght i s moved from one eye to the other to check for pupi l l a ry s i ze a nd di rect a nd cons ens ua l pupi l l a ry l i ght res pons es . In
pa ti ents who ha ve uni l a tera l eye pa i n, a l i ght i s s hi ned i n the una ffected eye whi l e the a ffected eye i s s hut; pa i n i n the a ffected eye repres ents
true photophobi a . Extra ocul a r movements a re checked. The orbi ta l a nd peri orbi ta l s tructures a re i ns pected. Conjuncti va l i njecti on tha t s eems mos t
i ntens e a nd confl uent a round the cornea a nd l i mbus i s ca l l ed ci l i a ry fl us h.
Sl i t-l a mp exa mi na ti on i s done i f pos s i bl e. The cornea i s s ta i ned wi th fl uores cei n a nd exa mi ned under ma gni fi ca ti on wi th coba l t bl ue l i ght. If a
s l i t l a mp i s una va i l a bl e, the cornea ca n be exa mi ned a fter fl uores cei n s ta i ni ng wi th a Wood's l i ght us i ng ma gni fi ca ti on. Ophtha l mos copy i s done,
a nd ocul a r pres s ures a re mea s ured (tonometry). In pa ti ents wi th a forei gn body s ens a ti on or unexpl a i ned cornea l a bra s i ons , the eyel i ds a re
everted a nd exa mi ned for forei gn bodi es .
Vomi ti ng, ha l os a round l i ghts , or cornea l edema
Si gns of s ys temi c i nfecti on (eg, fever, chi l l s )
Decrea s ed vi s ua l a cui ty
Proptos i s
Impa i red extra ocul a r moti l i ty
Interpretation of findings: Sugges ti ve fi ndi ngs a re l i s ted i n Ta bl e 60-9. Some fi ndi ngs s ugges t ca tegori es of di s orders .
Scra tchi nes s or a forei gn body s ens a ti on i s mos t often ca us ed by di s orders of the eyel i ds , conjuncti va e, or s uperfi ci a l cornea . Photos ens i ti vi ty i s
pos s i bl e.
Surfa ce pa i n wi th photophobi a i s often a ccompa ni ed by a forei gn body s ens a ti on a nd pa i n when bl i nki ng; i t s ugges ts a cornea l l es i on, mos t often
a forei gn body or a bra s i on.
Deeper pa i noften des cri bed a s a chi ng or throbbi ngus ua l l y i ndi ca tes a s eri ous di s order s uch a s gl a ucoma , uvei ti s , s cl eri ti s , endophtha l mi ti s ,
orbi ta l cel l ul i ti s , or orbi ta l ps eudotumor. Wi thi n thi s group, eyel i d s wel l i ng, proptos i s , or both a nd i mpa i red extra ocul a r movements or vi s ua l
a cui ty s ugges t orbi ta l ps eudotumor, orbi ta l cel l ul i ti s , or pos s i bl y s evere endophtha l mi ti s . Fever, chi l l s , a nd tendernes s s ugges t i nfecti on (eg,
orbi ta l cel l ul i ti s , s i nus i ti s ).
A red eye s ugges ts tha t the di s order ca us i ng pa i n i s ocul a r ra ther tha n referred.
If pa i n devel ops i n the a ffected eye i n res pons e to s hi ni ng l i ght i n the una ffected eye when the a ffected eye i s s hut (true photophobi a ), the ca us e
i s mos t often a cornea l l es i on or uvei ti s .
If topi ca l a nes theti c drops (eg, propa ra ca i ne) a bol i s h pa i n i n a red eye, the ca us e i s proba bl y a cornea l di s order.
Some fi ndi ngs a re more s ugges ti ve of pa rti cul a r di s orders . Pa i n a nd photophobi a da ys a fter bl unt eye tra uma s ugges t uvei ti s . Ha mmeri ng or
dri l l i ng meta l i s a ri s k fa ctor for occul t meta l i ntra ocul a r forei gn body. Pa i n wi th movement of extra ocul a r mus cl es a nd l os s of pupi l l a ry l i ght
res pons e tha t i s di s proporti ona te to l os s of vi s ua l a cui ty s ugges t opti c neuri ti s .
Testing: Tes ti ng i s not us ua l l y neces s a ry, wi th s ome excepti ons (s ee Ta bl e 60-9). Goni os copy i s done i f gl a ucoma i s s us pected ba s ed on i ncrea s ed
i ntra ocul a r pres s ure. Ima gi ng, us ua l l y wi th CT or MRI, i s done i f orbi ta l ps eudotumor or orbi ta l cel l ul i ti s i s s us pected or i f s i nus i ti s i s s us pected
but the di a gnos i s i s not cl i ni ca l l y cl ea r. MRI i s often done when opti c neuri ti s i s s us pected, l ooki ng for demyel i na ti ng l es i ons i n the bra i n
s ugges ti ng mul ti pl e s cl eros i s .
Intra ocul a r fl ui ds (vi treous a nd a queous humor) ma y be cul tured for s us pected endophtha l mi ti s . Vi ra l cul tures ca n be us ed to confi rm herpes
zos ter ophtha l mi cus or herpes
[Table 60-9. Some Ca us es of Eye Pa i n]
s i mpl ex kera ti ti s i f the di a gnos i s i s not cl ea r cl i ni ca l l y.
Treatment
The ca us e of pa i n i s trea ted. Pa i n i ts el f i s a l s o trea ted. Sys temi c a na l ges i cs a re us ed a s needed. Pa i n ca us ed by uvei ti s a nd ma ny cornea l l es i ons
i s a l s o rel i eved wi th cycl opl egi c eye drops (eg, homa tropi ne 5% qi d).
Key Points
Mos t di a gnos es ca n be ma de by cl i ni ca l eva l ua ti on.
Infecti on preca uti ons s houl d be ma i nta i ned when exa mi ni ng pa ti ents wi th bi l a tera l red eyes .
Importa nt da nger s i gns a re vomi ti ng, ha l os a round l i ghts , fever, decrea s ed vi s ua l a cui ty, proptos i s , a nd i mpa i red extra ocul a r moti l i ty.
Pa i n i n the a ffected eye i n res pons e to s hi ni ng l i ght i n the una ffected eye when the a ffected eye i s s hut (true photophobi a ) s ugges ts a cornea l
l es i on or uvei ti s .
If a topi ca l a nes theti c (eg, propa ra ca i ne) rel i eves pa i n, the ca us e of pa i n i s a cornea l l es i on.
Ha mmeri ng or dri l l i ng on meta l i s a ri s k fa ctor for occul t i ntra ocul a r forei gn body.
Proptosis
(Exophtha l mos )
Proptos i s i s protrus i on of the eyeba l l . Exophtha l mos mea ns the s a me thi ng, a nd thi s term i s us ua l l y us ed when des cri bi ng proptos i s due to
Gra ve's di s ea s e. Di s orders tha t ma y ca us e cha nges i n the a ppea ra nce of the fa ce a nd eyes tha t res embl e proptos i s but a re not i ncl ude
hyperthyroi di s m wi thout i nfi l tra ti ve eye di s ea s e, Cus hi ng's di s ea s e, a nd s evere obes i ty.
Etiology
The most common cause i s Gra ves ' di s ea s e (s ee
Ta bl e 60-10), whi ch ca us es edema a nd l ymphoi d i nfi l tra ti on of the orbi ta l ti s s ues .
Evaluation
Ra te of ons et ma y provi de a cl ue to di a gnos i s . Sudden uni l a tera l ons et s ugges ts i ntra orbi ta l hemorrha ge (whi ch ca n occur a fter s urgery,
retrobul ba r i njecti on, or tra uma ) or i nfl a mma ti on of the orbi t or pa ra na s a l s i nus es . A 2- to 3-wk ons et s ugges ts chroni c i nfl a mma ti on or orbi ta l
i nfl a mma tory ps eudotumor (non-neopl a s ti c cel l ul a r i nfi l tra ti on a nd prol i fera ti on); s l ower ons et s ugges ts a n orbi ta l tumor.
Ocul a r exa mi na ti on fi ndi ngs typi ca l of hyperthyroi di s m but unrel a ted to i nfi l tra ti ve eye di s ea s e i ncl ude eyel i d retra cti on, eyel i d l a g, tempora l
fl a re of the upper eyel i d, a nd s ta ri ng. Other s i gns i ncl ude eyel i d erythema a nd conjuncti va l hyperemi a . Prol onged expos ure of l a rger-tha n-us ua l
a rea s of the eyeba l l to a i r ca us es cornea l dryi ng a nd ca n l ea d to i nfecti on a nd ul cera ti on.
Testing: Proptos i s ca n be confi rmed wi th exophtha l mometry, whi ch mea s ures the di s ta nce between the l a tera l a ngl e of the bony orbi t a nd the
cornea ; norma l va l ues a re < 20 mm i n whi tes a nd < 22 mm i n bl a cks . CT or MRI i s often us eful to confi rm the di a gnos i s a nd to i denti fy s tructura l
ca us es of uni l a tera l proptos i s . Thyroi d functi on tes ti ng i s i ndi ca ted when Gra ves ' di s ea s e i s s us pected.
[Table 60-10. Some Ca us es of Proptos i s ]
Treatment
Lubri ca ti on to protect the cornea i s requi red i n s evere ca s es . When l ubri ca ti on i s not s uffi ci ent, s urgery to provi de better covera ge of the eye
s urfa ce or to reduce proptos i s ma y be requi red. Sys temi c corti cos teroi ds (eg, predni s one 1 mg/kg po once/da y for 1 wk, ta pered over 1 mo) a re
often hel pful i n control l i ng edema a nd orbi ta l conges ti on due to thyroi d eye di s ea s e or i nfl a mma tory orbi ta l ps eudotumor. Other i nterventi ons
va ry by eti ol ogy. Gra ves ' exophtha l mos i s not a ffected by trea tment of the thyroi d condi ti on but ma y l es s en over ti me. Tumors mus t be s urgi ca l l y
removed. Sel ecti ve embol i za ti on or, ra rel y, tra ppi ng procedures ma y be effecti ve i n ca s es of a rteri ovenous fi s tul a s i nvol vi ng the ca vernous s i nus .
Floaters
Fl oa ters a re opa ci ti es tha t move a cros s the vi s ua l fi el d a nd do not corres pond to externa l vi s ua l objects .
Pathophysiology
Wi th a gi ng, the vi treous humor ca n contra ct a nd s epa ra te from the reti na . The a ge a t whi ch thi s cha nge occurs va ri es but mos t often i s between 50
a nd 75 yr. Duri ng thi s s epa ra ti on, the vi treous ca n i ntermi ttentl y tug on the reti na . The mecha ni ca l tra cti on s ti mul a tes the reti na , whi ch s ends a
s i gna l tha t i s percei ved by the bra i n a nd i nterpreted a s l i ght. Compl ete s epa ra ti on of the vi treous l ea ds to a n i ncrea s e i n fl oa ters , whi ch ma y l a s t
for yea rs .
However, tra cti on on the reti na ma y crea te a hol e (reti na l tea r), a nd i f fl ui d l ea ks behi nd the tea r, the reti na ma y deta ch. Reti na l deta chment ma y
a l s o be ca us ed by other fa ctors (eg, tra uma , pri ma ry reti na l di s orders ). Li ghtni ng-l i ke fl a s hes , common i n reti na l deta chment, a re ca l l ed photopsias.
Photops i a s ca n a l s o occur when rubbi ng the eyes or when l ooki ng a round a fter a wa keni ng.
Etiology
The mos t common ca us e of vi treous fl oa ters i s
Contra cti on of the vi treous humor tha t occurs for unknown rea s ons (i di opa thi c)
Les s common ca us es a re l i s ted i n
Ta bl e 60-11.
Ra re ca us es of fl oa ters i ncl ude i ntra ocul a r tumors (eg, l ymphoma ). Intra ocul a r forei gn bodi es ca n ca us e fl oa ters but us ua l l y ma ni fes t wi th other
s ymptoms , s uch a s l os s of vi s i on, eye pa i n, or rednes s .
Evaluation
The mos t i mporta nt goa l i s to i denti fy s eri ous vi treous a nd reti na l di s orders . If thes e di s orders ca nnot be rul ed out, pa ti ents s houl d be exa mi ned
by a n ophtha l mol ogi s t us i ng a n i ndi rect ophtha l mos cope a fter pupi l l a ry di l a ti on. Recogni zi ng ocul a r mi gra i ne i s a l s o hel pful .
History: History of present illness s houl d a s certa i n ons et a nd dura ti on of s ymptoms a nd the s ha pe a nd vol ume of fl oa ters , a s wel l a s whether they
a re uni l a tera l or bi l a tera l a nd whether they ha ve been preceded by tra uma . The pa ti ent s houl d try to di s ti ngui s h fl oa ters from l i ghtni ng-l i ke
fl a s hes of l i ght (a s i n photops i a s ) or ja gged l i nes a cros s the vi s ua l fi el d (a s i n mi gra i ne). Importa nt a s s oci a ted s ymptoms i ncl ude l os s of vi s i on
(a nd i ts di s tri buti on i n the vi s ua l fi el d) a nd eye pa i n.
Review of systems s houl d s eek s ymptoms of pos s i bl e ca us es , s uch a s hea da ches (ocul a r mi gra i ne) a nd eye rednes s (vi treous i nfl a mma ti on).
Past medical history s houl d note di a betes (i ncl udi ng di a beti c reti nopa thy), mi gra i ne hea da ches , eye s urgery, s evere myopi a , a nd a ny di s orders tha t
coul d a ffect the i mmune s ys tem (eg, AIDS).
Physical examination: Eye exa mi na ti on s houl d be rea s ona bl y compl ete. Bes t corrected vi s ua l a cui ty i s mea s ured. The eyes a re i ns pected for
rednes s . Vi s ua l fi el ds a re a s s es s ed i n a l l pa ti ents . However, recogni ti on of vi s ua l fi el d defects by beds i de exa mi na ti on i s very i ns ens i ti ve, s o
i na bi l i ty to s how s uch a defect i s not evi dence tha t the pa ti ent ha s ful l vi s ua l fi el ds . Extra ocul a r movements a nd pupi l l a ry l i ght res pons es a re
a s s es s ed. If pa ti ents ha ve a red eye or eye pa i n, the cornea s a re exa mi ned under ma gni fi ca ti on a fter fl uores cei n s ta i ni ng, a nd s l i t-l a mp
exa mi na ti on i s done i f pos s i bl e. Ocul a r pres s ure i s mea s ured (tonometry).
Ophtha l mos copy i s the mos t i mporta nt pa rt of the exa mi na ti on. It i s done us i ng a di rect ophtha l mos cope a nd a fter di l a ti ng the pupi l s . To di l a te
the pupi l s , the phys i ci a n fi rs t ma kes s ure to record pupi l l a ry s i ze a nd l i ght res pons es , then i ns ti l l s drops , us ua l l y 1 drop ea ch of a s hort-a cti ng a drenergi c a goni s t (eg, 2.5% phenyl ephri ne) a nd a cycl opl egi c (eg, 1% tropi ca mi de or 1% cycl opentol a te). The pupi l s a re ful l y di l a ted a bout 20 mi n
a fter thes e drops a re i ns ti l l ed.
[Table 60-11. Some Ca us es of Fl oa ters ]
Sudden i ncrea s e i n fl oa ters
Li ghtni ng-l i ke fl a s hes (photops i a s )
Los s of vi s i on, di ffus e or foca l (vi s ua l fi el d defect)
Recent eye s urgery or eye tra uma
Eye pa i n
Los s of red refl ex
Abnorma l reti na l fi ndi ngs
Interpretation of findings: Reti na l deta chment i s s ugges ted by s udden i ncrea s es i n fl oa ters , photops i a s , or a ny of i ts other, more s peci fi c
cha ra cteri s ti cs (eg, vi s ua l fi el d defects , reti na l a bnorma l i ti es ). Bi l a tera l s ynchronous s ymptoms s ugges t ocul a r mi gra i ne, a l though pa ti ents often
ha ve di ffi cul ty deci pheri ng the l a tera l i ty of thei r s ymptoms (eg, they often i nterpret s ci nti l l a ti ng s cotoma of the l eft fi el d of both eyes a s l efteyed). Los s of red refl ex s ugges ts opa ci fi ca ti on of the vi treous (eg, vi treous hemorrha ge or i nfl a mma ti on), but i t a l s o ca n be ca us ed by a dva nced
ca ta ra cts . Los s of vi s i on s ugges ts a s eri ous di s order ca us i ng dys functi on of the vi treous or reti na .
Testing: Pa ti ents who requi re eva l ua ti on by a n ophtha l mol ogi s t ma y need tes ti ng. However, tes ts ca n be s el ected by or i n conjuncti on wi th the
ophtha l mol ogi s t. For exa mpl e, pa ti ents s us pected of ha vi ng chori oreti ni ti s ma y requi re mi crobi ol ogi c tes ti ng.
Treatment
Idi opa thi c vi treous fl oa ters requi re no trea tment. Other di s orders ca us i ng s ymptoms a re trea ted.
Key Points
Fl oa ters by thems el ves ra rel y i ndi ca te a s eri ous di s order.
Pa ti ents wi th a ny a bnorma l fi ndi ngs on exa mi na ti on requi re ophtha l mol ogi c referra l .
If fl oa ters a re a ccompa ni ed by a ny other s ymptoms (eg, pers i s tent fl a s hi ng l i ghts , vi s ua l defi ci t, s ens a ti on of a movi ng curta i n of vi s i on l os s ),
pa ti ents requi re ophtha l mol ogi c referra l , rega rdl es s of exa mi na ti on fi ndi ngs .
Red Eye
(Pi nk Eye)
Red eye refers to a red a ppea ra nce of the opened eye, refl ecti ng di l a ti on of the s uperfi ci a l ocul a r ves s el s .
Pathophysiology
Di l a ti on of s uperfi ci a l ocul a r ves s el s ca n res ul t from
Infecti on
Al l ergy
Infl a mma ti on (noni nfecti ous )
El eva ted i ntra ocul a r pres s ure
Severa l ocul a r components ma y be i nvol ved, mos t commonl y the conjuncti va , but a l s o the uvea l tra ct, epi s cl era , a nd s cl era .
Etiology
The mos t common ca us es of red eye i ncl ude
Infecti ous conjuncti vi ti s
Al l ergi c conjuncti vi ti s
Cornea l a bra s i ons a nd forei gn bodi es a re common ca us es (s ee
Ta bl e 60-12). Al though the eye i s red, pa ti ents us ua l l y pres ent wi th a compl a i nt of i njury, eye pa i n, or both. However, i n young chi l dren a nd i nfa nts ,
thi s i nforma ti on ma y be una va i l a bl e.
Evaluation
Mos t di s orders ca n be di a gnos ed by a genera l hea l th ca re pra cti ti oner.
History: History of present illness s houl d note the ons et a nd dura ti on of rednes s a nd pres ence of a ny cha nge i n vi s i on, i tchi ng, s cra tchy s ens a ti on,
pa i n, or di s cha rge. Na ture a nd s everi ty of pa i n, i ncl udi ng whether pa i n i s wors ened by l i ght (photophobi a ), a re noted. The cl i ni ci a n s houl d
determi ne whether di s cha rge i s wa tery or purul ent. Other ques ti ons a s s es s hi s tory of i njury, i ncl udi ng expos ure to i rri ta nts a nd us e of conta ct
l ens es (eg, pos s i bl e overus e, s uch a s wea ri ng them whi l e s l eepi ng). Pri or epi s odes of eye pa i n or rednes s a nd thei r ti me pa tterns a re el i ci ted.
Review of systems s houl d s eek s ymptoms s ugges ti ng pos s i bl e ca us es , i ncl udi ng hea da che, na us ea , vomi ti ng, a nd ha l os a round l i ghts (a cute
a ngl e-cl os ure gl a ucoma ); runny nos e a nd s neezi ng (a l l ergi es , URI); a nd cough, s ore throa t, a nd ma l a i s e (URI).
Past medical history i ncl udes ques ti ons a bout known a l l ergi es a nd a utoi mmune di s orders . Drug hi s tory s houl d s peci fi ca l l y a s k a bout recent us e of
topi ca l ophtha l mi c drugs (i ncl udi ng OTC drugs ), whi ch mi ght be s ens i ti zi ng.
Physical examination: Genera l exa mi na ti on s houl d i ncl ude hea d a nd neck exa mi na ti on for s i gns of a s s oci a ted di s orders (eg, URI, a l l ergi c rhi ni ti s ,
zos ter ra s h).
Eye exa mi na ti on i nvol ves a forma l mea s ure of vi s ua l a cui ty a nd us ua l l y requi res a penl i ght, fl uores cei n s ta i n, a nd s l i t l a mp.
Bes t corrected vi s ua l a cui ty i s mea s ured. Pupi l l a ry s i ze a nd rea cti vi ty to l i ght a re a s s es s ed. True photophobi a (s ometi mes ca l l ed
[Table 60-12. Some Ca us es of Red Eye]
cons ens ua l photophobi a ) i s pres ent i f s hi ni ng l i ght i nto a n una ffected eye ca us es pa i n i n the a ffected eye when the a ffected eye i s s hut.
Extra ocul a r movements a re a s s es s ed, a nd the eye a nd peri orbi ta l ti s s ues a re i ns pected for l es i ons a nd s wel l i ng. The ta rs a l s urfa ce i s i ns pected
for fol l i cl es . The cornea s a re s ta i ned wi th fl uores cei n a nd exa mi ned wi th ma gni fi ca ti on. If a cornea l a bra s i on i s found, the eyel i d i s everted a nd
exa mi ned for hi dden forei gn bodi es . Ins pecti on of the ocul a r s tructures a nd cornea i s bes t done us i ng a s l i t l a mp. A s l i t l a mp i s a l s o us ed to
exa mi ne the a nteri or cha mber for cel l s , fl a re, a nd pus (hypopyon). Ocul a r pres s ure i s mea s ured us i ng tonometry, a l though i t ma y be permi s s i bl e
to omi t thi s tes t i f there a re no s ymptoms or s i gns s ugges ti ng a di s order other tha n conjuncti vi ti s .
Sudden, s evere pa i n a nd vomi ti ng
Zos ter s ki n ra s h
Decrea s ed vi s ua l a cui ty
Cornea l cra ter
Bra nchi ng, dendri ti c cornea l l es i on
Ocul a r pres s ure > 40 mm Hg
Fa i l ure to bl a nch wi th phenyl ephri ne eye drop
Interpretation of findings: Conjunctival disorders a nd episcleritis a re di fferenti a ted from other ca us es of red eye by the a bs ence of pa i n, photophobi a ,
a nd cornea l s ta i ni ng. Among thes e di s orders , epi s cl eri ti s i s di fferenti a ted by i ts foca l i ty, a nd s ubconjuncti va l hemorrha ge i s us ua l l y
di fferenti a ted by the a bs ence of l a cri ma ti on, i tchi ng, a nd photos ens i ti vi ty. Cl i ni ca l cri teri a do not a ccura tel y di fferenti a te vi ra l from ba cteri a l
conjuncti vi ti s .
Corneal disorders a re di fferenti a ted from other ca us es of red eye (a nd us ua l l y from ea ch other) by fl uores cei n s ta i ni ng. Thes e di s orders a l s o tend to
be cha ra cteri zed by pa i n a nd photophobi a . If i ns ti l l a ti on of a n ocul a r a nes theti c drop (eg, propa ra ca i ne 0.5%), whi ch i s done before tonometry a nd
i dea l l y before fl uores cei n i ns ti l l a ti on, compl etel y rel i eves pa i n, the ca us e i s proba bl y l i mi ted to the cornea . If pa i n i s pres ent a nd i s not rel i eved
by a n ocul a r a nes theti c, the ca us e ma y be a nteri or uvei ti s , gl a ucoma , or s cl eri ti s . Beca us e pa ti ents ma y ha ve a nteri or uvei ti s s econda ry to cornea l
l es i ons , pers i s tence of pa i n a fter i ns ti l l a ti on of the a nes theti c does not excl ude a cornea l l es i on.
Anterior uveitis, glaucoma, acute angle-closure glaucoma, a nd scleritis ca n us ua l l y be di fferenti a ted from other ca us es of red eye by the pres ence of
pa i n a nd the a bs ence of cornea l s ta i ni ng. Anteri or uvei ti s i s l i kel y i n pa ti ents wi th pa i n, true photophobi a , a bs ence of cornea l fl uores cei n
s ta i ni ng, a nd norma l i ntra ocul a r pres s ure; i t i s defi ni ti vel y di a gnos ed ba s ed on the pres ence of cel l s a nd fl a re i n the a nteri or cha mber. However,
thes e fi ndi ngs ma y be di ffi cul t for genera l hea l th ca re pra cti ti oners to di s cern. Acute a ngl e-cl os ure gl a ucoma ca n us ua l l y be recogni zed by the
s udden ons et of i ts s evere a nd cha ra cteri s ti c s ymptoms , but tonometry i s defi ni ti ve.
Ins ti l l a ti on of phenyl ephri ne 2.5% ca us es bl a nchi ng i n a red eye unl es s the ca us e i s s cl eri ti s . Phenyl ephri ne i s i ns ti l l ed to di l a te the pupi l i n
pa ti ents needi ng a thorough reti na l exa mi na ti on. However, i t s houl d not be us ed i n pa ti ents who ha ve the fol l owi ng:
Sus pected a cute a ngl e-cl os ure gl a ucoma
A hi s tory of a ngl e-cl os ure gl a ucoma
A na rrow a nteri or cha mber
Testing: Tes ti ng i s us ua l l y unneces s a ry. Vi ra l cul tures ma y hel p i f herpes s i mpl ex or herpes zos ter i s s us pected a nd the di a gnos i s i s not cl ea r
cl i ni ca l l y. Cornea l ul cers a re cul tured by a n ophtha l mol ogi s t. Goni os copy i s done i n pa ti ents wi th gl a ucoma . Tes ti ng for a utoi mmune di s orders
ma y be worthwhi l e i n pa ti ents wi th uvei ti s a nd no obvi ous ca us e (eg, tra uma ). Pa ti ents wi th s cl eri ti s undergo further tes ti ng a s di rected by a n
ophtha l mol ogi s t.
Treatment
The ca us e i s trea ted. Red eye i ts el f does not requi re trea tment. Topi ca l va s ocons tri ctors a re not recommended.
Key Points
Mos t ca s es a re ca us ed by conjuncti vi ti s .
Pa i n a nd true photophobi a s ugges t other, more s eri ous di a gnos es .
In pa ti ents wi th pa i n, s l i t-l a mp exa mi na ti on wi th fl uores cei n s ta i ni ng a nd tonometry a re key.
Pers i s tence of pa i n des pi te a n ocul a r a nes theti c i n a pa ti ent wi th a norma l fl uores cei n exa mi na ti on s ugges ts a nteri or uvei ti s , s cl eri ti s , or a cute
a ngl e-cl os ure gl a ucoma . Thes e di a gnos es s houl d not be mi s s ed.
Tearing
(Epi phora )
Exces s tea ri ng ma y ca us e a s ens a ti on of wa tery eyes or res ul t i n tea rs fa l l i ng down the cheek (epi phora ).
Pathophysiology
Tea rs a re produced i n the l a cri ma l gl a nd a nd dra i n through the upper a nd l ower puncta i nto the ca na l i cul i a nd then i nto the l a cri ma l s a c a nd
na s ol a cri ma l duct (s ee
Fi g. 60-3). Obs tructi on of tea r dra i na ge ca n l ea d to s ta s i s a nd i nfecti on. Recurrent i nfecti on of the l a cri ma l s a c (da cryocys ti ti s ) ca n s ometi mes
s prea d, potenti a l l y l ea di ng to orbi ta l cel l ul i ti s .
Etiology
Overa l l , the mos t common ca us es of tea ri ng a re
URI
Al l ergi c rhi ni ti s
Tea ri ng ca n be ca us ed by i ncrea s ed tea r producti on or decrea s ed na s ol a cri ma l dra i na ge.
Increased tear production: The mos t common ca us es a re
URI
Al l ergi c rhi ni ti s
Al l ergi c conjuncti vi ti s
Dry eyes (refl ex tea ri ng produced i n res pons e to drynes s of the ocul a r s urfa ce)
Tri chi a s i s
Any di s order ca us i ng conjuncti va l or cornea l i rri ta ti on ca n i ncrea s e tea r producti on (s ee
Ta bl e 60-13). However, mos t pa ti ents wi th cornea l di s orders tha t ca us e exces s tea ri ng (eg, cornea l a bra s i on, cornea l ul cer, cornea l forei gn body,
kera ti ti s ) or wi th pri ma ry a ngl e-cl os ure gl a ucoma or a nteri or uvei ti s pres ent wi th eye s ymptoms other tha n tea ri ng (eg, eye pa i n, rednes s ). Mos t
peopl e who ha ve been cryi ng do not pres ent for eva l ua ti on of tea ri ng.
Decreased nasolacrimal drainage: The mos t common ca us es a re
Idi opa thi c a ge-rel a ted na s ol a cri ma l duct s tenos i s
Da cryocys ti ti s
Ectropi on
[Fig. 60-3. Ana tomy of the l a cri ma l s ys tem.]
Na s ol a cri ma l dra i na ge s ys tem obs tructi on ma y be ca us ed by s tri ctures , tumors , or forei gn bodi es (eg, s tones , often a s s oci a ted wi th s ubcl i ni ca l
i nfecti on by Actinomyces). Obs tructi on ca n a l s o be a congeni ta l ma l forma ti on. Ma ny di s orders a nd drugs ca n ca us e s tri cture or obs tructi on of
na s ol a cri ma l dra i na ge.
Other ca us es of na s ol a cri ma l dra i na ge s tri cture or obs tructi on i ncl ude
Burns
Chemothera py drugs
Eye drops (pa rti cul a rl y echothi opha te i odi de, epi nephri ne, a nd pi l oca rpi ne)
Infecti on, i ncl udi ng ca na l i cul i ti s (eg, ca us ed by Staphylococcus aureus, Actinomyces, Streptococcus, Pseudomonas, herpes zos ter vi rus , herpes s i mpl ex
conjuncti vi ti s , i nfecti ous mononucl eos i s , huma n pa pi l l oma vi rus , Ascaris, l epros y, TB)
Infl a mma tory di s orders (s a rcoi dos i s , Wegener's gra nul oma tos i s )
Injuri es (eg, na s oethmoi d fra ctures ; na s a l , orbi ta l , or endos copi c s i nus s urgery)
Obs tructi on of na s a l outl et des pi te a n i nta ct na s ol a cri ma l s ys tem (eg, URI, a l l ergi c rhi ni ti s , s i nus i ti s )
Ra di a ti on thera py
Stevens -Johns on s yndrome
Tumors (eg, pri ma ry l a cri ma l s a c tumors , beni gn pa pi l l oma s , s qua mous a nd ba s a l cel l ca rci noma , tra ns i ti ona l cel l ca rci noma , fi brous
hi s ti ocytoma s , mi dl i ne gra nul oma , l ymphoma )
Evaluation
History: History of present illness a ddres s es the dura ti on, ons et, a nd s everi ty of s ymptoms , i ncl udi ng whether tea rs dri p down the cheek (true
epi phora ). The effects of wea ther, envi ronmenta l humi di ty, a nd ci ga rette s moke a re a s certa i ned.
Review of symptoms s houl d s eek s ymptoms of pos s i bl e ca us es , i ncl udi ng i tchi ng, rhi norrhea , or s neezi ng, pa rti cul a rl y when occurri ng perenni a l l y
or a fter expos ure to s peci fi c potenti a l a l l ergens (a l l ergi c rea cti on); eye i rri ta ti on or pa i n (bl epha ri ti s , cornea l a bra s i on, i rri ta nt chemi ca l s ); a nd
pa i n nea r the medi a l ca nthus (da cryocys ti ti s ). Other s ymptoms a re of l ower yi el d but s houl d be s ought; they i ncl ude pos i ti ona l hea da che,
purul ent rhi norrhea , nocturna l cough, a nd fever (s i nus i ti s , Wegener's gra nul oma tos i s ); ra s h (Stevens -Johns on s yndrome); cough, dys pnea , a nd
ches t pa i n (s a rcoi dos i s ); a nd epi s ta xi s , hemoptys i s , pol ya rthra l gi a s , a nd mya l gi a s (Wegener's gra nul oma tos i s ).
Past medical history a s ks a bout known di s orders tha t ca n ca us e tea ri ng, i ncl udi ng Wegener's gra nul oma tos i s , s a rcoi dos i s , a nd
[Table 60-13. Some Ca us es of Tea ri ng]
ca ncer trea ted wi th chemothera py drugs ; di s orders tha t ca us e dry eyes (eg, RA, s a rcoi dos i s , Sjogren's s yndrome); a nd drugs , s uch a s echothi opha te,
epi nephri ne, a nd pi l oca rpi ne. Previ ous ocul a r a nd na s a l hi s tory, i ncl udi ng i nfecti ons , i njuri es , s urgi ca l procedures , a nd ra di a ti on expos ure, i s
a s certa i ned.
Physical examination: Exa mi na ti on focus es on the eye a nd s urroundi ng s tructures .
The fa ce i s i ns pected; a s ymmetry s ugges ts congeni ta l or a cqui red obs tructi on of na s ol a cri ma l duct dra i na ge. When a va i l a bl e, a s l i t l a mp s houl d
be us ed to exa mi ne the eyes . The conjuncti va e a nd cornea s a re i ns pected for l es i ons , i ncl udi ng puncta te s pots , a nd rednes s . The cornea i s
s ta i ned wi th fl uores cei n a nd exa mi ned. The l i ds a re everted to detect hi dden forei gn bodi es . The eyel i ds , i ncl udi ng the l a cri ma l puncta , a re
cl os el y i ns pected for forei gn bodi es , bl epha ri ti s , hordeol a , ectropi on, entropi on, a nd tri chi a s i s . The l a cri ma l s a c (nea r the medi a l ca nthus ) i s
pa l pa ted for wa rmth, tendernes s , a nd s wel l i ng. Any s wel l i ngs a re pa l pa ted for cons i s tency a nd to s ee whether pus i s expres s ed.
The nos e i s exa mi ned for conges ti on, purul ence, a nd bl eedi ng.
Repea ted, unexpl a i ned epi s odes of tea ri ng
Ha rd ma s s i n or nea r the na s ol a cri ma l dra i na ge s tructures
Interpretation of findings: Fi ndi ngs tha t s ugges t obs tructi on of na s ol a cri ma l dra i na ge i ncl ude
Tea rs runni ng down the cheek (true epi phora )
Abs ence of s i gns of a s peci fi c ca us e
A ca us e i s often evi dent from the cl i ni ca l eva l ua ti on (s ee
Ta bl e 60-14).
[Table 60-14. Fi ndi ngs tha t Sugges t the Ca us e of Na s ol a cri ma l Obs tructi on]
Testing: Tes ti ng i s often unneces s a ry beca us e the ca us e i s us ua l l y evi dent from the exa mi na ti on.
Schi rmer's tes t wi th a l a rge a mount of wetti ng (eg, > 25 mm) s ugges ts a n eva pora ti ve dry eye a s the eti ol ogy of tea ri ng. Schi rmer's tes t wi th very
l i ttl e wetti ng (< 5.5 mm) s ugges ts a n a queous tea rdefi ci ent dry eye. Us ua l l y, Schi rmer's tes t i s done by a n ophtha l mol ogi s t to ens ure i t i s done a nd
i nterpreted correctl y.
Probi ng a nd s a l i ne i rri ga ti on of the l a cri ma l dra i na ge s ys tem ca n hel p detect a na tomi c obs tructi on of dra i na ge, a s wel l a s s tenos i s due to
compl ete obs tructi on of the na s ol a cri ma l dra i na ge s ys tem. Irri ga ti on i s done wi th a nd wi thout fl uores cei n dye. Refl ux through the oppos i te
punctum or ca na l i cul us s i gna l s fi xed obs tructi on; refl ux a nd na s a l dra i na ge s i gni fy s tenos i s . Thi s tes t i s cons i dered a djuncti ve a nd i s done by
ophtha l mol ogi s ts .
Ima gi ng tes ts a nd procedures (da cryocys togra phy, CT, na s a l endos copy) a re s ometi mes us eful to del i nea te a bnorma l a na tomy when s urgery i s
bei ng cons i dered or occa s i ona l l y to detect a n a bs ces s .
Treatment
Underl yi ng di s orders (eg, a l l ergi es , forei gn bodi es , conjuncti vi ti s ) a re trea ted.
The us e of a rti fi ci a l tea rs l es s ens tea ri ng when dry eyes or cornea l epi thel i a l defects a re the ca us e.
Congeni ta l na s ol a cri ma l duct obs tructi on often res ol ves s ponta neous l y. In pa ti ents < 1 yr, ma nua l compres s i on of the l a cri ma l s a c 4 or 5
ti mes /da y ma y rel i eve the di s ta l obs tructi on. After 1 yr, the na s ol a cri ma l duct ma y need probi ng wi th the pa ti ent under genera l a nes thes i a . If
obs tructi on i s recurrent, a tempora ry dra i na ge tube ma y be i ns erted.
In a cqui red na s ol a cri ma l duct obs tructi on, i rri ga ti on of the na s ol a cri ma l duct ma y be thera peuti c when underl yi ng di s orders do not res pond to
trea tment. As a l a s t res ort, a pa s s a ge between the l a cri ma l s a c a nd the na s a l ca vi ty ca n be crea ted s urgi ca l l y (da cryocys torhi nos tomy).
In ca s es of puncta l or ca na l i cul a r s tenos i s , di l a ti on i s us ua l l y cura ti ve. If ca na l i cul a r s tenos i s i s s evere a nd bothers ome, a s urgi ca l procedure tha t
pl a ces a gl a s s tube l ea di ng from the ca runcl e i nto the na s a l ca vi ty ca n be cons i dered.
Idi opa thi c a ge-rel a ted na s ol a cri ma l duct s tenos i s i s the mos t common ca us e of unexpl a i ned epi phora i n el derl y pa ti ents ; however, tumors
s houl d a l s o be cons i dered.
Key Points
If tea rs do not run down the cheek, dry eyes i s often the ca us e.
If tea rs run down the cheek, obs tructi on of na s ol a cri ma l dra i na ge i s l i kel y.
Tes ti ng i s often unneces s a ry but i s needed i n ca s es of recurrent i nfecti ous da cryocys ti ti s , whi ch ca n progres s to more s eri ous condi ti ons s uch a s
orbi ta l cel l ul i ti s .
Other Eye Symptoms
Dry eyes a re di s cus s ed under Kera toconjuncti vi ti s s i cca (s ee p. 592) The di s order i s mos t often i di opa thi c or a s s oci a ted wi th ol der a ge but ca n a l s o
be ca us ed by connecti ve ti s s ue di s ea s es (eg, Sjogren's s yndrome, RA, SLE).
Eye discharge: Di s cha rge i s often a ccompa ni ed by a red eye (s ee p. 563) a nd commonl y i s ca us ed by a l l ergi c or i nfecti ous conjuncti vi ti s , bl epha ri ti s ,
a nd, i n i nfa nts , ophtha l mi a neona torum (neona ta l conjuncti vi ti s ). Infecti ous di s cha rge ma y be purul ent i n ba cteri a l i nfecti on, s uch a s
s ta phyl ococca l conjuncti vi ti s or gonorrhea . Les s common ca us es i ncl ude da cryocys ti ti s a nd ca na l i cul i ti s .
Di a gnos i s i s us ua l l y ma de cl i ni ca l l y. Al l ergi c conjuncti vi ti s ca n often be di s ti ngui s hed from i nfecti ous by predomi na nce of i tchi ng, cl ea r di s cha rge,
a nd pres ence of other a l l ergi c s ymptoms (eg, runny nos e, s neezi ng). Cl i ni ca l di fferenti a ti on between vi ra l a nd ba cteri a l conjuncti vi ti s i s di ffi cul t.
Cul tures a re not us ua l l y done, but a re i ndi ca ted for pa ti ents wi th the fol l owi ng:
Cl i ni ca l l y s us pected gonococca l or chl a mydi a l conjuncti vi ti s
Severe s ymptoms
Immunocompromi s e
A vul nera bl e eye (eg, a fter a cornea l tra ns pl a nt, i n exophtha l mos due to Gra ves ' di s ea s e)
Ineffecti ve i ni ti a l thera py
Halos: Ha l os a round l i ght ma y res ul t from ca ta ra cts ; condi ti ons tha t res ul t i n cornea l edema , s uch a s a cute a ngl e-cl os ure gl a ucoma or di s orders
tha t ca us e bul l ous kera topa thy; cornea l ha zi nes s ; mucus on the cornea ; or drugs , s uch a s di goxi n or chl oroqui ne.
Blue hues: Certa i n condi ti ons ma y ca us e a bl ue ti nt to the vi s ua l fi el d (cya nops i a ). Cya nops i a ma y occur for a few da ys a fter ca ta ra ct remova l or a s
a n a dvers e effect of s i l dena fi l a nd pos s i bl y other phos phodi es tera s e-5 (PDE5) i nhi bi tors .
Scotomata: Scotoma ta a re vi s ua l fi el d defi ci ts a nd a re di vi ded i nto
Nega ti ve s cotoma ta (bl i nd s pots )
Pos i ti ve s cotoma ta (l i ght s pots or s ci nti l l a ti ng fl a s hes )
Nega ti ve s cotoma ta ma y not be noti ced by pa ti ents unl es s they i nvol ve centra l vi s i on a nd i nterfere s i gni fi ca ntl y wi th vi s ua l a cui ty; the compl a i nt
i s mos t often decrea s ed vi s ua l a cui ty (s ee p. 541). Nega ti ve s cotoma ta ha ve mul ti pl e ca us es tha t ca n s ometi mes be di s ti ngui s hed by the s peci fi c
type of fi el d defi ci t (s ee Ta bl e 60-1) a s i denti fi ed by us e of a ta ngent s creen, Gol dma nn peri meter, or computeri zed a utoma ted peri metry (i n whi ch
the vi s ua l fi el d i s ma pped out i n deta i l ba s ed on pa ti ent res pons e to a s eri es of fl a s hi ng l i ghts i n di fferent l oca ti ons control l ed by a
s ta nda rdi zed computer progra m).
Pos i ti ve s cotoma ta repres ent a res pons e to a bnorma l s ti mul a ti on of s ome porti on of the vi s ua l s ys tem, a s occurs i n mi gra i nes .
Chapter 61. Refractive Error

Introduction
In the emmetropi c (norma l l y refra cted) eye, enteri ng l i ght ra ys a re focus ed on the reti na by the cornea a nd the l ens , crea ti ng a s ha rp i ma ge tha t i s
tra ns mi tted to the bra i n. The l ens i s el a s ti c, more s o i n younger peopl e. Duri ng a ccommoda ti on, the ci l i a ry mus cl es a djus t l ens s ha pe to properl y
focus i ma ges . Refra cti ve errors a re fa i l ure of the eye to focus i ma ges s ha rpl y on the reti na , ca us i ng bl urred vi s i on (s ee
Fi g. 61-1).
In myopia (nea rs i ghtednes s ), the poi nt of focus i s i n front of the reti na beca us e the cornea i s too s teepl y curved, the a xi a l l ength of the eye i s too
l ong, or both. Di s ta nt objects a re bl urred, but nea r objects ca n be s een cl ea rl y. To correct myopi a , a conca ve (mi nus ) l ens i s us ed. Myopi c refra cti ve
errors i n chi l dren frequentl y i ncrea s e unti l the chi l d s tops growi ng.
In hyperopia (fa rs i ghtednes s ), the poi nt of focus i s behi nd the reti na beca us e the cornea i s too fl a tl y curved, the a xi a l l ength i s too s hort, or both.
In a dul ts , both nea r a nd di s ta nt objects a re bl urred. Chi l dren a nd young a dul ts wi th mi l d hyperopi a ma y be a bl e to s ee cl ea rl y beca us e of thei r
a bi l i ty to a ccommoda te. To correct hyperopi a , a convex (pl us ) l ens i s us ed.
[Fig. 61-1. Errors of refra cti on.]
In astigmatism, nons pheri ca l (va ri a bl e) curva ture of the cornea or l ens ca us es l i ght ra ys of di fferent ori enta ti ons (eg, verti ca l , obl i que, hori zonta l )
to focus a t di fferent poi nts . To correct a s ti gma ti s m, a cyl i ndri c l ens (a s egment cut from a cyl i nder) i s us ed. Cyl i ndri c l ens es ha ve no refra cti ve
power a l ong one a xi s a nd a re conca ve or convex a l ong the other a xi s .
Presbyopia i s l os s of the l ens ' a bi l i ty to cha nge s ha pe to focus on nea r objects due to a gi ng. Typi ca l l y, pres byopi a becomes noti cea bl e by the ti me
a pers on rea ches the ea rl y or mi d 40s . A convex (pl us ) l ens i s us ed for correcti on when vi ewi ng nea r objects . Thes e l ens es ma y be s uppl i ed a s
s epa ra te gl a s s es or bui l t i nto a l ens a s bi foca l s or va ri a bl e focus l ens es .
Anisometropia i s a s i gni fi ca nt di fference between the refra cti ve errors of the 2 eyes (us ua l l y > 3 di opters ). When corrected wi th eyegl a s s es , a
di fference i n i ma ge s i ze (a ni s ei koni a ) i s produced; i t ca n l ea d to di ffi cul ti es wi th fus i on of the 2 di fferentl y s i zed i ma ges a nd even to s uppres s i on
of one of the i ma ges .
Symptoms and Signs
The pri ma ry s ymptom of refra cti ve errors i s bl urred vi s i on for di s ta nt objects , nea r objects , or both. Someti mes the exces s i ve ci l i a ry mus cl e tone
ca n ca us e hea da ches . Occa s i ona l l y, exces s i ve s ta ri ng ca n l ea d to ocul a r s urfa ce des i cca ti on, ca us i ng eye i rri ta ti on, i tchi ng, vi s ua l fa ti gue, forei gn
body s ens a ti on, a nd rednes s . Frowni ng when rea di ng a nd exces s i ve bl i nki ng or rubbi ng of the eyes a re s ymptoms i n chi l dren.
Diagnosis
Refra cti on s houl d be checked every 1 or 2 yr. Screeni ng chi l dren hel ps detect refra cti ve errors before they i nterfere wi th l ea rni ng. A comprehens i ve
eye exa mi na ti on (s ee p. 537) s houl d a ccompa ny refra cti on tes ti ng, whether done by a n ophtha l mol ogi s t or a n optometri s t.
Contact Lenses
Conta ct l ens es often provi de better vi s ua l a cui ty a nd peri phera l vi s i on tha n do eyegl a s s es a nd ca n be pres cri bed to correct myopi a , hyperopi a ,
a s ti gma ti s m, a ni s ometropi a , a ni s ei koni a , a pha ki a (a bs ence of the l ens ) a fter ca ta ra ct remova l , a nd kera toconus (a coni ca l -s ha ped cornea ). Ei ther
s oft or ri gi d l ens es a re us ed to correct myopi a a nd hyperopi a . Tori c s oft conta ct l ens es (whi ch ha ve di fferent curva tures mol ded onto the front l ens
s urfa ce) or ri gi d l ens es a re us ed to correct s i gni fi ca nt a s ti gma ti s m; they a re s a ti s fa ctory i n ma ny ca s es but requi re expert fi tti ng.
Pres byopi a ca n a l s o be corrected wi th conta ct l ens es . In one a pproa ch, termed monovi s i on, the nondomi na nt eye i s corrected for rea di ng a nd the
domi na nt eye i s corrected for di s ta nt vi s i on. Ri gi d a nd s oft bi foca l a nd mul ti foca l conta ct l ens es ca n a l s o be s ucces s ful , but the fi tti ng procedure
i s ti me-cons umi ng beca us e preci s e a l i gnment i s es s enti a l .
Nei ther ri gi d nor s oft conta ct l ens es offer the eyes the protecti on a ga i ns t bl unt or s ha rp i njury tha t eyegl a s s es do.
Care and Complications
Ins tructi ons for hygi ene a nd ha ndl i ng l ens es mus t be s tri ctl y obs erved. Poor conta ct l ens hygi ene ma y l ea d to pers i s tent i nfl a mma ti on or i nfecti on
of the cornea .
Conta ct l ens es occa s i ona l l y ca us e pa i nl es s s uperfi ci a l cornea l cha nges . Conta ct l ens es ca n be pa i nful when
The cornea l epi thel i um i s a bra ded (s ee p. 3236); the cornea becomes red a nd i nfl a med a nd s ta i ns wi th fl uores cei n.
The l ens es fi t poorl y (eg, too ti ght, too l oos e, poorl y centered).
There i s too l i ttl e moi s ture to keep the l ens fl oa ti ng a bove the cornea .
The l ens es a re worn i n a noni dea l envi ronment (eg, O2 -poor, s moky, wi ndy).
A l ens i s i mproperl y i ns erted or removed.
A s ma l l forei gn pa rti cl e (eg, s oot, dus t) becomes tra pped between the l ens a nd the cornea .
The l ens es a re worn for a l ong ti me (overwea r s yndrome).
In overwea r s yndrome, s ponta neous hea l i ng ma y occur i n a da y or s o i f l ens es a re not worn. In s ome ca s es , a cti ve trea tment i s requi redeg,
topi ca l a nti bi oti c eyedrops or oi ntments a nd di l a ti on of the pupi l wi th a mydri a ti c to ea s e photophobi a . (Mydri a ti cs work by pa ra l yzi ng the
mus cl es of the i ri s a nd ci l i a ry body [movement of the i nfl a med mus cl es ca us es pa i n].) Recovery i s us ua l l y ra pi d, compl ete, a nd wi thout vi s i on
i mpa i rment. An ophtha l mol ogi s t s houl d be cons ul ted before l ens es a re worn a ga i n.
Ri s k fa ctors for conta ct l ens -rel a ted cornea l i nfecti on (kera ti ti s ) i ncl ude the fol l owi ng:
Poor l ens hygi ene
Overni ght or extended wea r
Us e of ta p wa ter i n the cl ea ni ng regi men
Eyes wi th a compromi s ed ocul a r s urfa ce (eg, drynes s , poor cornea l s ens a ti on)
Infecti ons requi re ra pi d ma na gement by a n ophtha l mol ogi s t.
Corneal ulcer: A cornea l ul cer, whi ch i s a potenti a l l y vi s i on-threa teni ng i nfecti on of the cornea , i s s us pected when a conta ct l ens wea rer
experi ences i ntens e eye pa i n (both forei gn body s ens a ti on a nd a che), rednes s , photophobi a , a nd tea ri ng (s ee a l s o p. 588).
Di a gnos i s i s by s l i t-l a mp exa mi na ti on a nd fl uores cei n s ta i ni ng. A cornea l i nfi l tra te (col l ecti on of WBCs i n the cornea l s troma ) i s pres ent. At ti mes ,
the cornea l i nfi l tra te i s l a rge a nd dens e enough to be s een wi th ha ndhel d ma gni fi ca ti on or even wi th the na ked eye a s a whi te s pot on the
cornea . Mi crobi ol ogi c a na l ys i s of cul tures a nd s mea rs of the cornea l i nfi l tra te, conta ct l ens , a nd conta ct l ens ca s e i s i ndi ca ted.
Trea tment i ncl udes ces s a ti on of conta ct l ens wea r a nd a nti bi oti c drops . Ini ti a l thera py i ncl udes broa d-s pectrum a nti bi oti c covera ge us i ng a
fl uoroqui nol one a nti bi oti c drop q 15 to 60 mi n a round the cl ock for 24 to 72 h, then a t gra dua l l y l onger i nterva l s . Drops of a n a ddi ti ona l a nti bi oti c,
s uch a s cefa zol i n, va ncomyci n, or concentra ted tobra myci n, a re us ed i f the ul cer i s l a rge, deep, or cl os e to the vi s ua l a xi s . The a nti bi oti c ma y be
cha nged l a ter ba s ed on cul ture res ul ts . Negl ected ca s es ma y res pond poorl y or not a t a l l to trea tment, a nd s evere vi s i on l os s ma y res ul t.
Rigid Corneal Contact Lenses
Ol der pol ymethyl metha cryl a te ri gi d conta ct l ens es ha ve been repl a ced by ga s -permea bl e conta ct l ens es (GPCLs ) ma de of fl uoroca rbon a nd
pol ymethyl metha cryl a te a dmi xtures . GPCLs a re 6.5 to 10 mm i n di a meter a nd cover pa rt of the cornea , fl oa ti ng on the tea r l a yer overl yi ng i t.
Ri gi d conta ct l ens es ca n i mprove vi s i on for peopl e wi th myopi a , hyperopi a , a nd a s ti gma ti s m. If the cornea l s urfa ce i s i rregul a r, ri gi d l ens es often
provi de a s mooth refra cti ng s urfa ce a nd thus i mprove vi s ua l a cui ty noti cea bl y more tha n s oft conta ct l ens es or eyegl a s s es .
For compl ete wea ri ng comfort, ri gi d conta ct l ens es requi re a n a da pta ti on peri od, s ometi mes a s l ong a s 1 wk. Duri ng thi s ti me, the wea rer
gra dua l l y i ncrea s es the number of hours the l ens es a re worn ea ch da y. Importa ntl y, no pa i n s houl d occur a t a ny ti me. Pa i n i s a s i gn of a n i l l -fi tti ng
conta ct l ens or cornea l i rri ta ti on. Wea rers us ua l l y experi ence tempora ry (< 2 h) bl urred vi s i on (s pecta cl e bl ur) when wea ri ng eyegl a s s es a fter
removi ng ri gi d conta ct l ens es .
Soft Hydrophilic Contact Lenses
Soft conta ct l ens es a re ma de of pol y-2-hydroxyethyl metha cryl a te a nd other fl exi bl e pl a s ti cs a nd a re 30 to 79% wa ter. They a re 13 to 15 mm i n
di a meter a nd cover the enti re cornea . Soft conta ct l ens es ca n i mprove vi s i on for peopl e wi th myopi a a nd hyperopi a . Beca us e s oft conta ct l ens es
mol d to the exi s ti ng cornea l curva ture, a nythi ng grea ter tha n mi ni ma l a s ti gma ti s m ca nnot be trea ted unl es s a s peci a l tori c l ens , whi ch ha s
di fferent curva tures mol ded onto the front l ens s urfa ce, i s us ed. Wei ghti ng the l ower a s pect of the l ens ma i nta i ns i ts ori enta ti on.
Soft conta ct l ens es a re a l s o pres cri bed for trea tment of recurrent cornea l eros i ons a nd other cornea l di s orders (ca l l ed ba nda ge or thera peuti c
conta ct l ens es ). Prophyl a cti c a nti bi oti c eyedrops (eg, fl uoroqui nol one qi d) ma y be a dvi s a bl e wi th a ba nda ge l ens . Extended wea ri ng of conta ct
l ens es , es peci a l l y i n a pha ki a a fter ca ta ra ct s urgery, i s pra cti ca l , but a n ophtha l mol ogi s t s houl d exa mi ne the pa ti ent a t l ea s t 4 ti mes /yr. The
pa ti ent s houl d cl ea n the l ens es once/wk.
Beca us e of thei r l a rger s i ze, s oft conta ct l ens es a re ea s i er to ha ndl e, a re not a s l i kel y a s ri gi d l ens es to eject s ponta neous l y, a nd a re l es s l i kel y to
a l l ow forei gn bodi es to l odge benea th them. Immedi a te wea ri ng comfort a l l ows for a bri ef a da pta ti on peri od.
Soft conta ct l ens es ha ve a hi gher i nci dence of cornea l i nfecti ons , whi ch i ncrea s es for every ni ght a pers on wea rs them duri ng s l eep. When dry, s oft
conta ct l ens es a re bri ttl e a nd brea k ea s i l y. They a bs orb a certa i n a mount of moi s ture (ba s ed on the wa ter content) from the tea r fi l m to reta i n
a dequa te s ha pe a nd pl i a bi l i ty. Therefore, pa ti ents wi th dry eye a re us ua l l y more comforta bl e wea ri ng l ens es tha t ha ve a l ow wa ter content.
Refractive Surgery
Cornea l refra cti ve s urgery a l ters the curva ture of the cornea to focus l i ght more preci s el y on the reti na . The goa l of refra cti ve s urgery i s to decrea s e
dependence on eyegl a s s es or conta ct l ens es . Mos t peopl e who undergo refra cti ve s urgery a chi eve thi s goa l ; a bout 95% do not need correcti ve
l ens es for di s ta nce vi s i on. Idea l ca ndi da tes for refra cti ve s urgery a re peopl e wi th hea l thy eyes who a re not s a ti s fi ed wea ri ng eyegl a s s es or
conta ct l ens es . Preopera ti ve exa mi na ti on excl udes peopl e wi th a cti ve ocul a r di s ea s es , i ncl udi ng s evere dry eye. Ca ndi da tes s houl d not ha ve a
hi s tory of a utoi mmune or connecti ve ti s s ue di s ea s e beca us e of potenti a l probl ems wi th wound hea l i ng. La tent herpes s i mpl ex vi rus ma y be
rea cti va ted a fter s urgery; pa ti ents s houl d be a dvi s ed a ccordi ngl y. Refra cti on s houl d be s ta bl e for a t l ea s t 1 yr, a nd ca ndi da tes s houl d be > 18 yr.
Another contra i ndi ca ti on i s us e of i s otreti noi n or a mi oda rone.
Advers e effects of refra cti ve s urgery i ncl ude tempora ry forei gn body s ens a ti on, gl a re, ha l os , a nd drynes s ; occa s i ona l l y, thes e s ymptoms pers i s t.
Potenti a l compl i ca ti ons i ncl ude overcorrecti on a nd undercorrecti on, i nfecti on, a nd i rregul a r a s ti gma ti s m. In exci mer l a s er procedures performed
on the s uperfi ci a l cornea l s troma , ha ze forma ti on i s pos s i bl e. If i nfecti on, i rregul a r a s ti gma ti s m, or ha ze forma ti on ca us es perma nent cha nges i n
the centra l cornea , bes t-corrected a cui ty coul d be l os t. The overa l l compl i ca ti on ra te i s l ow; cha nce of vi s i on l os s i s < 1% i f the pa ti ent i s
cons i dered a good ca ndi da te for refra cti ve s urgery preopera ti vel y.
Laser In Situ Keratomileusis
In l a s er i n s i tu kera tomi l eus i s (LASIK), a fl a p of cornea l ti s s ue i s crea ted wi th a l a s er or mecha ni ca l mi crokera tome a nd turned ba ck, the
underl yi ng s troma l bed i s s cul pted (photo-a bl a ted) wi th the exci mer l a s er, a nd the fl a p i s repl a ced wi thout s uturi ng. Beca us e s urfa ce epi thel i um
i s not di s rupted centra l l y, vi s i on returns ra pi dl y. Mos t peopl e noti ce a s i gni fi ca nt i mprovement the next da y. LASIK ca n be us ed to trea t myopi a ,
a s ti gma ti s m, a nd hyperopi a .
Adva nta ges of LASIK over photorefra cti ve kera tectomy (PRK) i ncl ude the des i ra bl e l a ck of hea l i ng res pons e (the centra l cornea l epi thel i um i s not
removed, thereby decrea s i ng the ri s k of centra l ha ze forma ti on tha t occurs duri ng hea l i ng), the s horter vi s ua l reha bi l i ta ti on peri od, a nd mi ni ma l
pos topera ti ve pa i n. Di s a dva nta ges i ncl ude pos s i bl e i ntra opera ti ve a nd pos topera ti ve fl a p-rel a ted compl i ca ti ons , s uch a s i rregul a r fl a p
forma ti on, fl a p di s l oca ti on, a nd the need for a dequa te cornea l thi cknes s to prevent l ong-term cornea l ecta s i a . Ecta s i a occurs when the cornea ha s
become s o thi n tha t i ntra ocul a r pres s ure ca us es i ns ta bi l i ty a nd bul gi ng of the thi nned a nd wea kened cornea l s troma . Bl urri ng, i ncrea s i ng myopi a ,
a nd i rregul a r a s ti gma ti s m ca n res ul t.
Photorefractive Keratectomy
In PRK, the exci mer l a s er i s us ed to s cul pt (photoa bl a te) the a nteri or curva ture of the cornea l s troma l bed to trea t myopi a , hyperopi a , a nd
a s ti gma ti s m. The cornea l epi thel i um i s removed before photoa bl a ti on a nd genera l l y ta kes 3 to 4 da ys to regenera te; duri ng thi s ti me a ba nda ge
conta ct l ens i s worn. Unl i ke LASIK, no cornea l fl a p i s crea ted.
PRK ma y be more s ui ta bl e for pa ti ents wi th thi n cornea s or a nteri or ba s ement membra ne dys trophy.
Adva nta ges of PRK i ncl ude a n overa l l thi cker res i dua l s troma l bed (thereby reduci ng ri s k of ecta s i a ) a nd l a ck of fl a p-rel a ted compl i ca ti ons .
Di s a dva nta ges i ncl ude potenti a l for cornea l ha ze forma ti on i f a l a rge a mount of cornea l ti s s ue i s a bl a ted a nd the need for pos topera ti ve
corti cos teroi d drops for 3 to 4 mo. More tha n 95% of pa ti ents s ee 20/40 or better wi thout eyegl a s s es a fter s urgery.
Intracorneal Ring Segments
Intra cornea l ri ng s egments (INTACS) a re thi n a rc-s ha ped s egments of bi ocompa ti bl e pl a s ti c tha t a re i ns erted i n pa i rs through a s ma l l ra di a l
cornea l i nci s i on i nto the peri phera l cornea l s troma a t two-thi rds depth. After INTACS a re i ns erted, the centra l cornea l curva ture i s fl a ttened,
reduci ng myopi a . INTACS a re us ed for mi l d myopi a (< 3 di opters ) a nd mi ni ma l a s ti gma ti s m (< 1 di opter). INTACS ma i nta i n a centra l , cl ea r, opti ca l
zone beca us e the 2 s egments a re pl a ced i n the cornea l peri phery. INTACS ca n be repl a ced or removed i f des i red.
Ri s ks i ncl ude i nduced a s ti gma ti s m, undercorrecti on a nd overcorrecti on, i nfecti on, gl a re, ha l o, a nd i ncorrect depth pl a cement. Vi s i on res ul ts a re
very good; i n US cl i ni ca l s tudi es , 97% of pa ti ents s a w 20/40 or better a nd 74% of pa ti ents s a w 20/20 or better.
Conductive Keratoplasty
Conducti ve kera topl a s ty (CK) i s a therma l techni que tha t ca n trea t s pheri ca l hyperopi a (i e, hyperopi a wi thout a s s oci a ted a s ti gma ti s m) a nd
pres byopi a . CK us es ra di ofrequency energy a ppl i ed wi th a fi ne probe i n a ri ng pa ttern to the peri phera l cornea to contra ct the peri phery a nd
s teepen the center, thereby i ncrea s i ng the refra cti ve power of the cornea . For pres byopi c pa ti ents who wea r onl y rea di ng gl a s s es , CK i s typi ca l l y
done i n the nondomi na nt eye (monovi s i on) to i nduce myopi a i n tha t eye a nd ena bl e the pa ti ent to rega i n rea di ng vi s i on. As the pres byopi a
progres s es , a ddi ti ona l ri ngs of trea tment a re a dded. Ri s ks of CK i ncl ude i nduced a s ti gma ti s m a nd regres s i on of effect.
Phakic Intraocular Lenses
Pha ki c i ntra ocul a r l ens es (IOLs ) a re l ens i mpl a nts tha t a re us ed to trea t s evere myopi a i n pa ti ents who a re not s ui ta bl e ca ndi da tes for l a s er
vi s i on correcti on. Unl i ke i n ca ta ra ct s urgery, the pa ti ent's na tura l l ens i s not removed. The pha ki c IOL i s i ns erted di rectl y a nteri or or pos teri or to
the i ri s through a n i nci s i on i n the eye. Thi s procedure i s i ntra ocul a r s urgery a nd mus t be done i n a n opera ti ng room.
Ri s ks i ncl ude ca ta ra ct forma ti on, gl a ucoma , i nfecti on, a nd l os s of cornea l endothel i a l cel l s .
Beca us e pha ki c IOLs do not correct a s ti gma ti s m, pa ti ents ca n undergo s ubs equent l a s er vi s i on correcti on to refi ne refra cti ve res ul ts i n a techni que
known a s bi opti cs . Beca us e the bul k of the myopi a i s corrected wi th the pha ki c IOL, l es s cornea l ti s s ue i s removed wi th LASIK, a nd the ri s k of
ecta s i a i s thus l ow.
Clear Lensectomy
Cl ea r l ens ectomy ca n be cons i dered i n pa ti ents wi th hi gh hyperopi a who a re a l rea dy pres byopi c. Thi s procedure i s i denti ca l to ca ta ra ct s urgery
except the pa ti ent's l ens i s cl ea r a nd not ca ta ra ctous . A mul ti foca l i ntra ocul a r l ens , whi ch a l l ows the pa ti ent to focus over a wi de ra nge of
di s ta nces wi thout externa l l ens correcti on, ca n be i ns erted.
The ma i n ri s ks of cl ea r l ens ectomy a re i nfecti on a nd rupture of the pos teri or ca ps ul e of the l ens , whi ch woul d neces s i ta te further s urgery. Cl ea r
l ens ectomy s houl d be done wi th grea t ca uti on i n young myopi c pa ti ents beca us e they ha ve a n i ncrea s ed ri s k of reti na l deta chment.
Radial and Astigmatic Keratotomy
Ra di a l a nd a s ti gma ti c kera totomy procedures cha nge the s ha pe of the cornea by ma ki ng deep cornea l i nci s i ons us i ng a di a mond bl a de.
Ra di a l kera totomy ha s been repl a ced by l a s er vi s i on correcti on a nd i s ra rel y us ed beca us e i t offers no cl ea r a dva nta ges over l a s er vi s i on
correcti on, ha s a grea ter need for s ubs equent retrea tment, l ea ds to vi s ua l a nd refra cti ve res ul ts tha t cha nge through the da y, a nd tends to ca us e
hyperopi a i n the l ong term.
As ti gma ti c kera totomy i s us ed to trea t a s ti gma ti s m a t the ti me of ca ta ra ct s urgery or a fter cornea l tra ns pl a nta ti on.
Chapter 62. Eyelid and Lacrimal Disorders

Introduction
Common eyel i d a nd l a cri ma l di s orders i ncl ude bl epha ri ti s , bl epha ros pa s m, ca na l i cul i ti s , cha l a zi on a nd hordeol um, da cryocys ti ti s ,
da cryos tenos i s , entropi on a nd ectropi on, tri chi a s i s , a nd tumors .
Blepharitis
Blepharitis is inflammation of the eyelid margins that may be acute or chronic. Symptoms and signs include itching and burning of the eyelid margins with
redness and edema. Diagnosis is by history and examination. Acute ulcerative blepharitis is usually treated with topical antibiotics or systemic antivirals. Acute
nonulcerative blepharitis is occasionally treated with topical corticosteroids. Chronic disease is treated with tear supplements, warm compresses, and occasionally
oral antibiotics (eg, a tetracycline) for meibomian gland dysfunction or with eyelid hygiene and tear supplements for seborrheic blepharitis.
Etiology
Bl epha ri ti s ma y be a cute (ul cera ti ve or nonul cera ti ve) or chroni c (mei bomi a n gl a nd dys functi on, s eborrhei c bl epha ri ti s ).
Acute: Acute ul cera ti ve bl epha ri ti s i s us ua l l y ca us ed by ba cteri a l i nfecti on (us ua l l y s ta phyl ococca l ) of the eyel i d ma rgi n a t the ori gi ns of the
eyel a s hes ; the l a s h fol l i cl es a nd mei bomi a n gl a nds a re a l s o i nvol ved. It ma y a l s o be due to a vi rus (eg, herpes s i mpl ex, va ri cel l a zos ter).
Acute nonul cera ti ve bl epha ri ti s i s us ua l l y ca us ed by a n a l l ergi c rea cti on i nvol vi ng the s a me a rea (eg, a topi c bl epha roderma ti ti s a nd s ea s ona l
a l l ergi c bl epha roconjuncti vi ti s , whi ch ca us e i ntens e i tchi ng, rubbi ng, a nd a ra s h; conta ct s ens i ti vi ty [derma tobl epha ro-conjuncti vi ti s ]).
Chronic: Chroni c bl epha ri ti s i s noni nfecti ous i nfl a mma ti on of unknown ca us e. Mei bomi a n gl a nds i n the eyel i d produce l i pi ds (mei bum) tha t
reduce tea r eva pora ti on by formi ng a l i pi d l a yer on top of the a queous tea r l a yer. In mei bomi a n gl a nd dys functi on, the l i pi d compos i ti on i s
a bnorma l , a nd gl a nd ducts a nd ori fi ces become i ns pi s s a ted wi th ha rd, wa xy pl ugs . Ma ny pa ti ents ha ve ros a cea (s ee p. 654) a nd recurrent
hordeol a or cha l a zi a .
Ma ny pa ti ents wi th s eborrhei c bl epha ri ti s ha ve s eborrhei c derma ti ti s of the fa ce a nd s ca l p (s ee p. 671) or a cne ros a cea . Seconda ry ba cteri a l
col oni za ti on often occurs on the s ca l es tha t devel op on the eyel i d ma rgi n. Mei bomi a n gl a nds ca n become obs tructed.
Mos t pa ti ents wi th mei bomi a n gl a nd dys functi on or s eborrhei c bl epha ri ti s ha ve i ncrea s ed tea r eva pora ti on a nd s econda ry kera toconjuncti vi ti s
s i cca .
Symptoms and Signs
Symptoms common to a l l forms of bl epha ri ti s i ncl ude i tchi ng a nd burni ng of the eyel i d ma rgi ns a nd conjuncti va l i rri ta ti on wi th l a cri ma ti on,
photos ens i ti vi ty, a nd forei gn body s ens a ti on.
Acute: In a cute ul cera ti ve bl epha ri ti s , s ma l l pus tul es ma y devel op i n eyel a s h fol l i cl es a nd eventua l l y brea k down to form s ha l l ow ma rgi na l ul cers .
Tena ci ous a dherent crus ts l ea ve a bl eedi ng s urfa ce when removed. Duri ng s l eep, eyel i ds ca n become gl ued together by dri ed s ecreti ons .
Recurrent ul cera ti ve bl epha ri ti s ca n ca us e eyel i d s ca rs a nd l os s of eyel a s hes .
In a cute nonul cera ti ve bl epha ri ti s , eyel i d ma rgi ns become edema tous a nd erythema tous ; eyel a s hes ma y become crus ted wi th dri ed s erous fl ui d.
Chronic: In mei bomi a n gl a nd dys functi on, exa mi na ti on revea l s di l a ted, i ns pi s s a ted gl a nd ori fi ces tha t, when pres s ed, exude a wa xy, thi ck,
yel l owi s h s ecreti on wi th pres s ure. In s eborrhei c bl epha ri ti s , grea s y, ea s i l y remova bl e s ca l es devel op on eyel i d ma rgi ns . Mos t pa ti ents wi th
s eborrhei c bl epha ri ti s a nd mei bomi a n gl a nd dys functi on ha ve s ymptoms of kera toconjuncti vi ti s s i cca , s uch a s forei gn body s ens a ti on, gri tti nes s ,
eye s tra i n a nd fa ti gue, a nd bl urri ng wi th prol onged vi s ua l effort.
Diagnosis
Di a gnos i s i s us ua l l y by s l i t-l a mp exa mi na ti on. Chroni c bl epha ri ti s tha t does not res pond to trea tment ma y requi re bi ops y to excl ude eyel i d tumors
tha t ca n s i mul a te the condi ti on.
Prognosis
Acute bl epha ri ti s mos t often res ponds to trea tment but ma y recur, devel op i nto chroni c bl epha ri ti s , or both. Chroni c bl epha ri ti s i s i ndol ent,
recurrent, a nd res i s ta nt to trea tment. Exa cerba ti ons a re i nconveni ent, uncomforta bl e, a nd cos meti ca l l y una ppea l i ng but do not us ua l l y res ul t i n
cornea l s ca rri ng or vi s i on l os s .
Treatment
Acute: Acute ul cera ti ve bl epha ri ti s i s trea ted wi th a n a nti bi oti c oi ntment (eg, ba ci tra ci n/pol ymyxi n B, erythromyci n, or genta mi ci n 0.3% qi d for 7 to
10 da ys ). Acute vi ra l ul cera ti ve bl epha ri ti s i s trea ted wi th s ys temi c a nti vi ra l s (eg, for herpes s i mpl ex, a cycl ovi r 400 mg po ti d for 7 da ys ; for va ri cel l a
zos ter, fa mci cl ovi r 500 mg po ti d or va l a cycl ovi r 1 g po ti d for 7 da ys ).
Trea tment of a cute nonul cera ti ve bl epha ri ti s begi ns wi th a voi di ng the offendi ng a cti on (eg, rubbi ng) or s ubs ta nce (eg, new eye drops ). Wa rm
compres s es over the cl os ed eyel i d ma y rel i eve s ymptoms a nd s peed res ol uti on. If s wel l i ng pers i s ts > 24 h, topi ca l corti cos teroi ds (eg,
fl uoromethol one ophtha l mi c oi ntment 0.1% ti d for 7 da ys ) ca n be us ed.
Chronic: The i ni ti a l trea tment for both mei bomi a n gl a nd dys functi on a nd s eborrhei c bl epha ri ti s i s di rected towa rd the s econda ry
kera toconjuncti vi ti s s i cca (s ee p. 592). Tea r s uppl ements , bl a nd oi ntments a t ni ght, a nd, i f neces s a ry, puncta l pl ugs (i ns erts tha t obs truct the
puncta a nd thus decrea s e tea r dra i na ge) a re effecti ve i n mos t pa ti ents .
If needed, a ddi ti ona l trea tment for mei bomi a n gl a nd dys functi on i ncl udes wa rm compres s es to mel t the wa xy pl ugs a nd occa s i ona l l y eyel i d
ma s s a ge to extrude tra pped s ecreti ons a nd coa t the ocul a r s urfa ce. A tetra cycl i ne (eg, doxycycl i ne 100 mg po bi d ta pered over 3 to 4 mo) ma y a l s o
be effecti ve beca us e i t cha nges the compos i ti on of mei bomi a n gl a nd s ecreti ons .
If needed, a ddi ti ona l trea tment for s eborrhei c bl epha ri ti s i ncl udes gentl e cl ea ns i ng of the eyel i d ma rgi n 2 ti mes a da y wi th a cotton s wa b di pped
i n a di l ute s ol uti on of ba by s ha mpoo (2 to 3 drops i n 1/2 cup of wa rm wa ter). A topi ca l a nti bi oti c oi ntment (ba ci tra ci n/pol ymyxi n B or
s ul fa ceta mi de 10% bi d for up to 3 mo) ma y be a dded to reduce ba cteri a l counts on the eyel i d ma rgi n when ca s es a re unres pons i ve to weeks of
eyel i d hygi ene.
Blepharospasm
Blepharospasm is spasm of muscles around the eye causing involuntary blinking and eye closing.
The ca us e of bl epha ros pa s m i s mos t often unknown. It a ffects women more tha n men a nd tends to occur i n fa mi l i es . Bl epha ros pa s m ma y be
s econda ry to eye di s orders , i ncl udi ng thos e tha t ca us e ocul a r i rri ta ti on (eg, tri chi a s i s , cornea l forei gn body, kera toconjuncti vi ti s s i cca ) a nd
s ys temi c neurol ogi c di s ea s es tha t ca us e s pa s m (eg, Pa rki ns on's di s ea s e).
Symptoms a re i nvol unta ry bl i nki ng a nd cl os i ng of the eyes ; i n s evere ca s es , peopl e ca nnot open thei r eyes . Spa s ms ma y be ma de wors e by fa ti gue,
bri ght l i ght, a nd a nxi ety.
Trea tment i nvol ves i njecti ng botul i num toxi n type A i nto the eyel i d mus cl es ; trea tment mus t be repea ted i n mos t i ns ta nces . Anxi ol yti cs ma y hel p.
Surgery to cut the peri orbi ta l mus cl es i s a l s o effecti ve but, beca us e of potenti a l compl i ca ti ons , i s cons i dered onl y i f botul i num toxi n i s i neffecti ve.
Sungl a s s es hel p decrea s e the l i ght s ens i ti vi ty tha t ma y ca us e or a ccompa ny bl epha ros pa s m.
Canaliculitis
Canaliculitis is inflammation of the canaliculus (see
Fig. 60-3 on p. 567).
The mos t common ca us e i s i nfecti on wi th Actinomyces israelii, a gra m-pos i ti ve ba ci l l us wi th fi ne bra nchi ng fi l a ments , but other ba cteri a , fungi (eg,
Candida albicans), a nd vi rus es (eg, herpes s i mpl ex) ma y be ca us a ti ve. Symptoms a nd s i gns a re tea ri ng, di s cha rge, red eye (es peci a l l y na s a l l y), a nd
mi l d tendernes s over the i nvol ved s i de.
Di a gnos i s i s s us pected ba s ed on s ymptoms a nd s i gns , expres s i on of turbi d s ecreti ons wi th pres s ure over the l a cri ma l s a c, a nd a gri tty s ens a ti on
ca us ed by necroti c ma teri a l tha t ca n be fel t duri ng probi ng of the l a cri ma l s ys tem. Ca na l i cul i ti s ca n be di fferenti a ted from da cryocys ti ti s . In
ca na l i cul i ti s , the punctum a nd ca na l i cul us a re red a nd s wol l en; i n da cryocys ti ti s , the punctum a nd ca na l i cul us a re norma l , but a red, s wol l en,
tender ma s s i s l oca ted i n or nea r the l a cri ma l s a c.
Trea tment i s wa rm compres s es , i rri ga ti on of the ca na l i cul us wi th a nti bi oti c s ol uti on (by a n ophtha l mol ogi s t), a nd remova l of a ny concreti ons ,
whi ch us ua l l y requi res s urgery. Anti bi oti c s el ecti on i s us ua l l y empi ri c wi th a 1s t-genera ti on cepha l os pori n or peni ci l l i na s e-res i s ta nt s yntheti c
peni ci l l i n but ma y be gui ded by i rri ga ti on s a mpl es .
Chalazion and Hordeolum
Chalazia and hordeola are sudden-onset localized swellings of the eyelid. A chalazion is caused by noninfectious meibomian gland occlusion, whereas a hordeolum
is caused by infection. Both conditions initially cause eyelid hyperemia and edema, swelling, and pain. With time, a chalazion becomes a small nontender nodule
in the eyelid center, whereas a hordeolum remains painful and localizes to an eyelid margin. Diagnosis is clinical. Treatment is with hot compresses. Both
conditions improve spontaneously, but incision or, for chalazia, intralesional corticosteroids may be used to hasten resolution.
Chalazion: A cha l a zi on i s noni nfecti ous obs tructi on of a mei bomi a n gl a nd ca us i ng extra va s a ti on of i rri ta ti ng l i pi d ma teri a l i n the eyel i d s oft
ti s s ues wi th foca l s econda ry gra nul oma tous i nfl a mma ti on (s ee
Pl a te 7). Di s orders tha t ca us e a bnorma l l y thi ck mei bomi a n gl a nd s ecreti ons (eg, mei bomi a n gl a nd dys functi on, a cne ros a cea ) i ncrea s e the ri s k of
mei bomi a n gl a nd obs tructi on.
Hordeolum: A hordeol um (s tye) i s a n a cute, l oca l i zed, pyogeni c (us ua l l y s ta phyl ococca l ) i nfecti on or a bs ces s of the eyel i d tha t ma y be externa l or
i nterna l (s ee
Pl a te 16). Mos t hordeol a a re externa l a nd res ul t from obs tructi on a nd i nfecti on of a n eyel a s h fol l i cl e a nd a dja cent gl a nds of Zei s or Mol l 's gl a nds .
Fol l i cl e obs tructi on ma y be a s s oci a ted wi th bl epha ri ti s . An i nterna l hordeol um, whi ch i s very ra re, res ul ts from i nfecti on of a mei bomi a n gl a nd.
Someti mes cel l ul i ti s a ccompa ni es hordeol a .
Symptoms and Signs
Cha l a zi a a nd hordeol a ea ch ca us e eyel i d rednes s , s wel l i ng, a nd pa i n.
Chalazion: After 1 or 2 da ys , a cha l a zi on l oca l i zes to the body of the eyel i d. Typi ca l l y, a s ma l l nontender nodul e or l ump devel ops . A cha l a zi on
us ua l l y dra i ns through the i nner s urfa ce of the eyel i d or i s a bs orbed s ponta neous l y over 2 to 8 wk; ra rel y, i t pers i s ts l onger. Vi s i on ma y be s l i ghtl y
bl urred.
Hordeolum: After 1 to 2 da ys , a n externa l hordeol um l oca l i zes to the eyel i d ma rgi n. There ma y be tea ri ng, photophobi a , a nd a forei gn body
s ens a ti on. Typi ca l l y, a s ma l l yel l owi s h pus tul e devel ops a t the ba s e of a n eyel a s h, s urrounded by hyperemi a , i ndura ti on, a nd di ffus e edema .
Wi thi n 2 to 4 da ys , the l es i on ruptures a nd di s cha rges pus , thereby rel i evi ng pa i n a nd res ol vi ng the l es i on.
Symptoms of a n i nterna l hordeol um a re the s a me a s thos e of a cha l a zi on, wi th pa i n, rednes s , a nd edema l oca l i zed to the pos teri or ta rs a l
conjuncti va l s urfa ce. Infl a mma ti on ma y be s evere, s ometi mes wi th fever or chi l l s . Ins pecti on of the ta rs a l conjuncti va e s hows a s ma l l el eva ti on or
yel l ow a rea a t the s i te of the a ffected gl a nd. La ter, a n a bs ces s forms . Sponta neous rupture i s ra re; however, when i t does occur, i t us ua l l y occurs
on the conjuncti va l s i de of the eyel i d a nd s ometi mes erupts through the s ki n s i de. Recurrence i s common.
Diagnosis
Cl i ni ca l a s s es s ment
Di a gnos i s of cha l a zi on a nd both ki nds of hordeol a i s cl i ni ca l ; however, duri ng the fi rs t 2 da ys , they ma y be cl i ni ca l l y i ndi s ti ngui s ha bl e. Beca us e
i nterna l hordeol a a re s o ra re, they a re not us ua l l y s us pected unl es s i nfl a mma ti on i s s evere or fever or chi l l s a re pres ent. If the cha l a zi on or
hordeol um l i es nea r the i nner ca nthus of the l ower eyel i d, i t mus t be di fferenti a ted from da cryocys ti ti s (s ee bel ow), whi ch ca n us ua l l y be
excl uded by noti ng the l oca ti on of ma xi mum i ndura ti on a nd tendernes s (eg, eyel i d for a cha l a zi on, under the medi a l ca nthus nea r the s i de of the
nos e for da cryocys ti ti s ). Chroni c cha l a zi a tha t do not res pond to trea tment requi re bi ops y to excl ude tumor of the eyel i d.
Treatment
Hot compres s es
Someti mes dra i na ge or drug thera py
Hot compres s es for 5 to 10 mi n 2 or 3 ti mes a da y ca n be us ed to ha s ten res ol uti on of cha l a zi a a nd externa l hordeol a .
Chalazion: Inci s i on a nd curetta ge or i ntra cha l a zi on corti cos teroi d thera py (0.05 to 0.2 mL tri a mci nol one 25 mg/mL) ma y be i ndi ca ted i f cha l a zi a a re
l a rge, uns i ghtl y, a nd pers i s t for more tha n s evera l weeks des pi te cons erva ti ve thera py.
Hordeolum: An externa l hordeol um tha t does not res pond to hot compres s es ca n be i nci s ed wi th a s ha rp, fi ne-ti pped bl a de. Sys temi c a nti bi oti cs
(eg, di cl oxa ci l l i n or erythromyci n 250 mg po qi d) a re i ndi ca ted when cel l ul i ti s a ccompa ni es a hordeol um.
Trea tment of i nterna l hordeol a i s ora l a nti bi oti cs a nd i nci s i on a nd dra i na ge i f needed. Topi ca l a nti bi oti cs a re us ua l l y i neffecti ve.
Dacryocystitis
Dacryocystitis is infection of the lacrimal sac, usually with staphyloccocal or streptococcal species and usually as a consequence of nasolacrimal duct obstruction.
In a cute da cryocys ti ti s , the pa ti ent pres ents wi th pa i n, rednes s , a nd edema a round the l a cri ma l s a c. Di a gnos i s i s s us pected ba s ed on s ymptoms
a nd s i gns a nd when pres s ure over the l a cri ma l s a c ca us es refl ux of mucoi d ma teri a l through the puncta . Ini ti a l trea tment i s wi th wa rm
compres s es a nd ora l a nti bi oti cs for mi l d ca s es or IV a nti bi oti cs for more s evere ca s es . The a nti bi oti c i s us ua l l y a 1s t-genera ti on cepha l os pori n or
peni ci l l i na s e-res i s ta nt s yntheti c peni ci l l i n. If the i nfecti on does not res pond a s expected, cons i dera ti on s houl d be gi ven to methi ci l l i n-res i s ta nt
Staphylococcus aureus (MRSA), a nd a nti bi oti cs cha nged a ccordi ngl y. The a bs ces s ca n be dra i ned a nd the a nti bi oti cs ca n be cha nged ba s ed on cul ture
res ul ts i f the i ni ti a l a nti bi oti c proves i neffecti ve.
Pa ti ents wi th chroni c da cryocys ti ti s us ua l l y pres ent wi th a ma s s under the medi a l ca ntha l tendon a nd chroni c conjuncti vi ti s . Defi ni ti ve trea tment
for res ol ved a cute da cryocys ti ti s or chroni c conjuncti vi ti s i s us ua l l y s urgery tha t crea tes a pa s s a ge between the l a cri ma l s a c a nd the na s a l ca vi ty
(da cryocys torhi nos tomy).
Dacryostenosis
Dacryostenosis is obstruction or stenosis of the nasolacrimal duct, causing excess tearing.
Na s ol a cri ma l obs tructi on ma y be congeni ta l or a cqui red. One ca us e of congeni ta l obs tructi on i s i na dequa te devel opment of a ny pa rt of the
na s ol a cri ma l ducts . Typi ca l l y, a membra ne a t the di s ta l end of the na s ol a cri ma l duct pers i s ts . There i s tea ri ng a nd purul ent di s cha rge; the
condi ti on ma y ma ni fes t a s chroni c conjuncti vi ti s , us ua l l y begi nni ng a fter the a ge of 2 wk (mos t often a t a ge 3 to 12 wk).
Ca us es of a cqui red na s ol a cri ma l duct obs tructi on a re l i s ted i n
Ta bl e 62-1. The ca us e i s mos t often a ge-rel a ted s tenos i s of the na s ol a cri ma l duct. Other ca us es i ncl ude pa s t na s a l or fa ci a l bone fra ctures a nd
s i nus s urgery, whi ch di s rupt the na s ol a cri ma l duct; i nfl a mma tory di s ea s es (eg, s a rcoi dos i s , Wegener's gra nul oma tos i s ); a nd da cryocys ti ti s .
Ca us es of puncta l or ca na l i cul a r s tenos i s i ncl ude chroni c conjuncti vi ti s (es peci a l l y herpeti c), certa i n types of chemothera py, a dvers e rea cti ons to
eye drops (es peci a l l y topi ca l echothi opha te i odi de), a nd ra di a ti on.
Diagnosis
Di a gnos i s i s us ua l l y ba s ed on cl i ni ca l cri teri a . Someti mes ophtha l mol ogi s ts probe a nd i rri ga te the l a cri ma l dra i na ge s ys tem wi th s a l i ne, wi th or
wi thout fl uores cei n dye. Refl ux i ndi ca tes s tenos i s .
Treatment
Congeni ta l na s ol a cri ma l duct obs tructi on often res ol ves s ponta neous l y by a bout a ge 6 to 9 mo; before 1 yr, ma nua l compres s i on of the l a cri ma l
s a c 4 or 5 ti mes /da y ma y rel i eve the obs tructi on. After 1 yr, the na s ol a cri ma l duct ma y need probi ng, us ua l l y under genera l a nes thes i a ; i f
obs tructi on i s recurrent, a tempora ry s i l a s ti c tube ma y be i ns erted.
[Table 62-1. Ca us es of Acqui red Na s ol a cri ma l Duct Obs tructi on]
In a cqui red na s ol a cri ma l duct obs tructi on, the underl yi ng di s order i s trea ted when pos s i bl e. If trea tment i s not pos s i bl e or i s i neffecti ve, a
pa s s a ge between the l a cri ma l s a c a nd the na s a l ca vi ty ca n be crea ted s urgi ca l l y (da cryocys torhi nos tomy).
In ca s es of puncta l or ca na l i cul a r s tenos i s , di l a ti on i s us ua l l y cura ti ve. If ca na l i cul a r s tenos i s i s s evere a nd bothers ome, a s urgi ca l procedure tha t
pl a ces a gl a s s tube (Jones tube) l ea di ng from the ca runcl e i nto the na s a l ca vi ty ca n be cons i dered.
Entropion and Ectropion
Entropion is inversion of an eyelid. Ectropion is eversion of the lower eyelid.
Entropion: Entropi on (i nvers i on of a n eyel i d) i s ca us ed by a ge-rel a ted ti s s ue rel a xa ti on, pos ti nfecti ous or pos ttra uma ti c cha nges , or
bl epha ros pa s m. Eyel a s hes rub a ga i ns t the eyeba l l a nd ma y l ea d to cornea l ul cera ti on a nd s ca rri ng. Symptoms ca n i ncl ude forei gn body s ens a ti on,
tea ri ng, a nd red eye. Di a gnos i s i s cl i ni ca l . Defi ni ti ve trea tment i s s urgery.
Ectropion: Ectropi on (evers i on of the l ower eyel i ds ee
Pl a te 12) i s ca us ed by a ge-rel a ted ti s s ue rel a xa ti on, cra ni a l nerve VII pa l s y, a nd pos ttra uma ti c or pos ts urgi ca l cha nges . Symptoms a re tea ri ng (due
to poor dra i na ge of tea rs through the na s ol a cri ma l s ys tem, whi ch ma y no l onger conta ct the eyeba l l ) a nd s ymptoms of dry eyes (s ee p. 592),
pos s i bl y due to i na dequa te bl i nki ng. Di a gnos i s i s cl i ni ca l . Symptoma ti c trea tment ca n i ncl ude tea r s uppl ements a nd, a t ni ght, ocul a r l ubri ca nts ;
defi ni ti ve trea tment i s s urgery.
Trichiasis
Trichiasis is an anatomic misalignment of eyelashes, which rub against the eyeball, in a patient with no entropion.
Tri chi a s i s i s mos t often i di opa thi c, but known ca us es i ncl ude bl epha ri ti s , pos ttra uma ti c a nd pos ts urgi ca l cha nges , conjuncti va l s ca rri ng (eg,
s econda ry to ci ca tri ci a l pemphi goi d, a topi c kera toconjuncti vi ti s , Stevens -Johns on s yndrome, or chemi ca l i njury), epi bl epha ron (a n extra l ower
eyel i d s ki nfol d tha t di rects l a s hes i nto a verti ca l pos i ti on), a nd di s ti chi a s i s (a congeni ta l extra row of eyel a s hes ). Cornea l ul cera ti on a nd s ca rri ng
ca n occur i n chroni c ca s es . Symptoms a re forei gn body s ens a ti on, tea ri ng, a nd red eye. Di a gnos i s i s us ua l l y cl i ni ca l . Tri chi a s i s di ffers from
entropi on i n tha t the eyel i d pos i ti on i s norma l . Eva l ua ti on i ncl udes fl uores cei n s ta i ni ng to excl ude cornea l a bra s i on or ul cera ti on. Trea tment i s
eyel a s h remova l wi th forceps . If eyel a s hes grow ba ck, el ectrol ys i s or cryos urgery i s more effecti ve a t perma nentl y preventi ng recurrence.
Tumors
The s ki n of the eyel i ds i s a common s i te for growth of beni gn a nd ma l i gna nt tumors .
Xanthelasma: Xa nthel a s ma i s a common, beni gn depos i t of yel l ow-whi te fl a t pl a ques of l i pi d ma teri a l tha t occur s ubcuta neous l y on the upper a nd
l ower eyel i ds . Al though s ome peopl e wi th xa nthel a s ma s ha ve dys l i pi demi a s , mos t do not. Di a gnos i s i s by a ppea ra nce. No trea tment i s neces s a ry,
a l though xa nthel a s ma s ca n be removed for cos meti c rea s ons , a nd underl yi ng dys l i pi demi a s s houl d be trea ted.
Basal cell carcinoma: Thi s s ki n ca ncer frequentl y occurs a t the eyel i d ma rgi ns , a t the i nner ca nthus , a nd on the upper cheek (s ee a l s o p. 749).
Meta s ta s i s i s ra re. Bi ops y es ta bl i s hes the di a gnos i s . Trea tment i s s urgi ca l exci s i on us i ng conventi ona l techni ques or by Mohs ' s urgery.
Other malignant tumors: Thes e types of tumors a re l es s common; they i ncl ude s qua mous cel l ca rci noma , mei bomi a n gl a nd ca rci noma , a nd
mel a noma s . Eyel i d tumors ma y s i mul a te chroni c bl epha ri ti s or chroni c cha l a zi on. Therefore, chroni c bl epha ri ti s , chroni c cha l a zi on, or s i mi l a r
l es i ons s houl d be bi ops i ed i f unres pons i ve to i ni ti a l trea tment.
Chapter 63. Conjunctival and Scleral Disorders

Introduction
The conjuncti va l i nes the ba ck of the eyel i ds (pa l pebra l or ta rs a l conjuncti va ), cros s es the s pa ce between the l i d a nd the gl obe (forni cea l
conjuncti va ), then fol ds ba ck on i ts el f a s i t s prea ds over the s cl era to the cornea (bul ba r conjuncti va ). The conjuncti va hel ps ma i nta i n the tea r fi l m
a nd protect the eye from forei gn objects a nd i nfecti on.
The s cl era i s the thi ck whi te s phere of dens e connecti ve ti s s ue tha t encl os es the eye a nd ma i nta i ns i ts s ha pe. Anteri orl y, the s cl era fus es wi th the
cornea , a nd pos teri orl y i t bl ends wi th the meni nges where the opti c nerve penetra tes the gl obe.
The epi s cl era i s a thi n va s cul a r membra ne between the conjuncti va a nd the s cl era .
The mos t common di s orders a re i nfl a mma tory (eg, conjuncti vi ti s , epi s cl eri ti s , s cl eri ti s ). Conjuncti vi ti s ca n be a cute or chroni c a nd i s i nfecti ous ,
a l l ergi c, or i rri ta nt i n ori gi n. Scl eri ti s us ua l l y res ul ts from i mmune-medi a ted di s ea s e a nd epi s cl eri ti s often does a s wel l . Epi s cl eri ti s us ua l l y does
not threa ten vi s i on, but s cl eri ti s ca n des troy vi s i on a nd the eye. Ma jor s ymptoms of conjuncti vi ti des (eg, conjuncti va l hyperemi a ) a re s i mi l a r. Ea rl y,
a ccura te di a gnos i s i s i mporta nt.
Select eye findings in conjunctival disorders: Edema of the bul ba r conjuncti va res ul ts i n a tra ns l ucent, bl ui s h, thi ckened conjuncti va . Gros s edema wi th
ba l l ooni ng of the conjuncti va , often l ea di ng to prol a ps e of conjuncti va , i s known a s chemos i s .
Edema of the ta rs a l conjuncti va (typi ca l of a l l ergi c conjuncti vi ti s ) res ul ts i n fi ne, mi nute projecti ons (pa pi l l a e), gi vi ng the conjuncti va a vel vety
a ppea ra nce.
Hyperpl a s i a of l ymphoi d fol l i cl es i n the conjuncti va ca n occur i n vi ra l or chl a mydi a l conjuncti vi ti s . It a ppea rs a s s ma l l bumps wi th pa l e centers ,
res embl i ng cobbl es tones . It occurs mos t commonl y i n the i nferi or ta rs a l conjuncti va .
Cicatricial Pemphigoid
(Beni gn Mucous Membra ne Pemphi goi d; Mucous Membra ne Pemphi goi d; Ocul a r Ci ca tri ci a l Pemphi goi d)
Cicatricial pemphigoid is a chronic, bilateral, progressive scarring and shrinkage of the conjunctiva with opacification of the cornea. Early symptoms are
hyperemia, discomfort, itching, and discharge; progression leads to eyelid and corneal damage and sometimes blindness. Diagnosis may be confirmed by biopsy,
but biopsy is often not necessary. Treatment may require systemic immunosuppression.
Ci ca tri ci a l pemphi goi d i s a n a utoi mmune di s ea s e i n whi ch bi ndi ng of a nti conjuncti va l ba s ement membra ne a nti bodi es res ul ts i n conjuncti va l
i nfl a mma ti on. It i s unrel a ted to bul l ous pemphi goi d.
Symptoms and Signs
Us ua l l y begi nni ng a s a chroni c conjuncti vi ti s , the condi ti on progres s es to s ymbl epha ron (a dhes i on between the ta rs a l a nd bul ba r conjuncti va );
tri chi a s i s (i n-turni ng eyel a s hes ); kera toconjuncti vi ti s s i cca ; cornea l neova s cul a ri za ti on, opa ci fi ca ti on, a nd kera ti ni za ti on; a nd conjuncti va l
s hri nka ge a nd kera ti ni za ti on. Chroni c cornea l epi thel i a l defects ca n l ea d to s econda ry ba cteri a l ul cera ti on, s ca rri ng, a nd bl i ndnes s . Ora l mucous
membra ne i nvol vement wi th ul cera ti on a nd s ca rri ng i s common, but s ki n i nvol vement, cha ra cteri zed by s ca rri ng bul l a e a nd erythema tous pl a ques ,
i s uncommon.
Diagnosis
Unexpl a i ned s ymbl epha ron or bi ops y fi ndi ngs
Di a gnos i s i s s us pected cl i ni ca l l y i n pa ti ents wi th conjuncti va l s ca rri ng pl us cornea l cha nges , s ymbl epha ron, or both. The di fferenti a l di a gnos i s of
progres s i ve conjuncti va l s ca rri ng i ncl udes pos tra di a ti on a nd a topi c di s ea s e. Therefore, the cl i ni ca l di a gnos i s of ci ca tri ci a l pemphi goi d i s ma de
when there i s progres s i on of s ymbl epha ron wi thout a hi s tory of l oca l ra di a ti on or s evere perenni a l a l l ergi c conjuncti vi ti s . Di a gnos i s ca n be
confi rmed by conjuncti va l bi ops y s howi ng a nti body depos i ti on on the ba s ement membra ne.
Treatment
Epi l a ti on of i n-turni ng l a s hes
Someti mes s ys temi c i mmunos uppres s i on
Tea r s ubs ti tutes a nd epi l a ti on, cryoepi l a ti on, or el ectroepi l a ti on of the i n-turni ng eyel a s hes ma y i ncrea s e pa ti ent comfort a nd reduce the ri s k of
ocul a r i nfecti on a nd s econda ry s ca rri ng. For progres s i ve s ca rri ng or cornea l opa ci fi ca ti on or for nonhea l i ng cornea l epi thel i a l defects , s ys temi c
i mmunos uppres s i on wi th da ps one or cycl ophos pha mi de i s i ndi ca ted.
Conjunctivitis
Conjunctival inflammation typically results from infection, allergy, or irritation. Symptoms are conjunctival hyperemia and ocular discharge and, depending on the
etiology, discomfort and itching. Diagnosis is clinical; sometimes cultures are indicated. Treatment depends on etiology and may include topical antibiotics,
antihistamines, mast cell stabilizers, and corticosteroids.
Infecti ous conjuncti vi ti s i s mos t commonl y vi ra l or ba cteri a l a nd i s conta gi ous . Ra rel y, mi xed or uni denti fi a bl e pa thogens a re pres ent. Numerous
a l l ergens ca n ca us e a l l ergi c conjuncti vi ti s (s ee p. 584). Nona l l ergi c conjuncti va l i rri ta ti on ca n res ul t from forei gn bodi es ; wi nd, dus t, s moke, fumes ,
chemi ca l va pors , a nd other types of a i r pol l uti on; a nd i ntens e ul tra vi ol et l i ght of el ectri c a rcs , s unl a mps , a nd refl ecti on from s now.
Conjuncti vi ti s i s typi ca l l y a cute, but both i nfecti ous a nd a l l ergi c condi ti ons ca n be chroni c. Condi ti ons tha t ca us e chroni c conjuncti vi ti s i ncl ude
ectropi on, entropi on, bl epha ri ti s , a nd chroni c da cryocys ti ti s .
Symptoms and Signs
Any s ource of i nfl a mma ti on ca us es l a cri ma ti on or di s cha rge a nd di ffus e conjuncti va l va s cul a r di l a ti on. Di s cha rge ma y ca us e the eyes to crus t
overni ght. Thi ck di s cha rge ma y bl ur vi s i on, but once di s cha rge i s cl ea red, vi s ua l a cui ty s houl d be una ffected.
Itchi ng a nd wa tery di s cha rge predomi na te i n a l l ergi c conjuncti vi ti s . Chemos i s a nd pa pi l l a ry hyperpl a s i a a l s o s ugges t a l l ergi c conjuncti vi ti s .
Irri ta ti on or forei gn body s ens a ti on, photophobi a , a nd di s cha rge s ugges t i nfecti ous conjuncti vi ti s ; purul ent di s cha rge s ugges ts a ba cteri a l ca us e.
Severe eye pa i n s ugges ts s cl eri ti s (s ee p. 587).
Diagnosis
Someti mes cul ture
Us ua l l y, di a gnos i s i s ma de by hi s tory a nd exa mi na ti on (s ee a l s o
Ta bl e 63-1), us ua l l y i ncl udi ng s l i t-l a mp exa mi na ti on wi th fl uores cei n s ta i ni ng of the cornea a nd, i f gl a ucoma i s s us pected, mea s urement of
i ntra ocul a r pres s ure.
Other di s orders ca n ca us e a red eye (s ee p. 563). Deep pa i n i n the a ffected eye when a l i ght i s s hone i n the una ffected eye (true photophobi a )
does not occur i n uncompl i ca ted conjuncti vi ti s a nd s ugges ts a di s order of the cornea or a nteri or uvea l tra ct. Ci rcumcornea l conjuncti va l hyperemi a
(s ometi mes des cri bed a s ci l i a ry fl us h) i s ca us ed by di l a ted, fi ne, s tra i ght, deep ves s el s tha t ra di a te out 1 to 3 mm from the l i mbus , wi thout
s i gni fi ca nt hyperemi a of the bul ba r a nd ta rs a l conjuncti va e. Ci l i a ry fl us h occurs wi th uvei ti s , a cute gl a ucoma , a nd s ome types of kera ti ti s .
The ca us e of conjuncti vi ti s i s s ugges ted by cl i ni ca l fi ndi ngs . However, cul tures a re i ndi ca ted for pa ti ents wi th s evere s ymptoms ,
i mmunocompromi s e, a vul nera bl e eye (eg, a fter a cornea l tra ns pl a nt, i n exophtha l mos due to Gra ves ' di s ea s e), or i neffecti ve i ni ti a l thera py.
Cl i ni ca l di fferenti a ti on between vi ra l a nd ba cteri a l i nfecti ous conjuncti vi ti s i s not hi ghl y a ccura te. However, tempora ri l y mi s s i ng s ome ca s es of
mi l d ba cteri a l conjuncti vi ti s i s not l i kel y to be ha rmful beca us e the i nfecti on often res ol ves s ponta neous l y a nd a nti bi oti cs ca n be pres cri bed i f
s ymptoms pers i s t.
Treatment
Preventi on of s prea d
Trea tment of s ymptoms
Mos t i nfecti ous conjuncti vi ti s i s hi ghl y conta gi ous a nd s prea ds by dropl et, fomi tes , a nd ha nd-to-eye i nocul a ti on. To a voi d tra ns mi tti ng i nfecti on,
phys i ci a ns mus t wa s h thei r ha nds thoroughl y a nd di s i nfect equi pment a fter exa mi ni ng pa ti ents . Pa ti ents s houl d wa s h thei r ha nds thoroughl y
a fter touchi ng thei r eyes or na s a l s ecreti ons , a voi d touchi ng the noni nfected eye a fter touchi ng the i nfected eye, a voi d s ha ri ng towel s or pi l l ows ,
a nd a voi d s wi mmi ng i n pool s . Eyes s houl d be kept free of di s cha rge a nd s houl d not be pa tched. Sma l l chi l dren wi th conjuncti vi ti s s houl d be kept
home from s chool to a voi d s prea d. Cool wa s h-cl oths a ppl i ed to the eyes ma y hel p rel i eve l oca l burni ng a nd i tchi ng. Anti mi crobi a l s a re us ed for
certa i n i nfecti ons .
Viral Conjunctivitis
Viral conjunctivitis is a highly contagious acute conjunctival infection usually caused by adenovirus. Symptoms include irritation, photophobia, and watery
discharge. Diagnosis is clinical. Infection is self-limited, but severe cases sometimes require topical corticosteroids.
Etiology
Conjuncti vi ti s ma y a ccompa ny the common col d a nd other s ys temi c vi ra l i nfecti ons (es peci a l l y mea s l es , but a l s o chi ckenpox, rubel l a , a nd mumps ).
Is ol a ted vi ra l conjuncti vi ti s us ua l l y res ul ts from a denovi rus es a nd s ometi mes enterovi rus es .
Epi demi c kera toconjuncti vi ti s us ua l l y res ul ts from a denovi rus s erotypes Ad 5, 8, 11, 13, 19, a nd 37. Pha ryngoconjuncti va l fever us ua l l y res ul ts from
s erotypes Ad 3, 4, a nd 7. Outbrea ks of a cute hemorrha gi c conjuncti vi ti s , a ra re conjuncti vi ti s a s s oci a ted wi th i nfecti on by enterovi rus type 70, ha ve
occurred i n Afri ca a nd As i a .
Symptoms and Signs
After a n i ncuba ti on peri od of a bout 5 to 12 da ys , conjuncti va l hyperemi a , wa tery di s cha rge, a nd ocul a r i rri ta ti on us ua l l y begi n i n one eye a nd
s prea d ra pi dl y to the other. Fol l i cl es ma y be pres ent on the pa l pebra l conjuncti va . A prea uri cul a r l ymph node i s often enl a rged a nd pa i nful . Ma ny
pa ti ents ha ve ha d conta ct wi th s omeone wi th conjuncti vi ti s , a recent URI, or both.
[Table 63-1. Di fferenti a ti ng Fea tures i n Acute Conjuncti vi ti s ]
In s evere a denovi ra l conjuncti vi ti s , pa ti ents ma y ha ve photophobi a a nd forei gn body s ens a ti on. Chemos i s ma y be pres ent. Ps eudomembra nes of
fi bri n a nd i nfl a mma tory cel l s on the ta rs a l conjuncti va , foca l cornea l i nfl a mma ti on, or both ma y bl ur vi s i on. Even a fter conjuncti vi ti s ha s res ol ved,
res i dua l cornea l s ubepi thel i a l opa ci ti es (mul ti pl e, coi n-s ha ped, 0.5 to 1.0 mm i n di a meter) ma y be vi s i bl e wi th a s l i t l a mp for up to 2 yr. Cornea l
opa ci ti es occa s i ona l l y res ul t i n decrea s ed vi s i on a nd s i gni fi ca nt gl a re.
Diagnosis
Di a gnos i s of conjuncti vi ti s a nd di fferenti a ti on between ba cteri a l , vi ra l , a nd noni nfecti ous conjuncti vi ti s a re us ua l l y cl i ni ca l ; s peci a l ti s s ue
cul tures a re neces s a ry for growth of the vi rus but a re ra rel y i ndi ca ted. Fea tures tha t ma y hel p di fferenti a te between vi ra l a nd ba cteri a l
conjuncti vi ti s ca n i ncl ude purul ence of eye di s cha rge, pres ence of prea uri cul a r l ympha denopa thy, a nd, i n epi demi c kera toconjuncti vi ti s , chemos i s .
Pa ti ents wi th photophobi a a re s ta i ned wi th fl uores cei n a nd exa mi ned wi th a s l i t l a mp. Epi demi c kera toconjuncti vi ti s ma y ca us e puncta te cornea l
s ta i ni ng. Seconda ry ba cteri a l i nfecti on of vi ra l conjuncti vi ti s i s ra re. However, i f a ny s i gns s ugges t ba cteri a l conjuncti vi ti s (eg, purul ent di s cha rge),
s mea rs from the eye ma y be exa mi ned mi cros copi ca l l y a nd cul tured for ba cteri a .
Treatment
Vi ra l conjuncti vi ti s i s hi ghl y conta gi ous , a nd tra ns mi s s i on preca uti ons mus t be fol l owed (a s des cri bed previ ous l y). Chi l dren s houl d genera l l y be
kept out of s chool unti l res ol uti on.
Vi ra l conjuncti vi ti s i s s el f-l i mi ti ng, l a s ti ng 1 wk i n mi l d ca s es to up to 3 wk i n s evere ca s es . It requi res onl y wa rm or cool compres s es for
s ymptoma ti c rel i ef. However, pa ti ents who ha ve s evere photophobi a or whos e vi s i on i s a ffected ma y benefi t from topi ca l corti cos teroi ds (eg, 1%
predni s ol one a ceta te q 6 to 8 h). Corti cos teroi ds , i f pres cri bed, a re us ua l l y pres cri bed by a n ophtha l mol ogi s t. Herpes s i mpl ex kera ti ti s (s ee p. 589)
mus t be rul ed out fi rs t (by fl uores cei n s ta i ni ng a nd s l i t-l a mp exa mi na ti on) beca us e corti cos teroi ds ca n exa cerba te i t.
Acute Bacterial Conjunctivitis
Acute conjunctivitis can be caused by numerous bacteria. Symptoms are hyperemia, lacrimation, irritation, and discharge. Diagnosis is clinical. Treatment is with
topical antibiotics, augmented by systemic antibiotics in more serious cases.
Mos t ba cteri a l conjuncti vi ti s i s a cute; chroni c ba cteri a l conjuncti vi ti s ma y be ca us ed by Chlamydia a nd ra rel y Moraxella. Chl a mydi a l conjuncti vi ti s
i ncl udes tra choma a nd a dul t or neona ta l i ncl us i on conjuncti vi ti s .
Etiology
Ba cteri a l conjuncti vi ti s i s us ua l l y ca us ed by Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus s p, or, l es s commonl y, Chlamydia trachomatis
(s ee p. 583). Neisseria gonorrhoeae ca us es gonococca l conjuncti vi ti s , whi ch us ua l l y res ul ts from s exua l conta ct wi th a pers on who ha s a geni ta l
i nfecti on.
Ophtha l mi a neona torum (s ee a l s o p. 2824) i s conjuncti vi ti s tha t occurs i n 20 to 40% of neona tes del i vered through a n i nfected bi rth ca na l . It ca n be
ca us ed by ma terna l gonococca l or chl a mydi a l i nfecti on.
Symptoms and Signs
Symptoms a re typi ca l l y uni l a tera l but frequentl y s prea d to the oppos i te eye wi thi n a few da ys . Di s cha rge i s typi ca l l y purul ent.
The bul ba r a nd ta rs a l conjuncti va e a re i ntens el y hyperemi c a nd edema tous . Petechi a l s ubconjuncti va l hemorrha ges , chemos i s , photophobi a , a nd
a n enl a rged prea uri cul a r l ymph node a re typi ca l l y a bs ent. Eyel i d edema i s often modera te.
Wi th a dul t gonococca l conjuncti vi ti s , s ymptoms devel op 12 to 48 h a fter expos ure. Severe eyel i d edema , chemos i s , a nd a profus e purul ent exuda te
a re typi ca l . Ra re compl i ca ti ons i ncl ude cornea l ul cera ti on, a bs ces s , perfora ti on, pa nophtha l mi ti s , a nd bl i ndnes s .
Ophtha l mi a neona torum ca us ed by gonococca l i nfecti on a ppea rs 2 to 5 da ys a fter del i very. Wi th ophtha l mi a neona torum ca us ed by a chl a mydi a l
i nfecti on, s ymptoms a ppea r wi thi n 5 to 14 da ys . Symptoms of both a re bi l a tera l , i ntens e pa pi l l a ry conjuncti vi ti s wi th l i d edema , chemos i s , a nd
mucopurul ent di s cha rge.
Diagnosis
Di a gnos i s of conjuncti vi ti s a nd di fferenti a ti on between ba cteri a l , vi ra l , a nd noni nfecti ous conjuncti vi ti s a re us ua l l y cl i ni ca l . Smea rs a nd ba cteri a l
cul tures s houl d be done i n pa ti ents wi th s evere s ymptoms , i mmunocompromi s e, i neffecti ve i ni ti a l thera py, or a vul nera bl e eye (eg, a fter a cornea l
tra ns pl a nt, i n exophtha l mos due to Gra ves ' di s ea s e). Smea rs a nd conjuncti va l s cra pi ngs s houl d be exa mi ned mi cros copi ca l l y a nd s ta i ned wi th
Gra m s ta i n to i denti fy ba cteri a a nd s ta i ned wi th Gi ems a s ta i n to i denti fy the cha ra cteri s ti c epi thel i a l cel l ba s ophi l i c cytopl a s mi c i ncl us i on bodi es
of chl a mydi a l conjuncti vi ti s .
Treatment
Anti bi oti cs (topi ca l for a l l ca us es except gonococca l )
Ba cteri a l conjuncti vi ti s i s very conta gi ous , a nd s ta nda rd i nfecti on control mea s ures (s ee p. 581) s houl d be fol l owed.
If nei ther gonococca l nor chl a mydi a l i nfecti on i s s us pected, mos t cl i ni ci a ns trea t pres umpti vel y wi th moxi fl oxa ci n 0.5% drops ti d for 7 to 10 da ys or
a nother fl uoroqui nol one or tri methopri m/pol ymyxi n B qi d. A poor cl i ni ca l res pons e a fter 2 or 3 da ys i ndi ca tes tha t the ca us e i s res i s ta nt ba cteri a ,
a vi rus , or a n a l l ergy. Cul ture a nd s ens i ti vi ty s tudi es determi ne s ubs equent trea tment.
Adul t gonococca l conjuncti vi ti s requi res a s i ngl e dos e of ceftri a xone 1 g IM. Fl uoroqui nol ones a re no l onger recommended beca us e res i s ta nce i s
now wi des prea d. Ba ci tra ci n 500 U/g or genta mi ci n 0.3% ophtha l mi c oi ntment i ns ti l l ed i nto the a ffected eye q 2 h ma y be us ed i n a ddi ti on to
s ys temi c trea tment. Sex pa rtners s houl d a l s o be trea ted. Beca us e chl a mydi a l geni ta l i nfecti on i s often pres ent i n pa ti ents wi th gonorrhea ,
pa ti ents s houl d a l s o recei ve a s i ngl e dos e of a zi thromyci n 1 g or doxycycl i ne 100 mg po bi d for 7 da ys .
Ophtha l mi a neona torum i s prevented by the routi ne us e of s i l ver ni tra te eye drops or erythromyci n oi ntment a t bi rth. Infecti ons tha t devel op
des pi te thi s trea tment requi re s ys temi c trea tment. For gonococca l i nfecti on, ceftri a xone 25 to 50 mg/kg IV or IM i s gi ven once/da y for 7 da ys .
Chl a mydi a l i nfecti on i s trea ted wi th erythromyci n 12.5 mg/kg po or IV qi d for 14 da ys . The pa rents s houl d a l s o be trea ted.
Adult Inclusion Conjunctivitis
(Adul t Chl a mydi a l Conjuncti vi ti s ; Swi mmi ng Pool Conjuncti vi ti s )
Adult inclusion conjunctivitis is caused by sexually transmitted Chlamydia trachomatis. Symptoms include chronic unilateral hyperemia and mucopurulent
discharge. Diagnosis is clinical. Treatment is with systemic antibiotics.
Adul t i ncl us i on conjuncti vi ti s i s ca us ed by Chlamydia trachomatis s erotypes D through K. In mos t i ns ta nces , a dul t i ncl us i on conjuncti vi ti s res ul ts
from s exua l conta ct wi th a pers on who ha s a geni ta l i nfecti on. Us ua l l y, pa ti ents ha ve a cqui red a new s ex pa rtner i n the precedi ng 2 mo. Ra rel y,
a dul t i ncl us i on conjuncti vi ti s i s a cqui red from conta mi na ted, i ncompl etel y chl ori na ted s wi mmi ng pool wa ter.
Symptoms and Signs
Adul t i ncl us i on conjuncti vi ti s ha s a n i ncuba ti on peri od of 2 to 19 da ys . Mos t pa ti ents ha ve a uni l a tera l mucopurul ent di s cha rge. The ta rs a l
conjuncti va i s often more hyperemi c tha n the bul ba r conjuncti va . Cha ra cteri s ti ca l l y, there i s a ma rked ta rs a l fol l i cul a r res pons e. Occa s i ona l l y,
s uperi or cornea l opa ci ti es a nd va s cul a ri za ti on occur. Prea uri cul a r l ymph nodes ma y be s wol l en on the s i de of the i nvol ved eye. Often, s ymptoms
ha ve been pres ent for ma ny weeks or months a nd ha ve not res ponded to topi ca l a nti bi oti cs .
Diagnosis
La bora tory tes ti ng
Chroni ci ty, mucopurul ent di s cha rge, ma rked ta rs a l fol l i cul a r res pons e, a nd fa i l ure of topi ca l a nti bi oti cs di fferenti a te a dul t i ncl us i on conjuncti vi ti s
from other ba cteri a l conjuncti vi ti des . Smea rs , ba cteri a l cul tures , a nd chl a mydi a l s tudi es s houl d be done. Immunofl uores cent s ta i ni ng techni ques ,
PCR, a nd s peci a l cul tures a re us ed to detect C. trachomatis. Smea rs a nd conjuncti va l s cra pi ngs s houl d be exa mi ned mi cros copi ca l l y a nd s ta i ned
wi th Gra m s ta i n to i denti fy ba cteri a a nd s ta i ned wi th Gi ems a s ta i n to i denti fy the cha ra cteri s ti c epi thel i a l cel l ba s ophi l i c cytopl a s mi c i ncl us i on
bodi es of chl a mydi a l conjuncti vi ti s .
Treatment
Anti bi oti cs
Azi thromyci n 1 g po once onl y or ei ther doxycycl i ne 100 mg po bi d or erythromyci n 500 mg po qi d for 1 wk cures the conjuncti vi ti s a nd concomi ta nt
geni ta l i nfecti on. Sex pa rtners a l s o requi re trea tment.
Trachoma
(Egypti a n Ophtha l mi a ; Gra nul a r Conjuncti vi ti s )
Trachoma is a chronic conjunctivitis caused by Chlamydia trachomatis and is characterized by progressive exacerbations and remissions. It is the leading cause of
preventable blindness worldwide. Initial symptoms are conjunctival hyperemia, eyelid edema, photophobia, and lacrimation. Later, corneal neovascularization
and scarring of the conjunctiva, cornea, and eyelids occur. Diagnosis is usually clinical. Treatment is with topical or systemic antibiotics.
Tra choma i s endemi c i n poverty-s tri cken pa rts of North Afri ca , the Mi ddl e Ea s t, the Indi a n s ubconti nent, Aus tra l i a , a nd Southea s t As i a . The
ca us a ti ve orga ni s m i s Chlamydia trachomatis (s erotypes A, B, Ba , a nd C). In the US, tra choma i s ra re, occurri ng occa s i ona l l y a mong Na ti ve Ameri ca ns
a nd i mmi gra nts . The di s ea s e occurs ma i nl y i n chi l dren, pa rti cul a rl y thos e between the a ges of 3 a nd 6. Ol der chi l dren a nd a dul ts a re much l es s
s us cepti bl e beca us e of i ncrea s ed i mmuni ty a nd better pers ona l hygi ene. Tra choma i s hi ghl y conta gi ous i n i ts ea rl y s ta ges a nd i s tra ns mi tted by
eye-to-eye conta ct, ha nd-to-eye conta ct, eye-s eeki ng fl i es , or the s ha ri ng of conta mi na ted a rti cl es (eg, towel s , ha ndkerchi efs , eye ma keup).
Symptoms and Signs
Tra choma us ua l l y a ffects both eyes . After a n i ncuba ti on peri od of a bout 7 da ys , conjuncti va l hyperemi a , eyel i d edema , photophobi a , a nd
l a cri ma ti on gra dua l l y a ppea r, us ua l l y bi l a tera l l y. Sma l l fol l i cl es devel op i n the upper ta rs a l conjuncti va 7 to 10 da ys l a ter a nd gra dua l l y i ncrea s e
i n s i ze a nd number for 3 or 4 wk (s ee
Pl a te 20). Infl a mma tory pa pi l l a e a ppea r on the upper ta rs a l conjuncti va , a nd cornea l neova s cul a ri za ti on begi ns duri ng thi s s ta ge, wi th i nva s i on of
the upper ha l f of the cornea by l oops of ves s el s from the l i mbus (ca l l ed pa nnus ). The s ta ge of fol l i cul a r/pa pi l l a ry hypertrophy a nd cornea l
neova s cul a ri za ti on ma y l a s t from s evera l months to > 1 yr, dependi ng on res pons e to thera py. The enti re cornea ma y ul ti ma tel y be i nvol ved,
reduci ng vi s i on.
Wi thout trea tment, a ci ca tri ci a l (s ca rri ng) s ta ge fol l ows . The fol l i cl es a nd pa pi l l a e gra dua l l y s hri nk a nd a re repl a ced by s ca r ti s s ue tha t often
ca us es entropi on a nd l a cri ma l duct obs tructi on. Entropi on l ea ds to further cornea l s ca rri ng a nd neova s cul a ri za ti on. Seconda ry ba cteri a l i nfecti on
i s common, contri buti ng to s ca rri ng a nd di s ea s e progres s i on. The cornea l epi thel i um becomes dul l a nd thi ckened, a nd l a cri ma ti on i s decrea s ed.
Sma l l cornea l ul cers ma y a ppea r a t the s i te of peri phera l cornea l i nfi l tra tes , s ti mul a ti ng further neova s cul a ri za ti on.
Wi th trea tment a nd hea l i ng, the conjuncti va becomes s mooth a nd gra yi s h whi te. Ra rel y, cornea l neova s cul a ri za ti on regres s es compl etel y wi thout
trea tment, a nd cornea l tra ns pa rency i s res tored. Impa i red vi s i on or bl i ndnes s occurs i n a bout 5% of peopl e wi th tra choma .
Diagnosis
Cl i ni ca l fi ndi ngs (eg, ta rs a l l ymphoi d fol l i cl es , l i nea r conjuncti va l s ca rs , cornea l pa nnus )
Di a gnos i s i s us ua l l y cl i ni ca l beca us e tes ti ng i s ra rel y a va i l a bl e i n endemi c a rea s . Lymphoi d fol l i cl es on the ta rs a l pl a te or a l ong the cornea l
l i mbus , l i nea r conjuncti va l s ca rri ng, a nd cornea l pa nnus a re cons i dered di a gnos ti c i n the a ppropri a te cl i ni ca l s etti ng. If di a gnos i s i s uncerta i n, C.
trachomatis ca n be i s ol a ted i n cul ture or i denti fi ed by PCR a nd i mmunofl uores cence techni ques . In the ea rl y s ta ge, mi nute ba s ophi l i c cytopl a s mi c
i ncl us i on bodi es wi thi n conjuncti va l epi thel i a l cel l s i n Gi ems a -s ta i ned conjuncti va l s cra pi ngs di fferenti a te tra choma from nonchl a mydi a l
conjuncti vi ti s . Incl us i on bodi es a re a l s o found i n a dul t i ncl us i on conjuncti vi ti s (s ee p. 583), but the s etti ng a nd devel opi ng cl i ni ca l pi cture
di s ti ngui s h i t from tra choma . Pa l pebra l verna l conjuncti vi ti s a ppea rs s i mi l a r to tra choma i n i ts fol l i cul a r hypertrophi c s ta ge, but s ymptoms a re
di fferent, mi l ky fl a t-topped pa pi l l a e a re pres ent, a nd eos i nophi l s (not ba s ophi l i c i ncl us i on bodi es ) a re found i n the s cra pi ngs .
Treatment
Ora l a zi thromyci n
For i ndi vi dua l or s pora di c ca s es , a zi thromyci n 20 mg/kg (ma xi mum 1 g) po a s a s i ngl e dos e i s 78% effecti ve. Al terna ti ves a re doxycycl i ne 100 mg bi d
or tetra cycl i ne 250 mg qi d for 4 wk. In hyperendemi c a rea s , tetra cycl i ne or erythromyci n ophtha l mi c oi ntment a ppl i ed bi d for 5 cons ecuti ve da ys
ea ch month for 6 mo ha s been effecti ve a s trea tment a nd prophyl a xi s . Endemi c tra choma ha s been dra ma ti ca l l y reduced by us i ng communi ty-wi de
ora l a zi thromyci n i n a s i ngl e dos e or i n repea ted dos es . Rei nfecti on due to re-expos ure i s common a mong endemi c a rea s . Better pers ona l hygi ene
a nd envi ronmenta l mea s ures (eg, a cces s to pota bl e wa ter) ca n reduce rei nfecti on.
Eyel i d deformi ti es (eg, entropi on) s houl d be trea ted s urgi ca l l y.
Allergic Conjunctivitis
(Atopi c Conjuncti vi ti s ; Atopi c Kera toconjuncti vi ti s ; Ha y Fever Conjuncti vi ti s ; Perenni a l Al l ergi c Conjuncti vi ti s ; Sea s ona l Al l ergi c Conjuncti vi ti s ; Verna l
Kera toconjuncti vi ti s )
Allergic conjunctivitis is an acute, intermittent, or chronic conjunctival inflammation usually caused by airborne allergens. Symptoms include itching, lacrimation,
discharge, and conjunctival hyperemia. Diagnosis is clinical. Treatment is with topical antihistamines and mast cell stabilizers.
Etiology
Al l ergi c conjuncti vi ti s i s due to a type I hypers ens i ti vi ty rea cti on to a s peci fi c a nti gen.
Seasonal allergic conjunctivitis (ha y fever conjuncti vi ti s ) i s ca us ed by a i rborne pol l en of trees , gra s s es , or weeds . It tends to pea k duri ng the s pri ng,
l a te s ummer, or ea rl y fa l l a nd di s a ppea r duri ng the wi nter months corres pondi ng to the l i fe cycl e of the ca us a ti ve pl a nt.
Perennial allergic conjunctivitis (a topi c conjuncti vi ti s , a topi c kera toconjuncti vi ti s ) i s ca us ed by dus t mi tes , a ni ma l da nder, a nd other nons ea s ona l
a l l ergens . Thes e a l l ergens , pa rti cul a rl y thos e i n the home, tend to ca us e s ymptoms yea r-round.
Vernal keratoconjunctivitis i s a more s evere type of conjuncti vi ti s mos t l i kel y a l l ergi c i n ori gi n. It i s mos t common a mong ma l es a ged 5 to 20 who a l s o
ha ve eczema , a s thma , or s ea s ona l a l l ergi es . Verna l conjuncti vi ti s typi ca l l y rea ppea rs ea ch s pri ng a nd s ubs i des i n the fa l l a nd wi nter. Ma ny
chi l dren outgrow the condi ti on by ea rl y a dul thood.
Symptoms and Signs
General: Pa ti ents report bi l a tera l mi l d to i ntens e ocul a r i tchi ng, conjuncti va l hyperemi a , photos ens i ti vi ty (photophobi a i n s evere ca s es ), eyel i d
edema , a nd wa tery or s tri ngy di s cha rge. Concomi ta nt rhi ni ti s i s common. Ma ny pa ti ents ha ve other a topi c di s ea s es , s uch a s eczema , a l l ergi c
rhi ni ti s , or a s thma .
Fi ndi ngs cha ra cteri s ti ca l l y i ncl ude conjuncti va l edema a nd hyperemi a a nd a di s cha rge. The bul ba r conjuncti va ma y a ppea r tra ns l ucent, bl ui s h, a nd
thi ckened. Chemos i s a nd a cha ra cteri s ti c boggy bl epha redema of the l ower eyel i d a re common. Chroni c i tchi ng ca n l ea d to chroni c eyel i d rubbi ng,
peri ocul a r hyperpi gmenta ti on, a nd derma ti ti s .
Seasonal and perennial conjunctivitis: Fi ne pa pi l l a e on the upper ta rs a l conjuncti va gi ve i t a vel vety a ppea ra nce. In more s evere forms , l a rger ta rs a l
conjuncti va l pa pi l l a e, conjuncti va l s ca rri ng, cornea l neova s cul a ri za ti on, a nd cornea l s ca rri ng wi th va ri a bl e l os s of vi s ua l a cui ty ca n occur.
Vernal keratoconjunctivitis: Us ua l l y, the pa l pebra l conjuncti va of the upper eyel i d i s i nvol ved, but the bul ba r conjuncti va i s s ometi mes a ffected. In
the pa l pebra l form, s qua re, ha rd, fl a ttened, cl os el y pa cked, pa l e pi nk to gra yi s h cobbl es tone pa pi l l a e a re pres ent, chi efl y i n the upper ta rs a l
conjuncti va (s ee
Pl a te 8). The uni nvol ved ta rs a l conjuncti va i s mi l ky whi te. In the bul ba r (l i mba l ) form, the ci rcumcornea l conjuncti va becomes hypertrophi ed a nd
gra yi s h. Di s cha rge ma y be tena ci ous a nd mucoi d, conta i ni ng numerous eos i nophi l s .
Occa s i ona l l y, a s ma l l , ci rcums cri bed l os s of cornea l epi thel i um occurs , ca us i ng pa i n a nd i ncrea s ed photophobi a . Other cornea l cha nges (eg,
centra l pl a ques ) a nd whi te l i mba l depos i ts of eos i nophi l s (Tra nta s ' dots ) ma y be s een.
Diagnosis
The di a gnos i s i s us ua l l y cl i ni ca l . Eos i nophi l s a re pres ent i n conjuncti va l s cra pi ngs , whi ch ma y be ta ken from the l ower or upper ta rs a l conjuncti va ;
however, s uch tes ti ng i s ra rel y i ndi ca ted.
Treatment
Symptoma ti c mea s ures
Topi ca l a nti hi s ta mi nes , va s ocons tri ctors , NSAIDs , ma s t cel l s ta bi l i zers , or a combi na ti on
Topi ca l corti cos teroi ds or cycl os pori ne for reca l ci tra nt ca s es
Avoi da nce of known a l l ergens a nd us e of tea r s uppl ements ca n reduce s ymptoms ; a nti gen des ens i ti za ti on i s occa s i ona l l y hel pful . Topi ca l OTC
a nti hi s ta mi ne/va s ocons tri ctors (eg, na pha zol i ne/pheni ra mi ne) a re us eful for mi l d ca s es . If thes e drugs a re i ns uffi ci ent, topi ca l pres cri pti on
a nti hi s ta mi nes (eg, ol opa ta di ne, ketoti fen), NSAIDs (eg, ketorol a c), or ma s t cel l s ta bi l i zers (eg, pemi rol a s t, nedocromi l , a zel a s ti ne) ca n be us ed
s epa ra tel y or i n combi na ti on. Topi ca l corti cos teroi ds (eg, l oteprednol , fl uoromethol one 0.1%, predni s ol one a ceta te 0.12% to 1% drops ti d) ca n be
us eful i n reca l ci tra nt ca s es . Beca us e topi ca l corti cos teroi ds ca n exa cerba te ocul a r herpes s i mpl ex vi rus i nfecti ons , pos s i bl y l ea di ng to cornea l
ul cera ti on a nd perfora ti on a nd, wi th l ong-term us e, to gl a ucoma a nd pos s i bl y ca ta ra cts , thei r us e s houl d be i ni ti a ted a nd moni tored by a n
ophtha l mol ogi s t. Topi ca l cycl os pori ne ma y be i ndi ca ted when corti cos teroi ds a re needed but ca nnot be us ed.
Sea s ona l a l l ergi c conjuncti vi ti s i s l es s l i kel y to requi re mul ti pl e drugs or i ntermi ttent topi ca l corti cos teroi ds .
Other Conjunctival Disorders
Pinguecula and pterygium: Thes e l es i ons a re beni gn growths of the conjuncti va tha t ca n res ul t from chroni c a cti ni c i rri ta ti on. Both typi ca l l y a ppea r
a dja cent to the cornea a t the 3-o'cl ock pos i ti on, the 9-o'cl ock pos i ti on, or both (s ee
Fi g. 63-1).
A pinguecula i s a ra i s ed yel l owi s h whi te ma s s on the bul ba r conjuncti va , a dja cent to the cornea . It does not tend to grow onto the cornea . However,
i t ma y ca us e i rri ta ti on or cos meti c bl emi s h a nd, a l though ra rel y neces s a ry, ca n ea s i l y be removed.
A pterygium i s a fl es hy tri a ngul a r growth of bul ba r conjuncti va tha t ma y s prea d a cros s a nd di s tort the cornea , i nduce a s ti gma ti s m, a nd cha nge the
refra cti ve power of the eye. Symptoms ma y i ncl ude decrea s ed vi s i on a nd forei gn body s ens a ti on. It i s more common i n hot, dry cl i ma tes . Remova l
i s often i ndi ca ted for cos mes i s , to reduce i rri ta ti on, a nd to i mprove or pres erve vi s i on.
Subconjunctival hemorrhages: Thes e extra va s a ti ons of bl ood benea th the conjuncti va us ua l l y res ul t from mi nor tra uma , s tra i ni ng, s neezi ng, or
coughi ng; ra rel y, they occur s ponta neous l y. The extent a nd l oca ti on of hyperemi a ca n hel p determi ne eti ol ogy. Di ffus e hyperemi a of the bul ba r
a nd ta rs a l conjuncti va e i s typi ca l of conjuncti vi ti s . Subconjuncti va l hemorrha ges a l a rm the pa ti ent but a re of no pa thol ogi c s i gni fi ca nce except
when a s s oci a ted wi th bl ood dys cra s i a , whi ch i s ra re, or other fa ci a l or ocul a r i njuri es . They a re a bs orbed s ponta neous l y, us ua l l y wi thi n 2 wk.
Topi ca l corti cos teroi ds , a nti bi oti cs , va s ocons tri ctors , a nd compres s es do not s peed rea bs orpti on; rea s s ura nce i s a dequa te thera py.
Episcleritis
Episcleritis is self-limiting, recurring, idiopathic inflammation of the episcleral tissue that does not threaten vision. Symptoms are a localized area of hyperemia of
the globe, irritation, and lacrimation. Diagnosis is clinical. Treatment is symptomatic.
Epi s cl eri ti s occurs i n young a dul ts , more commonl y a mong women. It i s us ua l l y i di opa thi c; i t ca n be a s s oci a ted wi th connecti ve ti s s ue di s ea s es
a nd ra rel y wi th s eri ous s ys temi c di s ea s es .
Mi l d i rri ta ti on occurs . Addi ti ona l l y, a bri ght red pa tch i s pres ent jus t under the bul ba r conjuncti va (s i mpl e epi s cl eri ti s ). A hyperemi c, edema tous ,
ra i s ed nodul e (nodul a r epi s cl eri ti s ) ma y a l s o be pres ent. The pa l pebra l conjuncti va i s norma l .
Epi s cl eri ti s i s di s ti ngui s hed from conjuncti vi ti s beca us e hyperemi a i s l oca l i zed to a l i mi ted a rea of the gl obe a nd l a cri ma ti on i s much l es s . It i s
di s ti ngui s hed from s cl eri ti s by l a ck of photophobi a a nd l a ck of s evere pa i n.
The condi ti on i s s el f-l i mi ted, a nd a di a gnos ti c a s s es s ment for s ys temi c di s orders i s not routi nel y wa rra nted. A topi ca l corti cos teroi d (eg,
predni s ol one a ceta te, 1% drops qi d for 5 da ys , gra dua l l y reduced over 3 wk) or a n ora l NSAID us ua l l y s hortens the a tta ck; corti cos teroi ds a re
us ua l l y pres cri bed by a n ophtha l mol ogi s t. Topi ca l va s ocons tri ctors (eg, tetra hydrozol i ne) to i mprove a ppea ra nce a re opti ona l .
[Fig. 63-1. Pi nguecul a a nd pterygi um.]
Scleritis
Scleritis is a severe, destructive, vision-threatening inflammation involving the deep episclera and sclera. Symptoms are moderate to marked pain, hyperemia of
the globe, lacrimation, and photophobia. Diagnosis is clinical. Treatment is with systemic corticosteroids and possibly immunosuppressants.
Scl eri ti s i s mos t common a mong women a ged 30 to 50 yr, a nd ma ny ha ve connecti ve ti s s ue di s ea s es , s uch a s RA, SLE, pol ya rteri ti s nodos a ,
Wegener's gra nul oma tos i s , or rel a ps i ng pol ychondri ti s . A few ca s es a re i nfecti ous i n ori gi n. About ha l f of the ca s es of s cl eri ti s ha ve no known
ca us e. Scl eri ti s mos t commonl y i nvol ves the a nteri or s egment a nd occurs i n 3 types di ffus e, nodul a r, a nd necroti zi ng (s cl eroma l a ci a perfora ns ).
Symptoms and Signs
Pa i n (often cha ra cteri zed a s a deep, bori ng a che) i s s evere enough to i nterfere wi th s l eep a nd a ppeti te. Photophobi a a nd l a cri ma ti on ma y occur.
Hyperemi c pa tches devel op deep benea th the bul ba r conjuncti va a nd a re more vi ol a ceous tha n thos e of epi s cl eri ti s or conjuncti vi ti s . The
pa l pebra l conjuncti va i s norma l . The i nvol ved a rea ma y be foca l (us ua l l y one qua dra nt of the gl obe) or i nvol ve the enti re gl obe a nd ma y conta i n a
hyperemi c, edema tous , ra i s ed nodul e (nodul a r s cl eri ti s ) or a n a va s cul a r a rea (necroti zi ng s cl eri ti s ). Pos teri or s cl eri ti s i s l es s common a nd i s l es s
l i kel y to ca us e red eye but more l i kel y to ca us e bl urred or decrea s ed vi s i on.
In s evere ca s es of necroti zi ng s cl eri ti s , perfora ti on of the gl obe a nd l os s of the eye ma y res ul t. Connecti ve ti s s ue di s ea s e occurs i n 20% of pa ti ents
wi th di ffus e or nodul a r s cl eri ti s a nd i n 50% of pa ti ents wi th necroti zi ng s cl eri ti s . Necroti zi ng s cl eri ti s i n pa ti ents wi th connecti ve ti s s ue di s ea s e
s i gna l s underl yi ng s ys temi c va s cul i ti s .
Diagnosis
Di a gnos i s i s ma de cl i ni ca l l y a nd by s l i t-l a mp exa mi na ti on. Smea rs or ra rel y bi ops i es a re neces s a ry to confi rm i nfecti ous s cl eri ti s . CT or
ul tra s onogra phy ma y be needed for pos teri or s cl eri ti s .
Prognosis
Of pa ti ents wi th s cl eri ti s , 14% l os e s i gni fi ca nt vi s ua l a cui ty wi thi n 1 yr, a nd 30% l os e s i gni fi ca nt vi s ua l a cui ty wi thi n 3 yr. Pa ti ents wi th necroti zi ng
s cl eri ti s a nd underl yi ng s ys temi c va s cul i ti s ha ve a morta l i ty ra te of up to 50% i n 10 yr (mos tl y due to MI).
Treatment
Sys temi c corti cos teroi ds
Occa s i ona l l y, NSAIDs a re s uffi ci ent for mi l d ca s es . However, us ua l l y a s ys temi c corti cos teroi d (eg, predni s one 1 mg/kg po once/da y) i s the i ni ti a l
thera py. If pa ti ents a re unres pons i ve to or i ntol era nt of s ys temi c corti cos teroi ds or ha ve necroti zi ng s cl eri ti s a nd connecti ve ti s s ue di s ea s e,
s ys temi c i mmunos uppres s i on wi th cycl ophos pha mi de or a za thi opri ne i s i ndi ca ted, but onl y i n cons ul ta ti on wi th a rheuma tol ogi s t. Scl era l gra fts
ma y be i ndi ca ted for threa tened perfora ti on.
Chapter 64. Corneal Disorders

Introduction
The cornea i s s ubject to i nfecti on, noni nfecti ous i nfl a mma ti on, ul cera ti on, mecha ni ca l da ma ge, a nd envi ronmenta l i njury. Infecti on (kera ti ti s ),
frequentl y wi th s econda ry conjuncti vi ti s , ca n be due to vi rus es , ba cteri a , Acanthamoeba, or fungi . Ul cera ti on us ua l l y repres ents progres s i on of
kera ti ti s . Symptoms tha t s ugges t cornea l i nvol vement ra ther tha n s i mpl e conjuncti vi ti s i ncl ude pa i n, pa rti cul a rl y wi th expos ure to l i ght, a nd s l i ght
i mpa i rment of vi s i on. Eva l ua ti on of the cornea requi res s l i t-l a mp exa mi na ti on a nd s ometi mes mi crobi a l s tudi es .
Bullous Keratopathy
Bullous keratopathy is the presence of corneal epithelial bullae, resulting from corneal endothelial disease.
Bul l ous kera topa thy i s ca us ed by edema of the cornea , res ul ti ng from fa i l ure of the cornea l endothel i um to ma i nta i n the norma l l y dehydra ted
s ta te of the cornea . Mos t frequentl y, i t i s due to Fuchs ' cornea l endothel i a l dys trophy or cornea l endothel i a l tra uma . Fuchs ' dys trophy ca us es
bi l a tera l , progres s i ve cornea l endothel i a l cel l l os s , s ometi mes l ea di ng to s ymptoma ti c bul l ous kera topa thy by a ge 50 to 60. Cornea l endothel i a l
tra uma ca n occur duri ng i ntra ocul a r s urgery (eg, ca ta ra ct remova l ) or a fter pl a cement of a poorl y des i gned or ma l pos i ti oned i ntra ocul a r l ens
i mpl a nt, l ea di ng to bul l ous kera topa thy. Bul l ous kera topa thy a fter ca ta ra ct remova l i s ca l l ed ps eudopha ki c (i f a n i ntra ocul a r l ens i mpl a nt i s
pres ent) or a pha ki c (i f no i ntra ocul a r l ens i mpl a nt i s pres ent) bul l ous kera topa thy.
Subepi thel i a l fl ui d-fi l l ed bul l a e form on the cornea l s urfa ce a s the cornea l s troma s wel l s , l ea di ng to eye di s comfort, decrea s ed vi s ua l a cui ty, l os s
of contra s t, gl a re, a nd photophobi a . Someti mes bul l a e rupture, ca us i ng pa i n a nd forei gn body s ens a ti on. Ba cteri a ca n i nva de a ruptured bul l a ,
l ea di ng to a cornea l ul cer.
The bul l a e a nd s wel l i ng of the cornea l s troma ca n be s een on s l i t-l a mp exa mi na ti on.
Trea tment requi res a n ophtha l mol ogi s t a nd i ncl udes topi ca l dehydra ti ng a gents (eg, hypertoni c s a l i ne), i ntra ocul a r pres s ure-l oweri ng a gents , s oft
conta ct l ens es for s ome mi l d to modera te ca s es , a nd trea tment of a ny s econda ry mi crobi a l i nfecti on. Cornea l tra ns pl a nta ti on i s us ua l l y cura ti ve.
Corneal Ulcer
A corneal ulcer is a corneal epithelial defect with underlying inflammation (which soon results in necrosis of corneal tissue) due to invasion by bacteria, fungi,
viruses, or Acanthamoeba. It can be initiated by mechanical trauma or nutritional deficiencies. Symptoms are progressive redness, foreign body sensation, ache,
photophobia, and lacrimation. Diagnosis is by slit-lamp examination, fluorescein staining, and microbial studies. Treatment with topical antimicrobials and often
dilating drops is urgent and requires an ophthalmologist.
Etiology
Cornea l ul cers ha ve ma ny ca us es (s ee
Ta bl e 64-1). Ba cteri a l ul cers (mos t commonl y due to conta ct l ens wea r) ma y compl i ca te herpes s i mpl ex kera ti ti s a nd be pa rti cul a rl y refra ctory to
trea tment. Ul cers ca us ed by Acanthamoeba (a l s o mos t commonl y due to conta ct l ens wea r) a nd fungi (mos t commonl y due to tra uma wi th vegeta bl e
ma teri a l ) a re i ndol ent but progres s i ve; thos e ca us ed by Pseudomonas aeruginosa (s een a l mos t excl us i vel y i n conta ct l ens wea rers ) devel op ra pi dl y,
ca us i ng deep a nd extens i ve cornea l necros i s . Wea ri ng conta ct l ens es whi l e s l eepi ng or wea ri ng i na dequa tel y di s i nfected conta ct l ens es ca n
ca us e cornea l ul cers (s ee p. 572).
Pathophysiology
Ul cers a re cha ra cteri zed by cornea l epi thel i a l defects wi th underl yi ng i nfl a mma ti on, a nd s oon necros i s of the cornea l s troma devel ops . Cornea l
ul cers tend to hea l wi th s ca r ti s s ue, res ul ti ng i n opa ci fi ca ti on of the cornea a nd decrea s ed vi s ua l a cui ty. Uvei ti s , cornea l perfora ti on wi th i ri s
prol a ps e, pus i n the a nteri or cha mber (hypopyon), pa nophtha l mi ti s , a nd des tructi on of the eye ma y occur wi th or wi thout trea tment. More s evere
s ymptoms a nd compl i ca ti ons tend to occur wi th deeper ul cers .
Symptoms and Signs
Conjuncti va l rednes s , eye a che, forei gn body s ens a ti on, photophobi a , a nd l a cri ma ti on ma y be mi ni ma l i ni ti a l l y.
A cornea l ul cer begi ns a s a cornea l epi thel i a l defect tha t s ta i ns wi th fl uores cei n a nd a n underl yi ng dul l , gra yi s h, ci rcums cri bed s uperfi ci a l opa ci ty.
Subs equentl y, the ul cer s uppura tes a nd necros es to form a n exca va ted ul cer. Cons i dera bl e ci rcumcornea l conjuncti va l hyperemi a i s us ua l (s ee
Pl a te 9). In l ong-s ta ndi ng
[Table 64-1. Ca us es of Cornea l Ul cers ]
ca s es , bl ood ves s el s ma y grow i n from the l i mbus (cornea l neova s cul a ri za ti on). The ul cer ma y s prea d to i nvol ve the wi dth of the cornea , ma y
penetra te deepl y, or both. Hypopyon (l a yered WBCs i n the a nteri or cha mber) ma y occur.
Cornea l ul cers due to Acanthamoeba a re often i ntens el y pa i nful a nd ma y s how tra ns i ent cornea l epi thel i a l defects , mul ti pl e cornea l s troma l
i nfi l tra tes , a nd, l a ter, a l a rge ri ngs ha ped i nfi l tra te. Funga l ul cers , whi ch a re more chroni c tha n ba cteri a l ul cers , a re dens el y i nfi l tra ted a nd s how
occa s i ona l di s crete i s l a nds of i nfi l tra te (s a tel l i te l es i ons ) a t the peri phery.
Diagnosis
Sl i t-l a mp exa mi na ti on
Di a gnos i s i s ma de by s l i t-l a mp exa mi na ti on; a cornea l i nfi l tra te wi th a n epi thel i a l defect tha t s ta i ns wi th fl uores cei n i s di a gnos ti c. Al l but s ma l l
ul cers s houl d be cul tured by s cra pi ng wi th a s teri l e pl a ti num s pa tul a (typi ca l l y by a n ophtha l mol ogi s t). Mi cros copi c exa mi na ti on of s cra pi ngs ca n
i denti fy Acanthamoeba.
Treatment
Empi ri c topi ca l broa d-s pectrum a nti bi oti c thera py
More s peci fi c a nti mi crobi a l thera py di rected a t the ca us e
Trea tment for cornea l ul cers , rega rdl es s of ca us e, begi ns wi th moxi fl oxa ci n 0.5% or ga ti fl oxa ci n 0.3% for s ma l l ul cers a nd forti fi ed (hi gher tha n
s tock concentra ti on) a nti bi oti c drops , s uch a s tobra myci n 15 mg/mL a nd cefa zol i n 50 mg/mL, for more s i gni fi ca nt ul cers , pa rti cul a rl y thos e tha t a re
nea r the center of the cornea . Frequent dos i ng (eg, q 15 mi n for 4 dos es , fol l owed by q 1 h a round the cl ock) i s neces s a ry i ni ti a l l y. Pa tchi ng i s
contra i ndi ca ted beca us e i t crea tes a s ta gna nt, wa rm envi ronment tha t fa vors ba cteri a l growth a nd prevents the a dmi ni s tra ti on of topi ca l drugs .
Herpes s i mpl ex (s ee bel ow) i s trea ted wi th tri fl uri di ne 1% drops q 2 h whi l e the pa ti ent i s a wa ke or a cycl ovi r 400 mg po 5 ti mes /da y for a bout 14
da ys .
Funga l i nfecti ons a re trea ted wi th one of ma ny topi ca l a nti funga l drops (eg, na ta myci n 5%, a mphoteri ci n B 0.15%), i ni ti a l l y q 1 h duri ng the da y a nd
q 2 h overni ght. Deep i nfecti ons ma y requi re a ddi ti on of ora l ketocona zol e, fl ucona zol e, or i tra cona zol e.
If Acanthamoeba i s i denti fi ed, tra di ti ona l thera py i s propa mi di ne a nd neomyci n s uppl emented wi th mi cona zol e, cl otri ma zol e, or ora l
ketocona zol e. Addi ti ona l trea tments i ncl ude pol yhexa methyl ene bi gua ni de 0.02% or chl orhexi di ne 0.02% q 1 to 2 h unti l cl i ni ca l i mprovement i s
evi dent, then gra dua l l y reduced to 4 ti mes /da y a nd conti nued for a number of months unti l a l l i nfl a mma ti on ha s res ol ved. Pol yhexa methyl ene
bi gua ni de a nd chl orhexi di ne a re not commerci a l l y a va i l a bl e a s ocul a r a gents but ca n be prepa red by a compoundi ng pha rma cy. Topi ca l
propa mi di ne 0.1% q 1 to 2 h i s often a dded for 3 da ys .
For a l l ul cers , trea tment ma y a l s o i ncl ude a cycl opl egi c, s uch a s a tropi ne 1% or s copol a mi ne 0.25% 1 drop ti d, to decrea s e the a che of a cornea l
ul cer a nd to reduce the forma ti on of pos teri or s ynechi a e. In s evere ca s es , debri dement of the i nfected epi thel i um or even penetra ti ng
kera topl a s ty ma y be requi red. Pa ti ents who a re poorl y compl i a nt or who ha ve l a rge, centra l , or refra ctory ul cers ma y need to be hos pi ta l i zed.
Herpes Simplex Keratitis
(Herpes Si mpl ex Kera toconjuncti vi ti s )
Herpes simplex keratitis is corneal infection with herpes simplex virus (see also p. 1417). It may involve the iris. Symptoms and signs include foreign body
sensation, lacrimation, photophobia, and conjunctival hyperemia. Recurrences are common and may lead to corneal hypoesthesia, ulceration, and permanent
scarring. Diagnosis is based on the characteristic dendritic corneal ulcer and sometimes viral culture. Treatment is with topical and occasionally systemic antiviral
drugs.
Herpes s i mpl ex us ua l l y a ffects the cornea l s urfa ce but s ometi mes i nvol ves the deeper l a yers of the cornea (cornea l s troma ). Stroma l i nvol vement
i s proba bl y a n i mmunol ogi c res pons e to the vi rus .
As wi th a l l herpes s i mpl ex vi rus i nfecti ons , there i s a pri ma ry i nfecti on, fol l owed by a l a tent pha s e, i n whi ch the vi rus goes i nto the nerve roots .
La tent vi rus ma y rea cti va te, ca us i ng recurrent s ymptoms .
Symptoms and Signs
Primary infection: The i ni ti a l (pri ma ry) i nfecti on i s us ua l l y nons peci fi c s el f-l i mi ti ng conjuncti vi ti s , often i n ea rl y chi l dhood a nd s ometi mes wi thout
cornea l i nvol vement. If the cornea i s i nvol ved, ea rl y s ymptoms i ncl ude forei gn body s ens a ti on, l a cri ma ti on, photophobi a , a nd conjuncti va l
hyperemi a . Someti mes ves i cul a r bl epha ri ti s (bl i s ters on the eyel i d) fol l ows , s ymptoms wors en, vi s i on bl urs , a nd bl i s ters brea k down a nd
ul cera te, then res ol ve wi thout s ca rri ng i n a bout a week.
Recurrent infection: Recurrences us ua l l y ta ke the form of epi thel i a l kera ti ti s (a l s o ca l l ed dendri ti c kera ti ti s ) wi th tea ri ng, forei gn body s ens a ti on,
a nd a cha ra cteri s ti c bra nchi ng (dendri ti c or s erpenti ne) l es i on of the cornea l epi thel i um wi th knobl i ke termi na l s tha t s ta i n wi th fl uores cei n (s ee
Pl a te 14). Mul ti pl e recurrences ma y res ul t i n cornea l hypoes thes i a or a nes thes i a , ul cera ti on, a nd perma nent s ca rri ng.
Stromal involvement: Mos t pa ti ents wi th di s ci form kera ti ti s , whi ch i nvol ves the cornea l s troma , ha ve a hi s tory of epi thel i a l kera ti ti s . Di s ci form
kera ti ti s i s a deeper, di s k-s ha ped, l oca l i zed a rea of cornea l edema a nd ha ze a ccompa ni ed by a nteri or uvei ti s . Thi s form ma y ca us e pa i n a nd
vi s i on l os s .
Stroma l kera ti ti s ca n ca us e necros i s of the s troma a nd s evere a che, photophobi a , forei gn body s ens a ti on, a nd decrea s ed vi s i on.
Diagnosis
Sl i t-l a mp exa mi na ti on i s ma nda tory. Fi ndi ng a dendri te i s enough to confi rm the di a gnos i s i n mos t ca s es . When the a ppea ra nce i s not concl us i ve,
vi ra l cul ture of the l es i on ca n confi rm the di a gnos i s .
Treatment
Topi ca l tri fl uri di ne
Someti mes ora l or IV a cycl ovi r
For s troma l i nvol vement or uvei ti s , topi ca l corti cos teroi ds i n a ddi ti on to a nti vi ra l drugs
Mos t pa ti ents a re ma na ged by a n ophtha l mol ogi s t. If s troma l or uvea l i nvol vement occurs , trea tment i s more i nvol ved a nd referra l to a n
ophtha l mol ogi s t i s ma nda tory.
Topi ca l thera py (eg, tri fl uri di ne 1% drops 9 ti mes /da y) i s us ua l l y effecti ve. Occa s i ona l l y, a cycl ovi r 400 mg po 5 ti mes /da y i s i ndi ca ted.
Immunocompromi s ed pa ti ents ma y requi re IV a nti vi ra l s (eg, a cycl ovi r 5 mg/kg IV q 8 h for 7 da ys ). If the epi thel i um s urroundi ng the dendri te i s
l oos e a nd edema tous , debri dement by gentl e s wa bbi ng wi th a cotton-ti pped a ppl i ca tor before begi nni ng drug thera py ma y s peed hea l i ng.
Topical corticosteroids are contraindicated in epithelial keratitis but ma y be effecti ve when us ed wi th a n a nti vi ra l drug to ma na ge l a ter-s ta ge s troma l
i nvol vement (di s ci form or s troma l kera ti ti s ) or uvei ti s . In s uch ca s es , pa ti ents ma y be gi ven predni s ol one a ceta te 1% i ns ti l l ed q 2 h i ni ti a l l y,
l engtheni ng the i nterva l to q 4 to 8 h a s s ymptoms i mprove. Topi ca l drugs to rel i eve photophobi a i ncl ude a tropi ne 1% or s copol a mi ne 0.25% ti d.
Herpes Zoster Ophthalmicus
(Herpes Zos ter Vi rus Ophtha l mi cus ; Ophtha l mi c Herpes Zos ter; Va ri cel l a -Zos ter Vi rus Ophtha l mi cus )
Herpes zoster ophthalmicus is reactivation of a varicella-zoster virus infection (shingles) (see also p. 1420) involving the eye. Symptoms and signs, which may be
intense, include dermatomal forehead rash and painful inflammation of all the tissues of the anterior and, rarely, posterior structures of the eye. Diagnosis is
based on the characteristic appearance of the anterior structures of the eye plus zoster dermatitis of the first branch of the trigeminal nerve. Treatment is with
oral antiviral drugs, mydriatics, and topical corticosteroids.
Herpes zos ter of the forehea d i nvol ves the gl obe i n three fourths of ca s es when the na s oci l i a ry nerve i s a ffected (a s i ndi ca ted by a l es i on on the
ti p of the nos e) a nd i n one thi rd of ca s es not i nvol vi ng the ti p of the nos e. Overa l l , the gl obe i s i nvol ved i n ha l f of pa ti ents .
Symptoms and Signs
A prodrome of ti ngl i ng of the forehea d ma y occur. Duri ng a cute di s ea s e, i n a ddi ti on to the forehea d ra s h, s ymptoms a nd s i gns ma y i ncl ude s evere
pa i n; ma rked eyel i d edema ; conjuncti va l , epi s cl era l , a nd ci rcumcornea l conjuncti va l hyperemi a ; cornea l edema ; a nd photophobi a (s ee
Pl a te 15).
Complications: Kera ti ti s a ccompa ni ed by uvei ti s ma y be s evere a nd fol l owed by s ca rri ng. La te s equel a egl a ucoma , ca ta ra ct, chroni c or recurrent
uvei ti s , cornea l s ca rri ng, cornea l neova s cul a ri za ti on, a nd hypes thes i a a re common a nd ma y threa ten vi s i on. Pos therpeti c neura l gi a ma y devel op
l a te.
Diagnosis
Zos ter ra s h on the forehea d or eyel i d pl us eye fi ndi ngs
Di a gnos i s i s ba s ed on a typi ca l a cute herpes zos ter ra s h on the forehea d, eyel i d, or both or on a cha ra cteri s ti c hi s tory pl us s i gns of previ ous zos ter
ra s h. Ves i cul a r or bul l ous l es i ons i n thi s di s tri buti on tha t do not yet i nvol ve the eye s ugges t s i gni fi ca nt ri s k a nd s houl d prompt a n ophtha l mol ogi c
cons ul ta ti on to determi ne whether the eye i s i nvol ved. Cul ture a nd i mmunol ogi c or PCR s tudi es of s ki n a t i ni ti a l eva l ua ti on or s eri a l s erol ogi c
tes ts a re done onl y when l es i ons a re a typi ca l a nd the di a gnos i s uncerta i n.
Treatment
Ora l a nti vi ra l s (eg, a cycl ovi r, fa mci cl ovi r, va l a cycl ovi r)
Someti mes topi ca l corti cos teroi ds
Ea rl y trea tment wi th a cycl ovi r 800 mg po 5 ti mes /da y or fa mci cl ovi r 500 mg or va l a cycl ovi r 1 g po ti d for 7 da ys reduces ocul a r compl i ca ti ons . Pa ti ents
wi th kera ti ti s or uvei ti s requi re topi ca l corti cos teroi ds (eg, predni s ol one a ceta te 1% i ns ti l l ed qi d i ni ti a l l y, l engtheni ng the i nterva l a s s ymptoms
l es s en). The pupi l s houl d be di l a ted wi th a tropi ne 1% or s copol a mi ne 0.25% 1 drop ti d. Intra ocul a r pres s ure mus t be moni tored a nd trea ted i f i t
ri s es s i gni fi ca ntl y a bove norma l va l ues .
Us e of a bri ef cours e of hi gh-dos e ora l corti cos teroi ds to prevent pos therpeti c neura l gi a i n pa ti ents > 60 yr who a re i n good genera l hea l th
rema i ns controvers i a l .
Interstitial Keratitis
(Pa renchyma tous Kera ti ti s )
Interstitial keratitis is chronic, nonulcerative inflammation of the middle layers of the cornea (ie, mid-stroma) that is sometimes associated with uveitis. The
cause is usually infectious. Symptoms are photophobia, pain, lacrimation, and vision blurring. Diagnosis is by slit-lamp examination and serologic tests to
determine the cause. Treatment is directed at the cause and may require topical corticosteroids.
Inters ti ti a l kera ti ti s , a ma ni fes ta ti on of certa i n cornea l i nfecti ons , i s ra re i n the US. Mos t ca s es occur i n chi l dren or a dol es cents a s a l a te
compl i ca ti on of congeni ta l s yphi l i s (s ee p. 2821). Ul ti ma tel y, both eyes ma y be i nvol ved. A s i mi l a r but l es s dra ma ti c bi l a tera l kera ti ti s occurs i n
Coga n's s yndrome, Lyme di s ea s e, a nd Eps tei n-Ba rr vi rus i nfecti on. Ra rel y, a cqui red s yphi l i s , herpes s i mpl ex, herpes zos ter, or TB ma y ca us e a
uni l a tera l form i n a dul ts .
Symptoms and Signs
Photophobi a , pa i n, l a cri ma ti on, a nd vi s i on bl urri ng a re common. The l es i on begi ns a s pa tches of i nfl a mma ti on i n the mi ddl e cornea l l a yers (i e,
mi d-s troma ) tha t ca us e opa ci fi ca ti on. Typi ca l l y wi th s yphi l i s a nd occa s i ona l l y wi th other ca us es , the enti re cornea devel ops a ground-gl a s s
a ppea ra nce, obs curi ng the i ri s . New bl ood ves s el s grow i n from the l i mbus (neova s cul a ri za ti on) a nd produce ora nge-red a rea s (s a l mon pa tches ).
Anteri or uvei ti s a nd choroi di ti s a re common i n s yphi l i ti c i nters ti ti a l kera ti ti s . Infl a mma ti on a nd neova s cul a ri za ti on us ua l l y begi n to s ubs i de a fter
1 to 2 mo. Some cornea l opa ci ty us ua l l y rema i ns , ca us i ng mi l d to modera te vi s i on i mpa i rment.
Diagnosis
Cornea l opa ci fi ca ti on a nd other typi ca l fi ndi ngs on s l i t-l a mp exa mi na ti on
Serol ogi c tes ti ng to determi ne eti ol ogy
The s peci fi c eti ol ogy mus t be determi ned. The s ti gma s of congeni ta l s yphi l i s , ves ti bul oa udi tory s ymptoms , hi s tory of a n expa ndi ng ra s h, a nd ti ck
expos ure s upport a s peci fi c eti ol ogy. However, a l l pa ti ents s houl d ha ve s erol ogi c tes ti ng, i ncl udi ng a l l of the fol l owi ng:
Fl uores cent treponema l a nti body a bs orpti on tes t or the mi crohema ggl uti na ti on a s s a y for Treponema pallidum
Lyme ti ter
Eps tei n-Ba rr vi rus pa nel
Pa ti ents wi th nega ti ve s erol ogi c tes t res ul ts ma y ha ve Coga n's s yndrome, a n i di opa thi c s yndrome cons i s ti ng of i nters ti ti a l kera ti ti s a nd ves ti bul a r
a nd a udi tory defi ci ts . To prevent perma nent ves ti bul oa udi tory da ma ge, s ymptoms of hea ri ng l os s , ti nni tus , or verti go requi re referra l to a n
otol a ryngol ogi s t.
Treatment
Someti mes topi ca l corti cos teroi ds
Kera ti ti s ma y res ol ve wi th trea tment of the underl yi ng condi ti on. Addi ti ona l topi ca l trea tment wi th a corti cos teroi d, s uch a s predni s ol one 1% qi d,
i s often a dvi s a bl e. An ophtha l mol ogi s t s houl d be cons ul ted.
Cogan's Syndrome
Cogan's syndrome is a rare autoimmune disease involving the eye and the inner ear.
Coga n's s yndrome a ffects young a dul ts , wi th 80% of pa ti ents between 14 a nd 47 yr. The di s ea s e a ppea rs to res ul t from a n a utoi mmune rea cti on
di rected a ga i ns t a n unknown common a utoa nti gen i n the cornea a nd i nner ea r. About 10 to 30% of pa ti ents a l s o ha ve s evere s ys temi c va s cul i ti s ,
whi ch ma y i ncl ude l i fe-threa teni ng a orti ti s .
Symptoms and Signs
The pres enti ng s ymptoms i nvol ve the ocul a r s ys tem i n 38% of pa ti ents , the ves ti bul oa udi tory s ys tem i n 46%, a nd both i n 15%. By 5 mo, 75% of
pa ti ents ha ve both ocul a r a nd ves ti bul oa udi tory s ymptoms . Nons peci fi c s ys temi c compl a i nts i ncl ude fever, hea da che, joi nt pa i n, a nd mya l gi a .
Ocular: Ocul a r i nvol vement i ncl udes a ny combi na ti on of the fol l owi ng:
Bi l a tera l i nters ti ti a l kera ti ti s or other cornea l s troma l kera ti ti s
Epi s cl eri ti s or s cl eri ti s
Uvei ti s
Pa pi l l i ti s
Other orbi ta l i nfl a mma ti on (eg, vi tri ti s , choroi di ti s )
Ocul a r s ymptoms i ncl ude i rri ta ti on, pa i n, photophobi a , a nd decrea s ed vi s i on. Ocul a r exa mi na ti on s hows a pa tchy cornea l s troma l i nfi l tra te typi ca l
of i nters ti ti a l kera ti ti s (s ee p. 591), ocul a r rednes s , opti c nerve edema , proptos i s , or a combi na ti on of thes e s ymptoms .
Vestibuloauditory: Ves ti bul oa udi tory s ymptoms i ncl ude s ens ori neura l hea ri ng l os s , ti nni tus , a nd verti go.
Vascular: A di a s tol i c hea rt murmur ma y be pres ent when a orti ti s i s s i gni fi ca nt. Cl a udi ca ti on ma y be pres ent i f l i mb ves s el s a re a ffected.
Diagnosis
Di a gnos i s i s ba s ed on cl i ni ca l fi ndi ngs a nd excl us i on of other ca us es (eg, s yphi l i s , Lyme di s ea s e, Eps tei n-Ba rr vi rus i nfecti on) by a ppropri a te
s erol ogi c tes ts . Eva l ua ti on by a n ophtha l mol ogi s t a nd otol a ryngol ogi s t i s i mporta nt.
Treatment
Ini ti a l l y topi ca l a nd s ometi mes s ys temi c corti cos teroi ds
Untrea ted di s ea s e ma y l ea d to cornea l s ca rri ng a nd vi s ua l l os s a nd, i n 60 to 80% of pa ti ents , perma nent hea ri ng l os s . Kera ti ti s , epi s cl eri ti s , a nd
a nteri or uvei ti s ca n us ua l l y be trea ted wi th topi ca l predni s ol one a ceta te 1% q 1 h to qi d. To trea t deeper ocul a r i nfl a mma ti on a nd es peci a l l y to
trea t ves ti bul oa udi tory s ymptoms before they become perma nent, predni s one 1 mg/kg po once/da y i s begun a s s oon a s pos s i bl e a nd conti nued
for 2 to 6 mo. Some cl i ni ci a ns a dd cycl ophos pha mi de, methotrexa te, or cycl os pori ne for reca l ci tra nt ca s es .
Keratoconjunctivitis Sicca
(Dry Eyes ; Kera ti ti s Si cca )
Keratoconjunctivitis sicca is chronic, bilateral desiccation of the conjunctiva and cornea due to an inadequate tear film. Symptoms include itching, burning,
irritation, and photophobia. Diagnosis is clinical; the Schirmer test may be helpful. Treatment is with topical tear supplements and sometimes blockage of the
nasolacrimal openings.
Etiology
There a re 2 ma i n types :
Aqueous tea r-defi ci ent kera toconjuncti vi ti s s i cca i s ca us ed by i na dequa te tea r vol ume.
Eva pora ti ve kera toconjuncti vi ti s s i cca (more common) i s ca us ed by a ccel era ted tea r eva pora ti on due to poor tea r qua l i ty.
Aqueous tea r-defi ci ent kera toconjuncti vi ti s s i cca i s mos t commonl y a n i s ol a ted i di opa thi c condi ti on i n pos tmenopa us a l women. It i s a l s o
commonl y pa rt of Sjogren's s yndrome (s ee p. 303), RA, or SLE. Les s commonl y, i t i s s econda ry to other condi ti ons tha t s ca r the l a cri ma l ducts (eg,
ci ca tri ci a l pemphi goi d, Stevens -Johns on s yndrome, tra choma ). It ma y res ul t from a da ma ged or ma l functi oni ng l a cri ma l gl a nd due to gra ft-vs -hos t
di s ea s e, HIV (di ffus e i nfi l tra ti ve l ymphocytos i s s yndrome), l oca l ra di a ti on thera py, or fa mi l i a l dys a utonomi a .
Eva pora ti ve kera toconjuncti vi ti s s i cca i s ca us ed by l os s of the tea r fi l m due to a bnorma l l y ra pi d eva pora ti on ca us ed by a n i na dequa te oi l l a yer on
the s urfa ce of the a queous l a yer of tea rs . Symptoms ma y res ul t from a bnorma l oi l qua l i ty (i e, mei bomi a n gl a nd dys functi on) or a degra ded norma l
oi l l a yer (i e, s eborrhei c bl epha ri ti s ). Pa ti ents frequentl y ha ve a cne ros a cea .
Dryi ng ca n a l s o res ul t from expos ure due to i na dequa te eye cl os ure a t ni ght (nocturna l l a gophtha l mos ) or, ra rel y, from i na dequa te tea r vol ume
due to a n i ns uffi ci ent bl i nk ra te.
Symptoms and Signs
Pa ti ents report i tchi ng; burni ng; a gri tty, pul l i ng, or forei gn body s ens a ti on; or photophobi a . A s ha rp s ta bbi ng pa i n, eye s tra i n or fa ti gue, a nd
bl urred vi s i on ma y a l s o occur. Some pa ti ents note a fl ood of tea rs a fter s evere i rri ta ti on. Typi ca l l y, s ymptoms fl uctua te i n i ntens i ty a nd ma y be
i ntermi ttent. Certa i n fa ctors ca n wors en s ymptoms :
Prol onged vi s ua l efforts (eg, rea di ng, worki ng on the computer, dri vi ng, wa tchi ng tel evi s i on)
Loca l envi ronments tha t a re dry, wi ndy, dus ty, or s moky
Certa i n s ys temi c drugs , i ncl udi ng i s otreti noi n, s eda ti ves , di ureti cs , a nti hypertens i ves , ora l contra cepti ves , a nd a l l a nti chol i nergi cs (i ncl udi ng
a nti hi s ta mi nes a nd ma ny GI drugs )
Symptoms l es s en on cool , ra i ny, or foggy da ys or i n other hi gh-humi di ty envi ronments , s uch a s i n the s hower. Recurrent a nd prol onged bl urri ng a nd
frequent i ntens e i rri ta ti on ca n i mpa i r da i l y functi on. However, perma nent i mpa i rment of vi s i on i s ra re.
Wi th both forms , the conjuncti va i s hyperemi c, a nd there i s often s ca ttered, fi ne, puncta te l os s of cornea l epi thel i um (s uperfi ci a l puncta te
kera ti ti s ), conjuncti va l epi thel i um, or both. When the condi ti on i s s evere, the i nvol ved a rea s , ma i nl y between the eyel i ds (the i ntra pa l pebra l or
expos ure zone), s ta i n wi th fl uores cei n. Pa ti ents often bl i nk a t a n a ccel era ted ra te beca us e of i rri ta ti on.
Wi th the a queous tea r-defi ci ent form, the conjuncti va ca n a ppea r dry a nd l us terl es s wi th redunda nt fol ds . Wi th the eva pora ti ve form, a bunda nt
tea rs ma y be pres ent a s wel l a s foa m a t the eyel i d ma rgi n. Very ra rel y, s evere, a dva nced, chroni c dryi ng l ea ds to s i gni fi ca nt vi s i on l os s due to
kera ti ni za ti on of the ocul a r s urfa ce or l os s of cornea l epi thel i um, l ea di ng to s equel a e s uch a s s ca rri ng, neova s cul a ri za ti on, i nfecti ons , ul cera ti on,
a nd perfora ti on.
Diagnosis
Schi rmer tes t a nd tea r brea kup tes ts
Di a gnos i s i s ba s ed on cha ra cteri s ti c s ymptoms a nd cl i ni ca l a ppea ra nce. The Schi rmer tes t a nd tea r brea kup tes t ma y di fferenti a te type.
The Schi rmer tes t determi nes whether tea r producti on i s norma l . After bl otti ng the cl os ed eye to remove exces s tea rs , a s tri p of fi l ter pa per i s
pl a ced, wi thout topi ca l a nes thes i a , a t the juncti on of the mi ddl e a nd l a tera l thi rd of the l ower eyel i d. If < 5.5 mm of wetti ng occurs a fter 5 mi n on 2
s ucces s i ve occa s i ons , the pa ti ent ha s a queous tea r-defi ci ent kera toconjuncti vi ti s s i cca .
Wi th eva pora ti ve kera toconjuncti vi ti s s i cca , the Schi rmer tes t i s us ua l l y norma l . The tea r fi l m ca n be ma de vi s i bl e under coba l t bl ue l i ght a t the
s l i t l a mp by i ns ti l l a ti on of a s ma l l vol ume of hi ghl y concentra ted fl uores cei n (ma de by wetti ng a fl uores cei n s tri p wi th s a l i ne a nd s ha ki ng the
s tri p to remove a ny exces s moi s ture). Bl i nki ng s evera l ti mes rea ppl i es a compl ete tea r fi l m. The pa ti ent then s ta res , a nd the l ength of ti me unti l
the fi rs t dry s pot devel ops i s determi ned (tea r brea kup tes t, or TBUT). An a ccel era ted ra te of i nta ct tea r fi l m brea kup (< 10 s ec) i s cha ra cteri s ti c of
eva pora ti ve kera toconjuncti vi ti s s i cca .
If a queous tea r-defi ci ent kera toconjuncti vi ti s s i cca i s di a gnos ed, Sjogren's s yndrome (s ee p. 303) s houl d be s us pected, es peci a l l y i f xeros tomi a i s
a l s o pres ent. Serol ogi c tes ts a nd l a bi a l s a l i va ry gl a nd bi ops y a re us ed for di a gnos i s . Pa ti ents wi th pri ma ry or s econda ry Sjogren's s yndrome a re a t
i ncrea s ed ri s k of s evera l s eri ous di s ea s es (eg, pri ma ry bi l i a ry ci rrhos i s , non-Hodgki n l ymphoma ). Therefore, proper eva l ua ti on a nd moni tori ng a re
es s enti a l .
Treatment
Arti fi ci a l tea rs
Someti mes occl us i on of na s ol a cri ma l punctum or ta rs orrha phy
Frequent us e of a rti fi ci a l tea rs ca n be effecti ve for both forms . More vi s cous a rti fi ci a l tea rs coa t the ocul a r s urfa ce l onger, a nd a rti fi ci a l tea rs tha t
conta i n pol a r l i pi ds s uch a s gl yceri n reduce eva pora ti on; both types a re pa rti cul a rl y us eful i n eva pora ti ve kera toconjuncti vi ti s s i cca . Arti fi ci a l tea r
oi ntments a ppl i ed before s l eep a re pa rti cul a rl y us eful when pa ti ents ha ve nocturna l l a gophtha l mos or i rri ta ti on on wa ki ng. Mos t ca s es a re
trea ted a dequa tel y throughout the pa ti ent's l i fe wi th s uch s uppl ementa ti on. Sta yi ng hydra ted, us i ng humi di fi ers , a nd a voi di ng dry, dra fty
envi ronments ca n often hel p. Not s moki ng a nd a voi di ng s econda ry s moke a re i mporta nt. In reca l ci tra nt ca s es , occl us i on of the na s ol a cri ma l
punctum ma y be i ndi ca ted. In s evere ca s es , a pa rti a l ta rs orrha phy ca n reduce tea r l os s through eva pora ti on. Topi ca l cycl os pori ne a nd -3 fa tty
a ci d di eta ry s uppl ements ma y be a us eful a djunct i n s ome pa ti ents .
Pa ti ents wi th eva pora ti ve kera toconjuncti vi ti s s i cca often benefi t from trea tment of concomi ta nt bl epha ri ti s a nd a s s oci a ted ros a cea wi th
mea s ures s uch a s wa rm compres s es , eyel i d ma rgi n s crubs , a nd i ntermi ttent topi ca l eyel i d a nti bi oti c oi ntments (eg, ba ci tra ci n a t bedti me),
s ys temi c doxycycl i ne 50 to 100 mg po once or twi ce/da y (contra i ndi ca ted i n pregna nt or nurs i ng pa ti ents ), or both.
Cycl os pori ne drops tha t decrea s e the i nfl a mma ti on a s s oci a ted wi th drynes s of the eye a re a va i l a bl e. They l ea d to mea ni ngful i mprovement but
onl y i n a fra cti on of pa ti ents . Thes e drops s ti ng a nd ta ke months before a n effect i s noti ced.
Keratoconus
Keratoconus is a bulging distortion of the cornea, leading to loss of visual acuity.
Kera toconus i s a s l owl y progres s i ve thi nni ng a nd bul gi ng of the cornea , us ua l l y bi l a tera l , begi nni ng between a ges 10 a nd 25. Its ca us e i s
unknown.
The di s torted cone s ha pe of the cornea ca us es ma jor cha nges i n the refra cti ve cha ra cteri s ti cs of the cornea (i rregul a r a s ti gma ti s m) tha t ca nnot be
ful l y corrected wi th gl a s s es . Progres s i ng kera toconus neces s i ta tes frequent cha nge of eyegl a s s es . Conta ct l ens es ma y provi de better vi s i on
correcti on a nd s houl d be tri ed when eyegl a s s es a re not s a ti s fa ctory. Cornea l tra ns pl a nt s urgery ma y be neces s a ry i f vi s ua l a cui ty wi th conta ct
l ens es i s i na dequa te, conta ct l ens es a re not tol era ted, or a vi s ua l l y s i gni fi ca nt cornea l s ca r (ca us ed by tea ri ng of s troma l fi bers ) i s pres ent.
Newer trea tments s eem promi s i ng. Impl a nta ti on of cornea l ri ng s egments a ppea rs to ha ve the potenti a l to s a ve s el ected pa ti ents from
tra ns pl a nta ti on. Cornea l cros s -l i nki ng, a n ul tra vi ol et l i ght trea tment tha t s trengthens the cornea , ha s ha d pos i ti ve res ul ts i n Europea n s tudi es
a nd ma y become more common.
Keratomalacia
(Xeroti c Kera ti ti s ; Xerophtha l mi a )
Keratomalacia is degeneration of the cornea caused by nutritional deficiency.
Kera toma l a ci a i s ca us ed by vi ta mi n A defi ci ency typi ca l l y i n pa ti ents wi th protei n-ca l ori e undernutri ti on. It i s cha ra cteri zed by a ha zy, dry cornea .
Cornea l ul cera ti on wi th s econda ry i nfecti on i s common. The l a cri ma l gl a nds a nd conjuncti va a re a l s o a ffected. La ck of tea rs ca us es extreme
drynes s of the eyes , a nd foa my s pots a ppea r on the tempora l a nd often na s a l bul ba r conjuncti va (Bi tot's s pots ). Ni ght bl i ndnes s ma y occur. For
further deta i l s , i ncl udi ng s peci fi c thera py, s ee Vi ta mi n A Defi ci ency on p. 34.
Peripheral Ulcerative Keratitis
(Ma rgi na l Kera tol ys i s ; Peri phera l Rheuma toi d Ul cera ti on)
Peripheral ulcerative keratitis is inflammation and ulceration of the cornea that often occurs with chronic connective tissue diseases. Irritation and decreased
vision result.
Peri phera l ul cera ti ve kera ti ti s i s a s eri ous cornea l ul cera ti on; i t often occurs wi th a utoi mmune di s ea s es tha t a re a cti ve, l ong-s ta ndi ng, or both,
s uch a s RA, Wegener's gra nul oma tos i s , a nd rel a ps i ng pol ychondri ti s .
Pa ti ents often ha ve decrea s ed vi s ua l a cui ty, photophobi a , a nd forei gn body s ens a ti on. A cres centi c a rea of opa ci fi ca ti on i n the peri phery of the
cornea , due to i nfi l tra ti on by WBCs a nd ul cera ti on, s ta i ns wi th fl uores cei n. Infecti ous ca us es , s uch a s ba cteri a , fungi , a nd herpes s i mpl ex vi rus ,
mus t be rul ed out by cul turi ng the ul cer a nd eyel i d ma rgi ns .
Among pa ti ents wi th rheuma ti c di s ea s e a nd peri phera l ul cera ti ve kera ti ti s , the 10-yr morta l i ty ra te i s a bout 40% (us ua l l y due to MI) wi thout
trea tment a nd a bout 8% wi th s ys temi c cytotoxi c thera py.
Any pa ti ent wi th peri phera l ul cera ti ve kera ti ti s s houl d be promptl y referred to a n ophtha l mol ogi s t. Sys temi c cycl ophos pha mi de or other
i mmunos uppres s a nts trea t the kera ti ti s , l i fe-threa teni ng va s cul i ti s , a nd underl yi ng a utoi mmune di s ea s e. Trea tment a l s o i ncl udes l oca l
a pproa ches to control i nfl a mma ti on (eg, ti s s ue a dhes i ve a nd ba nda ge conta ct l ens es ) a nd repa i r da ma ge (eg, pa tch gra fts ). Other pos s i bl y hel pful
drugs i ncl ude col l a gena s e i nhi bi tors , s uch a s s ys temi c tetra cycl i ne or topi ca l 20% N-a cetyl cys tei ne.
Phlyctenular Keratoconjunctivitis
(Phl yctenul a r Conjuncti vi ti s ; Phl yctenul os i s )
Phlyctenular keratoconjunctivitis, a hypersensitivity reaction of the cornea and conjunctiva to bacterial antigens, is characterized by discrete nodular areas of
corneal or conjunctival inflammation.
Phl yctenul a r kera toconjuncti vi ti s res ul ts from a hypers ens i ti vi ty rea cti on to ba cteri a l a nti gens , pri ma ri l y s ta phyl ococca l , but TB, Chlamydia, a nd
other a gents ha ve been i mpl i ca ted. It i s more common i n chi l dren. Ma ny pa ti ents a l s o ha ve bl epha ri ti s .
Pa ti ents ha ve mul ti pl e l es i ons , cons i s ti ng of s ma l l yel l ow-gra y nodul es (phl yctenul es ) tha t a ppea r a t the l i mbus , on the cornea , or on the bul ba r
conjuncti va a nd pers i s t from s evera l da ys to 2 wk. On the conjuncti va , thes e nodul es ul cera te but hea l wi thout a s ca r. When the cornea i s a ffected,
s evere l a cri ma ti on, photophobi a , bl urred vi s i on, a chi ng, a nd forei gn body s ens a ti on ma y be promi nent. Frequent recurrence, es peci a l l y wi th
s econda ry i nfecti on, ma y l ea d to cornea l opa ci ty a nd neova s cul a ri za ti on wi th l os s of vi s ua l a cui ty.
Di a gnos i s i s by cha ra cteri s ti c cl i ni ca l a ppea ra nce. Tes ti ng for TB ma y be i ndi ca ted (eg, for pa ti ents a t ri s k).
Trea tment for nontubercul ous ca s es i s wi th a topi ca l corti cos teroi d-a nti bi oti c combi na ti on. If pa ti ents ha ve s eborrhei c bl epha ri ti s , eyel i d s crubs
ma y hel p prevent recurrence.
Superficial Punctate Keratitis
Superficial punctate keratitis is corneal inflammation of diverse causes characterized by scattered, fine, punctate corneal epithelial loss or damage. Symptoms
are redness, lacrimation, photophobia, and slightly decreased vision. Diagnosis is by slit-lamp examination. Treatment depends on the cause.
Superfi ci a l puncta te kera ti ti s i s a nons peci fi c fi ndi ng. Ca us es ma y i ncl ude a ny of the fol l owi ng:
Vi ra l conjuncti vi ti s (mos t commonl y a denovi rus )
Bl epha ri ti s
Kera toconjuncti vi ti s s i cca
Tra choma
Chemi ca l burns
Ul tra vi ol et (UV) l i ght expos ure (eg, wel di ng a rcs , s unl a mps , s now gl a re)
Conta ct l ens overwea r
Sys temi c drugs (eg, a deni ne a ra bi nos i de)
Topi ca l drug or pres erva ti ve toxi ci ty.
Symptoms i ncl ude photophobi a , forei gn body s ens a ti on, l a cri ma ti on, rednes s , a nd s l i ghtl y decrea s ed vi s i on. Sl i t-l a mp or ophtha l mos cope
exa mi na ti on of the cornea revea l s a cha ra cteri s ti c ha zy a ppea ra nce wi th mul ti pl e puncta te s peckl es tha t s ta i n wi th fl uores cei n. Wi th vi ra l
conjuncti vi ti s , prea uri cul a r a denopa thy i s common a nd chemos i s ma y occur.
Kera ti ti s tha t a ccompa ni es a denovi rus conjuncti vi ti s res ol ves s ponta neous l y i n a bout 3 wk. Bl epha ri ti s (s ee p. 575), kera toconjuncti vi ti s s i cca (s ee
p. 592), a nd tra choma (s ee p. 583) requi re s peci fi c thera py. When ca us ed by overwea ri ng conta ct l ens es , kera ti ti s i s trea ted wi th di s conti nua ti on of
the conta ct l ens a nd a n a nti bi oti c oi ntment (eg, ci profl oxa ci n 0.3% qi d), but the eye i s not pa tched beca us e s eri ous i nfecti on ma y res ul t. Conta ct
l ens wea rers wi th s uperfi ci a l puncta te kera ti ti s s houl d be exa mi ned the next da y. Sus pected ca us a ti ve topi ca l drugs (a cti ve i ngredi ent or
pres erva ti ve) s houl d be s topped.
Ultraviolet keratitis: UVB l i ght (wa vel ength < 300 nm) ca n burn the cornea , ca us i ng kera ti ti s or kera toconjuncti vi ti s . Arc wel di ng i s a common ca us e;
even a bri ef, unprotected gl a nce a t a wel di ng a rc ma y res ul t i n a burn. Other ca us es i ncl ude hi gh-vol ta ge el ectri c s pa rks , a rti fi ci a l s un l a mps , a nd
s unl i ght refl ected off s now a t hi gh a l ti tudes . UV ra di a ti on i ncrea s es 4 to 6% for every 1000-ft (305-m) i ncrea s e i n a l ti tude a bove s ea l evel , a nd
s now refl ects 85% of UVB.
Symptoms a re us ua l l y not a ppa rent for 8 to 12 h a fter expos ure a nd l a s t 24 to 48 h. Pa ti ents ha ve l a cri ma ti on, pa i n, rednes s , s wol l en eyel i ds ,
photophobi a , hea da che, forei gn body s ens a ti on, a nd decrea s ed vi s i on. Perma nent vi s i on l os s i s ra re.
Di a gnos i s i s by hi s tory, pres ence of s uperfi ci a l puncta te kera ti ti s , a nd a bs ence of a forei gn body or i nfecti on.
Trea tment cons i s ts of a n a nti bi oti c oi ntment (eg, ba ci tra ci n or genta mi ci n 0.3% oi ntment q 8 h) a nd occa s i ona l l y a s hort-a cti ng cycl opl egi c drug (eg,
cycl opentol a te 1% drop q 4 h). Severe pa i n ma y requi re s ys temi c a na l ges i cs . The cornea l s urfa ce regenera tes s ponta neous l y i n 24 to 48 h. The eye
mus t be rechecked i n 24 h. Da rk gl a s s es or wel der's hel mets tha t bl ock UV l i ght a re preventi ve.
Corneal Transplantation
(Cornea l Gra ft; Penetra ti ng Kera topl a s ty)
Indications: Cornea l tra ns pl a nta ti ons a re done for s evera l rea s ons :
To recons truct the cornea (eg, repl a ci ng a perfora ted cornea )
To rel i eve i ntra cta bl e pa i n (eg, s evere forei gn body s ens a ti on due to recurrent ruptured bul l a e i n bul l ous kera topa thy)
To trea t a di s order unres pons i ve to medi ca l ma na gement (eg, s evere, uncontrol l ed funga l cornea l ul cer)
To i mprove the opti ca l qua l i ti es of the cornea a nd thus i mprove vi s i on (eg, repl a ci ng a cornea tha t i s s ca rred a fter a cornea l ul cer, i s cl ouded
beca us e of edema a s occurs i n Fuchs ' dys trophy or a fter ca ta ra ct s urgery, i s opa que beca us e of depos i ts of nontra ns pa rent a bnorma l cornea l
s troma l protei ns a s occurs i n heredi ta ry cornea l s troma l dys trophy, or ha s i rregul a r a s ti gma ti s m a s occurs wi th kera toconus )
The mos t common i ndi ca ti ons a re the fol l owi ng:
Bul l ous kera topa thy (ps eudopha ki c or a pha ki c, Fuchs ' endothel i a l dys trophy)
Kera toconus
Repea t gra ft
Kera ti ti s or pos tkera ti ti s (ca us ed by vi ra l , ba cteri a l , funga l , or Acanthamoeba i nfecti on or perfora ti on)
Cornea l s troma l dys trophi es
Procedure: Ti s s ue ma tchi ng i s not routi nel y done. Ca da veri c donor ti s s ue ca nnot be us ed from a nyone s us pected of ha vi ng a communi ca bl e
di s ea s e.
Cornea l tra ns pl a nta ti on ca n be done us i ng genera l a nes thes i a or l oca l a nes thes i a pl us IV s eda ti on.
Topi ca l a nti bi oti cs a re us ed for s evera l weeks pos topera ti vel y a nd topi ca l corti cos teroi ds for s evera l months . To protect the eye from i na dvertent
tra uma a fter tra ns pl a nta ti on, the pa ti ent wea rs s hi el ds , gl a s s es , or s ungl a s s es . If tra ns pl a nta ti on i nvol ves the ful l thi cknes s of the cornea (a s i n
penetra ti ng kera topl a s ty, or PKP), a chi evement of ful l vi s ua l potenti a l ma y ta ke up to 18 mo beca us e of cha ngi ng refra cti on wi th wound hea l i ng
a nd a fter s uture remova l . If onl y the endothel i um i s repl a ced (a s i n Des cemet's s tri ppi ng endothel i a l kera topl a s ty), a chi evement of ful l vi s ua l
potenti a l us ua l l y occurs by 6 mo. In ma ny pa ti ents , ea rl i er a nd better vi s i on i s a tta i ned by wea ri ng a ri gi d conta ct l ens over the cornea l tra ns pl a nt.
Complications: Compl i ca ti ons i ncl ude the fol l owi ng:
Gra ft rejecti on
Infecti on (i ntra ocul a r a nd cornea l )
Wound l ea k
Gl a ucoma
Gra ft fa i l ure
Hi gh refra cti ve error (es peci a l l y a s ti gma ti s m, myopi a , or both)
Recurrence of di s ea s e (wi th herpes s i mpl ex or heredi ta ry cornea l s troma l dys trophy)
Gra ft rejecti on ra tes a re us ua l l y < 10% but ma y be up to 68% i n hi gher-ri s k pa ti ents . Rejecti on s ymptoms i ncl ude decrea s ed vi s i on,
photos ens i ti vi ty, ocul a r a che, a nd ocul a r rednes s . Gra ft rejecti on i s trea ted wi th topi ca l corti cos teroi ds (eg, predni s ol one 1% hourl y), s ometi mes
wi th a s uppl ementa l peri ocul a r i njecti on (eg, tri a mci nol one a cetoni de 40 mg). If gra ft rejecti on i s s evere or i f gra ft functi on i s ma rgi na l , a ddi ti ona l
corti cos teroi ds a re gi ven ora l l y (eg, predni s one 1 mg/kg once/da y) a nd occa s i ona l l y IV (eg, methyl predni s ol one 3 to 5 mg/kg once). Typi ca l l y, the
rejecti on epi s ode revers es , a nd gra ft functi on returns ful l y. The gra ft ma y fa i l i f the rejecti on epi s ode i s unus ua l l y s evere or l ong-s ta ndi ng or i f
mul ti pl e epi s odes of gra ft rejecti on occur. Regra ft i s pos s i bl e, but the l ong-term prognos i s i s wors e tha n for the ori gi na l gra ft.
Prognosis
The cha nce of l ong-term tra ns pl a nt s ucces s i s
> 90% for kera toconus , cornea l s ca rs , ea rl y bul l ous kera topa thy, or heredi ta ry cornea l s troma l dys trophi es
80 to 90% for more a dva nced bul l ous kera topa thy or i na cti ve vi ra l kera ti ti s
50% for a cti ve cornea l i nfecti on
0 to 50% for chemi ca l or ra di a ti on i njury
The genera l l y hi gh ra te of s ucces s of cornea l tra ns pl a nta ti on i s a ttri buta bl e to ma ny fa ctors , i ncl udi ng the a va s cul a ri ty of the cornea a nd the fa ct
tha t the a nteri or cha mber ha s venous dra i na ge but no l ympha ti c dra i na ge. Thes e condi ti ons promote l ow-zone tol era nce (a n i mmunol ogi c
tol era nce tha t res ul ts from cons ta nt expos ure to l ow dos es of a n a nti gen) a nd a proces s termed a nteri or cha mber-a s s oci a ted i mmune devi a ti on,
i n whi ch there i s a cti ve s uppres s i on of i ntra ocul a r l ymphocytes a nd del a yed-type hypers ens i ti vi ty to tra ns pl a nted i ntra ocul a r a nti gens . Another
i mporta nt fa ctor i s the effecti venes s of the corti cos teroi ds us ed topi ca l l y, l oca l l y, a nd s ys temi ca l l y to trea t gra ft rejecti on.
Corneal Limbal Stem Cell Transplantation
Cornea l l i mba l s tem cel l tra ns pl a nta ti on s urgi ca l l y repl a ces cri ti ca l s tem cel l s a t the l i mbus (the a rea where the conjuncti va meets the cornea ).
Hos t s tem cel l s norma l l y res i de i n thi s a rea . Tra ns pl a nta ti on i s done when the hos t s tem cel l s ha ve been too s everel y da ma ged to recover from
di s ea s e or i njury.
Condi ti ons s uch a s s evere chemi ca l burns , Stevens -Johns on s yndrome, a nd s evere conta ct l ens overwea r ma y ca us e pers i s tent nonhea l i ng cornea l
epi thel i a l defects . Thes e defects res ul t from fa i l ure of cornea l epi thel i a l s tem cel l s to produce s uffi ci ent epi thel i a l cel l s to repopul a te the
cornea . If untrea ted, pers i s tent nonhea l i ng cornea l epi thel i a l defects a re vul nera bl e to i nfecti on, whi ch ca n l ea d to s ca rri ng, perfora ti on, or both.
Under thes e ci rcums ta nces , a cornea l tra ns pl a nt, whi ch repl a ces onl y the centra l cornea a nd not the l i mbus , i s i ns uffi ci ent; s tem cel l s a re needed
to produce new cel l s tha t repopul a te the cornea , res tori ng the regenera ti ve ca pa ci ty of the ocul a r s urfa ce.
Cornea l l i mba l s tem cel l s ca n be tra ns pl a nted from the pa ti ent's hea l thy eye or from a ca da veri c donor eye. The pa ti ent's da ma ged cornea l
epi thel i a l s tem cel l s a re removed by a pa rti a l -thi cknes s di s s ecti on of the l i mbus (i e, a l l the epi thel i um a nd the s uperfi ci a l s troma of the l i mbus ).
Donor l i mba l ti s s ue, whi ch i s prepa red by a s i mi l a r di s s ecti on, i s s utured i nto the prepa red bed.
Chapter 65. Glaucoma

Introduction
Gl a ucoma s a re a group of eye di s orders cha ra cteri zed by progres s i ve opti c nerve da ma ge a t l ea s t pa rtl y due to i ncrea s ed i ntra ocul a r pres s ure
(IOP). Gl a ucoma i s the 3rd mos t common ca us e of bl i ndnes s worl dwi de a nd the 2nd mos t common ca us e of bl i ndnes s i n the US, where i t i s the
l ea di ng ca us e of bl i ndnes s for bl a cks a nd Hi s pa ni cs . About 3 mi l l i on Ameri ca ns a nd 14 mi l l i on peopl e worl dwi de ha ve gl a ucoma , but onl y ha l f
a re a wa re of i t. Gl a ucoma ca n occur a t a ny a ge but i s 6 ti mes more common a mong peopl e > 60 yr.
Gl a ucoma s a re ca tegori zed a s open-a ngl e or cl os ed-a ngl e (a ngl e-cl os ure)s ee
Ta bl es 65-1,
65-2, a nd
65-3. The "a ngl e" refers to the a ngl e formed by the juncti on of the i ri s a nd cornea a t the peri phery of the a nteri or cha mber (s ee
Fi g. 65-1). The a ngl e i s where > 98% of the a queous humor exi ts the eye vi a ei ther the tra becul a r mes hwork a nd Schl emm's ca na l (the ma jor
pa thwa y, pa rti cul a rl y i n the el derl y) or the ci l i a ry body fa ce a nd choroi da l va s cul a ture. Thes e outfl ow pa thwa ys a re not s i mpl y a mecha ni ca l fi l ter
a nd dra i n but i ns tea d i nvol ve a cti ve phys i ol ogi c proces s es .
Gl a ucoma s a re further s ubdi vi ded i nto pri ma ry (ca us e of outfl ow res i s ta nce or a ngl e cl os ure i s unknown) a nd s econda ry (outfl ow res i s ta nce
res ul ts from a nother di s order), a ccounti ng for > 20 a dul t types .
Pathophysiology
Axons of reti na l ga ngl i on cel l s tra vel through the opti c nerve ca rryi ng i ma ges from the eye to the bra i n. Da ma ge to thes e a xons ca us es ga ngl i on
cel l dea th wi th res ul ta nt opti c nerve a trophy a nd pa tchy vi s i on l os s . El eva ted IOP (i n una ffected eyes , the a vera ge ra nge i s 11 to 21 mm Hg) pl a ys a
rol e i n a xona l da ma ge, ei ther by di rect nerve compres s i on or di mi nuti on of bl ood fl ow. However, the rel a ti ons hi p between pres s ure a nd nerve
da ma ge i s va ri a bl e. Of peopl e wi th IOP > 21 mm Hg (i e, ocul a r hypertens i on), onl y a bout 1 to 2%/yr (a bout 10% over 5 yr) devel op gl a ucoma .
Addi ti ona l l y, a bout one thi rd of pa ti ents wi th gl a ucoma do not ha ve IOPs > 21 mm Hg (known a s l owtens i on gl a ucoma or norma l -tens i on
gl a ucoma ).
IOP i s determi ned by the ba l a nce of a queous s ecreti on a nd dra i na ge. El eva ted IOP i s ca us ed by i nhi bi ted or obs tructed outfl ow, not overs ecreti on.
In open-a ngl e gl a ucoma , IOP i s el eva ted beca us e outfl ow i s i na dequa te des pi te a n a ngl e tha t a ppea rs unobs tructed. In a ngl e-cl os ure gl a ucoma ,
IOP i s el eva ted when a phys i ca l di s torti on of the peri phera l i ri s mecha ni ca l l y bl ocks outfl ow.
Symptoms and Signs
Symptoms a nd s i gns va ry wi th the type of gl a ucoma , but the defi ni ng cha ra cteri s ti c i s opti c nerve da ma ge a s evi denced by a n a bnorma l opti c di s k
(s ee p. 601 a nd
Pl a te 13) a nd certa i n types of vi s ua l fi el d defi ci ts (s ee p. 601).
IOP ma y be el eva ted or wi thi n the a vera ge ra nge. (For techni ques of mea s urement, s ee p.
540)
Diagnosis
Cha ra cteri s ti c vi s ua l fi el d defects
IOP us ua l l y > 21 mm Hg (but not requi red for the di a gnos i s )
Gl a ucoma s houl d be s us pected i n a pa ti ent wi th a ny of the fol l owi ng:
Typi ca l vi s ua l fi el d defects
Abnorma l opti c nerve on ophtha l mos copy
El eva ted IOP
Such pa ti ents (a nd thos e wi th a ny ri s k fa ctors ) s houl d be referred to a n ophtha l mol ogi s t for a comprehens i ve exa mi na ti on tha t i ncl udes a
thorough hi s tory, fa mi l y hi s tory, exa mi na ti on of the opti c di s ks (prefera bl y us i ng a bi nocul a r exa mi na ti on techni que), forma l vi s ua l fi el d
exa mi na ti on, IOP mea s urement, a nd goni os copy (vi s ua l i za ti on of the a nteri or cha mber a ngl e wi th a s peci a l mi rrored conta ct l ens pri s m).
Gl a ucoma i s di a gnos ed when cha ra cteri s ti c fi ndi ngs of opti c nerve da ma ge a re pres ent a nd other ca us es (eg, mul ti pl e s cl eros i s )
[Table 65-1. Open-Angl e Gl a ucoma : Cl a s s i fi ca ti on Ba s ed on Mecha ni s ms of Outfl ow Obs tructi on*]
ha ve been excl uded. El eva ted IOP ma kes the di a gnos i s more l i kel y but i s not es s enti a l .
Screening: Screeni ng ca n be done by pri ma ry phys i ci a ns by checki ng vi s ua l fi el ds wi th frequency-doubl i ng technol ogy (FDT) peri metry a nd
ophtha l mos copi c eva l ua ti on of the opti c nerve. FDT peri metry i nvol ves us e of a des ktop devi ce tha t ca n s creen for vi s ua l fi el d a bnorma l i ti es
s ugges ti ve of gl a ucoma i n 2 to 3 mi n per eye. Al though IOP s houl d be mea s ured, s creeni ng ba s ed onl y on IOP ha s l ow s ens i ti vi ty, l ow s peci fi ci ty,
a nd l ow pos i ti ve
[Table 65-2. Angl e-Cl os ure Gl a ucoma : Cl a s s i fi ca ti on Ba s ed on Mecha ni s ms of Outfl ow Obs tructi on*]
predi cti ve va l ue. Pa ti ents > 40 yr a nd thos e who ha ve ri s k fa ctors for open-a ngl e or a ngl e-cl os ure gl a ucoma s houl d recei ve a comprehens i ve eye
exa mi na ti on every 1 to 2 yr.

Treatment
Decrea s i ng IOP by us i ng drugs or l a s er or i nci s i ona l s urgery
[Table 65-3. Devel opmenta l Abnorma l i ti es of the Anteri or Cha mber Angl e Ca us i ng Gl a ucoma : Cl a s s i fi ca ti on Ba s ed on Mecha ni s ms of Outfl ow
Obs tructi on*]
Pa ti ents wi th cha ra cteri s ti c opti c nerve a nd corres pondi ng vi s ua l fi el d cha nges a re trea ted rega rdl es s of IOP. Loweri ng the IOP i s the onl y cl i ni ca l l y
proven trea tment. For chroni c a dul t a nd juveni l e gl a ucoma s , the i ni ti a l ta rget IOP i s a t l ea s t 20% bel ow pretrea tment rea di ngs .
Three methods a re a va i l a bl e: drugs , l a s er s urgery, a nd i nci s i ona l s urgery. The type of gl a ucoma determi nes the a ppropri a te method. Drugs a nd
mos t l a s er s urgeri es (tra becul opl a s ty) modi fy the exi s ti ng a queous s ecreti on a nd dra i na ge s ys tem. Mos t i nci s i ona l s urgeri es (eg, gua rded
fi l tra ti on procedures [tra becul ectomy], gl a ucoma dra i na ge i mpl a nt devi ces [tube s hunts ]) crea te a new dra i na ge s ys tem.
Prophyl a cti c IOP l oweri ng i n pa ti ents wi th ocul a r hypertens i on del a ys the ons et of gl a ucoma . However, beca us e the ra te of convers i on from ocul a r
hypertens i on to gl a ucoma i n untrea ted peopl e i s l ow, the deci s i on to trea t prophyl a cti ca l l y s houl d be i ndi vi dua l i zed ba s ed on the pres ence of
ri s k fa ctors , ma gni tude of IOP el eva ti on, a nd pa ti ent fa ctors (i e, preference for drugs vs s urgery, drug a dvers e effects ). Genera l l y, trea tment i s
recommended for pa ti ents wi th IOP > 30 mm Hg even i f the vi s ua l fi el d i s ful l a nd the opti c nerve di s k a ppea rs hea l thy beca us e the l i kel i hood of
da ma ge i s s i gni fi ca nt a t tha t IOP l evel .
[Fig. 65-1. Aqueous humor producti on a nd fl ow.]
Primary Open-Angle Glaucoma
Primary open-angle glaucoma is a syndrome of optic nerve damage associated with an open anterior chamber angle and an elevated or sometimes average
intraocular pressure (IOP). Symptoms occur late and involve visual field loss. Diagnosis is by ophthalmoscopy, gonioscopy, visual field examination, and
measurement of IOP. Treatment includes topical drugs (eg, prostaglandin analogs, -blockers) and often requires laser or incisional surgery to increase aqueous
drainage.
Etiology
Al though open-a ngl e gl a ucoma s ca n ha ve numerous ca us es (s ee Ta bl e 65-1), 60 to 70% of ca s es ha ve no i denti fi a bl e ca us e a nd a re termed
pri ma ry open-a ngl e gl a ucoma . Both eyes us ua l l y a re a ffected, but typi ca l l y not equa l l y.
Ri s k fa ctors i ncl ude ol der a ge, pos i ti ve fa mi l y hi s tory, bl a ck ra ce, thi nner centra l cornea l thi cknes s , s ys temi c hypertens i on, di a betes , a nd myopi a .
In bl a cks , gl a ucoma i s more s evere a nd devel ops a t a n ea rl i er a ge, a nd bl i ndnes s i s 6 to 8 ti mes more l i kel y.
Pathophysiology
IOP ca n be el eva ted or wi thi n the a vera ge ra nge.
Elevated-pressure glaucoma: Two thi rds of pa ti ents wi th gl a ucoma ha ve el eva ted (> 21 mm Hg) IOP. Aqueous humor dra i na ge i s i na dequa te, wherea s
producti on by the ci l i a ry body i s norma l . Identi fi a bl e mecha ni s ms (i e, s econda ry open-a ngl e gl a ucoma s ) a re not pres ent. Thes e mecha ni s ms
i ncl ude devel opmenta l a noma l i es , s ca rri ng ca us ed by tra uma or i nfecti on, a nd pl uggi ng of cha nnel s by deta ched i ri s pi gment (i e, pi gment
di s pers i on s yndrome) or a bnorma l protei n depos i ts (eg, ps eudoexfol i a ti on s yndrome).
Normal- or low-pressure glaucoma: In a t l ea s t one thi rd of pa ti ents wi th gl a ucoma , IOP i s wi thi n the a vera ge ra nge, but opti c nerve da ma ge a nd
vi s ua l fi el d l os s typi ca l of gl a ucoma a re pres ent. Thes e pa ti ents ha ve a hi gher i nci dence of va s os pa s ti c di s ea s es (eg, mi gra i nes , Ra yna ud's
s yndrome) tha n the genera l popul a ti on, s ugges ti ng tha t a va s cul a r di s order compromi s i ng bl ood fl ow to the opti c nerve ma y pl a y a rol e.
Symptoms and Signs
Ea rl y s ymptoms a re uncommon. Us ua l l y, the pa ti ent becomes a wa re of vi s ua l fi el d l os s onl y when opti c nerve a trophy i s ma rked; the typi ca l l y
a s ymmetri c defi ci ts contri bute to del a y i n recogni ti on. However, s ome pa ti ents ha ve compl a i nts , s uch a s mi s s i ng s ta i rs i f thei r i nferi or vi s ua l fi el d
ha s been l os t, noti ci ng porti ons of words mi s s i ng when rea di ng, or ha vi ng di ffi cul ty wi th dri vi ng.
Exa mi na ti on fi ndi ngs i ncl ude a n unobs tructed open a ngl e on goni os copy a nd cha ra cteri s ti c opti c nerve a ppea ra nce a nd vi s ua l fi el d defects . IOP
ma y be norma l or hi gh but i s a l mos t a l wa ys hi gher i n the eye wi th more opti c nerve da ma ge.
Optic nerve appearance: The opti c nerve hea d (i e, di s k) i s norma l l y a s l i ghtl y verti ca l l y el onga ted ci rcl e wi th a centra l l y l oca ted depres s i on ca l l ed
the cup. The neuros ens ory ri m i s the ti s s ue between the ma rgi n of the cup a nd the edge of the di s k a nd i s compos ed of the ga ngl i on cel l a xons
from the reti na .
Cha ra cteri s ti c opti c nerve cha nges i ncl ude
Increa s ed cup:di s k ra ti o
Thi nni ng of the neuros ens ory ri m
Pi tti ng or notchi ng of the ri m
Nerve fi ber l a yer hemorrha ge tha t cros s es the di s k ma rgi n (i e, Dra nce hemorrha ge or s pl i nter hemorrha ges )
Verti ca l el onga ti on of the cup

Qui ck a ngul a ti ons i n the cours e of the exi ti ng bl ood ves s el s
Thi nni ng of the neuros ens ory ri m over ti me a l one ca n be di a gnos ti c of gl a ucoma rega rdl es s of the IOP or vi s ua l fi el d. However, mos t i ni ti a l
di a gnos es of gl a ucoma i nvol ve s ome vi s ua l fi el d cha nge.
Visual field defects: Vi s ua l fi el d cha nges ca us ed by l es i ons of the opti c nerve i ncl ude
Na s a l s tep defects (whi ch do not cros s the hori zonta l meri di a na n i ma gi na ry hori zonta l l i ne between the upper a nd l ower pa rts of the vi s ua l
fi el d)
Arcua te (a rc-s ha ped) s cotoma ta extendi ng na s a l l y from the bl i nd s pot
Tempora l wedge defects
Pa ra centra l s cotoma ta
In contra s t, defi ci ts of the more proxi ma l vi s ua l pa thwa ys (i e, from the l a tera l geni cul a te nucl eus to the occi pi ta l l obe) i nvol ve qua dra nts or
hemi s pheres of the vi s ua l fi el d; thus , defi ci ts do not cros s the verti ca l meri di a n.
Diagnosis
Vi s ua l fi el d tes ti ng
Ophtha l mos copy
Mea s urement of IOP
Excl us i on of other opti c neuropa thi es
Di a gnos i s i s s ugges ted by the exa mi na ti on, but s i mi l a r fi ndi ngs ca n res ul t from other opti c neuropa thi es (eg, ca us ed by i s chemi a , cytomega l ovi rus
i nfecti on, or vi ta mi n B 12 defi ci ency).
Before a di a gnos i s of norma l -pres s ure gl a ucoma ca n be es ta bl i s hed, the fol l owi ng fa ctors ma y need to be rul ed out: i na ccura te IOP rea di ngs ,
l a rge di urna l fl uctua ti ons (ca us i ng i ntermi ttent norma l rea di ngs ), opti c nerve da ma ge ca us ed by previ ous l y res ol ved gl a ucoma (eg, a previ ous l y
el eva ted IOP due to corti cos teroi d us e or uvei ti s ), i ntermi ttent a ngl e-cl os ure gl a ucoma , a nd other ocul a r or neurol ogi c di s orders tha t ca us e s i mi l a r
vi s ua l fi el d defects .
Opti c di s k photogra phy or a deta i l ed opti c di s k dra wi ng i s hel pful for future compa ri s on. The frequency of fol l ow-up exa mi na ti ons va ri es from
weeks to yea rs , dependi ng on the pa ti ent's rel i a bi l i ty, s everi ty of the gl a ucoma , a nd res pons e to trea tment.
Treatment
Decrea s i ng IOP 20 to 40%
Ini ti a l l y, drugs (eg, pros ta gl a ndi n a na l ogs , -bl ockers s uch a s ti mol ol )
Someti mes s urgery, s uch a s l a s er tra becul opl a s ty or gua rded fi l tra ti on procedure
Vi s i on l os t by gl a ucoma ca nnot be recovered. The goa l i s to prevent further opti c nerve a nd vi s ua l fi el d da ma ge by l oweri ng IOP. The ta rget l evel i s
20 to 40% bel ow pretrea tment rea di ngs . In genera l , the grea ter the da ma ge ca us ed by gl a ucoma , the l ower the IOP mus t be to prevent further
da ma ge. If da ma ge progres s es , the IOP goa l i s l owered further a nd a ddi ti ona l thera py i s i ni ti a ted.
Ini ti a l trea tment i s us ua l l y drug thera py, proceedi ng to l a s er thera py a nd then i nci s i ona l s urgery i f the ta rget IOP i s not met. Surgery ma y be the
i ni ti a l trea tment i f IOP i s extremel y hi gh.
Drug therapy: Mul ti pl e drugs a re a va i l a bl e (s ee
Ta bl e 65-4). Topi ca l a gents a re preferred. The mos t popul a r a re pros ta gl a ndi n a na l ogs , fol l owed by -bl ockers (pa rti cul a rl y ti mol ol ). Other drugs
i ncl ude 2 -s el ecti ve a drenergi c a goni s ts , chol i nergi c a goni s ts , a nd ca rboni c a nhydra s e i nhi bi tors . Ora l ca rboni c a nhydra s e i nhi bi tors a re effecti ve,
but a dvers e effects l i mi t thei r us e.
Pa ti ents ta ki ng topi ca l gl a ucoma drugs s houl d be ta ught pa s s i ve l i d cl os ure wi th puncta l occl us i on to hel p reduce s ys temi c a bs orpti on a nd
a s s oci a ted a dvers e effects , a l though the effecti venes s of thes e ma neuvers i s controvers i a l . Pa ti ents who ha ve di ffi cul ty i ns ti l l i ng drops di rectl y
onto the conjuncti va ma y pl a ce the drop on the nos e jus t medi a l to the medi a l ca nthus , then rol l the hea d s l i ghtl y towa rd the eye s o tha t the
l i qui d fl ows i nto the eye.
Typi ca l l y, to ga uge effecti venes s , cl i ni ci a ns s ta rt drugs i n onl y one eye (one-eye tri a l ); once i mprovement i n the trea ted eye ha s been confi rmed a t
a s ubs equent vi s i t (typi ca l l y 1 to 4 wk l a ter), both eyes a re trea ted.
Surgery: Surgery for pri ma ry open-a ngl e a nd norma l -pres s ure gl a ucoma i ncl udes l a s er tra becul opl a s ty, a gua rded fi l tra ti on procedure, a nd
pos s i bl y tube s hunts or ci l i odes tructi ve procedures .
Argon laser trabeculoplasty (ALT) ma y be the i ni ti a l trea tment for pa ti ents who do not res pond to or who ca nnot tol era te drug thera py. La s er energy i s
a ppl i ed to ei ther 180 or 360 of the tra becul a r mes hwork to i mprove the dra i na ge of a queous humor. Wi thi n 2 to 5 yr, a bout 50% of pa ti ents
requi re a ddi ti ona l drug thera py or s urgery beca us e of i ns uffi ci ent IOP control .
Selective laser trabeculoplasty (SLT) us es a pul s ed doubl e-frequency neodymi um:yttri um-a l umi num-ga rnet l a s er. SLT a nd ALT a re equa l l y effecti ve
i ni ti a l l y, but SLT ma y ha ve grea ter effecti venes s i n s ubs equent trea tments .
A guarded filtration procedure i s the mos t commonl y us ed fi l tra ti on procedure. A hol e i s ma de i n the l i mba l s cl era (tra becul ectomy), whi ch i s covered
by a pa rti a l -thi cknes s s cl era l fl a p tha t control s egres s of a queous from the eye to the s ubconjuncti va l s pa ce, formi ng a fi l tra ti on bl eb. Advers e
effects of gl a ucoma fi l tra ti on s urgery i ncl ude a ccel era ti on of ca ta ra ct growth, pres s ures tha t a re too l ow, a nd tra ns i ent s wel l i ng duri ng the
peri opera ti ve peri od. Pa ti ents wi th tra becul ectomi es a re a t i ncrea s ed ri s k of ba cteri a l endophtha l mi ti s a nd s houl d be i ns tructed to report a ny
s ymptoms or s i gns of bl eb i nfecti on (bl ebi ti s ) or endophtha l mi ti s i mmedi a tel y.
Vi s coca na l os tomy, ca na l opl a s ty, a nd Tra bectome s urgery a re newer fi l tra ti on procedures tha t do not i nvol ve crea ti ng a fi s tul a between the
a nteri or cha mber a nd s ubconjuncti va l s pa ce. Vi s coca na l os tomy a nd ca na l opl a s ty i nvol ve di l a ti ng Schl emm's ca na l . Tra bectome s urgery us es a
propri eta ry devi ce to remove a porti on of the i nner a s pect of one of the dra i ns of the eye (tra becul a r mes hwork). More l ong-term s tudi es wi th
thes e procedures a re needed a nd a re on-goi ng. Currentl y, thes e new procedures do not a ppea r a s effecti ve a s tra becul ectomy but s eem to offer
grea ter s a fety.
Angle-Closure Glaucoma
Angle-closure glaucoma is glaucoma associated with a physically obstructed anterior chamber angle, which may be chronic or, rarely, acute. Symptoms of acute
angle closure are severe ocular pain and redness, decreased vision, colored halos around lights, headache, nausea, and vomiting. Intraocular pressure (IOP) is
elevated. Immediate treatment of the acute condition with multiple topical and systemic drugs is required to prevent permanent vision loss, followed by the
definitive treatment, iridotomy.
Angl e-cl os ure gl a ucoma a ccounts for a bout 10% of a l l gl a ucoma s i n the US.
Etiology
Angl e-cl os ure gl a ucoma i s ca us ed by fa ctors tha t ei ther pul l or pus h the i ri s up i nto the a ngl e (i e, juncti on of the i ri s a nd cornea a t the peri phery
of the a nteri or cha mber), phys i ca l l y bl ocki ng dra i na ge of a queous a nd ra i s i ng IOP (s ee Ta bl e 65-2). El eva ted IOP da ma ges the opti c nerve.
Pathophysiology
Angl e cl os ure ma y be pri ma ry (ca us e i s unknown) or s econda ry to a nother condi ti on (s ee Ta bl e 65-2) a nd ca n be a cute, s uba cute (i ntermi ttent), or
chroni c.
[Table 65-4. Drugs Us ed to Trea t Gl a ucoma ]
Primary angle-closure glaucoma: Na rrow a ngl es a re not pres ent i n young peopl e. As peopl e a ge, the l ens of the eye conti nues to grow. In s ome but
not a l l peopl e, thi s growth pus hes the i ri s forwa rd, na rrowi ng the a ngl e. Ri s k fa ctors for devel opi ng na rrow a ngl es i ncl ude As i a n ethni ci ty,
hyperopi a , fa mi l y hi s tory, a nd a dva nced a ge.
In peopl e wi th na rrow a ngl es , the di s ta nce between the pupi l l a ry i ri s a nd the l ens i s a l s o very na rrow. When the i ri s di l a tes , forces pul l i t
centri peta l l y a nd pos teri orl y ca us i ng i ri s -l ens conta ct, whi ch prevents a queous from pa s s i ng between the l ens a nd i ri s i nto the a nteri or cha mber
(thi s mecha ni s m i s termed pupi l l a ry bl ock). Pres s ure from the conti nued s ecreti on of a queous i nto the pos teri or cha mber by the ci l i a ry body
pus hes the peri phera l i ri s a nteri orl y (ca us i ng a forwa rd-bowi ng i ri s ca l l ed i ri s bombe), cl os i ng the a ngl e. Thi s cl os ure bl ocks a queous outfl ow,
res ul ti ng i n ra pi d (wi thi n hours ) a nd s evere (> 40 mm Hg) el eva ti on of IOP. Beca us e of the ra pi d ons et, thi s condi ti on i s ca l l ed pri ma ry a cute a ngl ecl os ure gl a ucoma a nd i s a n ophtha l mi c emergency requi ri ng i mmedi a te trea tment.
Intermi ttent a ngl e-cl os ure gl a ucoma occurs i f the epi s ode of pupi l l a ry bl ock res ol ves s ponta neous l y a fter s evera l hours , us ua l l y a fter s l eepi ng
s upi ne.
Chroni c a ngl e-cl os ure gl a ucoma occurs i f the a ngl e na rrows s l owl y, a l l owi ng s ca rri ng between the peri phera l i ri s a nd tra becul a r mes hwork; IOP
el eva ti on i s s l ow.
Pupi l l a ry di l a ti on (mydri a s i s ) ca n pus h the i ri s i nto the a ngl e a nd preci pi ta te a cute a ngl e-cl os ure gl a ucoma i n a ny pers on wi th na rrow a ngl es .
Thi s devel opment i s of pa rti cul a r concern when a ppl yi ng topi ca l a gents to di l a te the eye for exa mi na ti on (eg, cycl opentol a te, phenyl ephri ne) or
for trea tment (eg, homa tropi ne) or when gi vi ng s ys temi c drugs tha t ha ve the potenti a l to di l a te the pupi l s (eg, s copol a mi ne, -a drenergi c a goni s ts
commonl y us ed to trea t uri na ry i nconti nence, drugs wi th a nti chol i nergi c effects ).
Secondary angle-closure glaucomas: The mecha ni ca l obs tructi on of the a ngl e i s due to a coexi s ti ng condi ti on, s uch a s prol i fera ti ve di a beti c
reti nopa thy (PDR), i s chemi c centra l vei n occl us i on, uvei ti s , or epi thel i a l down-growth. Contra cti on of a neova s cul a r membra ne (eg, i n PDR) or
i nfl a mma tory s ca rri ng a s s oci a ted wi th uvei ti s ca n pul l the i ri s i nto the a ngl e.
Symptoms and Signs
Acute angle-closure glaucoma: Pa ti ents ha ve s evere ocul a r pa i n a nd rednes s , decrea s ed vi s i on, col ored ha l os a round l i ghts , hea da che, na us ea , a nd
vomi ti ng. The s ys temi c compl a i nts ma y be s o s evere tha t pa ti ents a re mi s di a gnos ed a s ha vi ng a neurol ogi c or GI probl em. Exa mi na ti on typi ca l l y
revea l s conjuncti va l hyperemi a , a ha zy cornea , a fi xed mi d-di l a ted pupi l , a nd a nteri or cha mber i nfl a mma ti on. Vi s i on i s decrea s ed. IOP i s us ua l l y
40 to 80 mm Hg. The opti c nerve i s di ffi cul t to vi s ua l i ze beca us e of cornea l edema , a nd vi s ua l fi el d tes ti ng i s not done beca us e of di s comfort.
Chronic angle-closure glaucoma: Thi s type of gl a ucoma ma ni fes ts s i mi l a rl y to open-a ngl e gl a ucoma (s ee p. 600). Some pa ti ents ha ve ocul a r rednes s ,
di s comfort, bl urred vi s i on, or hea da che tha t l es s ens wi th s l eep (perha ps beca us e of s l eep-i nduced mi os i s a nd pos teri or di s pl a cement of the l ens
by gra vi ty). On goni os copy, the a ngl e i s na rrow, a nd peri phera l a nteri or s ynechi a e (PAS) ma y be s een. IOP ma y be norma l but i s us ua l l y hi gher i n
the a ffected eye.
Diagnosis
Acute: Mea s urement of IOP a nd cl i ni ca l fi ndi ngs
Chronic: Goni os copy s howi ng peri phera l a nteri or s ynechi a e a nd cha ra cteri s ti c opti c nerve a nd vi s ua l fi el d a bnorma l i ti es
Di a gnos i s of a cute a ngl e-cl os ure gl a ucoma i s cl i ni ca l a nd by mea s urement of IOP. Goni os copy ma y be di ffi cul t to perform i n the i nvol ved eye
beca us e of a cl ouded cornea wi th fri a bl e cornea l epi thel i um. However, exa mi na ti on of the other eye revea l s a na rrow or occl uda bl e a ngl e. If the
other eye ha s a wi de a ngl e, a di a gnos i s other tha n pri ma ry a ngl e-cl os ure gl a ucoma s houl d be cons i dered.
Di a gnos i s of chroni c a ngl e-cl os ure gl a ucoma i s ba s ed on the pres ence of PAS on goni os copy a nd cha ra cteri s ti c opti c nerve a nd vi s ua l fi el d
cha nges (s ee p. 601).
Treatment
Acute: Ti mol ol , pi l oca rpi ne, a nd a pra cl oni di ne drops a nd a s ys temi c os moti c drug fol l owed promptl y by l a s er peri phera l i ri dotomy
Chronic: Si mi l a r to pri ma ry open-a ngl e gl a ucoma except tha t l a s er peri phera l i ri dotomy ma y be done i f the cl i ni ci a n feel s tha t the procedure ma y
s l ow the mecha ni ca l cl os i ng of the a ngl e
Acute angle-closure glaucoma: Trea tment mus t be i ni ti a ted i mmedi a tel y beca us e vi s i on ca n be l os t qui ckl y a nd perma nentl y. The pa ti ent s houl d
recei ve s evera l drugs a t once. A s ugges ted regi men i s ti mol ol 0.5% one drop q 30 mi n for 2 dos es ; pi l oca rpi ne 2 to 4% one drop q 15 mi n for the fi rs t
1 to 2 h; a pra cl oni di ne 0.5 to 1% one drop q 30 mi n for 2 dos es ; a ceta zol a mi de 500 mg po i ni ti a l l y fol l owed by 250 mg q 6 h; a nd a n os moti c a gent,
s uch a s ora l gl ycerol 1 mL/kg di l uted wi th a n equa l a mount of col d wa ter, ma nni tol 1.0 to 1.5 mg/kg IV, or i s os orbi de 100 g po (220 mL of a 45%
s ol uti on [NOTE: Thi s form of i s os orbi de i s not i s os orbi de di ni tra te.]). Res pons e i s eva l ua ted by mea s uri ng IOP. Mi oti cs a re genera l l y not effecti ve
when IOP i s > 40 or 50 mm Hg beca us e of a n a noxi c pupi l l a ry s phi ncter.
Defi ni ti ve trea tment i s wi th l a s er peri phera l i ri dotomy (LPI), whi ch opens a nother pa thwa y for fl ui d to pa s s from the pos teri or to the a nteri or
cha mber, brea ki ng the pupi l l a ry bl ock. It i s done a s s oon a s the cornea i s cl ea r a nd i nfl a mma ti on ha s s ubs i ded. In s ome ca s es the cornea cl ea rs
wi thi n hours of l oweri ng the IOP; i n other ca s es , i t ca n ta ke 1 to 2 da ys . Beca us e the cha nce of ha vi ng a n a cute a tta ck i n the other eye i s 80%, LPI i s
done on both eyes .
The ri s k of compl i ca ti ons wi th LPI i s extremel y l ow compa red wi th i ts benefi ts . Gl a re, whi ch ca n be bothers ome, ma y occur i f the i ri dotomy i s not
pl a ced s uperi orl y enough for the upper l i d to cover i t.
Chronic angle-closure glaucoma: Pa ti ents wi th chroni c, s uba cute, or i ntermi ttent a ngl e-cl os ure gl a ucoma s houl d a l s o ha ve LPI. Addi ti ona l l y, pa ti ents
wi th a na rrow a ngl e, even i n the a bs ence of s ymptoms , s houl d undergo prompt LPI to prevent a ngl e-cl os ure gl a ucoma .
The drug a nd s urgi ca l trea tments a re the s a me a s wi th open-a ngl e gl a ucoma . La s er tra becul opl a s ty i s rel a ti vel y contra i ndi ca ted i f the a ngl e i s s o
na rrow tha t a ddi ti ona l PAS ma y form a fter the l a s er procedure.
Chapter 66. Cataract

(For devel opmenta l or congeni ta l ca ta ra cts , s ee p. 2920.)
A cataract is a congenital or degenerative opacity of the lens. The main symptom is gradual, painless vision blurring. Diagnosis is by ophthalmoscopy and slitlamp examination. Treatment is surgical removal and placement of an intraocular lens.
Lens opa ci ty ca n devel op i n s evera l l oca ti ons :
Centra l l ens nucl eus (nucl ea r ca ta ra ct)
Benea th the pos teri or l ens ca ps ul e (pos teri or s ubca ps ul a r ca ta ra ct)
Etiology
Ca ta ra cts occur wi th a gi ng. Other ri s k fa ctors ma y i ncl ude the fol l owi ng:
Tra uma (s ometi mes ca us i ng ca ta ra cts yea rs l a ter)
Smoki ng
Al cohol us e
Expos ure to x-ra ys
Hea t from i nfra red expos ure
Sys temi c di s ea s e (eg, di a betes )
Uvei ti s
Sys temi c drugs (eg, corti cos teroi ds )
Undernutri ti on
Da rk eyes
Pos s i bl y chroni c ul tra vi ol et expos ure
Ma ny peopl e ha ve no ri s k fa ctors other tha n a ge. Some ca ta ra cts a re congeni ta l , a s s oci a ted wi th numerous s yndromes a nd di s ea s es .
Symptoms and Signs
Ca ta ra cts genera l l y devel op s l owl y over yea rs . Ea rl y s ymptoms ma y be l os s of contra s t, gl a re (ha l os a nd s ta rburs ts a round l i ghts ), needi ng more
l i ght to s ee wel l , a nd probl ems di s ti ngui s hi ng da rk bl ue from bl a ck. Pa i nl es s bl urri ng eventua l l y occurs . The degree of bl urri ng depends on the
l oca ti on a nd extent of the opa ci ty. Doubl e vi s i on occurs ra rel y.
Wi th a nucl ea r ca ta ra ct (s ee
Pl a te 4), di s ta nce vi s i on wors ens . Nea r vi s i on ma y i mprove i n the ea rl y s ta ges beca us e of cha nges i n the refra cti ve i ndex of the l ens ; pres byopi c
pa ti ents ma y be tempora ri l y a bl e to rea d wi thout gl a s s es (s econd s i ght).
A pos teri or s ubca ps ul a r ca ta ra ct di s proporti ona tel y a ffects vi s i on beca us e the opa ci ty i s l oca ted a t the cros s i ng poi nt of i ncomi ng l i ght ra ys . Such
ca ta ra cts reduce vi s ua l a cui ty more when the pupi l cons tri cts (eg, i n bri ght l i ght, duri ng rea di ng). They a re a l s o the type mos t l i kel y to ca us e l os s of
contra s t a s wel l a s gl a re, es peci a l l y from bri ght l i ghts or from ca r hea dl i ghts whi l e dri vi ng a t ni ght.
Ra rel y, the ca ta ra ct s wel l s , occl udi ng the tra becul a r dra i na ge mes hwork a nd ca us i ng s econda ry cl os ed-a ngl e gl a ucoma a nd pa i n.
Diagnosis
Ophtha l mos copy fol l owed by s l i t-l a mp exa mi na ti on
Di a gnos i s i s bes t ma de wi th the pupi l di l a ted. Wel l -devel oped ca ta ra cts a ppea r a s gra y, whi te, or yel l ow-brown opa ci ti es i n the l ens .
Exa mi na ti on of the red refl ex through the di l a ted pupi l wi th the ophtha l mos cope hel d a bout 30 cm a wa y us ua l l y di s cl os es s ubtl e opa ci ti es . Sma l l
ca ta ra cts s ta nd out a s da rk defects i n the red refl ex. A l a rge ca ta ra ct ma y obl i tera te the red refl ex. Sl i t-l a mp exa mi na ti on provi des more deta i l s
a bout the cha ra cter, l oca ti on, a nd extent of the opa ci ty.
Treatment
Surgi ca l remova l of the ca ta ra ct
Pl a cement of a n i ntra ocul a r l ens
Frequent refra cti ons a nd correcti ve l ens pres cri pti on cha nges ma y hel p ma i nta i n us eful vi s i on duri ng ca ta ra ct devel opment. Occa s i ona l l y, l ongterm pupi l l a ry di l a ti on (wi th phenyl ephri ne 2.5% q 4 to 8 h) i s hel pful for s ma l l centra l l y l oca ted ca ta ra cts . Indi rect l i ghti ng whi l e rea di ng
mi ni mi zes pupi l l a ry cons tri cti on a nd ma y opti mi ze vi s i on for cl os e ta s ks . Pol a ri zed l ens es reduce gl a re.
Us ua l i ndi ca ti ons for s urgery i ncl ude the fol l owi ng:
Bes t vi s i on obta i ned wi th gl a s s es i s wors e tha n 20/40 (< 6/12), or vi s i on i s s i gni fi ca ntl y decrea s ed under gl a re condi ti ons (eg, obl i que l i ghti ng
whi l e tryi ng to rea d a cha rt) i n a pa ti ent wi th bothers ome ha l os or s ta rburs ts .
Pa ti ents s ens e tha t vi s i on i s l i mi ti ng (eg, by preventi ng a cti vi ti es of da i l y l i vi ng s uch a s dri vi ng, rea di ng, hobbi es , a nd occupa ti ona l a cti vi ti es ).
Vi s i on coul d potenti a l l y be mea ni ngful l y i mproved i f the ca ta ra ct i s removed (i e, a s i gni fi ca nt porti on of the vi s i on l os s mus t be ca us ed by the
ca ta ra ct).
Fa r l es s common i ndi ca ti ons i ncl ude ca ta ra cts tha t ca us e gl a ucoma or tha t obs cure the fundus i n pa ti ents who need peri odi c fundus
exa mi na ti ons for ma na gement of di s ea s es s uch a s di a beti c reti nopa thy a nd gl a ucoma . There i s no a dva nta ge to removi ng a ca ta ra ct ea rl y.
Ca ta ra ct extra cti on i s us ua l l y done us i ng a topi ca l or l oca l a nes theti c a nd IV s eda ti on. There a re 3 extra cti on techni ques . In intracapsular cataract
extraction, the ca ta ra ct a nd l ens ca ps ul e a re removed i n one pi ece; thi s techni que i s ra rel y us ed. In extracapsular cataract extraction, the ha rd centra l
nucl eus i s removed i n one pi ece a nd then the s oft cortex i s removed i n mul ti pl e s ma l l pi eces . In phacoemulsification, the ha rd centra l nucl eus i s
di s s ol ved by ul tra s ound a nd then the s oft cortex i s removed i n mul ti pl e s ma l l pi eces . Pha coemul s i fi ca ti on requi res the s ma l l es t i nci s i on, thus
ena bl i ng the fa s tes t hea l i ng, a nd i s us ua l l y the preferred procedure. In extra ca ps ul a r extra cti on a nd pha coemul s i fi ca ti on, the l ens ca ps ul e i s not
removed.
A pl a s ti c or s i l i cone l ens i s a l mos t a l wa ys i mpl a nted i ntra ocul a rl y to repl a ce the opti ca l focus i ng power l os t by remova l of the crys ta l l i ne l ens .
The l ens i mpl a nt i s us ua l l y pl a ced on or wi thi n the l ens ca ps ul e (pos teri or cha mber l ens ). The l ens ca n a l s o be pl a ced i n front of the i ri s (a nteri or
cha mber l ens ) or a tta ched to the i ri s a nd wi thi n the pupi l (i ri s pl a ne l ens ). Iri s pl a ne l ens es a re ra rel y us ed i n the US beca us e ma ny des i gns l ed
to a hi gh frequency of pos topera ti ve compl i ca ti ons . Mul ti foca l i ntra ocul a r l ens es a re newer a nd ha ve di fferent focus i ng zones tha t ma y reduce
dependence on gl a s s es a fter s urgery. Pa ti ents occa s i ona l l y experi ence gl a re or ha l os wi th thes e l ens es , es peci a l l y under l ow-l i ght condi ti ons .
In mos t ca s es , a ta peri ng s chedul e of topi ca l a nti bi oti cs (eg, moxi fl oxa ci n 0.5% 1 drop qi d) a nd topi ca l corti cos teroi ds (eg, predni s ol one a ceta te
1% 1 drop qi d) i s us ed for up to 4 wk pos ts urgery. Pa ti ents often wea r a n eye s hi el d whi l e s l eepi ng a nd s houl d a voi d the Va l s a l va ma neuver, hea vy
l i fti ng, exces s i ve forwa rd bendi ng, a nd eye rubbi ng for s evera l weeks .
Ma jor compl i ca ti ons of ca ta ra ct s urgery a re ra re. Compl i ca ti ons i ncl ude the fol l owi ng:
Intra opera ti ve: Bl eedi ng benea th the reti na , ca us i ng the i ntra ocul a r contents to extrude through the i nci s i on (choroi da l hemorrha ge), vi treous
prol a ps i ng out of the i nci s i on (vi treous l os s ), fra gments of the ca ta ra ct di s l oca ti ng i nto the vi treous , i nci s i ona l burn, a nd deta chment of cornea l
endothel i um a nd i ts ba s ement membra ne (Des cemet's membra ne)
Wi thi n the fi rs t week: Endophtha l mi ti s (i nfecti on wi thi n the eye) a nd gl a ucoma
Wi thi n the fi rs t month: Cys toi d ma cul a r edema
Months l a ter: Bul l ous kera topa thy (i e, s wel l i ng of the cornea due to da ma ge to the cornea l pump cel l s duri ng ca ta ra ct s urgery), reti na l
deta chment, a nd pos teri or ca ps ul a r opa ci fi ca ti on (common, but trea ta bl e wi th l a s er)
After s urgery, vi s i on returns to 20/40 (6/12) or better i n 95% of eyes i f there a re no preexi s ti ng di s orders s uch a s a mbl yopi a , reti nopa thy, ma cul a r
degenera ti on, a nd gl a ucoma . If a n i ntra ocul a r l ens i s not i mpl a nted, conta ct l ens es or thi ck gl a s s es a re needed to correct the res ul ti ng hyperopi a .
Prevention
Ma ny ophtha l mol ogi s ts recommend ul tra vi ol et-coa ted eyegl a s s es or s ungl a s s es a s a preventi ve mea s ure. Reduci ng ri s k fa ctors s uch a s a l cohol ,
toba cco, a nd corti cos teroi ds a nd control l i ng bl ood gl ucos e i n di a betes del a y ons et. A di et hi gh i n vi ta mi n C, vi ta mi n A, a nd ca rotenoi ds (conta i ned
i n vegeta bl es s uch a s s pi na ch a nd ka l e) ma y protect a ga i ns t ca ta ra cts .
Chapter 67. Uveitis

Introduction
Uveitis is inflammation of the uveal tractthe iris, ciliary body, and choroid. Most cases are idiopathic, but identifiable causes include various infections and
systemic diseases, many of which are autoimmune. Symptoms include decreased vision, ocular ache, redness, photophobia, and floaters. Although intraocular
inflammation is identified clinically, identifying the cause of the inflammation typically requires testing. Treatment depends on cause but typically includes
topical, locally injected, or systemic corticosteroids with a topical cycloplegic-mydriatic drug. Noncorticosteroid immunosuppressive drugs may be used in severe
and refractory cases. Infectious causes require antimicrobial therapy.
Infl a mma ti on of the uvea (uvei ti s ) ma y occur wi th or wi thout vi trei ti s , reti ni ti s , pa pi l l i ti s , or opti c neuri ti s . Uvei ti s i s cl a s s i fi ed a na tomi ca l l y a s
a nteri or, i ntermedi a te, or pos teri or uvei ti s or pa nuvei ti s .
Anterior uveitis i s l oca l i zed pri ma ri l y to the a nteri or s egment of the eye a nd i ncl udes i ri ti s (i nfl a mma ti on i n the a nteri or cha mber a l one) a nd
i ri docycl i ti s (i nfl a mma ti on i n the a nteri or cha mber a nd a nteri or vi treous ).
Intermediate uveitis (peri phera l uvei ti s or chroni c cycl i ti s ) occurs i n the vi treous .
Posterior uveitis refers to a ny form of reti ni ti s , choroi di ti s , or i nfl a mma ti on of the opti c di s k.
Panuveitis (a l s o ca l l ed di ffus e uvei ti s ) i mpl i es i nfl a mma ti on i n both the a nteri or a nd pos teri or cha mbers .
Etiology
Mos t ca s es a re i di opa thi c a nd pres umed to be a utoi mmune i n ori gi n. Identi fi a bl e ca us es i ncl ude
Tra uma
Ocul a r a nd s ys temi c i nfecti ons
Sys temi c a utoi mmune di s orders
The mos t common ca us e of a nteri or uvei ti s i s tra uma (tra uma ti c i ri docycl i ti s ). Other ca us es a re s pondyl oa rthropa thi es (20 to 25%), juveni l e
i di opa thi c a rthri ti s , a nd herpes vi rus (herpes s i mpl ex a nd va ri cel l a -zos ter) i nfecti on. Ha l f of a l l ca s es of a nteri or uvei ti s a re i di opa thi c.
Mos t i ntermedi a te uvei ti s i s i di opa thi c. Uncommon i denti fi a bl e ca us es i ncl ude mul ti pl e s cl eros i s , s a rcoi dos i s , TB, s yphi l i s , a nd, i n endemi c
regi ons , Lyme di s ea s e.
Mos t pos teri or uvei ti s (reti ni ti s ) i s i di opa thi c. The mos t commonl y recogni zed ca us e of pos teri or uvei ti s i n i mmunocompetent pa ti ents i s
toxopl a s mos i s ; the mos t commonl y recogni zed ca us e i n pa ti ents wi th HIV/AIDS i s cytomega l ovi rus (CMV).
The mos t commonl y i denti fi ed ca us e of pa nuvei ti s i s s a rcoi dos i s , but mos t ca s es rema i n i di opa thi c des pi te a ppropri a te tes ti ng.
Infrequentl y, s ys temi c drugs ca us e uvei ti s (us ua l l y a nteri or). Exa mpl es a re s ul fona mi des , pa mi drona te (a n i nhi bi tor of bone res orpti on), ri fa buti n,
a nd ci dofovi r.
Sys temi c di s ea s es ca us i ng uvei ti s a nd thei r trea tment a re di s cus s ed el s ewhere i n THE MANUAL.
Symptoms and Signs
Symptoms a nd s i gns ma y be s ubtl e a nd va ry dependi ng on the s i te a nd s everi ty of i nfl a mma ti on.
Anterior uveitis tends to be the mos t s ymptoma ti c, us ua l l y ma ni fes ti ng wi th pa i n (ocul a r a che), rednes s , photophobi a , a nd, to a va ri a bl e degree,
decrea s ed vi s i on. Si gns i ncl ude hyperemi a of the conjuncti va a dja cent to the cornea (ci l i a ry fl us h or l i mba l i njecti on). Sl i t-l a mp fi ndi ngs i ncl ude
cel l s a nd fl a re (a ha ze) i n the a nteri or cha mber (a queous humor), kera ti c preci pi ta tes (WBC cl umps on the i nner cornea l s urfa ce), a nd pos teri or
s ynechi a e. Wi th s evere a nteri or uvei ti s , WBCs ma y l a yer i n the a nteri or cha mber (hypopyon).
Intermediate uveitis i s typi ca l l y pa i nl es s a nd ma ni fes ts wi th fl oa ters a nd decrea s ed vi s i on. The pri ma ry s i gn i s cel l s i n the vi treous humor.
Aggrega tes a nd condens a ti ons of i nfl a mma tory cel l s often occur over the pa rs pl a na (nea r the juncti on of the i ri s a nd s cl era ), formi ng s nowba l l s .
Vi s i on ma y be decrea s ed beca us e of fl oa ters or cys toi d ma cul a r edema , whi ch res ul ts from fl ui d l ea ka ge from bl ood ves s el s i n the ma cul a .
Confl uent a nd condens ed vi treous cel l s a nd s nowba l l s over the pa rs pl a na ma y ca us e a cl a s s i c s nowba nk a ppea ra nce, whi ch ca n be a s s oci a ted
wi th neova s cul a ri za ti on of the reti na l peri phery.
Posterior uveitis ma y gi ve ri s e to di vers e s ymptoms but mos t commonl y ca us es fl oa ters a nd decrea s ed vi s i on a s occurs i n i ntermedi a te uvei ti s .
Si gns i ncl ude cel l s i n the vi treous humor; whi te or yel l ow-whi te l es i ons i n the reti na (reti ni ti s ), underl yi ng choroi d (choroi di ti s ), or both; exuda ti ve
reti na l deta chments ; reti na l va s cul i ti s ; a nd opti c di s k edema .
Panuveitis ma y ca us e a ny combi na ti on of the previ ous l y menti oned s ymptoms a nd s i gns .
Consequences: Cons equences of uvei ti s i ncl ude profound a nd i rrevers i bl e vi s i on l os s , es peci a l l y when uvei ti s i s unrecogni zed, i na dequa tel y
trea ted, or both. The mos t frequent compl i ca ti ons i ncl ude ca ta ra ct; gl a ucoma ; reti na l deta chment; neova s cul a ri za ti on of the reti na , opti c nerve, or
i ri s ; a nd cys toi d ma cul a r edema (the mos t common ca us e of decrea s ed vi s i on i n pa ti ents wi th uvei ti s ).
Diagnosis
Sl i t-l a mp exa mi na ti on
Ophtha l mos copy a fter pupi l di l a ti on
Uvei ti s s houl d be s us pected i n a ny pa ti ent who ha s ocul a r a che, rednes s , photophobi a , fl oa ters , or decrea s ed vi s i on. Pa ti ents wi th a nteri or
uvei ti s ha ve ocul a r a che i n the a ffected eye i f l i ght i s s hi ned i n the una ffected eye (true photophobi a ), whi ch i s uncommon i n conjuncti vi ti s .
Di a gnos i s of a nteri or uvei ti s i s by recogni zi ng cel l s a nd fl a re i n the a nteri or cha mber. Cel l s a nd fl a re a re s een wi th a s l i t l a mp a nd a re mos t
evi dent when us i ng a na rrow, i ntens el y bri ght l i ght focus ed on the a nteri or cha mber i n a da rk room. Fi ndi ngs of i ntermedi a te a nd pos teri or uvei ti s
a re mos t ea s i l y s een a fter di l a ti ng the pupi l (s ee p. 538). Indi rect ophtha l mos copy (us ua l l y done by a n ophtha l mol ogi s t) i s more s ens i ti ve tha n
di rect ophtha l mos copy. (NOTE: If uvei ti s i s s us pected, pa ti ents s houl d be referred i mmedi a tel y for compl ete ophtha l mol ogi c eva l ua ti on.)
Ma ny condi ti ons tha t ca us e i ntra ocul a r i nfl a mma ti on ca n mi mi c uvei ti s a nd s houl d be cons i dered i n the a ppropri a te cl i ni ca l s etti ngs . Such
condi ti ons i ncl ude i ntra ocul a r ca ncers i n the very young (typi ca l l y reti nobl a s toma a nd l eukemi a ) a nd i n the el derl y (i ntra ocul a r l ymphoma ). Les s
commonl y, reti ni ti s pi gmentos a (s ee p. 618) ca n ma ni fes t wi th mi l d i nfl a mma ti on, whi ch ma y be confus ed wi th uvei ti s .
Treatment
Corti cos teroi ds (us ua l l y topi ca l )
Cycl opl egi c-mydri a ti c drugs
Trea tment of a cti ve i nfl a mma ti on us ua l l y i nvol ves corti cos teroi ds gi ven topi ca l l y or by peri ocul a r or i ntra ocul a r i njecti on a l ong wi th a cycl opl egi cmydri a ti c drug (eg, homa tropi ne 2% or 5% drops bi d to qi d dependi ng on s everi ty). Anti mi crobi a l drugs a re us ed to trea t i nfecti ous uvei ti s .
Pa rti cul a rl y s evere or chroni c ca s es ma y requi re s ys temi c corti cos teroi ds , s ys temi c noncorti cos teroi d i mmunos uppres s i ve drugs , l a s er
photothera py, cryothera py a ppl i ed tra ns s cl era l l y to the reti na l peri phery, or s urgi ca l remova l of the vi treous (vi trectomy).
Uveitis Caused by Connective Tissue Disease
A number of connecti ve ti s s ue di s ea s es ca us e i nfl a mma ti on of the uvea l tra ct.
Spondyloarthropathies: The s eronega ti ve s pondyl oa rthropa thi es (s ee p. 341) a re a common ca us e of a nteri or uvei ti s . RA, i n contra s t, i s not
a s s oci a ted wi th uvei ti s . Ocul a r i nfl a mma ti on i s mos t common wi th a nkyl os i ng s pondyl i ti s but a l s o occurs wi th rea cti ve a rthri ti s , i nfl a mma tory
bowel di s ea s e (ul cera ti ve col i ti s a nd Crohn's di s ea s e), a nd ps ori a ti c a rthri ti s . Uvei ti s i s cl a s s i ca l l y uni l a tera l , but recurrences a re common a nd
a cti ve i nfl a mma ti on ma y a l terna te between eyes . Men a re a ffected more commonl y tha n women. Mos t pa ti ents , rega rdl es s of s ex, a re HLA-B27
pos i ti ve.
Trea tment requi res a topi ca l corti cos teroi d a nd a cycl opl egi c-mydri a ti c drug. Occa s i ona l l y, peri ocul a r corti cos teroi ds a re requi red.
Juvenile idiopathic arthritis (JIA, also known as juvenile RA): JIA cha ra cteri s ti ca l l y ca us es chroni c bi l a tera l i ri docycl i ti s i n chi l dren, pa rti cul a rl y thos e
wi th the pa uci a rti cul a r va ri ety (s ee p. 339). Unl i ke mos t forms of a nteri or uvei ti s , however, JIA tends not to ca us e pa i n, photophobi a , a nd
conjuncti va l i njecti on but onl y bl urri ng a nd mei os i s a nd i s , therefore, often referred to a s whi te i ri ti s . JIA-a s s oci a ted uvei ti s i s more common
a mong gi rl s .
Recurrent bouts of i nfl a mma ti on a re bes t trea ted wi th a topi ca l corti cos teroi d a nd a cycl opl egi c-mydri a ti c drug. Long-term control often requi res
us e of a noncorti cos teroi d i mmunos uppres s i ve drug (eg, methotrexa te, mycophenol a te mofeti l ).
Sarcoidosis: Sa rcoi dos i s (s ee a l s o p. 1965) a ccounts for 10 to 20% of ca s es of uvei ti s , a nd a bout 25% of pa ti ents wi th s a rcoi dos i s devel op uvei ti s .
Sa rcoi d uvei ti s i s more common a mong bl a cks a nd the el derl y.
Vi rtua l l y a ny s ymptoms a nd s i gns of a nteri or, i ntermedi a te, pos teri or, or pa nuvei ti s ca n occur. Sugges ti ve fi ndi ngs i ncl ude conjuncti va l
gra nul oma s , l a rge kera ti c preci pi ta tes on the cornea l endothel i um (s o-ca l l ed gra nul oma tous or mutton fa t preci pi ta tes ), i ri s gra nul oma s , a nd
reti na l va s cul i ti s . Bi ops y of s ugges ti ve l es i ons , whi ch provi des the mos t s ecure di a gnos i s , i s us ua l l y done on the conjuncti va ; i t i s ra rel y done on
i ntra ocul a r ti s s ues beca us e of the ri s k a s s oci a ted wi th the procedure.
Trea tment us ua l l y i nvol ves topi ca l , peri ocul a r, i ntra ocul a r, or s ys temi c corti cos teroi ds , or a combi na ti on, a l ong wi th a topi ca l cycl opl egi c-mydri a ti c
drug. Pa ti ents wi th modera te to s evere i nfl a mma ti on ma y requi re a noncorti cos teroi d i mmunos uppres s i ve drug (eg, methotrexa te, mycophenol a te
mofeti l , a za thi opri ne).
Behcet's syndrome: Thi s condi ti on i s ra re i n North Ameri ca but i s a fa i rl y common ca us e of uvei ti s i n the Mi ddl e Ea s t a nd Fa r Ea s t (s ee a l s o p. 315).
Typi ca l fi ndi ngs i ncl ude s evere a nteri or uvei ti s wi th hypopyon, reti na l va s cul i ti s , a nd opti c di s k i nfl a mma ti on. The cl i ni ca l cours e i s us ua l l y s evere
wi th mul ti pl e recurrences .
Di a gnos i s requi res the pres ence of a s s oci a ted s ys temi c ma ni fes ta ti ons , s uch a s ora l a phthous or geni ta l ul cers ; derma ti ti s , i ncl udi ng erythema
nodos um; thrombophl ebi ti s ; or epi di dymi ti s . Ora l a phtha e ma y be bi ops i ed to s how a n occl us i ve va s cul i ti s . There a re no l a bora tory tes ts for
Behcet's s yndrome.
Trea tment wi th l oca l a nd s ys temi c corti cos teroi ds a nd a cycl opl egi c-mydri a ti c drug ma y a l l evi a te a cute exa cerba ti ons , but mos t pa ti ents
eventua l l y requi re s ys temi c corti cos teroi ds a nd a noncorti cos teroi d i mmunos uppres s i ve drug (eg, cycl os pori ne, chl ora mbuci l ) to control the
i nfl a mma ti on a nd a voi d the s eri ous compl i ca ti ons of l ong-term corti cos teroi d trea tment. Bi ol ogi c a gents s uch a s i nterferons a nd tumor necros i s
fa ctor i nhi bi tors ha ve been effecti ve i n s el ected pa ti ents unres pons i ve to other thera pi es .
Vogt-Koyanagi-Harada (VKH) syndrome: VKH s yndrome i s a n uncommon s ys temi c di s order cha ra cteri zed by uvei ti s a ccompa ni ed by cuta neous a nd
neurol ogi c a bnorma l i ti es . VKH s yndrome i s pa rti cul a rl y common a mong peopl e of As i a n, As i a n Indi a n, a nd Ameri ca n Indi a n des cent. Women i n
thei r 20s a nd 30s a re a ffected more often tha n men. The eti ol ogy i s unknown, a l though a n a utoi mmune rea cti on di rected a ga i ns t mel a ni nconta i ni ng cel l s i n the uvea l tra ct, s ki n, i nner ea r, a nd meni nges i s s trongl y s us pected.
Neurol ogi c s ymptoms tend to occur ea rl y a nd i ncl ude ti nni tus , dys a cus i s (a udi tory a gnos i a ), verti go, hea da che, a nd meni ngi s mus . Cuta neous
fi ndi ngs frequentl y occur l a ter a nd i ncl ude pa tchy vi ti l i go (es peci a l l y common on the eyel i ds , l ow ba ck, a nd buttocks ), pol i os i s (a l oca l i zed pa tch
of whi te ha i r), a nd a l opeci a , often i nvol vi ng the hea d a nd neck. Common fi ndi ngs i ncl ude s erous reti na l deta chment, opti c di s k edema , a nd
choroi di ti s . Long-term compl i ca ti ons i ncl ude ca ta ra cts , gl a ucoma , s ubreti na l fi bros i s , a nd choroi da l neova s cul a ri za ti on.
Ea rl y trea tment i ncl udes l oca l a nd s ys temi c corti cos teroi ds a nd a cycl opl egi c-mydri a ti c drug. Ma ny pa ti ents a l s o requi re a noncorti cos teroi d
i mmunos uppres s i ve drug (eg, methotrexa te, a za thi opri ne, mycophenol a te mofeti l ).
Endophthalmitis
Endophthalmitis is an acute panuveitis resulting most often from bacterial infection.
Mos t ca s es of endophtha l mi ti s a re ca us ed by gra m-pos i ti ve ba cteri a , s uch a s Staphylococcus epidermidis or S. aureus. Gra m-nega ti ve orga ni s ms ca n
a l s o ca us e endophtha l mi ti s , tend to be more vi rul ent, a nd predi ct a poorer prognos i s . Funga l a nd protozoa n ca us es of endophtha l mi ti s a re ra re.
Mos t ca s es occur a fter penetra ti ng ocul a r tra uma or i ntra ocul a r s urgery (exogenous ). Les s commonl y, i nfecti on rea ches the eye vi a the
bl oods trea m a fter s ys temi c s urgery or denta l procedures or when IV l i nes or IV drugs a re us ed (endogenous ).
Endophtha l mi ti s i s a medi ca l emergency beca us e vi s i on prognos i s i s di rectl y rel a ted to the ti me from ons et to trea tment. Ra rel y, untrea ted
i ntra ocul a r i nfecti ons extend beyond the confi nes of the eye to i nvol ve the orbi t a nd CNS.
Exogenous endophtha l mi ti s typi ca l l y ca us es s evere ocul a r a che a nd decrea s ed vi s i on. Si gns i ncl ude i ntens e conjuncti va l hyperemi a a nd
i ntra ocul a r i nfl a mma ti on wi thi n the a nteri or cha mber a nd vi treous , occa s i ona l l y wi th eyel i d edema .
Di a gnos i s requi res a hi gh i ndex of s us pi ci on i n a t-ri s k pa ti ents , es peci a l l y thos e wi th recent eye s urgery or tra uma . Gra m s ta i n a nd cul ture of
a s pi ra tes from the a nteri or cha mber a nd vi treous a re s ta nda rd. Pa ti ents wi th s us pected endogenous endophtha l mi ti s s houl d a l s o ha ve bl ood
a nd uri ne cul tures .
Ini ti a l trea tment i ncl udes broa d-s pectrum i ntra vi trea l a nti bi oti cs , mos t commonl y va ncomyci n a nd cefta zi di me. Pa ti ents wi th endogenous
endophtha l mi ti s s houl d recei ve both i ntra vi trea l a nd IV a nti bi oti cs . Thera py i s modi fi ed ba s ed on cul ture a nd s ens i ti vi ty res ul ts .
Vi s i on prognos i s i s often poor, even wi th ea rl y a nd a ppropri a te trea tment. Pa ti ents wi th count-fi ngers or wors e vi s i on a t pres enta ti on s houl d be
cons i dered for vi trectomy a nd us e of i ntra ocul a r corti cos teroi ds . Corti cos teroi ds a re, however, contra i ndi ca ted i n funga l endophtha l mi ti s .
Infectious Uveitis
A number of i nfecti ous di s ea s es ca us e uvei ti s (s ee
Ta bl e 67-1). The mos t common a re
[Table 67-1. Infecti ous Ca us es of Uvei ti s ]
herpes s i mpl ex vi rus , va ri cel l a -zos ter vi rus , a nd CMV i nfecti on a nd toxopl a s mos i s . Di fferent orga ni s ms a ffect di fferent pa rts of the uvea l tra ct.
Herpesvirus: Herpes s i mpl ex vi rus (s ee a l s o p. 1417) ca us es a nteri or uvei ti s . Va ri cel l a zos ter vi rus does s o l es s commonl y, a l though the preva l ence
of zos ter-a s s oci a ted a nteri or uvei ti s i ncrea s es wi th a ge. Symptoms i ncl ude ocul a r a che, photophobi a , a nd decrea s ed vi s i on. Si gns i ncl ude
rednes s ; conjuncti va l i njecti on a nd a nteri or cha mber i nfl a mma ti on (cel l s a nd fl a re), often a ccompa ni ed by cornea l i nfl a mma ti on (kera ti ti s );
decrea s ed cornea l s ens a ti on; a nd pa tchy or s ectori a l i ri s a trophy. Intra ocul a r pres s ure ma y be el eva ted a s wel l ; el eva ti on ca n be detected by
us i ng a ppl i na ti on tonometry wi th a Schi otz tonometer, a Gol dma nn tonometer, or a pneumotonometer.
Trea tment s houl d genera l l y be i ni ti a ted by a n ophtha l mol ogi s t a nd s houl d i ncl ude a topi ca l corti cos teroi d a nd a cycl opl egi c-mydri a ti c drug.
Acycl ovi r (400 mg po 5 ti mes /da y for herpes s i mpl ex vi rus a nd 800 mg po 5 ti mes /da y for herpes zos ter vi rus ) ma y a l s o be gi ven. Drops to l ower
i ntra ocul a r pres s ure ma y be requi red i n pa ti ents wi th ocul a r hypertens i on.
Much l es s commonl y, va ri cel l a -zos ter a nd herpes s i mpl ex vi rus es ca us e a ra pi dl y progres s i ng form of reti ni ti s ca l l ed a cute reti na l necros i s (ARN),
whi ch typi ca l l y ma ni fes ts a s confl uent reti ni ti s , occl us i ve reti na l va s cul i ti s , a nd modera te to s evere vi treous i nfl a mma ti on. One thi rd of ARN ca s es
become bi l a tera l , a nd i n three fourths of eyes , reti na l deta chment occurs . ARN ma y a l s o occur i n pa ti ents wi th HIV/AIDS, but s everel y
i mmunocompromi s ed pa ti ents ca n ha ve l es s promi nent vi treous i nfl a mma ti on. Vi treous bi ops y for cul ture a nd PCR a na l ys i s ma y be us eful i n
di a gnos i ng ARN. Trea tment opti ons i ncl ude IV a cycl ovi r, IV ga nci cl ovi r or fos ca rnet, i ntra vi trea l ga nci cl ovi r or fos ca rnet, a nd ora l va l a cycl ovi r or
va l ga nci cl ovi r.
Toxoplasmosis: Toxopl a s mos i s (s ee a l s o p. 1390) i s the mos t common ca us e of reti ni ti s i n i mmunocompetent pa ti ents . Mos t ca s es a re tra ns mi tted
congeni ta l l y, a l though a cqui red ca s es occur. Symptoms of fl oa ters a nd decrea s ed vi s i on ma y be due to cel l s i n the vi treous humor or to reti na l
l es i ons or s ca rs . Concurrent a nteri or s egment i nvol vement ca n occur a nd ma y ca us e ocul a r a che, rednes s , a nd photophobi a . La bora tory tes ti ng
s houl d i ncl ude s erum a nti -Toxoplasma a nti body ti ters .
Trea tment i s recommended for pa ti ents wi th pos teri or l es i ons tha t threa ten vi ta l vi s ua l s tructures , s uch a s the opti c di s k or ma cul a , a nd for
i mmunocompromi s ed pa ti ents . Mul ti drug thera py i s commonl y pres cri bed; i t i ncl udes pyri metha mi ne, s ul fona mi des , cl i nda myci n, a nd, i n s el ect
ca s es , s ys temi c corti cos teroi ds . Corti cos teroi ds s houl d not, however, be us ed wi thout concurrent a nti mi crobi a l covera ge. Long-a cti ng peri ocul a r
a nd i ntra ocul a r corti cos teroi ds (eg, tri a mci nol one a cetoni de) s houl d be a voi ded. Pa ti ents wi th s ma l l peri phera l l es i ons tha t do not di rectl y
threa ten vi ta l vi s ua l s tructures ma y be obs erved wi thout trea tment a nd s houl d begi n to s how s l ow i mprovement i n 1 to 2 mo.
Cytomegalovirus: CMV (s ee a l s o p. 1416) i s the mos t common ca us e of reti ni ti s i n i mmunocompromi s ed pa ti ents , a ffecti ng 5% of pa ti ents wi th
HIV/AIDS recei vi ng hi ghl y a cti ve a nti retrovi ra l thera py (HAART). Mos t a ffected pa ti ents ha ve a CD4+ count < 100 cel l s /L. CMV reti ni ti s ma y a l s o
occur i n neona tes a nd i n pha rma col ogi ca l l y i mmunos uppres s ed pa ti ents but i s uncommon.
The di a gnos i s i s l a rgel y cl i ni ca l ba s ed on di rect or i ndi rect ophtha l mos copi c exa mi na ti on; s erol ogi c tes ts a re of l i mi ted us e. Trea tment i n
pa ti ents wi th HIV/AIDS i s wi th s ys temi c or l oca l (i mpl a nt) ga nci cl ovi r, s ys temi c fos ca rnet, or va l ga nci cl ovi r. Thera py i s typi ca l l y conti nued
i ndefi ni tel y, unl es s i mmune recons ti tuti on i s a chi eved wi th combi na ti on a nti retrovi ra l thera py (typi ca l l y a CD4+ count > 100 cel l s /L for a t l ea s t 3
mo).
Sympathetic Ophthalmia
Sympathetic ophthalmia is inflammation of the uveal tract after trauma or surgery to the other eye.
Sympa theti c ophtha l mi a i s a ra re gra nul oma tous uvei ti s tha t occurs a fter penetra ti ng tra uma or s urgery to the other eye. Sympa theti c ophtha l mi a
ha s been es ti ma ted to occur i n up to 0.5% of nons urgi ca l a nd i n < 0.1% of s urgi ca l penetra ti ng eye wounds . The underl yi ng mecha ni s m i s thought
to be a n a utoi mmune rea cti on di rected a ga i ns t mel a ni n-conta i ni ng cel l s i n the uvea . Uvei ti s a ppea rs wi thi n 2 to 12 wk a fter i njury i n a bout 80% of
ca s es . Is ol a ted ca s es of s ympa theti c ophtha l mi a ha ve occurred a s ea rl y a s 1 wk or a s l a te a s 30 yr a fter the i ni ti a l i njury or s urgery.
Symptoms typi ca l l y i ncl ude fl oa ters a nd decrea s ed vi s i on. Choroi di ti s , often wi th overl yi ng exuda ti ve reti na l deta chment, i s common.
Trea tment typi ca l l y requi res ora l corti cos teroi ds pl us a l ong-term noncorti cos teroi d i mmunos uppres s i ve drug. Prophyl a cti c enucl ea ti on of a
s everel y i njured eye s houl d be cons i dered wi thi n 2 wk of vi s i on l os s to mi ni mi ze the ri s k of s ympa theti c ophtha l mi a devel opi ng i n the other eye,
but onl y when the i njured eye ha s no vi s i on potenti a l .
Chapter 68. Retinal Disorders

Introduction
(For Reti nopa thy of Prema turi ty, s ee p. 2781.)
The reti na i s the l i ght-s ens i ng l a yer of ti s s ue a t the ba ck of the eye; i t conta i ns the rods , cones , a nd nerve endi ngs tha t tra ns form l i ght i nto neura l
i mpul s es . Reti na l di s orders ma y be i nheri ted or ca us ed by va s cul a r di s ea s e, i nfl a mma ti on, i nfecti on, ca ncer, or tra uma . Vi s ua l reha bi l i ta ti on i s
i ndi ca ted for a l l pa ti ents who ha ve s evere vi s i on l os s .
Age-Related Macular Degeneration
(Seni l e Ma cul a r Degenera ti on)
Age-related macular degeneration (AMD) is the most common cause of irreversible central vision loss in elderly patients. Funduscopic findings are diagnostic;
fluorescein angiography and optical coherence tomography assist in directing treatment. Treatment is with dietary supplements, intravitreal injection of antivascular endothelial growth factor, laser photocoagulation, photodynamic therapy, and low-vision devices.
AMD i s a l ea di ng ca us e of perma nent, i rrevers i bl e vi s i on l os s i n the el derl y. It i s more common a mong whi tes .
Etiology
Ri s k fa ctors i ncl ude the fol l owi ng:
Geneti c va ri a nts (eg, a bnorma l compl ement fa ctor H)
Smoki ng
Ca rdi ova s cul a r di s ea s e
Hypertens i on
A di et l ow i n -3 fa tty a ci ds a nd da rk green l ea fy vegeta bl es
Age
Pathophysiology
Two di fferent forms occur:
Dry (a trophi c), i n a bout 90% of ca s es
Wet (exuda ti ve or neova s cul a r), i n a bout 10% of ca s es
Ni nety percent of the bl i ndnes s ca us ed by AMD occurs i n pa ti ents who ha ve the wet form.
Dry AMD ca us es reti na l pi gmenta ti on cha nges , yel l ow s pots (drus ens ee
Pl a te 3), a nd a rea s of chori oreti na l a trophy (referred to a s geogra phi c a trophy). There i s no el eva ted ma cul a r s ca r, edema , hemorrha ge, or
exuda ti on.
Wet AMD begi ns a s dry AMD. Choroi da l neova s cul a ri za ti on (a bnorma l new ves s el forma ti on) occurs under the reti na . Loca l i zed ma cul a r edema or
hemorrha ge ma y el eva te a n a rea of the ma cul a or ca us e a l oca l i zed reti na l pi gment epi thel i a l deta chment. Eventua l l y, neova s cul a ri za ti on ca us es
a n el eva ted s ca r under the ma cul a .
Symptoms and Signs
Dry AMD: The l os s of centra l vi s i on i s s l ow, pa i nl es s , a nd us ua l l y mi l d. Centra l bl i nd s pots (s cotoma s ) us ua l l y occur l a te a nd ca n s ometi mes
become s evere. Symptoms a re us ua l l y bi l a tera l .
Fundus copi c cha nges i ncl ude the fol l owi ng:
Pi gment cha nges
Drus en
Area s of chori oreti na l a trophy
Wet AMD: Ra pi d vi s i on l os s i s more typi ca l of wet AMD. The fi rs t s ymptom i s us ua l l y vi s ua l di s torti on, s uch a s a centra l bl i nd s pot (s cotoma ) or
curvi ng of s tra i ght l i nes (meta morphops i a ). Peri phera l vi s i on a nd col or vi s i on a re genera l l y una ffected; however, the pa ti ent ma y become l ega l l y
bl i nd (< 20/200 vi s i on) i n the a ffected eye or eyes , pa rti cul a rl y i f AMD i s not trea ted. Wet ma cul a r degenera ti on us ua l l y a ffects one eye a t a ti me;
thus , s ymptoms of wet AMD a re often uni l a tera l .
Fundus copi c cha nges i ncl ude the fol l owi ng:
Subreti na l hemorrha ge i n or a round the ma cul a
Loca l i zed reti na l el eva ti on

Reti na l edema
Gra y di s col ora ti on of the s ubreti na l s pa ce
Exuda tes i n or a round the ma cul a
Deta chment of reti na l pi gment epi thel i um
Diagnosis
Fundus copi c exa mi na ti on
Fl uores cei n a ngi ogra phy
Opti ca l coherence tomogra phy
Both forms of AMD a re di a gnos ed by fundus copi c exa mi na ti on. Vi s ua l cha nges ca n often be detected wi th a n Ams l er gri d (s ee p. 539). Fl uores cei n
a ngi ogra phy i s done when fi ndi ngs s ugges t wet AMD. Angi ogra phy demons tra tes a nd cha ra cteri zes s ubreti na l choroi da l neova s cul a r membra nes
a nd ca n del i nea te a rea s of geogra phi c a trophy. Opti ca l coherence tomogra phy (OCT) a i ds i n i denti fyi ng i ntra reti na l a nd s ubreti na l fl ui d a nd ca n
hel p a s s es s res pons e to trea tment.
Treatment
Di eta ry s uppl ements for dry or uni l a tera l wet AMD
Intra vi trea l a nti -va s cul a r endothel i a l growth fa ctor drugs or l a s er trea tments for wet AMD
Dry AMD: There i s no wa y to revers e da ma ge ca us ed by dry AMD, but pa ti ents wi th extens i ve drus en, pi gment cha nges , or geogra phi c a trophy
benefi t from da i l y s uppl ements of the fol l owi ng:
Zi nc oxi de 80 mg
Copper 2 mg
Vi ta mi n C 500 mg
Vi ta mi n E 400 IU
-Ca rotene 15 mg (or vi ta mi n A 28,000 IU)
Vi ta mi n A i s s ometi mes s ubs ti tuted for -ca rotene. In s mokers , -ca rotene a nd vi ta mi n A ca n i ncrea s e the ri s k of l ung ca ncer. For thi s rea s on, they
a re contra i ndi ca ted i n pa ti ents who ha ve s moked i n the previ ous 7 yr. Reduci ng ca rdi ova s cul a r ri s k fa ctors , i ncl udi ng ea ti ng foods hi gh i n -3 fa tty
a ci ds a nd da rk green l ea fy vegeta bl es ma y hel p.
Wet AMD: Pa ti ents wi th wet AMD i n one eye ma y benefi t from da i l y s uppl ements tha t a re recommended for dry AMD. The choi ce of other trea tment
depends on the s i ze, l oca ti on, a nd type of neova s cul a ri za ti on. Intra vi trea l i njecti on of a nti -va s cul a r endothel i a l growth fa ctor (VEGF) drugs
(us ua l l y ra ni bi zuma b or beva ci zuma b or, occa s i ona l l y, pega pta ni b) ca n s ubs ta nti a l l y reduce the ri s k of vi s i on l os s a nd ca n hel p res tore rea di ng
vi s i on i n up to one thi rd of pa ti ents . Therma l l a s er photocoa gul a ti on of neova s cul a ri za ti on outs i de the fovea ma y prevent s evere vi s i on l os s .
Photodyna mi c thera py, a type of l a s er trea tment, hel ps under s peci fi c ci rcums ta nces . Corti cos teroi ds (eg, tri a mci nol one) a re s ometi mes i njected
i ntra ocul a rl y a l ong wi th a n a nti -VEGF drug. Other trea tments , i ncl udi ng tra ns pupi l l a ry thermothera py, s ubreti na l s urgery, a nd ma cul a r
tra ns l oca ti on s urgery, a re s el dom us ed.
Supportive measures: For pa ti ents who ha ve l os t centra l vi s i on, l ow-vi s i on devi ces s uch a s ma gni fi ers , hi gh-power rea di ng gl a s s es , computer
moni tors , a nd tel es copi c l ens es , a re a va i l a bl e. Al s o, certa i n types of s oftwa re ca n di s pl a y computer da ta i n l a rge pri nt or rea d i nforma ti on a l oud
i n a s yntheti c voi ce. Low-vi s i on couns el i ng i s a dvi s ed.
Central Retinal Artery Occlusion
(Reti na l Artery Occl us i on)
Central retinal artery occlusion is blockage of the central retinal artery, usually due to an embolism. Its symptom is sudden, painless, unilateral blindness.
Diagnosis is by history and characteristic retinal findings on funduscopy. Decreasing intraocular pressure can be attempted within the first 24 h of occlusion. If
patients present within the first few hours of occlusion, some centers catheterize the carotid artery and selectively inject thrombolytic drugs.
Etiology
Reti na l a rtery occl us i on ma y be due to embol i s m or thrombos i s .
Embol i ma y come from a ny of the fol l owi ng:
Atheros cl eroti c pl a ques

Endoca rdi ti s
Fa t
Atri a l myxoma
Gi a nt cel l a rteri ti s (s ee p. 319) i s a nother i mporta nt ca us e of a rteri a l occl us i on.
Occl us i on ca n a ffect a bra nch of the reti na l a rtery a s wel l a s the centra l reti na l a rtery.
Neova s cul a ri za ti on (a bnorma l new ves s el forma ti on) of the reti na or i ri s (rubeos i s i ri di s ) wi th s econda ry (neova s cul a r) gl a ucoma ca n occur weeks
to months a fter occl us i on. Vi treous hemorrha ge ma y res ul t from reti na l neova s cul a ri za ti on.
Symptoms and Signs
Reti na l a rtery occl us i on ca us es s udden, pa i nl es s bl i ndnes s or vi s ua l fi el d defect, us ua l l y uni l a tera l l y.
The pupi l ma y res pond poorl y to di rect l i ght but cons tri cts bri s kl y when the other eye i s i l l umi na ted (rel a ti ve a fferent pupi l l a ry defect). In a cute
ca s es , fundus copy di s cl os es a pa l e, opa que fundus wi th a red fovea (cherry-red s pots ee
Pl a te 5). Typi ca l l y, the a rteri es a re a ttenua ted a nd ma y even a ppea r bl oodl es s . An embol i c obs tructi on i s s ometi mes vi s i bl e. If a ma jor bra nch i s
occl uded ra ther tha n the enti re a rtery, fundus a bnorma l i ti es a nd vi s i on l os s a re l i mi ted to tha t s ector of the reti na .
Pa ti ents who ha ve gi a nt cel l a rteri ti s often ha ve hea da che, a tender a nd pa l pa bl e tempora l a rtery, ja w cl a udi ca ti on, fa ti gue, or a combi na ti on.
Diagnosis
Someti mes fl uores cei n a ngi ogra phy
The di a gnos i s i s s us pected when a pa ti ent ha s a cute, pa i nl es s vi s i on l os s . Fundus copy i s us ua l l y confi rma tory. Fl uores cei n a ngi ogra phy i s often
done a nd s hows obs tructi on cl ea rl y.
Once the di a gnos i s i s ma de, ca roti d Doppl er ul tra s onogra phy a nd echoca rdi ogra phy s houl d be done to l oca te a ny embol i c s ource s o tha t further
embol i za ti on ca n be prevented.
If gi a nt cel l a rteri ti s i s s us pected, ESR, C-rea cti ve protei n, a nd pl a tel et count a re done.
Prognosis
Pa ti ents wi th a bra nch a rtery occl us i on often ma i nta i n good to fa i r vi s i on, but vi s i on l os s i s often profound wi th centra l a rtery occl us i on, even wi th
trea tment. Once reti na l i nfa rcti on occurs (pos s i bl y i n < 2 h, a l mos t a l wa ys by 24 h), vi s i on l os s i s perma nent.
Treatment
Someti mes reducti on of i ntra ocul a r pres s ure
Immedi a te trea tment i s i ndi ca ted i f occl us i on occurred wi thi n 24 h of pres enta ti on. Reducti on of i ntra ocul a r pres s ure by ocul a r hypotens i ve drugs
(eg, topi ca l ti mol ol 0.5%, a ceta zol a mi de 500 mg IV or po), i ntermi ttent di gi ta l ma s s a ge over the cl os ed eyel i d, or a nteri or cha mber pa ra centes i s
ma y di s l odge a n embol us a nd a l l ow i t to enter a s ma l l er bra nch of the a rtery, thus reduci ng the a rea of reti na l i s chemi a . Some centers ha ve tri ed
i nfus i ng thrombol yti cs i nto the ca roti d a rtery to di s s ol ve the obs tructi ng cl ot. Nonethel es s , trea tments for reti na l a rtery occl us i ons ra rel y i mprove
vi s ua l a cui ty. Surgi ca l or l a s er-medi a ted embol ectomy i s a va i l a bl e but not commonl y done.
Pa ti ents wi th occl us i on s econda ry to tempora l a rteri ti s s houl d recei ve hi gh-dos e s ys temi c corti cos teroi ds .
Central Retinal Vein Occlusion
(Reti na l Vei n Occl us i on)
Central retinal vein occlusion is a blockage of the central retinal vein by a thrombus. It causes painless vision loss, usually suddenly. Diagnosis is by funduscopy.
Most treatments are ineffective.
Etiology
Ma jor ri s k fa ctors i ncl ude
Hypertens i on
Age
Other ri s k fa ctors i ncl ude
Gl a ucoma
Di a betes
Increa s ed bl ood vi s cos i ty
Occl us i on ma y a l s o be i di opa thi c. The condi ti on i s uncommon a mong young peopl e. Occl us i on ma y a ffect a bra nch of the reti na l vei n or the centra l
reti na l vei n.
Neova s cul a ri za ti on of the reti na or i ri s (rubeos i s i ri di s ) wi th s econda ry (neova s cul a r) gl a ucoma ca n occur weeks to months a fter occl us i on.
Vi treous hemorrha ge ma y res ul t from reti na l neova s cul a ri za ti on.
Symptoms and Signs
Pa i nl es s vi s ua l l os s i s us ua l l y s udden, but i t ca n a l s o occur gra dua l l y over a peri od of da ys to weeks . Fundus copy revea l s hemorrha ges throughout
the reti na , engorgement a nd tortuous nes s of the reti na l vei ns , a nd, us ua l l y, s i gni fi ca nt reti na l edema (s ee
Pl a te 6). Thes e cha nges a re l i mi ted to one qua dra nt i f obs tructi on i nvol ves onl y a bra nch of the centra l reti na l vei n.
Diagnosis
Fundus copy
The di a gnos i s i s s us pected i n pa ti ents wi th pa i nl es s vi s ua l l os s , pa rti cul a rl y thos e a t ri s k. Fundus copy confi rms the di a gnos i s . Pa ti ents wi th a
centra l reti na l vei n occl us i on a re eva l ua ted for hypertens i on a nd gl a ucoma a nd tes ted for di a betes . Young pa ti ents a re tes ted for i ncrea s ed bl ood
vi s cos i ty (wi th a CBC a nd other coa gul a bl e fa ctors a s deemed neces s a ry).
Prognosis
Mos t pa ti ents ha ve s ome vi s ua l defi ci t. In mi l d ca s es , there ca n be s ponta neous i mprovement to nea r-norma l vi s i on over a va ri a bl e peri od of
ti me. Vi s ua l a cui ty a t pres enta ti on i s a good i ndi ca tor of fi na l vi s i on. If vi s ua l a cui ty i s a t l ea s t 20/40, vi s ua l a cui ty wi l l l i kel y rema i n good,
occa s i ona l l y nea r norma l . If vi s ua l a cui ty i s wors e tha n 20/200, i t wi l l rema i n a t tha t l evel or wors en i n 80% of pa ti ents .
Treatment
Pa nreti na l photocoa gul a ti on i f neova s cul a ri za ti on devel ops
There i s no genera l l y a ccepted medi ca l thera py for occl us i on i ts el f. However, i f neova s cul a ri za ti on devel ops , pa nreti na l photocoa gul a ti on s houl d
be i ni ti a ted beca us e i t ma y decrea s e vi treous hemorrha ges a nd prevent neova s cul a r gl a ucoma .
Cl i ni ca l tri a l s a re i nves ti ga ti ng i ntra vi trea l i njecti on of corti cos teroi ds a nd a nti -va s cul a r endothel i a l growth fa ctor drugs .
Diabetic Retinopathy
Diabetic retinopathy includes microaneurysms, intraretinal hemorrhage, exudates, macular edema, macular ischemia, neovascularization, vitreous hemorrhage,
and traction retinal detachment. Symptoms may not develop until late in the disease. Diagnosis is by funduscopy; further details are elucidated by fluorescein
angiography and optical coherence tomography. Treatment includes control of diabetes and BP and ocular laser photocoagulation, intravitreal injection of drugs,
vitrectomy, or a combination.
Pathophysiology
Di a beti c reti nopa thy i s a ma jor ca us e of bl i ndnes s . The degree of reti nopa thy i s hi ghl y correl a ted wi th
Dura ti on of di a betes
Bl ood gl ucos e l evel s
BP l evel s
Pregna ncy ca n i mpa i r bl ood gl ucos e control a nd thus wors en reti nopa thy.
Nonproliferative retinopathy: (a l s o ca l l ed ba ckground reti nopa thy) devel ops fi rs t a nd ca us es i ncrea s ed ca pi l l a ry permea bi l i ty, mi croa neurys ms ,
hemorrha ges , exuda tes , ma cul a r i s chemi a , a nd ma cul a r edema (thi ckeni ng of the reti na ca us ed by fl ui d l ea ka ge from ca pi l l a ri es ).
Proliferative retinopathy: devel ops a fter nonprol i fera ti ve reti nopa thy a nd i s more s evere; i t ma y l ea d to vi treous hemorrha ge a nd tra cti on reti na l
deta chment. Prol i fera ti ve reti nopa thy i s cha ra cteri zed by a bnorma l new ves s el forma ti on (neova s cul a ri za ti on), whi ch occurs on the i nner (vi treous )
s urfa ce of the reti na a nd ma y extend i nto the vi treous ca vi ty a nd ca us e vi treous hemorrha ge. The neova s cul a ri za ti on i s often a ccompa ni ed by
prereti na l fi brous ti s s ue, whi ch, a l ong wi th the vi treous humor, ca n contra ct, res ul ti ng i n tra cti on reti na l deta chment. Neova s cul a ri za ti on ma y a l s o
occur i n the a nteri or s egment of the eye on the i ri s ; neova s cul a r membra ne growth i n the a ngl e of the eye a t the peri phera l ma rgi n of the i ri s ca n
res ul t, l ea di ng to neova s cul a r gl a ucoma . Vi s i on l os s wi th prol i fera ti ve reti nopa thy ma y be s evere.
Cl i ni ca l l y s i gni fi ca nt ma cul a r edema ca n occur wi th nonprol i fera ti ve or prol i fera ti ve reti nopa thy a nd i s the mos t common ca us e of vi s i on l os s due
to di a beti c reti nopa thy.
Symptoms and Signs

Nonproliferative retinopathy: Vi s i on s ymptoms a ccompa ny ma cul a r edema or ma cul a r i s chemi a . However, pa ti ents ma y be una wa re of vi s i on l os s .
The fi rs t s i gns of nonprol i fera ti ve reti nopa thy a re
Ca pi l l a ry mi croa neurys ms
Dot a nd bl ot reti na l hemorrha ges
Ha rd exuda tes
Cotton-wool s pots (s oft exuda tes )
Ha rd exuda tes a re di s crete, yel l ow, a nd genera l l y deeper tha n reti na l ves s el s a nd s ugges t reti na l edema . Cotton-wool s pots a re a rea s of
mi croi nfa rcti on tha t l ea d to reti na l opa ci fi ca ti on; they a re fuzzy-edged a nd whi te a nd obs cure underl yi ng ves s el s (s ee
Pl a te 10).
Si gns i n l a ter s ta ges a re
Ma cul a r edema (s een on s l i t-l a mp bi omi cros copy a s el eva ti on a nd bl urri ng of reti na l l a yers )
Venous di l a ti on a nd i ntra reti na l mi crova s cul a r a bnorma l i ti es
Proliferative retinopathy: Symptoms ma y i ncl ude bl urred vi s i on, bl a ck s pots or fl a s hi ng l i ghts i n the fi el d of vi s i on, a nd s udden, s evere pa i nl es s
vi s i on l os s . Some of thes e s ymptoms ma y be ca us ed by vi treous hemorrha ge or tra cti on reti na l deta chment.
Prol i fera ti ve reti nopa thy, unl i ke nonprol i fera ti ve reti nopa thy, ca us es fi ne prereti na l ca pi l l a ri es (newl y devel oped ca pi l l a ri es ) to a ppea r on the
opti c nerve or reti na l s urfa ce (s ee
Pl a tes 11 a nd
23). Ma cul a r edema or reti na l hemorrha ge ma y be vi s i bl e on fundus copy.
Diagnosis
Fundus copy
Fl uores cei n a ngi ogra phy
Someti mes opti ca l coherence tomogra phy
Di a gnos i s i s by fundus copy. Fl uores cei n a ngi ogra phy i s us ed to determi ne the extent of da ma ge, to devel op a trea tment pl a n, a nd to moni tor the
res ul ts of trea tment. Opti ca l coherence tomogra phy i s a l s o us eful to a s s es s s everi ty of ma cul a r edema a nd trea tment res pons e.
Screening: Beca us e ea rl y detecti on i s i mporta nt, a l l pa ti ents wi th di a betes s houl d ha ve a n a nnua l di l a ted ophtha l mol ogi c exa mi na ti on. Pregna nt
pa ti ents wi th di a betes s houl d be exa mi ned every tri mes ter. Vi s i on s ymptoms a re i ndi ca ti ons for ophtha l mol ogi c referra l .
Treatment
Control of bl ood gl ucos e a nd BP
For ma cul a r edema , foca l l a s er a nd pos s i bl y vi trectomy or i ntra vi trea l drugs
For hi gh-ri s k or compl i ca ted prol i fera ti ve reti nopa thy, pa nreti na l l a s er photocoa gul a ti on a nd s ometi mes vi trectomy
Control of bl ood gl ucos e a nd BP a re cri ti ca l ; i ntens i ve control of bl ood gl ucos e s l ows progres s i on of reti nopa thy. Cl i ni ca l l y s i gni fi ca nt di a beti c
ma cul a r edema i s trea ted wi th foca l l a s er. Intra vi trea l i njecti on of tri a mci nol one, a s wel l a s a nti -va s cul a r endothel i a l growth fa ctor (VEGF) drugs ,
ma y hel p i n more s evere ca s es . Vi trectomy ca n hel p i n reca l ci tra nt di a beti c ma cul a r edema . In s el ect ca s es of s evere nonprol i fera ti ve reti nopa thy,
pa nreti na l l a s er photocoa gul a ti on ma y be us ed; however, mos t pa ti ents ca n be fol l owed cl os el y unti l prol i fera ti ve reti nopa thy devel ops .
Prol i fera ti ve di a beti c reti nopa thy wi th hi gh-ri s k cha ra cteri s ti cs of vi treous hemorrha ge, extens i ve prereti na l neova s cul a ri za ti on, or a nteri or
s egment neova s cul a ri za ti on/neova s cul a r gl a ucoma , s houl d be trea ted wi th pa nreti na l l a s er photocoa gul a ti on. Thi s trea tment reduces the ri s k of
s evere vi s i on l os s s i gni fi ca ntl y.
Vi trectomy ca n hel p pres erve a nd often res tore l os t vi s i on i n pa ti ents wi th a ny of the fol l owi ng:
Vi treous hemorrha ge tha t pers i s ts for 3 mo
Extens i ve prereti na l membra ne forma ti on
Tra cti on reti na l deta chment
Prevention
Control of bl ood gl ucos e a nd BP i s cri ti ca l ; i ntens i ve control of bl ood gl ucos e del a ys ons et of reti nopa thy.
Hypertensive Retinopathy
Hypertensive retinopathy is retinal vascular damage caused by hypertension. Symptoms develop late. Funduscopic examination shows arteriolar constriction,
arteriovenous nicking, vascular wall changes, flame-shaped hemorrhages, cotton-wool spots, yellow hard exudates, and papilledema. Treatment is directed at
controlling BP and, when vision loss occurs, treating the retina.
Pathophysiology
Acute BP el eva ti on typi ca l l y ca us es revers i bl e va s ocons tri cti on i n reti na l bl ood ves s el s , a nd hypertens i ve cri s i s ma y ca us e pa pi l l edema . More
prol onged or s evere hypertens i on l ea ds to exuda ti ve va s cul a r cha nges , a cons equence of endothel i a l da ma ge a nd necros i s . Other cha nges (eg,
a rteri ol e wa l l thi ckeni ng) typi ca l l y requi re yea rs of el eva ted BP to devel op. Smoki ng compounds the a dvers e effects of hypertens i on on the reti na .
Hypertens i on i s a ma jor ri s k fa ctor for other reti na l di s orders (eg, reti na l a rtery or vei n occl us i on, di a beti c reti nopa thy). Al s o, hypertens i on
combi ned wi th di a betes grea tl y i ncrea s es ri s k of vi s i on l os s . Pa ti ents wi th hypertens i ve reti nopa thy a re a t hi gh ri s k of hypertens i ve da ma ge to
other end orga ns .
Symptoms and Signs
Symptoms us ua l l y do not devel op unti l l a te i n the di s ea s e.
In the ea rl y s ta ges , fundus copy i denti fi es a rteri ol a r cons tri cti on, wi th a decrea s e i n the ra ti o of the wi dth of the reti na l a rteri ol es to the reti na l
venul es .
Chroni c, poorl y control l ed hypertens i on ca us es the fol l owi ng:
Perma nent a rteri a l na rrowi ng
Arteri ovenous cros s i ng a bnorma l i ti es (a rteri ovenous ni cki ng)
Arteri os cl eros i s wi th modera te va s cul a r wa l l cha nges (copper wi ri ng) to more s evere va s cul a r wa l l hyperpl a s i a a nd thi ckeni ng (s i l ver wi ri ng)
Someti mes tota l va s cul a r occl us i on occurs . Arteri ovenous ni cki ng i s a ma jor predi s pos i ng fa ctor to the devel opment of a bra nch reti na l vei n
occl us i on.
If a cute di s ea s e i s s evere, the fol l owi ng ca n devel op:
Superfi ci a l fl a me-s ha ped hemorrha ges
Sma l l whi te s uperfi ci a l foci of reti na l i s chemi a (cotton-wool s pots s ee
Pl a te 18)
Yel l ow ha rd exuda tes
Opti c di s k edema (pa pi l l edema )
Yel l ow ha rd exuda tes repres ent i ntra reti na l l i pi d depos i ti on from l ea ki ng reti na l ves s el s . Thes e exuda tes ca n form a s ta r-s ha ped l es i on i n the
ma cul a , pa rti cul a rl y when hypertens i on i s s evere (s ee
Pl a te 17). In s evere hypertens i on, the opti c di s k becomes conges ted a nd edema tous (pa pi l l edema i ndi ca ti ng hypertens i ve cri s i s ).
Diagnosis
Di a gnos i s i s by hi s tory (dura ti on a nd s everi ty of hypertens i on) a nd fundus copy.
Treatment
Hypertens i ve reti nopa thy i s ma na ged pri ma ri l y by control l i ng hypertens i on. Other vi s i on-threa teni ng condi ti ons s houl d a l s o be a ggres s i vel y
control l ed. If vi s i on l os s occurs , trea tment of the reti na l edema wi th l a s er or wi th i ntra vi trea l i njecti on of corti cos teroi ds or a nti -va s cul a r
endothel i a l growth fa ctor (VEGF) drugs ma y be us eful .
Retinal Detachment
Retinal detachment is separation of the neural retina from the underlying retinal pigment epithelium. The most common cause is a retinal tear. Symptoms are
decreased peripheral or central vision, often described as a curtain or dark cloud coming across the field of vision. Associated symptoms can include painless
vision disturbances, including flashing lights and excessive floaters. Traction and serous retinal detachments cause either central or peripheral vision loss.
Diagnosis is by funduscopy; ultrasonography may help determine the presence and type of retinal detachment if it cannot be seen with funduscopy. Immediate
treatment is imperative if rhegmatogenous retinal detachment is acute and threatens central vision. Treatment of rhegmatogenous detachment may include
sealing retinal holes (by laser, diathermy, or cryotherapy), supporting the holes with scleral buckling, pneumatic retinopexy, and vitrectomy.
Etiology
There a re 3 types of deta chment: rhegma togenous , whi ch i nvol ves a reti na l tea r, a nd tra cti on a nd s erous (exuda ti ve) deta chment, whi ch do not
i nvol ve a tea r (nonrhegma togenous ).
Rhegmatogenous detachment i s the mos t common. Ri s k fa ctors i ncl ude the fol l owi ng:
Myopi a
Previ ous ca ta ra ct s urgery
Ocul a r tra uma
Traction retinal detachment ca n be ca us ed by vi treoreti na l tra cti on due to prereti na l fi brous membra nes a s ma y occur i n prol i fera ti ve di a beti c or
s i ckl e cel l reti nopa thy.
Serous detachment res ul ts from tra ns uda ti on of fl ui d i nto the s ubreti na l s pa ce. Ca us es i ncl ude s evere uvei ti s , es peci a l l y i n Vogt-Koya na gi -Ha ra da
s yndrome, choroi da l hema ngi oma s , a nd pri ma ry or meta s ta ti c choroi da l ca ncers (s ee p. 619).
Symptoms and Signs
Reti na l deta chment i s pa i nl es s . Ea rl y s ymptoms of rhegma togenous deta chment ma y i ncl ude da rk or i rregul a r vi treous fl oa ters (pa rti cul a rl y i n
l a rge numbers ), fl a s hes of l i ght (photops i a s ), a nd bl urred vi s i on. As deta chment progres s es , the pa ti ent noti ces a curta i n, vei l , or gra ynes s i n the
fi el d of vi s i on. If the ma cul a i s i nvol ved, centra l vi s i on becomes poor. Pa ti ents ma y ha ve s i mul ta neous vi treous hemorrha ge. Tra cti on a nd
exuda ti ve (s erous ) reti na l deta chments ca n ca us e bl urri nes s of vi s i on, but they ma y not ca us e a ny s ymptoms i n the ea rl y s ta ges .
Diagnosis
Indi rect fundus copy wi th pupi l l a ry di l a ti on
Reti na l deta chment s houl d be s us pected i n pa ti ents , pa rti cul a rl y thos e a t ri s k, who ha ve a ny of the fol l owi ng:
Sudden i ncrea s e or cha nge i n fl oa ters
Photops i a s
Curta i n or vei l a cros s the vi s ua l fi el d
Any s udden, unexpl a i ned l os s of vi s i on
Vi treous hemorrha ge tha t obs cures the reti na
Fundus copy s hows the reti na l deta chment a nd ca n di fferenti a te the s ubtypes of reti na l deta chment i n nea rl y a l l ca s es . Di rect fundus copy us i ng a
ha ndhel d ophtha l mos cope ca n mi s s s ome reti na l deta chments , whi ch ma y be peri phera l . Peri phera l fundus exa mi na ti on, us i ng ei ther i ndi rect
ophtha l mos copy wi th s cl era l depres s i on or us i ng a 3-mi rror l ens , s houl d be done.
If vi treous hemorrha ge (whi ch ma y be due to a reti na l tea r), ca ta ra ct, cornea l opa ci fi ca ti on, or tra uma ti c i njury obs cures the reti na , reti na l
deta chment s houl d be s us pected a nd B-s ca n ul tra s onogra phy s houl d be done.
Treatment
Sea l i ng reti na l hol es
Scl era l buckl i ng
Pneuma ti c reti nopexy
Vi trectomy
Al though often l oca l i zed, reti na l deta chments due to reti na l tea rs ca n expa nd to i nvol ve the enti re reti na i f they a re not trea ted promptl y. Any
patient with a suspected or established retinal detachment should be examined urgently by an ophthalmologist.
Rhegmatogenous detachment i s trea ted wi th one or more methods , dependi ng on the ca us e a nd l oca ti on of the l es i on. One method i nvol ves s ea l i ng
the reti na l hol es by l a s er, di a thermy, or cryothera py. The eye ma y be trea ted by s cl era l buckl i ng (whi ch i ndents the s cl era , pus hi ng the reti na
i nwa rd a nd thereby rel i evi ng vi treous tra cti on on the reti na ); duri ng thi s procedure, fl ui d ma y be dra i ned from the s ubreti na l s pa ce. Pneuma ti c
reti nopexy (i ntra vi trea l i njecti on of ga s ) a nd vi trectomy a re other trea tments . Reti na l tea rs wi thout deta chment ca n be s ea l ed by l a s er
photocoa gul a ti on or tra ns conjuncti va l cryopexy. Nea rl y a l l rhegma togenous deta chments ca n be rea tta ched s urgi ca l l y.
Nonrhegmatogenous detachments due to vi treoreti na l tra cti on ma y be trea ted by s urgi ca l vi trectomy; tra ns uda ti ve deta chments due to uvei ti s ma y
res pond to s ys temi c corti cos teroi ds , s ys temi c corti cos teroi d-s pa ri ng drugs (eg, methotrexa te, a za thi opri ne, a nti -tumor necros i s fa ctor drugs ), or a
s l ow-rel ea s e corti cos teroi d i mpl a nt, whi ch i s s urgi ca l l y i mpl a nted i nto the eye. Pri ma ry a nd meta s ta ti c choroi da l ca ncers a l s o requi re trea tment.
Choroi da l hema ngi oma s ma y res pond to l oca l i zed photocoa gul a ti on.
Retinitis Pigmentosa
Retinitis pigmentosa is a slowly progressive, bilateral degeneration of the retina and retinal pigment epithelium caused by various genetic mutations. Symptoms
include night blindness and loss of peripheral vision. Diagnosis is by funduscopy, which demonstrates pigmentation in a bone-spicule configuration in the
equatorial retina, narrowing of the retinal arterioles, a waxy pallor of the optic disk, posterior subcapsular cataracts, and cells in the vitreous. Electroretinography
helps confirm the diagnosis.
Abnorma l gene codi ng for reti na l protei ns a ppea rs to be the ca us e of reti ni ti s pi gmentos a ; s evera l genes ha ve been i denti fi ed. Tra ns mi s s i on ma y
be a utos oma l reces s i ve, a utos oma l domi na nt, or, i nfrequentl y, X-l i nked. It ma y occur a s pa rt of a s yndrome (eg, Ba s s en-Kornzwei g, La urenceMoon). Some of thes e s yndromes i ncl ude congeni ta l hea ri ng l os s a s wel l .
Symptoms and Signs
Reti na l rods a re a ffected, ca us i ng defecti ve ni ght vi s i on tha t becomes s ymptoma ti c a t va ryi ng a ges , s ometi mes i n ea rl y chi l dhood. Ni ght vi s i on
ma y eventua l l y be l os t. A peri phera l ri ng s cotoma (detecta bl e by vi s ua l fi el d tes ti ng) wi dens gra dua l l y, s o tha t centra l vi s i on ma y a l s o be a ffected
i n a dva nced ca s es .
The mos t cons pi cuous fundus copi c fi ndi ng i s hyperpi gmenta ti on i n a bone-s pi cul e confi gura ti on i n the mi dperi phera l reti na . Other fi ndi ngs
i ncl ude the fol l owi ng:
Na rrowi ng of the reti na l a rteri ol es
Cys toi d ma cul a r edema
Wa xy yel l ow a ppea ra nce of the di s k
Pos teri or s ubca ps ul a r ca ta ra cts
Cel l s i n the vi treous (l es s commonl y)
Myopi a
Diagnosis
Fundus copy
El ectroreti nogra phy
The di a gnos i s i s s us pected i n pa ti ents wi th poor ni ght vi s i on or a fa mi l y hi s tory. Di a gnos i s i s by fundus copy, us ua l l y s uppl emented wi th
el ectroreti nogra phy. Other reti nopa thi es tha t ca n s i mul a te reti ni ti s pi gmentos a s houl d be excl uded; they i ncl ude reti nopa thi es a s s oci a ted wi th
s yphi l i s , rubel l a , phenothi a zi ne or chl oroqui ne toxi ci ty, a nd nonocul a r ca ncer. Fa mi l y members s houl d be exa mi ned a nd tes ted a s neces s a ry or
des i red to es ta bl i s h the heredi ta ry pa ttern. Pa ti ents wi th a heredi ta ry s yndrome ma y wi s h to s eek geneti c couns el i ng before ha vi ng chi l dren.
Treatment
Vi ta mi n A
There i s no wa y to revers e da ma ge ca us ed by reti ni ti s pi gmentos a , but vi ta mi n A pa l mi ta te 20,000 uni ts po once/da y ma y hel p s l ow di s ea s e
progres s i on i n s ome pa ti ents . Pa ti ents ta ki ng vi ta mi n A pa l mi ta te s houl d ha ve regul a r l i ver functi on tes ts . Vi s i on decrea s es a s the ma cul a
becomes i ncrea s i ngl y i nvol ved a nd ca n evol ve to l ega l bl i ndnes s .
Epiretinal Membrane
(Ma cul a r Pucker; Cel l opha ne Ma cul opa thy; Prema cul a r Fi bros i s )
Epiretinal membrane is formation of a thin membrane over the retina, which interferes with vision.
Epi reti na l membra ne typi ca l l y occurs a fter a ge 50 a nd i s mos t common a mong peopl e > 75. An epi reti na l membra ne i s a thi n fi broti c membra ne
tha t forms over the reti na a nd contra cts , wri nkl i ng the reti na undernea th.
Ri s k fa ctors for epi reti na l membra ne a re the fol l owi ng:
Di a beti c reti nopa thy
Uvei ti s
Reti na l deta chment
Ocul a r i njury
Mos t ca s es a re i di opa thi c.
Symptoms ma y i ncl ude bl urred vi s i on or di s torted vi s i on (eg, s tra i ght l i nes ma y a ppea r wa vy). Ma ny pa ti ents s a y tha t i t s eems l i ke they a re l ooki ng
through pl a s ti c wra p or cel l opha ne. Di a gnos i s i s by fundus copy. Fl uores cei n a ngi ogra phy a nd opti ca l coherence tomogra phy ma y a l s o be hel pful .
Mos t peopl e need no trea tment. If probl ems wi th vi s i on a re s i gni fi ca nt, the membra ne ca n be removed s urgi ca l l y (membra ne peel ).
Cancers Affecting the Retina
Ca ncers a ffecti ng the reti na us ua l l y begi n i n the choroi d. Beca us e the reti na depends on the choroi d for i ts s upport a nd ha l f of i ts bl ood s uppl y,
da ma ge to the choroi d by a ca ncer i s l i kel y to a ffect vi s i on.
Choroidal melanoma: Choroi da l mel a noma ori gi na tes i n the choroi da l mel a nocytes . Choroi da l mel a noma i s the mos t common ca ncer ori gi na ti ng i n
the eye, wi th a n i nci dence of a bout 1 i n 2500 whi tes . It i s l es s common a mong da rker-s ki nned peopl e. It occurs mos t frequentl y a t a ge 55 to 60. It
ma y s prea d l oca l l y or meta s ta s i ze a nd be fa ta l .
Symptoms tend to devel op l a te a nd i ncl ude l os s of vi s i on a nd s ymptoms of reti na l deta chment (s ee p. 617).
Di a gnos i s i s by fundus copy, s uppl emented, when i ndi ca ted, by other tes ts , s uch a s ul tra s onogra phy, CT, fl uores cei n a ngi ogra phy, a nd s eri a l
photogra phs .
Sma l l ca ncers a re trea ted wi th l a s er, ra di a ti on, or ra di oa cti ve i mpl a nts , whi ch ma y pres erve vi s i on a nd s a ve the eye. Ra rel y, l oca l res ecti on i s
us ed. La rge ca ncers requi re enucl ea ti on.
Choroidal metastases: Choroi da l meta s ta s es a re common beca us e the choroi d i s hi ghl y va s cul a r. The mos t common pri ma ry ca ncers a re thos e of the
brea s t i n women a nd of the l ung a nd pros ta te i n men.
Symptoms tend to devel op l a te a nd i ncl ude l os s of vi s i on a nd s ymptoms of reti na l deta chment.
Di a gnos i s i s often i nci denta l duri ng routi ne ophtha l mos copy. Ul tra s onogra phy i s us ua l l y done, a nd the di a gnos i s i s confi rmed us i ng fi ne-needl e
bi ops y.
Trea tment i s us ua l l y wi th chemothera py, ra di a ti on thera py, or both.
Chapter 69. Optic Nerve Disorders

Introduction
The opti c pa thwa y i ncl udes the reti na , opti c nerve, opti c chi a s m, opti c ra di a ti ons , a nd occi pi ta l cortex (s ee
Fi g. 69-1). Da ma ge a l ong the opti c pa thwa y ca us es a va ri ety of vi s ua l fi el d cha nges (s ee
Ta bl e 60-1 on p. 540).
Hereditary Optic Neuropathies
Hereditary optic neuropathies are genetic defects that cause vision loss, occasionally with cardiac or neurologic abnormalities. There is no effective treatment.
Heredi ta ry opti c neuropa thi es typi ca l l y ma ni fes t i n chi l dhood or a dol es cence wi th
[Fig. 69-1. Hi gher vi s ua l pa thwa ys l es i on s i tes a nd corres pondi ng vi s ua l fi el d defects .]
bi l a tera l , s ymmetri c centra l vi s i on l os s . Opti c nerve da ma ge i s us ua l l y perma nent a nd i n s ome ca s es progres s i ve. By the ti me opti c a trophy i s
detected, s ubs ta nti a l opti c nerve i njury ha s a l rea dy occurred.
Dominant optic atrophy: Thi s di s order i s i nheri ted i n a n a utos oma l domi na nt fa s hi on. It i s bel i eved to be the mos t common of the heredi ta ry opti c
neuropa thi es , wi th preva l ence i n the ra nge of 1:10,000 to 1:50,000. It i s thought to be opti c a bi otrophy, prema ture degenera ti on of the opti c nerve
l ea di ng to progres s i ve vi s i on l os s . Ons et i s i n the 1s t deca de of l i fe.
Leber's hereditary optic neuropathy: Thi s di s order i nvol ves a mi tochondri a l DNA a bnorma l i ty tha t a ffects cel l ul a r res pi ra ti on. Al though mi tochondri a l
DNA throughout the body i s a ffected, vi s i on l os s i s the pri ma ry ma ni fes ta ti on. Mos t ca s es (80 to 90%) occur i n ma l es . The di s ea s e i s i nheri ted wi th
a ma terna l i nheri ta nce pa ttern, mea ni ng tha t a l l offs pri ng of a woma n wi th the a bnorma l i ty i nheri t the a bnorma l i ty, but onl y fema l es ca n pa s s on
the a bnorma l i ty beca us e the zygote recei ves mi tochondri a onl y from the mother.
Symptoms and Signs
Dominant optic atrophy: Mos t pa ti ents ha ve no a s s oci a ted neurol ogi c a bnorma l i ti es , a l though nys ta gmus a nd hea ri ng l os s ha ve been reported. The
onl y s ymptom i s s l owl y progres s i ve bi l a tera l vi s i on l os s , us ua l l y mi l d unti l l a te i n l i fe. The enti re opti c di s k or, a t ti mes , onl y the tempora l pa rt i s
pa l e wi thout vi s i bl e ves s el s . A bl ue-yel l ow col or vi s i on defi ci t i s cha ra cteri s ti c.
Leber's hereditary optic neuropathy: Vi s i on l os s typi ca l l y begi ns between 15 a nd 35 yr (ra nge, 1 to 80 yr). Pa i nl es s centra l vi s i on l os s i n one eye i s
us ua l l y fol l owed weeks to months l a ter by l os s i n the other eye. Si mul ta neous vi s i on l os s ha s been reported. Mos t pa ti ents l os e vi s i on to wors e
tha n 20/200 a cui ty. Ophtha l mos copi c exa mi na ti on ma y s how tel a ngi ecta ti c mi croa ngi opa thy, s wel l i ng of the nerve fi ber l a yer a round the opti c
di s k, a nd a n a bs ence of l ea ka ge on fl uores cei n a ngi ogra phy. Eventua l l y, opti c a trophy s upervenes .
Some pa ti ents wi th Leber's heredi ta ry opti c neuropa thy ha ve ca rdi a c conducti on defects . Other pa ti ents ha ve mi nor neurol ogi c a bnorma l i ti es ,
s uch a s a pos tura l tremor, l os s of a nkl e refl exes , dys toni a , s pa s ti ci ty, or a mul ti pl e s cl eros i s -l i ke i l l nes s .
Diagnosis
Mol ecul a r geneti c tes ti ng i s a va i l a bl e to confi rm the di a gnos i s of domi na nt opti c a trophy.
Di a gnos i s of Leber's heredi ta ry opti c a trophy i s ma i nl y cl i ni ca l . ECG s houl d be done to di a gnos e occul t ca rdi a c conducti on defects .
Treatment
There i s no effecti ve trea tment for the heredi ta ry opti c neuropa thi es . Low-vi s i on a i ds (eg, ma gni fi ers , l a rge-pri nt devi ces , ta l ki ng wa tches ) ma y be
hel pful . Geneti c couns el i ng i s s ugges ted.
Leber's hereditary optic neuropathy: Corti cos teroi ds , vi ta mi n s uppl ements , a nd a nti oxi da nts ha ve been tri ed wi thout s ucces s . A s ma l l s tudy found
benefi ts from qui none a na l ogs (ubi qui none a nd i debenone) duri ng the ea rl y pha s e. Sugges ti ons to a voi d a gents tha t mi ght s tres s mi tochondri a l
energy producti on (eg, a l cohol ) ha ve no proven benefi t but a re theoreti ca l l y rea s ona bl e. Pa ti ents s houl d a voi d toba cco products a nd exces s i ve
a l cohol i nta ke. Ca rdi a c a nd neurol ogi c a bnorma l i ti es s houl d be referred to a s peci a l i s t.
Ischemic Optic Neuropathy
Ischemic optic neuropathy is infarction of the optic disk. The only constant symptom is painless vision loss. Diagnosis is clinical. Treatment is ineffective.
Two va ri eti es of opti c nerve i nfa rcti on exi s t: nona rteri ti c a nd a rteri ti c. The nona rteri ti c va ri a nt occurs more frequentl y, typi ca l l y a ffecti ng peopl e
a bout 50 yr a nd ol der. Vi s i on l os s tends not to be a s s evere a s i n the a rteri ti c va ri a nt, whi ch typi ca l l y a ffects a n ol der group, typi ca l l y a bout 70 yr
a nd ol der.
Mos t i s chemi c opti c neuropa thy i s uni l a tera l . Bi l a tera l , s equenti a l ca s es occur i n a bout 20%, but bi l a tera l s i mul ta neous i nvol vement i s
uncommon. Atheros cl eroti c na rrowi ng of the pos teri or ci l i a ry a rteri es ma y predi s pos e to nona rteri ti c opti c nerve i nfa rcti on, pa rti cul a rl y a fter a
hypotens i ve epi s ode. Any of the i nfl a mma tory a rteri ti des , es peci a l l y gi a nt cel l a rteri ti s (s ee p. 319), ca n preci pi ta te the a rteri ti c form.
Acute i s chemi a ca us es nerve edema , whi ch further wors ens i s chemi a . A s ma l l opti c cup to opti c di s k ra ti o i s a ri s k fa ctor for nona rteri ti c i s chemi c
opti c neuropa thy but not for the a rteri ti c va ri ety. Us ua l l y, no medi ca l condi ti on i s a ppa rent to ca us e the nona rteri ti c va ri ety, a l though di a betes a nd
hypertens i on a re pres ent i n s ome pa ti ents a nd a re thought to be ri s k fa ctors . Vi s i on l os s on a wa keni ng l ea ds i nves ti ga tors to s us pect nocturna l
hypotens i on a s a potenti a l ca us e of the nona rteri ti c va ri ety.

Symptoms and Signs
Vi s i on l os s wi th both va ri eti es i s typi ca l l y ra pi d (over mi nutes , hours , or da ys ) a nd pa i nl es s . Some pa ti ents noti ce the l os s on a wa keni ng.
Symptoms s uch a s genera l ma l a i s e, mus cl e a ches a nd pa i ns , hea da ches over the templ e, pa i n when combi ng ha i r, ja w cl a udi ca ti on, a nd
tendernes s over the tempora l a rtery ma y be pres ent wi th tempora l a rteri ti s ; however, s uch s ymptoms ma y not occur unti l a fter vi s i on i s l os t. Vi s ua l
a cui ty i s reduced, a nd a n a fferent pupi l l a ry defect i s pres ent. The opti c di s k i s s wol l en wi th s urroundi ng hemorrha ges . Vi s ua l fi el d exa mi na ti on
often s hows a defect i n the i nferi or a nd centra l vi s ua l fi el ds .
Diagnosis
ESR
CT or MRI i f vi s i on l os s i s progres s i ve
Di a gnos i s i s ba s ed ma i nl y on a cl i ni ca l eva l ua ti on, but a nci l l a ry tes ti ng ma y be needed. Mos t i mporta nt i s to excl ude the a rteri ti c va ri ety beca us e
the other eye i s a t ri s k i f trea tment i s not s ta rted qui ckl y. ESR i s us ua l l y dra ma ti ca l l y el eva ted i n the a rteri ti c va ri ety a nd i s norma l i n the
nona rteri ti c va ri ety. C-rea cti ve protei n i s a l s o a us eful moni tori ng tes t. If tempora l a rteri ti s i s s us pected, tempora l a rtery bi ops y s houl d be done.
For i s ol a ted ca s es of progres s i ve vi s i on l os s , CT or MRI s houl d be done to rul e out compres s i ve l es i ons .
Prognosis
There i s no effecti ve trea tment, a nd mos t l os t vi s i on i s not recovered; however, i n the nona rteri ti c va ri ety, up to 40% of pa ti ents s ponta neous l y
recover s ome us eful vi s i on.
Treatment
Corti cos teroi ds for the a rteri ti c va ri ety
The a rteri ti c va ri ety i s trea ted wi th ora l corti cos teroi ds (predni s one 80 mg po once/da y a nd ta pered ba s ed on ESR) to protect the other eye.
Trea tment s houl d not be del a yed whi l e a wa i ti ng bi ops y res ul ts . Trea tment of the nona rteri ti c va ri ety wi th a s pi ri n or corti cos teroi ds ha s not been
hel pful . Ri s k fa ctors a re control l ed. Low-vi s i on a i ds (eg, ma gni fi ers , l a rge-pri nt devi ces , ta l ki ng wa tches ) ma y be hel pful i n both types .
Optic Neuritis
Optic neuritis is inflammation of the optic nerve. Symptoms are usually unilateral, with eye pain and partial or complete vision loss. Diagnosis is primarily
clinical. Treatment is directed at the underlying condition; most cases resolve spontaneously.
Etiology
Opti c neuri ti s i s mos t common a mong a dul ts 20 to 40 yr. Mos t ca s es res ul t from demyel i na ti ng di s ea s e, pa rti cul a rl y mul ti pl e s cl eros i s (s ee p.
1779), i n whi ch ca s e there ma y be recurrences . Opti c neuri ti s i s often the pres enti ng ma ni fes ta ti on of mul ti pl e s cl eros i s . Other ca us es i ncl ude the
fol l owi ng:
Infecti ous di s ea s es (eg, vi ra l encepha l i ti s [pa rti cul a rl y i n chi l dren], s i nus i ti s , meni ngi ti s , TB, s yphi l i s , HIV)
Tumor meta s ta s i s to the opti c nerve
Chemi ca l s a nd drugs (eg, l ea d, metha nol , qui ni ne, a rs eni c, a nti bi oti cs )
Ra re ca us es i ncl ude di a betes , perni ci ous a nemi a , Gra ves ' di s ea s e, bee s ti ngs , a nd tra uma . Often, the ca us e rema i ns obs cure des pi te thorough
eva l ua ti on.
Symptoms and Signs
The ma i n s ymptom i s vi s i on l os s , frequentl y ma xi ma l wi thi n 1 or 2 da ys a nd va ryi ng from a s ma l l centra l or pa ra centra l s cotoma to compl ete
bl i ndnes s . Mos t pa ti ents ha ve mi l d eye pa i n, whi ch often feel s wors e wi th eye movement.
If the opti c di s k i s s wol l en, the condi ti on i s ca l l ed pa pi l l i ti s . Otherwi s e, i t i s ca l l ed retrobul ba r neuri ti s . The mos t cha ra cteri s ti c fi ndi ngs i ncl ude
reduced vi s ua l a cui ty, a vi s ua l fi el d defi ci t, a nd di s turbed col or vi s i on (often out of proporti on to l os s of vi s ua l a cui ty). An a fferent pupi l l a ry defect
i s us ua l l y detecta bl e i f the contra l a tera l eye i s una ffected or i nvol ved to a l es s er degree. Tes ti ng of col or vi s i on i s a us eful a djunct. In a bout two
thi rds of pa ti ents , i nfl a mma ti on i s enti rel y retrobul ba r, ca us i ng no vi s i bl e cha nges i n the opti c fundus . In the res t, di s k hyperemi a , edema i n or
a round the di s k, ves s el engorgement, or a combi na ti on i s pres ent. A few exuda tes a nd hemorrha ges ma y be pres ent nea r or on the opti c di s k.
Diagnosis
MRI
Opti c neuri ti s i s s us pected i n pa ti ents wi th cha ra cteri s ti c pa i n a nd vi s i on l os s . Neuroi ma gi ng, prefera bl y wi th ga dol i ni um-enha nced MRI, i s
us ua l l y done a nd ma y s how a n enl a rged, enha nci ng opti c nerve. MRI ma y a l s o hel p di a gnos e mul ti pl e s cl eros i s . Fl ui d a ttenua ti ng i nvers i on
recovery (FLAIR) MRI s equences ma y s how typi ca l demyel i na ti ng l es i ons i n a peri ventri cul a r l oca ti on i f opti c neuri ti s i s rel a ted to demyel i na ti on.
Prognosis
Prognos i s depends on the underl yi ng condi ti on. Mos t epi s odes res ol ve s ponta neous l y, wi th return of vi s i on i n 2 to 3 mo. Mos t pa ti ents wi th a
typi ca l hi s tory of opti c neuri ti s a nd no underl yi ng s ys temi c di s ea s e, s uch a s a connecti ve ti s s ue di s ea s e, recover vi s i on, but > 25% ha ve a
recurrence i n the s a me eye or i n the other eye. MRI i s us ed to determi ne future ri s k of demyel i na ti ng di s ea s e.
Treatment
Corti cos teroi ds
Corti cos teroi ds a re a n opti on, es peci a l l y i f mul ti pl e s cl eros i s i s s us pected. Trea tment wi th methyl predni s ol one (500 mg to 1000 mg IV once/da y)
for 3 da ys fol l owed by predni s one (1 mg/kg po once/da y) for 11 da ys ma y s peed recovery, but ul ti ma te vi s i on res ul ts a re no di fferent from thos e
wi th obs erva ti on a l one. IV corti cos teroi ds ha ve been reported to del a y ons et of mul ti pl e s cl eros i s for a t l ea s t 2 yr. Trea tment wi th ora l predni s one
a l one does not i mprove vi s i on outcome a nd ma y i ncrea s e the ra te of recurrent epi s odes . Low-vi s i on a i ds (eg, ma gni fi ers , l a rge-pri nt devi ces ,
ta l ki ng wa tches ) ma y be hel pful .
Papilledema
Papilledema is swelling of the optic disk due to increased intracranial pressure. All other causes of optic disk swelling, such as that caused by malignant
hypertension or thrombosis of the central retinal vein, do not involve increased intracranial pressure and therefore are not causes of papilledema. There are no
early symptoms, although vision may be disturbed for a few seconds. Papilledema requires an immediate search for the cause. Diagnosis is by ophthalmoscopy
with further tests, usually brain imaging, to determine cause. Treatment is directed at the underlying condition.
Pa pi l l edema i s a s i gn of el eva ted i ntra cra ni a l pres s ure a nd i s a l mos t a l wa ys bi l a tera l . Ca us es i ncl ude the fol l owi ng:
Bra i n tumor or a bs ces s
Cerebra l tra uma or hemorrha ge
Meni ngi ti s
Ara chnoi da l a dhes i ons
Ca vernous or dura l s i nus thrombos i s
Encepha l i ti s
Idi opa thi c i ntra cra ni a l hypertens i on (ps eudotumor cerebri ), a condi ti on wi th el eva ted CSF pres s ure a nd no ma s s l es i on
Symptoms and Signs
Vi s i on i s us ua l l y not a ffected i ni ti a l l y, but s econds -l ong gra yi ng out of vi s i on, fl i ckeri ng, or bl urred or doubl e vi s i on ma y occur. Pa ti ents ma y ha ve
s ymptoms of i ncrea s ed i ntra cra ni a l pres s ure, s uch a s hea da che or na us ea a nd vomi ti ng.
Ophtha l mos copi c exa mi na ti on revea l s engorged a nd tortuous reti na l vei ns , a hyperemi c a nd s wol l en opti c di s k (opti c nerve hea d), a nd reti na l
hemorrha ges a round the di s k but not i nto the reti na l peri phery (s ee
Pl a te 19). Is ol a ted di s k edema (eg, ca us ed by opti c neuri ti s or i s chemi c opti c neuropa thy) wi thout el eva ted CSF pres s ure i s not cons i dered
pa pi l l edema .
In the ea rl y s ta ges , vi s ua l a cui ty a nd pupi l l a ry res pons e to l i ght a re us ua l l y norma l a nd become a bnorma l onl y a fter the condi ti on i s wel l
a dva nced. Vi s ua l fi el d tes ti ng ma y detect a n enl a rged bl i nd s pot. La ter, nerve fi ber bundl e defects ma y be a ppa rent.
Diagnosis
Immedi a te neuroi ma gi ng
The degree of di s k s wel l i ng ca n be qua nti fi ed by compa ri ng the pl us l ens numbers needed to focus a n ophtha l mos cope on the mos t el eva ted
porti on of the di s k a nd on the una ffected porti on of the reti na .
Di fferenti a ti ng pa pi l l edema from other ca us es of a s wol l en opti c di s k, s uch a s opti c neuri ti s , i s chemi c opti c neuropa thy, hypotony, centra l reti na l
vei n occl us i on, uvei ti s , or ps eudo s wol l en di s ks (eg, opti c nerve drus en), requi res a thorough ophtha l mol ogi c eva l ua ti on. If pa pi l l edema i s
s us pected cl i ni ca l l y, MRI wi th ga dol i ni um contra s t or CT wi th contra s t i s done i mmedi a tel y to excl ude ca us es s uch a s a n i ntra cra ni a l ma s s . Lumba r
puncture a nd mea s urement of CSF pres s ure s houl d be done i f a ma s s l es i on ha s been rul ed out. Lumba r puncture i n pa ti ents wi th i ntra cra ni a l
ma s s l es i ons ca n res ul t i n bra i n s tem herni a ti on. B-s ca n ul tra s onogra phy i s the bes t di a gnos ti c tool for the ps eudo di s k edema of opti c nerve
drus en.
Treatment
Trea tment of underl yi ng di s order
Urgent trea tment of the underl yi ng di s order i s i ndi ca ted to decrea s e i ntra cra ni a l pres s ure. If i ntra cra ni a l pres s ure i s not reduced, s econda ry opti c
nerve a trophy a nd vi s i on l os s eventua l l y occur, a l ong wi th other s eri ous neurol ogi c s equel a e.
Toxic Amblyopia
(Nutri ti ona l Ambl yopi a )
Toxic amblyopia is reduction in visual acuity believed to be the result of a toxic reaction in the orbital portion (papillomacular bundle) of the optic nerve. It can be
caused by various toxic and nutritional factors and probably unknown factors. The main symptom is painless vision loss. Diagnosis is by history and visual field
examination. Treatment is avoiding suspected toxic agents and improving nutrition.
Etiology
Toxi c a mbl yopi a i s us ua l l y bi l a tera l a nd s ymmetri c. In a l cohol i cs , undernutri ti on ma y be the ca us e. True toba cco-i nduced a mbl yopi a i s ra re. Lea d,
metha nol , chl ora mpheni col , di goxi n, etha mbutol , a nd ma ny other chemi ca l s ca n da ma ge the opti c nerve. Defi ci enci es of protei n a nd a nti oxi da nts
a re l i kel y ri s k fa ctors . Toxi c a mbl yopi a ma y occur wi th other nutri ti ona l di s orders , s uch a s Stra cha n's s yndrome (pol yneuropa thy a nd orogeni ta l
derma ti ti s ).
Symptoms and Signs
Vi s i on bl urri ng a nd di mnes s typi ca l l y devel op over da ys to weeks . An i ni ti a l l y s ma l l centra l or peri centra l s cotoma s l owl y enl a rges , typi ca l l y
i nvol vi ng both the fi xa ti on a nd the bl i nd s pot (centroceca l s cotoma ), a nd progres s i vel y i nterferes wi th vi s i on. Tota l bl i ndnes s ma y occur i n
metha nol i nges ti on, but other nutri ti ona l ca us es typi ca l l y do not ca us e profound vi s i on l os s . Reti na l a bnorma l i ti es do not us ua l l y occur, but
tempora l di s k pa l l or ma y devel op l a te.
Diagnosis
A hi s tory of undernutri ti on or toxi c or chemi ca l expos ure combi ned wi th typi ca l bi l a tera l s cotoma ta on vi s ua l fi el d tes ti ng jus ti fi es trea tment.
La bora tory tes ti ng for l ea d, metha nol , a nd other s us pected toxi ns i s done.
Prognosis
Vi s i on ma y i mprove i f the ca us e i s trea ted or removed qui ckl y. Once the opti c nerve ha s a trophi ed, vi s i on us ua l l y does not recover.
Treatment
The ca us e i s trea ted. Expos ure to toxi c s ubs ta nces s houl d s top i mmedi a tel y. Chel a ti on thera py i s i ndi ca ted i n l ea d poi s oni ng. Di a l ys i s ,
fomepi zol e, etha nol , or a combi na ti on i s us ed for metha nol poi s oni ng. Trea tment wi th ora l or pa rentera l B vi ta mi ns before vi s i on l os s becomes
s evere ma y revers e the condi ti on when undernutri ti on i s the pres umed ca us e.
Low-vi s i on a i ds (eg, ma gni fi ers , l a rge-pri nt devi ces , ta l ki ng wa tches ) ma y be hel pful .
The rol e of a nti oxi da nts ha s not been ful l y cha ra cteri zed. Thei r us e coul d be jus ti fi ed on a theoreti c ba s i s ; however, there i s no proof of effi ca cy,
a nd the a t-ri s k popul a ti on tha t s houl d recei ve s uch s uppl ements ha s not been defi ned.
Chapter 70. Orbital Diseases

Introduction
Orbi ta l di s ea s es ma y be va s cul a r, thyroi d-rel a ted (Gra ves ' di s ea s e), i nfecti ous , i nfl a mma tory, or neopl a s ti c. Ca vernous s i nus thrombos i s ca us es
ma ny of the s a me s ymptoms a nd s i gns a s orbi ta l di s ea s es . Infi l tra ti ve ophtha l mopa thy due to Gra ves ' di s ea s e, the mos t frequent ca us e of orbi ta l
di s ea s e, i s di s cus s ed on p. 780. Orbi ta l fra ctures a re di s cus s ed on p. 3232. (See
Fi g. 60-1 on p. 537 for a na tomy of the orbi t.)
Cavernous Sinus Thrombosis
Cavernous sinus thrombosis (CST) is a very rare, typically septic thrombosis of the cavernous sinus, usually caused by bacterial sinusitis. Symptoms and signs
include pain, proptosis, ophthalmoplegia, vision loss, papilledema, and fever. Diagnosis is confirmed by CT or MRI. Treatment is with IV antibiotics. Complications
are common, and prognosis is poor.
Etiology
The ca vernous s i nus es a re tra becul a ted s i nus es l oca ted a t the ba s e of the s kul l tha t dra i n venous bl ood from fa ci a l vei ns . CST i s a n extremel y
ra re compl i ca ti on of common fa ci a l i nfecti ons , mos t nota bl y na s a l furuncl es (50%), s phenoi da l or ethmoi da l s i nus i ti s (30%), a nd denta l i nfecti ons
(10%). Mos t common pa thogens a re Staphylococcus aureus (70%), fol l owed by Streptococcus s p; a na erobes a re more common when the underl yi ng
condi ti on i s denta l or s i nus i nfecti on.
Thrombos i s of the l a tera l s i nus (rel a ted to ma s toi di ti s ) a nd thrombos i s of the s uperi or s a gi tta l s i nus (rel a ted to ba cteri a l meni ngi ti s ) occur but
a re ra rer tha n CST.
Pathophysiology
The 3rd, 4th, a nd 6th cra ni a l nerves a nd the ophtha l mi c a nd ma xi l l a ry bra nches of the 5th cra ni a l nerve a re a dja cent to the ca vernous s i nus a nd
a re commonl y a ffected. Compl i ca ti ons i ncl ude meni ngoencepha l i ti s , bra i n a bs ces s , s troke, bl i ndnes s , a nd pi tui ta ry i ns uffi ci ency.
Symptoms and Signs
Ini ti a l s ymptoms a re progres s i vel y s evere hea da che or fa ci a l pa i n, us ua l l y uni l a tera l a nd l oca l i zed to retro-orbi ta l a nd fronta l regi ons . Hi gh fever
i s common. La ter, ophtha l mopl egi a (i ni ti a l l y the 6th cra ni a l nerve, l a tera l ga ze), proptos i s , a nd l i d edema devel op a nd often become bi l a tera l .
Fa ci a l s ens a ti on ma y be di mi ni s hed or a bs ent. Decrea s ed l evel of cons ci ous nes s , confus i on, s ei zures , a nd foca l neurol ogi c defi ci ts a re s i gns of
CNS s prea d. Pa ti ents ma y a l s o ha ve a ni s ocori a or mydri a s i s (3rd cra ni a l nerve dys functi on), pa pi l l edema , a nd vi s i on l os s .
Diagnosis
MRI or CT
CST i s often mi s di a gnos ed beca us e i t i s ra re. It s houl d be cons i dered i n pa ti ents who ha ve s i gns cons i s tent wi th orbi ta l cel l ul i ti s . Fea tures tha t
di s ti ngui s h CST from orbi ta l cel l ul i ti s i ncl ude cra ni a l nerve dys functi on, bi l a tera l eye i nvol vement, a nd menta l s ta tus cha nges .
Di a gnos i s i s ba s ed on neuroi ma gi ng. MRI i s the better s tudy, but CT i s a l s o hel pful . Us eful a djunct tes ti ng ma y i ncl ude bl ood cul tures a nd l umba r
puncture. Lumba r puncture ma y s how i nfl a mma tory cel l s (PMNs , l ymphocytes , monocytes ); other pos s i bl e a bnorma l i ti es i ncl ude l ow gl ucos e, hi gh
protei n, a nd pos i ti ve CSF cul tures . Cul tures of a ny s us pected s ource i nfecti ons a re a l s o done.
Prognosis
Morta l i ty i s 30% i n a l l pa ti ents a nd 50% i n thos e wi th underl yi ng s phenoi d s i nus i ti s . An a ddi ti ona l 30% devel op s eri ous s equel a e (eg,
ophtha l mopl egi a , bl i ndnes s , di s a bi l i ty due to s troke, pi tui ta ry i ns uffi ci ency), whi ch ma y be perma nent.
Treatment
IV hi gh-dos e a nti bi oti cs
Someti mes corti cos teroi ds
Ini ti a l a nti bi oti cs ca n i ncl ude na fci l l i n or oxa ci l l i n 1 to 2 g q 4 to 6 h combi ned wi th a 3rd-genera ti on cepha l os pori n (eg, ceftri a xone 1 g q 12 h). In
a rea s where methi ci l l i n-res i s ta nt S. aureus i s preva l ent, va ncomyci n 1 g IV q 12 h s houl d be s ubs ti tuted for na fci l l i n or oxa ci l l i n. A drug for
a na erobes (eg, metroni da zol e 500 mg q 8 h) s houl d be a dded i f a n underl yi ng s i nus i ti s or denta l i nfecti on i s pres ent.
In ca s es wi th underl yi ng s phenoi d s i nus i ti s , s urgi ca l s i nus dra i na ge i s i ndi ca ted, es peci a l l y i f there i s no cl i ni ca l res pons e to a nti bi oti cs wi thi n
24 h.
Seconda ry trea tment ma y i ncl ude corti cos teroi ds (eg, dexa metha s one 10 mg po q 6 h) for cra ni a l nerve dys functi on; a nti coa gul a ti on i s
controvers i a l beca us e mos t pa ti ents res pond to a nti bi oti cs , a nd a dvers e effects ma y exceed benefi ts .
Inflammatory Orbital Disease
Orbi ta l i nfl a mma ti on (i nfl a mma tory orbi ta l ps eudotumor) ca n a ffect a ny or a l l s tructures wi thi n the orbi t. The i nfl a mma tory res pons e ca n be
nons peci fi c, gra nul oma tous , or va s cul i ti c. The i nfl a mma ti on ca n be pa rt of a n underl yi ng medi ca l di s order or ca n exi s t i n i s ol a ti on. Pa ti ents of a l l
a ges ca n be a ffected. The proces s ca n be a cute or chroni c a nd ca n recur.
Symptoms and Signs

Symptoms a nd s i gns typi ca l l y i ncl ude a s udden ons et of pa i n a l ong wi th s wel l i ng a nd erythema of the eyel i ds . Proptos i s , di pl opi a , a nd vi s i on l os s
a re a l s o pos s i bl e.
Diagnosis
CT or MRI
Si mi l a r fi ndi ngs occur wi th orbi ta l i nfecti on, but there i s no hi s tory of tra uma or a dja cent focus of i nfecti on (eg, s i nus i ti s ). Neuroi ma gi ng wi th CT or
MRI i s requi red. For chroni c or recurrent di s ea s e, bi ops y ma y be us ed to fi nd evi dence of a n underl yi ng medi ca l condi ti on.
Treatment
Trea tment depends on the type of i nfl a mma tory res pons e a nd ma y i ncl ude ora l corti cos teroi ds , ra di a ti on thera py, a nd one of s evera l
i mmunomodul a ti ng drugs . In di ffi cul t ca s es , s ome i ni ti a l s ucces s ha s occurred wi th monocl ona l a nti bodi es a ga i ns t tumor necros i s fa ctor or wi th
a nother monocl ona l a nti body tha t ca us es l ymphocyte depl eti on.
Preseptal and Orbital Cellulitis
Preseptal cellulitis (periorbital cellulitis) is infection of the eyelid and surrounding skin anterior to the orbital septum. Orbital cellulitis (postseptal cellulitis) is
infection of the orbital tissues posterior to the orbital septum. Either can be caused by an external focus of infection (eg, a wound), infection that extends from
the nasal sinuses or teeth, or metastatic spread from infection elsewhere. Symptoms include eyelid pain, discoloration, and swelling; orbital cellulitis also causes
fever, malaise, proptosis, impaired ocular movement, and impaired vision. Diagnosis is based on history, examination, and CT or MRI. Treatment is with
antibiotics and sometimes surgical drainage.
Pres epta l cel l ul i ti s a nd orbi ta l cel l ul i ti s a re 2 di s ti nct di s ea s es tha t s ha re a few cl i ni ca l s ymptoms a nd s i gns . Pres epta l cel l ul i ti s us ua l l y begi ns
s uperfi ci a l to the orbi ta l s eptum. Orbi ta l cel l ul i ti s us ua l l y begi ns deep to the orbi ta l s eptum. Both a re more common a mong chi l dren; pres epta l
cel l ul i ti s i s fa r more common tha n orbi ta l cel l ul i ti s .
Etiology
Pres epta l cel l ul i ti s i s ca us ed by conti guous s prea d of i nfecti on from l oca l fa ci a l or eyel i d i njuri es , i ns ect or a ni ma l bi tes , conjuncti vi ti s , cha l a zi on,
or s i nus i ti s .
Orbi ta l cel l ul i ti s i s mos t often ca us ed by extens i on of i nfecti on from a dja cent s i nus es , es peci a l l y the ethmoi d s i nus (75 to 90%); i t i s l es s
commonl y ca us ed by di rect i nfecti on a ccompa nyi ng l oca l tra uma (eg, i ns ect or a ni ma l bi te, penetra ti ng eyel i d i njuri es ) or conti guous s prea d of
i nfecti on from the fa ce or teeth or by hema togenous s prea d.
Pa thogens va ry by eti ol ogy a nd pa ti ent a ge. Streptococcus pneumoniae i s the mos t frequent pa thogen a s s oci a ted wi th s i nus i nfecti on, wherea s
Staphylococcus aureus a nd Streptococcus pyogenes predomi na te when i nfecti on a ri s es from l oca l tra uma . Haemophilus influenzae type b, once a common
ca us e, i s now l es s common beca us e of wi des prea d va cci na ti on. Fungi a re uncommon pa thogens , ca us i ng orbi ta l cel l ul i ti s i n di a beti c or
i mmunos uppres s ed pa ti ents . Infecti on i n chi l dren < 9 yr i s typi ca l l y wi th a s i ngl e a erobi c orga ni s m; pa ti ents > 15 yr typi ca l l y ha ve pol ymi crobi a l
mi xed a erobi c a nd a na erobi c (Bacteroides, Peptostreptococcus) i nfecti ons .
Pathophysiology
Beca us e orbi ta l cel l ul i ti s ori gi na tes from l a rge a dja cent foci of ful mi na nt i nfecti on (eg, s i nus i ti s ) s epa ra ted by onl y a thi n bone ba rri er, orbi ta l
i nfecti on ca n be extens i ve a nd s evere. Subperi os tea l fl ui d col l ecti ons , s ome qui te l a rge, ca n a ccumul a te; they a re ca l l ed s ubperi os tea l
a bs ces s es , but ma ny a re s teri l e i ni ti a l l y.
Compl i ca ti ons i ncl ude vi s i on l os s (3 to 11%) due to i s chemi c reti nopa thy a nd opti c neuropa thy ca us ed by i ncrea s ed i ntra orbi ta l pres s ure;
res tri cted ocul a r movements (ophtha l mopl egi a ) ca us ed by s oft-ti s s ue i nfl a mma ti on; a nd i ntra cra ni a l s equel a e from centra l s prea d of i nfecti on,
i ncl udi ng ca vernous s i nus thrombos i s , meni ngi ti s , a nd cerebra l a bs ces s .
Symptoms and Signs
Symptoms a nd s i gns of pres epta l cel l ul i ti s i ncl ude tendernes s , s wel l i ng, wa rmth, a nd rednes s or di s col ora ti on (vi ol a ceous i n the ca s e of H.
influenzae) of the eyel i d. Pa ti ents ma y be una bl e to open thei r eyes beca us e of s wel l i ng, but vi s ua l a cui ty i s not a ffected.
Symptoms a nd s i gns of orbi ta l cel l ul i ti s i ncl ude s wel l i ng a nd rednes s of the eyel i d a nd s urroundi ng s oft ti s s ues , conjuncti va l hyperemi a a nd
chemos i s , decrea s ed ocul a r moti l i ty, pa i n wi th eye movements , decrea s ed vi s ua l a cui ty, a nd proptos i s ca us ed by orbi ta l s wel l i ng. Si gns of the
pri ma ry i nfecti on a re a l s o often pres ent (eg, na s a l di s cha rge a nd bl eedi ng wi th s i nus i ti s , peri odonta l pa i n a nd s wel l i ng wi th a bs ces s ). Fever,
ma l a i s e, a nd hea da che s houl d ra i s e s us pi ci on of a s s oci a ted meni ngi ti s . Some or a l l of thes e fi ndi ngs ma y be a bs ent ea rl y i n the cours e of the
i nfecti on.
Subperi os tea l a bs ces s es , i f l a rge enough, ca n contri bute to s ymptoms of orbi ta l cel l ul i ti s s uch a s s wel l i ng a nd rednes s of the eyel i d, decrea s ed
ocul a r moti l i ty, proptos i s , a nd decrea s ed vi s ua l a cui ty.
Diagnosis
CT or MRI i f orbi ta l cel l ul i ti s i s pos s i bl e
Di a gnos i s i s s us pected cl i ni ca l l y. Other di s orders to cons i der i ncl ude tra uma , i ns ect or a ni ma l bi tes wi thout cel l ul i ti s , reta i ned forei gn bodi es ,
a l l ergi c rea cti ons , tumors , a nd i nfl a mma tory orbi ta l ps eudotumor.
Eyel i d s wel l i ng ma y requi re the us e of l i d retra ctors for eva l ua ti on of the gl obe, a nd i ni ti a l s i gns of compl i ca ted i nfecti on ma y be s ubtl e. An
ophtha l mol ogi s t s houl d be cons ul ted when orbi ta l cel l ul i ti s i s s us pected.
Pres epta l cel l ul i ti s a nd orbi ta l cel l ul i ti s a re often di s ti ngui s ha bl e cl i ni ca l l y. Pres epta l cel l ul i ti s i s l i kel y i f eye fi ndi ngs a re norma l except for
eyel i d s wel l i ng. The pres ence of a l oca l ni dus of i nfecti on on the s ki n ma kes pres epta l cel l ul i ti s even more l i kel y.
If fi ndi ngs a re equi voca l , i f the exa mi na ti on i s di ffi cul t (a s i n young chi l dren), or i f na s a l di s cha rge i s pres ent (s ugges ti ng s i nus i ti s ), CT or MRI
s houl d be done to confi rm orbi ta l cel l ul i ti s , to excl ude tumor a nd ps eudotumor, a nd to di a gnos e s i nus i ti s i f pres ent. MRI i s better tha n CT i f
ca vernous s i nus thrombos i s i s bei ng cons i dered.
The di recti on of proptos i s ma y be a cl ue to the s i te of i nfecti on; eg, extens i on from the fronta l s i nus pus hes the gl obe down a nd out, a nd
extens i on from the ethmoi d s i nus pus hes the gl obe l a tera l l y a nd out.
Bl ood cul tures a re often done (i dea l l y before begi nni ng a nti bi oti cs ) i n pa ti ents wi th orbi ta l cel l ul i ti s but a re pos i ti ve i n l es s tha n one thi rd.
Lumba r puncture i s done i f meni ngi ti s i s s us pected. Cul tures of the pa ra na s a l s i nus fl ui d a re done i f s i nus i ti s i s the s us pected s ource. Other
l a bora tory tes ts a re not pa rti cul a rl y hel pful .
Treatment
Anti bi oti cs
Preseptal cellulitis: Ini ti a l thera py s houl d be di rected a ga i ns t s i nus i ti s pa thogens (S. pneumoniae, nontypa bl e H. influenzae, S. aureus, Moraxella
catarrhalis); however, i n a rea s where methi ci l l i n-res i s ta nt S. aureus i s preva l ent, cl i ni ci a ns s houl d a dd a ppropri a te a nti bi oti cs (eg, cl i nda myci n,
tri methopri m/s ul fa methoxa zol e, or doxycycl i ne for ora l trea tment a nd va ncomyci n for i npa ti ent trea tment). In pa ti ents wi th di rty wounds , gra mnega ti ve i nfecti on mus t be cons i dered.
Outpa ti ent trea tment i s a n opti on i f orbi ta l cel l ul i ti s ha s been defi ni ti vel y excl uded; chi l dren s houl d ha ve no s i gns of s ys temi c i nfecti on a nd
s houl d be i n the ca re of res pons i bl e pa rents or gua rdi a ns . Pa ti ents s houl d be cl os el y fol l owed by a n ophtha l mol ogi s t. Outpa ti ent trea tment
opti ons i ncl ude a moxi ci l l i n/cl a vul a na te 30 mg/kg po q 8 h (for chi l dren < 12 yr) or 500 mg po ti d or 875 mg po bi d (for a dul ts ) for 10 da ys .
For i npa ti ents , a mpi ci l l i n/s ul ba cta m 50 mg/kg IV q 6 h (for chi l dren) or 1.5 to 3 g (for a dul ts ) IV q 6 h (ma xi mum 8 g a mpi ci l l i n/da y) for 7 da ys i s a n
opti on.
Orbital cellulitis: Pa ti ents wi th orbi ta l cel l ul i ti s s houl d be hos pi ta l i zed a nd trea ted wi th meni ngi ti s -dos e a nti bi oti cs . A 2nd- or 3rd-genera ti on
cepha l os pori n, s uch a s cefota xi me 50 mg/kg IV q 6 h (for chi l dren < 12 yr) or 1 to 2 g IV q 6 h (for a dul ts ) for 14 da ys , i s a n opti on when s i nus i ti s i s
pres ent; i mi penem, ceftri a xone, a nd pi pera ci l l i n/ta zoba cta m a re other opti ons . If cel l ul i ti s i s rel a ted to tra uma or forei gn body, trea tment s houl d
cover gra m-pos i ti ve (va ncomyci n 1 g IV q 12 h) a nd gra m-nega ti ve (eg, erta penem 100 mg IV once/da y) pa thogens a nd be ta ken for 7 to 10 da ys or
unti l cl i ni ca l i mprovement.
Surgery to decompres s the orbi t, dra i n a n a bs ces s , open i nfected s i nus es , or a combi na ti on i s i ndi ca ted i n a ny of the fol l owi ng ci rcums ta nces :
Vi s i on i s compromi s ed.
Suppura ti on or forei gn body i s s us pected.
Ima gi ng s hows orbi ta l or l a rge s ubperi os tea l a bs ces s .
The i nfecti on does not res ol ve wi th a nti bi oti cs .
Tumors of the Orbit
Orbital tumors can be benign or malignant and arise primarily within the orbit or secondarily from an adjacent source, such as the eyelid, paranasal sinus, or
intracranial compartment.
Ca us es di ffer by a ge group. The more common beni gn pedi a tri c tumors i ncl ude dermoi d tumors a nd va s cul a r l es i ons s uch a s ca pi l l a ry
hema ngi oma a nd l ympha ngi oma . In a dul ts , ca vernous hema ngi oma s predomi na te.
Some orbi ta l tumors us ua l l y ca us e proptos i s a nd di s pl a cement of the gl obe i n a di recti on oppos i te the tumor. Pa i n, di pl opi a , a nd vi s i on l os s ma y
a l s o be pres ent. Di a gnos i s , i n mos t ca s es , i s ba s ed on the hi s tory, exa mi na ti on, a nd neuroi ma gi ng (CT, MRI, or both).
Treatment
Trea tment va ri es by tumor type. Trea tment of dermoi d tumors i s exci s i on. Ca pi l l a ry hema ngi oma s tend to s ponta neous l y i nvol ute a nd therefore do
not need a ny trea tment; however, es peci a l l y when l oca ted on the upper eyel i d, they ma y a ffect vi s i on a nd requi re trea tment wi th i nterl es i ona l
i njecti on of corti cos teroi ds or s urgi ca l debul ki ng.
Children: The common pedi a tri c ma l i gna nt tumors i ncl ude rha bdomyos a rcoma a nd meta s ta ti c l es i ons rel a ted to l eukemi a or neurobl a s toma . If
rha bdomyos a rcoma i s res ecta bl e, s urgery i s done, fol l owed by chemothera py a nd orbi ta l ra di a ti on thera py. Leukemi c di s ea s e i s us ua l l y ma na ged
by orbi ta l ra di a ti on thera py, chemothera py, or both.
Adults: The mos t common beni gn tumors a re meni ngi oma s , mucocel es , a nd ca vernous hema ngi oma s . When s ymptoma ti c, s phenoi d wi ng
meni ngi oma s a re trea ted wi th debul ki ng vi a cra ni otomy, s ometi mes fol l owed by a cours e of ra di a ti on thera py. Beca us e meni ngi oma cel l s
i nfi l tra te bone of the s kul l ba s e, compl ete res ecti on us ua l l y i s not pos s i bl e. Mucocel es a re trea ted by dra i ni ng them i nto the nos e beca us e they
mos t commonl y a ri s e from the ethmoi d or fronta l s i nus . Ca vernous hema ngi oma s a re exci s ed.
Common ma l i gna nt tumors i ncl ude l ymphoma , s qua mous cel l ca rci noma , a nd meta s ta ti c di s ea s e. Lymphoma s i nvol vi ng the orbi t a re typi ca l l y Bcel l a nd cha ra cteri s ti ca l l y l ow gra de. Lymphoma s ca n be bi l a tera l a nd s i mul ta neous a nd ca n be pa rt of a s ys temi c proces s or exi s t i n the orbi t i n
i s ol a ti on. Ra di a ti on thera py effecti vel y trea ts orbi ta l l ymphoma s wi th few a dvers e effects , a l though the a ddi ti on of monocl ona l a nti bodi es
a ga i ns t a s urfa ce receptor (CD20) on the l ymphocyte i s a l s o effecti ve. Mos t s qua mous cel l ca rci noma s a ri s e from the a dja cent pa ra na s a l s i nus es .
Surgery, ra di a ti on thera py, or both form the ba ckbone of thera py. Meta s ta ti c di s ea s e i s us ua l l y trea ted wi th ra di a ti on thera py. Meta s ta ti c di s ea s e
i nvol vi ng the orbi t i s us ua l l y a n unfa vora bl e prognos ti c s i gn; ca rci noi d tumors a re a nota bl e excepti on.
7 - Dermatologic Disorders
Chapter 71. Approach to the Dermatologic Patient
Introduction
Hi s tory a nd phys i ca l exa mi na ti on a re a dequa te for di a gnos i ng ma ny s ki n l es i ons . Some requi re bi ops y or other tes ti ng.
Importa nt i nforma ti on to obta i n from hi s tory i ncl udes
Pers ona l or fa mi l y hi s tory of a topy (s ugges ti ng a topi c derma ti ti s )
Occupa ti ona l expos ures (conta ct derma ti ti s )
Long-term expos ure to s unl i ght or other forms of ra di a ti on (beni gn a nd ma l i gna nt s ki n tumors )
Sys temi c di s ea s e (di a betes a nd Candida or ti nea , hepa ti ti s C a nd cryogl obul i nemi a )
Sexua l hi s tory (s yphi l i s a nd gonorrhea )
Us e of drugs (Stevens -Johns on s yndrome, toxi c epi derma l necrol ys i s )
Tra vel hi s tory (Lyme di s ea s e, s ki n i nfecti ons )
A nega ti ve hi s tory i s a s i mporta nt a s a pos i ti ve hi s tory. The hi s tory of the pa rti cul a r s ki n l es i ons i s a l s o i mporta nt, i ncl udi ng ti me a nd s i te of
i ni ti a l a ppea ra nce, s prea d, cha nge i n a ppea ra nce, a nd tri ggeri ng fa ctors .
Vi s ua l i ns pecti on i s the centra l eva l ua ti on tool ; ma ny s ki n di s orders a re di a gnos ed by the cha ra cteri s ti c a ppea ra nce or morphol ogy of the l es i ons .
Description of Skin Lesions
An extens i ve l a ngua ge ha s been devel oped to s ta nda rdi ze the des cri pti on of s ki n l es i ons , i ncl udi ng
Pri ma ry morphol ogy (l es i on type)
Seconda ry morphol ogy (confi gura ti on)
Texture
Di s tri buti on
Col or
Ra s h i s a genera l term for a tempora ry s ki n erupti on.
Primary Morphology
Macules a re fl a t, nonpa l pa bl e l es i ons us ua l l y < 10 mm i n di a meter. Ma cul es repres ent a cha nge i n col or a nd a re not ra i s ed or depres s ed
compa red to the s ki n s urfa ce. A pa tch i s a l a rge ma cul e. Exa mpl es i ncl ude freckl es , fl a t mol es , ta ttoos , port-wi ne s ta i ns , a nd the ra s hes of
ri cketts i a l i nfecti ons , rubel l a , mea s l es , a nd s ome a l l ergi c drug erupti ons .
Papules a re el eva ted l es i ons us ua l l y < 10 mm i n di a meter tha t ca n be fel t or pa l pa ted. Exa mpl es i ncl ude nevi , wa rts , l i chen pl a nus , i ns ect bi tes ,
s eborrhei c a nd a cti ni c kera tos es , s ome l es i ons of a cne, a nd s ki n ca ncers . The term ma cul opa pul a r i s often l oos el y a nd i mproperl y us ed to
des cri be ma ny red s ki n ra s hes ; beca us e thi s term i s nons peci fi c a nd ea s i l y mi s us ed, i t s houl d be a voi ded.
Plaques a re pa l pa bl e l es i ons > 10 mm i n di a meter tha t a re el eva ted or depres s ed compa red to the s ki n s urfa ce. Pl a ques ma y be fl a t topped or
rounded. Les i ons of ps ori a s i s a nd gra nul oma a nnul a re commonl y form pl a ques .
Nodules a re fi rm pa pul es or l es i ons tha t extend i nto the dermi s or s ubcuta neous ti s s ue. Exa mpl es i ncl ude cys ts , l i poma s , a nd fi broma s .
Vesicles a re s ma l l , cl ea r, fl ui d-fi l l ed bl i s ters < 10 mm i n di a meter. Ves i cl es a re cha ra cteri s ti c of herpes i nfecti ons , a cute a l l ergi c conta ct derma ti ti s ,
a nd s ome a utoi mmune bl i s teri ng di s orders (eg, derma ti ti s herpeti formi s ).
Bullae a re cl ea r fl ui d-fi l l ed bl i s ters > 10 mm i n di a meter. Thes e ma y be ca us ed by burns , bi tes , i rri ta nt or a l l ergi c conta ct derma ti ti s , a nd drug
rea cti ons . Cl a s s i c a utoi mmune bul l ous di s ea s es i ncl ude pemphi gus vul ga ri s a nd bul l ous pemphi goi d. Bul l a e a l s o ma y occur i n i nheri ted
di s orders of s ki n fra gi l i ty.
Pustules a re ves i cl es tha t conta i n pus . Pus tul es a re common i n ba cteri a l i nfecti ons a nd fol l i cul i ti s a nd ma y a ri s e i n s ome i nfl a mma tory di s orders
i ncl udi ng pus tul a r ps ori a s i s .
Urticaria (whea l s or hi ves s ee
Pl a te 53) i s cha ra cteri zed by el eva ted l es i ons ca us ed by l oca l i zed edema . Whea l s a re a common ma ni fes ta ti on of hypers ens i ti vi ty to drugs , s ti ngs
or bi tes , a utoi mmuni ty, a nd, l es s commonl y, phys i ca l s ti mul i i ncl udi ng tempera ture, pres s ure, a nd s unl i ght. The typi ca l whea l l a s ts < 24 h.
Scales a re hea ped-up a ccumul a ti ons of horny epi thel i um tha t occur i n di s orders s uch a s ps ori a s i s , s eborrhei c derma ti ti s , a nd funga l i nfecti ons .
Pi tyri a s i s ros ea a nd chroni c derma ti ti s of a ny type ma y be s ca l y.

Crusts (scabs) cons i s t of dri ed s erum, bl ood, or pus . Crus ti ng ca n occur i n i nfl a mma tory or i nfecti ous s ki n di s ea s es (eg, i mpeti go).
Erosions a re open a rea s of s ki n tha t res ul t from l os s of pa rt or a l l of the epi dermi s . Eros i ons ca n be tra uma ti c or ca n occur wi th va ri ous
i nfl a mma tory or i nfecti ous s ki n di s ea s es . An excori a ti on i s a l i nea r eros i on ca us ed by s cra tchi ng, rubbi ng, or pi cki ng.
Ulcers res ul t from l os s of the epi dermi s a nd a t l ea s t pa rt of the dermi s . Ca us es i ncl ude venous s ta s i s derma ti ti s , phys i ca l tra uma wi th or wi thout
va s cul a r compromi s e (eg, from decubi tus ul cers , peri phera l a rteri a l di s ea s e), i nfecti ons , a nd va s cul i ti s .
Petechiae a re nonbl a ncha bl e puncta te foci of hemorrha ge. Ca us es i ncl ude pl a tel et a bnorma l i ti es (eg, thrombocytopeni a , pl a tel et dys functi on),
va s cul i ti s , a nd i nfecti ons (eg, meni ngococcemi a , Rocky Mounta i n s potted fever, other ri cketts i os es ).
Purpura i s a l a rger a rea of hemorrha ge tha t ma y be pa l pa bl e. Pa l pa bl e purpura i s cons i dered the ha l l ma rk of l eukocytocl a s ti c va s cul i ti s . Purpura
ma y i ndi ca te a coa gul opa thy. La rge a rea s of purpura ma y be ca l l ed ecchymos es or, col l oqui a l l y, brui s es .
Atrophy i s thi nni ng of the s ki n, whi ch ma y a ppea r dry a nd wri nkl ed, res embl i ng ci ga rette pa per. Atrophy ma y be ca us ed by chroni c s un expos ure,
a gi ng, a nd s ome i nfl a mma tory a nd neopl a s ti c s ki n di s ea s es , i ncl udi ng cuta neous T-cel l l ymphoma a nd l upus erythema tos us . Atrophy a l s o ma y
res ul t from l ong-term us e of potent topi ca l corti cos teroi ds .
Scars a re a rea s of fi bros i s tha t repl a ce norma l s ki n a fter i njury. Some s ca rs become hypertrophi c or thi ckened a nd ra i s ed. Kel oi ds a re hypertrophi c
s ca rs tha t extend beyond the ori gi na l wound ma rgi n.
Telangiectases a re foci of s ma l l , perma nentl y di l a ted bl ood ves s el s tha t a re mos t often i di opa thi c but ma y occur i n ros a cea , s ys temi c di s ea s es
(es peci a l l y s ys temi c s cl eros i s ), or i nheri ted di s ea s es (eg, a ta xi a -tel a ngi ecta s i a , heredi ta ry hemorrha gi c tel a ngi ecta s i a ) or a fter l ong-term thera py
wi th topi ca l fl uori na ted corti cos teroi ds .
Secondary Morphology (Configuration)
Confi gura ti on i s the s ha pe of s i ngl e l es i ons a nd the a rra ngement of cl us ters of l es i ons .
Linear lesions ta ke on the s ha pe of a s tra i ght l i ne a nd a re s ugges ti ve of s ome forms of conta ct derma ti ti s , l i nea r epi derma l nevi , a nd l i chen
s tri a tus .
Annular lesions a re ri ngs wi th centra l cl ea ri ng. Exa mpl es i ncl ude gra nul oma a nnul a re, s ome drug erupti ons , s ome derma tophyte i nfecti ons (eg,
ri ngworm), a nd s econda ry s yphi l i s .
Nummular lesions a re ci rcul a r or coi n-s ha ped; a n exa mpl e i s nummul a r eczema .
Target (bull's-eye or iris) lesions a ppea r a s ri ngs wi th centra l dus ki nes s a nd a re cl a s s i c for erythema mul ti forme.
Serpiginous lesions ha ve l i nea r, bra nched, a nd curvi ng el ements . Exa mpl es i ncl ude s ome funga l a nd pa ra s i ti c i nfecti ons (eg, cuta neous l a rva
mi gra ns ).
Reticulated lesions ha ve a l a cy or networked pa ttern. Exa mpl es i ncl ude cuti s ma rmora ta a nd l i vedo reti cul a ri s .
Herpetiform des cri bes grouped pa pul es or ves i cl es a rra nged l i ke thos e of a herpes s i mpl ex i nfecti on.
Zosteriform des cri bes l es i ons cl us tered i n a derma toma l di s tri buti on s i mi l a r to herpes zos ter.
Texture
Some s ki n l es i ons ha ve vi s i bl e or pa l pa bl e texture tha t s ugges ts a di a gnos i s .
Verrucous lesions ha ve a n i rregul a r, pebbl y, or rough s urfa ce. Exa mpl es i ncl ude wa rts a nd s eborrhei c kera tos es .
Lichenification i s thi ckeni ng of the s ki n wi th a ccentua ti on of norma l s ki n ma rki ngs ; i t res ul ts from repea ted rubbi ng.
Induration, or deep thi ckeni ng of the s ki n, ca n res ul t from edema , i nfl a mma ti on, or i nfi l tra ti on, i ncl udi ng by ca ncer. Indura ted s ki n ha s a ha rd,
res i s ta nt feel i ng. Indura ti on i s cha ra cteri s ti c of pa nni cul i ti s , s ome s ki n i nfecti ons , a nd cuta neous meta s ta ti c ca ncers .
Umbilicated lesions ha ve a centra l i ndenta ti on a nd a re us ua l l y vi ra l . Exa mpl es i ncl ude mol l us cum conta gi os um a nd herpes s i mpl ex.
Xanthomas, whi ch a re yel l owi s h, wa xy l es i ons , ma y occur i n l i pi d di s orders .
Location and Distribution
It i s i mporta nt to note whether
Les i ons a re s i ngl e or mul ti pl e
Pa rti cul a r body pa rts a re a ffected (eg, pa l ms or s ol es , s ca l p, mucos a l membra nes )
Di s tri buti on i s ra ndom or pa tterned, s ymmetri c or a s ymmetri c
Les i ons a re on s un-expos ed or protected s ki n

Al though few pa tterns a re pa thognomoni c, s ome a re cons i s tent wi th certa i n di s ea s es .
Psoriasis frequentl y a ffects the s ca l p, extens or s urfa ces of the el bows a nd knees , umbi l i cus , a nd the gl utea l cl eft.
Lichen planus frequentl y a ri s es on the wri s ts , forea rms , geni ta l s , a nd l ower l egs .
Vitiligo ma y be pa tchy a nd i s ol a ted or ma y group a round the di s ta l extremi ti es a nd fa ce.
Chronic cutaneous lupus erythematosus ha s cha ra cteri s ti c l es i ons on s un-expos ed s ki n of the fa ce, es peci a l l y the forehea d, nos e, a nd the concha l
bowl of the ea r.
Hidradenitis suppurativa i nvol ves s ki n conta i ni ng a hi gh dens i ty of a pocri ne gl a nds , i ncl udi ng the a xi l l a e, groi n, a nd under the brea s ts .
Color
Red skin (erythema ) ca n res ul t from ma ny di fferent i nfl a mma tory or i nfecti ous di s ea s es . Cuta neous tumors a re often pi nk or red. Superfi ci a l
va s cul a r l es i ons s uch a s port-wi ne s ta i ns ma y a ppea r red.
Orange skin i s mos t often s een i n hyperca rotenemi a , a us ua l l y beni gn condi ti on of ca rotene depos i ti on a fter exces s di eta ry i nges ti on of ca rotene.
Yellow skin i s typi ca l of ja undi ce, xa nthel a s ma s a nd xa nthoma s , a nd ps eudoxa nthoma el a s ti cum.
Green fingernails s ugges t Pseudomonas aeruginosa i nfecti on.
Violet skin ma y res ul t from cuta neous hemorrha ge or va s cul i ti s . Va s cul a r l es i ons or tumors , s uch a s Ka pos i 's s a rcoma a nd hema ngi oma s , ca n
a ppea r purpl e. A l i l a c col or of the eyel i ds or hel i otrope erupti on i s cha ra cteri s ti c of derma tomyos i ti s .
Shades of blue, silver, and gray ca n res ul t from depos i ti on of drugs or meta l s i n the s ki n, i ncl udi ng mi nocycl i ne, a mi oda rone, a nd s i l ver (a rgyri a ).
Is chemi c s ki n a ppea rs purpl e to gra y i n col or. Deep derma l nevi a ppea r bl ue.
Black skin l es i ons ma y be mel a nocyti c, i ncl udi ng nevi a nd mel a noma . Bl a ck es cha rs a re col l ecti ons of dea d s ki n tha t ca n a ri s e from va s cul a r
i nfa rcti on, whi ch ma y be ca us ed by i nfecti on (eg, a nthra x, a ngi oi nva s i ve fungi i ncl udi ng Rhizopus, meni ngococcemi a ), ca l ci phyl a xi s , a rteri a l
i ns uffi ci ency, or va s cul i ti s .
Other Clinical Signs
Dermatographism i s the a ppea ra nce of a n urti ca ri a l whea l a fter foca l pres s ure (eg, s troki ng or s cra tchi ng the s ki n) i n the di s tri buti on of the
pres s ure. Up to 5% of norma l pa ti ents ma y exhi bi t thi s s i gn, whi ch i s a form of phys i ca l urti ca ri a .
Darier's sign refers to ra pi d s wel l i ng of a l es i on when s troked. It occurs i n pa ti ents wi th urti ca ri a pi gmentos a or ma s tocytos i s .
Nikolsky's sign i s epi derma l s hea ri ng tha t occurs wi th gentl e l a tera l pres s ure on s eemi ngl y uni nvol ved s ki n i n pa ti ents wi th toxi c epi derma l
necrol ys i s a nd s ome a utoi mmune bul l ous di s ea s es .
Auspitz sign i s the a ppea ra nce of pi npoi nt bl eedi ng a fter s ca l e i s removed from pl a ques i n ps ori a s i s .
Koebner phenomenon des cri bes the devel opment of l es i ons wi thi n a rea s of tra uma (eg, ca us ed by s cra tchi ng, rubbi ng, i njury). Ps ori a s i s frequentl y
exhi bi ts thi s phenomenon, a s ma y l i chen pl a nus .
Diagnostic Tests
Di a gnos ti c tes ts a re i ndi ca ted when the ca us e of a s ki n l es i on or di s ea s e i s not obvi ous from hi s tory a nd phys i ca l exa mi na ti on a l one (for pa tch
tes ti ng, s ee p.
667).
Biopsy: A s ki n bi ops y ca n be done by a pri ma ry ca re phys i ci a n. One procedure i s a punch bi ops y, i n whi ch a tubul a r punch (di a meter us ua l l y 4 mm)
i s i ns erted i nto deep derma l or s ubcuta neous ti s s ue to obta i n a s peci men, whi ch i s s ni pped off a t i ts ba s e. More s uperfi ci a l l es i ons ma y be
bi ops i ed by s ha vi ng wi th a s ca l pel or ra zor bl a de. Bl eedi ng i s control l ed by a l umi num chl ori de s ol uti on or el ectrodes i cca ti on; l a rge i nci s i ons a re
cl os ed by s utures . La rger or deeper bi ops i es ca n be done by exci s i ng a wedge of s ki n wi th a s ca l pel . Al l pi gmented l es i ons s houl d be exci s ed
deepl y for hi s tol ogi c eva l ua ti on of depth; s uperfi ci a l bi ops i es a re often i na dequa te. Di a gnos i s a nd cure a re a chi eved s i mul ta neous l y for mos t
s ma l l tumors by compl ete exci s i on tha t i ncl udes a s ma l l border of norma l s ki n.
Scrapings: Ski n s cra pi ngs hel p di a gnos e funga l i nfecti ons a nd s ca bi es . For funga l i nfecti on, s ca l es a re ta ken from the border of the l es i on a nd
pl a ced onto a mi cros cope s l i de. Then a drop of 10 to 20% pota s s i um hydroxi de (KOH) i s a dded. Hypha e, buddi ng yea s t, or both confi rm the
di a gnos i s of ti nea or ca ndi di a s i s . For s ca bi es , s cra pi ngs a re ta ken from s us pected burrows a nd pl a ced di rectl y under a covers l i p wi th mi nera l oi l ;
fi ndi ngs of mi tes , feces , or eggs confi rm the di a gnos i s .
Wood's light: Wood's l i ght (bl a ck l i ght) ca n hel p di s ti ngui s h hypopi gmenta ti on from depi gmenta ti on (depi gmenta ti on of vi ti l i go fl uores ces i vorywhi te a nd hypopi gmented l es i ons do not). Erythra s ma fl uores ces bri ght ora ngered. Ti nea ca pi ti s ca us ed by Microsporum canis a nd Microsporum
audouinii fl uores ces a l i ght, bri ght green. (NOTE: Mos t ti nea ca pi ti s i n the US i s ca us ed by Trichophyton s peci es , whi ch do not fl uores ce.) The ea rl i es t
cl ue to cuta neous Pseudomonas i nfecti on (eg, i n burns ) ma y be green fl uores cence.

Tzanck testing: Tza nck tes ti ng ca n be us ed to di a gnos e vi ra l di s ea s e, s uch a s herpes s i mpl ex a nd herpes zos ter, a nd i s done when a cti ve i nta ct
ves i cl es a re pres ent. Tza nck tes ti ng ca nnot di s ti ngui s h between herpes s i mpl ex a nd herpes zos ter i nfecti ons . An i nta ct bl i s ter i s the preferred
l es i on for exa mi na ti on. The bl i s ter roof i s removed wi th a s ha rp bl a de, a nd the ba s e of the unroofed ves i cl e i s s cra ped wi th a #15 s ca l pel bl a de.
The s cra pi ngs a re tra ns ferred to a s l i de a nd s ta i ned wi th Wri ght's s ta i n or Gi ems a s ta i n. Mul ti nucl ea ted gi a nt cel l s a re a s i gn of herpes i nfecti on.
Diascopy: Di a s copy i s us ed to determi ne whether a l es i on i s va s cul a r (i nfl a mma tory) or nonva s cul a r (nevus ) or hemorrha gi c (petechi a or purpura ).
A mi cros cope s l i de i s pres s ed a ga i ns t a l es i on to s ee whether i t bl a nches . Hemorrha gi c l es i ons a nd nonva s cul a r l es i ons do not bl a nch;
i nfl a mma tory l es i ons do. Di a s copy i s s ometi mes us ed to i denti fy s a rcoi d s ki n l es i ons , whi ch, when tes ted, turn a n a ppl e jel l y col or.
Itching
(Pruri tus )
Itchi ng i s a s ymptom tha t ca n ca us e s i gni fi ca nt di s comfort a nd i s one of the mos t common rea s ons for cons ul ta ti on wi th a derma tol ogi s t. Itchi ng
l ea ds to s cra tchi ng, whi ch ca n ca us e i nfl a mma ti on, s ki n degra da ti on, a nd pos s i bl e s econda ry i nfecti on. The s ki n ca n become l i cheni fi ed, s ca l y,
a nd excori a ted.
Pathophysiology
Itch ca n be prompted by di vers e s ti mul i , i ncl udi ng l i ght touch, vi bra ti on, a nd wool fi bers . There a re a number of chemi ca l medi a tors a s wel l a s
di fferent mecha ni s ms by whi ch the s ens a ti on of i tch occurs .
Mediators: Hi s ta mi ne i s one of the mos t s i gni fi ca nt medi a tors . It i s s ynthes i zed a nd s tored i n ma s t cel l s i n the s ki n a nd i s rel ea s ed i n res pons e to
va ri ous s ti mul i . Other medi a tors (eg, neuropepti des ) ca n ei ther ca us e the rel ea s e of hi s ta mi ne or a ct a s pruri togens thems el ves , thus expl a i ni ng
why a nti hi s ta mi nes a mel i ora te s ome ca s es of i tchi ng a nd not others . Opi oi ds ha ve a centra l pruri ti c a cti on a s wel l a s s ti mul a ti ng the peri phera l l y
medi a ted hi s ta mi ne i tch.
Mechanisms: There a re 4 mecha ni s ms of i tch:
Derma tol ogi ctypi ca l l y ca us ed by i nfl a mma tory or pa thol ogi c proces s es (eg, urti ca ri a , eczema )
Sys temi crel a ted to di s ea s es of orga ns other tha n s ki n (eg, chol es ta s i s )
Neuropa thi crel a ted to di s orders of the CNS or peri phera l nervous s ys tem (eg, mul ti pl e s cl eros i s )
Ps ychogeni crel a ted to ps ychi a tri c condi ti ons
Intens e i tchi ng s ti mul a tes vi gorous s cra tchi ng, whi ch i n turn ca n ca us e s econda ry s ki n condi ti ons (eg, i nfl a mma ti on, excori a ti on, i nfecti on), whi ch
ca n l ea d to more i tchi ng. However, s cra tch ca n tempora ri l y reduce the s ens a ti on of i tch by a cti va ti ng i nhi bi tory neurona l ci rcui ts .
Etiology
Itchi ng ca n be a s ymptom of a pri ma ry s ki n di s ea s e or, l es s commonl y, a s ys temi c di s ea s e (s ee
Ta bl e 71-1).
[Table 71-1. Some Ca us es of Itchi ng]
Skin disorders: Ma ny s ki n di s orders ca us e i tchi ng. The mos t common i ncl ude
Dry s ki n
Atopi c derma ti ti s (eczema )
Conta ct derma ti ti s
Funga l s ki n i nfecti ons
Systemic disorders: In s ys temi c di s orders , i tchi ng ma y occur wi th or wi thout s ki n l es i ons . However, when i tchi ng i s promi nent wi thout a ny
i denti fi a bl e s ki n l es i ons , s ys temi c di s orders a nd drugs s houl d be cons i dered more s trongl y. Sys temi c di s orders a re l es s often a ca us e of i tchi ng
tha n s ki n di s orders , but s ome of the more common ca us es i ncl ude
Al l ergi c rea cti on (eg, to foods , drugs , bi tes a nd s ti ngs )
Chol es ta s i s
Chroni c rena l fa i l ure
Les s common s ys temi c ca us es of i tchi ng i ncl ude hyperthyroi di s m, hypothyroi di s m, di a betes , i ron defi ci ency, derma ti ti s herpeti formi s , a nd
pol ycythemi a vera .
Drugs: Drugs ca n ca us e i tchi ng a s a n a l l ergi c rea cti on or by di rectl y tri ggeri ng hi s ta mi ne rel ea s e (mos t commonl y morphi ne, s ome IV contra s t
a gents ).
Evaluation
History: History of present illness s houl d determi ne ons et of i tchi ng, i ni ti a l l oca ti on, cours e, dura ti on, pa tterns of i tchi ng (eg, nocturna l or di urna l ,
i ntermi ttent or pers i s tent, s ea s ona l va ri a ti on), a nd whether a ny ra s h i s pres ent. A ca reful drug hi s tory s houl d be obta i ned; both ora l (eg, opi oi ds ,
coca i ne, a s pi ri n, pres cri pti on a nd OTC) a nd topi ca l (eg, hydrocorti s one, bena dryl , moi s turi zers ) drugs a re i ncl uded. Hi s tory a l s o s houl d i ncl ude a ny
fa ctors tha t ma ke the i tchi ng better or wors e.
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng s tea torrhea a nd ri ght upper qua dra nt pa i n (chol es ta s i s ); cons ti tuti ona l
s ymptoms of fever, wei ght l os s , a nd ni ght s wea ts (ca ncer); i ntermi ttent wea knes s , numbnes s , ti ngl i ng, a nd vi s ua l di s turba nces or l os s (mul ti pl e
s cl eros i s ); i rri ta bi l i ty, s wea ti ng, wei ght l os s , a nd pa l pi ta ti ons (hyperthyroi di s m) or depres s i on, dry s ki n, a nd wei ght ga i n (hypothyroi di s m); uri na ry
frequency, exces s i ve thi rs t, a nd wei ght l os s (di a betes ); a nd hea da che, pi ca , ha i r thi nni ng, a nd exerci s e i ntol era nce (i ron defi ci ency a nemi a ).
Past medical history s houl d i denti fy known ca us a ti ve di s orders (eg, rena l di s ea s e, chol es ta ti c di s order, ca ncer bei ng trea ted wi th chemothera py)
a nd the pa ti ent's emoti ona l s ta te. Soci a l hi s tory s houl d focus on fa mi l y members wi th s i mi l a r i tchi ng a nd s ki n s ymptoms (eg, s ca bi es ,
pedi cul os i s ); rel a ti ons hi p of i tchi ng to occupa ti on or expos ures to pl a nts , a ni ma l s , or chemi ca l s ; a nd hi s tory of recent tra vel .
Physical examination: Phys i ca l exa mi na ti on begi ns wi th a revi ew of cl i ni ca l a ppea ra nce for s i gns of ja undi ce, wei ght l os s or ga i n, a nd fa ti gue. Cl os e
exa mi na ti on of the s ki n s houl d be done, ta ki ng note of pres ence, morphol ogy, extent, a nd di s tri buti on of l es i ons . Cuta neous exa mi na ti on a l s o
s houl d ma ke note of s i gns of s econda ry i nfecti on (eg, erythema , s wel l i ng, wa rmth, yel l ow or honey-col ored crus ti ng).
The exa mi na ti on s houl d ma ke note of s i gni fi ca nt a denopa thy s ugges ti ve of ca ncer. Abdomi na l exa mi na ti on s houl d focus on orga nomega l y,
ma s s es , a nd tendernes s (chol es ta ti c di s order or ca ncer). Neurol ogi c exa mi na ti on focus es on wea knes s , s pa s ti ci ty, or numbnes s (mul ti pl e
s cl eros i s ).
Cons ti tuti ona l s ymptoms of wei ght l os s , fa ti gue, a nd ni ght s wea ts
Extremi ty wea knes s , numbnes s , or ti ngl i ng
Abdomi na l pa i n a nd ja undi ce
Uri na ry frequency, exces s i ve thi rs t, a nd wei ght l os s
Interpretation of findings: Genera l i zed i tchi ng tha t begi ns s hortl y a fter us e of a drug i s l i kel y ca us ed by tha t drug. Loca l i zed i tchi ng (often wi th ra s h)
tha t occurs i n the a rea of conta ct wi th a s ubs ta nce i s l i kel y ca us ed by tha t s ubs ta nce. However, ma ny s ys temi c a l l ergi es ca n be di ffi cul t to i denti fy
beca us e pa ti ents typi ca l l y ha ve cons umed mul ti pl e di fferent foods a nd ha ve been i n conta ct wi th ma ny s ubs ta nces before devel opi ng i tchi ng.
Si mi l a rl y, i denti fyi ng a drug ca us e i n a pa ti ent ta ki ng s evera l drugs ma y be di ffi cul t. Someti mes the pa ti ent ha s been ta ki ng the offendi ng drug for
months or even yea rs before devel opi ng a rea cti on.
If a n eti ol ogy i s not i mmedi a tel y obvi ous , the a ppea ra nce a nd l oca ti on of s ki n l es i ons ca n s ugges t a di a gnos i s (s ee Ta bl e 71-1).
In the mi nori ty of pa ti ents i n whom no s ki n l es i ons a re evi dent, a s ys temi c di s order s houl d be cons i dered. Some di s orders tha t ca us e i tchi ng a re
rea di l y a ppa rent on eva l ua ti on (eg, chroni c rena l fa i l ure, chol es ta ti c ja undi ce). Other s ys temi c di s orders tha t ca us e i tchi ng a re s ugges ted by
fi ndi ngs (s ee Ta bl e 71-1). Ra rel y, i tchi ng i s the fi rs t ma ni fes ta ti on of s i gni fi ca nt s ys temi c di s orders (eg, pol ycythemi a vera , certa i n ca ncers ,
hyperthyroi di s m).
Testing: Ma ny derma tol ogi c di s orders a re di a gnos ed cl i ni ca l l y. However, when i tchi ng i s a ccompa ni ed by di s crete s ki n l es i ons of uncerta i n
eti ol ogy, bi ops y ca n be a ppropri a te. When a n a l l ergi c rea cti on i s s us pected but the s ubs ta nce i s unknown, s ki n tes ti ng (ei ther pri ck or pa tch
tes ti ng dependi ng on s us pected eti ol ogy) i s often done. When a s ys temi c di s order i s s us pected, tes ti ng i s di rected by the s us pected ca us e a nd
us ua l l y i nvol ves CBC; l i ver, rena l , a nd thyroi d functi on mea s urements ; a nd a ppropri a te eva l ua ti on for underl yi ng ca ncer.
Treatment
Any underl yi ng di s order i s trea ted. Supporti ve trea tment i nvol ves the fol l owi ng (s ee a l s o
Ta bl e 71-2):
Loca l s ki n ca re
Topi ca l trea tment
Sys temi c trea tment
Skin care: Itchi ng due to a ny ca us e benefi ts from us e of cool or l ukewa rm (but not hot) wa ter when ba thi ng, mi l d or moi s turi zi ng s oa p, l i mi ted
ba thi ng dura ti on a nd frequency, frequent l ubri ca ti on, humi di fi ca ti on of dry a i r, a nd a voi da nce of i rri ta ti ng or ti ght cl othi ng. Avoi da nce of conta ct
i rri ta nts (eg, wool cl othi ng) a l s o ma y be hel pful .
Topical drugs: Topi ca l drugs ma y hel p l oca l i zed i tchi ng. Opti ons i ncl ude l oti ons or crea ms tha t conta i n ca mphor a nd/or menthol , pra moxi ne, or
corti cos teroi ds . Corti cos teroi ds a re effecti ve i n rel i evi ng i tch ca us ed by i nfl a mma ti on but s houl d be a voi ded for condi ti ons tha t ha ve no evi dence
of i nfl a mma ti on. Topi ca l di phenhydra mi ne a nd doxepi n s houl d be a voi ded beca us e they ma y s ens i ti ze the s ki n.
Systemic drugs: Sys temi c drugs a re i ndi ca ted for genera l i zed i tchi ng or l oca l i tchi ng res i s ta nt to topi ca l a gents . Anti hi s ta mi nes , mos t nota bl y
hydroxyzi ne, a re effecti ve, es peci a l l y for nocturna l i tch, a nd a re mos t commonl y us ed. Seda ti ng a nti hi s ta mi nes mus t be us ed ca uti ous l y i n el derl y
pa ti ents duri ng the da y beca us e they ca n l ea d to fa l l s ; newer nons eda ti ng a nti hi s ta mi nes s uch a s l ora ta di ne, fexofena di ne, a nd ceti ri zi ne ca n be
us eful for da yti me i tchi ng. Other drugs i ncl ude doxepi n (typi ca l l y ta ken a t ni ght due to hi gh l evel of s eda ti on), chol es tyra mi ne (for rena l fa i l ure,
chol es ta s i s , pol ycythemi a vera ), opi oi d a nta goni s ts s uch a s na l trexone (for bi l i a ry pruri tus ), a nd pos s i bl y ga ba penti n (for uremi c pruri tus ).
Phys i ca l a gents tha t ma y be effecti ve for i tchi ng i ncl ude ul tra vi ol et photothera py.
Xeroti c eczema i s very common a mong el derl y pa ti ents . It i s es peci a l l y l i kel y i f i tchi ng i s pri ma ri l y on the l ower extremi ti es .
Severe, di ffus e i tchi ng i n the el derl y s houl d ra i s e concern for ca ncer, es peci a l l y i f a nother eti ol ogy i s not i mmedi a tel y a ppa rent.
When trea ti ng the el derl y, s eda ti on ca n be a s i gni fi ca nt probl em wi th a nti hi s ta mi nes . Us e of nons eda ti ng a nti hi s ta mi nes duri ng the da y a nd
s eda ti ng a nti hi s ta mi nes a t ni ght, l i bera l us e of topi ca l oi ntments a nd corti cos teroi ds (when a ppropri a te), a nd cons i dera ti on of ul tra vi ol et
photothera py ca n hel p a voi d the compl i ca ti ons of s eda ti on.
Key Points
Itchi ng i s us ua l l y a s ymptom of a s ki n di s order or s ys temi c a l l ergi c rea cti on but ca n res ul t from a s ys temi c di s order.
If s ki n l es i ons a re not evi dent, s ys temi c ca us es s houl d be i nves ti ga ted.
Ski n ca re (eg, l i mi ti ng ba thi ng, a voi di ng i rri ta nts , moi s turi zi ng regul a rl y, humi di fyi ng envi ronment) s houl d be obs erved.
Symptoms ca n be rel i eved by topi ca l or s ys temi c drugs .
Urticaria
(Hi ves ; Whea l s )
Urti ca ri a i s mi gra tory, wel l -ci rcums cri bed, erythema tous , pruri ti c pl a ques on the s ki n (s ee Pl a te 53).
Urti ca ri a a l s o ma y be a ccompa ni ed by a ngi oedema , whi ch res ul ts from ma s t cel l a nd ba s ophi l a cti va ti on i n the deeper dermi s a nd s ubcuta neous
ti s s ues a nd ma ni fes ts a s edema of the fa ce a nd l i ps , extremi ti es , or geni ta l s . Angi oedema ca n be l i fe-threa teni ng i f a i rwa y obs tructi on occurs
beca us e of l a ryngea l edema or tongue s wel l i ng.
Pathophysiology
Urti ca ri a res ul ts from the rel ea s e of hi s ta mi ne, bra dyki ni n, ka l l i krei n, a nd other va s oa cti ve s ubs ta nces from ma s t cel l s a nd ba s ophi l s i n the
s uperfi ci a l dermi s , res ul ti ng i n i ntra derma l edema ca us ed by ca pi l l a ry a nd venous va s odi l a ti on a nd occa s i ona l l y ca us ed by l eukocyte i nfi l tra ti on.
The proces s ca n be i mmune medi a ted or noni mmune medi a ted.
Immune-mediated mast cell activation i ncl udes
Type I hypers ens i ti vi ty rea cti ons , i n whi ch a l l ergen-bound IgE a nti bodi es bi nd to hi gh-a ffi ni ty cel l s urfa ce receptors on ma s t cel l s a nd ba s ophi l s
Autoi mmune di s orders , i n whi ch a nti bodi es to a n IgE receptor functi ona l l y cros s -l i nk IgE receptors a nd ca us e ma s t cel l degra nul a ti on
Nonimmune-mediated mast cell activation i ncl udes
Di rect nona l l ergi c a cti va ti on of ma s t cel l s by certa i n drugs
Drug-i nduced cycl ooxygena s e i nhi bi ti on tha t a cti va tes ma s t cel l s by poorl y unders tood mecha ni s ms
[Table 71-2. Some Thera peuti c Approa ches to Itchi ng]
Acti va ti on by phys i ca l or emoti ona l s ti mul i ; mecha ni s m i s poorl y unders tood but pos s i bl y i nvol ves the rel ea s e of neuropepti des tha t i ntera ct
wi th ma s t cel l s
Etiology
Urti ca ri a i s cl a s s i fi ed a s a cute (< 6 wk) or chroni c (> 6 wk); a cute ca s es (70%) a re more common tha n chroni c (30%).
Acute urticaria (s ee
Ta bl e 71-3) mos t often res ul ts from
Type I hypers ens i ti vi ty rea cti ons
A pres umpti ve tri gger (eg, drug, food i nges ti on, i ns ect s ti ng, i nfecti on) occa s i ona l l y ca n be i denti fi ed.
Chronic urticaria mos t often res ul ts from
Idi opa thi c ca us es
Autoi mmune di s orders

Chroni c urti ca ri a often l a s ts months to yea rs , eventua l l y res ol vi ng wi thout a ca us e bei ng found.
Evaluation
Beca us e there a re no defi ni ti ve di a gnos ti c tes ts for urti ca ri a , eva l ua ti on l a rgel y rel i es on hi s tory a nd phys i ca l exa mi na ti on.
History: History of present illness s houl d i ncl ude a deta i l ed a ccount of the i ndi vi dua l epi s odes of urti ca ri a , i ncl udi ng di s tri buti on, s i ze, a nd
a ppea ra nce of l es i ons ; frequency of occurrence; dura ti on of i ndi vi dua l l es i ons ; a nd a ny pri or epi s odes . Acti vi ti es a nd expos ures duri ng,
i mmedi a tel y before, a nd wi thi n the pa s t 24 h of the a ppea ra nce of urti ca ri a s houl d be noted. Cl i ni ci a ns s peci fi ca l l y s houl d a s k a bout recent
exerci s e; expos ure to potenti a l a l l ergens (s ee Ta bl e 71-3), i ns ects , or a ni ma l s ; new l a undry detergent or s oa ps ; new foods ; recent i nfecti ons ; or
recent s tres s ful l i fe events . The pa ti ent s houl d be a s ked a bout the dura ti on between a ny s us pected tri gger a nd the a ppea ra nce of urti ca ri a a nd
whi ch pa rti cul a r tri ggers a re s us pected. Importa nt a s s oci a ted s ymptoms i ncl ude pruri tus , rhi norrhea , s wel l i ng of the fa ce a nd tongue, a nd
dys pnea .
Review of systems s houl d s eek s ymptoms of ca us a ti ve di s orders , i ncl udi ng fever, fa ti gue, a bdomi na l pa i n, a nd di a rrhea (i nfecti on); hea t or col d
i ntol era nce, tremor, or wei ght cha nge (a utoi mmune thyroi di ti s ); joi nt pa i n (cryogl obul i nemi a , SLE); ma l a r ra s h (SLE); dry eyes a nd dry mouth
(Sjogren's s yndrome); cuta neous ul cers a nd hyperpi gmented l es i ons a fter res ol uti on of urti ca ri a (urti ca ri a l va s cul i ti s ); s ma l l pi gmented pa pul es
(ma s tocytos i s ); l ympha denopa thy (vi ra l i l l nes s , ca ncer, s erum s i cknes s ); a cute or chroni c di a rrhea (vi ra l or pa ra s i ti c enterocol i ti s ); a nd fevers ,
ni ght s wea ts , or wei ght l os s (ca ncer).
Past medical history s houl d i ncl ude a deta i l ed a l l ergy hi s tory, i ncl udi ng known a topi c condi ti ons (eg, a l l ergi es , a s thma , eczema ) a nd known
pos s i bl e ca us es (eg, a utoi mmune di s orders , ca ncer). Al l drug us e s houl d be revi ewed, i ncl udi ng OTC drugs a nd herba l products , s peci fi ca l l y a ny
a gents pa rti cul a rl y a s s oci a ted wi th urti ca ri a (s ee Ta bl e 71-3). Fa mi l y hi s tory s houl d el i ci t a ny hi s tory of rheuma toi d di s ea s e, a utoi mmune
di s orders , or ca ncer. Soci a l hi s tory s houl d cover a ny recent tra vel a nd a ny ri s k fa ctors for tra ns mi s s i on of i nfecti ous di s ea s e (eg, hepa ti ti s , HIV).
Physical examination: Vi ta l s i gns s houl d note the pres ence of bra dyca rdi a or ta chyca rdi a a nd ta chypnea . Genera l exa mi na ti on s houl d i mmedi a tel y
s eek a ny s i gns of res pi ra tory di s tres s a nd a l s o note ca chexi a , ja undi ce, or a gi ta ti on.
Exa mi na ti on of the hea d s houl d note a ny s wel l i ng of the fa ce, l i ps , or tongue; s cl era l i cterus ; ma l a r ra s h; tender a nd enl a rged thyroi d;
l ympha denopa thy; or dry eyes a nd dry mouth. The oropha rynx s houl d be i ns pected a nd the s i nus es s houl d be pa l pa ted a nd tra ns i l l umi na ted for
s i gns of occul t i nfecti on (eg, s i nus i nfecti on, tooth a bs ces s ).
Abdomi na l exa mi na ti on s houl d note a ny ma s s es , hepa tomega l y, s pl enomega l y, or tendernes s . Neurol ogi c exa mi na ti on s houl d note a ny tremor or
hyperrefl exi a or hyporefl exi a . Mus cul os kel eta l exa mi na ti on s houl d note the pres ence of a ny i nfl a med or deformed joi nts .
Ski n exa mi na ti on s houl d note the pres ence a nd di s tri buti on of urti ca ri a l l es i ons a s wel l a s a ny cuta neous ul cera ti on, hyperpi gmenta ti on, s ma l l
pa pul es , or ja undi ce. Urti ca ri a l l es i ons us ua l l y a ppea r a s wel l -dema rca ted tra ns i ent s wel l i ngs i nvol vi ng the dermi s . Thes e s wel l i ngs a re typi ca l l y
red a nd va ry i n s i ze from pi npri ck to coveri ng wi de a rea s . Some l es i ons ca n be very l a rge. In other ca s es , s ma l l er urti ca ri a l l es i ons ma y become
confl uent. However, s ki n l es i ons a l s o ma y be a bs ent a t the ti me of the vi s i t. Ma neuvers to evoke phys i ca l urti ca ri a ca n be done duri ng the
exa mi na ti on, i ncl udi ng expos ure to vi bra ti on (tuni ng fork), wa rmth (tuni ng fork hel d under wa rm wa ter), col d (s tethos cope or chi l l ed tuni ng fork),
wa ter, or pres s ure (l i ghtl y s cra tchi ng a n una ffected a rea wi th a fi ngerna i l ).
Angi oedema (s wel l i ng of the fa ce, l i ps , or tongue)
[Table 71-3. Some Ca us es of Urti ca ri a ]
Stri dor, wheezi ng, or other res pi ra tory di s tres s
Hyperpi gmented l es i ons , ul cers , or urti ca ri a tha t pers i s t > 48 h
Si gns of s ys temi c i l l nes s (eg, fever, l ympha denopa thy, ja undi ce, ca chexi a )
Interpretation of findings: Acute urticaria i s nea rl y a l wa ys due to s ome defi ned expos ure to a drug or phys i ca l s ti mul us or a n a cute i nfecti ous i l l nes s .
However, the tri gger i s not a l wa ys cl ea r from the hi s tory, pa rti cul a rl y beca us e a l l ergy ma y devel op wi thout wa rni ng to a previ ous l y tol era ted
s ubs ta nce.
Mos t chronic urticaria i s i di opa thi c. The next mos t common ca us e i s a n a utoi mmune di s order. The ca us a ti ve a utoi mmune di s order i s s ometi mes
cl i ni ca l l y a ppa rent. Urti ca ri a l va s cul i ti s s ometi mes i s a s s oci a ted wi th connecti ve ti s s ue di s orders (pa rti cul a rl y SLE or Sjogren's s yndrome). In
urti ca ri a l va s cul i ti s , urti ca ri a i s a ccompa ni ed by fi ndi ngs of cuta neous va s cul i ti s ; i t s houl d be cons i dered when the urti ca ri a a re pa i nful ra ther
tha n pruri ti c, l a s t > 48 h, do not bl a nch, or a re a ccompa ni ed by ves i cl es or purpura .
Testing: Us ua l l y, no tes ti ng i s needed for a n i s ol a ted epi s ode of urti ca ri a unl es s s ymptoms a nd s i gns s ugges t a s peci fi c di s order (eg, i nfecti on).
Unus ua l , recurrent, or pers i s tent ca s es wa rra nt further eva l ua ti on. Referra l for a l l ergy s ki n tes ti ng s houl d be done, a nd routi ne l a bora tory tes ts
s houl d cons i s t of CBC, bl ood chemi s tri es , l i ver functi on tes ts , a nd thyroi d-s ti mul a ti ng hormone (TSH). Further tes ti ng s houl d be gui ded by
s ymptoms a nd s i gns (eg, of a utoi mmune di s orders ) a nd a ny a bnorma l i ti es on the s creeni ng tes ts (eg, hepa ti ti s s erol ogi es a nd ul tra s onogra phy
for a bnorma l l i ver functi on tes ts ; ova a nd pa ra s i tes for eos i nophi l i a ; cryogl obul i n ti ter for el eva ted l i ver functi on tes ts or el eva ted crea ti ni ne;
thyroi d a utoa nti bodi es for a bnorma l TSH).
Ski n bi ops y s houl d be done i f there i s a ny uncerta i nty a s to the di a gnos i s or i f whea l s pers i s t > 48 h (to rul e out urti ca ri a l va s cul i ti s ).
Cl i ni ci a ns s houl d not recommend the pa ti ent do a n empi ri c cha l l enge (eg, "Try s uch a nd s uch a ga i n a nd s ee whether you get a rea cti on") beca us e
s ubs equent rea cti ons ma y be more s evere.
Treatment
Any i denti fi ed ca us es a re trea ted or remedi ed. Impl i ca ted drugs or foods s houl d be s topped.
Nons peci fi c s ymptoma ti c trea tment (eg, ta ki ng cool ba ths , a voi di ng hot wa ter a nd s cra tchi ng, a nd wea ri ng l oos e cl othi ng) ma y be hel pful .
Drugs: Anti hi s ta mi nes rema i n the ma i ns ta y of trea tment. They mus t be ta ken on a regul a r ba s i s , ra ther tha n a s needed. Newer ora l
a nti hi s ta mi nes often a re preferred beca us e of once-da i l y dos i ng a nd beca us e s ome a re l es s s eda ti ng. Appropri a te choi ces i ncl ude
Ceti ri zi ne 10 mg once/da y
Fexofena di ne 180 mg once/da y
Des l ora ta di ne 5 mg once/da y
Levoceti ri zi ne 5 mg once/da y
Ol der ora l a nti hi s ta mi nes (eg, hydroxyzi ne 10 to 25 mg q 4 to 6 h; di phenhydra mi ne 25 to 50 mg q 6 h) a re s eda ti ng but i nexpens i ve a nd a l s o qui te
effecti ve.
Sys temi c corti cos teroi ds (eg, predni s one 30 to 40 mg po once/da y) a re gi ven for s evere s ymptoms but s houl d not be us ed l ong term. Topi ca l
corti cos teroi ds or a nti hi s ta mi nes a re not benefi ci a l .
Angioedema: Pa ti ents who ha ve a ngi oedema i nvol vi ng the oropha rynx or a ny i nvol vement of the a i rwa y s houl d recei ve epi nephri ne 0.3 mL of 1:1000
s ol uti on s c a nd be a dmi tted to the hos pi ta l . On di s cha rge, pa ti ents s houl d be s uppl i ed wi th a nd tra i ned i n the us e of a n a uto-i njecta bl e
epi nephri ne pen.
The ol der ora l a nti hi s ta mi nes (eg, hydroxyzi ne, di phenhydra mi ne) a re s eda ti ng a nd ca n ca us e confus i on, uri na ry retenti on, a nd del i ri um. They
s houl d be us ed ca uti ous l y to trea t urti ca ri a i n el derl y pa ti ents .
Key Points
Urti ca ri a ca n be ca us ed by a l l ergi c or nona l l ergi c mecha ni s ms .
Mos t a cute ca s es a re ca us ed by a n a l l ergi c rea cti on to a s peci fi c s ubs ta nce.
Mos t chroni c ca s es a re i di opa thi c or res ul t from a utoi mmune di s ea s e.
Trea tment i s ba s ed on s everi ty; nons eda ti ng a nti hi s ta mi nes a nd a voi da nce of tri ggers a re fi rs t-l i ne opti ons .
Topi ca l corti cos teroi ds a nd a nti hi s ta mi nes a re not benefi ci a l .
Concomi ta nt s ys temi c s ymptoms requi re a thorough eva l ua ti on for the eti ol ogy.
Skin Manifestations of Internal Disease
The s ki n frequentl y s erves a s a ma rker for underl yi ng i nterna l di s ea s e. The type of l es i on typi ca l l y rel a tes to a s peci fi c di s ea s e or type of di s ea s e.
Internal cancer: Of pa ti ents wi th derma tomyos i ti s , a bout 50% ha ve a s s oci a ted brea s t, l ung, ova ri a n, a nd GI ca ncers .
Acute ons et of mul ti pl e s eborrhei c kera tos es (Les er-Trel a t s i gn) ma y i ndi ca te underl yi ng i nterna l ca ncer, pa rti cul a rl y a denoca rci noma . However,
beca us e of the hi gh preva l ence of s eborrhei c kera tos es i n hea l thy a dul ts , thi s s i gn ma y be overdi a gnos ed.
Acute febri l e neutrophi l i c derma tos i s i s a s s oci a ted wi th hema tol ogi c ca ncer.
Aca nthos i s ni gri ca ns (s ee
Pl a te 24) tha t i s a s s oci a ted wi th ca ncer ca n be of ra pi d ons et a nd pa rti cul a rl y wi des prea d. Pruri tus wi thout a cl ea rl y a s s oci a ted derma ti ti s ma y
i ndi ca te occul t ca ncer, often l ymphoma .
Pa ra neopl a s ti c pemphi gus i s a rel a ti vel y ra re a utoi mmune bl i s teri ng di s ea s e tha t ha s been a s s oci a ted wi th va ri ous ca ncers , i ncl udi ng
l eukemi a s .
The ca rci noi d s yndrome (fl us hi ng a nd erythema of the neck) i s a s s oci a ted wi th ca rci noi d tumor.
Erythema gyra tum repens i s a ra re erupti on cons i s ti ng of concentri c erythema tous l es i ons , res embl i ng wood gra i n, whi ch ha s been a s s oci a ted
wi th va ri ous ca ncers .
Endocrinopathies: Ma ny s ki n fi ndi ngs a re a s s oci a ted wi th endocri nopa thi es but a re not s peci fi c.
Pa ti ents wi th di a betes mel l i tus ma y ha ve a ca nthos i s ni gri ca ns , necrobi os i s l i poi di ca , perfora ti ng di s orders , a nd s cl eredema a dul torum.
Thyroi d di s ea s e, both hypothyroi di s m a nd hyperthyroi di s m, ca n a ffect ha i r, na i l s , a nd s ki n.
Cus hi ng's di s ea s e ca us es s tri a e di s tens a e, moon fa ci es , a nd s ki n fra gi l i ty.
Addi s on's di s ea s e i s cha ra cteri zed by hyperpi gmenta ti on tha t i s a ccentua ted i n s ki n crea s es a nd a rea s of tra uma .
GI disorders: Ski n condi ti ons commonl y a s s oci a ted wi th GI di s orders i ncl ude
Pyoderma ga ngrenos um: Infl a mma tory bowel di s ea s e
Li chen pl a nus a nd porphyri a cuta nea ta rda : Hepa ti ti s C i nfecti on
Di ffus e hyperpi gmenta ti on, or bronze di a betes : Hemochroma tos i s
Erythema nodos um: Infl a mma tory bowel di s ea s e, s a rcoi dos i s , a nd va ri ous i nfecti ons
Erupti ve xa nthoma s : El eva ted s erum tri gl yceri des
Chapter 72. Principles of Topical Dermatologic Therapy

Introduction
Topi ca l derma tol ogi c trea tments i ncl ude
Cl ea ns i ng a gents
Abs orbents
Anti -i nfecti ve a gents
Anti -i nfl a mma tory a gents
As tri ngents (dryi ng a gents tha t preci pi ta te protei n a nd s hri nk a nd contra ct the s ki n)
Emol l i ents (s ki n hydra tors a nd s ofteners )
Kera tol yti cs (a gents tha t s often, l oos en, a nd fa ci l i ta te exfol i a ti on of the s qua mous cel l s of the epi dermi s )
Vehicles
Topi ca l thera pi es ca n be del i vered i n va ri ous vehi cl es , whi ch i ncl ude
Powders
Li qui ds
Combi na ti ons of l i qui d a nd oi l
The vehi cl e i nfl uences a thera py's effecti venes s a nd ma y i ts el f ca us e a dvers e effects (eg, conta ct or i rri ta nt derma ti ti s ). Genera l l y, a queous
prepa ra ti ons a re dryi ng (beca us e the l i qui d eva pora tes ) a nd a re us ed i n a cute i nfl a mma tory condi ti ons . Oi l -ba s ed prepa ra ti ons a re moi s turi zi ng
a nd a re preferred for chroni c i nfl a mma ti on.
Powders: Inert powders ma y be mi xed wi th a cti ve a gents (eg, a nti funga l s ) to del i ver thera py. They a re pres cri bed for l es i ons i n moi s t or
i ntertri gi nous a rea s .
Liquids: Li qui d vehi cl es i ncl ude
Ba ths a nd s oa ks
Sol uti ons
Loti ons
Gel s
Ba ths a nd s oa ks a re us ed when thera py mus t be a ppl i ed to l a rge a rea s , s uch a s wi th extens i ve conta ct derma ti ti s or a topi c derma ti ti s .
Sol uti ons a re i ngredi ents di s s ol ved i n a s ol vent, us ua l l y ethyl a l cohol , propyl ene gl ycol , pol yethyl ene gl ycol , or wa ter. Sol uti ons a re conveni ent to
a ppl y (es peci a l l y to the s ca l p for di s orders s uch a s ps ori a s i s or s eborrhea ) but tend to be dryi ng. Two common s ol uti ons a re Burow's s ol uti on a nd
Domeboro's s ol uti on.
Loti ons a re wa ter-ba s ed emul s i ons . They a re ea s i l y a ppl i ed to ha i ry s ki n. Loti ons cool a nd dry a cute i nfl a mma tory a nd exuda ti ve l es i ons , s uch a s
conta ct derma ti ti s , ti nea pedi s , a nd ti nea cruri s .
Gel s a re i ngredi ents s us pended i n a s ol vent thi ckened wi th pol ymers . Gel s a re often more effecti ve for control l ed rel ea s e of topi ca l a gents . They
a re often us ed i n a cne, ros a cea , a nd ps ori a s i s of the s ca l p.
Combination vehicles: Combi na ti ons i ncl ude
Crea ms
Oi ntments
Combi na ti on vehi cl es us ua l l y conta i n oi l a nd wa ter but ma y a l s o conta i n propyl ene or pol yethyl ene gl ycol .
Crea ms a re s emi -s ol i d emul s i ons of oi l a nd wa ter. They a re us ed for moi s turi zi ng a nd cool i ng a nd when exuda ti on i s pres ent. They va ni s h when
rubbed i nto s ki n.
Oi ntments a re oi l ba s ed (eg, petrol a tum) wi th l i ttl e i f a ny wa ter. Oi ntments a re opti ma l l ubri ca nts a nd i ncrea s e drug penetra ti on beca us e of thei r
occl us i ve na ture; a gi ven concentra ti on of drug i s genera l l y more potent i n a n oi ntment. They a re preferred for l i cheni fi ed l es i ons a nd l es i ons wi th
thi ck crus ts or hea ped-up s ca l es , i ncl udi ng ps ori a s i s a nd l i chen s i mpl ex chroni cus . Oi ntments a re l es s i rri ta ti ng tha n crea ms for eros i ons or
ul cers .
Dressings
Dres s i ngs protect open l es i ons , fa ci l i ta te hea l i ng, i ncrea s e drug a bs orpti on, a nd protect the pa ti ent's cl othi ng.
Nonocclusive dressings: The mos t common a re ga uze dres s i ngs . They ma xi ma l l y a l l ow a i r to rea ch the wound, whi ch i s often preferred i n hea l i ng,
a nd a l l ow the l es i on to dry. Nonoccl us i ve dres s i ngs wetted wi th s ol uti on, us ua l l y s a l i ne, a re us ed to hel p cl ea ns e a nd debri de thi ckened or
crus ted l es i ons . The dres s i ngs a re a ppl i ed wet a nd removed a fter the s ol uti on ha s eva pora ted (wet-to-dry dres s i ngs ); ma teri a l s from the s ki n
then a dhere to the dres s i ng.
Occlusive dressings: Occl us i ve dres s i ngs i ncrea s e the a bs orpti on a nd effecti venes s of topi ca l thera py. Mos t common a re tra ns pa rent fi l ms s uch a s
pol yethyl ene (pl a s ti c hous ehol d wra p) or fl exi bl e, tra ns pa rent, s emi -permea bl e dres s i ngs . Hydrocol l oi d dres s i ngs ca n be a ppl i ed wi th a ga uze
cover i n pa ti ents wi th cuta neous ul cera ti on. Zi nc oxi de gel a ti n (Unna 's pa s te boot) i s a n effecti ve occl us i ve dres s i ng for pa ti ents wi th s ta s i s
derma ti ti s a nd ul cers . Pl a s ti c ta pe i mpregna ted wi th fl ura ndrenol i de, a corti cos teroi d, ca n be us ed for i s ol a ted or reca l ci tra nt l es i ons .
Occl us i ve dres s i ngs a ppl i ed over topi ca l corti cos teroi ds to i ncrea s e a bs orpti on a re s ometi mes us ed to trea t ps ori a s i s , a topi c derma ti ti s , s ki n
l es i ons of l upus erythema tos us , a nd chroni c ha nd derma ti ti s , a mong other condi ti ons . Sys temi c a bs orpti on of topi ca l corti cos teroi ds ma y occur
a nd ca us e
Devel opment of mi l i a ri a
Ski n a trophy
Stri a e
Ba cteri a l or funga l i nfecti ons
Adrena l s uppres s i on
Acnei form erupti ons
Other occl us i ve dres s i ngs a re us ed to protect a nd hel p hea l open wounds , s uch a s burns (s ee p. 3242).
Categories and Indications
Ma jor ca tegori es of topi ca l a gents i ncl ude
Cl ea ns i ng
Moi s turi zi ng
Dryi ng
Anti -i nfl a mma tory
Anti mi crobi a l
Kera tol yti c
As tri ngent
Anti pruri ti c
Cleansing agents: The pri nci pa l cl ea ns i ng a gents a re s oa ps , detergents , a nd s ol vents . Soa p i s the mos t popul a r cl ea ns er, but s yntheti c detergents
a re a l s o us ed. Ba by s ha mpoos a re us ua l l y wel l tol era ted a round the eyes a nd for cl ea ns i ng wounds a nd a bra s i ons ; they a re us eful for removi ng
crus ts a nd s ca l es i n ps ori a s i s , eczema , a nd other forms of derma ti ti s . However, a cutel y i rri ta ted, weepi ng, or oozi ng l es i ons a re mos t comforta bl y
cl ea ns ed wi th wa ter or i s otoni c s a l i ne.
Wa ter i s the pri nci pa l s ol vent for cl ea ns i ng. Orga ni c s ol vents (eg, a cetone, petrol eum products , propyl ene gl ycol ) a re very dryi ng, ca n be i rri ta ti ng,
a nd ca us e i rri ta nt or, l es s commonl y, a l l ergi c conta ct derma ti ti s . Remova l of ha rdened ta r a nd dri ed pa i nt from the s ki n ma y requi re a petrol a tumba s ed oi ntment or commerci a l wa terl es s cl ea ns er.
Moisturizing agents: Moi s turi zers (emol l i ents ) res tore wa ter a nd oi l s to the s ki n a nd hel p to ma i nta i n s ki n hydra ti on. They typi ca l l y conta i n gl yceri n,
mi nera l oi l , or petrol a tum a nd a re a va i l a bl e a s l oti ons , crea ms , oi ntments , a nd ba th oi l s . Stronger moi s turi zers conta i n urea 2%, l a cti c a ci d 5 to
12%, a nd gl ycol i c a ci d 10% (hi gher concentra ti ons a re us ed a s kera ti nol yti cs , eg, for i chthyos i s ). They a re mos t effecti ve when a ppl i ed to a l rea dy
moi s tened s ki n (i e, a fter a ba th or s hower).
Drying agents: Exces s i ve moi s ture i n i ntertri gi nous a rea s (eg, between the toes ; i n the i ntergl utea l cl eft, a xi l l a e, groi n, a nd i nfra ma mma ry a rea s )
ca n ca us e i rri ta ti on a nd ma cera ti on. Powders dry ma cera ted s ki n a nd reduce fri cti on by a bs orbi ng moi s ture. However, s ome powders tend to
cl ump a nd ca n be i rri ta ti ng i f they become moi s t. Corns ta rch a nd ta l c a re mos t often us ed. Al though ta l c i s more effecti ve, ta l c ma y ca us e
gra nul oma s i f i nha l ed a nd i s no l onger us ed i n ba by powders . Corns ta rch ma y promote funga l growth. Al umi num chl ori de s ol uti ons a re a nother
type of dryi ng a gent (often us eful i n hyperhi dros i s ).
Anti-inflammatory agents: Topi ca l a nti -i nfl a mma tory a gents a re ei ther corti cos teroi ds or noncorti cos teroi ds .
Corticosteroids a re the ma i ns ta y of trea tment for mos t noni nfecti ous i nfl a mma tory derma tos es . Loti ons a re us eful on i ntertri gi nous a rea s a nd the
fa ce. Gel s a re us eful on the s ca l p a nd i n ma na gement of conta ct derma ti ti s . Crea ms a re us eful on the fa ce a nd i n i ntertri gi nous a rea s a nd for
ma na gement of i nfl a mma tory derma tos es . Oi ntments a re us eful for dry s ca l y a rea s a nd when i ncrea s ed potency i s requi red. Corti cos teroi di mpregna ted ta pe i s us eful to protect a n a rea from excori a ti on. It a l s o i ncrea s es corti cos teroi d a bs orpti on a nd therefore potency.
Topi ca l corti cos teroi ds ra nge i n potency from mi l d (cl a s s VII) to s uperpotent (cl a s s Is ee
Ta bl e 72-1). Intri ns i c di fferences i n potency a re a ttri buta bl e to fl uori na ti on or chl ori na ti on (ha l ogena ti on) of the compound.
Topi ca l corti cos teroi ds a re genera l l y a ppl i ed 2 to 3 ti mes da i l y, but hi gh-potency formul a ti ons ma y requi re a ppl i ca ti on onl y once/da y or even l es s
frequentl y. Mos t derma tos es a re trea ted wi th mi d-potency to hi gh-potency formul a ti ons ; mi l d formul a ti ons a re better for mi l d i nfl a mma ti on a nd
for us e on the fa ce or i ntertri gi nous a rea s , where s ys temi c a bs orpti on i s more l i kel y. Al l a gents ca n ca us e s ki n a trophy, s tri a e, a nd a cnei form
erupti ons when us ed for > 1 mo. Thi s effect i s pa rti cul a rl y probl ema ti c on the thi nner s ki n of the fa ce or geni ta l s . Corti cos teroi ds a l s o promote
funga l growth. Conta ct derma ti ti s i n rea cti on to pres erva ti ves a nd a ddi ti ves i s a l s o common wi th prol onged us e. Conta ct derma ti ti s to the
corti cos teroi d i ts el f ma y a l s o occur. Peri ora l derma ti ti s occurs wi th mi d-potency or hi gh-potency formul a ti ons us ed on the fa ce but i s uncommon
wi th mi l d formul a ti ons . Hi gh-potency formul a ti ons ma y ca us e a drena l s uppres s i on when us ed i n chi l dren, over extens i ve s ki n s urfa ces , or for l ong
peri ods . Rel a ti ve contra i ndi ca ti ons i ncl ude condi ti ons i n whi ch i nfecti on pl a ys a n underl yi ng rol e a nd a cnei form di s orders .
Noncorticosteroid anti-inflammatory agents i ncl ude ta r prepa ra ti ons . Ta r comes i n the form of crude coa l ta r a nd i s i ndi ca ted for ps ori a s i s . Advers e
effects i ncl ude i rri ta ti on, fol l i cul i ti s , s ta i ni ng of cl othes a nd furni ture, a nd photos ens i ti za ti on. Contra i ndi ca ti ons i ncl ude i nfected s ki n. Severa l
herba l products a re commonl y us ed i n commerci a l products , a l though thei r effecti venes s ha s not been wel l es ta bl i s hed. Among the mos t popul a r
a re cha momi l e a nd ca l endul a .
Antimicrobials: Topi ca l a nti mi crobi a l s i ncl ude
Anti bi oti cs
Anti funga l s
Ins ecti ci des
Nons peci fi c a nti s epti c a gents
Antibiotics ha ve few i ndi ca ti ons . Topi ca l cl i nda myci n a nd erythromyci n a re us ed a s pri ma ry or a djuncti ve trea tment for a cne vul ga ri s i n pa ti ents
who do not wa rra nt or tol era te ora l a nti bi oti cs . Mupi roci n ha s excel l ent gra m-pos i ti ve (Staphylococcus aureus, s treptococci ) covera ge a nd ca n be
us ed to trea t i mpeti go when deep ti s s ues a re not a ffected. OTC a nti bi oti cs s uch a s ba ci tra ci n a nd pol ymyxi n a re often us ed i n pos topera ti ve ca re
of a s ki n bi ops y s i te a nd to prevent i nfecti on i n s cra pes , mi nor burns , a nd excori a ti ons . Topi ca l neomyci n ca us es conta ct derma ti ti s more
frequentl y tha n other a nti bi oti cs . The us e of topi ca l a nti bi oti cs a nd wa s hi ng wi th a nti s epti c s oa ps i n hea l i ng wounds ma y, however, a ctua l l y s l ow
hea l i ng.
Antifungals a re us ed to trea t ca ndi di a s i s , a wi de va ri ety of derma tophytos es , a nd other funga l i nfecti ons (s ee
Ta bl e 82-1 on p. 704).
Insecticides (eg, permethri n, ma l a thi on) a re us ed trea t l i ce i nfes ta ti on a nd s ca bi es (s ee
Ta bl e 83-1 on p. 712).
Nonspecific antiseptic agents i ncl ude i odi ne s ol uti ons (eg, povi done i odi ne, cl i oqui nol ), genti a n vi ol et, s i l ver prepa ra ti ons (eg, s i l ver ni tra te, s i l ver
s ul fa di a zi ne), a nd zi nc pyri thi one. Iodi ne i s i ndi ca ted for pres urgi ca l s ki n prepa ra ti on. Genti a n vi ol et i s us ed when a n i nexpens i ve chemi ca l l y a nd
phys i ca l l y s ta bl e a nti s epti c/a nti mi crobi a l i s needed. Si l ver prepa ra ti ons a re effecti ve i n trea ti ng burns a nd ul cers a nd ha ve s trong a nti mi crobi a l
[Table 72-1. Rel a ti ve Potency of Sel ected Topi ca l Corti cos teroi ds ]
properti es ; s evera l wound dres s i ngs a re i mpregna ted wi th s i l ver. Zi nc pyri thi one i s a n a nti funga l a nd a common i ngredi ent i n s ha mpoos us ed to
trea t da ndruff due to ps ori a s i s or s eborrhei c derma ti ti s . Hea l i ng wounds s houl d genera l l y not be trea ted wi th topi ca l a nti s epti cs other tha n s i l ver
beca us e they a re i rri ta ti ng a nd tend to ki l l fra gi l e gra nul a ti on ti s s ue.
Keratolytics: Kera tol yti cs s often a nd fa ci l i ta te exfol i a ti on of epi derma l cel l s . Exa mpl es i ncl ude 3 to 6% s a l i cyl i c a ci d a nd urea . Sa l i cyl i c a ci d i s us ed
to trea t ps ori a s i s , s eborrhea , a cne, a nd wa rts . Advers e effects a re burni ng a nd s ys temi c toxi ci ty i f l a rge a rea s a re covered. It s houl d ra rel y be us ed
i n chi l dren a nd i nfa nts . Urea i s us ed to trea t pl a nta r kera toderma s a nd i chthyos i s . Advers e effects a re i rri ta ti on a nd i ntra cta bl e burni ng. It s houl d
not be a ppl i ed to l a rge a rea s .
Astringents: As tri ngents a re dryi ng a gents tha t preci pi ta te protei n a nd s hri nk a nd contra ct the s ki n. The mos t commonl y us ed a s tri ngents a re
a l umi num a ceta te (Burow's s ol uti on) a nd a l umi num s ul fa te pl us Ca a ceta te (Domeboro's s ol uti on). Us ua l l y a ppl i ed wi th dres s i ngs or a s s oa ks ,
a s tri ngents a re us ed to trea t i nfecti ous eczema , exuda ti ve s ki n l es i ons , a nd pres s ure ul cers . Wi tch ha zel i s a popul a r OTC a s tri ngent.
Antipruritics: Doxepi n i s a topi ca l a nti hi s ta mi ne tha t i s effecti ve i n trea ti ng i tchi ng of a topi c derma ti ti s , l i chen s i mpl ex chroni c derma ti ti s , a nd
nummul a r derma ti ti s . Topi ca l benzoca i ne a nd di phenhydra mi ne (pres ent i n certa i n OTC l oti ons ) a re s ens i ti zi ng a nd not recommended. Other
a nti pruri ti cs i ncl ude ca mphor 0.5 to 3%, menthol 0.1 to 0.2%, pra moxi ne hydrochl ori de, a nd eutecti c mi xture of l oca l a nes theti cs (EMLA), whi ch
conta i n equa l pa rts l i doca i ne a nd pri l oca i ne i n a n oi l -i n-wa ter vehi cl e. Topi ca l a nti pruri ti cs a re preferred over s ys temi c drugs (eg, ora l
a nti hi s ta mi nes ) when s ma l l er s urfa ce a rea s of s ki n a re a ffected a nd pruri tus i s not i ntra cta bl e. Ca l a mi ne l oti on i s s oothi ng but not s peci fi ca l l y
a nti pruri ti c.
Chapter 73. Acne and Related Disorders

Introduction
Acne vul ga ri s i s a common s ki n probl em, a ffecti ng mos t a dol es cents a nd ma ny a dul ts . Peri ora l derma ti ti s a nd ros a cea ca n produce s i mi l a r
l es i ons .
Acne Vulgaris
Acne vulgaris (acne) is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units
(hair follicles and their accompanying sebaceous gland). It most often affects adolescents. Diagnosis is by examination. Treatment is a variety of topical and
systemic agents intended to reduce sebum production, infection, and inflammation and to normalize keratinization.
Pathophysiology
Acne occurs when pi l os eba ceous uni ts become obs tructed wi th pl ugs of s ebum a nd des qua ma ted kera ti nocytes , then col oni zed a nd s ometi mes
i nfected wi th the norma l s ki n a na erobe Propionibacterium acnes. Ma ni fes ta ti ons di ffer dependi ng on whether P. acnes s ti mul a tes i nfl a mma ti on i n
the fol l i cl e; a cne ca n be noni nfl a mma tory or i nfl a mma tory.
Comedones , uni nfected s eba ceous pl ugs i mpa cted wi thi n fol l i cl es , a re the s i gna ture of noni nfl a mma tory a cne. Comedones a re termed open or
cl os ed dependi ng on whether the fol l i cl e i s di l a ted or cl os ed a t the s ki n s urfa ce. Infl a mma tory a cne compri s es pa pul es , pus tul es , nodul es , a nd
cys ts .
Pa pul es a ppea r when l i pa s es from P. acnes meta bol i ze tri gl yceri des i nto free fa tty a ci ds (FFA), whi ch i rri ta te the fol l i cul a r wa l l . Pus tul es occur
when a cti ve P. acnes i nfecti on ca us es i nfl a mma ti on wi thi n the fol l i cl e. Nodul es a nd cys ts occur when rupture of fol l i cl es due to i nfl a mma ti on,
phys i ca l ma ni pul a ti on, or ha rs h s crubbi ng rel ea s es FFAs , ba cteri a , a nd kera ti n i nto ti s s ues , tri ggeri ng s oft-ti s s ue i nfl a mma ti on.
Etiology
The mos t common tri gger i s puberty, when s urges i n a ndrogen s ti mul a te s ebum producti on a nd hyperprol i fera ti on of kera ti nocytes . Other tri ggers
i ncl ude hormona l cha nges tha t occur wi th pregna ncy or throughout the mens trua l cycl e; occl us i ve cos meti cs , cl ea ns i ng a gents , a nd cl othi ng; a nd
humi di ty a nd s wea ti ng. As s oci a ti ons between a cne exa cerba ti on a nd di et (eg, chocol a te), i na dequa te fa ce wa s hi ng, ma s turba ti on, a nd s ex a re
unfounded. Some s tudi es ques ti on a n a s s oci a ti on wi th mi l k products . Acne ma y i mprove i n s ummer months beca us e of s unl i ght's a nti i nfl a mma tory effects . Propos ed a s s oci a ti ons between a cne a nd hyperi ns ul i ni s m requi re further i nves ti ga ti on.
Symptoms and Signs
Cys ti c a cne ca n be pa i nful ; other types ca us e no phys i ca l s ymptoms but ca n be a s ource of s i gni fi ca nt emoti ona l di s tres s . Les i on types frequentl y
coexi s t a t di fferent s ta ges .
Comedones a ppea r a s whi tehea ds or bl a ckhea ds . Whi tehea ds (cl os ed comedones ) a re fl es h-col ored or whi ti s h pa l pa bl e l es i ons 1 to 3 mm i n
di a meter; bl a ckhea ds (open comedones ) a re s i mi l a r i n a ppea ra nce but wi th a da rk center.
Pa pul es a nd pus tul es a re red l es i ons 2 to 5 mm i n di a meter. In both, the fol l i cul a r epi thel i um becomes da ma ged wi th a ccumul a ti on of
neutrophi l s a nd then l ymphocytes . When the epi thel i um ruptures , the comedo contents el i ci t a n i ntens e i nfl a mma tory rea cti on i n the dermi s .
Rel a ti vel y deep i nfl a mma ti on produces pa pul es . Pus tul es a re more s uperfi ci a l .
Nodul es a re l a rger, deeper, a nd more s ol i d tha n pa pul es . Such l es i ons res embl e i nfl a med epi dermoi d cys ts , a l though they l a ck true cys ti c
s tructure.
Cys ts a re s uppura ti ve nodul es . Ra rel y cys ts become i nfected a nd form a bs ces s es . Long-term cys ti c a cne ca n ca us e s ca rri ng tha t ma ni fes ts a s ti ny,
deep pi ts (i cepi ck s ca rs ), l a rger pi ts , s ha l l ow depres s i ons , or a rea s of hypertrophi c s ca r.
Acne congl oba ta i s the mos t s evere form of a cne vul ga ri s , a ffecti ng men more tha n women. Pa ti ents ha ve a bs ces s es , dra i ni ng s i nus es , fi s tul a ted
comedones , a nd kel oi da l a nd a trophi c s ca rs . The ba ck a nd ches t a re s everel y i nvol ved. The a rms , a bdomen, buttocks , a nd even the s ca l p ma y be
a ffected.
Acne ful mi na ns i s a cute, febri l e, ul cera ti ve a cne, cha ra cteri zed by the s udden a ppea ra nce of confl uent a bs ces s es l ea di ng to hemorrha gi c
necros i s . Leukocytos i s a nd joi nt pa i n a nd s wel l i ng ma y a l s o be pres ent.
Pyoderma fa ci a l e (a l s o ca l l ed ros a cea ful mi na ns ) occurs s uddenl y on the mi dfa ce of young women. It ma y be a na l ogous to a cne ful mi na ns . The
erupti on cons i s ts of erythema tous pl a ques a nd pus tul es , i nvol vi ng the chi n, cheeks , a nd forehea d.
Diagnosis
As s es s ment for contri buti ng fa ctors (eg, hormona l , mecha ni ca l , or drug-rel a ted)
Determi na ti on of s everi ty (mi l d, modera te, s evere)
As s es s ment of ps ychos oci a l i mpa ct
Di a gnos i s i s by exa mi na ti on. Di fferenti a l di a gnos i s i ncl udes ros a cea (i n whi ch no comedones a re s een), corti cos teroi d-i nduced a cne (whi ch l a cks
comedones a nd i n whi ch pus tul es a re us ua l l y i n the s a me s ta ge of devel opment), peri ora l derma ti ti s (us ua l l y wi th a more peri ora l a nd
peri orbi ta l di s tri buti on), a nd a cnei form drug erupti ons . Acne s everi ty i s gra ded mi l d, modera te, or s evere ba s ed on the number a nd type of
l es i ons ; a s ta nda rdi zed s ys tem i s outl i ned i n
Ta bl e 73-1.
Prognosis
Acne of a ny s everi ty us ua l l y remi ts s ponta neous l y by the ea rl y to mi d-20s , but a s ubs ta nti a l mi nori ty of pa ti ents , us ua l l y women, ma y ha ve a cne
i nto thei r 40s ; opti ons for trea tment ma y be l i mi ted beca us e of chi l d-bea ri ng. Ma ny a dul ts occa s i ona l l y devel op mi l d, i s ol a ted a cne l es i ons .
Noni nfl a mma tory a nd mi l d i nfl a mma tory a cne us ua l l y hea l s wi thout s ca rs . Modera te to s evere i nfl a mma tory a cne hea l s but often l ea ves s ca rri ng.
Sca rri ng i s not onl y phys i ca l ; a cne ma y be a huge emoti ona l s tres s or for a dol es cents who ma y wi thdra w, us i ng the a cne a s a n excus e to a voi d
di ffi cul t pers ona l a djus tments . Supporti ve couns el i ng for pa ti ents a nd pa rents ma y be i ndi ca ted i n s evere ca s es .
Treatment
Comedones : Topi ca l treti noi n
Mi l d i nfl a mma tory a cne: Topi ca l a nti bi oti cs , benzoyl peroxi de, or both
Modera te a cne: Ora l a nti bi oti cs
Severe a cne: Ora l i s otreti noi n
Cys ti c a cne: Intra l es i ona l tri a mci nol one
Trea tments a re di rected a t reduci ng s ebum producti on, comedone forma ti on, i nfl a mma ti on, a nd i nfecti on (s ee
Fi g. 73-1). Sel ecti on of
[Table 73-1. Cl a s s i fi ca ti on of Acne Severi ty]
[Fig. 73-1. How va ri ous drugs work i n trea ti ng a cne.]
trea tment i s genera l l y ba s ed on s everi ty; opti ons a re s umma ri zed i n
Ta bl e 73-2. Affected a rea s s houl d be cl ea ns ed da i l y, but extra wa s hi ng, us e of a nti ba cteri a l s oa ps , a nd s crubbi ng confer no a dded benefi t.
Cha nges i n di et a re a l s o unneces s a ry a nd i neffecti ve, a l though modera ti on of mi l k i nta ke mi ght be cons i dered for trea tment-res i s ta nt a dol es cent
a cne. Peel i ng a gents s uch a s s ul fur, s a l i cyl i c a ci d, a nd res orci nol a re mi nor thera peuti c a djuncts .
Trea tment s houl d i nvol ve educa ti ng the pa ti ent a nd ta i l ori ng the pl a n to one tha t i s rea l i s ti c for the pa ti ent. Trea tment fa i l ure ca n frequentl y be
a ttri buted to l a ck of a dherence to the pl a n a nd a l s o to l a ck of fol l ow-up. Cons ul ta ti on wi th a s peci a l i s t ma y be neces s a ry.
Mild acne: Si ngl e-a gent thera py i s genera l l y s uffi ci ent for comedona l a cne; pa pul opus tul a r a cne genera l l y requi res dua l thera py (eg, the
combi na ti on of treti noi n wi th benzoyl peroxi de or topi ca l a nti bi oti cs ). Trea tment s houl d be conti nued for 6 wk or unti l l es i ons res pond.
Ma i ntena nce trea tment ma y be neces s a ry to ma i nta i n control .
A ma i ns ta y of trea tment for comedones i s da i l y topi ca l treti noi n a s tol era ted. Da i l y a da pa l ene gel , ta za rotene crea m or gel , a zel a i c a ci d crea m,
a nd gl ycol i c or s a l i cyl i c a ci d i n propyl ene gl ycol a re a l terna ti ves for pa ti ents who ca nnot tol era te topi ca l treti noi n. Advers e effects i ncl ude
erythema , burni ng, s ti ngi ng, a nd peel i ng. Ada pa l ene a nd ta za rotene a re reti noi ds ; l i ke treti noi n, they tend to be s omewha t i rri ta ti ng a nd
photos ens i ti zi ng. Azel a i c a ci d ha s comedol yti c a nd a nti ba cteri a l properti es by a n unrel a ted mecha ni s m a nd ma y be s ynergi s ti c wi th reti noi ds .
Mi l d i nfl a mma tory a cne s houl d be trea ted wi th topi ca l benzoyl peroxi de, topi ca l a nti bi oti cs (eg, erythromyci n, cl i nda myci n), gl yol i c a ci d, or a
combi na ti on. Combi na ti on prepa ra ti ons of thes e a gents ma y hel p l i mi t devel opment of res i s ta nce. None ha ve s i gni fi ca nt a dvers e effects other
tha n dryi ng a nd i rri ta ti on (a nd ra re a l l ergi c rea cti ons to benzoyl peroxi de). Topi ca l reti noi ds a re often us ed concomi ta ntl y.
Phys i ca l extra cti on of comedones us i ng a comedo extra ctor i s a n opti on for pa ti ents unres pons i ve to topi ca l trea tment. Comedo extra cti on ma y be
done by a phys i ci a n, nurs e, or phys i ci a n a s s i s ta nt. One end of the comedo extra ctor i s l i ke a bl a de or ba yonet tha t punctures the cl os ed comedo.
The other end exerts pres s ure to extra ct the comedo.
Ora l a nti bi oti cs (eg, tetra cycl i ne, mi nocycl i ne, doxycycl i ne, erythromyci n) ca n be us ed when wi de di s tri buti on of l es i ons ma kes topi ca l thera py
i mpra cti ca l .
Moderate acne: Modera te a cne res ponds bes t to ora l s ys temi c thera py wi th a nti bi oti cs . Anti bi oti cs effecti ve for a cne i ncl ude tetra cycl i ne,
mi nocycl i ne, erythromyci n, a nd doxycycl i ne. Ful l benefi t ta kes 12 wk. Topi ca l thera py a s for mi l d a cne i s us ua l l y us ed concomi ta ntl y wi th ora l
a nti bi oti cs .
Tetra cycl i ne i s us ua l l y a good fi rs t choi ce: 250 or 500 mg bi d (between mea l s a nd a t bedti me) for 4 wk or unti l l es i ons res pond, a fter whi ch i t ma y
be reduced to the l owes t effecti ve dos e. Ra rel y, dos a ge mus t be i ncrea s ed to
[Table 73-2. Drugs Us ed to Trea t Acne]
500 mg qi d. After control i s a chi eved, i t i s rea s ona bl e to a ttempt to ta per a nd di s conti nue the ora l a nti bi oti c a nd conti nue topi ca l thera py for
control . Beca us e rel a ps e often fol l ows s hort-term trea tment, thera py ma y need to be conti nued for months to yea rs , a l though for ma i ntena nce
tetra cycl i ne 250 or 500 mg once/da y i s often s uffi ci ent. Mi nocycl i ne 50 or 100 mg bi d ca us es fewer GI a dvers e effects , i s ea s i er to ta ke, a nd i s l es s
l i kel y to ca us e photos ens i ti za ti on, but i t i s the mos t cos tl y opti on. Erythromyci n a nd doxycycl i ne a re cons i dered 2nd-l i ne drugs beca us e both ca n
ca us e GI a dvers e effects , a nd doxycycl i ne i s a frequent photos ens i ti zer. Suba nti mi crobi a l dos es of doxycycl i ne ha ve a l s o been proven effecti ve for
a cne a nd ros a cea .
Long-term us e of a nti bi oti cs ma y ca us e a gra m-nega ti ve pus tul a r fol l i cul i ti s a round the nos e a nd i n the center of the fa ce. Thi s uncommon
s uperi nfecti on ma y be di ffi cul t to cl ea r a nd i s bes t trea ted wi th ora l i s otreti noi n a fter di s conti nui ng the ora l a nti bi oti c. Ampi ci l l i n i s a n
a l terna ti ve trea tment for gra m-nega ti ve fol l i cul i ti s . In women, prol onged a nti bi oti c us e ca n ca us e ca ndi da l va gi ni ti s ; i f l oca l a nd s ys temi c thera py
does not era di ca te thi s probl em, a nti bi oti c thera py for a cne mus t be s topped.
Severe acne: Ora l i s otreti noi n i s the bes t trea tment for pa ti ents wi th modera te a cne i n whom a nti bi oti cs a re uns ucces s ful a nd for thos e wi th
s evere i nfl a mma tory a cne. Dos a ge of i s otreti noi n i s us ua l l y 1 mg/kg once/da y for 16 to 20 wk, but the dos a ge ma y be i ncrea s ed to 2 mg/kg
once/da y. If a dvers e effects ma ke thi s dos a ge i ntol era bl e, i t ma y be reduced to 0.5 mg/kg once/da y. After thera py, a cne ma y conti nue to i mprove.
Mos t pa ti ents do not requi re a 2nd cours e of trea tment; when needed, i t s houl d be res umed onl y a fter the drug ha s been s topped for 4 mo.
Retrea tment i s requi red more often i f the i ni ti a l dos a ge i s l ow (0.5 mg/kg). Wi th thi s dos a ge (whi ch i s very popul a r i n Europe), fewer a dvers e
effects occur, but prol onged thera py i s us ua l l y requi red.
Is otreti noi n i s nea rl y a l wa ys effecti ve, but us e i s l i mi ted by a dvers e effects , i ncl udi ng drynes s of conjuncti va e a nd mucos a e of the geni ta l s ,
cha pped l i ps , a rthra l gi a s , depres s i on, el eva ted l i pi d l evel s , a nd the ri s k of bi rth defects i f trea tment occurs duri ng pregna ncy. Hydra ti on wi th
wa ter fol l owed by petrol a tum a ppl i ca ti on us ua l l y a l l evi a tes mucos a l a nd cuta neous drynes s . Arthra l gi a s (mos tl y of l a rge joi nts or the l ower ba ck)
occur i n a bout 15% of pa ti ents . Increa s ed ri s k for depres s i on a nd s ui ci de i s much publ i ci zed but proba bl y ra re. CBC; l i ver functi on; a nd fa s ti ng
gl ucos e, tri gl yceri de, a nd chol es terol l evel s s houl d be determi ned before trea tment. Ea ch s houl d be rea s s es s ed a t 4 wk a nd, unl es s
a bnorma l i ti es a re noted, need not be repea ted unti l the end of trea tment. Tri gl yceri des ra rel y i ncrea s e to a l evel a t whi ch the drug s houl d be
s topped. Li ver functi on i s s el dom a ffected. Beca us e i s otreti noi n i s tera togeni c, women of chi l dbea ri ng a ge a re urged to us e 2 methods of
contra cepti on for 1 mo before trea tment, duri ng trea tment, a nd for a t l ea s t 1 mo a fter s toppi ng trea tment. Pregna ncy tes ts s houl d be done before
begi nni ng thera py a nd monthl y unti l 1 mo a fter thera py s tops .
Intra l es i ona l i njecti on of 0.1 mL tri a mci nol one a cetoni de s us pens i on 2.5 mg/mL (the 10 mg/mL s us pens i on mus t be di l uted) i s i ndi ca ted for
pa ti ents wi th fi rm (cys ti c) a cne who s eek qui ck cl i ni ca l i mprovement a nd to reduce s ca rri ng. Loca l a trophy ma y occur but i s us ua l l y tra ns i ent. For
i s ol a ted, very boggy l es i ons , i nci s i on a nd dra i na ge a re often benefi ci a l but ma y res ul t i n res i dua l s ca rri ng.
Other forms of acne: Pyoderma fa ci a l e i s trea ted wi th ora l corti cos teroi ds a nd i s otreti noi n. Acne ful mi na ns i s trea ted wi th ora l corti cos teroi ds a nd
s ys temi c a nti bi oti cs . Acne congl oba ta i s trea ted wi th ora l i s otreti noi n i f s ys temi c a nti bi oti cs fa i l . For a cne wi th endocri ne a bnorma l i ti es ,
a nti a ndrogens a re i ndi ca ted. Spi ronol a ctone, whi ch ha s s ome a nti a ndrogen effects , i s s ometi mes pres cri bed to trea t a cne a t a dos e of 50 to 100
mg po once/da y. Cyproterone a ceta te i s us ed i n Europe. When other mea s ures fa i l , a n es trogen-proges terone-conta i ni ng contra cepti ve ma y be
tri ed; thera py 6 mo i s needed to eva l ua te effect.
Scarring: Sma l l s ca rs ca n be trea ted wi th chemi ca l peel s , l a s er res urfa ci ng, or derma bra s i on. Deeper, di s crete s ca rs ca n be exci s ed. Wi de, s ha l l ow
depres s i ons ca n be trea ted wi th s ubci s i on or col l a gen i njecti on. Col l a gen i mpl a nts a re tempora ry a nd mus t be repea ted every few yea rs .
Perioral Dermatitis
Perioral dermatitis is an erythematous, papulopustular facial eruption that resembles acne and/or rosacea but typically starts around the mouth.
A va ri ety of ca us es ha ve been propos ed, i ncl udi ng expos ure to topi ca l corti cos teroi ds a nd/or fl uori de i n wa ter a nd toothpa s te, but the eti ol ogy i s
unknown. Des pi te i ts na me, peri ora l derma ti ti s i s not a true derma ti ti s . It pri ma ri l y a ffects women of chi l dbea ri ng a ge a nd chi l dren. The erupti on
cl a s s i ca l l y s ta rts a t the na s ol a bi a l fol ds a nd s prea ds peri ora l l y s pa ri ng a zone a round the vermi l i on border of the l i ps . But the erupti on ca n a l s o
s prea d peri orbi ta l l y a nd to the forehea d.
Di a gnos i s i s by a ppea ra nce; peri ora l derma ti ti s i s di s ti ngui s hed from a cne by the a bs ence of comedones a nd from ros a cea by the l a tter's l a ck of
l es i ons a round the mouth a nd eyes . Seborrhei c derma ti ti s a nd conta ct derma ti ti s mus t be excl uded. Bi ops y, whi ch i s genera l l y not cl i ni ca l l y
neces s a ry, s hows s pongi os i s a nd a l ymphohi s ti ocyti c i nfi l tra te a ffecti ng vel l us ha i r fol l i cl es . In the l upoi d va ri a nt, gra nul oma s ma y be pres ent.
Trea tment i s to s top fl uori na ted denta l products a nd topi ca l corti cos teroi ds (i f bei ng us ed) a nd then ei ther us e topi ca l a nti bi oti cs (eg,
erythromyci n 2% or metroni da zol e 0.75% gel or crea m bi d), or ora l tetra cycl i ne 250 to 500 mg po bi d (between mea l s ) for 4 wk, ta pered to the l owes t
effecti ve dos e. Al terna ti ve ora l a nti bi oti cs i ncl ude doxycycl i ne 50 to 100 mg bi d a nd mi nocycl i ne 50 to 100 mg bi d. In contra s t to a cne, a nti bi oti cs
ca n us ua l l y be s topped. Rea s ons for effi ca cy of a nti bi oti cs a re uncl ea r gi ven the a bs ence of evi dence of i nfecti on. Is otreti noi n ha s been
s ucces s ful l y us ed to trea t gra nul oma tous peri ora l derma ti ti s .
Rosacea
Rosacea (acne rosacea) is a chronic inflammatory disorder characterized by facial flushing, telangiectasias, erythema, papules, pustules, and in severe cases,
rhinophyma (see
Plate 43). Diagnosis is based on the characteristic appearance and history. Treatment depends on severity and includes topical metronidazole, topical and oral
antibiotics, rarely isotretinoin, and, for severe rhinophyma, surgery.
Ros a cea mos t commonl y a ffects pa ti ents a ged 30 to 50 wi th fa i r compl exi ons , mos t nota bl y thos e of Iri s h a nd Northern Europea n des cent, but i t
a ffects a nd i s proba bl y under-recogni zed i n da rker-s ki nned pa ti ents .
Etiology
The eti ol ogy i s unknown, a l though a s s oci a ti ons wi th a bnorma l va s omotor control , i mpa i red fa ci a l venous dra i na ge, a n i ncrea s e i n fol l i cl e mi tes
(Demodex folliculorum), a nd Helicobacter pylori i nfecti on ha ve been propos ed. Peopl e wi th ros a cea ma y ha ve el eva ted l evel s of s ma l l a nti mi crobi a l
pepti des tha t a re pa rt of the body's na tura l defens e s ys tem. Peopl e wi th ros a cea ma y a l s o ha ve hi gher tha n norma l l evel s of ca thel i ci di n a s wel l
a s a nother group of enzymes ca l l ed s tra tum corneum trypti c enzymes .
Symptoms and Signs
Ros a cea i s l i mi ted to the fa ce a nd s ca l p a nd ma ni fes ts i n 4 pha s es :
Preros a cea pha s e

Va s cul a r pha s e
Infl a mma tory pha s e
La te s ta ge
In the preros a cea pha s e, pa ti ents des cri be emba rra s s i ng fl us hi ng a nd bl us hi ng, often a ccompa ni ed by uncomforta bl e s ti ngi ng. Common reported
tri ggers for thes e fl a res i ncl ude s un expos ure, emoti ona l s tres s , col d or hot wea ther, a l cohol , s pi cy foods , exerci s e, wi nd, cos meti cs , a nd hot ba ths
or hot dri nks . Thes e s ymptoms pers i s t throughout other pha s es of the di s order.
In the va s cul a r pha s e, pa ti ents devel op fa ci a l erythema a nd edema wi th mul ti pl e tel a ngi ecta s es , pos s i bl y a s a res ul t of pers i s tent va s omotor
i ns ta bi l i ty.
An i nfl a mma tory pha s e often fol l ows , i n whi ch s teri l e pa pul es a nd pus tul es (l ea di ng to the des i gna ti on of ros a cea a s a dul t a cne) devel op.
Some pa ti ents go on to devel op l a te-s ta ge ros a cea , cha ra cteri zed by coa rs e ti s s ue hyperpl a s i a of the cheeks a nd nos e (rhi nophyma ) ca us ed by
ti s s ue i nfl a mma ti on, col l a gen depos i ti on, a nd s eba ceous gl a nd hyperpl a s i a .
The pha s es of ros a cea a re us ua l l y s equenti a l . Some pa ti ents go di rectl y i nto the i nfl a mma tory s ta ge, bypa s s i ng the ea rl i er s ta ges . Trea tment ma y
ca us e ros a cea to return to a n ea rl i er s ta ge. Progres s i on to the l a te s ta ge i s not i nevi ta bl e.
Ocul a r ros a cea often a ccompa ni es fa ci a l ros a cea a nd ma ni fes ts a s s ome combi na ti on of bl epha roconjuncti vi ti s , i ri ti s , s cl eri ti s , a nd kera ti ti s ,
ca us i ng i tchi ng, forei gn body s ens a ti on, erythema , a nd edema of the eye.
Diagnosis
Di a gnos i s i s ba s ed on the cha ra cteri s ti c a ppea ra nce; there a re no s peci fi c di a gnos ti c tes ts . The a ge of ons et a nd a bs ence of comedones hel p
di s ti ngui s h ros a cea from a cne. Di fferenti a l di a gnos i s i ncl udes a cne vul ga ri s , SLE, s a rcoi dos i s , photoderma ti ti s , drug erupti ons (pa rti cul a rl y from
i odi des a nd bromi des ), gra nul oma s of the s ki n, a nd peri ora l derma ti ti s .
Treatment
Avoi da nce of tri ggers
Cons i dera ti on of topi ca l or ora l a nti bi oti cs
Cons i dera ti on of i s otreti noi n i f a nti bi oti cs a re uns ucces s ful
Cons i dera ti on of derma bra s i on a nd ti s s ue exci s i on for rhi nophyma
Pri ma ry i ni ti a l trea tment of ros a cea i nvol ves a voi da nce of tri ggers (i ncl udi ng us e of s uns creen). Anti bi oti cs ma y be us ed for i nfl a mma tory di s ea s e.
The objecti ve of trea tment i s control of s ymptoms , not cure.
Metroni da zol e crea m 1%, l oti on (0.75%), or gel (0.75%) a nd a zel a i c a ci d 20% crea m, a ppl i ed bi d, a re equa l l y effecti ve; 2.5% benzoyl peroxi de,
a ppl i ed once/da y or bi d, ca n be a dded for i mproved control . Les s effecti ve a l terna ti ves i ncl ude s odi um s ul fa ceta mi de 10%/s ul fur 5% l oti on;
cl i nda myci n 1% s ol uti on, gel , or l oti on; a nd erythromyci n 2% s ol uti on, a l l a ppl i ed bi d. Ma ny pa ti ents requi re i ndefi ni te trea tment for chroni c
control .
Ora l a nti bi oti cs a re i ndi ca ted for pa ti ents wi th mul ti pl e pa pul es or pus tul es a nd for thos e wi th ocul a r ros a cea ; opti ons i ncl ude tetra cycl i ne 250 to
500 mg bi d, doxycycl i ne 50 to 100 mg bi d, mi nocycl i ne 50 to 100 mg bi d, a nd erythromyci n 250 to 500 mg bi d. Dos e s houl d be reduced to the l owes t
one tha t control s s ymptoms once a benefi ci a l res pons e i s a chi eved. Reca l ci tra nt ca s es ma y res pond to ora l i s otreti noi n. Suba nti mi crobi a l dos es
of doxycycl i ne a re a l s o effecti ve for a cne a nd ros a cea .
Techni ques for trea tment of rhi nophyma i ncl ude derma bra s i on a nd ti s s ue exci s i on; cos meti c res ul ts a re good.
Chapter 74. Bullous Diseases

Introduction
Bul l a e a re el eva ted, fl ui d-fi l l ed bl i s ters 5 mm i n di a meter. Bul l ous di s ea s es i ncl ude bul l ous pemphi goi d, derma ti ti s herpeti formi s ,
epi dermol ys i s bul l os a a cqui s i ta , herpes ges ta ti oni s (pemphi goi d ges ta ti oni s s ee p. 2666), l i nea r IgA di s ea s e, pemphi gus vul ga ri s , a nd
pemphi gus fol i a ceus . Sta phyl ococca l s ca l ded s ki n s yndrome (s ee p. 701) a nd toxi c epi derma l necrol ys i s (s ee p. 689) a l s o ca us e bul l a e.
Bullous Pemphigoid
Bullous pemphigoid is an autoimmune skin disorder causing chronic, pruritic bullous eruptions in elderly patients. Diagnosis is by skin biopsy. Corticosteroids are
used initially. Most patients require long-term maintenance therapy, for which a variety of drugs can be used.
In bul l ous pemphi goi d, a nti bodi es a re di rected a ga i ns t the ba s ement membra ne zone of the epi dermi s , ca us i ng s epa ra ti on between the
epi dermi s a nd dermi s . Bul l ous pemphi goi d mus t be di s ti ngui s hed from pemphi gus vul ga ri s (s ee p. 658), a much more s eri ous di s ea s e.
Symptoms and Signs
Cha ra cteri s ti c tens e bul l a e devel op on norma l -a ppea ri ng or erythema tous s ki n, mos t often i n fl exura l a rea s . Ni kol s ky's s i gn, i n whi ch l a tera l
pres s ure on s ki n a dja cent to a bl i s ter ca us es epi derma l deta chment, i s nega ti ve. Bul l ous pemphi goi d ca n ma ni fes t i ni ti a l l y a s hi ves wi th a nnul a r,
dus ky-red, edema tous l es i ons , wi th or wi thout peri phera l ves i cl es . Itchi ng i s common, us ua l l y wi thout other s ymptoms . Ora l l es i ons occur i n
a bout one thi rd of pa ti ents but hea l ra pi dl y.
Diagnosis
Ski n bi ops y a nd a nti body ti ters
Pa ti ents s houl d ha ve a s ki n bi ops y a nd s erum a nti body ti ters for hemi des mos oma l BP a nti gens BP230 (BPAg1) a nd BP180 (BPAg2).
Bul l ous pemphi goi d mus t be di fferenti a ted from pemphi gus vul ga ri s (s ee
Ta bl e 74-1), l i nea r IgA di s ea s e, erythema mul ti forme, drug-i nduced erupti ons , beni gn mucous membra ne pemphi goi d, pa ra neopl a s ti c
pemphi goi d, derma ti ti s herpeti formi s , a nd epi dermol ys i s bul l os a a cqui s i ta .
Prognosis
Prognos i s i s good, a nd the di s order us ua l l y s ubs i des wi thi n months to yea rs ; however, the di s order i s potenti a l l y fa ta l , es peci a l l y i n the el derl y
a nd debi l i ta ted pa ti ents , wi th dea th bei ng ca us ed by i nfecti on a nd s eps i s or the effects of the drugs .
Treatment
Corti cos teroi ds , topi ca l or ora l
Anti -i nfl a mma tory drugs
Mi l d bul l ous pemphi goi d s ometi mes res ol ves wi thout trea tment, but res ol uti on us ua l l y
[Table 74-1. Di s ti ngui s hi ng Pemphi goi d from Pemphi gus Vul ga ri s ]
ta kes months or yea rs . Pa ti ents wi th more s evere di s ea s e recei ve predni s one 60 to 80 mg po once/da y, whi ch ca n be ta pered to a ma i ntena nce
l evel of 10 to 20 mg/da y a fter s evera l weeks . Mos t pa ti ents a chi eve remi s s i on a fter 2 to 10 mo. Occa s i ona l new l es i ons i n el derl y pa ti ents do not
requi re i ncrea s i ng the predni s one dos a ge.
The di s order occa s i ona l l y res ponds to a combi na ti on of tetra cycl i ne or mi nocycl i ne a nd ni coti na mi de. Other trea tment opti ons i ncl ude da ps one,
s ul fa pyri di ne, erythromyci n, a nd tetra cycl i ne us ed a l one for thei r a nti -i nfl a mma tory ra ther tha n thei r a nti bi oti c properti es . IV i mmune gl obul i n
ha s been us ed occa s i ona l l y. For pa ti ents wi th genera l i zed a nd reca l ci tra nt di s ea s e, i mmunos uppres s a nts s uch a s a za thi opri ne,
cycl ophos pha mi de, ri tuxi ma b, a nd cycl os pori ne ma y be us ed. However, us e of i mmunos uppres s a nts for bul l ous pemphi goi d i s controvers i a l .
Dermatitis Herpetiformis
Dermatitis herpetiformis is a cutaneous manifestation associated with gluten sensitivity. It produces a chronic eruption characterized by clusters of intensely
pruritic vesicles, papules, and urticaria-like lesions. The cause is autoimmune. Diagnosis is by skin biopsy with direct immunofluorescence testing. Treatment is
usually with dapsone or sulfapyridine and a gluten-free diet.
Thi s di s ea s e us ua l l y ma ni fes ts i n pa ti ents 30 to 40 yr ol d (but ma y occur from a ge 2 to 90 yr) a nd i s ra re i n bl a cks a nd As i a ns .
More tha n 90% of a ffected pa ti ents ha ve a gl uten-s ens i ti ve enteropa thy, whi ch i s often a s ymptoma ti c. Derma ti ti s herpeti formi s devel ops i n 15 to
25% of pa ti ents wi th cel i a c s prue. Pa ti ents ha ve a s l i ghtl y hi gher i nci dence of other a utoi mmune di s orders , i ncl udi ng type 1 di a betes mel l i tus ,
s a rcoi dos i s , SLE, a nd thyroi d a bnorma l i ti es . The i nci dence of enteropa thy-a s s oci a ted T-cel l l ymphoma i s a l s o i ncrea s ed.
The term herpeti formi s refers to the cl us tered a ppea ra nce of the l es i ons ra ther tha n a rel a ti ons hi p to herpes vi rus .
Symptoms and Signs
Ons et i s us ua l l y gra dua l . Ves i cl es , pa pul es , a nd urti ca ri a -l i ke l es i ons a re us ua l l y di s tri buted s ymmetri ca l l y on extens or a s pects (el bows , knees ,
s a crum, buttocks , occi put). Ves i cl es a nd pa pul es occur i n a bout one thi rd of pa ti ents . Itchi ng a nd burni ng a re s evere, a nd s cra tchi ng often
obs cures the pri ma ry l es i ons wi th eczema ti za ti on of nea rby s ki n, l ea di ng to a n erroneous di a gnos i s of eczema . NSAIDs a nd i odi des ma y wors en
the ra s h.
Diagnosis
Ski n bi ops y
Di a gnos i s i s ba s ed on s ki n bi ops y a nd di rect i mmunofl uores cence tes ti ng of a l es i on a nd a dja cent norma l -a ppea ri ng s ki n. Gra nul a r IgA
depos i ti on i n the derma l pa pi l l a ry ti ps i s i nva ri a bl y pres ent a nd i mporta nt for di a gnos i s . Pa ti ents s houl d be eva l ua ted for cel i a c s prue (s ee p.
158).
Treatment
Gl uten-free di et
Da ps one
Stri ct a dherence to a gl uten-free di et for a prol onged ti me (eg, 6 to 12 mo) control s the di s ea s e i n s ome pa ti ents , obvi a ti ng or reduci ng the need
for drug thera py. When drugs a re needed, da ps one genera l l y res ul ts i n rema rka bl e i mprovement. Ini ti a l dos a ges of da ps one a re 25 to 50 mg po
once/da y i n a dul ts a nd 0.5 mg/kg i n chi l dren. Us ua l l y, thi s dos e dra ma ti ca l l y rel i eves s ymptoms , i ncl udi ng i tchi ng, wi thi n 1 to 3 da ys ; i f i t does , the
dos e i s conti nued. If no i mprovement occurs , the dos e ca n be i ncrea s ed every week, up to 300 mg/da y. Mos t pa ti ents ca n be ma i nta i ned on 50 to
150 mg/da y, a nd s ome requi re a s l i ttl e a s 25 mg/wk. After i ni ti a l thera py a nd s ta bi l i za ti on of the di s ea s e, the ma jori ty of pa ti ents ca n be
ma i nta i ned on a s tri ct gl uten-free di et. Al though l es s effecti ve, s ul fa pyri di ne ma y be us ed a s a n a l terna ti ve for pa ti ents who ca nnot tol era te
da ps one. Ini ti a l ora l dos a ge i s 500 mg bi d, i ncrea s i ng by 1 g/da y q 1 to 2 wk unti l di s ea s e i s control l ed. Ma i ntena nce dos a ge va ri es from 500 mg
twi ce/wk to 1000 mg once/da y. Col chi ci ne i s a nother trea tment opti on. Trea tment conti nues unti l l es i ons res ol ve.
In pa ti ents wi th G6PD defi ci ency, da ps one ma y ca us e s evere hemol ys i s . Pa ti ents recei vi ng da ps one or s ul fa pyri di ne s houl d ha ve a ba s el i ne CBC;
CBC i s then done weekl y for 4 wk, then every 2 to 3 wk for 8 wk, a nd every 12 to 16 wk therea fter. Hemol yti c a nemi a a nd methemogl obi nemi a a re
the mos t frequentl y encountered a dvers e effects . CNS or l i ver toxi ci ty i s ra re. If da ps one thera py ca us es cons i dera bl e hemol ys i s , s i gni fi ca nt
ca rdi opul mona ry probl ems , or peri phera l neuropa thy, s ul fa pyri di ne ma y be us ed. Sul fa pyri di ne us ua l l y does not i nduce s i gni fi ca nt hemol ys i s .
Epidermolysis Bullosa Acquisita
Epidermolysis bullosa acquisita is a chronic autoimmune mucocutaneous disease causing blistering and skin fragility.
Epi dermol ys i s bul l os a a cqui s i ta us ua l l y a ppea rs i n a dul ts . Bul l ous l es i ons ma y devel op on norma l -a ppea ri ng s ki n s ponta neous l y or ma y be
ca us ed by mi nor tra uma . The tra uma -prone a rea s of the s ki n, s uch a s the extens or s urfa ces of el bows , knees , a nkl es , a nd buttocks , a re mos t
commonl y a ffected. Pa i n a nd s ca rri ng a re common. Beca us e the ha nds a nd feet a re often i nvol ved, di s a bi l i ty ca n be s i gni fi ca nt. Occa s i ona l l y,
mucos a of eyes , mouth, or geni ta l s i s i nvol ved. La ryngea l a nd es opha gea l i nvol vement a l s o occurs . Di a gnos i s i s by s ki n bi ops y. Les i ons res pond
poorl y to corti cos teroi ds . Mi l d di s ea s e ma y be trea ted wi th col chi ci ne, but more s evere di s ea s e ma y requi re cycl os pori ne or i mmune gl obul i n.
Linear Immunoglobulin A Disease
Linear immunoglobulin A (IgA) disease is an uncommon bullous disease distinguished from bullous pemphigoid and dermatitis herpetiformis by the linear deposits
of IgA in the basement membrane zone.
Li nea r IgA di s ea s e occurs i n a dul ts a nd chi l dren. The chi l dhood form i s mos t frequentl y termed chroni c bul l ous di s ea s e of chi l dhood.
In l i nea r IgA di s ea s e, ves i cul a r or bul l ous s ki n l es i ons occur frequentl y i n a cl us tered (herpeti form) a rra ngement. There i s a predi l ecti on for
fl exura l a rea s (eg, i ngui na l crea s e). As i n derma ti ti s herpeti formi s , s evere burni ng a nd pruri tus of cuta neous l es i ons a re promi nent fea tures . It
wa s previ ous l y cons i dered a form of derma ti ti s herpeti formi s but ha s no concomi ta nt gl uten-s ens i ti ve enteropa thy a nd i mmunopa thol ogy. Al s o,
geneti c s tudi es i ndi ca te tha t l i nea r IgA di s ea s e i s a s epa ra te di s order. Drug-i nduced l i nea r IgA di s ea s e, mos t commonl y a s s oci a ted wi th
va ncomyci n, ha s been reported.
Di a gnos i s i s by s ki n bi ops y. Da ps one i s the trea tment of choi ce. Dos es s houl d be s i mi l a r to thos e us ed for derma ti ti s herpeti formi s (s ee p. 657),
a nd CBC moni tori ng s houl d fol l ow the s a me pa ra meters . Other trea tment opti ons i ncl ude gl ucocorti coi ds (s ys temi c, topi ca l , a nd i ntra l es i ona l ),
cycl ophos pha mi de, a za thi opri ne, col chi ci ne, tetra cycl i ne a nd ni coti na mi de, a nd cycl os pori ne.
Pemphigus Vulgaris
Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently
healthy skin and mucous membranes. Diagnosis is by skin biopsy with direct immunofluorescence testing. Treatment is with corticosteroids and sometimes
immunosuppressants.
Pemphi gus vul ga ri s us ua l l y occurs i n mi ddl e-a ged or el derl y pa ti ents a nd i s ra re i n chi l dren. One va ri a nt, pa ra neopl a s ti c pemphi gus , occurs i n
ol der pa ti ents wi th ca ncer (pri ma ri l y l ymphoreti cul a r); outcome i s poor.
The di s order i s cha ra cteri zed by the pres ence of a utoa nti bodi es di rected a ga i ns t i ntercel l ul a r a dhes i on mol ecul es des mogl ei n-1 a nd
des mogl ei n-3 i n the epi dermi s . They a re Ca -dependent ca dheri ns , i nvol ved i n a dhes i on a nd cel l s i gna l i ng between epi derma l cel l s . Aca nthol ys i s
res ul ts from ei ther di rect i nhi bi ti on of functi on of the des mogl ei ns by a utoa nti body bi ndi ng or from a utoa nti body-i nduced cel l s i gna l i ng tha t
res ul ts i n down-regul a ti on of cel l -cel l a dhes i on a nd forma ti on of bl i s ters . Thes e a utoa nti bodi es a re pres ent i n both s erum a nd s ki n duri ng a cti ve
di s ea s e. Any a rea of s tra ti fi ed s qua mous epi thel i um ma y be a ffected, i ncl udi ng mucos a l s urfa ces .
Symptoms and Signs
The pri ma ry l es i ons a re fl a cci d bul l a e of va ri ous s i zes (s ee

Pl a te 41), but often s ki n or mucos a jus t s hea rs off, l ea vi ng pa i nful eros i ons . Les i ons typi ca l l y occur fi rs t i n the mouth, where they rupture a nd
rema i n a s chroni c, often pa i nful , eros i ons for va ri a bl e peri ods before the s ki n i s a ffected; dys pha gi a a nd poor ora l i nta ke a re common. Les i ons
a l s o ma y occur i n the upper es opha gus . Cuta neous bul l a e typi ca l l y a ri s e from norma l -a ppea ri ng s ki n, rupture, a nd l ea ve a ra w a rea a nd crus ti ng.
Itchi ng i s us ua l l y a bs ent. Open s ki n l es i ons often become i nfected. If l a rge porti ons of the body a re a ffected, fl ui d a nd el ectrol yte l os s ma y be
s i gni fi ca nt.
Diagnosis
Bi ops y wi th di rect i mmunofl uores cence tes ti ng
Someti mes ti ters of a nti bodi es a ga i ns t des mogl ei n-3 or des mogl ei n-1
Pemphi gus vul ga ri s s houl d be s us pected i n pa ti ents wi th a ny bul l ous di s order or chroni c mucos a l ul cera ti on. It mus t be di fferenti a ted from other
chroni c ora l ul cers a nd from other bul l ous derma tos es (eg, pemphi gus fol i a ceus , bul l ous pemphi goi d, mucous membra ne pemphi goi d, drug
erupti ons , toxi c epi derma l necrol ys i s , erythema mul ti forme, derma ti ti s herpeti formi s , bul l ous conta ct derma ti ti s ). Two phys i ca l s i gns i n
pemphi gus vul ga ri s a re hel pful :
La tera l pres s ure on s ki n a dja cent to a bl i s ter ca us es epi derma l deta chment (Ni kol s ky's s i gn).
Pres s ure on a bl i s ter ca n ca us e the bl i s ter to extend to a dja cent s ki n (As boe-Ha ns en s i gn).
Bi ops y of the edge of a fres h l es i on a nd of a nea rby a rea of norma l s ki n i s requi red; l i ght mi cros copy a nd di rect i mmunofl uores cence tes ti ng a re
us ua l l y di a gnos ti c. Serum a nti bodi es (eg, to des mogl ei n-3) ca n be us ed for di a gnos i s a nd for di fferenti a ti ng from pemphi gus fol i a ceus ; s eri a l
ti ters ca n hel p fol l ow di s ea s e a cti vi ty.
Prognosis
Before s ys temi c corti cos teroi ds were us ed, pemphi gus vul ga ri s wa s us ua l l y fa ta l ; mos t pa ti ents di ed wi thi n 5 yr of di s ea s e ons et. Even wi th
trea tment, pemphi gus vul ga ri s i s a s eri ous di s order wi th a n i ncons i s tent a nd unpredi cta bl e res pons e to trea tment, a prol onged cours e, a nd
vi rtua l l y i nevi ta bl e a dvers e drug effects .
Treatment
Corti cos teroi ds , ora l or IV
Someti mes i mmunos uppres s a nts
Someti mes pl a s ma pheres i s a nd IV i mmune gl obul i n (IVIG)
Referra l to a derma tol ogi s t wi th experti s e i n trea ti ng thi s di s order i s recommended. Hos pi ta l i za ti on i s requi red i ni ti a l l y for a l l but the mos t mi nor
ca s es . Cl ea ns i ng a nd dres s i ng of open s ki n l es i ons i s s i mi l a r to tha t done for pa rti a l -thi cknes s burns (eg, revers e i s ol a ti on, hydrocol l oi d or s i l ver
s ul fa di a zi ne dres s i ngs s ee p. 3246).
Drug trea tment a i ms to decrea s e the producti on of a utoa nti bodi es a nd s top the erupti on of new l es i ons . The ma i ns ta y i s s ys temi c corti cos teroi ds .
Some pa ti ents wi th few l es i ons ma y res pond to ora l predni s one 20 to 30 mg once/da y, but mos t requi re 1.0 mg/kg once/da y a s a n i ni ti a l dos e.
Some cl i ni ci a ns begi n wi th even hi gher dos es , whi ch ma y s l i ghtl y ha s ten i ni ti a l res pons e but does not a ppea r to i mprove outcome. If new l es i ons
conti nue to a ppea r a fter 5 to 7 da ys , IV pul s e thera py wi th methyl predni s ol one 1 g once/da y ca n be tri ed.
Immunos uppres s a nts s uch a s methotrexa te, cycl ophos pha mi de, a za thi opri ne, gol d, mycophenol a te mofeti l , cycl os pori ne, or ri tuxi ma b ca n reduce
the need for corti cos teroi ds a nd thus mi ni mi ze the undes i ra bl e effects of l ong-term corti cos teroi d us e. Pl a s ma pheres i s a nd hi gh-dos e IVIG to
reduce a nti body ti ters ha ve a l s o been effecti ve.
Once no new l es i ons ha ve a ppea red for 7 to 10 da ys , corti cos teroi d dos e s houl d be ta pered monthl y by a bout 10 mg/da y (ta peri ng conti nues more
s l owl y once 20 mg/da y i s rea ched). A rel a ps e requi res a return to the s ta rti ng dos e. If the pa ti ent ha s been s ta bl e a fter a yea r, a tri a l wi thout
trea tment ca n be a ttempted but mus t be cl os el y moni tored.
Pemphigus Foliaceus
Pemphigus foliaceus is a generally benign blistering disorder. It is characterized by splitting high in the epidermis, causing erosions to form on the skin.
Pemphi gus fol i a ceus us ua l l y occurs i n mi ddl e-a ged pa ti ents . Foci of hi gh i nci dence occur i n South Ameri ca , es peci a l l y Bra zi l .
The pri ma ry l es i on i s a fl a cci d bul l a . However, beca us e s pl i tti ng occurs hi gh i n the epi dermi s , bul l a e a re ra rel y s een; the bl i s ters a re s o fra gi l e
tha t they rupture. Cl i ni ca l l y, s ca l y, crus ted cuta neous eros i ons , often on a n erythema tous ba s e, ca n be s een. Mucos a l s urfa ces a re not us ua l l y
i nvol ved. In one va ri a nt, pemphi gus erythema tos us , l es i ons occur on l i ght-expos ed s ki n a nd a re often s i mi l a r to thos e of cuta neous l upus
erythema tos us .
Di a gnos i s i s by bi ops y of a l es i on a nd nei ghbori ng norma l s ki n a nd by s erum a nti body ti ters a ga i ns t the cel l a dhes i on mol ecul e des mogl ei n 1
(160 kd). Beca us e the di s order i s much more beni gn tha n pemphi gus vul ga ri s , trea tment i s genera l l y l es s a ggres s i ve. Superpotent topi ca l
corti cos teroi ds ma y be s uffi ci ent i n s ome pa ti ents . Others requi re ora l predni s one a nd a ddi ti ona l i mmunos uppres s a nts . A combi na ti on of
tetra cycl i ne 500 mg qi d a nd ni coti na mi de 1.5 g/da y ha s been effecti ve i n s ome pa ti ents . Pl a s ma pheres i s i s a n opti on for s evere di s ea s e.
Chapter 75. Cornification Disorders

Introduction
Corni fi ca ti on di s orders i ncl ude ca l l us es , corns , i chthyos i s , a nd kera tos i s pi l a ri s .
Calluses and Corns
(Tyl oma s ; Hel oma s ; Cl a vi )
Calluses and corns are circumscribed areas of hyperkeratosis at a site of intermittent pressure or friction. Calluses are more superficial, cover broader areas of
skin, and usually asymptomatic. Corns are deeper, more focal, and frequently painful. Diagnosis is by appearance. Treatment is with manual abrasion with or
without keratolytics. Prevention involves altering biomechanics, such as changing footwear. Rarely, surgery is required.
Ca l l us es a nd corns a re ca us ed by i ntermi ttent pres s ure or fri cti on, us ua l l y over a bony promi nence (eg, heel , meta ta rs a l hea ds ).
Corns cons i s t of a s ha rpl y ci rcums cri bed kera ti nous pl ug, pea -s i zed or s l i ghtl y l a rger, whi ch extends through mos t of the underl yi ng dermi s . An
underl yi ng a dventi ti a l burs i ti s ma y devel op. Ha rd corns occur over promi nent bony protubera nces , es peci a l l y on the toes a nd pl a nta r s urfa ce. Soft
corns occur between the toes . Mos t corns res ul t from poorl y fi tti ng footwea r, but s ma l l s eed-s i zed corns on non-wei ght-bea ri ng a s pects of the
s ol es a nd pa l ms ma y repres ent i nheri ted kera tos i s puncta ta .
Calluses l a ck a centra l pl ug a nd ha ve a more even a ppea ra nce. They us ua l l y occur on the ha nds or feet but ma y occur el s ewhere, es peci a l l y i n a
pers on whos e occupa ti on enta i l s repea ted tra uma to a pa rti cul a r a rea (eg, the ma ndi bl e a nd cl a vi cl e of a vi ol i ni s t).
Symptoms and Signs
Ca l l us es a re us ua l l y a s ymptoma ti c but, i f fri cti on i s extreme, ma y become i rri ta ted, ca us i ng mi l d burni ng di s comfort. At ti mes , the di s comfort ma y
mi mi c tha t of i nterdi gi ta l neura l gi a .
Corns ma y be pa i nful or tender when pres s ure i s a ppl i ed. A burs a or fl ui d-fi l l ed pocket s ometi mes forms benea th a corn.
Diagnosis
A corn ma y be di fferenti a ted from a pl a nta r wa rt or ca l l us by pa ri ng a wa y the horny s ki n. After pa ri ng, a ca l l us s hows s mooth tra ns l ucent s ki n,
wherea s a wa rt (s ee p. 715) a ppea rs s ha rpl y ci rcums cri bed, s ometi mes wi th s oft ma cera ted ti s s ue or wi th centra l bl a ck dots (bl eedi ng poi nts )
repres enti ng thrombos ed ca pi l l a ri es . A corn, when pa red, s hows a s ha rpl y outl i ned yel l owi s h to ta n tra ns l ucent core tha t i nterrupts the norma l
a rchi tecture of the pa pi l l a ry dermi s . Interdi gi ta l neura l gi a ca n be rul ed out by the a bs ence of i nters pa ce pa i n on pa l pa ti on.
Treatment
Ma nua l remova l
Kera tol yti cs
Cus hi oni ng
Al teri ng foot bi omecha ni cs
A na i l fi l e, emery boa rd, or pumi ce s tone us ed i mmedi a tel y a fter ba thi ng i s often a pra cti ca l wa y to ma nua l l y remove hyperkera toti c ti s s ue.
Kera tol yti cs (eg, 17% s a l i cyl i c a ci d i n col l odi on, 40% s a l i cyl i c a ci d pl a s ters , 40% urea ) ca n a l s o be us ed, ta ki ng ca re to a voi d a ppl yi ng the a gents to
norma l s ki n. Norma l s ki n ma y be protected by coveri ng i t wi th petrol a tum before a ppl i ca ti on of the kera tol yti c.
Cus hi oni ng a nd a l teri ng foot bi omecha ni cs ca n hel p prevent corns a nd hel p trea t exi s ti ng corns . Al though di ffi cul t to el i mi na te, pres s ure on the
a ffected s urfa ce s houl d be reduced a nd redi s tri buted. For foot l es i ons , s oft, wel l -fi tti ng s hoes a re i mporta nt; they s houl d ha ve a roomy toe box s o
tha t toes ca n move freel y i n the s hoe. Styl i s h s hoes often prevent thi s freedom of moti on. Shoes tha t i ncrea s e di s comfort of a l es i on s houl d be
el i mi na ted from the wa rdrobe. Pa ds or ri ngs of s ui ta bl e s ha pes a nd s i zes , mol es ki n or foa m-rubber protecti ve ba nda ges , a rch i ns erts (orthoti cs ),
or meta ta rs a l pl a tes or ba rs ma y hel p redi s tri bute the pres s ure. For corns a nd ca l l us es on the ba l l of the foot, a n orthoti c s houl d not be ful l
l ength but s houl d extend onl y to the ba l l or pa rt of the s hoe i mmedi a tel y behi nd the corn or ca l l us . Surgi ca l off-l oa di ng or remova l of the
offendi ng bone i s ra rel y neces s a ry.
Pa ti ents who ha ve a tendency to devel op ca l l us es a nd corns ma y need the regul a r s ervi ces of a podi a tri s t. Pa ti ents wi th i mpa i red peri phera l
ci rcul a ti on, es peci a l l y i f a s s oci a ted wi th di a betes , requi re expert ca re.
Ichthyosis
Ichthyosis is scaling and flaking of skin ranging from mild but annoying dryness (xeroderma) to severe disfiguring disease (inherited ichthyosis). Ichthyosis can
also be a sign of systemic disease. Diagnosis is clinical. Treatment involves emollients and sometimes oral retinoids.
Xeroderma: Xeroderma (xeros i s ), or dry s ki n, i s nei ther i nheri ted nor a s s oci a ted wi th s ys temi c a bnorma l i ti es . Dry s ki n res ul ts from l os s of the wa ter
content of the s ki n, res ul ti ng i n fi ne whi te s ca l es . Ri s k fa ctors for xeros i s i ncl ude the fol l owi ng:
Res i dence i n a dry, col d cl i ma te
Ol der a ge
Atopi c derma ti ti s
Frequent ba thi ng, pa rti cul a rl y i f us i ng ha rs h s oa ps
Inherited ichthyoses: Inheri ted i chthyos es , whi ch a re cha ra cteri zed by exces s i ve a ccumul a ti on of s ca l e on the s ki n s urfa ce, a re cl a s s i fi ed a ccordi ng
to cl i ni ca l a nd geneti c cri teri a (s ee
Ta bl e 75-1). Some occur i n i s ol a ti on wi thout
[Table 75-1. Cl i ni ca l a nd Geneti c Fea tures of Some Inheri ted Ichthyos es ]
a s s oci a ted a bnorma l i ti es (eg, i chthyos i s vul ga ri s , X-l i nked i chthyos i s , l a mel l a r i chthyos i s , epi dermol yti c hyperkera tos i s [bul l ous congeni ta l
i chthyos i form erythroderma ]). Other i chthyos es a re pa rt of a s yndrome tha t i nvol ves mul ti pl e orga ns . For i ns ta nce, Refs um's di s ea s e (s ee p. 3024)
a nd Sjogren-La rs s on s yndrome (heredi ta ry i ntel l ectua l di s a bi l i ty a nd s pa s ti c pa ra l ys i s ca us ed by a defect i n fa tty a l dehyde dehydrogena s e) a re
a utos oma l reces s i ve condi ti ons wi th s ki n a nd extra cuta neous orga n i nvol vement. A derma tol ogi s t s houl d a s s i s t i n di a gnos i s a nd ma na gement,
a nd a medi ca l geneti ci s t s houl d be cons ul ted for geneti c couns el i ng.
Acquired ichthyosis: Ichthyos i s ma y be a n ea rl y ma ni fes ta ti on of s ome s ys temi c di s orders (eg, l epros y, hypothyroi di s m, l ymphoma , AIDS). Some
drugs ca us e i chthyos i s (eg, ni coti ni c a ci d, tri pa ra nol , butyrophenones ). The dry s ca l i ng ma y be fi ne a nd l oca l i zed to the trunk a nd l egs , or i t ma y be
thi ck a nd wi des prea d. Bi ops y of i chthyoti c s ki n i s us ua l l y not di a gnos ti c of the s ys temi c di s order; however, there a re excepti ons , mos t nota bl y
s a rcoi dos i s , i n whi ch a thi ck s ca l i ng ma y a ppea r on the l egs , a nd bi ops y us ua l l y s hows the typi ca l gra nul oma s .
Treatment
Mi ni mi za ti on of exa cerba ti ng fa ctors
Moi s turi za ti on a nd kera tol yti cs
Someti mes i nfecti on prophyl a xi s
When i chthyos i s i s ca us ed by a s ys temi c di s order, a ba tement i s grea tes t i f the pri ma ry di s order ca n be corrected. Otherwi s e, trea tment i s
s ymptoma ti c, i ncl udi ng us i ng emol l i ents a nd kera tol yti cs a nd a voi di ng dryi ng.
Moisturization and keratolytics: In a ny i chthyos i s , there i s i mpa i red epi derma l ba rri er functi on, a nd moi s turi zers s houl d be a ppl i ed i mmedi a tel y
a fter ba thi ng. Subs ta nces tha t a re a ppl i ed to the s ki n ma y ha ve i ncrea s ed a bs orpti on. For exa mpl e, hexa chl orophene products s houl d not be us ed
beca us e of i ncrea s ed a bs orpti on a nd toxi ci ty.
An emol l i ent, prefera bl y pl a i n petrol a tum, mi nera l oi l , or l oti ons conta i ni ng urea or -hydroxy a ci ds (eg, l a cti c, gl ycol i c, a nd pyruvi c a ci ds ), s houl d
be a ppl i ed twi ce da i l y, es peci a l l y a fter ba thi ng whi l e the s ki n i s s ti l l wet. Bl otti ng wi th a towel removes exces s a ppl i ed ma teri a l .
Ichthyos i s typi ca l l y res ponds wel l to propyl ene gl ycol . To remove s ca l e (eg, i f i chthyos i s i s s evere), pa ti ents ca n a ppl y a prepa ra ti on conta i ni ng 40
to 60% propyl ene gl ycol i n wa ter under occl us i on (eg, a thi n pl a s ti c fi l m or ba g), every ni ght a fter hydra ti ng the s ki n (eg, by ba thi ng or s howeri ng);
i n chi l dren, the prepa ra ti on s houl d be a ppl i ed twi ce da i l y wi thout occl us i on. Occl us i on s houl d be ma i nta i ned overni ght. After s ca l i ng ha s
decrea s ed, l es s frequent a ppl i ca ti on i s requi red. Other us eful kera tol yti cs i ncl ude cera mi de-ba s ed crea ms , 6% s a l i cyl i c a ci d gel , hydrophi l i c
petrol a tum a nd wa ter (i n equa l pa rts ), a nd the -hydroxy a ci ds i n va ri ous ba s es . Topi ca l ca l ci potri ol crea m ha s been us ed wi th s ucces s ; however,
thi s vi ta mi n D deri va ti ve ca n res ul t i n hyperca l cemi a when us ed over broa d a rea s , es peci a l l y i n s ma l l chi l dren.
Retinoids a re effecti ve i n trea ti ng i chthyos i s . Ora l s yntheti c reti noi ds a re effecti ve for mos t i chthyos es . Aci treti n (s ee p. 679) i s effecti ve i n trea ti ng
mos t forms of i nheri ted i chthyos i s . In l a mel l a r i chthyos i s , 0.1% treti noi n crea m or ora l i s otreti noi n ma y be effecti ve. The l owes t effecti ve dos e
s houl d be us ed. Long-term (1 yr) trea tment wi th ora l i s otreti noi n ha s res ul ted i n bony exos tos es i n s ome pa ti ents , a nd other l ong-term a dvers e
effects ma y a ri s e. (CAUTION: Oral retinoids are contraindicated in pregnancy because of their teratogenicity, and acitretin should be avoided in women of
childbearing potential because of its teratogenicity and long half-life.)
Infection prophylaxis: Pa ti ents wi th epi dermol yti c hyperkera tos i s ma y need l ong-term trea tment wi th cl oxa ci l l i n 250 mg po ti d or qi d or erythromyci n
250 mg po ti d or qi d, a s l ong a s thi ck i ntertri gi nous s ca l i ng i s pres ent, to prevent ba cteri a l s uperi nfecti on from ca us i ng pa i nful , foul -s mel l i ng
pus tul es . Regul a rl y us i ng s oa ps conta i ni ng chl orhexi di ne ma y a l s o reduce the ba cteri a , but thes e s oa ps tend to dry the s ki n.
Keratosis Pilaris
Keratosis pilaris is a disorder of keratinization in which horny plugs fill the openings of hair follicles.
Kera tos i s pi l a ri s i s common. The ca us e i s unknown, but there i s often a n a utos oma l domi na nt i nheri ta nce. Mul ti pl e s ma l l , poi nted, kera toti c
fol l i cul a r pa pul es a ppea r ma i nl y on the l a tera l a s pects of the upper a rms , thi ghs , a nd buttocks . Fa ci a l l es i ons ma y a l s o occur, pa rti cul a rl y i n
chi l dren. Les i ons a re mos t promi nent i n col d wea ther a nd s ometi mes a ba te i n the s ummer. Ski n ma y a ppea r red. The probl em i s ma i nl y cos meti c,
but the di s order ma y ca us e i tchi ng or, ra rel y, fol l i cul a r pus tul es .
Trea tment i s us ua l l y unneces s a ry a nd often uns a ti s fa ctory. Hydrophi l i c petrol a tum a nd wa ter (i n equa l pa rts ), col d crea m, or petrol a tum wi th 3%
s a l i cyl i c a ci d ma y hel p fl a tten the l es i ons . Buffered l a cti c a ci d (a mmoni um l a cta te) l oti ons or crea ms , urea crea ms , 6% s a l i cyl i c a ci d gel , or 0.1%
treti noi n crea m ma y a l s o be effecti ve. Aci d crea ms s houl d be a voi ded i n young chi l dren beca us e of burni ng a nd s ti ngi ng. Pul s e-dye l a s er ha s been
us ed s ucces s ful l y to trea t fa ci a l rednes s .
Chapter 76. Dermatitis

Introduction
Derma ti ti s i s s uperfi ci a l i nfl a mma ti on of the s ki n cha ra cteri zed by rednes s , edema , oozi ng, crus ti ng, s ca l i ng, a nd s ometi mes ves i cl es . Pruri tus i s
common. Eczema i s a term often us ed i ntercha ngea bl y wi th derma ti ti s .
Atopic Dermatitis
Atopic dermatitis (AD) is an immune-mediated inflammation of the skin arising from an interaction between genetic and environmental factors. Recent research
suggests that a heritable epidermal barrier defect is a primary cause, and defects in the filaggrin gene have been specifically implicated. Pruritus is the primary
symptom; skin lesions range from mild erythema to severe lichenification. Diagnosis is by history and examination. Treatment is moisturizers, avoidance of
allergic and irritant triggers, and often topical corticosteroids. Atopic dermatitis frequently resolves completely by age 30.
Etiology
AD pri ma ri l y a ffects chi l dren i n urba n a rea s or devel oped countri es ; a t l ea s t 5% of chi l dren i n the US a re a ffected. Li ke a s thma , i t ma y be l i nked to
proa l l ergi c/proi nfl a mma tory T-cel l i mmune res pons es . Such res pons es a re becomi ng more common i n devel oped countri es beca us e trends
towa rd s ma l l er fa mi l i es , cl ea ner i ndoor envi ronments , a nd ea rl y us e of va cci na ti ons a nd a nti bi oti cs depri ve chi l dren of the ea rl y expos ure to
i nfecti ons a nd a l l ergens tha t otherwi s e s uppres s proa l l ergi c T cel l s a nd thereby i nduce tol era nce to va ri ous a nti gens .
Pathophysiology
AD ca n be di vi ded i nto 2 forms :
Extri ns i c: IgE-medi a ted (70 to 80% of ca s es )
Intri ns i c: Non-IgE-medi a ted (20 to 30% of ca s es )
Extrinsic AD: Thi s form occurs when envi ronmenta l expos ures tri gger i mmunol ogi c, us ua l l y a l l ergi c (i e, IgE-medi a ted), rea cti ons i n geneti ca l l y
s us cepti bl e peopl e. Common envi ronmenta l tri ggers i ncl ude
Foods (eg, mi l k, eggs , s oy, whea t, pea nuts , fi s h)
Ai rborne a l l ergens (eg, dus t mi tes , mol ds , da nder)
Staphylococcus aureus col oni za ti on on s ki n due to defi ci enci es i n endogenous a nti mi crobi a l pepti des
Topi ca l products (eg, cos meti cs )
AD i s common wi thi n fa mi l i es , s ugges ti ng a geneti c component. Ma ny pa ti ents wi th AD ha ve a muta ti on i n the gene encodi ng for the fi l a ggri n
protei n, whi ch i s a component of the corni fi ed cel l envel ope produced by di fferenti a ti ng kera ti nocytes . Al s o, res ea rch ha s s hown tha t s ki n
a ffected by AD i s defi ci ent i n cera mi des , whi ch i ncrea s es tra ns epi derma l wa ter l os s .
Intrinsic AD: Thi s form i s not medi a ted by IgE. Intri ns i c AD i s nonfa mi l i a l a nd i di opa thi c, a nd i ts pa thophys i ol ogy i s genera l l y not wel l unders tood.
Symptoms and Signs
Ma ni fes ta ti ons of i ntri ns i c a nd extri ns i c AD a re s i mi l a r. AD us ua l l y a ppea rs i n i nfa ncy, typi ca l l y by 3 mo. In the a cute pha s e, l a s ti ng 1 to 2 mo (s ee
Pl a te 27), red, weepi ng, crus ted l es i ons a ppea r on the fa ce a nd s prea d to the neck, s ca l p, extremi ti es , a nd a bdomen. In the chroni c pha s e (s ee
Pl a te 28), s cra tchi ng a nd rubbi ng crea te s ki n l es i ons (typi ca l l y erythema tous ma cul es a nd pa pul es tha t l i cheni fy wi th conti nued s cra tchi ng).
Les i ons typi ca l l y a ppea r i n a ntecubi ta l a nd popl i tea l fos s a e a nd on the eyel i ds , neck, a nd wri s ts a nd ma y occa s i ona l l y become genera l i zed.
Les i ons s l owl y res ol ve to dry s ca l y ma cul es (xeros i s ) tha t ca n fi s s ure a nd fa ci l i ta te expos ure to i rri ta nts a nd a l l ergens . In ol der chi l dren a nd
a dul ts , i ntens e pruri tus i s the key fea ture. Pa ti ents ha ve a reduced thres hol d for percei vi ng i tch, a nd i tch wors ens wi th a l l ergen expos ures , dry a i r,
s wea ti ng, l oca l i rri ta ti on, wool ga rments , a nd emoti ona l s tres s .
Complications: Seconda ry ba cteri a l i nfecti ons , es peci a l l y s ta phyl ococca l a nd s treptococca l , a nd regi ona l l ympha deni ti s a re common.
Eczema herpeti cum (Ka pos i 's va ri cel l i form erupti on) i s a di ffus e herpes s i mpl ex i nfecti on occurri ng i n pa ti ents wi th AD. It ma ni fes ts a s grouped
ves i cl es i n a rea s of a cti ve or recent derma ti ti s , a l though norma l s ki n ca n be i nvol ved. Hi gh fever a nd a denopa thy ma y devel op a fter s evera l da ys .
Occa s i ona l l y, thi s i nfecti on ca n become s ys temi c, whi ch ma y be fa ta l . Someti mes the eye i s i nvol ved, ca us i ng a pa i nful cornea l l es i on.
Funga l a nd nonherpeti c vi ra l s ki n i nfecti ons (eg, common wa rts , mol l us cum conta gi os um) ca n a l s o occur.
Pa ti ents wi th l ong-s ta ndi ng AD ma y devel op ca ta ra cts i n thei r 20s or 30s .
Frequent us e of topi ca l products expos es the pa ti ent to ma ny potenti a l a l l ergens , a nd conta ct derma ti ti s ma y a ggra va te a nd compl i ca te AD, a s
ma y the genera l l y dry s ki n tha t i s common a mong thes e pa ti ents .
Diagnosis
Someti mes tes ti ng for a l l ergi c tri ggers wi th s ki n pri ck tes ti ng or ra di oa l l ergos orbent tes ti ng l evel s
Di a gnos i s i s cl i ni ca l (s ee
Ta bl e 76-1). AD i s often ha rd to di fferenti a te from other derma tos es (eg, s eborrhei c derma ti ti s , conta ct derma ti ti s , nummul a r derma ti ti s ,
ps ori a s i s ), a l though a fa mi l y hi s tory of a topy a nd the di s tri buti on of l es i ons a re hel pful . For exa mpl e, ps ori a s i s i s us ua l l y extens or ra ther tha n
fl exura l l y di s tri buted, ma y i nvol ve the fi ngerna i l s , a nd ha s a s hi ni er (mi ca ceous ) s ca l e. Seborrhei c derma ti ti s a ffects the fa ce (eg, na s ol a bi a l
fol ds , eyebrows , gl a bel l a r regi on, s ca l p) mos t commonl y. Nummul a r derma ti ti s i s not fl exura l , a nd l i cheni fi ca ti on i s ra re. Beca us e pa ti ents ca n
s ti l l devel op other s ki n di s orders , not a l l s ubs equent s ki n probl ems s houl d be a ttri buted to AD.
There i s no defi ni ti ve l a bora tory tes t for AD. However, a l l ergi c preci pi ta nts of AD ca n be i denti fi ed wi th s ki n tes ti ng, mea s urement of a l l ergens peci fi c IgE l evel s , or both.
Prognosis
AD i n chi l dren often a ba tes by a ge 5 yr, a l though exa cerba ti ons a re common throughout a dol es cence a nd i nto a dul thood. Gi rl s a nd pa ti ents wi th
s evere di s ea s e, ea rl y a ge of ons et, fa mi l y hi s tory, a nd a s s oci a ted rhi ni ti s or a s thma a re more l i kel y to ha ve prol onged di s ea s e. Even i n thes e
pa ti ents , AD frequentl y res ol ves compl etel y by a ge 30. AD ma y ha ve l ong-term ps ychol ogi c s equel a e a s chi l dren confront ma ny cha l l enges of l i vi ng
wi th a vi s i bl e, s ometi mes di s a bl i ng, s ki n di s ea s e duri ng forma ti ve yea rs .
[Table 76-1. Cl i ni ca l Fi ndi ngs i n Atopi c Derma ti ti s *]
Treatment
Supporti ve ca re (eg, moi s turi zers , s ymptoma ti c trea tment for pruri tus )
Avoi da nce of preci pi ta ti ng fa ctors
Topi ca l corti cos teroi ds
Someti mes i mmune modul a tors (mos t often topi ca l but s ometi mes ora l )
Someti mes ul tra vi ol et (UV) thera py
Trea tment ca n us ua l l y be gi ven a t home, but pa ti ents who ha ve exfol i a ti ve derma ti ti s (s ee p. 668), cel l ul i ti s , or eczema herpeti cum ma y need to be
hos pi ta l i zed.
Supportive care: Ski n ca re i nvol ves moi s turi zi ng. Ba thi ng a nd ha nd wa s hi ng s houl d be i nfrequent, a nd l ukewa rm (not hot) wa ter s houl d be us ed;
s oa p us e s houl d be mi ni mi zed on derma ti ti c a rea s beca us e i t ma y be dryi ng a nd i rri ta ti ng. Col l oi da l oa tmea l ba ths ca n be hel pful . When
towel i ng dry, the s ki n s houl d be bl otted or pa tted dry ra ther tha n rubbed.
Body oi l s or emol l i ents s uch a s whi te petrol a tum, vegeta bl e oi l , or hydrophi l i c petrol a tum (unl es s the pa ti ent i s a l l ergi c to l a nol i n) a ppl i ed
i mmedi a tel y a fter ba thi ng ma y hel p reta i n s ki n moi s ture a nd reduce i tchi ng. Conti nuous l y wet dres s i ngs (not wet-to-dry) a re a n a l terna ti ve for
s evere l es i ons . Coa l ta r crea m or oi l ca n be a n effecti ve topi ca l a nti -pruri ti c but a l s o ca n be i nconveni ent beca us e i t s ta i ns cl othi ng.
Anti hi s ta mi nes ca n hel p rel i eve pruri tus . Opti ons i ncl ude hydroxyzi ne 25 mg po ti d or qi d (for chi l dren, 0.5 mg/kg q 6 h or 2 mg/kg i n a s i ngl e
bedti me dos e) a nd di phenhydra mi ne 25 to 50 mg po a t bedti me. Low-s eda ti ng H 1 receptor bl ockers , s uch a s l ora ta di ne 10 mg po once/da y,
fexofena di ne 60 mg po bi d or 180 mg po once/da y, a nd ceti ri zi ne 5 to 10 mg po once/da y, ma y be us eful , a l though thei r effi ca cy ha s not been
defi ned. Doxepi n (a tri cycl i c a nti depres s a nt a l s o wi th H 1 a nd H 2 receptor bl ocki ng a cti vi ty) 25 to 50 mg po a t bedti me ma y a l s o hel p, but i ts us e i s
not recommended for chi l dren < 12 yr. Fi ngerna i l s s houl d be cut s hort to mi ni mi ze excori a ti ons a nd s econda ry i nfecti ons .
Avoidance of precipitating factors: Hous ehol d a nti gens ca n be control l ed by us i ng s yntheti c fi ber pi l l ows a nd i mpermea bl e ma ttres s covers ; wa s hi ng
beddi ng i n hot wa ter; removi ng uphol s tered furni ture, s oft toys , ca rpets , a nd pets (to reduce dus t mi tes a nd a ni ma l da nder); us i ng a i r ci rcul a tors
equi pped wi th hi gh-effi ci ency pa rti cul a te a i r (HEPA) fi l ters i n bedrooms a nd other frequentl y occupi ed l i vi ng a rea s ; a nd us i ng dehumi di fi ers i n
ba s ements a nd other poorl y a era ted da mp rooms (to reduce mol ds ). Reducti on of emoti ona l s tres s i s us eful but often di ffi cul t. Anti s ta phyl ococca l
a nti bi oti cs , both topi ca l (eg, mupi roci n, fus i di c a ci d) a nd ora l (eg, di cl oxa ci l l i n, cepha l exi n, erythromyci n [a l l 250 mg qi d]), ca n control S. aureus
na s a l col oni za ti on a nd a re i ndi ca ted i n pa ti ents wi th s evere di s ea s e unres pons i ve to s peci fi c thera pi es a nd pos i ti ve na s a l cul tures . Extens i ve
di eta ry cha nges i ntended to el i mi na te expos ure to a l l ergeni c foods a re unneces s a ry a nd proba bl y i neffecti ve; food hypers ens i ti vi ti es ra rel y
pers i s t beyond chi l dhood.
Corticosteroids: Corti cos teroi ds a re the ma i ns ta y of thera py. Crea ms or oi ntments a ppl i ed twi ce da i l y a re effecti ve for mos t pa ti ents wi th mi l d or
modera te di s ea s e. Emol l i ents a re a ppl i ed between corti cos teroi d a ppl i ca ti ons a nd ca n be mi xed wi th them to decrea s e the corti cos teroi d
a mount requi red to cover a n a rea . Sys temi c corti cos teroi ds (predni s one 60 mg or, for chi l dren 1 mg/kg, po once/da y for s hort cours es of 7 to 14
da ys ) a re i ndi ca ted for extens i ve or refra ctory di s ea s e but s houl d be a voi ded whenever pos s i bl e, beca us e di s ea s e often recurs a nd topi ca l
thera py i s s a fer. Prol onged, wi des prea d us e of hi gh-potency corti cos teroi d crea ms or oi ntments s houl d be a voi ded i n i nfa nts beca us e a drena l
s uppres s i on ma y ens ue.
Other therapies: Ta crol i mus a nd pi mecrol i mus a re T-cel l i nhi bi tors effecti ve for AD. They s houl d be us ed when pa ti ents do not res pond to
corti cos teroi ds a nd ta r or when corti cos teroi d a dvers e effects s uch a s s ki n a trophy, s tri a e forma ti on, or a drena l s uppres s i on i s a concern.
Ta crol i mus or pi mecrol i mus crea m i s a ppl i ed twi ce da i l y. Burni ng or s ti ngi ng a fter a ppl i ca ti on i s us ua l l y tra ns i ent a nd a ba tes a fter a few da ys .
Fl us hi ng i s l es s common.
Repa i r of the s tra tum corneum a nd ba rri er functi on ma y hel p a l l evi a te AD. Res ea rch ha s s hown tha t s ki n a ffected by AD i s pa rti cul a rl y defi ci ent i n
cera mi des a nd tha t a defi ci ency i n cera mi des i ncrea s es tra ns epi derma l wa ter l os s . Severa l cera mi de-conta i ni ng emol l i ent products a re
cons i dered hel pful for AD control .
Photothera py i s hel pful for extens i ve AD. Na tura l s un expos ure a mel i ora tes di s ea s e i n ma ny pa ti ents , i ncl udi ng chi l dren. Al terna ti vel y, thera py
wi th ul tra vi ol et A (UVA) or B (UVB) ma y be us ed. Na rrowba nd UVB thera py i s provi ng more effecti ve tha n tra di ti ona l broa dba nd UVB thera py a nd i s
a l s o effecti ve i n chi l dren. Ps ora l en pl us UVA (PUVAs ee p. 679) thera py i s res erved for extens i ve, refra ctory AD. Advers e effects i ncl ude s un
da ma ge (eg, PUVA l enti gi nes , nonmel a noma s ki n ca ncer). Beca us e of thes e a dvers e effects , PUVA i s ra rel y i ndi ca ted for chi l dren or young a dul ts .
Sys temi c i mmune modul a tors effecti ve i n a t l ea s t s ome pa ti ents i ncl ude cycl os pori ne, i nterferon ga mma , mycophenol a te, methotrexa te, a nd
a za thi opri ne. Al l downregul a te or i nhi bi t T-cel l functi on a nd ha ve a nti -i nfl a mma tory properti es . Thes e a gents a re i ndi ca ted for wi des prea d,
reca l ci tra nt, or di s a bl i ng AD tha t fa i l s to a ba te wi th topi ca l thera py a nd photothera py.
Eczema herpeti cum i s trea ted wi th a cycl ovi r. Infa nts recei ve 10 to 20 mg/kg IV q 8 h; ol der chi l dren a nd a dul ts wi th mi l d i l l nes s ma y recei ve 200 mg
po 5 ti mes /da y. Invol vement of the eye i s cons i dered a n ophtha l mi c emergency, a nd i f eye i nvol vement i s s us pected, a n ophtha l mol ogy cons ul t
s houl d be obta i ned.
Contact Dermatitis
Contact dermatitis (CD) is acute inflammation of the skin caused by irritants or allergens. The primary symptom is pruritus. Skin changes range from erythema to
blistering and ulceration, often on or near the hands but occurring on any exposed skin surface. Diagnosis is by exposure history, examination, and sometimes
skin patch testing. Treatment entails antipruritics, topical corticosteroids, and avoidance of causes.
Pathophysiology
CD i s ca us ed by i rri ta nts or a l l ergens .
Irritant contact dermatitis (ICD): ICD a ccounts for 80% of a l l ca s es of CD. It i s a nons peci fi c i nfl a mma tory rea cti on to s ubs ta nces conta cti ng the s ki n;
the i mmune s ys tem i s not a cti va ted. Numerous s ubs ta nces a re i nvol ved, i ncl udi ng
Chemi ca l s (eg, a ci ds , a l ka l i s , s ol vents , meta l s a l ts )
Soa ps (eg, a bra s i ves , detergents )
Pl a nts (eg, poi ns etti a s , peppers )
Body fl ui ds (eg, uri ne, s a l i va )
Properti es of the i rri ta nt (eg, extreme pH, s ol ubi l i ty i n the l i pi d fi l m on s ki n), envi ronment (eg, l ow humi di ty, hi gh tempera ture, hi gh fri cti on), a nd
pa ti ent (eg, very young or ol d) i nfl uence the l i kel i hood of devel opi ng ICD. ICD i s more common a mong pa ti ents wi th a topi c di s orders , i n whom ICD
a l s o ma y i ni ti a te i mmunol ogi c s ens i ti za ti on a nd hence a l l ergi c CD.
Phototoxic dermatitis (s ee p. 675) i s a va ri a nt i n whi ch topi ca l (eg, perfumes , coa l ta r) or i nges ted (eg, ps ora l ens ) a gents genera te da ma gi ng free
ra di ca l s a nd i nfl a mma tory medi a tors onl y a fter a bs orpti on of ul tra vi ol et l i ght.
Allergic contact dermatitis (ACD): ACD i s a type IV cel l -medi a ted hypers ens i ti vi ty rea cti on tha t ha s 2 pha s es :
Sens i ti za ti on to a n a nti gen
Al l ergi c res pons e a fter reexpos ure
In the s ens i ti za ti on pha s e, a l l ergens a re ca ptured by La ngerha ns ' cel l s (dendri ti c epi derma l cel l s ), whi ch mi gra te to regi ona l l ymph nodes where
they proces s a nd pres ent the a nti gen to T cel l s . The proces s ma y be bri ef (6 to 10 da ys for s trong s ens i ti zers s uch a s poi s on i vy) or prol onged (yea rs
for wea k s ens i ti zers s uch a s s uns creens , fra gra nces , a nd gl ucocorti coi ds ). Sens i ti zed T cel l s then mi gra te ba ck to the epi dermi s a nd a cti va te on
a ny reexpos ure to the a l l ergen, rel ea s i ng cytoki nes , recrui ti ng i nfl a mma tory cel l s , a nd l ea di ng to the cha ra cteri s ti c s ymptoms a nd s i gns of ACD.
In autoeczematization, epi derma l T cel l s a cti va ted by a n a l l ergen mi gra te l oca l l y or through the ci rcul a ti on to ca us e derma ti ti s a t s i tes remote from
the i ni ti a l tri gger. However, conta ct wi th fl ui d from ves i cl es or bl i s ters ca nnot tri gger a rea cti on el s ewhere on the pa ti ent or on a nother pers on.
Mul ti pl e a l l ergens ca us e ACD (s ee
Ta bl e 76-2), a nd cros s -s ens i ti za ti on a mong a gents i s common (eg, between benzoca i ne a nd pa ra phenyl enedi a mi ne). Cros s -s ens i ti za ti on mea ns
tha t expos ure to one s ubs ta nce ca n res ul t i n a n a l l ergi c res pons e a fter expos ure to a di fferent but rel a ted s ubs ta nce.
ACD va ri a nts i ncl ude photoa l l ergi c CD a nd s ys temi ca l l y i nduced ACD. In photoa l l ergi c CD (s ee p. 675), a s ubs ta nce becomes s ens i ti zi ng onl y a fter i t
undergoes s tructura l cha nge tri ggered by ul tra vi ol et l i ght. Typi ca l ca us es i ncl ude a fters ha ve l oti ons , s uns creens , a nd topi ca l s ul fona mi des .
Rea cti ons ma y extend to non-s un-expos ed s ki n. In s ys temi ca l l y i nduced ACD, i nges ti on of a n a l l ergen a fter topi ca l s ens i ti za ti on ca us es di ffus e
derma ti ti s (eg, ora l di phenhydra mi ne a fter s ens i ti za ti on wi th topi ca l di phenhydra mi ne).
Symptoms and Signs
ICD: ICD i s more pa i nful tha n pruri ti c. Si gns ra nge from mi l d erythema to hemorrha ge, crus ti ng, eros i on, pus tul es , bul l a e, a nd edema .
ACD: In ACD, the pri ma ry s ymptom i s i ntens e pruri tus ; pa i n i s us ua l l y the res ul t of excori a ti on or i nfecti on. Ski n cha nges ra nge from tra ns i ent
erythema through ves i cul a ti on to s evere s wel l i ng wi th bul l a e, ul cera ti on, or both. Cha nges often occur i n a pa ttern, di s tri buti on, or combi na ti on
tha t s ugges ts a s peci fi c expos ure, s uch a s l i nea r s trea ki ng on a n a rm or l eg (eg, from brus hi ng a ga i ns t poi s on i vy) or ci rcumferenti a l erythema
(under a wri s twa tch or wa i s tba nd). Any s urfa ce ma y be i nvol ved, but ha nds a re the mos t common s urfa ce due to ha ndl i ng a nd touchi ng potenti a l
a l l ergens . Wi th a i rborne expos ure (eg,
[Table 76-2. Ca us es of Al l ergi c Conta ct Derma ti ti s ]
perfume a eros ol s ), a rea s not covered by cl othi ng a re predomi na ntl y a ffected. The derma ti ti s i s typi ca l l y l i mi ted to the s i te of conta ct but ma y l a ter
s prea d due to s cra tchi ng a nd a utoeczema ti za ti on. In s ys temi ca l l y i nduced ACD, s ki n cha nges ma y be di s tri buted over the enti re body.
Diagnosis
Someti mes pa tch tes ti ng
CD ca n often be di a gnos ed by s ki n cha nges a nd expos ure hi s tory. The pa ti ent's occupa ti on, hobbi es , hous ehol d duti es , va ca ti ons , cl othi ng, topi ca l
drug us e, cos meti cs , a nd s pous e's a cti vi ti es mus t be cons i dered. The "us e" tes t, i n whi ch a s us pected a gent i s a ppl i ed fa r from the ori gi na l a rea
of derma ti ti s , us ua l l y on the fl exor forea rm, i s us eful when perfumes , s ha mpoos , or other home a gents a re s us pected.
Pa tch tes ti ng i s i ndi ca ted when ACD i s s us pected a nd does not res pond to trea tment. In pa tch tes ti ng, s ta nda rd conta ct a l l ergens a re a ppl i ed to
the upper ba ck us i ng a dhes i ve-mounted pa tches conta i ni ng mi nute a mounts of a l l ergen or pl a s ti c (Fi nn) cha mbers conta i ni ng a l l ergen hel d i n
pl a ce wi th porous ta pe. Thi n-l a yer ra pi d us e epi cuta neous (TRUE) pa tch tes ti ng i nvol ves 2 a dhes i ve s tri ps tha t ca n be a ppl i ed a nd i nterpreted by
a ny provi der. Ski n under the pa tches i s eva l ua ted 48 a nd 96 h a fter a ppl i ca ti on. Fa l s e-pos i ti ve res ul ts occur when concentra ti ons provoke a n
i rri ta nt ra ther tha n a n a l l ergi c rea cti on, when rea cti on to one a nti gen tri ggers a nons peci fi c rea cti on to others , or wi th cros s -rea cti ng a nti gens .
Fa l s e-nega ti ve res ul ts occur when pa tch a l l ergens do not i ncl ude the offendi ng a nti gen. Defi ni ti ve di a gnos i s requi res a hi s tory of expos ure to the
tes t a gent i n the ori gi na l a rea of derma ti ti s .
Prognosis
Res ol uti on ma y ta ke up to 3 wk. Rea cti vi ty i s us ua l l y l i fel ong. Pa ti ents wi th photoa l l ergi c CD ca n ha ve fl a res for yea rs when expos ed to s un
(pers i s tent l i ght rea cti on).
Treatment
Avoi da nce of offendi ng a gents
Supporti ve ca re (eg, cool compres s es , dres s i ngs , a nti hi s ta mi nes )
Corti cos teroi ds (mos t often topi ca l but s ometi mes ora l )
CD i s prevented by a voi di ng the tri gger; pa ti ents wi th photos ens i ti ve CD s houl d a voi d expos ure to s un.
Topi ca l trea tment i ncl udes cool compres s es (s a l i ne or Burow's s ol uti on) a nd corti cos teroi ds ; pa ti ents wi th mi l d to modera te ACD a re gi ven mi dpotency topi ca l corti cos teroi ds (eg, tri a mci nol one 0.1% oi ntment or beta metha s one va l era te crea m 0.1%). Ora l corti cos teroi ds (eg, predni s one 60
mg once/da y for 7 to 14 da ys ) ca n be us ed for s evere bl i s teri ng or extens i ve di s ea s e. Sys temi c a nti hi s ta mi nes (eg, hydroxyzi ne, di phenhydra mi ne)
hel p pruri tus ; a nti hi s ta mi nes wi th l ow a nti chol i nergi c potency, s uch a s l ow-s eda ti ng H 1 bl ockers , a re not a s effecti ve. Wet-to-dry dres s i ngs ca n
s oothe oozi ng bl i s ters , dry the s ki n, a nd promote hea l i ng.
Exfoliative Dermatitis
(Erythroderma )
Exfoliative dermatitis is widespread erythema and scaling of the skin caused by preexisting skin disorders, drugs, cancer, or unknown causes. Symptoms and
signs are pruritus, diffuse erythema, and epidermal sloughing. Diagnosis is clinical. Treatment involves corticosteroids and correction of the cause.
Exfol i a ti ve derma ti ti s i s a ma ni fes ta ti on of ra pi d epi derma l cel l turnover. Its ca us e i s unknown, but i t mos t often occurs i n the context of
preexi s ti ng s ki n di s orders (eg, a topi c derma ti ti s , conta ct derma ti ti s , s eborrhei c derma ti ti s , ps ori a s i s , pi tyri a s i s rubra pi l a ri s ), us e of drugs (eg,
peni ci l l i n, s ul fona mi des , i s oni a zi d, phenytoi n, ba rbi tura tes ), a nd ca ncer (eg, mycos i s fungoi des , l eukemi a , a nd, ra rel y, a de-noca rci noma s ). Up to
25% of pa ti ents ha ve no i denti fi a bl e underl yi ng di s ea s e.
Symptoms and Signs
Symptoms i ncl ude pruri tus , ma l a i s e, a nd chi l l s . Di ffus e erythema i ni ti a l l y occurs i n pa tches but s prea ds a nd i nvol ves a l l or nea rl y a l l of the body.
Extens i ve epi derma l s l oughi ng l ea ds to a bnorma l thermoregul a ti on, nutri ti ona l defi ci enci es beca us e of extens i ve protei n l os s es , i ncrea s ed
meta bol i c ra te wi th a hyperca ta bol i c s ta te, a nd hypovol emi a due to tra ns derma l fl ui d l os s es .
Diagnosis
Di a gnos i s i s by hi s tory a nd exa mi na ti on. Preexi s ti ng s ki n di s ea s e ma y underl i e the extens i ve erythema a nd s ugges t a ca us e. Bi ops y i s often
nons peci fi c but i s i ndi ca ted when mycos i s fungoi des i s s us pected. Bl ood tes ts ma y revea l hypoprotei nemi a , hypoca l cemi a , a nd i ron defi ci ency,
ea ch a cons equence of extens i ve protei n, el ectrol yte, a nd RBC l os s ; however, thes e fi ndi ngs a re not di a gnos ti c.
Treatment
Supporti ve ca re (eg, rehydra ti on)
Topi ca l ca re (eg, emol l i ents , col l oi da l oa tmea l ba ths )
Sys temi c corti cos teroi ds for s evere di s ea s e

The di s ea s e ma y be l i fe threa teni ng; hos pi ta l i za ti on i s often neces s a ry. Any known ca us e i s trea ted. Supporti ve ca re cons i s ts of correcti on of
dehydra ti on, correcti on of el ectrol yte a bnorma l i ti es a nd nutri ti ona l defi ci enci es , a nd comprehens i ve wound ca re a nd dres s i ngs to prevent
ba cteri a l s uperi nfecti on. Beca us e drug erupti ons a nd conta ct derma ti ti s ca nnot be rul ed out by hi s tory a l one, a l l drugs s houl d be s topped i f
pos s i bl e or cha nged. Ski n ca re i s wi th emol l i ents a nd col l oi da l oa tmea l ba ths . Wea k topi ca l corti cos teroi ds (eg, 1 to 2.5% hydrocorti s one
oi ntment) ma y be us ed. Corti cos teroi ds (predni s one 40 to 60 mg po once/da y for 10 da ys , then ta pered) a re us ed for s evere di s ea s e.
Prognos i s depends on the ca us e. Ca s es rel a ted to drug rea cti ons ha ve the s hortes t dura ti on, l a s ti ng 2 to 6 wk a fter the drug i s wi thdra wn.
Hand and Foot Dermatitis
Hand and foot dermatitis is not a single disorder. Rather, it is a categorization of dermatitis that affects the hands and feet selectively due to one of several
causes.
Pa ti ents often pres ent wi th i s ol a ted derma ti ti s of the ha nds or feet. Ca us es i ncl ude
Funga l i nfecti on
Ps ori a s i s
Sca bi es
Other ca us es i ncl ude s ys temi c vi ra l i nfecti on i n chi l dren (ha nd-foot-a nd-mouth di s ea s es ee p. 1426) or certa i n chemothera pi es (ha nd-foot
s yndrome). Some ca s es a re i di opa thi c.
Di a gnos i s ca n s ometi mes be i nferred from l oca ti on a nd a ppea ra nce of the s ki n l es i ons (s ee
Ta bl e 76-3).
Trea tment of a l l forms of ha nd a nd foot derma ti ti s s houl d be di rected a t the ca us e when pos s i bl e. Topi ca l corti cos teroi ds or a nti funga l s ma y be
tri ed empi ri ca l l y. Pa ti ents s houl d a l s o a voi d prol onged conta ct wi th wa ter tha t woul d otherwi s e remove protecti ve oi l s a nd l ea d to pa ra doxi ca l
dryi ng of the s ki n.
Dyshidrotic dermatitis: Pruri ti c ves i cl es or bul l a e on the pa l ms , s i des of the fi ngers , or s ol es a re cha ra cteri s ti c of thi s di s order. Sca l i ng, rednes s , a nd
oozi ng often fol l ow ves i cul a ti on. Pomphol yx i s a s evere form wi th bul l a e. The ca us e i s unknown, but funga l i nfecti on, conta ct derma ti ti s , a nd i d
rea cti ons to ti nea pedi s ca n ca us e a s i mi l a r cl i ni ca l a ppea ra nce a nd s houl d be rul ed out. Trea tment i ncl udes topi ca l corti cos teroi ds , ta crol i mus
or pi mecrol i mus , ora l a nti bi oti cs , a nd ul tra vi ol et l i ght.
Keratolysis exfoliativa: Pa i nl es s pa tchy peel i ng of the pa l ms , s ol es , or both i s cha ra cteri s ti c of thi s di s order. The ca us e i s unknown; trea tment i s
unneces s a ry beca us e the condi ti on i s s el f-res ol vi ng.
Hyperkeratotic eczema: Thi ck yel l ow-brown pl a ques on the pa l ms a nd s ometi mes s ol es a re cha ra cteri s ti c of thi s di s order. The ca us e i s unknown.
Trea tment i s wi th topi ca l corti cos teroi ds a nd kera tol yti cs , ora l ps ora l en pl us ul tra vi ol et A (PUVA), a nd reti noi ds .
Id reaction: The a ppea ra nce of ves i cl es us ua l l y on the s i des of the fi ngers i n res pons e to a cti ve derma ti ti s el s ewhere i s cha ra cteri s ti c of thi s
di s order. The ca us e ma y be a n a l l ergi c rea cti on.
Housewives' eczema: Thi s i rri ta nt conta ct derma ti ti s a ffects peopl e whos e ha nds a re frequentl y i mmers ed i n wa ter. It i s wors ened by wa s hi ng
di s hes , cl othes , a nd ba bi es beca us e repea ted expos ure to even mi l d detergents a nd wa ter or prol onged s wea ti ng under rubber gl oves ma y
i rri ta te derma ti ti c s ki n or ca us e a n i rri ta nt conta ct derma ti ti s .
Hand-foot syndrome: Thi s di s order (a l s o ca l l ed a cra l erythema or pa l ma r-pl a nta r eryth-rodys es thes i a ) repres ents cuta neous toxi ci ty ca us ed by
certa i n s ys temi c chemothera pi es (eg, ca peci ta bi ne, cyta ra bi ne, fl uoroura ci l , i da rubi ci n, doxorubi ci n, ta xa nes , methotrexa te, ci s pl a ti n, tega fur).
Ma ni fes ta ti ons i ncl ude pa i n, s wel l i ng, numbnes s , ti ngl i ng, rednes s , a nd s ometi mes fl a ki ng or bl i s teri ng of the pa l ms or s ol es . Trea tment i s wi th
ora l or topi ca l corti cos teroi ds , topi ca l di methyl s ul foxi de, ora l vi ta mi n B 6 (pyri doxi ne), OTC a na l ges i cs (eg, a ceta mi nophen, i buprofen), a nd
s upporti ve mea s ures (eg, cool compres s es , mi ni mi zi ng ma nua l ta s ks ).
Lichen Simplex Chronicus
(Neuroderma ti ti s )
Lichen simplex chronicus is eczema caused by repeated scratching; by several mechanisms, chronic scratching causes further itching, creating a vicious circle.
Diagnosis is by examination.
[Table 76-3. Di fferenti a l Di a gnos i s of Ha nd Derma ti ti s ]
Treatment is through education and behavioral techniques to prevent scratching and corticosteroids and antihistamines.
Etiology
Li chen s i mpl ex chroni cus i s thi ckeni ng of the s ki n wi th va ri a bl e s ca l i ng tha t a ri s es s econda ry to repeti ti ve s cra tchi ng or rubbi ng. Li chen s i mpl ex
chroni cus i s not a pri ma ry proces s . Percei ved pruri tus i n a s peci fi c a rea of s ki n (wi th or wi thout underl yi ng pa thol ogy) provokes rubbi ng a nd
mecha ni ca l tra uma , res ul ti ng i n s econda ry l i cheni fi ca ti on a nd further pruri tus . Li chen s i mpl ex chroni cus frequentl y occurs i n peopl e wi th a nxi ety
di s orders a nd nons peci fi c emoti ona l s tres s a s wel l a s i n pa ti ents wi th a ny type of underl yi ng chroni c derma ti ti s .
Pathophysiology
The underl yi ng pa thophys i ol ogy i s unknown but ma y i nvol ve a l tera ti ons i n the wa y the nervous s ys tem percei ves a nd proces s es i tchy s ens a ti ons .
Ski n tha t tends towa rd eczema tous condi ti ons (eg, a topi c derma ti ti s ) i s more prone to l i cheni fi ca ti on.
Symptoms and Signs
Li chen s i mpl ex chroni cus i s cha ra cteri zed by pruri ti c, dry, s ca l i ng, hyperpi gmented, l i cheni fi ed pl a ques i n i rregul a r, ova l , or a ngul a r s ha pes . It
i nvol ves ea s i l y rea ched s i tes , mos t commonl y the l egs , a rms , neck, a nd upper trunk.
Diagnosis
Di a gnos i s i s by exa mi na ti on. A ful l y devel oped pl a que ha s a n outer zone of di s crete, browni s h pa pul es a nd a centra l zone of confl uent pa pul es
covered wi th s ca l es . Look-a l i ke condi ti ons i ncl ude ti nea corpori s , l i chen pl a nus , a nd ps ori a s i s ; l i chen s i mpl ex chroni cus ca n be di s ti ngui s hed
from thes e by pota s s i um hydroxi de wet mount a nd bi ops y.
Treatment
Educa ti on a nd beha vi ora l techni ques
Corti cos teroi ds (mos t often topi ca l but s ometi mes i ntra l es i ona l )
Anti hi s ta mi nes
Pri ma ry trea tment i s pa ti ent educa ti on a bout the effects of s cra tchi ng a nd rubbi ng. Seconda ry trea tment i s topi ca l corti cos teroi ds (eg,
tri a mci nol one a cetoni de, fl uoci noni de); s urgi ca l ta pe i mpregna ted wi th fl ura ndrenol i de (a ppl i ed i n the morni ng a nd repl a ced i n the eveni ng) ma y
be preferred beca us e occl us i on prevents s cra tchi ng. Sma l l a rea s ma y be l oca l l y i nfi l tra ted (i ntra l es i ona l i njecti ons ) wi th a l ong-a cti ng
corti cos teroi d s uch a s tri a mci nol one a cetoni de 2.5 mg/mL (di l uted wi th s a l i ne), 0.3 mL/cm 2 of l es i on; trea tment ca n be repea ted every 3 to 4 wk.
Ora l H 1 -bl ocki ng a nti hi s ta mi nes ma y be us eful . Emol l i ents ma y a l s o be hel pful .
Nummular Dermatitis
Nummular (discoid) dermatitis is inflammation of the skin characterized by coin-shaped or disc-shaped lesions. Diagnosis is clinical. Treatment may include
antibiotics, corticosteroids, and ultraviolet light therapy.
Nummul a r derma ti ti s i s mos t common a mong mi ddl e-a ged pa ti ents a nd i s often a s s oci a ted wi th dry s ki n, es peci a l l y duri ng the wi nter. The ca us e
i s unknown.
Symptoms and Signs
Di s coi d l es i ons often s ta rt a s pa tches of confl uent ves i cl es a nd pa pul es tha t l a ter ooze s erum a nd form crus ts . Les i ons a re erupti ve, wi des prea d,
a nd pruri ti c. They a re often more promi nent on the extens or a s pects of the extremi ti es a nd on the buttocks but a l s o a ppea r on the trunk.
Exa cerba ti ons a nd remi s s i ons ma y occur, a nd when they do, new l es i ons tend to rea ppea r a t the s i tes of hea l ed l es i ons .
Diagnosis
Di a gnos i s i s cl i ni ca l ba s ed on the cha ra cteri s ti c a ppea ra nce a nd di s tri buti on of the s ki n l es i ons .
Treatment
Supporti ve ca re
Anti bi oti cs
Corti cos teroi ds (mos t often topi ca l , but s ometi mes i ntra l es i ona l or ora l )
Ul tra vi ol et l i ght thera py
No trea tment i s uni forml y effecti ve. Ora l a nti bi oti cs (eg, di cl oxa ci l l i n or cepha l exi n 250 mg qi d) ma y be gi ven, a l ong wi th us e of ta p wa ter
compres s es , es peci a l l y when weepi ng a nd pus a re pres ent. Les s i nfl a med l es i ons ma y res pond to tetra cycl i ne 250 mg po qi d, whi ch ha s a
benefi ci a l (a l though not neces s a ri l y a nti ba cteri a l ) effect. Corti cos teroi d crea m or oi ntment s houl d be rubbed i n 3 ti mes da i l y. An occl us i ve
dres s i ng wi th a corti cos teroi d crea m under pol yethyl ene fi l m or wi th fl ura ndrenol i de-i mpregna ted ta pe ca n be a ppl i ed a t bedti me. Intra l es i ona l
corti cos teroi d i njecti ons ma y be benefi ci a l for the few l es i ons tha t do not res pond to thera py. In more wi des prea d, res i s ta nt, a nd recurrent ca s es ,
ul tra vi ol et B ra di a ti on a l one or ora l ps ora l en pl us ul tra vi ol et A (PUVA) ra di a ti on ma y be hel pful . Occa s i ona l l y, ora l corti cos teroi ds a re requi red,
but l ong-term us e s houl d be a voi ded; a rea s ona bl e s ta rti ng dos e i s predni s one 40 mg every other da y.
Seborrheic Dermatitis
Seborrheic dermatitis (SD) is inflammation of skin that has a high density of sebaceous glands (eg, face, scalp, upper trunk). The cause is unknown, but
Pityrosporum ovale, a normal skin organism, plays some role. SD occurs with increased frequency in patients with HIV and in those with certain neurologic
disorders. SD causes occasional pruritus, dandruff, and yellow, greasy scaling along the hairline and on the face. Diagnosis is made by examination. Treatment is
tar or other medicated shampoo and topical corticosteroids and antifungals.
Des pi te the na me, the compos i ti on a nd fl ow of s ebum a re us ua l l y norma l . The pa thogenes i s of SD i s uncl ea r, but i ts a cti vi ty ha s been l i nked to
the number of Pityrosporum yea s ts pres ent on the s ki n. The i nci dence a nd s everi ty of di s ea s e s eem to be a ffected by geneti c fa ctors , emoti ona l or
phys i ca l s tres s , a nd cl i ma te (us ua l l y wors e i n col d wea ther). SD ma y precede or be a s s oci a ted wi th ps ori a s i s (ca l l ed s eborrhi a s i s ). SD ma y be
more common a nd more s evere a mong pa ti ents wi th neurol ogi c di s orders (es peci a l l y Pa rki ns on's di s ea s e) or HIV/AIDS. Very ra rel y, the derma ti ti s
becomes genera l i zed.
Symptoms and Signs
Symptoms devel op gra dua l l y, a nd the derma ti ti s i s us ua l l y a ppa rent onl y a s dry or grea s y di ffus e s ca l i ng of the s ca l p (da ndruff) wi th va ri a bl e
pruri tus . In s evere di s ea s e, yel l ow-red s ca l i ng pa pul es a ppea r a l ong the ha i rl i ne, behi nd the ea rs , i n the externa l a udi tory ca na l s , on the
eyebrows , i n the a xi l l a e, on the bri dge of the nos e, i n the na s ol a bi a l fol ds , a nd over the s ternum. Ma rgi na l bl epha ri ti s wi th dry yel l ow crus ts a nd
conjuncti va l i rri ta ti on ma y devel op. SD does not ca us e ha i r l os s .
Neona tes ma y devel op SD wi th a thi ck, yel l ow, crus ted s ca l p l es i on (cra dl e ca p); fi s s uri ng a nd yel l ow s ca l i ng behi nd the ea rs ; red fa ci a l pa pul es ;
a nd s tubborn di a per ra s h. Ol der chi l dren ma y devel op thi ck, tena ci ous , s ca l y pl a ques on the s ca l p tha t ma y mea s ure 1 to 2 cm i n di a meter.
Diagnosis
Di a gnos i s i s ma de by phys i ca l exa mi na ti on. SD ma y occa s i ona l l y be di ffi cul t to di s ti ngui s h from other di s orders , i ncl udi ng ps ori a s i s , a topi c
derma ti ti s or conta ct derma ti ti s , ti nea , a nd ros a cea .
Treatment
Topi ca l thera py
Adults: In a dul ts , zi nc pyri thi one, s el eni um s ul fi de, s ul fur a nd s a l i cyl i c a ci d, or ta r s ha mpoo s houl d be us ed da i l y or every other da y unti l da ndruff
i s control l ed a nd twi ce/wk therea fter. A corti cos teroi d l oti on (eg, 0.01% fl uoci nol one a cetoni de s ol uti on, 0.025% tri a mci nol one a cetoni de l oti on)
ca n be rubbed i nto the s ca l p or other ha i ry a rea s twi ce da i l y unti l s ca l i ng a nd rednes s a re control l ed. For SD of the pos ta uri cul a r a rea s ,
na s ol a bi a l fol ds , eyel i d ma rgi ns , a nd bri dge of the nos e, 1% hydrocorti s one crea m i s rubbed i n 2 or 3 ti mes da i l y, decrea s i ng to once/da y when SD
i s control l ed; hydrocorti s one crea m i s the s a fes t corti cos teroi d for the fa ce beca us e fl uori na ted corti cos teroi ds ma y ca us e a dvers e effects (eg,
tel a ngi ecta s i a , a trophy, peri ora l derma ti ti s ). In s ome pa ti ents , 2% ketocona zol e crea m or other topi ca l i mi da zol es a ppl i ed twi ce da i l y for 1 to 2 wk
i nduce a remi s s i on tha t l a s ts for months . For eyel i d ma rgi n s eborrhea , a di l uti on of 1 pa rt ba by s ha mpoo to 9 pa rts wa ter i s a ppl i ed wi th a cotton
s wa b.
Infants and children: In i nfa nts , a ba by s ha mpoo i s us ed da i l y, a nd 1% hydrocorti s one crea m i s rubbed i n twi ce da i l y. For thi ck l es i ons on the s ca l p
of a young chi l d, 2% s a l i cyl i c a ci d i n ol i ve oi l or a corti cos teroi d gel i s a ppl i ed a t bedti me to a ffected a rea s a nd rubbed i n wi th a toothbrus h. The
s ca l p i s s ha mpooed da i l y unti l the thi ck s ca l e i s gone.
Stasis Dermatitis
Stasis dermatitis is inflammation of the skin of the lower legs caused by chronic venous insufficiency. Symptoms are itching, scaling, hyperpigmentation, and
sometimes ulceration. Diagnosis is clinical. Treatment is directed at the chronic venous insufficiency and preventing occurrence or progression of associated
ulcers.
Sta s i s derma ti ti s occurs i n pa ti ents wi th chroni c venous i ns uffi ci ency (s ee p. 2231) beca us e pool ed venous bl ood i n the l egs compromi s es the
endothel i a l i ntegri ty i n the mi crova s cul a ture, res ul ti ng i n fi bri n l ea ka ge, l oca l i nfl a mma ti on, a nd l oca l cel l necros i s .
Symptoms and Signs
Ini ti a l l y, hyperpi gmenta ti on a nd red-brown di s col ora ti on from RBC extra va s a ti on a ppea r. La ter, eczema tous cha nges devel op a nd ma ni fes t a s
erythema , s ca l i ng, weepi ng, a nd crus ti ng (s ee
Pl a te 46), a l l of whi ch ca n be ma de wors e by ba cteri a l s uperi nfecti on or by conta ct derma ti ti s ca us ed by the ma ny topi ca l trea tments often
a ppl i ed. When chroni c venous i ns uffi ci ency a nd s ta s i s derma ti ti s a re both i na dequa tel y trea ted, s ta s i s derma ti ti s progres s es to fra nk s ki n
ul cera ti on (s ee
Pl a te 47), chroni c edema , thi ckened fi broti c s ki n, or l i poderma tos cl eros i s (a pa i nful i ndura ti on res ul ti ng from pa nni cul i ti s , whi ch, i f s evere, gi ves
the l ower l eg a n i nverted bowl i ng pi n s ha pe wi th enl a rgement of the ca l f a nd na rrowi ng a t the a nkl e).
Diagnosis
Di a gnos i s i s cl i ni ca l ba s ed on the cha ra cteri s ti c a ppea ra nce of the s ki n l es i ons a nd other s i gns of chroni c venous i ns uffi ci ency.
Treatment
El eva ti on, compres s i on, a nd dres s i ngs
Someti mes topi ca l or ora l a nti bi oti cs
Chroni c venous i ns uffi ci ency mus t be a dequa tel y trea ted wi th l eg el eva ti on a nd compres s i on s tocki ngs (s ee p. 2232). For a cute s ta s i s derma ti ti s
(cha ra cteri zed by crus ts , exuda ti on, a nd s uperfi ci a l ul cera ti on), conti nuous a nd then i ntermi ttent ta p wa ter compres s es s houl d be a ppl i ed. For a
weepi ng l es i on, a hydrocol l oi d dres s i ng ma y be bes t. For l es s a cute derma ti ti s , a corti cos teroi d crea m or oi ntment s houl d be a ppl i ed 3 ti mes /da y
or i ncorpora ted i nto zi nc oxi de pa s te.
Ul cers a re bes t trea ted wi th compres s es a nd bl a nd dres s i ngs (eg, zi nc oxi de pa s te); other dres s i ngs (eg, hydrocol l oi ds ) a re a l s o effecti ve (s ee a l s o
p.
740). Ul cers i n a mbul a tory pa ti ents ma y be hea l ed wi th Unna 's pa s te boot (zi nc gel a ti n), the l es s mes s y zi nc gel a ti n ba nda ge, or a col l oi d dres s i ng
(a l l a re a va i l a bl e commerci a l l y). Col l oi d-type dres s i ngs us ed under el a s ti c s upport a re more effecti ve tha n Unna 's pa s te boot. It ma y be neces s a ry
to cha nge the dres s i ng every 2 or 3 da ys , but a s edema recedes a nd the ul cer hea l s , once or twi ce/wk i s s uffi ci ent. After the ul cer hea l s , a n el a s ti c
s upport s houl d be a ppl i ed before the pa ti ent ri s es i n the morni ng. Rega rdl es s of the dres s i ng us ed, reducti on of edema (us ua l l y wi th
compres s i on) i s pa ra mount for hea l i ng.
Ora l a nti bi oti cs (eg, cepha l os pori ns , di cl oxa ci l l i n) a re us ed to trea t s uperi mpos ed cel l ul i ti s . Topi ca l a nti bi oti cs (eg, mupi roci n, s i l ver
s ul fa di a zi ne) a re us eful for trea ti ng eros i ons a nd ul cers . When edema a nd i nfl a mma ti on s ubs i de, s pl i t-thi cknes s s ki n gra fts ma y be needed for
l a rge ul cers .
Compl ex or mul ti pl e topi ca l drugs or OTC remedi es s houl d not be us ed. The s ki n i n s ta s i s derma ti ti s i s more vul nera bl e to di rect i rri ta nts a nd to
potenti a l l y s ens i ti zi ng topi ca l a gents (eg, a nti bi oti cs ; a nes theti cs ; vehi cl es of topi ca l drugs , es peci a l l y l a nol i n or wool a l cohol s ).
Chapter 77. Reactions to Sunlight

Introduction
The s ki n ma y res pond to exces s i ve s unl i ght i n s evera l wa ys : va ri ous chroni c cha nges (eg, derma tohel i os i s , a cti ni c kera tos es ), photos ens i ti vi ty, or
s unburn.
Ultraviolet (UV) radiation: Al though the s un emi ts a wi de ra nge of UV el ectroma gneti c ra di a ti on (i e, UVA, 320 to 400 nm; UVB, 280 to 320 nm; UVC, 100
to 280 nm), onl y UVA a nd UVB rea ch the ea rth's s urfa ce. The cha ra cter a nd a mount of s uch ra di a ti on va ry grea tl y wi th the s ea s ons a nd wi th
cha ngi ng a tmos pheri c condi ti ons . Expos ure of s ki n to s unl i ght depends on mul ti pl e l i fes tyl e fa ctors , (eg, cl othi ng, occupa ti on), geogra phi c fa ctors
(eg, a l ti tude, l a ti tude), a nd ti me of yea r (UV i ntens i ty i s hi gher i n s ummer).
Sunburn-produci ng ra ys (pri ma ri l y wa vel engths < 320 nm) a re fi l tered out by gl a s s a nd to a grea t extent by s moke a nd s mog. Sunburn-produci ng
ra ys ma y pa s s through l i ght cl ouds , fog, or 30 cm of cl ea r wa ter, ca us i ng s evere burns i n uns us pecti ng peopl e. Snow, s a nd, a nd wa ter enha nce
expos ure by refl ecti ng the ra ys . Stra tos pheri c ozone, whi ch fi l ters out s horter wa vel engths of UV, i s depl eted by ma n-ma de chl orofl uoroca rbons
(eg, i n refri gera nts a nd a eros ol s ). A decrea s ed ozone l a yer i ncrea s es i na dvertent expos ure to UVA a nd UVB.
Sun-ta nni ng l a mps us e a rti fi ci a l l i ght tha t i s more UVA tha n UVB. Thi s UVA us e i s often a dverti s ed a s a "s a fer" wa y to ta n; however, ma ny of the
s a me l ong-term del eteri ous effects ma y occur a s wi th UVB expos ure, i ncl udi ng photoa gi ng a nd s ki n ca ncer. Qui te s i mpl y, there i s no "s a fe ta n."
Pathophysiology
After expos ure to s unl i ght, the epi dermi s thi ckens , a nd mel a nocytes produce the pi gment mel a ni n a t a n i ncrea s ed ra te, ca us i ng ta nni ng. Ta nni ng
provi des s ome na tura l protecti on a ga i ns t future expos ure. Expos ure l ea ds to both i na cti va ti on a nd l os s of epi derma l La ngerha ns ' cel l s , whi ch a re
i mmunol ogi ca l l y i mporta nt.
Peopl e di ffer grea tl y i n thei r s ens i ti vi ty a nd res pons e to s unl i ght ba s ed on the a mount of mel a ni n i n thei r s ki n. Ski n i s cl a s s i fi ed i nto 6 types (I to
VI) i n decrea s i ng order of s us cepti bi l i ty to s un i njury. Cl a s s i fi ca ti on i s ba s ed on s ki n col or, UV s ens i ti vi ty, a nd res pons e to s un expos ure. Ski n type
I i s whi te to l i ghtl y pi gmented, very s ens i ti ve to UV l i ght, ha s no i mmedi a te pi gment da rkeni ng, a l wa ys burns ea s i l y, a nd never ta ns . Ski n type VI i s
da rk brown or bl a ck, l ea s t s ens i ti ve to UV l i ght, ha s s i gni fi ca nt i mmedi a te pi gment da rkeni ng, a nd ta ns profus el y (deep bl a ck). Da rk-s ki nned
peopl e a re not i mmune to the effects of the s un a nd ca n become s unburned wi th s trong or prol onged expos ure. Long-term effects of UV expos ure
i n da rk-s ki nned peopl e a re the s a me a s thos e i n l i ght-s ki nned peopl e but a re often del a yed a nd l es s s evere. Peopl e wi th bl onde or red ha i r a re
es peci a l l y s us cepti bl e to the a cute a nd chroni c effects of UV ra di a ti on. Uneven mel a nocyte a cti va ti on occurs i n ma ny fa i r-ha i red peopl e a nd
res ul ts i n freckl i ng. There i s no s ki n pi gmenta ti on i n peopl e wi th a l bi ni s m (s ee p. 719) beca us e of a defect i n mel a ni n meta bol i s m. Pa tchy a rea s
of depi gmenta ti on a re pres ent i n pa ti ents wi th vi ti l i go (s ee p. 720) beca us e of i mmunol ogi c des tructi on of mel a nocytes .
Prevention
Avoidance: Si mpl e preca uti ons hel p prevent s unburn a nd the chroni c effects of s unl i ght. Thes e preca uti ons a re recommended for peopl e of a l l s ki n
types , pa rti cul a rl y thos e who a re fa i r s ki nned a nd burn ea s i l y. Expos ure to bri ght mi dda y s un s houl d not be > 30 mi n, even for peopl e wi th da rk
s ki n. In tempera te zones , expos ure i s l es s ha za rdous before 10 AM a nd a fter 3 PM beca us e more s unburn-produci ng wa vel engths a re fi l tered out.
Fog a nd cl ouds do not reduce ri s k, a nd ri s k i s i ncrea s ed a t hi gh a l ti tude.
Clothing: Ski n s houl d be covered. Fa bri cs wi th a ti ght wea ve bl ock the s un better tha n do thos e wi th a l oos e wea ve. Speci a l cl othi ng tha t provi des
hi gh s un protecti on i s commerci a l l y a va i l a bl e. Broa d-bri mmed ha ts protect the fa ce, ea rs , a nd neck. Regul a r us e of UV-protecti ve, wra p-a round
s ungl a s s es hel ps s hi el d the eyes .
Sunscreens: Al though s uns creens hel p protect the s ki n from s unburn a nd chroni c s un da ma ge, they do not a l wa ys prevent da ma ge. Ol der
s uns creens tended to fi l ter onl y UVB l i ght, but ma ny newer s uns creens a re now "ful l s pectrum" a nd effecti vel y fi l ter UVA l i ght a s wel l . In the US,
the FDA ra tes s uns creens by s un protecti on fa ctor (SPF): the hi gher the number, the grea ter the protecti on. Agents wi th SPF 15 a re recommended.
The SPF, however, onl y qua nti fi es the protecti on a ga i ns t UVB expos ure; there i s no s ca l e for UVA protecti on.
Suns creens a re a va i l a bl e i n a wi de va ri ety of formul a ti ons , i ncl udi ng crea ms , gel s , foa ms , s pra ys , a nd s ti cks . Sel f-ta nni ng products do not provi de
s i gni fi ca nt protecti on from UV expos ure.
Mos t s uns creens conta i n s evera l a gents tha t functi on a s chemi ca l s creens , a bs orbi ng l i ght or provi di ng a phys i ca l s creen tha t refl ects or s ca tters
l i ght. Common chemi ca l s uns creen a gents mos tl y a bs orb UVB ra ys a nd i ncl ude the a mi nobenzoa tes , whi ch i ncl ude p-a mi nobenzoi c a ci d (PABA),
s a l i cyl a tes , ci nna ma tes , benzophenones (eg, a vobenzone), a nd the a nthri l a tes (a n a mi nobenzoa te deri va ti ve). Of thes e, the benzophenones a re
pa rti cul a rl y effecti ve a t s creeni ng UVA ra ys .
Other s uns creens , ca l l ed s unbl ocks , conta i n zi nc oxi de a nd ti ta ni um di oxi de, whi ch phys i ca l l y bl ock both UVB a nd UVA ra ys . Mi croni zed
formul a ti ons of thes e products ha ve s i gni fi ca ntl y i mproved thei r cos meti c a ccepta bi l i ty.
Suns creen fa i l ure i s common a nd us ua l l y res ul ts from i ns uffi ci ent a ppl i ca ti on of the product, a ppl i ca ti on too l a te (s uns creens s houl d opti ma l l y
be a ppl i ed 30 mi n before expos ure), or fa i l ure to rea ppl y a fter s wi mmi ng or exerci s e.
Al l ergi c or photoa l l ergi c rea cti ons to s uns creens mus t be di s ti ngui s hed from other photos ens i ti ve s ki n erupti ons . Pa tch or photopa tch tes ti ng wi th
s uns creen components ma y be neces s a ry to ma ke the di a gnos i s . Thi s tes ti ng i s us ua l l y done by derma tol ogi s ts wi th a pa rti cul a r experti s e i n
a l l ergi c conta ct derma ti ti s .
Chronic Effects of Sunlight
Aging: Chroni c expos ure to s unl i ght a ges the s ki n (derma tohel i os i s , extri ns i c a gi ng), produci ng both fi ne a nd coa rs e wri nkl es , rough l ea thery
texture, mottl ed pi gmenta ti on, a nd tel a ngi ecta s i a . The a trophi c effects i n s ome peopl e ma y res embl e thos e s een a fter x-ra y thera py (chroni c
ra di a ti on derma ti ti s ).
Actinic keratoses: Acti ni c kera tos es a re preca ncerous cha nges i n s ki n cel l s (kera ti nocytes ) tha t a re a frequent, di s turbi ng cons equence of ma ny
yea rs of s un expos ure. Peopl e wi th bl onde or red ha i r, bl ue eyes , a nd s ki n type I or II a re pa rti cul a rl y s us cepti bl e.
The kera tos es a re us ua l l y pi nk or red, poorl y ma rgi na ted, a nd s ca l y on pa l pa ti on, a l though s ome a re l i ght gra y or pi gmented, gi vi ng them a brown
a ppea ra nce. They s houl d be di fferenti a ted from s eborrhei c kera tos es (s ee p. 746), whi ch i ncrea s e i n number a nd s i ze wi th a gi ng. Seborrhei c
kera tos es tend to a ppea r wa xy a nd s tuck-on but ca n often ta ke on a n a ppea ra nce s i mi l a r to a cti ni c kera tos es . Cl os e i ns pecti on us ua l l y revea l s
di s ti ngui s hi ng cha ra cteri s ti cs of the l es i on. Unl i ke a cti ni c kera tos es , s eborrhei c kera tos es a l s o occur on non-s un-expos ed a rea s of the body a nd
a re not prema l i gna nt.
Skin cancers (s ee p. 748): The i nci dence of s qua mous cel l ca rci noma a nd ba s a l cel l ca rci noma i n fa i r, l i ght-s ki nned peopl e i s di rectl y proporti ona l
to the tota l a nnua l s unl i ght i n the a rea . Such l es i ons a re es peci a l l y common a mong peopl e who were extens i vel y expos ed to s unl i ght a s chi l dren
a nd a dol es cents a nd a mong thos e who a re chroni ca l l y expos ed to the s un a s pa rt of thei r profes s i on or recrea ti ona l a cti vi ti es (eg, a thl etes ,
fa rmers , ra nchers , s a i l ors , frequent s unba thers ). Sun expos ure a l s o s ubs ta nti a l l y i ncrea s es the ri s k of ma l i gna nt mel a noma s .
Treatment
Va ri ous combi na ti on thera pi es , i ncl udi ng chemi ca l peel s , 5-fl uoroura ci l (5-FU), topi ca l -hydroxy a ci ds , i mi qui mod, photodyna mi c thera py, a nd
treti noi n, ha ve been us ed to reduce ca rci nogeni c cha nges a nd i mprove the cos meti c a ppea ra nce of chroni ca l l y s un-da ma ged s ki n. Thes e thera pi es
a re often effecti ve i n a mel i ora ti ng s uperfi ci a l s ki n cha nges (eg, coa rs e a nd fi ne wri nkl es , i rregul a r pi gmenta ti on, s a l l ownes s , roughnes s , mi nor
l a xi ty) but ha ve a much l es s pronounced effect on deeper cha nges (eg, tel a ngi ecta s i a s ). La s ers a re ca pa bl e of trea ti ng both s uperfi ci a l a nd deep
cha nges i n the dermi s a nd a re us ed to trea t cos meti c a nd preca ncerous s ki n cha nges . Ma ny chemi ca l s a re us ed i n OTC cos meti c products wi thout
s i gni fi ca nt evi dence tha t they i mprove chroni c cha nges of the s ki n ca us ed by s unl i ght.
Actinic keratoses: There a re s evera l opti ons , dependi ng on the number a nd l oca ti on of l es i ons .
Li qui d ni trogen
Topi ca l 5-FU
Topi ca l i mi qui mod
If onl y a few a cti ni c kera tos es a re pres ent, cryothera py (freezi ng wi th l i qui d ni trogen) i s the mos t ra pi d a nd s a ti s fa ctory trea tment.
If there a re too ma ny l es i ons to freeze, topi ca l 5-FU a ppl i ed to the a ffected a rea ni ghtl y or twi ce da i l y for 2 to 6 wk often cl ea rs the ma jori ty of
l es i ons . Severa l s trengths a nd formul a ti ons of 5-FU a re commerci a l l y a va i l a bl e. Ma ny pa ti ents tol era te 0.5% 5-FU crea m a ppl i ed once/da y for 4 wk
on the fa ce better tha n s tronger concentra ti ons . Acti ni c kera tos es on the a rms ma y requi re s tronger concentra ti ons , s uch a s 5% crea m. Topi ca l 5-FU
produces a bri s k rea cti on, wi th rednes s , s ca l i ng, a nd burni ng, often a ffecti ng a rea s wi th no vi s i bl e a cti ni c kera tos es . If the rea cti on i s too bri s k,
a ppl i ca ti on ma y be s us pended for 1 to 3 da ys . Topi ca l 5-FU ha s few s i gni fi ca nt a dvers e effects except for thi s uns i ghtl y a nd uncomforta bl e
rea cti on, whi ch ca n be ma s ked by cos meti cs a nd, when neces s a ry, s uppres s ed wi th topi ca l corti cos teroi ds . 5-FU s houl d not be us ed to trea t ba s a l
cel l ca rci noma s , except thos e s hown by bi ops y to be of the s uperfi ci a l type.
A rel a ti vel y new drug, i mi qui mod, i s often us ed for trea tment of a cti ni c kera tos es a nd s uperfi ci a l ba s a l cel l ca rci noma s . It s ti mul a tes the i mmune
s ys tem to recogni ze a nd des troy ca ncerous s ki n l es i ons . For trea tment of s ki n ca ncers , s ee Ch. 90.
Photosensitivity
Photosensitivity is a poorly understood cutaneous reaction to sunlight probably involving the immune system. It may be idiopathic or occur after exposure to
certain drugs or chemicals, and it is sometimes a feature of systemic disorders (eg, SLE, porphyria, pellagra, xeroderma pigmentosum). Diagnosis is clinical.
Treatment varies by type.
In a ddi ti on to the a cute a nd chroni c effects of s unl i ght, a va ri ety of unus ua l rea cti ons ma y occur s oon a fter onl y a bri ef s un expos ure. Unl es s the
ca us e i s obvi ous , pa ti ents wi th pronounced photos ens i ti vi ty s houl d be eva l ua ted for s ys temi c or cuta neous di s orders a s s oci a ted wi th l i ght
s ens i ti vi ty s uch a s SLE (s ee p. 305) a nd porphyri a (s ee p. 807). Trea tment for chemi ca l photos ens i ti vi ty i s topi ca l corti cos teroi ds a nd a voi da nce of
the ca us a ti ve s ubs ta nce.
Solar urticaria: In certa i n pa ti ents , urti ca ri a devel ops a t a s i te of s un expos ure wi thi n a few mi nutes . Ra rel y, i f l a rge a rea s a re i nvol ved, s yncope,
di zzi nes s , wheezi ng, a nd other s ys temi c s ymptoms ma y devel op. Eti ol ogy i s uncl ea r but ma y i nvol ve endogenous s ki n cons ti tuents functi oni ng a s
photoa l l ergens , l ea di ng to ma s t cel l degra nul a ti on a s i n other types of urti ca ri a . Sol a r urti ca ri a ca n be di s ti ngui s hed from other types of urti ca ri a
i n tha t whea l s i n s ol a r urti ca ri a occur onl y on expos ed s ki n a fter ul tra vi ol et (UV) l i ght expos ure. Sol a r urti ca ri a ca n be cl a s s i fi ed ba s ed on the
component of the UV s pectrum (UVA, UVB, a nd vi s i bl e l i ght) tha t produces them. Trea tment ca n be di ffi cul t a nd ma y i ncl ude H 1 bl ockers ,
a nti ma l a ri a l drugs , topi ca l corti cos teroi ds , s uns creens , a nd ps ora l en UV l i ght (PUVA). The whea l s of s ol a r urti ca ri a us ua l l y l a s t jus t mi nutes to
hours , but the di s order i s chroni c a nd ca n wa x a nd wa ne over yea rs .
Chemical photosensitivity: Over 100 s ubs ta nces , i nges ted or a ppl i ed topi ca l l y, a re known to predi s pos e to cuta neous rea cti ons fol l owi ng s un
expos ure. A l i mi ted number a re res pons i bl e for mos t rea cti ons (s ee
Ta bl e 77-1). Rea cti ons a re di vi ded i nto phototoxi ci ty a nd photoa l l ergy.
In phototoxicity, l i ght-a bs orbi ng compounds di rectl y genera te free ra di ca l s a nd i nfl a mma tory medi a tors , ca us i ng ti s s ue da ma ge ma ni fes ti ng a s
pa i n a nd erythema (l i ke s unburn). Thi s rea cti on does not requi re pri or s un expos ure a nd ca n a ppea r i n a ny pers on, a l though rea cti on i s hi ghl y
va ri a bl e. Typi ca l ca us es of phototoxi c rea cti ons i ncl ude topi ca l (eg, perfumes , coa l ta r) or i nges ted (eg, tetra cycl i nes , ps ora l en-conta i ni ng pl a nts )
a gents . Phototoxi c rea cti ons do not genera l i ze to non-s un-expos ed s ki n.
Photoallergy i s a type IV (cel l -medi a ted) i mmune res pons e; l i ght a bs orpti on ca us es s tructura l cha nges i n the drug or s ubs ta nce, a l l owi ng i t to bi nd
to ti s s ue protei n a nd functi on a s a ha pten. Pri or expos ure i s requi red. Typi ca l ca us es of photoa l l ergi c rea cti ons i ncl ude a fters ha ve l oti ons ,
s uns creens , a nd s ul fona mi des . Rea cti on ma y extend to non-s un-expos ed s ki n. Symptoms i ncl ude erythema , pruri tus , a nd s ometi mes ves i cl es .
[Table 77-1. Some Subs ta nces tha t Sens i ti ze the Ski n to Sunl i ght]
Polymorphous light eruption: Thes e erupti ons a re unus ua l rea cti ons to l i ght tha t do not s eem to be a s s oci a ted wi th s ys temi c di s ea s e or drugs .
Erupti ons a ppea r on s un-expos ed a rea s , us ua l l y 30 mi n to s evera l hours a fter expos ure. Les i ons a re pruri ti c, erythema tous , a nd often pa pul a r but
ma y be pa pul oves i cul a r or pl a quel i ke. They a re mos t common a mong women a nd peopl e from northern cl i ma tes when fi rs t expos ed to s pri ng or
s ummer s un tha n a mong thos e expos ed to s un yea r-round. Les i ons s ubs i de wi thi n s evera l da ys to 1 wk or s o. Acti ni c pruri go i s a s i mi l a r (perha ps
rel a ted) phenomenon wi th more nodul a r-a ppea ri ng l es i ons tha t ma y pers i s t yea r-round, wors eni ng wi th s un expos ure.
Di a gnos i s i s ma de by hi s tory, s ki n fi ndi ngs , a nd excl us i on of other s un-s ens i ti vi ty di s orders . Di a gnos i s s ometi mes requi res reproducti on of the
l es i ons wi th a rti fi ci a l or na tura l s unl i ght when the pa ti ent i s not us i ng a ny potenti a l l y s ens i ti zi ng drugs .
Often, l es i ons a re s el f-l i mi ted a nd s ponta neous l y i mprove a s s ummer progres s es . Trea tment i s by modera ti ng s un expos ure a nd a ppl yi ng topi ca l
corti cos teroi ds . More s everel y a ffected pa ti ents ma y benefi t from des ens i ti za ti on by gra dua ted expos ure to UV l i ght wi th PUVA (s ee p. 679) or
na rrow ba nd UVB (312 nm) photothera py. Pa ti ents wi th di s a bl i ng di s ea s e ma y requi re a cours e of ora l i mmunos uppres s i ve thera py s uch a s
predni s one, a za thi opri ne, cycl os pori ne, or hydroxychl oroqui ne.
Sunburn
Sunburn is characterized by erythema and sometimes pain and blisters caused by exposure to solar ultraviolet radiation. Treatment is similar to that for thermal
burns, including cool compresses, NSAIDs, and, for severe cases, sterile dressings and topical antimicrobials. Prevention by sun avoidance and use of sunscreens is
crucial.
Sunburn res ul ts from overexpos ure of the s ki n to ul tra vi ol et (UV) ra di a ti on; wa vel engths i n the UVB s pectrum (280 to 320 nm) ca us e the mos t
pronounced effects .
Symptoms and Signs
Symptoms a nd s i gns a ppea r i n 1 to 24 h a nd, except i n s evere rea cti ons , pea k wi thi n 72 h. Ski n cha nges ra nge from mi l d erythema , wi th
s ubs equent s uperfi ci a l s ca l i ng, to pa i n, s wel l i ng, s ki n tendernes s , a nd bl i s ters . Cons ti tuti ona l s ymptoms (eg, fever, chi l l s , wea knes s , s hock),
s i mi l a r to a therma l burn, ma y devel op i f a l a rge porti on of the body s urfa ce i s a ffected; thes e s ymptoms ma y be ca us ed by the rel ea s e of
i nfl a mma tory cytoki nes s uch a s IL-1.
Seconda ry i nfecti on, bl otchy pi gmenta ti on, a nd mi l i a ri a -l i ke erupti ons a re the mos t common l a te compl i ca ti ons . Exfol i a ted s ki n ma y be extremel y
vul nera bl e to s unl i ght for s evera l weeks .
Treatment
Further expos ure s houl d be a voi ded unti l s unburn ha s compl etel y s ubs i ded. Col d ta p wa ter compres s es a nd ora l NSAIDs hel p rel i eve s ymptoms ,
a s ma y topi ca l a l oe vera . Topi ca l corti cos teroi ds a re no more effecti ve tha n cool compres s es . Bl i s tered a rea s s houl d be ma na ged s i mi l a rl y to
other pa rti a l -thi cknes s burns (s ee p. 3246), wi th s teri l e dres s i ngs a nd topi ca l ba ci tra ci n or s i l ver s ul fa di a zi ne. Oi ntments or l oti ons conta i ni ng
l oca l a nes theti cs (eg, benzoca i ne) s houl d be a voi ded beca us e of the ri s k of a l l ergi c conta ct derma ti ti s .
Ea rl y trea tment of extens i ve, s evere s unburn wi th a s ys temi c corti cos teroi d (eg, predni s one 20 to 30 mg po bi d for 4 da ys for a dul ts or teena gers )
ma y decrea s e the di s comfort, but thi s us e i s controvers i a l .
Prevention
Si mpl e preca uti ons (eg, a voi di ng the s un es peci a l l y duri ng mi dda y, wea ri ng ti ghtl y woven cl othi ng, us i ng s uns creens ) us ua l l y prevent mos t ca s es
of s unburn (s ee p. 673).
Chapter 78. Psoriasis and Scaling Diseases

Introduction
Ps ori a s i s , pa ra ps ori a s i s , pi tyri a s i s ros ea , pi tyri a s i s rubra pi l a ri s , pi tyri a s i s l i chenoi des , l i chen pl a nus , a nd l i chen s cl eros us a re di s s i mi l a r
di s orders grouped together beca us e thei r pri ma ry l es i ons ha ve s i mi l a r cha ra cteri s ti cs : s ha rpl y ma rgi na ted, s ca l i ng pa pul es or pl a ques wi thout
wetnes s , crus ts , fi s s ures , a nd excori a ti ons . Les i on a ppea ra nce a nd di s tri buti on di s ti ngui s h thes e di s ea s es from ea ch other.
Psoriasis
Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Cause
is unclear but seems to involve the immune system. Common triggers include trauma, infection, and certain drugs. Symptoms are usually minimal with
occasional mild itching, but cosmetic implications may be major. Some people develop severe disease with painful arthritis. Diagnosis is based on appearance
and distribution of lesions. Treatment is with emollients, vitamin D analogs, retinoids, tar, anthralin, corticosteroids, phototherapy, and, when severe,
methotrexate, retinoids, immunomodulatory agents (biologics), or immunosuppressants.
Ps ori a s i s i s hyperprol i fera ti on of epi derma l kera ti nocytes combi ned wi th i nfl a mma ti on of the epi dermi s a nd dermi s . It a ffects a bout 1 to 5% of
the popul a ti on worl dwi de; l i ght-s ki nned peopl e a re a t grea ter ri s k. Pea k ons et i s roughl y bi moda l , mos t often a t a ges 16 to 22 a nd a t a ges 57 to
60, but the di s order ca n occur a t a ny a ge.
Etiology
The ca us e i s uncl ea r but i nvol ves i mmune s ti mul a ti on of epi derma l kera ti nocytes ; T cel l s s eem to pl a y a centra l rol e. Fa mi l y hi s tory i s common,
a nd certa i n genes a nd HLA a nti gens (Cw6, B13, B17) a re a s s oci a ted wi th ps ori a s i s . An envi ronmenta l tri gger i s thought to evoke a n i nfl a mma tory
res pons e a nd s ubs equent hyperprol i fera ti on of kera ti nocytes .
Wel l -i denti fi ed tri ggers i ncl ude
Injury (Koebner phenomenon)
Sunburn
HIV
-Hemol yti c s treptococca l i nfecti on
Drugs (es peci a l l y -bl ockers , chl oroqui ne, l i thi um, ACE i nhi bi tors , i ndometha ci n, terbi na fi ne, a nd i nterferon a l fa )
Emoti ona l s tres s
Al cohol cons umpti on
Symptoms and Signs
Les i ons a re ei ther a s ymptoma ti c or pruri ti c a nd a re mos t often l oca l i zed on the s ca l p, extens or s urfa ces of the el bows a nd knees , s a crum,
buttocks , a nd peni s . The na i l s , eyebrows , a xi l l a e, umbi l i cus , a nd peri a na l regi on ma y a l s o be a ffected. The di s ea s e ca n be wi des prea d, i nvol vi ng
confl uent a rea s of s ki n extendi ng between thes e regi ons . Les i ons di ffer i n a ppea ra nce dependi ng on type.
Among the va ri ous s ubtypes (s ee
Ta bl e 78-1), pl a que ps ori a s i s (ps ori a s i s vul ga ri s or chroni c pl a que ps ori a s i s ) i s the mos t common pa ttern; l es i ons a re di s crete, erythema tous
pa pul es or pl a ques covered wi th thi ck, s i l very, s hi ny s ca l es . Les i ons a ppea r gra dua l l y a nd remi t a nd recur ei ther s ponta neous l y or wi th
a ppea ra nce a nd res ol uti on of tri ggers .
Arthri ti s devel ops i n 5 to 30% of pa ti ents a nd ca n be di s a bl i ng (s ee p. 344); joi nt des tructi on ma y ul ti ma tel y occur.
Ps ori a s i s i s ra rel y l i fe-threa teni ng but ca n a ffect a pa ti ent's s el f-i ma ge. Bes i des i ma ge, the s heer a mount of ti me requi red to trea t extens i ve s ki n
or s ca l p l es i ons a nd to ma i nta i n cl othi ng a nd beddi ng ma y a dvers el y a ffect qua l i ty of l i fe.
Diagnosis
Ra rel y bi ops y
Di a gnos i s i s mos t often by cl i ni ca l a ppea ra nce a nd di s tri buti on of l es i ons . Di fferenti a l di a gnos i s i ncl udes s eborrhei c derma ti ti s ,
derma tophytos es , cuta neous l upus erythema tos us , eczema , l i chen pl a nus , pi tyri a s i s ros ea , s qua mous cel l ca rci noma i n s i tu (Bowen's di s ea s e,
es peci a l l y when on the trunk), l i chen s i mpl ex chroni cus , a nd s econda ry s yphi l i s . Bi ops y i s ra rel y neces s a ry a nd ma y not be di a gnos ti c.
Di s ea s e i s gra ded a s mi l d, modera te, or s evere ba s ed on the body s urfa ce a rea a ffected a nd how the l es i ons a ffect pa ti ents ' qua l i ty of l i fe. There
a re ma ny more compl ex s cori ng s ys tems for di s ea s e s everi ty (eg, the Ps ori a s i s Area a nd Severi ty Index), but thes e s ys tems a re us eful ma i nl y i n
res ea rch protocol s .
Treatment
Topi ca l trea tments
Sys temi c trea tments

Ul tra vi ol et (UV) l i ght thera py
Trea tment opti ons a re extens i ve a nd i ncl ude emol l i ents , s a l i cyl i c a ci d, coa l ta r, a nthra l i n, corti cos teroi ds , vi ta mi n D 3 a na l ogs , methotrexa te,
topi ca l a nd ora l reti noi ds , topi ca l a nd ora l ca l ci neuri n i nhi bi tors , i mmunos uppres s a nts , i mmunomodul a tory a gents (bi ol ogi cs ), a nd ul tra vi ol et
l i ght thera py.
Topical treatments: Emollients i ncl ude emol l i ent crea ms , oi ntments , petrol a tum, pa ra ffi n, a nd even hydrogena ted vegeta bl e (cooki ng) oi l s . They
reduce s ca l i ng a nd a re mos t effecti ve when a ppl i ed twi ce da i l y a nd i mmedi a tel y a fter ba thi ng. Les i ons ma y a ppea r redder a s s ca l i ng decrea s es or
becomes more tra ns pa rent. Emol l i ents a re s a fe a nd s houl d proba bl y a l wa ys be us ed for mi l d to modera te pl a que ps ori a s i s .
Salicylic acid i s a kera ti nol yti c tha t s oftens s ca l es , fa ci l i ta tes thei r remova l , a nd i ncrea s es a bs orpti on of other topi ca l a gents . It i s es peci a l l y us eful
a s a component of s ca l p trea tments ; s ca l p s ca l e ca n be qui te thi ck.
Coal tar oi ntments , s ol uti ons , or s ha mpoos a re a nti -i nfl a mma tory a nd decrea s e kera ti nocyte hyperprol i fera ti on vi a a n unknown mecha ni s m. They
a re typi ca l l y a ppl i ed a t ni ght a nd wa s hed off i n the morni ng. They ca n be us ed i n combi na ti on wi th topi ca l corti cos teroi ds or wi th expos ure to
na tura l or a rti fi ci a l broa d-ba nd UVB l i ght (280 to 320 nm) i n s l owl y i ncrea s i ng i ncrements (Goeckerma n regi men).
Anthralin i s a topi ca l a nti prol i fera ti ve, a nti -i nfl a mma tory a gent. Its mecha ni s m i s unknown. Effecti ve dos e i s 0.1% crea m or oi ntment i ncrea s ed to
1% a s tol era ted. Anthra l i n ma y be i rri ta ti ng a nd s houl d be us ed wi th ca uti on i n i ntertri gi nous a rea s ; i t a l s o s ta i ns . Irri ta ti on a nd s ta i ni ng ca n be
a voi ded
[Table 78-1. Subtypes of Ps ori a s i s ]
by wa s hi ng off the a nthra l i n 20 to 30 mi n a fter a ppl i ca ti on. Us i ng a l i pos ome-enca ps ul a ted prepa ra ti on ma y a l s o a voi d s ome di s a dva nta ges of
a nthra l i n.
Corticosteroids a re us ua l l y us ed topi ca l l y but ma y be i njected i nto s ma l l or reca l ci tra nt l es i ons . (CAUTION: Systemic corticosteroids may precipitate
exacerbations or development of pustular psoriasis and should not be used to treat psoriasis.) Topi ca l corti cos teroi ds a re us ed twi ce da i l y, s ometi mes wi th
a nthra l i n or coa l ta r a ppl i ed a t bedti me. Corti cos teroi ds a re mos t effecti ve when us ed overni ght under occl us i ve pol yethyl ene coveri ngs or
i ncorpora ted i nto ta pe; a corti cos teroi d crea m i s a ppl i ed wi thout occl us i on duri ng the da y. Corti cos teroi d potency (s ee p. 647) i s s el ected a ccordi ng
to the extent of i nvol vement. As l es i ons a ba te, the corti cos teroi d s houl d be a ppl i ed l es s frequentl y or a t a l ower potency to mi ni mi ze l oca l
a trophy, s tri a e forma ti on, a nd tel a ngi ecta s es . Idea l l y, a fter a bout 3 wk, a n emol l i ent s houl d be s ubs ti tuted for the corti cos teroi d for 1 to 2 wk (a s
a res t peri od); thi s s ubs ti tuti on l i mi ts corti cos teroi d dos a ge a nd prevents ta chyphyl a xi s . Topi ca l corti cos teroi d us e ca n be expens i ve beca us e
l a rge qua nti ti es (a bout 1 oz or 30 g) a re needed for ea ch a ppl i ca ti on when a l a rge body s urfa ce a rea i s a ffected. Topi ca l corti cos teroi ds a ppl i ed
for l ong dura ti on to l a rge a rea s of the body ma y ca us e s ys temi c effects a nd exa cerba te ps ori a s i s . For s ma l l , thi ck, l oca l i zed, or reca l ci tra nt l es i ons ,
hi gh-potency corti cos teroi ds a re us ed wi th a n occl us i ve dres s i ng or fl ura ndrenol i de ta pe; thes e dres s i ngs a re l eft on overni ght a nd cha nged i n the
morni ng. Rel a ps e a fter topi ca l corti cos teroi ds a re s topped i s often fa s ter tha n wi th other a gents .
Vitamin D 3 analogs (eg, ca l ci potri ol , ca l ci tri ol ) a re topi ca l vi ta mi n D a na l ogs tha t i nduce norma l kera ti nocyte prol i fera ti on a nd di fferenti a ti on; they
ca n be us ed a l one or i n combi na ti on wi th topi ca l corti cos teroi ds . Some cl i ni ci a ns ha ve pa ti ents a ppl y ca l ci potri ol on weekda ys a nd
corti cos teroi ds on weekends .
Calcineurin inhibitors (eg, ta crol i mus , pi mecrol i mus ) a re a va i l a bl e i n topi ca l form a nd a re genera l l y wel l -tol era ted. They a re not a s effecti ve a s
corti cos teroi ds but ma y a voi d the compl i ca ti ons of corti cos teroi ds when trea ti ng fa ci a l a nd i ntertri gi nous ps ori a s i s . They ma y be a s s oci a ted wi th
a n i ncrea s ed ri s k of l ymphoma a nd s ki n ca ncer.
Tazarotene i s a topi ca l reti noi d. It i s l es s effecti ve tha n corti cos teroi ds a s monothera py but i s a us eful a djunct.
Systemic treatments: Methotrexate ta ken ora l l y i s the mos t effecti ve trea tment for s evere di s a bl i ng ps ori a s i s , es peci a l l y s evere ps ori a ti c a rthri ti s or
wi des prea d erythrodermi c or pus tul a r ps ori a s i s unres pons i ve to topi ca l a gents or ps ora l en pl us ul tra vi ol et A (PUVA) l i ght thera py. Methotrexa te
s eems to i nterfere wi th the ra pi d prol i fera ti on of epi derma l cel l s . Hema tol ogi c, rena l , a nd hepa ti c functi on s houl d be moni tored. Dos a ge
regi mens va ry, s o onl y phys i ci a ns experi enced i n i ts us e for ps ori a s i s s houl d underta ke methotrexa te thera py.
Systemic retinoids (eg, a ci treti n, i s otreti noi n) ma y be effecti ve for s evere a nd reca l ci tra nt ca s es of ps ori a s i s vul ga ri s , pus tul a r ps ori a s i s (i n whi ch
i s otreti noi n ma y be preferred), a nd hyperkera toti c pa l mopl a nta r ps ori a s i s . Beca us e of the tera togeni c potenti a l a nd l ong-term retenti on of
a ci treti n i n the body, women who us e i t mus t not be pregna nt a nd s houl d be wa rned a ga i ns t becomi ng pregna nt for a t l ea s t 2 yr a fter trea tment
ends . Pregna ncy res tri cti ons a l s o a ppl y to i s otreti noi n, but the a gent i s not reta i ned i n the body beyond 1 mo. Long-term trea tment ma y ca us e
di ffus e i di opa thi c s kel eta l hyperos tos i s (DISHs ee p. 342).
Immunosuppressants ca n be us ed for s evere ps ori a s i s . Cycl os pori ne i s a commonl y us ed i mmunos uppres s a nt. It s houl d be l i mi ted to cours es of
s evera l months (ra rel y, up to 1 yr) a nd a l terna ted wi th other thera pi es . Its effect on the ki dneys a nd potenti a l l ong-term effects on the i mmune
s ys tem precl ude more l i bera l us e. Other i mmunos uppres s a nts (eg, hydroxyurea , 6-thi ogua ni ne, mycophenol a te mofeti l ) ha ve na rrow s a fety
ma rgi ns a nd a re res erved for s evere, reca l ci tra nt ps ori a s i s .
Immunomodulatory agents (bi ol ogi cs s ee p.
1086) i ncl ude tumor necros i s fa ctor (TNF)- i nhi bi tors (eta nercept, a da l i muma b, i nfl i xi ma b) a nd the T-cel l modul a tor a l efa cept. TNF- i nhi bi tors
l ea d to cl ea ri ng of ps ori a s i s , but thei r s a fety profi l e i s s ti l l under s tudy. Efa l i zuma b i s no l onger a va i l a bl e i n the US due to i ncrea s ed ri s k of
progres s i ve mul ti foca l l eukoencepha l opa thy.
Phototherapy: UV light therapy i s typi ca l l y us ed i n pa ti ents wi th extens i ve ps ori a s i s . The mecha ni s m of a cti on i s unknown, a l though UVB l i ght
reduces DNA s ynthes i s a nd ca n i nduce mi l d s ys temi c i mmunos uppres s i on. In PUVA, ora l methoxyps ora l en, a photos ens i ti zer, i s fol l owed by
expos ure to l ong-wa ve UVA l i ght (330 to 360 nm). PUVA ha s a n a nti prol i fera ti ve effect a nd a l s o hel ps to norma l i ze kera ti nocyte di fferenti a ti on.
Dos es of l i ght a re s ta rted l ow a nd i ncrea s ed a s tol era ted. Severe burns ca n res ul t i f the dos e of drug or UVA i s too hi gh. Al though the trea tment i s
l es s mes s y tha n topi ca l trea tment a nd ma y produce remi s s i ons l a s ti ng s evera l months , repea ted trea tments ma y i ncrea s e the i nci dence of UVi nduced s ki n ca ncer a nd mel a noma . Les s UV l i ght i s requi red when us ed wi th ora l reti noi ds (the s o-ca l l ed re-PUVA regi men). Na rrow-ba nd UVB
l i ght (311 to 312 nm) us ed wi thout ps ora l ens i s s i mi l a r i n effecti venes s to PUVA. Exci mer l a s er thera py i s a type of photothera py us i ng extremel y
pure wa vel engths .
Choice of therapy: Choi ce of s peci fi c a gents a nd combi na ti ons requi res cl os e coopera ti on wi th the pa ti ent, a l wa ys keepi ng i n mi nd the untowa rd
effects of the trea tments . There i s no s i ngl e i dea l combi na ti on or s equence of a gents , but trea tment s houl d be kept a s s i mpl e a s pos s i bl e.
Monothera py i s preferred, but combi na ti on thera py i s the norm. Rota ti ona l thera py refers to the s ubs ti tuti on of one thera py for a nother a fter 1 to 2
yr to reduce the a dvers e effects ca us ed by chroni c us e a nd to ci rcumvent di s ea s e res i s ta nce. Sequenti a l thera py refers to i ni ti a l us e of potent
a gents (eg, cycl os pori ne) to qui ckl y ga i n control fol l owed by us e of a gents wi th a better s a fety profi l e.
Mild plaque psoriasis ca n be trea ted wi th emol l i ents , kera tol yti cs , ta r, topi ca l corti cos teroi ds , vi ta mi n D 3 a na l ogs , or a nthra l i n a l one or i n
combi na ti on. Expos ure to s unl i ght i s benefi ci a l , but s unburn ca n i nduce exa cerba ti ons .
Moderate to severe plaque psoriasis s houl d be trea ted wi th topi ca l a gents a nd ei ther photothera py or s ys temi c a gents . Immunos uppres s a nts a re
us ed for qui ck, s hort-term control (eg, i n a l l owi ng a brea k from other moda l i ti es ) a nd for the mos t s evere di s ea s e. Immunomodul a tory a gents
(bi ol ogi cs ) a re us ed for modera te to s evere di s ea s e unres pons i ve to other a gents .
Scalp plaques a re notori ous l y di ffi cul t to trea t beca us e they res i s t s ys temi c thera py, a nd beca us e ha i r bl ocks a ppl i ca ti on of topi ca l a gents a nd
s ca l e remova l a nd s hi el ds s ki n from UV l i ght. A s us pens i on of 10% s a l i cyl i c a ci d i n mi nera l oi l ma y be rubbed i nto the s ca l p a t bedti me ma nua l l y
or wi th a toothbrus h, covered wi th a s hower ca p (to enha nce penetra ti on a nd a voi d mes s i nes s ), a nd wa s hed out the next morni ng wi th a ta r (or
other) s ha mpoo. More cos meti ca l l y a ccepta bl e corti cos teroi d s ol uti ons ca n be a ppl i ed to the s ca l p duri ng the da y. Thes e trea tments a re
conti nued unti l the des i red cl i ni ca l res pons e i s a chi eved. Res i s ta nt s ki n or s ca l p pa tches ma y res pond to l oca l s uperfi ci a l i ntra l es i ona l i njecti on
of tri a mci nol one a cetoni de s us pens i on di l uted wi th s a l i ne to 2.5 or 5 mg/mL, dependi ng on the s i ze a nd s everi ty of the l es i on. Injecti ons ma y
ca us e l oca l a trophy, whi ch i s us ua l l y revers i bl e.
Speci a l trea tment needs for s ubtypes a re des cri bed i n Ta bl e 78-1.
For ps ori a ti c a rthri ti s , trea tment wi th s ys temi c thera py i s i mporta nt to prevent joi nt des tructi on; methotrexa te or a TNF- i nhi bi tor ma y be effecti ve.
Parapsoriasis
Pa ra ps ori a s i s des cri bes a poorl y unders tood a nd poorl y di s ti ngui s hed group of di s ea s es tha t s ha re cl i ni ca l fea tures . There a re 2 genera l forms : a
s ma l l -pl a que type, whi ch i s us ua l l y beni gn, a nd a l a rge-pl a que type, whi ch i s a precurs or of cuta neous T-cel l l ymphoma (CTCL). It i s extremel y ra re
for s ma l l -pl a que pa ra ps ori a s i s to tra ns form i nto CTCL.
The pl a ques a re us ua l l y a s ymptoma ti c; thei r typi ca l a ppea ra nce i s thi n, s ca l i ng, dul l pi nk pa tches a nd pl a ques wi th a s l i ghtl y a trophi c or wri nkl ed
a ppea ra nce. Sma l l -pl a que pa ra ps ori a s i s i s defi ned by l es i ons < 5 cm i n di a meter, wherea s l a rge-pl a que pa ra ps ori a s i s ha s l es i ons > 6 cm i n
di a meter. Someti mes di gi ta te pl a ques devel op a l ong the derma tomes , es peci a l l y on the fl a nks a nd a bdomen, i n s ma l l -pl a que pa ra ps ori a s i s .
Trea tment of s ma l l -pl a que pa ra ps ori a s i s i s unneces s a ry but ca n i ncl ude emol l i ents , topi ca l ta r prepa ra ti ons or corti cos teroi ds , photothera py, or a
combi na ti on. Trea tment of l a rge-pl a que pa ra ps ori a s i s i s photothera py or topi ca l corti cos teroi ds .
Cours e for both types i s unpredi cta bl e; peri odi c cl i ni ca l fol l ow-up a nd bi ops i es gi ve the bes t i ndi ca ti on of ri s k of devel opi ng CTCL.
Pityriasis Rosea
Pityriasis rosea (PR) is an inflammatory disease characterized by diffuse, scaling papules or plaques. Treatment is usually unnecessary.
PR mos t commonl y occurs between a ges 10 a nd 35. It a ffects women more often a nd pea ks i n i nci dence i n cool er months i n tempera te cl i ma tes .
The ca us e ma y be vi ra l i nfecti on (s ome res ea rch ha s i mpl i ca ted huma n herpes vi rus es 6 a nd 7). Drugs ma y ca us e a PR-l i ke rea cti on.
Symptoms and Signs
The condi ti on cl a s s i ca l l y begi ns wi th a s i ngl e, pri ma ry, 2- to 10-cm hera l d pa tch tha t a ppea rs on the trunk or proxi ma l l i mbs (s ee
Pl a te 42). A genera l centri peta l erupti on of 0.5- to 2-cm ros e- or fa wn-col ored ova l pa pul es a nd pl a ques fol l ows wi thi n 7 to 14 da ys . The l es i ons
ha ve a s ca l y, s l i ghtl y ra i s ed border (col l a rette) a nd res embl e ri ngworm (ti nea corpori s ). Mos t pa ti ents i tch, occa s i ona l l y s everel y. Pa pul es ma y
domi na te wi th l i ttl e or no s ca l i ng i n bl a cks , chi l dren, a nd pregna nt women. The ros e or fa wn col or i s not a s evi dent i n bl a cks ; bl a cks a l s o more
commonl y ha ve i nvers e PR (l es i ons i n the a xi l l a e or groi n tha t s prea d centri fuga l l y). Cl a s s i ca l l y, l es i ons ori ent a l ong s ki n l i nes , gi vi ng PR a
Chri s tma s tree-l i ke di s tri buti on when mul ti pl e l es i ons a ppea r on the ba ck. A prodrome of ma l a i s e a nd hea da che precedes the l es i ons i n a
mi nori ty of pa ti ents .
Diagnosis
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce a nd di s tri buti on. Di fferenti a l di a gnos i s i ncl udes ti nea corpori s , ti nea vers i col or, drug erupti ons ,
ps ori a s i s , pa ra ps ori a s i s , pi tyri a s i s l i chenoi des chroni ca , l i chen pl a nus , a nd s econda ry s yphi l i s . Serol ogi c tes ti ng for s yphi l i s i s i ndi ca ted when
the pa l ms or s ol es a re a ffected, when a hera l d pa tch i s not s een, or when l es i ons occur i n a n unus ua l s equence or di s tri buti on.
Treatment
Anti pruri ti c thera py

No s peci fi c trea tment i s neces s a ry beca us e the erupti on us ua l l y remi ts wi thi n 5 wk a nd recurrence i s ra re. Arti fi ci a l or na tura l s unl i ght ma y ha s ten
res ol uti on. Anti pruri ti c thera py s uch a s topi ca l corti cos teroi ds , ora l a nti hi s ta mi nes , or topi ca l mea s ures ma y be us ed a s needed.
Pityriasis Rubra Pilaris
Pityriasis rubra pilaris is a rare chronic disorder that causes hyperkeratotic yellowing of the palms and soles and red follicular papules that merge to form redorange scaling plaques and confluent areas of erythema with islands of normal skin between lesions.
The ca us e of pi tyri a s i s rubra pi l a ri s i s unknown.
The 2 mos t common forms of the di s order a re
Juveni l e cl a s s i c (cha ra cteri zed by a utos oma l domi na nt i nheri ta nce a nd chi l dhood ons et)
Adul t cl a s s i c (cha ra cteri zed by no a ppa rent i nheri ta nce a nd a dul t ons et)
Atypi ca l forms exi s t i n both a ge groups . Sunl i ght ca n tri gger a fl a re.
Di a gnos i s i s by cl i ni ca l a ppea ra nce a nd ma y be s upported by bi ops y. Di fferenti a l di a gnos i s i ncl udes s eborrhei c derma ti ti s (i n chi l dren) a nd
ps ori a s i s when di s ea s e occurs on the s ca l p, el bows , a nd knees .
Trea tment i s exceedi ngl y di ffi cul t a nd empi ri c. The di s order ma y be a mel i ora ted but a l mos t never cured; cl a s s i c forms of the di s order res ol ve
s l owl y over 3 yr, wherea s non-cl a s s i c forms pers i s t. Sca l i ng ma y be reduced wi th emol l i ents or 12% l a cti c a ci d under occl us i ve dres s i ng, fol l owed
by topi ca l corti cos teroi ds . Ora l vi ta mi n A ma y be effecti ve. Ora l reti noi ds or methotrexa te i s a n opti on when a pa ti ent i s res i s ta nt to topi ca l
trea tment.
Pityriasis Lichenoides
Pityriasis lichenoides is a clonal T-cell disorder that may develop in response to foreign antigens (eg, infections or drugs) and may be associated with cutaneous Tcell lymphoma.
Pi tyri a s i s l i chenoi des ha s a cute a nd chroni c forms exi s ti ng i n a cl i ni ca l conti nuum. The a cute form typi ca l l y a ppea rs i n chi l dren a nd young a dul ts ,
wi th crops of a s ymptoma ti c chi ckenpox-l i ke l es i ons tha t typi ca l l y res ol ve wi thi n weeks to months . Anti bi oti cs (eg, tetra cycl i ne, erythromyci n) or
photothera py ma y hel p.
The chroni c form i ni ti a l l y ma ni fes ts a s fl a tter, reddi s h brown, s ca l i ng pa pul es tha t ma y ta ke months or l onger to res ol ve. No trea tment ha s proved
effecti ve.
Lichen Planus
Lichen planus (LP) is a recurrent, pruritic, inflammatory eruption characterized by small, discrete, polygonal, flat-topped, violaceous papules that may coalesce
into rough scaly patches, often accompanied by oral lesions. Diagnosis is usually clinical and supported by skin biopsy. Treatment generally requires topical or
intralesional corticosteroids. Severe cases may require phototherapy or systemic immunosuppressants.
Etiology
LP i s thought to be ca us ed by a T cel l -medi a ted a utoi mmune rea cti on a ga i ns t ba s a l epi thel i a l kera ti nocytes i n peopl e wi th geneti c
predi s pos i ti on. Drugs (es peci a l l y -bl ockers , NSAIDs , ACE i nhi bi tors , s ul fonyl urea s , gol d, a nti ma l a ri a l drugs , peni ci l l a mi ne, a nd thi a zi des ) ca n
ca us e LP; drug-i nduced LP (s ometi mes ca l l ed l i chenoi d drug erupti on) ma y be i ndi s ti ngui s ha bl e from nondrug-i nduced LP or ma y ha ve a pa ttern
tha t i s more eczema tous . As s oci a ti ons wi th hepa ti ti s C-i nduced l i ver i ns uffi ci ency, pri ma ry bi l i a ry ci rrhos i s , a nd other forms of hepa ti ti s ha ve
been reported.
Symptoms and Signs
Typi ca l l es i ons a re pruri ti c, purpl e, pol ygona l , fl a t-topped pa pul es a nd pl a ques (s ee
Pl a te 39). Les i ons i ni ti a l l y a re 2 to 4 mm i n di a meter, wi th a ngul a r borders , a vi ol a ceous col or, a nd a di s ti nct s heen i n cros s -l i ghti ng. They a re
us ua l l y s ymmetri ca l l y di s tri buted, mos t commonl y on the fl exor s urfa ces of the wri s ts , l egs , trunk, gl a ns peni s , a nd ora l a nd va gi na l mucos a e but
ca n be wi des prea d. The fa ce i s ra rel y i nvol ved. Ons et ma y be a brupt or gra dua l . Chi l dren a re a ffected i nfrequentl y. Duri ng the a cute pha s e, new
pa pul es ma y a ppea r a t s i tes of mi nor s ki n i njury (Koebner phenomenon), s uch a s a s uperfi ci a l s cra tch. Les i ons ma y coa l es ce or cha nge over ti me,
becomi ng hyperpi gmented, a trophi c, hyperkera toti c (hypertrophi c LP), or ves i cul obul l ous . Al though pruri ti c, l es i ons a re ra rel y excori a ted or crus ted.
If the s ca l p i s a ffected, pa tchy s ca rri ng a l opeci a (l i chen pl a nopi l a ri s ) ma y occur.
The ora l mucos a i s i nvol ved i n a bout 50% of ca s es ; ora l l es i ons ma y occur wi thout cuta neous l es i ons a nd us ua l l y pers i s t for l i fe. Reti cul a ted, l a cy,
bl ui s h-whi te, l i nea r l es i ons (Wi ckha m's s tri a e) a re a ha l l ma rk of ora l LP, es peci a l l y on the bucca l mucos a e. Tongue ma rgi ns a nd gi ngi va l mucos a e
i n edentul ous a rea s ma y a l s o be a ffected. An eros i ve form of LP ma y occur i n whi ch the pa ti ent devel ops s ha l l ow, often pa i nful , recurrent ora l
ul cers , whi ch, i f l ong-s ta ndi ng, ra rel y become ca ncerous . Chroni c exa cerba ti ons a nd remi s s i ons a re common. Vul va r a nd va gi na l mucos a e a re
often i nvol ved. Up to 50% of women wi th ora l mucos a l fi ndi ngs ha ve undi a gnos ed vul va r LP. In men, geni ta l i nvol vement i s common, es peci a l l y of
the gl a ns peni s .
Na i l s a re i nvol ved i n up to 10% of ca s es . Fi ndi ngs va ry i n i ntens i ty wi th na i l bed di s col ora ti on, l ongi tudi na l ri dgi ng a nd l a tera l thi nni ng, a nd
compl ete l os s of the na i l ma tri x a nd na i l , wi th s ca rri ng of the proxi ma l na i l fol d onto the na i l bed (pterygi um forma ti on).
Diagnosis
Bi ops y
Al though di a gnos i s i s s ugges ted by a ppea ra nce of the l es i ons , s i mi l a r l es i ons ma y res ul t from a ny of the pa pul os qua mous di s orders , l upus
erythema tos us , a nd s econda ry s yphi l i s , a mong others . Ora l or va gi na l LP ma y res embl e l eukopl a ki a , a nd the ora l l es i ons mus t a l s o be
di s ti ngui s hed from ca ndi di a s i s , ca rci noma , a phthous ul cers , pemphi gus , ci ca tri ci a l pemphi goi d, a nd chroni c erythema mul ti forme. Typi ca l l y,
bi ops y i s done.
If LP i s di a gnos ed, s ome cl i ni ci a ns do l a bora tory tes ti ng for l i ver dys functi on, i ncl udi ng hepa ti ti s B a nd C i nfecti ons .
Prognosis
Ma ny ca s es res ol ve wi thout i nterventi on, pres uma bl y beca us e the i nci ti ng a gent i s no l onger pres ent. Recurrence a fter yea rs ma y be due to
reexpos ure to the tri gger or s ome cha nge i n the tri ggeri ng mecha ni s m. Someti mes trea tment of a previ ous l y occul t i nfecti on, s uch a s a denta l
a bs ces s , res ul ts i n res ol uti on.
Vul vova gi na l LP ma y be chroni c a nd refra ctory to thera py, ca us i ng decrea s ed qua l i ty of l i fe.
Treatment
Topi ca l trea tments
Sys temi c trea tments
Someti mes l i ght thera py
As ymptoma ti c LP does not requi re trea tment. Drugs s us pected of tri ggeri ng LP s houl d be s topped.
Few control l ed s tudi es ha ve eva l ua ted trea tments . Opti ons di ffer by l oca ti on a nd extent of di s ea s e. Mos t ca s es of LP on the trunk or extremi ti es
ca n be trea ted wi th l oca l drugs . Topi ca l corti cos teroi ds a re fi rs t-l i ne trea tment for mos t ca s es of l oca l i zed di s ea s e. Hi gh-potency oi ntments or
crea ms (eg, cl obeta s ol , fl uoci noni de) ma y be us ed on the thi cker l es i ons on the extremi ti es ; l ower-potency drugs (eg, tri a mci nol one, des oni de)
ma y be us ed on the fa ce, groi n, a nd a xi l l a e. As a l wa ys , cours es s houl d be l i mi ted to reduce ri s k of corti cos teroi d a trophy. Potency ma y be
enha nced wi th us e of pol yethyl ene wra ppi ng or fl ura ndrenol i de ta pe. Intra l es i ona l corti cos teroi ds (tri a mci nol one a cetoni de s ol uti on di l uted
wi th s a l i ne to 5 to 10 mg/mL) ca n be us ed every 4 wk for hyperkera toti c pl a ques a nd thos e res i s ta nt to other thera pi es .
Topi ca l thera py i s i mpra cti ca l for genera l i zed LP; ora l drugs or photothera py i s us ed. Ora l corti cos teroi ds (eg, predni s one 20 mg once/da y for 2 to 6
wk fol l owed by a ta per) ma y be us ed for s evere ca s es . The di s ea s e ma y rebound when thera py cea s es ; however, l ong-term s ys temi c
corti cos teroi ds s houl d not be us ed.
Ora l reti noi ds (eg, a ci treti n 30 mg once/da y for 8 wk) a re i ndi ca ted for otherwi s e reca l ci tra nt ca s es . Gri s eoful vi n 250 mg po bi d gi ven for 3 to 6 mo
ma y be effecti ve. Cycl os pori ne (1.25 to 2.5 mg/kg bi d) ca n be us ed when corti cos teroi ds or reti noi ds fa i l . Li ght thera py us i ng ps ora l en pl us
ul tra vi ol et A (PUVA) or na rrow-ba nd UVB i s a n a l terna ti ve to ora l thera pi es , es peci a l l y i f they ha ve fa i l ed or a re contra i ndi ca ted for medi ca l
rea s ons .
Trea tment of ora l LP di ffers s l i ghtl y. Vi s cous l i doca i ne ma y hel p rel i eve s ymptoms of eros i ve ul cers . Ta crol i mus 0.1% oi ntment a ppl i ed twi ce da i l y
ma y i nduce l a s ti ng remi s s i on, a l though i t ha s not been ful l y eva l ua ted. Other trea tment opti ons i ncl ude topi ca l (i n a n a dhes i ve ba s e),
i ntra l es i ona l , a nd s ys temi c corti cos teroi ds . Eros i ve ora l LP ma y res pond to ora l da ps one or cycl os pori ne. Cycl os pori ne ri ns es a l s o ma y be hel pful .
Da ps one, hydroxychl oroqui ne, a za thi opri ne, s ys temi c cycl os pori ne, a nd topi ca l treti noi n ma y a l s o be us eful . As wi th a ny di s ea s e wi th s o ma ny
thera pi es , i ndi vi dua l drugs ha ve not been uni forml y s ucces s ful .
Lichen Sclerosus
Lichen sclerosus is an inflammatory dermatosis of unknown cause, possibly autoimmune, that usually affects the anogenital area.
The ea rl i es t s i gns a re s ki n fra gi l i ty, brui s i ng, a nd s ometi mes bl i s teri ng. Les i ons typi ca l l y ca us e mi l d to s evere i tchi ng. When l i chen s cl eros us
ma ni fes ts i n chi l dren, the a ppea ra nce ma y be confus ed wi th s exua l a bus e. Wi th ti me, the i nvol ved ti s s ue becomes a trophi c, thi nned,
hypopi gmented (there ma y be fl ecks of pos ti nfl a mma tory hyperpi gmenta ti on), fi s s ured, a nd s ca l y. Hyperkera toti c a nd fi broti c forms exi s t. Severe
a nd l ongs ta ndi ng ca s es ca us e s ca rri ng a nd di s torti on of norma l a nogeni ta l a rchi tecture. In women, thi s di s torti on ca n even l ea d to tota l
a bs orpti on of the l a bi a mi nora a nd fus i on over the cl i tori s . In men, phi mos i s or fus i on of the fores ki n to the corona l s ul cus ca n occur.
Di a gnos i s ca n us ua l l y be ba s ed on a ppea ra nce, es peci a l l y i n a dva nced ca s es ; however, bi ops y s houl d be done on a ny a nogeni ta l derma tos i s tha t
does not res ol ve wi th mi l d conventi ona l thera py (eg, topi ca l hydrocorti s one, a nti funga l drug). It i s es peci a l l y i mporta nt to bi ops y a ny a rea tha t
becomes thi ckened or ul cera ted, beca us e l i chen s cl eros us i s a precurs or of s qua mous cel l ca rci noma .
Treatment
Trea tment cons i s ts of potent topi ca l corti cos teroi ds (drugs tha t otherwi s e s houl d be us ed wi th extreme ca uti on i n thi s a rea ). The di s ea s e i s
genera l l y i ntra cta bl e, s o l ong-term fol l ow-up, es peci a l l y to moni tor for s qua mous cel l ca rci noma a nd s exua l functi on a nd for ps ychol ogi c s upport,
i s i ndi ca ted.
Chapter 79. Hypersensitivity and Inflammatory Disorders

Introduction
The i mmune s ys tem pl a ys a s i gni fi ca nt rol e i n a l a rge number of s ki n di s orders , i ncl udi ng derma ti ti s , s unl i ght rea cti ons , a nd bul l ous di s ea s es .
Al though a l l of thes e di s orders i nvol ve s ome l evel of i nfl a mma ti on, certa i n s ki n di s orders a re pri ma ri l y cha ra cteri zed by thei r i nfl a mma tory
component or a s a hypers ens i ti vi ty rea cti on, be i t to a drug, i nfecti on, or ca ncer.
Acute Febrile Neutrophilic Dermatosis
(Sweet's Syndrome)
Acute febrile neutrophilic dermatosis is characterized by tender, indurated, dark-red papules and plaques with prominent edema in the upper dermis and dense
infiltrate of neutrophils. Cause is not known. It frequently occurs with underlying cancer, especially hematologic cancers.
Etiology
Acute febri l e neutrophi l i c derma tos i s ma y occur wi th va ri ous di s orders , i ncl udi ng
Acute res pi ra tory i l l nes s
GI i nfecti on
Ca ncer
Drug expos ure
Infl a mma tory or a utoi mmune di s orders
Pregna ncy
About 25% of pa ti ents ha ve a n underl yi ng ca ncer, 75% of whi ch a re hema tol ogi c ca ncers , es peci a l l y myel odys pl a s ti c s yndromes a nd a cute myel oi d
l eukemi a . When not due to ca ncer, a cute febri l e neutrophi l i c derma tos i s a ffects mos tl y women a ges 30 to 50, wi th a fema l e: ma l e ra ti o of 3:1. In
contra s t, men who devel op the condi ti on tend to be ol der (60 to 90).
The ca us e i s unknown; however, type 1 hel per T-cel l cytoki nes , i ncl udi ng IL-2 a nd i nterferon-, a re predomi na nt a nd ma y pl a y a rol e i n l es i on
forma ti on.
Symptoms and Signs
Pa ti ents a re febri l e, wi th a n el eva ted neutrophi l count, a nd ha ve tender, da rk-red pl a ques or pa pul es , mos t often on the fa ce, neck, a nd upper
extremi ti es , es peci a l l y the dors um of ha nds . Ora l l es i ons ca n a l s o occur. Ra rel y, bul l ous a nd pus tul a r l es i ons a re pres ent. The l es i ons often
devel op i n crops . Ea ch crop i s preceded by fever a nd pers i s ts for da ys to weeks .
Extra cuta neous ma ni fes ta ti ons ca n i nvol ve the eyes (eg, conjuncti vi ti s , epi s cl eri ti s , i ri docycl i ti s ), joi nts (eg, a rthra l gi a , mya l gi a , a rthri ti s ), a nd
i nterna l orga ns (eg, neutrophi l i c a l veol i ti s ; s teri l e os teomyel i ti s ; ps ychi a tri c or neurol ogi c cha nges ; tra ns i ent ki dney, l i ver, a nd pa ncrea ti c
i ns uffi ci ency).
Diagnosis
Ski n bi ops y
Di a gnos i s i s s ugges ted by the a ppea ra nce of the l es i ons a nd i s s upported by the pres ence of a s s oci a ted condi ti ons . Di fferenti a l di a gnos i s
i ncl udes erythema mul ti forme, erythema el eva ti on di uti num, a cute cuta neous l upus erythema tos us , pyoderma ga ngrenos um, a nd erythema
nodos um. If di a gnos i s i s uncl ea r, s ki n bi ops y s houl d be done. The hi s topa thol ogi c pa ttern i s tha t of edema i n the upper dermi s wi th a dens e
i nfi l tra te of neutrophi l s i n the dermi s . Va s cul i ti s ma y be pres ent but i s s econda ry.
Treatment
Corti cos teroi ds
Trea tment i nvol ves s ys temi c corti cos teroi ds , chi efl y predni s one 0.5 to 1.5 mg/kg po once/da y ta pered over 3 wk. Anti pyreti cs a re a l s o
recommended. In di ffi cul t ca s es , da ps one 100 to 200 mg po once/da y, i ndometha ci n 150 mg po once/da y for 1 wk a nd 100 mg po once/da y for 2
a ddi ti ona l wk, or K i odi de 900 mg po once/da y or 300 mg po ti d ca n be gi ven.
Drug Eruptions and Reactions
Drugs ca n ca us e mul ti pl e s ki n erupti ons a nd rea cti ons . The mos t s eri ous of thes e a re di s cus s ed el s ewhere i n THE MANUAL a nd i ncl ude Stevens Johns on s yndrome a nd toxi c epi derma l necrol ys i s , hypers ens i ti vi ty s yndrome, s erum s i cknes s , exfol i a ti ve derma ti ti s , a ngi oedema a nd
a na phyl a xi s , a nd drug-i nduced va s cul i ti s . Drugs ca n a l s o be i mpl i ca ted i n ha i r l os s , l i chen pl a nus , erythema nodos um, pi gmenta ti on cha nges , SLE,
photos ens i ti vi ty rea cti ons , pemphi gus , a nd pemphi goi d. Other drug rea cti ons a re cl a s s i fi ed by l es i on type (s ee
Ta bl e 79-1).
[Table 79-1. Types of Drug Rea cti ons a nd Typi ca l Ca us a ti ve Agents ]

Symptoms and Signs
Symptoms a nd s i gns va ry ba s ed on the ca us e a nd the s peci fi c rea cti on (s ee Ta bl e 79-1).
Diagnosis
Cl i ni ca l eva l ua ti on a nd drug expos ure hi s tory
Someti mes s ki n bi ops y
A deta i l ed hi s tory i s often requi red for di a gnos i s , i ncl udi ng recent us e of OTC drugs . Beca us e the rea cti on ma y not occur unti l s evera l da ys or even
weeks a fter fi rs t expos ure to the drug, i t i s i mporta nt to cons i der a l l new drugs a nd not onl y the one tha t ha s been mos t recentl y s ta rted. No
l a bora tory tes ts rel i a bl y a i d di a gnos i s , a l though bi ops y of a ffected s ki n i s often s ugges ti ve. Sens i ti vi ty ca n be defi ni ti vel y es ta bl i s hed onl y by
recha l l enge wi th the drug, whi ch ma y be ha za rdous a nd unethi ca l i n pa ti ents who ha ve ha d s evere rea cti ons .
Treatment
Di s conti nua ti on of offendi ng drug
Someti mes a nti hi s ta mi nes a nd corti cos teroi ds
Mos t drug rea cti ons res ol ve when drugs a re s topped a nd requi re no further thera py. Whenever pos s i bl e, chemi ca l l y unrel a ted compounds s houl d
be s ubs ti tuted for s us pect drugs . If no s ubs ti tute drug i s a va i l a bl e a nd i f the rea cti on i s a mi l d one, i t mi ght be neces s a ry to conti nue the
trea tment under ca reful wa tch des pi te the rea cti on. Pruri tus ca n be control l ed wi th a nti hi s ta mi nes a nd topi ca l corti cos teroi ds . For IgE-medi a ted
rea cti ons (eg, urti ca ri a ), des ens i ti za ti on (s ee p. 1124) ca n be cons i dered when there i s cri ti ca l need for a drug.
When progres s i on from urti ca ri a to a na phyl a xi s i s a concern, trea tment i s wi th a queous epi nephri ne (1:1000) 0.2 mL s c or IM a nd wi th the s l owera cti ng but more pers i s tent s ol ubl e hydrocorti s one 100 mg IV, whi ch ma y be fol l owed by a n ora l corti cos teroi d for a s hort peri od (s ee a l s o p. 1121).
Erythema Multiforme
Erythema multiforme (EM) is an inflammatory reaction, characterized by target or iris skin lesions. Oral mucosa may be involved. Diagnosis is clinical. Lesions
spontaneously resolve but frequently recur. Erythema multiforme can occur as reaction to a drug or an infectious agent such as herpes simplex virus or
mycoplasma. Suppressive antiviral therapy may be indicated for patients with frequent or symptomatic recurrence due to herpes simplex virus.
For yea rs , EM wa s thought to repres ent the mi l der end of a s pectrum of drug hypers ens i ti vi ty di s orders tha t i ncl uded Stevens -Johns on s yndrome
a nd toxi c epi derma l necrol ys i s . Recent evi dence s ugges ts tha t EM i s di fferent from thes e other di s orders .
Etiology
The ma jori ty of ca s es a re ca us ed by herpes s i mpl ex vi rus (HSV) i nfecti on (HSV-1 more s o tha n HSV-2), a l though i t i s uncl ea r whether EM l es i ons
repres ent a s peci fi c or nons peci fi c rea cti on to the vi rus . Current thi nki ng hol ds tha t EM i s ca us ed by a T-cel l -medi a ted cytol yti c rea cti on to HSV DNA
fra gments pres ent i n kera ti nocytes . A geneti c di s pos i ti on i s pres umed gi ven tha t EM i s s uch a ra re cl i ni ca l ma ni fes ta ti on of HSV i nfecti on, a nd
s evera l HLA s ubtypes ha ve been l i nked wi th the predi s pos i ti on to devel op l es i ons . Les s commonl y, ca s es a re ca us ed by drugs , va cci nes , other vi ra l
di s ea s es (es peci a l l y hepa ti ti s C), or pos s i bl y SLE. EM tha t occurs i n pa ti ents wi th SLE i s s ometi mes referred to a s Rowel l 's s yndrome.
Symptoms and Signs
EM ma ni fes ts a s the s udden ons et of a s ymptoma ti c, erythema tous ma cul es , pa pul es , whea l s , ves i cl es , bul l a e, or a combi na ti on on the di s ta l
extremi ti es (i ncl udi ng pa l ms a nd s ol es ) a nd fa ce. The cl a s s i c l es i on i s a nnul a r, wi th a vi ol a ceous center a nd pi nk ha l o s epa ra ted by a pa l e ri ng
(ta rget or i ri s l es i on). Di s tri buti on i s s ymmetri c a nd centri peta l ; s prea d to the trunk i s common. Some pa ti ents ha ve i tchi ng. Ora l l es i ons i ncl ude
ta rget l es i ons on the l i ps a nd ves i cl es a nd eros i ons on the pa l a te a nd gi ngi va e.
Diagnosis
Di a gnos i s i s by cl i ni ca l a ppea ra nce; bi ops y i s ra rel y neces s a ry. Di fferenti a l di a gnos i s i ncl udes es s enti a l urti ca ri a , va s cul i ti s , bul l ous pemphi goi d,
pemphi gus , l i nea r IgA derma tos i s , a cute febri l e neutrophi l i c derma tos i s , a nd derma ti ti s herpeti formi s ; ora l l es i ons mus t be di s ti ngui s hed from
a phthous s toma ti ti s , pemphi gus , herpeti c s toma ti ti s , a nd ha nd-foot-a nd-mouth di s ea s e. Pa ti ents wi th wi del y di s s emi na ted purpuri c ma cul es a nd
bl i s ters a nd promi nent i nvol vement of the trunk a nd fa ce a re l i kel y to ha ve Stevens -Johns on s yndrome ra ther tha n EM.
Treatment
Supporti ve ca re
Someti mes prophyl a cti c a nti vi ra l s
EM s ponta neous l y res ol ves , s o trea tment i s us ua l l y unneces s a ry. Topi ca l corti cos teroi ds a nd a nes theti cs ma y a mel i ora te s ymptoms a nd rea s s ure
pa ti ents . Recurrences a re common, a nd empi ri c ora l ma i ntena nce thera py wi th a cycl ovi r 400 mg po q 12 h, fa mci cl ovi r 250 mg po q 12 h, or
va l a cycl ovi r 1000 mg po q 24 h ca n be a ttempted i f s ymptoms recur more tha n 5 ti mes /yr a nd HSV a s s oci a ti on i s s us pected or i f recurrent EM i s
cons i s tentl y preceded by herpes fl a res .
Panniculitis
Panniculitis describes inflammation of the subcutaneous fat that can result from multiple causes. Diagnosis is by clinical evaluation and biopsy. Treatment
depends on the cause.
Etiology
There a re mul ti pl e ca us es of pa nni cul i ti s , i ncl udi ng
Infecti ons (the mos t common)
Phys i ca l fa ctors (eg, col d, tra uma )
Prol i fera ti ve di s orders
Connecti ve ti s s ue di s orders (eg, SLE, s ys temi c s cl eros i s )
Idi opa thi c pa nni cul i ti s i s s ometi mes referred to a s Weber-Chri s ti a n di s ea s e.
Symptoms and Signs
Pa nni cul i ti s i s cha ra cteri zed by tender a nd erythema tous s ubcuta neous nodul es l oca ted over the extremi ti es a nd s ometi mes over the pos teri or
thora x, a bdomi na l a rea , brea s ts , fa ce, or buttocks . Ra rel y, nodul es ca n i nvol ve the mes entery, l ungs , s crotum, a nd cra ni um. Si gns of s ys temi c
i nfl a mma ti on ca n a ccompa ny pa nni cul i ti s . In Weber-Chri s ti a n di s ea s e, s ys temi c i nvol vement ca n res ul t i n fever a s wel l a s s i gns of orga n
dys functi on, i ncl udi ng hepa ti c, pa ncrea ti c, a nd bone ma rrow i ns uffi ci ency, whi ch i s potenti a l l y fa ta l .
Diagnosis
Exci s i ona l bi ops y
Di a gnos i s i s by us ua l l y by cl i ni ca l a ppea ra nce a nd ca n be confi rmed by exci s i ona l bi ops y.
Treatment
Supporti ve ca re
Immunos uppres s a nts
There i s no s peci fi c defi ni ti ve trea tment for pa nni cul i ti s . A va ri ety of s tra tegi es ha ve been us ed wi th modes t res ul ts , i ncl udi ng NSAIDs ,
a nti ma l a ri a l s , da ps one, a nd tha l i domi de. Corti cos teroi ds (1 to 2 mg/kg po or IV once/da y) a nd other i mmunos uppres s i ve or chemothera peuti c
drugs ha ve been us ed to trea t pa ti ents wi th progres s i ve s ymptoms or s i gns of s ys temi c i nvol vement. Surgi ca l a bdomi na l pa nni cul ectomy ha s been
us ed wi th va ryi ng l evel s of s ucces s i n morbi dl y obes e pa ti ents but s houl d be res erved for pa ti ents wi th s eri ous di s ea s e tha t does not res pond to
other mea s ures .
Erythema Nodosum
Erythema nodosum (EN) is a specific form of panniculitis (see p. 687) characterized by tender, red or violet, palpable, subcutaneous nodules on the shins and
occasionally other locations. It often occurs with an underlying systemic disease, notably streptococcal infections, sarcoidosis, inflammatory bowel disease, and
TB. Diagnosis is by clinical evaluation and biopsy. Treatment depends on the cause.
Etiology
EN pri ma ri l y a ffects peopl e i n thei r 20s a nd 30s but ca n occur a t a ny a ge; women a re more often a ffected. Eti ol ogy i s unknown, but a n i mmunol ogi c
rea cti on i s s us pected beca us e EN i s frequentl y a ccompa ni ed by other di s orders ; the mos t common a re
Streptococca l i nfecti on (es peci a l l y i n chi l dren)
Sa rcoi dos i s
Infl a mma tory bowel di s ea s e
TB
Other pos s i bl e tri ggers i ncl ude
Other ba cteri a l i nfecti ons (eg, Yersinia, Salmonella, mycopl a s ma , chl a mydi a , l epros y, l ymphogra nul oma venereum)
Funga l i nfecti ons (eg, cocci di oi domycos i s , bl a s tomycos i s , hi s topl a s mos i s )
Ri cketts i a l i nfecti ons

Vi ra l i nfecti ons (eg, Eps tei n-Ba rr, hepa ti ti s B)
Us e of drugs (eg, s ul fona mi des , i odi des , bromi des , ora l contra cepti ves )
Hema tol ogi c a nd s ol i d ca ncers
Pregna ncy
Up to one thi rd of ca s es of EN a re i di opa thi c.
Symptoms and Signs
EN i s a s ubs et of pa nni cul i ti s tha t ma ni fes ts a s erythema tous , tender pl a ques or nodul es , pri ma ri l y i n the preti bi a l regi on (s ee
Pl a te 34), a ccompa ni ed by fever, ma l a i s e, a nd a rthra l gi a .
Diagnosis
Exci s i ona l bi ops y
Di a gnos i s i s us ua l l y by cl i ni ca l a ppea ra nce a nd ca n be confi rmed by exci s i ona l bi ops y of a nodul e when neces s a ry. A di a gnos i s of EN s houl d
prompt eva l ua ti on for ca us es . Eva l ua ti on mi ght i ncl ude bi ops y, s ki n tes ti ng (PPD or a nergy pa nel ), a nti nucl ea r a nti bodi es , CBC, ches t x-ra y, a nd
a nti s treptol ys i n O ti ter or pha ryngea l cul ture. ESR i s often hi gh.
Treatment
Supporti ve ca re
Corti cos teroi ds
EN a l mos t a l wa ys res ol ves s ponta neous l y. Trea tment i ncl udes bed res t, el eva ti on, cool compres s es , a nd NSAIDs . K i odi de 300 to 500 mg po ti d ca n
be gi ven to decrea s e i nfl a mma ti on. Sys temi c corti cos teroi ds a re effecti ve but a re a n i nterventi on of l a s t res ort a s they ca n wors en a n occul t
i nfecti on. If a n underl yi ng di s order i s i denti fi ed, i t s houl d be trea ted.
Granuloma Annulare
Granuloma annulare is a benign, chronic, idiopathic condition characterized by papules or nodules that spread peripherally to form a ring around normal or slightly
depressed skin.
Etiology
Eti ol ogy i s uncl ea r but propos ed mecha ni s ms i ncl ude cel l -medi a ted i mmuni ty (type IV), i mmune compl ex va s cul i ti s , a nd a n a bnorma l i ty of ti s s ue
monocytes . Gra nul oma a nnul a re i s not a s s oci a ted wi th s ys temi c di s orders , except tha t the i nci dence of a bnorma l gl ucos e meta bol i s m i s
i ncrea s ed a mong a dul ts wi th ma ny l es i ons . In s ome ca s es , expos ure to s unl i ght, i ns ect bi tes , TB s ki n tes ti ng, BCG va cci na ti on, tra uma , Borrelia
i nfecti on, a nd vi ra l i nfecti ons ha ve i nduced di s ea s e fl a res . The condi ti on i s twi ce a s preva l ent a mong women.
Symptoms and Signs
Les i ons a re erythema tous , yel l owi s h ta n, bl ui s h, or the col or of the s urroundi ng s ki n; one or more l es i ons ma y occur, mos t often on dors a l feet,
l egs , ha nds , or fi ngers . They a re us ua l l y a s ymptoma ti c but ma y occa s i ona l l y be tender. The l es i ons often expa nd or joi n to form ri ngs . The center of
ea ch ri ng ma y be a s l i ghtl y depres s ed, pa l e or l i ght brown. In s ome ca s es , l es i ons ma y become genera l i zed a nd wi des prea d.
Diagnosis
Di a gnos i s i s us ua l l y cl i ni ca l but ca n be confi rmed by s ki n bi ops y.
Treatment
Someti mes corti cos teroi ds , a nti -i nfl a mma tory drugs , or ps ora l en pl us ul tra vi ol et A (PUVA) thera py
Us ua l l y no trea tment i s neces s a ry; s ponta neous res ol uti on i s common. For pa ti ents wi th more wi des prea d or bothers ome l es i ons , qui cker
res ol uti on ma y be promoted by the us e of hi gh-s trength topi ca l corti cos teroi ds under occl us i ve dres s i ngs every ni ght, fl ura ndrenol i dei mpregna ted ta pe, a nd i ntra l es i ona l corti cos teroi ds . PUVA thera py i s a l s o effecti ve a nd pra cti ca l for pa ti ents wi th wi des prea d di s ea s e. Recent
reports ha ve s ugges ted tha t tumor necros i s fa ctor- i nhi bi tors (eg, i nfl i xi ma b, a da l i muma b), 595-nm pul s ed dye l a s er, a nd fra cti ona l
photothermol ys i s a re us eful i n ma na gi ng di s s emi na ted a nd reca l ci tra nt l es i ons .
Pyoderma Gangrenosum
Pyoderma gangrenosum is a chronic progressive skin necrosis of unknown etiology often associated with systemic illness.
Etiology
Eti ol ogy i s unknown, but pyoderma ga ngrenos um ca n be a s s oci a ted wi th va s cul i ti s , ga mmopa thi es , RA, l eukemi a , l ymphoma , hepa ti ti s C vi rus
i nfecti on, SLE, s a rcoi dos i s , pol ya rthri ti s , a nd es peci a l l y i nfl a mma tory bowel di s ea s e a nd i s thought to be ca us ed by a n a bnorma l i mmune
res pons e.
Pathophysiology
Pa thophys i ol ogy i s poorl y unders tood but ma y i nvol ve probl ems wi th neutrophi l chemota xi s . Ul cera ti ons of pyoderma ga ngrenos um ma y occur
a fter tra uma or i njury to the s ki n i n 30% of pa ti ents ; thi s proces s i s termed pa thergy.
Symptoms and Signs
Pyoderma ga ngrenos um begi ns a s a n i nfl a med erythema tous pa pul e, pus tul e, or nodul e. The l es i on, whi ch ma y res embl e a furuncl e or a n
a rthropod bi te a t thi s s ta ge, then ul cera tes a nd expa nds ra pi dl y, devel opi ng a s wol l en necroti c ba s e a nd a ra i s ed dus ky to vi ol a ceous border. An
undermi ned border i s common, i f not pa thognomoni c. Sys temi c s ymptoms s uch a s fever, ma l a i s e, a nd a rthra l gi a s a re common. The ul cers coa l es ce
to form l a rger ul cers , often wi th cri bri form or s i eve-l i ke s ca rri ng.
Diagnosis
Di a gnos i s i s cl i ni ca l . Bi ops i es of l es i ons a re not often di a gnos ti c but ma y be s upporti ve; 40% of bi ops i es from a l ea di ng edge s how va s cul i ti s wi th
neutrophi l s a nd fi bri n i n s uperfi ci a l ves s el s .
Treatment
Corti cos teroi ds
Someti mes other a nti -i nfl a mma tory drugs or i mmunos uppres s a nts
Avoi da nce of s urgi ca l debri dement
Predni s one 60 to 80 mg po once/da y i s s ti l l the ma i ns ta y of trea tment, a l though cycl os pori ne 3 mg/kg po once/da y i s a l s o qui te effecti ve. Da ps one,
cl ofa zi mi ne, tha l i domi de, tumor necros i s fa ctor- i nhi bi tors (eg, i nfl i xi ma b), a nd mycophenol a te mofeti l ha ve a l s o been us ed s ucces s ful l y.
Surgi ca l trea tments a re a voi ded beca us e of the ri s k of wound extens i on.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs,
antiepileptics, and antibiotics, are the most common causes. Macules rapidly spread and coalesce, leading to epidermal blistering, necrosis, and sloughing.
Diagnosis is usually obvious by appearance of initial lesions and clinical syndrome. Treatment is supportive care; corticosteroids, cyclophosphamide, and other
drugs may be tried. Prognosis depends on how early the disorders are diagnosed and treated. Mortality can be as high as 7.5% in children and 20 to 25% in adults.
SJS a nd TEN a re cl i ni ca l l y s i mi l a r except for thei r di s tri buti on. By one commonl y a ccepted defi ni ti on, cha nges a ffect < 10% of body s urfa ce a rea i n
SJS a nd > 30% of body s urfa ce a rea i n TEN; i nvol vement of 15 to 30% of body s urfa ce a rea i s cons i dered SJS-TEN overl a p.
The di s orders a ffect between 1 a nd 5 peopl e/mi l l i on. Inci dence, s everi ty, or both of thes e di s orders ma y be hi gher i n bone-ma rrow tra ns pl a nt
reci pi ents , i n Pneumocystis jirovecii-i nfected HIV pa ti ents , i n pa ti ents wi th SLE, a nd i n pa ti ents wi th other chroni c rheuma tol ogi c di s ea s es .
Etiology
Drugs preci pi ta te over 50% of SJS ca s es a nd up to 95% of TEN ca s es . The mos t common drug ca us es i ncl ude
Sul fa drugs (eg, cotri moxa zol e, s ul fa s a l a zi ne)
Other a nti bi oti cs (eg, a mi nopeni ci l l i ns , fl uoroqui nol ones , cepha l os pori ns )
Anti epi l epti cs (eg, phenytoi n, ca rba ma zepi ne, phenoba rbi ta l , va l proa te, l a motri gi ne)
Mi s cel l a neous i ndi vi dua l drugs (eg, pi roxi ca m, a l l opuri nol , chl ormeza none)
Ca s es tha t a re not ca us ed by drugs a re a ttri buted to
Infecti on (mos tl y wi th Mycoplasma pneumoniae)
Va cci na ti on
Gra ft-vs -hos t di s ea s e
Ra rel y, a ca us e ca nnot be i denti fi ed.
Pathophysiology
Exa ct mecha ni s m i s unknown; however, one theory hol ds tha t a l tered drug meta bol i s m i n s ome pa ti ents ca us es forma ti on of rea cti ve meta bol i tes
tha t bi nd to a nd a l ter cel l protei ns , tri ggeri ng a T-cel l -medi a ted cytotoxi c rea cti on to drug a nti gens i n kera ti nocytes .
Another pos s i bl e mecha ni s m i nvol ves i ntera cti ons between Fa s (a cel l -s urfa ce receptor tha t i nduces a poptos i s ) a nd i ts l i ga nd, pa rti cul a rl y a
s ol ubl e form of Fa s l i ga nd rel ea s ed from mononucl ea r cel l s . Recent fi ndi ngs s ugges t tha t gra nul ys i n rel ea s ed from cytotoxi c T cel l s a nd na tura l
ki l l er cel l s mi ght pl a y a rol e i n kera ti nocyte dea th.
Symptoms and Signs
Wi thi n 1 to 3 wk a fter the s ta rt of the offendi ng drug, pa ti ents devel op a prodrome of ma l a i s e, fever, hea da che, cough, a nd conjuncti vi ti s . Ma cul es ,
often i n a ta rget confi gura ti on, then a ppea r s uddenl y, us ua l l y on the fa ce, neck, a nd upper trunk. Thes e ma cul es s i mul ta neous l y a ppea r
el s ewhere on the body, coa l es ce i nto l a rge fl a cci d bul l a e, a nd s l ough over a peri od of 1 to 3 da ys . Na i l s a nd eyebrows ma y be l os t a l ong wi th
epi thel i um.
In s evere ca s es of TEN, l a rge s heets of epi thel i um s l i de off the enti re body a t pres s ure poi nts (Ni kol s ky's s i gn), expos i ng weepy, pa i nful , a nd
erythema tous s ki n. Pa i nful ora l crus ts a nd eros i ons , kera toconjuncti vi ti s , a nd geni ta l probl ems (eg, phi mos i s , va gi na l s ynechi a e) a ccompa ny s ki n
s l oughi ng i n up to 90% of ca s es . Bronchi a l epi thel i um ma y a l s o s l ough, ca us i ng cough, dys pnea , pneumoni a , pul mona ry edema , a nd hypoxemi a .
Gl omerul onephri ti s a nd hepa ti ti s ma y devel op.
Diagnosis
Often s ki n bi ops y
Di a gnos i s i s often obvi ous from a ppea ra nce of l es i ons a nd ra pi d progres s i on of s ymptoms . Hi s tol ogi c exa mi na ti on of s l oughed s ki n s hows
necroti c epi thel i um, a di s ti ngui s hi ng fea ture.
Di fferenti a l di a gnos i s i n SJS a nd ea rl y TEN i ncl udes erythema mul ti forme, vi ra l exa nthems , a nd drug ra s h; a nd, i n l a ter s ta ges of TEN,
pa ra neopl a s ti c pemphi gus , toxi c s hock s yndrome, exfol i a ti ve erythroderma , a nd therma l burn. In chi l dren, TEN i s l es s common a nd mus t be
di s ti ngui s hed from s ta phyl ococca l s ca l ded s ki n s yndrome.
Prognosis
Severe TEN i s s i mi l a r to extens i ve burns ; pa ti ents a re a cutel y i l l , ma y be una bl e to ea t or open thei r eyes , a nd s uffer ma s s i ve fl ui d a nd el ectrol yte
l os s es . They a re a t hi gh ri s k of i nfecti on, mul ti orga n fa i l ure, a nd dea th. Wi th ea rl y thera py, s urvi va l ra tes a pproa ch 90%. The s everi ty-of-i l l nes s
s core for TEN (s ee
Ta bl e 79-2) s ys tema ti ca l l y s cores 7 i ndependent ri s k fa ctors wi thi n the fi rs t 24 h of pres enta ti on to the hos pi ta l to determi ne the morta l i ty ra te for
a pa rti cul a r pa ti ent.
Treatment
Supporti ve ca re
Pos s i bl y i mmune modul a tor trea tment
Pos s i bl y pl a s ma pheres i s
Trea tment i s mos t s ucces s ful when SJS or TEN i s recogni zed ea rl y a nd trea ted i n a n i npa ti ent derma tol ogi c or ICU s etti ng; trea tment i n a burn uni t
ma y be needed for s evere di s ea s e. Ophtha l mol ogy cons ul ta ti on i s ma nda tory for pa ti ents wi th ocul a r i nvol vement. Drugs s houl d be s topped
i mmedi a tel y. Pa ti ents
[Table 79-2. Severi ty-of-Il l nes s Score for Toxi c Epi derma l Necrol ys i s (Scorten)]
a re i s ol a ted to mi ni mi ze expos ure to i nfecti on a nd a re gi ven fl ui ds , el ectrol ytes , bl ood products , a nd nutri ti ona l s uppl ements a s needed. Ski n
ca re i ncl udes prompt trea tment of s econda ry ba cteri a l i nfecti ons . Prophyl a cti c a nti bi oti cs a re controvers i a l .
Drug trea tment of STS a nd TEN i s controvers i a l . Hi gh-dos e s ys temi c corti cos teroi ds (eg, methyl predni s ol one 80 to 200 mg IV or predni s one 80 mg po
once/da y for 7 to 10 da ys or unti l progres s i on s tops ) or cycl ophos pha mi de (300 mg IV q 24 h for 7 da ys or unti l s i gni fi ca nt i mprovement) ca n be
gi ven to i nhi bi t T-cel l -medi a ted cytol ys i s . Cycl os pori ne (3 to 5 mg/kg po once/da y) i nhi bi ts CD8 cel l s a nd ha s been s hown to decrea s e the dura ti on
of a cti ve di s ea s e by 2 to 3 da ys i n s ome i ns ta nces . However, corti cos teroi ds a re controvers i a l a nd a re thought by s ome to i ncrea s e morta l i ty.
Pl a s ma pheres i s ca n remove rea cti ve drug meta bol i tes or a nti bodi es . Ea rl y hi gh-dos e IV i mmune gl obul i n (IVIG) 2.7 g/kg over 3 da ys bl ocks
a nti bodi es a nd Fa s l i ga nd. Des pi te s ome rema rka bl e res ul ts us i ng hi gh-dos e IVIG for TEN, cl i ni ca l tri a l s i nvol vi ng s ma l l cohorts ha ve reported
confl i cti ng res ul ts .
Chapter 80. Sweating Disorders

Introduction
There a re two types of s wea t gl a nds : a pocri ne a nd eccri ne.
Apocri ne gl a nds a re cl us tered i n the a xi l l a e, a reol a e, geni ta l s , a nd a nus ; modi fi ed a pocri ne gl a nds a re found i n the externa l a udi tory mea tus .
Apocri ne gl a nds become a cti ve a t puberty; thei r excreti ons a re oi l y a nd vi s ci d a nd a re pres umed to pl a y a rol e i n s exua l ol fa ctory mes s a ges . The
mos t common di s orders of a pocri ne gl a nds a re bromhi dros i s a nd hi dra deni ti s s uppura ti va (s ee p. 698).
Eccri ne gl a nds a re s ympa theti ca l l y i nnerva ted, di s tri buted over the enti re body, a nd a cti ve from bi rth. Thei r s ecreti ons a re wa tery a nd s erve to cool
the body i n hot envi ronments or duri ng a cti vi ty. Di s orders of eccri ne gl a nds i ncl ude hyperhi dros i s , hypohi dros i s , a nd mi l i a ri a .
Bromhidrosis
Bromhidrosis is excessive or abnormal body odor caused by decomposition by bacteria and yeasts of apocrine secretions and cellular debris.
Apocri ne s ecreti ons a re l i pi d-ri ch, s teri l e, a nd odorl es s but become odori ferous when decompos ed. Eccri ne bromhi dros i s i s not a s fra gra nt
beca us e eccri ne s wea t i s nea rl y 100% wa ter. The ca us e of a pocri ne bromhi dros i s i s poor hygi ene of s ki n a nd cl othi ng.
In s ome peopl e, a few da ys of wa s hi ng wi th a n a nti s epti c s oa p, whi ch ma y be combi ned wi th us e of a nti ba cteri a l crea ms conta i ni ng cl i nda myci n
or erythromyci n, ma y be neces s a ry. Sha vi ng the ha i r i n the a rmpi ts ma y a l s o hel p control odor.
Hyperhidrosis
Hyperhidrosis is excessive sweating, which can be focal or diffuse and has multiple causes. Sweating of the axillae, palms, and soles is most often due to stress;
diffuse sweating is usually idiopathic but should raise suspicions for cancer, infection, and endocrine disease. Diagnosis is obvious, but tests for underlying causes
may be indicated. Treatment is topical aluminum chloride, tap water iontophoresis, botulinum toxin, and, in extreme cases, surgery.
Etiology
Hyperhi dros i s ca n be foca l or genera l i zed.
Focal sweating: Emoti ona l ca us es a re common, ca us i ng s wea ti ng on the pa l ms , s ol es , a xi l l a e, a nd forehea d a t ti mes of a nxi ety, exci tement, a nger,
or fea r. It ma y be due to a genera l i zed s tres s -i ncrea s ed s ympa theti c outfl ow. Al though s uch s wea ti ng i s a norma l res pons e, pa ti ents wi th
hyperhi dros i s s wea t exces s i vel y a nd under condi ti ons tha t do not ca us e s wea ti ng i n mos t peopl e.
Gus ta tory s wea ti ng occurs a round the l i ps a nd mouth when i nges ti ng foods a nd bevera ges tha t a re s pi cy or hot i n tempera ture. There i s no known
ca us e i n mos t ca s es , but gus ta tory s wea ti ng ca n be i ncrea s ed i n di a beti c neuropa thy, fa ci a l herpes zos ter, cervi ca l s ympa theti c ga ngl i on i nva s i on,
CNS i njury or di s ea s e, or pa roti d gl a nd i njury. In the ca s e of pa roti d gl a nd i njury, s urgery, i nfecti on, or tra uma ma y di s rupt pa roti d gl a nd i nnerva ti on
a nd l ea d to regrowth of pa roti d pa ra s ympa theti c fi bers i nto s ympa theti c fi bers i nnerva ti ng l oca l s wea t gl a nds i n s ki n where the i njury took pl a ce,
us ua l l y over the pa roti d gl a nd. Thi s condi ti on i s ca l l ed Frey's s yndrome.
Other ca us es of foca l s wea ti ng i ncl ude preti bi a l myxedema (s hi ns ), hypertrophi c os teoa rthropa thy (pa l ms ), a nd bl ue rubber bl eb nevus s yndrome
a nd gl omus tumor (over l es i ons ). Compens a tory s wea ti ng i s i ntens e s wea ti ng a fter s ympa thectomy.
Generalized sweating: Genera l i zed s wea ti ng i nvol ves mos t of the body. Al though mos t ca s es a re i di opa thi c, numerous condi ti ons ca n be i nvol ved
(s ee
Ta bl e 80-1).
Symptoms and Signs
Swea ti ng i s often pres ent duri ng exa mi na ti on a nd s ometi mes i s extreme. Cl othi ng ca n be s oa ked, a nd pa l ms or s ol es ma y become ma cera ted a nd
fi s s ured. Hyperhi dros i s ca n ca us e emoti ona l di s tres s to pa ti ents a nd ma y l ea d to s oci a l wi thdra wa l . Pa l ma r or pl a nta r s ki n ma y a ppea r pa l e.
Diagnosis
Hi s tory a nd exa mi na ti on
Iodi ne a nd s ta rch tes t
Tes ts to i denti fy a ca us e
Hyperhi dros i s i s di a gnos ed by hi s tory a nd exa mi na ti on but ca n be confi rmed wi th the i odi ne a nd s ta rch tes t (a ppl y i odi ne s ol uti on to the a ffected
a rea , l et dry, dus t on corn s ta rch: a rea s of s wea ti ng a ppea r da rk). Tes ti ng i s neces s a ry onl y to confi rm foci of s wea ti ng (a s i n Frey's s yndrome or to
l oca te the
[Table 80-1. Some Ca us es of Genera l i zed Swea ti ng]
a rea needi ng s urgi ca l or botul i num toxi n trea tment) or i n a s emi qua nti ta ti ve wa y when fol l owi ng the cours e of trea tment.
Tes ts to i denti fy a ca us e of hyperhi dros i s a re gui ded by a revi ew of s ymptoms a nd mi ght i ncl ude CBC to detect l eukemi a , s erum gl ucos e to detect
di a betes , a nd thyroi d-s ti mul a ti ng hormone to s creen for thyroi d dys functi on.
Treatment
Al umi num chl ori de hexa hydra te s ol uti on

Ta p wa ter i ontophores i s
Botul i num toxi n type A
Surgery
Ini ti a l trea tment of foca l a nd genera l i zed s wea ti ng i s s i mi l a r.
Al umi num chl ori de hexa hydra te 6 to 20% s ol uti on i n a bs ol ute ethyl a l cohol i s i ndi ca ted for topi ca l trea tment of a xi l l a ry, pa l ma r, a nd pl a nta r
s wea ti ng; thes e prepa ra ti ons requi re a pres cri pti on. The s ol uti on bl ocks s wea t ducts a nd i s mos t effecti ve when a ppl i ed ni ghtl y a nd covered
ti ghtl y wi th a thi n pol yvi nyl i dene or pol yethyl ene fi l m; i t s houl d be wa s hed off i n the morni ng. Someti mes a n a nti chol i nergi c drug i s ta ken before
a ppl yi ng to prevent s wea t from wa s hi ng the a l umi num chl ori de a wa y. Ini ti a l l y, s evera l a ppl i ca ti ons weekl y a re needed to a chi eve control , then a
ma i ntena nce s chedul e of once or twi ce weekl y i s fol l owed. If trea tment under occl us i on i s i rri ta ti ng, i t s houl d be tri ed wi thout occl us i on. Thi s
s ol uti on s houl d not be a ppl i ed to i nfl a med, broken, wet, or recentl y s ha ved s ki n. Hi gh-concentra ti on, wa ter-ba s ed a l umi num chl ori de s ol uti ons
ma y provi de a dequa te rel i ef i n mi l der ca s es . Topi ca l a l terna ti ves to a l umi num chl ori de, i ncl udi ng gl uta ra l dehyde, forma l dehyde, a nd ta nni c a ci d,
a re effecti ve but ca n ca us e conta ct derma ti ti s a nd s ki n di s col ora ti on. A s ol uti on of methena mi ne a l s o ma y hel p.
Ta p wa ter i ontophores i s , i n whi ch s a l t i ons a re i ntroduced i nto the s ki n us i ng el ectri c current, i s a n opti on for pa ti ents unres pons i ve to topi ca l
trea tments . The a ffected a rea s (typi ca l l y pa l ms or s ol es ) a re pl a ced i n 2 ta p wa ter ba s i ns ea ch conta i ni ng a n el ectrode a cros s whi ch a 15- to 25mA current i s a ppl i ed for 10 to 20 mi n. Thi s routi ne i s done da i l y for 1 wk a nd then repea ted weekl y or bi monthl y. Trea tments ma y be ma de more
effecti ve wi th topi ca l or ora l a nti chol i nergi c drugs . Al though the trea tments a re us ua l l y effecti ve, the techni que i s ti me-cons umi ng a nd s omewha t
cumbers ome, a nd s ome pa ti ents ti re of the routi ne.
Botul i num toxi n type A i s a neurotoxi n tha t decrea s es the rel ea s e of a cetyl chol i ne from s ympa theti c nerves s ervi ng eccri ne gl a nds . Injected
di rectl y i nto the a xi l l a e, pa l ms , or forehea d, botul i num toxi n i nhi bi ts s wea ti ng for a bout 5 mo dependi ng on dos e. Compl i ca ti ons i ncl ude l oca l
mus cl e wea knes s a nd hea da che. Injecti ons a re effecti ve but pa i nful a nd expens i ve.
Surgery i s i ndi ca ted i f more cons erva ti ve trea tments fa i l . Pa ti ents wi th a xi l l a ry s wea ti ng ca n be trea ted wi th s urgi ca l exci s i on of a xi l l a ry s wea t
gl a nds ei ther through open di s s ecti on or by l i pos ucti on (the l a tter s eems to ha ve l ower morbi di ty). Pa ti ents wi th pa l ma r s wea ti ng ca n be trea ted
wi th endos copi c tra ns thora ci c s ympa thectomy. The potenti a l morbi di ty of s urgery mus t be cons i dered, es peci a l l y i n s ympa thectomy. Potenti a l
compl i ca ti ons i ncl ude pha ntom s wea ti ng, compens a tory s wea ti ng, gus ta tory s wea ti ng, neura l gi a , a nd Horner's s yndrome.
Hypohidrosis
Hypohidrosis is inadequate sweating.
Hypohi dros i s due to s ki n a bnorma l i ti es i s ra rel y cl i ni ca l l y s i gni fi ca nt. It i s mos t commonl y foca l a nd ca us ed by l oca l s ki n i njury (eg, from tra uma ,
ra di a ti on, i nfecti on [eg, l epros y], or i nfl a mma ti on) or by a trophy of gl a nds from connecti ve ti s s ue di s ea s e (eg, s ys temi c s cl eros i s , SLE, Sjogren's
s yndrome). Hypohi dros i s ma y be ca us ed by drugs , es peci a l l y thos e wi th a nti chol i nergi c properti es . It i s a l s o ca us ed by di a beti c neuropa thy a nd a
va ri ety of congeni ta l s yndromes . Hea ts troke ca us es i na dequa te s wea ti ng but i s a CNS ra ther tha n a s ki n di s order (s ee p. 3265). A ra re pres enta ti on
i s fever of unknown ori gi n.
Di a gnos i s i s by cl i ni ca l obs erva ti on of decrea s ed s wea ti ng or by hea t i ntol era nce. Trea tment i s by cool i ng mea s ures (eg, a i r-condi ti oni ng, wet
ga rments ).
Miliaria
In miliaria, sweat flow is obstructed and trapped within the skin, causing papular lesions.
Mi l i a ri a mos t often occurs i n wa rm humi d wea ther but ma y occur i n cool wea ther i n a n overdres s ed pa ti ent. Les i ons va ry dependi ng on the depth
of ti s s ue a t whi ch the s wea t duct i s obs tructed.
Miliaria crystallina i s ducta l obs tructi on i n the uppermos t epi dermi s , wi th retenti on of s wea t s ubcornea l l y. It ca us es cl ea r dropl i ke ves i cl es tha t
rupture wi th l i ght pres s ure.
Miliaria rubra (pri ckl y hea t) i s ducta l obs tructi on i n the mi d-epi dermi s wi th retenti on of s wea t i n the epi dermi s a nd dermi s . It ca us es i rri ta ted,
pruri ti c pa pul es (pri ckl i ng).
Miliaria pustulosa i s s i mi l a r to mi l i a ri a rubra but ma ni fes ts a s pus tul es ra ther tha n pa pul es .
Miliaria profunda i s ducta l obs tructi on a t the entra nce of the duct i nto the derma l pa pi l l a e a t the dermo-epi derma l juncti on, wi th retenti on of
s wea t i n the dermi s . It ca us es pa pul es tha t a re l a rger a nd more deepl y s ea ted tha n thos e of mi l i a ri a pus tul os a . Pa pul es a re frequentl y
pa i nful .
Di a gnos i s i s by cl i ni ca l a ppea ra nce i n the context of hot envi ronment.
Trea tment i s cool i ng a nd dryi ng of the i nvol ved a rea s a nd a voi da nce of condi ti ons tha t ma y i nduce s wea ti ng; a n a i r-condi ti oned envi ronment i s
i dea l . Once the ra s h devel ops , corti cos teroi d crea ms or l oti ons a re us ed, s ometi mes wi th a bi t of menthol a dded.
Chapter 81. Bacterial Skin Infections

Introduction
Ba cteri a l s ki n i nfecti ons ma y be uncompl i ca ted or compl i ca ted. Uncompl i ca ted i nfecti ons us ua l l y res pond promptl y to s ys temi c a nti bi oti cs a nd
l oca l wound ca re. A s ki n i nfecti on i s cons i dered compl i ca ted when i t meets 2 of the fol l owi ng 5 cri teri a :
Invol ves a preexi s ti ng wound or ul cera ti on of the s ki n
Invol ves the deeper s oft ti s s ues
Requi res s urgi ca l i nterventi on
Is ca us ed or exa cerba ted by underl yi ng comorbi d di s ea s e s ta tes (eg di a betes , s ys temi c i mmunos uppres s i on)
Is unres pons i ve to conventi ona l a nti bi oti c thera py or i s recurrent
Al l uncompl i ca ted s ki n i nfecti ons ha ve the potenti a l to become compl i ca ted. Compl i ca ted s ki n a nd s oft-ti s s ue i nfecti ons ma y requi re mul ti drug
thera py a nd the a s s i s ta nce of other cons ul ta nts (eg, s urgeons , i nfecti ous di s ea s e s peci a l i s ts ), pa rti cul a rl y i n l i ght of res i s ta nce i n ma ny s tra i ns of
ba cteri a a nd the ra pi d l os s of effi ca cy a mong more potent a nti bi oti cs . Recurrent s ki n i nfecti ons s houl d ra i s e s us pi ci on of col oni za ti on (eg,
s ta phyl ococca l na s a l ca rri a ge), res i s ta nt s tra i ns of ba cteri a (eg, methi ci l l i n-res i s ta nt Staphylococcus aureus [MRSA]), ca ncer, poorl y control l ed
di a betes , or other rea s ons for i mmunocompromi s e (eg, HIV, hepa ti ti s , a dva nced a ge, congeni ta l s us cepti bi l i ty). Ba cteri a a re i nvol ved i n the
pa thophys i ol ogy of a cne, but a cne i s not pri ma ri l y cons i dered a ba cteri a l s ki n i nfecti on.
Cellulitis
Cellulitis is acute bacterial infection of the skin and subcutaneous tissue most often caused by streptococci or staphylococci. Symptoms and signs are pain, rapidly
spreading erythema, and edema; fever may occur, and regional lymph nodes may enlarge. Diagnosis is by appearance; cultures are sometimes helpful but
awaiting culture results should not delay empiric therapy. Treatment is with antibiotics. Prognosis is excellent with timely treatment.
Etiology
Streptococcus pyogenes
Staphylococcus aureus
Cel l ul i ti s i s mos t often ca us ed by group A -hemol yti c s treptococci (eg, Streptococcus pyogenes) or Staphylococcus aureus. Streptococci ca us e di ffus e,
ra pi dl y s prea di ng i nfecti on beca us e enzymes produced by the orga ni s m (s treptoki na s e, DNa s e, hya l uroni da s e) brea k down cel l ul a r components
tha t woul d otherwi s e conta i n a nd l oca l i ze the i nfl a mma ti on. Sta phyl ococca l cel l ul i ti s i s typi ca l l y more l oca l i zed a nd us ua l l y occurs i n open
wounds or cuta neous a bs ces s es .
Recentl y, methi ci l l i n-res i s ta nt S. aureus (MRSA) ha s become more common i n the communi ty (communi ty-a s s oci a ted MRSA [CA-MRSA]). Hi s tori ca l l y,
MRSA wa s typi ca l l y confi ned to pa ti ents who were expos ed to the orga ni s m i n a hos pi ta l or nurs i ng fa ci l i ty. MRSA i nfecti on s houl d now be
cons i dered i n pa ti ents wi th communi ty-a cqui red cel l ul i ti s , pa rti cul a rl y i n thos e wi th cel l ul i ti s tha t i s recurrent or unres pons i ve to monothera py.
Les s common ca us es a re group B s treptococci (eg, Streptococcus agalactiae) i n ol der pa ti ents wi th di a betes ; gra m-nega ti ve ba ci l l i (eg, Haemophilus
influenzae) i n chi l dren; a nd Pseudomonas aeruginosa i n pa ti ents wi th di a betes or neutropeni a , hot tub or s pa us ers , a nd hos pi ta l i zed pa ti ents .
Ani ma l bi tes ma y res ul t i n cel l ul i ti s ; Pasteurella multocida i s the ca us e i n ca t bi tes , a nd Capnocytophaga s p i s res pons i bl e i n dog bi tes . Immers i on
i njuri es i n fres h wa ter ma y res ul t i n cel l ul i ti s ca us ed by Aeromonas hydrophila; i n wa rm s a l t wa ter, by Vibrio vulnificus.
Ri s k fa ctors i ncl ude s ki n a bnorma l i ti es (eg, tra uma , ul cera ti on, funga l i nfecti on, other s ki n ba rri er compromi s e due to preexi s ti ng s ki n di s ea s e),
whi ch a re common i n pa ti ents wi th chroni c venous i ns uffi ci ency or l ymphedema . Sca rs from s a phenous vei n remova l for ca rdi a c or va s cul a r s urgery
a re common s i tes for recurrent cel l ul i ti s , es peci a l l y i f ti nea pedi s i s pres ent. Frequentl y, no predi s pos i ng condi ti on or s i te of entry i s evi dent.
Symptoms and Signs
Infecti on i s mos t common i n the l ower extremi ti es . Cel l ul i ti s i s typi ca l l y uni l a tera l ; s ta s i s derma ti ti s cl os el y mi mi cs cel l ul i ti s but i s us ua l l y
bi l a tera l . The ma jor fi ndi ngs a re l oca l erythema a nd tendernes s , frequentl y wi th l ympha ngi ti s a nd regi ona l l ympha denopa thy. The s ki n i s hot, red,
a nd edema tous (s ee
Pl a te 31), often wi th s urfa ce a ppea ra nce res embl i ng the s ki n of a n ora nge (pea u d'ora nge). The borders a re us ua l l y i ndi s ti nct, except i n erys i pel a s
(a type of cel l ul i ti s wi th s ha rpl y dema rca ted ma rgi ns s ee p. 696). Petechi a e a re common; l a rge a rea s of ecchymos i s a re ra re. Ves i cl es a nd bul l a e
ma y devel op a nd rupture, occa s i ona l l y wi th necros i s of the i nvol ved s ki n. Cel l ul i ti s ma y mi mi c deep venous thrombos i s but ca n often be
di fferenti a ted by one or more fea tures (s ee
Ta bl e 81-1). Fever, chi l l s , ta chyca rdi a , hea da che, hypotens i on, a nd del i ri um ma y precede cuta neous fi ndi ngs by s evera l hours , but ma ny pa ti ents
do not a ppea r i l l . Leukocytos i s i s common.
[Table 81-1. Di fferenti a ti ng Cel l ul i ti s a nd Deep Venous Thrombos i s ]
Diagnosis
Exa mi na ti on
Bl ood a nd s ometi mes ti s s ue cul tures for i mmunocompromi s ed pa ti ents
Di a gnos i s i s by exa mi na ti on. Ski n a nd (when pres ent) wound cul tures a re genera l l y not i ndi ca ted beca us e they ra rel y i denti fy the i nfecti ng
orga ni s m. Bl ood cul tures a re us eful i n i mmunocompromi s ed pa ti ents to detect or rul e out ba cteremi a . Cul ture of i nvol ved ti s s ue ma y be requi red
i n i mmunocompromi s ed pa ti ents i f they a re not res pondi ng to empi ri c thera py or i f bl ood cul tures do not i s ol a te a n orga ni s m.
Prognosis
Mos t cel l ul i ti s res ol ves qui ckl y wi th a nti bi oti c thera py. Loca l a bs ces s es occa s i ona l l y form, requi ri ng i nci s i on a nd dra i na ge. Seri ous but ra re
compl i ca ti ons i ncl ude s evere necroti zi ng s ubcuta neous i nfecti on (s ee p. 700) a nd ba cteremi a wi th meta s ta ti c foci of i nfecti on.
Recurrences i n the s a me a rea a re common, s ometi mes ca us i ng s eri ous da ma ge to the l ympha ti cs , chroni c l ympha ti c obs tructi on, a nd
l ymphedema .
Treatment
Anti bi oti cs
Trea tment i s wi th a nti bi oti cs . For mos t pa ti ents , empi ri c trea tment effecti ve a ga i ns t both group A s treptococci a nd S. aureus i s us ed. Ora l thera py i s
us ua l l y a dequa te wi th di cl oxa ci l l i n 250 mg or cepha l exi n 500 mg qi d for mi l d i nfecti ons . Levofl oxa ci n 500 mg po once/da y or moxi fl oxa ci n 400 mg
once/da y works wel l for pa ti ents who a re unl i kel y to a dhere to mul ti pl e da i l y dos i ng s chedul es . For more s eri ous i nfecti ons , oxa ci l l i n or na fci l l i n
1 g IV q 6 h i s gi ven. Us e of i ni ti a l empi ri c thera py a ga i ns t MRSA i s not typi ca l l y a dvi s ed unl es s there i s compel l i ng cl i ni ca l evi dence (eg, conta ct
wi th a documented ca s e or outbrea k; cul ture-documented preva l ence of > 10% or 15% i n a pra cti ce a rea ). For peni ci l l i n-a l l ergi c pa ti ents or thos e
wi th s us pected or confi rmed MRSA i nfecti on, va ncomyci n 1 g IV q 12 h i s the drug of choi ce (s ee a l s o p. 1230). Li nezol i d i s a nother opti on for the
trea tment of MRSA a t a dos e of 600 mg IV or po q 12 h for 10 to 14 da ys . Tei copl a ni n ha s a mecha ni s m of a cti on s i mi l a r to va ncomyci n. It i s
commonl y us ed outs i de the US to trea t MRSA; the us ua l dos e i s 6 mg/kg IV q 12 h for 2 dos es , fol l owed by 6 mg/kg (or 3 mg/kg) IV or IM once/da y.
Immobi l i za ti on a nd el eva ti on of the a ffected a rea hel p reduce edema ; cool , wet dres s i ngs rel i eve l oca l di s comfort.
Cel l ul i ti s i n a pa ti ent wi th neutropeni a requi res empi ri c a nti ps eudomona l a nti bi oti cs (eg, tobra myci n 1.5 mg/kg IV q 8 h a nd pi pera ci l l i n 3 g IV q 4
h) unti l bl ood cul ture res ul ts a re a va i l a bl e. Peni ci l l i n i s the drug of choi ce for cel l ul i ti s ca us ed by P. multocida; a n a mi nogl ycos i de (eg, genta mi ci n)
i s effecti ve a ga i ns t A. hydrophila, a nd tetra cycl i ne i s preferred for V. vulnificus i nfecti ons .
Recurrent l eg cel l ul i ti s i s prevented by trea ti ng concomi ta nt ti nea pedi s , whi ch often el i mi na tes the s ource of ba cteri a res i di ng i n the i nfl a med,
ma cera ted ti s s ue. If s uch thera py i s uns ucces s ful or not i ndi ca ted, recurrent cel l ul i ti s ca n s ometi mes be prevented by benza thi ne peni ci l l i n 1.2
mi l l i on uni ts IM monthl y or peni ci l l i n V or erythromyci n 250 mg po qi d for 1 wk/mo. If thes e regi mens prove uns ucces s ful , ti s s ue cul ture ma y be
requi red.
Erysipelas
Erysipelas is a type of superficial cellulitis (see p. 694) with dermal lymphatic involvement.
Erys i pel a s s houl d not be confus ed wi th erys i pel oi d, a s ki n i nfecti on ca us ed by Erysipelothrix (s ee p. 1241). Erys i pel a s i s cha ra cteri zed cl i ni ca l l y by
s hi ny, ra i s ed, i ndura ted, a nd tender pl a que-l i ke l es i ons wi th di s ti nct ma rgi ns (s ee
Pl a te 33). There i s a l s o a bul l ous form of erys i pel a s . Erys i pel a s i s mos t often ca us ed by group A (or ra rel y group C or G) -hemol yti c s treptococci
a nd occurs mos t frequentl y on the l egs a nd fa ce. However, other ca us es ha ve been reported, i ncl udi ng Staphylococcus aureus (i ncl udi ng methi ci l l i nres i s ta nt S. aureus [MRSA]), Klebsiella pneumoniae, Haemophilus influenzae, Escherichia coli, S. warneri, Streptococcus pneumoniae, S. pyogenes, a nd Moraxella
s p. Erys i pel a s of the fa ce mus t be di fferenti a ted from herpes zos ter, a ngi oedema , a nd conta ct derma ti ti s . It i s commonl y a ccompa ni ed by hi gh
fever, chi l l s , a nd ma l a i s e; MRSA i s more common i n fa ci a l erys i pel a s tha n i n l ower-extremi ty erys i pel a s . Erys i pel a s ma y be recurrent a nd ma y
res ul t i n chroni c l ymphedema .
Diagnosis
Di a gnos i s i s by cha ra cteri s ti c a ppea ra nce; bl ood cul ture i s done i n toxi c-a ppea ri ng pa ti ents . Di ffus e i nfl a mma tory ca rci noma of the brea s t ma y
a l s o be mi s ta ken for erys i pel a s .
Treatment
Us ua l l y peni ci l l i n for l ower-extremi ty erys i pel a s
Ini ti a l l y va ncomyci n for fa ci a l erys i pel a s
Trea tment of choi ce for l ower-extremi ty erys i pel a s i s peni ci l l i n V 500 mg po qi d for 2 wk. In s evere ca s es , peni ci l l i n G 1.2 mi l l i on uni ts IV q 6 h i s
i ndi ca ted, whi ch ca n be repl a ced by ora l thera py a fter 36 to 48 h. Di cl oxa ci l l i n 500 mg po qi d for 10 da ys ca n be us ed for i nfecti ons wi th
s ta phyl ococci . Erythromyci n 500 mg po qi d for 10 da ys ma y be us ed i n peni ci l l i n-a l l ergi c pa ti ents ; however, there i s growi ng ma crol i de res i s ta nce i n
s treptococci . In i nfecti ons res i s ta nt to thes e a nti bi oti cs , cl oxa ci l l i n or na fci l l i n ca n be us ed. In Europe, pri s ti na myci n a nd roxi thromyci n ha ve been
s hown to be good choi ces for erys i pel a s . If fa ci a l erys i pel a s i s pres ent or i f MRSA i s otherwi s e s us pected, empi ri c thera py s houl d be i ni ti a ted wi th
va ncomyci n 1 g IV q 12 h (whi ch i s a cti ve a ga i ns t MRSA). Col d pa cks a nd a na l ges i cs ma y rel i eve l oca l di s comfort. Funga l foot i nfecti ons ma y be a n
entry s i te for i nfecti on a nd ma y requi re a nti funga l trea tment to prevent recurrence.
Cutaneous Abscess
A cutaneous abscess is a localized collection of pus in the skin and may occur on any skin surface. Symptoms and signs are pain and a tender, firm or fluctuant
swelling. Diagnosis is usually obvious by examination. Treatment is incision and drainage.
Ba cteri a ca us i ng cuta neous a bs ces s es a re typi ca l l y i ndi genous to the s ki n of the i nvol ved a rea . For a bs ces s es on the trunk, extremi ti es , a xi l l a e, or
hea d a nd neck, the mos t common orga ni s ms a re Staphylococcus aureus a nd s treptococci . In recent yea rs , methi ci l l i n-res i s ta nt S. aureus (MRSA) ha s
become a more common ca us e.
Abs ces s es i n the peri nea l (i e, i ngui na l , va gi na l , buttock, peri recta l ) regi on conta i n orga ni s ms found i n the s tool , commonl y a na erobes or a
combi na ti on of a erobes a nd a na erobes . Ca rbuncl es a nd furuncl es a re fol l i cl e-ba s ed cuta neous a bs ces s es wi th cha ra cteri s ti c fea tures (s ee p.
697).
Cuta neous a bs ces s es tend to form i n pa ti ents wi th ba cteri a l overgrowth, a ntecedent tra uma (pa rti cul a rl y when a forei gn body i s pres ent), or
i mmunol ogi c or ci rcul a tory compromi s e.
Symptoms and Signs
Cuta neous a bs ces s es a re pa i nful , tender, i ndura ted, a nd s ometi mes erythema tous . They va ry i n s i ze, typi ca l l y 1 to 3 cm i n l ength, but s ometi mes
much l a rger. Ini ti a l l y the s wel l i ng i s fi rm; l a ter, a s the a bs ces s "poi nts ," the overl yi ng s ki n becomes thi n a nd feel s fl uctua nt. The a bs ces s ma y
then s ponta neous l y dra i n. Loca l cel l ul i ti s , l ympha ngi ti s , regi ona l l ympha denopa thy, fever, a nd l eukocytos i s a re va ri a bl e a ccompa nyi ng fea tures .
Diagnosis
Exa mi na ti on
Gra m s ta i n a nd cul ture to i denti fy MRSA
Di a gnos i s i s us ua l l y obvi ous by exa mi na ti on. Gra m s ta i n a nd cul ture a re recommended, pri ma ri l y to i denti fy MRSA.
Condi ti ons res embl i ng s i mpl e cuta neous a bs ces s es i ncl ude hi dra deni ti s s uppura ti va (s ee p. 698) a nd ruptured epi derma l cys ts . Epi derma l cys ts
(often i ncorrectl y referred to a s s eba ceous cys ts ) ra rel y become i nfected; however, rupture rel ea s es kera ti n i nto the dermi s , ca us i ng a n exubera nt
i nfl a mma tory rea cti on s ometi mes cl i ni ca l l y res embl i ng i nfecti on. Cul ture of thes e ruptured cys ts s el dom revea l s a ny ba cteri a . Peri nea l a bs ces s es
ma y repres ent cuta neous emergence of a deeper peri recta l a bs ces s or dra i na ge from Crohn's di s ea s e vi a a fi s tul ous tra ct. Thes e other condi ti ons
a re us ua l l y recogni za bl e by hi s tory a nd recta l exa mi na ti on.
Treatment
Inci s i on a nd dra i na ge
Some s ma l l a bs ces s es res ol ve wi thout trea tment, comi ng to a poi nt a nd dra i ni ng. Wa rm compres s es hel p a ccel era te the proces s . Inci s i on a nd
dra i na ge a re i ndi ca ted when s i gni fi ca nt pa i n, tendernes s , a nd s wel l i ng a re pres ent; i t i s unneces s a ry to a wa i t fl uctua nce. Under s teri l e
condi ti ons , l oca l a nes thes i a i s a dmi ni s tered a s ei ther a l i doca i ne i njecti on or a freezi ng s pra y.
Pa ti ents wi th l a rge, extremel y pa i nful a bs ces s es ma y benefi t from IV s eda ti on a nd a na l ges i a duri ng dra i na ge. A s i ngl e puncture wi th the ti p of a
s ca l pel i s often s uffi ci ent to open the a bs ces s . After the pus dra i ns , the ca vi ty s houl d be bl untl y probed wi th a gl oved fi nger or curette to cl ea r
l ocul a ti ons , a nd then i rri ga ted wi th 0.9% s a l i ne s ol uti on. Some cl i ni ci a ns pa ck the ca vi ty l oos el y wi th a ga uze wi ck tha t i s removed 24 to 48 h l a ter.
Loca l hea t a nd el eva ti on ma y ha s ten res ol uti on of i nfl a mma ti on.
Anti bi oti cs a re unneces s a ry unl es s the pa ti ent ha s s i gns of s ys temi c i nfecti on, cel l ul i ti s , mul ti pl e a bs ces s es , i mmunocompromi s e, or a fa ci a l
a bs ces s i n the a rea dra i ned by the ca vernous s i nus . In thes e ca s es , empi ri c thera py s houl d be s ta rted wi th a drug a cti ve a ga i ns t MRSA (eg,
tri methopri m/s ul fa methoxa zol e, cl i nda myci n; for s evere i nfecti on, va ncomyci n) pendi ng res ul ts of ba cteri a l cul ture.
Folliculitis
Folliculitis is a bacterial infection of hair follicles.
Fol l i cul i ti s i s us ua l l y ca us ed by Staphylococcus aureus but occa s i ona l l y Pseudomonas aeruginosa (hot tub fol l i cul i ti s ) or other orga ni s ms . Hot tub
fol l i cul i ti s occurs beca us e of i na dequa te trea tment of wa ter wi th chl ori ne or bromi ne.
Symptoms of fol l i cul i ti s a re mi l d pa i n, pruri tus , or i rri ta ti on. Si gns of fol l i cul i ti s a re a s uperfi ci a l pus tul e or i nfl a mma tory nodul e s urroundi ng a
ha i r fol l i cl e. Infected ha i rs ea s i l y fa l l out or a re removed, but new pa pul es tend to devel op. Growth of s ti ff ha i rs i nto the s ki n ma y ca us e chroni c
l ow-gra de i rri ta ti on or i nfl a mma ti on tha t ma y mi mi c i nfecti ous fol l i cul i ti s (ps eudofol l i cul i ti s ba rba es ee p. 731).
Treatment
Beca us e mos t fol l i cul i ti s i s ca us ed by S. aureus, cl i nda myci n 1% l oti on or gel ma y be a ppl i ed topi ca l l y bi d for 7 to 10 da ys . Al terna ti vel y, benzoyl
peroxi de 5% wa s h ma y be us ed when s howeri ng for 5 to 7 da ys . Extens i ve cuta neous i nvol vement ma y wa rra nt s ys temi c thera py (eg, cepha l exi n 250
to 500 mg po ti d to qi d for 10 da ys ). If thes e mea s ures do not res ul t i n a cure, or fol l i cul i ti s recurs , pus tul es a re Gra m s ta i ned a nd cul tured to rul e
out gra m-nega ti ve or methi ci l l i n-res i s ta nt S. aureus (MRSA) eti ol ogy, a nd na res a re cul tured to rul e out na s a l s ta phyl ococca l ca rri a ge. Pota s s i um
hydroxi de wet mount s houl d be done on a pl ucked ha i r to rul e out funga l fol l i cul i ti s .
Trea tment for MRSA us ua l l y requi res 2 ora l a nti bi oti cs , a nd the choi ce of thera peuti c drugs s houl d be ba s ed on cul ture a nd s ens i ti vi ty reports .
Hot tub fol l i cul i ti s us ua l l y res ol ves wi thout trea tment. However, a dequa te chl ori na ti on of the hot tub i s neces s a ry to prevent recurrences a nd to
protect others from i nfecti on.
Furuncles and Carbuncles
Furuncles are skin abscesses caused by staphylococcal infection, which involve a hair follicle and surrounding tissue. Carbuncles are clusters of furuncles
connected subcutaneously, causing deeper suppuration and scarring. They are smaller and more superficial than subcutaneous abscesses (see p. 696). Diagnosis is
by appearance. Treatment is warm compresses and often oral antistaphylococcal antibiotics.
Both furuncl es a nd ca rbuncl es ma y a ffect hea l thy young peopl e but a re more common i n the obes e, the i mmunocompromi s ed (i ncl udi ng thos e
wi th neutrophi l defects ), the el derl y, a nd pos s i bl y thos e wi th di a betes . Cl us tered ca s es ma y occur a mong thos e l i vi ng i n crowded qua rters wi th
rel a ti vel y poor hygi ene or a mong conta cts of pa ti ents i nfected wi th vi rul ent s tra i ns . Predi s pos i ng fa ctors i ncl ude ba cteri a l col oni za ti on of s ki n or
na res , hot a nd humi d cl i ma tes , a nd occl us i on or a bnorma l fol l i cul a r a na tomy (eg, comedones i n a cne). Methi ci l l i n-res i s ta nt Staphylococcus aureus
(MRSA) i s a common ca us e.
Furuncl es a re common on the neck, brea s ts , fa ce, a nd buttocks . They a re uncomforta bl e a nd ma y be pa i nful when cl os el y a tta ched to underl yi ng
s tructures (eg, on the nos e, ea r, or fi ngers ). Appea ra nce i s a nodul e or pus tul e tha t di s cha rges necroti c ti s s ue a nd s a ngui neous pus . Ca rbuncl es
ma y be a ccompa ni ed by fever a nd pros tra ti on.
Diagnosis
Di a gnos i s i s by exa mi na ti on. Ma teri a l for cul ture s houl d be obta i ned.
Treatment
Dra i na ge
Often a nti bi oti cs effecti ve a ga i ns t MRSA
Abs ces s es a re i nci s ed a nd dra i ned. Intermi ttent hot compres s es a re us ed to fa ci l i ta te dra i na ge. Anti bi oti cs , when us ed, s houl d be effecti ve
a ga i ns t MRSA, pendi ng cul ture a nd s ens i ti vi ty tes t res ul ts . In a febri l e pa ti ents , trea tment of a s i ngl e l es i on < 5 mm requi res no a nti bi oti cs . If a
s i ngl e l es i on i s 5 mm, a n ora l a nti bi oti c i s gi ven for 5 to 10 da ys ; choi ces i ncl ude tri methopri m/s ul fa methoxa zol e (TMP/SMX) 160/800 mg to
320/1600 mg bi d, cl i nda myci n 300 to 600 mg q 6 to 8 h, a nd doxycycl i ne or mi nocycl i ne 100 mg q 12 h. Pa ti ents wi th fever, mul ti pl e a bs ces s es , or
ca rbuncl es a re gi ven 10 da ys of TMP/SMX 160/800 mg to 320/1600 mg bi d pl us ri fa mpi n 300 mg bi d. Sys temi c a nti bi oti cs a re a l s o needed for
Les i ons < 5 mm tha t do not res ol ve wi th dra i na ge
Evi dence of expa ndi ng cel l ul i ti s
Immunocompromi s ed pa ti ents
Pa ti ents a t ri s k of endoca rdi ti s
Furuncl es frequentl y recur a nd ca n be prevented by a ppl yi ng l i qui d s oa p conta i ni ng ei ther chl orhexi di ne gl ucona te wi th i s opropyl a l cohol or 2 to
3% chl oroxyl enol a nd by gi vi ng ma i ntena nce a nti bi oti cs over 1 to 2 mo. Pa ti ents wi th recurrent furuncul os i s s houl d be trea ted for predi s pos i ng
fa ctors s uch a s obes i ty, di a betes , occupa ti ona l or i ndus tri a l expos ure to i nci ti ng fa ctors , a nd na s a l ca rri a ge of S. aureus or MRSA col oni za ti on.
Erythrasma
Erythrasma is an intertriginous infection with Corynebacterium minutissimum that is most common among patients with diabetes and among people living in the
tropics.
Erythra s ma res embl es ti nea or i ntertri go. It i s mos t common i n the foot, where i t ma ni fes ts a s s uperfi ci a l s ca l i ng, fi s s uri ng, a nd ma cera ti on mos t
commonl y confi ned to the 3rd a nd 4th web s pa ces . Erythra s ma i s a l s o common i n the groi n, where i t ma ni fes ts a s i rregul a r but s ha rpl y ma rgi na ted
pi nk or brown pa tches wi th fi ne s ca l i ng. Erythra s ma ma y a l s o i nvol ve the a xi l l a e, s ubma mma ry or a bdomi na l fol ds , a nd peri neum, pa rti cul a rl y i n
obes e mi ddl e-a ged women a nd i n pa ti ents wi th di a betes .
Erythra s ma fl uores ces a cha ra cteri s ti c cora l -red col or under Wood's l i ght. Abs ence of hypha e i n s ki n s cra pi ngs a l s o di s ti ngui s hes erythra s ma from
ti nea .
Trea tment i s erythromyci n or tetra cycl i ne 250 mg po qi d for 14 da ys . Topi ca l erythromyci n or cl i nda myci n i s a l s o effecti ve. Recurrence i s common.
Hidradenitis Suppurativa
Hidradenitis suppurativa is a chronic, scarring inflammation of apocrine glands of the axillae, groin, and around the nipples and anus.
Bl ocka ge of a pocri ne ducts ha s been s ugges ted a s the ca us e, l ea di ng to s ubs equent i nfl a mma ti on, ba cteri a l overgrowth, a nd s ca rri ng.
Staphylococcus aureus i s a l mos t a l wa ys i mpl i ca ted i n a cute ca s es , but gra m-nega ti ve orga ni s ms s uch a s Proteus ma y predomi na te i n chroni c ca s es .
Swol l en, tender ma s s es res embl i ng cuta neous a bs ces s es devel op. Pa i n, fl uctua nce, di s cha rge, a nd s i nus tra ct forma ti on a re cha ra cteri s ti c i n
chroni c ca s es . In chroni c a xi l l a ry ca s es , coa l es cence of i nfl a med nodul es ca us es pa l pa bl e cordl i ke fi broti c ba nds . The condi ti on ma y become
di s a bl i ng beca us e of pa i n a nd foul odor.
Diagnosis
Di a gnos i s i s by exa mi na ti on. Ba cteri a l cul tures ma y be hel pful i f there a ppea rs to be a concomi ta nt cel l ul i ti s or l ocul a ted a bs ces s .
Treatment
Trea tment of a cute ca s es cons i s ts of hi gh-dos e ora l tetra cycl i ne (500 mg bi d), doxycycl i ne (100 to 200 mg once/da y), mi nocycl i ne (100 mg once/da y),
or erythromyci n (250 to 500 mg qi d) unti l the l es i ons res ol ve. Topi ca l cl i nda myci n a ppl i ed bi d ma y be equa l l y effecti ve. Inci s i on a nd dra i na ge a re
neces s a ry for a n a bs ces s or fl uctua nce of the a ffected a rea but a l one do not res ol ve the probl em (unl i ke i n cuta neous a bs ces s es ). Is otreti noi n 1
mg/kg po bi d ha s a l s o been effecti ve i n s ome pa ti ents , but recurrences a re common. Intra l es i ona l corti cos teroi d i njecti ons (eg, tri a mci nol one 1 to
10% s us pens i on i ntra derma l l y) ma y hel p wi th i nfl a mma ti on a nd pa i n. Surgi ca l exci s i on a nd repa i r or gra fti ng of the a ffected a rea s i s often
neces s a ry i f the di s ea s e pers i s ts . Abl a ti ve l a s er thera py (CO2 or erbi um:YAG) i s a n a l terna te s urgi ca l trea tment. Severa l s tudi es report s ucces s i n
trea ti ng hi dra deni ti s s uppura ti va wi th eta nercept or i nfl i xi ma b, i njecta bl e tumor necros i s fa ctor- i nhi bi tors . Al though not the gol d s ta nda rd, thi s
opti on ma y be us eful when a l l other trea tment moda l i ti es ha ve fa i l ed.
Impetigo and Ecthyma
Impetigo is a superficial skin infection with crusting or bullae caused by streptococci, staphylococci, or both. Ecthyma is an ulcerative form of impetigo.
No predi s pos i ng l es i on i s i denti fi ed i n mos t pa ti ents , but i mpeti go ma y fol l ow a ny type of brea k i n the s ki n. Genera l ri s k fa ctors s eem to be moi s t
envi ronment, poor hygi ene, a nd chroni c na s a l ca rri a ge of s ta phyl ococci . Impeti go ma y be bul l ous or nonbul l ous . Staphylococcus aureus i s the
predomi na nt ca us e of nonbul l ous i mpeti go a nd the ca us e of a l l bul l ous i mpeti go. Bul l a e a re ca us ed by exfol i a ti ve toxi n produced by
s ta phyl ococci . Methi ci l l i n-res i s ta nt S. aureus (MRSA) ha s been i s ol a ted i n a bout 20% of recent ca s es of i mpeti go.
Symptoms and Signs
Nonbul l ous i mpeti go typi ca l l y ma ni fes ts a s cl us ters of ves i cl es or pus tul es tha t rupture a nd devel op a honey-col ored crus t (exuda te from the
l es i on ba s e) over the l es i ons (s ee
Pl a te 35). Bul l ous i mpeti go i s s i mi l a r except tha t ves i cl es typi ca l l y enl a rge ra pi dl y to form bul l a e. The bul l a e burs t a nd expos e l a rger ba s es , whi ch
become covered wi th honey-col ored va rni s h or crus t. Ecthyma i s cha ra cteri zed by s ma l l , purul ent, s ha l l ow, punched-out ul cers wi th thi ck, brownbl a ck crus ts a nd s urroundi ng erythema .
Impeti go a nd ecthyma ca us e mi l d pa i n or di s comfort. Pruri tus i s common; s cra tchi ng ma y s prea d i nfecti on, i nocul a ti ng a dja cent a nd nona dja cent
s ki n.
Diagnosis
Di a gnos i s i s by cha ra cteri s ti c a ppea ra nce. Cul tures of l es i ons a re i ndi ca ted onl y when the pa ti ent does not res pond to empi ri c thera py. Pa ti ents
wi th recurrent i mpeti go s houl d ha ve na s a l cul ture. Pers i s tent i nfecti ons s houl d be cul tured to i denti fy MRSA.
Treatment
Topi ca l mupi roci n or reta pa mul i n
Someti mes ora l a nti bi oti cs
The a ffected a rea s houl d be wa s hed gentl y wi th s oa p a nd wa ter s evera l ti mes a da y to remove a ny crus ts . Trea tment for l oca l i zed di s ea s e i s
topi ca l mupi roci n a nti bi oti c oi ntment ti d for 7 da ys or reta pa mul i n oi ntment bi d for 5 da ys . Ora l a nti bi oti cs (eg, di cl oxa ci l l i n or cepha l exi n 250 to
500 mg qi d, 12.5 mg/kg qi d for chi l dren, for 10 da ys ) ma y be needed i n pa ti ents wi th extens i ve or res i s ta nt l es i ons . Us e of i ni ti a l empi ri c thera py
a ga i ns t MRSA i s not typi ca l l y a dvi s ed unl es s there i s compel l i ng cl i ni ca l evi dence (eg, conta ct wi th a documented ca s e or outbrea k; hi gh cul turedocumented preva l ence i n a pra cti ce a rea ). Trea tment of MRSA s houl d be di rected by cul ture a nd s ens i ti vi ty tes t res ul ts ; typi ca l l y, cl i nda myci n,
ri fa mpi n, a nd tri methopri m/s ul fa methoxa zol e a re effecti ve a ga i ns t mos t s tra i ns of communi ty-a s s oci a ted MRSA.
Other thera py i ncl udes res tori ng a norma l cuta neous ba rri er i n pa ti ents wi th underl yi ng a topi c derma ti ti s or extens i ve xeros i s us i ng topi ca l
emol l i ents a nd corti cos teroi ds i f wa rra nted. Chroni c s ta phyl ococca l na s a l ca rri ers a re gi ven topi ca l a nti bi oti cs (mupi roci n) for 1 wk ea ch of 3
cons ecuti ve months .
Prompt recovery us ua l l y fol l ows ti mel y trea tment. Del a y ca n ca us e cel l ul i ti s , l ympha ngi ti s , furuncul os i s , a nd hyperpi gmenta ti on or
hypopi gmenta ti on wi th or wi thout s ca rri ng. Chi l dren a ged 2 to 4 yr a re a t ri s k of a cute gl omerul onephri ti s i f nephri togeni c s tra i ns of group A
s treptococci a re i nvol ved; nephri ti s s eems to be more common i n the s outhern US tha n i n other regi ons .
Lymphadenitis
(See a l s o Lympha ngi ti s , bel ow.)
Lymphadenitis is an acute infection of one or more lymph nodes.
Lympha deni ti s i s a fea ture of ma ny ba cteri a l , vi ra l , funga l , a nd protozoa l i nfecti ons . Foca l l ympha deni ti s i s promi nent i n s treptococca l i nfecti on,
TB or nontubercul ous mycoba cteri a l i nfecti on, tul a remi a , pl a gue, ca t-s cra tch di s ea s e, pri ma ry s yphi l i s , l ymphogra nul oma venereum, cha ncroi d,
a nd geni ta l herpes s i mpl ex. Mul ti foca l l ympha deni ti s i s common i n i nfecti ous mononucl eos i s , cytomega l ovi rus i nfecti on, toxopl a s mos i s ,
brucel l os i s , s econda ry s yphi l i s , a nd di s s emi na ted hi s topl a s mos i s .
Symptoms and Signs
Lympha deni ti s typi ca l l y ca us es pa i n, tendernes s , a nd l ymph node enl a rgement. Pa i n a nd tendernes s typi ca l l y di s ti ngui s h l ympha deni ti s from
l ympha denopa thy. Wi th s ome i nfecti ons , the overl yi ng s ki n i s i nfl a med, occa s i ona l l y wi th cel l ul i ti s . Abs ces s es ma y form, a nd penetra ti on to the
s ki n produces dra i ni ng s i nus es . Fever i s common.
Diagnosis
The underl yi ng di s order i s us ua l l y s ugges ted by hi s tory a nd exa mi na ti on. If not, a s pi ra ti on a nd cul ture or exci s i ona l bi ops y i s i ndi ca ted.
Treatment
Trea tment i s di rected a t the ca us e a nd i s us ua l l y empi ri c. Opti ons i ncl ude IV a nti bi oti cs , a nti funga l s , a nd a nti pa ra s i ti cs dependi ng upon eti ol ogy
or cl i ni ca l s us pi ci on. Ma ny pa ti ents wi th l ympha deni ti s ma y res pond to outpa ti ent thera py wi th ora l a nti bi oti cs . However, ma ny a l s o go on to form
a bs ces s es , whi ch requi re s urgi ca l dra i na ge; a n extens i ve procedure i s done wi th a ccompa nyi ng IV a nti bi oti cs . In chi l dren, IV a nti bi oti cs a re
commonl y needed. Hot, wet compres s es ma y rel i eve s ome pa i n. Lympha deni ti s us ua l l y res ol ves wi th ti mel y trea tment, a l though res i dua l ,
pers i s tent, nontender l ympha denopa thy i s common.
Lymphangitis
(See a l s o Lympha deni ti s , a bove.)
Lymphangitis is acute bacterial infection (usually streptococcal) of peripheral lymphatic channels.
Ba cteri a enter the l ympha ti c cha nnel s from a n a bra s i on, wound, or coexi s ti ng i nfecti on (us ua l l y cel l ul i ti s ). Pa ti ents wi th underl yi ng l ymphedema
a re a t pa rti cul a r ri s k. Red, i rregul a r, wa rm, tender s trea ks devel op on a n extremi ty a nd extend proxi ma l l y from a peri phera l l es i on towa rd regi ona l
l ymph nodes , whi ch a re typi ca l l y enl a rged a nd tender. Sys temi c ma ni fes ta ti ons (eg, fever, s ha ki ng chi l l s , ta chyca rdi a , hea da che) ma y occur a nd
ma y be more s evere tha n cuta neous fi ndi ngs s ugges t. Leukocytos i s i s common. Ba cteremi a ma y occur. Ra rel y, cel l ul i ti s wi th s uppura ti on, necros i s ,
a nd ul cera ti on devel ops a l ong the i nvol ved l ymph cha nnel s a s a cons equence of pri ma ry l ympha ngi ti s .
Di a gnos i s i s cl i ni ca l . Is ol a ti on of the res pons i bl e orga ni s m i s us ua l l y unneces s a ry. Mos t ca s es res pond ra pi dl y to a nti s treptococca l a nti bi oti cs
(s ee Cel l ul i ti s on p. 694).
Necrotizing Subcutaneous Infection
(Necroti zi ng Fa s ci i ti s )
Necrotizing subcutaneous infection (NSI) is typically caused by a mixture of aerobic and anaerobic organisms that cause necrosis of subcutaneous tissue, usually
including the fascia. This infection most commonly affects the extremities and perineum. Affected tissues become red, hot, and swollen, resembling severe
cellulitis (see p. 694). Without timely treatment, the area becomes gangrenous. Patients are acutely ill. Diagnosis is by history and examination and is supported
by evidence of overwhelming infection. Treatment involves antibiotics and surgical debridement. Prognosis is poor without early, aggressive treatment.
Etiology
NSI typi ca l l y res ul ts from i nfecti on wi th group A s treptococci (eg, Streptococcus pyogenes) or a mi xture of a erobi c a nd a na erobi c ba cteri a (eg,
Bacteroides s p). Thes e orga ni s ms typi ca l l y extend to s ubcuta neous ti s s ue from a conti guous ul cer, a n i nfecti on, or a fter tra uma . Streptococci ca n
a rri ve from a remote s i te of i nfecti on vi a the bl oods trea m. Peri nea l i nvol vement (a l s o ca l l ed Fourni er's ga ngrene) i s us ua l l y a compl i ca ti on of
recent s urgery, peri recta l a bs ces s , peri urethra l gl a nd i nfecti on, or retroperi tonea l i nfecti on from perfora ted a bdomi na l vi s cera . Pa ti ents wi th
di a betes a re a t pa rti cul a r ri s k of NSI.
Pathophysiology
NSI ca us es ti s s ue i s chemi a by wi des prea d occl us i on of s ma l l s ubcuta neous ves s el s . Ves s el occl us i on res ul ts i n s ki n i nfa rcti on a nd necros i s ,
whi ch fa ci l i ta tes the growth of obl i ga te a na erobes (eg, Bacteroides) whi l e promoti ng a na erobi c meta bol i s m by fa cul ta ti ve orga ni s ms (eg,
Escherichia coli), res ul ti ng i n ga ngrene. Ana erobi c meta bol i s m produces hydrogen a nd ni trogen, rel a ti vel y i ns ol ubl e ga s es tha t ma y a ccumul a te i n
s ubcuta neous ti s s ues .
Symptoms and Signs
The pri ma ry s ymptom i s i ntens e pa i n. However, i n a rea s denerva ted by peri phera l neuropa thy, pa i n ma y be mi ni ma l or a bs ent. Affected ti s s ue i s
red, hot, a nd s wol l en a nd ra pi dl y becomes di s col ored. Bul l a e, crepi tus (from s oft-ti s s ue ga s ), a nd ga ngrene ma y devel op. Subcuta neous ti s s ues
(i ncl udi ng a dja cent fa s ci a ) necros e, wi th wi des prea d undermi ni ng of s urroundi ng ti s s ue. Mus cl es a re s pa red i ni ti a l l y. Pa ti ents a re a cutel y i l l , wi th
hi gh fever, ta chyca rdi a , a l tered menta l s ta tus ra ngi ng from confus i on to obtunda ti on, a nd hypotens i on. Pa ti ents ma y be ba cteremi c or s epti c a nd
ma y requi re a ggres s i ve hemodyna mi c s upport.
Diagnosis
Cl i ni ca l exa mi na ti on
Bl ood a nd wound cul tures
Di a gnos i s , ma de by hi s tory a nd exa mi na ti on, i s s upported by l eukocytos i s , s oft-ti s s ue ga s on x-ra y, pos i ti ve bl ood cul tures , a nd deteri ora ti ng
meta bol i c a nd hemodyna mi c s ta tus .
NSI mus t be di fferenti a ted from cl os tri di a l s oft-ti s s ue i nfecti ons , i n whi ch cel l ul i ti s , myos i ti s , a nd myonecros i s often occur (s ee p. 1295). Such
i nfecti ons a re a na erobi c. Ana erobi c cel l ul i ti s produces l ots of ga s but l i ttl e pa i n, edema , or cha nge i n s ki n; i t very s el dom tra vel s i nto the mus cl e.
Ana erobi c myonecros i s ha s pronounced s ki n cha nges , pa i n, a nd edema a nd us ua l l y penetra tes i nto mus cl e.
Prognosis
Morta l i ty ra te i s a bout 30%. Ol d a ge, underl yi ng medi ca l probl ems , del a yed di a gnos i s a nd thera py, a nd i ns uffi ci ent s urgi ca l debri dement wors en
prognos i s .
Treatment
Surgi ca l debri dement
Anti bi oti cs
Amputa ti on i f neces s a ry
Trea tment of ea rl y NSI i s pri ma ri l y s urgi ca l . IV a nti bi oti cs a re a djuncts , us ua l l y i ncl udi ng 2 or more drugs , but regi mens va ry dependi ng on res ul ts
of Gra m s ta i n a nd cul ture (eg, peni ci l l i n G 4 mi l l i on uni ts q 4 h combi ned wi th cl i nda myci n 600 to 900 mg q 8 h or ceftri a xone 2 g q 12 h). Evi dence of
bul l a e, ecchymos i s , fl uctua nce, crepi tus , a nd s ys temi c s prea d of i nfecti on requi res i mmedi a te s urgi ca l expl ora ti on a nd debri dement. The i ni ti a l
i nci s i on s houl d be extended unti l a n i ns trument or fi nger ca n no l onger s epa ra te the s ki n a nd s ubcuta neous ti s s ue from the deep fa s ci a . The
mos t common error i s i ns uffi ci ent s urgi ca l i nterventi on; repea t opera ti on every 1 to 2 da ys , wi th further i nci s i on a nd debri dement a s needed,
s houl d be ca rri ed out routi nel y. Amputa ti on of a n extremi ty ma y be neces s a ry.
IV fl ui ds ma y be needed i n l a rge vol umes before a nd a fter s urgery. Anti bi oti c choi ces s houl d be revi ewed ba s ed on Gra m s ta i n a nd cul ture of
ti s s ues obta i ned duri ng s urgery. Hyperba ri c O2 thera py a s a djuva nt thera py ma y a l s o be of benefi t; however, the evi dence i s i nconcl us i ve.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) is an acute epidermolysis caused by a staphylococcal toxin. Infants and children are most susceptible. Symptoms
are widespread bullae with epidermal sloughing. Diagnosis is by examination and sometimes biopsy. Treatment is antistaphylococcal antibiotics and local care.
Prognosis is excellent with timely treatment.
SSSS a l mos t a l wa ys a ffects chi l dren < 6 yr (es peci a l l y i nfa nts ); i t ra rel y occurs i n ol der pa ti ents unl es s they ha ve rena l fa i l ure or a re
i mmunocompromi s ed. Epi demi cs ma y occur i n nurs eri es , pres uma bl y tra ns mi tted by the ha nds of pers onnel who a re i n conta ct wi th a n i nfected
i nfa nt or who a re na s a l ca rri ers of Staphylococcus aureus. Spora di c ca s es a l s o occur.
SSSS i s ca us ed by group II coa gul a s e-pos i ti ve s ta phyl ococci , us ua l l y pha ge type 71, whi ch el a bora te exfol i a ti n (a l s o ca l l ed epi dermol ys i n), a toxi n
tha t s pl i ts the upper pa rt of the epi dermi s jus t benea th the gra nul a r cel l l a yer (s ee a l s o p. 1228). The pri ma ry i nfecti on often begi ns duri ng the
fi rs t few da ys of l i fe i n the umbi l i ca l s tump or di a per a rea ; i n ol der chi l dren, the fa ce i s the typi ca l s i te. Toxi n produced i n thes e a rea s enters the
ci rcul a ti on a nd a ffects the enti re s ki n.
[
Table 81-2. Di fferenti a ti ng Sta phyl ococca l Sca l ded Ski n Syndrome (SSSS) a nd Toxi c Epi derma l Necrol ys i s (TEN)]
Symptoms and Signs
The i ni ti a l l es i on i s us ua l l y s uperfi ci a l a nd crus ted. Wi thi n 24 h, the s urroundi ng s ki n becomes pa i nful a nd s ca rl et, cha nges tha t qui ckl y s prea d to
other a rea s . The s ki n ma y be exqui s i tel y tender a nd ha ve a wri nkl ed ti s s ue pa per-l i ke cons i s tency. La rge, fl a cci d bl i s ters a ri s e on the
erythema tous s ki n a nd qui ckl y brea k to produce eros i ons . Inta ct bl i s ters extend l a tera l l y wi th gentl e pres s ure (Ni kol s ky's s i gn). The epi dermi s
ma y peel ea s i l y, often i n l a rge s heets (s ee
Pl a te 45). Wi des prea d des qua ma ti on occurs wi thi n 36 to 72 h, a nd pa ti ents become very i l l wi th s ys temi c ma ni fes ta ti ons (eg, ma l a i s e, chi l l s ,
fever). Des qua ma ted a rea s a ppea r s ca l ded. Los s of the protecti ve s ki n ba rri er ca n l ea d to s eps i s a nd to fl ui d a nd el ectrol yte i mba l a nce.
Diagnosis
Bi ops y
Cul tures ma y be us eful i n a dul ts
Di a gnos i s i s s us pected cl i ni ca l l y, but confi rma ti on us ua l l y requi res bi ops y (frozen s ecti on ma y gi ve ea rl i er res ul ts ). Speci mens s how
noni nfl a mma tory s uperfi ci a l s pl i tti ng of the epi dermi s . In chi l dren, s ki n cul tures a re s el dom pos i ti ve; i n a dul ts , they a re frequentl y pos i ti ve.
Cul tures s houl d be ta ken from the nos e, conjuncti va , throa t, a nd na s opha rynx.
Differential diagnosis: Di fferenti a l di a gnos i s i ncl udes drug hypers ens i ti vi ty, vi ra l exa nthema s , s ca rl et fever, therma l burns , geneti c bul l ous di s ea s es
(eg, s ome types of epi dermol ys i s bul l os a ), a cqui red bul l ous di s ea s es (eg, pemphi gus vul ga ri s , bul l ous pemphi goi d), a nd toxi c epi derma l
necrol ys i s (s ee p. 689 a nd Ta bl e 81-2). Stevens -Johns on s yndrome i s cha ra cteri zed by mucos a l i nvol vement, whi ch i s a bs ent i n SSSS.
Treatment
Anti bi oti cs
Corti cos teroi ds not recommended
Gel dres s i ngs for weepi ng l es i ons
Wi th prompt di a gnos i s a nd thera py, dea th ra rel y occurs ; the s tra tum corneum i s qui ckl y repl a ced, a nd hea l i ng us ua l l y occurs wi thi n 5 to 7 da ys
a fter s ta rt of trea tment.
Peni ci l l i na s e-res i s ta nt a nti s ta phyl ococca l a nti bi oti cs gi ven IV mus t be s ta rted i mmedi a tel y. Na fci l l i n 12.5 to 25 mg/kg IV q 6 h for neona tes > 2 kg
a nd 25 to 50 mg/kg for ol der chi l dren i s gi ven unti l i mprovement i s noted, fol l owed by ora l cl oxa ci l l i n 12.5 mg/kg q 6 h (for i nfa nts a nd chi l dren
wei ghi ng 20 kg) a nd 250 to 500 mg q 6 h (for ol der chi l dren). Corti cos teroi ds a re contra i ndi ca ted. Topi ca l thera py a nd pa ti ent ha ndl i ng mus t be
mi ni mi zed.
If di s ea s e i s wi des prea d a nd l es i ons a re weepi ng, the s ki n s houl d be trea ted a s for burns (s ee p.
3245). Hydrol yzed pol ymer gel dres s i ngs ma y be very us eful , a nd the number of dres s i ng cha nges s houl d be mi ni mi zed.
Steps to detect ca rri ers a nd prevent or trea t nurs ery epi demi cs a re di s cus s ed el s ewhere (s ee p. 2828).
Chapter 82. Fungal Skin Infections

Introduction
Funga l s ki n i nfecti ons a re ca us ed by yea s ts (Candida s p) or derma tophytes (Epidermophyton, Microsporum, a nd Trichophyton s pp).
Candidiasis
Candidiasis (moniliasis) is skin infection with Candida sp, most commonly Candida albicans. Infections can occur anywhere and are most common in skinfolds and
web spaces and on the genitals, cuticles, and oral mucosa. Symptoms and signs vary by site. Diagnosis is by clinical appearance and potassium hydroxide wet
mount of skin scrapings. Treatment is with drying agents and antifungals.
Mos t ca ndi da l i nfecti ons a re of the s ki n a nd mucous membra nes , but i nva s i ve ca ndi di a s i s i s common i n i mmunos uppres s ed pa ti ents a nd ca n be
l i fe threa teni ng. Sys temi c ca ndi di a s i s i s di s cus s ed i n Ch. 142.
Etiology
Candida i s a group of a bout 150 yea s t s peci es . C. albicans i s res pons i bl e for a bout 70 to 80% of a l l ca ndi da l i nfecti ons . Other s i gni fi ca nt s peci es
i ncl ude C. glabrata, C. tropicalis, C. krusei, a nd C. dubliniensis.
Candida i s a ubi qui tous yea s t tha t res i des ha rml es s l y on s ki n a nd mucous membra nes unti l da mpnes s , hea t, a nd i mpa i red l oca l a nd s ys temi c
defens es provi de a ferti l e envi ronment for i t to grow. Ri s k fa ctors for ca ndi di a s i s i ncl ude
Hot wea ther
Res tri cti ve cl othi ng
Poor hygi ene
Infrequent di a per or underga rment cha nges i n chi l dren a nd el derl y pa ti ents
Al tered fl ora from a nti bi oti c thera py
Infl a mma tory di s ea s es (eg, ps ori a s i s ) tha t occur i n s ki nfol ds
Immunos uppres s i on res ul ti ng from corti cos teroi ds a nd i mmunos uppres s i ve drugs , pregna ncy, di a betes , other endocri nopa thi es (eg, Cus hi ng's
di s ea s e, hypoa drena l i s m, hypothyroi di s m), bl ood dys cra s i a s , or T-cel l defects
Ca ndi di a s i s occurs mos t commonl y i n i ntertri gi nous a rea s s uch a s the a xi l l a e, groi n, a nd gl utea l fol ds (eg, di a per ra s hs ee
Pl a te 30), i n di gi ta l web s pa ces , i n the gl a ns peni s , a nd benea th the brea s ts . Vul vova gi na l ca ndi di a s i s i s common i n women (s ee p. 2544).
Ca ndi da l na i l i nfecti ons a nd pa ronychi a ma y devel op a fter i mproperl y done ma ni cures a nd i n ki tchen workers a nd others whos e ha nds a re
conti nua l l y expos ed to wa ter (s ee p. 734). In obes e peopl e, ca ndi da l i nfecti ons ma y occur benea th the pa nnus (a bdomi na l fol d). Oropha ryngea l
ca ndi di a s i s (s ee
Pl a te 32) i s a common s i gn of l oca l or s ys temi c i mmunos uppres s i on.
Chroni c mucocuta neous ca ndi di a s i s typi ca l l y a ffects the na i l s , s ki n, a nd oropha rynx. Pa ti ents ha ve cuta neous a nergy to Candida, a bs ent
prol i fera ti ve res pons es to Candida a nti gen (but norma l prol i fera ti ve res pons es to mi togens ), a nd a n i nta ct a nti body res pons e to Candida a nd other
a nti gens . Chroni c mucocuta neous ca ndi di a s i s ma y occur a s a n a utos oma l reces s i ve i l l nes s a s s oci a ted wi th hypopa ra thyroi di s m a nd Addi s on's
di s ea s e (Candida-endocri nopa thy s yndrome).
Symptoms and Signs
Intertri gi nous i nfecti ons ma ni fes t a s pruri ti c, wel l -dema rca ted, erythema tous pa tches of va ryi ng s i ze a nd s ha pe; erythema ma y be di ffi cul t to
detect i n da rker-s ki nned pa ti ents . Pri ma ry pa tches ma y ha ve a dja cent s a tel l i te pa pul es a nd pus tul es . Peri a na l ca ndi di a s i s produces whi te
ma cera ti on a nd pruri tus a ni . Vul vova gi na l ca ndi di a s i s ca us es pruri tus a nd di s cha rge (s ee p. 2544).
Ca ndi da l i nfecti on i s a frequent ca us e of chroni c pa ronychi a , whi ch ma ni fes ts a s pa i nful red peri ungua l s wel l i ng. Subungua l i nfecti ons a re
cha ra cteri zed by di s ta l s epa ra ti on of one or s evera l fi ngerna i l s (onychol ys i s ), wi th whi te or yel l ow di s col ora ti on of the s ubungua l a rea (s ee p.
735).
Oropha ryngea l ca ndi di a s i s ca us es whi te pl a ques on ora l mucous membra nes tha t ma y bl eed when s cra ped.
Perl eche i s ca ndi di a s i s a t the corners of the mouth, whi ch ca us es cra cks a nd ti ny fi s s ures . It ma y s tem from chroni c l i p l i cki ng, thumb s ucki ng, i l l fi tti ng dentures , or other condi ti ons tha t ma ke the corners of the mouth moi s t enough tha t yea s t ca n grow.
Chroni c mucocuta neous ca ndi di a s i s i s cha ra cteri zed by red, pus tul a r, crus ted, a nd thi ckened pl a ques res embl i ng ps ori a s i s , es peci a l l y on the nos e
a nd forehea d, a nd i s i nva ri a bl y a s s oci a ted wi th chroni c ora l ca ndi di a s i s .
Diagnosis
Cl i ni ca l a ppea ra nce
Pota s s i um hydroxi de wet mounts
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce a nd i denti fi ca ti on of yea s t a nd ps eudohypha e i n pota s s i um hydroxi de wet mounts of s cra pi ngs from a
l es i on. Pos i ti ve cul ture i s us ua l l y mea ni ngl es s beca us e Candida i s omni pres ent.
Treatment
Someti mes dryi ng a gents
Topi ca l or ora l a nti funga l s
Intertriginous infection i s trea ted wi th dryi ng a gents a s needed (eg, Burow's s ol uti on for oozi ng l es i ons , genti a n vi ol et for toe web s pa ces ) a nd
topi ca l a nti funga l s (s ee
Ta bl e 82-1). Powdered formul a ti ons a re i dea l for dry l es i ons (eg, mi cona zol e powder bi d for 2 to 3 wk). Fl ucona zol e 150 mg po once/wk for 2 to 4 wk
i s i ndi ca ted for extens i ve i ntertri gi nous ca ndi di a s i s ; topi ca l a nti funga l a gents ma y be us ed a t the s a me ti me.
Candidal diaper rash i s trea ted wi th more frequent cha nge of di a pers , a voi da nce of di s pos a bl e di a pers wi th pl a s ti c coveri ngs , a nd a n i mi da zol e
crea m bi d. Ora l nys ta ti n i s a n opti on for i nfa nts wi th coexi s ti ng oropha ryngea l ca ndi di a s i s ; 1 mL of s us pens i on (100,000 uni ts /mL) i s pl a ced i n
ea ch bucca l pouch qi d.
Candidal paronychia i s trea ted by protecti ng the a rea from wetnes s a nd gi vi ng topi ca l or ora l a nti funga l s . Thes e i nfecti ons a re often res i s ta nt to
trea tment.
Oral candidiasis i s trea ted wi th fl ucona zol e 200 mg po on the fi rs t da y, then 100 mg po once/da y for 2 to 3 wk therea fter.
Chronic mucocutaneous candidiasis requi res l ong-term ora l a nti funga l trea tment wi th ketocona zol e 400 mg once/da y or i tra cona zol e 200 mg once/da y.
[Table 82-1. Opti ons for Trea tment of Superfi ci a l Funga l Infecti ons *]
Dermatophytoses
Dermatophytoses are fungal infections of keratin in the skin and nails (nail infection is called tinea unguiumsee p. 734). Symptoms and signs vary by site of
infection. Diagnosis is by clinical appearance and by examination of skin scrapings on potassium hydroxide wet mount. Treatment varies by site but always
involves topical or oral antifungal drugs.
Derma tophytes a re mol ds tha t requi re kera ti n for nutri ti on a nd mus t l i ve on s tra tum corneum, ha i r, or na i l s to s urvi ve. Huma n i nfecti ons a re
ca us ed by Epidermophyton, Microsporum, a nd Trichophyton s pp. Thes e i nfecti ons di ffer from ca ndi di a s i s i n tha t they a re ra rel y i f ever i nva s i ve.
Tra ns mi s s i on i s pers on-to-pers on, a ni ma l -to-pers on, a nd ra rel y, s oi l -to-pers on. The orga ni s m ma y pers i s t i ndefi ni tel y. Mos t peopl e do not
devel op cl i ni ca l i nfecti on; thos e who do ma y ha ve i mpa i red T-cel l res pons es from a n a l tera ti on i n l oca l defens es (eg, from tra uma wi th va s cul a r
compromi s e) or from pri ma ry (heredi ta ry) or s econda ry (eg, di a betes , HIV) i mmunos uppres s i on.
Symptoms and Signs
Symptoms a nd s i gns va ry by s i te (s ki n, ha i r, na i l s ). Orga ni s m vi rul ence a nd hos t s us cepti bi l i ty a nd hypers ens i ti vi ty determi ne s everi ty. Mos t often,
there i s l i ttl e or no i nfl a mma ti on; a s ymptoma ti c or mi l dl y i tchi ng l es i ons wi th a s ca l i ng, s l i ghtl y ra i s ed border remi t a nd recur i ntermi ttentl y.
Occa s i ona l l y, i nfl a mma ti on i s more s evere a nd ma ni fes ts a s s udden ves i cul a r or bul l ous di s ea s e (us ua l l y of the foot) or a s a n i nfl a med boggy
l es i on of the s ca l p (keri on).
Diagnosis
Pota s s i um hydroxi de wet mount
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce a nd s i te of i nfecti on a nd confi rmed by s ki n s cra pi ngs a nd demons tra ti on of hypha e on pota s s i um
hydroxi de (KOH) wet mount. Identi fi ca ti on of s peci fi c orga ni s ms by cul ture i s unneces s a ry except for s ca l p i nfecti on (where a n a ni ma l s ource ma y
be i denti fi ed a nd trea ted) a nd na i l i nfecti on (whi ch ma y be ca us ed by a nonderma tophyte). Cul ture ma y a l s o be us eful when overl yi ng
i nfl a mma ti on a nd ba cteri a l i nfecti on a re s evere a nd/or a ccompa ni ed by a l opeci a .
Di fferenti a l di a gnos i s i ncl udes
Fol l i cul i ti s deca l va ns
Ba cteri a l pyoderma s
Enti ti es tha t ca us e s ca rri ng a l opeci a , s uch a s di s coi d l upus , l i chen pl a nopi l a ri s , a nd ps eudopel a de
Treatment
Topi ca l a nti funga l s a re genera l l y a dequa te (s ee Ta bl e 82-1). In genera l , OTC terbi na fi ne i s bes t; econa zol e or ci cl opi rox ma y be better i f ca ndi da l
i nfecti on ca nnot be excl uded. Ora l a nti funga l s a re us ed for mos t na i l a nd s ca l p i nfecti ons , res i s ta nt s ki n i nfecti ons , a nd pa ti ents unwi l l i ng or
una bl e to a dhere to prol onged topi ca l regi mens ; dos es a nd dura ti on di ffer by s i te of i nfecti on.
Corti cos teroi d crea ms ca n be us ed to hel p rel i eve i tchi ng a nd pa i n for the fi rs t few da ys . Low-dos e hydrocorti s one ca n be a ppl i ed s epa ra tel y, or
more potent corti cos teroi ds ma y be a dded to the a nti funga l crea m. Ora l corti cos teroi ds a re occa s i ona l l y us ed for trea tment of s evere
i nfl a mma tory l es i ons .
Tinea Barbae
(Ba rber's Itch)
Tinea barbae is a dermatophyte infection of the beard area most often caused by Trichophyton mentagrophytes or T. verrucosum.
Ti nea ba rba e ma ni fes ts a s s uperfi ci a l a nnul a r l es i ons , but deeper i nfecti on s i mi l a r to fol l i cul i ti s ma y occur. It ma y a l s o occur a s a n i nfl a mma tory
keri on tha t ca n res ul t i n s ca rri ng ha i r l os s . Di a gnos i s i s by KOH wet mount, cul ture, or bi ops y.
Trea tment i s mi croni zed gri s eoful vi n 500 mg to 1 g po once/da y unti l 2 to 3 wk a fter cl i ni ca l cl ea ra nce. Terbi na fi ne 250 mg po once/da y a nd
i tra cona zol e 200 mg po once/da y ha ve a l s o been us ed. If the l es i ons a re s everel y i nfl a med, a s hort cours e of predni s one s houl d be a dded (to
l es s en s ymptoms a nd perha ps reduce the cha nce of s ca rri ng), s ta rti ng wi th 40 mg po once/da y (for a dul ts ) a nd ta peri ng the dos e over 2 wk.
Tinea Capitis
(Sca l p Ri ngworm)
Tinea capitis is a dermatophyte infection of the scalp.
Ti nea ca pi ti s ma i nl y a ffects chi l dren, i s conta gi ous , a nd ca n be epi demi c. T. tonsurans i s the mos t common ca us e i n the US, fol l owed by
Microsporum canis a nd M. audouinii; other Trichophyton s p (eg, T. schoenleinii, T. violaceum) a re common el s ewhere.
Ti nea ca pi ti s ca us es the gra dua l a ppea ra nce of round pa tches of dry s ca l e, a l opeci a , or both. T. tonsurans i nfecti on ca us es "bl a ck dot ri ngworm," i n
whi ch ha i r s ha fts brea k a t the s ca l p s urfa ce; M. audouinii i nfecti on ca us es "gra y pa tch ri ngworm," i n whi ch ha i r s ha fts brea k a bove the s urfa ce,
l ea vi ng s hort s tubs . Ti nea ca pi ti s l es s commonl y ma ni fes ts a s di ffus e s ca l i ng, l i ke da ndruff, or i n a di ffus e pus tul a r pa ttern.
Kerion: Derma tophyte i nfecti on occa s i ona l l y l ea ds to forma ti on of a keri on, whi ch i s a l a rge, boggy, i nfl a mma tory s ca l p ma s s (s ee
Pl a te 48) ca us ed by a s evere i nfl a mma tory rea cti on to the derma tophyte. A keri on ma y ha ve pus tul es a nd crus ti ng a nd ca n be mi s ta ken for a n
a bs ces s . A keri on ma y res ul t i n s ca rri ng ha i r l os s .
Diagnosis
KOH wet mount
Someti mes Wood's l i ght exa mi na ti on
Ti nea ca pi ti s i s di a gnos ed by cl i ni ca l a ppea ra nce a nd by KOH wet mount of pl ucked ha i rs or of ha i rs a nd s ca l e obta i ned by s cra pi ng or brus hi ng.
Spore s i ze a nd a ppea ra nce i ns i de (endothri x) or outs i de (ectothri x) the ha i r s ha ft di s ti ngui s h orga ni s ms a nd ca n hel p gui de trea tment. Bl ue-green
fl uores cence duri ng Wood's l i ght exa mi na ti on i s di a gnos ti c for i nfecti on wi th M. canis a nd M. audouinii a nd ca n di s ti ngui s h ti nea from erythra s ma .
Di fferenti a l di a gnos i s of ti nea ca pi ti s i ncl udes
Seborrhei c derma ti ti s
Ps ori a s i s
Treatment
Ora l a nti funga l s
Sel eni um s ul fi de s ha mpoo
Someti mes predni s one
Chi l dren a re trea ted wi th mi croni zed gri s eoful vi n s us pens i on 10 to 20 mg/kg po once/da y (dos es va ry by s evera l pa ra meters , but ma xi mum dos e i s
genera l l y 1 g/da y) or, i f > 2 yr, wi th ul tra mi croni zed gri s eoful vi n 5 to 10 mg/kg (ma xi mum 750 mg/da y) po once/da y or i n 2 di vi ded dos es wi th mea l s
or mi l k for 4 to 6 wk or unti l a l l s i gns of i nfecti on a re gone. Terbi na fi ne a l s o ma y be us ed; chi l dren < 20 kg a re gi ven 62.5 mg once/da y; thos e 20 to
40 kg, 125 mg once/da y, a nd thos e > 40 kg, 250 mg once/da y. An i mi da zol e or ci cl opi rox crea m s houl d be a ppl i ed to the s ca l p to prevent s prea d,
es peci a l l y to other chi l dren, unti l ti nea ca pi ti s i s cured; s el eni um s ul fi de 2.5% s ha mpoo s houl d a l s o be us ed a t l ea s t twi ce/wk. Chi l dren ma y
a ttend s chool duri ng trea tment.
Adul ts a re trea ted wi th terbi na fi ne 250 mg po once/da y for 2 to 4 wk, whi ch i s more effecti ve for endothri x i nfecti ons , or i tra cona zol e 200 mg
once/da y for 2 to 4 wk or 200 mg bi d gi ven for 1 wk, fol l owed by 3 wk wi thout the drug (pul s ed) for 2 to 3 mo.
For s everel y i nfl a med l es i ons a nd for keri on, a s hort cours e of predni s one s houl d be a dded (to l es s en s ymptoms a nd perha ps reduce the cha nce
of s ca rri ng), s ta rti ng wi th 40 mg po once/da y (1 mg/kg for chi l dren) a nd ta peri ng the dos e over 2 wk.
Tinea Corporis
(Body Ri ngworm)
Tinea corporis is a dermatophyte infection of the face, trunk, and extremities.
Common ca us es a re T. mentagrophytes, T. rubrum, a nd M. canis.
Ti nea corpori s ca us es pi nk-to-red a nnul a r pa tches a nd pl a ques wi th ra i s ed s ca l y borders tha t expa nd peri phera l l y a nd tend to cl ea r centra l l y (s ee
Pl a te 49). A va ri a nt form a ppea rs a s nummul a r s ca l i ng pa tches s tudded wi th s ma l l pa pul es or pus tul es .
Diagnosis
Pi tyri a s i s ros ea
Drug erupti ons
Nummul a r derma ti ti s
Erythema mul ti forme
Ti nea vers i col or
Erythra s ma
Ps ori a s i s
Seconda ry s yphi l i s
Treatment
Trea tment of mi l d-to-modera te l es i ons i s a n i mi da zol e, ci cl opi rox, na fti fi ne, or terbi na fi ne i n crea m, l oti on, or gel . The drug s houl d be rubbed i n
bi d conti nui ng a t l ea s t 7 to 10 da ys a fter l es i ons di s a ppea r, typi ca l l y a t a bout 2 to 3 wk.
Extens i ve a nd res i s ta nt l es i ons occur i n pa ti ents i nfected wi th T. rubrum a nd i n peopl e wi th debi l i ta ti ng s ys temi c di s ea s es . For s uch ca s es , the
mos t effecti ve thera py i s ora l i tra cona zol e 200 mg once/da y or terbi na fi ne 250 mg once/da y for 2 to 3 wk.
Tinea Cruris
(Jock Itch)
Tinea cruris is a dermatophyte infection of the groin.
Common orga ni s ms i ncl ude T. rubrum or T. mentagrophytes. The pri ma ry ri s k fa ctors a re a s s oci a ted wi th a moi s t envi ronment (i e, wa rm wea ther, wet
a nd res tri cti ve cl othi ng, obes i ty ca us i ng cons ta nt a ppos i ti on of s ki n fol ds ). Men a re a ffected more tha n women beca us e of a ppos i ti on of the
s crotum a nd thi gh.
Typi ca l l y, a pruri ti c, ri nged l es i on extends from the crura l fol d over the a dja cent upper i nner thi gh (s ee
Pl a te 50). Infecti on ma y be bi l a tera l . Les i ons ma y be compl i ca ted by ma cera ti on, mi l i a ri a , s econda ry ba cteri a l or ca ndi da l i nfecti on, a nd rea cti ons
to trea tment. In a ddi ti on, s cra tch derma ti ti s a nd l i cheni fi ca ti on ca n occur. Recurrence i s common beca us e fungi ma y repea tedl y i nfect s us cepti bl e
peopl e. Fl a re-ups occur more often duri ng s ummer.
Diagnosis
Ps ori a s i s
Erythra s ma
Ca ndi di a s i s
Scrota l i nvol vement i s us ua l l y a bs ent or s l i ght; by contra s t, the s crotum i s often i nfl a med i n ca ndi da l i ntertri go or l i chen s i mpl ex chroni cus .
Treatment
Topi ca l a nti funga l crea m or l oti on

Anti funga l choi ces i ncl ude terbi na fi ne, mi cona zol e, cl otri ma zol e, ketocona zol e, econa zol e, na fti fi ne, a nd ci cl opi rox a ppl i ed bi d for 10 to 14 da ys .
Itra cona zol e 200 mg po once/da y or terbi na fi ne 250 mg po once/da y for 3 to 6 wk ma y be needed i n pa ti ents who ha ve refra ctory, i nfl a mma tory, or
wi des prea d i nfecti ons .
Tinea Pedis
(Athl ete's Foot)
Tinea pedis is a dermatophyte infection of the feet.
Ti nea pedi s i s the mos t common derma tophytos i s beca us e moi s ture from foot s wea ti ng fa ci l i ta tes funga l growth. Ti nea pedi s ma y occur a s a ny of
4 cl i ni ca l forms or i n combi na ti on:
Chroni c hyperkera toti c
Chroni c i ntertri gi nous
Acute ul cera ti ve
Ves i cul obul l ous
Chronic hyperkeratotic ti nea pedi s due to T. rubrum ca us es a di s ti ncti ve pa ttern of l es i on, ma ni fes ti ng a s s ca l i ng a nd thi ckeni ng of the s ol es , whi ch
often extends beyond the pl a nta r s urfa ce i n a mocca s i n di s tri buti on. Di fferenti a l di a gnos i s i s s teri l e ma cera ti on (due to hyperhi dros i s a nd
occl us i ve footgea r), conta ct derma ti ti s (due to type IV del a yed hypers ens i ti vi ty to va ri ous ma teri a l s i n s hoes , pa rti cul a rl y a dhes i ve cement,
thi ura m compounds i n footwea r tha t conta i ns rubber, a nd chroma te ta nni ng a gents us ed i n l ea ther footwea r), i rri ta nt derma ti ti s , a nd ps ori a s i s .
Chronic intertriginous ti nea pedi s i s cha ra cteri zed by s ca l i ng, erythema , a nd eros i on of the i nterdi gi ta l a nd s ubdi gi ta l s ki n of the feet, mos t
commonl y a ffecti ng the l a tera l 3 toes .
Acute ulcerative ti nea pedi s (mos t often ca us ed by T. mentagrophytes va r. interdigitale) typi ca l l y begi ns i n the 3rd a nd 4th i nterdi gi ta l s pa ces a nd
extends to the l a tera l dors um a nd/or the pl a nta r s urfa ce of the a rch. Thes e toe web l es i ons a re us ua l l y ma cera ted a nd ha ve s ca l i ng borders (s ee
Pl a te 51). Seconda ry ba cteri a l i nfecti on, cel l ul i ti s , a nd l ympha ngi ti s a re common compl i ca ti ons .
Vesiculobullous ti nea pedi s , i n whi ch ves i cl es devel op on the s ol es a nd coa l es ce i nto bul l a e, i s the l es s common res ul t of a fl a re of i nterdi gi ta l
ti nea pedi s ; ri s k fa ctors a re occl us i ve s hoes a nd envi ronmenta l hea t a nd humi di ty.
Diagnosis
Di a gnos i s i s us ua l l y obvi ous ba s ed on cl i ni ca l exa mi na ti on a nd revi ew of ri s k fa ctors .
Treatment
Moi s ture reducti on a nd dryi ng a gents
Topi ca l a nd ora l a nti funga l s
The s a fes t trea tment i s topi ca l a nti funga l s , but recurrence i s common a nd trea tment mus t often be prol onged. Al terna ti ves tha t provi de a more
dura bl e res pons e i ncl ude i tra cona zol e 200 mg po once/da y for 1 mo (or pul s e thera py wi th 200 mg bi d 1 wk/mo for 1 to 2 mo) a nd terbi na fi ne 250
mg po once/da y for 2 to 6 wk. Concomi ta nt topi ca l a nti funga l us e ma y reduce recurrences .
Moi s ture reducti on on the feet a nd i n footwea r i s neces s a ry for preventi ng recurrence. Permea bl e or open-toe footwea r a nd s ock cha nges a re
i mporta nt es peci a l l y duri ng wa rm wea ther. Interdi gi ta l s pa ces s houl d be ma nua l l y dri ed a fter ba thi ng. Dryi ng a gents a re a l s o recommended;
opti ons i ncl ude a nti funga l powders (eg, mi cona zol e), genti a n vi ol et, Burow's s ol uti on (5% a l umi num s ub-a ceta te) s oa ks bi d, a nd 20 to 25%
a l umi num chl ori de hexa hydra te powder once/da y.
Dermatophytid Reaction
Dermatophytid is an inflammatory reaction to dermatophytosis at a cutaneous site distant from the primary infection.
Derma tophyti d (i denti ty or i d) rea cti ons a re protea n; they a re not rel a ted to l oca l i zed growth of the fungus but ra ther a re a n i nfl a mma tory rea cti on
el s ewhere on the body. Les i ons a re typi ca l l y pruri ti c but ma y ma ni fes t a s
Ves i cul a r erupti ons on the ha nds a nd feet
Fol l i cul a r pa pul es
Erys i pel a s -l i ke pl a ques
Erythema nodos um
Erythema a nnul a re centri fugum
Urti ca ri a
Di s tri buti on ma y be extens i ve.
Di a gnos i s i s by KOH wet mounts tha t a re nega ti ve a t the s i te of the i d rea cti on a nd pos i ti ve a t the di s ta nt s i te of derma tophyte i nfecti on.
Trea tment of the pri ma ry i nfecti on cures derma tophyti d; pendi ng cure, topi ca l corti cos teroi ds a nd/or a nti pruri ti cs (eg, hydroxyzi ne 25 mg qi d) ca n
be us ed to rel i eve s ymptoms .
Intertrigo
Intertrigo is skinfold changes caused by moisture and infection.
Intertri go devel ops when fri cti on a nd tra pped moi s ture i n i ntertri gi nous a rea s ca us e s ki n ma cera ti on wi th forma ti on of pa tches or pl a ques ;
ba cteri a l , yea s t, a nd derma tophyte i nfecti on i s common. Typi ca l l oca ti ons a re the i nfra ma mma ry, i nfra pa nni cul a r, i nterdi gi ta l , a xi l l a ry,
i nfra gl utea l , a nd geni tocrura l fol ds .
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce; pota s s i um hydroxi de wet mounts a nd cul tures ca n gui de trea tment.
If no ba cteri a or yea s t a re detected, dryi ng a gents (powders s uch a s ta l c ra ther tha n corns ta rch, whi ch ca n s upport funga l growth, Burow's s ol uti on)
to decrea s e moi s ture s houl d be thera peuti c. If ba cteri a or yea s ts a re pres ent, topi ca l a nti ba cteri a l l oti ons or a nti funga l crea ms a re gi ven i n
a ddi ti on to dryi ng a gents .
Tinea Versicolor
(Pi tyri a s i s Vers i col or)
Tinea versicolor is skin infection with Malassezia furfur that manifests as multiple asymptomatic scaly patches varying in color from white to brown. Diagnosis is
based on clinical appearance and skin scrapings. Treatment is topical antifungals.
Malassezia furfur i s a di morphi c fungus tha t i s norma l l y a ha rml es s component of norma l s ki n fl ora but tha t i n s ome peopl e ca us es ti nea
vers i col or. The hi gh preva l ence of ti nea vers i -col or i n young a dul ts s ugges ts a l i nk to i ncrea s ed s eba ceous s ecreti ons ; other ri s k fa ctors i ncl ude
hea t a nd humi di ty a nd i mmunos uppres s i on due to corti cos teroi ds , pregna ncy, undernutri ti on, di a betes , a nd other di s orders .
Symptoms and Signs
Ti nea vers i col or us ua l l y i s a s ymptoma ti c. Cl a s s i ca l l y, i t ca us es the a ppea ra nce of mul ti pl e ta n, brown, s a l mon, or whi te s ca l i ng l es i ons (s ee
Pl a te 52) on the trunk, neck, a bdomen, a nd occa s i ona l l y fa ce. The l es i ons coa l es ce. In whi tes , the condi ti on i s often di a gnos ed i n s ummer months
beca us e the l es i ons , whi ch do not ta n, become more obvi ous a ga i ns t ta nned s ki n.
Diagnosis
Pota s s i um hydroxi de wet mount
Someti mes Wood's l i ght exa mi na ti on
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce a nd by i denti fi ca ti on of hypha e a nd buddi ng cel l s ("s pa ghetti a nd mea tba l l s ") on pota s s i um hydroxi de
wet mount. Wood's l i ght exa mi na ti on revea l s gol den-whi te fl uores cence.
Treatment
Topi ca l a nti funga l s
Someti mes ora l a nti funga l s
Trea tment i s a ny topi ca l a nti funga l drug. Exa mpl es i ncl ude s el eni um s ul fi de s ha mpoo 2.5% (i n 10-mi n a ppl i ca ti ons da i l y for 1 wk or 24-h
a ppl i ca ti ons weekl y for 1 mo); topi ca l a zol es (eg, ketocona zol e 2% da i l y for 2 wk); a nd ba thi ng wi th zi nc pyri thi one s oa p 2% or s ul fur-s a l i cyl i c
s ha mpoo 2% for 1 to 2 wk.
Ora l trea tment i s i ndi ca ted for pa ti ents wi th extens i ve di s ea s e a nd thos e wi th frequent recurrences . Two conveni ent regi mens a re a s i ngl e 400-mg
dos e of fl ucona zol e a nd ketocona zol e 200 mg once/da y for 1 to 5 da ys .
Hypopi gmenta ti on from ti nea vers i col or i s revers i bl e i n months to yea rs a fter the yea s t ha s cl ea red. Recurrence i s a l mos t uni vers a l a fter
trea tment beca us e the ca us a ti ve orga ni s m i s a norma l s ki n i nha bi ta nt. Fa s ti di ous hygi ene, regul a r us e of zi nc pyri thi one s oa p, or once-monthl y
us e of topi ca l a nti funga l thera py l owers the l i kel i hood of recurrence.
Chapter 83. Parasitic Skin Infections

Introduction
Pa ra s i ti c s ki n i nfecti ons ca n ca us e s evere i tchi ng a nd be di s tres s i ng. Mos t s ki n pa ra s i tes a re i ns ects or worms tha t burrow i nto the s ki n for pa rt or
a l l of thei r l i fe cycl e. Al s o, s ome s ys temi c pa ra s i ti c i nfecti ons ha ve cuta neous ma ni fes ta ti ons ; thes e i ncl ude certa i n nema todes (a ncyl os tomi a s i s ,
dra cuncul os i s , s trongyl oi di a s i s , toxoca ri a s i s s ee p. 1342) a nd fl ukes (s chi s tos omi a s i s s ee p. 1358). Very ra rel y, pa ti ents ha ve del us i ona l
pa ra s i tos i s .
Cutaneous Larva Migrans
(Creepi ng Erupti on)
Cutaneous larva migrans (CLM) is the skin manifestation of hookworm infestation.
CLM i s ca us ed by Ancylostoma s p, mos t commonl y dog or ca t hookworm Ancylostoma braziliense. Hookworm ova i n dog or ca t feces devel op i nto
i nfecti ve l a rva e when l eft i n wa rm moi s t ground or s a nd; tra ns mi s s i on occurs when s ki n di rectl y conta cts conta mi na ted s oi l or s a nd a nd l a rva e
penetra te unprotected s ki n, us ua l l y of the feet, l egs , buttocks , or ba ck. CLM occurs worl dwi de but mos t commonl y i n tropi ca l envi ronments .
CLM ca us es i ntens e pruri tus ; s i gns a re erythema a nd pa pul es a t the s i te of entry, wi th a wi ndi ng, threa dl i ke s ubcuta neous tra i l of reddi s h-brown
i nfl a mma ti on. Di a gnos i s i s by hi s tory a nd cl i ni ca l a ppea ra nce.
Topi ca l thi a benda zol e 15% l i qui d or crea m (compounded) bi d to ti d for 5 da ys i s extremel y effecti ve. Ora l thi a benda zol e i s not wel l tol era ted a nd
not us ua l l y us ed. Al benda zol e (400 mg po once/da y for 7 da ys ) a nd i vermecti n ca n cure the i nfes ta ti on a nd a re wel l tol era ted.
CLM ma y be compl i ca ted by a s el f-l i mi ti ng pul mona ry rea cti on ca l l ed Loffl er's s yndrome (pa tchy pul mona ry i nfi l tra tes a nd peri phera l bl ood
eos i nophi l i a ).
Cutaneous Myiasis
Cutaneous myiasis is skin infestation by the larvae of certain fly species.
Myi a s i s i nvol ves the l a rva e of two-wi nged (di pterous ) fl i es . Three types of cuta neous i nfes ta ti on exi s t, dependi ng on the s peci es i nvol ved:
Furuncul a r
Wound
Mi gra tory
Other orga ns s ometi mes a re i nvol ved (eg, na s opha rynx, GI tra ct, GU tra ct). Infes ta ti on us ua l l y occurs i n tropi ca l countri es , s o mos t ca s es i n the US
occur i n peopl e who ha ve recentl y a rri ved from endemi c a rea s .
Furuncular myiasis: Ma ny of the common s ources a re known a s bot fl i es . Dermatobia hominis, na ti ve to South a nd Centra l Ameri ca , i s the mos t
common ca us e i n tra vel ers returni ng to the US. Other s peci es i ncl ude Cordylobia anthropophaga (i n s ub-Sa ha ra n Afri ca ), a nd va ri ous Cuterebra s p (i n
tropi ca l Afri ca ). Ma ny of the fl i es do not l a y thei r eggs on huma ns but on other i ns ects (eg, mos qui toes ) or objects (eg, dryi ng l a undry) tha t ma y
conta ct s ki n. Eggs on the s ki n ha tch i nto l a rva e, whi ch burrow i nto the s ki n a nd devel op through s ucces s i ve s ta ges (i ns ta rs ) i nto ma ture l a rva e;
ma ture l a rva e ma y be 1 to 2 cm l ong, dependi ng on the s peci es . If the i nfes ta ti on i s untrea ted, l a rva e eventua l l y emerge from the s ki n a nd drop to
the ground to conti nue thei r l i fe cycl e.
Typi ca l s ymptoms i ncl ude i tchi ng, a s ens a ti on of movement, a nd s ometi mes l a nci na ti ng pa i n. The i ni ti a l l es i on ma y res embl e a n a rthropod bi te
or ba cteri a l furuncl e but ma y be di s ti ngui s hed by the pres ence of a centra l punctum wi th s eros a ngui neous dra i na ge; s ometi mes a s ma l l porti on
of the end of the l a rva i s vi s i bl e.
Beca us e l a rva e requi re a tmos pheri c O2 , occl us i on of the s ki n openi ng ma y ca us e them to depa rt or a t l ea s t come cl os er to the s urfa ce, fa ci l i ta ti ng
ma nua l remova l . The numerous occl us a l methods i ncl ude us e of petrol a tum, na i l pol i s h, ba con, or a pa s te of toba cco. However, l a rva e tha t di e
duri ng occl us i on a re di ffi cul t to remove a nd often tri gger a n i ntens e i nfl a mma tory rea cti on. Other opti ons for remova l i ncl ude ma nua l expres s i on
(i e, s queezi ng) a nd extra cti on through a s ma l l i nci s i on. Ivermecti n, ora l (200 g/kg, one dos e) or topi ca l , ma y ki l l the l a rva e or i nduce mi gra ti on.
Wound myiasis: Open wounds , typi ca l l y i n the homel es s , a l cohol i cs , a nd other peopl e i n poor s oci a l ci rcums ta nces , ma y be i nfes ted by fl y l a rva e,
mos t often from green or bl a ck bl owfl i es . Unl i ke l a rva e of common hous efl i es , mos t a gents of wound myi a s i s i nva de hea l thy a s wel l a s necroti c
ti s s ue. Trea tment i s us ua l l y wi th i rri ga ti on a nd ma nua l debri dement.
Migratory myiasis: The mos t common a gents a re Gasterophilus intestinalis a nd Hypoderma s p. Thes e fl i es typi ca l l y i nfes t hors es a nd ca ttl e; peopl e
a cqui re them vi a conta ct wi th i nfes ted a ni ma l s or, l es s often, vi a di rect egg-l a yi ng on thei r s ki n. La rva e of thes e a gents burrow under the s ki n,
ca us i ng pruri ti c, a dva nci ng l es i ons , whi ch ma y be mi s ta ken for cuta neous l a rva mi gra ns ; however, fl y l a rva e a re much l a rger tha n nema todes , a nd
the l es i ons crea ted by fl y l a rva e l a s t l onger. Trea tment i s s i mi l a r to tha t of furuncul a r myi a s i s .
Delusional Parasitosis
In delusional parasitosis, patients mistakenly believe that they are infested with parasites.
Pa ti ents ha ve a n uns ha ka bl e bel i ef tha t they a re i nfes ted wi th i ns ects , worms , mi tes , l i ce, or other orga ni s ms . They often provi de vi vi d
des cri pti ons of how the orga ni s ms enter thei r s ki n a nd move a round thei r bodi es , a nd bri ng s a mpl es of ha i r, s ki n, a nd debri s s uch a s dri ed s ca bs ,
dus t, a nd l i nt on s l i des or i n conta i ners (the ma tchbox s i gn) to prove tha t the i nfes ta ti on i s rea l . The condi ti on i s cons i dered a hypochondri a ca l
ps ychos i s , but the ca us e i s unknown.

Di a gnos i s i s s us pected by hi s tory. Work-up requi res rul i ng out true i nfes ta ti ons a nd other phys i ol ogi c di s ea s e by phys i ca l exa mi na ti on a nd
judi ci ous tes ti ng, s uch a s s ki n s cra pi ngs a nd CBC.
Trea tment i s wi th a nti ps ychoti c drugs (s ee p. 1562). Typi ca l l y, the pa ti ent s eeks confi rma ti on tha t the drug trea ts the i nfes ta ti on i ts el f, a nd a ny
s ugges ti on tha t the trea tment i s for s omethi ng el s e i s met wi th res i s ta nce a nd/or rejecti on. Thus , effecti ve trea tment often requi res di pl oma cy
a nd a del i ca te ba l a nce between offeri ng proper trea tment a nd res pecti ng the pa ti ent's ri ght to know.
Lice
(Pedi cul os i s )
Lice can infect the scalp, body, pubis, and eyelashes. Head lice are transmitted by close contact; body lice, in cramped, crowded conditions; and pubic lice, by
sexual contact. Symptoms, signs, diagnosis, and treatment differ by location of infestation.
Li ce a re wi ngl es s , bl ood-s ucki ng i ns ects tha t i nfes t the hea d (Pediculus humanus va r. capitis), body (P. humanus va r. corporis), or pubi s (Phthirus pubis).
The 3 ki nds of l i ce di ffer s ubs ta nti a l l y i n morphol ogy a nd cl i ni ca l fea tures . Hea d l i ce a nd pubi c l i ce l i ve di rectl y on the hos t; body l i ce l i ve i n
ga rments . Al l types occur worl dwi de.
Head lice: Hea d l i ce a re mos t common i n gi rl s a ged 5 to 11 but ca n a ffect a l mos t a nyone; i nfes ta ti ons a re ra re i n bl a cks . Hea d l i ce a re ea s i l y
tra ns mi tted from pers on to pers on wi th cl os e conta ct (a s occurs wi thi n hous ehol ds a nd cl a s s rooms ) a nd ma y be ejected from ha i r by s ta ti c
el ectri ci ty or wi nd; tra ns mi s s i on by thes e routes (or by s ha ri ng of combs , brus hes , a nd ha ts ) i s l i kel y but unproven. There i s no a s s oci a ti on
between hea d l i ce a nd poor hygi ene or l ow s oci oeconomi c s ta tus .
Infes ta ti on typi ca l l y i nvol ves the ha i r a nd s ca l p, but the eyebrows , eyel a s hes , a nd bea rd ma y be i nvol ved a s wel l . Acti ve i nfecti on us ua l l y i nvol ves
20 l i ce a nd ca us es s evere pruri tus . Exa mi na ti on i s mos t often norma l but ma y revea l s ca l p excori a ti ons a nd pos teri or cervi ca l a denopa thy.
Di a gnos i s depends on demons tra ti on of l i vi ng l i ce. Li ce a re detected by a thorough combi ng-through of wet ha i r from the s ca l p wi th a fi ne-tooth
detecti on comb; l i ce a re us ua l l y found a t the ba ck of the hea d or behi nd the ea rs . Ni ts a re ovoi d, gra yi s h whi te eggs fi xed to the ba s e of ha i r
s ha fts (s ee
Pl a te 38). Ea ch a dul t fema l e l ous e l a ys 3 to 5 eggs /da y, s o ni ts typi ca l l y va s tl y outnumber l i ce a nd a re not a mea s ure of s everi ty of i nfes ta ti on.
Trea tment i s outl i ned i n
Ta bl e 83-1. Drug res i s ta nce i s common a nd s houl d be ma na ged wi th us e of ora l i vermecti n a nd by a ttempti ng to rota te pedi cul i ci des . Termi na ti on
of l i ve (vi a bl e) ni ts i s i mporta nt i n preventi ng rei nfes ta ti on; l i ve ni ts fl uores ce on i l l umi na ti on wi th a Wood's l a mp. Mos t pedi cul i ci des a l s o ki l l
ni ts . Dea d ni ts rema i n a fter s ucces s ful trea tment a nd do not s i gni fy a cti ve i nfecti on; they do not ha ve to be removed. Ni ts grow a wa y from the
s ca l p wi th ti me; the a bs ence of ni ts l es s tha n one fourth of a n i nch from the s ca l p rul es out current a cti ve i nfecti on. Hot a i r ha s been s hown to ki l l
> 88% of eggs but ha s been va ri a bl y effecti ve i n ki l l i ng ha tched l i ce. Thi rty mi nutes of hot a i r, s l i ghtl y cool er tha n a bl ow dri er, ma y be a n effecti ve
a djuncti ve mea s ure to trea t hea d l i ce.
Controvers y s urrounds the need to cl ea n the pers ona l i tems of peopl e wi th l i ce or ni ts a nd the need to excl ude chi l dren wi th hea d l i ce or ni ts from
s chool ; there a re no concl us i ve da ta s upporti ng ei ther a pproa ch.
Body lice: Body l i ce pri ma ri l y l i ve on beddi ng a nd cl othi ng, not peopl e, a nd a re mos t frequentl y found i n cra mped, crowded condi ti ons (eg, mi l i ta ry
ba rra cks ) a nd i n peopl e of l ow s oci oeconomi c s ta tus . Tra ns mi s s i on i s by s ha ri ng of conta mi na ted cl othi ng a nd beddi ng. Body l i ce a re i mporta nt
vectors of epi demi c typhus , trench fever, a nd rel a ps i ng fever.
Body l i ce ca us e pruri tus ; s i gns a re s ma l l red puncta ca us ed by bi tes , us ua l l y a s s oci a ted wi th l i nea r s cra tch ma rks , urti ca ri a , or s uperfi ci a l
ba cteri a l i nfecti on. Thes e fi ndi ngs a re es peci a l l y common on the s houl ders , buttocks , a nd a bdomen. Ni ts ma y be pres ent on body ha i rs .
Di a gnos i s i s by demons tra ti on of l i ce a nd ni ts i n cl othi ng, es peci a l l y a t the s ea ms .
Pri ma ry trea tment i s thorough cl ea ni ng or repl a cement of cl othi ng a nd beddi ng, whi ch i s often di ffi cul t beca us e a ffected peopl e often ha ve few
res ources a nd l i ttl e control over thei r envi ronment.
[Table 83-1. Trea tment Opti ons for Sca bi es a nd Li ce]
Pubic lice: Pubi c l i ce ("cra bs ") a re s exua l l y tra ns mi tted i n a dol es cents a nd a dul ts a nd ma y be tra ns mi tted to chi l dren by cl os e pa renta l conta ct.
They ma y a l s o be tra ns mi tted by fomi tes (towel s , beddi ng, cl othi ng). They mos t commonl y i nfes t pubi c a nd peri a na l ha i rs but ma y s prea d to
thi ghs , trunk, a nd fa ci a l ha i r (bea rd, mus ta che, a nd, i n chi l dren, eyel a s hes ).
Pubi c l i ce ca us e pruri tus . Phys i ca l s i gns a re few, but s ome pa ti ents ha ve excori a ti ons a nd regi ona l l ympha denopa thy a nd/or l ympha deni ti s . Pa l e,
bl ui s h gra y s ki n ma cul es (ma cul a e ca erul ea e) on the trunk, buttocks , a nd thi ghs a re ca us ed by a nti coa gul a nt a cti vi ty of l ous e s a l i va whi l e feedi ng;
they a re unus ua l but cha ra cteri s ti c of i nfes ta ti on. Eyel a s h i nfes ta ti on ma ni fes ts a s eye i tchi ng, burni ng, a nd i rri ta ti on.
Di a gnos i s i s by demons tra ti on of ni ts a nd/or l i vi ng l i ce by cl os e i ns pecti on (Wood's l i ght) or mi cros copi c a na l ys i s . A s upporti ng s i gn of i nfes ta ti on
i s s ca tteri ng of da rk brown s pecks (l ous e excreta ) on s ki n or underga rments .
Trea tment i s outl i ned i n Ta bl e 83-1. Trea tment of eyel i d a nd eyel a s h i nfes ta ti on i s often di ffi cul t a nd i nvol ves us e of petrol a tum, phys os ti gmi ne
oi ntment, ora l i vermecti n, or phys i ca l remova l of l i ce wi th forceps . Sex pa rtners s houl d a l s o be trea ted.
Scabies
Scabies is an infestation of the skin with the mite Sarcoptes scabiei. Scabies causes intensely pruritic lesions with erythematous papules and burrows in web
spaces, wrists, waistline, and genitals. Diagnosis is based on examination and scrapings. Treatment is with topical scabicides or, rarely, oral ivermectin.
Etiology
Sca bi es i s ca us ed by the mi te Sarcoptes scabiei va r. hominis, a n obl i ga te huma n pa ra s i te tha t l i ves i n burrowed tunnel s i n the s tra tum corneum.
Sca bi es i s ea s i l y tra ns mi tted from pers on to pers on through phys i ca l conta ct; a ni ma l a nd fomi te tra ns mi s s i on proba bl y a l s o occurs . The pri ma ry
ri s k fa ctor i s crowded condi ti ons (a s i n s chool s , s hel ters , ba rra cks , a nd s ome hous ehol ds ); there i s no cl ea r a s s oci a ti on wi th poor hygi ene. For
unknown rea s ons , crus ted s ca bi es i s more common i n i mmunos uppres s ed pa ti ents (eg, thos e wi th HIV i nfecti on, hema tol ogi c ca ncer, chroni c
corti cos teroi d or other i mmunos uppres s a nt us e), pa ti ents wi th s evere phys i ca l di s a bi l i ti es or i ntel l ectua l di s a bi l i ty, a nd Aus tra l i a n Abori gi nes .
Infes ta ti ons occur worl dwi de. Pa ti ents i n wa rm cl i ma tes devel op s ma l l erythema tous pa pul es wi th few burrows . Severi ty i s rel a ted to the
pa ti ent's i mmune s ta tus , not geogra phy.
Symptoms and Signs
The pri ma ry s ymptom i s i ntens e pruri tus , cl a s s i ca l l y wors e a t ni ght, a l though tha t ti mi ng i s not s peci fi c to s ca bi es .
Classic scabies: Erythema tous pa pul es i ni ti a l l y a ppea r i n fi nger web s pa ces , fl exor s urfa ces of the wri s t a nd el bow, a xi l l a ry fol ds , a l ong the bel t
l i ne, or on the l ower buttocks . Pa pul es ca n s prea d to a ny a rea of the body, i ncl udi ng the brea s ts a nd peni s . The fa ce rema i ns uni nvol ved i n a dul ts .
Burrows a re pa thognomoni c for di s ea s e, ma ni fes ti ng a s fi ne, wa vy, a nd s l i ghtl y s ca l y l i nes s evera l mm to 1 cm l ong. A ti ny da rk pa pul ethe mi te
i s often vi s i bl e a t one end.
Si gns of cl a s s i c s ca bi es ma y be a typi ca l . In bl a cks a nd other peopl e wi th da rk s ki n, s ca bi es ca n ma ni fes t a s gra nul oma tous nodul es . In i nfa nts ,
the pa l ms , s ol es , fa ce, a nd s ca l p ma y be i nvol ved, es peci a l l y i n the pos teri or a uri cul a r fol ds . In el derl y pa ti ents , s ca bi es ca n ca us e i ntens e
pruri tus wi th s ubtl e s ki n fi ndi ngs , ma ki ng i t a cha l l enge to di a gnos e. In i mmunocompromi s ed pa ti ents , there ma y be wi des prea d nonpruri ti c
s ca l i ng (pa rti cul a rl y on the pa l ms a nd s ol es i n a dul ts a nd on the s ca l p i n chi l dren).
Other forms: Crus ted (Norwegi a n) s ca bi es i s due to a n i mpa i red hos t i mmune res pons e, a l l owi ng mi tes to prol i fera te a nd number i n the mi l l i ons .
Nodul a r s ca bi es i s more common i n i nfa nts a nd young chi l dren a nd ma y be due to hypers ens i ti vi ty to reta i ned orga ni s ms . Bul l ous s ca bi es occurs
more commonl y i n chi l dren. When i t occurs i n the el derl y, i t ca n mi mi c bul l ous pemphi goi d, res ul ti ng i n a del a y i n di a gnos i s . Sca l p s ca bi es occurs
i n i nfa nts a nd i mmunocompromi s ed peopl e a nd ca n mi mi c derma ti ti s , pa rti cul a rl y a topi c or s eborrhei c derma ti ti s . Sca bi es i ncogni to i s a
wi des prea d a typi ca l form res ul ti ng from a ppl i ca ti on of topi ca l corti cos teroi ds .
Diagnosis
Burrow s cra pi ngs
Di a gnos i s i s s us pected by phys i ca l fi ndi ngs , es peci a l l y burrows , a nd confi rmed by mi tes , ova , or feca l pel l ets on mi cros copi c exa mi na ti on of
burrow s cra pi ngs . Scra pi ngs s houl d be obta i ned by pl a ci ng gl ycerol , mi nera l oi l , or i mmers i on oi l over a burrow or pa pul e (to prevent di s pers i on of
mi tes a nd ma teri a l duri ng s cra pi ng), whi ch i s then unroofed wi th the edge of a s ca l pel . The ma teri a l i s then pl a ced on a s l i de a nd covered wi th a
covers l i p; pota s s i um hydroxi de s houl d be a voi ded beca us e i t di s s ol ves feca l pel l ets .
Treatment
Topi ca l permethri n or l i nda ne
Someti mes ora l i vermecti n
Pri ma ry trea tment i s topi ca l or ora l s ca bi ci des (s ee Ta bl e 83-1). Permethri n i s the 1s t-l i ne topi ca l drug.
Ol der chi l dren a nd a dul ts s houl d a ppl y permethri n or l i nda ne to the enti re body from the neck down a nd wa s h i t off a fter 8 to 14 h. Trea tments
s houl d be repea ted i n 7 da ys .
For i nfa nts a nd young chi l dren, permethri n s houl d be a ppl i ed to the hea d a nd neck, a voi di ng peri orbi ta l a nd peri ora l regi ons . Speci a l a ttenti on
s houl d be gi ven to i ntertri gi nous a rea s , fi ngerna i l s , toena i l s , a nd the umbi l i cus . Mi ttens on i nfa nts ca n keep permethri n out of the mouth.
Li nda ne i s not recommended i n chi l dren < 2 yr a nd i n pa ti ents wi th a s ei zure di s order beca us e of potenti a l neurotoxi ci ty.
Preci pi ta ted s ul fur 6 to 10% i n petrol a tum, a ppl i ed for 24 h for 3 cons ecuti ve da ys , i s s a fe a nd effecti ve.
Ivermecti n i s i ndi ca ted for pa ti ents who do not res pond to topi ca l trea tment, a re una bl e to a dhere to topi ca l regi mens , or a re
i mmunocompromi s ed wi th Norwegi a n s ca bi es . Ivermecti n ha s been us ed wi th s ucces s i n epi demi cs i nvol vi ng cl os e conta cts , s uch a s nurs i ng
homes .
Cl os e conta cts s houl d a l s o be trea ted, a nd pers ona l i tems (eg, towel s , cl othi ng, beddi ng) s houl d be wa s hed or i s ol a ted for a t l ea s t 3 da ys .
Pruri tus ca n be trea ted wi th corti cos teroi d oi ntments a nd/or ora l a nti hi s ta mi nes (eg, hydroxyzi ne 25 mg po qi d). Seconda ry i nfecti on s houl d be
cons i dered i n pa ti ents wi th weepi ng, yel l ow-crus ted l es i ons a nd trea ted wi th the a ppropri a te s ys temi c or topi ca l a nti s ta phyl ococca l or
a nti s treptococca l a nti bi oti c.
Symptoms a nd l es i ons ta ke up to 3 wk to res ol ve des pi te ki l l i ng of the mi tes , ma ki ng fa i l ed trea tment due to res i s ta nce, poor penetra ti on,
i ncompl etel y a ppl i ed thera py, rei nfecti on, or nodul a r s ca bi es di ffi cul t to recogni ze. Ski n s cra pi ngs ca n be done peri odi ca l l y to check for pers i s tent
s ca bi es .
Chapter 84. Viral Skin Diseases

Introduction
Ma ny s ys temi c vi ra l i nfecti ons ca us e s ki n l es i ons . Mol l us cum conta gi os um a nd wa rts a re the 2 mos t common pri ma ry vi ra l s ki n di s ea s es wi thout
s ys temi c ma ni fes ta ti ons . Herpes s i mpl ex vi rus i nfecti on i s di s cus s ed on p. 1417.
Molluscum Contagiosum
Molluscum contagiosum is clusters of smooth, waxy, or pearly umbilicated papules 1 to 5 mm in diameter caused by molluscum contagiosum virus, a poxvirus.
Mol l us cum conta gi os um vi rus commonl y ca us es a l oca l i zed chroni c i nfecti on. Tra ns mi s s i on i s by di rect conta ct; s prea d occurs by a utoi nocul a ti on
a nd vi a fomi tes (eg, towel s , ba th s ponges ).
Symptoms and Signs
Mol l us cum conta gi os um ca n a ppea r a nywhere on the s ki n except the pa l ms a nd s ol es . Les i ons cons i s t of cl us ters of fl es h-col ored pa pul es , whi ch
occur mos t commonl y on the fa ce, trunk, a nd extremi ti es i n chi l dren a nd on the pubi s , peni s , or vul va i n a dul ts . Les i ons ma y grow to 10 to 15 mm i n
di a meter, es peci a l l y a mong pa ti ents wi th HIV i nfecti on a nd other i mmunocompromi s ed pa ti ents . Les i ons a re us ua l l y not pruri ti c or pa i nful a nd
ma y be di s covered onl y coi nci denta l l y duri ng a phys i ca l exa mi na ti on. However, the l es i ons ca n become i nfl a med a nd i tchy a s the body fi ghts off
the vi rus .
Diagnosis
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce; hema toxyl i n a nd eos i n s ta i ni ng of expres s ed fl ui d demons tra tes i ncl us i on bodi es but i s neces s a ry
onl y when di a gnos i s i s uncerta i n. Di fferenti a l di a gnos i s i ncl udes fol l i cul i ti s , mi l i a , a nd wa rts (for l es i ons < 2 mm) a nd juveni l e xa nthogra nul oma
a nd Spi tz nevus (for l es i ons > 2 mm).
Treatment
Curetta ge, cryos urgery, l a s er thera py, or el ectroca utery
Topi ca l i rri ta nts (eg, tri chl oroa ceti c a ci d, ca ntha ri di n, treti noi n, ta za rotene), i mi qui mod, or both
Someti mes combi na ti on thera pi es
Mos t l es i ons s ponta neous l y regres s i n 1 to 2 yr, but they ca n rema i n for 2 to 3 yr. Trea tment i s i ndi ca ted for cos meti c rea s ons or for preventi on of
s exua l s prea d. Opti ons i ncl ude curetta ge, cryos urgery, l a s er thera py, el ectroca utery, tri chl oroa ceti c a ci d (25 to 40% s ol uti on), ca ntha ri di n, treti noi n,
ta za rotene a nd i mi qui mod 5% crea m. Es peci a l l y i n chi l dren, trea tments tha t ca us e mi ni ma l pa i n (eg, treti noi n, i mi qui mod, ta za rotene,
ca ntha ri di n) a re us ed fi rs t. Curetta ge or l i qui d ni trogen ca n be us ed a fter a ppl i ca ti on of a topi ca l a nes theti c s uch a s EMLA (eutecti c mi xture of
l oca l a nes theti cs ) or 4% l i doca i ne crea m. EMLA crea m mus t be a ppl i ed judi ci ous l y beca us e i t ca n ca us e s ys temi c toxi ci ty, es peci a l l y i n chi l dren. In
a dul ts , curetta ge i s very effecti ve but pa i nful . Derma tol ogi s ts often us e combi na ti on thera py s uch a s l i qui d ni trogen or ca ntha ri di n i n the offi ce
a nd i mi qui mod crea m a t home. Thi s form of thera py i s typi ca l l y s ucces s ful , but res ol uti on often ta kes 1 to 2 mo i n s ome pa ti ents .
Nonderma tol ogi s ts s houl d feel comforta bl e us i ng i mi qui mod crea m. The crea m i s a ppl i ed a t ni ght, 1 drop to ea ch mol l us cum l es i on a nd rubbed
i n wel l , unti l the crea m turns cl ea r. The a rea i s wa s hed wi th s oa p a nd wa ter. The crea m ca n be a ppl i ed 3 to 7 ti mes /wk. Mol l us cum l es i ons wi thi n
the orbi ta l ri m s houl d not be trea ted, a nd thos e i n the geni ta l regi on ca n ea s i l y become i rri ta ted. Les i ons s houl d be trea ted unti l they devel op a
s ca nt a mount of rednes s ; trea tment i s then wi thhel d to a voi d weepi ng a nd crus ti ng.
Ca ntha ri di n i s s a fe a nd effecti ve but ca n ca us e bl i s teri ng. Ca ntha ri di n i s a ppl i ed i n 1 s ma l l drop di rectl y to the mol l us cum l es i on. Area s tha t
pa ti ents (es peci a l l y chi l dren) ma y rub a re covered wi th a ba nda ge beca us e conta ct wi th the fi ngers s houl d be a voi ded. Ca ntha ri di n s houl d not be
a ppl i ed to the fa ce or nea r the eyes beca us e bl i s teri ng i s unpredi cta bl e. If ca ntha ri di n comes i nto conta ct wi th the cornea , i t ca n s ca r the cornea .
Ca ntha ri di n s houl d be wa s hed off wi th s oa p a nd wa ter i n 6 h. Pa rents s houl d be wa rned a bout bl i s teri ng i f thei r chi l dren a re pres cri bed thi s drug.
Warts
(Verruca e Vul ga ri s )
Warts are common, benign epidermal lesions caused by human papillomavirus infection. They can appear anywhere on the body in a variety of morphologies.
Diagnosis is by examination. Warts are usually self limited but may be treated by excision, cautery, cryotherapy, liquid nitrogen, and topical or injected agents.
Wa rts a re a l mos t uni vers a l i n the popul a ti on; they a ffect a l l a ges but a re mos t common a mong chi l dren a nd a re uncommon a mong the el derl y.
Etiology
Wa rts a re ca us ed by huma n pa pi l l oma vi rus (HPV) i nfecti on; there a re over 100 HPV s ubtypes . Tra uma a nd ma cera ti on fa ci l i ta te i ni ti a l epi derma l
i nocul a ti on. Sprea d ma y then occur by a utoi nocul a ti on. Loca l a nd s ys temi c i mmune fa ctors a ppea r to i nfl uence s prea d; i mmunos uppres s ed
pa ti ents (es peci a l l y thos e wi th HIV i nfecti on or a rena l tra ns pl a nt) a re a t pa rti cul a r ri s k of devel opi ng genera l i zed l es i ons tha t a re di ffi cul t to
trea t. Humora l i mmuni ty provi des res i s ta nce to HPV i nfecti on; cel l ul a r i mmuni ty hel ps es ta bl i s hed i nfecti on to regres s .
Symptoms and Signs
Wa rts a re na med by thei r cl i ni ca l a ppea ra nce a nd l oca ti on; di fferent forms a re l i nked to di fferent HPV types (for unus ua l ma ni fes ta ti ons , s ee
Ta bl e 84-1).
Common warts: Common wa rts (verruca e vul ga ri s ) a re ca us ed by HPV 1, 2, 4, 27, a nd 29. They a re us ua l l y a s ymptoma ti c but s ometi mes ca us e mi l d
pa i n, es peci a l l y when they a re l oca ted on a wei ght-bea ri ng s urfa ce (eg, bottom of the feet). They a re s ha rpl y dema rca ted, rough, round or
i rregul a r, fi rm, a nd l i ght gra y, yel l ow, brown, or gra y-bl a ck nodul es 2 to 10 mm i n di a meter. They a ppea r mos t often on s i tes s ubject to tra uma (eg,
fi ngers , el bows , knees , fa ce) but ma y s prea d el s ewhere. Va ri a nts of unus ua l s ha pe (eg, peduncul a ted or res embl i ng a ca ul i fl ower) a ppea r mos t
frequentl y on the hea d a nd neck, es peci a l l y the s ca l p a nd bea rd a rea .
Filiform warts: Thes e wa rts a re l ong, na rrow, frondl i ke growths , us ua l l y l oca ted on the eyel i ds , fa ce, neck, or l i ps . They a re us ua l l y a s ymptoma ti c.
Thi s morphol ogi ca l l y di s ti nct va ri a nt of the common wa rt i s beni gn a nd ea s y to trea t.
Flat warts: Fl a t wa rts , ca us ed by HPV 3, 10, 28, a nd 49, a re s mooth, fl a t-topped, yel l ow-brown pa pul es , mos t often l oca ted on the fa ce a nd a l ong
s cra tch ma rks ; they a re more common a mong chi l dren a nd young a dul ts a nd devel op by a utoi nocul a ti on. They genera l l y ca us e no s ymptoms but
ca n be di ffi cul t to trea t.
Palmar and plantar warts: Thes e wa rts , ca us ed by HPV 1, occur on the pa l ms a nd s ol es ; they a re fl a ttened by pres s ure a nd s urrounded by corni fi ed
epi thel i um (s ee
Pl a te 55). They a re
[Table 84-1. Wa rt Va ri a nts ]
often tender a nd ca n ma ke wa l ki ng a nd s ta ndi ng uncomforta bl e. They ca n be di s ti ngui s hed from corns a nd ca l l us es by thei r tendency to pi npoi nt
bl eedi ng when the s urfa ce i s pa red a wa y. Cl a s s i ca l l y, wa rts hurt wi th s i de-to-s i de pres s ure, a nd ca l l us es hurt wi th di rect pres s ure; i n rea l i ty, thi s
i s not a rel i a bl e s i gn.
Mosaic warts: Mos a i c wa rts a re pl a ques formed by the coa l es cence of myri a d s ma l l er, cl os el y s et pl a nta r wa rts . As wi th other pl a nta r wa rts , they
a re often tender.
Periungual warts: Thes e wa rts a ppea r a s thi ckened, fi s s ured ca ul i fl ower-l i ke s ki n a round the na i l pl a te. Pa ti ents frequentl y l os e the cuti cl e a nd a re
s us cepti bl e to pa ronychi a . Peri ungua l wa rts a re more common a mong pa ti ents who bi te thei r na i l s .
Genital warts: Geni ta l wa rts (s ee p. 1470) ma ni fes t a s di s crete fl a t to broa d-ba s ed s mooth to vel vety pa pul es on the peri nea l , peri recta l , l a bi a l ,
a nd peni l e a rea s . Infecti on wi th hi gh-ri s k HPV types (mos t nota bl y types 16 a nd 18) i s the ma i n ca us e of cervi ca l ca ncer. Thes e wa rts a re us ua l l y
a s ymptoma ti c.
Diagnosis
Ra rel y bi ops y
Di a gnos i s i s ba s ed on cl i ni ca l a ppea ra nce; bi ops y i s ra rel y needed. A ca rdi na l s i gn of wa rts i s the a bs ence of s ki n l i nes cros s i ng thei r s urfa ce a nd
the pres ence of pi npoi nt bl a ck dots (thrombos ed ca pi l l a ri es ) or bl eedi ng when wa rts a re s ha ved. Di fferenti a l di a gnos i s i ncl udes corns (cl a vi ),
l i chen pl a nus , s eborrhei c kera tos i s , s ki n ta gs , a nd s qua mous cel l ca rci noma s . DNA typi ng i s a va i l a bl e i n s ome medi ca l centers but i s genera l l y
not needed.
Prognosis
Ma ny wa rts regres s s ponta neous l y; others pers i s t for yea rs a nd recur a t the s a me or di fferent s i tes , even wi th trea tment. Fa ctors i nfl uenci ng
recurrence a ppea r to be rel a ted to the pa ti ent's overa l l i mmune s ta tus a s wel l a s l oca l fa ctors . Pa ti ents who s ubject thems el ves to l oca l tra uma
(eg, a thl etes , mecha ni cs , butchers ) ma y ha ve reca l ci tra nt a nd recurrent HPV i nfecti on. Geni ta l HPV i nfecti on ha s ma l i gna nt potenti a l , but
ma l i gna nt tra ns forma ti on i s ra re i n HPV-i nduced s ki n wa rts , except a mong i mmunos uppres s ed pa ti ents .
Treatment
Topi ca l i rri ta nts (eg, s a l i cyl i c a ci d, ca ntha ri di n, podophyl l um res i n)
Des tructi ve methods (eg, cryos urgery, el ectroca utery, curetta ge, exci s i on, l a s er)
Trea tment i s a i med a t el i ci ti ng a n i mmune res pons e to HPV. In mos t i ns ta nces , thi s res pons e i s a chi eved by a ppl yi ng a n i rri ta nt (eg, s a l i cyl i c a ci d
[SCA], tri chl oroa ceti c a ci d, 5-fl uoroura ci l , podophyl l um res i n, treti noi n, ca ntha ri di n).
Thes e compounds ca n be us ed i n combi na ti on or wi th a des tructi ve method (eg, cryos urgery, el ectroca utery, curetta ge, exci s i on, l a s er). Di rect
a nti vi ra l effects ca n be a chi eved wi th bl eomyci n a nd i nterferon a l fa -2b, but thes e trea tments a re res erved for the mos t reca l ci tra nt wa rts . Topi ca l
i mi qui mod 5% crea m i nduces s ki n cel l s to l oca l l y produce a nti vi ra l cytoki nes . Topi ca l ci dofovi r, HPV va cci nes , a nd conta ct i mmunothera py (eg,
s qua ri c a ci d di butyl es ter a nd Candida a l l ergen) ha ve been us ed to trea t wa rts . Ora l trea tments i ncl ude ci meti di ne, i s otreti noi n, a nd ora l zi nc. In
mos t i ns ta nces , moda l i ti es s houl d be combi ned to i ncrea s e the l i kel i hood of s ucces s .
Common warts: In i mmunocompetent pa ti ents , common wa rts us ua l l y s ponta neous l y regres s wi thi n 2 to 4 yr, but s ome l i nger for ma ny yea rs .
Numerous trea tments a re a va i l a bl e. Des tructi ve methods i ncl ude
El ectroca utery
Cryos urgery wi th l i qui d ni trogen
SCA prepa ra ti ons

Whi ch method i s us ed depends on the l oca ti on a nd s everi ty of i nvol vement. For exa mpl e, 17% l i qui d SCA ca n be us ed on the fi ngers , a nd 40%
pl a s ter SCA ca n be us ed on the s ol es .
The mos t common topi ca l a gent to be us ed i s SCA. SCA i s a va i l a bl e i n a l i qui d, pl a s ter, or i mpregna ted wi thi n ta pe. Pa ti ents a ppl y SCA to thei r
wa rts a t ni ght a nd l ea ve on for 8 to 48 h dependi ng on the s i te.
Ca ntha ri di n ca n be us ed a l one or i n combi na ti on (1%) wi th SCA (30%) a nd podophyl l um (5%) i n a col l odi on ba s e. Ca ntha ri di n a l one i s removed
wi th s oa p a nd wa ter a fter 6 h; ca ntha ri di n wi th SCA or podophyl l um i s removed i n 2 h. The l onger thes e a gents a re l eft i n conta ct wi th the s ki n, the
more bri s k the bl i s teri ng res pons e.
Cryos urgery i s pa i nful but extremel y effecti ve. El ectrodes i cca ti on wi th curetta ge, l a s er s urgery, or both i s effecti ve a nd i ndi ca ted for i s ol a ted
l es i ons but ma y ca us e s ca rri ng. Recurrent or new wa rts occur i n a bout 35% of pa ti ents wi thi n 1 yr, s o methods tha t s ca r s houl d be a voi ded a s much
a s pos s i bl e.
Filiform warts: Trea tment i s remova l wi th s ca l pel , s ci s s ors , curetta ge, or l i qui d ni trogen. Li qui d ni trogen s houl d be a ppl i ed s o tha t up to 2 mm of
s ki n s urroundi ng the wa rt turns whi te. Da ma ge to the s ki n occurs when the s ki n tha ws , whi ch us ua l l y ta kes 10 to 20 s ec. Bl i s ters ca n occur 24 to 48
h a fter trea tment wi th l i qui d ni trogen. Ca re mus t be ta ken when trea ti ng cos meti ca l l y s ens i ti ve s i tes , s uch a s the fa ce a nd neck, beca us e
hypopi gmenta ti on frequentl y occurs a fter trea tment wi th l i qui d ni trogen. Pa ti ents wi th da rkl y pi gmented s ki n ca n devel op perma nent
depi gmenta ti on.
Flat warts: Trea tment i s da i l y treti noi n (reti noi c a ci d 0.05% crea m). If peel i ng i s not s uffi ci ent for wa rt remova l , a nother i rri ta nt (eg, 5% benzoyl
peroxi de) or 5% SCA crea m ca n be a ppl i ed s equenti a l l y wi th treti noi n. Imi qui mod 5% crea m ca n be us ed a l one or i n combi na ti on wi th topi ca l
drugs or des tructi ve mea s ures . Topi ca l 5-fl uoroura ci l (1% or 5% crea m) ca n a l s o be us ed. Sponta neous res ol uti on ma y fol l ow unprovoked
i nfl a mma ti on of the l es i ons ; however, fl a t wa rts a re frequentl y reca l ci tra nt to trea tment.
Plantar warts: Trea tment i s vi gorous ma cera ti on wi th 40% SCA pl a s ter kept i n pl a ce for s evera l da ys . The wa rt i s debri ded whi l e da mp a nd s oft, then
des troyed by freezi ng or us i ng ca us ti cs (eg, 30 to 70% tri chl oroa ceti c a ci d). Other des tructi ve trea tments (eg, CO2 l a s er, pul s ed-dye l a s er, va ri ous
a ci ds ) a re often effecti ve. Duct ta pe i s effecti ve when a ppl i ed for 6-da y i nterva l s , fol l owed by debri dement of ma cera ted ti s s ue.
Periungual warts: Combi na ti on thera py wi th l i qui d ni trogen a nd i mi qui mod 5% crea m, treti noi n, or SCA i s effecti ve.
Recalcitrant warts: Severa l methods whos e l ong-term va l ue a nd ri s ks a re not ful l y known a re a va i l a bl e for reca l ci tra nt wa rts . Intra l es i ona l i njecti on
of s ma l l a mounts of a 0.1% s ol uti on of bl eomyci n i n s a l i ne often cures s tubborn pl a nta r a nd peri ungua l wa rts . However, Ra yna ud's s yndrome or
va s cul a r da ma ge ma y devel op i n i njected di gi ts , es peci a l l y when the drug i s i njected a t the ba s e of the di gi t, s o ca uti on i s wa rra nted. Interferon,
es peci a l l y i nterferon a l fa , a dmi ni s tered i ntra l es i ona l l y (3 ti mes /wk for 3 to 5 wk) or IM, ha s a l s o cl ea red reca l ci tra nt s ki n a nd geni ta l wa rts .
Extens i ve wa rts s ometi mes i mprove or cl ea r wi th ora l i s otreti noi n or a ci treti n. Ci meti di ne a t dos es up to 800 mg po ti d ha s been us ed wi th s ucces s
but i s more effecti ve when combi ned wi th a nother thera py.
Zoonotic Diseases
Two vi ra l s ki n di s ea s es a re ra rel y tra ns mi tted from a ni ma l s to huma ns .
Contagious ecthyma: Conta gi ous ecthyma (conta gi ous pus tul a r derma ti ti s ) i s ca us ed by orf vi rus , a poxvi rus tha t i nfects rumi na nts (mos t often s heep
a nd goa ts ). Fa rmers , veteri na ri a ns , zoo ca reta kers , a nd others wi th di rect a ni ma l conta ct a re a t ri s k. The cuta neous fi ndi ngs pa s s through 6 s ta ges
tha t together l a s t a bout 1 wk:
Sta ge 1 (pa pul a r): A s i ngl e red edema tous pa pul e on a fi nger (mos t commonl y ri ght i ndex fi nder)
Sta ge 2 (ta rget): A l a rger nodul e wi th a red center s urrounded by a whi te ri ng wi th a red peri phery
Sta ge 3 (a cute): A ra pi dl y growi ng i nfected-l ooki ng tumor
Sta ge 4 (regenera ti ve): A nodul e wi th bl a ck dots covered wi th a thi n tra ns pa rent crus t
Sta ge 5 (pa pi l l oma tous ): A nodul e wi th a s urfa ce s tudded wi th s ma l l projecti ons
Sta ge 6 (regres s i ve): A fl a ttened nodul e wi th a thi ck crus t
Pa ti ents ca n devel op regi ona l a denopa thy, l ympha ngi ti s , a nd fever.
Di a gnos i s i s by hi s tory of conta ct; di fferenti a l di a gnos i s i s extens i ve dependi ng upon the s ta ge of the l es i on. Acute l es i ons mus t be di fferenti a ted
from mi l ker's nodul es , Mycobacterium marinum i nfecti on, a nd other ba cteri a l i nfecti ons ; regres s ed l es i ons mus t be di fferenti a ted from cuta neous
tumors , s uch a s Bowen's di s ea s e or s qua mous cel l ca rci noma . Les i ons s ponta neous l y hea l ; no trea tment i s neces s a ry.
Milker's nodules: Thes e nodul es a re ca us ed by pa ra va cci ni a vi rus , a pa ra poxvi rus tha t ca us es udder l es i ons i n cows . Infecti on requi res di rect
conta ct a nd produces ma cul es tha t progres s to pa pul es , ves i cl es , a nd nodul es . Thi s i nfecti on ha s 6 s ta ges , whi ch a re s i mi l a r to thos e of
conta gi ous ecthyma . Fever a nd l ympha denopa thy a re uncommon. Di a gnos i s i s by hi s tory of conta ct a nd cuta neous fi ndi ngs . Di fferenti a l di a gnos i s
va ri es dependi ng upon morphol ogy but i ncl udes pri ma ry i nocul a ti on TB, s porotri chos i s , a nthra x, a nd tul a remi a . Les i ons hea l s ponta neous l y; no
trea tment i s neces s a ry.
Chapter 85. Pigmentation Disorders

Introduction
Pi gmenta ti on di s orders i nvol ve hypopi gmenta ti on, depi gmenta ti on, or hyperpi gmenta ti on. Area s ma y be foca l or di ffus e.
Focal hypopigmentation i s mos t commonl y a cons equence of
Injury
Infl a mma tory derma tos es (eg, a topi c derma ti ti s , ps ori a s i s )
Burns
Chemi ca l expos ure
Foca l hypopi gmenta ti on or depi gmenta ti on i s a l s o a fea ture of vi ti l i go (whi ch ma y i nvol ve l a rge a rea s of s ki n), l epros y, nutri ti ona l defi ci enci es
(kwa s hi orkor), a nd geneti c condi ti ons (tuberous s cl eros i s , pi eba l di s m, Wa a rdenburg's s yndrome).
Diffuse hypopigmentation i s mos t often ca us ed by
Al bi ni s m
Vi ti l i go
Focal hyperpigmentation typi ca l l y occurs a fter i nfl a mma ti on of va ri ous ca us es , but i t a l s o ma y occur i n pa ti ents wi th a s ys temi c di s order or ca ncer.
Albinism
Albinism (officially called oculocutaneous albinism) is an inherited defect in melanin formation that causes diffuse hypopigmentation of the skin, hair, and eyes;
deficiency of melanin (and hence pigmentary dilution) may be total or partial, but all areas of the skin are involved. Ocular involvement causes strabismus,
nystagmus, and decreased vision. Diagnosis is usually obvious from the skin, but ocular evaluation is necessary. No treatment for the skin involvement is
available other than protection from sunlight.
Pathophysiology
Ocul ocuta neous a l bi ni s m (OCA) i s a group of ra re i nheri ted di s orders i n whi ch a norma l number of mel a nocytes a re pres ent but mel a ni n
producti on i s a bs ent or grea tl y decrea s ed. Cuta neous a nd ocul a r pa thol ogi es (ocul a r a l bi ni s m) a re both pres ent. Ocul a r a l bi ni s m i nvol ves
a bnorma l opti c tra ct CNS devel opment ma ni fes ted by fovea l hypopl a s i a wi th decrea s ed photoreceptors a nd mi s routi ng of opti c chi a s ma l fi bers .
Ocul a r a l bi ni s m ma y occur wi thout cuta neous a bnorma l i ti es .
Mos t ca s es a re a utos oma l reces s i ve; a utos oma l domi na nt i nheri ta nce i s ra re. There a re 4 ma i n geneti c forms :
Type I i s ca us ed by a bs ent (OCA1A; 40% of a l l OCA) or reduced (OCA1B) tyros i na s e a cti vi ty; tyros i na s e ca ta l yzes s evera l s teps i n mel a ni n s ynthes i s .
Type II (50% of a l l OCA) i s ca us ed by muta ti ons i n the P (pi nk-eyed) gene. The functi on of the P protei n i s not yet known. Tyros i na s e a cti vi ty i s
pres ent.
Type III occurs onl y i n peopl e wi th da rk s ki n (s ki n types III to V). It i s ca us ed by muta ti ons i n a tyros i na s e-rel a ted protei n 1 gene whos e product
i s i mporta nt i n eumel a ni n s ynthes i s .
Type IV i s a n extremel y ra re form i n whi ch the geneti c defect i s i n a gene tha t codes a membra ne tra ns porter protei n. Type IV i s the mos t
common form of OCA i n Ja pa n.
In a group of i nheri ted di s ea s es , a cl i ni ca l phenotype of OCA occurs i n conjuncti on wi th bl eedi ng di s orders . In the Herma ns ky-Pudl a k s yndrome,
OCA-l i ke fi ndi ngs occur wi th pl a tel et a bnorma l i ti es a nd a ceroi d-l i pofus ci n l ys os oma l s tora ge di s ea s e. Thi s s yndrome i s ra re except i n peopl e
wi th fa mi l y ori gi n i n Puerto Ri co, where i ts i nci dence i s 1 i n 1800. In the Chedi a k-Hi ga s hi s yndrome, OCA-l i ke fi ndi ngs occur (ha i r i s s i l very gra y),
a nd a decrea s e i n pl a tel et-dens e gra nul es res ul ts i n a bl eedi ng di a thes i s . Pa ti ents ha ve s evere i mmunodefi ci ency due to a bnorma l l ymphocyte
l yti c gra nul es . Progres s i ve neurol ogi c degenera ti on occurs .
Symptoms and Signs
The di fferent geneti c forms ha ve a va ri ety of phenotypes .
Type I (OCA1A) i s cl a s s i c tyros i na s e-nega ti ve a l bi ni s m; s ki n a nd ha i r a re mi l ky whi te, a nd eyes a re bl ue-gra y. Pi gmenta ry di l uti on i n OCA1B ra nges
from obvi ous to s ubtl e.
Type II ha s phenotypes wi th pi gmenta ry di l uti on tha t ra nges from mi ni ma l to modera te. Pi gmented nevi a nd l enti gi nes ma y devel op i f s ki n i s
expos ed to the s un; s ome l enti gi nes become l a rge a nd da rk. Eye col or va ri es grea tl y.
In type III, s ki n i s brown, ha i r i s rufous (reddi s h), a nd eye col or ca n be bl ue or brown.
In type IV, the phenotype i s s i mi l a r to tha t for type II.
Pa ti ents wi th ocul a r i nvol vement ma y ha ve decrea s ed reti na l pi gmenta ti on (s ee
Pl a te 25), l ea di ng to photophobi a . In a ddi ti on, nys ta gmus , s tra bi s mus , reduced vi s ua l a cui ty, a nd l os s of bi nocul a r vi s i on l i kel y res ul t from
defecti ve routi ng of the opti c fi bers .
Diagnosis
Di a gnos i s of a l l types of OCA i s ba s ed on exa mi na ti on of the s ki n. Ea rl y ocul a r exa mi na ti on ma y detect i ri s tra ns l ucency, reduced reti na l
pi gmenta ti on, fovea l hypopl a s i a , reduced vi s ua l a cui ty, a nd ocul a r movement di s orders (s tra bi s mus a nd nys ta gmus ).
Treatment
Sun protecti on
Someti mes s urgi ca l i nterventi on for ocul a r movement di s orders
There i s no trea tment for a l bi ni s m. Pa ti ents a re a t hi gh ri s k of s unburn a nd s ki n ca ncers (es peci a l l y s qua mous cel l ca rci noma ) a nd s houl d a voi d
di rect s unl i ght, us e s ungl a s s es wi th UV fi l tra ti on, wea r protecti ve cl othi ng, a nd us e s uns creen wi th a n SPF of 30 tha t protects a ga i ns t UVA a nd
UVB wa vel engths (s ee p. 673). Some s urgi ca l i nterventi ons ma y l es s en ocul a r movement di s orders .
Vitiligo
Vitiligo is a loss of skin melanocytes that causes areas of skin depigmentation of varying sizes. Cause is unknown, but the condition may be autoimmune; up to
one third of patients have evidence of other autoimmune disease. Diagnosis is often obvious on examination. First-line treatment is topical corticosteroids.
Calcineurin inhibitors (tacrolimus and pimecrolimus) and psoralens plus ultraviolet A are commonly used. For severe widespread pigment loss, depigmentation
(bleaching) of residual patches of normal skin may be done with hydroquinone.
Vi ti l i go a ffects 0.5 to 2% of the popul a ti on.
Etiology
Eti ol ogy i s uncl ea r, but mel a nocytes a re l a cki ng i n a ffected a rea s . It i s both fa mi l i a l (a utos oma l domi na nt, wi th i ncompl ete penetra nce a nd
va ri a bl e expres s i on) a nd a cqui red. Propos ed mecha ni s ms i ncl ude a utoi mmune des tructi on of mel a nocytes , reduced s urvi va l of mel a nocytes , a nd
pri ma ry mel a nocyte defects . Occa s i ona l l y, vi ti l i go occurs a fter a di rect phys i ca l i njury to the s ki n (eg, a s a res pons e to s unburn). Thi s form of
vi ti l i go i s ca l l ed the Koebner phenomenon. Pa ti ents ma y a s s oci a te the ons et of vi ti l i go wi th emoti ona l s tres s .
Some pa ti ents ha ve a nti bodi es to mel a ni n. Up to 30% ha ve other a utoi mmune a nti bodi es (to thyrogl obul i n, a drena l cel l s , a nd pa ri eta l cel l s ) or
cl i ni ca l a utoi mmune endocri nopa thi es (Addi s on's di s ea s e, di a betes mel l i tus , perni ci ous a nemi a , a nd thyroi d dys functi on), l ea di ng to
s pecul a ti on tha t vi ti l i go i s a n a utoi mmune di s ea s e. However, the rel a ti ons hi p i s uncl ea r a nd ma y be coi nci denta l . The s tronges t a s s oci a ti on i s
wi th hyperthyroi di s m (Gra ves ' di s ea s e) a nd hypothyroi di s m (Ha s hi moto's thyroi di ti s ).
Symptoms and Signs
Vi ti l i go i s cha ra cteri zed by depi gmented a rea s (s ee
Pl a te 54), us ua l l y s ha rpl y dema rca ted a nd often s ymmetri c. Depi gmenta ti on ma y be l oca l i zed, i nvol vi ng 1 or 2 s pots or enti re body s egments
(s egmenta l vi ti l i go); ra rel y, i t ma y be genera l i zed, i nvol vi ng mos t of the s ki n s urfa ce (uni vers a l vi ti l i go). However, vi ti l i go mos t commonl y i nvol ves
the fa ce (es peci a l l y a round the ori fi ces ), di gi ts , dors a l ha nds , fl exor wri s ts , el bows , knees , s hi ns , dors a l a nkl es , a rmpi ts , i ngui na l a rea ,
a nogeni ta l a rea , umbi l i cus , a nd ni ppl es . Cos meti c di s fi gurement ca n be es peci a l l y deva s ta ti ng i n da rk-s ki nned pa ti ents . Ha i r i n vi ti l i gi nous a rea s
i s us ua l l y whi te.
Diagnosis
Depi gmented s ki n i s typi ca l l y obvi ous on exa mi na ti on. Ski n l es i ons a re a ccentua ted under Wood's l i ght. Di fferenti a l di a gnos i s i ncl udes
pos ti nfl a mma tory hypopi gmenta ti on, morphea , l epros y, chemi ca l l eukoderma , a nd l eukoderma due to mel a noma . Addi ti ona l tes ti ng for
a utoi mmune endocri ne di s ea s e i s proba bl y unneces s a ry unl es s s ymptoms or s i gns s ugges t a pa rti cul a r di s order.
Treatment
Protecti on of a ffected a rea s from s unl i ght
Topi ca l ca l ci neuri n i nhi bi tors when fa ce or groi n i nvol ved
Someti mes ps ora l en pl us ul tra vi ol et A (PUVA) thera py
Trea tment i s s upporti ve a nd cos meti c. Phys i ci a ns mus t be a wa re of i ndi vi dua l a nd ethni c s ens i bi l i ti es rega rdi ng uni form s ki n col ori ng; the
di s ea s e ca n be ps ychol ogi ca l l y deva s ta ti ng. Al l depi gmented a rea s a re prone to s evere s unburn a nd mus t be protected wi th cl othi ng or s uns creen.
Sma l l , s ca ttered l es i ons ma y be ca moufl a ged wi th ma keup. Fi rs t-l i ne thera py for more extens i ve i nvol vement i s potent topi ca l corti cos teroi ds ,
whi ch ma y ca us e hypopi gmenta ti on or a trophy i n norma l s urroundi ng s ki n. Ca l ci neuri n i nhi bi tors (ta crol i mus a nd pi mecrol i mus ) ma y be
pa rti cul a rl y us eful for trea ti ng a rea s of the s ki n (s uch a s the fa ce a nd groi n) where a dvers e effects of topi ca l corti cos teroi d thera py mos t
commonl y occur. Ora l a nd topi ca l PUVA i s often s ucces s ful , a l though hundreds of trea tment s es s i ons ma y be neces s a ry. Na rrowba nd UVB i s a s
effecti ve a s topi ca l PUVA a nd ha s few a dvers e effects . La s ers ma y be us eful , pa rti cul a rl y for l oca l i zed di s ea s e tha t does not res pond to i ni ti a l
topi ca l thera py.
Surgery i s rea s ona bl e onl y for pa ti ents wi th s ta bl e, l i mi ted di s ea s e when medi ca l thera py ha s fa i l ed. Thera pi es i ncl ude a utol ogous mi crogra fti ng,
s ucti on bl i s ter gra fti ng, a nd ta ttooi ng; ta ttooi ng i s es peci a l l y us eful for di ffi cul t-to-repi gment a rea s s uch a s the ni ppl es , l i ps , a nd fi ngerti ps .
Depi gmenta ti on of una ffected s ki n to a chi eve homogeneous s ki n tone i s pos s i bl e wi th 20% monobenzyl ether of hydroqui none a ppl i ed twi ce
da i l y a nd i s i ndi ca ted onl y when mos t of the s ki n i s i nvol ved a nd the pa ti ent i s prepa red for perma nent pi gment l os s . Thi s trea tment ca n be
extremel y i rri ta ti ng, s o a s ma l l er tes t a rea s houl d be trea ted before wi des prea d us e. Trea tment for 1 yr ma y be requi red.
Hyperpigmentation
Hyperpi gmenta ti on ha s mul ti pl e ca us es a nd ma y be foca l or di ffus e. Mos t ca s es a re due to a n i ncrea s e i n mel a ni n producti on a nd depos i ti on.
Foca l hyperpi gmenta ti on i s mos t often pos ti nfl a mma tory i n na ture, occurri ng a fter i njury (eg, cuts a nd burns ) or other ca us es of i nfl a mma ti on (eg,
a cne, l upus ). Foca l l i nea r hyperpi gmenta ti on i s commonl y due to phytophotoderma ti ti s , whi ch res ul ts from ul tra vi ol et l i ght combi ned wi th
furocouma ri ns i n l i mes , cel ery, a nd other pl a nts .
Hyperpi gmenta ti on a l s o ha s s ys temi c a nd neopl a s ti c ca us es .
Melasma (chloasma): Mel a s ma cons i s ts of da rk brown, s ha rpl y ma rgi na ted, roughl y s ymmetri c pa tches of hyperpi gmenta ti on on the fa ce (us ua l l y on
the forehea d, templ es , a nd cheeks ). It occurs pri ma ri l y i n pregna nt women (mel a s ma gra vi da rum, or the ma s k of pregna ncy) a nd i n women ta ki ng
ora l contra cepti ves . Ten percent of ca s es occur i n nonpregna nt women a nd da rk-s ki nned men. Mel a s ma i s more preva l ent a nd l a s ts l onger i n
peopl e wi th da rk s ki n.
Beca us e a l l ca s es a re a s s oci a ted wi th s un expos ure, the mecha ni s m proba bl y i nvol ves overproducti on of mel a ni n by hyperfuncti ona l
mel a nocytes . Other tha n s un expos ure, a ggra va ti ng fa ctors i ncl ude
Autoi mmune thyroi d di s orders
Photos ens i ti zi ng drugs
In women, mel a s ma fa des s l owl y a nd i ncompl etel y a fter chi l dbi rth or ces s a ti on of hormone us e. In men, mel a s ma ra rel y fa des .
Trea tment depends on whether the pi gmenta ti on i s epi derma l or derma l ; epi derma l pi gmenta ti on becomes a ccentua ted wi th Wood's l i ght or ca n
be di a gnos ed wi th bi ops y. Onl y epi derma l pi gmenta ti on res ponds to trea tment. Fi rs t-l i ne thera py i ncl udes a combi na ti on of hydroqui none 2 to
4%, treti noi n 0.05 to 1%, a nd a cl a s s V to VII topi ca l corti cos teroi d. Hydroqui none 3 to 4% a ppl i ed twi ce da i l y i s often effecti ve, but l ong cours es a re
us ua l l y requi red; 2% hydroqui none i s us eful a s ma i ntena nce. Hydroqui none s houl d be tes ted behi nd one ea r or on a s ma l l pa tch on the forea rm
for 1 wk before us e on the fa ce beca us e i t ma y ca us e i rri ta ti on. Bl ea chi ng a gents , s uch a s 0.1% treti noi n a nd a zel a i c a ci d 15 to 20% crea m, ca n be
us ed i n pl a ce of or wi th hydroqui none. Chemi ca l peel i ng wi th gl ycol i c a ci d or 30 to 50% tri chl oroa ceti c a ci d i s a n opti on for pa ti ents wi th s evere
mel a s ma unres pons i ve to topi ca l bl ea chi ng a gents .
Lentigines: Lenti gi nes (s i ngul a r: l enti go) a re fl a t, ta n to brown ova l s pots . They a re commonl y due to chroni c s un expos ure (s ol a r l enti gi nes ;
s ometi mes ca l l ed l i ver s pots ) a nd occur mos t frequentl y on the fa ce a nd ba ck of the ha nds . They typi ca l l y fi rs t a ppea r duri ng mi ddl e a ge a nd
i ncrea s e i n number wi th a ge. Al though progres s i on from l enti gi nes to mel a noma ha s not been es ta bl i s hed, l enti gi nes a re a n i ndependent ri s k
fa ctor for mel a noma . They a re trea ted wi th cryothera py or l a s er; hydroqui none i s not effecti ve.
Nons ol a r l enti gi nes a re s ometi mes a s s oci a ted wi th s ys temi c di s orders , s uch a s Peutz-Jeghers s yndrome (i n whi ch profus e l enti gi nes of the l i ps
occur), mul ti pl e l enti gi nes s yndrome (Leopa rd s yndrome), or xeroderma pi gmentos um.
[
Table 85-1. Hyperpi gmenta ti on Effects of Some Drugs a nd Chemi ca l s ]
Diffuse hyperpigmentation due to systemic disorders: Common s ys temi c ca us es i ncl ude Addi s on's di s ea s e (s ee p. 792), hemochroma tos i s (s ee p. 1032),
a nd pri ma ry bi l i a ry ci rrhos i s (s ee p. 244). Ski n fi ndi ngs a re nondi a gnos ti c a s to ca us e.
Drug-induced hyperpigmentation: Cha nges a re us ua l l y di ffus e but s ometi mes ha ve drug-s peci fi c di s tri buti on pa tterns or hues (s ee Ta bl e 85-1).
Mecha ni s ms i ncl ude
Increa s ed mel a ni n i n the epi dermi s (tends to be more brown)
Mel a ni n i n the epi dermi s a nd hi gh dermi s (mos tl y brown wi th hi nts of gra y or bl ue)
Increa s ed mel a ni n i n the dermi s (tends to be more gra yi s h or bl ue)
Derma l depos i ti on of the drug or meta bol i te (us ua l l y s l a te or bl ui s h gra y)
Foca l hyperpi gmenta ti on frequentl y fol l ows drug-i nduced l i chen pl a nus (a l s o known a s l i chenoi d drug rea cti ons ).
In fi xed drug erupti ons , red pl a ques or bl i s ters form a t the s a me s i te ea ch ti me a drug i s ta ken; res i dua l pos ti nfl a mma tory hyperpi gmenta ti on
us ua l l y pers i s ts . Typi ca l l es i ons occur on the fa ce (es peci a l l y the l i ps ), ha nds , feet, a nd geni ta l s . Typi ca l i nci ti ng drugs i ncl ude s ul fona mi des ,
tetra cycl i ne, NSAIDs (es peci a l l y phena zone deri va ti ves ), ba rbi tura tes , a nd ca rba ma zepi ne.
Chapter 86. Hair Disorders

Introduction
Ha i r growth i n both men a nd women i s regul a ted by a ndrogens . Tes tos terone s ti mul a tes ha i r growth i n the pubi c a rea a nd undera rms .
Di hydrotes tos terone s ti mul a tes bea rd ha i r growth a nd s ca l p ha i r l os s .
Ha i r di s orders i ncl ude a l opeci a , hypertri chos i s , hi rs uti s m, a nd ps eudofol l i cul i ti s ba rba e. Al though mos t ha i r di s orders a re not s eri ous , they a re
often percei ved a s ma jor cos meti c i s s ues tha t dema nd trea tment. Da ndruff i s not a ha i r di s order but ra ther a s ki n di s order (s eborrhei c derma ti ti s )
of the s ca l p (s ee p. 671).
Alopecia
(Ba l dnes s )
Al opeci a i s defi ned a s l os s of ha i r. Ha i r l os s i s often a ca us e of grea t concern to the pa ti ent for cos meti c a nd ps ychol ogi c rea s ons , but i t ca n a l s o
be a n i mporta nt s i gn of s ys temi c di s ea s e.
Pathophysiology
Growth cycle: Ha i r grows i n cycl es . Ea ch cycl e cons i s ts of a l ong growi ng pha s e (a na gen), a bri ef tra ns i ti ona l a poptoti c pha s e (ca ta gen), a nd a s hort
res ti ng pha s e (tel ogen). At the end of the res ti ng pha s e, the ha i r fa l l s out (exogen) a nd a new ha i r s ta rts growi ng i n the fol l i cl e, begi nni ng the
cycl e a ga i n. Norma l l y, a bout 100 s ca l p ha i rs rea ch the end of res ti ng pha s e ea ch da y a nd fa l l out. When s i gni fi ca ntl y more tha n 100 ha i rs /da y go
i nto res ti ng pha s e, cl i ni ca l ha i r l os s (tel ogen effl uvi um) ma y occur. A di s rupti on of the growi ng pha s e ca us i ng a bnorma l l os s of a na gen ha i rs i s a n
a na gen effl uvi um.
Classification: Al opeci a ca n be cl a s s i fi ed a s foca l or di ffus e a nd by the pres ence or a bs ence of s ca rri ng.
Sca rri ng a l opeci a i s the res ul t of a cti ve des tructi on of the ha i r fol l i cl e. The fol l i cl e i s i rrepa ra bl y da ma ged a nd repl a ced by fi broti c ti s s ue. Severa l
ha i r di s orders s how a bi pha s i c pa ttern i n whi ch nons ca rri ng a l opeci a occurs ea rl y i n the cours e of the di s ea s e, a nd then perma nent ha i r l os s
occurs a s the di s ea s e progres s es . Sca rri ng a l opeci a s ca n be s ubdi vi ded further i nto pri ma ry forms , where the ta rget of i nfl a mma ti on i s the fol l i cl e
i ts el f, a nd s econda ry forms , where the fol l i cl e i s des troyed a s a res ul t of nons peci fi c i nfl a mma ti on (s ee
Ta bl e 86-1).
Nons ca rri ng a l opeci a res ul ts from proces s es tha t reduce or s l ow ha i r growth wi thout i rrepa ra bl y da ma gi ng the ha i r fol l i cl e. Di s orders tha t
pri ma ri l y a ffect the ha i r s ha ft a l s o a re cons i dered nons ca rri ng a l opeci a .
Etiology
The a l opeci a s compri s e a l a rge group of di s orders wi th mul ti pl e a nd va ryi ng eti ol ogi es (s ee Ta bl e 86-1).
The most common cause of a l opeci a i s
Androgeneti c a l opeci a (ma l e-pa ttern or fema l e-pa ttern ha i r l os s )
Androgeneti c a l opeci a i s a n a ndrogen-dependent heredi ta ry di s order i n whi ch di hydrotes tos terone pl a ys a ma jor rol e.
Other common causes of ha i r l os s a re
Drugs (i ncl udi ng chemothera peuti c a gents )
Infecti on
Sys temi c i l l nes s es (pa rti cul a rl y thos e tha t ca us e hi gh fever, s ys temi c l upus , endocri ne di s orders , a nd nutri ti ona l defi ci enci es )
Less common causes a re pri ma ry ha i r s ha ft a bnorma l i ti es , a utoi mmune di s ea s e, hea vy meta l poi s oni ng, a nd ra re derma tol ogi c condi ti ons .
Evaluation
History: History of present illness s houl d cover the ons et a nd dura ti on of ha i r l os s , whether ha i r s heddi ng i s i ncrea s ed, a nd whether ha i r l os s i s
genera l i zed or l oca l i zed. As s oci a ted s ymptoms s uch a s pruri tus a nd s ca l i ng s houl d be noted. Pa ti ents s houl d be a s ked a bout typi ca l ha i r ca re
pra cti ces , i ncl udi ng us e of bra i ds , rol l ers , a nd ha i r dryers , a nd whether they routi nel y pul l or twi s t thei r ha i r.
Review of systems s houl d i ncl ude recent expos ures to noxi ous s ti mul i (eg, drugs , toxi ns , ra di a ti on) a nd s tres s ors (eg, s urgery, chroni c i l l nes s , fever,
ps ychol ogi c s tres s ors ). Symptoms of pos s i bl e ca us es s houl d be s ought, i ncl udi ng fa ti gue a nd col d i ntol era nce (hypothyroi di s m) a nd, i n women,
hi rs uti s m, deepeni ng of the voi ce, a nd i ncrea s ed l i bi do (vi ri l i zi ng s yndrome). Other fea tures , i ncl udi ng dra ma ti c wei ght l os s , di eta ry pra cti ces
(i ncl udi ng vegeta ri a ni s m), a nd obs es s i ve-compul s i ve beha vi or, s houl d be noted. In women, a hormona l /gynecol ogi c/obs tetri c hi s tory s houl d be
obta i ned.
Past medical history s houl d note known pos s i bl e ca us es of ha i r l os s , i ncl udi ng endocri ne a nd s ki n di s orders . Current a nd recent
[Table 86-1. Cl a s s i fi ca ti on a nd Ca us es of Al opeci a ]
drug us e s houl d be revi ewed for offendi ng a gents (s ee Ta bl e 86-1). A fa mi l y hi s tory of ha i r l os s s houl d be recorded.
Physical examination: Exa mi na ti on of the s ca l p s houl d note the di s tri buti on of ha i r l os s , the pres ence a nd cha ra cteri s ti cs of a ny s ki n l es i ons , a nd
whether there i s s ca rri ng. Pa rt wi dths s houl d be mea s ured. Abnorma l i ti es of the ha i r s ha fts s houl d be noted.
A ful l s ki n exa mi na ti on s houl d be done to eva l ua te ha i r l os s el s ewhere on the body (eg, eyebrows , eyel a s hes , a rms , l egs ), ra s hes tha t ma y be
a s s oci a ted wi th certa i n types of a l opeci a (eg, l i chen pl a nus , a topy, ps ori a s i s , di s coi d l upus l es i ons , hi dra deni ti s , s i gns of s econda ry s yphi l i s or of
other ba cteri a l or funga l i nfecti ons ), a nd s i gns of vi ri l i za ti on i n women (eg, hi rs uti s m, a cne, deepeni ng voi ce, cl i toromega l y). Si gns of potenti a l
underl yi ng s ys temi c di s orders s houl d be s ought, a nd a thyroi d exa mi na ti on s houl d be done.
Vi ri l i za ti on i n women
Si gns of s ys temi c i l l nes s or cons tel l a ti ons of nons peci fi c fi ndi ngs pos s i bl y i ndi ca ti ng poi s oni ng
Interpretation of findings: Ha i r l os s tha t begi ns a t the templ es or vertex a nd s prea ds to di ffus e thi nni ng or nea rl y compl ete ha i r l os s i s typi ca l of
ma l e-pa ttern ha i r l os s . Ha i r thi nni ng i n the fronta l , pa ri eta l , a nd crown regi ons i s typi ca l of fema l e-pa ttern ha i r l os s (s ee
Fi g. 86-1).
Ha i r l os s tha t occurs 2 to 4 wk a fter chemothera py or ra di a ti on thera py (a na gen effl uvi um) ca n typi ca l l y be a s cri bed to thos e ca us es . Ha i r l os s tha t
occurs 3 to 4 mo a fter a ma jor s tres s or (pregna ncy, febri l e i l l nes s , s urgery, medi ca ti on cha nge, or s evere ps ychol ogi c s tres s or) s ugges ts a di a gnos i s
of tel ogen effl uvi um.
Other fi ndi ngs hel p s ugges t a l terna ti ve di a gnos es (s ee
Ta bl e 86-2).
Other tha n ha i r l os s , s ca l p s ymptoms (eg, i tchi ng, burni ng, ti ngl i ng) a re often a bs ent a nd, when pres ent, a re not s peci fi c to a ny ca us e.
Si gns of ha i r l os s i n pa tterns other tha n thos e des cri bed a bove a re nondi a gnos ti c a nd ma y requi re mi cros copi c ha i r exa mi na ti on or s ca l p bi ops y
for defi ni ti ve di a gnos i s .
Testing: Eva l ua ti on for ca us a ti ve di s orders (eg, endocri nol ogi c, a utoi mmune, toxi c) s houl d be done ba s ed on cl i ni ca l s us pi ci on.
Ma l e-pa ttern or fema l e-pa ttern ha i r l os s genera l l y requi res no tes ti ng. When i t occurs i n young men wi th no fa mi l y hi s tory, the phys i ci a n s houl d
ques ti on the pa ti ent a bout us e of a na bol i c s teroi ds a nd other drugs . In a ddi ti on to ques ti ons rega rdi ng drug a nd i l l i ci t drug us e, women wi th
s i gni fi ca nt ha i r l os s a nd evi dence of vi ri l i za ti on s houl d ha ve tes tos terone a nd dehydroepi a ndros terone s ul fa te (DHEAS) l evel s mea s ured (s ee p.
730).
The pull test hel ps eva l ua te di ffus e s ca l p ha i r l os s . Gentl e tra cti on i s exerted on a bunch of ha i rs (40 to 60) on a t l ea s t 3 di fferent a rea s of the
s ca l p, a nd the number of extra cted ha i rs i s counted a nd exa mi ned mi cros copi ca l l y. Norma l l y, < 3 tel ogen-pha s e ha i rs s houl d come out wi th ea ch
pul l . If a t l ea s t 3 ha i rs a re obta i ned wi th ea ch pul l or i f > 10 ha i rs tota l a re obta i ned, the pul l tes t i s pos i ti ve a nd s ugges ti ve of tel ogen effl uvi um.
The pluck test pul l s i ndi vi dua l ha i rs out a bruptl y ("by the roots "). The roots of the pl ucked ha i rs a re exa mi ned mi cros copi ca l l y to determi ne the
pha s e of growth a nd thus hel p di a gnos e a defect of tel ogen or a na gen or a n occul t s ys temi c di s ea s e. Ana gen ha i rs ha ve s hea ths a tta ched to thei r
roots ; tel ogen ha i rs ha ve ti ny bul bs wi thout s hea ths a t thei r roots . Norma l l y, 85 to 90% of ha i rs a re i n the
[Fig. 86-1. Ma l e-pa ttern a nd fema l e-pa ttern ha i r l os s .]
a na gen pha s e; a bout 10 to 15% a re i n tel ogen pha s e; a nd < 1% a re i n ca ta gen pha s e. Tel ogen effl uvi um s hows a n i ncrea s ed percenta ge of
tel ogen-pha s e ha i rs on mi cros copi c exa mi na ti on, wherea s a na gen effl uvi um s hows a decrea s e i n tel ogen-pha s e ha i rs a nd a n i ncrea s ed number
of broken ha i rs . Pri ma ry ha i r s ha ft a bnorma l i ti es a re us ua l l y obvi ous on mi cros copi c exa mi na ti on of the ha i r s ha ft.
Scalp biopsy i s i ndi ca ted when a l opeci a pers i s ts a nd di a gnos i s i s i n doubt. Bi ops y ma y di fferenti a te s ca rri ng from nons ca rri ng forms . Speci mens
s houl d be ta ken from a rea s of a cti ve i nfl a mma ti on, i dea l l y a t the border of a ba l d pa tch. Funga l a nd ba cteri a l cul tures ma y be us eful ;
i mmunofl uores cence s tudi es ma y hel p i denti fy l upus erythema tos us , l i chen pl a nopi l a ri s , a nd s ys temi c s cl eros i s .
Daily hair counts ca n be done by the pa ti ent to qua nti fy ha i r l os s when the pul l tes t i s nega ti ve. Ha i rs l os t i n the fi rs t morni ng combi ng or duri ng
wa s hi ng a re col l ected i n cl ea r pl a s ti c ba gs da i l y for 14 da ys . The number of ha i rs i n ea ch ba g i s then recorded. Sca l p ha i r counts of > 100/da y a re
a bnorma l except a fter s ha mpooi ng, when ha i r counts of up to 250 ma y be norma l . Ha i rs ma y be brought i n by the pa ti ent for mi cros copi c
exa mi na ti on.
Treatment
Androgenetic alopecia: Minoxidil (2% for women, 2% or 5% for men) prol ongs the a na gen growth pha s e a nd gra dua l l y enl a rges mi ni a turi zed fol l i cl es
(vel l us ha i rs ) i nto ma ture termi na l ha i rs . Topi ca l mi noxi di l 1 mL bi d a ppl i ed to the s ca l p i s mos t effecti ve for vertex a l opeci a i n ma l e-pa ttern or
fema l e-pa ttern ha i r l os s . However, us ua l l y onl y 30 to 40% of pa ti ents experi ence s i gni fi ca nt ha i r growth, a nd mi noxi di l i s genera l l y not effecti ve or
i ndi ca ted for other ca us es of ha i r l os s except pos s i bl y a l opeci a a rea ta . Ha i r regrowth ca n ta ke 8 to 12 mo. Trea tment i s conti nued i ndefi ni tel y
beca us e, once trea tment i s s topped, ha i r l os s res umes . The mos t frequent a dvers e effects a re mi l d s ca l p i rri ta ti on, a l l ergi c conta ct derma ti ti s ,
a nd i ncrea s ed fa ci a l ha i r.
Finasteride i nhi bi ts the 5-reducta s e enzyme, bl ocki ng convers i on of tes tos terone to di hydrotes tos terone, a nd i s us eful for ma l e-pa ttern ha i r l os s .
Fi na s teri de 1 mg po once/da y ca n s top ha i r l os s a nd ca n s ti mul a te ha i r
[Table 86-2. Interpreti ng Fi ndi ngs i n Al opeci a ]
growth. Effi ca cy i s us ua l l y evi dent wi thi n 6 to 8 mo of trea tment. Advers e effects i ncl ude decrea s ed l i bi do, erecti l e a nd eja cul a tory dys functi on,
hypers ens i ti vi ty rea cti ons , gynecoma s ti a , a nd myopa thy. There ma y be a decrea s e i n pros ta te-s peci fi c a nti gen l evel s i n ol der men, whi ch s houl d
be ta ken i nto a ccount when tha t tes t i s us ed for ca ncer s creeni ng. Common pra cti ce i s to conti nue trea tment for a s l ong a s pos i ti ve res ul ts pers i s t.
Once trea tment i s s topped, ha i r l os s returns to previ ous l evel s . Fi na s teri de i s not i ndi ca ted for women a nd i s contra i ndi ca ted i n pregna nt women
beca us e i t ha s tera togeni c effects i n a ni ma l s .
Hormonal modulators s uch a s ora l contra cepti ves or s pi ronol a ctone ma y be us eful for fema l e-pa ttern ha i r l os s a s s oci a ted wi th hypera ndrogenemi a .
Surgical options i ncl ude fol l i cl e tra ns pl a nt, s ca l p fl a ps , a nd a l opeci a reducti on. Few procedures ha ve been s ubjected to s ci enti fi c s cruti ny, but
pa ti ents who a re s el f-cons ci ous a bout thei r ha i r l os s ma y cons i der them.
Hair loss due to other causes: Underl yi ng di s orders a re trea ted.
Mul ti pl e trea tment opti ons for a l opeci a a rea ta exi s t a nd i ncl ude topi ca l , i ntra l es i ona l , or, i n s evere ca s es , s ys temi c corti cos teroi ds , topi ca l
mi noxi di l , topi ca l a nthra l i n, topi ca l i mmunothera py (di phencyprone or s qua ri c a ci d di butyl es ter), or ps ora l en pl us ul tra vi ol et A (PUVA).
Trea tment for tra cti on a l opeci a i s el i mi na ti on of phys i ca l tra cti on or s tres s to the s ca l p.
Trea tment for ti nea ca pi ti s i s topi ca l or ora l a nti funga l s (s ee p. 707).
Tri choti l l oma ni a i s di ffi cul t to trea t, but beha vi or modi fi ca ti on, cl omi pra mi ne, or a n SSRI (eg, fl uoxeti ne, fl uvoxa mi ne, pa roxeti ne, s ertra l i ne,
ci ta l opra m) ma y be of benefi t.
Sca rri ng a l opeci a a s s een i n centra l centri fuga l s ca rri ng a l opeci a , di s s ecti ng cel l ul i ti s of the s ca l p, a nd a cne kel oi da l i s nucha e i s bes t trea ted by
a l ong-a cti ng ora l tetra cycl i ne i n combi na ti on wi th a potent topi ca l corti cos teroi d.
Li chen pl a nopi l a ri s a nd chroni c cuta neous l upus l es i ons ma y be trea ted wi th ora l a nti ma l a ri a l s , corti cos teroi ds , reti noi ds , or
i mmunos uppres s a nts .
Ha i r l os s due to chemothera py i s tempora ry a nd i s bes t trea ted wi th a wi g; when ha i r regrows , i t ma y be di fferent i n col or a nd texture from the
ori gi na l ha i r. Ha i r l os s due to tel ogen effl uvi um or a na gen effl uvi um i s us ua l l y tempora ry a s wel l a nd a ba tes a fter the preci pi ta ti ng a gent i s
el i mi na ted.
Key Points
Androgeneti c a l opeci a (ma l e-pa ttern a nd fema l e-pa ttern ha i r l os s ) i s the mos t common type of ha i r l os s .
Concomi ta nt vi ri l i za ti on i n women or s ca rri ng ha i r l os s s houl d prompt a thorough eva l ua ti on for the underl yi ng di s order.
Mi cros copi c ha i r exa mi na ti on or s ca l p bi ops y ma y be requi red for defi ni ti ve di a gnos i s .
Alopecia Areata
Alopecia areata is sudden patchy hair loss in people with no obvious skin or systemic disorder.
The s ca l p a nd bea rd a re mos t frequentl y a ffected, but a ny ha i ry a rea ma y be i nvol ved. Ha i r l os s ma y a ffect mos t or a l l of the body (a l opeci a
uni vers a l i s ). Al opeci a a rea ta i s thought to be a n a utoi mmune di s order a ffecti ng geneti ca l l y s us cepti bl e peopl e expos ed to uncl ea r envi ronmenta l
tri ggers , s uch a s i nfecti on or emoti ona l s tres s . It occa s i ona l l y coexi s ts wi th a utoi mmune vi ti l i go or thyroi di ti s .
Diagnosis
Exa mi na ti on
Di a gnos i s i s by i ns pecti on. Al opeci a a rea ta typi ca l l y ma ni fes ts a s di s crete ci rcul a r pa tches of ha i r l os s cha ra cteri zed by s hort broken ha i rs a t the
ma rgi ns , whi ch res embl e excl a ma ti on poi nts . Na i l s a re s ometi mes pi tted or di s pl a y tra chyonychi a , a roughnes s of the na i l a l s o s een i n l i chen
pl a nus . Di fferenti a l di a gnos i s i ncl udes ti nea ca pi ti s , tri choti l l oma ni a , di s coi d l upus , a nd s econda ry s yphi l i s . Mea s ures of thyroi d-s ti mul a ti ng
hormone, vi ta mi n B 12 , a nd a utoa nti bodi es a re i ndi ca ted onl y when coexi s ti ng di s ea s e i s s us pected.
Treatment
Corti cos teroi ds
Someti mes topi ca l a nthra l i n, mi noxi di l or both
Trea tment i s wi th corti cos teroi ds . Tri a mci nol one a cetoni de s us pens i on (i n dos es not to exceed 0.1 mL per i njecti on s i te, eg, 10 mg/mL
concentra ti on to del i ver 1 mg) ca n be i njected i ntra derma l l y i f the l es i ons a re s ma l l . Potent topi ca l corti cos teroi ds (s uch a s beta metha s one 0.05%
bi d) ca n be us ed; however, they often do not penetra te to the depth of the ha i r bul b where the i nfl a mma tory proces s i s l oca ted. Ora l
corti cos teroi ds a re effecti ve, but ha i r l os s recurs a fter ces s a ti on of thera py a nd a dvers e effects l i mi t us e. Topi ca l a nthra l i n (0.5 to 1% for 10 to 20
mi n da i l y, then wa s hed off, frequency ti tra ted a s tol era ted up to 30 mi n bi d) a nd/or mi noxi di l ma y be us ed. Inducti on of a l l ergi c conta ct derma ti ti s
us i ng di phencyprone or s qua ri c a ci d di butyl es ter l ea ds to ha i r growth due to unknown mecha ni s ms , but thi s trea tment i s bes t res erved for
pa ti ents wi th di ffus e i nvol vement who ha ve not res ponded to other thera pi es .
Al opeci a a rea ta ma y s ponta neous l y regres s , become chroni c, or s prea d di ffus el y. Ri s k fa ctors for chroni ci ty i ncl ude extens i ve i nvol vement, ons et
before a dol es cence, a topy, a nd i nvol vement of the peri phera l s ca l p (ophi a s i s ).
Hirsutism
Hirsutism i s the exces s i ve growth of thi ck or da rk ha i r i n women i n l oca ti ons tha t a re more typi ca l of ma l e ha i r pa tterns (eg, mus ta che, bea rd,
centra l ches t, s houl ders , l ower a bdomen, ba ck, i nner thi gh). The a mount of ha i r growth tha t i s cons i dered exces s i ve ma y di ffer dependi ng on
ethni c ba ckground a nd cul tura l i nterpreta ti on. Men va ry s i gni fi ca ntl y i n a mount of body ha i r, s ome bei ng qui te ha i ry, but ra rel y pres ent for medi ca l
eva l ua ti on.
Hypertrichosis i s a s epa ra te condi ti on. It i s s i mpl y a n i ncrea s e i n the a mount of ha i r growth a nywhere on the body. Hypertri chos i s ma y be
genera l i zed or l oca l i zed.
Pathophysiology
Ha i r growth depends on the ba l a nce between a ndrogens (eg, tes tos terone, dehydroepi a ndros terone s ul fa te [DHEAS], di hydrotes tos terone [DHT])
a nd es trogens . Androgens promote thi ck, da rk ha i r growth, wherea s es trogens s l ow ha i r growth or modul a te i t towa rd fi ner, l i ghter ha i rs .
When ca us ed by i ncrea s ed a ndrogen a cti vi ty, hi rs uti s m i s often a ccompa ni ed by vi ri l i za ti on, whi ch ma y ma ni fes t a s l os s of mens es , i ncrea s ed
mus cl e ma s s , voi ce deepeni ng, a nd cl i tora l hypertrophy.
Etiology
There a re a number of ca us es of hi rs uti s m (s ee
Ta bl e 86-3). Overa l l , the mos t common ca us es a re the fol l owi ng:
Pol ycys ti c ova ry s yndrome
Fa mi l i a l hi rs uti s m
Androgen excess: Hi rs uti s m typi ca l l y res ul ts from a bnorma l l y hi gh a ndrogen a cti vi ty a s a res ul t of i ncrea s ed centra l producti on of a ndrogens (eg,
from ova ri a n or a drena l di s orders ) or i ncrea s ed peri phera l convers i on of tes tos terone to DHT by 5-reducta s e. Free a ndrogen l evel s a l s o ca n
i ncrea s e a s a res ul t of decrea s ed producti on of s ex hormone-bi ndi ng gl obul i n, whi ch ca n occur i n a va ri ety of condi ti ons , i ncl udi ng
hyperi ns ul i nemi a a nd l i ver di s ea s e. However, the s everi ty of hi rs uti s m does not correl a te wi th the l evel of ci rcul a ti ng
[Table 86-3. Some Ca us es of Hi rs uti s m]
a ndrogens beca us e of i ndi vi dua l di fferences i n a ndrogen s ens i ti vi ty of the ha i r fol l i cl e.
No androgen excess: Hi rs uti s m not a s s oci a ted wi th a ndrogen exces s ma y be phys i ol ogi c (eg, pos tmenopa us a l , duri ng pregna ncy), the res ul t of
s ys temi c nona ndrogeni c endocri ne condi ti ons , or a fa mi l i a l phenomenon, es peci a l l y i n peopl e of Medi terra nea n or Mi ddl e Ea s tern a nces try.
Hypertrichosis i nvol ves nona ndrogeni c ha i r growth a nd i s us ua l l y ca us ed by a drug, s ys temi c i l l nes s (s ee Ta bl e 86-4), or pa ra neopl a s ti c s yndrome. It
a l s o occurs a s pa rt of a ra re fa mi l i a l di s order.
Evaluation
History: History of present illness s houl d cover the extent a nd a cui ty of ha i r growth a s wel l a s the a ge of ons et.
Review of systems s houl d s eek s i gns of vi ri l i za ti on (eg, deepeni ng of the voi ce, i ncrea s ed l i bi do) a nd revi ew mens trua l a nd ferti l i ty hi s tory.
Symptoms of ca us a ti ve di s orders s houl d be s ought, i ncl udi ng col d i ntol era nce, fa ti gue, a nd wei ght ga i n (hypothyroi di s m); pol yuri a (di a betes );
bi ngei ng a nd purgi ng (ea ti ng di s orders ); a nd wei ght l os s a nd fevers (ca ncer).
Past medical history s houl d s peci fi ca l l y s eek known ca us a ti ve di s orders s uch a s endocri ne di s orders , a drena l or ova ri a n pa thol ogy, a nd ca ncer.
Family history s houl d i nqui re a bout exces s ha i r growth i n fa mi l y members . Drug hi s tory s houl d revi ew a l l pres cri bed drugs a nd s peci fi ca l l y query
for the s urrepti ti ous us e of a na bol i c s teroi ds .
Physical examination: The pres ence of exces s coa rs e a nd da rk ha i r growth s houl d be a s s es s ed a t mul ti pl e s i tes , i ncl udi ng the fa ce, ches t, l ower
a bdomen, ba ck, buttocks , a nd i nner thi gh. Si gns of vi ri l i za ti on s houl d be s ought, i ncl udi ng cl i toromega l y, a cne, ma l e-pa ttern ha i r l os s , brea s t
a trophy, a nd i ncrea s ed mus cl e ma s s .
Genera l phys i ca l exa mi na ti on s houl d note s i gns of potenti a l l y ca us a ti ve di s orders .
The eyes s houl d be exa mi ned for extra ocul a r movements , a nd the vi s ua l fi el ds s houl d be a s s es s ed.
The brea s ts s houl d be exa mi ned for ga l a ctorrhea .
The a bdomen (i ncl udi ng pel vi c exa mi na ti on) s houl d be exa mi ned for ma s s es .
The s ki n s houl d be exa mi ned for vel vety, bl a ck pi gmenta ti on on the a xi l l a e a nd neck a nd under the brea s ts (a ca nthos i s ni gri ca ns ); a cne; a nd
s tri a e.
The genera l ha bi tus s houl d be exa mi ned for fa t di s tri buti on (pa rti cul a rl y a round fa ce a nd a ccumul a ti on of fa t a t the ba s e of the neck pos teri orl y).
[Table 86-4. Ca us es of Hypertri chos i s ]
Vi ri l i za ti on
Abrupt a ppea ra nce of hi rs uti s m
Pel vi c or a bdomi na l ma s s
Interpretation of findings: Exces s ha i r growth begi nni ng a fter us e of a n a na bol i c s teroi d or other ca us a ti ve drug (s ee Ta bl es 86-3 a nd 86-4) i n a n
otherwi s e hea l thy fema l e i s l i kel y due to tha t drug. Symptoms a nd s i gns s ometi mes poi nt to a di a gnos i s (s ee
Ta bl e 86-5).
Testing: Di a gnos ti c tes ti ng i n men wi th no other s i gns of i l l nes s i s unneces s a ry.
Women s houl d ha ve l a bora tory mea s urement of s erum hormone l evel s , i ncl udi ng the fol l owi ng:
Free a nd tota l tes tos terone
DHEAS
Fol l i cl e-s ti mul a ti ng hormone (FSH) a nd l utei ni zi ng hormone (LH)
Andros tenedi one
Thyroi d-s ti mul a ti ng hormone
Prol a cti n
Hi gh l evel s of tes tos terone a ccompa ni ed by a norma l l evel of DHEAS i ndi ca te tha t the ova ri es , a nd not the a drena l gl a nds , a re produci ng the
exces s a ndrogen. Hi gh l evel s of tes tos terone a ccompa ni ed by modera te el eva ti ons i n DHEAS s ugges t a n a drena l ori gi n for the hi rs uti s m.
Often, i n women wi th pol ycys ti c ova ry s yndrome, LH l evel s a re el eva ted a nd FSH l evel s a re depres s ed, whi ch res ul ts i n el eva ted LH/FSH ra ti os (> 3
i s common).
Imaging: Pel vi c ul tra s onogra phy, CT, or both s houl d be done to rul e out pel vi c or a drena l ca ncer, pa rti cul a rl y when a pel vi c ma s s i s a ppreci a ted,
when the tota l tes tos terone l evel i s > 200 ng/dL (> 100 ng/dL i n pos tmenopa us a l women), or when the DHEAS l evel i s > 7000 ng/dL (> 4000 ng/dL i n
pos tmenopa us a l women). However, the ma jori ty of pa ti ents wi th el eva ted DHEAS ha ve a drena l hyperpl a s i a ra ther tha n a drena l ca rci noma .
Pa ti ents wi th s i gns of Cus hi ng's s yndrome or a n a drena l ma s s on i ma gi ng s tudi es s houl d ha ve 24-h uri ne corti s ol l evel s mea s ured.
Treatment
The underl yi ng di s order s houl d be trea ted, i ncl udi ng s toppi ng or cha ngi ng ca us a ti ve drugs . Trea tment for hi rs uti s m i ts el f i s unneces s a ry i f the
pa ti ent does not fi nd the exces s ha i r cos meti ca l l y objecti ona bl e.
Nona ndrogen-dependent exces s ha i r growth, s uch a s hypertri chos i s , i s trea ted pri ma ri l y wi th phys i ca l ha i r remova l methods . Pa ti ents wi th
a ndrogen-dependent hi rs uti s m requi re a combi na ti on of ha i r remova l a nd medi ca l a nti a ndrogen thera py.
Hair removal: There a re s evera l techni ques . Depi l a tory techni ques remove ha i r from the s urfa ce of the s ki n a nd i ncl ude s ha vi ng a nd OTC depi l a tory
crea ms , s uch a s thos e conta i ni ng ba ri um s ul fa te a nd Ca thi ogl ycol a te.
Epi l a ti on i nvol ves removi ng i nta ct ha i rs a nd the roots a nd ca n be a chi eved vi a mecha ni ca l mea ns (eg, tweezi ng, pl ucki ng, wa xi ng) or home
epi l a ti ng devi ces . Perma nent epi l a ti on techni ques , i ncl udi ng el ectrol ys i s , thermol ys i s , a nd l a s er epi l a ti on, ca n res ul t i n more l ong-term ha i r
remova l but often requi re mul ti pl e trea tments .
As a n a l terna ti ve to ha i r remova l , ha i r bl ea chi ng i s i nexpens i ve a nd works wel l when hi rs uti s m i s not exces s i ve. Bl ea ches l i ghten the col or of the
ha i r, renderi ng i t l es s noti cea bl e. There a re s evera l types of commerci a l
[Table 86-5. Some Symptoms a nd Si gns for Di a gnos i s of Hi rs uti s m]
ha i r-bl ea chi ng products , mos t of whi ch us e hydrogen peroxi de a s the a cti ve i ngredi ent.
Topi ca l efl orni thi ne, a ppl i ed twi ce da i l y, decrea s es ha i r growth a nd, wi th l ong-term us e, ma y decrea s e the need to ma nua l l y remove ha i r.
Hormonal treatment: Hi rs uti s m res ul ti ng from a ndrogen exces s us ua l l y requi res l ong-term thera py beca us e the s ource of exces s a ndrogen ra rel y ca n
be el i mi na ted perma nentl y. Hormona l trea tments i ncl ude
Ora l contra cepti ves
Anti a ndrogeni c drugs
Someti mes other drugs
Ora l contra cepti ves i n s ta nda rd dos es often a re the i ni ti a l trea tment for hi rs uti s m ca us ed by ova ri a n hypera ndrogeni s m. Ora l contra cepti ves
reduce ova ri a n a ndrogen s ecreti on a nd i ncrea s e s ex hormone-bi ndi ng gl obul i n, thereby decrea s i ng free tes tos terone l evel s .
Anti a ndrogeni c thera py i s a l s o us ed a nd ca n i ncl ude fi na s teri de (5 mg po once/da y), s pi ronol a ctone (25 to 100 mg po bi d), or fl uta mi de (125 mg po
once/da y or bi d). Thes e drugs a re contra i ndi ca ted duri ng pregna ncy a s they ma y ca us e femi ni za ti on of a ma l e fetus .
Ins ul i n s ens i ti zers s uch a s metformi n decrea s e i ns ul i n res i s ta nce, ca us i ng a decl i ne i n tes tos terone l evel s . However, they a re l es s effecti ve tha n
other a nti a ndrogeni c drugs . Corti cos teroi ds a re us ed for a drena l s uppres s i on. Gona dotropi n-rel ea s i ng hormone a goni s ts (eg, l euprol i de a ceta te,
na fa rel i n, tri ptorel i n) ca n be us ed for s evere forms of ova ri a n hypera ndrogeni s m under the di recti on of a gynecol ogi s t or endocri nol ogi s t.
Key Points
Hi rs uti s m ma y be fa mi l i a l , a nd the degree of ha i r growth ma y va ry wi th ethni ci ty.
Pol ycys ti c ova ry s yndrome i s the mos t frequent ca us e of hi rs uti s m.
Vi ri l i za ti on s ugges ts a n a ndrogeni c di s order tha t requi res further eva l ua ti on.
Abrupt ons et of hi rs uti s m ma y i ndi ca te ca ncer.
Pseudofolliculitis Barbae
Pseudofolliculitis barbae (PFB) is irritation of the skin due to beard hairs that penetrate the skin before leaving the hair follicle or that leave the follicle and curve
back into the skin, causing a foreign-body reaction.
PFB predomi na ntl y a ffects bl a ck men. It i s mos t noti cea bl e a round the bea rd a nd neck. It ca us es s ma l l pa pul es a nd pus tul es tha t ca n be confus ed
wi th ba cteri a l fol l i cul i ti s .
Di a gnos i s i s by phys i ca l exa mi na ti on.
Treatment
Acute PFB ca n be trea ted wi th wa rm compres s es a nd ma nua l remova l of i ngrown ha i rs wi th a needl e or tweezers . Topi ca l hydrocorti s one 1% or
topi ca l a nti bi oti cs ca n be us ed for mi l d i nfl a mma ti on. Ora l tetra cycl i ne (250 to 500 mg qi d) or ora l erythromyci n (250 to 500 mg qi d, 333 mg ti d, 500
mg bi d) ca n be us ed for modera te to s evere i nfl a mma ti on. Treti noi n (reti noi c a ci d) l i qui d or crea m or benzoyl peroxi de crea m ma y a l s o be
effecti ve i n mi l d or modera te ca s es but ma y i rri ta te the s ki n. Topi ca l efl orni thi ne hydrochl ori de crea m ma y hel p by s l owi ng ha i r growth. Ha i rs
s houl d be a l l owed to grow out; grown ha i rs ca n then be cut to a bout 0.5 cm l ength. Depi l a tori es a re a n a l terna ti ve but ma y i rri ta te the s ki n. Ha i r
fol l i cl es ca n be perma nentl y removed by el ectrol ys i s or l a s er trea tment.
Chapter 87. Nail Disorders

Introduction
A va ri ety of di s orders ca n a ffect na i l s , i ncl udi ng deformi ti es , i nfecti ons of the na i l , pa ronychi a , a nd i ngrown toena i l s . Na i l cha nges ma y occur i n
ma ny s ys temi c condi ti ons a nd geneti c s yndromes .
Na i l s ma y a l s o undergo cha nges due to l oca l i nfecti on or tra uma . For exa mpl e, tra uma to the fi nger ma y ca us e cha nges i n the na i l . The na i l ma y
devel op a whi te col ora ti on tha t s ta rts a t the na i l bed a nd grows up wi th the na i l . Someti mes , i f a na i l becomes s epa ra ted from the na i l bed, a
new na i l grows bel ow the exi s ti ng na i l a nd repl a ces i t when ful l y grown i n.
Mos t na i l i nfecti ons a re funga l (onychomycos i s s ee p. 734), but ba cteri a l a nd vi ra l i nfecti ons ca n occur (eg, green-na i l s yndrome [Pseudomonas],
herpeti c whi tl ow [herpes s i mpl ex vi rus -1]). Pa ronychi a i s not a ctua l l y a n i nfecti on of the na i l but ra ther of peri ungua l ti s s ues .
Common wa rts (verruca e vul ga ri s ) res ul t from pa pi l l oma vi rus i nfecti on a nd frequentl y i nfect the proxi ma l na i l fol d a nd s ometi mes the s ubungua l
a rea . Onychopha gi a (na i l -bi ti ng) ca n hel p to s prea d thi s i nfecti on. Wa rts i nvol vi ng thes e a rea s a re es peci a l l y di ffi cul t to trea t. Freezi ng wi th l i qui d
ni trogen ma y be effecti ve.
Toena i l s requi re s peci a l a ttenti on i n the el derl y a nd i n peopl e wi th di a betes or peri phera l va s cul a r di s ea s e; a podi a tri s t ca n hel p a voi d l oca l
brea kdown a nd s econda ry i nfecti ons .
Deformities
About 50% of na i l deformi ti es res ul t from funga l i nfecti on. The rema i nder res ul t from va ri ous ca us es , i ncl udi ng tra uma , ps ori a s i s , l i chen pl a nus ,
a nd occa s i ona l l y ca ncer. Di a gnos i s ma y be obvi ous on exa mi na ti on, but s ometi mes funga l s cra pi ngs a nd cul ture ma y be done. Deformi ti es ma y
res ol ve wi th trea tment of the ca us e, but i f not, ma ni curi s ts ma y be a bl e to hi de na i l deformi ti es wi th a ppropri a te tri mmi ng a nd pol i s hes .
Dys trophi es a re often cons i dered together wi th deformi ti es , but the two a re s l i ghtl y di fferent; deformi ti es a re genera l l y cons i dered to be gros s
cha nges i n na i l s ha pe, wherea s dys trophi es a re cha nges i n na i l texture or compos i ti on (eg, onychomycos i s ).
Congenital deformities: In s ome congeni ta l ectoderma l dys pl a s i a s , pa ti ents ha ve no na i l s (a nonychi a ). In pa chyonychi a congeni ta , the na i l beds a re
thi ckened, di s col ored, a nd hypercurved wi th a pi ncer na i l deformi ty. Na i l -pa tel l a s yndrome (s ee p. 2910) ca us es tri a ngul a r l unul a e a nd pa rti a l l y
a bs ent thumb na i l s . Pa ti ents wi th Da ri er's di s ea s e ca n ha ve na i l s wi th red a nd whi te s trea ks a nd a di s ta l V-s ha ped ni ck.
Deformities associated with systemic problems: In Pl ummer-Vi ns on s yndrome, 50% of pa ti ents ha ve koi l onychi a (conca ve, s poon-s ha ped na i l s ). Yel l ow
na i l s yndrome (cha ra cteri zed by ha rd, hypercurved, tra ns vers el y thi ckened, yel l ow na i l s wi th l os s of the cuti cl e) occurs i n pa ti ents wi th
l ymphedema of l i mbs , pl eura l effus i on, a nd a s ci tes . Ha l f-a nd-ha l f na i l s occur wi th rena l fa i l ure; the proxi ma l ha l f of the na i l i s whi te, a nd the
di s ta l ha l f i s pi nk or pi gmented. Whi te na i l s occur wi th ci rrhos i s , a l though the di s ta l thi rd ma y rema i n pi nker.
Deformities associated with dermatologic conditions: In ps ori a s i s , na i l s ma y ha ve a number of cha nges , i ncl udi ng i rregul a r pi ts , oi l s pots (l oca l i zed
a rea s of ta n-brown di s col ora ti on), onychol ys i s , a nd thi ckeni ng a nd crumbl i ng of the na i l pl a te. Li chen pl a nus of the na i l ma tri x ca us es s ca rri ng
wi th ea rl y l ongi tudi na l ri dgi ng a nd s pl i tti ng of the na i l a nd l a ter l ea ds to pterygi um forma ti on. Pterygi um of the na i l i s cha ra cteri zed by s ca rri ng
from the proxi ma l na i l outwa rd i n a V forma ti on, whi ch l ea ds ul ti ma tel y to l os s of the na i l . Al opeci a a rea ta ca n be a ccompa ni ed by regul a r pi ts
tha t form a pa ttern.
Discoloration: Ca ncer chemothera py drugs (es peci a l l y the ta xa nes ) ca n ca us e mel a nonychi a (na i l pl a te pi gmenta ti on), whi ch ca n be di ffus e or ma y
occur i n tra ns vers e ba nds . Some drugs ca us e cha ra cteri s ti c cha nges i n na i l col ora ti on. For exa mpl e, qui na cri ne ca n ca us e na i l s to a ppea r greeni s h
yel l ow or whi te under ul tra vi ol et l i ght. Cycl ophos pha mi de ca n ca us e the onychoderma l ba nds (s ea l formed a t the juncti on of the na i l pl a te a nd
di s ta l na i l bed a t the free edge of the na i l pl a te) to become s l a te-gra y or bl ui s h. Wi th a rs eni c i ntoxi ca ti on, the na i l s ma y turn di ffus el y brown.
Tetra cycl i nes , ketocona zol e, phenothi a zi nes , s ul fona mi des , a nd pheni ndi one ca n a l l ca us e browni s h or bl ue di s col ora ti on. Gol d thera py ca n turn
na i l s l i ght or da rk brown. Toba cco us e ca n res ul t i n yel l ow or browni s h di s col ora ti on. In a rgyri a , the na i l s ma y be di ffus el y bl ue-gra y.
Whi te tra ns vers e l i nes of the na i l s (Mees ' l i nes ) ma y occur wi th chemothera py, a cute a rs eni c i ntoxi ca ti on, ma l i gna nt tumors , MI, tha l l i um a nd
a nti mony i ntoxi ca ti on, fl uoros i s , a nd even duri ng etreti na te thera py. They a l s o devel op wi th tra uma to the fi nger, a l though tra uma ti c whi te l i nes
us ua l l y do not s pa n the enti re na i l . The fungus Trichophyton mentagrophytes ca us es a cha l ky whi te di s col ora ti on of the na i l pl a te.
Green-na i l s yndrome i s ca us ed by i nfecti on wi th Pseudomonas. It i s genera l l y a ha rml es s i nfecti on, us ua l l y of 1 or 2 na i l s , a nd i s noteworthy for i ts
s tri ki ng bl ue-green col or. It often occurs i n pa ti ents wi th onychol ys i s or chroni c pa ronychi a whos e na i l s ha ve been i mmers ed i n fres h wa ter for a
l ong peri od. Trea tment i s mos t effecti ve wi th s oa ks of 1% a ceti c a ci d s ol uti on or a l cohol di l uted 1:4 wi th wa ter. Pa ti ents s houl d s oa k thei r a ffected
na i l s twi ce a da y for 10 mi n a nd s houl d a voi d tra uma a nd exces s moi s ture. Frequent cl i ppi ng of the na i l i ncrea s es the res pons e to trea tment.
Melanonychia striata: Mel a nonychi a s tri a ta a re hyperpi gmented ba nds tha t a re l ongi tudi na l a nd extend from the proxi ma l na i l fol d a nd cuti cl e to
the free di s ta l end of the na i l pl a te. In da rk-s ki nned peopl e, thes e ba nds ma y be a norma l phys i ol ogi c va ri a nt requi ri ng no trea tment. Other
ca us es i ncl ude tra uma ; pregna ncy; Addi s on's di s ea s e; pos t-i nfl a mma tory hyperpi gmenta ti on; a nd the us e of certa i n drugs , i ncl udi ng doxorubi ci n,
5-fl uoroura ci l , zi dovudi ne (AZT), a nd ps ora l ens . Mel a nonychi a s tri a ta ca n a l s o occur i n beni gn mel a nocyti c nevi a nd ma l i gna nt mel a noma .
Hutchi ns on's s i gn of the na i l (mel a ni n extendi ng through the l unul a , cuti cl e, a nd proxi ma l na i l fol d) ma y s i gna l a mel a noma i n the na i l ma tri x.
Ra pi d bi ops y a nd trea tment a re es s enti a l .
Onychogryphosis: Onychogryphos i s i s a na i l dys trophy i n whi ch the na i l , mos t often on the bi g toe, becomes thi ckened a nd curved. It ma y be ca us ed
by i l l -fi tti ng s hoes . It i s common a mong the el derl y. Trea tment cons i s ts of tri mmi ng the deformed na i l s .
Onycholysis: Onychol ys i s i s s epa ra ti on of the na i l pl a te from the na i l bed or compl ete na i l pl a te l os s . It ca n occur a s a drug rea cti on i n pa ti ents
trea ted wi th tetra cycl i nes (photo-onychol ys i s ), doxorubi ci n, 5-fl uoroura ci l , ca rdi ova s cul a r drugs (pa rti cul a rl y pra ctol ol a nd ca ptopri l ), cl oxa ci l l i n
a nd cepha l ori di ne (ra rel y), tri methopri m/s ul fa methoxa zol e, di fl uni s a l , etreti na te, i ndometha ci n, i s oni a zi d, a nd i s otreti noi n. Pa rti a l onychol ys i s
ma y a l s o res ul t from i nfecti on wi th Candida albicans a s a component of onychomycos i s or from tra uma . Pa rti a l onychol ys i s ma y occur i n pa ti ents
wi th ps ori a s i s or thyrotoxi cos i s .
Onychotillomania: In thi s di s order, pa ti ents pi ck a t a nd s el f-muti l a te thei r na i l s , whi ch ca n l ea d to pa ra l l el tra ns vers e grooves a nd ri dges
(wa s hboa rd deformi ty or ha bi t-ti c na i l s ). It mos t commonl y ma ni fes ts i n pa ti ents who ha bi tua l l y pus h ba ck the cuti cl e on one fi nger, ca us i ng
dys trophy of the na i l pl a te a s i t grows . Subungua l hemorrha ges ca n a l s o devel op i n onychoti l l oma ni a .
Pincer nail deformity: Pi ncer na i l deformi ty i s a tra ns vers e over-curva ture of the na i l pl a te. It ca n occur i n pa ti ents wi th ps ori a s i s , SLE, Ka wa s a ki
di s ea s e, ca ncer, end-s ta ge rena l di s ea s e, a nd s ome geneti c s yndromes . Pa ti ents often ha ve pa i n a t the borders of the na i l where the na i l pl a te
curves i nto the ti ps of the fi ngers .
Subungual hematoma and nail bed trauma: Subungua l hema toma occurs when bl ood becomes tra pped between the na i l pl a te a nd na i l bed, us ua l l y
a s a res ul t of tra uma . Subungua l hema toma ca us es s i gni fi ca nt pa i n a nd eventua l s epa ra ti on of a nd tempora ry l os s of the na i l pl a te. When the
ca us e i s a crus h i njury, underl yi ng fra cture a nd na i l bed da ma ge a re common. Na i l bed da ma ge ma y res ul t i n perma nent na i l deformi ty.
If the i njury i s a cute, na i l trephi na ti on (eg, crea ti ng a hol e i n the na i l pl a te us i ng a ca utery devi ce, 18-ga uge needl e, or red-hot pa percl i p) ca n hel p
rel i eve pa i n by dra i ni ng a ccumul a ted bl ood. It i s not cl ea r whether removi ng the na i l a nd repa i ri ng a ny na i l bed da ma ge reduces ri s k of
perma nent na i l deformi ty.
Trachyonychia: Tra chyonychi a (rough, opa que na i l s ) ma y occur wi th a l opeci a a rea ta , l i chen pl a nus , a topi c derma ti ti s , a nd ps ori a s i s . It i s mos t
common a mong chi l dren.
Tumors: Beni gn a nd ma l i gna nt tumors ca n a ffect the na i l uni t, ca us i ng deformi ty. Thes e tumors i ncl ude beni gn myxoi d cys ts , pyogeni c gra nul oma s ,
gl omus tumors , Bowen's di s ea s e, s qua mous cel l ca rci noma , a nd ma l i gna nt mel a noma . When ca ncer i s s us pected, expedi ti ous bi ops y fol l owed by
referra l to a s urgeon i s s trongl y a dvi s ed.
Onychomycosis
Onychomycosis is fungal infection of the nail plate, nail bed, or both. The nails typically are deformed and discolored white or yellow. Diagnosis is by appearance,
wet mount, culture, PCR, or a combination. Treatment, when indicated, is with selective use of oral terbinafine or itraconazole.
About 10% (ra nge 2 to 14%) of the popul a ti on ha s onychomycos i s . Ri s k fa ctors i ncl ude
Ti nea pedi s
Preexi s ti ng na i l dys trophy (eg, i n pa ti ents wi th ps ori a s i s )
Ol der a ge
Ma l e s ex
Expos ure to s omeone wi th ti nea pedi s or onychomycos i s (eg, a fa mi l y member or through publ i c ba thi ng)
Peri phera l va s cul a r di s ea s e or di a betes
Immunocompromi s e
Toena i l s a re 10 ti mes more commonl y i nfected tha n fi ngerna i l s . About 60 to 80% of ca s es a re ca us ed by derma tophytes (eg, Trichophyton rubrum);
derma tophyte i nfecti on of the na i l s i s ca l l ed ti nea ungui um. Ma ny of the rema i ni ng ca s es a re ca us ed by nonderma tophyte mol ds (eg, Aspergillus,
Scopulariopsis, Fusarium). Immunocompromi s ed pa ti ents a nd thos e wi th chroni c mucocuta neous ca ndi di a s i s ma y ha ve ca ndi da l onychomycos i s
(whi ch i s more common on the fi ngers ). Subcl i ni ca l onychomycos i s ca n a l s o occur i n pa ti ents wi th recurrent ti nea pedi s . Onychomycos i s ma y
predi s pos e pa ti ents to l ower extremi ty cel l ul i ti s .
Symptoms and Signs
Na i l s ha ve a s ymptoma ti c pa tches of whi te or yel l ow di s col ora ti on a nd deformi ty. There a re 3 cha ra cteri s ti c ma ni fes ta ti ons :
Di s ta l s ubungua l , i n whi ch the na i l s thi cken a nd yel l ow, kera ti n a nd debri s a ccumul a te di s ta l l y a nd undernea th, a nd the na i l s epa ra tes from
the na i l bed (onychol ys i s )
Proxi ma l s ubungua l , a form tha t s ta rts proxi ma l l y a nd i s a ma rker of i mmunos uppres s i on
Whi te s uperfi ci a l , i n whi ch a cha l ky whi te s ca l e s l owl y s prea ds benea th the na i l s urfa ce
Diagnosis
Pota s s i um hydroxi de wet mount exa mi na ti on
Cul ture
Onychomycos i s i s s us pected by a ppea ra nce; predi cti ve cl i ni ca l fea tures i ncl ude i nvol vement of the 3rd or 5th toena i l , i nvol vement of the 1s t a nd
5th toena i l s on the s a me foot, a nd uni l a tera l na i l deformi ty. Subcl i ni ca l onychomycos i s s houl d be cons i dered i n pa ti ents wi th recurrent ti nea
pedi s . Di fferenti a ti on from ps ori a s i s or l i chen pl a nus i s i mporta nt, beca us e the thera pi es di ffer, s o di a gnos i s i s typi ca l l y confi rmed by
mi cros copi c exa mi na ti on a nd cul ture of s cra pi ngs . Scra pi ngs a re ta ken from the mos t proxi ma l pos i ti on tha t ca n be a cces s ed on the a ffected na i l
a nd a re exa mi ned for hypha e on pota s s i um hydroxi de wet mount a nd cul tured. Obta i ni ng a n a dequa te s a mpl e of na i l ca n be di ffi cul t beca us e the
di s ta l s ubungua l debri s , whi ch i s ea s y to s a mpl e, often does not conta i n l i vi ng fungus . Therefore, removi ng the di s ta l porti on of the na i l wi th
cl i ppers before s a mpl i ng or us i ng a s ma l l curette to rea ch more proxi ma l l y benea th the na i l i ncrea s es the yi el d. PCR ca n a l s o be done on na i l
cl i ppi ngs i f cul tures a re nega ti ve a nd the cos t of fi ndi ng a defi ni ti ve di a gnos i s i s wa rra nted.
Treatment
Someti mes ora l terbi na fi ne or i tra cona zol e
Onychomycos i s i s not a l wa ys trea ted beca us e ma ny ca s es a re a s ymptoma ti c or mi l d a nd unl i kel y to ca us e compl i ca ti ons , a nd the ora l drugs tha t
a re the mos t effecti ve trea tments ca n potenti a l l y ca us e hepa totoxi ci ty a nd s eri ous drug i ntera cti ons . Some propos ed i ndi ca ti ons for trea tment
i ncl ude the fol l owi ng:
Previ ous i ps i l a tera l cel l ul i ti s
Di a betes or other ri s k fa ctors for cel l ul i ti s
Pres ence of bothers ome s ymptoms
Ps ychos oci a l i mpa ct
Des i re for cos meti c i mprovement (controvers i a l )
Trea tment i s ora l terbi na fi ne or i tra cona zol e. Terbi na fi ne 250 mg once/da y for 12 wk (6 wk for fi ngerna i l ) or i tra cona zol e 200 mg bi d 1 wk/mo for 3
mo i s us ed a nd a chi eves a cure ra te of 60 to 75%, but the recurrence ra te i s es ti ma ted to be a s hi gh a s 10 to 50%. It i s not neces s a ry to trea t unti l
a l l a bnorma l na i l i s gone beca us e thes e drugs rema i n bound to the na i l pl a te a nd conti nue to be effecti ve a fter ora l a dmi ni s tra ti on ha s cea s ed.
The a ffected na i l wi l l not revert to norma l ; however, newl y growi ng na i l wi l l a ppea r norma l . Topi ca l a nti funga l na i l l a cquer conta i ni ng ci cl opi rox
8% or a morol fi ne 5% (not a va i l a bl e i n the US) i s ra rel y effecti ve a s pri ma ry trea tment but ca n i mprove cure ra te when us ed a s a n a djunct wi th ora l
drugs , pa rti cul a rl y i n res i s ta nt i nfecti ons .
To l i mi t rel a ps e, the pa ti ent s houl d tri m na i l s s hort, dry feet a fter ba thi ng, wea r a bs orbent s ocks , a nd us e a nti funga l foot powder. Ol d s hoes ma y
ha rbor a hi gh dens i ty of s pores a nd, i f pos s i bl e, s houl d not be worn.
Paronychia
Paronychia is infection of the periungual tissues. Acute paronychia causes redness, warmth, and pain along the nail margin. Diagnosis is by inspection. Treatment
is with antistaphylococcal antibiotics and drainage of any pus.
Pa ronychi a i s us ua l l y a cute, but chroni c ca s es occur. In a cute pa ronychi a , the ca us a ti ve orga ni s ms a re us ua l l y Staphylococcus aureus or s treptococci
a nd, l es s commonl y, Pseudomonas or Proteus s pp. Orga ni s ms enter through a brea k i n the epi dermi s res ul ti ng from a ha ngna i l , tra uma to a na i l
fol d, l os s of the cuti cl e, or chroni c i rri ta ti on (eg, res ul ti ng from wa ter a nd detergents ). Bi ti ng or s ucki ng the fi ngers ca n a l s o predi s pos e peopl e to
devel opi ng the i nfecti on. In toes , i nfecti on often begi ns a t a n i ngrown toena i l (s ee p. 736).
In pa ti ents wi th di a betes a nd thos e wi th peri phera l va s cul a r di s ea s e, toe pa ronychi a ca n threa ten the l i mb.
Symptoms and Signs
Pa ronychi a devel ops a l ong the na i l ma rgi n (l a tera l a nd proxi ma l na i l fol ds ), ma ni fes ti ng over hours to da ys wi th pa i n, wa rmth, rednes s , a nd
s wel l i ng. Pus us ua l l y devel ops a l ong the na i l ma rgi n a nd s ometi mes benea th the na i l . Infecti on ca n s prea d to the fi ngerti p pul p, ca us i ng a fel on.
Ra rel y, i nfecti on penetra tes deep i nto the fi nger, s ometi mes ca us i ng i nfecti ous fl exor tenos ynovi ti s .
Diagnosis
Di a gnos i s i s by i ns pecti on. Severa l s ki n condi ti ons ca n ca us e cha nges tha t mi mi c pa ronychi a a nd s houl d be cons i dered, pa rti cul a rl y when
trea tment i s not effecti ve i ni ti a l l y. Thes e condi ti ons i ncl ude s qua mous cel l ca rci noma , proxi ma l onychomycos i s , pyogeni c gra nul oma , pyoderma
ga ngrenos um, a nd herpeti c whi tl ow.
Treatment
Anti s ta phyl ococca l a nti bi oti cs
Dra i na ge of pus
Ea rl y trea tment i s wa rm compres s es or s oa ks a nd a n a nti s ta phyl ococca l a nti bi oti c (eg, di cl oxa ci l l i n or cepha l exi n 250 mg po qi d, cl i nda myci n 300
mg po qi d). In a rea s where methi ci l l i n-res i s ta nt S. aureus i s common, a nti bi oti cs tha t a re effecti ve a ga i ns t thi s orga ni s m (eg,
tri methopri m/s ul fa methoxa zol e) s houl d be chos en ba s ed on res ul ts of l oca l s ens i ti vi ty tes ti ng. In pa ti ents wi th di a betes a nd others wi th
peri phera l va s cul a r di s ea s e, toe pa ronychi a s houl d be moni tored for s i gns of cel l ul i ti s or more s evere i nfecti on (eg, extens i on of edema or
erythema , l ympha denopa thy, fever).
Fl uctua nt s wel l i ng or vi s i bl e pus s houl d be dra i ned wi th a Freer el eva tor, s ma l l hemos ta t, or #11 s ca l pel bl a de i ns erted between the na i l a nd
na i l fol d. Ski n i nci s i on i s unneces s a ry. A thi n ga uze wi ck s houl d be i ns erted for 24 to 48 h to a l l ow dra i na ge.
Chronic Paronychia
Chronic paronychia is recurrent or persistent nail fold inflammation, typically of the fingers.
Chroni c pa ronychi a occurs a l mos t a l wa ys i n peopl e whos e ha nds a re chroni ca l l y wet (eg, di s hwa s hers , ba rtenders , hous ekeepers ), pa rti cul a rl y i f
they a re di a beti c or i mmunocompromi s ed. Candida i s often pres ent, but i ts rol e i n eti ol ogy i s uncl ea r; funga l era di ca ti on does not a l wa ys res ol ve
the condi ti on. The condi ti on ma y be a n i rri ta nt derma ti ti s wi th s econda ry funga l col oni za ti on.
The na i l fol d i s pa i nful a nd red a s i n a cute pa ronychi a , but there i s a l mos t never pus a ccumul a ti on. Eventua l l y, there i s l os s of the cuti cl e a nd
s epa ra ti on of the na i l fol d from the na i l pl a te. Thi s forms a s pa ce tha t a l l ows entry of i rri ta nts a nd mi croorga ni s ms . The na i l becomes di s torted.
Di a gnos i s i s cl i ni ca l .
Treatment
Keepi ng ha nds dry
Topi ca l corti cos teroi d or ta crol i mus
Pri ma ry trea tment i s to keep the ha nds dry a nd to a s s i s t the cuti cl e i n reformi ng to cl os e the s pa ce between the na i l fol d a nd na i l pl a te. Gl oves or
ba rri er crea ms a re us ed i f wa ter conta ct i s neces s a ry. Topi ca l drugs tha t ma y hel p i ncl ude corti cos teroi ds a nd, for thei r corti cos teroi d-s pa ri ng
effects , i mmunos uppres s a nts (eg, ta crol i mus ). Anti funga l trea tments a re hel pful onl y i n reduci ng col oni zi ng funga l orga ni s ms . Thymol 3% i n
etha nol a ppl i ed s evera l ti mes a da y to the s pa ce l eft by l os s of cuti cl e a i ds i n keepi ng thi s s pa ce dry a nd free of mi croorga ni s ms . If there i s no
res pons e to thera py, s qua mous cel l ca rci noma s houl d be cons i dered a nd a bi ops y s houl d be done.
Ingrown Toenail
(Onychocryptos i s )
An ingrown toenail is incurvation or impingement of a nail border into its adjacent nail fold, causing pain.
Ca us es i ncl ude ti ght s hoes , a bnorma l ga i t (eg, toe-wa l ki ng), bul bous toe s ha pe, exces s i ve tri mmi ng of the na i l pl a te, or congeni ta l va ri a ti ons i n
na i l contour (congeni ta l pi ncer na i l deformi ty). Someti mes a n underl yi ng os teochondroma i s res pons i bl e, es peci a l l y i n the young. In the el derl y,
peri phera l edema i s a ri s k fa ctor. Eventua l l y, i nfecti on ca n occur a l ong the na i l ma rgi n (pa ronychi a s ee p. 735).
Symptoms and Signs
Pa i n occurs a t the corner of the na i l fol d or, l es s commonl y, a l ong i ts enti re l a tera l ma rgi n. Ini ti a l l y onl y mi l d di s comfort ma y be pres ent,
es peci a l l y when wea ri ng certa i n s hoes . In chroni c ca s es , gra nul a ti on ti s s ue becomes vi s i bl e, more often i n the young.
Diagnosis
Rednes s , s wel l i ng, a nd pa i n s ugges t pa ronychi a . In young pa ti ents (eg, < 20 yr) wi th i ngrown toena i l s , x-ra ys s houl d be cons i dered to excl ude
underl yi ng os teochondroma . In the el derl y, a ppa rent gra nul a ti on ti s s ue a round the toe s ugges ts the pos s i bi l i ty of a mel a noti c mel a noma , whi ch
i s often overl ooked; bi ops y i s neces s a ry.
Treatment
Us ua l l y na i l exci s i on a nd des tructi on of a dja cent na i l ma tri x
In mi l d ca s es , i ns erti ng cotton between the i ngrown na i l pl a te a nd pa i nful fol d (us i ng a thi n toothpi ck) ma y provi de i mmedi a te rel i ef a nd, i f
conti nued, correct the probl em. If the s hoes a re too ti ght, a l a rger toe box i s i ndi ca ted. In mos t ca s es , however, pa rti cul a rl y wi th pa ronychi a ,
exci s i on of the i ngrown toena i l a fter i njecti ng a l oca l a nes theti c i s the onl y effecti ve trea tment. If i ngrown toena i l s recur, perma nent des tructi on
of the nea rby l a tera l na i l ma tri x by a ppl yi ng phenol or tri chl oroa ceti c a ceti c a ci d or by s urgi ca l exci s i on i s i ndi ca ted. Phenol s houl d not be us ed i f
there i s a rteri a l i ns uffi ci ency.
Chapter 88. Pressure Ulcers

Introduction
(Pres s ure Sores ; Beds ores ; Decubi tus Ul cers ; Decubi ti )
Pressure ulcers (PUs) are areas of necrosis and ulceration where tissues are compressed between bony prominences and hard surfaces; they result from pressure
alone or pressure in combination with friction, shearing forces, or both. Risk factors include old age, impaired circulation, immobilization, undernutrition, and
incontinence. Severity ranges from nonblanchable skin erythema to full-thickness skin loss with extensive soft-tissue necrosis. Diagnosis is clinical. Prognosis is
excellent for early-stage ulcers; neglected and late-stage ulcers pose risk of serious infection and nutritional stress and are difficult to heal. Treatment includes
pressure reduction, avoidance of friction and shearing forces, local care, and sometimes skin grafts or myocutaneous flaps.
Etiology
An es ti ma ted 1.3 to 3 mi l l i on pa ti ents i n the US ha ve PUs ; i nci dence i s hi ghes t i n ol der pa ti ents , es peci a l l y thos e who a re hos pi ta l i zed or i n l ongterm ca re fa ci l i ti es . Agi ng i ncrea s es ri s k, i n pa rt beca us e of reduced s ubcuta neous fa t a nd decrea s ed ca pi l l a ry bl ood fl ow. Immobi l i ty a nd
comorbi di ti es i ncrea s e ri s k further.
Pa ti ents who a re cogni ti vel y i mpa i red, i mmobi l e, or both a re a t i ncrea s ed ri s k. Immobi l i tybeca us e of decrea s ed s ponta neous movement (eg,
due to s troke, s eda ti on, or s evere i l l nes s ) or i na bi l i ty to cha nge pos i ti on frequentl y beca us e of wea knes s i s the mos t i mporta nt fa ctor. Other ri s k
fa ctors i ncl ude uri na ry a nd feca l i nconti nence; poor nutri ti ona l s ta tus , i ncl udi ng dehydra ti on; di a betes ; a nd ca rdi ova s cul a r di s ea s e. Cl i ni ca l
a s s es s ment i s s uffi ci ent to i denti fy pa ti ents a t ri s k; s evera l s ca l es (eg, Norton, Bra dens ee
Fi g. 88-1) a re us eful for predi cti ng ri s k. The Na ti ona l Pres s ure Ul cer Advi s ory Pa nel ha s a l s o i s s ued gui del i nes for the predi cti on a nd preventi on of
PUs .
Pathophysiology
PUs devel op when s oft ti s s ues a re compres s ed between bony promi nences a nd conta ct s urfa ces
[Fig. 88-1. Bra den s ca l e for predi cti ng ri s k for pres s ure ul cers .]
[
Table 88-1. Pres s ure Ul cer Sta gi ng]
or when fri cti on (eg, rubbi ng a ga i ns t cl othi ng or beddi ng) or s hea ri ng forces (whi ch devel op when s ki n cl i ngs to s urfa ces ) ca us e eros i on, ti s s ue
i s chemi a , a nd i nfa rcti on. PUs mos t frequentl y devel op over the s a crum, i s chi a l tuberos i ti es , trocha nters , ma l l eol i , a nd heel s , but they ca n devel op
el s ewhere, i ncl udi ng behi nd the ea rs when na s a l ca nnul a e a re us ed for prol onged peri ods . Al s o, poorl y fi tti ng pros theti c devi ces ca n ca us e PUs
to devel op over bony promi nences . Increa s ed force a nd dura ti on of pres s ure di rectl y i nfl uence ri s k a nd s everi ty, but PUs ca n devel op i n a s l i ttl e a s
3 to 4 h i n s ome s etti ngs (eg, tra uma pa ti ents who a re i mmobi l i zed on ri gi d s pi ne-i mmobi l i za ti on boa rds ). Ul cers wors en when s ki n i s overl y
moi s t a nd ma cera ted (eg, from pers pi ra ti on or i nconti nence).
Other causes of skin ulcers: Chroni c a rteri a l a nd venous i ns uffi ci ency ca n res ul t i n s ki n ul cers , pa rti cul a rl y on the l ower extremi ti es . Al though the
underl yi ng mecha ni s m i s va s cul a r, the s a me forces tha t ca us e PUs ca n wors en thes e ul cers , a nd pri nci pl es of trea tment a re s i mi l a r.
Symptoms and Signs
Severa l s ta gi ng s ys tems exi s t; the mos t common cl a s s i fi es ul cers a ccordi ng to the depth of s oft-ti s s ue da ma ge (s ee Ta bl e 88-1). PUs do not a l wa ys
pres ent a s Sta ge I a nd then progres s to hi gher s ta ges . Someti mes the fi rs t s i gn of a PU i s a deep, necroti c s ta ge III or IV ul cer. In a ra pi dl y
devel opi ng PU, s ubcuta neous ti s s ue ca n become necroti c before the epi dermi s erodes . A s ma l l ul cer mi ght, l i ke a n i ceberg, be qui te l a rge under
the s urfa ce.
Stage I PUs ma ni fes t a s nonbl a ncha bl e erythema , us ua l l y over a bony promi nence. Col or cha nges ma y not be a s vi s i bl e i n da rkl y pi gmented s ki n.
The l es i on ma y a l s o be wa rmer, cool er, fi rmer, s ofter, or more tender tha n a dja cent or contra l a tera l ti s s ue. Thi s s ta ge i s a mi s nomer i n the s ens e
tha t a n a ctua l ul cer (a defect of s ki n i nto the dermi s ) i s not yet pres ent. However, ul cera ti on wi l l occur i f the cours e i s not a rres ted a nd revers ed.
Stage II PUs i nvol ve l os s of epi dermi s wi th or wi thout eros i on (defect of epi dermi s ) or true ul cera ti on (pa rti a l -thi cknes s l os s of dermi s );
s ubcuta neous ti s s ue i s not expos ed. The ul cers a re s ha l l ow wi th a reddi s h ba s e. Inta ct or pa rti a l l y ruptured bl i s ters due to pres s ure a re a l s o
s ta ge II PUs . (NOTE: Non-pres s ure-rel a ted ca us es of eros i on, ul cera ti on, or bl i s teri ngeg, s ki n tea rs , ta pe burns , peri nea l derma ti ti s , ma cera ti on,
excori a ti ona re excl uded from s ta ge II des cri pti on.)
Stages III and IV PUs ha ve deeper i nvol vement of underl yi ng ti s s ue wi th more extens i ve des tructi on.
Ul cers covered wi th debri s or es cha r a re by defi ni ti on uns ta gea bl e. However, s ta bl e, nonfl uctua nt heel l es i ons wi th dry es cha r s houl d not be
debri ded for the s a ke of s ta gi ng. Brui s i ng of a n a ppa rent s ta ge II ul cer s houl d ra i s e the s us pi ci on of a deeper-s ta ge PU. PUs a t a ny s ta ge ma y be
pa i nful or pruri ti c but ma y not be noti ced by pa ti ents wi th bl unted a wa renes s or s ens a ti on. Tendernes s , erythema of s urroundi ng s ki n, exuda te, or
foul odor s ugges ts i nfecti on. Fever s houl d ra i s e s us pi ci on of ba cteremi a or underl yi ng os teomyel i ti s .
Complications
Nonhea l i ng ul cers ma y be due to i na dequa te trea tment but s houl d ra i s e s us pi ci on of os teomyel i ti s or, ra rel y, s qua mous cel l ca rci noma wi thi n the
ul cer (Ma rjol i n's ul cer). Other compl i ca ti ons of nonhea l i ng PUs i ncl ude s i nus tra cts , whi ch ca n be s uperfi ci a l or connect the ul cer to deep a dja cent
s tructures (eg, to the bowel i n s a cra l ul cers ), a nd ti s s ue ca l ci fi ca ti on. In a ddi ti on, PUs a re a res ervoi r for hos pi ta l -a cqui red a nti bi oti c-res i s ta nt
orga ni s ms , whi ch ca n s l ow hea l i ng a nd ca us e ba cteremi a a nd s eps i s .
Diagnosis
Cl i ni ca l eva l ua ti on wi th conti nuous a s s es s ment

Someti mes bone s ca n or MRI
Di a gnos i s i s us ua l l y a ppa rent cl i ni ca l l y, but depth a nd extent ca n be di ffi cul t to determi ne. PUs a re a l wa ys col oni zed by ba cteri a , s o wound
s urfa ce cul tures a re uni nterpreta bl e. Underl yi ng os teomyel i ti s i s di a gnos ed wi th ra di onucl i de bone s ca nni ng or ga dol i ni um-enha nced MRI, but
both techni ques ha ve poor s ens i ti vi ty a nd s peci fi ci ty. Di a gnos i s ma y requi re bone bi ops y a nd cul ture.
Conti nuous a s s es s ment i s ma nda tory for effecti ve ma na gement. Seri a l photogra phs ca n a l s o document hea l i ng.
Prognosis
Prognos i s for ea rl y-s ta ge PUs i s excel l ent wi th ti mel y, a ppropri a te trea tment, but hea l i ng typi ca l l y requi res weeks . PUs often devel op i n pa ti ents
wi th s ubopti ma l ca re. If ca re ca nnot be i mproved, l ong-term outcome i s poor, even i f s hort-term wound hea l i ng i s a ccompl i s hed.
Treatment
Pres s ure reducti on
Di rect ul cer ca re
Ma na gement of pa i n, i nfecti on, a nd undernutri ti on
Someti mes a djuncti ve thera py or s urgery
Trea tment requi res mul ti pl e s i mul ta neous el ements .
Reducing pressure: Reduci ng ti s s ue pres s ure i s a ccompl i s hed through ca reful pos i ti oni ng of the pa ti ent, protecti ve devi ces , a nd va ri a ti on of s upport
s urfa ces .
Frequent repositioning (a nd s el ecti on of the proper pos i ti on) i s mos t i mporta nt. A wri tten s chedul e s houl d be us ed to di rect a nd document
repos i ti oni ng. Bedbound pa ti ents s houl d be turned a mi ni mum of every 2 h, s houl d be pl a ced a t a 30 a ngl e to the ma ttres s when on thei r s i de
(i e, l a tera l decubi tus ) to a voi d di rect trocha nteri c pres s ure, a nd s houl d be el eva ted a s mi ni ma l l y a s pos s i bl e to a voi d the s hea r forces on ti s s ues
tha t res ul t from s l i di ng down the bed. For repos i ti oni ng pa ti ents , l i fti ng devi ces (eg, a Stryker fra me) or bed l i nen s houl d be us ed i ns tea d of
dra ggi ng the pa ti ent (whi ch ca us es fri cti on a nd s hea r forces ). Pa ti ents pl a ced i n cha i rs s houl d be repos i ti oned every hour, a nd they s houl d be
encoura ged to cha nge pos i ti on on thei r own every 15 mi n.
Protective padding i ncl udes pi l l ows or foa m wedges pl a ced between knees , a nkl es , a nd heel s when pa ti ents a re on thei r s i de a nd pi l l ows , foa m,
or heel protectors when pa ti ents a re s upi ne. Wi ndows s houl d be cut out of pl a s ter ca s ts a t pres s ure s i tes i n pa ti ents i mmobi l i zed by fra ctures .
Soft s ea t cus hi ons s houl d be provi ded for pa ti ents a bl e to s i t i n a cha i r. Donut-s ha ped devi ces a nd s heeps ki ns s houl d be a voi ded a s a trea tment
for PUs .
Support surfaces under bedbound pa ti ents ca n be cha nged to reduce pres s ure. A cha nge from s ta nda rd ma ttres s es i s i ndi ca ted when pa ti ents a re
una bl e to repos i ti on thems el ves a nd peri odi c repos i ti oni ng ca re i s una va i l a bl e.
Support s urfa ces a re s ta ti c or dyna mi c.
Sta ti c s urfa ces , whi ch do not requi re el ectri ci ty, i ncl ude a i r, foa m, gel , a nd wa ter overl a ys a nd ma ttres s es . Ol d-fa s hi oned "egg cra te" ma ttres s es
offer no a dva nta ge. In genera l , s ta ti c s urfa ces i ncrea s e s urfa ce s upport a rea s a nd decrea s e pres s ure a nd s hea r forces ; they a re i ndi ca ted for hi ghri s k pa ti ents wi thout PUs a nd for pa ti ents wi th s ta ge I PUs .
Dyna mi c s urfa ces requi re el ectri ci ty. Al terna ti ng-a i r ma ttres s es ha ve a i r cel l s tha t a re a l terna tel y i nfl a ted a nd defl a ted by a pump, thus s hi fti ng
s upporti ve pres s ure from s i te to s i te. Low-a i r-l os s ma ttres s es a re gi a nt a i r-permea bl e pi l l ows tha t a re conti nuous l y i nfl a ted wi th a i r; the a i r fl ow
ha s a dryi ng effect on ti s s ues . Thes e s peci a l i zed ma ttres s es a re i ndi ca ted for pa ti ents wi th s ta ge I ul cers who devel op hyperemi a on s ta ti c
s urfa ces a nd for pa ti ents wi th s ta ge III or IV ul cers . Ai r-fl ui di zed (hi gh-a i r-l os s ) ma ttres s es conta i n s i l i cone-coa ted bea ds tha t l i quefy when a i r i s
pumped through the bed. Adva nta ges i ncl ude reducti on of moi s ture on s urfa ces a nd cool i ng. They a re i ndi ca ted for pa ti ents wi th nonhea l i ng
s ta ge III a nd IV ul cers or numerous trunca l ul cers (s ee
Ta bl e 88-2). Al though s peci a l i zed ma ttres s es a re des i gned to s hi ft
[Table 88-2. Opti ons for Support Surfa ces ]
pres s ure a nd reduce forces tha t l ea d to PUs , they a re bes t thought of a s a n a djunct to comprehens i ve ca re.
Ulcer care: Appropri a te ul cer ca re i nvol ves cl ea ni ng, debri dement, a nd dres s i ngs .
Cleaning s houl d be done i ni ti a l l y a nd wi th ea ch dres s i ng cha nge; ordi na ry s oa p a nd wa ter (not hot) i s us ua l l y bes t. Cl ea ni ng often i nvol ves
i rri ga ti on wi th s a l i ne s ol uti on a t pres s ures s uffi ci ent to remove ba cteri a wi thout tra uma ti zi ng ti s s ue; commerci a l s yri nges , s queeze bottl es , or
el ectri ca l l y pres s uri zed s ys tems ca n be us ed. Al terna ti vel y, a 35-mL s yri nge a nd a n 18-ga uge IV ca theter ca n be us ed. Irri ga ti on s houl d conti nue
unti l no further debri s ca n be l oos ened. Anti s epti cs (eg, i odi ne, hydrogen peroxi de) a nd a nti s epti c wa s hes i nterfere wi th ti s s ue hea l i ng a nd
s houl d be a voi ded. Rubbi ng of s ki n s houl d be mi ni mi zed, a nd moi s turi zer s houl d be a ppl i ed gentl y a fter ea ch cl ea ns i ng.
Debridement i s neces s a ry to remove dea d ti s s ue. Methods i ncl ude
Autol yti c debri dement: Syntheti c occl us i ve dres s i ngs a re us ed to fa ci l i ta te di ges ti on of dea d ti s s ues by enzymes norma l l y pres ent i n wound
fl ui ds . Autol yti c debri dement ma y be us ed for s ma l l wounds wi th s i mpl e a ccumul a ti on of ti s s ue protei ns a nd wounds tha t need to be s ea l ed
off a nywa y (eg, for protecti on from feces or uri ne). DuoDERM or Contreet (whi ch i s i mpregna ted wi th s i l ver a nd thus offers a nti mi crobi a l effects )
a re commonl y a ppl i ed. Infected wounds , however, s houl d not be occl uded.
Mecha ni ca l debri dement: Hydrothera py (whi rl pool ba ths ), ul tra s ound, medi ca l ma ggots , wound i rri ga ti on, or dextra nomers (s ma l l ca rbohydra teba s ed bea ds tha t hel p a bs orb exuda te a nd l i qui d debri s ) s houl d be us ed to remove thi ck exuda te or l oos e necroti c ti s s ue. A s ca l pel or s ci s s ors
ca n be us ed to remove es cha r (except i n heel ul cers , i n whi ch dry es cha r i n the a bs ence of edema , erythema , fl uctua nce, or dra i na ge ca n be
s a fel y l eft a l one) or extens i ve a rea s of dea d ti s s ue. Modes t a mounts of es cha r or ti s s ue ca n be debri ded a t the pa ti ent's beds i de, but
extens i ve or deep a rea s s houl d be debri ded i n the opera ti ng room. Urgent debri dement i s i ndi ca ted i n a dva nci ng cel l ul i ti s or s eps i s .
Debri dement wi th wet-to-dry dres s i ngs s houl d be done onl y for wounds wi th very l oos e exuda te a nd onl y wi th grea t ca re beca us e i t i s often
pa i nful a nd i t ma y remove hea l thy ti s s ue or overdry the wound.
Enzyma ti c debri dement (us i ng col l a gena s e, pa pa i n, fi bri nol ys i n, or s treptoki na s e/s treptodorna s e): Thi s method ca n be us ed for pa ti ents whos e
ca reta kers a re not tra i ned to do mecha ni ca l debri dement or for pa ti ents una bl e to tol era te s urgery. It i s mos t effecti ve a fter ca reful a nd
judi ci ous cros s -ha tchi ng of the wound wi th a s ca l pel to i mprove penetra ti on. Col l a gena s e i s es peci a l l y effecti ve a s col l a gen compri s es 75% of
the dry wei ght of s ki n.
Dressings s houl d be us ed for s ta ge I ul cers tha t a re s ubject to fri cti on or i nconti nence a nd for a l l other ul cers (s ee
Ta bl e 88-3). Objecti ves a re to keep the ul cer bed moi s t to reta i n ti s s ue growth fa ctors whi l e a l l owi ng s ome eva pora ti on a nd i nfl ow of O2 , to keep
s urroundi ng s ki n
[Table 88-3. Opti ons for Pres s ure Ul cer Dres s i ngs ]
dry, to fa ci l i ta te a utol yti c debri dement, a nd to es ta bl i s h a ba rri er to i nfecti on. Tra ns pa rent fi l ms (eg, OpSi te, Tega derm, Bi ocl us i ve) a re s uffi ci ent
for ul cers wi th l i mi ted exuda te; they s houl d not be us ed over ca vi ti es a nd mus t be cha nged every 3 to 7 da ys . Some experts recommend a s ma l l
a mount of tri pl e a nti bi oti c oi ntment under the dres s i ng. Hydrogel s (Cl ea r-Si te, Vi gi l on, Fl exi Gel ), whi ch a re cros s -l i nked pol ymer dres s i ngs tha t
come i n s heets or gel s , a re i ndi ca ted for very s ha l l ow wounds , s uch a s re-epi thel i a l i zi ng wounds wi th mi ni ma l exuda te.
Hydrocol l oi ds (eg, Repl i Ca re, DuoDERM, Res tore, Tega s orb), whi ch combi ne gel a ti n, pecti n, a nd ca rboxymethyl cel l ul os e i n the form of wa fers ,
powders , a nd pa s tes , a re i ndi ca ted for l i ght-to-modera te exuda te; s ome ha ve a dhes i ve ba cki ngs a nd others a re typi ca l l y covered wi th tra ns pa rent
fi l ms to ens ure a dherence to the ul cer a nd mus t be cha nged every 3 da ys . Al gi na tes (pol ys a ccha ri de s ea weed deri va ti ves conta i ni ng a l gi ni c a ci d),
whi ch come a s pa ds , ropes , a nd ri bbons (Al gi Si te, Sorbs a n, Cura s orb), a re i ndi ca ted for a bs orbi ng extens i ve exuda te a nd for control l i ng bl eedi ng
a fter s urgi ca l debri dement. Foa m dres s i ngs (Al l evyn, LYOfoa m, Hydra s orb, Mepi l ex, Cura foa m, Contreet) a re us eful a s they ca n ha ndl e va ri ous
l evel s of exuda te a nd provi de a moi s t envi ronment for wound hea l i ng. Wa terproof vers i ons protect the s ki n from i nconti nence. Dres s i ngs wi th
a dhes i ve ba cki ngs s ta y i n pl a ce l onger a nd need l es s frequent cha ngi ng.
Pain management: Pri ma ry trea tment of pa i n i s trea tment of the PU i ts el f, but NSAIDs or a ceta mi nophen i s us ed for mi l d-to-modera te pa i n. Opi oi ds
s houl d be a voi ded i f pos s i bl e beca us e s eda ti on promotes i mmobi l i ty. Opi oi ds ma y be neces s a ry duri ng dres s i ng cha nges a nd debri dement. In
cogni ti vel y i mpa i red pa ti ents , cha nges i n vi ta l s i gns ca n be us ed a s a n i ndi ca ti on of pa i n.
Infection management: PUs s houl d be conti nua l l y rea s s es s ed for ba cteri a l i nfecti on us i ng cl i ni ca l s i gns of erythema , wa rmth, i ncrea s ed dra i na ge,
fever, a nd el eva ted WBC count. Opti ons for topi ca l trea tment i ncl ude s i l ver s ul fa di a zi ne, tri pl e a nti bi oti c, a nd metroni da zol e (the l a tter for
a na erobi c ba cteri a , whi ch a re often foul s mel l i ng). Sys temi c a nti bi oti cs s houl d be a dmi ni s tered for cel l ul i ti s , ba cteremi a , or os teomyel i ti s ; us a ge
s houl d be gui ded by ti s s ue cul ture or cl i ni ca l s us pi ci on a nd not by s urfa ce cul ture.
Nutrition: Undernutri ti on i s common a mong pa ti ents wi th PUs a nd i s a ri s k fa ctor for nonhea l i ng. Ma rkers of undernutri ti on i ncl ude a l bumi n < 3.5
mg/dL or wei ght < 80% of i dea l . Protei n i nta ke of 1.25 to 1.5 g/kg/da y, s ometi mes requi ri ng ora l or pa rentera l s uppl ementa ti on (s ee p. 20), i s
des i ra bl e for opti ma l hea l i ng. Zi nc s uppl ementa ti on s upports wound hea l i ng, a nd repl a cement a t a dos e of 50 mg ti d ma y be us eful .
Suppl ementa l vi ta mi n C 1 g/da y ma y be provi ded. Provi di ng a dri nk of wa ter to pa ti ents a t ea ch repos i ti oni ng ma y be us eful to a i d hydra ti on.
Adjuncts: Mul ti pl e a djuncti ve trea tments ha ve been tri ed or a re under i nves ti ga ti on. Nega ti ve pres s ure thera py (for cl ea n wounds ) a nd the us e of
va ri ous topi ca l recombi na nt growth fa ctors (eg, nerve growth fa ctor, pl a tel et-deri ved growth fa ctor-BB) a nd s ki n equi va l ents a re s howi ng promi s e
i n wound ma na gement; however, they do not a mel i ora te mecha ni ca l forces a nd ti s s ue i s chemi a . El ectri ca l s ti mul a ti on, hea t thera py, ma s s a ge
thera py, a nd hyperba ri c O2 thera py ha ve not proven effecti ve.
Surgery: Surgi ca l debri dement i s neces s a ry for a ny ul cer wi th devi ta l i zed ti s s ue, except for s ta bl e, dry, nonfl uctua nt heel ul cers . La rge defects ,
es peci a l l y wi th expos ure of mus cul os kel eta l s tructures , requi re s urgi ca l cl os ure. Ski n gra fts a re us eful for l a rge, s ha l l ow defects . However,
beca us e gra fts do not a dd to bl ood s uppl y, mea s ures mus t be ta ken to prevent pres s ure from devel opi ng to the poi nt of i s chemi a a nd further
brea kdown. Myocuta neous fl a ps , beca us e of thei r pres s ure-s ha ri ng bul k a nd ri ch va s cul a ture, a re the cl os ures of choi ce over l a rge bony
promi nences (eg, s a crum, i s chi a , trocha nters ).
Ischemic and venous ulcers: Wound ca re trea tments a l s o a re us eful for i s chemi c ul cers , but the underl yi ng pa thophys i ol ogy mus t be a ddres s ed (eg,
better control of the i nfl a mma tory proces s i n a rheuma toi d ul cer or s urgi ca l s tenti ng or bypa s s s urgery to i mprove ci rcul a ti on i n a theros cl eros i s ).
Pentoxi fyl l i ne ha s been tri ed wi th mi ni ma l s ucces s . Some evi dence s upports the us e of da l tepa ri n for di a beti c foot ul cers (5000 uni ts s c once/da y
unti l hea l ed); however, thi s fi ndi ng ha s not been corrobora ted. Is chemi c ul cers ca n become i nfected, often wi th a na erobi c orga ni s ms , a nd the
i nfecti on ma y s prea d, ca us i ng s epti cemi a or os teomyel i ti s .
Venous ul cers a re typi ca l l y s teri l e a t fi rs t but tend to l ea d to cel l ul i ti s . The s a me l oca l ca re a s for PUs ca n be us ed. In a ddi ti on, trea tment i ncl udes
mea s ures to reduce venous hypertens i on, s uch a s us i ng compres s i on s tocki ngs or Unna boot ba nda ges (a ppl i ed a t a pres s ure of 35 to 40 mm Hg)
a nd el eva ti ng the l eg a bove the hea rt. Pentoxi fyl l i ne 800 mg po ti d for up to 24 wk ma y be us eful .
Prevention
Preventi on requi res

Identi fi ca ti on of hi gh-ri s k pa ti ents
Repos i ti oni ng
Cons ci enti ous s ki n ca re a nd hygi ene
Avoi da nce of overs eda ti on
The ma i ns ta y of preventi on i s frequent repos i ti oni ng. Pres s ure s houl d not conti nue over a ny bony s urfa ce for > 2 h. Pa ti ents who ca nnot move
thems el ves mus t be repos i ti oned us i ng pi l l ows . Even when on l ow-pres s ure ma ttres s es , pa ti ents mus t be turned. Pres s ure poi nts s houl d be
checked for erythema or tra uma a t l ea s t once/da y under a dequa te l i ghti ng. Pa ti ents a nd fa mi l y members mus t be ta ught a routi ne of da i l y vi s ua l
i ns pecti on a nd pa l pa ti on of s i tes for potenti a l ul cer forma ti on.
Da i l y a ttenti on to hygi ene a nd drynes s i s neces s a ry to prevent ma cera ti on a nd s econda ry i nfecti on. Al though s heeps ki n s houl d not be us ed to
redi s tri bute pres s ure a fter ul cera ti on ha s occurred, l yi ng on a s heeps ki n a s a preventi ve mea s ure hel ps keep the s ki n i n good condi ti on.
Protecti ve pa ddi ng, pi l l ows , or a s heeps ki n ca n be us ed to s epa ra te body s urfa ces . Beddi ng a nd cl othi ng s houl d be cha nged frequentl y; s heets
s houl d be s oft, cl ea n, a nd free from wri nkl es a nd pa rti cul a te ma tter. In hot wea ther, the s ki n s houl d be s ponge-ba thed a nd thoroughl y dri ed
a fterwa rd. In i nconti nent pa ti ents , ul cers s houl d be protected from conta mi na ti on; s yntheti c dres s i ngs ca n hel p. Ski n brea kdown ca n be prevented
wi th ca reful cl ea ns i ng a nd dryi ng (pa tti ng a nd not rubbi ng the s ki n) a nd us i ng a nti ca ndi da l crea ms a nd moi s ture ba rri er crea ms or s ki n protecti ve
wi pes (eg, Ski n-Prep). Us e of a dhes i ve ta pe s houl d be mi ni mi zed beca us e i t ca n i rri ta te a nd even tea r fra gi l e s ki n.
Area s s ubject to fri cti on ma y be powdered wi th pl a i n ta l c. Us e of corns ta rch i s di s coura ged beca us e i t ma y a l l ow mi crobi a l growth.
Overs eda ti on s houl d be a voi ded, a nd a cti vi ty s houl d be encoura ged. Adequa te nutri ti on i s i mporta nt.
Chapter 89. Benign Tumors

Introduction
(See a l s o Wa rts on p. 715 a nd Geni ta l Wa rts on p. 1470)
Mos t s ki n tumors a re beni gn. However, beca us e s ki n ca ncers mus t be trea ted ea rl y, proper di a gnos i s of unus ua l s ki n growths s houl d a l wa ys be
ma de defi ni ti vel y a nd wi thout undue del a y.
Dermatofibroma
(Fi brous Hi s ti ocytoma )
Dermatofibroma is a firm, red-to-brown, small papule or nodule composed of fibroblastic tissue. It usually occurs on the thighs or legs.
Derma tofi broma s a re common, more s o i n women, a nd typi ca l l y a ppea r when peopl e a re i n thei r 20s . Thei r ca us e i s unknown. Les i ons a re us ua l l y
0.5 to 1 cm i n di a meter a nd feel l i ke a l enti l embedded i n the s ki n. Mos t a re a s ymptoma ti c, but s ome i tch or ul cera te fol l owi ng mi nor tra uma .
Di a gnos i s i s cl i ni ca l ; l es i ons typi ca l l y di mpl e when gra s ped between the fi ngers . They ma y regres s s ponta neous l y, but they ca n be exci s ed i f
troubl es ome.
Epidermal Cysts
(Kera ti nous Cys t; Epi derma l Incl us i on Cys t; Seba ceous Cys t; Mi l i a ; Pi l a r Cys t [Wen]; Stea tocys toma )
Epidermal cysts are slow-growing benign cysts containing material that is keratinous (keratinous or epidermal inclusion cyst, sebaceous cyst, milia), follicular
(pilar cyst, or wen), or sebaceous (steatocystoma). They frequently occur on the scalp, ears, face, back, or scrotum.
On pa l pa ti on, the cys ti c ma s s i s fi rm, gl obul a r, mova bl e, a nd nontender; cys ts ra nge from a bout 1 to 5 cm i n di a meter. Thi s ki nd of cys t s el dom
ca us es di s comfort unl es s i t ha s ruptured i nterna l l y, ca us i ng a ra pi dl y enl a rgi ng, pa i nful forei gn body rea cti on a nd a bs ces s . Kera ti nous cys ts , the
mos t common, often a re s urmounted wi th a punctum or pore; thei r contents a re chees y a nd often feti d (due to s econda ry ba cteri a l col oni za ti on).
Mi l i a a re mi nute s uperfi ci a l kera ti nous cys ts noted on the fa ce.
Treatment
Cys ts ma y be l eft or removed. A s ma l l i nci s i on ma y be ma de to eva cua te the contents , then the cys t wa l l i ts el f s houl d be removed wi th a curet or
hemos ta t; otherwi s e, the l es i on wi l l recur. Surgi ca l exci s i on wi th compl ete remova l of the cys t wa l l i s a l s o effecti ve. Interna l l y ruptured cys ts
s houl d be i nci s ed a nd dra i ned; a ga uze dra i n i s i ns erted a nd removed a fter 2 to 3 da ys . Anti bi oti cs a re not needed unl es s cel l ul i ti s i s pres ent.
Mi l i a ma y be eva cua ted wi th a #11 bl a de.
Keloids
Keloids are smooth overgrowths of fibroblastic tissue that arise in an area of injury (eg, lacerations, surgical scars, truncal acne) or, occasionally, spontaneously.
Kel oi ds a re more frequent i n bl a cks . They tend to a ppea r on the upper trunk, es peci a l l y the upper ba ck a nd mi d ches t, a nd on del toi d a rea s .
Unl i ke hyperpl a s ti c s ca rs , kel oi da l s ca r ti s s ue a l wa ys extends beyond the a rea of ori gi na l i njury.
Kel oi ds a re s hi ny, fi rm, s mooth, us ua l l y ovoi d but s ometi mes contra cted or webbed, a nd s l i ghtl y pi nk or hyperpi gmented (s ee
Pl a te 37). Di a gnos i s i s cl i ni ca l .
Treatment
Trea tment i s often i neffecti ve. Monthl y corti cos teroi d i njecti ons (eg, tri a mci nol one a cetoni de 5 to 40 mg/mL) i nto the l es i on s ometi mes fl a tten the
kel oi d. Surgi ca l or l a s er exci s i on ma y debul k l es i ons , but they us ua l l y recur l a rger tha n before. Exci s i on i s more s ucces s ful i f preceded a nd
fol l owed by a s eri es of i ntra l es i ona l corti cos teroi d i njecti ons . Gel s heeti ng (a ppl yi ng a s oft, s emi occl us i ve dres s i ng ma de of cros s -l i nked
pol ymethyl s i l oxa ne pol ymer, or s i l i cone) or pres s ure ga rments a re other a djuncts to prevent recurrence.
Keratoacanthoma
Keratoacanthoma is a round, firm, usually flesh-colored nodule with sharply sloping borders and a characteristic central crater containing keratinous material; it
usually resolves spontaneously.
Eti ol ogy i s unknown. Mos t cons i der thes e l es i ons to be wel l -di fferenti a ted s qua mous cel l ca rci noma s wi th a tendency to i nvol ute.
Devel opment i s ra pi d. Us ua l l y the l es i on rea ches i ts ful l s i ze, typi ca l l y 1 to 3 cm but ma y be > 5 cm, wi thi n 1 or 2 mo. Common s i tes a re s unexpos ed a rea s , the fa ce, the forea rm, a nd the dors um of the ha nd. Sponta neous i nvol uti on ma y s ta rt wi thi n a few months . However, beca us e thi s
l es i on ca nnot be rel i ed upon to i nvol ute, bi ops y or exci s i on i s recommended. Sponta neous i nvol uti on ma y l ea ve s ubs ta nti a l s ca rri ng; s urgery or
i ntra l es i ona l i njecti ons wi th methotrexa te or 5-fl uoroura ci l us ua l l y yi el d better cos meti c res ul ts , a nd exci s i on a l l ows hi s tol ogi c confi rma ti on of
the di a gnos i s .
Lipomas
Lipomas are soft, movable, subcutaneous nodules of adipocytes (fat cells); overlying skin is normal.
A pa ti ent ma y ha ve one or ma ny l i poma s . They occur more often i n women tha n men, ra rel y grow to be > 7 to 8 cm i n di a meter, a nd a ppea r mos t
commonl y on the trunk, na pe, a nd forea rms . They a re ra rel y s ymptoma ti c, but they ma y be pa i nful , es peci a l l y i n pa ti ents wi th fa mi l i a l va ri a nts
pres enti ng wi th mul ti pl e l es i ons .

Diagnosis
Us ua l l y cl i ni ca l
A l i poma i s us ua l l y ea s i l y mova bl e wi thi n the s ubcuti s . Li poma s a re genera l l y s oft, but s ome become fi rmer. Some s uperfi ci a l di mpl i ng ma y occur,
but fra nk i nfl a mma ti on i s not norma l .
A ra pi dl y growi ng l es i on s houl d be bi ops i ed, a l though l i poma s ra rel y become ma l i gna nt.
Treatment
Trea tment i s not us ua l l y requi red, but bothers ome l i poma s ma y be removed by exci s i on or l i pos ucti on.
Moles
(Pi gmented, Mel a nocyti c, or Nevus Cel l Nevi )
Moles are pigmented macules, papules, or nodules composed of clusters of melanocytes or nevus cells. Their main significance (other than cosmetic) is their
potential for being or becoming malignant. Lesions with characteristics of concern (changing or highly irregular borders, color changes, pain, bleeding, ulceration,
or itching) are biopsied.
Al mos t everyone ha s a few mol es , whi ch us ua l l y a ppea r i n chi l dhood or a dol es cence. There a re di fferent types of mol es (s ee
Ta bl e 89-1). Duri ng a dol es cence a nd pregna ncy, more mol es often a ppea r, a nd exi s ti ng ones ma y enl a rge or da rken. Mol es typi ca l l y become more
ra i s ed a nd l es s pi gmented over the deca des .
An i ndi vi dua l mol e i s unl i kel y to become ma l i gna nt (l i feti me ri s k i s a bout 1 i n 3,000 to 10,000), but the s i ngl e bes t predi ctor for ri s k of
devel opment of mel a noma i s the tota l number of mol es . The pres ence of > 20 mol es i ndi ca tes a hi gher tha n a vera ge ri s k for mel a noma ; pa ti ents
s houl d be ta ught to s el f-moni tor for wa rni ng s i gns a nd ha ve s ki n s urvei l l a nce a s pa rt of thei r pri ma ry ca re.
Diagnosis
Bi ops y
Beca us e mol es a re extremel y common a nd mel a noma s a re uncommon, prophyl a cti c remova l i s not jus ti fi a bl e. However, a mol e s houl d be
bi ops i ed a nd exa mi ned hi s tol ogi ca l l y i f i t ha s certa i n cha ra cteri s ti cs of concern:
Cha ngi ng or hi ghl y i rregul a r borders
Col or cha nges
Pa i n
Bl eedi ng
Ul cera ti on
Itchi ng
The bi ops y s peci men mus t be deep enough for a ccura te mi cros copi c di a gnos i s a nd s houl d conta i n the enti re l es i on i f pos s i bl e, es peci a l l y i f the
concern for ca ncer i s s trong. However, wi de pri ma ry exci s i on s houl d not be the i ni ti a l procedure, even for hi ghl y a bnorma l -a ppea ri ng l es i ons ,
beca us e ma ny s uch l es i ons a re not mel a noma s . Inci s i ona l bi ops y does not i ncrea s e the l i kel i hood of meta s ta s i s i f the l es i on i s ma l i gna nt, a nd i t
a voi ds extens i ve s urgery for a beni gn l es i on.
Treatment
Someti mes exci s i on
Mol es ca n be removed by s ha vi ng or exci s i on for cos meti c purpos es , a nd a l l mol es removed s houl d be exa mi ned hi s tol ogi ca l l y. If ha i r growth i s a
concern for the pa ti ent, a ha i ry mol e s houl d be a dequa tel y exci s ed ra ther tha n removed by s ha vi ng. Otherwi s e, ha i r regrowth wi l l occur.
Atypical Moles
(Dys pl a s ti c Nevi )
Atypical moles (AM) are melanocytic nevi with irregular and ill-defined borders, variegated
[Table 89-1. Cl a s s i fi ca ti on of Mol es ]
colors usually of brown and tan tones, and macular or papular components. Management is by monitoring and biopsy of highly atypical or changed lesions.
Patients should reduce sun exposure and conduct regular self-examinations for new moles or changes in existing ones.
AM a re nevi wi th a s l i ghtl y di fferent cl i ni ca l a nd hi s tol ogi c a ppea ra nce (di s ordered a rchi tecture a nd a typi a of mel a nocytes ). Pa ti ents wi th AM a re
a t i ncrea s ed ri s k of mel a noma ; ri s k i ncrea s es a s the number of AM a nd a s s un expos ure i ncrea s e. Some pa ti ents ha ve onl y one or a few AM;
others ha ve ma ny.
The propens i ty to devel op AM ma y be i nheri ted (a utos oma l domi na nt) or s pora di c wi thout a ppa rent fa mi l i a l a s s oci a ti on. Fa mi l i a l a typi ca l mol emel a noma s yndrome refers to the pres ence of mul ti pl e AM a nd mel a noma i n 2 1s t-degree rel a ti ves . Thes e pa ti ents a re a t ma rkedl y i ncrea s ed
ri s k (25 ti mes ) for mel a noma .
Symptoms and Signs
AM a re often l a rger tha n other nevi (> 6 mm di a meter) a nd pri ma ri l y round (unl i ke ma ny mel a noma s ) but wi th i ndi s ti nct borders a nd mi l d
a s ymmetry. In contra s t, mel a noma s ha ve grea ter i rregul a ri ty of col or, not jus t ta n a nd brown, but da rk brown, bl a ck, red, a nd bl ue or whi ti s h a rea s
of depi gmenta ti on.
Diagnosis
Regul a r phys i ca l exa mi na ti ons
Bi ops y
Al though cl i ni ca l fi ndi ngs s ugges t the di a gnos i s of AM (s ee
Ta bl e 89-2), bi ops y of the wors t-a ppea ri ng l es i ons s houl d be done to es ta bl i s h the di a gnos i s a nd to determi ne the degree of a typi a .
One or more a typi ca l -a ppea ri ng l es i ons s houl d be bi ops i ed. Pa ti ents wi th mul ti pl e AM a nd a pers ona l or fa mi l y hi s tory of mel a noma s houl d be
exa mi ned regul a rl y (eg, yea rl y for fa mi l y hi s tory, more often for pers ona l hi s tory, of mel a noma ).
Treatment
Atypi ca l mol es ca n be removed by exci s i on or s ha vi ng.
Prevention
Pa ti ents wi th AM s houl d a voi d exces s i ve s un expos ure a nd us e s uns creens . Al s o, they
[Table 89-2. Cha ra cteri s ti cs of Atypi ca l vs Typi ca l Mol es ]
s houl d be ta ught s el f-exa mi na ti on to detect cha nges i n exi s ti ng mol es a nd to recogni ze fea tures of mel a noma s . Some experts recommend yea rl y
photogra phs of the s ki n s urfa ce. Regul a r fol l ow-up exa mi na ti ons ma y be combi ned wi th ba s el i ne a nd fol l ow-up col or photogra phs of mos t of the
pa ti ent's body; thi s method i s mos t us eful i n pa ti ents wi th ma ny AM.
If pa ti ents ha ve a fa mi l y hi s tory of mel a noma (whether devel opi ng from AM or de novo) or other s ki n ca ncers , 1s t-degree rel a ti ves s houl d be
exa mi ned. Pa ti ents who a re from mel a noma -prone fa mi l i es (i e, 2 1s t-degree rel a ti ves wi th cuta neous mel a noma s ) ha ve a hi gh l i feti me ri s k of
devel opi ng mel a noma s . The enti re s ki n (i ncl udi ng the s ca l p) of members of a n a t-ri s k fa mi l y s houl d be exa mi ned.
Seborrheic Keratoses
Seborrheic keratoses are pigmented superficial epithelial lesions that are usually warty but may occur as smooth papules.
The ca us e i s unknown. The l es i ons commonl y occur i n mi ddl e or ol d a ge a nd mos t often a ppea r on the trunk or templ es ; i n bl a cks a nd As i a ns ,
es peci a l l y women, l es i ons tha t a re 1 to 3 mm often occur on the cheekbones ; thi s condi ti on i s termed derma tos i s pa pul os a ni gra .
Seborrhei c kera tos es va ry i n s i ze a nd grow s l owl y. They ma y be round or ova l a nd fl es h-col ored, brown, or bl a ck. They us ua l l y a ppea r s tuck on a nd
ma y ha ve a verrucous , vel vety, wa xy, s ca l i ng, or crus ted s urfa ce (s ee
Pl a te 44).
They a re not prema l i gna nt a nd need no trea tment unl es s they a re i rri ta ted, i tchy, or cos meti ca l l y bothers ome. Les i ons ma y be removed wi th l i ttl e
or no s ca rri ng by cryothera py (whi ch ca n ca us e hypopi gmenta ti on) or by el ectro-des i cca ti on a nd curetta ge a fter l oca l i njecti on of l i doca i ne.
Skin Tags
Skin tags (acrochordons, soft fibromas) are common soft, small, flesh-colored or hyperpigmented, pedunculated lesions; there are usually multiple lesions,
typically on the neck, axilla, and groin.
Ski n ta gs a re us ua l l y a s ymptoma ti c but ma y be i rri ta ti ng. Irri ta ti ng or uns i ghtl y s ki n ta gs ca n be removed by freezi ng wi th l i qui d ni trogen, l i ght
el ectrodes i cca ti on, or exci s i on wi th a s ca l pel or s ci s s ors . The s ta nda rd of ca re i s to s ubmi t a l l s ki n ta gs i ndi vi dua l l y for hi s tol ogi c exa mi na ti on,
es peci a l l y i f there i s a ny ques ti on of the di a gnos i s . However, for a pa ti ent wi th dozens of i denti ca l l es i ons , a n i ndi vi dua l l es i on i s unl i kel y to be
a nythi ng other tha n a s ki n ta g.
Vascular Lesions
Va s cul a r l es i ons i ncl ude a cqui red l es i ons (eg, pyogeni c gra nul oma ) a nd thos e tha t a re pres ent a t bi rth or a ri s e s hortl y a fter bi rth (va s cul a r
bi rthma rks ). Va s cul a r bi rthma rks i ncl ude va s cul a r tumors (eg, i nfa nti l e hema ngi oma ) a nd va s cul a r ma l forma ti ons . Va s cul a r ma l forma ti ons a re
congeni ta l , l i fe-l ong, l oca l i zed defects i n va s cul a r morphogenes i s a nd i ncl ude ca pi l l a ry (eg, nevus fl a mmeus ), venous , a rteri ovenous (eg, ci rs oi d
a neurys m), a nd l ympha ti c ma l forma ti ons . Va s cul a r bi rthma rks us ua l l y i nvol ve onl y the s ki n a nd s ubcuta neous ti s s ues a nd ra rel y a ffect the CNS.
Infantile Hemangioma
Infantile hemangiomas (IH) are raised, red or purplish, hyperplastic vascular lesions appearing in the first year of life. Most spontaneously involute; those
obstructing vision, the airway, or other structures require treatment, usually with oral corticosteroids. Surgery is rarely recommended.
IH i s the mos t common tumor of i nfa ncy, a ffecti ng 10 to 12% of i nfa nts by a ge 1 yr. IH i s pres ent a t bi rth i n 10 to 20% of thos e a ffected a nd a l mos t
a l wa ys wi thi n the fi rs t s evera l weeks of l i fe; occa s i ona l l y, deeper l es i ons ma y not be a ppa rent unti l a few months a fter bi rth. Si ze a nd va s cul a ri ty
i ncrea s e ra pi dl y, us ua l l y pea ki ng a t a bout a ge 1 yr.
IH ca n be cl a s s i fi ed by genera l a ppea ra nce (s uperfi ci a l , deep, or ca vernous ) or by other des cri pti ve terms (eg, s tra wberry hema ngi oma ). However,
beca us e a l l of thes e l es i ons s ha re a common pa thophys i ol ogy a nd na tura l hi s tory, the i ncl us i ve term i nfa nti l e hema ngi oma i s preferred.
Symptoms and Signs
Superfi ci a l l es i ons ha ve a bri ght red a ppea ra nce; deeper l es i ons ha ve a bl ui s h col or. Les i ons ca n bl eed or ul cera te from mi nor tra uma ; ul cers ma y
be pa i nful . IH i n certa i n l oca ti ons ca n i nterfere wi th functi on. Les i ons on the fa ce or oropha rynx ma y i nterfere wi th vi s i on or obs truct the a i rwa y;
thos e nea r the urethra l mea tus or a nus ma y i nterfere wi th el i mi na ti on. A peri ocul a r hema ngi oma i n a n i nfa nt i s a n emergency beca us e even a
few da ys of di s rupted vi s i on ca n res ul t i n perma nent vi s ua l defects . Lumbos a cra l hema ngi oma s ma y be a s i gn of neurol ogi c or GU a noma l i es .
Les i ons s l owl y i nvol ute s ta rti ng a t 12 to 18 mo, decrea s i ng i n s i ze a nd va s cul a ri ty. Genera l l y, IH i nvol ute by 10%/yea r of a ge (eg, 50% by a ge 5, 60%
by a ge 6), wi th ma xi ma l i nvol uti on by a ge 10. Invol uted l es i ons commonl y ha ve a yel l owi s h or tel a ngi ecta ti c col or a nd a wri nkl ed or l a x fi brofa tty
texture. Res i dua l cha nges a re a l mos t a l wa ys proporti ona l to the l es i on's ma xi ma l s i ze a nd va s cul a ri ty.
Diagnosis
Di a gnos i s i s cl i ni ca l ; the extent ca n be eva l ua ted by MRI i f l es i ons a ppea r to encroa ch on vi ta l s tructures .
Treatment
Someti mes l a s er thera py
Someti mes i ntra l es i ona l or s ys temi c corti cos teroi d thera py
Genera l wound ca re for ul cera ted l es i ons
Trea tment i s controvers i a l . Ma ny phys i ci a ns trea t l es i ons ea rl y to prevent s ubs equent enl a rgement or to ma ke them l es s noti cea bl e; others do not
trea t unl es s a l es i on ca us es (or ri s ks ) functi ona l probl ems by i ts l oca ti on. When trea tment i s el ected, l a s er thera py or i ntra l es i ona l or s ys temi c
corti cos teroi ds a re chos en ba s ed on the l oca ti on, extent, a nd ra te of growth of the l es i on. For s ys temi c corti cos teroi d thera py, predni s one 1 to 3
mg/kg po bi d or ti d i s gi ven for 2 wk. If res ol uti on s ta rts , the predni s one s houl d be decrea s ed s l owl y; i f not, the drug s houl d be s topped.
Topi ca l trea tments a nd wound ca re a re us eful for ul cera ted l es i ons a nd hel p prevent s ca rri ng, bl eedi ng, a nd pa i n. Compres s es , topi ca l mupi roci n
or metroni da zol e, ba rri er dres s i ngs (pol yuretha ne fi l m dres s i ng or petrol a tum-i mpregna ted ga uze), or ba rri er crea ms ma y be us ed.
Unl es s compl i ca ti ons a re l i fe threa teni ng or vi ta l orga ns a re compromi s ed, s urgi ca l exci s i on or other des tructi ve procedures s houl d be a voi ded
beca us e they frequentl y ca us e more s ca rri ng tha n occurs wi th s ponta neous i nvol uti on. To hel p pa rents a ccept noni nterventi on, the phys i ci a n ca n
revi ew the na tura l hi s tory (photogra phi c exa mpl es a re hel pful ), provi de s eri a l photogra phy of the l es i on to document i nvol uti on, a nd l i s ten
s ympa theti ca l l y to pa rents ' concerns .
Nevus Flammeus and Port-Wine Stain
Nevus flammeus and port-wine stains are capillary vascular malformations that are present at birth and appear as flat, pink, red, or purplish lesions.
Nevi flammei a re fl a t pi nk ma rks tha t a re very common on the na pe, gl a bel l a , a nd eyel i ds . Les i ons a round the eyes di s a ppea r i n a few months .
Na pe l es i ons ma y di s a ppea r i n ea rl y chi l dhood, onl y to recur i n mi ddl e a ge.
Port-wine stains a re fl a t, reddi s h to purpl e l es i ons a ppea ri ng a nywhere on the body. Les i ons become da rker a nd more pa l pa bl e wi th ti me (often
becomi ng qui te hyperpl a s ti c by l a te mi ddl e a ge), but the l a tera l extent i ncrea s es onl y i n proporti on to the growth of the pa ti ent. Port-wi ne s ta i ns
of the tri gemi na l a rea ma y be a component of the Sturge-Weber s yndrome (i n whi ch a s i mi l a r va s cul a r l es i on a ppea rs on the underl yi ng meni nges
a nd cerebra l cortex a nd i s a s s oci a ted wi th epi l eps y).
Trea tment wi th va s cul a r l a s ers produces excel l ent res ul ts i n ma ny ca s es , es peci a l l y i f the l es i on i s trea ted a s ea rl y i n l i fe a s pos s i bl e. The l es i on
ca n a l s o be hi dden wi th a n opa que cos meti c crea m prepa red to ma tch the pa ti ent's s ki n col or.
Nevus Araneus
(Spi der Nevus ; Spi der Angi oma ; Va s cul a r Spi der)
Nevus araneus is a bright red, faintly pulsatile vascular lesion consisting of a central arteriole with slender projections resembling spider legs (see
Plate 26).
Thes e l es i ons a re a cqui red. One l es i on or s ma l l numbers of l es i ons unrel a ted to i nterna l di s ea s e ma y occur i n chi l dren or a dul ts . Pa ti ents wi th
ci rrhos i s devel op ma ny s pi der a ngi oma s tha t ma y become qui te promi nent. Ma ny women devel op l es i ons duri ng pregna ncy or whi l e ta ki ng ora l
contra cepti ves .
The l es i ons a re a s ymptoma ti c a nd us ua l l y res ol ve s ponta neous l y a bout 6 to 9 mo pos tpa rtum or a fter ora l contra cepti ves a re s topped. Les i ons a re
not uncommon on the fa ces of chi l dren. Compres s i on of the centra l ves s el tempora ri l y obl i tera tes the l es i on.
Trea tment i s not us ua l l y requi red. If res ol uti on i s not s ponta neous or trea tment i s des i red for cos meti c purpos es , the centra l a rteri ol e ca n be
des troyed wi th fi ne-needl e el ectrodes i cca ti on; va s cul a r l a s er trea tment ma y a l s o be done.
Pyogenic Granuloma
Pyogenic granuloma is a fleshy, moist or crusty, usually scarlet vascular nodule composed of proliferating capillaries in an edematous stroma.
The l es i on, compos ed of va s cul a r ti s s ue, i s nei ther of ba cteri a l ori gi n nor a true gra nul oma . It devel ops ra pi dl y, often a t the s i te of recent i njury
(a l though i njury ma y not be reca l l ed), typi ca l l y grows no l a rger tha n 2 cm i n di a meter, a nd proba bl y repres ents a va s cul a r a nd fi brous res pons e to
i njury. There i s no s ex or a ge predi l ecti on. The overl yi ng epi dermi s i s thi n, a nd the l es i on tends to be fri a bl e, bl eeds ea s i l y, a nd does not bl a nch
on pres s ure. The ba s e ma y be peduncul a ted a nd s urrounded by a col l a rette of epi dermi s .
Duri ng pregna ncy, pyogeni c gra nul oma s ma y become l a rge a nd exubera nt (eg, gi ngi va l pregna ncy tumors , or tel a ngi ecta ti c epul i s ).
Di a gnos i s i nvol ves bi ops y a nd hi s tol ogi c exa mi na ti on. Hi s tol ogi c a na l ys i s i s requi red for a l l removed ti s s ue beca us e thes e l es i ons occa s i ona l l y
res embl e a nd mus t be di fferenti a ted from mel a noma s or other ma l i gna nt tumors .
Trea tment cons i s ts of remova l by exci s i on or curetta ge a nd el ectrodes i cca ti on, but the l es i ons ma y recur.
Lymphatic Malformations
(Lympha ngi oma ; Lympha ngi oma Ci rcums cri ptum; Cys ti c Hygroma ; Ca vernous Lympha ngi oma )
Lymphatic vascular malformations are elevated lesions composed of dilated lymphatic vessels.
Mos t l ympha ti c ma l forma ti ons a re pres ent a t bi rth or devel op wi thi n the fi rs t 2 yr. Les i ons a re us ua l l y yel l owi s h ta n but occa s i ona l l y reddi s h or
purpl e i f s ma l l bl ood ves s el s a re i ntermi ngl ed. Puncture of the l es i on yi el ds a col orl es s or bl ood-ti nged fl ui d.
Di a gnos i s i s ma de cl i ni ca l l y a nd by MRI.
Trea tment i s us ua l l y not needed. If the l es i on i s exci s ed, recurrence i s common, even when remova l of derma l a nd s ubcuta neous ti s s ues i s
extens i ve.
Chapter 90. Cancers of the Skin

Introduction
Ski n ca ncer i s the mos t common type of ca ncer a nd us ua l l y devel ops i n s un-expos ed a rea s of s ki n. The i nci dence i s hi ghes t a mong outdoor
workers , s ports men, a nd s unba thers a nd i s i nvers el y rel a ted to the a mount of mel a ni n s ki n pi gmenta ti on; fa i r-s ki nned peopl e a re mos t
s us cepti bl e. Ski n ca ncers ma y a l s o devel op yea rs a fter thera peuti c x-ra ys or expos ure to ca rci nogens (eg, a rs eni c i nges ti on).
Over one mi l l i on new ca s es of s ki n ca ncer a re di a gnos ed i n the US yea rl y. About 80% a re ba s a l cel l ca rci noma , 16% a re s qua mous cel l ca rci noma ,
a nd 4% a re mel a noma . Pa get's di s ea s e of the ni ppl e or extra ma mma ry Pa get's (us ua l l y nea r the a nus ), Ka pos i 's s a rcoma , tumors of a dnexa , a nd
cuta neous T-cel l l ymphoma (mycos i s fungoi des s ee p. 1024) ma ke up the rema i ni ng, l es s common, forms of s ki n ca ncer.
Ini ti a l l y, s ki n ca ncers a re often a s ymptoma ti c. The mos t frequent pres enta ti on i s a pa pul e or bl i nd pi mpl e tha t does not go a wa y. Any l es i on tha t
a ppea rs to be enl a rgi ng s houl d be bi ops i edwhether tendernes s , mi l d i nfl a mma ti on, crus ti ng, or occa s i ona l bl eedi ng i s pres ent or not. If
trea ted ea rl y, mos t s ki n ca ncers a re cura bl e.
Screening: Routi ne s creeni ng for s ki n ca ncer i s by pa ti ent s el f-exa mi na ti on, phys i ci a n exa mi na ti on, or both.
Prevention: Beca us e ma ny s ki n ca ncers s eem to be rel a ted to ul tra vi ol et (UV) expos ure, a number of mea s ures a re recommended to l i mi t expos ure.
Sun a voi da nce: Seeki ng s ha de, mi ni mi zi ng outdoor a cti vi ti es between 10 AM a nd 4 PM (when s un's ra ys a re s tronges t), a nd a voi di ng s unba thi ng
a nd the us e of ta nni ng beds
Us e of protecti ve cl othi ng: Long-s l eeved s hi rt, pa nts , a nd broa d-bri mmed ha t
Us e of s uns creen: At l ea s t s un protecti on fa ctor (SPF) 30 wi th UVA protecti on, us ed a s di rected; s houl d not be us ed to prol ong s un expos ure
Current evi dence i s i na dequa te to determi ne whether thes e mea s ures reduce i nci dence or morta l i ty of mel a noma ; i n nonmel a noma s ki n ca ncers
(ba s a l cel l a nd s qua mous cel l ca rci noma ), s un protecti on does decrea s e the i nci dence of new ca ncers .
Basal Cell Carcinoma
(Rodent Ul cer)
Basal cell carcinoma is a superficial, slowly growing papule or nodule (see
Plate 29) that derives from certain epidermal cells. Basal cell carcinomas arise from keratinocytes near the basal layer and can be referred to as basaloid
keratinocytes. Metastasis is rare, but local growth can be highly destructive. Diagnosis is by biopsy. Treatment depends on the tumor's characteristics and may
involve curettage and electrodesiccation, surgical excision, cryosurgery, topical chemotherapy, or, occasionally, radiation therapy.
Ba s a l cel l ca rci noma i s the mos t common type of s ki n ca ncer, wi th > 800,000 new ca s es yea rl y i n the US. It i s more common i n fa i r-s ki nned peopl e
wi th a hi s tory of s un expos ure a nd i s very ra re i n bl a cks .
Symptoms and Signs
The cl i ni ca l ma ni fes ta ti ons a nd bi ol ogi c beha vi or of ba s a l cel l ca rci noma s a re hi ghl y va ri a bl e. They ma y a ppea r a s
Sma l l , s hi ny, fi rm, a l mos t tra ns l ucent nodul es
Ul cera ted, crus ted pa pul es or nodul es
Fl a t, s ca rl i ke, i ndura ted pl a ques
Red, ma rgi na ted, thi n pa pul es or pl a ques tha t a re di ffi cul t to di fferenti a te from ps ori a s i s or l oca l i zed derma ti ti s
Mos t commonl y, the ca rci noma begi ns a s a s hi ny pa pul e, enl a rges s l owl y, a nd, a fter a few months or yea rs , s hows a s hi ny, pea rl y border wi th
promi nent engorged ves s el s (tel a ngi ecta s es ) on the s urfa ce a nd a centra l del l or ul cer. Recurrent crus ti ng or bl eedi ng i s not unus ua l . Commonl y,
the ca rci noma s ma y a l terna tel y crus t a nd hea l , whi ch ma y unjus ti fi a bl y decrea s e pa ti ents ' a nd phys i ci a ns ' concern a bout the i mporta nce of the
l es i on.
Ba s a l cel l ca rci noma s ra rel y meta s ta s i ze but ma y i nva de hea l thy ti s s ues . Ra rel y, pa ti ents di e beca us e the ca rci noma i nva des or i mpi nges on
underl yi ng vi ta l s tructures or ori fi ces (eyes , ea rs , mouth, bone, dura ma ter).
Diagnosis
Bi ops y a nd hi s tol ogi c exa mi na ti on
Treatment
Trea tment s houl d be done by a s peci a l i s t. The cl i ni ca l a ppea ra nce, s i ze, s i te, a nd hi s tol ogi c s ubtype determi ne choi ce of trea tmentcuretta ge
a nd el ectrodes i cca ti on, s urgi ca l exci s i on, cryos urgery, topi ca l chemothera py (i mi qui mod, 5-fl uoroura ci l , a nd photodyna mi c thera py), or,
occa s i ona l l y, ra di a ti on thera py. Recurrent or i ncompl etel y trea ted ca ncers , l a rge ca ncers , ca ncers a t recurrence-prone s i tes , a nd morphea -l i ke
ca ncers wi th va gue borders a re often trea ted wi th Mohs mi cros copi ca l l y control l ed s urgery, i n whi ch ti s s ue borders a re progres s i vel y exci s ed unti l
s peci mens a re tumor-free (a s determi ned by mi cros copi c exa mi na ti on duri ng s urgery). Al mos t 25% of pa ti ents wi th a hi s tory of ba s a l cel l
ca rci noma devel op a new ba s a l cel l ca ncer wi thi n 5 yr of the ori gi na l ca rci noma . Cons equentl y, pa ti ents wi th a hi s tory of ba s a l cel l ca rci noma
s houl d be s een a nnua l l y for a s ki n exa mi na ti on.
Bowen's Disease
(Intra epi derma l Squa mous Cel l Ca rci noma )
Bowen's disease is a superficial squamous cell carcinoma in situ.
Bowen's di s ea s e i s mos t common i n s un-expos ed a rea s but ma y a ri s e a t a ny l oca ti on. Les i ons ca n be s ol i ta ry or mul ti pl e. They a re red-brown a nd
s ca l y or crus ted, wi th l i ttl e i ndura ti on; they frequentl y res embl e a l oca l i zed thi n pl a que of ps ori a s i s , derma ti ti s , or a derma tophyte i nfecti on.
Di a gnos i s i s by bi ops y.
Trea tment depends on the tumor's cha ra cteri s ti cs a nd ma y i nvol ve topi ca l chemothera py, curetta ge a nd el ectrodes i cca ti on, s urgi ca l exci s i on, or
cryos urgery.
Squamous Cell Carcinoma
Squamous cell carcinoma is a malignant tumor of epidermal keratinocytes that invades the dermis; this cancer usually occurs in sun-exposed areas. Local
destruction may be extensive, and metastases occur in advanced stages. Diagnosis is by biopsy. Treatment depends on the tumor's characteristics and may
involve curettage and electrodesiccation, surgical excision, cryosurgery, or, occasionally, radiation therapy.
Squa mous cel l ca rci noma , the 2nd mos t common type of s ki n ca ncer, ma y devel op i n norma l ti s s ue, i n a preexi s ti ng a cti ni c kera tos i s (s ee p. 674),
i n a pa tch of l eukopl a ki a , or i n a burn s ca r. The i nci dence i n the US i s 200,000 to 300,000 ca s es a nnua l l y, wi th 2000 dea ths .
The cl i ni ca l a ppea ra nce i s hi ghl y va ri a bl e, but a ny nonhea l i ng l es i on on s un-expos ed s urfa ces s houl d be s us pect. The tumor ma y begi n a s a red
pa pul e or pl a que wi th a s ca l y or crus ted s urfa ce a nd ma y become nodul a r, s ometi mes wi th a wa rty s urfa ce. In s ome ca s es , the bul k of the l es i on
ma y l i e bel ow the l evel of the s urroundi ng s ki n. Eventua l l y the tumor ul cera tes a nd i nva des the underl yi ng ti s s ue.
Diagnosis
Bi ops y i s es s enti a l . Di fferenti a l di a gnos i s i ncl udes ma ny types of beni gn a nd ma l i gna nt l es i ons , s uch a s ba s a l cel l ca rci noma , kera toa ca nthoma ,
a cti ni c kera tos i s , verruca vul ga ri s , a nd s eborrhei c kera tos i s .
Prognosis
In genera l , the prognos i s for s ma l l l es i ons removed ea rl y a nd a dequa tel y i s excel l ent. Regi ona l a nd di s ta nt meta s ta s es of s qua mous cel l
ca rci noma s on s un-expos ed s ki n a re uncommon but do occur, pa rti cul a rl y wi th poorl y di fferenti a ted tumors . However, a bout one thi rd of l i ngua l or
mucos a l ca ncers ha ve meta s ta s i zed before di a gnos i s (s ee p. 491).
La te-s ta ge di s ea s e, whi ch ma y requi re extens i ve s urgery, i s fa r more l i kel y to meta s ta s i ze. It s prea ds i ni ti a l l y regi ona l l y to s urroundi ng s ki n a nd
l ymph nodes a nd eventua l l y to nea rby orga ns . Ca ncers tha t occur nea r the ea rs , the vermi l i on, a nd i n s ca rs a re more l i kel y to meta s ta s i ze. The
overa l l 5-yr s urvi va l ra te for meta s ta ti c di s ea s e i s 34% des pi te thera py.
Treatment
Trea tment i s s i mi l a r to tha t for ba s a l cel l ca rci noma a nd i ncl udes curetta ge a nd el ectrodes i cca ti on, s urgi ca l exci s i on, cryos urgery, topi ca l
chemothera py (i mi qui mod, 5-fl uoroura ci l ), a nd photodyna mi c thera py, or, occa s i ona l l y, ra di a ti on thera py (s ee p. 749). Trea tment a nd fol l ow-up
mus t be moni tored cl os el y beca us e of the grea ter ri s k of meta s ta s i s . Squa mous cel l ca rci noma on the l i p or other mucocuta neous juncti on s houl d
be exci s ed; a t ti mes , cure i s di ffi cul t. Recurrences a nd l a rge tumors s houl d be trea ted a ggres s i vel y wi th Mohs mi cros copi ca l l y control l ed s urgery,
or by a tea m a pproa ch wi th s urgery a nd ra di a ti on thera py.
Meta s ta ti c di s ea s e i s res pons i ve to ra di a ti on thera py i f meta s ta s es ca n be i denti fi ed a nd a re i s ol a ted. Wi des prea d meta s ta s es do not res pond
wel l to chemothera peuti c regi mens .
Melanoma
(Ma l i gna nt Mel a noma )
Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or CNS). Metastasis is correlated with depth of dermal
invasion. With spread, prognosis is poor. Diagnosis is by biopsy. Wide surgical excision is the rule for operable tumors. Metastatic disease requires chemotherapy
but is difficult to cure.
About 60,000 new ca s es of mel a noma occur yea rl y i n the US, ca us i ng a bout 8400 dea ths . Inci dence ha s rema i ned s tea dy over the l a s t 8 yr (i t ha d
previ ous l y been i ncrea s i ng a t a fa s ter ra te tha n a ny other ma l i gna nt tumor).
Mel a noma s occur ma i nl y on the s ki n but a l s o on the mucos a of the ora l a nd geni ta l regi ons a nd conjuncti va . Mel a noma s va ry i n s i ze, s ha pe, a nd
col or (us ua l l y pi gmented) a nd i n thei r propens i ty to i nva de a nd meta s ta s i ze. Meta s ta s i s occurs vi a l ympha ti cs a nd bl ood ves s el s . Loca l
meta s ta s i s res ul ts i n the forma ti on of nea rby s a tel l i te pa pul es or nodul es tha t ma y or ma y not be pi gmented. Di rect meta s ta s i s to s ki n or i nterna l
orga ns ma y occur, a nd occa s i ona l l y, meta s ta ti c nodul es or enl a rged l ymph nodes a re di s covered before the pri ma ry l es i on i s i denti fi ed.
Etiology
Ri s k fa ctors i ncl ude
Sun expos ure
Fa mi l y a nd pers ona l hi s tory

Fa i r s ki n
Increa s ed numbers of mel a nocyti c nevi
Immunos uppres s i on
Occurrence of l enti go ma l i gna
La rge congeni ta l mel a nocyti c nevus
Dys pl a s ti c nevus s yndrome
Pa ti ents wi th a pers ona l hi s tory of mel a noma ha ve a n i ncrea s ed ri s k of a ddi ti ona l mel a noma s . Peopl e who ha ve one or more 1s t-degree rel a ti ves
wi th a hi s tory of mel a noma ha ve a n i ncrea s ed ri s k (up to 6 or 8 ti mes ) over thos e wi thout a fa mi l y hi s tory. Mel a noma i s ra re i n bl a cks .
About 40 to 50% of mel a noma s devel op from pi gmented mol es (s ee a l s o p. 744); a l mos t a l l the res t a ri s e from mel a nocytes i n norma l s ki n.
Atypi ca l mol es (dys pl a s ti c nevi ) ma y be precurs ors to mel a noma (s ee p. 744). The very ra re mel a noma s of chi l dhood a l mos t a l wa ys a ri s e from
l a rge pi gmented mol es (gi a nt congeni ta l nevi ) pres ent a t bi rth. Al though mel a noma s occur duri ng pregna ncy, pregna ncy does not i ncrea s e the
l i kel i hood tha t a mol e wi l l become a mel a noma ; mol es frequentl y cha nge i n s i ze a nd da rken uni forml y duri ng pregna ncy. However, the fol l owi ng
s i gns of ma l i gna nt tra ns forma ti on s houl d be ca reful l y s ought:
Cha nge i n s i ze
Irregul a r cha nge i n col or, es peci a l l y s prea d of red, whi te, a nd bl ue pi gmenta ti on to s urroundi ng norma l s ki n
Cha nge i n s urfa ce cha ra cteri s ti cs , cons i s tency, or s ha pe
Si gns of i nfl a mma ti on i n s urroundi ng s ki n, wi th pos s i bl e bl eedi ng, ul cera ti on, i tchi ng, or tendernes s
Classification
There a re 4 ma i n types of mel a noma .
Lentigo maligna melanoma: Thi s type a ccounts for 5 to 15% of mel a noma s . It tends to a ri s e i n ol der pa ti ents . It a ri s es from l enti go ma l i gna
(Hutchi ns on's freckl e or ma l i gna nt mel a noma i n s i tu). It a ppea rs on the fa ce or other s un-expos ed a rea s a s a n a s ymptoma ti c, fl a t, ta n or brown,
i rregul a rl y s ha ped ma cul e or pa tch wi th da rker brown or bl a ck s pots s ca ttered i rregul a rl y on i ts s urfa ce. In l enti go ma l i gna , both norma l a nd
ma l i gna nt mel a nocytes a re confi ned to the epi dermi s . When ma l i gna nt mel a nocytes i nva de the dermi s , the l es i on i s ca l l ed l enti go ma l i gna
mel a noma , a nd the ca ncer ma y meta s ta s i ze.
Superficial spreading melanoma: Thi s type a ccounts for two thi rds of mel a noma s . Typi ca l l y a s ymptoma ti c, i t occurs mos t commonl y on women's l egs
a nd men's tors os . The l es i on i s us ua l l y a pl a que wi th i rregul a r, ra i s ed, i ndura ted, ta n or brown a rea s , whi ch often ha ve red, whi te, bl a ck, a nd bl ue
s pots or s ma l l , s ometi mes protubera nt bl ue-bl a ck nodul es (s ee
Pl a te 40). Sma l l notchl i ke i ndenta ti ons of the ma rgi ns ma y be noted, a l ong wi th enl a rgement or col or cha nge. Hi s tol ogi ca l l y, a typi ca l mel a nocytes
cha ra cteri s ti ca l l y i nva de the dermi s a nd epi dermi s .
Nodular melanoma: Thi s type a ccounts for 10 to 15% of mel a noma s . It ma y occur a nywhere on the body a s a da rk, protubera nt pa pul e or a pl a que
tha t va ri es from pea rl to gra y to bl a ck. Occa s i ona l l y, a l es i on conta i ns l i ttl e i f a ny pi gment or ma y l ook l i ke a va s cul a r tumor. Unl es s i t ul cera tes ,
nodul a r mel a noma i s a s ymptoma ti c, but pa ti ents us ua l l y s eek a dvi ce beca us e the l es i on enl a rges ra pi dl y.
Acral-lentiginous melanoma: Thi s type a ccounts for onl y 5 to 10% of mel a noma s , but i t i s the mos t common form of mel a noma i n bl a cks . It a ri s es on
pa l ma r, pl a nta r, a nd s ubungua l s ki n a nd ha s a cha ra cteri s ti c hi s tol ogi c pi cture s i mi l a r to tha t of l enti go ma l i gna mel a noma .
Diagnosis
Bi ops y
The di fferenti a l di a gnos i s i ncl udes ba s a l cel l a nd s qua mous cel l ca rci noma s , s eborrhei c kera tos es , a typi ca l mol es , bl ue nevi , derma tofi broma s ,
mol es , hema toma s (es peci a l l y on the ha nds or feet), venous l a kes , pyogeni c gra nul oma s , a nd wa rts wi th foca l thrombos es . If doubt exi s ts , bi ops y
s houl d i ncl ude the ful l depth of the dermi s a nd extend s l i ghtl y beyond the edges of the l es i on. Bi ops y s houl d be exci s i ona l for s ma l l l es i ons a nd
i nci s i ona l for l a rger l es i ons . By doi ng s tep s ecti ons , the pa thol ogi s t ca n determi ne the ma xi ma l thi cknes s of the mel a noma . Defi ni ti ve ra di ca l
s urgery s houl d not precede hi s tol ogi c di a gnos i s .
Pi gmented l es i ons wi th the fol l owi ng fea tures s houl d be exci s ed or bi ops i ed:
Recent enl a rgement
Da rkeni ng
Bl eedi ng
Ul cera ti on
However, thes e fea tures us ua l l y i ndi ca te tha t the mel a noma ha s a l rea dy i nva ded the s ki n deepl y. Ea rl i er di a gnos i s i s pos s i bl e i f bi ops y
s peci mens ca n be obta i ned from l es i ons ha vi ng va ri ega ted col ors (eg, brown or bl a ck wi th s ha des of red, whi te, or bl ue), i rregul a r el eva ti ons tha t
a re vi s i bl e or pa l pa bl e, a nd borders wi th a ngul a r i ndenta ti ons or notches . Pol a ri zed l i ght a nd i mmers i on conta ct dermos copy, whi ch i s us ed to
exa mi ne pi gmented l es i ons , ma y be us eful for di s ti ngui s hi ng mel a noma s from beni gn l es i ons .
Staging: The s ta gi ng of mel a noma i s ba s ed on cl i ni ca l a nd pa thol ogi c cri teri a a nd cl os el y corres ponds to the tra di ti ona l tumor-node-meta s ta s i s
(TNM) cl a s s i fi ca ti on s ys tem. The s ta gi ng s ys tem cl a s s i fi es mel a noma s ba s ed on l oca l , regi ona l , or di s ta nt di s ea s e.
Sta ge I a nd II: Loca l i zed pri ma ry mel a noma
Sta ge III: Meta s ta s i s to regi ona l l ymph nodes
Sta ge IV: Di s ta nt meta s ta ti c di s ea s e
Sta ge s trongl y correl a tes wi th s urvi va l . A mi ni ma l l y i nva s i ve mi cros ta gi ng techni que, the s o-ca l l ed s enti nel l ymph node bi ops y (SLNB), i s a ma jor
a dva nce i n the a bi l i ty to s ta ge ca ncers more a ccura tel y. Recommended s ta gi ng s tudi es depend on the Bres l ow depth (how deepl y tumor cel l s ha ve
i nva ded) a nd hi s tol ogi c cha ra cteri s ti cs of the mel a noma . Sta gi ng s tudi es ma y i ncl ude SLNB, l a bora tory tes ts (CBC, LDH, l i ver functi on tes ts ), ches t xra y, CT, a nd PET a nd a re done by a coordi na ted tea m tha t i ncl udes derma tol ogi s ts , oncol ogi s ts , genera l s urgeons , pl a s ti c s urgeons , a nd
derma topa thol ogi s ts .
Prognosis
Mel a noma ma y s prea d ra pi dl y, ca us i ng dea th wi thi n months of i ts recogni ti on, yet the 5-yr cure ra te of ea rl y, very s uperfi ci a l l es i ons i s nea rl y
100%. Thus , cure depends on ea rl y di a gnos i s a nd ea rl y trea tment. For tumors of cuta neous ori gi n (not CNS a nd s ubungua l mel a noma s ) tha t ha ve
not meta s ta s i zed, the s urvi va l ra te va ri es dependi ng on the thi cknes s of the tumor a t the ti me of di a gnos i s (s ee
Ta bl e 90-1). Mucos a l mel a noma s (es peci a l l y a norecta l mel a noma s ), whi ch a re more common i n nonwhi tes , ha ve a poor prognos i s , a l though they
often s eem qui te l i mi ted when di s covered. Once mel a noma ha s meta s ta s i zed to the l ymph nodes , 5-yr s urvi va l ra nges from 25 to 70% dependi ng
on the degree of ul cera ti on a nd number of nodes i nvol ved. Once mel a noma ha s meta s ta s i zed to di s ta nt s i tes , 5-yr s urvi va l i s a bout 10%.
Degree of l ymphocyti c i nfi l tra ti on, whi ch repres ents rea cti on by the pa ti ent's i mmunol ogi c defens e s ys tem, ma y correl a te wi th the l evel of
i nva s i on a nd prognos i s . Cha nces of cure a re ma xi ma l when l ymphocyti c i nfi l tra ti on i s l i mi ted to the mos t s uperfi ci a l l es i ons a nd decrea s e wi th
deeper l evel s of tumor cel l i nva s i on, ul cera ti on, a nd va s cul a r or l ympha ti c i nva s i on.
[Table 90-1. 5-yr Survi va l * for Ma l i gna nt Mel a noma Rel a ti ve to Thi cknes s a nd Ul cera ti on]
Treatment
Surgi ca l exci s i on
Pos s i bl y a djuva nt ra di a ti on thera py
Pos s i bl y a djuva nt i nterferon a l fa
Someti mes exci s i on, i mi qui mod, a nd cryothera py
Trea tment i s pri ma ri l y by s urgi ca l exci s i on. Al though the wi dth of ma rgi ns i s deba ted, mos t experts a gree tha t a 1-cm l a tera l tumor-free ma rgi n i s
a dequa te for l es i ons < 1 mm thi ck. Thi cker l es i ons ma y des erve l a rger ma rgi ns , more ra di ca l s urgery, a nd SLNB.
Lenti go ma l i gna mel a noma a nd l enti go ma l i gna a re us ua l l y trea ted wi th wi de l oca l exci s i on a nd, i f neces s a ry, s ki n gra fti ng. Intens i ve ra di a ti on
thera py i s much l es s effecti ve. Trea tment of l enti go ma l i gna i ncl udes ea rl y exci s i on (before the l es i on i s very l a rge), i mi qui mod, a nd control l ed
cryothera py. Mos t other trea tment methods us ua l l y do not penetra te deepl y enough i nto i nvol ved fol l i cl es , whi ch mus t be removed.
Sprea di ng or nodul a r mel a noma s a re us ua l l y trea ted wi th wi de l oca l exci s i on extendi ng down to the fa s ci a . Lymph node di s s ecti on ma y be
recommended when nodes a re i nvol ved. (See a l s o the Ameri ca n Aca demy of Derma tol ogy As s oci a ti on's Gui del i nes of Ca re for Pri ma ry Cuta neous
Mel a noma .)
Metastatic disease: Meta s ta ti c di s ea s e i s genera l l y i nopera bl e, but i n certa i n ca s es , l oca l i zed a nd regi ona l meta s ta s es ca n be exci s ed.
Chemothera py wi th da ca rba zi ne or temozol a mi de (ora l da ca rba zi ne a na l og) a nd a l des l euki n ca n be us ed for the trea tment of meta s ta ti c
mel a noma . Adjuva nt thera py wi th recombi na nt bi ol ogi c res pons e modi fi ers (pa rti cul a rl y i nterferon a l fa ) to s uppres s cl i ni ca l l y i na ppa rent
mi crometa s ta s es ma y a l s o be us ed for i nopera bl e meta s ta ti c mel a noma . Bra i n meta s ta s es ma y be trea ted wi th pa l l i a ti ve ra di a ti on, but the
res pons e i s poor.
The fol l owi ng a re under s tudy:
Infus i on of l ymphoki ne-a cti va ted ki l l er cel l s or a nti bodi es (for a dva nced-s ta ge di s ea s e)
Va cci ne thera py
Kaposi's Sarcoma
(Mul ti pl e Idi opa thi c Hemorrha gi c Sa rcoma )
Kaposi's sarcoma (KS) is a multicentric vascular tumor caused by herpesvirus type 8. It can occur in classic, AIDS-associated, endemic, and iatrogenic forms.
Diagnosis is by biopsy. Treatment for indolent superficial lesions involves cryotherapy, electrocoagulation, excision, or electron beam radiation therapy. Radiation
therapy is used for more extensive disease. In the AIDS-associated form, antiretrovirals provide the most improvement.
KS ori gi na tes from endothel i a l cel l s i n res pons e to i nfecti on by huma n herpes vi rus 8 (HHV-8). Immunos uppres s i on (pa rti cul a rl y by AIDS a nd drugs
for orga n tra ns pl a nt reci pi ents ) ma rkedl y i ncrea s es the l i kel i hood of KS i n HHV-8-i nfected pa ti ents . The tumor cel l s ha ve a s pi ndl e s ha pe,
res embl i ng s mooth mus cl e cel l s , fi brobl a s ts , a nd myofi brobl a s ts .
Classification
Classic KS: Thi s form occurs mos t often i n ol der (> 60 yr) men of Ita l i a n, Jewi s h, or Ea s tern Europea n a nces try. The cours e i s i ndol ent, a nd the
di s ea s e i s us ua l l y confi ned to a s ma l l number of l es i ons on the s ki n of the l ower extremi ti es (s ee
Pl a te 36); vi s cera l i nvol vement occurs i n < 10%. Thi s form i s us ua l l y not fa ta l .
AIDS-associated (epidemic) KS: Thi s form i s the mos t common AIDS-a s s oci a ted ca ncer a nd i s more a ggres s i ve tha n cl a s s i c KS. Mul ti pl e cuta neous
l es i ons a re typi ca l l y pres ent, often i nvol vi ng the fa ce a nd trunk. Mucos a l , l ymph node, a nd GI i nvol vement i s common. Someti mes KS i s the fi rs t
ma ni fes ta ti on of AIDS.
Endemic KS: Thi s form occurs i n Afri ca i ndependent of HIV i nfecti on. There a re 2 ma i n types :
Prepuberta l l ympha denopa thi c form: It predomi na ntl y a ffects chi l dren; pri ma ry tumors i nvol ve l ymph nodes , wi th or wi thout s ki n l es i ons . The
cours e i s us ua l l y ful mi na nt a nd fa ta l .
Adul t form: Thi s form res embl es cl a s s i c KS.
Iatrogenic (immunosuppressive) KS: Thi s form typi ca l l y devel ops s evera l yea rs a fter orga n tra ns pl a nta ti on. The cours e i s more or l es s ful mi na nt,
dependi ng on the degree of i mmunos uppres s i on.
Symptoms and Signs
Cuta neous l es i ons a re a s ymptoma ti c purpl e, pi nk, or red ma cul es tha t ma y coa l es ce i nto bl ue-vi ol et to bl a ck pl a ques a nd nodul es . Some edema
ma y be pres ent. Occa s i ona l l y, nodul es funga te or penetra te s oft ti s s ue a nd i nva de bone. Mucos a l l es i ons a ppea r a s bl ui s h to vi ol a ceous
ma cul es , pl a ques , a nd tumors . GI l es i ons ca n bl eed, s ometi mes extens i vel y, but us ua l l y a re a s ymptoma ti c.
Diagnosis
Bi ops y
Di a gnos i s i s confi rmed by punch bi ops y. Pa ti ents wi th AIDS or i mmunos uppres s i on requi re eva l ua ti on for vi s cera l s prea d by CT of the ches t a nd
a bdomen. If CT i s nega ti ve but pul mona ry or GI s ymptoms a re pres ent, bronchos copy or GI endos copy s houl d be cons i dered.
Treatment
Surgi ca l exci s i on, cryothera py, or el ectrocoa gul a ti on for s uperfi ci a l l es i ons
Loca l ra di a ti on thera py for mul ti pl e l es i ons or l ymph node di s ea s e
Anti retrovi ra l thera py or s ometi mes IV i nterferon a l fa for AIDS-a s s oci a ted KS
Reducti on of i mmunos uppres s a nts for i a trogeni c KS
Indol ent l es i ons often requi re no trea tment. One or a few s uperfi ci a l l es i ons ca n be removed by exci s i on, cryothera py, or el ectrocoa gul a ti on.
Intra l es i ona l vi nbl a s ti ne or i nterferon a l fa i s a l s o us eful . Mul ti pl e l es i ons a nd l ymph node di s ea s e a re trea ted l oca l l y wi th 10 to 20 Gy of
ra di a ti on thera py.
AIDS-a s s oci a ted KS res ponds ma rkedl y to hi ghl y a cti ve a nti retrovi ra l thera py (HAART), proba bl y beca us e CD4+ count i mproves a nd HIV vi ra l l oa d
decrea s es ; however, there i s s ome evi dence tha t protea s e i nhi bi tors i n thi s regi men ma y bl ock a ngi ogenes i s . AIDS pa ti ents wi th i ndol ent di s ea s e
a nd CD4+ counts > 150/L a nd HIV RNA < 500 copi es /mL ca n be trea ted wi th IV i nterferon a l fa . Pa ti ents wi th more extens i ve or vi s cera l di s ea s e ca n
be gi ven l i pos oma l doxorubi ci n 20 mg/m 2 IV q 2 to 3 wk. If thi s regi men fa i l s , pa ti ents ma y recei ve pa cl i ta xel . Other a gents bei ng i nves ti ga ted a s
a djuncts i ncl ude IL-12, des ferri oxa mi ne, a nd ora l reti noi ds . Trea tment of KS does not prol ong l i fe i n mos t AIDS pa ti ents beca us e i nfecti ons
domi na te the cl i ni ca l cours e.
Ia trogeni c KS res ponds bes t to s toppi ng i mmunos uppres s a nts . In orga n tra ns pl a nt pa ti ents , reducti on of i mmunos uppres s a nt dos a ge often
res ul ts i n reducti on of KS l es i ons . If dos a ge reducti on i s not pos s i bl e, conventi ona l l oca l a nd s ys temi c thera pi es us ed i n other forms of KS s houl d
be i ns ti tuted. Si rol i mus ma y a l s o i mprove i a trogeni c KS.
Trea tment of endemi c KS i s cha l l engi ng a nd typi ca l l y pa l l i a ti ve.
Paget's Disease of the Nipple
Paget's disease is a rare type of carcinoma that appears as a unilateral eczematous to psoriasiform plaque surrounding the nipple. It involves extension to the
epidermis of an underlying ductal adenocarcinoma of the breast.
Pa get's di s ea s e of the ni ppl e s houl d not be confus ed wi th the meta bol i c bone di s ea s e tha t i s a l s o ca l l ed Pa get's di s ea s e. In Pa get's di s ea s e of
the ni ppl e, meta s ta ti c di s ea s e i s often pres ent a t the ti me of the di a gnos i s .
Pa get's di s ea s e of the ni ppl e a l s o occurs a t other s i tes , mos t often i n the groi n or peri a na l a rea (extra ma mma ry Pa get's di s ea s e). The bl a dder,
a nus , a nd rectum a re the mos t common s i tes . Extra ma mma ry Pa get's di s ea s e i s a ra re i ntra epi thel i a l a denoca rci noma of a pocri ne gl a nd-bea ri ng
s i tes .
Diagnosis
Bi ops y
The rednes s , oozi ng, a nd crus ti ng cl os el y res embl e derma ti ti s ; but phys i ci a ns s houl d s us pect ca rci noma beca us e the l es i on i s s ha rpl y
ma rgi na ted, uni l a tera l , a nd unres pons i ve to topi ca l thera py. Bi ops y s hows typi ca l hi s tol ogi c cha nges . Beca us e thi s tumor i s a s s oci a ted wi th
underl yi ng ca ncer, s ys temi c eva l ua ti on i s requi red.
Treatment
Trea tment i nvol ves s urgi ca l remova l of di s covered tumors , i ncl udi ng pos s i bl e ma s tectomy for di s ea s e i nvol vi ng the ni ppl e. Trea tment ma y a l s o
i nvol ve a bl a ti on of overl yi ng cuta neous i nvol vement, ei ther s urgi ca l l y or by CO2 l a s er a bl a ti on.
8 - Endocrine and Metabolic Disorders

Chapter 91. Principles of Endocrinology
Introduction
The endocri ne s ys tem coordi na tes functi oni ng between di fferent orga ns through hormones , whi ch a re rel ea s ed i nto the bl oods trea m from s peci fi c
types of cel l s wi thi n endocri ne (ductl es s ) gl a nds . Once i n ci rcul a ti on, hormones a ffect functi on of the ta rget ti s s ue. Some hormones exert a n effect
on cel l s of the orga n from whi ch they were rel ea s ed (pa ra cri ne effect), s ome even on the s a me cel l type (a utocri ne effect). Hormones ca n be
pepti des of va ri ous s i zes , s teroi ds (deri ved from chol es terol ), or a mi no a ci d deri va ti ves .
Hormones bi nd s el ecti vel y to receptors l oca ted i ns i de or on the s urfa ce of ta rget cel l s . Receptors i ns i de cel l s i ntera ct wi th hormones tha t regul a te
gene functi on (eg, corti cos teroi ds , vi ta mi n D, thyroi d hormone). Receptors on the cel l s urfa ce bi nd wi th hormones tha t regul a te enzyme a cti vi ty or
a ffect i on cha nnel s (eg, growth hormone, thyrotropi n-rel ea s i ng hormone).
Hypothalamic-Pituitary Relationships
Peri phera l endocri ne orga n functi ons a re control l ed to va ryi ng degrees by pi tui ta ry hormones (s ee a l s o Ch. 92). Some functi ons (eg, s ecreti on of
i ns ul i n by the pa ncrea s , pri ma ri l y control l ed by the bl ood gl ucos e l evel ) a re control l ed to a mi ni ma l extent, wherea s ma ny (eg, s ecreti on of thyroi d
or gona da l hormones ) a re control l ed to a grea t extent. Secreti on of pi tui ta ry hormones i s control l ed by the hypotha l a mus .
The i ntera cti on between the hypotha l a mus a nd pi tui ta ry (hypotha l a mi c-pi tui ta ry a xi s ) i s a feedba ck control s ys tem. The hypotha l a mus recei ves
i nput from vi rtua l l y a l l other a rea s of the CNS a nd us es i t to provi de i nput to the pi tui ta ry. In res pons e, the pi tui ta ry rel ea s es va ri ous hormones
tha t s ti mul a te certa i n endocri ne gl a nds throughout the body. Cha nges i n ci rcul a ti ng l evel s of hormones produced by thes e endocri ne gl a nds a re
detected by the hypotha l a mus , whi ch then i ncrea s es or decrea s es i ts s ti mul a ti on of the pi tui ta ry to ma i nta i n homeos ta s i s .
The hypotha l a mus modul a tes the a cti vi ti es of the a nteri or a nd pos teri or l obes of the pi tui ta ry i n di fferent wa ys . Neurohormones s ynthes i zed i n
the hypotha l a mus rea ch the a nteri or pi tui ta ry (a denohypophys i s ) through a s peci a l i zed porta l va s cul a r s ys tem a nd regul a te s ynthes i s a nd rel ea s e
of the 6 ma jor pepti de hormones of the a nteri or pi tui ta ry. Thes e a nteri or pi tui ta ry hormones regul a te peri phera l endocri ne gl a nds (the thyroi d,
a drena l s , a nd gona ds ) a s wel l a s growth a nd l a cta ti on. No di rect neura l connecti on exi s ts between the hypotha l a mus a nd the a nteri or pi tui ta ry.
In contra s t, the pos teri or pi tui ta ry (neurohypophys i s ) compri s es a xons ori gi na ti ng from neurona l cel l bodi es l oca ted i n the hypotha l a mus . Thes e
a xons s erve a s s tora ge s i tes for 2 pepti de hormones s ynthes i zed i n the hypotha l a mus ; thes e hormones a ct i n the peri phery to regul a te wa ter
ba l a nce, mi l k ejecti on, a nd uteri ne contra cti on.
Vi rtua l l y a l l hormones produced by the hypotha l a mus a nd the pi tui ta ry a re rel ea s ed i n a pul s a ti l e fa s hi on; peri ods of s uch rel ea s e a re
i nters pers ed wi th peri ods of i na cti vi ty. Some hormones (eg, a drenocorti cotropi c hormone [ACTH], growth hormone, prol a cti n) ha ve defi ni te
ci rca di a n rhythms ; others (eg, l utei ni zi ng hormone a nd fol l i cl e-s ti mul a ti ng hormone duri ng the mens trua l cycl e) ha ve month-l ong rhythms wi th
s uperi mpos ed ci rca di a n rhythms .
Hypothalamic Controls
Thus fa r, 7 phys i ol ogi ca l l y i mporta nt hypotha l a mi c neurohormones ha ve been i denti fi ed (s ee
Ta bl e 91-1). Except for the bi ogeni c a mi ne dopa mi ne, a l l a re s ma l l pepti des . Severa l a re produced i n the peri phery a s wel l a s i n the hypotha l a mus
a nd functi on i n l oca l pa ra cri ne s ys tems , es peci a l l y i n the GI tra ct. Va s oa cti ve i ntes ti na l pepti de, whi ch a l s o s ti mul a tes the rel ea s e of prol a cti n, i s
one. Neurohormones ma y control the rel ea s e of mul ti pl e pi tui ta ry hormones . Regul a ti on of mos t a nteri or pi tui ta ry hormones depends on
s ti mul a tory s i gna l s from the hypotha l a mus ; the excepti on i s prol a cti n, whi ch i s regul a ted by i nhi bi tory s ti mul i . If the pi tui ta ry s ta l k (whi ch
connects the pi tui ta ry to the hypotha l a mus ) i s s evered, prol a cti n rel ea s e i ncrea s es , wherea s rel ea s e of a l l other a nteri or pi tui ta ry hormones
decrea s es .
Ma ny hypotha l a mi c a bnorma l i ti es (i ncl udi ng tumors a nd encepha l i ti s a nd other i nfl a mma tory l es i ons ) ca n a l ter the rel ea s e of hypotha l a mi c
neurohormones . Beca us e neurohormones a re s ynthes i zed i n di fferent centers wi thi n the hypotha l a mus , s ome di s orders a ffect onl y one
neuropepti de, wherea s others a ffect s evera l . The res ul t ca n be unders ecreti on or overs ecreti on of neurohormones . Cl i ni ca l s yndromes tha t res ul t
from the ens ui ng pi tui ta ry hormone dys functi on (eg, di a betes i ns i pi dus , a cromega l y, hypopi tui ta ri s m) a re di s cus s ed i n Ch. 92.
Anterior Pituitary Function
The cel l s of the a nteri or l obe (whi ch cons ti tutes 80% of the pi tui ta ry by wei ght) s ynthes i ze a nd rel ea s e s evera l hormones neces s a ry for norma l
growth a nd devel opment a nd a l s o s ti mul a te the a cti vi ty of s evera l ta rget gl a nds .
Adrenocorticotropic hormone (ACTH): ACTH i s a l s o known a s corti cotropi n. Corti cotropi n-rel ea s i ng hormone (CRH) i s the pri ma ry s ti mul a tor of ACTH
rel ea s e, but a nti di ureti c hormone pl a ys a rol e duri ng s tres s . ACTH i nduces the a drena l cortex to rel ea s e corti s ol a nd s evera l wea k a ndrogens ,
s uch a s dehydroepi a ndros terone (DHEA). Ci rcul a ti ng corti s ol a nd other corti cos teroi ds (i ncl udi ng exogenous corti cos teroi ds ) i nhi bi t the rel ea s e of
CRH a nd ACTH. The CRH-ACTH-corti s ol a xi s i s a centra l component of the res pons e to s tres s . Wi thout ACTH, the a drena l cortex a trophi es a nd
corti s ol rel ea s e vi rtua l l y cea s es .
[Table 91-1. Hypotha l a mi c Neurohormones ]
Thyroid-stimulating hormone (TSH): TSH regul a tes the s tructure a nd functi on of the thyroi d gl a nd a nd s ti mul a tes s ynthes i s a nd rel ea s e of thyroi d
hormones . TSH s ynthes i s a nd rel ea s e a re s ti mul a ted by the hypotha l a mi c hormone thyrotropi n-rel ea s i ng hormone (TRH) a nd s uppres s ed (by
nega ti ve feedba ck) by ci rcul a ti ng thyroi d hormones .
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): LH a nd FSH control the producti on of the s ex hormones . Synthes i s a nd rel ea s e of LH
a nd FSH a re s ti mul a ted by gona dotropi n-rel ea s i ng hormone (GnRH) a nd s uppres s ed by es trogen a nd tes tos terone. In women, LH a nd FSH
s ti mul a te ova ri a n fol l i cul a r devel opment a nd ovul a ti on (s ee p. 2497). In men, FSH a cts on Sertol i cel l s a nd i s es s enti a l for s perma togenes i s ; LH
a cts on Leydi g cel l s of the tes tes to s ti mul a te tes tos terone bi os ynthes i s (s ee p. 2339).
Growth hormone (GH): GH s ti mul a tes s oma ti c growth a nd regul a tes meta bol i s m. Growth hormone-rel ea s i ng hormone (GHRH) i s the ma jor
s ti mul a tor a nd s oma tos ta ti n i s the ma jor i nhi bi tor of the s ynthes i s a nd rel ea s e of GH. GH control s s ynthes i s of i ns ul i n-l i ke growth fa ctor 1 (IGF-1,
a l s o ca l l ed s oma tomedi n-C), whi ch l a rgel y control s growth. Al though IGF-1 i s produced by ma ny ti s s ues , the l i ver i s the ma jor s ource. A va ri a nt of
IGF-1 occurs i n mus cl e, where i t pl a ys a rol e i n enha nci ng mus cl e s trength. It i s l es s under control of GH tha n i s the l i ver va ri a nt.
The meta bol i c effects of GH a re bi pha s i c. GH i ni ti a l l y exerts i ns ul i n-l i ke effects , i ncrea s i ng gl ucos e upta ke i n mus cl e a nd fa t, s ti mul a ti ng a mi no
a ci d upta ke a nd protei n s ynthes i s i n l i ver a nd mus cl e, a nd i nhi bi ti ng l i pol ys i s i n a di pos e ti s s ue. Severa l hours l a ter, more profound a nti -i ns ul i nl i ke meta bol i c effects occur. They i ncl ude i nhi bi ti on of gl ucos e upta ke a nd us e, ca us i ng bl ood gl ucos e a nd l i pol ys i s to i ncrea s e, whi ch i ncrea s es
pl a s ma free fa tty a ci ds . GH l evel s i ncrea s e duri ng fa s ti ng, ma i nta i ni ng bl ood gl ucos e l evel s a nd mobi l i zi ng fa t a s a n a l terna ti ve meta bol i c fuel .
Producti on of GH decrea s es wi th a gi ng. Ghrel i n, a hormone produced i n the fundus of the s toma ch, promotes GH rel ea s e from the pi tui ta ry,
i ncrea s es food i nta ke, a nd i mproves memory.
Prolactin: Prol a cti n i s produced i n cel l s ca l l ed l a ctotrophs tha t cons ti tute a bout 30% of the cel l s of the a nteri or pi tui ta ry. The pi tui ta ry doubl es i n
s i ze duri ng pregna ncy, l a rgel y beca us e of hyperpl a s i a a nd hypertrophy of l a ctotrophs . In huma ns , the ma jor functi on of prol a cti n i s s ti mul a ti ng
mi l k producti on. Al s o, prol a cti n rel ea s e occurs duri ng s exua l a cti vi ty a nd s tres s . Prol a cti n ma y be a s ens i ti ve i ndi ca tor of pi tui ta ry dys functi on;
prol a cti n i s the hormone mos t frequentl y produced i n exces s by pi tui ta ry tumors , a nd i t ma y be one of the hormones to become defi ci ent from
i nfi l tra ti ve di s ea s e or tumor compres s i on of the pi tui ta ry.
Other hormones: Severa l other hormones a re produced by the a nteri or pi tui ta ry. Thes e i ncl ude pro-opi omel a nocorti n (POMC, whi ch gi ves ri s e to
ACTH), - a nd -mel a nocyte-s ti mul a ti ng hormone (MSH), -l i potropi n (-LPH), the enkepha l i ns , a nd the endorphi ns . POMC a nd MSH ca n ca us e
hyperpi gmenta ti on of the s ki n a nd a re onl y s i gni fi ca nt cl i ni ca l l y i n di s orders i n whi ch ACTH l evel s a re ma rkedl y el eva ted (eg, Addi s on's di s ea s e,
Nel s on s yndrome). The functi on of -LPH i s unknown. Enkepha l i ns a nd endorphi ns a re endogenous opi oi ds tha t bi nd to a nd a cti va te opi oi d
receptors throughout the CNS.
Posterior Pituitary Function
The pos teri or pi tui ta ry rel ea s es a nti di ureti c hormone (a l s o ca l l ed va s opres s i n or a rgi ni ne va s opres s i n) a nd oxytoci n. Both hormones a re rel ea s ed
i n res pons e to neura l i mpul s es a nd ha ve ha l f-l i ves of a bout 10 mi n.
Antidiuretic hormone (ADH): ADH a cts pri ma ri l y to promote wa ter cons erva ti on by the ki dney by i ncrea s i ng the permea bi l i ty of the di s ta l tubul a r
epi thel i um to wa ter. At hi gh concentra ti ons , ADH a l s o ca us es va s ocons tri cti on. Li ke a l dos terone, ADH pl a ys a n i mporta nt rol e i n ma i nta i ni ng fl ui d
homeos ta s i s a nd va s cul a r a nd cel l ul a r hydra ti on. The ma i n s ti mul us for ADH rel ea s e i s i ncrea s ed os moti c pres s ure of wa ter i n the body, whi ch i s
s ens ed by os moreceptors i n the hypotha l a mus . The other ma jor s ti mul us i s vol ume depl eti on, whi ch i s s ens ed by ba roreceptors i n the l eft a tri um,
pul mona ry vei ns , ca roti d s i nus , a nd a orti c a rch, a nd then tra ns mi tted to the CNS through the va gus a nd gl os s opha ryngea l nerves . Other s ti mul a nts
for ADH rel ea s e i ncl ude pa i n, s tres s , emes i s , hypoxi a , exerci s e, hypogl ycemi a , chol i nergi c a goni s ts , -bl ockers , a ngi otens i n, a nd pros ta gl a ndi ns .
Inhi bi tors of ADH rel ea s e i ncl ude a l cohol , -bl ockers , a nd gl ucocorti coi ds .
A l a ck of ADH ca us es centra l di a betes i ns i pi dus (s ee p. 772); a n i na bi l i ty of the ki dneys to res pond norma l l y to ADH ca us es nephrogeni c di a betes
i ns i pi dus (s ee p. 2424). Remova l of the pi tui ta ry gl a nd us ua l l y does not res ul t i n perma nent di a betes i ns i pi dus beca us e s ome of the rema i ni ng
hypotha l a mi c neurons produce s ma l l a mounts of ADH. Copepti n i s coproduced wi th ADH i n the pos teri or pi tui ta ry. Mea s uri ng i t ma y be us eful i n
di s ti ngui s hi ng the ca us e of hypona tremi a .
Oxytocin: Oxytoci n ha s 2 ma jor ta rgets : the myoepi thel i a l cel l s of the brea s t, whi ch s urround the a l veol i of the ma mma ry gl a nd, a nd the s mooth
mus cl e cel l s of the uterus . Suckl i ng s ti mul a tes the producti on of oxytoci n, whi ch ca us es the myoepi thel i a l cel l s to contra ct. Thi s contra cti on
ca us es mi l k to move from the a l veol i to l a rge s i nus es for ejecti on (i e, the mi l k l etdown refl ex of nurs i ng mothers ). Oxytoci n s ti mul a tes contra cti on
of uteri ne s mooth mus cl e cel l s , a nd uteri ne s ens i ti vi ty to oxytoci n i ncrea s es throughout pregna ncy. However, pl a s ma l evel s do not i ncrea s e
s ha rpl y duri ng pa rturi ti on, a nd the rol e of oxytoci n i n the i ni ti a ti on of l a bor i s uncl ea r. There i s no recogni zed s ti mul us for oxytoci n rel ea s e i n
men, a l though men ha ve extremel y l ow l evel s .
Endocrine Disorders
Endocri ne di s orders ca n res ul t from dys functi on ori gi na ti ng i n the peri phera l endocri ne gl a nd i ts el f (pri ma ry di s orders ) or from unders ti mul a ti on
or overs ti mul a ti on by the pi tui ta ry (s econda ry di s orders ). The di s orders ca n res ul t i n hormone overproducti on (hyperfuncti on) or underproducti on
(hypofuncti on). Ra rel y, endocri ne di s orders (us ua l l y hypofuncti on) occur beca us e of a bnorma l ti s s ue res pons es to hormones . Cl i ni ca l
ma ni fes ta ti ons of hypofuncti on di s orders a re often i ns i di ous a nd nons peci fi c.
Hyperfunction: Hyperfuncti on of endocri ne gl a nds ma y res ul t from overs ti mul a ti on by the pi tui ta ry but i s mos t commonl y due to hyperpl a s i a or
neopl a s i a of the gl a nd i ts el f. In s ome ca s es , ca ncers from other ti s s ues ca n produce hormones (ectopi c hormone producti on). Hormone exces s
a l s o ca n res ul t from exogenous hormone a dmi ni s tra ti on. In s ome ca s es , pa ti ents ta ke hormones wi thout tel l i ng the phys i ci a n (fa cti ti ous
di s ea s e). Ti s s ue hypers ens i ti vi ty to hormones ca n occur. Anti bodi es ca n s ti mul a te peri phera l endocri ne gl a nds , a s occurs i n hyperthyroi di s m of
Gra ves ' di s ea s e. Des tructi on of a peri phera l endocri ne gl a nd ca n ra pi dl y rel ea s e s tored hormone (eg, thyroi d hormones i n thyroi di ti s ). Enzyme
defects i n the s ynthes i s of a peri phera l endocri ne hormone ca n res ul t i n overproducti on of hormones proxi ma l to the bl ock. Fi na l l y,
overproducti on of a hormone ca n occur a s a n a ppropri a te res pons e to a di s ea s e s ta te.
Hypofunction: Hypofuncti on of a n endocri ne gl a nd ca n res ul t from unders ti mul a ti on by the pi tui ta ry. Hypofuncti on ori gi na ti ng wi thi n the peri phera l
gl a nd i ts el f ca n res ul t from congeni ta l or a cqui red di s orders (i ncl udi ng a utoi mmune di s orders , tumors , i nfecti ons , va s cul a r di s orders , a nd toxi ns ).
Geneti c di s orders ca us i ng hypofuncti on ca n res ul t from del eti on of a gene or by producti on of a n a bnorma l hormone. A decrea s e i n hormone
producti on by the peri phera l endocri ne gl a nd wi th a res ul ti ng i ncrea s e i n producti on of pi tui ta ry regul a ti ng hormone ca n l ea d to peri phera l
endocri ne gl a nd hyperpl a s i a . For exa mpl e, i f s ynthes i s of thyroi d hormone i s defecti ve, thyroi d-s ti mul a ti ng hormone (TSH) i s produced i n
exces s i ve a mounts , ca us i ng goi ter.
Severa l hormones requi re convers i on to a n a cti ve form a fter s ecreti on from the peri phera l endocri ne gl a nd. Certa i n di s orders ca n bl ock thi s s tep
(eg, rena l di s ea s e ca n i nhi bi t producti on of the a cti ve form of vi ta mi n D). Anti bodi es to the ci rcul a ti ng hormone or i ts receptor ca n bl ock the a bi l i ty
of the hormone to bi nd to i ts receptor. Di s ea s e or drugs ca n ca us e i ncrea s ed ra te of cl ea ra nce of hormones . Ci rcul a ti ng s ubs ta nces ma y a l s o bl ock
the functi on of hormones . Abnorma l i ti es of the receptor or el s ewhere i n the peri phera l endocri ne ti s s ue ca n a l s o ca us e hypofuncti on.
Laboratory Testing
Beca us e s ymptoms of endocri ne di s orders ca n begi n i ns i di ous l y a nd ma y be nons peci fi c, cl i ni ca l recogni ti on i s often del a yed for months or yea rs .
For thi s rea s on, bi ochemi ca l di a gnos i s i s us ua l l y es s enti a l ; i t typi ca l l y requi res mea s uri ng l evel s of the peri phera l endocri ne hormone, the
pi tui ta ry hormone, or both i n the bl ood.
Free or bi oa va i l a bl e hormone (i e, hormone not bound to a s peci fi c bi ndi ng hormone) i s genera l l y bel i eved to be the a cti ve form. Free or
bi oa va i l a bl e hormones a re mea s ured us i ng equi l i bri um di a l ys i s , ul tra fi l tra ti on, or a s ol vent-extra cti on method to s epa ra te the free a nd a l bumi nbound hormone from the bi ndi ng gl obul i n. Thes e methods ca n be expens i ve a nd ti me-cons umi ng. Ana l og a nd competi ti ve free hormone a s s a ys ,
a l though often us ed commerci a l l y, a re not a l wa ys a ccura te a nd s houl d not be us ed.
Free hormone l evel s ca n a l s o be es ti ma ted i ndi rectl y by a s s es s i ng l evel s of the bi ndi ng protei n a nd us i ng them to a djus t l evel s of the tota l s erum
hormone. However, i ndi rect methods a re i na ccura te i f the bi ndi ng ca pa ci ty of the hormone-bi ndi ng protei n ha s been a l tered (eg, by a di s order).
Beca us e mos t hormones ha ve ci rca di a n rhythms , mea s urements need to be ma de a t a pres cri bed ti me of da y. Hormones tha t va ry over s hort
peri ods (eg, l utei ni zi ng hormone) neces s i ta te obta i ni ng 3 or 4 va l ues over 1 or 2 h or us i ng a pool ed bl ood s a mpl e. Hormones wi th week-to-week
va ri a ti on (eg, tes tos terone) neces s i ta te obta i ni ng s epa ra te va l ues a week a pa rt.
In s ome ca s es , i ndi rect es ti ma tes a re us ed. For exa mpl e, beca us e growth hormone (GH) ha s a s hort s erum ha l f-l i fe a nd i s di ffi cul t to detect i n
s erum, s erum i ns ul i n-l i ke growth fa ctor 1 (IGF-1), whi ch i s produced i n res pons e to GH, i s often mea s ured a s a n i ndex of GH a cti vi ty. Someti mes ,
uri ne (eg, free corti s ol when tes ti ng for Cus hi ng's di s ea s e) or s a l i va ry hormone l evel s ma y be us ed. Whether mea s urement of ci rcul a ti ng hormone
meta bol i tes i ndi ca tes the a mount of bi oa va i l a bl e hormone i s under i nves ti ga ti on.
In ma ny ca s es , a dyna mi c tes t i s neces s a ry. Thus , i n the ca s e of hypofuncti oni ng orga ns , a s ti mul a ti ng tes t ca n be us ed. In hyperfuncti on, a
s uppres s i ve tes t ca n be us ed.
Treatment
Hypofuncti on di s orders a re us ua l l y trea ted by repl a cement of the peri phera l endocri ne hormone rega rdl es s of whether the defect i s pri ma ry or
s econda ry (a n excepti on i s GH repl a cement for pi tui ta ry dwa rfi s m). If res i s ta nce to the hormone exi s ts , drugs tha t reduce res i s ta nce ca n be us ed
(eg, metformi n or thi a zol i di nedi ones for type 2 di a betes mel l i tus ). Occa s i ona l l y, a hormone-s ti mul a ti ng drug i s us ed.
Ra di a ti on thera py, s urgery, a nd drugs tha t s uppres s hormone producti on a re us ed to trea t hyperfuncti on di s orders . In s ome ca s es , a receptor
a nta goni s t i s us ed.
Aging and Endocrinology
Hormones undergo ma ny cha nges a s a pers on a ges . Mos t hormone l evel s decrea s e. Some rema i n norma l , i ncl udi ng TSH, ACTH (ba s a l ), thyroxi ne,
corti s ol (ba s a l ), 1,25-di hydroxychol eca l ci ferol , i ns ul i n (s ometi mes i ncrea s es ), a nd es tra di ol (i n men). Hormones tha t i ncrea s e, i ncl udi ng ACTH
(i ncrea s ed res pons e to corti cotropi n-rel ea s i ng hormone), fol l i cl e-s ti mul a ti ng hormone, s ex-hormone bi ndi ng gl obul i n, a nd a cti vi n (i n men),
gona dotropi ns (i n women), epi nephri ne (i n the ol des t ol d), pa ra thyroi d hormone, norepi nephri ne, chol ecys toki ni n, va s oa cti ve i ntes ti na l pepti de
a nd ADH (a l s o l os s of ci rca di a n rhythm), a nd a tri a l na tri ureti c fa ctor, a re a s s oci a ted wi th ei ther receptor defects or pos treceptor defects , res ul ti ng
i n hypofuncti on. Ma ny a ge-rel a ted cha nges a re s i mi l a r to thos e i n pa ti ents wi th hormone defi ci ency, l ea di ng to the hypothes i s of a hormona l
founta i n of youth (i e, s pecul a ti on tha t s ome cha nges a s s oci a ted wi th a gi ng ca n be revers ed by the repl a cement of one or more defi ci ent
hormones ). Some evi dence s ugges ts tha t repl a ci ng certa i n hormones i n the el derl y ca n i mprove functi ona l outcomes (eg, mus cl e s trength, bone
mi nera l dens i ty), but l i ttl e evi dence exi s ts rega rdi ng effects on morta l i ty. In s ome ca s es , repl a ci ng hormones ma y be ha rmful , a s i n es trogen
repl a cement i n mos t ol der women.
A competi ng theory i s tha t the a ge-rel a ted decl i ne i n hormone l evel s repres ents a protecti ve s l owi ng down of cel l ul a r meta bol i s m. Thi s concept i s
ba s ed on the ra te of l i vi ng theory of a gi ng (i e, the fa s ter the meta bol i c ra te of a n orga ni s m, the qui cker i t di es ). Thi s concept i s s eemi ngl y
s upported by s tudi es on the effects of di eta ry res tri cti on. Res tri cti on decrea s es l evel s of hormones tha t s ti mul a te meta bol i s m, thereby s l owi ng
meta bol i c ra te; thi s prol ongs l i fe i n rodents .
Dehydroepi a ndros terone (DHEA) a nd i ts s ul fa te l evel s decl i ne dra ma ti ca l l y wi th a ge. Des pi te opti mi s m for the rol e of DHEA s uppl ementa ti on i n
ol der peopl e, mos t control l ed tri a l s fa i l ed to s how a ny ma jor benefi ts .
Pregnenol one i s the precurs or of a l l known s teroi d hormones . As wi th DHEA, i ts l evel s decl i ne wi th a ge. Studi es i n the 1940s s howed i ts s a fety
a nd benefi ts i n peopl e wi th a rthri ti s , but a ddi ti ona l s tudi es fa i l ed to s how a ny benefi ci a l effects on memory a nd mus cl e s trength.
Level s of GH a nd i ts peri phera l endocri ne hormone (IGF-1) decl i ne wi th a ge. GH repl a cement i n ol der peopl e s ometi mes i ncrea s es mus cl e ma s s
but does not i ncrea s e mus cl e s trength (a l though i t ma y i n ma l nouri s hed peopl e). Advers e effects (eg, ca rpa l tunnel s yndrome, a rthra l gi a s , wa ter
retenti on) a re very common. GH ma y ha ve a rol e i n the s hort-term trea tment of s ome undernouri s hed ol der pa ti ents , but i n cri ti ca l l y i l l
undernouri s hed pa ti ents GH i ncrea s es morta l i ty. Secreta gogues tha t s ti mul a te GH producti on i n a more phys i ol ogi c pa ttern ma y i mprove benefi t
a nd decrea s e ri s k.
Level s of mel a toni n, a hormone produced by the pi nea l gl a nd, a l s o decl i ne wi th a gi ng. Thi s decl i ne ma y pl a y a n i mporta nt rol e i n the l os s of
ci rca di a n rhythms wi th a gi ng. Es trogen repl a cement i n ol der women i s di s cus s ed i n Ch. 247. Tes tos terone repl a cement i n ol der men i s di s cus s ed
i n Ch. 229.
Chapter 92. Pituitary Disorders

Introduction
The pi tui ta ry gl a nd control s the functi ons of peri phera l endocri ne gl a nds . Pi tui ta ry s tructure a nd functi on a nd rel a ti ons hi ps between the
hypotha l a mus a nd the pi tui ta ry gl a nd a re di s cus s ed i n Ch. 91.
Pituitary Lesions
Pa ti ents wi th hypotha l a mi c-pi tui ta ry l es i ons genera l l y pres ent wi th s ome combi na ti on of s ymptoms a nd s i gns of a ma s s l es i on (eg, hea da ches ,
vi s ua l fi el d defects pa rti cul a rl y bi tempora l hemi a nopi a or the hemi fi el d s l i de phenomenon [i ma ges dri fti ng a pa rt]a l tered a ppeti te, thi rs t);
i ma gi ng evi dence of a ma s s l es i on a s a n i nci denta l fi ndi ng; or hypers ecreti on or hypos ecreti on of one or more pi tui ta ry hormones .
The mos t common ca us e of hypopi tui ta ry or hyperpi tui ta ry s ecreti on i s a pi tui ta ry or hypotha l a mi c tumor. A pi tui ta ry tumor tends to produce a n
enl a rged s el l a (s el l a turci ca ). Al terna ti vel y, a n enl a rged s el l a ma y repres ent empty s el l a s yndrome.
Empty sella syndrome: In thi s di s order, the s el l a a ppea rs empty beca us e i t i s fi l l ed wi th CSF, whi ch fl a ttens the pi tui ta ry gl a nd a ga i ns t the wa l l of
the s el l a . The s yndrome ma y be congeni ta l , pri ma ry, or s econda ry to i njury (eg, i s chemi a a fter chi l dbi rth, s urgery, hea d tra uma , or ra di a ti on
thera py). The typi ca l pa ti ent i s fema l e (> 80%), obes e (a bout 75%), a nd hypertens i ve (30%) a nd ma y ha ve i di opa thi c i ntra cra ni a l hypertens i on (10%)
or s pi na l fl ui d rhi norrhea (10%). Pi tui ta ry functi on i n pa ti ents wi th empty s el l a s yndrome i s frequentl y norma l . However, hypopi tui ta ri s m ma y
occur, a s ma y hea da ches a nd vi s ua l fi el d defects . Occa s i ona l l y, pa ti ents ha ve s ma l l coexi s ti ng pi tui ta ry tumors tha t s ecrete growth hormone (GH),
prol a cti n, or ACTH. Di a gnos i s ca n be confi rmed by CT or MRI. No s peci fi c thera py i s needed for a n empty s el l a a l one.
Anterior lobe lesions: Hypers ecreti on of a nteri or l obe hormones (hyperpi tui ta ri s m) i s a l mos t a l wa ys s el ecti ve. The a nteri or pi tui ta ry hormones mos t
commonl y s ecreted i n exces s a re GH (a s i n a cromega l y, gi ga nti s m), prol a cti n (a s i n ga l a ctorrhea ), a nd ACTH (a s i n the pi tui ta ry type of Cus hi ng's
s yndrome). Hypos ecreti on of a nteri or l obe hormones (hypopi tui ta ri s m) ma y be genera l i zed, us ua l l y due to a pi tui ta ry tumor, or i s i di opa thi c, or
ma y i nvol ve the s el ecti ve l os s of one or a few pi tui ta ry hormones .
Posterior lobe lesions: The 2 pos teri or l obe hormones a re oxytoci n a nd ADH. In women, oxytoci n ca us es myoepi thel i a l cel l s of the brea s t a nd
myometri a l cel l s of the uterus to contra ct. Oxytoci n i s pres ent i n men but ha s no proven functi on. Defi ci ency of ADH res ul ts i n centra l di a betes
i ns i pi dus (s ee p. 772). Exces s ADH s ecreti on res ul ts i n the s yndrome of i na ppropri a te ADH s ecreti on (s ee Si deba r 97-1 on p. 826).
Generalized Hypopituitarism
Generalized hypopituitarism refers to endocrine deficiency syndromes due to partial or complete loss of anterior lobe pituitary function. Various clinical features
occur depending on the specific hormones that are deficient. Diagnosis involves imaging tests and measurement of pituitary hormone levels basally and after
various provocative stimuli. Treatment depends on cause but generally includes removal of any tumor and administration of replacement hormones.
The ma ny ca us es of hypopi tui ta ri s m a re l i s ted i n
Ta bl e 92-1.
Symptoms and Signs
Symptoms a nd s i gns rel a te to the underl yi ng di s order a nd to the s peci fi c pi tui ta ry hormones tha t a re defi ci ent or a bs ent. Ons et i s us ua l l y
i ns i di ous a nd ma y not be recogni zed by the pa ti ent; occa s i ona l l y, ons et i s s udden or dra ma ti c.
Mos t commonl y, growth hormone (GH) i s l os t fi rs t, then gona dotropi ns , a nd fi na l l y thyroi d-s ti mul a ti ng hormone (TSH) a nd ACTH. ADH defi ci ency i s
ra re i n pri ma ry pi tui ta ry di s ea s e but i s common wi th s ta l k a nd hypotha l a mi c l es i ons . Functi on of a l l ta rget gl a nds decrea s es when a l l hormones
a re defi ci ent (pa nhypopi tui ta ri s m).
La ck of l utei ni zi ng hormone (LH) a nd fol l i cl e-s ti mul a ti ng hormone (FSH) i n chi l dren l ea ds to del a yed puberty (s ee Hypopi tui ta ri s m i n Chi l dren
Res ul ti ng i n Short Sta ture on p. 767). Premenopa us a l women devel op a menorrhea , reduced l i bi do, regres s i on of s econda ry s exua l cha ra cteri s ti cs ,
a nd i nferti l i ty. Men devel op erecti l e dys functi on, tes ti cul a r
[Table 92-1. Ca us es of Hypopi tui ta ri s m]
a trophy, reduced l i bi do, regres s i on of s econda ry s exua l cha ra cteri s ti cs , a nd decrea s ed s perma togenes i s wi th cons equent i nferti l i ty.
GH defi ci ency ma y contri bute to decrea s ed energy but i s us ua l l y a s ymptoma ti c a nd cl i ni ca l l y undetecta bl e i n a dul ts (s ee p. 767 for effects i n
chi l dren). Sugges ti ons tha t GH defi ci ency a ccel era tes a theros cl eros i s a re unproved. TSH defi ci ency l ea ds to hypothyroi di s m, wi th s uch s ymptoms
a s fa ci a l puffi nes s , hoa rs e voi ce, bra dyca rdi a , a nd col d i ntol era nce. ACTH defi ci ency res ul ts i n hypoa drena l i s m wi th a ttenda nt fa ti gue,
hypotens i on, a nd i ntol era nce to s tres s a nd i nfecti on. ACTH defi ci ency does not res ul t i n the hyperpi gmenta ti on cha ra cteri s ti c of pri ma ry a drena l
fa i l ure.
Hypotha l a mi c l es i ons , whi ch ca n res ul t i n hypopi tui ta ri s m, ca n a l s o di s turb the centers tha t control a ppeti te, ca us i ng a s yndrome res embl i ng
a norexi a nervos a , or s ometi mes hyperpha gi a wi th ma s s i ve obes i ty.
Sheehan's syndrome, whi ch a ffects pos tpa rtum women, i s pi tui ta ry necros i s due to hypovol emi a a nd s hock occurri ng i n the i mmedi a te peri pa rtum
peri od. La cta ti on does not s ta rt a fter chi l dbi rth, a nd the pa ti ent ma y compl a i n of fa ti gue a nd l os s of pubi c a nd a xi l l a ry ha i r.
Pituitary apoplexy i s a s ymptom compl ex ca us ed by hemorrha gi c i nfa rcti on of ei ther a norma l pi tui ta ry gl a nd or, more commonl y, a pi tui ta ry tumor.
Acute s ymptoms i ncl ude s evere hea da che, s ti ff neck, fever, vi s ua l fi el d defects , a nd ocul omotor pa l s i es . The res ul ti ng edema ma y compres s the
hypotha l a mus , res ul ti ng i n s omnol ence or coma . Va ryi ng degrees of hypopi tui ta ri s m ma y devel op s uddenl y, a nd the pa ti ent ma y pres ent wi th
va s cul a r col l a ps e beca us e of defi ci ent ACTH a nd corti s ol . The CSF often conta i ns bl ood, a nd MRI documents hemorrha ge.
Diagnosis
MRI or CT
Free thyroxi ne (T4 ), TSH, a nd prol a cti n l evel s
Corti s ol l evel s pl us provoca ti ve tes ti ng of pi tui ta ry-a drena l a xi s
Someti mes other provoca ti ve tes ti ng
Cl i ni ca l fea tures a re often nons peci fi c, a nd the di a gnos i s mus t be es ta bl i s hed wi th certa i nty before commi tti ng the pa ti ent to a l i feti me of
hormone repl a cement thera py. Pi tui ta ry dys functi on mus t be di s ti ngui s hed from a norexi a nervos a , chroni c l i ver di s ea s e, myotoni a dys trophi ca ,
pol ygl a ndul a r a utoi mmune di s ea s e (s ee
Ta bl e 92-2), a nd di s orders of the other endocri ne gl a nds . The cl i ni ca l pi cture ma y be
[Table 92-2. Di fferenti a ti on of Genera l i zed Hypopi tui ta ri s m from Other Sel ected Di s orders ]
pa rti cul a rl y confus i ng when the functi on of more tha n one gl a nd decrea s es a t the s a me ti me. Evi dence of s tructura l pi tui ta ry a bnorma l i ti es a nd of
hormona l defi ci enci es s houl d be s ought wi th i ma gi ng a nd l a bora tory tes ts .
Imaging tests: Pa ti ents s houl d undergo hi gh-res ol uti on CT or MRI, wi th contra s t medi a a s requi red (to rul e out s tructura l a bnorma l i ti es , s uch a s
pi tui ta ry a denoma s ). PET i s a res ea rch tool us ed i n a few s peci a l i zed centers a nd therefore i s ra rel y done. When no modern neurora di ol ogi c
fa ci l i ti es a re a va i l a bl e, a s i mpl e cone-down l a tera l x-ra y of the s el l a turci ca ca n i denti fy pi tui ta ry ma croa denoma s wi th a di a meter > 10 mm.
Cerebra l a ngi ogra phy i s i ndi ca ted onl y when other i ma gi ng tes ts s ugges t peri s el l a r va s cul a r a noma l i es or a neurys ms .
Laboratory testing: Ini ti a l eva l ua ti on s houl d i ncl ude tes ti ng for TSH a nd ACTH defi ci enci es , beca us e both condi ti ons a re potenti a l l y l i fe threa teni ng.
Tes ti ng for defi ci enci es of other hormones i s a l s o di s cus s ed el s ewhere (s ee p. 766).
Free T4 a nd TSH l evel s s houl d be determi ned. Level s of both a re us ua l l y l ow i n genera l i zed hypopi tui ta ri s m; a pa ttern of norma l TSH l evel wi th
l ow free T4 ma y a l s o occur. In contra s t, el eva ted TSH l evel s wi th l ow free T4 i ndi ca te a pri ma ry a bnorma l i ty of the thyroi d gl a nd.
Syntheti c thyrotropi n-rel ea s i ng hormone (TRH), 200 to 500 g IV gi ven over 15 to 30 s ec, ma y hel p i denti fy pa ti ents wi th hypotha l a mi c a s oppos ed to
pi tui ta ry dys functi on, a l though thi s tes t i s not often done. Serum TSH l evel s a re genera l l y mea s ured a t 0, 20, a nd 60 mi n a fter i njecti on. If pi tui ta ry
functi on i s i nta ct, TSH s houl d ri s e by > 5 mU/L, pea ki ng by 30 mi n a fter i njecti on. A del a yed ri s e i n s erum TSH l evel s ma y occur i n pa ti ents wi th
hypotha l a mi c di s ea s e. However, s ome pa ti ents wi th pri ma ry pi tui ta ry di s ea s e a l s o s how a del a yed ri s e.
Serum corti s ol l evel s a l one a re not rel i a bl e i ndi ca tors of ACTH-a drena l a xi s functi on. One of s evera l provoca ti ve tes ts s houl d be done. The short
ACTH stimulation test i s a s a fer a nd l es s l a bor-i ntens i ve tes t for corti s ol defi ci ency tha n the i ns ul i n tol era nce tes t. In the s hort ACTH s ti mul a ti on
tes t, s yntheti c ACTH 250 g IV or IM (s ta nda rd tes t) or 1 g IV (l ow-dos e tes t) i s gi ven, a nd the bl ood corti s ol res pons e i s mea s ured 30 a nd 60 mi n
l a ter. Corti s ol s houl d ri s e s i gni fi ca ntl y; a pea k of < 20 g/dL i s a bnorma l . However, the s hort ACTH s ti mul a ti on tes t i s a bnorma l i n s econda ry
corti s ol defi ci ency onl y when done a t l ea s t 2 to 4 wk a fter ons et of the defi ci ency; before thi s ti me, the a drena l gl a nds ha ve not a trophi ed a nd
rema i n res pons i ve to exogenous ACTH.
The insulin tolerance test i s cons i dered the mos t a ccura te wa y of eva l ua ti ng ACTH (a s wel l a s GH a nd prol a cti n) res erve, but beca us e of i ts dema nds ,
i t i s proba bl y bes t res erved for pa ti ents who fa i l the s hort s yna cthen tes t (i f confi rma ti on i s needed) or when a tes t mus t be done wi thi n 2 to 4 wk
of a pos s i bl e pi tui ta ry i njury. Regul a r i ns ul i n a t a dos a ge of 0.1 uni ts /kg body wei ght IV i s gi ven over 15 to 30 s ec, a nd venous bl ood s a mpl es a re
obta i ned to determi ne GH, corti s ol , a nd gl ucos e l evel s a t ba s el i ne (before i ns ul i n a dmi ni s tra ti on) a nd 20, 30, 45, 60, a nd 90 mi n l a ter. If gl ucos e
drops to < 40 mg/dL (< 2.22 mmol /L) or s ymptoms of hypogl ycemi a devel op, corti s ol s houl d i ncrea s e by > 7 g/dL or to > 20 g/dL. (CAUTION: This test
is hazardous in patients with severe documented panhypopituitarism or diabetes mellitus and in the elderly and is contraindicated in patients with coronary artery
disease or epilepsy. A health care practitioner should be present during the test.) Us ua l l y, onl y tra ns i ent pers pi ra ti on, ta chyca rdi a , a nd nervous nes s occur.
If the pa ti ent compl a i ns of pa l pi ta ti ons , l os es cons ci ous nes s , or ha s a s ei zure, the tes t s houl d be s topped promptl y by gi vi ng 50 mL of 50% gl ucos e
s ol uti on IV.
Nei ther the s hort ACTH s ti mul a ti on tes t nor the i ns ul i n tol era nce tes t a l one wi l l di fferenti a te between pri ma ry (Addi s on's di s ea s e) a nd s econda ry
(hypopi tui ta ry) a drena l i ns uffi ci ency. Tes ts to ma ke thi s di s ti ncti on a nd to eva l ua te the hypotha l a mi c-pi tui ta ry-a drena l a xi s a re des cri bed under
Addi s on's di s ea s e (s ee p. 792). An a l terna ti ve provoca ti ve tes t tha t i s done much l es s often i s the corti cotropi n-rel ea s i ng hormone (CRH) tes t. CRH
1 g/kg IV i s gi ven by ra pi d i njecti on. Serum ACTH a nd corti s ol l evel s a re mea s ured 15 mi n before, then a t ba s el i ne, a nd 15, 30, 60, 90, a nd 120 mi n
a fter the i njecti on. Advers e effects i ncl ude tempora ry fl us hi ng, a meta l l i c ta s te i n the mouth, a nd s l i ght a nd tra ns i ent hypotens i on.
Prol a cti n l evel s a re routi nel y mea s ured. Thes e l evel s a re often el eva ted up to 5 ti mes norma l va l ues when a l a rge pi tui ta ry tumor i s pres ent, even
i f i t does not produce prol a cti n. The tumor compres s es the pi tui ta ry s ta l k, preventi ng dopa mi ne, whi ch i nhi bi ts pi tui ta ry prol a cti n producti on a nd
rel ea s e, from rea chi ng the pi tui ta ry. Pa ti ents wi th s uch hyperprol a cti nemi a often ha ve hypogona dotropi s m a nd s econda ry hypogona di s m.
Mea s urement of ba s a l l evel s of LH a nd FSH i s mos t hel pful i n eva l ua ti ng hypopi tui ta ri s m i n pos tmenopa us a l women not ta ki ng exogenous
es trogens i n whom ci rcul a ti ng gona dotropi n concentra ti ons a re norma l l y hi gh (> 30 mIU/mL). Al though gona dotropi n l evel s tend to be l ow i n other
pa ti ents wi th pa nhypopi tui ta ri s m, overl a p exi s ts wi th the norma l ra nge. Level s of both hormones s houl d i ncrea s e i n res pons e to s yntheti c
gona dotropi n-rel ea s i ng hormone (GnRH) a t a dos e of 100 g IV, wi th LH pea ki ng a bout 30 mi n a nd FSH pea ki ng 40 mi n a fter GnRH a dmi ni s tra ti on.
However, norma l , di mi ni s hed, or a bs ent res pons es to GnRH ma y occur i n hypotha l a mi c-pi tui ta ry dys functi on. Norma l i ncrea s es i n LH a nd FSH i n
res pons e to GnRH va ry. Admi ni s tra ti on of exogenous GnRH i s not hel pful i n di s ti ngui s hi ng pri ma ry hypotha l a mi c di s orders from pri ma ry pi tui ta ry
di s orders .
Screeni ng for GH defi ci ency i n a dul ts i s not recommended unl es s GH trea tment i s contempl a ted (eg, for unexpl a i ned reduced energy a nd qua l i ty
of l i fe i n pa ti ents wi th hypopi tui ta ri s m i n whi ch other hormones ha ve been ful l y repl a ced). GH defi ci ency i s s us pected i f 2 other pi tui ta ry
hormones a re defi ci ent. Beca us e GH l evel s va ry by ti me of da y a nd other fa ctors a nd a re di ffi cul t to i nterpret, l evel s of i ns ul i n-l i ke growth fa ctor 1
(IGF-1), whi ch refl ect GH, a re us ed; l ow l evel s s ugges t GH defi ci ency, but norma l l evel s do not rul e i t out. A provoca ti ve tes t of GH rel ea s e (s ee p.
767) ma y be neces s a ry.
Al though the us eful nes s of provoca ti ve tes ti ng of pi tui ta ry functi on us i ng rel ea s i ng hormones rema i ns to be es ta bl i s hed, i f s uch tes ti ng i s
el ected, i t i s mos t effi ci ent to eva l ua te mul ti pl e hormones s i mul ta neous l y. Growth hormone-rel ea s i ng hormone (1 g/kg), CRH (1 g/kg), TRH (200
g), a nd GnRH (100 g) a re gi ven together IV over 15 to 30 s ec. Gl ucos e, corti s ol , GH, TSH, prol a cti n, LH, FSH, a nd ACTH a re mea s ured a t frequent
i nterva l s for the ens ui ng 180 mi n. The norma l res pons es a re the s a me a s thos e del i nea ted ea rl i er for i ndi vi dua l tes ti ng.
Treatment
Hormone repl a cement
Trea tment of ca us e (eg, tumor)
Trea tment i s repl a cement of the hormones of the hypofuncti oni ng ta rget gl a nds , a s di s cus s ed i n the perti nent cha pters i n thi s s ecti on a nd
el s ewhere i n THE MANUAL. Adul ts 50 yr defi ci ent i n GH a re now s ometi mes trea ted wi th GH dos es of 0.002 to 0.012 mg/kg s c once/da y. Benefi ts of
trea tment i ncl ude i mproved energy a nd qua l i ty of l i fe, i ncrea s ed body mus cl e ma s s , a nd decrea s ed body fa t ma s s . Sugges ti ons tha t GH
repl a cement ca n prevent a n a ccel era ti on of a theros cl eros i s i nduced by GH defi ci ency a re unproved.
When hypopi tui ta ri s m i s due to a pi tui ta ry tumor, s peci fi c trea tment mus t be di rected a t the tumor a s wel l a s repl a ci ng hormones . The
a ppropri a te ma na gement of s uch tumors i s controvers i a l . If the tumor i s s ma l l a nd does not s ecrete prol a cti n, mos t endocri nol ogi s ts fa vor
tra ns s phenoi da l remova l . Mos t endocri nol ogi s ts cons i der dopa mi ne a goni s ts , s uch a s bromocri pti ne or the l onger-a cti ng ca bergol i ne, the i ni ti a l
trea tment of prol a cti noma s , rega rdl es s of s i ze, i f there i s a menorrhea i n a woma n or erecti l e dys functi on i n a ma n (s ee Ga l a ctorrhea on p. 770).
Pa ti ents wi th ma croa denoma s > 2 cm wi th extremel y hi gh ci rcul a ti ng l evel s of prol a cti n ma y requi re s urgery or i rra di a ti on i n a ddi ti on to dopa mi ne
a goni s t trea tment. Supervol ta ge i rra di a ti on of the pi tui ta ry ma y be a dded or us ed a l one. Wi th l a rger tumors a nd s upra s el l a r extens i on, res ecti on
of the enti re tumor, ei ther tra ns s phenoi da l l y or tra ns fronta l l y, ma y not be pos s i bl e, a nd a djuncti ve s upervol ta ge i rra di a ti on ma y be wa rra nted.
In pi tui ta ry a popl exy, i mmedi a te s urgery i s wa rra nted i f vi s ua l fi el d di s turba nces or ocul omotor pa l s i es devel op s uddenl y or i f s omnol ence
progres s es to coma beca us e of hypotha l a mi c compres s i on. Al though ma na gement wi th hi gh-dos e corti cos teroi ds a nd genera l s upport ma y s uffi ce
i n a few ca s es , tra ns s phenoi da l decompres s i on of the tumor s houl d genera l l y be underta ken promptl y.
Surgery a nd i rra di a ti on ma y be fol l owed by the l os s of other pi tui ta ry hormone functi ons . Irra di a ted pa ti ents ma y l os e endocri ne functi on s l owl y
over yea rs . Therefore, pos ttrea tment hormona l s ta tus s houl d be eva l ua ted frequentl y, prefera bl y a t 3 a nd 6 mo a nd yea rl y therea fter. Such
eva l ua ti on s houl d i ncl ude a t l ea s t a s s es s ment of thyroi d a nd a drena l functi on. Pa ti ents ma y a l s o devel op vi s ua l di ffi cul ti es rel a ted to fi bros i s of
the opti c chi a s m. Sel l a r i ma gi ng a nd vi s ua l fi el d a s s es s ment s houl d be done a t l ea s t every 2 yr i ni ti a l l y for a bout 10 yr, pa rti cul a rl y i f res i dua l
tumor ti s s ue i s pres ent.
Selective Pituitary Hormone Deficiencies
Sel ecti ve defi ci enci es of pi tui ta ry hormones ma y repres ent a n ea rl y s ta ge i n the devel opment of more genera l i zed hypopi tui ta ri s m. Pa ti ents mus t
be obs erved for s i gns of other pi tui ta ry hormone defi ci enci es , a nd s el l a r i ma gi ng s houl d be done a t i nterva l s to check for s i gns of a pi tui ta ry
tumor.
Isolated growth hormone (GH) defi ci ency i s res pons i bl e for ma ny ca s es of pi tui ta ry dwa rfi s m (s ee p. 767). Al though one a utos oma l domi na nt form of
compl ete GH defi ci ency i s a s s oci a ted wi th a del eti on of the GH s tructura l gene, s uch gene defects proba bl y a ccount for a mi nori ty of ca s es .
Trea tment of GH defi ci ency i n a dul ts < 50 yr i s di s cus s ed on p. 765.
Isolated gonadotropin deficiency occurs i n both s exes a nd mus t be di s ti ngui s hed from pri ma ry hypogona di s m; men ha ve l ow s erum tes tos terone
l evel s a nd i nferti l i ty, a nd women ha ve a menorrhea , l ow s erum es trogen l evel s , a nd i nferti l i ty. A eunuchoi d ha bi tus i s genera l l y pres ent. However,
pa ti ents wi th pri ma ry hypogona di s m (s ee p. 2341) ha ve el eva ted l evel s of l utei ni zi ng hormone (LH) a nd fol l i cl e-s ti mul a ti ng hormone (FSH),
wherea s thos e wi th gona dotropi n defi ci ency, ei ther s econda ry (pi tui ta ry) or terti a ry (hypotha l a mi c), ha ve l ow-norma l , l ow, or unmea s ura bl e l evel s
of LH a nd FSH. Al though mos t ca s es of hypogona dotropi c hypogona di s m i nvol ve defi ci enci es of both LH a nd FSH, i n ra re ca s es the s ecreti on of onl y
one i s i mpa i red. Is ol a ted gona dotropi n defi ci ency mus t a l s o be di s ti ngui s hed from hypogona dotropi c a menorrhea s econda ry to exerci s e, di et, or
menta l s tres s (s ee p. 2501). Al though the hi s tory ma y be hel pful , di fferenti a l di a gnos i s ma y be i mpos s i bl e.
In Kallmann syndrome, the s peci fi c l a ck of gona dotropi n-rel ea s i ng hormone (GnRH) i s a s s oci a ted wi th mi dl i ne fa ci a l defects , i ncl udi ng a nos mi a
a nd cl eft l i p or pa l a te, a nd wi th col or bl i ndnes s . Embryol ogi c s tudi es ha ve s hown tha t GnRH neurons ori gi na l l y devel op i n the epi thel i um of the
ol fa ctory pl a code a nd mi gra te i nto the s epta l -preopti c regi on of the hypotha l a mus ea rl y i n devel opment. In a t l ea s t s ome ca s es , gene defects ,
l oca l i zed to the X chromos ome i n the X-l i nked form of the di s order a nd termed the KALIG-1 (Ka l l ma nn s yndrome i nterva l gene 1) gene, ha ve been
found i n the a dhes i on protei ns fa ci l i ta ti ng thi s neurona l mi gra ti on. Admi ni s tra ti on of GnRH ma y be i ndi ca ted (s ee p. 2894).
Isolated ACTH deficiency i s ra re. Wea knes s , hypogl ycemi a , wei ght l os s , a nd decrea s ed a xi l l a ry a nd pubi c ha i r s ugges t the di a gnos i s . Bl ood a nd
uri na ry s teroi d l evel s a re l ow a nd ri s e to norma l a fter ACTH repl a cement. Cl i ni ca l a nd l a bora tory evi dence of other hormona l defi ci enci es i s
a bs ent. Trea tment i s wi th corti s ol repl a cement, a s for Addi s on's di s ea s e (s ee p. 794).
Isolated thyroid-stimulating hormone (TSH) deficiency i s l i kel y when cl i ni ca l fea tures of hypothyroi di s m exi s t, s erum TSH l evel s a re not el eva ted, a nd
no other pi tui ta ry hormone defi ci enci es exi s t. Serum TSH l evel s , a s mea s ured by i mmunoa s s a y, a re not a l wa ys l ower tha n norma l , s ugges ti ng tha t
the TSH s ecreted i s bi ol ogi ca l l y i na cti ve. Admi ni s tra ti on of recombi na nt huma n TSH i ncrea s es thyroi d hormone l evel s (s ee a l s o Hypothyroi di s m on
p. 785).
Isolated prolactin deficiency ha s been noted ra rel y i n women who fa i l to l a cta te a fter del i very. Ba s a l prol a cti n l evel s a re l ow a nd do not i ncrea s e i n
res pons e to provoca ti ve s ti mul i , s uch a s thyroi d-rel ea s i ng hormone. Admi ni s tra ti on of prol a cti n i s not i ndi ca ted.
Hypopituitarism in Children Resulting in Short Stature
(Pi tui ta ry Dwa rfi s m)

Hypopituitarism in children typically results in abnormally slow growth and short stature with normal proportions. It is usually due to a pituitary tumor but may
be idiopathic. Diagnosis involves measurement of growth hormone (GH) levels at baseline and in response to pharmacologic stimuli. Treatment usually involves
removal of the causative tumor and GH replacement.
Hypopi tui ta ri s m i n chi l dren ma y be genera l i zed, i nvol vi ng defi ci ency of s evera l pi tui ta ry hormones , but i t i s us ua l l y fi rs t expres s ed cl i ni ca l l y a s
s hort s ta ture res ul ti ng from defi ci ency of GH. Is ol a ted defi ci ency of GH ma y a l s o occur.
Hypopi tui ta ri s m i n chi l dren i s us ua l l y due to a pi tui ta ry tumor (mos t commonl y a cra ni opha ryngi oma ) or i s i di opa thi c. The combi na ti on of l yti c
l es i ons of the bone or s kul l a nd di a betes i ns i pi dus s ugges ts La ngerha ns ' cel l hi s ti ocytos i s (s ee p. 993). Hypotha l a mi c or pi tui ta ry hormone
defi ci ency a s wel l a s i s ol a ted GH defi ci ency ma y occur i n pa ti ents wi th mi dl i ne defects , s uch a s cl eft pa l a te or s epto-opti c dys pl a s i a , whi ch
i nvol ves a bs ence of the s eptum pel l uci dum, opti c nerve a trophy, a nd hypopi tui ta ri s m. GH defi ci ency, ei ther a l one or i n pa ti ents wi th other
a bnorma l i ti es , i s heredi ta ry i n a bout 5% of ca s es .
Thera peuti c ra di a ti on of the CNS for va ri ous ca ncers ca us es s l owi ng of l i nea r growth, whi ch ca n often be l i nked to res ul ti ng GH defi ci ency.
Ra di a ti on of the s pi ne, ei ther prophyl a cti c or thera peuti c, ma y further i mpa i r the growth potenti a l of the vertebra e a nd further jeopa rdi ze hei ght
ga i n.
Symptoms and Signs
In a chi l d wi th hypopi tui ta ri s m, hei ght i s bel ow the 3rd percenti l e, a nd growth vel oci ty i s < 6 cm/yr before a ge 4 yr, < 5 cm/yr from a ge 4 to 8 yr, a nd <
4 cm/yr before puberty. Skel eta l ma tura ti on, a s s es s ed by bone a ge determi na ti on, i s > 2 yr behi nd chronol ogi c a ge.
Al though of s ma l l s ta ture, a chi l d wi th hypopi tui ta ri s m reta i ns norma l proporti ona l i ty between upper a nd l ower body s egments . The chi l d fa i l s to
begi n puberta l devel opment. However, a chi l d wi th i s ol a ted GH defi ci ency s econda ry to hypopi tui ta ri s m ma y undergo del a yed puberta l
devel opment.
Growth da ta for hei ght a nd wei ght s houl d be pl otted on a growth cha rt (a uxol ogi c a s s es s ment) for a l l chi l dren. When growth i s a bnorma l , bone
a ge s houl d be determi ned from a n x-ra y of the l eft ha nd (by conventi on). In GH defi ci ency, s kel eta l ma tura ti on i s us ua l l y del a yed to the s a me
extent a s hei ght. Eva l ua ti ng the pi tui ta ry gl a nd a nd s el l a turci ca wi th CT or MRI i s i ndi ca ted to rul e out ca l ci fi ca ti ons a nd tumors ; the s el l a turci ca
i s a bnorma l l y s ma l l i n 10 to 20% of pa ti ents .
Diagnosis
Ins ul i n-l i ke growth fa ctor 1 (IGF-1) l evel s a nd s ometi mes IGF bi ndi ng protei n type 3 (IGFBP-3) l evel s
Us ua l l y confi rma ti on by provoca ti ve tes ti ng
In mi d to l a te chi l dhood, IGF-1 l evel s , whi ch refl ect GH a cti vi ty, a re mea s ured beca us e GH l evel s a re hi ghl y va ri a bl e a nd di ffi cul t to i nterpret.
Norma l IGF-1 l evel s hel p excl ude GH defi ci ency. However, IGF-1 l evel s a re l ow i n condi ti ons other tha n GH defi ci ency, s uch a s ps ychos oci a l
depri va ti on, undernutri ti on, a nd hypothyroi di s m. Beca us e IGF-1 l evel s a re norma l l y l ow i n i nfa ncy a nd ea rl y chi l dhood, they do not a l l ow rel i a bl e
di s cri mi na ti on between norma l a nd s ubnorma l i n thes e a ge groups . In thes e chi l dren, l evel s of IGFBP-3 (the ma jor ca rri er of IGF pepti des ) a re
mea s ured. IGFBP-3 i s l es s a ffected by undernutri ti on tha n i s IGF-1.
In chi l dren wi th l ow l evel s of IGF-1 a nd IGFBP-3, GH defi ci ency i s us ua l l y confi rmed by mea s uri ng GH l evel s . Beca us e ba s a l GH l evel s a re typi ca l l y
l ow or undetecta bl e (except a fter the ons et of s l eep), a s s es s ment of GH l evel s requi res provoca ti ve tes ti ng. However, provoca ti ve tes ti ng i s
nonphys i ol ogi c, s ubject to l a bora tory error, a nd poorl y reproduci bl e, a nd i nterpreta ti on of da ta rel i es on a rbi tra ry defi ni ti ons of "norma l " tha t va ry
by a ge a nd s ex.
The i ns ul i n tol era nce tes t ma y be the mos t effecti ve provoca ti ve tes t for s ti mul a ti ng GH rel ea s e. Les s da ngerous , but a l s o l es s rel i a bl e, a re tes ts
us i ng a rgi ni ne i nfus i on (500 mg/kg IV gi ven over 30 mi n), l evodopa (10 mg/kg to chi l dren; 500 mg po to a dul ts ), s l eep, or 20 mi n of vi gorous
exerci s e. Genera l l y, a ny GH l evel > 10 ng/mL or a ny res pons e of > 5 ng/mL a fter a s ti mul us i s s uffi ci ent to rul e out GH defi ci ency. Increa s es i n GH of
< 5 ng/mL or to l evel s < 10 ng/mL a re di ffi cul t to i nterpret. Wha t cons ti tutes a norma l res pons e, however, i s a rbi tra ry, a nd a l l provoca ti ve tes ts of
GH s ecreti on occa s i ona l l y produce mi s l ea di ng res ul ts . Beca us e no s i ngl e tes t i s 100% effecti ve i n el i ci ti ng GH rel ea s e, a 2nd provoca ti ve tes t
s houl d be done i f the fi rs t i s a bnorma l . GH l evel s genera l l y pea k 30 to 90 mi n a fter a dmi ni s tra ti on of i ns ul i n or the ons et of a rgi ni ne i nfus i on, 30
to 120 mi n a fter l evodopa , 60 to 120 mi n a fter the ons et of s l eep, a nd a fter 20 mi n of vi gorous exerci s e. Beca us e GH res pons es a re genera l l y
a bnorma l i n pa ti ents wi th di mi ni s hed thyroi d or a drena l functi on, tes ti ng s houl d be conducted i n thes e pa ti ents onl y a fter a dequa te hormone
repl a cement thera py.
The va l ue of exogenous growth hormone-rel ea s i ng hormone (GHRH) a l one i n eva l ua ti ng GH s ecreti on i s not es ta bl i s hed. In norma l peopl e, a
dos e of 1 g/kg GHRH IV a dmi ni s tered over 15 to 30 s ec res ul ts i n ma xi ma l but va ri a bl e rel ea s e of GH, typi ca l l y rea chi ng a pea k a bout 60 mi n a fter
GHRH i njecti on. The va ri a bi l i ty i n pi tui ta ry res pons i venes s to GHRH i s cons i s tent wi th the hypothes i s tha t i ntermi ttent s ecreti on of s oma tos ta ti n,
whi ch oppos es GHRH, i s res pons i bl e for modul a ti ng pi tui ta ry GH output. Pres uma bl y, a bs ent or di mi ni s hed i ncrea s es i n GH i n res pons e to GHRH
i denti fy pa ti ents wi th GH defi ci ency, but whether the pa ttern of res pons e di s ti ngui s hes pri ma ry hypotha l a mi c di s ea s e from pi tui ta ry di s ea s e i s
uncl ea r. In chi l dren wi th GH defi ci ency pres uma bl y s econda ry to GHRH defi ci ency, hi ghl y va ri a bl e GH res pons es to GHRH occur. The combi na ti on of
a rgi ni ne a nd GHRH i mproves the s ens i ti vi ty for di a gnos i ng GH defi ci ency.
Provoca ti ve tes ti ng ma y not detect s ubtl e defects i n the regul a ti on of GH rel ea s e. For exa mpl e, i n chi l dren wi th s hort s ta ture s econda ry to GH
s ecretory dys functi on, res ul ts of provoca ti ve tes ti ng for GH rel ea s e a re us ua l l y norma l . However, s eri a l mea s urements of GH l evel s over 12 to 24 h
i ndi ca te a bnorma l l y l ow 12- or 24-h i ntegra ted GH s ecreti on.
If di mi ni s hed GH rel ea s e i s confi rmed, s ecreti on of other pi tui ta ry hormones a nd (i f a bnorma l ) hormones of thei r ta rget peri phera l endocri ne
gl a nds a l s o mus t be eva l ua ted.

Treatment
Recombi na nt GH s uppl ements
Recombi na nt GH i s i ndi ca ted for a l l chi l dren wi th s hort s ta ture who ha ve documented GH defi ci ency. Dos i ng i s us ua l l y from 0.03 to 0.05 mg/kg s c
once/da y. Wi th thera py, hei ght vel oci ty often i ncrea s es to 10 to 12 cm/yr i n the fi rs t yea r a nd, a l though i t i ncrea s es more s l owl y therea fter, rema i ns
a bove pretrea tment ra tes . Thera py i s conti nued unti l a n a ccepta bl e hei ght i s rea ched or growth ra te fa l l s bel ow 2.5 cm/yr.
Advers e effects of GH thera py a re few but i ncl ude i di opa thi c i ntra cra ni a l hypertens i on (ps eudotumor cerebri ), s l i pped ca pi ta l femora l epi phys i s ,
a nd tra ns i ent mi l d peri phera l edema . Before the a dvent of recombi na nt GH, GH extra cted from pi tui ta ry gl a nds wa s us ed. Thi s prepa ra ti on ra rel y
l ed to Creutzfel dt-Ja kob di s ea s e 20 to 40 yr a fter trea tment (s ee p. 1729). Pi tui ta ry-extra cted GH wa s l a s t us ed i n the 1980s .
It i s controvers i a l whether s hort chi l dren wi th cl i ni ca l fea tures of GH defi ci ency but wi th norma l GH s ecreti on a nd norma l IGF-1 l evel s s houl d be
trea ted wi th GH. Ma ny experts recommend a tri a l of GH thera py for 6 to 12 mo, conti nui ng GH onl y i f there i s a doubl i ng of or a n i ncrea s e of 3 cm/yr
over the pretrea tment hei ght vel oci ty. Others object to thi s a pproa ch beca us e i t i s expens i ve, i s experi menta l , ma y l ea d to a dvers e effects , l a bel s
otherwi s e hea l thy chi l dren a s a bnorma l , a nd ra i s es ethi ca l a nd ps ychos oci a l concerns tha t feed i nto the bi a s of "hei ghti s m."
Corti s ol a nd thyroi d hormone s houl d be repl a ced throughout chi l dhood, a dol es cence, a nd a dul thood i n pa ti ents wi th s hort s ta ture due to
pi tui ta ry dwa rfi s m when ci rcul a ti ng l evel s of thes e hormones a re l ow (s ee pp. 786 a nd 794). When puberty fa i l s to occur norma l l y, trea tment wi th
gona da l s ex s teroi ds i s i ndi ca ted (s ee p. 2894).
GH thera py i n chi l dren wi th s hort s ta ture due to thera peuti c ra di a ti on of the pi tui ta ry gl a nd for ca ncer ca rri es a theoreti c ri s k of ca us i ng ca ncer
recurrence. However, s tudi es ha ve not s hown a grea ter-tha n-expected i nci dence of new ca ncers or a grea ter recurrence ra te. GH repl a cement ca n
proba bl y be s a fel y i ns ti tuted a t l ea s t 1 yr a fter the s ucces s ful compl eti on of a nti ca ncer thera py.
Gigantism and Acromegaly
Gigantism and acromegaly are syndromes of excessive secretion of growth hormone (hypersomatotropism) that are nearly always due to a pituitary adenoma.
Before closure of the epiphyses, the result is gigantism. Later, the result is acromegaly, which causes distinctive facial and other features. Diagnosis is clinical and
by skull and hand x-rays and measurement of growth hormone levels. Treatment involves removal or destruction of the responsible adenoma.
Ma ny growth hormone (GH)-s ecreti ng a denoma s conta i n a muta nt form of the G s protei n, whi ch i s a s ti mul a tory regul a tor of a denyl a te cycl a s e.
Cel l s wi th the muta nt form of G s protei n s ecrete GH even i n the a bs ence of growth hormone-rel ea s i ng hormone (GHRH). A few ca s es of ectopi c
GHRH-produci ng tumors , es peci a l l y of the pa ncrea s a nd l ung, a l s o ha ve been des cri bed.
Symptoms and Signs
Pituitary gigantism: Thi s ra re condi ti on occurs i f GH hypers ecreti on begi ns i n chi l dhood, before cl os ure of the epi phys es . Skel eta l growth vel oci ty
a nd ul ti ma te s ta ture a re i ncrea s ed, but l i ttl e bony deformi ty occurs . However, s oft-ti s s ue s wel l i ng occurs , a nd the peri phera l nerves a re enl a rged.
Del a yed puberty or hypogona dotropi c hypogona di s m i s a l s o frequentl y pres ent, res ul ti ng i n a eunuchoi d ha bi tus .
Acromegaly: In a cromega l y, GH hypers ecreti on us ua l l y s ta rts between the 20s a nd 40s . When GH hypers ecreti on begi ns a fter epi phys ea l cl os ure,
the ea rl i es t cl i ni ca l ma ni fes ta ti ons a re coa rs eni ng of the fa ci a l fea tures (s ee
Pl a te 21) a nd s oft-ti s s ue s wel l i ng of the ha nds a nd feet. Appea ra nce cha nges , a nd l a rger ri ngs , gl oves , a nd s hoes a re needed. Photogra phs of the
pa ti ent a re i mporta nt i n del i nea ti ng the cours e of the di s ea s e.
In a dul ts wi th a cromega l y, coa rs e body ha i r i ncrea s es a nd the s ki n thi ckens a nd frequentl y da rkens . The s i ze a nd functi on of s eba ceous a nd
s wea t gl a nds i ncrea s e, s uch tha t pa ti ents frequentl y compl a i n of exces s i ve pers pi ra ti on a nd offens i ve body odor. Overgrowth of the ma ndi bl e
l ea ds to protrus i on of the ja w (progna thi s m) a nd ma l occl us i on of teeth. Ca rti l a gi nous prol i fera ti on of the l a rynx l ea ds to a deep, hus ky voi ce. The
tongue i s frequentl y enl a rged a nd furrowed. In l ongs ta ndi ng a cromega l y, cos ta l ca rti l a ge growth l ea ds to a ba rrel ches t. Arti cul a r ca rti l a gi nous
prol i fera ti on occurs ea rl y i n res pons e to GH exces s , wi th the a rti cul a r ca rti l a ge pos s i bl y undergoi ng necros i s a nd eros i on. Joi nt s ymptoms a re
common, a nd cri ppl i ng degenera ti ve a rthri ti s ma y occur.
Peri phera l neuropa thi es occur commonl y beca us e of compres s i on of nerves by a dja cent fi brous ti s s ue a nd endoneura l fi brous prol i fera ti on.
Hea da ches a re common beca us e of the pi tui ta ry tumor. Bi tempora l hemi a nopi a ma y devel op i f s upra s el l a r extens i on compres s es the opti c
chi a s m. The hea rt, l i ver, ki dneys , s pl een, thyroi d, pa ra thyroi d gl a nds , a nd pa ncrea s a re l a rger tha n norma l . Ca rdi a c di s ea s e occurs i n perha ps one
thi rd of pa ti ents , wi th a doubl i ng i n the ri s k of dea th from ca rdi a c di s ea s e. Hypertens i on occurs i n up to one thi rd of pa ti ents . The ri s k of ca ncer,
pa rti cul a rl y of the GI tra ct, i ncrea s es 2-fol d to 3-fol d. GH i ncrea s es tubul a r rea bs orpti on of phos pha te a nd l ea ds to mi l d hyperphos pha temi a .
Impa i red gl ucos e tol era nce occurs i n nea rl y one ha l f the pa ti ents wi th a cromega l y a nd i n gi ga nti s m, but cl i ni ca l l y s i gni fi ca nt di a betes mel l i tus
occurs i n onl y a bout 10% of pa ti ents .
Ga l a ctorrhea occurs i n s ome women wi th a cromega l y, us ua l l y i n a s s oci a ti on wi th hyperprol a cti nemi a (s ee p. 770). However, ga l a ctorrhea ma y
occur wi th GH exces s a l one, beca us e GH i ts el f s ti mul a tes l a cta ti on. Decrea s ed gona dotropi n s ecreti on often occurs wi th GH-s ecreti ng tumors .
About one thi rd of men wi th a cromega l y devel op erecti l e dys functi on, a nd nea rl y a l l women devel op mens trua l i rregul a ri ti es or a menorrhea .
Diagnosis
CT or MRI
Ins ul i n-l i ke growth fa ctor 1 (IGF-1) l evel s
Us ua l l y GH l evel s
Di a gnos i s ca n be ma de from the cha ra cteri s ti c cl i ni ca l fi ndi ngs . CT, MRI, or s kul l x-ra ys di s cl os e corti ca l thi ckeni ng, enl a rgement of the fronta l
s i nus es , a nd enl a rgement a nd eros i on of the s el l a turci ca . X-ra ys of the ha nds s how tufti ng of the termi na l pha l a nges a nd s oft-ti s s ue thi ckeni ng.
Genera l l y, gl ucos e tol era nce i s a bnorma l a nd s erum phos pha te l evel s a re mi l dl y el eva ted.
Serum IGF-1 s houl d be mea s ured i n pa ti ents wi th s us pected a cromega l y; IGF-1 l evel s a re typi ca l l y s ubs ta nti a l l y el eva ted (3-fol d to 10-fol d), a nd
beca us e IGF-1 l evel s do not fl uctua te l i ke GH l evel s do, they a re the s i mpl es t wa y to a s s es s GH hypers ecreti on. IGF-1 l evel s a l s o ca n be us ed to
moni tor res pons e to thera py.
Pl a s ma GH l evel s mea s ured by ra di oi mmunoa s s a y a re typi ca l l y el eva ted. Bl ood s houl d be ta ken before the pa ti ent ea ts brea kfa s t (ba s a l s ta te);
i n norma l peopl e, ba s a l GH l evel s a re < 5 ng/mL. Tra ns i ent el eva ti ons of GH a re norma l a nd mus t be di s ti ngui s hed from pa thol ogi c
hypers ecreti on. The degree of GH s uppres s i on a fter a gl ucos e l oa d rema i ns the s ta nda rd a nd thus s houl d be mea s ured i n pa ti ents wi th el eva ted
pl a s ma GH; however, the res ul ts a re a s s a y-dependent, a nd the cutoff for norma l s uppres s i on i s controvers i a l . Secreti on i n norma l peopl e i s
s uppres s ed to < 2 ng/mL (a cutoff of < 1 ng/mL i s often us ed) wi thi n 90 mi n of a dmi ni s tra ti on of gl ucos e 75 g po. Mos t pa ti ents wi th a cromega l y
ha ve s ubs ta nti a l l y hi gher va l ues . Ba s a l pl a s ma GH l evel s a re a l s o i mporta nt i n moni tori ng res pons e to thera py.
CT or MRI of the hea d s houl d be done to l ook for a tumor. If a tumor i s not vi s i bl e, exces s i ve s ecreti on of pi tui ta ry GH ma y be due to a non-CNS
tumor produci ng exces s i ve a mounts of ectopi c GHRH. Demons tra ti on of el eva ted l evel s of pl a s ma GHRH ca n confi rm the di a gnos i s . Lungs a nd
pa ncrea s ma y be fi rs t eva l ua ted i n s ea rchi ng for the s i tes of ectopi c producti on.
Treatment
Surgery or ra di a ti on thera py
Abl a ti ve thera py wi th s urgery or ra di a ti on i s genera l l y i ndi ca ted. Tra ns s phenoi da l res ecti on i s preferred, but choi ces va ry a t di fferent i ns ti tuti ons .
Stereota cti c s upervol ta ge ra di a ti on, del i veri ng a bout 5000 cGy to the pi tui ta ry, i s us ed, but GH l evel s ma y not fa l l to norma l for s evera l yea rs .
Trea tment wi th a ccel era ted protons (hea vy pa rti cl e ra di a ti on) permi ts del i very of l a rger dos es of ra di a ti on (equi va l ent to 10,000 cGy) to the
pi tui ta ry; s uch thera py pos es hi gher ri s k of cra ni a l nerve a nd hypotha l a mi c da ma ge a nd i s a va i l a bl e onl y i n a few centers . Devel opment of
hypopi tui ta ri s m s evera l yea rs a fter i rra di a ti on i s common. Beca us e ra di a ti on da ma ge i s cumul a ti ve, proton bea m thera py s houl d not be us ed
a fter conventi ona l -i rra di a ti on. A combi ned a pproa ch wi th both s urgery a nd ra di a ti on thera py i s i ndi ca ted for pa ti ents wi th progres s i ve
extra s el l a r i nvol vement by a pi tui ta ry tumor a nd for pa ti ents whos e enti re tumor ca nnot be res ected, whi ch i s often the ca s e.
Surgi ca l remova l of the tumor i s l i kel y to ha ve been cura ti ve i f GH l evel s a fter the gl ucos e tol era nce tes t a nd IGF-1 l evel s rea ch norma l va l ues . If
one or both va l ues a re a bnorma l , further thera py i s us ua l l y needed. If GH exces s i s poorl y control l ed, hypertens i on, hea rt fa i l ure, a nd a doubl i ng
i n the dea th ra te occur. If GH l evel s a re < 5 ng/mL, however, morta l i ty does not i ncrea s e.
In genera l , drug thera py i s i ndi ca ted i f s urgery a nd ra di a ti on thera py a re contra i ndi ca ted, i f they ha ve not been cura ti ve, or i f ra di a ti on thera py i s
bei ng gi ven ti me to work. In s uch i ns ta nces , a s oma tos ta ti n a na l og, octreoti de, i s gi ven a t 0.05 to 0.15 mg s c q 8 to 12 h; i t s uppres s es GH s ecreti on
effecti vel y i n pa ti ents refra ctory to bromocri pti ne, s urgery, or i rra di a ti on. Longer-a cti ng s oma tos ta ti n a na l ogs , s uch a s ma nni tol -modi fi ed rel ea s e
octreoti de (octreoti de LAR) gi ven 10 to 30 mg IM q 4 to 6 wk a nd l a nreoti de gi ven 30 mg IM q 10 to 14 da ys , a re more conveni ent. Bromocri pti ne
mes yl a te (1.25 to 5 mg po bi d) ma y effecti vel y l ower GH l evel s i n a s ma l l percenta ge of pa ti ents but i s l es s effecti ve tha n s oma tos ta ti n a na l ogs .
Pegvi s oma nt, a GH receptor bl ocker, ha s been s hown to reduce the effects of GH a nd l ower IGF-1 l evel s i n peopl e wi th a cromega l y, wi thout
a ppa rent i ncrea s e i n pi tui ta ry tumor s i ze. Thi s drug ma y fi nd a pl a ce i n trea ti ng pa ti ents who a re pa rti a l l y or tota l l y unres pons i ve to s oma tos ta ti n
a na l ogs .
Galactorrhea
Galactorrhea is lactation in men or in women who are not breastfeeding. It is generally due to a prolactin-secreting pituitary adenoma. Diagnosis is by
measurement of prolactin levels and imaging tests. Treatment involves tumor inhibition with dopamine agonist drugs and sometimes removal or destruction of
the adenoma.
Etiology
Ga l a ctorrhea i s genera l l y due to a prol a cti n-s ecreti ng pi tui ta ry a denoma (prol a cti noma ). Mos t tumors i n women a re mi croa denoma s (< 10 mm i n
di a meter), but a s ma l l percenta ge a re ma croa denoma s (> 10 mm) when di a gnos ed. The frequency of mi croa denoma s i s much l ower i n men,
perha ps beca us e of l a ter recogni ti on.
Hyperprol a cti nemi a a nd ga l a ctorrhea a l s o ma y be ca us ed by i nges ti on of certa i n drugs , i ncl udi ng phenothi a zi nes , other a nti ps ychoti cs , certa i n
a nti hypertens i ves (es peci a l l y -methyl dopa ), a nd opi oi ds . Pri ma ry hypothyroi di s m ca n ca us e hyperprol a cti nemi a a nd ga l a ctorrhea , beca us e
i ncrea s ed l evel s of thyroi d-rel ea s i ng hormone i ncrea s e s ecreti on of prol a cti n a s wel l a s thyroi d-s ti mul a ti ng hormone (TSH). It i s uncl ea r why
hyperprol a cti nemi a i s a s s oci a ted wi th hypogona dotropi s m a nd hypogona di s m. Ca us es of hyperprol a cti nemi a a re l i s ted i n
Ta bl e 92-3.
Symptoms and Signs
Abnorma l l a cta ti on i s not defi ned qua nti ta ti vel y; i t i s mi l k rel ea s e tha t i s i na ppropri a te, pers i s tent, or worri s ome to the pa ti ent. Sponta neous
l a cta ti on i s more unus ua l tha n mi l k rel ea s ed i n res pons e to ma nua l expres s i on. The mi l k i s whi te. Women wi th ga l a ctorrhea commonl y a l s o ha ve
a menorrhea or ol i gomenorrhea . Women wi th ga l a ctorrhea a nd a menorrhea ma y a l s o ha ve s ymptoms a nd s i gns of es trogen defi ci ency, i ncl udi ng
dys pa reuni a , due to i nhi bi ti on of pul s a ti l e l utei ni zi ng hormone a nd fol l i cl e-s ti mul a ti ng hormone rel ea s e
[Table 92-3. Ca us es of Hyperprol a cti nemi a ]
by hi gh prol a cti n l evel s . However, es trogen producti on ma y be norma l , a nd s i gns of a ndrogen exces s ha ve been obs erved i n s ome women wi th
hyperprol a cti nemi a . Hyperprol a cti nemi a ma y occur wi th other mens trua l cycl e di s turba nces bes i des a menorrhea , i ncl udi ng i nfrequent ovul a ti on
a nd corpus l uteum dys functi on.
Men wi th prol a cti n-s ecreti ng pi tui ta ry tumors typi ca l l y ha ve hea da ches or vi s ua l di ffi cul ti es . About two thi rds of a ffected men ha ve l os s of l i bi do
a nd erecti l e dys functi on.
Diagnosis
Prol a cti n l evel s
Thyroxi ne (T4 ) a nd TSH l evel s
CT or MRI
Di a gnos i s of ga l a ctorrhea due to a prol a cti n-s ecreti ng pi tui ta ry a denoma i s ba s ed on el eva ted prol a cti n l evel s . In genera l , prol a cti n l evel s
correl a te wi th the s i ze of a pi tui ta ry tumor a nd ca n be us ed to fol l ow pa ti ents over ti me. Serum gona dotropi n a nd es tra di ol l evel s a re ei ther l ow
or i n the norma l ra nge i n women wi th hyperprol a cti nemi a . Pri ma ry hypothyroi di s m i s ea s i l y rul ed out by a bs ence of el eva ted TSH.
Hi gh-res ol uti on CT or MRI i s the method of choi ce i n i denti fyi ng mi croa denoma s . Vi s ua l fi el d exa mi na ti on i s i ndi ca ted i n a l l pa ti ents wi th
ma croa denoma s a nd i n a ny pa ti ent who el ects drug thera py or s urvei l l a nce onl y.
Treatment
Depends on ca us e, s ymptoms , a nd other fa ctors
The trea tment of mi croprol a cti noma s i s controvers i a l . As ymptoma ti c pa ti ents who ha ve prol a cti n l evel s < 100 ng/mL a nd norma l CT or MRI res ul ts
or who ha ve onl y mi croa denoma s ca n proba bl y be obs erved; s erum prol a cti n often norma l i zes wi thi n yea rs . Pa ti ents wi th hyperprol a cti nemi a
s houl d be moni tored wi th qua rterl y mea s urement of prol a cti n l evel s a nd undergo s el l a r CT or MRI a nnua l l y for a t l ea s t a n a ddi ti ona l 2 yr. The
frequency of s el l a r i ma gi ng ca n then be reduced i f prol a cti n l evel s do not i ncrea s e. Indi ca ti ons for trea tment i n women i ncl ude the des i re for
pregna ncy, a menorrhea or s i gni fi ca nt ol i gomenorrhea (beca us e of the ri s k of os teoporos i s ), hi rs uti s m, l ow l i bi do, a nd troubl es ome ga l a ctorrhea .
Indi ca ti ons i n men i ncl ude hypogona di s m (beca us e of the ri s k of os teoporos i s ), erecti l e dys functi on, l ow l i bi do, a nd troubl es ome i nferti l i ty.
The i ni ti a l trea tment i s us ua l l y a dopa mi ne a goni s t s uch a s bromocri pti ne (1.25 to 5 mg po bi d) or the l onger-a cti ng ca bergol i ne (0.25 to 1.0 mg po
once/wk or twi ce/wk). Ca bergol i ne i s the trea tment of choi ce beca us e i t s eems to be more ea s i l y tol era ted a nd more potent tha n bromocri pti ne.
Women tryi ng to become pregna nt s houl d s wi tch to bromocri pti ne a t l ea s t 1 mo before pl a nned concepti on a nd s top bromocri pti ne us e a t the
ti me of a pos i ti ve pregna ncy tes t; l ong-term s a fety da ta a re better es ta bl i s hed for bromocri pti ne tha n for ca bergol i ne. Exogenous es trogen ca n be
gi ven to women wi th a mi croa denoma who a re cl i ni ca l l y hypoes trogeni c or ha ve l ow es tra di ol l evel s . Exogenous es trogen i s unl i kel y to ca us e
tumor expa ns i on.
Pa ti ents wi th ma croa denoma s genera l l y s houl d be trea ted wi th dopa mi ne a goni s ts or s urgi ca l l y but onl y a fter thorough tes ti ng of pi tui ta ry
functi on a nd eva l ua ti on for ra di a ti on thera py. Dopa mi ne a goni s ts a re us ua l l y the i ni ti a l trea tment of choi ce a nd us ua l l y s hri nk the tumor. If
prol a cti n l evel s fa l l a nd s ymptoms a nd s i gns of compres s i on by the tumor a ba te, no other thera py ma y be neces s a ry. Surgery or ra di a ti on thera py
ma y be ea s i er to do or yi el d better res ul ts a fter tumor s hri nka ge i nduced by a dopa mi ne a goni s t. Al though dopa mi ne a goni s t trea tment us ua l l y
needs to be conti nued l ong-term, prol a cti n-s ecreti ng tumors s ometi mes remi t, ei ther s ponta neous l y or perha ps a i ded by the drug thera py.
Someti mes , therefore, dopa mi ne a goni s ts ca n be s topped wi thout a recurrence of the tumor or a ri s e i n prol a cti n l evel s ; remi s s i on i s more l i kel y
wi th mi croa denoma s tha n ma croa denoma s . Remi s s i on i s a l s o more l i kel y a fter pregna ncy.
Hi gh dos es of dopa mi ne a goni s ts , pa rti cul a rl y ca bergol i ne a nd pergol i de, a re thought to ha ve ca us ed va l vul a r hea rt di s ea s e i n s ome pa ti ents
wi th Pa rki ns on's di s ea s e. It i s not cl ea r whether the l ower dos es of dopa mi ne a goni s ts us ed for hyperprol a cti nemi a s i mi l a rl y i ncrea s e the ri s k of
va l vul a r hea rt di s ea s e, but the pos s i bi l i ty s houl d be di s cus s ed wi th pa ti ents , a nd echoca rdi ogra phi c s urvei l l a nce s houl d be cons i dered. The ri s k
ma y be l es s wi th bromocri pti ne or a nonergot-deri ved dopa mi ne a goni s t (eg, qui na gol i de).
Ra di a ti on thera py s houl d be us ed onl y i n pa ti ents wi th progres s i ve di s ea s e who do not res pond to other forms of thera py. Wi th i rra di a ti on,
hypopi tui ta ri s m often devel ops s evera l yea rs a fter thera py. Moni tori ng endocri ne functi on a nd s el l a r i ma gi ng a re i ndi ca ted yea rl y for l i fe.
Central Diabetes Insipidus
(Va s opres s i n-Sens i ti ve Di a betes Ins i pi dus )
(See a l s o Si deba r 97-1 on p. 826 a nd Nephrogeni c Di a betes Ins i pi dus on p. 2424.)
Diabetes insipidus (DI) results from a deficiency of ADH due to a hypothalamic-pituitary disorder (central DI [CDI]) or from resistance of the kidney to ADH
(nephrogenic DI [NDI]). Polyuria and polydipsia develop. Diagnosis is by water deprivation test showing failure to maximally concentrate urine; ADH levels and
response to exogenous ADH help distinguish CDI from NDI. Treatment is with intranasal desmopressin or lypressin. Nonhormonal treatment includes use of
diuretics (mainly thiazides) and ADH-releasing drugs, such as chlorpropamide.
Pathophysiology
Pol yuri a ma y res ul t from CDI, a defi ci ency of ADH, NDI, or compul s i ve or ha bi tua l wa ter dri nki ng (ps ychogeni c pol ydi ps i a ). The pos teri or l obe of the
pi tui ta ry i s the ma jor s i te of ADH s tora ge a nd rel ea s e, but ADH i s s ynthes i zed wi thi n the hypotha l a mus . Newl y s ynthes i zed hormone ca n s ti l l be
rel ea s ed i nto the ci rcul a ti on a s l ong a s the hypotha l a mi c nucl ei a nd pa rt of the neurohypophys ea l tra ct a re i nta ct. Onl y a bout 10% of
neuros ecretory neurons mus t rema i n i nta ct to a voi d CDI. The pa thol ogy of CDI thus a l wa ys i nvol ves the s upra opti c a nd pa ra ventri cul a r nucl ei of
the hypotha l a mus or a ma jor porti on of the pi tui ta ry s ta l k.
CDI ma y be compl ete (a bs ence of ADH) or pa rti a l (i ns uffi ci ent a mounts of ADH). CDI ma y be pri ma ry, i n whi ch there i s a ma rked decrea s e i n the
hypotha l a mi c nucl ei of the neurohypophys ea l s ys tem.
Etiology
Primary CDI: Geneti c a bnorma l i ti es of the ADH gene on chromos ome 20 a re res pons i bl e for a utos oma l domi na nt forms of pri ma ry CDI, but ma ny
ca s es a re i di opa thi c.
Secondary CDI: CDI ma y a l s o be s econda ry (a cqui red), ca us ed by va ri ous l es i ons , i ncl udi ng hypophys ectomy, cra ni a l i njuri es (pa rti cul a rl y ba s a l s kul l
fra ctures ), s upra s el l a r a nd i ntra s el l a r tumors (pri ma ry or meta s ta ti c), La ngerha ns ' cel l hi s ti ocytos i s (Ha nd-Schul l er-Chri s ti a n di s ea s e), gra nul oma s
(s a rcoi dos i s or TB), va s cul a r l es i ons (a neurys m a nd thrombos i s ), a nd i nfecti ons (encepha l i ti s or meni ngi ti s ).
Symptoms and Signs
Ons et ma y be i ns i di ous or a brupt, occurri ng a t a ny a ge. The onl y s ymptoms i n pri ma ry CDI a re pol ydi ps i a a nd pol yuri a . In s econda ry CDI, s ymptoms
a nd s i gns of the a s s oci a ted l es i ons a re a l s o pres ent. Enormous qua nti ti es of fl ui d ma y be i nges ted, a nd l a rge vol umes (3 to 30 L/da y) of very
di l ute uri ne (s p gr us ua l l y < 1.005 a nd os mol a l i ty < 200 mOs m/L) a re excreted. Nocturi a a l mos t a l wa ys occurs . Dehydra ti on a nd hypovol emi a ma y
devel op ra pi dl y i f uri na ry l os s es a re not conti nuous l y repl a ced.
Diagnosis
Wa ter depri va ti on tes t
Someti mes ADH l evel s
CDI mus t be di fferenti a ted from other ca us es of pol yuri a (s ee
Ta bl e 92-4), pa rti cul a rl y ps ychogeni c pol ydi ps i a a nd NDI. Al l tes ts for CDI (a nd for NDI) a re ba s ed on the pri nci pl e tha t i ncrea s i ng the pl a s ma
os mol a l i ty i n norma l peopl e wi l l l ea d to decrea s ed excreti on of uri ne wi th i ncrea s ed os mol a l i ty.
The wa ter depri va ti on tes t i s the s i mpl es t a nd mos t rel i a bl e method for di a gnos i ng CDI but should be done only while the patient is under constant
supervision. Serious dehydration may result. Addi ti ona l l y, i f ps ychogeni c
[Table 92-4. Common Ca us es of Pol yuri a ]
pol ydi ps i a i s s us pected, the pa ti ent mus t be obs erved to prevent s urrepti ti ous dri nki ng. The tes t i s s ta rted i n the morni ng by wei ghi ng the pa ti ent,
obta i ni ng venous bl ood to determi ne el ectrol yte concentra ti ons a nd os mol a l i ty, a nd mea s uri ng uri na ry os mol a l i ty. Voi ded uri ne i s col l ected
hourl y, a nd i ts s p gr or, prefera bl y, os mol a l i ty i s mea s ured. Dehydra ti on i s conti nued unti l orthos ta ti c hypotens i on a nd pos tura l ta chyca rdi a
a ppea r, 5% of the i ni ti a l body wei ght ha s been l os t, or the uri na ry concentra ti on does not i ncrea s e > 0.001 s p gr or > 30 mOs m/L i n s equenti a l l y
voi ded s peci mens . Serum el ectrol ytes a nd os mol a l i ty a re a ga i n determi ned, a nd 5 uni ts of a queous va s opres s i n a re i njected s c. Uri ne for s p gr or
os mol a l i ty mea s urement i s col l ected one fi na l ti me 60 mi n pos ti njecti on, a nd the tes t i s termi na ted.
A norma l res pons e produces ma xi mum uri ne os mol a l i ty a fter dehydra ti on (often > 1.020 s p gr or > 700 mOs m/L), exceedi ng the pl a s ma os mol a l i ty;
os mol a l i ty does not i ncrea s e more tha n a n a ddi ti ona l 5% a fter i njecti on of va s opres s i n. Pa ti ents wi th CDI a re genera l l y una bl e to concentra te
uri ne to grea ter tha n the pl a s ma os mol a l i ty but a re a bl e to i ncrea s e thei r uri ne os mol a l i ty by > 50% a fter va s opres s i n a dmi ni s tra ti on. Pa ti ents
wi th pa rti a l CDI a re often a bl e to concentra te uri ne to a bove the pl a s ma os mol a l i ty but s how a ri s e i n uri ne os mol a l i ty of > 9% a fter va s opres s i n
a dmi ni s tra ti on. Pa ti ents wi th NDI a re una bl e to concentra te uri ne to grea ter tha n the pl a s ma os mol a l i ty a nd s how no a ddi ti ona l res pons e to
va s opres s i n a dmi ni s tra ti on.
Mea s urement of ci rcul a ti ng ADH i s the mos t di rect method of di a gnos i ng CDI; l evel s a t the end of the wa ter depri va ti on tes t (before the
va s opres s i n i njecti on) a re l ow i n CDI a nd a ppropri a tel y el eva ted i n NDI. However, ADH l evel s a re di ffi cul t to mea s ure, a nd the tes t i s not routi nel y
a va i l a bl e. In a ddi ti on, wa ter depri va ti on i s s o a ccura te tha t di rect mea s urement of ADH i s unneces s a ry. Pl a s ma ADH l evel s a re di a gnos ti c a fter
ei ther dehydra ti on or i nfus i on of hypertoni c s a l i ne.
Psychogenic polydipsia: Ps ychogeni c pol ydi ps i a ma y pres ent a di ffi cul t probl em i n di fferenti a l di a gnos i s . Pa ti ents ma y i nges t a nd excrete up to 6 L of
fl ui d/da y a nd a re often emoti ona l l y di s turbed. Unl i ke pa ti ents wi th CDI a nd NDI, they us ua l l y do not ha ve nocturi a , nor does thei r thi rs t wa ke
them a t ni ght. Conti nued i nges ti on of l a rge vol umes of wa ter i n thi s s i tua ti on ca n l ea d to l i fe-threa teni ng hypona tremi a (s ee p. 823).
Pa ti ents wi th a cute ps ychogeni c wa ter dri nki ng a re a bl e to concentra te thei r uri ne duri ng wa ter depri va ti on. However, beca us e chroni c wa ter
i nta ke di mi ni s hes medul l a ry toni ci ty i n the ki dney, pa ti ents wi th l ongs ta ndi ng pol ydi ps i a a re not a bl e to concentra te thei r uri ne to ma xi ma l
l evel s duri ng wa ter depri va ti on, a res pons e s i mi l a r to tha t of pa ti ents wi th pa rti a l CDI. However, unl i ke CDI, pa ti ents wi th ps ychogeni c pol ydi ps i a
s how no res pons e to exogenous ADH a fter wa ter depri va ti on. Thi s res pons e res embl es NDI, except tha t ba s a l ADH l evel s a re l ow compa red wi th
the el eva ted l evel s pres ent i n NDI. After prol onged res tri cti on of fl ui d i nta ke to 2 L/da y, norma l concentra ti ng a bi l i ty returns wi thi n s evera l
weeks .
Treatment
Des mopres s i n
CDI ca n be trea ted wi th hormone repl a cement a nd trea tment of a ny correcta bl e ca us e. In the a bs ence of a ppropri a te ma na gement, perma nent
rena l da ma ge ca n res ul t.
Des mopres s i n, a s yntheti c a na l og of ADH wi th mi ni ma l va s ocons tri cti ve properti es , ha s prol onged a nti di ureti c a cti vi ty l a s ti ng for 12 to 24 h i n
mos t pa ti ents a nd ma y be a dmi ni s tered i ntra na s a l l y, s c, IV, or ora l l y. Des mopres s i n i s the prepa ra ti on of choi ce for both a dul ts a nd chi l dren a nd
i s a va i l a bl e a s a n i ntra na s a l s ol uti on i n 2 forms . A dropper bottl e wi th a ca l i bra ted na s a l ca theter ha s the a dva nta ge of del i veri ng i ncrementa l
dos es from 5 to 20 g but i s a wkwa rd to us e. A s pra y bottl e tha t del i vers 10 g of des mopres s i n i n 0.1 mL of fl ui d i s ea s i er to us e but del i vers a
fi xed qua nti ty. For ea ch pa ti ent, the dura ti on of a cti on of a gi ven dos e mus t be es ta bl i s hed, beca us e va ri a ti on a mong i ndi vi dua l s i s grea t. The
dura ti on of a cti on ca n be es ta bl i s hed by fol l owi ng ti med uri ne vol umes a nd os mol a l i ty. The ni ghtl y dos e i s the l owes t dos e requi red to prevent
nocturi a . The morni ng a nd eveni ng dos es s houl d be a djus ted s epa ra tel y. The us ua l dos a ge ra nge i n a dul ts i s 10 to 40 g, wi th mos t a dul ts
requi ri ng 10 g bi d. For chi l dren a ge 3 mo to 12 yr, the us ua l dos a ge ra nge i s 2.5 to 10 g bi d. Overdos a ge ca n l ea d to fl ui d retenti on a nd decrea s ed
pl a s ma os mol a l i ty, pos s i bl y res ul ti ng i n s ei zures i n s ma l l chi l dren. In s uch i ns ta nces , furos emi de ca n be gi ven to i nduce di ures i s . Hea da che ma y
be a troubl es ome a dvers e effect but genera l l y di s a ppea rs i f the dos a ge i s reduced. Infrequentl y, des mopres s i n ca us es a s l i ght i ncrea s e i n BP.
Abs orpti on from the na s a l mucos a ma y be erra ti c, es peci a l l y when URI or a l l ergi c rhi ni ti s occurs . When i ntra na s a l del i very of des mopres s i n i s
i na ppropri a te, i t ma y be a dmi ni s tered s c us i ng a bout one tenth the i ntra na s a l dos e. Des mopres s i n ma y be us ed IV i f a ra pi d effect i s neces s a ry
(eg, for hypovol emi a ). Wi th ora l des mopres s i n, dos e equi va l ence wi th the i ntra na s a l formul a ti on i s unpredi cta bl e, s o i ndi vi dua l dos e ti tra ti on i s
needed. The i ni ti a l dos e i s 0.1 mg po ti d, a nd the ma i ntena nce dos e i s us ua l l y 0.1 to 0.2 mg ti d.
Lypres s i n (l ys i ne-8-va s opres s i n), a s yntheti c a gent, i s gi ven by na s a l s pra y a t dos es of 2 to 4 uni ts (7.5 to 15 g) q 3 to 8 h but, beca us e of i ts s hort
dura ti on of a cti on, ha s been l a rgel y repl a ced by des mopres s i n.
Aqueous va s opres s i n 5 to 10 uni ts s c or IM ca n be gi ven to provi de a n a nti di ureti c res pons e tha t us ua l l y l a s ts 6 h. Thus , thi s drug ha s l i ttl e us e i n
l ong-term trea tment but ca n be us ed i n the i ni ti a l thera py of uncons ci ous pa ti ents a nd i n pa ti ents wi th CDI who a re undergoi ng s urgery. Syntheti c
va s opres s i n ca n a l s o be a dmi ni s tered bi d to qi d a s a na s a l s pra y, wi th the dos a ge a nd i nterva l ta i l ored to ea ch pa ti ent. Va s opres s i n ta nna te i n
oi l 0.3 to 1 mL (1.5 to 5 uni ts ) IM ma y control s ymptoms for up to 96 h.
At l ea s t 3 groups of nonhormona l drugs a re us eful i n reduci ng pol yuri a : va ri ous di ureti cs , pri ma ri l y thi a zi des ; ADH-rel ea s i ng drugs , s uch a s
chl orpropa mi de, ca rba ma zepi ne, a nd cl ofi bra te; a nd pros ta gl a ndi n i nhi bi tors , whi ch a re modes tl y effecti ve. Thes e drugs ha ve been pa rti cul a rl y
us eful i n pa rti a l CDI a nd do not ca us e the a dvers e effects of exogenous ADH.
The thi a zi des pa ra doxi ca l l y reduce uri ne vol ume i n pa rti a l a nd compl ete CDI (a nd NDI), pri ma ri l y a s a cons equence of reduci ng ECF vol ume a nd
i ncrea s i ng proxi ma l tubul a r res orpti on. Uri ne vol umes ma y fa l l by 25 to 50% wi th 15 to 25 mg/kg of chl orothi a zi de. Res tri cti ng s a l t i nta ke ma y a l s o
hel p beca us e i t reduces uri ne output by reduci ng s ol ute l oa d.
Chl orpropa mi de, ca rba ma zepi ne, a nd cl ofi bra te ca n reduce or el i mi na te the need for va s opres s i n i n s ome pa ti ents wi th pa rti a l CDI. None a re
effecti ve i n NDI. Chl orpropa mi de (3 to 5 mg/kg po once/da y or bi d) ca us es s ome rel ea s e of ADH a nd a l s o potenti a tes the a cti on of ADH on the
ki dney. Cl ofi bra te (500 to 1000 mg po bi d) or ca rba ma zepi ne (100 to 400 mg po bi d) i s recommended for a dul ts onl y. Thes e drugs ma y be us ed
s ynergi s ti ca l l y wi th a di ureti c. However, s i gni fi ca nt hypogl ycemi a ma y res ul t from chl orpropa mi de.
Pros ta gl a ndi n i nhi bi tors (s uch a s i ndometha ci n 0.5 to 1.0 mg/kg po ti d, a l though mos t NSAIDs a re effecti ve) ma y reduce uri ne vol ume, but
genera l l y by no more tha n 10 to 25%, perha ps by decrea s i ng rena l bl ood fl ow a nd GFR. Together wi th i ndometha ci n, res tri cti on of Na i nta ke a nd a
thi a zi de di ureti c hel p further reduce uri ne vol ume i n NDI.
Chapter 93. Thyroid Disorders

Introduction
The thyroi d gl a nd, l oca ted i n the a nteri or neck jus t bel ow the cri coi d ca rti l a ge, cons i s ts of 2 l obes connected by a n i s thmus . Fol l i cul a r cel l s i n the
gl a nd produce the 2 ma i n thyroi d hormones , tetra i odothyroni ne (thyroxi ne, T4 ) a nd tri i odothyroni ne (T3 ). Thes e hormones a ct on cel l s i n vi rtua l l y
every body ti s s ue by combi ni ng wi th nucl ea r receptors a nd a l teri ng expres s i on of a wi de ra nge of gene products . Thyroi d hormone i s requi red for
norma l bra i n a nd s oma ti c ti s s ue devel opment i n the fetus a nd neona te, a nd, i n peopl e of a l l a ges , regul a tes protei n, ca rbohydra te, a nd fa t
meta bol i s m.
T3 i s the mos t a cti ve form; T4 ha s onl y mi ni ma l hormona l a cti vi ty. However, T4 i s much l onger l a s ti ng a nd ca n be converted to T3 (i n mos t ti s s ues )
a nd thus s erves a s a res ervoi r for T3 . A 3rd form of thyroi d hormone, revers e T3 (rT3 ), ha s no meta bol i c a cti vi ty; l evel s of rT3 i ncrea s e i n certa i n
di s ea s es .
Addi ti ona l l y, pa ra fol l i cul a r cel l s (C cel l s ) s ecrete the hormone ca l ci toni n, whi ch i s rel ea s ed i n res pons e to hyperca l cemi a a nd l owers s erum Ca
l evel s (s ee p. 838).
Synthesis and Release of Thyroid Hormones
Synthes i s of thyroi d hormones requi res i odi ne (s ee
Fi g. 93-1). Iodi ne, i nges ted i n food a nd wa ter a s i odi de, i s a cti vel y concentra ted by the thyroi d a nd converted to orga ni c i odi ne (orga ni fi ca ti on)
wi thi n fol l i cul a r cel l s by thyroi d peroxi da s e. The fol l i cul a r cel l s s urround a s pa ce fi l l ed wi th col l oi d, whi ch cons i s ts of thyrogl obul i n, a
gl ycoprotei n conta i ni ng tyros i ne wi thi n i ts ma tri x. Tyros i ne i n conta ct wi th the membra ne of the fol l i cul a r cel l s i s i odi na ted a t 1
(monoi odotyros i ne) or 2 (di i odotyros i ne) s i tes a nd then coupl ed to produce the 2 forms of thyroi d hormone (di i odotyros i ne + di i odotyros i ne
T4 ;
di i odotyros i ne + monoi odotyros i ne
T3 ).
[Fig. 93-1. Synthes i s of thyroi d hormones .]
T3 a nd T4 rema i n i ncorpora ted i n thyrogl obul i n wi thi n the fol l i cl e unti l the fol l i cul a r cel l s ta ke up thyrogl obul i n a s col l oi d dropl ets . Once i ns i de
the thyroi d fol l i cul a r cel l s , T3 a nd T4 a re cl ea ved from thyrogl obul i n. Free T3 a nd T4 a re then rel ea s ed i nto the bl oods trea m, where they a re bound
to s erum protei ns for tra ns port, the ma jor one bei ng thyroxi ne-bi ndi ng gl obul i n (TBG), whi ch ha s hi gh a ffi ni ty but l ow ca pa ci ty for T3 a nd T4 . TBG
norma l l y ca rri es a bout 75% of bound thyroi d hormones . The other bi ndi ng protei ns a re thyroxi ne-bi ndi ng prea l bumi n (tra ns thyreti n), whi ch ha s
hi gh a ffi ni ty but l ow ca pa ci ty for T4 , a nd a l bumi n, whi ch ha s l ow a ffi ni ty but hi gh ca pa ci ty for T3 a nd T4 . About 0.3% of tota l s erum T3 a nd 0.03% of
tota l s erum T4 a re free a nd i n equi l i bri um wi th bound hormones . Onl y free T3 a nd free T4 a re a va i l a bl e to a ct on the peri phera l ti s s ues .
Al l rea cti ons neces s a ry for the forma ti on a nd rel ea s e of T3 a nd T4 a re control l ed by thyroi d-s ti mul a ti ng hormone (TSH), whi ch i s s ecreted by
pi tui ta ry thyrotropi c cel l s . TSH s ecreti on i s control l ed by a nega ti ve feedba ck mecha ni s m i n the pi tui ta ry: Increa s ed l evel s of free T4 a nd T3 i nhi bi t
TSH s ynthes i s a nd s ecreti on, wherea s decrea s ed l evel s i ncrea s e TSH s ecreti on. TSH s ecreti on i s a l s o i nfl uenced by thyrotropi n-rel ea s i ng hormone
(TRH), whi ch i s s ynthes i zed i n the hypotha l a mus . The preci s e mecha ni s ms regul a ti ng TRH s ynthes i s a nd rel ea s e a re uncl ea r, a l though nega ti ve
feedba ck from thyroi d hormones i nhi bi ts TRH s ynthes i s .
Mos t ci rcul a ti ng T3 i s produced outs i de the thyroi d by monodei odi na ti on of T4 . Onl y one fi fth of ci rcul a ti ng T3 i s s ecreted di rectl y by the thyroi d.
Laboratory Testing of Thyroid Function
TSH mea s urement i s the bes t mea ns of determi ni ng thyroi d dys functi on (s ee
Ta bl e 93-1). Norma l res ul ts es s enti a l l y rul e out hyperthyroi di s m or hypothyroi di s m, except i n ra re pa ti ents wi th pi tui ta ry res i s ta nce to thyroi d
hormone or wi th centra l hypothyroi di s m due to di s ea s e i n the hypotha l a mus , pi tui ta ry gl a nd, or both. Serum TSH ca n be fa l s el y l ow i n very s i ck
peopl e. The s erum TSH l evel a l s o defi nes the s yndromes of s ubcl i ni ca l hyperthyroi di s m (l ow s erum TSH) a nd s ubcl i ni ca l hypothyroi di s m (el eva ted
s erum TSH), both
[Table 93-1. Res ul ts of Thyroi d Functi on Tes ts i n Va ri ous Cl i ni ca l Si tua ti ons ]
of whi ch a re cha ra cteri zed by norma l s erum T4 , free T4 , s erum T3 , a nd free T3 l evel s .
Tota l s erum T4 i s a mea s ure of bound a nd free hormone. Cha nges i n l evel s of thyroi d hormone-bi ndi ng s erum protei ns produce corres pondi ng
cha nges i n tota l T4 , even though l evel s of phys i ol ogi ca l l y a cti ve free T4 a re uncha nged. Thus , a pa ti ent ma y be phys i ol ogi ca l l y norma l but ha ve a n
a bnorma l tota l s erum T4 l evel . Free T4 i n the s erum ca n be mea s ured di rectl y, a voi di ng the pi tfa l l s of i nterpreti ng tota l T4 l evel s .
Free T4 i ndex i s a ca l cul a ted va l ue tha t corrects tota l T4 for the effects of va ryi ng a mounts of thyroi d hormone-bi ndi ng s erum protei ns a nd thus
gi ves a n es ti ma te of free T4 when tota l T4 i s mea s ured. The thyroi d hormone-bi ndi ng ra ti o or T3 res i n upta ke i s us ed to es ti ma te protei n bi ndi ng.
Free T4 i ndex i s rea di l y a va i l a bl e a nd compa res wel l wi th di rect mea s urement of free T4 .
Tota l s erum T3 a nd free T3 ca n a l s o be mea s ured. Beca us e T3 i s ti ghtl y bound to TBG (a l though 10 ti mes l es s s o tha n T4 ), tota l s erum T3 l evel s a re
i nfl uenced by a l tera ti ons i n s erum TBG l evel a nd by drugs tha t a ffect bi ndi ng to TBG. Free T3 l evel s i n the s erum a re mea s ured by the s a me di rect
a nd i ndi rect methods (free T3 i ndex) des cri bed for T4 a nd a re us ed ma i nl y for eva l ua ti ng thyrotoxi cos i s .
TBG ca n be mea s ured; i t i s i ncrea s ed i n pregna ncy, by es trogen thera py or ora l contra cepti ve us e, a nd i n the a cute pha s e of i nfecti ous hepa ti ti s .
TBG ma y a l s o be i ncrea s ed by a n X-l i nked a bnorma l i ty. It i s mos t commonl y decrea s ed by i l l nes s es tha t reduce hepa ti c protei n s ynthes i s , us e of
a na bol i c s teroi ds , a nd exces s i ve corti cos teroi d us e. La rge dos es of certa i n drugs , s uch a s phenytoi n a nd a s pi ri n a nd thei r deri va ti ves , di s pl a ce T4
from i ts bi ndi ng s i tes on TBG, whi ch s puri ous l y l owers tota l s erum T4 l evel s .
Autoa nti bodi es to thyroi d peroxi da s e a re pres ent i n a l mos t a l l pa ti ents wi th Ha s hi moto's thyroi di ti s (s ome of whom a l s o ha ve a utoa nti bodi es to
thyrogl obul i n) a nd i n mos t pa ti ents wi th Gra ves ' di s ea s e. Thes e a utoa nti bodi es a re ma rkers of a utoi mmune di s ea s e but proba bl y do not ca us e
di s ea s e. However, a n a utoa nti body di rected a ga i ns t the TSH receptor on the thyroi d fol l i cul a r cel l i s res pons i bl e for the hyperthyroi di s m i n
Gra ves ' di s ea s e. Anti bodi es a ga i ns t T4 a nd T3 ma y be found i n pa ti ents wi th a utoi mmune thyroi d di s ea s e a nd ma y a ffect T4 a nd T3 mea s urements
but a re ra rel y cl i ni ca l l y s i gni fi ca nt.
The thyroi d i s the onl y s ource of thyrogl obul i n, whi ch i s rea di l y detecta bl e i n the s erum of hea l thy peopl e a nd i s us ua l l y el eva ted i n pa ti ents wi th
nontoxi c or toxi c goi ter. The pri nci pa l us e of s erum thyrogl obul i n mea s urement i s i n eva l ua ti ng pa ti ents a fter nea r-tota l or tota l thyroi dectomy
(wi th or wi thout 131 I a bl a ti on) for di fferenti a ted thyroi d ca ncer. Norma l or el eva ted s erum thyrogl obul i n va l ues i ndi ca te the pres ence of res i dua l
norma l or ca ncerous thyroi d ti s s ue i n pa ti ents recei vi ng TSH-s uppres s i ve dos es of L-thyroxi ne or a fter wi thdra wa l of L-thyroxi ne. However,
thyrogl obul i n a nti bodi es ca n i nterfere wi th thyrogl obul i n mea s urement.
Ra di oa cti ve i odi ne upta ke ca n be mea s ured. A tra ce a mount of ra di oi odi ne i s gi ven ora l l y or IV; a s ca nner then detects the a mount of ra di oi odi ne
ta ken up by the thyroi d. The preferred ra di oi odi ne i s otope i s 123 I, whi ch expos es the pa ti ent to mi ni ma l ra di a ti on (much l es s tha n 131 I). Thyroi d
123
I upta ke va ri es wi del y wi th i odi ne i nges ti on a nd i s l ow i n pa ti ents expos ed to exces s i odi ne.
The tes t i s va l ua bl e i n the di fferenti a l di a gnos i s of hyperthyroi di s m (hi gh upta ke i n Gra ves ' di s ea s e, l ow upta ke i n thyroi di ti s s ee p. 782). It ma y
a l s o hel p i n the ca l cul a ti on of the dos e of 131 I needed for trea tment of hyperthyroi di s m.
Ima gi ng by a s ci nti l l a ti on ca mera ca n be done a fter ra di oi s otope a dmi ni s tra ti on (ra di oi odi ne or techneti um 99m pertechneta te) to produce a
gra phi c repres enta ti on of i s otope upta ke. Foca l a rea s of i ncrea s ed (hot) or decrea s ed (col d) upta ke hel p di s ti ngui s h a rea s of pos s i bl e ca ncer
(thyroi d ca ncers exi s t i n < 1% of hot nodul es compa red wi th 10 to 20% of col d nodul es ).
Screening: Screeni ng every 5 yr by mea s uri ng s erum TSH i s recommended for a l l men 65 a nd for a l l women 35. For thos e wi th ri s k fa ctors for
thyroi d di s ea s e, the s erum TSH s houl d be checked more often. Screeni ng for hypothyroi di s m i s a s cos t effecti ve a s s creeni ng for hypertens i on,
hyperchol es terol emi a , a nd brea s t ca ncer. Thi s s i ngl e tes t i s hi ghl y s ens i ti ve a nd s peci fi c i n di a gnos i ng or excl udi ng two preva l ent a nd s eri ous
di s orders (hypothyroi di s m a nd hyperthyroi di s m), both of whi ch ca n be trea ted effecti vel y. Beca us e of the hi gh i nci dence of hypothyroi di s m i n ol der
peopl e, s creeni ng on a n a nnua l ba s i s i s rea s ona bl e for thos e > a ge 70.
Approach to the Patient With a Thyroid Nodule
Thyroi d nodul es a re common, i ncrea s i ngl y s o wi th i ncrea s i ng a ge. The reported i nci dence va ri es wi th the method of a s s es s ment. In mi ddl e-a ged
a nd el derl y pa ti ents , pa l pa ti on revea l s nodul es i n a bout 5%. Res ul ts of ul tra s onogra phy a nd a utops y s tudi es s ugges t tha t nodul es a re pres ent i n
a bout 50% of a dul ts . Ma ny nodul es a re found i nci denta l l y on thyroi d i ma gi ng s tudi es done for other di s orders .
Etiology
Mos t nodul es a re beni gn. Beni gn ca us es i ncl ude hyperpl a s ti c col l oi d goi ter, thyroi d cys ts , thyroi di ti s , a nd thyroi d a denoma s . Ma l i gna nt ca us es
i ncl ude thyroi d ca ncers (s ee p. 789).
Evaluation
History: Pa i n s ugges ts thyroi di ti s or hemorrha ge i nto a cys t. An a s ymptoma ti c nodul e ma y be ma l i gna nt but i s us ua l l y beni gn. Symptoms of
hyperthyroi di s m s ugges t a hyperfuncti oni ng a denoma or thyroi di ti s , wherea s s ymptoms of hypothyroi di s m s ugges t Ha s hi moto's thyroi di ti s . Ri s k
fa ctors for thyroi d ca ncer i ncl ude
Hi s tory of thyroi d i rra di a ti on, es peci a l l y i n i nfa ncy or chi l dhood
Age < 20 yr
Ma l e s ex
Fa mi l y hi s tory of thyroi d ca ncer or mul ti pl e endocri ne neopl a s i a
A s ol i ta ry nodul e
Dys pha gi a
Dys phoni a
Increa s i ng s i ze (pa rti cul a rl y ra pi d growth or growth whi l e recei vi ng thyroi d s uppres s i on trea tment)
Physical examination: Si gns tha t s ugges t thyroi d ca ncer i ncl ude s tony ha rd cons i s tency or fi xa ti on to s urroundi ng s tructures , cervi ca l
l ympha denopa thy, a nd hoa rs enes s due to recurrent l a ryngea l nerve pa ra l ys i s .
Testing: Ini ti a l eva l ua ti on of a thyroi d nodul e cons i s ts of mea s urement of l evel s of
Thyroi d-s ti mul a ti ng hormone (TSH)
Free thyroxi ne (T4 )
Anti thyroi d peroxi da s e a nti bodi es
If TSH i s s uppres s ed, ra di oi odi ne s ca nni ng i s done. Nodul es wi th i ncrea s ed ra di onucl i de upta ke (hot) a re s el dom ma l i gna nt. If thyroi d functi on
tes ts do not i ndi ca te hyperthyroi di s m or Ha s hi moto's thyroi di ti s , or i f nodul es a re i ndetermi na te or col d, fi ne-needl e a s pi ra ti on bi ops y i s done to
di s ti ngui s h beni gn from ma l i gna nt nodul es . Ea rl y us e of fi ne-needl e a s pi ra ti on bi ops y i s a more economi c a pproa ch tha n routi ne us e of
ra di oi odi ne s ca ns . Ul tra s onogra phy i s us eful i n determi ni ng the s i ze of the nodul e but i s ra rel y di a gnos ti c of ca ncer, a l though ca ncer i s s ugges ted
by ul tra s onogra phi c or x-ra y evi dence of fi ne, s ti ppl ed, ps a mmoma tous ca l ci fi ca ti on (pa pi l l a ry ca rci noma ) or dens e, homogeneous ca l ci fi ca ti on
(medul l a ry ca rci noma ). Fi ne-needl e a s pi ra ti on bi ops y i s not routi nel y i ndi ca ted for nodul es < 1 cm on ul tra s onogra phy.
Treatment
Trea tment i s di rected a t the underl yi ng di s order. Thyroxi ne s uppres s i on of TSH to s hri nk s ma l l er beni gn nodul es i s effecti ve i n no more tha n ha l f
the ca s es .
Euthyroid Sick Syndrome
Euthyroid sick syndrome is low serum levels of thyroid hormones in clinically euthyroid patients with nonthyroidal systemic illness. Diagnosis is based on
excluding hypothyroidism. Treatment is of the underlying illness; thyroid hormone replacement is not indicated.
Pa ti ents wi th va ri ous a cute or chroni c nonthyroi d di s orders ma y ha ve a bnorma l thyroi d functi on tes ts . Such di s orders i ncl ude a cute a nd chroni c
i l l nes s , pa rti cul a rl y fa s ti ng, s ta rva ti on, protei n-energy undernutri ti on, ma jor tra uma , MI, chroni c rena l fa i l ure, di a beti c ketoa ci dos i s , a norexi a
nervos a , ci rrhos i s , therma l i njury, a nd s eps i s .
Decrea s ed tri i odothyroni ne (T3 ) l evel s a re mos t common. Pa ti ents wi th more s evere or prol onged i l l nes s a l s o ha ve decrea s ed thyroxi ne (T4 ) l evel s .
Serum revers e T3 (rT3 ) i s i ncrea s ed. Pa ti ents a re cl i ni ca l l y euthyroi d a nd do not ha ve el eva ted thyroi d-s ti mul a ti ng hormone (TSH) l evel s .
Pa thogenes i s i s unknown but ma y i ncl ude decrea s ed peri phera l convers i on of T4 to T3 , decrea s ed cl ea ra nce of rT3 genera ted from T4 , a nd
decrea s ed bi ndi ng of thyroi d hormones to thyroxi ne-bi ndi ng gl obul i n (TBG). Proi nfl a mma tory cytoki nes (eg, tumor necros i s fa ctor-, IL-1) ma y be
res pons i bl e for s ome cha nges .
Interpreta ti on of a bnorma l thyroi d functi on tes t res ul ts i n i l l pa ti ents i s compl i ca ted by the effects of va ri ous drugs , i ncl udi ng the i odi ne-ri ch
contra s t a gents a nd a mi oda rone, whi ch i mpa i rs the peri phera l convers i on of T4 to T3 , a nd by drugs s uch a s dopa mi ne a nd corti cos teroi ds , whi ch
decrea s e pi tui ta ry s ecreti on of TSH, res ul ti ng i n l ow s erum TSH l evel s a nd s ubs equent decrea s ed T4 s ecreti on.
Diagnosis
TSH
Serum corti s ol
Cl i ni ca l judgment
The di a gnos ti c di l emma i s whether the pa ti ent ha s hypothyroi di s m or euthyroi d s i ck s yndrome. The bes t tes t i s mea s urement of TSH, whi ch i n
euthyroi d s i ck s yndrome i s l ow, norma l , or s l i ghtl y el eva ted but not a s hi gh a s i t woul d be i n hypothyroi di s m. Serum rT3 i s el eva ted, a l though thi s
mea s urement i s ra rel y done. Serum corti s ol i s often el eva ted i n euthyroi d s i ck s yndrome a nd l ow or l ow-norma l i n hypothyroi di s m due to
pi tui ta ry-hypotha l a mi c di s ea s e. Beca us e tes ts a re nons peci fi c, cl i ni ca l judgment i s requi red to i nterpret a bnorma l thyroi d functi on tes ts i n the
a cutel y or chroni ca l l y i l l pa ti ent. Unl es s thyroi d dys functi on i s hi ghl y s us pected, thyroi d functi on tes ts s houl d not be ordered for pa ti ents i n the
ICU.
Treatment
Trea tment wi th thyroi d hormone repl a cement i s not a ppropri a te. When the underl yi ng di s order i s trea ted, res ul ts of thyroi d tes ts norma l i ze.
Hashimoto's Thyroiditis
(Autoi mmune Thyroi di ti s ; Chroni c Lymphocyti c Thyroi di ti s ; Ha s hi moto's Struma )
Hashimoto's thyroiditis is chronic autoimmune inflammation of the thyroid with lymphocytic infiltration. Findings include painless thyroid enlargement and
symptoms of hypothyroidism. Diagnosis involves demonstration of high titers of thyroid peroxidase antibodies. Lifelong L-thyroxine replacement is typically
required.
Ha s hi moto's thyroi di ti s i s bel i eved to be the mos t common ca us e of pri ma ry hypothyroi di s m i n North Ameri ca . It i s twi ce a s preva l ent a mong
women. Inci dence i ncrea s es wi th a ge a nd i n pa ti ents wi th chromos oma l di s orders , i ncl udi ng Down, Turner's , a nd Kl i nefel ter's s yndromes . A
fa mi l y hi s tory of thyroi d di s orders i s common.
Ha s hi moto's thyroi di ti s , l i ke Gra ves ' di s ea s e, i s s ometi mes a s s oci a ted wi th other a utoi mmune di s orders , i ncl udi ng Addi s on's di s ea s e (a drena l
i ns uffi ci ency), type 1 di a betes mel l i tus , hypopa ra thyroi di s m, vi ti l i go, prema ture gra yi ng of ha i r, perni ci ous a nemi a , connecti ve ti s s ue di s ea s es
(eg, RA, SLE, Sjogren's s yndrome), a nd Schmi dt's s yndrome (Addi s on's di s ea s e, di a betes , a nd hypothyroi di s m s econda ry to Ha s hi moto's thyroi di ti s ).
There ma y be a n i ncrea s ed i nci dence of thyroi d tumors , ra rel y thyroi d l ymphoma . Pa thol ogi ca l l y, there i s extens i ve i nfi l tra ti on of l ymphocytes wi th
l ymphoi d fol l i cl es a nd s ca rri ng.
Symptoms and Signs
Pa ti ents compl a i n of pa i nl es s enl a rgement of the thyroi d or ful l nes s i n the throa t. Exa mi na ti on revea l s a nontender goi ter tha t i s s mooth or
nodul a r, fi rm, a nd more rubbery tha n the norma l thyroi d. Ma ny pa ti ents pres ent wi th s ymptoms of hypothyroi di s m, but s ome pres ent wi th
hyperthyroi di s m.
Diagnosis
Thyroxi ne (T4 )
Thyroi d-s ti mul a ti ng hormone (TSH)
Thyroi d a utoa nti bodi es
Tes ti ng cons i s ts of mea s uri ng T4 , TSH, a nd thyroi d a utoa nti bodi es ; ea rl y i n the di s ea s e T4 a nd TSH l evel s a re norma l a nd there a re hi gh l evel s of
thyroi d peroxi da s e a nti bodi es a nd l es s commonl y of a nti thyrogl obul i n a nti bodi es . Thyroi d ra di oa cti ve i odi ne upta ke ma y be i ncrea s ed, perha ps
beca us e of defecti ve i odi de orga ni fi ca ti on together wi th a gl a nd tha t conti nues to tra p i odi ne. Pa ti ents l a ter devel op hypothyroi di s m wi th
decrea s ed T4 , decrea s ed thyroi d ra di oa cti ve i odi ne upta ke, a nd i ncrea s ed TSH. Tes ti ng for other a utoi mmune di s orders i s wa rra nted onl y when
cl i ni ca l ma ni fes ta ti ons a re pres ent.
Treatment
Occa s i ona l l y, the hypothyroi di s m i s tra ns i ent, but mos t pa ti ents requi re l i fel ong thyroi d hormone repl a cement, typi ca l l y L-thyroxi ne 75 to 150 g po
once/da y.
Hyperthyroidism
(Thyrotoxi cos i s )
Hyperthyroidism is characterized by hypermetabolism and elevated serum levels of free thyroid hormones. Symptoms are many but include tachycardia, fatigue,
weight loss, nervousness, and tremor. Diagnosis is clinical and with thyroid function tests. Treatment depends on cause.
Hyperthyroi di s m ca n be cl a s s i fi ed on the ba s i s of thyroi d ra di oa cti ve i odi ne upta ke a nd the pres ence or a bs ence of ci rcul a ti ng thyroi d s ti mul a tors
(s ee Ta bl e 93-1).
Etiology
Hyperthyroi di s m ma y res ul t from i ncrea s ed s ynthes i s a nd s ecreti on of thyroi d hormones (thyroxi ne [T4 ] a nd tri i odothyroni ne [T3 ]) from the thyroi d,
ca us ed by thyroi d s ti mul a tors i n the bl ood or by a utonomous thyroi d hyperfuncti on. It ca n a l s o res ul t from exces s i ve rel ea s e of thyroi d hormone
from the thyroi d wi thout i ncrea s ed s ynthes i s . Such rel ea s e i s commonl y ca us ed by the des tructi ve cha nges of va ri ous types of thyroi di ti s . Va ri ous
cl i ni ca l s yndromes a l s o ca us e hyperthyroi di s m.
Graves' disease (toxic diffuse goiter), the mos t common ca us e of hyperthyroi di s m, i s cha ra cteri zed by hyperthyroi di s m a nd one or more of the
fol l owi ng:
Goi ter
Exophtha l mos
Infi l tra ti ve dermopa thy
Gra ves ' di s ea s e i s ca us ed by a n a utoa nti body a ga i ns t the thyroi d receptor for thyroi d-s ti mul a ti ng hormone (TSH); unl i ke mos t a utoa nti bodi es ,
whi ch a re i nhi bi tory, thi s a utoa nti body i s s ti mul a tory, thus ca us i ng conti nuous s ynthes i s a nd s ecreti on of exces s T4 a nd T3 . Gra ves ' di s ea s e (l i ke
Ha s hi moto's thyroi di ti s ) s ometi mes occurs wi th other a utoi mmune di s orders , i ncl udi ng type 1 di a betes mel l i tus , vi ti l i go, prema ture gra yi ng of
ha i r, perni ci ous a nemi a , connecti ve ti s s ue di s ea s es , a nd pol ygl a ndul a r defi ci ency s yndrome. The pa thogenes i s of i nfi l tra ti ve ophtha l mopa thy
(res pons i bl e for the exophtha l mos i n Gra ves ' di s ea s e) i s poorl y unders tood but ma y res ul t from i mmunogl obul i ns di rected to s peci fi c receptors i n
the orbi ta l fi brobl a s ts a nd fa t tha t res ul t i n rel ea s e of proi nfl a mma tory cytoki nes , i nfl a mma ti on, a nd a ccumul a ti on of gl ycos a mi nogl yca ns .
Ophtha l mopa thy ma y a l s o occur before the ons et of hyperthyroi di s m or a s l a te a s 20 yr a fterwa rd a nd frequentl y wors ens or a ba tes i ndependentl y
of the cl i ni ca l cours e of hyperthyroi di s m. Typi ca l ophtha l mopa thy i n the pres ence of norma l thyroi d functi on i s ca l l ed euthyroi d Gra ves ' di s ea s e.
Inappropriate TSH secretion i s a ra re ca us e. Pa ti ents wi th hyperthyroi di s m ha ve es s enti a l l y undetecta bl e TSH except for thos e wi th a TSH-s ecreti ng
a nteri or pi tui ta ry a denoma or pi tui ta ry res i s ta nce to thyroi d hormone. TSH l evel s a re hi gh, a nd the TSH produced i n both di s orders i s bi ol ogi ca l l y
more a cti ve tha n norma l TSH. An i ncrea s e i n the -s ubuni t of TSH i n the bl ood (hel pful i n di fferenti a l di a gnos i s ) occurs i n pa ti ents wi th a TSHs ecreti ng pi tui ta ry a denoma .
Molar pregnancy, choriocarcinoma, and hyperemesis gravidarum produce hi gh l evel s of s erum huma n chori oni c gona dotropi n (hCG), a wea k thyroi d
s ti mul a tor. Level s of hCG a re hi ghes t duri ng the 1s t tri mes ter of pregna ncy a nd res ul t i n the decrea s e i n s erum TSH a nd mi l d i ncrea s e i n s erum
free T4 s ometi mes obs erved a t tha t ti me. The i ncrea s ed thyroi d s ti mul a ti on ma y be ca us ed by i ncrea s ed l evel s of pa rti a l l y des i a l a ted hCG, a n hCG
va ri a nt tha t s eems to be a more potent thyroi d s ti mul a tor tha n more s i a l a ted hCG. Hyperthyroi di s m i n mol a r pregna ncy, chori oca rci noma , a nd
hyperemes i s gra vi da rum i s tra ns i ent; norma l thyroi d functi on res umes when the mol a r pregna ncy i s eva cua ted, the chori oca rci noma i s
a ppropri a tel y trea ted, or the hyperemes i s gra vi da rum a ba tes .
Nonautoimmune autosomal dominant hyperthyroidism ma ni fes ts duri ng i nfa ncy. It res ul ts from muta ti ons i n the TSH receptor gene tha t produce
conti nuous thyroi d s ti mul a ti on.
Toxic solitary or multinodular goiter (Plummer's disease) s ometi mes res ul ts from TSH receptor gene muta ti ons produci ng conti nuous thyroi d
s ti mul a ti on. Pa ti ents wi th toxi c nodul a r goi ter ha ve none of the a utoi mmune ma ni fes ta ti ons or ci rcul a ti ng a nti bodi es obs erved i n pa ti ents wi th
Gra ves ' di s ea s e. Al s o, i n contra s t to Gra ves ' di s ea s e, toxi c s ol i ta ry a nd mul ti nodul a r goi ters us ua l l y do not remi t.
Inflammatory thyroid disease (thyroiditis) i ncl udes s uba cute gra nul oma tous thyroi di ti s , Ha s hi moto's thyroi di ti s , a nd s i l ent l ymphocyti c thyroi di ti s , a
va ri a nt of Ha s hi moto's thyroi di ti s (s ee p. 787). Hyperthyroi di s m res ul ts from des tructi ve cha nges i n the gl a nd a nd rel ea s e of s tored hormone, not
from i ncrea s ed s ynthes i s . Hypothyroi di s m ma y fol l ow.
Drug-induced hyperthyroidism ca n res ul t from a mi oda rone a nd i nterferon a l fa , whi ch ma y i nduce thyroi di ti s wi th hyperthyroi di s m a nd other thyroi d
di s orders . Al though more commonl y ca us i ng hypothyroi di s m, l i thi um ca n ra rel y ca us e hyperthyroi di s m. Pa ti ents recei vi ng thes e drugs s houl d be
cl os el y moni tored.
Thyrotoxicosis factitia i s hyperthyroi di s m res ul ti ng from cons ci ous or a cci denta l overi nges ti on of thyroi d hormone.
Excess iodine ingestion ca us es hyperthyroi di s m wi th a l ow thyroi d ra di oa cti ve i odi ne upta ke. It mos t often occurs i n pa ti ents wi th underl yi ng
nontoxi c nodul a r goi ter (es peci a l l y el derl y pa ti ents ) who a re gi ven drugs tha t conta i n i odi ne (eg, a mi oda rone, i odi ne-conta i ni ng expectora nts ) or
who undergo ra di ol ogi c s tudi es us i ng i odi ne-ri ch contra s t a gents . The eti ol ogy ma y be tha t the exces s i odi ne provi des s ubs tra te for functi ona l l y
a utonomous (i e, not under TSH regul a ti on) a rea s of the thyroi d to produce hormone. Hyperthyroi di s m us ua l l y pers i s ts a s l ong a s exces s i odi ne
rema i ns i n the ci rcul a ti on.
Metastatic thyroid cancer i s a pos s i bl e ca us e. Overproducti on of thyroi d hormone occurs ra rel y from functi oni ng meta s ta ti c fol l i cul a r ca rci noma ,
es peci a l l y i n pul mona ry meta s ta s es .
Struma ovarii devel ops when ova ri a n tera toma s conta i n enough thyroi d ti s s ue to ca us e true hyperthyroi di s m. Ra di oa cti ve i odi ne upta ke occurs i n
the pel vi s , a nd upta ke by the thyroi d i s us ua l l y s uppres s ed.
Pathophysiology
In hyperthyroi di s m, s erum T3 us ua l l y i ncrea s es more tha n does T4 , proba bl y beca us e of i ncrea s ed s ecreti on of T3 a s wel l a s convers i on of T4 to T3
i n peri phera l ti s s ues . In s ome pa ti ents , onl y T3 i s el eva ted (T3 toxi cos i s ). T3 toxi cos i s ma y occur i n a ny of the us ua l di s orders tha t ca us e
hyperthyroi di s m, i ncl udi ng Gra ves ' di s ea s e, mul ti nodul a r goi ter, a nd the a utonomous l y functi oni ng s ol i ta ry thyroi d nodul e. If T3 toxi cos i s i s
untrea ted, the pa ti ent us ua l l y a l s o devel ops l a bora tory a bnorma l i ti es typi ca l of hyperthyroi di s m (i e, el eva ted T4 a nd
forms of thyroi di ti s commonl y ha ve a hyperthyroi d pha s e fol l owed by a hypothyroi d pha s e.
123
I upta ke). The va ri ous
Symptoms and Signs

Mos t s ymptoms a nd s i gns a re the s a me rega rdl es s of the ca us e. Excepti ons i ncl ude i nfi l tra ti ve ophtha l mopa thy a nd dermopa thy, whi ch occur onl y
i n Gra ves ' di s ea s e.
The cl i ni ca l pres enta ti on ma y be dra ma ti c or s ubtl e. A goi ter or nodul e ma y be pres ent. Ma ny common s ymptoms a nd s i gns of hyperthyroi di s m a re
s i mi l a r to thos e of a drenergi c exces s , s uch a s nervous nes s , pa l pi ta ti ons , hypera cti vi ty, i ncrea s ed s wea ti ng, hea t hypers ens i ti vi ty, fa ti gue,
i ncrea s ed a ppeti te, wei ght l os s , i ns omni a , wea knes s , a nd frequent bowel movements (occa s i ona l l y di a rrhea ). Hypomenorrhea ma y be pres ent.
Si gns ma y i ncl ude wa rm, moi s t s ki n; tremor; ta chyca rdi a ; wi dened pul s e pres s ure; a tri a l fi bri l l a ti on; a nd pa l pi ta ti ons .
El derl y pa ti ents , pa rti cul a rl y thos e wi th toxi c nodul a r goi ter, ma y pres ent a typi ca l l y (a pa theti c or ma s ked hyperthyroi di s m) wi th s ymptoms more
a ki n to depres s i on or dementi a . Mos t do not ha ve exophtha l mos or tremor. Atri a l fi bri l l a ti on, s yncope, a l tered s ens ori um, hea rt fa i l ure, a nd
wea knes s a re more l i kel y. Symptoms a nd s i gns ma y i nvol ve onl y a s i ngl e orga n s ys tem.
Eye s i gns i ncl ude s ta re, eyel i d l a g, eyel i d retra cti on, a nd mi l d conjuncti va l i njecti on a nd a re l a rgel y due to exces s i ve a drenergi c s ti mul a ti on. They
us ua l l y remi t wi th s ucces s ful trea tment. Infi l tra ti ve ophtha l mopa thy, a more s eri ous devel opment, i s s peci fi c to Gra ves ' di s ea s e a nd ca n occur
yea rs before or a fter hyperthyroi di s m. It i s cha ra cteri zed by orbi ta l pa i n, l a cri ma ti on, i rri ta ti on, photophobi a , i ncrea s ed retro-orbi ta l ti s s ue,
exophtha l mos , a nd l ymphocyti c i nfi l tra ti on of the extra ocul a r mus cl es , ca us i ng ocul a r mus cl e wea knes s tha t frequentl y l ea ds to doubl e vi s i on.
Infi l tra ti ve dermopa thy, a l s o ca l l ed preti bi a l myxedema (a confus i ng term, beca us e myxedema s ugges ts hypothyroi di s m), i s cha ra cteri zed by
nonpi tti ng i nfi l tra ti on by protei na ceous ground s ubs ta nce, us ua l l y i n the preti bi a l a rea . It ra rel y occurs i n the a bs ence of Gra ves ' ophtha l mopa thy.
The l es i on i s often pruri ti c a nd erythema tous i n i ts ea rl y s ta ges a nd s ubs equentl y becomes bra wny. Infi l tra ti ve dermopa thy ma y a ppea r yea rs
before or a fter hyperthyroi di s m.
Thyroid storm: Thyroi d s torm i s a n a cute form of hyperthyroi di s m tha t res ul ts from untrea ted or i na dequa tel y trea ted s evere hyperthyroi di s m. It i s
ra re, occurri ng i n pa ti ents wi th Gra ves ' di s ea s e or toxi c mul ti nodul a r goi ter (a s ol i ta ry toxi c nodul e i s l es s common a nd genera l l y l es s s evere). It
ma y be preci pi ta ted by i nfecti on, tra uma , s urgery, embol i s m, di a beti c ketoa ci dos i s , or preecl a mps i a . Thyroi d s torm ca us es a brupt fl ori d s ymptoms
of hyperthyroi di s m wi th one or more of the fol l owi ng: fever, ma rked wea knes s a nd mus cl e wa s ti ng, extreme res tl es s nes s wi th wi de emoti ona l
s wi ngs , confus i on, ps ychos i s , coma , na us ea , vomi ti ng, di a rrhea , a nd hepa tomega l y wi th mi l d ja undi ce. The pa ti ent ma y pres ent wi th
ca rdi ova s cul a r col l a ps e a nd s hock. Thyroid storm is a life-threatening emergency requiring prompt treatment.
Diagnosis
TSH
Free T4
Someti mes ra di oa cti ve i odi ne upta ke
Di a gnos i s i s ba s ed on hi s tory, phys i ca l exa mi na ti on, a nd thyroi d functi on tes ts . Serum TSH mea s urement i s the bes t tes t, beca us e TSH i s
s uppres s ed i n hyperthyroi d pa ti ents except i n the ra re i ns ta nce when the eti ol ogy i s a TSH-s ecreti ng pi tui ta ry a denoma or pi tui ta ry res i s ta nce to
thyroi d hormone. Screeni ng s el ected popul a ti ons for TSH l evel i s wa rra nted (s ee p. 776). Free T4 i s i ncrea s ed i n hyperthyroi di s m. However, T4 ca n
be fa l s el y norma l i n true hyperthyroi di s m i n pa ti ents wi th a s evere s ys temi c i l l nes s (s i mi l a r to the fa l s el y l ow l evel s tha t occur i n euthyroi d s i ck
s yndrome) a nd i n T3 toxi cos i s . If free T4 l evel i s norma l a nd TSH i s l ow i n a pa ti ent wi th s ubtl e s ymptoms a nd s i gns of hyperthyroi di s m, then s erum
T3 s houl d be mea s ured to detect T3 toxi cos i s ; a n el eva ted l evel confi rms tha t di a gnos i s .
The ca us e ca n often be di a gnos ed cl i ni ca l l y (eg, expos ure to a drug, the pres ence of s i gns s peci fi c to Gra ves ' di s ea s e). If not, thyroi d ra di oa cti ve
i odi ne upta ke ma y be obta i ned by us i ng 123 I. When hyperthyroi di s m i s due to hormone overproducti on, thyroi d ra di oa cti ve i odi ne upta ke i s
us ua l l y el eva ted.
TSH receptor a nti bodi es ca n be mea s ured to detect Gra ves ' di s ea s e, but mea s urement i s ra rel y neces s a ry except duri ng the 3rd tri mes ter of
pregna ncy to a s s es s the ri s k of neona ta l Gra ves ' di s ea s e; TSH receptor a nti bodi es rea di l y cros s the pl a centa to s ti mul a te the feta l thyroi d. Mos t
pa ti ents wi th Gra ves ' di s ea s e ha ve ci rcul a ti ng a nti thyroi d peroxi da s e a nti bodi es , a nd fewer ha ve a nti thyrogl obul i n a nti bodi es .
Ina ppropri a te TSH s ecreti on i s uncommon. The di a gnos i s i s confi rmed when hyperthyroi di s m occurs wi th el eva ted ci rcul a ti ng free T4 a nd T3
concentra ti ons a nd norma l or el eva ted s erum TSH.
If thyrotoxi cos i s fa cti ti a i s s us pected, s erum thyrogl obul i n ca n be mea s ured; i t i s us ua l l y l ow or l ow-norma l unl i ke i n a l l other ca us es of
hyperthyroi di s m.
In hyperthyroi di s m ca us ed by exces s i odi ne i nges ti on, l ow ra di oa cti ve i odi ne upta ke i s typi ca l beca us e thyroi d ra di oa cti ve i odi ne upta ke i s
i nvers el y proporti ona l to i odi ne i nta ke.
Treatment
Trea tment depends on ca us e but ma y i ncl ude
Propyl thi oura ci l or methi ma zol e
-Bl ockers
Iodi ne
Ra di oa cti ve i odi ne
Surgery
Iodine: Iodi ne i n pha rma col ogi c dos es i nhi bi ts the rel ea s e of T3 a nd T4 wi thi n hours a nd i nhi bi ts the orga ni fi ca ti on of i odi ne, a tra ns i tory effect
l a s ti ng from a few da ys to a week, a fter whi ch i nhi bi ti on us ua l l y cea s es . Iodi ne i s us ed for emergency ma na gement of thyroi d s torm, for
hyperthyroi d pa ti ents undergoi ng emergency nonthyroi d s urgery, a nd (beca us e i t a l s o decrea s es the va s cul a ri ty of the thyroi d) for preopera ti ve
prepa ra ti on of hyperthyroi d pa ti ents undergoi ng s ubtota l thyroi dectomy. Iodi ne genera l l y i s not us ed for routi ne trea tment of hyperthyroi di s m.
The us ua l dos a ge i s 2 to 3 drops (100 to 150 mg) of a s a tura ted K i odi de s ol uti on po ti d or qi d or 0.5 to 1 g Na i odi de i n 1 L 0.9% s a l i ne s ol uti on
gi ven IV s l owl y q 12 h.
Compl i ca ti ons of i odi ne thera py i ncl ude i nfl a mma ti on of the s a l i va ry gl a nds , conjuncti vi ti s , a nd ra s h.
Propylthiouracil and methimazole: Thes e a nti thyroi d drugs bl ock thyroi d peroxi da s e, decrea s i ng the orga ni fi ca ti on of i odi de, a nd i mpa i r the coupl i ng
rea cti on. Propyl thi oura ci l i n hi gh dos es a l s o i nhi bi ts the peri phera l convers i on of T4 to T3 . About 20 to 50% of pa ti ents wi th Gra ves ' di s ea s e rema i n
i n remi s s i on a fter a 1- to 2-yr cours e of ei ther drug. The return to norma l or a ma rked decrea s e i n gl a nd s i ze, the res tora ti on of a norma l s erum TSH
l evel , a nd l es s s evere hyperthyroi di s m before thera py a re good prognos ti c s i gns of l ong-term remi s s i on. The concomi ta nt us e of a nti thyroi d drug
thera py a nd L-thyroxi ne does not i mprove the remi s s i on ra te i n pa ti ents wi th Gra ves ' di s ea s e. Beca us e toxi c nodul a r goi ter ra rel y goes i nto
remi s s i on, a nti thyroi d drug thera py i s gi ven onl y i n prepa ra ti on for s urgi ca l trea tment or 131 I thera py.
The us ua l s ta rti ng dos a ge of propyl thi oura ci l i s 100 to 150 mg po q 8 h a nd of methi ma zol e 5 to 20 mg po ti d. When T4 a nd T3 l evel s norma l i ze, the
dos a ge i s decrea s ed to the l owes t effecti ve a mount, us ua l l y propyl thi oura ci l 50 mg ti d or methi ma zol e 5 to 15 mg once/da y. Us ua l l y, control i s
a chi eved i n 2 to 3 mo. More ra pi d control ca n be a chi eved by i ncrea s i ng the dos a ge of propyl thi oura ci l to 150 to 200 mg q 8 h. Such dos a ges or
hi gher ones (up to 400 mg q 8 h) a re genera l l y res erved for s everel y i l l pa ti ents , i ncl udi ng thos e wi th thyroi d s torm. Ma i ntena nce dos es ca n be
conti nued for one or ma ny yea rs dependi ng on the cl i ni ca l ci rcums ta nces . Ca rbi ma zol e, whi ch i s us ed wi del y i n Europe, i s ra pi dl y converted to
methi ma zol e. The us ua l s ta rti ng dos e i s s i mi l a r to tha t of methi ma zol e; ma i ntena nce dos a ge i s 5 to 20 mg po once/da y, 2.5 to 10 mg bi d, or 1.7 to
6.7 mg ti d.
Advers e effects i ncl ude ra s h, a l l ergi c rea cti ons , a bnorma l l i ver functi on, a nd, i n a bout 0.1% of pa ti ents , revers i bl e a gra nul ocytos i s . Pa ti ents
a l l ergi c to one drug ca n be s wi tched to the other, but cros s -s ens i ti vi ty ma y occur. If a gra nul ocytos i s occurs , the pa ti ent ca nnot be s wi tched to the
other drug; other thera py (eg, ra di oi odi ne, s urgery) s houl d be us ed.
Ea ch drug ha s a dva nta ges a nd di s a dva nta ges . Methi ma zol e need onl y be gi ven once/da y, whi ch i mproves a dherence. Furthermore, when
methi ma zol e i s us ed i n dos a ges of < 40 mg/da y, a gra nul ocytos i s i s l es s common; wi th propyl thi oura ci l , a gra nul ocytos i s ma y occur a t a ny dos a ge.
Propyl thi oura ci l ma y be preferred i f a nti thyroi d drugs mus t be us ed duri ng pregna ncy or brea s tfeedi ng beca us e i t i s l es s l i kel y to cros s the
pl a centa or enter brea s t mi l k. Methi ma zol e ha s been us ed s ucces s ful l y i n pregna nt a nd nurs i ng women wi thout feta l or i nfa nt compl i ca ti ons , but
ra rel y methi ma zol e ha s been a s s oci a ted wi th s ca l p a nd GI defects i n the neona te. Propyl thi oura ci l i s a l s o preferred for the trea tment of thyroi d
s torm, beca us e the dos a ges us ed (800 to 1200 mg/da y) pa rti a l l y bl ock the peri phera l convers i on of T4 to T3 .
The combi na ti on of hi gh-dos e propyl thi oura ci l a nd dexa metha s one, a l s o a potent i nhi bi tor of T4 to T3 convers i on, ca n rel i eve s ymptoms of
hyperthyroi di s m a nd res tore the s erum T3 l evel to norma l wi thi n a week.

-Blockers: Symptoms a nd s i gns of hyperthyroi di s m due to a drenergi c s ti mul a ti on ma y res pond to -bl ockers ; propra nol ol ha s ha d the grea tes t us e,
but a tenol ol or metoprol ol ma y be prefera bl e.
Other ma ni fes ta ti ons typi ca l l y do not res pond.
Ma ni fes ta ti ons typi ca l l y res pondi ng to -bl ockers : Ta chyca rdi a , tremor, menta l s ymptoms , eyel i d l a g; occa s i ona l l y hea t i ntol era nce a nd
s wea ti ng, di a rrhea , proxi ma l myopa thy
Ma ni fes ta ti ons typi ca l l y not res pondi ng to -bl ockers : O2 cons umpti on, exophtha l mos , goi ter, brui t, ci rcul a ti ng thyroxi ne l evel s , wei ght l os s
Propra nol ol i s i ndi ca ted i n thyroi d s torm (s ee
Ta bl e 93-2). It ra pi dl y decrea s es hea rt ra te, us ua l l y wi thi n 2 to 3 h when gi ven ora l l y a nd wi thi n mi nutes when gi ven IV. Es mol ol ma y be us ed i n
the ICU beca us e i t requi res ca reful ti tra ti on a nd moni tori ng. Propra nol ol i s a l s o i ndi ca ted for ta chyca rdi a wi th hyperthyroi di s m, es peci a l l y i n
el derl y pa ti ents , beca us e a nti thyroi d drugs us ua l l y ta ke s evera l weeks to become ful l y effecti ve. Ca cha nnel bl ockers ma y control ta chya rrhythmi a s
i n pa ti ents i n whom -bl ockers a re contra i ndi ca ted.
Radioactive sodium iodine (131 I, radioiodine): In the US, 131 I i s the mos t common trea tment for hyperthyroi di s m. Ra di oi odi ne i s often recommended a s
the trea tment of choi ce for
[Table 93-2. Trea tment of Thyroi d Storm]
Gra ves ' di s ea s e a nd toxi c nodul a r goi ter i n a l l pa ti ents , i ncl udi ng chi l dren. Dos a ge of 131 I i s di ffi cul t to a djus t beca us e the res pons e of the gl a nd
ca nnot be predi cted; s ome phys i ci a ns gi ve a s ta nda rd dos e of 8 to 10 mCi . Others a djus t the dos e ba s ed on es ti ma ted thyroi d s i ze a nd the 24-h
upta ke to provi de a dos e of 80 to 120 Ci /g thyroi d ti s s ue.
When s uffi ci ent 131 I i s gi ven to ca us e euthyroi di s m, a bout 25% of pa ti ents become hypothyroi d 1 yr l a ter, a nd the i nci dence conti nues to i ncrea s e
yea rl y. Thus , mos t pa ti ents eventua l l y become hypothyroi d. However, i f s ma l l er dos es a re us ed, i nci dence of recurrence i s hi gher. La rger dos es ,
s uch a s 10 to 15 mCi , often ca us e hypothyroi di s m wi thi n 6 mo.
Ra di oa cti ve i odi ne i s not us ed duri ng pregna ncy. There i s no proof tha t ra di oi odi ne i ncrea s es the i nci dence of tumors , l eukemi a , thyroi d ca ncer, or
bi rth defects i n chi l dren born to women who become pregna nt l a ter i n l i fe.
Surgery: Surgery i s i ndi ca ted for pa ti ents wi th Gra ves ' di s ea s e whos e hyperthyroi di s m ha s recurred a fter cours es of a nti thyroi d drugs a nd who
refus e 131 I thera py, pa ti ents who ca nnot tol era te a nti thyroi d drugs , pa ti ents wi th very l a rge goi ters , a nd i n s ome younger pa ti ents wi th toxi c
a denoma a nd mul ti nodul a r goi ter. Surgery ma y be done i n el derl y pa ti ents wi th gi a nt nodul a r goi ters .
Surgery us ua l l y res tores norma l functi on. Pos topera ti ve recurrences va ry between 2 a nd 16%; ri s k of hypothyroi di s m i s di rectl y rel a ted to the extent
of s urgery a nd occurs i n a bout one ha l f of pa ti ents . Voca l cord pa ra l ys i s a nd hypopa ra thyroi di s m a re uncommon compl i ca ti ons . Sa tura ted s ol uti on
of K i odi de 3 drops (a bout 100 to 150 mg) po ti d s houl d be gi ven for 10 da ys before s urgery to reduce the va s cul a ri ty of the gl a nd. Propyl thi oura ci l or
methi ma zol e mus t a l s o be gi ven, beca us e the pa ti ent s houl d be euthyroi d before i odi de i s gi ven. Dexa metha s one ca n be a dded to ra pi dl y res tore
euthyroi di s m. Surgi ca l procedures a re more di ffi cul t i n pa ti ents who previ ous l y underwent thyroi dectomy or ra di oi odi ne thera py.
Treatment of thyroid storm: A trea tment regi men for thyroi d s torm i s s hown i n Ta bl e 93-2.
Treatment of infiltrative dermopathy and ophthalmopathy: In i nfi l tra ti ve dermopa thy (i n Gra ves ' di s ea s e), topi ca l corti cos teroi ds s ometi mes rel i eve the
pruri tus . Dermopa thy us ua l l y remi ts s ponta neous l y a fter months or yea rs . Ophtha l mopa thy s houl d be trea ted joi ntl y by the endocri nol ogi s t a nd
ophtha l mol ogi s t a nd ma y requi re corti cos teroi ds , orbi ta l ra di a ti on, a nd s urgery.
Subclinical Hyperthyroidism
Subclinical hyperthyroidism is low serum TSH in patients with normal serum free T4 and T3 and absent or minimal symptoms of hyperthyroidism.
Subcl i ni ca l hyperthyroi di s m i s fa r l es s common tha n s ubcl i ni ca l hypothyroi di s m (s ee p. 787). Pa ti ents wi th s erum TSH < 0.1 mU/L ha ve a n i ncrea s ed
i nci dence of a tri a l fi bri l l a ti on (pa rti cul a rl y el derl y pa ti ents ), reduced bone mi nera l dens i ty, i ncrea s ed fra ctures , a nd i ncrea s ed morta l i ty. Pa ti ents
wi th s erum TSH tha t i s onl y s l i ghtl y bel ow norma l a re l es s l i kel y to ha ve thes e fea tures . Ma ny pa ti ents wi th s ubcl i ni ca l hyperthyroi di s m a re ta ki ng
L-thyroxi ne; i n thes e pa ti ents , reducti on of the dos e i s the mos t a ppropri a te ma na gement unl es s thera py i s a i med a t ma i nta i ni ng a s uppres s ed
TSH i n pa ti ents wi th thyroi d ca ncer or nodul es . The other ca us es of s ubcl i ni ca l hyperthyroi di s m a re the s a me a s thos e for cl i ni ca l l y a ppa rent
hyperthyroi di s m.
Thera py i s i ndi ca ted for pa ti ents wi th endogenous s ubcl i ni ca l hyperthyroi di s m (s erum TSH < 0.1 mU/L), es peci a l l y thos e wi th a tri a l fi bri l l a ti on or
reduced bone mi nera l dens i ty. The us ua l trea tment i s 131 I. In pa ti ents wi th mi l der s ymptoms (eg, nervous nes s ), a tri a l of a nti thyroi d drug thera py
i s worthwhi l e.
Hypothyroidism
(Myxedema )
Hypothyroidism is thyroid hormone deficiency. It is diagnosed by clinical features such as a typical facies, hoarse slow speech, and dry skin and by low levels of
thyroid hormones. Management includes treatment of the cause and administration of thyroxine.
Hypothyroi di s m occurs a t a ny a ge but i s pa rti cul a rl y common a mong the el derl y. It occurs i n cl os e to 10% of women a nd 6% of men > 65. Al though
typi ca l l y ea s y to di a gnos e i n younger a dul ts , i t ma y be s ubtl e a nd ma ni fes t a typi ca l l y i n the el derl y.

Primary hypothyroidism: Pri ma ry hypothyroi di s m i s due to di s ea s e i n the thyroi d; thyroi d-s ti mul a ti ng hormone (TSH) i s i ncrea s ed. The mos t common
ca us e i s proba bl y a utoi mmune. It us ua l l y res ul ts from Ha s hi moto's thyroi di ti s a nd i s often a s s oci a ted wi th a fi rm goi ter or, l a ter i n the di s ea s e
proces s , wi th a s hrunken fi broti c thyroi d wi th l i ttl e or no functi on. The 2nd mos t common ca us e i s pos t-thera peuti c hypothyroi di s m, es peci a l l y
a fter ra di oa cti ve i odi ne thera py or s urgery for hyperthyroi di s m or goi ter. Hypothyroi di s m duri ng overtrea tment wi th propyl thi oura ci l , methi ma zol e,
a nd i odi de a ba tes a fter thera py i s s topped.
Mos t pa ti ents wi th non-Ha s hi moto's goi ters a re euthyroi d or ha ve hyperthyroi di s m, but goi trous hypothyroi di s m ma y occur i n endemi c goi ter.
Iodi ne defi ci ency decrea s es thyroi d hormonogenes i s . In res pons e, TSH i s rel ea s ed, whi ch ca us es the thyroi d to enl a rge a nd tra p i odi ne a vi dl y;
thus , goi ter res ul ts . If i odi ne defi ci ency i s s evere, the pa ti ent becomes hypothyroi d, a ra re occurrence i n the US s i nce the a dvent of i odi zed s a l t.
Iodi ne defi ci ency ca n ca us e endemi c creti ni s m i n chi l dren; endemi c creti ni s m i s the mos t common ca us e of congeni ta l hypothyroi di s m i n s everel y
i odi ne-defi ci ent regi ons a nd a ma jor ca us e of menta l defi ci ency worl dwi de.
Ra re i nheri ted enzyma ti c defects ca n a l ter the s ynthes i s of thyroi d hormone a nd ca us e goi trous hypothyroi di s m (s ee p. 2887).
Hypothyroi di s m ma y occur i n pa ti ents ta ki ng l i thi um, perha ps beca us e l i thi um i nhi bi ts hormone rel ea s e by the thyroi d. Hypothyroi di s m ma y a l s o
occur i n pa ti ents ta ki ng a mi oda rone or other i odi ne-conta i ni ng drugs , a nd i n pa ti ents ta ki ng i nterferon a l fa . Hypothyroi di s m ca n res ul t from
ra di a ti on thera py for ca ncer of the l a rynx or Hodgki n l ymphoma (Hodgki n's di s ea s e). The i nci dence of perma nent hypothyroi di s m a fter ra di a ti on
thera py i s hi gh, a nd thyroi d functi on (through mea s urement of s erum TSH) s houl d be eva l ua ted a t 6- to 12-mo i nterva l s .
Secondary hypothyroidism: Seconda ry hypothyroi di s m occurs when the hypotha l a mus produces i ns uffi ci ent thyrotropi n-rel ea s i ng hormone (TRH) or
the pi tui ta ry produces i ns uffi ci ent TSH. Someti mes , defi ci ent TSH s ecreti on due to defi ci ent TRH s ecreti on i s termed terti a ry hypothyroi di s m.
Symptoms and Signs
Symptoms a nd s i gns of pri ma ry hypothyroi di s m a re often s ubtl e a nd i ns i di ous . Symptoms ma y i ncl ude col d i ntol era nce, cons ti pa ti on,
forgetful nes s , a nd pers ona l i ty cha nges . Modes t wei ght ga i n i s l a rgel y the res ul t of fl ui d retenti on a nd decrea s ed meta bol i s m. Pa res thes i a s of the
ha nds a nd feet a re common, often due to ca rpa l -ta rs a l tunnel s yndrome ca us ed by depos i ti on of protei na ceous ground s ubs ta nce i n the
l i ga ments a round the wri s t a nd a nkl e. Women wi th hypothyroi di s m ma y devel op menorrha gi a or s econda ry a menorrhea .
The fa ci a l expres s i on i s dul l ; the voi ce i s hoa rs e a nd s peech i s s l ow; fa ci a l puffi nes s a nd peri orbi ta l s wel l i ng occur due to i nfi l tra ti on wi th the
mucopol ys a ccha ri des hya l uroni c a ci d a nd chondroi ti n s ul fa te; eyel i ds droop beca us e of decrea s ed a drenergi c dri ve; ha i r i s s pa rs e, coa rs e, a nd
dry; a nd the s ki n i s coa rs e, dry, s ca l y, a nd thi ck. The rel a xa ti on pha s e of deep tendon refl exes i s s l owed. Hypothermi a i s common. Dementi a or
fra nk ps ychos i s (myxedema ma dnes s ) ma y occur.
Ca rotenemi a i s common, pa rti cul a rl y nota bl e on the pa l ms a nd s ol es , ca us ed by depos i ti on of ca rotene i n the l i pi d-ri ch epi derma l l a yers .
Depos i ti on of protei na ceous ground s ubs ta nce i n the tongue ma y ca us e ma crogl os s i a . A decrea s e i n both thyroi d hormone a nd a drenergi c
s ti mul a ti on ca us es bra dyca rdi a . The hea rt ma y be enl a rged, pa rtl y beca us e of di l a ti on but chi efl y beca us e of peri ca rdi a l effus i on. Pl eura l or
a bdomi na l effus i ons a l s o ma y be noted. The peri ca rdi a l a nd pl eura l effus i ons devel op s l owl y a nd onl y ra rel y ca us e res pi ra tory or hemodyna mi c
di s tres s .
El derl y pa ti ents ha ve s i gni fi ca ntl y fewer s ymptoms tha n do younger a dul ts , a nd compl a i nts a re often s ubtl e a nd va gue. Ma ny el derl y pa ti ents wi th
hypothyroi di s m pres ent wi th nons peci fi c geri a tri c s yndromes confus i on, a norexi a , wei ght l os s , fa l l i ng, i nconti nence, a nd decrea s ed mobi l i ty.
Mus cul os kel eta l s ymptoms (es peci a l l y a rthra l gi a s ) occur often, but a rthri ti s i s ra re. Mus cul a r a ches a nd wea knes s , often mi mi cki ng pol ymya l gi a
rheuma ti ca or pol ymyos i ti s , a nd a n el eva ted CK l evel ma y occur. In the el derl y, hypothyroi di s m ma y mi mi c dementi a or pa rki ns oni s m.
Al though s econda ry hypothyroi di s m i s uncommon, i ts ca us es often a ffect other endocri ne orga ns control l ed by the hypotha l a mi c-pi tui ta ry a xi s . In
a woma n wi th hypothyroi di s m, i ndi ca ti ons of s econda ry hypothyroi di s m a re a hi s tory of a menorrhea ra ther tha n menorrha gi a a nd s ome
s ugges ti ve di fferences on phys i ca l exa mi na ti on. Seconda ry hypothyroi di s m i s cha ra cteri zed by s ki n a nd ha i r tha t a re dry but not very coa rs e, s ki n
depi gmenta ti on, onl y mi ni ma l ma crogl os s i a , a trophi c brea s ts , a nd l ow BP. Al s o, the hea rt i s s ma l l , a nd s erous peri ca rdi a l effus i ons do not occur.
Hypogl ycemi a i s common beca us e of concomi ta nt a drena l i ns uffi ci ency or growth hormone defi ci ency.
Myxedema coma: Myxedema coma i s a l i fe-threa teni ng compl i ca ti on of hypothyroi di s m, us ua l l y occurri ng i n pa ti ents wi th a l ong hi s tory of
hypothyroi di s m. Its cha ra cteri s ti cs i ncl ude coma wi th extreme hypothermi a (tempera ture 24 to 32.2 C), a refl exi a , s ei zures , a nd res pi ra tory
depres s i on wi th CO2 retenti on. Severe hypothermi a ma y be mi s s ed unl es s l ow-rea di ng thermometers a re us ed. Ra pi d di a gnos i s ba s ed on cl i ni ca l
judgment, hi s tory, a nd phys i ca l exa mi na ti on i s i mpera ti ve, beca us e dea th i s l i kel y wi thout ra pi d trea tment. Preci pi ta ti ng fa ctors i ncl ude i l l nes s ,
i nfecti on, tra uma , drugs tha t s uppres s the CNS, a nd expos ure to col d.
Diagnosis
TSH
Free thyroxi ne (T4 )
Serum TSH i s the mos t s ens i ti ve tes t, a nd s creeni ng of s el ected popul a ti ons i s wa rra nted (s ee p. 776). In pri ma ry hypothyroi di s m, there i s no
feedba ck i nhi bi ti on of the i nta ct pi tui ta ry, a nd s erum TSH i s a l wa ys el eva ted, wherea s s erum free T4 i s l ow. In s econda ry hypothyroi di s m, free T4
a nd s erum TSH a re l ow (s ometi mes TSH i s norma l but wi th decrea s ed bi oa cti vi ty).
Ma ny pa ti ents wi th pri ma ry hypothyroi di s m ha ve norma l ci rcul a ti ng l evel s of tri i odothyroni ne (T3 ), proba bl y ca us ed by s us ta i ned TSH s ti mul a ti on
of the fa i l i ng thyroi d, res ul ti ng i n preferenti a l s ynthes i s a nd s ecreti on of bi ol ogi ca l l y a cti ve T3 . Therefore, s erum T3 i s not s ens i ti ve for
hypothyroi di s m.
Anemi a i s often pres ent, us ua l l y normocyti c-normochromi c a nd of unknown eti ol ogy, but i t ma y be hypochromi c beca us e of menorrha gi a a nd
s ometi mes ma crocyti c beca us e of a s s oci a ted perni ci ous a nemi a or decrea s ed a bs orpti on of fol a te. Anemi a i s ra rel y s evere (Hb > 9 g/dL). As the
hypometa bol i c s ta te i s corrected, a nemi a s ubs i des , s ometi mes requi ri ng 6 to 9 mo.
Serum chol es terol i s us ua l l y hi gh i n pri ma ry hypothyroi di s m but l es s s o i n s econda ry hypothyroi di s m.
In a ddi ti on to pri ma ry a nd s econda ry hypothyroi di s m, other condi ti ons ma y ca us e decrea s ed l evel s of tota l T4 , s uch a s s erum thyroxi ne-bi ndi ng
gl obul i n (TBG) defi ci ency, s ome drugs (s ee p. 785), a nd euthyroi d s i ck s yndrome (s ee p. 779).
Treatment
L-Thyroxi ne, a djus ted unti l TSH l evel s a re i n mi dnorma l ra nge
Va ri ous thyroi d hormone prepa ra ti ons a re a va i l a bl e for repl a cement thera py, i ncl udi ng s yntheti c prepa ra ti ons of T4 (L-thyroxi ne), T3 (l i othyroni ne),
combi na ti ons of the 2 s yntheti c hormones , a nd des i cca ted a ni ma l thyroi d extra ct. L-Thyroxi ne i s preferred; the us ua l ma i ntena nce dos e i s 75 to 150
g po once/da y, dependi ng on a ge, body ma s s i ndex, a nd a bs orpti on (for pedi a tri c dos es , s ee p. 2888). Thera py i s begun wi th l ow dos es ,
es peci a l l y i n the el derl y, us ua l l y 25 g once/da y. The dos e i s a djus ted every 6 wk unti l ma i ntena nce dos e i s a chi eved. The ma i ntena nce dos e ma y
need to be decrea s ed i n el derl y pa ti ents a nd i ncrea s ed i n pregna nt women. Dos e ma y a l s o need to be i ncrea s ed i f drugs tha t decrea s e T4
a bs orpti on or i ncrea s e i ts bi l i a ry excreti on a re a dmi ni s tered concomi ta ntl y. The dos e us ed s houl d be the l owes t tha t res tores s erum TSH l evel s to
the mi dnorma l ra nge (though thi s cri teri on ca nnot be us ed i n pa ti ents wi th s econda ry hypothyroi di s m).
Li othyroni ne s houl d not be us ed a l one for l ong-term repl a cement beca us e of i ts s hort ha l f-l i fe a nd the l a rge pea ks i n s erum T3 l evel s i t produces .
The a dmi ni s tra ti on of s ta nda rd repl a cement a mounts (25 to 37.5 g bi d) res ul ts i n ra pi dl y i ncrea s i ng s erum T3 to between 300 a nd 1000 ng/dL (4.62
to 15.4 nmol /L) wi thi n 4 h due to i ts a l mos t compl ete a bs orpti on; thes e l evel s return to norma l by 24 h. Addi ti ona l l y, pa ti ents recei vi ng
l i othyroni ne a re chemi ca l l y hyperthyroi d for a t l ea s t s evera l hours a da y, potenti a l l y i ncrea s i ng ca rdi a c ri s ks .
Si mi l a r pa tterns of s erum T3 occur when mi xtures of T3 a nd T4 a re ta ken po, a l though pea k T3 i s l ower beca us e l es s T3 i s gi ven. Repl a cement
regi mens wi th s yntheti c T4 prepa ra ti ons refl ect a di fferent pa ttern i n s erum T3 res pons e. Increa s es i n s erum T3 occur gra dua l l y, a nd norma l l evel s
a re ma i nta i ned when a dequa te dos es of T4 a re gi ven. Des i cca ted a ni ma l thyroi d prepa ra ti ons conta i n va ri a bl e a mounts of T3 a nd T4 a nd s houl d
not be pres cri bed unl es s the pa ti ent i s a l rea dy ta ki ng the prepa ra ti on a nd ha s norma l s erum TSH.
In pa ti ents wi th s econda ry hypothyroi di s m, L-thyroxi ne s houl d not be gi ven unti l there i s evi dence of a dequa te corti s ol s ecreti on (or corti s ol
thera py i s gi ven), beca us e L-thyroxi ne coul d preci pi ta te a drena l cri s i s .
Myxedema coma: Myxedema coma i s trea ted a s fol l ows :
T4 gi ven IV
Corti cos teroi ds
Supporti ve ca re a s needed
Convers i on to ora l T4 when pa ti ent i s s ta bl e
Pa ti ents requi re a l a rge i ni ti a l dos e of T4 (300 to 500 g IV) or T3 (25 to 50 g IV). The IV ma i ntena nce dos e of T4 i s 75 to 100 g once/da y a nd of T3 ,
10 to 20 g bi d unti l T4 ca n be gi ven ora l l y. Corti cos teroi ds a re a l s o gi ven, beca us e the pos s i bi l i ty of centra l hypothyroi di s m us ua l l y ca nnot be
i ni ti a l l y rul ed out. The pa ti ent s houl d not be rewa rmed ra pi dl y, whi ch ma y preci pi ta te hypotens i on or a rrhythmi a s . Hypoxemi a i s common, s o Pa O2
s houl d be moni tored. If venti l a ti on i s compromi s ed, i mmedi a te mecha ni ca l venti l a tory a s s i s ta nce i s requi red. The preci pi ta ti ng fa ctor s houl d be
ra pi dl y a nd a ppropri a tel y trea ted a nd fl ui d repl a cement gi ven ca reful l y, beca us e hypothyroi d pa ti ents do not excrete wa ter a ppropri a tel y. Fi na l l y,
a l l drugs s houl d be gi ven ca uti ous l y beca us e they a re meta bol i zed more s l owl y tha n i n hea l thy peopl e.
Subclinical Hypothyroidism
Subclinical hypothyroidism is elevated serum TSH in patients with absent or minimal symptoms of hypothyroidism and normal serum levels of free T4 .
Subcl i ni ca l thyroi d dys functi on i s rel a ti vel y common; i t occurs i n more tha n 15% of el derl y women a nd 10% of el derl y men, pa rti cul a rl y i n thos e
wi th underl yi ng Ha s hi moto's thyroi di ti s .
In pa ti ents wi th s erum TSH > 10 mU/L, there i s a hi gh l i kel i hood of progres s i on to overt hypothyroi di s m wi th l ow s erum l evel s of free T4 i n the next
10 yr. Thes e pa ti ents a re a l s o more l i kel y to ha ve hyperchol es terol emi a a nd a theros cl eros i s . They s houl d be trea ted wi th L-thyroxi ne, even i f they
a re a s ymptoma ti c. For pa ti ents wi th TSH l evel s between 4.5 a nd 10 mU/L, a tri a l of L-thyroxi ne i s rea s ona bl e i f s ymptoms of ea rl y hypothyroi di s m
(eg, fa ti gue, depres s i on) a re pres ent. L-Thyroxi ne thera py i s a l s o i ndi ca ted i n pregna nt women a nd i n women who pl a n to become pregna nt to
a voi d del eteri ous effects of hypothyroi di s m on the pregna ncy a nd feta l devel opment. Pa ti ents s houl d ha ve a nnua l mea s urement of s erum TSH
a nd free T4 to a s s es s progres s of the condi ti on i f untrea ted or to a djus t the L-thyroxi ne dos a ge.
Silent Lymphocytic Thyroiditis
Silent lymphocytic thyroiditis is a self-limited, subacute disorder occurring most commonly in women during the postpartum period. Symptoms are initially of
hyperthyroidism, then hypothyroidism, and then generally recovery to the euthyroid state. Treatment of the hyperthyroid phase is with a -blocker. If
hypothyroidism is permanent, lifelong thyroxine supplementation is needed.
The term "s i l ent" refers to the a bs ence of thyroi d tendernes s i n contra s t wi th s uba cute thyroi di ti s , whi ch us ua l l y ca us es thyroi d tendernes s . Si l ent
l ymphocyti c thyroi di ti s ca us es mos t ca s es of pos tpa rtum thyroi d dys functi on. It occurs i n a bout 5 to 10% of pos tpa rtum women.
Thyroi d bi ops y revea l s l ymphocyti c i nfi l tra ti on a s i n Ha s hi moto's thyroi di ti s but wi thout l ymphoi d fol l i cl es a nd s ca rri ng. Thyroi d peroxi da s e
a utoa nti bodi es a nd, l es s commonl y, a nti thyrogl obul i n a nti bodi es a re a l mos t a l wa ys pos i ti ve duri ng pregna ncy a nd the pos tpa rtum peri od. Thus ,
thi s di s order woul d s eem to be a va ri a nt of Ha s hi moto's thyroi di ti s (s ee p. 779).
Symptoms and Signs
The condi ti on begi ns i n the pos tpa rtum peri od, us ua l l y wi thi n 12 to 16 wk. Si l ent l ymphocyti c thyroi di ti s i s cha ra cteri zed by a va ri a bl e degree of
pa i nl es s thyroi d enl a rgement wi th a hyperthyroi d pha s e of s evera l weeks , often fol l owed by tra ns i ent hypothyroi di s m due to depl eted thyroi d
hormone s tores but us ua l l y eventua l recovery to the euthyroi d s ta te (a s noted for pa i nful s uba cute thyroi di ti s ). The hyperthyroi d pha s e i s s el fl i mi ted a nd ma y be bri ef or overl ooked. Ma ny women wi th thi s di s order a re di a gnos ed when they become hypothyroi d, whi ch occa s i ona l l y i s
perma nent.
Diagnosis
Serum thyroxi ne (T4 ), tri i odothyroni ne (T3 ), a nd thyroi d-s ti mul a ti ng hormone (TSH) l evel s
Si l ent l ymphocyti c thyroi di ti s i s frequentl y undi a gnos ed. Sus pi ci on of the di a gnos i s genera l l y depends on cl i ni ca l fi ndi ngs , typi ca l l y once
hypothyroi di s m ha s occurred. Eye s i gns a nd preti bi a l myxedema do not occur.
Thyroi d functi on tes t res ul ts va ry dependi ng on the pha s e of i l l nes s . Ini ti a l l y, s erum T4 a nd T3 a re el eva ted a nd TSH i s s uppres s ed. In the
hypothyroi d pha s e, thes e fi ndi ngs a re revers ed. WBC count a nd ESR a re norma l . Needl e bi ops y provi des defi ni ti ve di a gnos i s but i s us ua l l y
unneces s a ry.
Treatment
Us ua l l y a -bl ocker
Someti mes thyroi d hormone repl a cement
Beca us e s i l ent l ymphocyti c thyroi di ti s l a s ts onl y a few months , trea tment i s cons erva ti ve, us ua l l y requi ri ng onl y a -bl ocker (eg, propra nol ol )
duri ng the hyperthyroi d pha s e (s ee p. 783). Anti thyroi d drugs , s urgery, a nd ra di oi odi ne thera py a re contra i ndi ca ted. Thyroi d hormone repl a cement
ma y be requi red duri ng the hypothyroi d pha s e. Mos t pa ti ents recover norma l thyroi d functi on, a l though s ome rema i n perma nentl y hypothyroi d.
Therefore, thyroi d functi on s houl d be reeva l ua ted a fter 9 to 12 mo of thyroxi ne thera py; repl a cement i s s topped for 5 wk, a nd TSH i s remea s ured.
Thi s di s order us ua l l y recurs a fter s ubs equent pregna nci es .
Subacute Thyroiditis
(de Querva i n's Thyroi di ti s ; Gi a nt Cel l Thyroi di ti s ; Gra nul oma tous Thyroi di ti s )
Subacute thyroiditis is an acute inflammatory disease of the thyroid probably caused by a virus. Symptoms include fever and thyroid tenderness. Initial
hyperthyroidism is common, sometimes followed by a transient period of hypothyroidism. Diagnosis is clinical and with thyroid function tests. Treatment is with
high doses of NSAIDs or with corticosteroids. The disease usually resolves spontaneously within months.
Hi s tory of a n a ntecedent vi ra l URI i s common. Hi s tol ogi c s tudi es s how l es s l ymphocyti c i nfi l tra ti on of the thyroi d tha n i n Ha s hi moto's thyroi di ti s or
s i l ent thyroi di ti s , but there i s cha ra cteri s ti c gi a nt cel l i nfi l tra ti on, PMNs , a nd fol l i cul a r di s rupti on.
Symptoms and Signs
There i s pa i n i n the a nteri or neck a nd fever of 37.8 to 38.3 C. Neck pa i n cha ra cteri s ti ca l l y s hi fts from s i de to s i de a nd ma y s ettl e i n one a rea ,
frequentl y ra di a ti ng to the ja w a nd ea rs . It i s often confus ed wi th denta l pa i n, pha ryngi ti s , or oti ti s a nd i s a ggra va ted by s wa l l owi ng or turni ng of
the hea d. Symptoms of hyperthyroi di s m a re common ea rl y i n the di s ea s e beca us e of hormone rel ea s e from the di s rupted fol l i cl es . There i s more
l a s s i tude a nd pros tra ti on tha n i n other thyroi d di s orders . On phys i ca l exa mi na ti on, the thyroi d i s a s ymmetri ca l l y enl a rged, fi rm, a nd tender.
Diagnosis
Free thyroxi ne (T4 ) a nd thyroi d-s ti mul a ti ng hormone (TSH) l evel s
ESR
Ra di oa cti ve i odi ne upta ke
Di a gnos i s i s pri ma ri l y cl i ni ca l , ba s ed on fi ndi ng a n enl a rged, tender thyroi d i n pa ti ents wi th the a ppropri a te cl i ni ca l hi s tory. Thyroi d tes ti ng wi th
TSH a nd a t l ea s t a free T4 mea s urement i s us ua l l y a l s o done. Ra di oa cti ve i odi ne upta ke s houl d be mea s ured to confi rm the di a gnos i s . When the
di a gnos i s i s uncerta i n, fi ner needl e a s pi ra ti on bi ops y i s us eful . Thyroi d ul tra s onogra phy wi th col or Doppl er s hows reduced bl ood fl ow i n contra s t
wi th the i ncrea s ed fl ow of Gra ves ' di s ea s e. La bora tory fi ndi ngs ea rl y i n the di s ea s e i ncl ude a n i ncrea s e i n free T4 a nd tri i odothyroni ne (T3 ), a
ma rked decrea s e i n TSH a nd thyroi d ra di oa cti ve i odi ne upta ke (often 0), a nd a hi gh ESR. After s evera l weeks , the thyroi d i s depl eted of T4 a nd T3
s tores , a nd tra ns i ent hypothyroi di s m devel ops a ccompa ni ed by a decrea s e i n free T4 a nd T3 , a ri s e i n TSH, a nd recovery of thyroi d ra di oa cti ve
i odi ne upta ke. Wea kl y pos i ti ve thyroi d a nti bodi es ma y be pres ent. Mea s urement of free T4 , T3 , a nd TSH a t 2- to 4-wk i nterva l s i denti fi es the s ta ges
of the di s ea s e.
Prognosis
Suba cute thyroi di ti s i s s el f-l i mi ted, genera l l y s ubs i di ng i n a few months ; occa s i ona l l y, i t recurs a nd ma y res ul t i n perma nent hypothyroi di s m when
fol l i cul a r des tructi on i s extens i ve.
Treatment
NSAIDs
Someti mes corti cos teroi ds , a -bl ocker, or both
Di s comfort i s trea ted wi th hi gh dos es of a s pi ri n or NSAIDs . In s evere a nd protra cted ca s es , corti cos teroi ds (eg, predni s one 30 to 40 mg po
once/da y, gra dua l l y decrea s i ng the dos e over 3 to 4 wk) era di ca te a l l s ymptoms wi thi n 48 h.
Bothers ome hyperthyroi d s ymptoms ma y be trea ted wi th a s hort cours e of a -bl ocker. If hypothyroi di s m i s pronounced or pers i s ts , thyroi d
hormone repl a cement thera py ma y be requi red, ra rel y perma nentl y.
Simple Nontoxic Goiter
(Euthyroi d Goi ter)
Simple nontoxic goiter, which may be diffuse or nodular, is noncancerous hypertrophy of the thyroid without hyperthyroidism, hypothyroidism, or inflammation.
Except in severe iodine deficiency, thyroid function is normal and patients are asymptomatic except for an obviously enlarged, nontender thyroid. Diagnosis is
clinical and with determination of normal thyroid function. Treatment is directed at the underlying cause, but partial surgical removal may be required for very
large goiters.
Si mpl e nontoxi c goi ter, the mos t common type of thyroi d enl a rgement, i s frequentl y noted a t puberty, duri ng pregna ncy, a nd a t menopa us e. The
ca us e a t thes e ti mes i s us ua l l y uncl ea r. Known ca us es i ncl ude i ntri ns i c thyroi d hormone producti on defects a nd, i n i odi ne-defi ci ent countri es ,
i nges ti on of foods tha t conta i n s ubs ta nces tha t i nhi bi t thyroi d hormone s ynthes i s (goi trogens , eg, ca s s a va , broccol i , ca ul i fl ower, ca bba ge). Other
ca us es i ncl ude the us e of drugs tha t ca n decrea s e the s ynthes i s of thyroi d hormone (eg, a mi oda rone or other i odi ne-conta i ni ng compounds ,
l i thi um).
Iodi ne defi ci ency i s ra re i n North Ameri ca but rema i ns the mos t common ca us e of goi ter worl dwi de (termed endemi c goi ter). Compens a tory s ma l l
el eva ti ons i n thyroi d-s ti mul a ti ng hormone (TSH) occur, preventi ng hypothyroi di s m, but the TSH s ti mul a ti on res ul ts i n goi ter forma ti on. Recurrent
cycl es of s ti mul a ti on a nd i nvol uti on ma y res ul t i n nontoxi c nodul a r goi ters . However, the true eti ol ogy of mos t nontoxi c goi ters i n i odi ne-s uffi ci ent
a rea s i s unknown.
Symptoms and Signs
The pa ti ent ma y ha ve a hi s tory of l ow i odi ne i nta ke or overi nges ti on of food goi trogens , but thes e phenomena a re ra re i n North Ameri ca . In the
ea rl y s ta ges , the goi ter i s typi ca l l y s oft, s ymmetri c, a nd s mooth. La ter, mul ti pl e nodul es a nd cys ts ma y devel op.
Diagnosis
Thyroi da l ra di oa cti ve i odi ne upta ke
Thyroi d s ca n
Thyroxi ne (T4 ), tri i odothyroni ne (T3 ), a nd TSH l evel s
In the ea rl y s ta ges , thyroi da l ra di oa cti ve i odi ne upta ke ma y be norma l or hi gh wi th norma l thyroi d s ca ns . Thyroi d functi on tes ts a re us ua l l y
norma l . Thyroi d a nti bodi es a re mea s ured to rul e out Ha s hi moto's thyroi di ti s .
In endemi c goi ter, s erum TSH ma y be s l i ghtl y el eva ted, a nd s erum T4 ma y be l ow-norma l or s l i ghtl y l ow, but s erum T3 i s us ua l l y norma l or s l i ghtl y
el eva ted.
Treatment
Depends on ca us e
In i odi ne-defi ci ent a rea s , i odi ne s uppl ementa ti on of s a l t; ora l or IM a dmi ni s tra ti on of i odi zed oi l yea rl y; a nd i odi na ti on of wa ter, crops , or a ni ma l
fodder el i mi na tes i odi ne-defi ci ency goi ter. Goi trogens bei ng i nges ted s houl d be s topped.
In other i ns ta nces , s uppres s i on of the hypotha l a mi c-pi tui ta ry a xi s wi th thyroi d hormone bl ocks TSH producti on (a nd hence s ti mul a ti on of the
thyroi d). Ful l TSH-s uppres s i ve dos es of L-thyroxi ne (100 to 150 g/da y po dependi ng on the s erum TSH) a re us eful i n younger pa ti ents . L-Thyroxi ne
i s contra i ndi ca ted i n ol der pa ti ents wi th nontoxi c nodul a r goi ter, beca us e thes e goi ters ra rel y s hri nk a nd ma y ha rbor a rea s of a utonomy s o tha t Lthyroxi ne thera py ca n res ul t i n hyperthyroi di s m. La rge goi ters occa s i ona l l y requi re s urgery or 131 I to s hri nk the gl a nd enough to prevent
i nterference wi th res pi ra ti on or s wa l l owi ng or to correct cos meti c probl ems .
Thyroid Cancers
The 4 general types of thyroid cancer are papillary, follicular, medullary, and anaplastic. Papillary and follicular carcinoma together are called differentiated
thyroid cancer because of their histologic resemblance to normal thyroid tissue and because differentiated function (eg, thyroglobulin secretion) is preserved.
Most thyroid cancers manifest as asymptomatic nodules. Rarely, lymph node, lung, or bone metastases cause the presenting symptoms of small thyroid cancers.
Diagnosis is often by fine-needle aspiration biopsy but may involve other tests. Except for anaplastic and metastatic medullary carcinoma, most thyroid cancers
are not highly malignant and are seldom fatal. Treatment is surgical removal, usually followed by ablation of residual tissue with radioactive iodine.
Papillary Carcinoma
Pa pi l l a ry ca rci noma a ccounts for 70 to 80% of a l l thyroi d ca ncers . The fema l e:ma l e ra ti o i s 3:1. It ma y be fa mi l i a l i n up to 5% of pa ti ents . Mos t
pa ti ents pres ent between a ges 30 a nd 60. The tumor i s often more a ggres s i ve i n el derl y pa ti ents . Ma ny pa pi l l a ry ca rci noma s conta i n fol l i cul a r
el ements .
The tumor s prea ds vi a l ympha ti cs to regi ona l l ymph nodes i n one thi rd of pa ti ents a nd ma y meta s ta s i ze to the l ungs . Pa ti ents < 45 yr wi th s ma l l
tumors confi ned to the thyroi d ha ve a n excel l ent prognos i s .
Treatment
Someti mes ra di oa cti ve i odi ne
Trea tment for enca ps ul a ted tumors < 1.5 cm l oca l i zed to one l obe i s us ua l l y nea r-tota l thyroi dectomy, a l though s ome experts recommend onl y
l obectomy a nd i s thmectomy; s urgery i s a l mos t a l wa ys cura ti ve. Thyroi d hormone i n thyroi d-s ti mul a ti ng hormone (TSH)-s uppres s i ve dos es i s gi ven
to mi ni mi ze cha nces of regrowth a nd ca us e regres s i on of a ny mi cros copi c remna nts of pa pi l l a ry ca rci noma .
Tumors > 4 cm or tha t a re di ffus el y s prea di ng requi re tota l or nea r-tota l thyroi dectomy wi th pos topera ti ve ra di oi odi ne a bl a ti on of res i dua l thyroi d
ti s s ue wi th a ppropri a tel y l a rge dos es of 131 I a dmi ni s tered when the pa ti ent i s hypothyroi d or a fter recombi na nt TSH i njecti ons . Trea tment ma y be
repea ted every 6 to 12 mo to a bl a te a ny rema i ni ng thyroi d ti s s ue. TSH-s uppres s i ve dos es of L-thyroxi ne a re gi ven a fter trea tment, a nd s erum
thyrogl obul i n l evel s hel p detect recurrent or pers i s tent di s ea s e. About 20 to 30% of pa ti ents , ma i nl y ol der pa ti ents , ha ve recurrent or pers i s tent
di s ea s e.
Follicular Carcinoma
Fol l i cul a r ca rci noma , i ncl udi ng the Hurthl e cel l va ri a nt, a ccounts for a bout 15% of thyroi d ca ncers . It i s more common a mong ol der pa ti ents a nd i n
regi ons of i odi ne defi ci ency. It i s more ma l i gna nt tha n pa pi l l a ry ca rci noma , s prea di ng hema togenous l y wi th di s ta nt meta s ta s es .
Trea tment requi res nea r-tota l thyroi dectomy wi th pos topera ti ve ra di oi odi ne a bl a ti on of res i dua l thyroi d ti s s ue a s i n trea tment for pa pi l l a ry
ca rci noma . Meta s ta s es a re more res pons i ve to ra di oi odi ne thera py tha n a re thos e of pa pi l l a ry ca rci noma . TSH-s uppres s i ve dos es of L-thyroxi ne
a re gi ven a fter trea tment. Serum thyrogl obul i n s houl d be moni tored to detect recurrent or pers i s tent di s ea s e.
Medullary Carcinoma
Medul l a ry (s ol i d) ca rci noma cons ti tutes a bout 3% of thyroi d ca ncers a nd i s compos ed of pa ra fol l i cul a r cel l s (C cel l s ) tha t produce ca l ci toni n. It ma y
be s pora di c (us ua l l y uni l a tera l ); however, i t i s often fa mi l i a l , ca us ed by a muta ti on of the ret proto-oncogene. The fa mi l i a l form ma y occur i n
i s ol a ti on or a s a component of mul ti pl e endocri ne neopl a s i a (MEN) s yndromes types 2A a nd 2B (s ee pp. 912 a nd 913). Al though ca l ci toni n ca n
l ower s erum Ca a nd phos pha te, s erum Ca i s norma l beca us e the hi gh l evel of ca l ci toni n ul ti ma tel y down-regul a tes i ts receptors . Cha ra cteri s ti c
a myl oi d depos i ts tha t s ta i n wi th Congo red a re a l s o pres ent.
Meta s ta s es s prea d vi a the l ympha ti c s ys tem to cervi ca l a nd medi a s ti na l nodes a nd s ometi mes to l i ver, l ungs , a nd bone.
Symptoms and Signs
Pa ti ents typi ca l l y pres ent wi th a n a s ymptoma ti c thyroi d nodul e, a l though ma ny ca s es a re now di a gnos ed duri ng routi ne s creeni ng of a ffected
ki ndreds wi th MEN-2A or MEN-2B before a pa l pa bl e tumor devel ops .
Medul l a ry ca rci noma ma y ha ve a dra ma ti c bi ochemi ca l pres enta ti on when a s s oci a ted wi th ectopi c producti on of other hormones or pepti des (eg,
ACTH, va s oa cti ve i ntes ti na l pol ypepti de, pros ta gl a ndi ns , ka l l i krei ns , s erotoni n).
Diagnosis
Serum ca l ci toni n l evel s
The bes t tes t i s mea s urement of s erum ca l ci toni n, whi ch i s grea tl y el eva ted. A cha l l enge wi th Ca (15 mg/kg IV over 4 h) provokes exces s i ve
s ecreti on of ca l ci toni n. X-ra ys ma y s how a dens e, homogenous , congl omera te ca l ci fi ca ti on.
Al l pa ti ents wi th medul l a ry ca rci noma s houl d ha ve geneti c tes ti ng; rel a ti ves of thos e wi th muta ti ons s houl d ha ve geneti c tes ti ng a nd
mea s urement of ba s a l a nd s ti mul a ted ca l ci toni n l evel s .
Treatment
Tota l thyroi dectomy i s i ndi ca ted even i f bi l a tera l i nvol vement i s not obvi ous . Lymph nodes a re a l s o di s s ected. If hyperpa ra thyroi di s m i s pres ent,
remova l of hyperpl a s ti c or a denoma tous pa ra thyroi ds i s requi red. Pheochromocytoma , i f pres ent, i s us ua l l y bi l a tera l . Pheochromocytoma s s houl d
be i denti fi ed a nd removed before thyroi dectomy beca us e of the da nger of provoki ng hypertens i ve cri s i s duri ng the opera ti on. Long-term s urvi va l i s
common i n pa ti ents wi th medul l a ry ca rci noma a nd MEN-IIA; more tha n two thi rds of a ffected pa ti ents a re a l i ve a t 10 yr. Medul l a ry ca rci noma of
the s pora di c type ha s a wors e prognos i s .
Rel a ti ves wi th a n el eva ted ca l ci toni n l evel wi thout a pa l pa bl e thyroi d a bnorma l i ty s houl d undergo thyroi dectomy, beca us e there i s a grea ter
cha nce of cure a t thi s s ta ge. Some experts recommend s urgery i n rel a ti ves who ha ve norma l ba s a l a nd s ti mul a ted s erum ca l ci toni n l evel s but who
ha ve the ret proto-oncogene muta ti on.
Anaplastic Carcinoma
Ana pl a s ti c ca rci noma i s a n undi fferenti a ted ca ncer tha t a ccounts for a bout 2% of thyroi d ca ncers . It occurs mos tl y i n el derl y pa ti ents a nd s l i ghtl y
more often i n women. The tumor i s cha ra cteri zed by ra pi d, pa i nful enl a rgement. Ra pi d enl a rgement of the thyroi d ma y a l s o s ugges t thyroi d
l ymphoma , pa rti cul a rl y i f found i n a s s oci a ti on wi th Ha s hi moto's thyroi di ti s .
No effecti ve thera py exi s ts , a nd the di s ea s e i s genera l l y fa ta l . About 80% of pa ti ents di e wi thi n 1 yr of di a gnos i s . In a few pa ti ents wi th s ma l l er
tumors , thyroi dectomy fol l owed by externa l ra di a ti on ha s been cura ti ve. Chemothera py i s ma i nl y experi menta l .
Radiation-Induced Thyroid Cancer
Thyroi d tumors devel op i n peopl e expos ed to l a rge a mounts of envi ronmenta l thyroi d ra di a ti on, a s occurs from a tomi c bomb bl a s ts , nucl ea r
rea ctor a cci dents , or i nci denta l thyroi d i rra di a ti on due to ra di a ti on thera py. Tumors ma y be detected 10 yr a fter expos ure, but ri s k rema i ns
i ncrea s ed for 30 to 40 yr. Such tumors a re us ua l l y beni gn; however, a bout 10% a re pa pi l l a ry thyroi d ca rci noma . The tumors a re frequentl y
mul ti centri c or di ffus e.
Pa ti ents who ha d thyroi d i rra di a ti on s houl d undergo yea rl y thyroi d pa l pa ti on, ul tra s onogra phy, a nd mea s urement of thyroi d a utoa nti bodi es (to
excl ude Ha s hi moto's thyroi di ti s ). A thyroi d s ca n does not a l wa ys refl ect a rea s of i nvol vement.
If ul tra s onogra phy revea l s a nodul e, fi ne-needl e a s pi ra ti on bi ops y s houl d be done. In the a bs ence of s us pi ci ous or ma l i gna nt l es i ons , ma ny
phys i ci a ns recommend l i fel ong TSH-l oweri ng dos es of thyroi d hormone to s uppres s thyroi d functi on a nd thyrotropi n s ecreti on a nd pos s i bl y
decrea s e the cha nce of devel opi ng a thyroi d tumor.
Surgery i s requi red i f fi ne-needl e a s pi ra ti on bi ops y s ugges ts ca ncer. Nea r-tota l or tota l thyroi dectomy i s the trea tment of choi ce, to be fol l owed by
ra di oi odi ne a bl a ti on of a ny res i dua l thyroi d ti s s ue i f a ca ncer i s found (dependi ng on the s i ze, hi s tol ogy, a nd i nva s i venes s ).
Chapter 94. Adrenal Disorders

Introduction
The a drena l gl a nds , l oca ted on the cepha l a d porti on of ea ch ki dney, cons i s t of a cortex a nd medul l a , ea ch wi th s epa ra te endocri ne functi ons .
Cortex: The a drena l cortex produces gl ucocorti coi ds (pri ma ri l y corti s ol ), mi nera l ocorti coi ds (pri ma ri l y a l dos terone), a nd a ndrogens (pri ma ri l y
dehydroepi a ndros terone a nd a ndros tenedi one). Phys i ol ogy of the hypotha l a mi c-pi tui ta ry-a drenocorti ca l s ys tem i s further di s cus s ed i n Ch. 91.
Gl ucocorti coi ds promote a nd i nhi bi t gene tra ns cri pti on i n ma ny cel l s a nd orga n s ys tems . Promi nent effects i ncl ude a nti -i nfl a mma tory a cti ons a nd
i ncrea s ed hepa ti c gl uconeogenes i s .
Mi nera l ocorti coi ds regul a te el ectrol yte tra ns port a cros s epi thel i a l s urfa ces , pa rti cul a rl y rena l cons erva ti on of Na i n excha nge for K.
Adrena l a ndrogens ' chi ef phys i ol ogi c a cti vi ty occurs a fter convers i on to tes tos terone a nd di hydrotes tos terone.
Medulla: The a drena l medul l a i s compos ed of chroma ffi n cel l s , whi ch s ynthes i ze a nd s ecrete ca techol a mi nes (ma i nl y epi nephri ne a nd l es s er
a mounts of norepi nephri ne). Chroma ffi n cel l s a l s o produce bi oa cti ve a mi nes a nd pepti des (eg, hi s ta mi ne, s erotoni n, chromogra ni ns ,
neuropepti de hormones ). Epi nephri ne a nd norepi nephri ne, the ma jor effector a mi nes of the s ympa theti c nervous s ys tem, a re res pons i bl e for the
"fl i ght or fi ght" res pons e (i e, chronotropi c a nd i notropi c effects on the hea rt; bronchodi l a ti on; peri phera l a nd s pl a nchni c va s ocons tri cti on wi th
s kel eta l mus cul a r va s odi l a ti on; meta bol i c effects i ncl udi ng gl ycogenol ys i s , l i pol ys i s , a nd reni n rel ea s e).
Clinical syndromes: Mos t defi ci ency s yndromes a ffect output of a l l a drenocorti ca l hormones . Hypofuncti on ma y be pri ma ry (ma l functi on of the
a drena l gl a nd i ts el f, a s i n Addi s on's di s ea s e) or s econda ry (due to l a ck of a drena l s ti mul a ti on by the pi tui ta ry or hypotha l a mus , a l though s ome
experts refer to hypotha l a mi c ma l functi on a s terti a ry).
Hyperfuncti on ca us es di s ti nct cl i ni ca l s yndromes . Hypers ecreti on of a ndrogens res ul ts i n a drena l vi ri l i s m; of gl ucocorti coi ds , Cus hi ng's s yndrome;
a nd of a l dos terone, hypera l dos teroni s m (a l dos teroni s m). Thes e s yndromes frequentl y ha ve overl a ppi ng fea tures . Hyperfuncti on ma y be
compens a tory, a s i n congeni ta l a drena l hyperpl a s i a (s ee p. 2889), or due to a cqui red hyperpl a s i a , a denoma s , or a denoca rci noma s . Exces s
qua nti ti es of epi nephri ne a nd norepi nephri ne a re produced i n pheochromocytoma .
Addison's Disease
(Pri ma ry or Chroni c Adrenocorti ca l Ins uffi ci ency)
Addison's disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and
hyperpigmentation, and can lead to adrenal crisis with cardiovascular collapse. Diagnosis is clinical and by finding elevated plasma ACTH with low plasma
cortisol. Treatment depends on the cause but generally includes hydrocortisone and sometimes other hormones.
Addi s on's di s ea s e devel ops i n a bout 4/100,000 a nnua l l y. It occurs i n a l l a ge groups , a bout equa l l y i n ea ch s ex, a nd tends to become cl i ni ca l l y
a ppa rent duri ng meta bol i c s tres s or tra uma . Ons et of s evere s ymptoms (a drena l cri s i s ) ma y be preci pi ta ted by a cute i nfecti on (a common ca us e,
es peci a l l y wi th s epti cemi a ). Other ca us es i ncl ude tra uma , s urgery, a nd Na l os s from exces s i ve s wea ti ng. Wi th trea tment, Addi s on's di s ea s e
s houl d not typi ca l l y reduce l i fe expecta ncy.
Etiology
About 70% of ca s es i n the US a re due to i di opa thi c a trophy of the a drena l cortex, proba bl y ca us ed by a utoi mmune proces s es . The rema i nder res ul t
from des tructi on of the a drena l gl a nd by gra nul oma (eg, TB), tumor, a myl oi dos i s , hemorrha ge, or i nfl a mma tory necros i s . Hypoa drenocorti ci s m ca n
a l s o res ul t from a dmi ni s tra ti on of drugs tha t bl ock corti cos teroi d s ynthes i s (eg, ketocona zol e, the a nes theti c etomi da te). Addi s on's di s ea s e ma y
coexi s t wi th di a betes mel l i tus or hypothyroi di s m i n pol ygl a ndul a r defi ci ency s yndrome (s ee p. 804). In chi l dren, the mos t common ca us e of pri ma ry
a drena l i ns uffi ci ency i s congeni ta l a drena l hyperpl a s i a (CAHs ee a l s o Congeni ta l Adrena l Hyperpl a s i a on p. 2889).
Pathophysiology
Both mi nera l ocorti coi ds a nd gl ucocorti coi ds a re defi ci ent.
Mineralocorticoid deficiency: Beca us e mi nera l ocorti coi ds s ti mul a te Na rea bs orpti on a nd K excreti on, defi ci ency res ul ts i n i ncrea s ed excreti on of Na
a nd decrea s ed excreti on of K, chi efl y i n uri ne but a l s o i n s wea t, s a l i va , a nd the GI tra ct. A l ow s erum concentra ti on of Na a nd a hi gh concentra ti on
of K res ul t. Ina bi l i ty to concentra te the uri ne, combi ned wi th cha nges i n el ectrol yte ba l a nce, ca us e s evere dehydra ti on, pl a s ma hypertoni ci ty,
a ci dos i s , decrea s ed ci rcul a tory vol ume, hypotens i on, a nd, eventua l l y, ci rcul a tory col l a ps e. However, when a drena l i ns uffi ci ency i s ca us ed by
i na dequa te ACTH producti on (s econda ry a drena l i ns uffi ci encys ee p. 795), el ectrol yte l evel s a re often norma l or onl y mi l dl y dera nged.
Glucocorticoid deficiency: Gl ucocorti coi d defi ci ency contri butes to hypotens i on a nd ca us es s evere i ns ul i n s ens i ti vi ty a nd di s turba nces i n
ca rbohydra te, fa t, a nd protei n meta bol i s m. In the a bs ence of corti s ol , i ns uffi ci ent ca rbohydra te i s formed from protei n; hypogl ycemi a a nd
di mi ni s hed l i ver gl ycogen res ul t. Wea knes s fol l ows , due i n pa rt to defi ci ent neuromus cul a r functi on. Res i s ta nce to i nfecti on, tra uma , a nd other
s tres s i s di mi ni s hed. Myoca rdi a l wea knes s a nd dehydra ti on reduce ca rdi a c output, a nd ci rcul a tory fa i l ure ca n occur. Decrea s ed bl ood corti s ol
res ul ts i n i ncrea s ed pi tui ta ry ACTH producti on a nd i ncrea s ed bl ood -l i potropi n, whi ch ha s mel a nocyte-s ti mul a ti ng a cti vi ty a nd, together wi th
ACTH, ca us es the hyperpi gmenta ti on of s ki n a nd mucous membra nes cha ra cteri s ti c of Addi s on's di s ea s e. Thus , a drena l i ns uffi ci ency s econda ry to
pi tui ta ry fa i l ure (s ee p. 795) does not ca us e hyperpi gmenta ti on.
Symptoms and Signs
Wea knes s , fa ti gue, a nd orthos ta ti c hypotens i on a re ea rl y s ymptoms a nd s i gns . Hyperpi gmenta ti on i s cha ra cteri zed by di ffus e ta nni ng of expos ed
a nd, to a l es s er extent, unexpos ed porti ons of the body, es peci a l l y on pres s ure poi nts (bony promi nences ), s ki n fol ds , s ca rs , a nd extens or
s urfa ces . Bl a ck freckl es a re common on the forehea d, fa ce, neck, a nd s houl ders . Area s of vi ti l i go devel op, a s do bl ui s h bl a ck di s col ora ti ons of the
a reol a e a nd mucous membra nes of the l i ps , mouth, rectum, a nd va gi na . Anorexi a , na us ea , vomi ti ng, a nd di a rrhea often occur. Decrea s ed
tol era nce to col d, wi th hypometa bol i s m, ma y be noted. Di zzi nes s a nd s yncope ma y occur. The gra dua l ons et a nd nons peci fi c na ture of ea rl y
s ymptoms often l ea d to a n i ncorrect i ni ti a l di a gnos i s of neuros i s . Wei ght l os s , dehydra ti on, a nd hypotens i on a re cha ra cteri s ti c of the l a ter s ta ges
of Addi s on's di s ea s e.
Adrenal crisis: Adrena l cri s i s i s cha ra cteri zed by profound a s theni a ; s evere pa i n i n the a bdomen, l ower ba ck, or l egs ; peri phera l va s cul a r col l a ps e;
a nd, fi na l l y, rena l s hutdown wi th a zotemi a . Body tempera ture ma y be l ow, a l though s evere fever often occurs , pa rti cul a rl y when cri s i s i s
preci pi ta ted by a cute i nfecti on. A s i gni fi ca nt number of pa ti ents wi th pa rti a l l os s of a drena l functi on (l i mi ted a drenocorti ca l res erve) a ppea r wel l
but experi ence a drena l cri s i s when under phys i ol ogi c s tres s (eg, s urgery, i nfecti on, burns , cri ti ca l i l l nes s ). Shock a nd fever ma y be the onl y s i gns .
Diagnosis
El ectrol ytes
Serum corti s ol
Serum ACTH
Someti mes ACTH s ti mul a ti on tes ti ng
Cl i ni ca l s ymptoms a nd s i gns s ugges t a drena l i ns uffi ci ency. Someti mes the di a gnos i s i s cons i dered onl y on di s covery of cha ra cteri s ti c
a bnorma l i ti es of s erum el ectrol ytes , i ncl udi ng l ow Na (< 135 mEq/L), hi gh K (> 5 mEq/L), l ow HCO3 (15 to 20 mEq/L), a nd hi gh BUN (s ee
Ta bl e 94-1).
Differential diagnosis: Hyperpi gmenta ti on ca n res ul t from bronchogeni c ca rci noma , i nges ti on of hea vy meta l s (eg, i ron, s i l ver), chroni c s ki n
condi ti ons , or hemochroma tos i s . Peutz-Jeghers s yndrome i s cha ra cteri zed by pi gmenta ti on of the bucca l a nd recta l mucos a . Frequentl y,
hyperpi gmenta ti on occurs wi th vi ti l i go, whi ch ma y i ndi ca te Addi s on's di s ea s e, a l though other di s ea s es ca n ca us e thi s a s s oci a ti on.
Wea knes s res ul ti ng from Addi s on's di s ea s e s ubs i des wi th res t, unl i ke neurops ychi a tri c wea knes s , whi ch i s often wors e i n the morni ng tha n a fter
a cti vi ty. Mos t myopa thi es tha t ca us e wea knes s ca n be di fferenti a ted by thei r di s tri buti on, l a ck of a bnorma l pi gmenta ti on, a nd cha ra cteri s ti c
l a bora tory fi ndi ngs .
[Table 94-1. Tes t Res ul ts tha t Sugges t Addi s on's Di s ea s e]
Pa ti ents wi th a drena l i ns uffi ci ency devel op hypogl ycemi a a fter fa s ti ng beca us e of decrea s ed gl uconeogenes i s . In contra s t, pa ti ents wi th
hypogl ycemi a due to overs ecreti on of i ns ul i n ca n ha ve a tta cks a t a ny ti me, us ua l l y ha ve i ncrea s ed a ppeti te wi th wei ght ga i n, a nd ha ve norma l
a drena l functi on. Low s erum Na due to Addi s on's di s ea s e mus t be di fferenti a ted from tha t of edema tous pa ti ents wi th ca rdi a c or l i ver di s ea s e
(pa rti cul a rl y thos e ta ki ng di ureti cs ), the di l uti ona l hypona tremi a of the s yndrome of i na ppropri a te ADH s ecreti on, a nd s a l t-l os i ng nephri ti s . Thes e
pa ti ents a re not l i kel y to ha ve hyperpi gmenta ti on, hyperka l emi a , a nd i ncrea s ed BUN.
Testing: La bora tory tes ts , begi nni ng wi th s erum corti s ol a nd ACTH l evel s , confi rm a drena l i ns uffi ci ency. El eva ted ACTH ( 50 pg/mL) wi th l ow corti s ol
(< 5 g/dL [< 138 nmol /L]) i s di a gnos ti c, pa rti cul a rl y i n pa ti ents who a re s everel y s tres s ed or i n s hock. Low ACTH (< 5 pg/mL) a nd corti s ol s ugges t
s econda ry a drena l i ns uffi ci ency (s ee p. 795); i t i s i mporta nt to note tha t ACTH l evel s wi thi n the norma l ra nge a re i na ppropri a te for very l ow corti s ol
l evel s .
If ACTH a nd corti s ol l evel s a re borderl i ne a nd a drena l i ns uffi ci ency i s cl i ni ca l l y s us pectedpa rti cul a rl y i n a pa ti ent who i s a bout to undergo ma jor
s urgeryprovoca ti ve tes ti ng mus t be done. If ti me i s too s hort (eg, emergency s urgery), the pa ti ent i s gi ven hydrocorti s one empi ri ca l l y (eg, 100 mg
IV or IM), a nd provoca ti ve tes ti ng i s done s ubs equentl y.
Addi s on's di s ea s e i s di a gnos ed by s howi ng fa i l ure of exogenous ACTH to i ncrea s e s erum corti s ol . Seconda ry a drena l i ns uffi ci ency i s di a gnos ed by
a prol onged ACTH s ti mul a ti on tes t, i ns ul i n tol era nce tes t, or gl uca gon tes t.
ACTH s ti mul a ti on tes ti ng i s done by i njecti ng cos yntropi n (s yntheti c ACTH) 250 g IV or IM. Some a uthori ti es bel i eve tha t i n pa ti ents wi th s us pected
s econda ry a drena l i ns uffi ci ency, a l ow-dos e ACTH s ti mul a ti on tes t us i ng 1 g IV i ns tea d of the s ta nda rd 250 g s houl d be done, beca us e s uch
pa ti ents ma y rea ct norma l l y to the hi gher dos e. Pa ti ents ta ki ng gl ucocorti coi d s uppl ements or s pi ronol a ctone s houl d not ta ke them on the da y of
the tes t. Norma l prei njecti on s erum corti s ol ra nges from 5 to 25 g/dL (138 to 690 nmol /L) a nd doubl es i n 30 to 90 mi n, rea chi ng a t l ea s t 20 g/dL
(552 nmol /L). Pa ti ents wi th Addi s on's di s ea s e ha ve l ow or l ow-norma l va l ues tha t do not ri s e a bove 20 g/dL a t 30 mi n. A norma l res pons e to
cos yntropi n ma y occur i n s econda ry a drena l i ns uffi ci ency. However, beca us e pi tui ta ry fa i l ure ma y ca us e a drena l a trophy (a nd hence fa i l ure to
res pond to ACTH), the pa ti ent ma y need to be pri med wi th l ong-a cti ng ACTH 1 mg IM once/da y for 3 da ys before the cos yntropi n tes t i f pi tui ta ry
di s ea s e i s s us pected.
A prol onged ACTH s ti mul a ti on tes t (s a mpl i ng for 24 h) ma y be us ed to di a gnos e s econda ry (or terti a ryhypotha l a mi c) a drena l i ns uffi ci ency.
Cos yntropi n 1 mg IM i s gi ven a nd corti s ol mea s ured a t i nterva l s for 24 h. Res ul ts for the fi rs t hour a re s i mi l a r for both the s hort (s a mpl i ng s topped
a fter 1 h) a nd prol onged tes ts , but i n Addi s on's di s ea s e there i s no further ri s e beyond 60 mi n. In s econda ry a nd terti a ry a drena l i ns uffi ci ency,
corti s ol l evel s conti nue to ri s e for 24 h. Onl y i n ca s es of prol onged a drena l a trophy i s a drena l pri mi ng (wi th l ong-a cti ng ACTH) neces s a ry. The
s i mpl e s hort tes t i s us ua l l y done i ni ti a l l y, beca us e a norma l res pons e obvi a tes the need for further i nves ti ga ti on.
If a drena l cri s i s i s s us pected, confi rma ti on of Addi s on's di s ea s e by ACTH s ti mul a ti on tes ti ng i s deferred unti l the pa ti ent ha s recovered. If ACTH
s ti mul a ti on tes ti ng i s done, el eva ted ACTH l evel s together wi th l ow corti s ol l evel s confi rm the di a gnos i s .
In Wes tern s oci eti es , the ca us e i s us ua l l y a s s umed to be a utoi mmune, unl es s there i s evi dence otherwi s e. Adrena l a utoa nti bodi es ca n be
a s s es s ed. A ches t x-ra y s houl d be done for TB; i f doubt exi s ts , CT of the a drena l s i s hel pful . In pa ti ents wi th a utoi mmune di s ea s e, the a drena l s
a re a trophi ed, wherea s i n pa ti ents wi th TB or other gra nul oma s , the a drena l s a re enl a rged (i ni ti a l l y) wi th frequent ca l ci fi ca ti on. Bi l a tera l a drena l
hyperpl a s i a s ugges ts a n enzyme defect.
Treatment
Hydrocorti s one or predni s one
Fl udrocorti s one
Dos e i ncrea s e duri ng i ntercurrent i l l nes s
Norma l l y, corti s ol i s s ecreted ma xi ma l l y i n the ea rl y morni ng a nd mi ni ma l l y a t ni ght. Thus , hydrocorti s one (i denti ca l to corti s ol ) i s gi ven i n 2 or 3
di vi ded dos es wi th a typi ca l tota l da i l y dos e of 15 to 30 mg. One regi men gi ves ha l f the tota l i n the morni ng, a nd the rema i ni ng ha l f s pl i t between
l unchti me a nd ea rl y eveni ng (eg, 10 mg, 5 mg, 5 mg). Others gi ve two thi rds i n the morni ng a nd one thi rd i n the eveni ng. Dos es i mmedi a tel y before
reti ri ng s houl d genera l l y be a voi ded beca us e they ma y ca us e i ns omni a . Al terna ti vel y, predni s one 5 mg po i n the morni ng a nd 2.5 mg po i n the
eveni ng ma y be us ed. Addi ti ona l l y, fl udrocorti s one 0.1 to 0.2 mg po once/da y i s recommended to repl a ce a l dos terone. The ea s i es t wa y to a djus t
the dos a ge i s to ens ure tha t the reni n l evel i s wi thi n the norma l ra nge. Norma l hydra ti on a nd a bs ence of orthos ta ti c hypotens i on a re evi dence of
a dequa te repl a cement thera py. In s ome pa ti ents , fl udrocorti s one ca us es hypertens i on, whi ch i s trea ted by reduci ng the dos a ge or s ta rti ng a
nondi ureti c a nti hypertens i ve. Some cl i ni ci a ns tend to gi ve too l i ttl e fl udrocorti s one i n a n effort to a voi d us e of a nti hypertens i ves .
Intercurrent i l l nes s es (eg, i nfecti ons ) a re potenti a l l y s eri ous a nd s houl d be vi gorous l y trea ted; the pa ti ent's hydrocorti s one dos e s houl d be
doubl ed duri ng the i l l nes s . If na us ea a nd vomi ti ng precl ude ora l thera py, pa rentera l thera py i s neces s a ry. Pa ti ents s houl d be i ns tructed when to
ta ke s uppl ementa l predni s one a nd ta ught to s el f-a dmi ni s ter pa rentera l hydrocorti s one for urgent s i tua ti ons . A prel oa ded s yri nge wi th 100 mg
hydrocorti s one s houl d be a va i l a bl e to the pa ti ent. A bra cel et or wa l l et ca rd gi vi ng the di a gnos i s a nd corti cos teroi d dos e ma y hel p i n ca s e of
a drena l cri s i s tha t renders the pa ti ent una bl e to communi ca te. When s a l t l os s i s s evere, a s i n very hot cl i ma tes , the dos e of fl udrocorti s one ma y
need to be i ncrea s ed.
In coexi s ti ng di a betes mel l i tus a nd Addi s on's di s ea s e, the hydrocorti s one dos e us ua l l y s houl d not be > 30 mg/da y; otherwi s e, i ns ul i n
requi rements a re i ncrea s ed.
Adrenal crisis: Thera py s houl d be i ns ti tuted i mmedi a tel y upon s us pi ci on. (CAUTION: In adrenal crisis, a delay in instituting corticosteroid therapy,
particularly if there is hypoglycemia and hypotension, may be fatal.) If the pa ti ent i s a cutel y i l l , confi rma ti on by a n ACTH s ti mul a ti on tes t s houl d be
pos tponed unti l the pa ti ent ha s recovered.
Hydrocorti s one 100 mg i s i njected IV over 30 s ec a nd repea ted q 6 to 8 h for the fi rs t 24 h. Immedi a te i ntra va s cul a r vol ume expa ns i on i s done by
gi vi ng 1 L of a 5% dextros e i n 0.9% s a l i ne s ol uti on over 1 to 2 h. Addi ti ona l 0.9% s a l i ne i s gi ven IV unti l hypotens i on, dehydra ti on, a nd
hypona tremi a ha ve been corrected. Serum K ma y fa l l duri ng rehydra ti on, requi ri ng repl a cement. Mi nera l ocorti coi ds a re not requi red when hi ghdos e hydrocorti s one i s gi ven. When i l l nes s i s l es s a cute, hydrocorti s one 50 or 100 mg ca n be gi ven IM q 6 h. Res tora ti on of BP a nd genera l
i mprovement s houl d occur wi thi n 1 h a fter the i ni ti a l dos e of hydrocorti s one. Inotropi c a gents ma y be needed unti l the effects of hydrocorti s one
a re a chi eved.
A tota l dos e of 150 mg hydrocorti s one i s us ua l l y gi ven over the 2nd 24-h peri od i f the pa ti ent ha s i mproved ma rkedl y, a nd 75 mg i s gi ven on the 3rd
da y. Ma i ntena nce ora l dos es of hydrocorti s one (15 to 30 mg) a nd fl udrocorti s one (0.1 mg) a re gi ven da i l y therea fter, a s des cri bed a bove. Recovery
depends on trea tment of the underl yi ng ca us e (eg, i nfecti on, tra uma , meta bol i c s tres s ) a nd a dequa te hydrocorti s one thera py.
For pa ti ents wi th s ome res i dua l a drena l functi on who devel op a drena l cri s i s when under s tres s , hydrocorti s one trea tment i s the s a me, but fl ui d
requi rements ma y be much l ower.
Treatment of complications: Fever > 40.6 C occa s i ona l l y a ccompa ni es the rehydra ti on proces s . Except i n the pres ence of fa l l i ng BP, a nti pyreti cs (eg,
a s pi ri n 650 mg) ma y be gi ven po wi th ca uti on. Compl i ca ti ons of corti cos teroi d thera py ma y i ncl ude ps ychoti c rea cti ons . If ps ychoti c rea cti ons occur
a fter the fi rs t 12 h of thera py, the hydrocorti s one dos e s houl d be reduced to the l owes t l evel cons i s tent wi th ma i nta i ni ng BP a nd good
ca rdi ova s cul a r functi on. Anti ps ychoti cs ma y be tempora ri l y requi red, but us e s houl d not be prol onged.
Secondary Adrenal Insufficiency
Secondary adrenal insufficiency is adrenal hypofunction due to a lack of ACTH. Symptoms are the same as for Addison's disease, but there is usually less
hypovolemia (see p. 792). Diagnosis is clinical and by laboratory findings, including low plasma ACTH with low plasma cortisol. Treatment depends on the cause
but generally includes hydrocortisone.
Seconda ry a drena l i ns uffi ci ency ma y occur i n pa nhypopi tui ta ri s m, i n i s ol a ted fa i l ure of ACTH producti on, i n pa ti ents recei vi ng corti cos teroi ds , or
a fter corti cos teroi ds a re s topped. Ina dequa te ACTH ca n a l s o res ul t from fa i l ure of the hypotha l a mus to s ti mul a te pi tui ta ry ACTH producti on, whi ch
i s s ometi mes ca l l ed terti a ry a drena l i ns uffi ci ency.
Pa nhypopi tui ta ri s m (s ee p. 762) ma y occur s econda ry to pi tui ta ry tumors ; cra ni opha ryngi oma i n younger peopl e; a nd va ri ous tumors , gra nul oma s ,
a nd, ra rel y, i nfecti on or tra uma tha t des troys pi tui ta ry ti s s ue. Pa ti ents recei vi ng corti cos teroi ds for > 4 wk ma y ha ve i ns uffi ci ent ACTH s ecreti on
duri ng meta bol i c s tres s to s ti mul a te the a drena l s to produce a dequa te qua nti ti es of corti cos teroi ds , or they ma y ha ve a trophi c a drena l s tha t a re
unres pons i ve to ACTH. Thes e probl ems ma y pers i s t for up to 1 yr a fter corti cos teroi d trea tment i s s topped.
Symptoms and Signs
Symptoms a nd s i gns a re s i mi l a r to thos e of Addi s on's di s ea s e (s ee p. 792). Di fferenti a ti ng cl i ni ca l or genera l l a bora tory fea tures i ncl ude the
a bs ence of hyperpi gmenta ti on a nd rel a ti vel y norma l el ectrol yte a nd BUN l evel s ; hypona tremi a , i f i t occurs , i s us ua l l y di l uti ona l .
Pa ti ents wi th pa nhypopi tui ta ri s m ha ve depres s ed thyroi d a nd gona da l functi on a nd hypogl ycemi a , a nd coma ma y s upervene when s ymptoma ti c
s econda ry a drena l i ns uffi ci ency occurs . Adrena l cri s i s i s es peci a l l y l i kel y i f a pa ti ent i s trea ted for a s i ngl e endocri ne gl a nd probl em, pa rti cul a rl y
wi th thyroxi ne, wi thout hydrocorti s one repl a cement.
Diagnosis
Serum corti s ol
Serum ACTH
ACTH s ti mul a ti on tes ti ng
CNS i ma gi ng
Tes ts to di fferenti a te pri ma ry a nd s econda ry a drena l i ns uffi ci ency a re di s cus s ed under Addi s on's di s ea s e (s ee p. 793). Pa ti ents wi th confi rmed
s econda ry a drena l i ns uffi ci ency s houl d ha ve CT or MRI of the bra i n to rul e out pi tui ta ry tumor or a trophy. Adequa cy of the hypotha l a mi c-pi tui ta rya drena l a xi s duri ng ta peri ng or a fter s toppi ng l ong-term corti cos teroi d trea tment ca n be determi ned by i njecti ng cos yntropi n 250 g IV or IM. After
30 mi n, s erum corti s ol s houl d be > 20 g/dL (> 552 nmol /L). An i ns ul i n s tres s tes t to i nduce hypogl ycemi a a nd a ri s e i n corti s ol i s the gol d s ta nda rd
for tes ti ng i ntegri ty of the hypotha l a mi c-pi tui ta ry-a drena l a xi s .
The corti cotropi n-rel ea s i ng hormone (CRH) tes t ca n be us ed to di s ti ngui s h between hypotha l a mi c a nd pi tui ta ry ca us es but i s ra rel y us ed i n
cl i ni ca l pra cti ce. After a dmi ni s tra ti on of CRH 100 g (or 1 g/kg) IV, the norma l res pons e i s a ri s e of s erum ACTH of 30 to 40 pg/mL; pa ti ents wi th
pi tui ta ry fa i l ure do not res pond, wherea s thos e wi th hypotha l a mi c di s ea s e us ua l l y do.
Treatment
Hydrocorti s one or predni s one
Fl udrocorti s one not i ndi ca ted
Dos e i ncrea s e duri ng i ntercurrent i l l nes s
Gl ucocorti coi d repl a cement i s s i mi l a r to tha t des cri bed for Addi s on's di s ea s e. Ea ch ca s e va ri es rega rdi ng the type a nd degree of s peci fi c hormone
defi ci enci es . Fl udrocorti s one i s not requi red beca us e the i nta ct a drena l s produce a l dos terone. Duri ng a cute febri l e i l l nes s or a fter tra uma ,
pa ti ents recei vi ng corti cos teroi ds for nonendocri ne di s orders ma y requi re s uppl ementa l dos es to a ugment thei r endogenous hydrocorti s one
producti on. In pa nhypopi tui ta ri s m, other pi tui ta ry defi ci enci es s houl d be trea ted a ppropri a tel y (s ee p. 766).
Adrenal Virilism
(Adrenogeni ta l Syndrome)
Adrenal virilism is a syndrome in which excessive adrenal androgens cause virilization. Diagnosis is clinical and confirmed by elevated androgen levels with and
without dexamethasone suppression; determining the cause may involve adrenal imaging. Treatment depends on the cause.
Adrena l vi ri l i s m i s ca us ed by a n a ndrogen-s ecreti ng a drena l tumor or by a drena l hyperpl a s i a . Ma l i gna nt a drena l tumors ma y s ecrete exces s
a ndrogens , corti s ol , or mi nera l ocorti coi ds (or a l l three), res ul ti ng i n Cus hi ng's s yndrome (s ee p. 797) wi th s uppres s i on of ACTH s ecreti on a nd
a trophy of the contra l a tera l a drena l a s wel l a s hypertens i on. Adrena l hyperpl a s i a i s us ua l l y congeni ta l ; del a yed vi ri l i zi ng a drena l hyperpl a s i a i s
a va ri a nt of congeni ta l a drena l hyperpl a s i a (s ee p. 2889). Both a re ca us ed by a defect i n hydroxyl a ti on of corti s ol precurs ors ; corti s ol precurs ors
a ccumul a te a nd a re s hunted i nto the producti on of a ndrogens . The defect i s onl y pa rti a l i n del a yed vi ri l i zi ng a drena l hyperpl a s i a , s o cl i ni ca l
di s ea s e ma y not devel op unti l a dul thood.
Symptoms and Signs
Effects depend on the pa ti ent's s ex a nd a ge a t ons et a nd a re more noti cea bl e i n women tha n i n men. Symptoms a nd s i gns i ncl ude hi rs uti s m
(s ometi mes the onl y s i gn i n mi l d ca s es ), ba l dnes s , a cne, a nd deepeni ng of the voi ce. Li bi do ma y i ncrea s e. In prepuberta l chi l dren, growth ma y
a ccel era te. If untrea ted, prema ture epi phys ea l cl os ure a nd s hort s ta ture occur. Affected prepuberta l ma l es ma y experi ence prema ture s exua l
ma tura ti on. Fema l es ma y ha ve a menorrhea , a trophy of the uterus , cl i tora l hypertrophy, decrea s ed brea s t s i ze, a nd i ncrea s ed mus cul a ri ty. In a dul t
men, the exces s a drena l a ndrogens ma y s uppres s gona da l functi on a nd ca us e i nferti l i ty. Ectopi c a drena l ti s s ue i n the tes tes ma y enl a rge a nd
s i mul a te tumors .
Diagnosis
Tes tos terone
Other a drena l a ndrogens (dehydroepi a ndros terone s ul fa te [DHEAS], a ndros tenedi one)
Dexa metha s one s uppres s i on tes t
Adrena l i ma gi ng
17-hydroxyproges terone
Adrena l vi ri l i s m i s s us pected cl i ni ca l l y, a l though mi l d hi rs uti s m a nd vi ri l i za ti on wi th hypomenorrhea a nd el eva ted pl a s ma tes tos terone ma y a l s o
occur i n pol ycys ti c ova ry (Stei n-Leventha l ) s yndrome (s ee p. 2514). Adrena l vi ri l i s m i s confi rmed by s howi ng el eva ted l evel s of a drena l a ndrogens .
In a drena l hyperpl a s i a , uri na ry dehydroepi a ndros terone (DHEA) a nd i ts s ul fa te (DHEAS) a re el eva ted, pregna netri ol excreti on i s often i ncrea s ed,
a nd uri na ry free corti s ol i s norma l or di mi ni s hed. Pl a s ma DHEA, DHEAS, 17-hydroxyproges terone, tes tos terone, a nd a ndros tenedi one ma y be
el eva ted. A l evel of > 30 nmol /L of 17-hydroxyproges terone 30 mi n a fter a dmi ni s tra ti on of cos yntropi n 0.25 mg IM s trongl y s ugges ts the mos t
common form of a drena l hyperpl a s i a .

Vi ri l i zi ng tumors a re excl uded i f dexa metha s one 0.5 mg po q 6 h for 48 h s uppres s es producti on of exces s a ndrogens . If exces s i ve a ndrogen
excreti on i s not s uppres s ed, CT or MRI of the a drena l s a nd ul tra s onogra phy of the ova ri es a re done to s ea rch for a tumor.
Treatment
Ora l corti cos teroi ds for hyperpl a s i a
Remova l of tumors
Recommended trea tment for a drena l hyperpl a s i a i s dexa metha s one 0.5 to 1 mg po a t bedti me, but even thes e s ma l l dos es ma y ca us e s i gns of
Cus hi ng's s yndrome. Corti s ol 25 mg po once/da y or predni s one 5 to 10 mg po once/da y ca n be us ed i ns tea d. Al though mos t s ymptoms a nd s i gns of
vi ri l i s m di s a ppea r, hi rs uti s m a nd ba l dnes s di s a ppea r s l owl y, the voi ce ma y rema i n deep, a nd ferti l i ty ma y be i mpa i red.
Tumors requi re a drena l ectomy. For pa ti ents wi th corti s ol -s ecreti ng tumors , hydrocorti s one s houl d be gi ven preopera ti vel y a nd pos topera ti vel y
beca us e thei r nontumerous a drena l cortex wi l l be a trophi c a nd s uppres s ed.
Cushing's Syndrome
Cushing's syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing's disease is
Cushing's syndrome that results from excess pituitary production of ACTH, usually secondary to a pituitary adenoma. Typical symptoms include moon facies and
truncal obesity with thin arms and legs. Diagnosis is by history of receiving corticosteroids or by finding elevated serum cortisol. Treatment depends on the cause.
Etiology
Hyperfuncti on of the a drena l cortex ca n be ACTH dependent or ACTH i ndependent. ACTH-dependent hyperfuncti on ma y res ul t from
Hypers ecreti on of ACTH by the pi tui ta ry gl a nd
Secreti on of ACTH by a nonpi tui ta ry tumor, s uch a s s ma l l cel l ca rci noma of the l ung or a ca rci noi d tumor (ectopi c ACTH s yndrome)
Admi ni s tra ti on of exogenous ACTH
ACTH-i ndependent hyperfuncti on us ua l l y res ul ts from thera peuti c a dmi ni s tra ti on of corti cos teroi ds or from a drena l a denoma s or ca rci noma s . Ra re
ca us es i ncl ude pri ma ry pi gmented nodul a r a drena l dys pl a s i a (us ua l l y i n a dol es cents ) a nd ma cronodul a r dys pl a s i a (i n ol der pa ti ents ).
Wherea s the term Cus hi ng's s yndrome denotes the cl i ni ca l pi cture res ul ti ng from corti s ol exces s from a ny ca us e, Cus hi ng's di s ea s e refers to
hyperfuncti on of the a drena l cortex from pi tui ta ry ACTH exces s . Pa ti ents wi th Cus hi ng's di s ea s e us ua l l y ha ve a s ma l l a denoma of the pi tui ta ry
gl a nd.
Symptoms and Signs
Cl i ni ca l ma ni fes ta ti ons i ncl ude moon fa ci es wi th a pl ethori c a ppea ra nce (s ee
Pl a te 22), trunca l obes i ty wi th promi nent s upra cl a vi cul a r a nd dors a l cervi ca l fa t pa ds (buffa l o hump), a nd, us ua l l y, very s l ender di s ta l extremi ti es
a nd fi ngers . Mus cl e wa s ti ng a nd wea knes s a re pres ent. The s ki n i s thi n a nd a trophi c, wi th poor wound hea l i ng a nd ea s y brui s i ng. Purpl e s tri a e
ma y a ppea r on the a bdomen. Hypertens i on, rena l ca l cul i , os teoporos i s , gl ucos e i ntol era nce, reduced res i s ta nce to i nfecti on, a nd menta l
di s turba nces a re common. Ces s a ti on of l i nea r growth i s cha ra cteri s ti c i n chi l dren. Fema l es us ua l l y ha ve mens trua l i rregul a ri ti es . In fema l es wi th
a drena l tumors , i ncrea s ed producti on of a ndrogens ma y l ea d to hypertri chos i s , tempora l ba l di ng, a nd other s i gns of vi ri l i s m.
Diagnosis
Dexa metha s one s uppres s i on tes t
Uri na ry free corti s ol (UFC) l evel
ACTH l evel s ; i f detecta bl e, provoca ti ve tes ti ng
Di a gnos i s i s us ua l l y s us pected ba s ed on the cha ra cteri s ti c s ymptoms a nd s i gns . Confi rma ti on (a nd i denti fi ca ti on of the ca us e) genera l l y requi res
hormona l a nd i ma gi ng tes ts .
In s ome centers , tes ti ng begi ns wi th mea s urement of UFC, the bes t a s s a y for uri na ry excreti on (norma l , 20 to 100 g/24 h [55.2 to 276 nmol /24 h]).
UFC i s el eva ted > 120 g/24 h (> 331 nmol /24 h) i n a l mos t a l l pa ti ents wi th Cus hi ng's s yndrome. However, ma ny pa ti ents wi th UFC el eva ti ons
between 100 a nd 150 g/24 h (276 a nd 414 nmol /24 h) ha ve obes i ty, depres s i on, or pol ycys ti c ova ri es but not Cus hi ng's s yndrome. A pa ti ent wi th
s us pected Cus hi ng's s yndrome wi th gros s l y el eva ted UFC (> 4 ti mes the upper l i mi t of norma l ) a l mos t certa i nl y ha s Cus hi ng's s yndrome. Two to 3
norma l col l ecti ons vi rtua l l y excl ude the di a gnos i s . Sl i ghtl y el eva ted l evel s genera l l y neces s i ta te further i nves ti ga ti on.
An a l terna ti ve a pproa ch to i nves ti ga ti on us es the dexa metha s one s uppres s i on tes t, i n whi ch 1, 1.5, or 2 mg of dexa metha s one i s gi ven po a t 11 to
12 PM a nd s erum corti s ol i s mea s ured a t 8 to 9 AM the next morni ng. In mos t norma l pa ti ents , thi s drug s uppres s es morni ng s erum corti s ol to 1.8
g/mL ( 50 nmol /L), wherea s pa ti ents wi th Cus hi ng's s yndrome vi rtua l l y a l wa ys ha ve a hi gher l evel . A more s peci fi c but equa l l y s ens i ti ve tes t i s to
gi ve dexa metha s one 0.5 mg po q 6 h for 2 da ys (l ow dos e). In genera l , a cl ea r fa i l ure to s uppres s l evel s i n res pons e to l ow-dos e dexa metha s one
es ta bl i s hes the di a gnos i s .
If res ul ts of thes e tes ts a re i ndetermi na te, the pa ti ent i s hos pi ta l i zed for mea s urement of s erum corti s ol a t mi dni ght, whi ch i s more l i kel y to be
concl us i ve. Corti s ol norma l l y ra nges from 5 to 25 g/dL (138 to 690 nmol /L) i n the ea rl y morni ng (6 to 8 AM) a nd decl i nes gra dua l l y to < 1.8 g/dL (<
50 nmol /L) a t mi dni ght. Pa ti ents wi th Cus hi ng's s yndrome occa s i ona l l y ha ve a norma l morni ng corti s ol l evel but l a ck norma l di urna l decl i ne i n
corti s ol producti on, s uch tha t the mi dni ght s erum corti s ol l evel s a re a bove norma l a nd the tota l 24-h corti s ol producti on i s el eva ted. Al terna ti vel y,
s a l i va ry corti s ol s a mpl es ma y be col l ected a nd s tored i n the refri gera tor a t home. Serum corti s ol ma y be s puri ous l y el eva ted i n pa ti ents wi th
congeni ta l i ncrea s es of corti cos teroi d-bi ndi ng gl obul i n or i n thos e recei vi ng es trogen thera py, but di urna l va ri a ti on i s norma l i n thes e pa ti ents .
ACTH l evel s a re mea s ured to determi ne the ca us e of Cus hi ng's s yndrome. Undetecta bl e l evel s , both ba s a l l y a nd pa rti cul a rl y i n res pons e to
corti cotropi n-rel ea s i ng hormone (CRH), s ugges t a pri ma ry a drena l ca us e. Hi gh l evel s s ugges t a pi tui ta ry ca us e. If ACTH i s detecta bl e (ACTHdependent Cus hi ng's s yndrome), provoca ti ve tes ts hel p di fferenti a te Cus hi ng's di s ea s e from ectopi c ACTH s yndrome, whi ch i s ra rer. In res pons e to
hi gh-dos e dexa metha s one (2 mg po q 6 h for 48 h), the 9 AM s erum corti s ol fa l l s by > 50% i n mos t pa ti ents wi th Cus hi ng's di s ea s e but i nfrequentl y
i n thos e wi th ectopi c ACTH s yndrome. Convers el y, ACTH ri s es by > 50% a nd corti s ol ri s es by > 20% i n res pons e to huma n or ovi ne-s equence CRH (100
g IV or 1 g/kg IV) i n mos t pa ti ents wi th Cus hi ng's di s ea s e but very ra rel y i n thos e wi th ectopi c ACTH s yndrome (s ee
Ta bl e 94-2). An a l terna ti ve a pproa ch to l oca l i za ti on, whi ch i s more a ccura te but more i nva s i ve, i s to ca theteri ze both petros a l vei ns (whi ch dra i n
the pi tui ta ry) a nd mea s ure ACTH from thes e vei ns 5 mi n a fter a bol us of CRH 100 g or 1 g/kg. A centra l -to-peri phera l ACTH ra ti o > 3 vi rtua l l y
excl udes ectopi c ACTH s yndrome, wherea s a ra ti o < 3 s ugges ts a need to s eek s uch a s ource.
Pi tui ta ry i ma gi ng i s done i f ACTH l evel s a nd provoca ti ve tes ts s ugges t a pi tui ta ry ca us e; ga dol i ni um-enha nced MRI i s mos t a ccura te, but s ome
mi croa denoma s a re vi s i bl e on CT. If tes ti ng s ugges ts a nonpi tui ta ry ca us e, i ma gi ng i ncl udes hi gh-res ol uti on CT of the ches t, pa ncrea s , a nd
a drena l s ; s ci nti s ca nni ng wi th ra di ol a bel ed octreoti de; a nd PET s ca nni ng.
In chi l dren wi th Cus hi ng's di s ea s e, pi tui ta ry tumors a re very s ma l l a nd us ua l l y ca nnot be detected wi th MRI. Petros a l s i nus s a mpl i ng i s
pa rti cul a rl y us eful i n thi s s i tua ti on. MRI i s preferred to CT i n pregna nt women to a voi d feta l expos ure to ra di a ti on.
Treatment
Metyra pone or ketocona zol e
Surgery or ra di a ti on to remove tumors
[Table 94-2. Di a gnos ti c Tes ts i n Cus hi ng's Syndrome]
Ini ti a l l y, the pa ti ent's genera l condi ti on s houl d be s upported by hi gh protei n i nta ke a nd a ppropri a te a dmi ni s tra ti on of K. If cl i ni ca l
ma ni fes ta ti ons a re s evere, i t ma y be rea s ona bl e to bl ock corti cos teroi d s ecreti on wi th metyra pone 250 mg to 1 g po ti d or ketocona zol e 400 mg po
once/da y, i ncrea s i ng to a ma xi mum of 400 mg ti d. Ketocona zol e i s more rea di l y a va i l a bl e but s l ower i n ons et a nd s ometi mes hepa totoxi c.
Pi tui ta ry tumors tha t produce exces s i ve ACTH a re removed s urgi ca l l y or exti rpa ted wi th ra di a ti on. If no tumor i s s hown on i ma gi ng but a pi tui ta ry
s ource i s l i kel y, tota l hypophys ectomy ma y be a ttempted, pa rti cul a rl y i n ol der pa ti ents . Younger pa ti ents us ua l l y recei ve s upervol ta ge i rra di a ti on
of the pi tui ta ry, del i veri ng 45 Gy. Improvement us ua l l y occurs i n < 1 yr. However, i n chi l dren, i rra di a ti on ma y reduce s ecreti on of growth hormone
a nd occa s i ona l l y ca us e precoci ous puberty. In s peci a l centers , hea vy pa rti cl e bea m i rra di a ti on, provi di ng a bout 100 Gy, i s often s ucces s ful , a s i s a
s i ngl e focus ed bea m of ra di a ti on thera py gi ven a s a s i ngl e dos era di os urgery. Res pons e to i rra di a ti on occa s i ona l l y requi res s evera l yea rs , but
res pons e i s more ra pi d i n chi l dren.
Bi l a tera l a drena l ectomy i s res erved for pa ti ents wi th pi tui ta ry hypera drenocorti ci s m who do not res pond to both pi tui ta ry expl ora ti on (wi th
pos s i bl e a denomectomy) a nd i rra di a ti on. Adrena l ectomy requi res l i fe-l ong corti cos teroi d repl a cement.
Nel s on s yndrome occurs when the pi tui ta ry gl a nd conti nues to expa nd a fter a drena l ectomy, ca us i ng a ma rked i ncrea s e i n the s ecreti on of ACTH
a nd i ts precurs ors , res ul ti ng i n s evere hyperpi gmenta ti on. It occurs i n 50% of pa ti ents who undergo a drena l ectomy. The ri s k i s proba bl y reduced
i f the pa ti ent undergoes pi tui ta ry ra di a ti on. Al though i rra di a ti on ma y a rres t conti nued pi tui ta ry growth, ma ny pa ti ents a l s o requi re
hypophys ectomy. The i ndi ca ti ons for hypophys ectomy a re the s a me a s for a ny pi tui ta ry tumor: a n i ncrea s e i n s i ze s uch tha t the tumor encroa ches
on s urroundi ng s tructures , ca us i ng vi s ua l fi el d defects , pres s ure on the hypotha l a mus , or other compl i ca ti ons . Routi ne i rra di a ti on i s often done
a fter hypophys ectomy i f i t wa s not done previ ous l y, es peci a l l y when a tumor i s cl ea rl y pres ent. Ra di os urgery, or focus ed ra di a ti on thera py, ca n be
gi ven i n a s i ngl e fra cti on when s ta nda rd externa l bea m ra di a ti on thera py ha s a l rea dy been done, a s l ong a s the l es i on i s a t a rea s ona bl e
di s ta nce from the opti c nerve a nd chi a s m.
Adrenocorti ca l tumors a re removed s urgi ca l l y. Pa ti ents mus t recei ve corti s ol duri ng the s urgi ca l a nd pos topera ti ve peri ods beca us e thei r
nontumorous a drena l cortex wi l l be a trophi c a nd s uppres s ed. Beni gn a denoma s ca n be removed l a pa ros copi ca l l y. Wi th mul ti nodul a r a drena l
hyperpl a s i a , bi l a tera l a drena l ectomy ma y be neces s a ry. Even a fter a pres umed tota l a drena l ectomy, functi ona l regrowth occurs i n a few pa ti ents .
Ectopi c ACTH s yndrome i s trea ted by removi ng the nonpi tui ta ry tumor tha t i s produci ng the ACTH. However, i n s ome ca s es , the tumor i s
di s s emi na ted a nd ca nnot be exci s ed. Adrena l i nhi bi tors , s uch a s metyra pone 500 mg po ti d (a nd up to a tota l of 6 g/da y) or mi tota ne 0.5 g po
once/da y, i ncrea s i ng to a ma xi mum of 3 to 4 g/da y, us ua l l y control s evere meta bol i c di s turba nces (eg, hypoka l emi a ). When mi tota ne i s us ed, l a rge
dos es of hydrocorti s one or dexa metha s one ma y be needed. Mea s ures of corti s ol producti on ma y be unrel i a bl e, a nd s evere hyperchol es terol emi a
ma y devel op. Ketocona zol e 400 to 1200 mg po once/da y a l s o bl ocks corti cos teroi d s ynthes i s , a l though i t ma y ca us e l i ver toxi ci ty a nd ca n ca us e
a ddi s oni a n s ymptoms . Al terna ti vel y, the corti cos teroi d receptors ca n be bl ocked wi th mi fepri s tone (RU 486). Mi fepri s tone i ncrea s es s erum corti s ol
but bl ocks effects of the corti cos teroi d. Someti mes ACTH-s ecreti ng tumors res pond to l ong-a cti ng s oma tos ta ti n a na l ogs , a l though a dmi ni s tra ti on
for > 2 yr requi res cl os e fol l ow-up, beca us e mi l d ga s tri ti s , ga l l s tones , chol a ngi ti s , a nd ma l a bs orpti on ma y devel op.
Primary Aldosteronism
(Conn's Syndrome)
Primary aldosteronism is aldosteronism caused by autonomous production of aldosterone by the adrenal cortex (due to hyperplasia, adenoma, or carcinoma).
Symptoms and signs include episodic weakness, elevated BP, and hypokalemia. Diagnosis includes measurement of plasma aldosterone levels and plasma renin
activity. Treatment depends on cause. A tumor is removed if possible; in hyperplasia, spironolactone or related drugs may normalize BP and eliminate other
clinical features.
Al dos terone i s the mos t potent mi nera l ocorti coi d produced by the a drena l s . It ca us es Na retenti on a nd K l os s . In the ki dney, a l dos terone ca us es
tra ns fer of Na from the l umen of the di s ta l tubul e i nto the tubul a r cel l s i n excha nge for K a nd hydrogen. The s a me effect occurs i n s a l i va ry gl a nds ,
s wea t gl a nds , cel l s of the i ntes ti na l mucos a , a nd i n excha nges between ICFs a nd ECFs .
Al dos terone s ecreti on i s regul a ted by the reni n-a ngi otens i n s ys tem a nd, to a l es s er extent, by ACTH. Reni n, a proteol yti c enzyme, i s s tored i n the
juxta gl omerul a r cel l s of the ki dneys . Reducti on i n bl ood vol ume a nd fl ow i n the a fferent rena l a rteri ol es i nduces s ecreti on of reni n. Reni n
tra ns forms a ngi otens i nogen from the l i ver to a ngi otens i n I, whi ch i s tra ns formed by ACE to a ngi otens i n II. Angi otens i n II ca us es s ecreti on of
a l dos terone a nd, to a much l es s er extent, s ecreti on of corti s ol a nd deoxycorti cos terone; i t a l s o ha s pres s or a cti vi ty. Na a nd wa ter retenti on
res ul ti ng from i ncrea s ed a l dos terone s ecreti on i ncrea s es the bl ood vol ume a nd reduces reni n s ecreti on.
Pri ma ry a l dos teroni s m i s ca us ed by a n a denoma , us ua l l y uni l a tera l , of the gl omerul os a cel l s of the a drena l cortex or, more ra rel y, by a drena l
ca rci noma or hyperpl a s i a . Adenoma s a re extremel y ra re i n chi l dren, but the s yndrome s ometi mes occurs i n chi l dhood a drena l ca rci noma or
hyperpl a s i a . In a drena l hyperpl a s i a , whi ch i s more common a mong ol der men, both a drena l s a re overa cti ve, a nd no a denoma i s pres ent. The
cl i ni ca l pi cture ca n a l s o occur wi th congeni ta l a drena l hyperpl a s i a from defi ci ency of 11 -hydroxyl a s e a nd the domi na ntl y i nheri ted
dexa metha s one-s uppres s i bl e hypera l dos teroni s m. Hyperpl a s i a a s a ca us e of hypera l dos teroni s m ma y be more common tha n previ ous l y
recogni zed but rema i ns a n i nfrequent ca us e i n the pres ence of hypoka l emi a .
Symptoms and Signs
Hyperna tremi a , hypervol emi a , a nd a hypoka l emi c a l ka l os i s ma y occur, ca us i ng epi s odi c wea knes s , pa res thes i a s , tra ns i ent pa ra l ys i s , a nd teta ny.
Di a s tol i c hypertens i on a nd hypoka l emi c nephropa thy wi th pol yuri a a nd pol ydi ps i a a re common. In ma ny ca s es , the onl y ma ni fes ta ti on i s mi l d to
modera te hypertens i on. Edema i s uncommon.
Diagnosis
El ectrol ytes
Pl a s ma a l dos terone
Pl a s ma reni n a cti vi ty (PRA)
Adrena l i ma gi ng
Bi l a tera l a drena l vei n ca theteri za ti on (for corti s ol a nd a l dos terone l evel s )
Di a gnos i s i s s us pected i n pa ti ents wi th hypertens i on a nd hypoka l emi a . Ini ti a l l a bora tory tes ti ng cons i s ts of pl a s ma a l dos terone l evel s a nd PRA.
Idea l l y, tes ts a re done a fter the pa ti ent ha s not ta ken a ny drugs tha t a ffect the reni n-a ngi otens i n s ys tem (eg, thi a zi de di ureti cs , ACE i nhi bi tors ,
a ngi otens i n a nta goni s ts , -bl ockers ) for 4 to 6 wk. PRA i s us ua l l y mea s ured i n the morni ng wi th the pa ti ent recumbent. Pa ti ents wi th pri ma ry
a l dos teroni s m typi ca l l y ha ve pl a s ma a l dos terone > 15 ng/dL (> 0.42 nmol /L) a nd l ow l evel s of PRA, wi th a ra ti o of pl a s ma a l dos terone (i n ng/dL) to
PRA (i n ng/mL/h) > 20.
Low l evel s of both PRA a nd a l dos terone s ugges t nona l dos terone mi nera l ocorti coi d exces s (eg, due to l i cori ce i nges ti on, Cus hi ng's s yndrome, or
Li ddl e s yndrome). Hi gh l evel s of both PRA a nd a l dos terone s ugges t s econda ry hypera l dos teroni s m (s ee p. 801). The pri nci pa l di fferences between
pri ma ry a nd s econda ry a l dos teroni s m a re s hown i n
Ta bl e 94-3. In chi l dren, Ba rtter s yndrome
[Table 94-3. Di fferenti a l Di a gnos i s of Al dos teroni s m]
(s ee p. 2988) i s di s ti ngui s hed from pri ma ry hypera l dos teroni s m by the a bs ence of hypertens i on a nd ma rked el eva ti on of reni n.
Pa ti ents wi th fi ndi ngs s ugges ti ng pri ma ry hypera l dos teroni s m s houl d undergo CT or MRI to determi ne whether the ca us e i s a tumor or
hyperpl a s i a . Al dos terone l evel s mea s ured on a wa keni ng a nd 2 to 4 h l a ter whi l e s ta ndi ng a l s o ma y hel p ma ke thi s di s ti ncti on; i n a denoma ,
l evel s decl i ne a nd i n hyperpl a s i a , l evel s i ncrea s e. In mos t ca s es , bi l a tera l ca theteri za ti on of the a drena l vei ns to mea s ure corti s ol a nd
a l dos terone s houl d be us ed to confi rm whether the a l dos terone exces s i s uni l a tera l (tumor) or bi l a tera l (hyperpl a s i a ).
Treatment
Surgi ca l remova l of tumors
Spi ronol a ctone or epl erenone for hyperpl a s i a
Tumors s houl d be removed l a pa ros copi ca l l y. After remova l of a n a denoma , BP decrea s es i n a l l pa ti ents ; compl ete remi s s i on occurs i n 50 to 70%.
Wi th a drena l hyperpl a s i a , 70% rema i n hypertens i ve a fter bi l a tera l a drena l ectomy; thus , s urgery i s not recommended. Hypera l dos teroni s m i n
thes e pa ti ents ca n us ua l l y be control l ed by s pi ronol a ctone, s ta rti ng wi th 300 mg po once/da y a nd decrea s i ng over 1 mo to a ma i ntena nce dos e,
us ua l l y a round 100 mg once/da y; or by a mi l ori de 5 to 10 mg po once/da y or a nother K-s pa ri ng di ureti c. The newer more s peci fi c drug epl erenone
ma y be us ed beca us e, unl i ke s pi ronol a ctone, i t does not bl ock the a ndrogen receptor. About ha l f of pa ti ents wi th hyperpl a s i a need a ddi ti ona l
a nti hypertens i ve trea tment (s ee p. 2069).
Secondary Aldosteronism
Secondary aldosteronism is increased adrenal production of aldosterone in response to nonpituitary, extra-adrenal stimuli, including renal artery stenosis and
hypovolemia. Symptoms are those of primary aldosteronism. Treatment involves correcting the cause.
Seconda ry a l dos teroni s m i s ca us ed by reduced rena l bl ood fl ow, whi ch s ti mul a tes the reni n-a ngi otens i n mecha ni s m wi th res ul ta nt
hypers ecreti on of a l dos terone. Ca us es of reduced rena l bl ood fl ow i ncl ude obs tructi ve rena l a rtery di s ea s e (eg, a theroma , s tenos i s ), rena l
va s ocons tri cti on (a s occurs i n a ccel era ted hypertens i on), a nd edema tous di s orders (eg, hea rt fa i l ure, ci rrhos i s wi th a s ci tes , nephroti c s yndrome).
Secreti on ma y be norma l i n hea rt fa i l ure, but hepa ti c bl ood fl ow a nd a l dos terone meta bol i s m a re reduced, s o ci rcul a ti ng l evel s of the hormone
a re hi gh.
Pheochromocytoma
A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension.
Diagnosis is by measuring catecholamine products in blood or urine. Imaging tests, especially CT or MRI, help localize tumors. Treatment involves removal of the
tumor when possible. Drug therapy for control of BP includes -blockade, usually combined with -blockade.
The ca techol a mi nes s ecreted i ncl ude norepi nephri ne, epi nephri ne, dopa mi ne, a nd dopa i n va ryi ng proporti ons . About 90% of pheochromocytoma s
a re i n the a drena l medul l a , but they ma y a l s o be l oca ted i n other ti s s ues deri ved from neura l cres t cel l s . Pos s i bl e s i tes i ncl ude the fol l owi ng:
Pa ra ga ngl i a of the s ympa theti c cha i n
Retroperi tonea l l y a l ong the cours e of the a orta
Ca roti d body
Orga n of Zuckerka ndl (a t the a orti c bi furca ti on)
GU s ys tem
Bra i n
Peri ca rdi a l s a c
Dermoi d cys ts
Pheochromocytoma s i n the a drena l medul l a occur equa l l y i n both s exes , a re bi l a tera l i n 10% of ca s es (20% i n chi l dren), a nd a re ma l i gna nt i n <
10%. Of extra -a drena l tumors , 30% a re ma l i gna nt. Al though pheochromocytoma s occur a t a ny a ge, pea k i nci dence i s between the 20s a nd 40s .
About 25% a re now thought to be due to germl i ne muta ti ons .
Pheochromocytoma s va ry i n s i ze but a vera ge 5 to 6 cm i n di a meter. They wei gh 50 to 200 g, but tumors wei ghi ng s evera l ki l ogra ms ha ve been
reported. Ra rel y, they a re l a rge enough to be pa l pa ted or ca us e s ymptoms due to pres s ure or obs tructi on. Rega rdl es s of the hi s tol ogi c
a ppea ra nce, the tumor i s cons i dered beni gn i f i t ha s not i nva ded the ca ps ul e a nd no meta s ta s es a re found, a l though excepti ons occur.
Pheochromocytoma s ma y be pa rt of the s yndrome of fa mi l i a l mul ti pl e endocri ne neopl a s i a (MEN), types 2A a nd 2B, i n whi ch other endocri ne
tumors (pa ra thyroi d or medul l a ry ca rci noma of the thyroi d) coexi s t or devel op s ubs equentl y (s ee p. 909). Pheochromocytoma devel ops i n 1% of
pa ti ents wi th neurofi broma tos i s (von Reckl i ngha us en's di s ea s e) a nd ma y occur wi th hema ngi oma s a nd rena l cel l ca rci noma , a s i n von Hi ppel Li nda u di s ea s e. Fa mi l i a l pheochromocytoma s a nd ca roti d body tumors ma y be due to muta ti ons of the enzyme s ucci na te dehydrogena s e.
Symptoms and Signs
Hypertens i on, whi ch i s pa roxys ma l i n 45% of pa ti ents , i s promi nent. About 1/1000 hypertens i ve pa ti ents ha s a pheochromocytoma . Common
s ymptoms a nd s i gns a re ta chyca rdi a , di a phores i s , pos tura l hypotens i on, ta chypnea , col d a nd cl a mmy s ki n, s evere hea da che, a ngi na , pa l pi ta ti ons ,
na us ea , vomi ti ng, epi ga s tri c pa i n, vi s ua l di s turba nces , dys pnea , pa res thes i a s , cons ti pa ti on, a nd a s ens e of i mpendi ng doom. Pa roxys ma l a tta cks
ma y be provoked by pa l pa ti on of the tumor, pos tura l cha nges , a bdomi na l compres s i on or ma s s a ge, i nducti on of a nes thes i a , emoti ona l tra uma ,
unoppos ed -bl ocka de (whi ch pa ra doxi ca l l y i ncrea s es BP by bl ocki ng -medi a ted va s odi l a ti on), or mi cturi ti on (i f the tumor i s i n the bl a dder). In
el derl y pa ti ents , s evere wei ght l os s wi th pers i s tent hypertens i on i s s ugges ti ve of pheochromocytoma .
Phys i ca l exa mi na ti on, except for the pres ence of hypertens i on, i s us ua l l y norma l unl es s done duri ng a pa roxys ma l a tta ck. Reti nopa thy a nd
ca rdi omega l y a re often l es s s evere tha n mi ght be expected for the degree of hypertens i on, but a s peci fi c ca techol a mi ne ca rdi omyopa thy ca n occur.
Diagnosis
Pl a s ma free meta nephri nes or uri na ry meta nephri nes
Ches t a nd a bdomen i ma gi ng (CT or MRI) i f ca techol a mi ne s creen pos i ti ve
Pos s i bl y nucl ea r i ma gi ng wi th
123
I-meta -i odobenzyl gua ni di ne (MIBG)
Pheochromocytoma i s s us pected i n pa ti ents wi th typi ca l s ymptoms or pa rti cul a rl y s udden, s evere, or i ntermi ttent unexpl a i ned hypertens i on.
Di a gnos i s i nvol ves demons tra ti ng hi gh l evel s of ca techol a mi ne products i n the s erum or uri ne.
Blood tests: Pl a s ma free meta nephri ne i s up to 99% s ens i ti ve. Thi s tes t ha s s uperi or s ens i ti vi ty to mea s urement of ci rcul a ti ng epi nephri ne a nd
norepi nephri ne beca us e pl a s ma meta nephri nes a re el eva ted conti nuous l y, unl i ke epi nephri ne a nd norepi nephri ne, whi ch a re s ecreted
i ntermi ttentl y; however, gros s l y el eva ted pl a s ma norepi nephri ne renders the di a gnos i s hi ghl y proba bl e.
Urine tests: Uri na ry meta nephri ne i s l es s s peci fi c tha n pl a s ma free meta nephri ne, but s ens i ti vi ty i s a bout 95%. Two or 3 norma l res ul ts whi l e the
pa ti ent i s hypertens i ve render the di a gnos i s extremel y unl i kel y. Mea s urement of uri na ry norepi nephri ne a nd epi nephri ne i s nea rl y a s a ccura te.
The pri nci pa l uri na ry meta bol i c products of epi nephri ne a nd norepi nephri ne a re the meta nephri nes va ni l l yl ma ndel i c a ci d (VMA) a nd
homova ni l l i c a ci d (HVA). Hea l thy peopl e excrete onl y very s ma l l a mounts of thes e s ubs ta nces . Norma l va l ues for 24 h a re a s fol l ows : free
epi nephri ne a nd norepi nephri ne < 100 g (< 582 nmol ), tota l meta nephri ne < 1.3 mg (< 7.1 mol ), VMA < 10 mg (< 50 mol ), HVA < 15 mg (< 82.4
mol ). In pheochromocytoma , i ncrea s ed uri na ry excreti on of epi nephri ne a nd norepi nephri ne a nd thei r meta bol i c products i s i ntermi ttent.
El eva ted excreti on of thes e compounds ma y a l s o occur i n other di s orders (eg, neurobl a s toma , coma , dehydra ti on, s l eep a pnea ) or extreme s tres s ;
i n pa ti ents bei ng trea ted wi th ra uwol fi a a l ka l oi ds , methyl dopa , or ca techol a mi nes ; or a fter i nges ti on of foods conta i ni ng l a rge qua nti ti es of
va ni l l a (es peci a l l y i f rena l i ns uffi ci ency i s pres ent).
Other tests: Bl ood vol ume i s cons tri cted a nd ma y fa l s el y el eva te Hb a nd Hct l evel s . Hypergl ycemi a , gl ycos uri a , or overt di a betes mel l i tus ma y be
pres ent, wi th el eva ted fa s ti ng l evel s of pl a s ma free fa tty a ci d a nd gl ycerol . Pl a s ma i ns ul i n l evel i s i na ppropri a tel y l ow for the pl a s ma gl ucos e.
After remova l of the pheochromocytoma , hypogl ycemi a ma y occur, es peci a l l y i n pa ti ents trea ted wi th ora l a nti hypergl ycemi cs .
Provocative tests wi th hi s ta mi ne or tyra mi ne are hazardous and should not be used. Gl uca gon 0.5 to 1 mg i njected ra pi dl y IV provokes a ri s e i n BP of >
35/25 mm Hg wi thi n 2 mi n i n normotens i ve pa ti ents wi th pheochromocytoma but i s now genera l l y unneces s a ry. Phentolamine mesylate must be
available to terminate any hypertensive crisis.
Screening tests a re preferred to provoca ti ve tes ts . The genera l a pproa ch i s to mea s ure pl a s ma meta nephri nes , 24-h uri na ry ca techol a mi nes , or thei r
meta bol i tes a s a s creeni ng tes t a nd to a voi d provoca ti ve tes ts . In pa ti ents wi th el eva ted pl a s ma ca techol a mi nes , a s uppres s i on tes t us i ng ora l
cl oni di ne or IV pentol i ni um ca n be us ed but i s ra rel y neces s a ry.
Imaging tests to localize tumors a re us ua l l y done i n pa ti ents wi th a bnorma l s creeni ng res ul ts . Tes ts s houl d i ncl ude CT a nd MRI of the ches t a nd
a bdomen wi th a nd wi thout contra s t. Wi th i s otoni c contra s t medi a , no a drenoceptor bl ocka de i s neces s a ry. PET ha s a l s o been us ed s ucces s ful l y.
Repea ted s a mpl i ng of pl a s ma ca techol a mi ne concentra ti ons duri ng ca theteri za ti on of the vena ca va wi th s a mpl i ng a t di fferent l oca ti ons ,
i ncl udi ng the a drena l vei ns , ca n hel p l oca l i ze the tumor: there wi l l be a s tep up i n norepi nephri ne l evel i n a vei n dra i ni ng the tumor. Adrena l vei n
norepi nephri ne:epi nephri ne ra ti os ma y hel p i n the hunt for a s ma l l a drena l s ource. Ra di opha rma ceuti ca l s wi th nucl ea r i ma gi ng techni ques ca n
a l s o hel p l oca l i ze pheochromocytoma s . 123 I-MIBG i s the mos t us ed compound outs i de the US; 0.5 mCi i s i njected IV, a nd the pa ti ent i s s ca nned on
da ys 1, 2, a nd 3. Norma l a drena l ti s s ue ra rel y pi cks up thi s i s otope, but 85% of pheochromocytoma s do. The i ma gi ng i s us ua l l y pos i ti ve onl y when
the l es i on i s l a rge enough to be obvi ous on CT or MRI, but i t ca n hel p confi rm tha t a ma s s i s l i kel y to be the s ource of the ca techol a mi nes . 131 IMIBG i s a l es s s ens i ti ve a l terna ti ve.
Signs of an associated genetic disorder (eg, ca fe-a u-l a i t pa tches i n neurofi broma tos i s ) s houl d be s ought. Pa ti ents s houl d be s creened for MEN wi th a
s erum Ca (a nd pos s i bl y ca l ci toni n) a nd a ny other tes ts a s di rected by cl i ni ca l fi ndi ngs .
Treatment
Hypertens i on control wi th combi na ti on of -bl ockers a nd -bl ockers
Surgi ca l remova l of tumor
Surgi ca l remova l i s the trea tment of choi ce. The opera ti on i s us ua l l y del a yed unti l hypertens i on i s control l ed by a combi na ti on of -bl ockers a nd
-bl ockers (us ua l l y phenoxybenza mi ne 20 to 40 mg po ti d a nd propra nol ol 20 to 40 mg po ti d). -Bl ockers s houl d not be us ed unti l a dequa te bl ocka de ha s been a chi eved. Some -bl ockers , s uch a s doxa zos i n, ma y be equa l l y effecti ve but better tol era ted.
The mos t effecti ve a nd s a fes t preopera ti ve -bl ocka de i s phenoxybenza mi ne 0.5 mg/kg IV i n 0.9% s a l i ne over 2 h on ea ch of the 3 da ys before the
opera ti on. Na ni troprus s i de ca n be i nfus ed for hypertens i ve cri s es preopera ti vel y or i ntra opera ti vel y. When bi l a tera l tumors a re documented or
s us pected (a s i n a pa ti ent wi th MEN), s uffi ci ent hydrocorti s one (100 mg IV bi d) gi ven before a nd duri ng s urgery a voi ds a cute gl ucocorti coi d
i ns uffi ci ency due to bi l a tera l a drena l ectomy.
Mos t pheochromocytoma s ca n be removed l a pa ros copi ca l l y. BP mus t be conti nuous l y moni tored vi a a n i ntra -a rteri a l ca theter, a nd vol ume s ta tus
i s cl os el y moni tored. Anes thes i a s houl d be i nduced wi th a nona rrhythmogeni c drug (eg, a thi oba rbi tura te) a nd conti nued wi th enfl ura ne. Duri ng
s urgery, pa roxys ms of hypertens i on s houl d be control l ed wi th i njecti ons of phentol a mi ne 1 to 5 mg IV or ni troprus s i de i nfus i on (2 to 4 g/kg/mi n),
a nd ta chya rrhythmi a s s houl d be control l ed wi th propra nol ol 0.5 to 2 mg IV. If a mus cl e rel a xa nt i s needed, drugs tha t do not rel ea s e hi s ta mi ne a re
preferred. Atropine should not be used preoperatively. Preopera ti ve bl ood tra ns fus i on (1 to 2 uni ts ) ma y be gi ven before the tumor i s removed i n
a nti ci pa ti on of bl ood l os s . If BP ha s been wel l control l ed before s urgery, a di et hi gh i n s a l t i s recommended to i ncrea s e bl ood vol ume. An
i nfus i on of norepi nephri ne 4 to 12 mg/L i n a dextros e-conta i ni ng s ol uti on s houl d be s ta rted i f hypotens i on devel ops . Some pa ti ents whos e
hypotens i on res ponds poorl y to l eva rterenol ma y benefi t from hydrocorti s one 100 mg IV, but a dequa te fl ui d repl a cement i s us ua l l y a l l tha t i s
requi red.
Malignant metastatic pheochromocytoma s houl d be trea ted wi th - a nd -bl ockers . The tumor ma y be i ndol ent a nd s urvi va l l ong-l a s ti ng. However,
even wi th ra pi d tumor growth, BP ca n be control l ed. 131 I-MIBG prol ongs l i fe when us ed to trea t res i dua l di s ea s e. Ra di a ti on thera py ma y reduce
bone pa i n; chemothera py i s ra rel y effecti ve but ca n be a ttempted i f a l l el s e fa i l s .
Nonfunctional Adrenal Masses
Nonfunctional adrenal masses are spaceoccupying lesions of the adrenal glands that have no hormonal activity. Symptoms, signs, and treatment depend on the
nature and size of the mass.
The mos t common nonfuncti oni ng a drena l ma s s i n a dul ts i s a n a denoma (50%), fol l owed by ca rci noma s a nd meta s ta ti c tumors . Cys ts a nd l i poma s
ma ke up mos t of the rema i nder. However, the preci s e proporti ons depend on the cl i ni ca l pres enta ti on. Ma s s es di s covered on i nci denta l
s creeni ng a re us ua l l y a denoma s . Les s commonl y, i n neona tes , s ponta neous a drena l hemorrha ge ma y ca us e l a rge a drena l ma s s es , s i mul a ti ng
neurobl a s toma or Wi l ms ' tumor. In a dul ts , bi l a tera l ma s s i ve a drena l hemorrha ge ma y res ul t from thromboembol i c di s ea s e or coa gul opa thy.
Beni gn cys ts a re obs erved i n el derl y pa ti ents a nd ma y be due to cys ti c degenera ti on, va s cul a r a cci dents , l ymphoma s , ba cteri a l i nfecti ons , funga l
i nfecti ons (eg, hi s topl a s mos i s ), or pa ra s i ti c i nfes ta ti ons (eg, due to Echinococcus). Hema togenous s prea d of TB orga ni s ms ma y ca us e a drena l
ma s s es . A nonfuncti ona l a drena l ca rci noma produces a di ffus e a nd i nfi l tra ti ng retroperi tonea l proces s . Hemorrha ge ca n occur, ca us i ng a drena l
hema toma s .
Symptoms and Signs
Mos t pa ti ents a re a s ymptoma ti c. Wi th a ny a drena l ma s s , a drena l i ns uffi ci ency i s ra re unl es s both gl a nds a re i nvol ved.
The ma jor s i gns of bi l a tera l ma s s i ve a drena l hemorrha ge a re a bdomi na l pa i n, fa l l i ng Hct, s i gns of a cute a drena l fa i l ure, a nd s upra rena l ma s s es
on CT or MRI. TB of the a drena l s ma y ca us e ca l ci fi ca ti on a nd Addi s on's di s ea s e. Nonfuncti ona l a drena l ca rci noma us ua l l y ma ni fes ts a s meta s ta ti c
di s ea s e a nd ma y therefore not be a mena bl e to s urgery, though mi tota ne ma y a fford chemothera peuti c control when us ed wi th s upporti ve
exogenous corti cos teroi ds .
Diagnosis
Adrena l hormone mea s urements
Fi ne-needl e bi ops y
Nonfuncti ona l a drena l ma s s es a re us ua l l y found i nci denta l l y duri ng tes ts s uch a s CT or MRI conducted for other rea s ons . Nonfuncti ona l i ty i s
es ta bl i s hed cl i ni ca l l y a nd confi rmed by a drena l hormona l mea s urements (s ee p. 797). If meta s ta ti c di s ea s e i s pos s i bl e, fi ne-needl e bi ops y ca n
be di a gnos ti c but i s contra i ndi ca ted i f a drena l ca rci noma i s s trongl y s us pected.
Treatment
Exci s i on
Peri odi c moni tori ng
If the tumor i s s ol i d, of a drena l ori gi n, a nd > 4 cm, i t s houl d be exci s ed, beca us e bi ops y ca nnot a l wa ys di s ti ngui s h beni gn from ma l i gna nt tumors .
Tumors 2 to 4 cm i n di a meter a re a pa rti cul a rl y di ffi cul t cl i ni ca l probl em. If s ca nni ng does not s ugges t ca ncer a nd hormona l functi on does not
s eem a l tered (eg, norma l el ectrol ytes a nd ca techol a mi nes , no evi dence of Cus hi ng's s yndrome), i t i s rea s ona bl e to reeva l ua te peri odi ca l l y,
us ua l l y for up to 4 yr. If no progres s i on i s s een by then, further fol l ow-up i s unneces s a ry. However, ma ny of thes e tumors s ecrete corti s ol i n
qua nti ti es too s ma l l to ca us e s ymptoms , a nd whether they woul d eventua l l y ca us e s ymptoms a nd morbi di ty i f untrea ted i s uncl ea r. Mos t
cl i ni ci a ns merel y obs erve pa ti ents wi th thes e tumors .
Adrena l a denoma s < 2 cm requi re no s peci a l trea tment but s houl d be obs erved for growth or devel opment of s ecretory functi on (s uch a s by l ooki ng
for cl i ni ca l s i gns a nd peri odi ca l l y mea s uri ng el ectrol ytes ).
Chapter 95. Polyglandular Deficiency Syndromes

Introduction
(Autoi mmune Pol ygl a ndul a r Syndromes ; Pol yendocri ne Defi ci ency Syndromes )
Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a
common cause. Etiology is most often autoimmune. Symptoms depend on the combination of deficiencies, which fall within 1 of 3 types. Diagnosis requires
measurement of hormone levels and autoantibodies against affected endocrine glands. Treatment includes replacement of missing or deficient hormones and
sometimes immunosuppressants.
Etiology
Al though i ndi vi dua l endocri ne gl a nds ca n be da ma ged by numerous ca us es , i ncl udi ng i nfecti on, i nfa rcti on, a nd tumors , thes e s yndromes us ua l l y
res ul t from a n a utoi mmune rea cti on, proba bl y tri ggered by a vi rus or other envi ronmenta l a nti gen.
Geneti c fa ctors i ncrea s e s us cepti bi l i ty to thes e s yndromes , a s s hown by the i ncrea s ed pres ence of certa i n HLA s ubtypes i n a ffected peopl e a nd
the recogni ti on of s evera l i nheri ta nce pa tterns (s ee
Ta bl e 95-1).
Pathophysiology
The underl yi ng a utoi mmune rea cti on i nvol ves a utoa nti bodi es a ga i ns t endocri ne ti s s ues , cel l -medi a ted a utoi mmuni ty, or both a nd l ea ds to
i nfl a mma ti on, l ymphocyti c i nfi l tra ti on, a nd pa rti a l or compl ete gl a nd des tructi on. More
[Table 95-1. Cha ra cteri s ti cs of Types I, II, a nd III Pol ygl a ndul a r Defi ci ency Syndromes ]
tha n one endocri ne gl a nd i s i nvol ved, a l though cl i ni ca l ma ni fes ta ti ons a re not a l wa ys s i mul ta neous . The a utoi mmune rea cti on a nd a s s oci a ted
i mmune s ys tem dys functi on ca n a l s o da ma ge nonendocri ne ti s s ues .
Classification
Three pa tterns of a utoi mmune fa i l ure ha ve been des cri bed (s ee Ta bl e 95-1), whi ch l i kel y refl ect di fferent a utoi mmune a bnorma l i ti es .
Type I: Type I us ua l l y begi ns i n chi l dhood. The 3 pri ma ry components a re
Chroni c mucocuta neous ca ndi di a s i s
Hypopa ra thyroi di s m
Adrena l i ns uffi ci ency (Addi s on's di s ea s e)
Ca ndi di a s i s i s us ua l l y the i ni ti a l cl i ni ca l ma ni fes ta ti on, mos t often occurri ng i n pa ti ents < 5 yr. Hypopa ra thyroi di s m occurs next, us ua l l y i n
pa ti ents < 10 yr. La s tl y, a drena l i ns uffi ci ency occurs i n pa ti ents < 15 yr. Accompa nyi ng endocri ne a nd nonendocri ne di s orders (s ee Ta bl e 95-1)
conti nue to a ppea r a t l ea s t unti l pa ti ents a re a bout a ge 40.
Type II (Schmidt's syndrome): Type II us ua l l y occurs i n a dul ts ; pea k i nci dence i s a ge 30. It occurs 3 ti mes more often i n women. It typi ca l l y ma ni fes ts
wi th
Adrena l i ns uffi ci ency
Hypothyroi di s m or hyperthyroi di s m
Type 1 di a betes (a utoi mmune eti ol ogy)
More ra re fea tures ma y a l s o be pres ent (s ee Ta bl e 95-1).
Type III: Type III i s cha ra cteri zed by
Gl a ndul a r fa i l ure occurri ng i n a dul ts , pa rti cul a rl y mi ddl e-a ged women
Hypothyroi di s m
At l ea s t one of a va ri ety of other di s orders (s ee Ta bl e 95-1)
Type III does not i nvol ve the a drena l cortex.
Symptoms and Signs
The cl i ni ca l a ppea ra nce of pa ti ents wi th PDS i s the s um of the i ndi vi dua l endocri ne defi ci enci es a nd a s s oci a ted nonendocri ne di s orders ; thei r
s ymptoms a nd s i gns a re di s cus s ed el s ewhere i n THE MANUAL. The defi ci enci es do not a l wa ys a ppea r a t the s a me ti me a nd ma y requi re a peri od
of yea rs to ma ni fes t; i n s uch ca s es they do not fol l ow a pa rti cul a r s equence.
Diagnosis
Mea s urement of hormone l evel s

Someti mes a utoa nti body ti ters
Di a gnos i s i s s ugges ted cl i ni ca l l y a nd confi rmed by detecti ng defi ci ent hormone l evel s . Other ca us es of mul ti pl e endocri ne defi ci enci es i ncl ude
hypotha l a mi c-pi tui ta ry dys functi on a nd coi nci denta l endocri ne dys functi on due to s epa ra te ca us es (eg, tubercul ous hypoa drena l i s m a nd
nona utoi mmune hypothyroi di s m i n the s a me pa ti ent). Detecti ng a utoa nti bodi es to ea ch a ffected gl a ndul a r ti s s ue ca n hel p di fferenti a te PDS from
the other ca us es , a nd el eva ted l evel s of pi tui ta ry tropi c hormones (eg, thyroi d-s ti mul a ti ng hormone) s ugges t the hypotha l a mi c-pi tui ta ry a xi s i s
i nta ct (a l though s ome pa ti ents wi th type II PDS ha ve hypotha l a mi c-pi tui ta ry i ns uffi ci ency).
Beca us e deca des ma y pa s s before the a ppea ra nce of a l l ma ni fes ta ti ons , l i fel ong fol l ow-up i s prudent; unrecogni zed hypopa ra thyroi di s m or
a drena l i ns uffi ci ency ca n be l i fe threa teni ng.
Rel a ti ves s houl d be ma de a wa re of the di a gnos i s a nd s creened when a ppropri a te; mea s urement of gl uta mi c a ci d deca rboxyl a s e a nti bodi es ma y
be us eful i n determi ni ng ri s k.
Treatment
Hormone repl a cement
Trea tment of the va ri ous i ndi vi dua l gl a ndul a r defi ci enci es i s di s cus s ed el s ewhere i n THE MANUAL; the trea tment of mul ti pl e defi ci enci es ca n be
more compl ex tha n trea tment of a n i s ol a ted endocri ne defi ci ency.
Chroni c mucocuta neous ca ndi di a s i s us ua l l y requi res l i fel ong a nti funga l thera py (eg, ora l fl ucona zol e or ketocona zol es ee p. 1103). If gi ven ea rl y
(wi thi n the fi rs t few weeks to months ) i n the cours e of endocri ne fa i l ure, i mmunos uppres s i ve dos es of cycl os pori ne ma y benefi t s ome pa ti ents .
IPEX Syndrome
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is a recessive syndrome involving aggressive autoimmunity.
Thi s ra re di s order res ul ts from muta ti on of the tra ns cri pti ona l a cti va tor, FoxP3, whi ch ca us es regul a tory T-cel l dys functi on a nd a s ubs equent
a utoi mmune di s order.
IPEX s yndrome ma ni fes ts a s s evere enl a rgement of the s econda ry l ymphoi d orga ns , type 1 di a betes mel l i tus , eczema , food a l l ergi es , a nd
i nfecti ons . Seconda ry enteropa thy l ea ds to pers i s tent di a rrhea .
Di a gnos i s i s s ugges ted by cl i ni ca l fea tures a nd confi rmed by geneti c a na l ys i s .
Untrea ted, IPEX s yndrome i s us ua l l y fa ta l i n the fi rs t yea r of l i fe. Immunos uppres s a nts a nd bone ma rrow tra ns pl a nta ti on ca n prol ong l i fe but a re
ra rel y cura ti ve.
POEMS Syndrome
(Crow-Fuka s e Syndrome)
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is a nonautoimmune polyglandular deficiency syndrome.
POEMS s yndrome i s proba bl y ca us ed by ci rcul a ti ng i mmunogl obul i ns ca us ed by a pl a s ma cel l dys cra s i a (s ee a l s o p. 1025). Ci rcul a ti ng cytoki nes (IL1-, IL-6), va s cul a r endothel i a l growth fa ctor, a nd tumor necros i s fa ctor- a re a l s o i ncrea s ed.
Pa ti ents ma y ha ve the fol l owi ng:
Hepa tomega l y
Lympha denopa thy
Hypogona di s m
Di a betes mel l i tus type 2
Pri ma ry hypothyroi di s m
Hyperpa ra thyroi di s m
Adrena l i ns uffi ci ency
Exces s producti on of monocl ona l IgA a nd IgG due to pl a s ma cytoma s a nd s ki n a bnorma l i ti es (eg, hyperpi gmenta ti on, derma l thi ckeni ng,
hi rs uti s m, a ngi oma s , hypertri chos i s )
Other s ymptoms a nd s i gns ma y i ncl ude edema , a s ci tes , pl eura l effus i on, pa pi l l edema , a nd fever.
Li ke other s yndromes of undefi ned pa thophys i ol ogy, POEMS s yndrome i s di a gnos ed ba s ed on the cons tel l a ti on of s ymptoms a nd s i gns . Cri teri a
i ncl ude the pres ence of pol yneuropa thy a nd monocl ona l pa ra protei nemi a pl us a ny 2 of the other ma ni fes ta ti ons of the di s order.
Trea tment cons i s ts of chemothera py a nd ra di a ti on thera py fol l owed by a utol ogous hema topoi eti c or s tem cel l tra ns pl a nta ti on. Fi ve-yea r s urvi va l
i s a bout 60%.
Chapter 96. Porphyrias

Introduction
Porphyrias result from genetic deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies allow heme precursors to accumulate, causing
toxicity. Porphyrias are defined by the specific enzyme deficiency. Two major clinical manifestations occur: neurovisceral abnormalities (the acute porphyrias)
and cutaneous photosensitivity (the cutaneous porphyrias).
Heme, a n i ron-conta i ni ng pi gment, i s s ynthes i zed mos tl y i n the bone ma rrow (by erythrobl a s ts a nd reti cul ocytes ) a nd i s i ncorpora ted i nto
hemogl obi n. Heme i s a l s o s ynthes i zed i n the l i ver a nd i ncorpora ted i nto certa i n enzymes (eg, cytochromes ). Heme s ynthes i s requi res 8 enzymes
(s ee
Ta bl e 96-1). Thes e enzymes produce a nd tra ns form mol ecul a r s peci es ca l l ed porphyri ns (a nd thei r precurs ors ), whi ch a re toxi c i f they a ccumul a te.
Etiology
Mos t porphyri a s a re a utos oma l domi na nt. Homozygous or doubl e heterozygous s ta tes ma y be i ncompa ti bl e wi th l i fe, genera l l y ca us i ng feta l
dea th; the excepti ons a re -a mi nol evul i ni c a ci d (ALA) dehydra ta s e (ALAD)-defi ci ency porphyri a a nd uroporphyri nogen III cos yntha s e defi ci ency, i n
whi ch onl y homozygous or doubl e heterozygous condi ti ons (i e, 2 s epa ra te heterozygous muta ti ons i n the s a me gene i n the s a me pa ti ent) ca us e
di s ea s e. Di s ea s e penetra nce i n heterozygotes va ri es . In terms of geneti c preva l ence, the 2 mos t common porphyri a s a re a cute i ntermi ttent
porphyri a (AIP) a nd porphyri a cuta nea ta rda (PCT). The preva l ence of ea ch i s a bout 1/10,000.
Pathophysiology
Porphyri a s res ul t from a defi ci ency of a ny of the l a s t 7 enzymes of the heme bi os yntheti c pa thwa y (defi ci ency of the fi rs t enzyme i n the pa thwa y,
ALA s yntha s e, ca us es s i derobl a s ti c a nemi a ). Si ngl e genes encode ea ch enzyme; a ny of numerous pos s i bl e muta ti ons ca n i nca pa ci ta te the enzyme
encoded by tha t gene. When a n enzyme of heme s ynthes i s i s defi ci ent or defecti ve, i ts s ubs tra te a nd a ny other heme precurs ors norma l l y
modi fi ed by tha t enzyme ma y a ccumul a te i n bone ma rrow, l i ver, s ki n, or other ti s s ues a nd ha ve toxi c effects . Thes e precurs ors ma y a ppea r i n
exces s i n the bl ood a nd be excreted i n uri ne, bi l e, or s tool .
[Table 96-1. Subs tra tes a nd Enzymes of the Heme Bi os yntheti c Pa thwa y a nd the Di s ea s es As s oci a ted wi th thei r Defi ci ency]
Al though porphyri a s a re mos t preci s el y defi ned a ccordi ng to the defi ci ent enzyme, cl a s s i fi ca ti on by ma jor cl i ni ca l fea tures (phenotype) i s often
us eful . Thus , porphyri a s a re us ua l l y di vi ded i nto 2 cl a s s es :
Acute
Cuta neous
Acute porphyri a s ma ni fes t a s i ntermi ttent a tta cks of a bdomi na l , menta l , a nd neurol ogi c s ymptoms . They a re typi ca l l y tri ggered by drugs a nd other
exogenous fa ctors . Cuta neous porphyri a s tend to ca us e conti nuous or undul a ti ng s ymptoms i nvol vi ng cuta neous photos ens i ti vi ty. Some a cute
porphyri a s a l s o ha ve cuta neous ma ni fes ta ti ons . Beca us e of va ri a bl e penetra nce i n heterozygous porphyri a s , cl i ni ca l l y expres s ed di s ea s e i s l es s
common tha n geneti c preva l ence (s ee
Ta bl e 96-2).
Uri ne di s col ora ti on (red or reddi s h brown) ma y occur i n the s ymptoma ti c pha s e of a l l porphyri a s except erythropoi eti c protoporphyri a (EPP) a nd
ALAD-defi ci ency porphyri a . Di s col ora ti on res ul ts from oxi di zed porphyri ns , the porphyri n
[Table 96-2. Ma jor Fea tures of the Two Mos t Common Porphyri a s ]
precurs or porphobi l i nogen (PBG), or both. Someti mes the col or devel ops a fter the uri ne ha s s tood i n l i ght for a bout 30 mi n, a l l owi ng ti me for
oxi da ti on. In the a cute porphyri a s , except i n ALAD-defi ci ency porphyri a , a bout 1 i n 3 heterozygotes (more frequentl y i n fema l es tha n ma l es ) a l s o
ha ve i ncrea s ed uri na ry excreti on of PBG (a nd uri ne di s col ora ti on) i n the l a tent pha s e.
Diagnosis
Pa ti ents wi th s ymptoms s ugges ti ng porphyri a a re s creened by bl ood or uri ne tes ts for porphyri ns or the porphyri n precurs ors PBG a nd ALA (s ee
Ta bl e 96-3). Abnorma l res ul ts on s creeni ng a re confi rmed by further tes ti ng.
As ymptoma ti c pa ti ents , i ncl udi ng s us pected ca rri ers a nd peopl e who a re between a tta cks , a re eva l ua ted s i mi l a rl y. However, the tes ts a re l es s
s ens i ti ve i n thes e ci rcums ta nces ; mea s urement of RBC or WBC enzyme a cti vi ty i s cons i dera bl y more s ens i ti ve. Geneti c a na l ys i s i s hi ghl y a ccura te
a nd preferenti a l l y us ed wi thi n fa mi l i es when the muta ti on i s known. Prena ta l tes ti ng (i nvol vi ng a mni ocentes i s or chori oni c vi l l us s a mpl i ng) i s
pos s i bl e but ra rel y i ndi ca ted.
Acute Porphyrias
Acute porphyrias cause intermittent attacks of abdominal pain and neurologic symptoms. Attacks are precipitated by certain drugs and other factors. Patients
with variegate porphyria and hereditary coproporphyria may develop
[Table 96-3. Screeni ng for Porphyri a s ]
bullous eruptions due to sunlight exposure. Diagnosis is based on elevated levels of -aminolevulinic acid and porphyrin precursor porphobilinogen in the urine
during attacks. Attacks are treated with glucose or, if more severe, IV heme. Symptomatic treatment, including analgesia, is given as necessary.
Acute porphyri a s i ncl ude, i n order of preva l ence, a cute i ntermi ttent porphyri a (AIP), va ri ega te porphyri a (VP), heredi ta ry coproporphyri a (HCP), a nd
the exceedi ngl y ra re -a mi nol evul i ni c a ci d dehydra ta s e (ALAD)-defi ci ency porphyri a .
Among heterozygotes , a cute porphyri a s a re ra rel y expres s ed cl i ni ca l l y before puberty a nd, a fter puberty, i n onl y a bout 20 to 30%. Among
homozygotes a nd doubl e heterozygotes , ons et genera l l y i s i n chi l dhood, a nd s ymptoms a re often s evere.
Precipitating Factors
Ma ny preci pi ta ti ng fa ctors exi s t, typi ca l l y a ccel era ti ng heme bi os ynthes i s a bove the ca ta l yti c ca pa ci ty of the defecti ve enzyme. Accumul a ti on of
porphyri n precurs or porphobi l i nogen (PBG) a nd -a mi nol evul i ni c a ci d (ALA), or i n the ca s e of ALAD-defi ci ency porphyri a , ALA a l one, res ul ts .
Hormona l fa ctors a re i mporta nt. Women a re more prone to a tta cks tha n men, pa rti cul a rl y duri ng peri ods of hormona l cha nge (eg, jus t before
mens trua ti on, duri ng us e of ora l contra cepti ves , duri ng the ea rl y weeks of ges ta ti on, jus t a fter del i very). Neverthel es s , pregna ncy i s not
contra i ndi ca ted.
Other fa ctors i ncl ude drugs (i ncl udi ng ba rbi tura tes , other a nti epi l epti c drugs , a nd s ul fona mi de a nti bi oti cs s ee
Ta bl e 96-4) a nd reproducti ve hormones (proges terone a nd rel a ted s teroi ds ), pa rti cul a rl y thos e tha t i nduce hepa ti c ALA s yntha s e a nd cytochrome P450 enzymes . Atta cks us ua l l y occur wi thi n 24 h a fter expos ure to a preci pi ta ti ng drug. Low-ca l ori e a nd l ow-ca rbohydra te di ets , a l cohol i nges ti on,
a nd expos ure to orga ni c s ol vents ca n a l s o preci pi ta te s ymptoms . Infecti on or other i l l nes s , s urgery, a nd menta l probl ems a re s ometi mes
i mpl i ca ted. Atta cks us ua l l y res ul t from s evera l , s ometi mes uni denti fi a bl e, fa ctors .
Sunl i ght preci pi ta tes cuta neous s ymptoms i n VP a nd HCP.
Symptoms and Signs
Symptoms a nd s i gns i nvol ve the nervous s ys tem, a bdomen, or both (neurovi s cera l ). Atta cks devel op over hours or da ys a nd ca n l a s t
[Table 96-4. Drugs a nd Porphyri a *]
up to s evera l weeks . Mos t gene ca rri ers experi ence no, or onl y a few, a tta cks i n thei r l i feti me. Others experi ence recurrent s ymptoms . In women,
a tta cks often coi nci de wi th pha s es of the mens trua l cycl e.
The acute porphyric attack: Cons ti pa ti on, fa ti gue, i rri ta bi l i ty, a nd i ns omni a typi ca l l y precede a n a cute a tta ck. The mos t common s ymptoms wi th a n
a tta ck a re a bdomi na l pa i n a nd vomi ti ng. The pa i n ma y be excruci a ti ng a nd i s di s proporti ona te to a bdomi na l tendernes s . Abdomi na l
ma ni fes ta ti ons ma y res ul t from effects on vi s cera l nerves or from l oca l va s ocons tri cti ve i s chemi a . Beca us e there i s no i nfl a mma ti on, the a bdomen
i s not tender a nd there a re no peri tonea l s i gns . Tempera ture a nd WBC count a re norma l or s l i ghtl y i ncrea s ed. Bowel di s tenti on ma y devel op a s a
res ul t of pa ra l yti c i l eus . The uri ne i s red or reddi s h brown a nd pos i ti ve for PBG duri ng a n a tta ck.
Al l components of the peri phera l a nd centra l nervous s ys tems ma y be i nvol ved. Motor neuropa thy i s common wi th s evere a nd prol onged a tta cks .
Mus cl e wea knes s us ua l l y begi ns i n the extremi ti es but ca n i nvol ve a ny motor neuron or cra ni a l nerve a nd proceed to tetra pl egi a . Bul ba r
i nvol vement ca n ca us e venti l a tory fa i l ure.
CNS i nvol vement ma y ca us e s ei zures or menta l di s turba nces (eg, a pa thy, depres s i on, a gi ta ti on, fra nk ps ychos i s , ha l l uci na ti ons ). Sei zures ,
ps ychoti c beha vi or, a nd ha l l uci na ti ons ma y be due to hypona tremi a or hypoma gnes emi a , whi ch ca n a l s o contri bute to ca rdi a c a rrhythmi a s .
Exces s ca techol a mi nes genera l l y ca us e res tl es s nes s a nd ta chyca rdi a . Ra rel y, ca techol a mi ne-i nduced a rrhythmi a s ca us e s udden dea th. La bi l e
hypertens i on wi th tra ns i entl y hi gh BP ma y ca us e va s cul a r cha nges progres s i ng to i rrevers i bl e hypertens i on i f untrea ted. Rena l fa i l ure i n a cute
porphyri a i s mul ti fa ctori a l ; a cute hypertens i on (pos s i bl y l ea di ng to chroni c hypertens i on) i s l i kel y a ma i n preci pi ta ti ng fa ctor.
Subacute or subchronic symptoms: Some pa ti ents ha ve prol onged s ymptoms of l es s er i ntens i ty (eg, obs ti pa ti on, fa ti gue, hea da che, ba ck or thi gh
pa i n, pa res thes i a , ta chyca rdi a , dys pnea , i ns omni a , menta l di s turba nce, s ei zures ).
Skin symptoms in VP and HCP: Fra gi l e s ki n a nd bul l ous erupti ons ma y devel op on s un-expos ed a rea s , even i n the a bs ence of neurovi s cera l
s ymptoms . Often pa ti ents a re not a wa re of the connecti on to s un expos ure. Cuta neous ma ni fes ta ti ons a re i denti ca l to thos e of porphyri a cuta nea
ta rda .
Late manifestations: Motor i nvol vement duri ng a cute a tta cks ma y ca us e pers i s tent wea knes s between a tta cks . Hepa tocel l ul a r ca ncer, hypertens i on,
a nd rena l i mpa i rment become more common a fter mi ddl e a ge i n AIP a nd pos s i bl y a l s o i n VP a nd HCP, es peci a l l y i n pa ti ents wi th previ ous
porphyri c a tta cks .
Diagnosis
Uri ne s creen for PBG
If uri ne res ul ts a re pos i ti ve, qua nti ta ti ve ALA a nd PBG determi na ti on
Geneti c a na l ys i s i f type mus t be i denti fi ed
Acute attack: Mi s di a gnos i s i s common beca us e the a cute a tta ck i s confus ed wi th other ca us es of a cute a bdomen (s ometi mes l ea di ng to
unneces s a ry s urgery) or wi th a pri ma ry neurol ogi c or menta l di s order. However, i n pa ti ents previ ous l y di a gnos ed a s gene ca rri ers or who ha ve a
pos i ti ve fa mi l y hi s tory, porphyri a s houl d be s us pected. Sti l l , even i n known gene ca rri ers , other ca us es mus t be cons i dered.
Red or reddi s h brown uri ne, not pres ent before ons et of s ymptoms , i s a ca rdi na l s i gn a nd i s pres ent duri ng ful l -bl own a tta cks . A uri ne s peci men
s houl d be exa mi ned i n pa ti ents wi th a bdomi na l pa i n of unknown ca us e, es peci a l l y i f s evere cons ti pa ti on, vomi ti ng, ta chyca rdi a , mus cl e
wea knes s , bul ba r i nvol vement, or menta l s ymptoms occur.
If porphyri a i s s us pected, the uri ne i s a na l yzed for PBG us i ng a ra pi d qua l i ta ti ve or s emi qua nti ta ti ve determi na ti on. A pos i ti ve res ul t or hi gh
cl i ni ca l s us pi ci on neces s i ta tes qua nti ta ti ve ALA a nd PBG mea s urements preferenti a l l y obta i ned from the s a me s peci men. PBG a nd ALA l evel s > 5
ti mes norma l i ndi ca te a n a cute porphyri c a tta ck unl es s pa ti ents a re gene ca rri ers i n whom porphyri n precurs or excreti on occurs a t s i mi l a r l evel s
even duri ng the l a tent pha s e of the di s order.
If uri na ry PBG a nd ALA l evel s a re norma l , a n a l terna ti ve di a gnos i s mus t be cons i dered. El eva ted ALA wi th norma l or s l i ghtl y i ncrea s ed PBG
s ugges ts l ea d poi s oni ng or ALAD-defi ci ency porphyri a . Ana l ys i s of a 24-h uri ne s peci men i s not us eful . Ins tea d, a ra ndom uri ne s peci men i s us ed,
a nd PBG a nd ALA l evel s a re corrected for di l uti on by rel a ti ng to the crea ti ni ne l evel of the s a mpl e. El ectrol ytes a nd Mg s houl d be mea s ured.
Hypona tremi a ma y be pres ent beca us e of exces s i ve vomi ti ng or di a rrhea a fter hypotoni c fl ui d repl a cement or beca us e of the s yndrome of
i na ppropri a te ADH s ecreti on (SIADH).
Determination of type: Beca us e trea tment does not depend on the type of a cute porphyri a , i denti fi ca ti on of the s peci fi c type i s va l ua bl e ma i nl y for
fi ndi ng gene ca rri ers a mong rel a ti ves . When the type a nd muta ti on a re a l rea dy known from previ ous tes ti ng of rel a ti ves , the di a gnos i s i s cl ea r but
ma y be confi rmed by gene a na l ys i s . Enzyma ti c di a gnos i s i s not neces s a ry. If there i s no fa mi l y hi s tory to gui de the di a gnos i s , the di fferent forms of
a cute porphyri a a re di s ti ngui s hed by cha ra cteri s ti c pa tterns of porphyri n (a nd precurs or) a ccumul a ti on a nd excreti on i n pl a s ma , uri ne, a nd s tool .
When uri ne a na l ys i s revea l s i ncrea s ed l evel s of ALA a nd PBG, feca l porphyri ns ma y be mea s ured. Feca l porphyri ns a re us ua l l y norma l or
mi ni ma l l y i ncrea s ed i n AIP but el eva ted i n HCP a nd VP. Often, thes e ma rkers a re not pres ent i n the qui es cent pha s e of the di s order. In HCP a nd VP,
pl a s ma porphyri ns wi th cha ra cteri s ti c fl uores cence a re s ought. RBC PBG dea mi na s e l evel s tha t a re a bout 50% of norma l s ugges t AIP. Di mi ni s hed
WBC protoporphyri nogen oxi da s e l evel s s ugges t VP, a nd di mi ni s hed coproporphyri nogen oxi da s e l evel s s ugges t HCP.
Family studies: Chi l dren of a gene ca rri er ha ve a 50% ri s k of i nheri ti ng the di s order. Beca us e di a gnos i s fol l owed by couns el i ng reduces the ri s k of
morbi di ty, chi l dren i n a ffected fa mi l i es s houl d be tes ted before the ons et of puberty. Geneti c tes ti ng i s us ed i f the muta ti on ha s been i denti fi ed
i n the i ndex ca s e. If not, perti nent RBC or WBC enzyme l evel s a re mea s ured. Gene a na l ys i s ca n be us ed for i n utero di a gnos i s (us i ng
a mni ocentes i s or chori oni c vi l l us s a mpl i ng) but i s s el dom i ndi ca ted beca us e of the fa vora bl e outl ook for mos t gene ca rri ers .
Prognosis
Adva nces i n medi ca l ca re a nd s el f-ca re ha ve i mproved the prognos i s for s ymptoma ti c pa ti ents . Sti l l , s ome pa ti ents devel op recurrent cri s es or
progres s i ve di s ea s e wi th perma nent pa ra l ys i s or rena l fa i l ure. Al s o, frequent need for potent a na l ges i cs ma y gi ve ri s e to drug a ddi cti on.
Treatment
Tri ggers el i mi na ted i f pos s i bl e
Dextros e (ora l or IV)
IV heme
Trea tment of the a cute a tta ck i s i denti ca l for a l l the a cute porphyri a s . Pos s i bl e tri ggers (eg, drugs ) a re i denti fi ed a nd el i mi na ted. Unl es s the
a tta ck i s mi l d, pa ti ents a re hos pi ta l i zed i n a da rkened, qui et, pri va te room. Hea rt ra te, BP, a nd fl ui d a nd el ectrol yte ba l a nce a re moni tored.
Neurol ogi c s ta tus , bl a dder functi on, mus cl e a nd tendon functi on, res pi ra tory functi on, a nd pul s e oxi metry a re conti nuous l y moni tored. Symptoms
(eg, pa i n, vomi ti ng) a re trea ted wi th nonporphyri nogeni c drugs a s needed (s ee Ta bl e 96-4).
Dextros e 300 to 500 g da i l y i nhi bi ts ALA s yntha s e a nd rel i eves s ymptoms . It ca n be gi ven by mouth i f pa ti ents a re not vomi ti ng; otherwi s e, i t i s
gi ven IV. To a voi d overhydra ti on wi th cons equent hypona tremi a , 1 L of a 50% dextros e s ol uti on ca n be gi ven by centra l venous ca theter over 24 h.
IV heme i s more effecti ve tha n dextros e a nd s houl d be gi ven i mmedi a tel y i n s evere a tta cks , el ectrol yte i mba l a nce, or mus cl e wea knes s . Heme
us ua l l y res ol ves s ymptoms i n 3 to 4 da ys . If heme thera py i s del a yed, nerve da ma ge i s more s evere a nd recovery i s s l ower a nd pos s i bl y
i ncompl ete. Heme i s a va i l a bl e i n the US a s l yophi l i zed hema ti n to be recons ti tuted i n a gl a s s vi a l wi th s teri l e wa ter. The dos e i s 3 mg/kg IV
once/da y for 4 da ys . In thi s form, heme degra da ti on products form ra pi dl y a nd ma y ca us e phl ebi ti s a t the i nfus i on s i te; they a l s o ha ve a tra ns i ent
a nti coa gul a nt effect. Advers e effects ca n be reduced by recons ti tuti on wi th, eg, 20% huma n a l bumi n. Heme a rgi na te i s a more s ta bl e, genera l l y
toxi ci ty-free a l terna ti ve.
In pa ti ents wi th s evere recurrent a tta cks , who a re a t ri s k of rena l da ma ge or perma nent neurol ogi c da ma ge, l i ver tra ns pl a nta ti on i s a n opti on.
Rena l tra ns pl a nta ti on, wi th or wi thout s i mul ta neous l i ver excha nge, s houl d be cons i dered i n pa ti ents wi th a cti ve di s ea s e a nd termi na l rena l
fa i l ure, beca us e there i s cons i dera bl e ri s k tha t nerve da ma ge wi l l progres s a t the s ta rt of di a l ys i s .
Prevention
Ca rri ers of a cute porphyri a s houl d a voi d the fol l owi ng:
Potenti a l l y ha rmful drugs (s ee Ta bl e 96-4)
Al cohol
Emoti ona l s tres s
Expos ure to orga ni c s ol vents (eg, i n pa i nti ng or dry cl ea ni ng)
Cra s h di ets
Peri ods of s ta rva ti on
Di ets for obes i ty s houl d provi de gra dua l wei ght l os s a nd be a dopted onl y duri ng peri ods of remi s s i on. Ca rri ers of VP or HCP s houl d mi ni mi ze s un
expos ure; s uns creens tha t bl ock onl y ul tra vi ol et B l i ght a re i neffecti ve, but opa que ti ta ni um di oxi de prepa ra ti ons a re benefi ci a l . Support
a s s oci a ti ons for porphyri a pa ti ents ca n provi de wri tten i nforma ti on a nd di rect couns el i ng.
Pa ti ents s houl d be i denti fi ed promi nentl y i n the medi ca l record a s ca rri ers a nd s houl d ca rry a ca rd veri fyi ng the ca rri er s ta te a nd preca uti ons to be
obs erved.
A hi gh-ca rbohydra te di et ma y decrea s e the ri s k of a cute a tta cks . A hi gh-ca rbohydra te di et or a l ump of s uga r every hour ma y hel p rel i eve s ymptoms
of a n a cute a tta ck. Prol onged us e s houl d be a voi ded i n order to decrea s e ri s k of obes i ty a nd denta l ca ri es .
Pa ti ents who experi ence recurrent a nd predi cta bl e a tta cks (typi ca l l y women wi th a tta cks rel a ted to the mens trua l cycl e) ma y benefi t from
prophyl a cti c heme thera py gi ven s hortl y before the expected ons et. There i s no s ta nda rdi zed regi men; a s peci a l i s t s houl d be cons ul ted. Frequent
premens trua l a tta cks i n s ome women a re a borted by a dmi ni s tra ti on of a gona dotropi n-rel ea s i ng hormone a na l og pl us l ow-dos e es trogen. Ora l
contra cepti ves a re s ometi mes us ed s ucces s ful l y, but the proges ti n component i s l i kel y to exa cerba te the porphyri a .
To prevent rena l da ma ge, chroni c hypertens i on i s trea ted (us i ng s a fe drugs ). Pa ti ents wi th evi dence of i mpa i red rena l functi on a re referred to a
nephrol ogi s t.
The i nci dence of hepa tocel l ul a r ca ncer i s hi gh a mong ca rri ers of a cute porphyri a , es peci a l l y i n pa ti ents wi th a cti ve di s ea s e. Pa ti ents who a re > 50
s houl d undergo yea rl y or twi ce yea rl y s urvei l l a nce, i ncl udi ng l i ver s creeni ng wi th contra s t-enha nced ul tra s onogra phy. Ea rl y i nterventi on ca n be
cura ti ve a nd i ncrea s es l i fe expecta ncy.
Cutaneous Porphyrias
Cutaneous porphyrias tend to manifest as undulating or unremitting disease with a relatively steady production of phototoxic porphyrins in the liver or bone
marrow. These porphyrins accumulate in the skin and, on sunlight exposure (visible light, including near-ultraviolet [UV]), generate cytotoxic radicals that cause
cutaneous manifestations.
Cuta neous porphyri a s i ncl ude porphyri a cuta nea ta rda , erythropoi eti c protoporphyri a (EPP), a nd the extremel y ra re hepa toerythropoi eti c porphyri a
a nd congeni ta l erythropoi eti c porphyri a (s ee
Ta bl e 96-5). The a cute porphyri a s va ri ega te porphyri a a nd heredi ta ry coproporphyri a a l s o ha ve cuta neous ma ni fes ta ti ons .
In a l l cuta neous porphyri a s except EPP, cuta neous photos ens i ti vi ty ma ni fes ts a s fra gi l e s ki n a nd bul l ous erupti ons . Ski n cha nges genera l l y occur
on s un-expos ed a rea s (eg, fa ce, neck, dors a l s i des of fi ngers a nd ha nds ) or tra uma ti zed s ki n. The cuta neous rea cti on i s
[Table 96-5. Some Les s Common Porphyri a s ]
i ns i di ous , a nd often pa ti ents a re una wa re of the connecti on to s un expos ure. In contra s t, the photos ens i ti vi ty i n EPP occurs wi thi n mi nutes or
hours a fter s un expos ure, ma ni fes ti ng a s a burni ng pa i n tha t pers i s ts for hours , often wi thout a ny objecti ve s i gns on the s ki n.
Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) is a comparatively common porphyria affecting mainly the skin. Liver disease is common. Symptoms include fragile skin and
blisters affecting sun-exposed areas. Iron plays a key role in pathogenesis. Several environmental factors lower the threshold for the phototoxic skin reaction,
including alcohol ingestion, estrogens, hepatitis C infection, and possibly HIV infection. Drugs, with the exceptions of iron and estrogens, are not triggers.
Diagnosis is by porphyrin analysis of urine and stool. Differentiation from the acute cutaneous porphyrias hereditary coproporphyria and variegate porphyria is
important. Treatment includes iron depletion by phlebotomy and forced porphyrin excretion by treatment with chloroquine. Prevention is by avoidance of
sunlight, alcohol, estrogens, and iron-containing drugs.
Pathophysiology
PCT res ul ts from hepa ti c defi ci ency of uroporphyri nogen deca rboxyl a s e (UPGDs ee Ta bl e 96-1). In a bout 80% of pa ti ents , the res pons i bl e muta ti on
i s s pora di c; the rema i ni ng 20% a re heredi ta ry.
Porphyri ns a ccumul a te i n the l i ver a nd a re tra ns ported to the s ki n, where they ca us e photos ens i ti vi ty. The 50% decrea s e i n UPGD a cti vi ty i n
heterozygous pa ti ents i s i ns uffi ci ent to ca us e cl i ni ca l PCT. Other fa ctors mus t further i mpa i r enzyme a cti vi ty. Iron pl a ys a centra l rol e, proba bl y by
genera ti ng oxygen ra di ca l s tha t i nhi bi t UPGD by oxi di zi ng i ts s ubs tra te; thus , hemochroma tos i s i s a s i gni fi ca nt ri s k fa ctor. Al cohol , es trogens , a nd
chroni c vi ra l i nfecti on proba bl y contri bute i n di fferent wa ys by i ncrea s i ng i ron a cti vi ty i n hepa ti c ti s s ue. The drugs tha t commonl y tri gger a cute
porphyri a (s ee Ta bl e 96-4) do not tri gger PCT.
Li ver di s ea s e i s common i n PCT a nd ma y be due pa rtl y to porphyri n a ccumul a ti on, chroni c hepa ti ti s C i nfecti on, concomi ta nt hemos i deros i s , or
exces s a l cohol i nges ti on. Ci rrhos i s occurs i n 35% of pa ti ents , a nd hepa tocel l ul a r ca rci noma occurs i n 7 to 24% (more common a mong mi ddl ea ged men).
The 2 ma jor forms of the di s ea s e, types 1 a nd 2, ha ve the s a me preci pi ta nts , s ymptoms , a nd trea tment. Overa l l preva l ence ma y be on the order of
1/10,000.
In type 1 PCT (s pora di c), deca rboxyl a s e defi ci ency i s res tri cted to the l i ver a nd no geneti c ba ckground i s recogni zed. It us ua l l y ma ni fes ts i n mi ddl e
a ge or l a ter.
In type 2 PCT (fa mi l i a l ), deca rboxyl a s e defi ci ency i s i nheri ted i n a n a utos oma l domi na nt fa s hi on wi th l i mi ted penetra nce. Preva l ence i s l ower tha n
i n s pora di c PCT. Defi ci ency occurs i n a l l cel l s , i ncl udi ng RBCs . It ma y devel op ea rl i er tha n type 1, occa s i ona l l y i n chi l dhood.
Seconda ry PCT-l i ke condi ti ons (ps eudoporphyri a ) ma y occur wi th certa i n photos ens i ti zi ng drugs (eg, furos emi de, tetra cycl i nes , s ul fona mi des , s ome
NSAIDs ). Beca us e porphyri ns a re poorl y di a l yzed, s ome pa ti ents recei vi ng l ong-term hemodi a l ys i s devel op a s ki n condi ti on tha t res embl es PCT;
thi s condi ti on i s termed ps eudoporphyri a of end-s ta ge rena l di s ea s e.

Symptoms and Signs
Pa ti ents pres ent wi th fra gi l e s ki n, ma i nl y on s un-expos ed a rea s . Phototoxi ci ty i s del a yed: pa ti ents do not a l wa ys connect s un expos ure wi th
s ymptoms .
Sponta neous l y or a fter mi nor tra uma , tens e bul l a e devel op. Accompa nyi ng eros i ons a nd ul cers ma y devel op s econda ry i nfecti on; they hea l s l owl y,
l ea vi ng a trophi c s ca rs . Sun expos ure occa s i ona l l y l ea ds to erythema , edema , or i tchi ng. Hyperemi c conjuncti vi ti s ma y devel op, but other mucos a l
s i tes a re not a ffected. Area s of hypopi gmenta ti on or hyperpi gmenta ti on ma y devel op, a s ma y fa ci a l hypertri chos i s a nd ps eudos cl erodermoi d
cha nges .
Diagnosis
Level s of pl a s ma porphyri ns , uri na ry uroporphyri n a nd hepta ca rboxyl porphyri n, a nd feca l i s ocoproporphyri n
In otherwi s e hea l thy pa ti ents , fra gi l e s ki n a nd bl i s ter forma ti on s ugges t PCT. Di fferenti a ti on from a cute porphyri a s wi th cuta neous s ymptoms
(va ri ega te porphyri a [VP] a nd heredi ta ry coproporphyri a [HCP]) i s i mporta nt beca us e i n pa ti ents wi th VP a nd HCP, the erroneous pres cri pti on of
porphyrogeni c drugs ma y tri gger the s evere neurovi s cera l s ymptoms of the a cute porphyri a s . Previ ous unexpl a i ned neurol ogi c s ymptoms or
a bdomi na l pa i n ma y s ugges t a n a cute porphyri a . A hi s tory of expos ure to chemi ca l s tha t ca n ca us e ps eudoporphyri a s houl d be s ought.
Al though a l l porphyri a s tha t ca us e s ki n l es i ons a re a ccompa ni ed by el eva ted pl a s ma porphyri ns , el eva ted uri na ry uroporphyri n a nd hepta ca rboxyl
porphyri n a nd feca l i s ocoproporphyri n i ndi ca te PCT. Uri ne l evel s of porphyri n precurs or porphobi l i nogen (PBG) a nd, us ua l l y, -a mi nol evul i ni c a ci d
(ALA) a re norma l i n PCT. RBC a cti vi ty of UPGD i s norma l i n type 1 PCT but decrea s ed i n type 2.
Beca us e concurrent hepa ti ti s C i nfecti on i s common a nd ma y be a s ymptoma ti c, s erum ma rkers for hepa ti ti s C (s ee p.
253) s houl d be i nves ti ga ted.
Treatment
Two di fferent thera peuti c s tra tegi es a re a va i l a bl e:
Reducti on of body i ron s tores
Increa s e i n porphyri n excreti on
Thes e s tra tegi es ca n be combi ned for more ra pi d remi s s i on. The trea tment i s moni tored by determi na ti ons of uri na ry porphyri n excreti on every
other or every 3rd month unti l ful l remi s s i on.
Iron remova l by phl ebotomy i s us ua l l y effecti ve. A pi nt of bl ood i s removed every 2nd or every 3rd week; s horter i nterva l s unneces s a ri l y ri s k
ca us i ng a nemi a . When s erum ferri ti n fa l l s s l i ghtl y bel ow norma l , phl ebotomy i s s topped. Us ua l l y, onl y 5 to 6 s es s i ons a re needed. Uri ne a nd
pl a s ma porphyri ns fa l l gra dua l l y wi th trea tment, l a ggi ng behi nd but pa ra l l el i ng the fa l l i n ferri ti n. The s ki n eventua l l y becomes norma l . After
remi s s i on, further phl ebotomy i s needed onl y i f there i s a recurrence.
Low-dos e chl oroqui ne or hydroxychl oroqui ne (100 to 125 mg po twi ce/wk) removes exces s porphyri ns from the l i ver by i ncrea s i ng the excreti on ra te.
Hi gher dos es ca n ca us e tra ns i ent l i ver da ma ge a nd wors eni ng of porphyri a . When remi s s i on i s a chi eved, the regi men i s s topped.
Chl oroqui ne a nd hydroxychl oroqui ne a re not effecti ve i n a dva nced rena l di s ea s e, a nd phl ebotomy i s us ua l l y contra i ndi ca ted beca us e of
underl yi ng a nemi a . However, recombi na nt erythropoi eti n mobi l i zes exces s i ron a nd res ol ves the a nemi a enough to permi t phl ebotomy. In ends ta ge rena l di s ea s e, deferoxa mi ne i s a n a djunct to phl ebotomy for reducti on of hepa ti c i ron, the compl exed i ron bei ng removed duri ng di a l ys i s .
Di a l yzers wi th ul tra permea bl e membra nes a nd extra hi gh bl ood fl ow ra tes a re needed.
Pa ti ents wi th overt PCT a nd hepa ti ti s C i nfecti on a re preferenti a l l y trea ted wi th pegyl a ted i nterferon a l fa -2a a nd ri ba vi ri n. Previ ous i ron depl eti on
a ugments the res pons e to a nti vi ra l thera py.
Chi l dren wi th s ymptoma ti c PCT a re trea ted wi th s ma l l -vol ume phl ebotomi es or ora l chl oroqui ne; dos a ge i s determi ned by body wei ght.
Ski n s ymptoms occurri ng duri ng pregna ncy a re trea ted wi th phl ebotomy. In refra ctory ca s es , l ow-dos e chl oroqui ne ca n be a dded; no tera togeni c
effects ha ve been recogni zed. Dependi ng on degree of hemodi l uti on a nd i ron depl eti on, the s ki n s ymptoms us ua l l y a ba te a s pregna ncy a dva nces .
Pos tmenopa us a l es trogen s uppl ementa ti on i s i nterrupted duri ng trea tment for PCT. Stoppi ng es trogens often i nduces remi s s i on. After remi s s i on,
es trogens ca n be rei ntroduced, preferenti a l l y i n tra ns derma l a dmi ni s tra ti on to reduce hepa ti c porphyrogeni c expos ure.
Prevention
Pa ti ents s houl d a voi d s un expos ure; ha ts a nd cl othi ng protect bes t, a s do zi nc or ti ta ni um oxi de s uns creens . Typi ca l s uns creens tha t bl ock UV l i ght
a re i neffecti ve, but UVA-a bs orbi ng s uns creens , s uch a s thos e conta i ni ng di benzyl metha nes , ma y hel p s omewha t. Al cohol i nges ti on s houl d be
a voi ded perma nentl y, but es trogen s uppl ementa ti on ca n us ua l l y be res umed s a fel y a fter a di s ea s e remi s s i on.
Erythropoietic Protoporphyria
Erythropoietic protoporphyria (EPP) typically manifests in infancy with burning skin pain after even short exposure to sunlight. Gallstones are common later in
life, and acute liver failure occurs in about 10%. Diagnosis is based on symptoms and increased levels of protoporphyrin in RBCs and plasma. Treatment is with carotene or dihydroxyacetone and avoidance of sunlight. In patients with liver failure, combined liver and bone marrow transplantation may be life saving as well
as curative.
Etiology
EPP res ul ts from defi ci ency of the enzyme ferrochel a ta s e i n erythroi d ti s s ue. Cl i ni ca l preva l ence i s a bout1/75,000. Phototoxi c protoporphyri ns
a ccumul a te i n bone ma rrow a nd RBCs , enter the pl a s ma , a nd a re depos i ted i n the s ki n or excreted by the l i ver i nto bi l e a nd s tool . Hea vy bi l i a ry
protoporphyri n excreti on ca n ca us e ga l l s tones . Thes e cytotoxi c mol ecul es s ometi mes da ma ge the hepa tobi l i a ry tra ct, res ul ti ng i n hepa ti c
protoporphyri n a ccumul a ti on tha t l ea ds to a cute l i ver fa i l ure; l i ver fa i l ure ma y become cl i ni ca l l y a cute wi thi n da ys .
Inheri ta nce pa ttern i s ba s i ca l l y a utos oma l domi na nt but compl ex. Cl i ni ca l ma ni fes ta ti ons occur onl y i n peopl e who ha ve both the defecti ve EPP
gene a nd a n unus ua l l ow-output (but otherwi s e norma l ) a l l el e from the hea l thy pa rent.
Symptoms and Signs
Severi ty va ri es grea tl y, even a mong pa ti ents wi thi n a s i ngl e fa mi l y. Us ua l l y, a n i nfa nt or young chi l d wi th EPP cri es for hours a fter even s hort
expos ure to s un. However, beca us e cuta neous s i gns a re us ua l l y a bs ent a nd young chi l dren ca nnot des cri be thei r s ymptoms , EPP often goes
undi a gnos ed.
If unrecogni zed, EPP ca us es ps ychos oci a l probl ems beca us e chi l dren i nexpl i ca bl y refus e to go outdoors . The pa i n ma y be s o di s tres s i ng tha t i t
ca us es nervous nes s , tens enes s , a ggres s i venes s , or even feel i ngs of deta chment from the s urroundi ngs or s ui ci da l thoughts .
Duri ng chi l dhood, crus ti ng ma y devel op a round the l i ps a nd on the ba ck of the ha nds a fter prol onged s un expos ure. Bl i s teri ng a nd s ca rri ng do not
occur. If s ki n protecti on i s chroni ca l l y negl ected, rough, thi ckened, a nd l ea thery s ki n ma y devel op, es peci a l l y over the knuckl es . Li nea r peri ora l
furrows (ca rp mouth) ma y devel op.
Bi l i a ry excreti on of l a rge a mounts of protoporphyri n ca n ca us e chol es ta s i s tha t progres s es to nodul a r ci rrhos i s a nd a cute l i ver fa i l ure i n 10% of
pa ti ents ; s ymptoms i ncl ude ja undi ce, ma l a i s e, upper a bdomi na l pa i n, a nd tender hepa ti c enl a rgement.
Diagnosis
RBC a nd pl a s ma protoporphyri n mea s urement
EPP s houl d be s us pected i n chi l dren a nd a dul ts wi th pa i nful cuta neous photos ens i ti vi ty who experi ence no bl i s ters or s ca rri ng. Fa mi l y hi s tory i s
us ua l l y nega ti ve. The di a gnos i s i s confi rmed by fi ndi ng i ncrea s ed RBC a nd pl a s ma protoporphyri n l evel s . A geneti c ma rker for s us cepti bi l i ty to
chol es ta ti c compl i ca ti ons ha s been i denti fi ed.
Screeni ng of potenti a l ca rri ers a mong rel a ti ves i s by s howi ng i ncrea s ed RBC protoporphyri n contents a nd decrea s ed ferrochel a ta s e a cti vi ty
(a s s a yed i n l ymphocytes ) or by geneti c tes ti ng i f the muta ti on ha s been i denti fi ed i n the i ndex ca s e. Sus cepti bi l i ty for cuta neous di s ea s e i n
ca rri ers i s i ndi ca ted by fi ndi ng the l ow-output ferrochel a ta s e a l l el e.
Treatment
Avoi da nce of tri ggers (eg, s un expos ure, a l cohol , fa s ti ng)
Someti mes ora l -ca rotene
Acute s ki n s ymptoms a re a l l evi a ted by col d ba ths or wet towel s , a na l ges i cs , a nd a nti hi s ta mi nes . Regul a r phys i ci a n-pa ti ent cons ul ta ti ons tha t
provi de i nforma ti on, di s cus s i on, a nd opportuni ti es for geneti c couns el i ng together wi th phys i ca l checkups a re i mporta nt.
Pa ti ents s houl d a voi d s un expos ure; opa que ti ta ni um di oxi de or zi nc oxi de s uns creens a re benefi ci a l , a nd UVA-a bs orbi ng s uns creens , s uch a s
thos e conta i ni ng di benzyl metha nes , ma y hel p s omewha t. Protecti on a ga i ns t the opera ti ng l i ght i s s tri ctl y requi red i n l i ver tra ns pl a nta ti on to
a voi d s eri ous phototoxi c i njury to i nner orga ns . Coveri ng of l i ght s ources wi th fi l ters tha t bl ock wa vel engths < 470 nm i s requi red. Endos copy,
l a pa ros copy, a nd nontra ns pl a nt a bdomi na l s urgery a re not connected wi th ri s k of phototoxi c da ma ge.
[
Table 96-6. Dos es of -Ca rotene i n Erythropoi eti c Protoporphyri a ]
Pa ti ents s houl d a voi d a l cohol a nd fa s ti ng, both of whi ch i ncrea s e the ra te of RBC producti on a nd thus the protoporphyri n l oa d. Drugs tha t tri gger
a cute porphyri a s (s ee Ta bl e 96-4) need not be a voi ded.
Sys temi c -ca rotene ca us es s l i ght yel l ow protecti ve s ki n col ora ti on a nd neutra l i zes the toxi c ra di ca l s i n the s ki n tha t ca us e s ymptoms . Dos e
depends on pa ti ent a ge (s ee Ta bl e 96-6).
Another a nti oxi da nt, cys tei ne, ma y a l s o l es s en photos ens i ti vi ty. The brown protecti ve s ki n col or obta i ned wi th topi ca l l y a ppl i ed di hydroxya cetone
i s genera l l y cos meti ca l l y prefera bl e to the yel l owi s h ti nt ca us ed by -ca rotene.
If the a bove-menti oned mea s ures a re i neffecti ve (eg, pa ti ents ha ve i ncrea s i ng photos ens i ti vi ty, ri s i ng porphyri n l evel s , or progres s i ve ja undi ce),
RBC hypertra ns fus i on (i e, to a bovenorma l Hb l evel s ) ca n reduce the producti on ra te of porphyri n-l oa ded RBCs . Admi ni s tra ti on of bi l e a ci ds
fa ci l i ta tes bi l i a ry excreti on of protoporphyri n. Ora l chol es tyra mi ne or cha rcoa l i nterrupts the enterohepa ti c ci rcul a ti on. Li ver fa i l ure ma y requi re
i mmedi a te l i ver tra ns pl a nta ti on. Bone ma rrow excha nge corrects the ba s i c meta bol i c defect.
Pa ti ents wi th EPP s houl d undergo a nnua l s urvei l l a nce for ri s ks of chol es ta s i s . Tes ts i ncl ude RBC porphyri n l evel s , porphyri n excreti on pa tterns ,
a nd l i ver functi on. Abnorma l fi ndi ngs s houl d be eva l ua ted by a porphyri a s peci a l i s t a nd a hepa tol ogi s t. If the l i ver a ppea rs i nvol ved, bi ops y i s
done to i denti fy progres s i ve di s ea s e. Pa ti ents s houl d be va cci na ted a ga i ns t hepa ti ti s A a nd B a nd a dvi s ed to a voi d a l cohol .
Chapter 97. Fluid and Electrolyte Metabolism

Introduction
Body fl ui d vol ume a nd el ectrol yte concentra ti on a re norma l l y ma i nta i ned wi thi n very na rrow l i mi ts des pi te wi de va ri a ti ons i n di eta ry i nta ke,
meta bol i c a cti vi ty, a nd envi ronmenta l s tres s es . Homeos ta s i s of body fl ui ds i s pres erved pri ma ri l y by the ki dneys .
Water and Sodium Balance
Wa ter a nd Na ba l a nce a re cl os el y i nterdependent. Tota l body wa ter (TBW) i s a bout 60% of body wei ght (ra ngi ng from a bout 50% i n obes e peopl e
to 70% i n l ea n peopl e). Al mos t two thi rds of TBW i s i n the i ntra cel l ul a r compa rtment (i ntra cel l ul a r fl ui d, or ICF); the other one thi rd i s extra cel l ul a r
(extra cel l ul a r fl ui d, or ECF). Norma l l y, a bout 25% of the ECF i s i n the i ntra va s cul a r compa rtment; the other 75% i s i nters ti ti a l fl ui d (s ee
Fi g. 97-1).
The ma jor i ntra cel l ul a r ca ti on i s K, wi th a n a vera ge concentra ti on of 140 mEq/L. The extra cel l ul a r K concentra ti on i s 3.5 to 5 mEq/L. The ma jor
extra cel l ul a r ca ti on i s Na , wi th a n a vera ge concentra ti on of 140 mEq/L a nd a n i ntra cel l ul a r Na concentra ti on of 12 mEq/L.
Osmotic forces: The concentra ti on of combi ned s ol utes i n wa ter i s os mol a ri ty (a mount of s ol ute per L of s ol uti on), whi ch, i n body fl ui ds , i s s i mi l a r
to os mol a l i ty (a mount of s ol ute per kg of s ol uti on). Pl a s ma os mol a l i ty ca n be mea s ured i n the l a bora tory or es ti ma ted a ccordi ng to the formul a
Pl a s ma os mol a l i ty (mOs m/kg) =
where s erum Na i s expres s ed i n mEq/L a nd gl ucos e a nd BUN a re expres s ed i n mg/dL. Os mol a l i ty of body fl ui ds i s norma l l y between 275 a nd 290
mOs m/kg. Na i s the ma jor determi na nt of s erum os mol a l i ty. Appa rent cha nges i n os mol a l i ty ma y res ul t from errors i n the mea s urement of Na wi th
el ectrodes tha t a re not i on s el ecti ve (s ee under Di a gnos i s on p. 826). An os mol a r ga p i s pres ent when mea s ured os mol a l i ty exceeds es ti ma ted
os mol a l i ty by 10 mOs m/kg. It i s ca us ed by unmea s ured os moti ca l l y a cti ve s ubs ta nces pres ent i n the pl a s ma . The mos t common a re a l cohol s
(etha nol , metha nol , i s opropa nol , ethyl ene gl ycol ), ma nni tol , a nd gl yci ne.
Wa ter cros s es cel l membra nes freel y from a rea s of l ow s ol ute concentra ti on to a rea s of hi gh s ol ute concentra ti on. Thus , os mol a l i ty tends to
equa l i ze a cros s the va ri ous body fl ui d compa rtments , res ul ti ng pri ma ri l y from movement of wa ter, not s ol utes . Sol utes s uch a s urea tha t freel y
di ffus e a cros s cel l membra nes ha ve l i ttl e or no effect on wa ter s hi fts (l i ttl e or no os moti c a cti vi ty), wherea s s ol utes tha t a re res tri cted pri ma ri l y to
one fl ui d compa rtment, s uch a s Na a nd K, ha ve the grea tes t os moti c a cti vi ty. Toni ci ty, or effecti ve os mol a l i ty, refl ects os moti c a cti vi ty a nd
determi nes the force dra wi ng wa ter a cros s fl ui d compa rtments (the os moti c force). Os moti c force ca n be oppos ed by other forces . For exa mpl e,
pl a s ma protei ns ha ve a s ma l l os moti c effect tha t tends to dra w wa ter i nto the pl a s ma ; thi s os moti c effect i s norma l l y countera cted by va s cul a r
hydros ta ti c forces tha t dri ve wa ter out of the pl a s ma .
Water intake and excretion: The a vera ge da i l y fl ui d i nta ke i s a bout 2.5 L. The a mount needed to repl a ce l os s es from the uri ne a nd other s ources i s
a bout 1 to 1.5 L/da y i n hea l thy a dul ts . However, on a s hort-term ba s i s , a n a vera ge
[Fig. 97-1. Fl ui d compa rtments i n a n a vera ge 70-kg ma n.]
young a dul t wi th norma l ki dney functi on ma y i nges t a s l i ttl e a s 200 mL of wa ter ea ch da y to excrete the ni trogenous a nd other wa s tes genera ted by
cel l ul a r meta bol i s m. More i s needed i n peopl e wi th a ny l os s of rena l concentra ti ng ca pa ci ty. Rena l concentra ti ng ca pa ci ty i s l os t i n
The el derl y
Peopl e wi th di a betes i ns i pi dus , certa i n rena l di s orders , hyperca l cemi a , s evere s a l t res tri cti on, chroni c overhydra ti on, or hyperka l emi a
Peopl e who i nges t etha nol , phenytoi n, l i thi um, demecl ocycl i ne, or a mphoteri ci n B
Peopl e wi th os moti c di ures i s (eg, due to hi gh-protei n di ets or hypergl ycemi a )
Other obl i ga tory wa ter l os s es a re mos tl y i ns ens i bl e l os s es from the l ungs a nd s ki n, a vera gi ng a bout 0.4 to 0.5 mL/kg/h or a bout 650 to 850 mL/da y
i n a 70-kg a dul t. Wi th fever, a nother 50 to 75 mL/da y ma y be l os t for ea ch degree C of tempera ture el eva ti on a bove norma l . GI l os s es a re us ua l l y
negl i gi bl e, except when ma rked vomi ti ng, di a rrhea , or both occur. Swea t l os s es ca n be s i gni fi ca nt duri ng envi ronmenta l hea t expos ure or
exces s i ve exerci s e.
Wa ter i nta ke i s regul a ted by thi rs t. Thi rs t i s tri ggered by receptors i n the a nterol a tera l hypotha l a mus tha t res pond to i ncrea s ed s erum os mol a l i ty
(a s l i ttl e a s 2%) or decrea s ed body fl ui d vol ume. Ra rel y hypotha l a mi c dys functi on decrea s es the ca pa ci ty for thi rs t.
Wa ter excreti on by the ki dneys i s regul a ted pri ma ri l y by ADH (va s opres s i n). ADH i s rel ea s ed by the pos teri or pi tui ta ry a nd res ul ts i n i ncrea s ed
wa ter rea bs orpti on i n the di s ta l nephron. ADH rel ea s e i s s ti mul a ted by a ny of the fol l owi ng:
Increa s ed s erum os mol a l i ty
Decrea s ed bl ood vol ume
Decrea s ed BP
Stres s
ADH rel ea s e ma y be i mpa i red by certa i n s ubs ta nces (eg, etha nol , phenytoi n) a nd centra l di a betes i ns i pi dus (s ee p. 772).
Wa ter i nta ke decrea s es s erum os mol a l i ty. Low s erum os mol a l i ty i nhi bi ts ADH s ecreti on, a l l owi ng the ki dneys to produce di l ute uri ne. The di l uti ng
ca pa ci ty of hea l thy ki dneys i n young a dul ts i s s uch tha t ma xi mum da i l y fl ui d i nta ke ca n be a s much a s 25 L; grea ter a mounts qui ckl y l ower s erum
os mol a l i ty.
Disorders of Fluid Volume
Beca us e Na i s the ma jor os moti ca l l y a cti ve i on i n the ECF, tota l body Na content determi nes ECF vol ume. Defi ci ency or exces s of tota l body Na
content ca us es ECF vol ume depl eti on or overl oa d. Pl a s ma Na concentra ti on does not neces s a ri l y refl ect tota l body Na .
Di eta ry i nta ke a nd rena l excreti on regul a te tota l body Na content. When tota l Na content a nd ECF vol ume a re l ow, the ki dneys i ncrea s e Na
cons erva ti on. When tota l Na content a nd ECF vol ume a re hi gh, Na excreti on (na tri ures i s ) i ncrea s es s o tha t vol ume decrea s es .
Rena l Na excreti on ca n be a djus ted wi del y to ma tch Na i nta ke. Rena l Na excreti on requi res del i very of Na to the ki dneys a nd s o depends on rena l
bl ood fl ow a nd GFR. Thus , i na dequa te Na excreti on ma y be s econda ry to decrea s ed rena l bl ood fl ow, a s i n chroni c ki dney di s ea s e or hea rt fa i l ure.
Renin-angiotensin-aldosterone axis: The reni n-a ngi otens i n-a l dos terone a xi s i s the ma i n regul a tory mecha ni s m of rena l Na excreti on. In vol umedepl eted s ta tes , GFR a nd Na del i very to the di s ta l nephrons decrea s es , ca us i ng rel ea s e of reni n. Reni n cl ea ves a ngi otens i nogen (reni n s ubs tra te)
to form a ngi otens i n I. ACE then cl ea ves a ngi otens i n I to a ngi otens i n II. Angi otens i n II does the fol l owi ng:
Increa s es Na retenti on by decrea s i ng the fi l tered l oa d of Na a nd enha nci ng proxi ma l tubul a r Na rea bs orpti on.
Increa s es BP (ha s pres s or a cti vi ty)
Increa s es thi rs t
Di rectl y i mpa i rs wa ter excreti on
Sti mul a tes the a drena l cortex to s ecrete a l dos terone, whi ch i ncrea s es Na rea bs orpti on vi a mul ti pl e rena l mecha ni s ms
Angi otens i n I ca n a l s o be tra ns formed to a ngi otens i n III, whi ch s ti mul a tes a l dos terone rel ea s e a s much a s a ngi otens i n II but ha s much l es s
pres s or a cti vi ty. Al dos terone rel ea s e i s a l s o s ti mul a ted by hyperka l emi a .
Other natriuretic factors: Severa l other na tri ureti c fa ctors ha ve been i denti fi ed, i ncl udi ng a tri a l na tri ureti c pepti de (ANP), bra i n na tri ureti c pepti de
(BNP), a nd a C-type na tri ureti c pepti de (CNP).
ANP i s s ecreted by ca rdi a c a tri a l ti s s ue. Concentra ti on i ncrea s es i n res pons e to ECF vol ume overl oa d (eg, hea rt fa i l ure, chroni c ki dney di s ea s e,
ci rrhos i s wi th a s ci tes ) a nd pri ma ry a l dos teroni s m a nd i n s ome pa ti ents wi th pri ma ry hypertens i on. Decrea s es ha ve occurred i n the s ubs et of
pa ti ents wi th nephroti c s yndrome who ha ve pres umed ECF vol ume contra cti on. Hi gh concentra ti ons i ncrea s e Na excreti on a nd i ncrea s e GFR even
when BP i s l ow.
BNP i s s ynthes i zed ma i nl y i n the a tri a a nd l eft ventri cl e a nd ha s s i mi l a r tri ggers a nd effects to ANP. BNP a s s a ys a re rea di l y a va i l a bl e. Hi gh BNP
concentra ti on i s us ed to di a gnos e vol ume overl oa d.
CNP, i n contra s t to ANP a nd BNP, i s pri ma ri l y va s odi l a tory.
Na depletion and excess: Na depl eti on requi res i na dequa te Na i nta ke pl us a bnorma l l os s es from the s ki n, GI tra ct, or ki dneys (defecti ve rena l Na
cons erva ti on). Defecti ve rena l Na cons erva ti on ma y be ca us ed by pri ma ry rena l di s ea s e, a drena l i ns uffi ci ency, or di ureti c thera py.
Na overl oa d requi res hi gher Na i nta ke tha n excreti on; however, beca us e norma l ki dneys ca n excrete l a rge a mounts of Na , Na overl oa d genera l l y
refl ects defecti ve regul a ti on of rena l bl ood fl ow a nd Na excreti on (eg, a s occurs i n hea rt fa i l ure, ci rrhos i s , or chroni c ki dney di s ea s e).
Volume Depletion
Volume depletion, or ECF volume contraction, occurs as a result of loss of total body Na. Causes include vomiting, excessive sweating, diarrhea, burns, diuretic
use, and kidney failure. Clinical features include diminished skin turgor, dry mucous membranes, tachycardia, and orthostatic hypotension. Diagnosis is clinical.
Treatment involves administration of Na and water.
Beca us e wa ter cros s es pl a s ma membra nes i n the body through pa s s i ve os mos i s , l os s of the ma jor extra cel l ul a r ca ti on (Na ) qui ckl y res ul ts i n
wa ter l os s from the ECF s pa ce a s wel l . In thi s wa y, Na l os s a l wa ys ca us es wa ter l os s . However, dependi ng on ma ny fa ctors , s erum Na
concentra ti on ca n be hi gh, l ow, or norma l i n vol ume-depl eted pa ti ents (des pi te the decrea s ed tota l body Na content). ECF vol ume i s rel a ted to
effecti ve ci rcul a ti ng vol ume. A decrea s e i n ECF (hypovol emi a ) genera l l y ca us es a decrea s e i n effecti ve ci rcul a ti ng vol ume, whi ch i n turn ca us es
decrea s ed orga n perfus i on a nd l ea ds to cl i ni ca l s equel a e. Common ca us es of vol ume depl eti on a re l i s ted i n
Ta bl e 97-1.
Symptoms and Signs
In mi l d vol ume depl eti on (< 5% of ECF), the onl y s i gn ma y be di mi ni s hed s ki n turgor (bes t a s s es s ed a t the upper tors o). Ski n turgor ma y be l ow i n
el derl y pa ti ents rega rdl es s of vol ume s ta tus . Pa ti ents ma y compl a i n of thi rs t. Dry mucous membra nes do not a l wa ys correl a te wi th vol ume
depl eti on, es peci a l l y i n the el derl y a nd i n mouth-brea thers . Ol i guri a i s typi ca l .
When ECF vol ume ha s di mi ni s hed by 5 to 10%, orthos ta ti c ta chyca rdi a , hypotens i on, or both a re us ua l l y, but not a l wa ys , pres ent. Al s o, orthos ta ti c
cha nges ca n occur i n pa ti ents wi thout ECF vol ume depl eti on, pa rti cul a rl y pa ti ents decondi ti oned or bedri dden. Ski n turgor ma y decrea s e further.
[Table 97-1. Common Ca us es of Vol ume Depl eti on]

When fl ui d l os s exceeds 10% of ECF vol ume, s i gns of s hock ca n occur (eg, ta chypnea , ta chyca rdi a , hypotens i on, confus i on, poor ca pi l l a ry refi l l ).
Diagnosis
Someti mes s erum el ectrol ytes , BUN, a nd crea ti ni ne
Ra rel y s erum os mol a l i ty a nd uri ne chemi s tri es
Vol ume depl eti on i s s us pected i n pa ti ents a t ri s k, mos t often i n pa ti ents wi th a hi s tory of i na dequa te fl ui d i nta ke (es peci a l l y i n coma tos e or
di s ori ented pa ti ents ), i ncrea s ed fl ui d l os s es , di ureti c thera py, a nd rena l or a drena l di s orders .
Di a gnos i s i s us ua l l y cl i ni ca l . When the ca us e i s obvi ous a nd ea s i l y correcta bl e (eg, a cute ga s troenteri ti s i n otherwi s e hea l thy pa ti ents ),
l a bora tory tes ti ng i s unneces s a ry; otherwi s e, s erum el ectrol ytes , BUN, a nd crea ti ni ne a re mea s ured. Serum os mol a l i ty a nd uri ne Na , crea ti ni ne,
a nd os mol a l i ty a re mea s ured when there i s s us pi ci on of cl i ni ca l l y mea ni ngful el ectrol yte a bnorma l i ty tha t i s not cl ea r from s erum tes ts a nd for
pa ti ents wi th ca rdi a c or rena l di s ea s e. When meta bol i c a l ka l os i s i s pres ent, uri ne Cl i s a l s o mea s ured.
Centra l venous pres s ure a nd pul mona ry a rtery occl us i on pres s ure a re decrea s ed i n vol ume depl eti on, but mea s urement i s ra rel y requi red.
Mea s urement, whi ch requi res a n i nva s i ve procedure, i s occa s i ona l l y neces s a ry for pa ti ents for whom even s ma l l a mounts of a dded vol ume ma y
be detri menta l , s uch a s thos e wi th uns ta bl e hea rt fa i l ure or a dva nced chroni c ki dney di s ea s e.
The fol l owi ng concepts a re hel pful when i nterpreti ng uri ne el ectrol yte a nd os mol a l i ty va l ues :
Duri ng vol ume depl eti on, norma l l y functi oni ng ki dneys cons erve Na . Thus , the uri ne Na concentra ti on i s us ua l l y < 15 mEq/L; the fra cti ona l
excreti on of Na (uri ne Na /s erum Na di vi ded by uri ne crea ti ni ne/s erum crea ti ni ne) i s us ua l l y < 1%; a l s o, uri ne os mol a l i ty i s often > 450
mOs m/kg.
When meta bol i c a l ka l os i s i s combi ned wi th vol ume depl eti on, uri ne Na concentra ti on ma y be hi gh beca us e l a rge a mounts of HCO3 a re s pi l l ed
i n the uri ne, obl i ga ti ng the excreti on of Na to ma i nta i n el ectri ca l neutra l i ty. In thi s i ns ta nce, a uri ne Cl concentra ti on of < 10 mEq/L more
rel i a bl y i ndi ca tes vol ume depl eti on.
Mi s l ea di ngl y hi gh uri na ry Na (genera l l y > 20 mEq/L) or l ow uri ne os mol a l i ty ca n a l s o occur due to rena l Na l os s es res ul ti ng from rena l di s ea s e,
di ureti cs , or a drena l i ns uffi ci ency.
Vol ume depl eti on frequentl y i ncrea s es the BUN a nd s erum crea ti ni ne concentra ti ons wi th the ra ti o of BUN to crea ti ni ne often > 20:1. Va l ues s uch
a s Hct often i ncrea s e i n vol ume depl eti on but a re di ffi cul t to i nterpret unl es s ba s el i ne va l ues a re known.
Treatment
Repl a cement of Na a nd wa ter
The ca us e of vol ume depl eti on i s corrected a nd fl ui ds a re gi ven to repl a ce exi s ti ng vol ume defi ci ts a s wel l a s a ny ongoi ng fl ui d l os s es a nd to
provi de da i l y fl ui d requi rements . Mi l d-to-modera te vol ume defi ci ts ma y be repl a ced by i ncrea s ed ora l i nta ke of Na a nd wa ter when pa ti ents a re
cons ci ous a nd not vomi ti ng. When vol ume defi ci ts a re s evere or when ora l fl ui d repl a cement i s i mpra cti ca l , IV 0.9% s a l i ne i s gi ven. Typi ca l IV
regi mens a re di s cus s ed on p. 2297; ora l regi mens a re di s cus s ed on p.
2809.
Volume Overload
Volume overload generally refers to expansion of the ECF volume. ECF volume expansion typically occurs in heart failure, nephrotic syndrome, and cirrhosis.
Renal Na retention leads to increased total body Na content. This increase results in varying degrees of volume overload. In heart failure, the increased ECF
volume results in decreased effective circulating volume, which in turn causes decreased organ perfusion leading to clinical sequelae. Serum Na concentration can
be high, low, or normal in volume-overloaded patients (despite the increased total body Na content).
An i ncrea s e i n tota l body Na i s the key pa thophys i ol ogi c event. It i ncrea s es os mol a l i ty, whi ch tri ggers compens a tory mecha ni s ms tha t ca us e wa ter
retenti on. When s uffi ci ent fl ui d a ccumul a tes i n the ECF (us ua l l y > 2.5 L), edema (s ee p. 2031) devel ops .
Among the mos t common ca us es of ECF vol ume overl oa d a re the fol l owi ng:
Hea rt fa i l ure
Ci rrhos i s
Rena l fa i l ure
Nephroti c s yndrome
Premens trua l edema
Pregna ncy
Cl i ni ca l fea tures i ncl ude wei ght ga i n a nd edema . Di a gnos i s i s cl i ni ca l . Trea tment a i ms to correct the ca us e.
Hyponatremia
Hyponatremia is decrease in serum Na concentration < 136 mEq/L caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea,
heart failure, and renal disease. Clinical manifestations are primarily neurologic (due to an osmotic shift of water into brain cells causing edema), especially in
acute hyponatremia, and include headache, confusion, and stupor; seizures and coma may occur. Diagnosis is by measuring serum Na. Serum and urine
electrolytes and osmolality help determine the cause. Treatment involves restricting water intake and promoting its loss, replacing any Na deficit, and treating
the cause.
Etiology
Hypona tremi a refl ects a n exces s of tota l body wa ter (TBW) rel a ti ve to tota l body Na content. Beca us e tota l body Na content i s refl ected by ECF
vol ume s ta tus , hypona tremi a mus t be cons i dered a l ong wi th s ta tus of the ECF vol ume: hypovol emi a , euvol emi a , a nd hypervol emi a (s ee
Ta bl e 97-2). Note tha t the ECF vol ume i s not the s a me a s effecti ve pl a s ma vol ume. For exa mpl e, decrea s ed effecti ve pl a s ma vol ume ma y occur wi th
decrea s ed ECF vol ume, but i t ma y a l s o occur wi th a n i ncrea s ed ECF vol ume (eg, i n hea rt fa i l ure, hypoa l bumi nemi a , or ca pi l l a ry l ea k s yndrome).
Hypovolemic hyponatremia: Defi ci enci es i n both TBW a nd tota l body Na exi s t, a l though proporti ona l l y more Na tha n wa ter ha s been l os t; the Na
defi ci t ca us es hypovol emi a . In hypovol emi c hypona tremi a , both s erum os mol a l i ty a nd bl ood vol ume decrea s e. ADH s ecreti on i ncrea s es des pi te a
decrea s e i n os mol a l i ty to ma i nta i n bl ood vol ume. The res ul ti ng wa ter retenti on i ncrea s es pl a s ma di l uti on a nd hypona tremi a .
[Table 97-2. Pri nci pa l Ca us es of Hypona tremi a ]
Extrarenal fluid losses, s uch a s thos e tha t occur wi th the l os s es of Na -conta i ni ng fl ui ds a s i n protra cted vomi ti ng, s evere di a rrhea , or s eques tra ti on
of fl ui ds i n a 3rd s pa ce (s ee
Ta bl e 97-3), ca n ca us e hypona tremi a typi ca l l y when l os s es a re repl a ced by i nges ti ng pl a i n wa ter or l i qui ds l ow i n Na (s ee
Ta bl e 97-4) or by hypotoni c IV fl ui d. Si gni fi ca nt ECF fl ui d l os s es a l s o ca us e rel ea s e of ADH, ca us i ng wa ter retenti on by the ki dneys , whi ch ca n
ma i nta i n or wors en hypona tremi a . In extra rena l ca us es of hypovol emi a , beca us e the norma l rena l res pons e to vol ume l os s i s Na cons erva ti on,
uri ne Na concentra ti on i s typi ca l l y < 10 mEq/L.
Renal fluid losses res ul ti ng i n hypovol emi c hypona tremi a ma y occur wi th mi nera l ocorti coi d defi ci ency, di ureti c thera py, os moti c di ures i s , or s a l tl os i ng nephropa thy. Sa l t-l os i ng nephropa thy encompa s s es a l oos el y defi ned group of i ntri ns i c rena l di s orders wi th pri ma ri l y rena l tubul a r
dys functi on. Thi s group i ncl udes i nters ti ti a l nephri ti s , medul l a ry cys ti c di s ea s e, pa rti a l uri na ry tra ct obs tructi on, a nd, occa s i ona l l y, pol ycys ti c
ki dney di s ea s e. Rena l ca us es of hypovol emi c hypona tremi a ca n us ua l l y be di fferenti a ted from extra rena l ca us es by the hi s tory. Pa ti ents wi th
ongoi ng rena l fl ui d l os s es ca n a l s o be di s ti ngui s hed from pa ti ents wi th extra rena l fl ui d l os s es beca us e the uri ne Na concentra ti on i s
i na ppropri a tel y hi gh (> 20 mEq/L). Uri ne Na concentra ti on ma y not hel p i n di fferenti a ti on when meta bol i c a l ka l os i s (a s occurs wi th protra cted
vomi ti ng) i s pres ent a nd l a rge a mounts of HCO3 a re s pi l l ed i n the uri ne, obl i ga ti ng the excreti on of Na to ma i nta i n el ectri ca l neutra l i ty. In
meta bol i c a l ka l os i s , uri ne Cl concentra ti on frequentl y di fferenti a tes rena l from extra rena l s ources of vol ume depl eti on (s ee p. 862).
[Table 97-3. Compos i ti on of Body Fl ui ds ]
[Table 97-4. Approxi ma te Na Content of Common Bevera ges ]
Diuretics ma y a l s o ca us e hypovol emi c hypona tremi a . Thi a zi de di ureti cs , i n pa rti cul a r, decrea s e the ki dneys ' di l uti ng ca pa ci ty a nd i ncrea s e Na
excreti on. Once vol ume depl eti on occurs , the nonos moti c rel ea s e of ADH ca us es wa ter retenti on a nd wors ens hypona tremi a . Concomi ta nt
hypoka l emi a s hi fts Na i ntra cel l ul a rl y a nd enha nces ADH rel ea s e, thereby wors eni ng hypona tremi a . Thi s effect of thi a zi des ma y l a s t for up to 2 wk
a fter ces s a ti on of thera py; however, hypona tremi a us ua l l y res ponds to repl a cement of K a nd vol ume defi ci ts a l ong wi th judi ci ous moni tori ng of
wa ter i nta ke unti l the drug effect di s s i pa tes . El derl y pa ti ents ma y ha ve i ncrea s ed Na di ures i s a nd a re es peci a l l y s us cepti bl e to thi a zi de-i nduced
hypona tremi a , pa rti cul a rl y when they ha ve a preexi s ti ng defect i n rena l ca pa ci ty to excrete free wa ter. Ra rel y, s uch pa ti ents devel op s evere, l i fethrea teni ng hypona tremi a wi thi n a few weeks a fter the i ni ti a ti on of a thi a zi de di ureti c. Loop di ureti cs much l es s commonl y ca us e hypona tremi a .
Euvolemic hyponatremia: In euvol emi c (di l uti ona l ) hypona tremi a , tota l body Na a nd thus ECF vol ume a re norma l or nea r-norma l ; however, TBW i s
i ncrea s ed.
Pri ma ry pol ydi ps i a ca n ca us e hypona tremi a onl y when wa ter i nta ke overwhel ms the ki dneys ' a bi l i ty to excrete wa ter. Beca us e norma l ki dneys ca n
excrete up to 25 L uri ne/da y, hypona tremi a due s ol el y to pol ydi ps i a res ul ts onl y from the i nges ti on of l a rge a mounts of wa ter or from defects i n
rena l ca pa ci ty to excrete free wa ter. Pa ti ents a ffected i ncl ude thos e wi th ps ychos i s or more modes t degrees of pol ydi ps i a pl us rena l i ns uffi ci ency.
Euvol emi c hypona tremi a ma y a l s o res ul t from exces s i ve wa ter i nta ke i n the pres ence of Addi s on's di s ea s e, hypothyroi di s m, or nonos moti c ADH
rel ea s e (eg, due to s tres s ; pos topera ti ve s ta tes ; us e of drugs s uch a s chl orpropa mi de, tol buta mi de, opi oi ds , ba rbi tura tes , vi ncri s ti ne, cl ofi bra te, or
ca rba ma zepi ne). Pos topera ti ve hypona tremi a mos t commonl y occurs beca us e of a combi na ti on of nonos moti c ADH rel ea s e a nd exces s i ve
a dmi ni s tra ti on of hypotoni c fl ui ds a fter s urgery. Certa i n drugs (eg, cycl ophos pha mi de, NSAIDs , chl orpropa mi de) potenti a te the rena l effect of
endogenous ADH, wherea s others (eg, oxytoci n) ha ve a di rect ADH-l i ke effect on the ki dneys . A defi ci ency i n wa ter excreti on i s common i n a l l thes e
condi ti ons . Di ureti cs ca n ca us e or contri bute to euvol emi c hypona tremi a i f a nother fa ctor ca us es wa ter retenti on or exces s i ve wa ter i nta ke. The
s yndrome of i na ppropri a te ADH s ecreti on (SIADHs ee Si deba r 97-1) i s a nother ca us e of euvol emi c hypona tremi a .
Hypervolemic hyponatremia: Hypervol emi c hypona tremi a i s cha ra cteri zed by a n i ncrea s e i n both tota l body Na (a nd thus ECF vol ume) a nd TBW wi th a
rel a ti vel y grea ter i ncrea s e i n TBW. Va ri ous edema tous di s orders , i ncl udi ng hea rt fa i l ure a nd ci rrhos i s , ca us e hypervol emi c hypona tremi a . Ra rel y,
hypona tremi a occurs i n nephroti c s yndrome, a l though ps eudohypona tremi a ma y be due to i nterference wi th Na mea s urement by el eva ted l i pi ds .
In ea ch of thes e di s orders , a decrea s e i n effecti ve ci rcul a ti ng vol ume res ul ts i n the rel ea s e of ADH a nd a ngi otens i n II. The fol l owi ng fa ctors
contri bute to hypona tremi a :
The a nti di ureti c effect of ADH on the ki dneys
Di rect i mpa i rment of rena l wa ter excreti on by a ngi otens i n II

Decrea s ed GFR
Sti mul a ti on of thi rs t by a ngi otens i n II
Uri ne Na excreti on i s us ua l l y < 10 mEq/L, a nd uri ne os mol a l i ty i s hi gh rel a ti ve to s erum os mol a l i ty.
Hyponatremia in AIDS: Hypona tremi a ha s been reported i n > 50% of hos pi ta l i zed pa ti ents wi th AIDS. Among the ma ny potenti a l contri buti ng fa ctors
a re
Admi ni s tra ti on of hypotoni c fl ui ds
Impa i red rena l functi on
Nonos moti c ADH rel ea s e due to i ntra va s cul a r vol ume depl eti on
Admi ni s tra ti on of drugs tha t i mpa i r rena l wa ter excreti on
In a ddi ti on, a drena l i ns uffi ci ency ha s become i ncrea s i ngl y common a mong AIDS pa ti ents a s the res ul t of cytomega l ovi rus a drena l i ti s ,
mycoba cteri a l i nfecti on, or i nterference wi th a drena l gl ucocorti coi d a nd mi nera l ocorti coi d s ynthes i s by ketocona zol e. SIADH ma y be pres ent
beca us e of coexi s tent pul mona ry or CNS i nfecti ons .
Sidebar 97-1 Syndrome of Inappropriate ADH Secretion

The s yndrome of i na ppropri a te ADH s ecreti on (SIADH) i s a ttri buted to exces s i ve ADH rel ea s e. It i s defi ned a s l es s -tha n-ma xi ma l l y-di l ute uri ne i n
the pres ence of pl a s ma hypo-os mol a l i ty (hypona tremi a ) wi thout vol ume depl eti on or overl oa d, emoti ona l s tres s , pa i n, di ureti cs , or other drugs
tha t s ti mul a te ADH s ecreti on i n pa ti ents wi th norma l ca rdi a c, hepa ti c, rena l , a drena l , a nd thyroi d functi on. SIADH i s a s s oci a ted wi th myri a d
di s orders (s ee
Ta bl e 97-5).
Symptoms and Signs

Symptoms ma i nl y i nvol ve CNS dys functi on. However, when hypona tremi a i s a ccompa ni ed by di s turba nces i n tota l body Na content, s i gns of ECF
vol ume depl eti on or overl oa d a l s o occur (s ee p. 823). In genera l , ol der chroni ca l l y i l l pa ti ents wi th hypona tremi a devel op more s ymptoms tha n
younger otherwi s e hea l thy pa ti ents . Symptoms a re a l s o more s evere wi th fa s ter-ons et hypona tremi a . Symptoms genera l l y occur when the effecti ve
pl a s ma os mol a l i ty fa l l s to < 240 mOs m/kg. Symptoms ca n be s ubtl e a nd cons i s t ma i nl y of cha nges i n menta l s ta tus , i ncl udi ng a l tered pers ona l i ty,
l etha rgy, a nd confus i on. As the s erum Na fa l l s to < 115 mEq/L, s tupor, neuromus cul a r hyperexci ta bi l i ty, hyperrefl exi a , s ei zures , coma , a nd dea th
ca n res ul t.
Severe cerebra l edema ma y occur i n premenopa us a l women wi th a cute hypona tremi a , perha ps beca us e es trogen a nd proges terone i nhi bi t bra i n
Na +, K+-ATPa s e a nd decrea s e s ol ute extrus i on from bra i n cel l s . Sequel a e i ncl ude hypotha l a mi c a nd pos teri or pi tui ta ry i nfa rcti on a nd occa s i ona l l y
bra i n s tem herni a ti on.
Diagnosis
Serum a nd uri ne el ectrol ytes a nd os mol a l i ty
Cl i ni ca l a s s es s ment of vol ume s ta tus
Hypona tremi a i s occa s i ona l l y s us pected i n pa ti ents who ha ve neurol ogi c a bnorma l i ti es a nd a re a t ri s k. However, beca us e fi ndi ngs a re
nons peci fi c, hypona tremi a i s often recogni zed onl y a fter s erum el ectrol yte mea s urement.
[Table 97-5. Di s orders As s oci a ted wi th Syndrome of Ina ppropri a te ADH Secreti on]
Serum Na ma y be l ow when s evere hypergl ycemi a i ncrea s es os mol a l i ty a nd wa ter moves out of cel l s i nto the ECF. Serum Na concentra ti on fa l l s
a bout 1.6 mEq/L for every 100-mg/dL (5.55-mmol /L) ri s e i n the s erum gl ucos e concentra ti on a bove norma l . Thi s condi ti on i s often ca l l ed
tra ns l oca ti ona l hypona tremi a beca us e i t i s ca us ed by tra ns l oca ti on of Na a cros s cel l membra nes . Ps eudohypona tremi a wi th norma l s erum
os mol a l i ty ma y occur i n hyperl i pi demi a or extreme hyperprotei nemi a , beca us e the l i pi d or protei n occupi es s pa ce i n the vol ume of s erum ta ken
for a na l ys i s ; the concentra ti on of Na i n s erum i ts el f i s not a ffected. Newer methods of mea s uri ng s erum el ectrol ytes wi th i on-s el ecti ve el ectrodes
ci rcumvent thi s probl em.
Identification of the cause: Identi fyi ng the ca us e ca n be compl ex. The hi s tory s ometi mes s ugges ts a ca us e (eg, s i gni fi ca nt fl ui d l os s due to vomi ti ng
or di a rrhea , rena l di s ea s e, compul s i ve fl ui d i nges ti on, i nta ke of drugs tha t s ti mul a te ADH rel ea s e or enha nce ADH a cti on).
The vol ume s ta tus , pa rti cul a rl y the pres ence of obvi ous vol ume depl eti on or overl oa d, s ugges ts certa i n ca us es (s ee Ta bl e 97-1). Overtl y
hypovol emi c pa ti ents us ua l l y ha ve a n obvi ous s ource of fl ui d l os s (typi ca l l y trea ted wi th hypotoni c fl ui d repl a cement). Overtl y hypervol emi c
pa ti ents us ua l l y ha ve a rea di l y recogni za bl e condi ti on, s uch a s hea rt fa i l ure or hepa ti c or rena l di s ea s e. Euvol emi c pa ti ents a nd pa ti ents wi th
equi voca l vol ume s ta tus requi re more l a bora tory tes ti ng to i denti fy a ca us e.
La bora tory tes ts s houl d i ncl ude s erum a nd uri ne os mol a l i ty a nd el ectrol ytes . Euvol emi c pa ti ents s houl d a l s o ha ve thyroi d a nd a drena l functi on
tes ted. Hypo-os mol a l i ty i n euvol emi c pa ti ents s houl d ca us e excreti on of a l a rge vol ume of di l ute uri ne (eg, os mol a l i ty < 100 mOs m/kg a nd s p gr <
1.003). Serum Na concentra ti on a nd s erum os mol a l i ty tha t a re l ow a nd uri ne os mol a l i ty tha t i s i na ppropri a tel y hi gh (120 to 150 mmol /L) wi th
res pect to the l ow s erum os mol a l i ty s ugges t vol ume overl oa d, vol ume contra cti on, or SIADH. Vol ume overl oa d a nd vol ume contra cti on a re
di fferenti a ted cl i ni ca l l y (s ee pp. 822 a nd 823). When nei ther vol ume overl oa d nor vol ume contra cti on a ppea rs l i kel y, SIADH i s cons i dered. Pa ti ents
wi th SIADH a re us ua l l y euvol emi c or s l i ghtl y hypervol emi c. BUN a nd crea ti ni ne va l ues a re norma l , a nd s erum uri c a ci d i s genera l l y l ow. Uri ne Na
concentra ti on i s us ua l l y > 30 mmol /L, a nd fra cti ona l excreti on of Na i s > 1% (for ca l cul a ti on, s ee p.
2310).
In pa ti ents wi th hypovol emi a a nd norma l rena l functi on, Na rea bs orpti on res ul ts i n a uri ne Na of < 20 mmol /L. Uri ne Na > 20 mmol /L i n
hypovol emi c pa ti ents s ugges ts mi nera l ocorti coi d defi ci ency or s a l t-l os i ng nephropa thy. Hyperka l emi a s ugges ts a drena l i ns uffi ci ency.
Treatment
When hypovol emi c, 0.9% s a l i ne
When hypervol emi c, fl ui d res tri cti on a nd s ometi mes a di ureti c
When euvol emi c, trea tment of ca us e
Ra rel y ca uti ous correcti on wi th hypertoni c (3%) s a l i ne
Ra pi d correcti on of hypona tremi a , even mi l d hypona tremi a , ri s ks neurol ogi c compl i ca ti ons (s ee p. 828). Except pos s i bl y i n the fi rs t few hours of
trea tment of s evere hypona tremi a , Na s houl d be corrected no fa s ter tha n 0.5 mEq/L/h. Even wi th s evere hypona tremi a , i ncrea s e i n s erum Na
concentra ti on s houl d not exceed 10 mEq/L over the fi rs t 24 h. Any i denti fi ed ca us e of hypona tremi a i s trea ted concurrentl y.
Mild hyponatremia: Mi l d, a s ymptoma ti c hypona tremi a (i e, s erum Na > 120 mEq/L) requi res res tra i nt beca us e s ma l l a djus tments a re genera l l y
s uffi ci ent. In di ureti c-i nduced hypona tremi a , el i mi na ti on of the di ureti c ma y be enough; s ome pa ti ents need s ome Na or K repl a cement. Si mi l a rl y,
when mi l d hypona tremi a res ul ts from i na ppropri a te hypotoni c pa rentera l fl ui d a dmi ni s tra ti on i n pa ti ents wi th i mpa i red wa ter excreti on, merel y
a l teri ng fl ui d thera py ma y s uffi ce.
Wi th hypovolemia a nd norma l a drena l functi on, a dmi ni s tra ti on of 0.9% s a l i ne us ua l l y corrects both hypona tremi a a nd hypovol emi a . When the
s erum Na i s < 120 mEq/L, hypona tremi a ma y not compl etel y correct upon res tora ti on of i ntra va s cul a r vol ume; res tri cti on of free wa ter i nges ti on to
500 to 1000 mL/24 h ma y be needed.
In hypervolemic patients, i n whom hypona tremi a i s due to rena l Na retenti on (eg, hea rt fa i l ure, ci rrhos i s , nephroti c s yndrome) a nd di l uti on, wa ter
res tri cti on combi ned wi th trea tment of the underl yi ng di s order i s requi red. In pa ti ents wi th hea rt fa i l ure, a n ACE i nhi bi tor, i n conjuncti on wi th a
l oop di ureti c, ca n correct refra ctory hypona tremi a . In other pa ti ents i n whom s i mpl e fl ui d res tri cti on i s i neffecti ve, a l oop di ureti c i n es ca l a ti ng
dos es ca n be us ed, s ometi mes i n conjuncti on wi th IV 0.9% norma l s a l i ne. K a nd other el ectrol ytes l os t i n the uri ne mus t be repl a ced. When
hypona tremi a i s more s evere a nd unres pons i ve to di ureti cs , i ntermi ttent or conti nuous hemofi l tra ti on ma y be needed to control ECF vol ume whi l e
hypona tremi a i s corrected wi th IV 0.9% norma l s a l i ne.
In euvolemia, trea tment i s di rected a t the ca us e (eg, hypothyroi di s m, a drena l i ns uffi ci ency, di ureti c us e). When SIADH i s pres ent, s evere wa ter
res tri cti on (eg, 250 to 500 mL/24 h) i s genera l l y requi red. Addi ti ona l l y, a l oop di ureti c ma y be combi ned wi th IV 0.9% s a l i ne a s i n hypervol emi c
hypona tremi a . La s ti ng correcti on depends on s ucces s ful trea tment of the underl yi ng di s order. When the underl yi ng di s order i s not correcta bl e, a s
i n meta s ta ti c ca ncer, a nd pa ti ents fi nd s evere wa ter res tri cti on una ccepta bl e, demecl ocycl i ne (300 to 600 mg q 12 h) ma y be hel pful by i nduci ng a
concentra ti ng defect i n the ki dneys . However, demecl ocycl i ne ma y ca us e a cute rena l fa i l ure. Rena l fa i l ure i s us ua l l y revers i bl e when the drug i s
s topped. IV coni va pta n, a n ADH receptor a nta goni s t, ca us es effecti ve wa ter di ures i s wi thout s i gni fi ca nt l os s of el ectrol ytes i n the uri ne a nd ca n be
us ed i n hos pi ta l i zed pa ti ents for trea tment of res i s ta nt hypona tremi a .
Severe hyponatremia: Severe hypona tremi a (s erum Na < 109 mEq/L; effecti ve os mol a l i ty < 238 mOs m/kg) i n a s ymptoma ti c pa ti ents ca n be trea ted
s a fel y wi th s tri ngent res tri cti on of wa ter i nta ke. Trea tment i s more controvers i a l when neurol ogi c s ymptoms (eg, confus i on, l etha rgy, s ei zures ,
coma ) a re pres ent. The deba te pri ma ri l y concerns the pa ce a nd degree of hypona tremi a correcti on. Ma ny experts recommend tha t s erum Na be
ra i s ed no fa s ter tha n 1 mEq/L/h, but repl a cement ra tes of up to 2 mEq/L/h for the fi rs t 2 to 3 h ha ve been s ugges ted for pa ti ents wi th s ei zures .
Rega rdl es s , the ri s e s houl d be 10 mEq/L over the fi rs t 24 h. More vi gorous correcti on ri s ks preci pi ta ti on of os moti c demyel i na ti on s yndrome.
Hypertoni c (3%) s a l i ne (conta i ni ng 513 mEq Na /L) ma y be us ed, but onl y wi th frequent (q 2 to 4 h) el ectrol yte determi na ti ons . For pa ti ents wi th
s ei zures or coma , 100 mL/h ma y be a dmi ni s tered over 4 to 6 h i n a mounts s uffi ci ent to ra i s e the s erum Na 4 to 6 mEq/L. Thi s a mount (i n mEq) ma y
be ca l cul a ted us i ng the Na defi ci t formul a a s
(Des i red cha nge i n Na ) TBW
where TBW i s 0.6 body wei ght i n kg i n men a nd 0.5 body wei ght i n kg i n women.
For exa mpl e, the a mount of Na needed to ra i s e the Na from 106 to 112 i n a 70-kg ma n ca n be ca l cul a ted a s fol l ows :
(112 mEq/L - 106 mEq/L) (0.6 L/kg 70 kg) = 252 mEq
Beca us e there i s 513 mEq Na /L i n hypertoni c s a l i ne, roughl y 0.5 L of hypertoni c s a l i ne i s needed to ra i s e the Na from 106 to 112 mEq/L.
Adjus tments ma y be needed ba s ed on s erum Na concentra ti ons , whi ch a re moni tored cl os el y for the fi rs t few hours of trea tment. Pa ti ents wi th
s ei zures , coma , or a l tered menta l s ta tus need s upporti ve trea tment, whi ch ma y i nvol ve endotra chea l i ntuba ti on, mecha ni ca l venti l a ti on, a nd
benzodi a zepi nes (eg, l ora zepa m 1 to 2 mg IV q 5 to 10 mi n prn) for s ei zures .
Osmotic demyelination syndrome: Os moti c demyel i na ti on s yndrome (previ ous l y ca l l ed centra l ponti ne myel i nol ys i s ) ma y fol l ow too-ra pi d correcti on
of hypona tremi a . Demyel i na ti on ma y a ffect the pons a nd other a rea s of the bra i n. Les i ons a re more common a mong pa ti ents wi th a l cohol i s m,
undernutri ti on, or other chroni c debi l i ta ti ng i l l nes s . Fl a cci d pa ra l ys i s , dys a rthri a , a nd dys pha gi a ca n evol ve over a few da ys or weeks . The l es i on
ma y extend dors a l l y to i nvol ve s ens ory tra cts a nd l ea ve pa ti ents wi th a l ocked-i n s yndrome (a n a wa ke a nd s enti ent s ta te i n whi ch pa ti ents ,
beca us e of genera l i zed motor pa ra l ys i s , ca nnot communi ca te, except pos s i bl y by coded eye movements ). Da ma ge often i s perma nent. When Na i s
repl a ced too ra pi dl y (eg, > 14 mEq/L/8 h) a nd neurol ogi c s ymptoms s ta rt to devel op, i t i s cri ti ca l to prevent further s erum Na i ncrea s es by s toppi ng
hypertoni c fl ui ds . In s uch ca s es , i nduci ng hypona tremi a wi th hypotoni c fl ui d ma y mi ti ga te the devel opment of perma nent neurol ogi c da ma ge.
Hypernatremia
(For hyperna tremi a i n neona tes , s ee p. 2797.)
Hypernatremia is serum Na concentration > 145 mEq/L. It implies a deficit of total body water relative to total body Na, caused by water intake being less than
water losses. A major symptom is thirst; other clinical manifestations are primarily neurologic (due to an osmotic shift of water out of brain cells), including
confusion, neuromuscular excitability, seizures, and coma. Diagnosis requires measurement of serum Na and sometimes other tests. Treatment is usually
controlled water replacement. When the response is poor, testing (eg, monitored water deprivation or administration of vasopressin) is directed at detecting
causes other than decreased water intake.
Etiology
Hyperna tremi a refl ects a defi ci t of tota l body wa ter (TBW) rel a ti ve to tota l body Na content. Beca us e tota l body Na content i s refl ected by ECF
vol ume s ta tus , hyperna tremi a mus t be cons i dered a l ong wi th s ta tus of the ECF vol ume: hypovol emi a , euvol emi a , a nd hypervol emi a . Note tha t the
ECF vol ume i s not the s a me a s effecti ve pl a s ma vol ume. For exa mpl e, decrea s ed effecti ve pl a s ma vol ume ma y occur wi th decrea s ed ECF vol ume,
but i t ma y a l s o occur wi th a n i ncrea s ed ECF vol ume (eg, i n hea rt fa i l ure, hypoa l bumi nemi a , or ca pi l l a ry l ea k s yndrome).
Hyperna tremi a us ua l l y i mpl i es ei ther a n i mpa i red thi rs t mecha ni s m or l i mi ted a cces s to wa ter. The s everi ty of the underl yi ng di s order tha t res ul ts
i n a n i na bi l i ty to dri nk i n res pons e to thi rs t a nd the effects of bra i n hyperos mol a l i ty a re thought to be res pons i bl e for a hi gh morta l i ty ra te i n
hos pi ta l i zed a dul ts wi th hyperna tremi a . There a re s evera l common ca us es of hyperna tremi a (s ee
Ta bl e 97-6).
Hypovolemic hypernatremia: Hyperna tremi a a s s oci a ted wi th hypovol emi a occurs wi th Na l os s a ccompa ni ed by a rel a ti vel y grea ter l os s of wa ter from
the body. Common extra rena l ca us es i ncl ude mos t of thos e tha t ca us e hypona tremi a a nd vol ume depl eti on (s ee p. 823). Ei ther hyperna tremi a or
hypona tremi a ca n occur wi th s evere vol ume l os s , dependi ng on the rel a ti ve a mounts of Na a nd wa ter l os t a nd the a mount of wa ter i nges ted
before pres enta ti on.
Rena l ca us es of hyperna tremi a a nd vol ume depl eti on i ncl ude thera py wi th di ureti cs . Loop di ureti cs i nhi bi t Na rea bs orpti on i n the concentra ti ng
porti on of the nephrons a nd ca n i ncrea s e wa ter cl ea ra nce. Os moti c di ures i s ca n a l s o i mpa i r rena l concentra ti ng ca pa ci ty beca us e of a hypertoni c
s ubs ta nce pres ent i n the tubul a r l umen of the di s ta l nephron. Gl ycerol , ma nni tol , a nd occa s i ona l l y urea ca n ca us e os moti c di ures i s res ul ti ng i n
hyperna tremi a . The mos t common ca us e of hyperna tremi a due to os moti c di ures i s i s hypergl ycemi a i n pa ti ents wi th di a betes . Beca us e gl ucos e
does not penetra te cel l s i n the a bs ence of i ns ul i n, hypergl ycemi a further dehydra tes the ICF compa rtment. The degree of hyperos mol a l i ty i n
hypergl ycemi a ma y be obs cured by the l oweri ng of s erum Na res ul ti ng from movement of wa ter out of cel l s i nto the ECF (tra ns l a ti ona l
hypona tremi a s ee Hypona tremi a on p. 823). Pa ti ents wi th rena l di s ea s e ca n a l s o be predi s pos ed to hyperna tremi a when thei r ki dneys a re
una bl e to ma xi ma l l y concentra te uri ne.
Euvolemic hypernatremia: Hyperna tremi a wi th euvol emi a i s a decrea s e i n TBW wi th nea rnorma l tota l body Na (pure wa ter defi ci t). Extra rena l ca us es
of wa ter l os s , s uch a s exces s i ve s wea ti ng, res ul t i n s ome Na l os s , but beca us e s wea t i s hypotoni c, hyperna tremi a ca n res ul t before s i gni fi ca nt
hypovol emi a . A defi ci t of a l mos t purel y wa ter a l s o occurs i n centra l a nd nephrogeni c di a betes i ns i pi dus .
Es s enti a l hyperna tremi a (pri ma ry hypodi ps i a ) occa s i ona l l y occurs i n chi l dren wi th bra i n da ma ge a nd i n chroni ca l l y i l l el derl y a dul ts . It i s
cha ra cteri zed by a n i mpa i red thi rs t mecha ni s m (eg, ca us ed by l es i ons of the bra i n's thi rs t center). Al tered os moti c tri gger for ADH rel ea s e i s
a nother pos s i bl e ca us e of euvol emi c hyperna tremi a ; s ome l es i ons ca us e both a n i mpa i red thi rs t mecha ni s m a nd a n a l tered os moti c tri gger. The
nonos moti c rel ea s e of ADH s eems i nta ct, a nd thes e pa ti ents a re genera l l y euvol emi c.
Hypervolemic hypernatremia: Hyperna tremi a i n ra re ca s es i s a s s oci a ted wi th vol ume overl oa d. In thi s ca s e, hyperna tremi a res ul ts from a gros s l y
el eva ted Na i nta ke a s s oci a ted wi th l i mi ted a cces s to wa ter. One exa mpl e i s the exces s i ve a dmi ni s tra ti on of hypertoni c Na HCO3 duri ng trea tment
of l a cti c a ci dos i s . Hyperna tremi a ca n a l s o be ca us ed by the a dmi ni s tra ti on of hypertoni c s a l i ne or i ncorrectl y formul a ted hypera l i menta ti on.
Hypernatremia in the elderly: Hyperna tremi a i s common a mong the el derl y, pa rti cul a rl y pos topera ti ve pa ti ents a nd thos e recei vi ng tube feedi ngs or
pa rentera l nutri ti on. Other contri buti ng fa ctors ma y i ncl ude the fol l owi ng:
[Table 97-6. Pri nci pa l Ca us es of Hyperna tremi a ]
Dependence on others to obta i n wa ter
Impa i red thi rs t mecha ni s m
Impa i red rena l concentra ti ng ca pa ci ty (due to di ureti cs , i mpa i red ADH rel ea s e, or nephron l os s a ccompa nyi ng a gi ng or other rena l di s ea s e)
Impa i red a ngi otens i n II producti on (whi ch ma y contri bute di rectl y to the i mpa i red thi rs t mecha ni s m)
Symptoms and Signs
The ma jor s ymptom of hyperna tremi a i s thi rs t. The a bs ence of thi rs t i n cons ci ous pa ti ents wi th hyperna tremi a s ugges ts a n i mpa i red thi rs t
mecha ni s m. Pa ti ents wi th di ffi cul ty communi ca ti ng ma y be una bl e to expres s thi rs t or obta i n a cces s to wa ter.
The ma jor s i gns of hyperna tremi a res ul t from CNS dys functi on due to bra i n cel l s hri nka ge. Confus i on, neuromus cul a r exci ta bi l i ty, hyperrefl exi a ,
s ei zures , or coma ma y res ul t; cerebrova s cul a r da ma ge wi th s ubcorti ca l or s uba ra chnoi d hemorrha ge a nd venous thrombos es a re common a mong
pa ti ents who di ed from s evere hyperna tremi a .
In chroni c hyperna tremi a , os moti ca l l y a cti ve s ubs ta nces occur i n CNS cel l s (i di ogeni c os mol es ) a nd i ncrea s e i ntra cel l ul a r os mol a l i ty. Therefore,
the degree of bra i n cel l dehydra ti on a nd res ul ta nt CNS s ymptoms a re l es s s evere i n chroni c tha n i n a cute hyperna tremi a .
When hyperna tremi a occurs wi th a bnorma l tota l body Na , the typi ca l s ymptoms of vol ume depl eti on or overl oa d a re pres ent (s ee Vol ume
Depl eti on on p. 822 a nd Vol ume Overl oa d on p. 823). A l a rge vol ume of hypotoni c uri ne i s cha ra cteri s ti ca l l y excreted i n pa ti ents wi th rena l
concentra ti ng defects . When l os s es a re extra rena l , the route of wa ter l os s i s often evi dent (eg, vomi ti ng, di a rrhea , exces s i ve s wea ti ng), a nd the
uri na ry Na concentra ti on i s l ow.
Diagnosis
Serum Na
The di a gnos i s i s cl i ni ca l a nd by mea s uri ng s erum Na . In pa ti ents who do not res pond to s i mpl e rehydra ti on or i n whom hyperna tremi a recurs
des pi te a dequa te a cces s to wa ter, further di a gnos ti c tes ti ng i s wa rra nted. Determi na ti on of the underl yi ng di s order requi res a s s es s ment of uri ne
vol ume a nd os mol a l i ty, pa rti cul a rl y a fter wa ter depri va ti on.
In pa ti ents wi th i ncrea s ed uri ne output, a wa ter depri va ti on tes t (s ee p. 773) i s occa s i ona l l y us ed to di fferenti a te a mong s evera l pol yuri c s ta tes ,
s uch a s centra l a nd nephrogeni c di a betes i ns i pi dus .
Treatment
Repl a cement of i ntra va s cul a r vol ume a nd of free wa ter
Repl a cement of i ntra va s cul a r vol ume a nd of free wa ter i s the ma i n goa l of trea tment. Ora l hydra ti on i s effecti ve i n cons ci ous pa ti ents wi thout
s i gni fi ca nt GI dys functi on. In s evere hyperna tremi a or i n pa ti ents una bl e to dri nk beca us e of conti nued vomi ti ng or menta l s ta tus cha nges , IV
hydra ti on i s preferred. Hyperna tremi a tha t l a s ts < 24 h s houl d be corrected wi thi n 24 h. However, hyperna tremi a tha t i s chroni c or of unknown
dura ti on s houl d be corrected over 48 h, a nd the s erum os mol a l i ty s houl d be l owered a t a ra te of no fa s ter tha n 2 mOs m/L/h to a voi d cerebra l
edema ca us ed by exces s bra i n s ol ute. The a mount of wa ter (i n l i ters ) neces s a ry to repl a ce exi s ti ng defi ci ts ma y be es ti ma ted by the fol l owi ng
formul a :
Free wa ter defi ci t = TBW [s erum Na /140) - 1]
where TBW i s i n l i ters a nd i s es ti ma ted by mul ti pl yi ng wei ght i n ki l ogra ms by 0.6; s erum Na i s i n mEq/L. Thi s formul a a s s umes cons ta nt tota l body
Na content. In pa ti ents wi th hyperna tremi a a nd depl eti on of tota l body Na content (i e, who ha ve vol ume depl eti on), the free wa ter defi ci t i s
grea ter tha n tha t es ti ma ted by the formul a .
In pa ti ents wi th hyperna tremi a a nd ECF vol ume overl oa d (exces s tota l body Na content), the free wa ter defi ci t ca n be repl a ced wi th 5% D/W, whi ch
ca n be s uppl emented wi th a l oop di ureti c. However, too-ra pi d i nfus i on of 5% D/W ma y ca us e gl ycos uri a , thereby i ncrea s i ng s a l t-free wa ter
excreti on a nd hypertoni ci ty, es peci a l l y i n pa ti ents wi th di a betes mel l i tus . Other el ectrol ytes , i ncl udi ng s erum K, s houl d be moni tored a nd s houl d
be repl a ced a s needed.
In pa ti ents wi th hyperna tremi a a nd euvol emi a , free wa ter ca n be repl a ced us i ng ei ther 5% D/W or 0.45% s a l i ne.
Trea tment of pa ti ents wi th centra l di a betes i ns i pi dus i s di s cus s ed on p. 774. Acqui red nephrogeni c di a betes i ns i pi dus i s di s cus s ed on p. 2424.
In pa ti ents wi th hyperna tremi a a nd hypovol emi a , pa rti cul a rl y i n pa ti ents wi th di a betes wi th nonketoti c hypergl ycemi c coma , 0.45% s a l i ne ca n be
gi ven a s a n a l terna ti ve to a combi na ti on of 0.9% norma l s a l i ne a nd 5% D/W to repl eni s h Na a nd free wa ter. Al terna ti vel y, ECF vol ume a nd free
wa ter ca n be repl a ced s epa ra tel y, us i ng the formul a gi ven previ ous l y to es ti ma te the free wa ter defi ci t. When s evere a ci dos i s (pH < 7.10) i s
pres ent, Na HCO3 s ol uti on ca n be a dded to 5% D/W or 0.45% s a l i ne, a s l ong a s the fi na l s ol uti on rema i ns hypotoni c.
Disorders of Potassium Concentration
K i s the mos t a bunda nt i ntra cel l ul a r ca ti on, but onl y a bout 2% of tota l body K i s extra cel l ul a r. Beca us e mos t i ntra cel l ul a r K i s conta i ned wi thi n
mus cl e cel l s , tota l body K i s roughl y proporti ona l to l ea n body ma s s . An a vera ge 70-kg a dul t ha s a bout 3500 mEq of K.
K i s a ma jor determi na nt of i ntra cel l ul a r os mol a l i ty. The ra ti o between ICF a nd ECF K concentra ti ons s trongl y i nfl uences cel l membra ne
pol a ri za ti on, whi ch i n turn i nfl uences i mporta nt cel l proces s es , s uch a s the conducti on of nerve i mpul s es a nd mus cl e (i ncl udi ng myoca rdi a l ) cel l
contra cti on. Thus , rel a ti vel y s ma l l a l tera ti ons i n s erum K concentra ti on ca n ha ve s i gni fi ca nt cl i ni ca l ma ni fes ta ti ons .
In the a bs ence of fa ctors tha t s hi ft K i n or out of cel l s (s ee p. 832), the s erum K concentra ti on correl a tes cl os el y wi th tota l body K content. Once
i ntra cel l ul a r a nd extra cel l ul a r concentra ti ons a re s ta bl e, a decrea s e i n s erum K concentra ti on of a bout 1 mEq/L i ndi ca tes a tota l K defi ci t of a bout
200 to 400 mEq. Pa ti ents wi th K < 3 mEq/L typi ca l l y ha ve a s i gni fi ca nt K defi ci t.
K shifts: Fa ctors tha t s hi ft K i n or out of cel l s i ncl ude the fol l owi ng:
Ins ul i n concentra ti ons
-Adrenergi c a cti vi ty
Aci d-ba s e s ta tus
Ins ul i n moves K i nto cel l s ; hi gh concentra ti ons of i ns ul i n thus l ower s erum K concentra ti on. Low i ns ul i n concentra ti ons , a s i n di a beti c
ketoa ci dos i s , ca us e K to move out of cel l s , thus ra i s i ng s erum K, s ometi mes even i n the pres ence of tota l body K defi ci ency.
-Adrenergi c a goni s ts , es peci a l l y s el ecti ve 2 -a goni s ts , move K i nto cel l s , wherea s -bl ocka de a nd -a goni s ts promote movement of K out of cel l s .
Acute meta bol i c a ci dos i s ca us es K to move out of cel l s , wherea s a cute meta bol i c a l ka l os i s ca us es K to move i nto cel l s . However, cha nges i n s erum
HCO3 concentra ti on ma y be more i mporta nt tha n cha nges i n pH; a ci dos i s ca us ed by a ccumul a ti on of mi nera l a ci ds (nona ni on ga p, hyperchl oremi c
a ci dos i s ) i s more l i kel y to el eva te s erum K. In contra s t, meta bol i c a ci dos i s due to a ccumul a ti on of orga ni c a ci ds (i ncrea s ed a ni on ga p a ci dos i s ) i s
not a s s oci a ted wi th hyperka l emi a . Thus , the hyperka l emi a common i n di a beti c ketoa ci dos i s res ul ts more from i ns ul i n defi ci ency tha n from
a ci dos i s . Acute res pi ra tory a ci dos i s a nd a l ka l os i s a ffect s erum K concentra ti on l es s tha n meta bol i c a ci dos i s a nd a l ka l os i s . Nonethel es s , s erum K
concentra ti on s houl d a l wa ys be i nterpreted i n the context of the s erum pH (a nd HCO3 concentra ti on).
K metabolism: Di eta ry K i nta ke norma l l y va ri es between 40 a nd 150 mEq/da y. In the s tea dy s ta te, feca l l os s es a re us ua l l y cl os e to 10% of i nta ke.
Uri na ry excreti on contri butes to K ba l a nce.
When K i nta ke i s > 150 mEq/da y, a bout 50% of the exces s K a ppea rs i n the uri ne over the next s evera l hours . Mos t of the rema i nder i s tra ns ferred
i nto the i ntra cel l ul a r compa rtment, thus mi ni mi zi ng the ri s e i n s erum K. When el eva ted K i nta ke conti nues , a l dos terone s ecreti on i s s ti mul a ted
a nd thus rena l K excreti on ri s es . In a ddi ti on, K a bs orpti on from s tool a ppea rs to be under s ome regul a ti on a nd ma y fa l l by 50% i n chroni c K exces s .
When K i nta ke fa l l s , i ntra cel l ul a r K a ga i n s erves to buffer wi de s wi ngs i n s erum K concentra ti on. Rena l K cons erva ti on devel ops rel a ti vel y s l owl y i n
res pons e to decrea s es i n di eta ry K a nd i s fa r l es s effi ci ent tha n the ki dneys ' a bi l i ty to cons erve Na . Thus , K depl eti on i s a frequent cl i ni ca l
probl em. Uri na ry K excreti on of 10 mEq/da y repres ents nea r-ma xi ma l rena l K cons erva ti on a nd i mpl i es s i gni fi ca nt K depl eti on.
Acute a ci dos i s i mpa i rs K excreti on, wherea s chroni c a ci dos i s a nd a cute a l ka l os i s ca n promote K excreti on. Increa s ed del i very of Na to the di s ta l
nephrons , a s occurs wi th hi gh Na i nta ke or l oop di ureti c thera py, promotes K excreti on.
False K concentrations: Ps eudohypoka l emi a , or fa l s el y l ow s erum K, occa s i ona l l y occurs i n pa ti ents wi th chroni c myel ocyti c l eukemi a wi th a WBC
count > 105 /L when the s peci men rema i ns a t room tempera ture before bei ng proces s ed beca us e of upta ke of s erum K by a bnorma l l eukocytes i n
the s a mpl e. It i s prevented by prompt s epa ra ti on of pl a s ma or s erum i n bl ood s a mpl es .
Ps eudohyperka l emi a , or fa l s el y el eva ted s erum K, i s more common, typi ca l l y occurri ng due to hemol ys i s a nd rel ea s e of i ntra cel l ul a r K. To prevent
fa l s e res ul ts , phl ebotomy pers onnel s houl d not ra pi dl y a s pi ra te bl ood through a na rrow-ga uge needl e or exces s i vel y a gi ta te bl ood s a mpl es .
Ps eudohyperka l emi a ca n a l s o res ul t from pl a tel et count > 400,000/L due to rel ea s e of K from pl a tel ets duri ng cl otti ng. In ca s es of
ps eudohyperka l emi a , the pl a s ma K (uncl otted bl ood), a s oppos ed to s erum K, i s norma l .
Hypokalemia
Hypokalemia is serum K concentration < 3.5 mEq/L caused by a deficit in total body K stores or abnormal movement of K into cells. The most common causes are
excess losses from the kidneys or GI tract. Clinical features include muscle weakness and polyuria; cardiac hyperexcitability may occur with severe hypokalemia.
Diagnosis is by serum measurement. Treatment is giving K and managing the cause.
Etiology
Hypoka l emi a ca n be ca us ed by decrea s ed i nta ke of K but i s us ua l l y ca us ed by exces s i ve l os s es of K i n the uri ne or from the GI tra ct.
GI tract losses: Abnorma l GI K l os s es occur i n a l l of the fol l owi ng:
Chroni c di a rrhea , i ncl udi ng chroni c l a xa ti ve a bus e a nd bowel di vers i on
Cl a y (bentoni te) i nges ti on, whi ch bi nds K a nd grea tl y decrea s es a bs orpti on
Vomi ti ng
Protra cted ga s tri c s ucti on (whi ch removes vol ume a nd HCl , ca us i ng the ki dneys to excrete HCO3 a nd, to el ectri ca l l y ba l a nce l os t HCO3 , K)
Ra rel y, vi l l ous a denoma of the col on, whi ch ca us es ma s s i ve K s ecreti on
GI K l os s es ma y be compounded by concomi ta nt rena l K l os s es due to meta bol i c a l ka l os i s a nd s ti mul a ti on of a l dos terone due to vol ume
depl eti on.
Intracellular shift: The tra ns cel l ul a r s hi ft of K i nto cel l s ma y a l s o ca us e hypoka l emi a . Thi s s hi ft ca n occur i n a ny of the fol l owi ng:
Gl ycogenes i s duri ng TPN or entera l hypera l i menta ti on (s ti mul a ti ng i ns ul i n rel ea s e)
After a dmi ni s tra ti on of i ns ul i n
Sti mul a ti on of the s ympa theti c nervous s ys tem, pa rti cul a rl y wi th 2 -a goni s ts (eg, a l buterol , terbuta l i ne), whi ch ma y i ncrea s e cel l ul a r K upta ke
Thyrotoxi cos i s (occa s i ona l l y) due to exces s i ve -s ympa theti c s ti mul a ti on (hypoka l emi c thyrotoxi c peri odi c pa ra l ys i s )
Fa mi l i a l peri odi c pa ra l ys i s (s ee p. 3008), a ra re a utos oma l domi na nt di s order cha ra cteri zed by tra ns i ent epi s odes of profound hypoka l emi a
thought to be due to s udden a bnorma l s hi fts of K i nto cel l s . Epi s odes frequentl y i nvol ve va ryi ng degrees of pa ra l ys i s . They a re typi ca l l y
preci pi ta ted by a l a rge ca rbohydra te mea l or s trenuous exerci s e.
Renal losses: Va ri ous di s orders ca n i ncrea s e rena l K excreti on. Exces s mi nera l ocorti coi d effect ca n di rectl y i ncrea s e K s ecreti on by the di s ta l
nephrons a nd occurs i n a ny of the fol l owi ng:
Adrena l s teroi d exces s tha t i s due to Cus hi ng's s yndrome, pri ma ry hypera l dos teroni s m, ra re reni n-s ecreti ng tumors , gl ucocorti coi d-remedi a bl e
a l dos teroni s m (a ra re i nheri ted di s order i nvol vi ng a bnorma l a l dos terone meta bol i s m), a nd congeni ta l a drena l hyperpl a s i a .
Inges ti on of s ubs ta nces s uch a s gl ycyrrhi zi n (pres ent i n na tura l l i cori ce a nd us ed i n the ma nufa cture of chewi ng toba cco), whi ch i nhi bi ts the
enzyme 11-hydroxys teroi d dehydrogena s e (11-HSDH), preventi ng the convers i on of corti s ol , whi ch ha s s ome mi nera l ocorti coi d a cti vi ty, to
corti s one, whi ch does not, res ul ti ng i n hi gh ci rcul a ti ng concentra ti ons of corti s ol a nd rena l K wa s ti ng.
Ba rtter a nd Gi tel ma n's s yndromes , uncommon geneti c di s orders cha ra cteri zed by rena l K a nd Na wa s ti ng, exces s i ve producti on of reni n a nd
a l dos terone, a nd normotens i on. Ba rtter s yndrome (s ee a l s o p. 2988) i s ca us ed by muta ti ons i n a l oop di ureti c-s ens i ti ve i on tra ns port
mecha ni s m i n the l oop of Henl e. Gi tel ma n's s yndrome i s ca us ed by l os s of functi on muta ti ons i n a thi a zi de-s ens i ti ve i on tra ns port mecha ni s m
i n the di s ta l nephron.
Li ddl e s yndrome (s ee a l s o p. 2423) i s a ra re a utos oma l domi na nt di s order cha ra cteri zed by s evere hypertens i on a nd hypoka l emi a . Li ddl e
s yndrome i s ca us ed by unres tra i ned Na rea bs orpti on i n the di s ta l nephron due to one of s evera l muta ti ons found i n genes encodi ng for epi thel i a l
Na cha nnel s ubuni ts . Ina ppropri a tel y hi gh rea bs orpti on of Na res ul ts i n both hypertens i on a nd rena l K wa s ti ng.
Rena l K wa s ti ng ca n a l s o be ca us ed by numerous congeni ta l a nd a cqui red rena l tubul a r di s ea s es , s uch a s the rena l tubul a r a ci dos es a nd Fa nconi
s yndrome, a n unus ua l s yndrome res ul ti ng i n rena l wa s ti ng of K, gl ucos e, phos pha te, uri c a ci d, a nd a mi no a ci ds .
Hypoma gnes emi a i s a common correl a te of hypoka l emi a . Much of thi s i s a ttri buta bl e to common underl yi ng ca us es (i e, di ureti cs , di a rrhea ), but
hypoma gnes emi a i ts el f ma y a l s o res ul t i n i ncrea s ed rena l K l os s es .
Drugs: Di ureti cs a re by fa r the mos t commonl y us ed drugs tha t ca us e hypoka l emi a . K-wa s ti ng di ureti cs tha t bl ock Na rea bs orpti on proxi ma l to the
di s ta l nephron i ncl ude
Thi a zi des
Loop di ureti cs
Os moti c di ureti cs
By i nduci ng di a rrhea , l a xa ti ves , es peci a l l y when a bus ed, ca n ca us e hypoka l emi a . Surrepti ti ous di ureti c or l a xa ti ve a bus e or both i s a frequent
ca us e of pers i s tent hypoka l emi a , pa rti cul a rl y a mong pa ti ents preoccupi ed wi th wei ght l os s a nd a mong hea l th ca re pra cti ti oners wi th a cces s to
pres cri pti on drugs .
Other drugs tha t ca n ca us e hypoka l emi a i ncl ude
Amphoteri ci n B
Anti ps eudomona l peni ci l l i ns (eg, ca rbeni ci l l i n)
Peni ci l l i n i n hi gh dos es
Theophyl l i ne i ntoxi ca ti on (both a cute a nd chroni c)
Symptoms and Signs
Mi l d hypoka l emi a (s erum K 3 to 3.5 mEq/L) ra rel y ca us es s ymptoms . Serum K < 3 mEq/L genera l l y ca us es mus cl e wea knes s a nd ma y l ea d to
pa ra l ys i s a nd res pi ra tory fa i l ure. Other mus cul a r dys functi on i ncl udes cra mpi ng, fa s ci cul a ti ons , pa ra l yti c i l eus , hypoventi l a ti on, hypotens i on,
teta ny, a nd rha bdomyol ys i s . Pers i s tent hypoka l emi a ca n i mpa i r rena l concentra ti ng a bi l i ty, ca us i ng pol yuri a wi th s econda ry pol ydi ps i a .
Diagnosis
Serum K mea s urement
ECG
When the mecha ni s m not evi dent cl i ni ca l l y, 24-h uri na ry K excreti on a nd s erum Mg concentra ti on
Hypoka l emi a (s erum K < 3.5 mEq/L) ma y be found on routi ne s erum el ectrol yte mea s urement. It s houl d be s us pected i n pa ti ents wi th typi ca l
cha nges on a n ECG or who ha ve mus cul a r s ymptoms a nd ri s k fa ctors a nd confi rmed by bl ood tes ti ng.
ECG: ECG s houl d be done on pa ti ents wi th hypoka l emi a . Ca rdi a c effects of hypoka l emi a a re us ua l l y mi ni ma l unti l s erum K concentra ti ons a re < 3
mEq/L. Hypoka l emi a ca us es s a ggi ng of the ST s egment, depres s i on of the T wa ve, a nd el eva ti on of the U wa ve. Wi th ma rked hypoka l emi a , the T
wa ve becomes progres s i vel y s ma l l er a nd the U wa ve becomes i ncrea s i ngl y l a rger. Someti mes , a fl a t or pos i ti ve T wa ve merges wi th a pos i ti ve U
wa ve, whi ch ma y be confus ed wi th QT prol onga ti on (s ee
Fi g. 97-2). Hypoka l emi a ma y ca us e prema ture ventri cul a r a nd a tri a l contra cti ons , ventri cul a r a nd a tri a l ta chya rrhythmi a s , a nd 2nd- or 3rd-degree
a tri oventri cul a r bl ock. Such a rrhythmi a s become more s evere wi th i ncrea s i ngl y s evere hypoka l emi a ; eventua l l y, ventri cul a r fi bri l l a ti on ma y occur.
Pa ti ents wi th s i gni fi ca nt preexi s ti ng hea rt di s ea s e a nd pa ti ents recei vi ng di goxi n a re a t ri s k of ca rdi a c conducti on a bnorma l i ti es even from mi l d
hypoka l emi a .
Diagnosis of cause: The ca us e i s us ua l l y a ppa rent by hi s tory (pa rti cul a rl y the drug hi s tory); when i t i s not, further i nves ti ga ti on i s wa rra nted. After
a ci dos i s a nd other ca us es of i ntra cel l ul a r K s hi ft (i ncrea s ed -a drenergi c effect, hyperi ns ul i nemi a ) ha ve been el i mi na ted, 24-h uri na ry K a nd
s erum Mg concentra ti ons a re mea s ured. In hypoka l emi a , K s ecreti on i s norma l l y < 15 mEq/L. Extra rena l (GI) K l os s or decrea s ed K i nges ti on i s
s us pected i n chroni c unexpl a i ned hypoka l emi a when rena l K s ecreti on i s < 15 mEq/L. Secreti on of > 15 mEq/L s ugges ts a rena l ca us e for K l os s .
Unexpl a i ned hypoka l emi a wi th i ncrea s ed rena l K s ecreti on a nd hypertens i on s ugges ts a n a l dos terone-s ecreti ng tumor or Li ddl e s yndrome.
Unexpl a i ned hypoka l emi a wi th i ncrea s ed rena l K l os s a nd norma l BP s ugges ts Ba rtter or Gi tel ma n's s yndrome, but hypoma gnes emi a ,
s urrepti ti ous vomi ti ng, a nd di ureti c a bus e a re more common a nd s houl d a l s o be cons i dered.
Treatment
Ora l K s uppl ements
IV K s uppl ements for s evere hyperka l emi a or ongoi ng K l os s es
Ma ny ora l K s uppl ements a re a va i l a bl e. Beca us e hi gh s i ngl e dos es ca n ca us e GI i rri ta ti on a nd occa s i ona l bl eedi ng, defi ci ts a re us ua l l y repl a ced
i n di vi ded dos es . Li qui d KCl gi ven ora l l y el eva tes concentra ti ons wi thi n 1 to 2 h but ha s a bi tter ta s te a nd i s tol era ted pa rti cul a rl y poorl y i n dos es >
25 to 50 mEq. Wa x-i mpregna ted KCl prepa ra ti ons a re s a fe a nd better tol era ted. GI bl eedi ng ma y be even l es s common wi th mi croenca ps ul a ted KCl
prepa ra ti ons . Severa l of thes e prepa ra ti ons conta i n 8 or 10 mEq/ca ps ul e. Beca us e a decrea s e i n s erum K of 1 mEq/L correl a tes wi th a bout a 200- to
400-mEq defi ci t i n tota l body K s tores , tota l defi ci t ca n be es ti ma ted a nd repl a ced over a number of da ys a t 20 to 80 mEq/da y.
When hypoka l emi a i s s evere (eg, wi th ECG cha nges or s evere s ymptoms ), i s unres pons i ve
[Fig. 97-2. ECG pa tterns i n hypoka l emi a a nd hyperka l emi a .]
to ora l thera py, or occurs i n hos pi ta l i zed pa ti ents who a re ta ki ng di gi ta l i s or who ha ve s i gni fi ca nt hea rt di s ea s e or ongoi ng l os s es , K mus t be
repl a ced IV. Beca us e K s ol uti ons ca n i rri ta te peri phera l vei ns , the concentra ti on s houl d not exceed 40 mEq/L. The ra te of correcti on of hypoka l emi a
i s l i mi ted beca us e of the l a g i n K movement i nto cel l s . Routine infusion rates should not exceed 10 mEq/h. In hypoka l emi c-i nduced a rrhythmi a , IV KCl
mus t be gi ven more ra pi dl y, us ua l l y through a centra l vei n or us i ng mul ti pl e peri phera l vei ns s i mul ta neous l y. Infus i on of 40 mEq KCl /h ca n be
underta ken but onl y wi th conti nuous ca rdi a c moni tori ng a nd hourl y s erum K determi na ti ons . Gl ucos e s ol uti ons a re a voi ded beca us e el eva ti on i n
the s erum i ns ul i n concentra ti ons coul d res ul t i n tra ns i ent wors eni ng of hypoka l emi a .
Even when K defi ci ts a re s evere, i t i s ra rel y neces s a ry to gi ve > 100 to 120 mEq of K i n a 24-h peri od unl es s K l os s conti nues . In K defi ci t wi th hi gh
s erum K concentra ti on, a s i n di a beti c ketoa ci dos i s , IV K i s deferred unti l the s erum K s ta rts to fa l l . When hypoka l emi a occurs wi th
hypoma gnes emi a , both the K a nd Mg defi ci enci es mus t be corrected to s top ongoi ng rena l K wa s ti ng (s ee Hypoma gnes emi a on p. 852).
Prevention
Routi ne K repl a cement i s not neces s a ry i n mos t pa ti ents recei vi ng di ureti cs . However, s erum K s houl d be moni tored duri ng di ureti c us e when ri s k
of hyperka l emi a or of i ts compl i ca ti ons i s hi gh. Ri s k i s hi gh i n
Pa ti ents wi th decrea s ed l eft ventri cul a r functi on
Pa ti ents ta ki ng di goxi n
Pa ti ents wi th di a betes (i n whom i ns ul i n concentra ti ons ca n fl uctua te)
Pa ti ents wi th a s thma who a re ta ki ng 2 -a goni s ts
Tri a mterene 100 mg po once/da y or s pi ronol a ctone 25 mg po qi d does not i ncrea s e K excreti on a nd ma y be us eful i n pa ti ents who become
hypoka l emi c but mus t us e di ureti cs . When hypoka l emi a devel ops , K s uppl ementa ti on, us ua l l y wi th ora l KCl , i s i ndi ca ted.
Hyperkalemia
Hyperkalemia is serum K concentration > 5.5 mEq/L resulting from excess total body K stores or abnormal movement of K out of cells. There are usually several
simultaneous contributing factors, including increased K intake, drugs that impair renal K excretion, and acute or chronic kidney disease. It can also occur in
metabolic acidosis as in diabetic ketoacidosis. Clinical manifestations are generally neuromuscular, resulting in muscle weakness and cardiac toxicity that, when
severe, can degenerate to ventricular fibrillation or asystole. Diagnosis is by measuring serum K. Treatment may involve decreasing K intake, adjusting drugs,
giving a cation exchange resin and, in emergencies, Ca gluconate, insulin, and dialysis.
Etiology
The mos t common ca us e of i ncrea s ed s erum K concentra ti on i s proba bl y ps eudohyperka l emi a ca us ed by hemol ys i s of RBCs i n the bl ood s a mpl e.
Norma l ki dneys eventua l l y excrete K l oa ds , s o s us ta i ned, nona rti fa ctua l hyperka l emi a us ua l l y i mpl i es di mi ni s hed rena l K excreti on. However,
other fa ctors us ua l l y contri bute. They ca n i ncl ude i ncrea s ed K i nta ke, i ncrea s ed K rel ea s e from cel l s , or both (s ee
Ta bl e 97-7). When s uffi ci ent KCl i s i nges ted or gi ven pa rentera l l y, s evere hyperka l emi a ma y res ul t even wi th norma l rena l functi on but i s us ua l l y
tempora ry.
Hyperka l emi a due to tota l body K exces s i s pa rti cul a rl y common i n ol i guri c s ta tes (es peci a l l y a cute rena l fa i l ure) a nd wi th rha bdomyol ys i s , burns ,
bl eedi ng i nto s oft ti s s ue or the GI tra ct, a nd a drena l i ns uffi ci ency. In chroni c rena l fa i l ure, hyperka l emi a i s uncommon unti l the GFR fa l l s to < 10 to
15 mL/mi n unl es s di eta ry or IV K i nta ke i s exces s i ve.
Symptoms and Signs
Al though fl a cci d pa ra l ys i s occa s i ona l l y occurs , hyperka l emi a i s us ua l l y a s ymptoma ti c unti l ca rdi a c toxi ci ty devel ops .
In the ra re di s order hyperka l emi c fa mi l i a l peri odi c pa ra l ys i s , wea knes s frequentl y devel ops duri ng a tta cks a nd ca n progres s to fra nk pa ra l ys i s .
Diagnosis
Serum K mea s urement
ECG
Revi ew of drug us e
As s es s ment of rena l functi on
Hyperka l emi a (s erum K > 5.5 mEq/L) ma y be found on routi ne s erum el ectrol yte mea s urement. It s houl d be s us pected i n pa ti ents wi th typi ca l
cha nges on a n ECG or pa ti ents a t hi gh ri s k, s uch a s thos e wi th rena l fa i l ure, a dva nced hea rt fa i l ure trea ted wi th ACE i nhi bi tors a nd K-s pa ri ng
di ureti cs , or uri na ry obs tructi on.
ECG: ECG s houl d be done on pa ti ents wi th hyperka l emi a . ECG cha nges (s ee Fi g. 97-2) a re frequentl y vi s i bl e when s erum K i s > 5.5 mEq/L. Sl owi ng of
conducti on cha ra cteri zed by a n i ncrea s ed PR i nterva l a nd s horteni ng of the QT i nterva l a s wel l a s ta l l , s ymmetri c, pea ked T
[Table 97-7. Fa ctors Contri buti ng to Hyperka l emi a ]
wa ves a re vi s i bl e i ni ti a l l y. K > 6.5 mEq/L ca us es further s l owi ng of conducti on wi th wi deni ng of the QRS i nterva l , di s a ppea ra nce of the P wa ve, a nd
noda l a nd es ca pe ventri cul a r a rrhythmi a s . Fi na l l y, the QRS compl ex degenera tes i nto a s i ne wa ve pa ttern, a nd ventri cul a r fi bri l l a ti on or a s ys tol e
ens ues .
Diagnosis of the cause: Ps eudohyperka l emi a s houl d be cons i dered i n pa ti ents wi thout ri s k fa ctors or ECG a bnorma l i ti es . Hemol ys i s ma y be reported
by the l a bora tory. When ps eudohyperka l emi a i s s us pected, K concentra ti on s houl d be repea ted, ta ki ng mea s ures to a voi d hemol ys i s of the
s a mpl e.
Di a gnos i s of the ca us e of hyperka l emi a requi res a deta i l ed hi s tory, i ncl udi ng a revi ew of drugs , a phys i ca l exa mi na ti on wi th empha s i s on vol ume
s ta tus , a nd mea s urement of el ectrol ytes , BUN, a nd crea ti ni ne. In ca s es i n whi ch rena l fa i l ure i s pres ent, a ddi ti ona l tes ts , i ncl udi ng rena l
ul tra s onogra phy to excl ude obs tructi on, a re needed (s ee p. 2438).
Treatment
Trea tment of the ca us e
For mi l d hyperka l emi a , Na pol ys tyrene s ul fona te
For modera te or s evere hyperka l emi a , IV i ns ul i n a nd gl ucos e, a n IV Ca s ol uti on, pos s i bl y a n i nha l ed 2 -a goni s t, a nd us ua l l y hemodi a l ys i s
Mild hyperkalemia: Pa ti ents wi th s erum K < 6 mEq/L a nd no ECG a bnorma l i ti es ma y res pond to di mi ni s hed K i nta ke or s toppi ng K-el eva ti ng drugs .
The a ddi ti on of a l oop di ureti c enha nces rena l K excreti on a s l ong a s vol ume depl eti on i s not pres ent.
Na pol ys tyrene s ul fona te i n s orbi tol ca n be gi ven (15 to 30 g i n 30 to 70 mL of 70% s orbi tol po q 4 to 6 h). It a cts a s a ca ti on excha nge res i n a nd
removes K through the GI mucos a . Sorbi tol i s a dmi ni s tered wi th the res i n to ens ure pa s s a ge through the GI tra ct. Pa ti ents una bl e to ta ke drugs
ora l l y beca us e of na us ea or other rea s ons ma y be gi ven s i mi l a r dos es by enema . Enema s a re not a s effecti ve a t l oweri ng K i n pa ti ents wi th i l eus .
Enema s s houl d not be us ed i f a cute a bdomen i s s us pected. About 1 mEq of K i s removed per gra m of res i n gi ven. Res i n thera py i s s l ow a nd often
fa i l s to l ower s erum K s i gni fi ca ntl y i n hyperca ta bol i c s ta tes . Beca us e Na i s excha nged for K when Na pol ys tyrene s ul fona te i s us ed, Na overl oa d
ma y occur, pa rti cul a rl y i n ol i guri c pa ti ents wi th preexi s ti ng vol ume overl oa d.
Moderate to severe hyperkalemia: Serum K between 6 a nd 6.5 mEq/L needs prompt a ttenti on, but the a ctua l trea tment depends on the cl i ni ca l
s i tua ti on. If no ECG cha nges a re pres ent a nd rena l functi on i s i nta ct, ma neuvers des cri bed previ ous l y a re us ua l l y effecti ve. Fol l ow-up s erum K
l evel s a re needed to ens ure tha t the hyperka l emi a ha s been s ucces s ful l y trea ted. If s erum K i s > 6.5 mEq/L, more a ggres s i ve thera py i s requi red.
Admi ni s tra ti on of regul a r i ns ul i n 5 to 10 uni ts IV i s fol l owed i mmedi a tel y by or a dmi ni s tered s i mul ta neous l y wi th ra pi d i nfus i on of 50 mL 50%
gl ucos e. Infus i on of 10% D/W s houl d fol l ow a t 50 mL/h to prevent hypogl ycemi a . The effect on s erum K pea ks i n 1 h a nd l a s ts for s evera l hours .
If ECG cha nges i ncl ude the l os s of P-wa ve or wi deni ng of the QRS compl ex, trea tment wi th IV Ca a s wel l a s i ns ul i n a nd gl ucos e i s i ndi ca ted; 10 to
20 mL 10% Ca gl ucona te (or 5 to 10 mL 22% Ca gl ucepta te) i s gi ven IV over 5 to 10 mi n. Ca a nta goni zes the effect of hyperka l emi a on ca rdi a c mus cl e.
Ca s houl d be gi ven wi th ca uti on to pa ti ents ta ki ng di goxi n beca us e of the ri s k of preci pi ta ti ng hypoka l emi a -rel a ted a rrhythmi a s . If the ECG s hows
a s i ne wa ve pa ttern or a s ys tol e, Ca gl ucona te ma y be gi ven more ra pi dl y (5 to 10 mL IV over 2 mi n). Ca Cl ca n a l s o be us ed but ca n be i rri ta ti ng to
peri phera l vei ns a nd ca us e ti s s ue necros i s i f extra va s a ted. Ca Cl s houl d be gi ven onl y through a correctl y pos i ti oned centra l venous ca theter. The
benefi ts of Ca occur wi thi n mi nutes but l a s t onl y 20 to 30 mi n. Ca i nfus i on i s a tempori zi ng mea s ure whi l e a wa i ti ng the effects of other trea tments
or i ni ti a ti on of hemodi a l ys i s a nd ma y need to be repea ted.
A hi gh-dos e 2 -a goni s t, s uch a s a l buterol 10 to 20 mg i nha l ed over 10 mi n (5 mg/mL concentra ti on), ca n l ower s erum K by 0.5 to 1.5 mEq/L a nd ma y
be a hel pful a djunct. The pea k effect occurs i n 90 mi n. However, 2 -a goni s ts a re contra i ndi ca ted i n pa ti ents wi th uns ta bl e a ngi na a nd a cute MI.
Admi ni s tra ti on of IV Na HCO3 i s controvers i a l . It ma y l ower s erum K over s evera l hours . Reducti on ma y res ul t from a l ka l i ni za ti on or the
hypertoni ci ty due to the concentra ted Na i n the prepa ra ti on. The hypertoni c Na tha t i t conta i ns ma y be ha rmful for di a l ys i s pa ti ents who a l s o ma y
ha ve vol ume overl oa d. When gi ven, the us ua l dos e i s 45 mEq (1 a mpul e of 7.5% Na HCO3 ) i nfus ed over 5 mi n a nd repea ted i n 30 mi n. HCO3 thera py
ha s l i ttl e effect when us ed by i ts el f i n pa ti ents wi th s evere rena l i ns uffi ci ency unl es s a ci demi a i s a l s o pres ent.
In a ddi ti on to s tra tegi es for l oweri ng K by s hi fti ng i t i nto cel l s , ma neuvers to remove K from the body s houl d a l s o be done ea rl y i n the trea tment of
s evere or s ymptoma ti c hyperka l emi a . K ca n be removed vi a the GI tra ct by a dmi ni s tra ti on of Na pol ys tyrene s ul fona te (s ee p. 836) or by
hemodi a l ys i s . Hemodi a l ys i s s houl d be i ns ti tuted promptl y a fter emergency mea s ures i n pa ti ents wi th rena l fa i l ure or when emergency trea tment
i s i neffecti ve. Di a l ys i s s houl d be cons i dered ea rl y i n pa ti ents wi th end-s ta ge rena l di s ea s e a nd hyperka l emi a beca us e they a re a t i ncrea s ed ri s k
of progres s i on to more s evere hyperka l emi a a nd s eri ous ca rdi a c a rrhythmi a s . Peri tonea l di a l ys i s i s rel a ti vel y i neffi ci ent a t removi ng K.
Disorders of Calcium Concentration
Ca i s requi red for the proper functi oni ng of mus cl e contra cti on, nerve conducti on, hormone rel ea s e, a nd bl ood coa gul a ti on. In a ddi ti on, proper Ca
concentra ti on i s requi red for va ri ous other meta bol i c proces s es .
Ma i ntena nce of body Ca s tores depends on
Di eta ry Ca i nta ke
Abs orpti on of Ca from the GI tra ct
Rena l Ca excreti on
In a ba l a nced di et, roughl y 1000 mg of Ca i s i nges ted ea ch da y a nd a bout a nother 200 mg/da y i s s ecreted i nto the GI tra ct i n the bi l e a nd other GI
s ecreti ons . Dependi ng on the concentra ti on of ci rcul a ti ng vi ta mi n D, pa rti cul a rl y 1,25(OH) 2 D (1,25-di hydroxychol eca l ci ferol , ca l ci tri ol , or a cti ve
vi ta mi n D, whi ch i s converted i n the ki dney from 25(OH)D, the i na cti ve form), roughl y 200 to 400 mg of Ca i s a bs orbed from the i ntes ti ne ea ch da y.
The rema i ni ng 800 to 1000 mg a ppea rs i n the s tool . Ca ba l a nce i s ma i nta i ned through rena l Ca excreti on a vera gi ng 200 mg/da y.
Both extra cel l ul a r a nd i ntra cel l ul a r Ca concentra ti ons a re ti ghtl y regul a ted by bi di recti ona l Ca tra ns port a cros s the pl a s ma membra ne of cel l s a nd
i ntra cel l ul a r orga nel l es , s uch a s the endopl a s mi c reti cul um, the s a rcopl a s mi c reti cul um of mus cl e cel l s , a nd the mi tochondri a . Cytos ol i c i oni zed
Ca i s ma i nta i ned wi thi n the mi cromol a r ra nge (< 1/1000 of the s erum concentra ti on). Ioni zed Ca a cts a s a n i ntra cel l ul a r 2nd mes s enger; i t i s
i nvol ved i n s kel eta l mus cl e contra cti on, exci ta ti on-contra cti on coupl i ng i n ca rdi a c a nd s mooth mus cl e, a nd a cti va ti on of protei n ki na s es a nd
enzyme phos phoryl a ti on. Ca i s a l s o i nvol ved i n the a cti on of other i ntra cel l ul a r mes s engers , s uch a s cAMP a nd i nos i tol 1,4,5-tri phos pha te, a nd
thus medi a tes the cel l ul a r res pons e to numerous hormones , i ncl udi ng epi nephri ne, gl uca gon, ADH (va s opres s i n), s ecreti n, a nd chol ecys toki ni n.
Pa ra thyroi d hormone (PTH) i ncrea s es uri na ry cAMP.
Des pi te i ts i mporta nt i ntra cel l ul a r rol es , a bout 99% of body Ca i s i n bone, ma i nl y a s hydroxya pa ti te crys ta l s . About 1% of bone Ca i s freel y
excha ngea bl e wi th the ECF a nd, therefore, i s a va i l a bl e for bufferi ng cha nges i n Ca ba l a nce.
Norma l tota l s erum Ca concentra ti on ra nges from 8.8 to 10.4 mg/dL (2.20 to 2.60 mmol /L). About 40% of the tota l bl ood Ca i s bound to pl a s ma
protei ns , pri ma ri l y a l bumi n. The rema i ni ng 60% i ncl udes i oni zed Ca pl us Ca compl exed wi th phos pha te (PO4 ) a nd ci tra te. Tota l Ca (i e, protei nbound, compl exed, a nd i oni zed Ca ) i s us ua l l y wha t i s determi ned by cl i ni ca l l a bora tory mea s urement. Idea l l y, i oni zed or free Ca s houl d be
determi ned beca us e i t i s the phys i ol ogi ca l l y a cti ve form of Ca i n pl a s ma ; thi s determi na ti on, beca us e of i ts techni ca l di ffi cul ty, i s us ua l l y
res tri cted to pa ti ents i n whom s i gni fi ca nt a l tera ti on of protei n bi ndi ng of s erum Ca i s s us pected. Ioni zed Ca i s genera l l y a s s umed to be a bout 50%
of the tota l s erum Ca .
Regulation of Calcium Metabolism
The meta bol i s m of Ca a nd of PO4 (s ee p. 850) i s i nti ma tel y rel a ted. The regul a ti on of both Ca a nd PO4 ba l a nce i s grea tl y i nfl uenced by
concentra ti ons of ci rcul a ti ng PTH, vi ta mi n D, a nd, to a l es s er extent, ca l ci toni n. Ca a nd i norga ni c PO4 concentra ti ons a re a l s o l i nked by thei r a bi l i ty
to chemi ca l l y rea ct to form Ca PO4 . The product of concentra ti ons of Ca a nd PO4 (i n mEq/L) i s es ti ma ted to be 60 norma l l y; when the product exceeds
70, preci pi ta ti on of Ca PO4 crys ta l s i n s oft ti s s ue i s much more l i kel y. Ca l ci fi ca ti on of va s cul a r ti s s ue a ccel era tes a rteri os cl eroti c va s cul a r di s ea s e
a nd ma y occur when the Ca PO4 product i s even l ower (> 55), es peci a l l y i n pa ti ents wi th chroni c ki dney di s ea s e.
PTH i s s ecreted by the pa ra thyroi d gl a nds . It ha s s evera l a cti ons , but perha ps the mos t i mporta nt i s to defend a ga i ns t hypoca l cemi a . Pa ra thyroi d
cel l s s ens e decrea s es i n s erum Ca a nd, i n res pons e, rel ea s e preformed PTH i nto the ci rcul a ti on. PTH i ncrea s es s erum Ca wi thi n mi nutes by
i ncrea s i ng rena l a nd i ntes ti na l a bs orpti on of Ca a nd by ra pi dl y mobi l i zi ng Ca a nd PO4 from bone (bone res orpti on). Rena l Ca excreti on genera l l y
pa ra l l el s Na excreti on a nd i s i nfl uenced by ma ny of the s a me fa ctors tha t govern Na tra ns port i n the proxi ma l tubul e. However, PTH enha nces
di s ta l tubul a r Ca rea bs orpti on i ndependentl y of Na . PTH a l s o decrea s es rena l PO4 rea bs orpti on a nd thus i ncrea s es rena l PO4 l os s es . Rena l PO4
l os s prevents the s ol ubi l i ty product of Ca a nd PO4 from bei ng exceeded i n pl a s ma a s Ca concentra ti ons ri s e i n res pons e to PTH. PTH a l s o i ncrea s es
s erum Ca by s ti mul a ti ng convers i on of vi ta mi n D (s ee p. 41) to i ts mos t a cti ve form, ca l ci tri ol . Thi s form of vi ta mi n D i ncrea s es the percenta ge of
di eta ry Ca a bs orbed by the i ntes ti ne. Des pi te i ncrea s ed Ca a bs orpti on, l ong-term i ncrea s es i n PTH s ecreti on genera l l y res ul t i n further bone
res orpti on by i nhi bi ti ng os teobl a s ti c functi on a nd promoti ng os teocl a s ti c a cti vi ty. PTH a nd vi ta mi n D both functi on a s i mporta nt regul a tors of bone
growth a nd bone remodel i ng (s ee p. 41).
Ra di oi mmunoa s s a ys for the i nta ct PTH mol ecul e a re s ti l l the recommended wa y to tes t for PTH. Second-genera ti on a s s a ys for i nta ct PTH a re
a va i l a bl e. Thes e tes ts mea s ure bi oa va i l a bl e PTH or compl ete PTH. They gi ve va l ues equa l to 50 to 60% of thos e obta i ned wi th the ol der a s s a y.
Us eful nes s of the newer a s s a ys i s under i nves ti ga ti on. Someti mes tota l or nephrogenous cAMP excreti on i s mea s ured i n di a gnos i s of
ps eudohypopa ra thyroi di s m.
Ca l ci toni n i s s ecreted by the thyroi d pa ra fol l i cul a r cel l s (C cel l s ). Ca l ci toni n tends to l ower s erum Ca concentra ti on by enha nci ng cel l ul a r upta ke,
rena l excreti on, a nd bone forma ti on. The effects of ca l ci toni n on bone meta bol i s m a re much wea ker tha n thos e of ei ther PTH or vi ta mi n D.
Hypocalcemia
(Hypoca l cemi a i n neona tes i s di s cus s ed on p. 2794.)
Hypocalcemia is total serum Ca concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized Ca
concentration < 4.7 mg/dL (< 1.17 mmol/L). Causes include hypoparathyroidism, vitamin D deficiency, and renal disease. Manifestations include paresthesias,
tetany, and, when severe, seizures, encephalopathy, and heart failure. Diagnosis involves measurement of serum Ca with adjustment for serum albumin
concentration. Treatment is administration of Ca, sometimes with vitamin D.
Etiology
Hypoca l cemi a ha s a number of ca us es , i ncl udi ng
Ps eudohypopa ra thyroi di s m
Vi ta mi n D defi ci ency a nd dependency
Rena l di s ea s e
Hypoparathyroidism: Hypopa ra thyroi di s m i s cha ra cteri zed by hypoca l cemi a a nd hyperphos pha temi a a nd often ca us es chroni c teta ny.
Hypopa ra thyroi di s m res ul ts from defi ci ent pa ra thyroi d hormone (PTH), whi ch ca n occur i n a utoi mmune di s orders or a fter the a cci denta l remova l of
or da ma ge to s evera l pa ra thyroi d gl a nds duri ng thyroi dectomy. Tra ns i ent hypopa ra thyroi di s m i s common a fter s ubtota l thyroi dectomy, but
perma nent hypopa ra thyroi di s m occurs a fter < 3% of s uch thyroi dectomi es done by experi enced s urgeons . Ma ni fes ta ti ons of hypoca l cemi a us ua l l y
begi n a bout 24 to 48 h pos topera ti vel y but ma y occur a fter months or yea rs . PTH defi ci ency i s more common a fter ra di ca l thyroi dectomy for ca ncer or
a s the res ul t of s urgery on the pa ra thyroi d gl a nds (s ubtota l or tota l pa ra thyroi dectomy). Ri s k fa ctors for s evere hypoca l cemi a a fter s ubtota l
pa ra thyroi dectomy i ncl ude
Severe preopera ti ve hyperca l cemi a
Remova l of a l a rge a denoma
El eva ted a l ka l i ne phos pha ta s e
Chroni c ki dney di s ea s e
Idi opa thi c hypopa ra thyroi di s m i s a n uncommon s pora di c or i nheri ted condi ti on i n whi ch the pa ra thyroi d gl a nds a re a bs ent or a trophi ed. It
ma ni fes ts i n chi l dhood. The pa ra thyroi d gl a nds a re occa s i ona l l y a bs ent a nd thymi c a pl a s i a a nd a bnorma l i ti es of the a rteri es a ri s i ng from the
bra chi a l a rches (Di George s yndrome) a re pres ent. Other i nheri ted forms i ncl ude Addi s on's di s ea s e, a utoi mmune hypopa ra thyroi di s m a s s oci a ted
wi th mucocuta neous ca ndi di a s i s , a nd X-l i nked reces s i ve i di opa thi c hypopa ra thyroi di s m.
Pseudohypoparathyroidism: Ps eudohypopa ra thyroi di s m i s a n uncommon group of di s orders cha ra cteri zed not by hormone defi ci ency but by ta rget
orga n res i s ta nce to PTH. Compl ex geneti c tra ns mi s s i on of thes e di s orders occurs .
Pa ti ents wi th type Ia ps eudohypopa ra thyroi di s m (Al bri ght's heredi ta ry os teodys trophy) ha ve a muta ti on i n the s ti mul a tory Gs -1 protei n of the
a denyl yl cycl a s e compl ex (GNAS1). The res ul t i s fa i l ure of norma l rena l phos pha turi c res pons e or i ncrea s e i n uri na ry cAMP to PTH. Pa ti ents a re
us ua l l y hypoca l cemi c a s a res ul t of hyperphos pha temi a . Seconda ry hyperpa ra thyroi di s m a nd hyperpa ra thyroi d bone di s ea s e ca n occur. As s oci a ted
a bnorma l i ti es i ncl ude s hort s ta ture, round fa ci es , i ntel l ectua l di s a bi l i ty wi th ca l ci fi ca ti on of the ba s a l ga ngl i a , s hortened meta ca rpa l a nd
meta ta rs a l bones , mi l d hypothyroi di s m, a nd other s ubtl e endocri ne a bnorma l i ti es . Beca us e onl y the ma terna l a l l el e for GNAS1 i s expres s ed i n
the ki dneys , pa ti ents whos e a bnorma l gene i s pa terna l , a l though they ha ve ma ny of the s oma ti c fea tures of the di s ea s e, do not ha ve
hypoca l cemi a , hyperphos pha temi a , or s econda ry hyperpa ra thyroi di s m; thi s condi ti on i s s ometi mes des cri bed a s
ps eudops eudohypopa ra thyroi di s m.
Les s i s known a bout type Ib ps eudohypopa ra thyroi di s m. Affected pa ti ents ha ve hypoca l cemi a , hyperphos pha temi a , a nd s econda ry
hyperpa ra thyroi di s m but do not ha ve the other a s s oci a ted a bnorma l i ti es .
Type II ps eudohypopa ra thyroi di s m i s even l es s common tha n type I. In a ffected pa ti ents , exogenous PTH ra i s es the uri na ry cAMP norma l l y but
does not ra i s e s erum Ca or uri na ry phos pha te (PO4 ). An i ntra cel l ul a r res i s ta nce to cAMP ha s been propos ed.
Vitamin D deficiency and dependency: Vi ta mi n D defi ci ency a nd dependency a re di s cus s ed i n ful l el s ewhere (s ee p. 41). Vi ta mi n D i s i nges ted i n
foods na tura l l y hi gh i n vi ta mi n D or forti fi ed wi th i t. It i s a l s o formed i n the s ki n i n res pons e to s unl i ght. Vi ta mi n D defi ci ency ma y res ul t from
i na dequa te di eta ry i nta ke or decrea s ed a bs orpti on due to hepa tobi l i a ry di s ea s e or i ntes ti na l ma l a bs orpti on. It ca n a l s o res ul t from a l tera ti ons
i n vi ta mi n D meta bol i s m a s occur wi th certa i n drugs (eg, phenytoi n, phenoba rbi ta l , ri fa mpi n) or decrea s ed forma ti on i n the s ki n due to l a ck of
expos ure to s unl i ght. Agi ng a l s o decrea s es s ki n s yntheti c ca pa ci ty. Decrea s ed s ki n s ynthes i s i s a n i mporta nt ca us e of a cqui red vi ta mi n D
defi ci ency a mong peopl e who s pend a grea t dea l of ti me i ndoors , who l i ve i n hi gh northern or s outhern l a ti tudes , a nd who wea r cl othi ng tha t
covers them compl etel y. Accordi ngl y, s ubcl i ni ca l vi ta mi n D defi ci ency i s fa i rl y common, es peci a l l y duri ng wi nter months i n tempera te cl i ma tes
a mong the el derl y. The i ns ti tuti ona l i zed el derl y a re a t pa rti cul a r ri s k beca us e of decrea s ed s ki n s yntheti c ca pa ci ty, undernutri ti on, a nd l a ck of s un
expos ure. In fa ct, mos t peopl e wi th defi ci ency ha ve both decrea s ed s ki n s ynthes i s a nd di eta ry defi ci ency (s ee a l s o p. 41).
Type I vi ta mi n D-dependent ri ckets (ps eudovi ta mi n D-defi ci ency ri ckets ) i s a n a utos oma l reces s i ve di s order i nvol vi ng a muta ti on i n the gene
encodi ng the 1--hydroxyl a s e enzyme. Norma l l y expres s ed i n the ki dney, 1--hydroxyl a s e i s needed to convert i na cti ve vi ta mi n D to the a cti ve form
ca l ci tri ol .
In type II vi ta mi n D-dependent ri ckets , ta rget orga ns ca nnot res pond to ca l ci tri ol . Vi ta mi n D defi ci ency, hypoca l cemi a , a nd s evere
hypophos pha temi a occur. Mus cl e wea knes s , pa i n, a nd typi ca l bone deformi ti es ca n occur.
Renal disease: Rena l tubul a r di s ea s e, i ncl udi ng a cqui red proxi ma l rena l tubul a r a ci dos i s due to nephrotoxi ns (eg, hea vy meta l s ) a nd di s ta l rena l
tubul a r a ci dos i s , ca n ca us e s evere hypoca l cemi a due to a bnorma l rena l l os s of Ca a nd decrea s ed rena l convers i on to 1,25(OH) 2 D. Ca dmi um, i n
pa rti cul a r, ca us es hypoca l cemi a by i njuri ng proxi ma l tubul a r cel l s a nd i nterferi ng wi th vi ta mi n D convers i on.
Rena l fa i l ure ca n res ul t i n hypoca l cemi a due to di mi ni s hed forma ti on of 1,25(OH) 2 D from di rect rena l cel l da ma ge a s wel l a s s uppres s i on of 1-hydroxyl a s e by hyperphos pha temi a .
Other causes: Other ca us es of hypoca l cemi a i ncl ude
Mg depl eti on (ca n ca us e rel a ti ve PTH defi ci ency a nd end-orga n res i s ta nce to PTH a cti on, us ua l l y when s erum Mg concentra ti ons a re < 1.0 mg/dL
[< 0.5 mmol /L]; Mg repl eti on i ncrea s es PTH concentra ti ons a nd i mproves rena l Ca cons erva ti on)
Acute pa ncrea ti ti s (when l i pol yti c products rel ea s ed from the i nfl a med pa ncrea s chel a te Ca )
Hypoprotei nemi a (reduces the protei n-bound fra cti on of s erum Ca ; hypoca l cemi a due to di mi ni s hed protei n bi ndi ng i s a s ymptoma ti cbeca us e
i oni zed Ca i s uncha nged, thi s enti ty ha s been termed fa cti ti ous hypoca l cemi a )
Hungry bone s yndrome (pers i s tent hypoca l cemi a a nd hypophos pha temi a occurri ng a fter s urgi ca l or medi ca l correcti on of modera te to s evere
hyperpa ra thyroi di s m i n pa ti ents i n whom s erum Ca l evel s ha d been s upported by hi gh bone turnover i nduced by grea tl y el eva ted PTHhungry
bone s yndrome ha s been des cri bed a fter pa ra thyroi dectomy, a fter rena l tra ns pl a nta ti on, a nd ra rel y i n pa ti ents wi th end-s ta ge rena l di s ea s e
trea ted wi th ca l ci mi meti cs )
Septi c s hock (due to s uppres s i on of PTH rel ea s e a nd decrea s ed convers i on of 25(OH)D to 1,25(OH) 2 D)
Hyperphos pha temi a (ca us es hypoca l cemi a by poorl y unders tood mecha ni s ms ; pa ti ents wi th rena l fa i l ure a nd s ubs equent PO4 retenti on a re
pa rti cul a rl y prone)
Drugs i ncl udi ng a nti convul s a nts (eg, phenytoi n, phenoba rbi ta l ) a nd ri fa mpi n, whi ch a l ter vi ta mi n D meta bol i s m, a nd drugs genera l l y us ed to
trea t hyperca l cemi a (s ee p. 847)
Tra ns fus i on of > 10 uni ts of ci tra te-a nti coa gul a ted bl ood a nd us e of ra di ocontra s t a gents conta i ni ng the di va l ent i on-chel a ti ng a gent
ethyl enedi a mi netetra a ceta te (ca n decrea s e the concentra ti on of bi oa va i l a bl e i oni zed Ca whi l e tota l s erum Ca concentra ti ons rema i n
uncha nged)
Infus i on of ga dol i ni um (ma y s puri ous l y l ower Ca concentra ti on)
Al though exces s i ve s ecreti on of ca l ci toni n mi ght be expected to ca us e hypoca l cemi a , l ow s erum Ca concentra ti ons ra rel y occur i n pa ti ents wi th
l a rge a mounts of ci rcul a ti ng ca l ci toni n due to medul l a ry ca rci noma of the thyroi d.
Symptoms and Signs
Hypoca l cemi a i s frequentl y a s ymptoma ti c. The pres ence of hypopa ra thyroi di s m i s often s ugges ted by the cl i ni ca l ma ni fes ta ti ons of the underl yi ng
di s order (eg, s hort s ta ture, round fa ci es , i ntel l ectua l di s a bi l i ty, ba s a l ga ngl i a ca l ci fi ca ti on i n type Ia ps eudohypopa ra thyroi di s m).
Ma jor cl i ni ca l ma ni fes ta ti ons of hypoca l cemi a a re due to di s turba nces i n cel l ul a r membra ne potenti a l , res ul ti ng i n neuromus cul a r i rri ta bi l i ty.
Neurologic manifestations: Mus cl e cra mps i nvol vi ng the ba ck a nd l egs a re common. Ins i di ous hypoca l cemi a ma y ca us e mi l d, di ffus e encepha l opa thy
a nd s houl d be s us pected i n pa ti ents wi th unexpl a i ned dementi a , depres s i on, or ps ychos i s . Pa pi l l edema occa s i ona l l y occurs . Severe
hypoca l cemi a wi th s erum Ca < 7 mg/dL (< 1.75 mmol /L) ma y ca us e hyperrefl exi a , teta ny, l a ryngos pa s m, or genera l i zed s ei zures .
Teta ny cha ra cteri s ti ca l l y res ul ts from s evere hypoca l cemi a but ca n res ul t from reducti on i n the i oni zed fra cti on of s erum Ca wi thout ma rked
hypoca l cemi a , a s occurs i n s evere a l ka l os i s . Teta ny i s cha ra cteri zed by the fol l owi ng:
Sens ory s ymptoms cons i s ti ng of pa res thes i a s of the l i ps , tongue, fi ngers , a nd feet
Ca rpopeda l s pa s m, whi ch ma y be prol onged a nd pa i nful
Genera l i zed mus cl e a chi ng
Spa s m of fa ci a l mus cul a ture
Teta ny ma y be overt wi th s ponta neous s ymptoms or l a tent a nd requi ri ng provoca ti ve tes ts to el i ci t. La tent teta ny genera l l y occurs a t l es s s everel y
decrea s ed s erum Ca concentra ti ons : 7 to 8 mg/dL (1.75 to 2.20 mmol /L).
Chvos tek's a nd Trous s ea u's s i gns a re ea s i l y el i ci ted a t the beds i de to i denti fy l a tent teta ny. Chvos tek's s i gn i s a n i nvol unta ry twi tchi ng of the
fa ci a l mus cl es el i ci ted by a l i ght ta ppi ng of the fa ci a l nerve jus t a nteri or to the exteri or a udi tory mea tus . It i s pres ent i n 10% of hea l thy peopl e
a nd i n mos t peopl e wi th a cute hypoca l cemi a but i s often a bs ent i n chroni c hypoca l cemi a . Trous s ea u's s i gn i s the preci pi ta ti on of ca rpopeda l
s pa s m by reducti on of the bl ood s uppl y to the ha nd wi th a tourni quet or BP cuff i nfl a ted to 20 mm Hg a bove s ys tol i c BP a ppl i ed to the forea rm for 3
mi n. Trous s ea u's s i gn a l s o occurs i n a l ka l os i s , hypoma gnes emi a , hypoka l emi a , a nd hyperka l emi a a nd i n a bout 6% of peopl e wi th no i denti fi a bl e
el ectrol yte di s turba nce.
Other manifestations: Ma ny other a bnorma l i ti es ma y occur wi th chroni c hypoca l cemi a , s uch a s dry a nd s ca l y s ki n, bri ttl e na i l s , a nd coa rs e ha i r.
Candida i nfecti ons occa s i ona l l y occur i n hypoca l cemi a but mos t commonl y occur i n pa ti ents wi th i di opa thi c hypopa ra thyroi di s m. Ca ta ra cts
occa s i ona l l y occur wi th l ong-s ta ndi ng hypoca l cemi a a nd a re not revers i bl e by correcti on of s erum Ca .
Diagnosis
Es ti ma ti on or mea s urement of i oni zed Ca
Someti mes further tes ti ng wi th Mg, PTH, PO4 , a l ka l i ne phos pha ta s e, a nd vi ta mi n D concentra ti ons i n bl ood a nd cAMP a nd PO4 concentra ti ons i n
uri ne
Hypoca l cemi a ma y be s us pected i n pa ti ents wi th cha ra cteri s ti c neurol ogi c ma ni fes ta ti ons or ca rdi a c a rrhythmi a s but i s often found i nci denta l l y.
Hypoca l cemi a i s di a gnos ed by a tota l s erum Ca concentra ti on < 8.8 mg/dL (< 2.20 mmol /L). However, beca us e l ow pl a s ma protei n ca n l ower tota l ,
but not i oni zed, s erum Ca , i oni zed Ca s houl d be es ti ma ted ba s ed on a l bumi n concentra ti on (s ee Si deba r 97-2). Sus pi ci on of l ow i oni zed Ca
ma nda tes i ts di rect mea s urement, des pi te norma l tota l s erum Ca . Hypoca l cemi c pa ti ents s houl d undergo mea s urement of rena l functi on (eg, BUN,
crea ti ni ne), s erum PO4 , Mg, a nd a l ka l i ne phos pha ta s e.
When no eti ol ogy (eg, a l ka l os i s , rena l fa i l ure, drugs , or ma s s i ve bl ood tra ns fus i on) i s obvi ous , further tes ti ng i s needed (s ee
Ta bl e 97-8). Addi ti ona l tes ti ng begi ns wi th s erum concentra ti ons of Mg, PO4 , PTH, a l ka l i ne phos pha ta s e, a nd occa s i ona l l y vi ta mi n D l evel s
(25(OH)D, a nd 1,25(OH) 2 D). Uri na ry PO4 a nd cAMP concentra ti ons a re mea s ured when ps eudohypopa ra thyroi di s m i s s us pected.
PTH concentra ti on s houl d be mea s ured a s a n a s s a y of the i nta ct mol ecul e. Beca us e hypoca l cemi a i s the ma jor s ti mul us for PTH s ecreti on, PTH
s houl d be el eva ted i n hypoca l cemi a . Thus ,
Low or even l ow-norma l PTH concentra ti ons a re i na ppropri a te a nd s ugges t hypopa ra thyroi di s m.
An undetecta bl e PTH concentra ti on s ugges ts i di opa thi c hypopa ra thyroi di s m.
A hi gh PTH concentra ti on s ugges ts ps eudohypopa ra thyroi di s m or a n a bnorma l i ty of vi ta mi n D meta bol i s m.
Sidebar 97-2 Estimation of Ionized Calcium Concentration

Ioni zed Ca concentra ti on ca n be es ti ma ted from routi ne l a bora tory tes ts , us ua l l y wi th rea s ona bl e a ccura cy. In hypoa l bumi nemi a , mea s ured s erum
Ca i s often l ow, ma i nl y refl ecti ng a l ow concentra ti on of protei n-bound Ca , whi l e i oni zed Ca ca n be norma l . Mea s ured tota l s erum Ca decrea s es or
i ncrea s es by a bout 0.8 mg/dL (0.20 mmol /L) for every 1-g/dL decrea s e or i ncrea s e i n a l bumi n. Thus , a n a l bumi n concentra ti on of 2.0 g/dL (norma l ,
4.0 g/dL) s houl d i ts el f reduce mea s ured s erum Ca by 1.6 mg/dL. Si mi l a rl y, i ncrea s es i n s erum protei ns , a s occur i n mul ti pl e myel oma , ca n ra i s e
tota l s erum Ca . Aci dos i s i ncrea s es i oni zed Ca by decrea s i ng protei n bi ndi ng, wherea s a l ka l os i s decrea s es i oni zed Ca .
Hypopa ra thyroi di s m i s further cha ra cteri zed by hi gh s erum PO4 a nd norma l a l ka l i ne phos pha ta s e.
In type I ps eudohypopa ra thyroi di s m, des pi te the pres ence of a hi gh concentra ti on of ci rcul a ti ng PTH, uri na ry cAMP a nd uri na ry PO4 a re a bs ent.
Provoca ti ve tes ti ng by i njecti on of pa ra thyroi d extra ct or recombi na nt huma n PTH fa i l s to ra i s e s erum or uri na ry cAMP. Pa ti ents wi th type Ia
ps eudohypopa ra thyroi di s m frequentl y a l s o ha ve s kel eta l a bnorma l i ti es , i ncl udi ng s hort s ta ture a nd s hortened 1s t, 4th, a nd 5th meta ca rpa l s .
Pa ti ents wi th type Ib di s ea s e ha ve rena l ma ni fes ta ti ons wi thout s kel eta l a bnorma l i ti es .
In vi ta mi n D defi ci ency, os teoma l a ci a or ri ckets ma y be pres ent, us ua l l y wi th typi ca l s kel eta l a bnorma l i ti es on x-ra y. Di a gnos i s of vi ta mi n D
defi ci ency a nd dependency a nd mea s urement of vi ta mi n D concentra ti ons a re di s cus s ed on p. 42.
Severe hypoca l cemi a ca n a ffect the ECG. It typi ca l l y s hows prol onga ti on of the QTc a nd ST i nterva l s . Cha nges i n repol a ri za ti on, s uch a s T-wa ve
pea ki ng or i nvers i on, a l s o occur. ECG ma y s how a rrhythmi a or hea rt bl ock occa s i ona l l y i n pa ti ents wi th s evere hypoca l cemi a . However, eva l ua ti on
of hypoca l cemi a does not ma nda te ECG tes ti ng.
Treatment
IV Ca gl ucona te for teta ny
Ora l Ca for pos topera ti ve hypopa ra thyroi di s m
Ora l Ca a nd vi ta mi n D for chroni c hypoca l cemi a
[Table 97-8. Typi ca l La bora tory Tes t Res ul ts i n Some Di s orders Ca us i ng Hypoca l cemi a ]
For teta ny, Ca gl ucona te 10 mL of 10% s ol uti on IV over 10 mi n i s gi ven. Res pons e ca n be dra ma ti c but ma y l a s t for onl y a few hours . Repea ted
bol us es or a conti nuous i nfus i on wi th 20 to 30 mL of 10% Ca gl ucona te i n 1 L of 5% D/W over the next 12 to 24 h ma y be needed. Infus i ons of Ca a re
ha za rdous i n pa ti ents recei vi ng di goxi n a nd s houl d be gi ven s l owl y a nd wi th conti nuous ECG moni tori ng. When teta ny i s a s s oci a ted wi th
hypoma gnes emi a , i t ma y res pond tra ns i entl y to Ca or K a dmi ni s tra ti on but i s perma nentl y rel i eved onl y by repl eti on of Mg, typi ca l l y gi ven a s a 10%
Mg s ul fa te (MgSO4 ) s ol uti on (1 g/10 mL) IV, fol l owed by ora l Mg s a l ts (eg, Mg gl ucona te 500 to 1000 mg po ti d).
In tra ns i ent hypopa ra thyroi di s m a fter thyroi dectomy or pa rti a l pa ra thyroi dectomy, s uppl ementa l ora l Ca ma y be s uffi ci ent; 1 to 2 g of el ementa l
Ca /da y ma y be gi ven a s Ca gl ucona te (90 mg el ementa l Ca /1 g) or Ca ca rbona te (400 mg el ementa l Ca /1 g). However, hypoca l cemi a ma y be
pa rti cul a rl y s evere a nd prol onged a fter s ubtota l pa ra thyroi dectomy, pa rti cul a rl y i n pa ti ents wi th chroni c ki dney di s ea s e or i n pa ti ents from whom
a l a rge tumor wa s removed. Prol onged pa rentera l a dmi ni s tra ti on of Ca ma y be neces s a ry pos topera ti vel y; s uppl ementa ti on wi th a s much a s 1
g/da y of el ementa l Ca (eg, 111 mL of Ca gl ucona te, whi ch conta i ns 90 mg el ementa l Ca /10 mL) ma y be requi red for 5 to 10 da ys before ora l Ca a nd
vi ta mi n D a re s uffi ci ent. El eva ted s erum a l ka l i ne phos pha ta s e i n s uch pa ti ents ma y be a s i gn of ra pi d upta ke of Ca i nto bone. The need for l a rge
a mounts of pa rentera l Ca us ua l l y does not fa l l unti l the a l ka l i ne phos pha ta s e concentra ti on begi ns to decrea s e.
In chroni c hypoca l cemi a , ora l Ca a nd occa s i ona l l y vi ta mi n D s uppl ements a re us ua l l y s uffi ci ent: 1 to 2 g of el ementa l Ca /da y ma y be gi ven a s Ca
gl ucona te or Ca ca rbona te. In pa ti ents wi thout rena l fa i l ure, vi ta mi n D i s gi ven a s a s ta nda rd ora l s uppl ement (eg, chol eca l ci ferol 800 IU
once/da y). Vi ta mi n D thera py i s not effecti ve unl es s a dequa te di eta ry or s uppl ementa l Ca a nd PO4 (s ee p. 851) a re s uppl i ed.
For pa ti ents wi th rena l fa i l ure, ca l ci tri ol or a nother 1,25(OH) 2 D a na l og i s us ed beca us e thes e drugs requi re no rena l meta bol i c a l tera ti on. Pa ti ents
wi th hypopa ra thyroi di s m ha ve di ffi cul ty converti ng chol eca l ci ferol to i ts a cti ve form a nd a l s o us ua l l y requi re ca l ci tri ol , us ua l l y 0.5 to 2 g po
once/da y. Ps eudohypopa ra thyroi di s m ca n occa s i ona l l y be ma na ged wi th ora l Ca s uppl ementa ti on a l one. When us ed, ca l ci tri ol requi res 1 to 3
g/da y.
Vi ta mi n D a na l ogs i ncl ude di hydrota chys terol (us ua l l y gi ven ora l l y a t 0.8 to 2.4 once/da y for a few da ys , fol l owed by 0.2 to 1.0 mg once/da y) a nd
ca l ci di ol (eg, 4000 to 6000 IU po once/wk). Us e of vi ta mi n D a na l ogs , pa rti cul a rl y the l onger-a cti ng ca l ci di ol , ca n be compl i ca ted by vi ta mi n D
toxi ci ty, wi th s evere s ymptoma ti c hyperca l cemi a . Serum Ca concentra ti on s houl d be moni tored weekl y a t fi rs t a nd then a t 1- to 3-mo i nterva l s a fter
Ca concentra ti ons ha ve s ta bi l i zed. The ma i ntena nce dos e of ca l ci tri ol or i ts a na l og, di hydrota chys terol , us ua l l y decrea s es wi th ti me.
Hypercalcemia
Hypercalcemia is total serum Ca concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum Ca > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include
hyperparathyroidism, vitamin D toxicity, and cancer. Clinical features include polyuria, constipation, muscle weakness, confusion, and coma. Diagnosis is by
serum ionized Ca and parathyroid hormone concentrations. Treatment to increase Ca excretion and reduce bone resorption of Ca involves saline, Na diuresis, and
drugs such as pamidronate.
Etiology
Hyperca l cemi a us ua l l y res ul ts from exces s i ve bone res orpti on. There a re ma ny ca us es of hyperca l cemi a (s ee
Ta bl e 97-9), but the mos t common a re hyperpa ra thyroi di s m a nd ca ncer.
Pathophysiology
Primary hyperparathyroidism i s a genera l i zed di s order res ul ti ng from exces s i ve s ecreti on of pa ra thyroi d hormone (PTH) by one or more pa ra thyroi d
gl a nds . It proba bl y i s the mos t common ca us e of hyperca l cemi a , pa rti cul a rl y a mong pa ti ents who a re not hos pi ta l i zed. Inci dence i ncrea s es wi th
a ge a nd i s hi gher i n pos tmenopa us a l women. It a l s o occurs i n hi gh frequency 3 deca des a fter neck i rra di a ti on. Fa mi l i a l a nd s pora di c forms
exi s t. Fa mi l i a l forms due to pa ra thyroi d a denoma occur i n pa ti ents wi th other endocri ne tumors (s ee p. 909). Pri ma ry hyperpa ra thyroi di s m ca us es
hypophos pha temi a a nd exces s i ve bone res orpti on. Al though a s ymptoma ti c hyperca l cemi a i s the mos t frequent pres enta ti on, nephrol i thi a s i s i s
a l s o common, pa rti cul a rl y when hyperca l ci uri a occurs due to l ong-s ta ndi ng hyperca l cemi a . Hi s tol ogi c exa mi na ti on s hows a pa ra thyroi d a denoma
i n a bout 85% of pa ti ents wi th pri ma ry hyperpa ra thyroi di s m, a l though i t i s s ometi mes di ffi cul t to di s ti ngui s h a n a denoma from a norma l gl a nd.
About 15% of ca s es a re due to hyperpl a s i a of 2 gl a nds . Pa ra thyroi d ca ncer occurs i n < 1% of ca s es .
The s yndrome of familial hypocalciuric hypercalcemia (FHH) i s tra ns mi tted a s a n a utos oma l domi na nt tra i t. Mos t ca s es i nvol ve a n i na cti va ti ng
muta ti on of the Ca -s ens i ng receptor gene, res ul ti ng i n hi gher concentra ti ons of s erum Ca bei ng needed to i nhi bi t PTH s ecreti on. Subs equent PTH
s ecreti on i nduces rena l phos pha te (PO4 ) excreti on. Pers i s tent hyperca l cemi a (us ua l l y a s ymptoma ti c), often from a n ea rl y a ge; norma l to s l i ghtl y
el eva ted concentra ti ons of PTH; hypoca l ci uri a ; a nd hyperma gnes emi a occur. Rena l functi on i s norma l , a nd nephrol i thi a s i s i s unus ua l . However,
s evere pa ncrea ti ti s occa s i ona l l y occurs . Thi s s yndrome, whi ch i s a s s oci a ted wi th pa ra thyroi d hyperpl a s i a , i s not rel i eved by s ubtota l
pa ra thyroi dectomy.
Secondary hyperparathyroidism occurs mos t commonl y i n a dva nced chroni c ki dney
[Table 97-9. Pri nci pa l Ca us es of Hyperca l cemi a ]
di s ea s e when decrea s ed forma ti on of a cti ve vi ta mi n D i n the ki dneys a nd other fa ctors l ea d to hypoca l cemi a a nd chroni c s ti mul a ti on of PTH
s ecreti on. Hyperphos pha temi a tha t devel ops i n res pons e to chroni c ki dney di s ea s e a l s o contri butes . Once es ta bl i s hed, hyperca l cemi a or
normoca l cemi a ma y occur. The s ens i ti vi ty of the pa ra thyroi d to Ca ma y be di mi ni s hed beca us e of pronounced gl a ndul a r hyperpl a s i a a nd el eva ti on
of the Ca s et poi nt (i e, the a mount of Ca neces s a ry to reduce s ecreti on of PTH).
Tertiary hyperparathyroidism res ul ts i n a utonomous hypers ecreti on of PTH rega rdl es s of s erum Ca concentra ti on. Terti a ry hyperpa ra thyroi di s m
genera l l y occurs i n pa ti ents wi th l ong-s ta ndi ng s econda ry hyperpa ra thyroi di s m, a s i n pa ti ents wi th end-s ta ge rena l di s ea s e of s evera l yea rs '
dura ti on.
Cancer i s a common ca us e of hyperca l cemi a , us ua l l y i n hos pi ta l i zed pa ti ents . Al though there a re s evera l mecha ni s ms , el eva ted s erum Ca
ul ti ma tel y occurs a s a res ul t of bone res orpti on. Humora l hyperca l cemi a of ca ncer (i e, hyperca l cemi a wi th no or mi ni ma l bone meta s ta s es ) occurs
mos t commonl y wi th s qua mous cel l ca rci noma , rena l cel l ca rci noma , brea s t ca ncer, pros ta te ca ncer, a nd ova ri a n ca ncer. Ma ny ca s es of humora l
hyperca l cemi a of ca ncer were formerl y a ttri buted to ectopi c producti on of PTH. However, s ome of thes e tumors s ecrete a PTH-rel a ted pepti de tha t
bi nds to PTH receptors i n both bone a nd ki dney a nd mi mi cs ma ny of the effects of the hormone, i ncl udi ng os teocl a s ti c bone res orpti on.
Hema tol ogi c ca ncers , mos t often mul ti pl e myel oma , but a l s o certa i n l ymphoma s a nd l ymphos a rcoma s , ca us e hyperca l cemi a by el a bora ti ng a
group of cytoki nes tha t s ti mul a te os teocl a s ts to res orb bone, res ul ti ng i n os teol yti c l es i ons , di ffus e os teopeni a , or both. Hyperca l cemi a ma y res ul t
from l oca l el a bora ti on of os teocl a s t-a cti va ti ng cytoki nes or pros ta gl a ndi ns , di rect bone res orpti on by the meta s ta ti c tumor cel l s , or both.
Vitamin D toxicity ca n be ca us ed by hi gh concentra ti ons of endogenous 1,25(OH) 2 D. Al though s erum concentra ti ons a re l ow i n mos t pa ti ents wi th
s ol i d tumors , pa ti ents wi th l ymphoma a nd T-cel l l eukemi a s ometi mes ha ve el eva ted concentra ti ons due to dys regul a ti on of the 1--hydroxyl a s e
enzyme pres ent i n tumor cel l s . Exogenous vi ta mi n D i n pha rma col ogi c dos es ca us es exces s i ve bone res orpti on a s wel l a s i ncrea s ed i ntes ti na l Ca
a bs orpti on, res ul ti ng i n hyperca l cemi a a nd hyperca l ci uri a (s ee p. 44).
Granulomatous disorders, s uch a s s a rcoi dos i s , TB, l epros y, beryl l i os i s , hi s topl a s mos i s , a nd cocci di oi domycos i s , l ea d to hyperca l cemi a a nd
hyperca l ci uri a . In s a rcoi dos i s , hyperca l cemi a a nd hyperca l ci uri a s eem to be due to unregul a ted convers i on of 25(OH)D to 1,25(OH) 2 D, pres uma bl y
due to expres s i on of the 1--hydroxyl a s e enzyme i n mononucl ea r cel l s wi thi n s a rcoi d gra nul oma s . Si mi l a rl y, el eva ted s erum concentra ti ons of
1,25(OH) 2 D ha ve been reported i n hyperca l cemi c pa ti ents wi th TB a nd s i l i cos i s . Other mecha ni s ms mus t a ccount for hyperca l cemi a i n s ome
i ns ta nces , beca us e depres s ed 1,25(OH) 2 D concentra ti ons occur i n s ome pa ti ents wi th hyperca l cemi a a nd l epros y.
Immobilization, pa rti cul a rl y compl ete prol onged bed res t i n pa ti ents a t ri s k (s ee Ta bl e 97-9), ca n res ul t i n hyperca l cemi a due to a ccel era ted bone
res orpti on. Hyperca l cemi a devel ops wi thi n da ys to weeks of ons et of bed res t. Revers a l of hyperca l cemi a occurs promptl y on res umpti on of wei ght
bea ri ng. Young a dul ts wi th s evera l bone fra ctures a nd peopl e wi th Pa get's di s ea s e of bone a re pa rti cul a rl y prone to hyperca l cemi a when a t bed
res t.
Idiopathic infantile hypercalcemia (Wi l l i a ms s yndromes ee
Ta bl e 299-2 on p. 3003) i s a n extremel y ra re s pora di c di s order wi th dys morphi c fa ci a l fea tures , ca rdi ova s cul a r a bnorma l i ti es , renova s cul a r
hypertens i on, a nd hyperca l cemi a . PTH a nd vi ta mi n D meta bol i s m a re norma l , but the res pons e of ca l ci toni n to Ca i nfus i on ma y be a bnorma l .
In milk-alkali syndrome, exces s i ve a mounts of Ca a nd a bs orba bl e a l ka l i a re i nges ted, us ua l l y duri ng s el f-trea tment wi th Ca ca rbona te a nta ci ds for
dys peps i a or to prevent os teoporos i s , res ul ti ng i n hyperca l cemi a , meta bol i c a l ka l os i s , a nd rena l i ns uffi ci ency. The a va i l a bi l i ty of effecti ve drugs
for pepti c ul cer di s ea s e a nd os teoporos i s ha s grea tl y reduced the i nci dence of thi s s yndrome.
Symptoms and Signs
In mi l d hyperca l cemi a , ma ny pa ti ents a re a s ymptoma ti c. Cl i ni ca l ma ni fes ta ti ons of hyperca l cemi a i ncl ude cons ti pa ti on, a norexi a , na us ea a nd
vomi ti ng, a bdomi na l pa i n, a nd i l eus . Impa i rment of the rena l concentra ti ng mecha ni s m l ea ds to pol yuri a , nocturi a , a nd pol ydi ps i a . El eva ti on of
s erum Ca > 12 mg/dL (> 3.00 mmol /L) ca n ca us e emoti ona l l a bi l i ty, confus i on, del i ri um, ps ychos i s , s tupor, a nd coma . Hyperca l cemi a ma y ca us e
neuromus cul a r s ymptoms , i ncl udi ng s kel eta l mus cl e wea knes s . Hyperca l ci uri a wi th nephrol i thi a s i s i s common. Les s often, prol onged or s evere
hyperca l cemi a ca us es revers i bl e a cute rena l fa i l ure or i rrevers i bl e rena l da ma ge due to nephroca l ci nos i s (preci pi ta ti on of Ca s a l ts wi thi n the
ki dney pa renchyma ). Pepti c ul cers a nd pa ncrea ti ti s ma y occur i n pa ti ents wi th hyperpa ra thyroi di s m for rea s ons tha t a re not rel a ted to
hyperca l cemi a .
Severe hyperca l cemi a ca us es a s hortened QTc i nterva l on ECG, a nd a rrhythmi a s ma y occur, pa rti cul a rl y i n pa ti ents ta ki ng di goxi n. Hyperca l cemi a >
18 mg/dL (> 4.50 mmol /L) ma y ca us e s hock, rena l fa i l ure, a nd dea th.
Diagnosis
Tota l s erum Ca concentra ti on
Ches t x-ra y; mea s urement of el ectrol ytes , BUN, crea ti ni ne, i oni zed Ca , PO4 , a nd a l ka l i ne phos pha ta s e; a nd s erum protei n
i mmunoel ectrophores i s to determi ne the ca us e
Someti mes PTH a nd uri na ry excreti on of Ca wi th or wi thout PO4
Hyperca l cemi a i s di a gnos ed by a s erum Ca concentra ti on > 10.4 mg/dL (> 2.60 mmol /L) or i oni zed s erum Ca > 5.2 mg/dL (> 1.30 mmol /L). The
condi ti on i s frequentl y di s covered duri ng routi ne l a bora tory s creeni ng. Serum Ca ca n be a rti fa ctua l l y el eva ted (s ee
Ta bl e 97-10). Hyperca l cemi a ca n a l s o be ma s ked by l ow s erum protei n. When protei n a nd a l bumi n a re a bnorma l a nd when i oni zed hyperca l cemi a
i s s us pected beca us e of cl i ni ca l fi ndi ngs (eg, beca us e of s ymptoms of hyperca l cemi a ), i oni zed s erum Ca s houl d be mea s ured.
Initial evaluation: Ini ti a l eva l ua ti on s houl d i ncl ude a revi ew of the hi s tory, pa rti cul a rl y of pa s t s erum Ca concentra ti on; phys i ca l exa mi na ti on; a
ches t x-ra y; a nd l a bora tory s tudi es , i ncl udi ng el ectrol ytes , BUN, crea ti ni ne, i oni zed Ca , PO4 , a l ka l i ne phos pha ta s e, a nd s erum protei n
i mmunoel ectrophores i s . The ca us e i s a ppa rent from cl i ni ca l da ta a nd res ul ts of thes e tes ts i n 95% of pa ti ents . Pa ti ents wi thout a n obvi ous
ca us e of hyperca l cemi a a fter thi s eva l ua ti on s houl d undergo mea s urement of i nta ct PTH a nd 24-h uri na ry Ca . When hyperpa ra thyroi di s m i s
s us pected, PO4 rena l excreti on i s often mea s ured.
As ymptoma ti c hyperca l cemi a tha t ha s been pres ent for yea rs or i s pres ent i n s evera l fa mi l y members ra i s es the pos s i bi l i ty of FHH. Pri ma ry
hyperpa ra thyroi di s m genera l l y ma ni fes ts l a te i n l i fe but ca n be pres ent for s evera l yea rs before s ymptoms occur. When no ca us e i s obvi ous ,
concentra ti ons of s erum Ca < 11 mg/dL (< 2.75 mmol /L) s ugges t hyperpa ra thyroi di s m or other nonma l i gna nt ca us es , wherea s concentra ti on > 13
mg/dL (> 3.25 mmol /L) s ugges t ca ncer.
Mea s urement of i nta ct PTH l evel s hel p di fferenti a te PTH-medi a ted hyperca l cemi a (eg, ca us ed by hyperpa ra thyroi di s m or FHH), i n whi ch PTH l evel s
a re hi gh or hi gh-norma l ,
[Table 97-10. La bora tory a nd Cl i ni ca l Fi ndi ngs i n Some Di s orders Ca us i ng Hyperca l cemi a ]
from mos t other (PTH-i ndependent) ca us es . In PTH-i ndependent ca us es , l evel s a re us ua l l y < 20 pg/mL.
The ches t x-ra y i s pa rti cul a rl y hel pful , revea l i ng mos t gra nul oma tous di s orders , s uch a s TB, s a rcoi dos i s , a nd s i l i cos i s , a s wel l a s pri ma ry l ung
ca ncer a nd l yti c a nd Pa get's l es i ons i n bones of the s houl der, ri bs , a nd thora ci c s pi ne.
Ches t a nd bone (eg, s kul l , extremi ty) x-ra ys ca n a l s o s how the bony effects of s econda ry hyperpa ra thyroi di s m, mos t commonl y i n l ong-term di a l ys i s
pa ti ents . In os tei ti s fi bros a cys ti ca (often due to pri ma ry hyperpa ra thyroi di s m), i ncrea s ed os teocl a s ti c a cti vi ty from over-s ti mul a ti on by PTH ca us es
ra refa cti on of bone wi th fi brous degenera ti on a nd cys t a nd fi brous nodul e forma ti on. Beca us e cha ra cteri s ti c bone l es i ons occur onl y wi th
rel a ti vel y a dva nced di s ea s e, bone x-ra ys a re recommended onl y for s ymptoma ti c pa ti ents . X-ra ys typi ca l l y s how bone cys ts , a heterogeneous
a ppea ra nce of the s kul l , a nd s ubperi os tea l res orpti on of bone i n the pha l a nges a nd di s ta l cl a vi cl es .
Hyperparathyroidism: In hyperpa ra thyroi di s m, the s erum Ca i s ra rel y > 12 mg/dL (> 3.00 mmol /L), but the i oni zed s erum Ca i s a l mos t a l wa ys el eva ted.
Low s erum PO4 concentra ti on s ugges ts hyperpa ra thyroi di s m, es peci a l l y when coupl ed wi th el eva ted PO4 rena l excreti on. When
hyperpa ra thyroi di s m res ul ts i n i ncrea s ed bone turnover, s erum a l ka l i ne phos pha ta s e i s frequentl y i ncrea s ed. Increa s ed i nta ct PTH, pa rti cul a rl y
i na ppropri a te el eva ti on (i e, a hi gh concentra ti on i n the a bs ence of hypoca l cemi a ) or a n i na ppropri a te hi gh-norma l concentra ti on (i e, des pi te
hyperca l cemi a ), i s di a gnos ti c. Uri na ry Ca excreti on i s us ua l l y norma l or hi gh i n hyperpa ra thyroi di s m. Pri ma ry hyperpa ra thyroi di s m i s s ugges ted by
a n a bs ence of a fa mi l y hi s tory of endocri ne neopl a s i a , chi l dhood neck i rra di a ti on, or other obvi ous ca us e. Chroni c ki dney di s ea s e s ugges ts the
pres ence of s econda ry hyperpa ra thyroi di s m, but pri ma ry hyperpa ra thyroi di s m ca n a l s o be pres ent. In pa ti ents wi th chroni c ki dney di s ea s e, hi gh
s erum Ca a nd norma l s erum PO4 s ugges t pri ma ry hyperpa ra thyroi di s m, wherea s el eva ted PO4 s ugges ts s econda ry hyperpa ra thyroi di s m.
The need for l oca l i za ti on of pa ra thyroi d ti s s ue before s urgery on the pa ra thyroi d(s ) i s controvers i a l . Hi gh-res ol uti on CT wi th or wi thout CT-gui ded
bi ops y a nd i mmunoa s s a y of thyroi d venous dra i na ge, MRI, hi gh-res ol uti on ul tra s onogra phy, di gi ta l s ubtra cti on a ngi ogra phy, a nd tha l l i um-201techneti um-99 s ca nni ng a l l ha ve been us ed a nd a re hi ghl y a ccura te, but they ha ve not i mproved the us ua l l y hi gh cure ra te of pa ra thyroi dectomy
done by experi enced s urgeons . Techneti um-99 s es ta mi bi , a newer ra di onucl i de a gent for pa ra thyroi d i ma gi ng, i s more s ens i ti ve a nd s peci fi c tha n
ol der a gents a nd ma y be us eful for i denti fyi ng s ol i ta ry a denoma s .
For res i dua l or recurrent hyperpa ra thyroi di s m a fter i ni ti a l pa ra thyroi d s urgery, i ma gi ng i s neces s a ry a nd ma y revea l a bnorma l l y functi oni ng
pa ra thyroi d gl a nds i n unus ua l l oca ti ons throughout the neck a nd medi a s ti num. Techneti um-99 s es ta mi bi i s proba bl y the mos t s ens i ti ve i ma gi ng
tes t. Us e of s evera l i ma gi ng s tudi es (MRI, CT, or hi gh-res ol uti on ul tra s onogra phy i n a ddi ti on to techneti um-99 s es ta mi bi ) before repea t
pa ra thyroi dectomy i s s ometi mes neces s a ry.
Cancer: A s erum Ca > 13 mg/dL (> 3.00 mmol /L) s ugges ts s ome ca us e of hyperca l cemi a other tha n hyperpa ra thyroi di s m. Uri na ry Ca excreti on i s
us ua l l y norma l or hi gh i n ca ncer. In humora l hyperca l cemi a of ca ncer, PTH i s often decrea s ed or undetecta bl e; PO4 i s often decrea s ed; a nd
meta bol i c a l ka l os i s , hypochl oremi a , a nd hypoa l bumi nemi a a re often pres ent. Suppres s ed PTH di fferenti a tes humora l hyperca l cemi a of ca ncer
from pri ma ry hyperpa ra thyroi di s m. Humora l hyperca l cemi a of ca ncer ca n a l s o be di a gnos ed by detecti on of PTH-rel a ted pepti de i n s erum.
Mul ti pl e myel oma i s s ugges ted by s i mul ta neous a nemi a , a zotemi a , a nd hyperca l cemi a or by the pres ence of a monocl ona l ga mmopa thy.
Myel oma i s confi rmed by bone ma rrow exa mi na ti on.
FHH: FHH s houl d be cons i dered i n pa ti ents wi th hyperca l cemi a a nd el eva ted or hi gh-norma l i nta ct PTH l evel s . FHH i s di s ti ngui s hed from pri ma ry
hyperpa ra thyroi di s m by the ea rl y a ge of ons et, frequent occurrence of hyperma gnes emi a , a nd pres ence of hyperca l cemi a wi thout hyperca l ci uri a i n
other fa mi l y members . The fra cti ona l excreti on of Ca (ra ti o of Ca cl ea ra nce to crea ti ni ne cl ea ra nce) i s l ow (< 1%) i n FHH; i t i s a l mos t a l wa ys
el eva ted (1 to 4%) i n pri ma ry hyperpa ra thyroi di s m. Inta ct PTH ca n be el eva ted or norma l , perha ps refl ecti ng a l tered feedba ck regul a ti on of the
pa ra thyroi d gl a nds .
Milk-alkali syndrome: In a ddi ti on to a hi s tory of i ncrea s ed i nta ke of Ca a nta ci ds , mi l k-a l ka l i s yndrome i s recogni zed by the combi na ti on of
hyperca l cemi a , meta bol i c a l ka l os i s , a nd, occa s i ona l l y, a zotemi a wi th hypoca l ci uri a . The di a gnos i s ca n be confi rmed when the s erum Ca
concentra ti on ra pi dl y returns to norma l when Ca a nd a l ka l i i nges ti on s tops , a l though rena l i ns uffi ci ency ca n pers i s t when nephroca l ci nos i s i s
pres ent. Ci rcul a ti ng PTH us ua l l y i s s uppres s ed.
Other causes: In hyperca l cemi a due to s a rcoi dos i s , other gra nul oma tous di s orders , a nd s ome l ymphoma s , s erum concentra ti on of 1,25(OH) 2 D ma y
be el eva ted. Vi ta mi n D toxi ci ty i s a l s o cha ra cteri zed by el eva ted 1,25(OH) 2 D concentra ti on. In other endocri ne ca us es of hyperca l cemi a , s uch a s
thyrotoxi cos i s a nd Addi s on's di s ea s e, typi ca l l a bora tory fi ndi ngs of the underl yi ng di s order hel p es ta bl i s h the di a gnos i s . When Pa get's di s ea s e i s
s us pected, pl a i n x-ra ys (s ee p. 361) a re done fi rs t a nd ma y s how cha ra cteri s ti c a bnorma l i ti es .
Treatment
Ora l PO4 for s erum Ca < 11.5 mg/dL wi th mi l d s ymptoms a nd no ki dney di s ea s e
IV s a l i ne a nd furos emi de for more ra pi d correcti on for s erum Ca < 18 mg/dL
Bi s phos phona tes or other Ca -l oweri ng drugs for s erum Ca < 18 mg/dL a nd > 11.5 mg/dL or modera te s ymptoms
Hemodi a l ys i s for s erum Ca > 18 mg/dL
Surgi ca l remova l for modera te, progres s i ve pri ma ry hyperpa ra thyroi di s m a nd s ometi mes for mi l d di s ea s e
PO4 res tri cti on a nd bi nders a nd s ometi mes ca l ci tri ol for s econda ry hyperpa ra thyroi di s m
There a re 4 ma i n s tra tegi es for l oweri ng s erum Ca : Decrea s e i ntes ti na l Ca a bs orpti on
Increa s e uri na ry Ca excreti on
Decrea s e bone res orpti on
Remove exces s Ca through di a l ys i s
The trea tment us ed depends on both the degree a nd the ca us e of hyperca l cemi a .
Mild hypercalcemia: In mi l d hyperca l cemi a (s erum Ca < 11.5 mg/dL [< 2.88 mmol /L]), i n whi ch s ymptoms a re mi l d, trea tment i s deferred pendi ng
defi ni ti ve di a gnos i s . After di a gnos i s , the underl yi ng di s order i s trea ted. When s ymptoms a re s i gni fi ca nt, trea tment a i med a t l oweri ng s erum Ca i s
neces s a ry. Ora l PO4 ca n be us ed. When ta ken wi th mea l s , i t bi nds s ome Ca , preventi ng i ts a bs orpti on. A s ta rti ng dos e i s 250 mg of el ementa l PO4
(a s Na or K s a l t) qi d. The dos e ca n be i ncrea s ed to 500 mg qi d prn unl es s di a rrhea devel ops . Another trea tment i s i ncrea s i ng uri na ry Ca excreti on
by gi vi ng i s otoni c s a l i ne pl us a l oop di ureti c. Ini ti a l l y, 1 to 2 L of s a l i ne i s gi ven over 2 to 4 h unl es s s i gni fi ca nt hea rt fa i l ure i s pres ent, beca us e
nea rl y a l l pa ti ents wi th s i gni fi ca nt hyperca l cemi a a re hypovol emi c. Furos emi de 20 to 40 mg IV q 2 to 4 h i s gi ven a s needed to ma i nta i n a uri ne
output of roughl y 250 mL/h (moni tored hourl y). Ca re mus t be ta ken to a voi d vol ume depl eti on. K a nd Mg a re moni tored a s often a s every 4 h duri ng
trea tment a nd repl a ced IV a s needed to a voi d hypoka l emi a a nd hypoma gnes emi a . Serum Ca begi ns to decrea s e i n 2 to 4 h a nd fa l l s to
nea rnorma l wi thi n 24 h.
Moderate hypercalcemia: Modera te hyperca l cemi a (s erum Ca > 11.5 mg/dL [< 2.88 mmol /L] a nd < 18 mg/dL [< 4.51 mmol /L]) ca n be trea ted wi th
i s otoni c s a l i ne a nd a l oop di ureti c a s i s done for mi l d hyperca l cemi a or, dependi ng on i ts ca us e, a gents tha t decrea s e bone res orpti on (us ua l l y
bi s phos phona tes , ca l ci toni n, or i nfrequentl y pl i ca myci n or ga l l i um ni tra te), corti cos teroi ds , or chl oroqui ne.
Bisphosphonates i nhi bi t os teocl a s ts . They a re us ua l l y the drugs of choi ce for ca ncer-a s s oci a ted hyperca l cemi a . Pa mi drona te ca n be gi ven for ca ncera s s oci a ted hyperca l cemi a a s a one-ti me dos e of 30 to 90 mg IV, repea ted onl y a fter 7 da ys . It l owers s erum Ca for 2 wk. Zol edrona te ca n a l s o be
gi ven i n dos es of 4 to 8 mg IV a nd l owers s erum Ca very effecti vel y for a n a vera ge of > 40 da ys . Iba ndrona te 4 to 6 mg IV ca n be gi ven for ca ncera s s oci a ted hyperca l cemi a ; i t i s effecti ve for a bout 14 da ys . Eti drona te 7.5 mg/kg IV once/da y for 3 to 5 da ys i s us ed to trea t Pa get's di s ea s e a nd
ca ncer-a s s oci a ted hyperca l cemi a . Ma i ntena nce dos a ge i s 20 mg/kg po once/da y, but the dos e mus t be reduced when GFR i s l ow. Repeti ti ve us e of
IV bi s phos phona tes to trea t hyperca l cemi a a s s oci a ted wi th meta s ta ti c bone di s ea s e or myel oma ha s been a s s oci a ted wi th os teonecros i s of the
ja w. Some reports s ugges t thi s fi ndi ng ma y be more common wi th zol edrona te. Rena l toxi ci ty ha s been reported i n pa ti ents recei vi ng zol edrona te.
Ora l bi s phos phona tes (eg, a l endrona te or ri s edrona te) ca n be gi ven to ma i nta i n Ca i n the norma l ra nge but a re not genera l l y us ed for trea ti ng
hyperca l cemi a a cutel y.
Calcitonin (thyroca l ci toni n) i s a ra pi dl y a cti ng pepti de hormone norma l l y s ecreted i n res pons e to hyperca l cemi a by the C cel l s of the thyroi d.
Ca l ci toni n s eems to l ower s erum Ca by i nhi bi ti ng os teocl a s ti c a cti vi ty. A dos a ge of 4 to 8 IU/kg s c q 12 h of s a l mon ca l ci toni n i s s a fe. Its us eful nes s
i n the trea tment of ca ncer-a s s oci a ted hyperca l cemi a i s l i mi ted by i ts s hort dura ti on of a cti on wi th the devel opment of ta chyphyl a xi s (often a fter
a bout 48 h) a nd by the l a ck of res pons e i n 40% of pa ti ents . However, the combi na ti on of s a l mon ca l ci toni n a nd predni s one ma y control s erum Ca
for s evera l months i n s ome pa ti ents wi th ca ncer. If ca l ci toni n s tops worki ng, i t ca n be s topped for 2 da ys (whi l e predni s one i s conti nued) a nd then
res umed.
Corticosteroids (eg, predni s one 20 to 40 mg po once/da y) ca n hel p control hyperca l cemi a a s a djuncti ve thera py by decrea s i ng ca l ci tri ol producti on
a nd thus i ntes ti na l Ca a bs orpti on i n mos t pa ti ents wi th vi ta mi n D toxi ci ty, i di opa thi c hyperca l cemi a of i nfa ncy, a nd s a rcoi dos i s . Some pa ti ents
wi th myel oma , l ymphoma , l eukemi a , or meta s ta ti c ca ncer requi re 40 to 60 mg of predni s one once/da y. However, > 50% of s uch pa ti ents fa i l to
res pond to corti cos teroi ds , a nd res pons e, when i t occurs , ta kes s evera l da ys ; thus , other trea tment us ua l l y i s neces s a ry.
Chloroquine PO4 500 mg po once/da y i nhi bi ts 1,25(OH) 2 D s ynthes i s a nd reduces s erum Ca concentra ti on i n pa ti ents wi th s a rcoi dos i s . Routi ne
ophtha l mol ogi c s urvei l l a nce (eg, reti na l exa mi na ti ons every 6 to 12 mo) i s ma nda tory to detect dos e-rel a ted reti na l da ma ge.
Plicamycin 25 g/kg IV once/da y i n 50 mL of 5% D/W over 4 to 6 h i s effecti ve i n pa ti ents wi th hyperca l cemi a due to ca ncer but i s ra rel y us ed beca us e
other trea tments a re s a fer.
Gallium nitrate i s a l s o effecti ve i n hyperca l cemi a due to ca ncer but i s us ed i nfrequentl y beca us e of rena l toxi ci ty a nd l i mi ted cl i ni ca l experi ence.
Severe hypercalcemia: In s evere hyperca l cemi a (s erum Ca > 18 mg/dL [> 4.50 mmol /L] or wi th s evere s ymptoms ), hemodi a l ys i s wi th l ow-Ca di a l ys a te
ma y be needed i n a ddi ti on to other trea tments . Al though there i s no compl etel y s a ti s fa ctory wa y to correct s evere hyperca l cemi a i n pa ti ents wi th
rena l fa i l ure, hemodi a l ys i s i s proba bl y the s a fes t a nd mos t rel i a bl e s hort-term trea tment.
IV PO4 (di s odi um PO4 or monopota s s i um PO4 ) s houl d be us ed onl y when hyperca l cemi a i s l i fe threa teni ng a nd unres pons i ve to other methods a nd
when s hort-term hemodi a l ys i s i s not pos s i bl e. No more tha n 1 g s houl d be gi ven IV i n 24 h; us ua l l y 1 or 2 dos es over 2 da ys l ower s erum Ca for 10
to 15 da ys . Soft-ti s s ue ca l ci fi ca ti on a nd a cute rena l fa i l ure ma y res ul t. (NOTE: IV i nfus i on of Na s ul fa te i s even more ha za rdous a nd l es s effecti ve
tha n PO4 i nfus i on a nd s houl d not be us ed.)
Hyperparathyroidism: Trea tment for hyperpa ra thyroi di s m depends on s everi ty.
Pa ti ents wi th asymptomatic primary hyperparathyroidism wi th no i ndi ca ti ons for s urgery ma y be trea ted cons erva ti vel y wi th methods to ens ure tha t
s erum Ca concentra ti ons rema i n l ow. Pa ti ents s houl d rema i n a cti ve (i e, a voi d i mmobi l i za ti on tha t coul d exa cerba te hyperca l cemi a ), fol l ow a l owCa di et, dri nk pl enty of fl ui ds to mi ni mi ze the cha nce of nephrol i thi a s i s , a nd a voi d drugs tha t ca n ra i s e s erum Ca , s uch a s thi a zi de di ureti cs . Serum
Ca a nd rena l functi on a re moni tored every 6 mo. Bone dens i ty i s moni tored every 12 mo. However, s ubcl i ni ca l bone di s ea s e, hypertens i on, a nd
l ongevi ty a re concerns . Os teoporos i s i s trea ted wi th bi s phos phona tes .
Surgery i s i ndi ca ted for pa ti ents wi th s ymptoma ti c or progres s i ve hypopa ra thyroi di s m. The i ndi ca ti ons for s urgery i n pa ti ents wi th a s ymptoma ti c,
pri ma ry hyperpa ra thyroi di s m a re controvers i a l . Surgi ca l pa ra thyroi dectomy i ncrea s es bone dens i ty a nd ma y ha ve modes t effects on s ome qua l i ty
of l i fe s ymptoms , but mos t pa ti ents do not ha ve progres s i ve deteri ora ti on i n bi ochemi ca l a bnorma l i ti es or bone dens i ty. Sti l l , concerns a bout
hypertens i on a nd l ongevi ty rema i n. Ma ny experts recommend s urgery i n the fol l owi ng ci rcums ta nces :
Serum Ca 1 mg/dL (0.25 mmol /L) grea ter tha n the upper l i mi ts of norma l Ca l ci uri a > 400 mg/da y (> 10 mmol /da y)
Crea ti ni ne cl ea ra nce 30% l es s tha n tha t of a ge-ma tched control s
Pea k bone dens i ty a t the hi p, l umba r s pi ne, or ra di us 2.5 s ta nda rd devi a ti ons bel ow control s (T s core = -2.5)
Age < 50 yr
The pos s i bi l i ty of poor a dherence wi th fol l ow-up
Surgery cons i s ts of remova l of a denoma tous gl a nds . PTH concentra ti on ca n be mea s ured before a nd a fter remova l of the pres umed a bnorma l
gl a nd us i ng ra pi d a s s a ys . A fa l l of 50% or more 10 mi n a fter remova l of the a denoma i ndi ca tes s ucces s ful trea tment. In pa ti ents wi th di s ea s e of >
1 gl a nd, s evera l gl a nds a re removed, a nd often a s ma l l porti on of a norma l a ppea ri ng pa ra thyroi d gl a nd i s rei mpl a nted i n the bel l y of the
s ternocl ei doma s toi d mus cl e or s ubcuta neous l y i n the forea rm to prevent hypopa ra thyroi di s m. Pa ra thyroi d ti s s ue i s a l s o occa s i ona l l y pres erved
us i ng cryopres erva ti on to a l l ow for l a ter a utol ogous tra ns pl a nta ti on i n ca s e pers i s tent hypopa ra thyroi di s m devel ops .
When hyperpa ra thyroi di s m i s mi l d, the s erum Ca concentra ti on drops to jus t bel ow norma l wi thi n 24 to 48 h a fter s urgery; s erum Ca mus t be
moni tored. In pa ti ents wi th s evere os tei ti s fi bros a cys ti ca , prol onged, s ymptoma ti c hypoca l cemi a ma y occur pos topera ti vel y unl es s 10 to 20 g
el ementa l Ca i s gi ven i n the da ys before s urgery. Even wi th preopera ti ve Ca a dmi ni s tra ti on, l a rge dos es of Ca a nd vi ta mi n D ma y be requi red (s ee
p. 841) whi l e bone Ca i s repl eted.
Hyperparathyroidism in renal failure i s us ua l l y s econda ry. Mea s ures us ed for trea tment ca n a l s o be us ed for preventi on. One a i m i s to prevent
hyperphos pha temi a . Trea tment combi nes di eta ry PO4 res tri cti on a nd PO4 -bi ndi ng a gents , s uch a s Ca ca rbona te or s evel a mer. Des pi te the us e of
PO4 bi nders , di eta ry res tri cti on of PO4 i s needed. Al umi num-conta i ni ng compounds ha ve been us ed to l i mi t PO4 concentra ti on, but they s houl d be
a voi ded, es peci a l l y i n pa ti ents recei vi ng l ong-term di a l ys i s , to prevent a l umi num a ccumul a ti on i n bone res ul ti ng i n s evere os teoma l a ci a . Vi ta mi n
D a dmi ni s tra ti on i s potenti a l l y ha za rdous i n rena l fa i l ure beca us e i t ca n i ncrea s e PO4 a bs orpti on a nd contri bute to hyperca l cemi a ; a dmi ni s tra ti on
requi res frequent moni tori ng of Ca a nd PO4 . Trea tment s houl d be l i mi ted to pa ti ents wi th a ny of the fol l owi ng:
Symptoma ti c os teoma l a ci a (unrel a ted to a l umi num)
Seconda ry hyperpa ra thyroi di s m
Pos tpa ra thyroi dectomy hypoca l cemi a
Al though ora l ca l ci tri ol i s often gi ven a l ong wi th ora l Ca to s uppres s s econda ry hyperpa ra thyroi di s m, the res ul ts a re va ri a bl e i n pa ti ents wi th ends ta ge rena l di s ea s e. The pa rentera l form of ca l ci tri ol , or vi ta mi n D a na l ogs s uch a s pa ri ca l ci tol , ma y better prevent s econda ry hyperpa ra thyroi di s m
i n s uch pa ti ents , beca us e the hi gher a tta i ned s erum concentra ti on of 1,25(OH) 2 D di rectl y s uppres s es PTH rel ea s e. Si mpl e os teoma l a ci a ma y
res pond to 0.25 to 0.5 g once/da y of ora l ca l ci tri ol , wherea s correcti on of pos tpa ra thyroi dectomy hypoca l cemi a ma y requi re prol onged
a dmi ni s tra ti on of a s much a s 2 g of ca l ci tri ol once/da y a nd 2 g of el ementa l Ca /da y. The ca l ci mi meti c, ci na ca l cet, modul a tes the s et poi nt of the
Ca -s ens i ng receptor on pa ra thyroi d cel l s a nd decrea s es PTH concentra ti on i n di a l ys i s pa ti ents wi thout i ncrea s i ng s erum Ca . In pa ti ents wi th
os teoma l a ci a ca us ed by ha vi ng ta ken l a rge a mounts of a l umi num-conta i ni ng PO4 bi nders , remova l of a l umi num wi th deferoxa mi ne i s neces s a ry
before ca l ci trol a dmi ni s tra ti on reduces bone l es i ons .
FHH: Al though FHH res ul ts from hi s tol ogi ca l l y a bnorma l pa ra thyroi d ti s s ue, the res pons e to s ubtota l pa ra thyroi dectomy i s uns a ti s fa ctory. Beca us e
overt cl i ni ca l ma ni fes ta ti ons a re ra re, drug thera py i s not routi nel y i ndi ca ted.
Disorders of Phosphate Concentration
Phos phorus i s one of the mos t a bunda nt el ements i n the huma n body. Mos t phos phorus i n the body i s compl exed wi th O2 a s phos pha te (PO4 ).
About 85% of the a bout 500 to 700 g of PO4 i n the body i s conta i ned i n bone, where i t i s a n i mporta nt cons ti tuent of crys ta l l i ne hydroxya pa ti te. In
s oft ti s s ues , PO4 i s ma i nl y found i n the i ntra cel l ul a r compa rtment a s a n i ntegra l component of s evera l orga ni c compounds , i ncl udi ng nucl ei c a ci ds
a nd cel l membra ne phos phol i pi ds . PO4 i s a l s o i nvol ved i n a erobi c a nd a na erobi c energy meta bol i s m. RBC 2,3-di phos phogl ycera te (2,3-DPG) pl a ys
a cruci a l rol e i n O2 del i very to ti s s ue. Adenos i ne di phos pha te (ADP) a nd ATP conta i n PO4 a nd us e chemi ca l bonds between PO4 groups to s tore
energy. Inorga ni c PO4 i s a ma jor i ntra cel l ul a r a ni on but i s a l s o pres ent i n pl a s ma . The norma l s erum i norga ni c PO4 concentra ti on i n a dul ts ra nges
from 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol /L). PO4 concentra ti on i s 50% hi gher i n i nfa nts a nd 30% hi gher i n chi l dren, pos s i bl y beca us e of the i mporta nt
rol es thes e PO4 -dependent proces s es pl a y i n growth.
The typi ca l Ameri ca n di et conta i ns a bout 800 to 1500 mg of PO4 . The a mount i n the s tool va ri es dependi ng on the a mount of PO4 bi ndi ng
compounds (ma i nl y Ca ) i n the di et. Al s o, l i ke Ca , GI PO4 a bs orpti on i s enha nced by vi ta mi n D. Rena l PO4 excreti on roughl y equa l s GI a bs orpti on to
ma i nta i n PO4 ba l a nce. PO4 depl eti on ca n occur i n va ri ous di s orders a nd norma l l y res ul ts i n cons erva ti on of PO4 by the ki dneys . Bone PO4 s erves a s
a res ervoi r, whi ch ca n buffer cha nges i n pl a s ma a nd i ntra cel l ul a r PO4 .
Hypophosphatemia
Hypophosphatemia is serum phosphate (PO4 ) concentration < 2.5 mg/dL (0.81 mmol/L). Causes include alcoholism, burns, starvation, and diuretic use. Clinical
features include muscle weakness, respiratory failure, and heart failure; seizures and coma can occur. Diagnosis is by serum PO4 concentration. Treatment
consists of PO4 supplementation.
Etiology
Hypophos pha temi a occurs i n 2% of hos pi ta l i zed pa ti ents but i s more preva l ent i n certa i n popul a ti ons (eg, i t occurs i n up to 10% of hos pi ta l i zed
pa ti ents wi th a l cohol i s m).
Hypophos pha temi a ha s numerous ca us es , but cl i ni ca l l y s i gni fi ca nt a cute hypophos pha temi a occurs i n rel a ti vel y few cl i ni ca l s etti ngs , i ncl udi ng
the fol l owi ng:
The recovery pha s e of di a beti c ketoa ci dos i s
Acute a l cohol i s m
Severe burns
When recei vi ng TPN
Refeedi ng a fter prol onged undernutri ti on
Severe res pi ra tory a l ka l os i s

Acute s evere hypophos pha temi a wi th s erum PO4 < 1 mg/dL (< 0.32 mmol /L) i s mos t often ca us ed by tra ns cel l ul a r s hi fts of PO4 , often s uperi mpos ed
on chroni c PO4 depl eti on.
Chroni c hypophos pha temi a us ua l l y i s the res ul t of decrea s ed rena l PO4 rea bs orpti on. Ca us es i ncl ude the fol l owi ng:
Hyperpa ra thyroi di s m
Other hormona l di s turba nces , s uch a s Cus hi ng's s yndrome a nd hypothyroi di s m
El ectrol yte di s orders , s uch a s hypoma gnes emi a a nd hypoka l emi a
Theophyl l i ne i ntoxi ca ti on
Long-term di ureti c us e
Severe chroni c hypophos pha temi a us ua l l y res ul ts from a prol onged nega ti ve PO4 ba l a nce. Ca us es i ncl ude
Chroni c s ta rva ti on or ma l a bs orpti on, es peci a l l y when combi ned wi th vomi ti ng or copi ous di a rrhea
Long-term i nges ti on of l a rge a mounts of PO4 -bi ndi ng a l umi num, us ua l l y i n the form of a nta ci ds
Inges ti on of a l umi num i s pa rti cul a rl y prone to ca us e PO4 depl eti on when combi ned wi th decrea s ed di eta ry i nta ke a nd di a l ys i s l os s es of PO4 i n
pa ti ents wi th end-s ta ge rena l di s ea s e.
Symptoms and Signs
Al though hypophos pha temi a us ua l l y i s a s ymptoma ti c, a norexi a , mus cl e wea knes s , a nd os teoma l a ci a ca n occur i n s evere chroni c depl eti on.
Seri ous neuromus cul a r di s turba nces ma y occur, i ncl udi ng progres s i ve encepha l opa thy, s ei zures , coma , a nd dea th. The mus cl e wea knes s of
profound hypophos pha temi a ma y be a ccompa ni ed by rha bdomyol ys i s , es peci a l l y i n a cute a l cohol i s m. Hema tol ogi c di s turba nces of profound
hypophos pha temi a i ncl ude hemol yti c a nemi a , decrea s ed rel ea s e of O2 from Hb, a nd i mpa i red l eukocyte a nd pl a tel et functi on.
Diagnosis
Serum PO4 l evel s
Hypophos pha temi a i s di a gnos ed by a s erum PO4 concentra ti on < 2.5 mg/dL (< 0.81 mmol /L). Mos t ca us es of hypophos pha temi a (eg, di a beti c
ketoa ci dos i s , burns , refeedi ng) a re rea di l y a ppa rent. Tes ti ng to di a gnos e the ca us e i s done when cl i ni ca l l y i ndi ca ted (eg, s ugges ti ve l i ver functi on
tes t res ul ts or s i gns of ci rrhos i s i n pa ti ents wi th s us pected a l cohol i s m).
Treatment
Ora l PO4 repl a cement
IV PO4 when s erum PO4 i s < 0.5 mEq/L or s ymptoms a re s evere
Oral treatment: Trea tment of the underl yi ng di s order a nd ora l PO4 repl a cement a re us ua l l y a dequa te i n a s ymptoma ti c pa ti ents , even when the
s erum concentra ti on i s very l ow. PO4 ca n be gi ven i n dos es up to a bout 1 g po ti d i n ta bl ets conta i ni ng Na or K PO4 . Ora l Na or K PO4 ma y be poorl y
tol era ted beca us e of di a rrhea . Inges ti on of 1 L of l ow-fa t or s ki m mi l k provi des 1 g of PO4 a nd ma y be more a ccepta bl e. Remova l of the ca us e of
hypophos pha temi a ma y i ncl ude s toppi ng PO4 -bi ndi ng a nta ci ds or di ureti cs or correcti ng hypoma gnes emi a .
Parenteral treatment: Pa rentera l PO4 i s us ua l l y gi ven IV. It s houl d be a dmi ni s tered i n a ny of the fol l owi ng ci rcums ta nces :
When s erum PO4 i s < 0.5 mEq/L (< 0.16 mmol /L)
Rha bdomyol ys i s , hemol ys i s , or CNS s ymptoms a re pres ent
Ora l repl a cement i s not fea s i bl e due to underl yi ng di s order
IV a dmi ni s tra ti on of KPO4 (a s buffered mi x of K2 HPO4 a nd KH 2 PO4 ) i s rel a ti vel y s a fe when rena l functi on i s wel l pres erved. Na PO4 (ra ther tha n KPO4 )
prepa ra ti ons genera l l y s houl d be us ed i n pa ti ents wi th i mpa i red rena l functi on. The us ua l pa rentera l dos e of KPO4 i s 2.5 mg (0.08 mmol )/kg IV
over 6 h. Pa ti ents wi th a l cohol i s m ma y requi re 1 g/da y duri ng TPN; s uppl ementa l PO4 i s s topped when ora l i nta ke i s res umed. Serum Ca a nd PO4
concentra ti ons s houl d be moni tored duri ng thera py, pa rti cul a rl y when PO4 i s gi ven IV or to pa ti ents wi th i mpa i red rena l functi on. In mos t ca s es ,
no more tha n 7 mg/kg (a bout 500 mg for a 70-kg a dul t) of PO4 s houl d be gi ven over 6 h. Cl os e moni tori ng i s done a nd more ra pi d ra tes of PO4
a dmi ni s tra ti on s houl d be a voi ded to prevent hypoca l cemi a , hyperphos pha temi a , a nd meta s ta ti c ca l ci fi ca ti on due to exces s i ve Ca PO4 product.
Hyperphosphatemia
Hyperphosphatemia is serum phosphate (PO4 ) concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic renal failure, hypoparathyroidism, and
metabolic or respiratory acidosis. Clinical features may be due to accompanying hypocalcemia and include tetany. Diagnosis is by serum PO4 . Treatment includes
restriction of PO4 intake and administration of PO4 -binding antacids, such as Ca carbonate.
The us ua l ca us e of hyperphos pha temi a i s a decrea s e i n rena l excreti on of PO4 . Adva nced rena l i ns uffi ci ency (GFR < 30 mL/mi n) reduces excreti on
s uffi ci entl y to i ncrea s e s erum PO4 . Defects i n rena l excreti on of PO4 i n the a bs ence of rena l fa i l ure a l s o occur i n ps eudohypopa ra thyroi di s m a nd
hypopa ra thyroi di s m. Hyperphos pha temi a ca n a l s o occur wi th exces s i ve ora l PO4 a dmi ni s tra ti on a nd occa s i ona l l y wi th overzea l ous us e of enema s
conta i ni ng PO4 .
Hyperphos pha temi a occa s i ona l l y res ul ts from a tra ns cel l ul a r s hi ft of PO4 i nto the extra cel l ul a r s pa ce tha t i s s o l a rge tha t the rena l excretory
ca pa ci ty i s overwhel med. Thi s tra ns cel l ul a r s hi ft occurs mos t frequentl y i n di a beti c ketoa ci dos i s (des pi te tota l body PO4 depl eti on), crus h i njuri es ,
a nd nontra uma ti c rha bdomyol ys i s a s wel l a s i n overwhel mi ng s ys temi c i nfecti ons a nd tumor l ys i s s yndrome.
Ma jor ca us es of hyperphos pha temi a i ncl ude
GFR < 30 mL/mi n
Ps eudohypopa ra thyroi di s m
Exces s i ve ora l PO4 a dmi ni s tra ti on
Overzea l ous us e of enema s conta i ni ng PO4
Shi fts of PO4 i nto the extra cel l ul a r s pa ce (eg, i n di a beti c ketoa ci dos i s , rha bdomyol ys i s , overwhel mi ng s ys temi c i nfecti ons , a nd tumor l ys i s
s yndrome)
Hyperphos pha temi a pl a ys a cri ti ca l rol e i n the devel opment of s econda ry hyperpa ra thyroi di s m a nd rena l os teodys trophy i n pa ti ents wi th
a dva nced chroni c ki dney di s ea s e a s wel l a s i n pa ti ents on di a l ys i s . La s tl y, hyperphos pha temi a ca n be s puri ous i n ca s es of hyperprotei nemi a
(mul ti pl e myel oma or Wa l dens trom's ma crogl obul i nemi a ), hyperl i pi demi a , hemol ys i s , or hyperbi l i rubi nemi a .
Hyperphos pha temi a ca n l ea d to hypoca l cemi a by ca us i ng Ca a nd PO4 preci pi ta ti on i nto s oft ti s s ues , es peci a l l y when the s erum Ca PO4 product i s
chroni ca l l y > 55 i n pa ti ents wi th chroni c ki dney di s ea s e.
Symptoms and Signs
Mos t pa ti ents wi th hyperphos pha temi a a re a s ymptoma ti c, a l though s ymptoms of hypoca l cemi a , i ncl udi ng teta ny, ca n occur when concomi ta nt
hypoca l cemi a i s pres ent. Soft-ti s s ue ca l ci fi ca ti ons a re common a mong pa ti ents wi th chroni c ki dney di s ea s e.
Diagnosis
PO4 concentra ti on > 4.5 mg/dL (> 1.46 mmol /L)
Hyperphos pha temi a i s di a gnos ed by PO4 concentra ti on. When the eti ol ogy i s not obvi ous (eg, rha bdomyol ys i s , tumor l ys i s s yndrome, rena l fa i l ure,
overi nges ti on of PO4 ,-conta i ni ng l a xa ti ves ), a ddi ti ona l eva l ua ti on i s wa rra nted to excl ude hypopa ra thyroi di s m or ps eudohypopa ra thyroi di s m,
whi ch i s end-orga n res i s ta nce to pa ra thyroi d hormone (PTHs ee p. 839). Fa l s e el eva ti on of s erum PO4 a l s o s houl d be excl uded by mea s uri ng
s erum protei n, l i pi d, a nd bi l i rubi n concentra ti ons .
Treatment
PO4 res tri cti on
PO4 bi nders
The ma i ns ta y of trea tment i n pa ti ents wi th rena l fa i l ure i s reducti on of PO4 i nta ke, whi ch i s us ua l l y a ccompl i s hed wi th a voi da nce of foods
conta i ni ng hi gh a mounts of PO4 a nd wi th us e of PO4 -bi ndi ng drugs ta ken wi th mea l s . Beca us e of the pos s i bi l i ty of a l umi num-rel a ted
os teoma l a ci a , Ca ca rbona te a nd Ca a ceta te repl a ce a l umi num-conta i ni ng a nta ci ds i n pa ti ents wi th end-s ta ge rena l di s ea s e. Beca us e of the
pos s i bi l i ty of exces s i ve Ca PO4 product ca us i ng va s cul a r ca l ci fi ca ti on i n di a l ys i s pa ti ents ta ki ng Ca -conta i ni ng bi nders , a PO4 -bi ndi ng res i n
wi thout Ca , s evel a mer, i s wi del y us ed i n di a l ys i s pa ti ents i n dos es of 800 to 2400 mg ti d wi th mea l s . La ntha num ca rbona te, a nother PO4 bi nder
tha t l a cks Ca , ca n a l s o be us ed i n di a l ys i s pa ti ents . It i s gi ven i n dos es of 500 to 1000 mg ti d wi th mea l s .
Disorders of Magnesium Concentration
Mg i s the 4th mos t pl enti ful ca ti on i n the body. A 70-kg a dul t ha s a bout 2000 mEq of Mg. About 50% i s s eques tered i n bone a nd i s not rea di l y
excha ngea bl e wi th Mg i n other compa rtments . The ECF conta i ns onl y a bout 1% of tota l body Mg. The rema i nder res i des i n the i ntra cel l ul a r
compa rtment. Norma l s erum Mg concentra ti on ra nges from 1.4 to 2.1 mEq/L (0.70 to 1.05 mmol /L).
The ma i ntena nce of s erum Mg concentra ti on i s l a rgel y a functi on of di eta ry i nta ke a nd effecti ve rena l a nd i ntes ti na l cons erva ti on. Wi thi n 7 da ys
of i ni ti a ti on of a Mg-defi ci ent di et, rena l a nd s tool Mg excreti on ea ch fa l l to a bout 1 mEq/da y (0.5 mmol /da y).
About 70% of s erum Mg i s ul tra fi l tered (fi l tered through mi nute pores ) by the ki dney; the rema i nder i s bound to protei n. Protei n bi ndi ng of Mg i s
pH dependent. Serum Mg concentra ti on i s not cl os el y rel a ted to ei ther tota l body Mg or i ntra cel l ul a r Mg content. However, s evere s erum
hypoma gnes emi a ma y refl ect di mi ni s hed tota l body Mg.
Ma ny enzymes a re a cti va ted by or a re dependent on Mg. Mg i s requi red by a l l enzyma ti c proces s es i nvol vi ng ATP a nd by ma ny of the enzymes
i nvol ved i n nucl ei c a ci d meta bol i s m. Mg i s requi red for thi a mi ne pyrophos pha te cofa ctor a cti vi ty a nd s eems to s ta bi l i ze the s tructure of
ma cromol ecul es s uch a s DNA a nd RNA. Mg i s a l s o rel a ted to Ca a nd K meta bol i s m i n a n i nti ma te but poorl y unders tood wa y.
Hypomagnesemia
Hypomagnesemia is serum Mg concentration < 1.4 mEq/L (< 0.70 mmol/L). Causes include inadequate Mg intake and absorption or increased excretion due to
hypercalcemia or drugs such as furosemide. Clinical features are often due to accompanying hypokalemia and hypocalcemia and include lethargy, tremor, tetany,
seizures, and arrhythmias. Treatment is with Mg replacement.
Serum Mg concentra ti on, even when free Mg i on i s mea s ured, ma y be norma l even wi th decrea s ed i ntra cel l ul a r or bone Mg s tores . Mg depl eti on
us ua l l y res ul ts from i na dequa te i nta ke pl us i mpa i rment of rena l cons erva ti on or GI a bs orpti on. There a re numerous ca us es of cl i ni ca l l y
s i gni fi ca nt Mg defi ci ency (s ee
Ta bl e 97-11).
Symptoms and Signs
Cl i ni ca l ma ni fes ta ti ons a re a norexi a , na us ea , vomi ti ng, l etha rgy, wea knes s , pers ona l i ty cha nge, teta ny (eg, pos i ti ve Trous s ea u's or Chvos tek's s i gn
or s ponta neous ca rpopeda l s pa s m, hyperrefl exi a ), a nd tremor a nd mus cl e fa s ci cul a ti ons . The neurol ogi c s i gns , pa rti cul a rl y teta ny, correl a te wi th
devel opment of concomi ta nt hypoca l cemi a , hypoka l emi a , or both. Myopa thi c potenti a l s a re found on el ectromyogra phy but a re a l s o compa ti bl e
wi th hypoca l cemi a or hypoka l emi a . Severe hypoma gnes emi a ma y ca us e genera l i zed toni ccl oni c s ei zures , es peci a l l y i n chi l dren.
Diagnosis
Cons i dered i n pa ti ents wi th ri s k fa ctors a nd wi th unexpl a i ned hypoca l cemi a or hypoka l emi a
Serum Mg concentra ti on < 1.4 mEq/L (< 0.70 mmol /L)
Hypoma gnes emi a i s di a gnos ed by a s erum Mg concentra ti on. Severe hypoma gnes emi a us ua l l y res ul ts i n concentra ti ons of < 1.0 mEq/L (< 0.50
mmol /L). As s oci a ted hypoca l cemi a a nd hypoca l ci uri a a re common. Hypoka l emi a wi th i ncrea s ed uri na ry K excreti on a nd meta bol i c a l ka l os i s ma y
be pres ent. Mg defi ci ency s houl d be s us pected even when s erum Mg concentra ti on i s norma l i n pa ti ents wi th unexpl a i ned hypoca l cemi a or
refra ctory hypoka l emi a . Mg defi ci ency s houl d a l s o be s us pected i n pa ti ents wi th unexpl a i ned neurol ogi c s ymptoms a nd a l cohol i s m, wi th chroni c
di a rrhea , or a fter cycl os pori ne, ci s pl a ti num-ba s ed chemothera py or prol onged thera py wi th a mphoteri ci n B or a mi nogl ycos i des .
[Table 97-11. Ca us es of Hypoma gnes emi a ]
Treatment
Ora l Mg s a l ts
IV or IM Mg s ul fa te for s evere hypoma gnes emi a or i na bi l i ty to tol era te or a dhere to ora l thera py
Trea tment wi th Mg s a l ts i s i ndi ca ted when Mg defi ci ency i s s ymptoma ti c or pers i s tentl y < 1 mEq/L (< 0.50 mmol /L). Pa ti ents wi th a l cohol i s m a re
trea ted empi ri ca l l y. In s uch ca s es , defi ci ts a pproa chi ng 12 to 24 mg/kg a re pos s i bl e. About twi ce the a mount of the es ti ma ted defi ci t s houl d be
gi ven i n pa ti ents wi th i nta ct rena l functi on, beca us e a bout 50% of the a dmi ni s tered Mg i s excreted i n uri ne. Ora l Mg s a l ts (eg, Mg gl ucona te 500 to
1000 mg po ti d) a re gi ven for 3 to 4 da ys . Ora l trea tment i s l i mi ted by the ons et of di a rrhea . Pa rentera l a dmi ni s tra ti on i s res erved for pa ti ents wi th
s evere, s ymptoma ti c hypoma gnes emi a who ca nnot tol era te ora l drugs . Someti mes a s i ngl e i njecti on i s gi ven i n pa ti ents wi th a l cohol i s m who a re
unl i kel y to a dhere to ongoi ng ora l thera py. When Mg mus t be repl a ced pa rentera l l y, a 10% Mg s ul fa te (MgSO4 ) s ol uti on (1 g/10 mL) i s a va i l a bl e for
IV us e a nd a 50% s ol uti on (1 g/2 mL) i s a va i l a bl e for IM us e. The s erum Mg concentra ti on s houl d be moni tored frequentl y duri ng Mg thera py,
pa rti cul a rl y when Mg i s gi ven to pa ti ents wi th rena l i ns uffi ci ency or i n repea ted pa rentera l dos es . In thes e pa ti ents , trea tment i s conti nued unti l
a norma l s erum Mg concentra ti on i s a chi eved.
In s evere, s ymptoma ti c hypoma gnes emi a (eg, Mg < 1 mEq/L [< 0.5 mmol /L] wi th s ei zures or other s evere s ymptoms ), 2 to 4 g of MgSO4 IV i s gi ven
over 5 to 10 mi n. When s ei zures pers i s t, the dos e ma y be repea ted up to a tota l of 10 g over the next 6 h. In pa ti ents i n whom s ei zures s top, 10 g i n
1 L of 5% D/W ca n be i nfus ed over 24 h, fol l owed by up to 2.5 g q 12 h to repl a ce the defi ci t i n tota l Mg s tores a nd prevent further drops i n s erum
Mg. When s erum Mg i s 1 mEq/L (< 0.5 mmol /L) but s ymptoms a re l es s s evere, MgSO4 ma y be gi ven IV i n 5% D/W a t a ra te of 1 g/h a s s l ow i nfus i on
for up to 10 h. In l es s s evere ca s es of hypoma gnes emi a , gra dua l repl eti on ma y be a chi eved by a dmi ni s tra ti on of s ma l l er pa rentera l dos es over 3
to 5 da ys unti l the s erum Mg concentra ti on i s norma l .
Hypermagnesemia
Hypermagnesemia is a serum Mg concentration > 2.1 mEq/L (> 1.05 mmol/L). The major cause is renal failure. Symptoms include hypotension, respiratory
depression, and cardiac arrest. Diagnosis is by serum Mg concentration. Treatment includes IV administration of Ca gluconate and possibly furosemide;
hemodialysis can be helpful in severe cases.
Symptoma ti c hyperma gnes emi a i s fa i rl y uncommon. It occurs mos t commonl y i n pa ti ents wi th rena l fa i l ure a fter i nges ti on of Mg-conta i ni ng drugs ,
s uch a s a nta ci ds or purga ti ves .
Symptoms a nd s i gns i ncl ude hyporefl exi a , hypotens i on, res pi ra tory depres s i on, a nd ca rdi a c a rres t.
Diagnosis
Serum Mg concentra ti ons > 2.1 mEq/L (> 1.05 mmol /L)
At s erum Mg concentra ti ons of 5 to 10 mEq/L (2.5 to 5 mmol /L), the ECG s hows prol onga ti on of the PR i nterva l , wi deni ng of the QRS compl ex, a nd
i ncrea s ed T-wa ve a mpl i tude. Deep tendon refl exes di s a ppea r a s the s erum Mg concentra ti on a pproa ches 10 mEq/L (5.0 mmol /L); hypotens i on,
res pi ra tory depres s i on, a nd na rcos i s devel op wi th i ncrea s i ng hyperma gnes emi a . Ca rdi a c a rres t ma y occur when bl ood Mg concentra ti on i s > 12 to
15 mEq/L (6.0 to 7.5 mmol /L).
Treatment
Ca gl ucona te
Di ures i s or di a l ys i s
Trea tment of s evere Mg toxi ci ty cons i s ts of ci rcul a tory a nd res pi ra tory s upport wi th a dmi ni s tra ti on of 10% Ca gl ucona te 10 to 20 mL IV. Ca gl ucona te
ma y revers e ma ny of the Mg-i nduced cha nges , i ncl udi ng res pi ra tory depres s i on. Admi ni s tra ti on of IV furos emi de ca n i ncrea s e Mg excreti on when
rena l functi on i s a dequa te; vol ume s ta tus s houl d be ma i nta i ned. Hemodi a l ys i s ma y be va l ua bl e i n s evere hyperma gnes emi a , beca us e a
rel a ti vel y l a rge fra cti on (a bout 70%) of bl ood Mg i s not protei n bound a nd thus remova bl e wi th hemodi a l ys i s . When hemodyna mi c compromi s e
occurs a nd hemodi a l ys i s i s i mpra cti ca l , peri tonea l di a l ys i s i s a n opti on.
Chapter 98. Acid-Base Regulation and Disorders

Introduction
Meta bol i c proces s es conti nua l l y produce a ci d a nd, to a l es s er degree, ba s e. Hydrogen i on (H +) i s es peci a l l y rea cti ve; i t ca n a tta ch to nega ti vel y
cha rged protei ns a nd, i n hi gh concentra ti ons , a l ter thei r overa l l cha rge, confi gura ti on, a nd functi on. To ma i nta i n cel l ul a r functi on, the body ha s
el a bora te mecha ni s ms tha t ma i nta i n bl ood H + concentra ti on wi thi n a na rrow ra ngetypi ca l l y 37 to 43 nmol /L (pH 7.43 to 7.37, where pH = -l og [H +])
a nd i dea l l y 40 nmol /L (pH = 7.40). Di s turba nces of thes e mecha ni s ms ca n ha ve s eri ous cl i ni ca l cons equences .
Aci d-ba s e equi l i bri um i s cl os el y ti ed to fl ui d a nd el ectrol yte ba l a nce, a nd di s turba nces i n one of thes e s ys tems often a ffect a nother. Fl ui d a nd
el ectrol ytes a re di s cus s ed i n Ch. 97.
Acid-Base Physiology
Mos t a ci d comes from ca rbohydra te a nd fa t meta bol i s m, whi ch genera tes 15,000 to 20,000 mmol of CO2 da i l y. CO2 i s not a n a ci d i ts el f but combi nes
wi th wa ter (H 2 O) i n the bl ood to crea te ca rboni c a ci d (H 2 CO3 ), whi ch i n the pres ence of the enzyme ca rboni c a nhydra s e di s s oci a tes i nto H + a nd
HCO3 -. The H + bi nds wi th Hb i n RBCs a nd i s rel ea s ed wi th oxygena ti on i n the a l veol i , a t whi ch ti me the rea cti on i s revers ed, crea ti ng H 2 O a nd CO2 ,
whi ch i s exha l ed i n ea ch brea th.
Les s er a mounts of orga ni c a ci d deri ve from the fol l owi ng:
Incompl ete meta bol i s m of gl ucos e a nd fa tty a ci ds i nto l a cti c a ci d a nd ketoa ci ds
Meta bol i s m of s ul fur-conta i ni ng a mi no a ci ds (cys tei ne, methi oni ne) i nto s ul furi c a ci d
Meta bol i s m of ca ti oni c a mi no a ci ds (a rgi ni ne, l ys i ne)
Hydrol ys i s of di eta ry phos pha te
Thi s "fi xed" or "meta bol i c" a ci d l oa d ca nnot be exha l ed a nd therefore mus t be neutra l i zed or excreted.
Mos t ba s e comes from meta bol i s m of a ni oni c a mi no a ci ds (gl uta ma te a nd a s pa rta te) a nd from oxi da ti on a nd cons umpti on of orga ni c a ni ons s uch
a s l a cta te a nd ci tra te, whi ch produce HCO3 -.
Acid-Base Balance
Aci d-ba s e ba l a nce i s ma i nta i ned by chemi ca l bufferi ng a nd by pul mona ry a nd rena l el i mi na ti on.
Chemical buffering: Chemi ca l buffers a re s ol uti ons tha t res i s t cha nges i n pH. Intra cel l ul a r a nd extra cel l ul a r buffers provi de a n i mmedi a te res pons e
to a ci d-ba s e di s turba nces . Bone a l s o pl a ys a n i mporta nt bufferi ng rol e. A buffer i s ma de up of a wea k a ci d a nd i ts conjuga te ba s e. The conjuga te
ba s e ca n a ccept H + a nd the wea k a ci d ca n rel i nqui s h i t thereby mi ni mi zi ng cha nges i n free H + concentra ti on.
The mos t i mporta nt extra cel l ul a r buffer i s the HCO3 -/CO2 s ys tem, des cri bed by the equa ti on:
H + + HCO3 - H 2 CO3 CO2 + H 2 O
An i ncrea s e i n H + dri ves the equa ti on to the ri ght a nd genera tes CO2 . Thi s i mporta nt buffer s ys tem i s hi ghl y regul a ted; CO2 concentra ti ons ca n be
fi nel y control l ed by a l veol a r venti l a ti on, a nd H + a nd HCO3 - concentra ti ons ca n be fi nel y regul a ted by rena l excreti on.
The rel a ti ons hi p between HCO3 - a nd CO2 i n the s ys tem ca n be des cri bed by the Ka s s i rer-Bl ei ch equa ti on, deri ved from the Henders on-Ha s s el ba l ch
equa ti on:
H + = 24 PCO2 /HCO3 Thi s equa ti on i l l us tra tes tha t a ci d-ba s e ba l a nce depends on the ra ti o of PCO2 a nd HCO3 -, not on the a bs ol ute va l ue of ei ther one a l one. Wi th thi s
formul a , a ny 2 va l ues (us ua l l y H + a nd PCO2 ) ca n be us ed to ca l cul a te the other (us ua l l y HCO3 -).
Other i mporta nt phys i ol ogi c buffers i ncl ude i ntra cel l ul a r orga ni c a nd i norga ni c phos pha tes a nd protei ns , i ncl udi ng Hb i n RBCs . Les s i mporta nt a re
extra cel l ul a r phos pha te a nd pl a s ma protei ns . Bone becomes a n i mporta nt buffer a fter cons umpti on of extra cel l ul a r HCO3 -. Bone i ni ti a l l y rel ea s es
s odi um ca rbona te (Na HCO3 ) a nd pota s s i um ca rbona te (KHCO3 ) i n excha nge for H +. Wi th prol onged a ci d l oa ds , bone rel ea s es ca l ci um ca rbona te
(Ca CO3 ) a nd ca l ci um phos pha te (Ca PO4 ). Long-s ta ndi ng a ci demi a therefore contri butes to bone demi nera l i za ti on a nd os teoporos i s .
Pulmonary regulation: CO2 concentra ti on i s fi nel y regul a ted by cha nges i n ti da l vol ume a nd res pi ra tory ra te (mi nute venti l a ti on). A decrea s e i n pH i s
s ens ed by a rteri a l chemoreceptors a nd l ea ds to i ncrea s es i n ti da l vol ume or res pi ra tory ra te; CO2 i s exha l ed a nd bl ood pH i ncrea s es . In contra s t to
chemi ca l bufferi ng, whi ch i s i mmedi a te, pul mona ry regul a ti on occurs over mi nutes to hours . It i s a bout 50 to 75% effecti ve; i t does not compl etel y
norma l i ze pH.
Renal regulation: The ki dneys control pH by a djus ti ng the a mount of HCO3 - tha t i s rea bs orbed a nd the a mount of H + tha t i s excreted; i ncrea s e i n
HCO3 - i s equi va l ent to removi ng free H +. Cha nges i n rena l a ci d-ba s e ha ndl i ng occur hours to da ys a fter cha nges i n a ci d-ba s e s ta tus .
HCO3 - rea bs orpti on occurs mos tl y i n the proxi ma l tubul e a nd, to a l es s er degree, i n the col l ecti ng tubul e. H 2 O wi thi n the tubul a r cel l di s s oci a tes
i nto H + a nd hydroxi de (OH -); i n the pres ence of ca rboni c a nhydra s e, the OH - combi nes wi th CO2 to form HCO3 -, whi ch i s tra ns ported ba ck i nto the
peri tubul a r ca pi l l a ry, whi l e the H + i s s ecreted i nto the tubul a r l umen a nd joi ns wi th freel y fi l tered HCO3 - to form CO2 a nd H 2 O, whi ch a re a l s o
rea bs orbed. Thus , rea bs orbed HCO3 - i ons a re newl y genera ted a nd not the s a me a s thos e tha t were fi l tered. Decrea s es i n effecti ve ci rcul a ti ng
vol ume (s uch a s occur wi th di ureti c thera py) i ncrea s e HCO3 - rea bs orpti on, whi l e i ncrea s es i n pa ra thyroi d hormone i n res pons e to a n a ci d l oa d
decrea s e HCO3 - rea bs orpti on. Al s o, i ncrea s ed PCO2 l ea ds to i ncrea s ed HCO3 - rea bs orpti on, whi l e Cl - depl eti on (typi ca l l y from vol ume depl eti on)
l ea ds to i ncrea s ed Na + rea bs orpti on a nd HCO3 - genera ti on by the proxi ma l tubul e.
Aci d i s a cti vel y excreted i nto the proxi ma l a nd di s ta l tubul es where i t combi nes wi th uri na ry buffers pri ma ri l y freel y fi l tered HPO4 -2 , crea ti ni ne,
uri c a ci d, a nd a mmoni a to be tra ns ported outs i de the body. The a mmoni a bufferi ng s ys tem i s es peci a l l y i mporta nt beca us e other buffers a re
fi l tered i n fi xed concentra ti ons a nd ca n be depl eted by hi gh a ci d l oa ds ; by contra s t, tubul a r cel l s a cti vel y regul a te a mmoni a producti on i n
res pons e to cha nges i n a ci d l oa d. Arteri a l pH i s the ma i n determi na nt of a ci d s ecreti on, but excreti on i s a l s o i nfl uenced by K+, Cl -, a nd a l dos terone
l evel s . Intra cel l ul a r K+ concentra ti on a nd H + s ecreti on a re reci proca l l y rel a ted; K+ depl eti on ca us es i ncrea s ed H + s ecreti on a nd hence meta bol i c
a l ka l os i s .
Acid-Base Disorders
Aci d-ba s e di s orders a re cha nges i n a rteri a l PCO2 , s erum HCO3 -, a nd s erum pH.
Aci demi a i s s erum pH < 7.35.
Al ka l emi a i s s erum pH > 7.45.
Aci dos i s refers to phys i ol ogi c proces s es tha t ca us e a ci d a ccumul a ti on or a l ka l i l os s .
Al ka l os i s refers to phys i ol ogi c proces s es tha t ca us e a l ka l i a ccumul a ti on or a ci d l os s .
Actua l cha nges i n pH depend on the degree of phys i ol ogi c compens a ti on a nd whether mul ti pl e proces s es a re pres ent.
Classification
Pri ma ry a ci d-ba s e di s turba nces a re defi ned a s meta bol i c or res pi ra tory ba s ed on cl i ni ca l context a nd whether the pri ma ry cha nge i n pH i s due to
a n a l tera ti on i n s erum HCO3 - or i n PCO2 .
Metabolic acidosis i s s erum HCO3 - < 24 mEq/L. Ca us es a re
Increa s ed a ci d producti on
Aci d i nges ti on
Decrea s ed rena l a ci d excreti on
GI or rena l HCO3 - l os s
Metabolic alkalosis i s s erum HCO3 - > 24 mEq/L. Ca us es a re
Aci d l os s
HCO3 - retenti on
Respiratory acidosis i s PCO2 > 40 mm Hg (hyperca pni a ). Ca us e i s
Decrea s e i n mi nute venti l a ti on (hypoventi l a ti on)
Respiratory alkalosis i s PCO2 < 40 mm Hg (hypoca pni a ). Ca us e i s
Increa s e i n mi nute venti l a ti on (hyperventi l a ti on)
Whenever a n a ci d-ba s e di s order i s pres ent, compens a tory mecha ni s ms begi n to correct the pH (s ee
Ta bl e 98-1). Compens a ti on ca nnot return pH compl etel y to norma l a nd never overs hoots .
[Table 98-1. Pri ma ry Cha nges a nd Compens a ti ons i n Si mpl e Aci d-Ba s e Di s orders ]
[
Table 98-2. Cl i ni ca l Cons equences of Aci d-Ba s e Di s orders ]
A s i mpl e a ci d-ba s e di s order i s a s i ngl e a ci d-ba s e di s turba nce wi th i ts a ccompa nyi ng compens a tory res pons e.
Mi xed a ci d-ba s e di s orders compri s e 2 or more pri ma ry di s turba nces .
Symptoms and Signs
Compens a ted or mi l d a ci d-ba s e di s orders ca us e few s ymptoms or s i gns . Severe, uncompens a ted di s orders ha ve mul ti pl e ca rdi ova s cul a r,
res pi ra tory, neurol ogi c, a nd meta bol i c cons equences (s ee Ta bl e 98-2 a nd
Fi g. 189-4 on p. 1857).
Diagnosis
ABG
Serum el ectrol ytes
Ani on ga p ca l cul a ted
If meta bol i c a ci dos i s i s pres ent, del ta ga p ca l cul a ted a nd Wi nter's formul a a ppl i ed
Sea rch for compens a tory cha nges
Eva l ua ti on i s wi th ABG a nd s erum el ectrol ytes . The ABG di rectl y mea s ures a rteri a l pH a nd PCO2 . HCO3 - l evel s on ABG a re ca l cul a ted us i ng the
Henders on-Ha s s el ba l ch equa ti on; l evel s on s erum chemi s try pa nel s a re di rectl y mea s ured a nd a re more a ccura te. Aci d-ba s e ba l a nce i s genera l l y
mos t a ccura tel y a s s es s ed wi th mea s urement of pH a nd pCO2 on a rteri a l bl ood. In ca s es of ci rcul a tory fa i l ure or duri ng ca rdi opul mona ry
res us ci ta ti on, mea s urements on venous bl ood ma y more a ccura tel y refl ect condi ti ons a t the ti s s ue l evel a nd ma y be a more us eful gui de to
bi ca rbona te a dmi ni s tra ti on a nd a dequa cy of venti l a ti on.
The pH es ta bl i s hes the pri ma ry proces s (a ci dos i s or a l ka l os i s ), a l though i t moves towa rd the norma l ra nge wi th compens a ti on. Cha nges i n PCO2
refl ect the res pi ra tory component, a nd cha nges i n HCO3 - refl ect the meta bol i c component. However, s evera l ca l cul a ti ons ma y be requi red to
determi ne whether cha nges i n PCO2 a nd HCO3 - a re pri ma ry or compens a tory a nd whether a mi xed di s order i s pres ent; i n mi xed di s orders , va l ues
ma y be decepti vel y norma l . Interpreta ti on mus t a l s o cons i der cl i ni ca l condi ti ons (eg, chroni c l ung di s ea s e, rena l fa i l ure, drug overdos e).
Sidebar 98-1 The Anion Gap

The a ni on ga p i s defi ned a s pl a s ma Na concentra ti on mi nus the s um of Cl - a nd HCO3 - concentra ti ons ; Na + - (Cl - + HCO3 -). The term "ga p" i s
mi s l ea di ng, beca us e the l a w of el ectroneutra l i ty requi res the s a me number of pos i ti ve a nd nega ti ve cha rges i n a n open s ys tem; the ga p a ppea rs
on l a bora tory tes ti ng beca us e certa i n ca ti ons (+) a nd a ni ons (-) a re not mea s ured on routi ne l a bora tory chemi s try pa nel s . Thus
Na + + unmea s ured ca ti ons (UC) = Cl - + HCO3 - + unmea s ured a ni ons (UA)
a nd
+
the a ni on ga p, Na - (Cl - + HCO3 -) = UA - UC

The predomi na nt unmea s ured a ni ons a re PO4 3-, s ul fa te (SO4 -), va ri ous nega ti vel y cha rged protei ns , a nd s ome orga ni c a ci ds , a ccounti ng for 20 to 24
mEq/L. The predomi na nt unmea s ured extra cel l ul a r ca ti ons a re K+, Ca ++, a nd Mg++ a nd a ccount for a bout 11 mEq/L. Thus the typi ca l a ni on ga p i s 23 11 = 12 mEq/L. The a ni on ga p ca n be a ffected by i ncrea s es or decrea s es i n the UC or UA.
Increased anion gap i s mos t commonl y ca us ed by meta bol i c a ci dos i s i n whi ch nega ti vel y cha rged a ci ds mos tl y ketones , l a cta te, s ul fa tes , or
meta bol i tes of metha nol , ethyl ene gl ycol , a nd s a l i cyl a tecons ume (a re buffered by) HCO3 -. Other ca us es of i ncrea s ed a ni on ga p i ncl ude
hypera l bumi nemi a a nd uremi a (i ncrea s ed a ni ons ) a nd hypoca l cemi a or hypoma gnes emi a (decrea s ed ca ti ons ).
Decreased anion gap i s unrel a ted to meta bol i c a ci dos i s but i s ca us ed by hypoa l bumi nemi a (decrea s ed a ni ons ); hyperca l cemi a , hyperma gnes emi a ,
l i thi um i ntoxi ca ti on, a nd hyperga mma gl obul i nemi a (i ncrea s ed ca ti ons ); or hypervi s cos i ty or ha l i de (bromi de or i odi de) i ntoxi ca ti on. The effect of
l ow a l bumi n ca n be a ccounted for by a djus ti ng the norma l ra nge for the a ni on ga p 2.5 mEq/L upwa rd for every 1-g/dL fa l l i n a l bumi n.
Negative anion gap occurs ra rel y a s a l a bora tory a rti fa ct i n s evere ca s es of hyperna tremi a , hyperl i pi demi a , a nd bromi de i ntoxi ca ti on.
The delta gap: The di fference between the pa ti ent's a ni on ga p a nd the norma l a ni on ga p i s termed the del ta ga p. Thi s a mount i s cons i dered a n
HCO3 - equi va l ent, beca us e for every uni t ri s e i n the a ni on ga p, the HCO3 - s houl d l ower by 1 (by bufferi ng). Thus , i f the del ta ga p i s a dded to the
mea s ured HCO3 -, the res ul t s houl d be i n the norma l ra nge for HCO3 -; el eva ti on i ndi ca tes the a ddi ti ona l pres ence of a meta bol i c a l ka l os i s .
Example: A vomi ti ng, i l l -a ppea ri ng a l cohol i c pa ti ent ha s l a bora tory res ul ts s howi ng
Na , 137; K, 3.8; Cl , 90; HCO3 -, 22; pH, 7.40; PCO2 , 41; PO2 , 85
At fi rs t gl a nce, res ul ts a ppea r unrema rka bl e. However, ca l cul a ti ons s how el eva ti on of the a ni on ga p:
137 - (90 + 22) = 25 (norma l , 10)

i ndi ca ti ng a meta bol i c a ci dos i s . Res pi ra tory compens a ti on i s eva l ua ted by Wi nter's formul a :
Predi cted PCO2 = 1.5 (22) + 8 2
= 41 2
Predi cted = mea s ured, s o res pi ra tory compens a ti on i s a ppropri a te.
Beca us e there i s meta bol i c a ci dos i s , the del ta ga p i s ca l cul a ted, a nd the res ul t i s a dded to mea s ured HCO3 -:
25 - 10 = 15
15 + 22 = 37
The res ul ti ng corrected HCO3 - i s a bove the norma l ra nge for HCO3 -, i ndi ca ti ng a pri ma ry meta bol i c a l ka l os i s i s a l s o pres ent. Thus , the pa ti ent ha s a
mi xed a ci d-ba s e di s order. Us i ng cl i ni ca l i nforma ti on, one coul d theori ze a meta bol i c a ci dos i s a ri s i ng from a l cohol i c ketoa ci dos i s combi ned wi th
a meta bol i c a l ka l os i s from recurrent vomi ti ng wi th l os s of Cl - a nd vol ume.
The a ni on ga p (s ee Si deba r 98-1) s houl d a l wa ys be ca l cul a ted; el eva ti on a l mos t a l wa ys i ndi ca tes a meta bol i c a ci dos i s . A norma l a ni on ga p wi th a
l ow HCO3 - (eg, < 24 mEq/L) a nd hi gh s erum Cl - i ndi ca tes a non-a ni on ga p (hyperchl oremi c) meta bol i c a ci dos i s . If meta bol i c a ci dos i s i s pres ent, a
del ta ga p i s ca l cul a ted (s ee Si deba r 98-1) to i denti fy concomi ta nt meta bol i c a l ka l os i s , a nd Wi nter's formul a i s a ppl i ed to s ee whether res pi ra tory
compens a ti on i s a ppropri a te or refl ects a 2nd a ci d-ba s e di s order (predi cted PCO2 = 1.5 [HCO3 -] + 8 2; i f PCO2 i s hi gher, there i s a l s o a pri ma ry
res pi ra tory a ci dos i s i f l ower, res pi ra tory a l ka l os i s ).
Res pi ra tory a ci dos i s i s s ugges ted by PCO2 > 40 mm Hg; HCO3 - s houl d compens a te a cutel y by i ncrea s i ng 3 to 4 mEq/L for ea ch 10-mm Hg ri s e i n PCO2
s us ta i ned for 4 to 12 h (there ma y be no i ncrea s e or onl y 1 to 2 mEq/L, whi ch s l owl y i ncrea s es to 3 to 4 mEq/L over da ys ). Grea ter i ncrea s e i n HCO3 i mpl i es a pri ma ry meta bol i c a l ka l os i s ; l es s er i ncrea s e s ugges ts no ti me for compens a ti on or coexi s ti ng pri ma ry meta bol i c a ci dos i s .
Meta bol i c a l ka l os i s i s s ugges ted by HCO3 - > 28 mEq/L. The PCO2 s houl d compens a te by i ncrea s i ng a bout 0.6 to 0.75 mm Hg for ea ch 1 mEq/L
i ncrea s e i n HCO3 - (up to a bout 55 mm Hg). Grea ter i ncrea s e i mpl i es concomi ta nt res pi ra tory a ci dos i s ; l es s er i ncrea s e, res pi ra tory a l ka l os i s .
Res pi ra tory a l ka l os i s i s s ugges ted by PCO2 < 38 mm Hg. The HCO3 - s houl d compens a te over 4 to 12 h by decrea s i ng 5 mEq/L for every 10-mm Hg
decrea s e i n PCO2 . Les s er decrea s e mea ns there ha s been no ti me for compens a ti on or exi s tence of a pri ma ry meta bol i c a l ka l os i s . Grea ter
decrea s e i mpl i es a pri ma ry meta bol i c a ci dos i s .
Nomogra ms (a ci d-ba s e ma ps ) a re a n a l terna ti ve wa y to di a gnos e mi xed di s orders , a l l owi ng for s i mul ta neous pl otti ng of pH, HCO3 -, a nd PCO2 .
Metabolic Acidosis
Metabolic acidosis is primary reduction in HCO3 -, typically with compensatory reduction in PCO2 ; pH may be markedly low or slightly subnormal. Metabolic
acidoses are categorized as high or normal anion gap based on the presence or absence of unmeasured anions in serum. Causes include accumulation of ketones
and lactic acid, renal failure, and drug or toxin ingestion (high anion gap) and GI or renal HCO3 - loss (normal anion gap). Symptoms and signs in severe cases
include nausea and vomiting, lethargy, and hyperpnea. Diagnosis is clinical and with ABG and serum electrolyte measurement. The cause is treated; IV NaHCO3
may be indicated when pH is very low.
Etiology
Meta bol i c a ci dos i s i s a ci d a ccumul a ti on due to i ncrea s ed a ci d producti on or a ci d i nges ti on; decrea s ed a ci d excreti on; or GI or rena l HCO3 - l os s .
Aci demi a (a rteri a l pH < 7.35) res ul ts when a ci d l oa d overwhel ms res pi ra tory compens a ti on. Ca us es a re cl a s s i fi ed by thei r effect on the a ni on ga p
(s ee Si deba r 98-1 a nd
Ta bl e 98-3).
High anion gap acidosis: The mos t common ca us es of a hi gh a ni on ga p meta bol i c a ci dos i s a re
Ketoa ci dos i s ,
La cti c a ci dos i s
Rena l fa i l ure
Toxi c i nges ti ons
Ketoa ci dos i s i s a common compl i ca ti on of type 1 di a betes mel l i tus , but i t a l s o occurs wi th chroni c a l cohol i s m, undernutri ti on, a nd, to a l es s er
degree, fa s ti ng. In thes e condi ti ons , the body converts from gl ucos e to free fa tty a ci d (FFA) meta bol i s m; FFAs a re converted by the l i ver i nto
ketoa ci ds , a cetoa ceti c a ci d, a nd -hydroxybutyra te (a l l unmea s ured a ni ons ). Ketoa ci dos i s i s a l s o a ra re ma ni fes ta ti on of congeni ta l i s ova l eri c a nd
methyl ma l oni c a ci demi a .
La cti c a ci dos i s (s ee p. 861) i s the mos t common ca us e of meta bol i c a ci dos i s i n hos pi ta l i zed pa ti ents . La cta te a ccumul a ti on res ul ts from a
combi na ti on of exces s forma ti on a nd decrea s ed uti l i za ti on of l a cta te. Exces s l a cta te producti on occurs duri ng s ta tes of a na erobi c meta bol i s m.
The mos t s eri ous form occurs duri ng the va ri ous types of s hock. Decrea s ed uti l i za ti on genera l l y occurs wi th hepa tocel l ul a r dys functi on from
decrea s ed l i ver perfus i on or a s a pa rt of genera l i zed s hock.
Rena l fa i l ure ca us es a ni on ga p a ci dos i s by decrea s ed a ci d excreti on a nd decrea s ed HCO3 - rea bs orpti on. Accumul a ti on of s ul fa tes , phos pha tes ,
ura te, a nd hi ppura te a ccounts for the hi gh a ni on ga p.
Toxi ns ma y ha ve a ci di c meta bol i tes or tri gger l a cti c a ci dos i s . Rha bdomyol ys i s i s a ra re ca us e of meta bol i c a ci dos i s thought to be due to rel ea s e of
protons a nd a ni ons di rectl y from mus cl e.
Normal anion gap acidosis: The mos t common ca us es of norma l a ni on ga p a ci dos i s a re
GI or rena l HCO3 - l os s
Impa i red rena l a ci d excreti on
Norma l a ni on ga p meta bol i c a ci dos i s i s a l s o ca l l ed hyperchl oremi c a ci dos i s beca us e the ki dneys res orb Cl - wi th Na i ns tea d of rea bs orbi ng HCO3 -.
Ma ny GI s ecreti ons a re ri ch i n HCO3 - (eg, bi l i a ry, pa ncrea ti c, a nd i ntes ti na l fl ui ds ); l os s due to di a rrhea , tube dra i na ge, or fi s tul a s ca n ca us e
a ci dos i s . In ureteros i gmoi dos tomy (i ns erti on of ureters i nto the s i gmoi d col on a fter obs tructi on or cys tectomy), the col on s ecretes a nd l os es HCO3 i n excha nge for uri na ry Cl [Table 98-3. Ca us es of Meta bol i c Aci dos i s ]
a nd a bs orbs uri na ry a mmoni um, whi ch di s s oci a tes i nto a mmoni a (NH 3 +) a nd hydrogen i on (H +). Ion-excha nge res i n uncommonl y ca us es HCO3 - l os s
by bi ndi ng HCO3 -.
The rena l tubul a r a ci dos es (s ee p. 2426) ei ther i mpa i r H + s ecreti on (types 1 a nd 4) or HCO3 - a bs orpti on (type 2). Impa i red a ci d excreti on a nd a
norma l a ni on ga p a l s o occur i n ea rl y rena l fa i l ure, tubul oi nters ti ti a l rena l di s ea s e, a nd when ca rboni c a nhydra s e i nhi bi tors (eg, a ceta zol a mi de)
a re ta ken.
Symptoms and Signs
Symptoms a nd s i gns (s ee Ta bl e 98-2) a re pri ma ri l y thos e of the ca us e. Mi l d a ci demi a i s i ts el f a s ymptoma ti c. More s evere a ci demi a (pH < 7.10) ma y
ca us e na us ea , vomi ti ng, a nd ma l a i s e. Symptoms ma y a ppea r a t hi gher pH i f a ci dos i s devel ops ra pi dl y. The mos t cha ra cteri s ti c s i gn i s hyperpnea
(l ong, deep brea ths a t a norma l ra te), refl ecti ng a compens a tory i ncrea s e i n a l veol a r venti l a ti on.
Severe, a cute a ci demi a predi s pos es to ca rdi a c dys functi on wi th hypotens i on a nd s hock, ventri cul a r a rrhythmi a s , a nd coma . Chroni c a ci demi a
ca us es bone demi nera l i za ti on di s orders (eg, ri ckets , os teoma l a ci a , os teopeni a ).
Diagnosis
ABG a nd s erum el ectrol ytes
Ani on ga p a nd del ta ga p ca l cul a ted
Wi nter's formul a for ca l cul a ti ng compens a tory cha nges
Tes ti ng for ca us e
Recogni ti on of meta bol i c a ci dos i s a nd a ppropri a te res pi ra tory compens a ti on a re di s cus s ed on p. 857. Determi ni ng the ca us e of meta bol i c
a ci dos i s begi ns wi th the a ni on ga p.
The ca us e of a n el eva ted a ni on ga p ma y be cl i ni ca l l y obvi ous (eg, hypovol emi c s hock, mi s s ed hemodi a l ys i s ), but i f not, bl ood tes ti ng s houl d
i ncl ude gl ucos e, BUN, crea ti ni ne, l a cta te, a nd tes ts for pos s i bl e toxi ns . Sa l i cyl a te l evel s ca n be mea s ured i n mos t l a bora tori es , but metha nol a nd
ethyl ene gl ycol frequentl y ca nnot; thei r pres ence ma y be s ugges ted by pres ence of a n os mol a r ga p. Ca l cul a ted s erum os mol a ri ty (2 [Na ] +
[gl ucos e]/18 + BUN/2.8 + bl ood a l cohol /5) i s s ubtra cted from mea s ured os mol a ri ty. A di fference > 10 i mpl i es the pres ence of a n os moti ca l l y a cti ve
s ubs ta nce, whi ch i n the ca s e of a hi gh a ni on ga p a ci dos i s i s metha nol or ethyl ene gl ycol . Al though i nges ti on of etha nol ma y ca us e a n os mol a r
ga p a nd a mi l d a ci dos i s , i t s houl d never be cons i dered the ca us e of a s i gni fi ca nt meta bol i c a ci dos i s .
If the a ni on ga p i s norma l a nd no ca us e i s obvi ous (eg, ma rked di a rrhea ), uri na ry el ectrol ytes a re mea s ured a nd the uri na ry a ni on ga p i s
ca l cul a ted a s [Na ] + [K] - [Cl ]. A norma l uri na ry a ni on ga p (i ncl udi ng i n pa ti ents wi th GI l os s es ) i s 30 to 50 mEq/L; a n el eva ti on s ugges ts rena l HCO3 l os s (for eva l ua ti on of rena l tubul a r a ci dos i s , s ee p. 2427). In a ddi ti on, when meta bol i c a ci dos i s i s pres ent, a del ta ga p i s ca l cul a ted (s ee Si deba r
98-1) to i denti fy concomi ta nt meta bol i c a l ka l os i s , a nd Wi nter's formul a (s ee p. 858) i s a ppl i ed to s ee whether res pi ra tory compens a ti on i s
a ppropri a te or refl ects a 2nd a ci d-ba s e di s order.
Treatment
Ca us e trea ted
Na HCO3 ra rel y i ndi ca ted

Trea tment i s di rected a t the underl yi ng ca us e. Hemodi a l ys i s i s requi red for rena l fa i l ure a nd s ometi mes for ethyl ene gl ycol , metha nol , a nd
s a l i cyl a te poi s oni ng.
Trea tment of a ci demi a wi th Na HCO3 i s cl ea rl y i ndi ca ted onl y i n certa i n ci rcums ta nces a nd i s proba bl y del eteri ous i n others . When meta bol i c
a ci dos i s res ul ts from l os s of HCO3 - or a ccumul a ti on of i norga ni c a ci ds (i e, norma l a ni on ga p a ci dos i s ), HCO3 - thera py i s genera l l y s a fe a nd
a ppropri a te. However, when a ci dos i s res ul ts from orga ni c a ci d a ccumul a ti on (i e, hi gh a ni on ga p a ci dos i s ), HCO3 - thera py i s controvers i a l ; i t does
not cl ea rl y decrea s e morta l i ty i n thes e condi ti ons , a nd there a re s evera l pos s i bl e ri s ks . Wi th trea tment of the underl yi ng condi ti on, l a cta te a nd
ketoa ci ds a re meta bol i zed ba ck to HCO3 -; exogenous HCO3 - l oa di ng ma y therefore ca us e a n "overs hoot" meta bol i c a l ka l os i s . In a ny condi ti on,
HCO3 - ma y a l s o ca us e Na a nd vol ume overl oa d, hypoka l emi a , a nd, by i nhi bi ti ng res pi ra tory dri ve, hyperca pni a . Furthermore, beca us e HCO3 - does
not di ffus e a cros s cel l membra nes , i ntra cel l ul a r a ci dos i s i s not corrected a nd ma y pa ra doxi ca l l y wors en beca us e s ome of the a dded HCO3 - i s
converted to CO2 , whi ch does cros s i nto the cel l a nd i s hydrol yzed to H + a nd HCO3 -.
Des pi te thes e a nd other controvers i es , mos t experts s ti l l recommend HCO3 - IV for s evere meta bol i c a ci dos i s (pH < 7.00), wi th a ta rget pH of 7.20.
Trea tment requi res 2 ca l cul a ti ons . The fi rs t i s the l evel to whi ch HCO3 - mus t be ra i s ed, ca l cul a ted by the Ka s s i rer-Bl ei ch equa ti on, us i ng a va l ue for
[H +] of 63 nmol /L a t a pH of 7.2:
63 = 24 PCO2 /HCO3 or
des i red HCO3 - = 0.38 PCO2
The a mount of HCO3 - needed to a chi eve tha t l evel i s
Na HCO3 requi red (mEq) = (des i red [HCO3 -] - obs erved [HCO3 -]) 0.4 body wei ght (kg)
Thi s a mount of Na HCO3 i s gi ven over s evera l hours . Serum pH a nd HCO3 - l evel s ca n be checked 30 mi n to 1 h a fter a dmi ni s tra ti on, whi ch a l l ows for
equi l i bra ti on wi th extra va s cul a r HCO3 -.
Al terna ti ves to Na HCO3 i ncl ude
Trometha mi ne, a n a mi no a l cohol tha t buffers both meta bol i c (H +) a nd res pi ra tory (ca rboni c a ci d [H 2 CO3 ]) a ci d
Ca rbi ca rb, a n equi mol a r mi xture of Na HCO3 a nd ca rbona te (the l a tter cons umes CO2 a nd genera tes HCO3 -)
Di chl oroa ceta te, whi ch enha nces oxi da ti on of l a cta te
Thes e a l terna ti ves a re a l l of unproven benefi t a nd ca us e compl i ca ti ons of thei r own.
K+ depl eti on, common i n meta bol i c a ci dos i s , s houl d be i denti fi ed through frequent s erum K+ moni tori ng a nd trea ted a s needed wi th ora l or
pa rentera l KCl .
Lactic Acidosis
Lactic acidosis results from overproduction of lactate, decreased metabolism of lactate, or both.
La cta te i s a norma l byproduct of gl ucos e a nd a mi no a ci d meta bol i s m. The mos t s eri ous form of l a cti c a ci dos i s , type A, occurs when l a cti c a ci d i s
overproduced i n i s chemi c ti s s ue to genera te ATP duri ng O2 defi ci t. Overproducti on typi ca l l y occurs duri ng ti s s ue hypoperfus i on i n hypovol emi c,
ca rdi a c, or s epti c s hock a nd i s wors ened by decrea s ed l a cta te meta bol i s m i n the poorl y perfus ed l i ver. It ma y a l s o occur wi th pri ma ry hypoxi a due
to l ung di s ea s e a nd wi th va ri ous hemogl obi nopa thi es .
Type B l a cti c a ci dos i s occurs i n s ta tes of norma l gl oba l ti s s ue perfus i on (a nd hence ATP producti on) a nd i s l es s omi nous . La cta te producti on ma y
be i ncrea s ed from l oca l rel a ti ve hypoxi a a s wi th vi gorous mus cl e us e (eg, exerti on, s ei zures , hypothermi c s hi veri ng) a nd wi th ca ncer a nd i nges ti on
of certa i n drugs or toxi ns (s ee Ta bl e 98-3). Drugs i ncl ude the nucl eos i de revers e tra ns cri pta s e i nhi bi tors a nd the bi gua ni des phenformi n a nd, l es s
s o, metformi n; a l though phenformi n ha s been removed from the ma rket i n mos t of the worl d, i t i s s ti l l a va i l a bl e from Chi na (i ncl udi ng a s a
component of s ome Chi nes e propri eta ry medi ci nes ). Meta bol i s m ma y be decrea s ed due to hepa ti c i ns uffi ci ency or thi a mi n defi ci ency.
D-La cti c a ci dos i s i s a n unus ua l form of l a cti c a ci dos i s i n whi ch D-l a cti c a ci d, the product of ba cteri a l ca rbohydra te meta bol i s m i n the col on of
pa ti ents wi th jejunoi l ea l bypa s s or i ntes ti na l res ecti on, i s s ys temi ca l l y a bs orbed. It pers i s ts i n ci rcul a ti on beca us e huma n l a cta te dehydrogena s e
ca n meta bol i ze onl y L-l a cta te.
Fi ndi ngs i n a nd trea tment of types A a nd B l a cti c a ci dos i s a re a s for other meta bol i c a ci dos es . In D-l a cti c a ci dos i s , the a ni on ga p i s l ower tha n
expected for the decrea s e i n HCO3 -, a nd there ma y be a uri na ry os mol a r ga p (di fference between ca l cul a ted a nd mea s ured uri ne os mol a ri ty).
Trea tment i s IV fl ui ds , res tri cti on of ca rbohydra tes , a nd s ometi mes a nti bi oti cs (eg, metroni da zol e).
Metabolic Alkalosis
Metabolic alkalosis is primary increase in HCO3 - with or without compensatory increase in PCO2 ; pH may be high or nearly normal. Common causes include
prolonged vomiting, hypovolemia, diuretic use, and hypokalemia. Renal impairment of HCO3 - excretion must be present to sustain alkalosis. Symptoms and signs
in severe cases include headache, lethargy, and tetany. Diagnosis is clinical and with ABG and serum electrolyte measurement. The underlying cause is treated;
oral or IV acetazolamide or HCl is sometimes indicated.
Etiology
Meta bol i c a l ka l os i s i s HCO3 - a ccumul a ti on due to a ci d l os s , a l ka l i a dmi ni s tra ti on, i ntra cel l ul a r s hi ft of hydrogen i on (H +a s occurs i n
hypoka l emi a ), or HCO3 - retenti on. Rega rdl es s of i ni ti a l ca us e, pers i s tence of meta bol i c a l ka l os i s i ndi ca tes tha t the ki dneys ha ve i ncrea s ed thei r
HCO3 - rea bs orpti on, beca us e HCO3 - i s norma l l y freel y fi l tered by the ki dneys a nd hence excreted. Vol ume depl eti on a nd hypoka l emi a a re the mos t
common s ti mul i for i ncrea s ed HCO3 - rea bs orpti on, but a ny condi ti on tha t el eva tes a l dos terone or mi nera l ocorti coi ds (whi ch enha nce Na
rea bs orpti on a nd K a nd H + excreti on) ca n el eva te HCO3 -. Thus , hypoka l emi a i s both a ca us e a nd a frequent cons equence of meta bol i c a l ka l os i s .
Ca us es a re l i s ted; the mos t common a re vol ume depl eti on (pa rti cul a rl y when i nvol vi ng l os s of ga s tri c a ci d a nd Cl from recurrent vomi ti ng or
na s oga s tri c s ucti on) a nd di ureti c us e (s ee
Ta bl e 98-4).
Meta bol i c a l ka l os i s i nvol vi ng l os s or exces s s ecreti on of Cl i s termed Cl -res pons i ve, beca us e i t typi ca l l y corrects wi th IV a dmi ni s tra ti on of Na Cl conta i ni ng fl ui d. Cl -unres pons i ve meta bol i c a l ka l os i s does not, a nd i t typi ca l l y i nvol ves s evere Mg or K defi ci ency or mi nera l ocorti coi d exces s . The
2 forms ca n coexi s t, eg, i n pa ti ents wi th vol ume overl oa d ma de hypoka l emi c from hi gh-dos e di ureti cs .
Symptoms and Signs
Symptoms a nd s i gns of mi l d a l ka l emi a a re us ua l l y rel a ted to the underl yi ng di s order. More s evere a l ka l emi a i ncrea s es protei n bi ndi ng of i oni zed
Ca ++, l ea di ng to hypoca l cemi a a nd s ubs equent hea da che, l etha rgy, a nd neuromus cul a r exci ta bi l i ty, s ometi mes wi th del i ri um, teta ny, a nd s ei zures .
Al ka l emi a a l s o l owers thres hol d for a ngi na l s ymptoms a nd a rrhythmi a s . Concomi ta nt hypoka l emi a ma y ca us e wea knes s .
Diagnosis
ABG a nd s ercum el ectrol ytes
Di a gnos i s of ca us e us ua l l y cl i ni ca l
Someti mes mea s urement of uri na ry Cl - a nd K+
Recogni ti on of meta bol i c a l ka l os i s a nd a ppropri a te res pi ra tory compens a ti on i s di s cus s ed on p. 857 a nd requi res ABG a nd mea s urement of s erum
el ectrol ytes (i ncl udi ng Ca a nd Mg).
Common ca us es ca n often be determi ned by hi s tory a nd phys i ca l exa mi na ti on. If hi s tory i s unrevea l i ng a nd rena l functi on i s norma l , uri na ry Cl a nd K+ concentra ti ons a re mea s ured (va l ues a re not di a gnos ti c i n rena l i ns uffi ci ency). Uri na ry Cl < 20 mEq/L i ndi ca tes s i gni fi ca nt rena l Cl rea bs orpti on a nd hence a Cl -res pons i ve ca us e (s ee Ta bl e 98-4). Uri na ry Cl > 20 mEq/L s ugges ts a Cl -unres pons i ve form.
Uri na ry K a nd pres ence or a bs ence of hypertens i on hel p di fferenti a te Cl -unres pons i ve a l ka l os es . Uri na ry K < 30 mEq/da y s i gni fi es hypoka l emi a or
l a xa ti ve mi s us e. Uri na ry K > 30 mEq/da y wi thout hypertens i on s ugges ts di ureti c a bus e or Ba rtter or Gi tel ma n's s yndrome. Uri na ry K > 30 mEq/da y
wi th hypertens i on requi res eva l ua ti on for hypera l dos teroni s m, mi nera l ocorti coi d exces s , a nd
[Table 98-4. Ca us es of Meta bol i c Al ka l os i s ]
renova s cul a r di s ea s e. Tes ts typi ca l l y i ncl ude pl a s ma reni n a cti vi ty a nd a l dos terone a nd corti s ol l evel s (s ee pp. 797 a nd 800).
Treatment
Ca us e trea ted
IV 0.9% s a l i ne s ol uti on for Cl -res pons i ve meta bol i c a l ka l os i s
Underl yi ng condi ti ons a re trea ted, wi th pa rti cul a r a ttenti on pa i d to correcti on of hypovol emi a a nd hypoka l emi a .
Pa ti ents wi th Cl -res pons i ve meta bol i c a l ka l os i s a re gi ven 0.9% s a l i ne s ol uti on IV; i nfus i on ra te i s typi ca l l y 50 to 100 mL/h grea ter tha n uri na ry a nd
other s ens i bl e a nd i ns ens i bl e fl ui d l os s es unti l uri na ry Cl ri s es to > 25 mEq/L a nd uri na ry pH norma l i zes a fter a n i ni ti a l ri s e from bi ca rbona turi a .
Pa ti ents wi th Cl -unres pons i ve meta bol i c a l ka l os i s ra rel y benefi t from rehydra ti on a l one.
Pa ti ents wi th s evere meta bol i c a l ka l os i s (eg, pH > 7.6) s ometi mes requi re more urgent correcti on of s erum pH. Hemofi l tra ti on or hemodi a l ys i s i s
a n opti on, pa rti cul a rl y i f vol ume overl oa d a nd rena l dys functi on a re pres ent. Aceta zol a mi de 250 to 375 mg po or IV once/da y or bi d i ncrea s es HCO3 excreti on but ma y a l s o a ccel era te uri na ry l os s es of K+ a nd phos pha te (PO4 -); vol ume-overl oa ded pa ti ents wi th di ureti c-i nduced meta bol i c
a l ka l os i s a nd thos e wi th pos thyperca pni c meta bol i c a l ka l os i s ma y es peci a l l y benefi t.
Hydrochl ori c a ci d i n a 0.1 to 0.2 norma l s ol uti on IV i s s a fe a nd effecti ve but mus t be gi ven through a centra l ca theter beca us e i t i s hyperos moti c
a nd s cl eros es peri phera l vei ns . Dos a ge i s 0.1 to 0.2 mmol /kg/h. Frequent moni tori ng of ABG a nd el ectrol ytes i s needed.
Respiratory Acidosis
Respiratory acidosis is primary increase in PCO2 with or without compensatory increase in HCO3 -; pH is usually low but may be near normal. Cause is a decrease
in respiratory rate, volume (hypoventilation), or both due to CNS, pulmonary, or iatrogenic conditions. Respiratory acidosis can be acute or chronic; the chronic
form is asymptomatic, but the acute, or worsening, form causes headache, confusion, and drowsiness. Signs include tremor, myoclonic jerks, and asterixis.
Diagnosis is clinical and with ABG and serum electrolyte measurements. The cause is treated; O2 and mechanical ventilation are often required.
Res pi ra tory a ci dos i s i s CO2 a ccumul a ti on (hyperca pni a ) due to a decrea s e i n res pi ra tory ra te, res pi ra tory vol ume (hypoventi l a ti on), or both. Ca us es
of hypoventi l a ti on (di s cus s ed under Venti l a tory Fa i l ure on p. 2288) i ncl ude
Condi ti ons tha t i mpa i r CNS res pi ra tory dri ve
Condi ti ons tha t i mpa i r neuromus cul a r tra ns mi s s i on a nd other condi ti ons tha t ca us e mus cul a r wea knes s
Obs tructi ve, res tri cti ve, a nd pa renchyma l pul mona ry di s orders
Hypoxi a typi ca l l y a ccompa ni es hypoventi l a ti on.
Res pi ra tory a ci dos i s ma y be a cute or chroni c. Di s ti ncti on i s ba s ed on the degree of meta bol i c compens a ti on; CO2 i s i ni ti a l l y buffered i neffi ci entl y,
but over 3 to 5 da ys the ki dneys i ncrea s e HCO3 - rea bs orpti on s i gni fi ca ntl y.
Symptoms and Signs
Symptoms a nd s i gns depend on the ra te a nd degree of PCO2 i ncrea s e. CO2 ra pi dl y di ffus es a cros s the bl ood-bra i n ba rri er. Symptoms a nd s i gns a re
a res ul t of hi gh CNS CO2 concentra ti ons (l ow CNS pH) a nd a ny a ccompa nyi ng hypoxemi a .
Acute (or a cutel y wors eni ng chroni c) res pi ra tory a ci dos i s ca us es hea da che, confus i on, a nxi ety, drows i nes s , a nd s tupor (CO2 na rcos i s ). Sl owl y
devel opi ng, s ta bl e res pi ra tory a ci dos i s (a s i n COPD) ma y be wel l tol era ted, but pa ti ents ma y ha ve memory l os s , s l eep di s turba nces , exces s i ve
da yti me s l eepi nes s , a nd pers ona l i ty cha nges . Si gns i ncl ude ga i t di s turba nce, tremor, bl unted deep tendon refl exes , myocl oni c jerks , a s teri xi s , a nd
pa pi l l edema .
Diagnosis
Di a gnos i s of ca us e us ua l l y cl i ni ca l
Recogni ti on of res pi ra tory a ci dos i s a nd a ppropri a te rena l compens a ti on (s ee p. 857) requi res ABG a nd mea s urement of s erum el ectrol ytes . Ca us es
a re us ua l l y obvi ous from hi s tory a nd exa mi na ti on. Ca l cul a ti on of the a l veol a r-a rteri a l (A-a ) O2 gra di ent (i ns pi red PO2 - [a rteri a l PO2 + 5/4 a rteri a l
PCO2 ]) ca n hel p di s ti ngui s h pul mona ry from extra pul mona ry di s ea s e; a norma l gra di ent es s enti a l l y excl udes pul mona ry di s orders .
Treatment
Adequa te venti l a ti on
Na HCO3 a l mos t a l wa ys contra i ndi ca ted
Trea tment i s provi s i on of a dequa te venti l a ti on by ei ther endotra chea l i ntuba ti on or noni nva s i ve pos i ti ve pres s ure venti l a ti on (for s peci fi c
i ndi ca ti ons a nd procedures , s ee Ch. 225). Adequa te venti l a ti on i s a l l tha t i s needed to correct res pi ra tory a ci dos i s , a l though chroni c hyperca pni a
genera l l y mus t be corrected s l owl y (eg, over s evera l hours or more), beca us e too-ra pi d PCO2 l oweri ng ca n ca us e a pos thyperca pni c "overs hoot"
a l ka l os i s when the underl yi ng compens a tory hyperbi ca rbona temi a becomes unma s ked; the a brupt ri s e i n CNS pH tha t res ul ts ca n l ea d to s ei zures
a nd dea th. Any K+ a nd Cl - defi ci ts a re corrected.
Na HCO3 i s a l mos t a l wa ys contra i ndi ca ted, beca us e HCO3 - ca n be converted to PCO2 i n s erum but cros s es the bl ood-bra i n ba rri er s l owl y, thus
i ncrea s i ng s erum pH wi thout a ffecti ng CNS pH. One excepti on ma y be i n ca s es of s evere bronchos pa s m, i n whi ch HCO3 - ma y i mprove
res pons i venes s of bronchi a l s mooth mus cl e to -a goni s ts .
Respiratory Alkalosis
(See a l s o Hyperventi l a ti on Syndrome on p. 1836.)
Respiratory alkalosis is a primary decrease in Pco2 with or without compensatory decrease in HCO3 -; pH may be high or near normal. Cause is an increase in
respiratory rate or volume (hyperventilation) or both. Respiratory alkalosis can be acute or chronic. The chronic form is asymptomatic, but the acute form causes
light-headedness, confusion, paresthesias, cramps, and syncope. Signs include hyperpnea or tachypnea and carpopedal spasms. Diagnosis is clinical and with ABG
and serum electrolyte measurements. Treatment is directed at the cause.
Etiology
Res pi ra tory a l ka l os i s i s a pri ma ry decrea s e i n PCO2 (hypoca pni a ) due to a n i ncrea s e i n res pi ra tory ra te or vol ume (hyperventi l a ti on) or both.
Venti l a ti on i ncrea s e occurs mos t often a s a phys i ol ogi c res pons e to hypoxi a , meta bol i c a ci dos i s , a nd i ncrea s ed meta bol i c dema nds (eg, fever)
a nd, a s s uch, i s pres ent i n ma ny s eri ous condi ti ons . In a ddi ti on, pa i n a nd a nxi ety a nd s ome CNS di s orders ca n i ncrea s e res pi ra ti ons wi thout a
phys i ol ogi c need.
Pathophysiology
Res pi ra tory a l ka l os i s ca n be a cute or chroni c. Di s ti ncti on i s ba s ed on the degree of meta bol i c compens a ti on. Exces s HCO3 - i s buffered by
extra cel l ul a r hydrogen i on (H +) wi thi n mi nutes , but more s i gni fi ca nt compens a ti on occurs over 2 to 3 da ys a s the ki dneys decrea s e H + excreti on.
Pseudorespiratory alkalosis: Ps eudores pi ra tory a l ka l os i s i s l ow a rteri a l PCO2 a nd hi gh pH i n mecha ni ca l l y venti l a ted pa ti ents wi th s evere meta bol i c
a ci dos i s due to poor s ys temi c perfus i on (eg, ca rdi ogeni c s hock, duri ng CPR). Ps eudores pi ra tory a l ka l os i s occurs when mecha ni ca l venti l a ti on
(often hyperventi l a ti on) el i mi na tes l a rger-tha n-norma l a mounts of a l veol a r CO2 . Exha l a ti on of l a rge a mounts of CO2 ca us es res pi ra tory a l ka l os i s
i n a rteri a l bl ood (hence on ABG mea s urements ), but poor s ys temi c perfus i on a nd cel l ul a r i s chemi a ca us e cel l ul a r a ci dos i s , l ea di ng to a ci dos i s of
venous bl ood. Di a gnos i s i s by demons tra ti on of ma rked a rteri ovenous di fferences i n PCO2 a nd pH a nd by el eva ted l a cta te l evel s ; trea tment i s
i mprovement of s ys temi c hemodyna mi cs .
Symptoms and Signs
Symptoms a nd s i gns depend on the ra te a nd degree of fa l l i n PCO2 . Acute res pi ra tory a l ka l os i s ca us es l i ght-hea dednes s , confus i on, peri phera l
a nd ci rcumora l pa res thes i a s , cra mps , a nd s yncope. Mecha ni s m i s thought to be cha nge i n cerebra l bl ood fl ow a nd pH. Ta chypnea or hyperpnea i s
often the onl y s i gn; ca rpopeda l s pa s m ma y occur i n s evere ca s es . Chroni c res pi ra tory a l ka l os i s i s us ua l l y a s ymptoma ti c a nd ha s no di s ti ncti ve
s i gns .
Diagnosis
If hypoxi a pres ent, ca us e vi gorous l y purs ued
Recogni ti on of res pi ra tory a l ka l os i s a nd a ppropri a te rena l compens a ti on (di s cus s ed on p. 857) requi res ABG a nd s erum el ectrol yte
mea s urements . Mi nor hypophos pha temi a a nd hypoka l emi a due to i ntra cel l ul a r s hi fts a nd decrea s ed i oni zed Ca ++ due to a n i ncrea s e i n protei n
bi ndi ng ma y be pres ent.
Pres ence of hypoxi a or a n i ncrea s ed a l veol a r-a rteri a l (A-a ) O2 gra di ent (i ns pi red PO2 - [a rteri a l PO2 + 5/4 a rteri a l PCO2 ]) requi res s ea rch for a ca us e.
Other ca us es a re often a ppa rent on hi s tory a nd exa mi na ti on. However, beca us e pul mona ry embol i s m often ma ni fes ts wi thout hypoxi a (s ee p.
1908), embol i s m mus t be s trongl y cons i dered i n a hyperventi l a ti ng pa ti ent before a s cri bi ng the ca us e to a nxi ety.
Treatment
Trea tment i s di rected a t the underl yi ng ca us e. Res pi ra tory a l ka l os i s i s not l i fe threa teni ng, s o no i nterventi ons to l ower pH a re neces s a ry.
Increa s i ng i ns pi red CO2 through rebrea thi ng (s uch a s from a pa per ba g) i s common pra cti ce but ma y be da ngerous i n a t l ea s t s ome pa ti ents wi th
CNS di s orders i n whom CSF pH ma y a l rea dy be bel ow norma l .
Chapter 99. Diabetes Mellitus and Disorders of Carbohydrate Metabolism

Introduction
Di a betes mel l i tus a nd i ts compl i ca ti ons (di a beti c ketoa ci dos i s , nonketoti c hyperos mol a r s yndrome) a re the mos t common di s orders of
ca rbohydra te meta bol i s m, but a l cohol i c ketoa ci dos i s a nd hypogl ycemi a a re a l s o i mporta nt.
Diabetes Mellitus
Diabetes mellitus (DM) is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related
to hyperglycemia and include polydipsia, polyphagia, and polyuria. Later complications include vascular disease, peripheral neuropathy, and predisposition to
infection. Diagnosis is by measuring plasma glucose. Treatment is diet, exercise, and drugs that reduce glucose levels, including insulin and oral
antihyperglycemic drugs. Prognosis varies with degree of glucose control.
There a re 2 ma i n ca tegori es of DMtype 1 a nd type 2, whi ch ca n be di s ti ngui s hed by a combi na ti on of fea tures (s ee
Ta bl e 99-1). Terms tha t des cri be the a ge of ons et (juveni l e or a dul t) or type of trea tment (i ns ul i n- or non-i ns ul i n-dependent) a re no l onger
a ccura te beca us e of overl a p i n a ge groups a nd trea tments between di s ea s e types .
Impa i red gl ucos e regul a ti on (i mpa i red gl ucos e tol era nce, or i mpa i red fa s ti ng gl ucos es ee
Ta bl e 99-2) i s a n i ntermedi a te, pos s i bl y tra ns i ti ona l , s ta te between norma l gl ucos e meta bol i s m a nd DM tha t becomes common wi th a ge. It i s a
s i gni fi ca nt ri s k fa ctor for DM a nd ma y be pres ent for ma ny yea rs before ons et of DM. It i s a s s oci a ted wi th a n i ncrea s ed
[Table 99-1. Genera l Cha ra cteri s ti cs of Types 1 a nd 2 Di a betes Mel l i tus ]
[Table 99-2. Di a gnos ti c Cri teri a for Di a betes Mel l i tus a nd Impa i red Gl ucos e Regul a ti on]
ri s k of ca rdi ova s cul a r di s ea s e, but typi ca l di a beti c mi crova s cul a r compl i ca ti ons genera l l y do not devel op.
Etiology
Type 1: In Type 1 DM (previ ous l y ca l l ed juveni l e-ons et or i ns ul i n-dependent), i ns ul i n producti on i s a bs ent beca us e of a utoi mmune pa ncrea ti c cel l des tructi on pos s i bl y tri ggered by a n envi ronmenta l expos ure i n geneti ca l l y s us cepti bl e peopl e. Des tructi on progres s es s ubcl i ni ca l l y over
months or yea rs unti l -cel l ma s s decrea s es to the poi nt tha t i ns ul i n concentra ti ons a re no l onger a dequa te to control pl a s ma gl ucos e l evel s .
Type 1 DM genera l l y devel ops i n chi l dhood or a dol es cence a nd unti l recentl y wa s the mos t common form di a gnos ed before a ge 30; however, i t ca n
a l s o devel op i n a dul ts (l a tent a utoi mmune di a betes of a dul thood, whi ch often i ni ti a l l y s eems to be type 2 DM). Some ca s es of type 1 DM,
pa rti cul a rl y i n nonwhi te popul a ti ons , do not s eem to be a utoi mmune i n na ture a nd a re cons i dered i di opa thi c. Type 1 a ccounts for < 10% of a l l
ca s es of DM.
The pa thogenes i s of the a utoi mmune -cel l des tructi on i nvol ves i ncompl etel y unders tood i ntera cti ons between s us cepti bi l i ty genes ,
a utoa nti gens , a nd envi ronmenta l fa ctors . Sus cepti bi l i ty genes i ncl ude thos e wi thi n the ma jor hi s tocompa ti bi l i ty compl ex (MHC)es peci a l l y HLADR3, DQB1*0201 a nd HLA-DR4, DQB1*0302, whi ch a re pres ent i n > 90% of pa ti ents wi th type 1 DMa nd thos e outs i de the MHC, whi ch s eem to
regul a te i ns ul i n producti on a nd proces s i ng a nd confer ri s k of DM i n concert wi th MHC genes . Sus cepti bi l i ty genes a re more common a mong s ome
popul a ti ons tha n a mong others a nd expl a i n the hi gher preva l ence of type 1 DM a mong s ome ethni c groups (Sca ndi na vi a ns , Sa rdi ni a ns ).
Autoa nti gens i ncl ude gl uta mi c a ci d deca rboxyl a s e, i ns ul i n, i ns ul i noma -a s s oci a ted protei n, a nd other protei ns i n cel l s . It i s thought tha t thes e
protei ns a re expos ed or rel ea s ed duri ng norma l -cel l turnover or -cel l i njury (eg, due to i nfecti on), a cti va ti ng a cel l -medi a ted i mmune res pons e
res ul ti ng i n -cel l des tructi on (i ns ul i ti s ). Gl uca gon-s ecreti ng cel l s rema i n unha rmed. Anti bodi es to a utoa nti gens , whi ch ca n be detected i n
s erum, s eem to be a res pons e to (not a ca us e of) -cel l des tructi on.
Severa l vi rus es (i ncl udi ng coxs a cki evi rus , rubel l a vi rus , cytomega l ovi rus , Eps tei n-Ba rr vi rus , a nd retrovi rus es ) ha ve been l i nked to the ons et of type
1 DM. Vi rus es ma y di rectl y i nfect a nd des troy cel l s , or they ma y ca us e -cel l des tructi on i ndi rectl y by expos i ng a utoa nti gens , a cti va ti ng
a utorea cti ve l ymphocytes , mi mi cki ng mol ecul a r s equences of a utoa nti gens tha t s ti mul a te a n i mmune res pons e (mol ecul a r mi mi cry), or other
mecha ni s ms .
Di et ma y a l s o be a fa ctor. Expos ure of i nfa nts to da i ry products (es peci a l l y cow's mi l k a nd the mi l k protei n ca s ei n), hi gh ni tra tes i n dri nki ng
wa ter, a nd l ow vi ta mi n D cons umpti on ha ve been l i nked to i ncrea s ed ri s k of type 1 DM. Ea rl y (< 4 mo) or l a te (> 7 mo) expos ure to gl uten a nd
cerea l s i ncrea s es i s l et cel l a utoa nti body producti on. Mecha ni s ms for thes e a s s oci a ti ons a re uncl ea r.
Type 2: In type 2 DM (previ ous l y ca l l ed a dul t-ons et or non-i ns ul i n-dependent), i ns ul i n s ecreti on i s i na dequa te. Often i ns ul i n l evel s a re very hi gh,
es peci a l l y ea rl y i n the di s ea s e, but peri phera l i ns ul i n res i s ta nce a nd i ncrea s ed hepa ti c producti on of gl ucos e ma ke i ns ul i n l evel s i na dequa te to
norma l i ze pl a s ma gl ucos e l evel s . Ins ul i n producti on then fa l l s , further exa cerba ti ng hypergl ycemi a . The di s ea s e genera l l y devel ops i n a dul ts a nd
becomes more common wi th a ge. Pl a s ma gl ucos e l evel s rea ch hi gher l evel s a fter ea ti ng i n ol der tha n i n younger a dul ts , es peci a l l y a fter hi gh
ca rbohydra te l oa ds , a nd ta ke l onger to return to norma l , i n pa rt beca us e of i ncrea s ed a ccumul a ti on of vi s cera l a nd a bdomi na l fa t a nd decrea s ed
mus cl e ma s s .
Type 2 DM i s becomi ng i ncrea s i ngl y common a mong chi l dren a s chi l dhood obes i ty ha s become epi demi c: 40 to 50% of new-ons et DM i n chi l dren i s
now type 2. Over 90% of a dul ts wi th DM ha ve type 2 di s ea s e. There a re cl ea r geneti c determi na nts , a s evi denced by the hi gh preva l ence of the
di s ea s e wi thi n ethni c groups (es peci a l l y Ameri ca n Indi a ns , Hi s pa ni cs , a nd As i a ns ) a nd i n rel a ti ves of peopl e wi th the di s ea s e. Al though s evera l
geneti c pol ymorphi s ms ha ve been i denti fi ed, no gene res pons i bl e for the mos t common forms of type 2 DM ha s been i denti fi ed.
Pa thogenes i s i s compl ex a nd i ncompl etel y unders tood. Hypergl ycemi a devel ops when i ns ul i n s ecreti on ca n no l onger compens a te for i ns ul i n
res i s ta nce. Al though i ns ul i n res i s ta nce i s cha ra cteri s ti c i n peopl e wi th type 2 DM a nd thos e a t ri s k for i t, evi dence a l s o exi s ts for -cel l dys functi on
a nd i mpa i red i ns ul i n s ecreti on, i ncl udi ng i mpa i red fi rs t-pha s e i ns ul i n s ecreti on i n res pons e to IV gl ucos e i nfus i on, a l os s of norma l l y pul s a ti l e
i ns ul i n s ecreti on, a n i ncrea s e i n proi ns ul i n s ecreti on s i gna l i ng i mpa i red i ns ul i n proces s i ng, a nd a n a ccumul a ti on of i s l et a myl oi d pol ypepti de (a
protei n norma l l y s ecreted wi th i ns ul i n). Hypergl ycemi a i ts el f ma y i mpa i r i ns ul i n s ecreti on, beca us e hi gh gl ucos e l evel s des ens i ti ze cel l s , ca us e
-cel l dys functi on (gl ucos e toxi ci ty), or both. Thes e cha nges typi ca l l y ta ke yea rs to devel op i n the pres ence of i ns ul i n res i s ta nce.
Obes i ty a nd wei ght ga i n a re i mporta nt determi na nts of i ns ul i n res i s ta nce i n type 2 DM. They ha ve s ome geneti c determi na nts but a l s o refl ect di et,
exerci s e, a nd l i fes tyl e. Adi pos e ti s s ue i ncrea s es pl a s ma l evel s of free fa tty a ci ds tha t ma y i mpa i r i ns ul i n-s ti mul a ted gl ucos e tra ns port a nd
mus cl e gl ycogen s yntha s e a cti vi ty. Adi pos e ti s s ue a l s o s eems to functi on a s a n endocri ne orga n, rel ea s i ng mul ti pl e fa ctors (a di pocytoki nes ) tha t
fa vora bl y (a di ponecti n) a nd a dvers el y (tumor necros i s fa ctor-, IL-6, l epti n, res i s ti n) i nfl uence gl ucos e meta bol i s m. Intra uteri ne growth res tri cti on
a nd l ow bi rth wei ght ha ve a l s o been a s s oci a ted wi th i ns ul i n res i s ta nce i n l a ter l i fe a nd ma y refl ect prena ta l envi ronmenta l i nfl uences on gl ucos e
meta bol i s m.
Miscellaneous types: Mi s cel l a neous ca us es of DM tha t a ccount for a s ma l l proporti on of ca s es i ncl ude geneti c defects a ffecti ng -cel l functi on,
i ns ul i n a cti on, a nd mi tochondri a l DNA (eg, ma turi ty-ons et di a betes of youth); pa ncrea ti c di s ea s es (eg, cys ti c fi bros i s , pa ncrea ti ti s ,
hemochroma tos i s ); endocri nopa thi es (eg, Cus hi ng's s yndrome, a cromega l y); toxi ns (eg, the rodenti ci de pyri mi nyl [Va cor]); a nd drug-i nduced
di a betes , mos t nota bl y from gl ucocorti coi ds , -bl ockers , protea s e i nhi bi tors , a nd thera peuti c dos es of ni a ci n. Pregna ncy ca us es s ome i ns ul i n
res i s ta nce i n a l l women, but onl y a few devel op ges ta ti ona l DM (s ee p. 2638).
Symptoms and Signs
The mos t common s ymptoms of DM a re thos e of hypergl ycemi a : a n os moti c di ures i s ca us ed by gl ycos uri a l ea di ng to uri na ry frequency, pol yuri a ,
a nd pol ydi ps i a tha t ma y progres s to orthos ta ti c hypotens i on a nd dehydra ti on. Severe dehydra ti on ca us es wea knes s , fa ti gue, a nd menta l s ta tus
cha nges . Symptoms ma y come a nd go a s pl a s ma gl ucos e l evel s fl uctua te. Pol ypha gi a ma y a ccompa ny s ymptoms of hypergl ycemi a but i s not
typi ca l l y a pri ma ry pa ti ent concern. Hypergl ycemi a ca n a l s o ca us e wei ght l os s , na us ea a nd vomi ti ng, a nd bl urred vi s i on, a nd i t ma y predi s pos e to
ba cteri a l or funga l i nfecti ons .
Pa ti ents wi th type 1 DM typi ca l l y pres ent wi th s ymptoma ti c hypergl ycemi a a nd s ometi mes wi th di a beti c ketoa ci dos i s (DKAs ee p. 883). Some
pa ti ents experi ence a l ong but tra ns i ent pha s e of nea r-norma l gl ucos e l evel s a fter a cute ons et of the di s ea s e (honeymoon pha s e) due to pa rti a l
recovery of i ns ul i n s ecreti on.
Pa ti ents wi th type 2 DM ma y pres ent wi th s ymptoma ti c hypergl ycemi a but a re often a s ymptoma ti c, a nd thei r condi ti on i s detected onl y on routi ne
tes ti ng. In s ome pa ti ents , i ni ti a l s ymptoms a re thos e of di a beti c compl i ca ti ons , s ugges ti ng tha t the di s ea s e ha s been pres ent for s ome ti me. In
s ome pa ti ents , hyperos moti c coma occurs i ni ti a l l y, es peci a l l y duri ng a peri od of s tres s or when gl ucos e meta bol i s m i s further i mpa i red by drugs ,
s uch a s corti cos teroi ds .
Complications
Yea rs of poorl y control l ed hypergl ycemi a l ea d to mul ti pl e, pri ma ri l y va s cul a r compl i ca ti ons tha t a ffect s ma l l (mi crova s cul a r) ves s el s , l a rge
(ma crova s cul a r) ves s el s , or both. The mecha ni s ms by whi ch va s cul a r di s ea s e devel ops i ncl ude gl ycos yl a ti on of s erum a nd ti s s ue protei ns wi th
forma ti on of a dva nced gl yca ti on end products ; s uperoxi de producti on; a cti va ti on of protei n ki na s e C, a s i gna l i ng mol ecul e tha t i ncrea s es va s cul a r
permea bi l i ty a nd ca us es endothel i a l dys functi on; a ccel era ted hexos a mi ne bi os yntheti c a nd pol yol pa thwa ys l ea di ng to s orbi tol a ccumul a ti on
wi thi n ti s s ues ; hypertens i on a nd dys l i pi demi a s tha t commonl y a ccompa ny DM; a rteri a l mi crothrombos es ; a nd proi nfl a mma tory a nd prothromboti c
effects of hypergl ycemi a a nd hyperi ns ul i nemi a tha t i mpa i r va s cul a r a utoregul a ti on. Immune dys functi on i s a nother ma jor compl i ca ti on a nd
devel ops from the di rect effects of hypergl ycemi a on cel l ul a r i mmuni ty.
Mi crova s cul a r di s ea s e underl i es the 3 mos t common a nd deva s ta ti ng ma ni fes ta ti ons of DM:
Reti nopa thy
Nephropa thy
Neuropa thy
Mi crova s cul a r di s ea s e ma y a l s o i mpa i r s ki n hea l i ng, s o tha t even mi nor brea ks i n s ki n i ntegri ty ca n devel op i nto deeper ul cers a nd ea s i l y become
i nfected, pa rti cul a rl y i n the l ower extremi ti es . Intens i ve control of pl a s ma gl ucos e ca n prevent ma ny of thes e compl i ca ti ons but ma y not revers e
them once es ta bl i s hed.
Diabetic retinopathy: Di a beti c reti nopa thy i s the mos t common ca us e of a dul t bl i ndnes s i n the US (s ee a l s o p. 615). It i s cha ra cteri zed i ni ti a l l y by
reti na l ca pi l l a ry mi croa neurys ms a nd l a ter by ma cul a r edema a nd neova s cul a ri za ti on (s ee
Pl a te 23). There a re no ea rl y s ymptoms or s i gns , but foca l bl urri ng, vi treous or reti na l deta chment, a nd pa rti a l or tota l vi s i on l os s eventua l l y
devel op; ra te of progres s i on i s hi ghl y va ri a bl e. Di a gnos i s i s by reti na l exa mi na ti on. Trea tment i s a rgon l a s er photocoa gul a ti on or vi trectomy. Stri ct
gl ycemi c control a nd ea rl y detecti on a nd trea tment a re cri ti ca l to preventi ng vi s i on l os s .
Diabetic nephropathy: Di a beti c nephropa thy (s ee a l s o p. 2401) i s a l ea di ng ca us e of chroni c rena l fa i l ure i n the US. It i s cha ra cteri zed by thi ckeni ng
of the gl omerul a r ba s ement membra ne, mes a ngi a l expa ns i on, a nd gl omerul a r s cl eros i s . Thes e cha nges ca us e gl omerul a r hypertens i on a nd
progres s i ve decl i ne i n GFR. Sys temi c hypertens i on ma y a ccel era te progres s i on. The di s ea s e i s us ua l l y a s ymptoma ti c unti l nephroti c s yndrome or
rena l fa i l ure devel ops .
Di a gnos i s i s by detecti on of uri na ry a l bumi n. A uri ne di ps ti ck pos i ti ve for protei n s i gni fi es a l bumi n excreti on > 300 mg/da y a nd a dva nced di a beti c
nephropa thy (or a n i mproperl y col l ected or s tored s peci men). If the di ps ti ck i s nega ti ve for protei n, the a l bumi n:crea ti ni ne ra ti o on a s pot uri ne
s peci men or uri na ry a l bumi n i n a 24-h col l ecti on s houl d be mea s ured. A ra ti o > 30 mg/g or a n a l bumi n concentra ti on 30 to 300 mg/24 h s i gni fi es
mi croa l bumi nuri a a nd ea rl y di a beti c nephropa thy.
Trea tment i s ri gorous gl ycemi c control combi ned wi th BP control . An ACE i nhi bi tor, a n a ngi otens i n II receptor bl ocker, or both s houl d be us ed to
trea t hypertens i on a t the ea rl i es t s i gn of mi croa l bumi nuri a or even before, beca us e thes e drugs l ower i ntra gl omerul a r BP a nd thus ha ve
renoprotecti ve effects .
Diabetic neuropathy: Di a beti c neuropa thy i s the res ul t of nerve i s chemi a due to mi crova s cul a r di s ea s e, di rect effects of hypergl ycemi a on neurons ,
a nd i ntra cel l ul a r meta bol i c cha nges tha t i mpa i r nerve functi on. There a re mul ti pl e types , i ncl udi ng
Symmetri c pol yneuropa thy (wi th s ma l l -a nd l a rge-fi ber va ri a nts )
Autonomi c neuropa thy
Ra di cul opa thy
Cra ni a l neuropa thy
Mononeuropa thy
Symmetri c pol yneuropa thy i s mos t common a nd a ffects the di s ta l feet a nd ha nds (s tocki ng-gl ove di s tri buti on); i t ma ni fes ts a s pa res thes i a s ,
dys es thes i a s , or a pa i nl es s l os s of s ens e of touch, vi bra ti on, propri ocepti on, or tempera ture. In the l ower extremi ti es , thes e s ymptoms ca n l ea d to
bl unted percepti on of foot tra uma due to i l l -fi tti ng s hoes a nd a bnorma l wei ght bea ri ng, whi ch ca n i n turn l ea d to foot ul cera ti on a nd i nfecti on or
to fra ctures , s ubl uxa ti on, a nd di s l oca ti on or des tructi on of norma l foot a rchi tecture (Cha rcot's joi nt).
Sma l l -fi ber neuropa thy i s cha ra cteri zed by pa i n, numbnes s , a nd l os s of tempera ture s ens a ti on wi th pres erved vi bra ti on a nd pos i ti on s ens e.
Pa ti ents a re prone to foot ul cera ti on a nd neuropa thi c joi nt degenera ti on a nd ha ve a hi gh i nci dence of a utonomi c neuropa thy.
Predomi na nt l a rge-fi ber neuropa thy i s cha ra cteri zed by mus cl e wea knes s , l os s of vi bra ti on a nd pos i ti on s ens e, a nd l a ck of deep tendon refl exes .
Atrophy of i ntri ns i c mus cl es of the feet a nd foot drop a re common.
Autonomi c neuropa thy ca n ca us e orthos ta ti c hypotens i on, exerci s e i ntol era nce, res ti ng ta chyca rdi a , dys pha gi a , na us ea a nd vomi ti ng (due to
ga s tropa res i s ), cons ti pa ti on a nd di a rrhea (i ncl udi ng dumpi ng s yndrome), feca l i nconti nence, uri na ry retenti on a nd i nconti nence, erecti l e
dys functi on a nd retrogra de eja cul a ti on, a nd decrea s ed va gi na l l ubri ca ti on.
Ra di cul opa thi es mos t often a ffect the proxi ma l L2 through L4 nerve roots , ca us i ng pa i n, wea knes s , a nd a trophy of the l ower extremi ti es (di a beti c
a myotrophy), or the proxi ma l T4 through T12 nerve roots , ca us i ng a bdomi na l pa i n (thora ci c pol yra di cul opa thy).
Cra ni a l neuropa thi es ca us e di pl opi a , ptos i s , a nd a ni s ocori a when they a ffect the 3rd cra ni a l nerve or motor pa l s i es when they a ffect the 4th or 6th
cra ni a l nerve.
Mononeuropa thi es ca us e fi nger wea knes s a nd numbnes s (medi a n nerve) or foot drop (peronea l nerve). Pa ti ents wi th DM a re a l s o prone to nerve
compres s i on di s orders , s uch a s ca rpa l tunnel s yndrome. Mononeuropa thi es ca n occur i n s evera l pl a ces s i mul ta neous l y (mononeuri ti s mul ti pl ex).
Al l tend to a ffect ol der pa ti ents predomi na ntl y a nd us ua l l y a ba te s ponta neous l y over months ; however, nerve compres s i on di s orders do not.
Di a gnos i s of s ymmetri c pol yneuropa thy i s by detecti on of s ens ory defi ci ts a nd di mi ni s hed a nkl e refl exes . Los s of a bi l i ty to detect the l i ght touch
of a nyl on monofi l a ment i denti fi es pa ti ents a t hi ghes t ri s k of foot ul cera ti on (s ee
Fi g. 99-1). El ectromyogra phy a nd nerve conducti on s tudi es ma y be needed for a l l forms of neuropa thy a nd a re s ometi mes us ed to excl ude other
ca us es of neuropa thi c s ymptoms , s uch a s nondi a beti c ra di cul opa thy a nd ca rpa l tunnel s yndrome. Stri ct gl ycemi c control ma y l es s en neuropa thy.
Trea tments for rel i ef of s ymptoms i ncl ude topi ca l ca ps a i ci n crea m, tri cycl i c a nti depres s a nts (eg, i mi pra mi ne), SNRIs (eg, dul oxeti ne),
a nti convul s a nts (eg, ga ba penti n, ca rba ma zepi ne), a nd mexi l eti ne. Pa ti ents wi th s ens ory l os s s houl d exa mi ne thei r feet da i l y to detect mi nor foot
tra uma a nd prevent i t from progres s i ng to l i mb-threa teni ng i nfecti on.
Macrovascular disease: La rge-ves s el a theros cl eros i s i s a res ul t of the hyperi ns ul i nemi a , dys l i pi demi a s , a nd hypergl ycemi a cha ra cteri s ti c of DM.
Ma ni fes ta ti ons a re
Angi na pectori s a nd MI
Tra ns i ent i s chemi c a tta cks a nd s trokes
Peri phera l a rteri a l di s ea s e
[Fig. 99-1. Di a beti c foot s creeni ng.]
Di a gnos i s i s by hi s tory a nd exa mi na ti on; the rol e of s creeni ng tes ts i s evol vi ng. Trea tment i s ri gorous control of a theros cl eroti c ri s k fa ctors ,
i ncl udi ng norma l i za ti on of pl a s ma gl ucos e, l i pi ds , a nd BP, combi ned wi th s moki ng ces s a ti on a nd da i l y i nta ke of a s pi ri n a nd ACE i nhi bi tors . In
contra s t wi th mi crova s cul a r di s ea s e, i ntens i ve control of pl a s ma gl ucos e a l one i s not a n effecti ve preventi ve mea s ure.
Cardiomyopathy: Di a beti c ca rdi omyopa thy i s thought to res ul t from ma ny fa ctors , i ncl udi ng epi ca rdi a l a theros cl eros i s , hypertens i on a nd l eft
ventri cul a r hypertrophy, mi crova s cul a r di s ea s e, endothel i a l a nd a utonomi c dys functi on, obes i ty, a nd meta bol i c di s turba nces . Pa ti ents devel op
hea rt fa i l ure due to i mpa i rment i n l eft ventri cul a r s ys tol i c a nd di a s tol i c functi on a nd a re more l i kel y to devel op hea rt fa i l ure a fter MI.
Infection: Pa ti ents wi th poorl y control l ed DM a re prone to ba cteri a l a nd funga l i nfecti ons beca us e of a dvers e effects of hypergl ycemi a on
gra nul ocyte a nd T-cel l functi on. Mos t common a re mucocuta neous funga l i nfecti ons (eg, ora l a nd va gi na l ca ndi di a s i s ) a nd ba cteri a l foot
i nfecti ons (i ncl udi ng os teomyel i ti s ), whi ch a re typi ca l l y exa cerba ted by l ower extremi ty va s cul a r i ns uffi ci ency a nd di a beti c neuropa thy.
Other complications: Di a beti c foot compl i ca ti ons (s ki n cha nges , ul cera ti on, i nfecti on, ga ngrene) a re common a nd a re a ttri buta bl e to va s cul a r
di s ea s e, neuropa thy, a nd rel a ti ve i mmunos uppres s i on.
Pa ti ents wi th DM ha ve a n i ncrea s ed ri s k of devel opi ng s ome rheuma tol ogi c di s ea s es , i ncl udi ng mus cl e i nfa rcti on, ca rpa l tunnel s yndrome,
Dupuytren's contra cture, a dhes i ve ca ps ul i ti s , a nd s cl eroda ctyl y. They ma y a l s o devel op ophtha l mol ogi c di s ea s e unrel a ted to di a beti c reti nopa thy
(eg, ca ta ra cts , gl a ucoma , cornea l a bra s i ons , opti c neuropa thy); hepa tobi l i a ry di s ea s es (eg, nona l cohol i c fa tty l i ver di s ea s e [s tea tos i s a nd
s tea tohepa ti ti s ], ci rrhos i s , ga l l s tones ); a nd derma tol ogi c di s ea s e (eg, ti nea i nfecti ons , l ower-extremi ty ul cers , di a beti c dermopa thy, necrobi os i s
l i poi di ca di a beti corum, di a beti c s ys temi c s cl eros i s , vi ti l i go, gra nul oma a nnul a re, a ca nthos i s ni gri ca ns [a s i gn of i ns ul i n res i s ta nce]). Depres s i on
a nd dementi a a re a l s o common.
Diagnosis
Fa s ti ng pl a s ma gl ucos e l evel s
Someti mes ora l gl ucos e tol era nce tes ti ng
DM i s i ndi ca ted by typi ca l s ymptoms a nd s i gns a nd confi rmed by mea s urement of pl a s ma gl ucos e. Mea s urement a fter a n 8- to 12-h fa s t (fa s ti ng
pl a s ma gl ucos e [FPG]) or 2 h a fter i nges ti on of a concentra ted gl ucos e s ol uti on (ora l gl ucos e tol era nce tes ti ng [OGTT]) i s bes t (s ee Ta bl e 99-2).
OGTT i s more s ens i ti ve for di a gnos i ng DM a nd i mpa i red gl ucos e tol era nce but i s l es s conveni ent a nd reproduci bl e tha n FPG. It i s therefore ra rel y
us ed routi nel y, except for di a gnos i ng ges ta ti ona l DM (s ee p. 2638) a nd for res ea rch purpos es .
In pra cti ce, DM or i mpa i red fa s ti ng gl ucos e regul a ti on i s often di a gnos ed us i ng ra ndom mea s ures of pl a s ma gl ucos e or of gl ycos yl a ted Hg (HbA1c).
A ra ndom gl ucos e va l ue > 200 mg/dL (> 11.1 mmol /L) ma y be di a gnos ti c, but va l ues ca n be a ffected by recent mea l s a nd mus t be confi rmed by
repea t tes ti ng; tes ti ng twi ce ma y not be neces s a ry i n the pres ence of di a beti c s ymptoms . HbA1c mea s urements refl ect gl ucos e l evel s over the
precedi ng 2 to 3 mo. HbA1c mea s urements a re now i ncl uded i n the di a gnos ti c cri teri a for DM: HbA1c 6.5% = DM
HbA1c 5.7 to 6.4% = predi a betes or a t ri s k of DM
However, va l ues ma y be fa l s el y hi gh or l ow (s ee Moni tori ng on p. 873), a nd tes ts mus t be done i n a certi fi ed cl i ni ca l l a bora tory. HbA1c i s a l s o us ed
for moni tori ng DM control .
Uri ne gl ucos e mea s urement, once commonl y us ed, i s no l onger us ed for di a gnos i s or moni tori ng beca us e i t i s nei ther s ens i ti ve nor s peci fi c.
Screening for disease: Screeni ng for DM s houl d be conducted for peopl e a t ri s k of the di s ea s e. Pa ti ents wi th DM a re s creened for compl i ca ti ons .
Peopl e a t hi gh ri s k of type 1 DM (eg, s i bl i ngs a nd chi l dren of peopl e wi th type 1 DM) ca n be tes ted for the pres ence of i s l et cel l or a nti gl uta mi c
a ci d deca rboxyl a s e a nti bodi es , whi ch precede ons et of cl i ni ca l di s ea s e. However, there a re no proven preventi ve s tra tegi es for peopl e a t hi gh
ri s k, s o s uch s creeni ng i s us ua l l y res erved for res ea rch s etti ngs .
Ri s k fa ctors for type 2 DM i ncl ude a ge > 45; obes i ty; s edenta ry l i fes tyl e; fa mi l y hi s tory of DM; hi s tory of i mpa i red gl ucos e regul a ti on; ges ta ti ona l
DM or del i very of a ba by > 4.1 kg; hi s tory of hypertens i on or dys l i pi demi a ; pol ycys ti c ova ry s yndrome; a nd bl a ck, Hi s pa ni c, or Ameri ca n Indi a n
ethni ci ty.
Ri s k of i ns ul i n res i s ta nce a mong overwei ght peopl e (body ma s s i ndex 25 kg/m 2 ) i s i ncrea s ed wi th s erum tri gl yceri des 130 mg/dL ( 1.47
mmol /L); tri gl yceri de/hi gh-dens i ty l i poprotei n (HDL) ra ti o 3.0 ( 1.8); a nd i ns ul i n 108 pmol /L. Peopl e wi th thes e cha ra cteri s ti cs a re a t pa rti cul a rl y
hi gh ri s k a nd s houl d be s creened for DM wi th a n FPG l evel a t l ea s t once every 3 yr a s l ong a s pl a s ma gl ucos e mea s urements a re norma l a nd a t
l ea s t a nnua l l y i f res ul ts revea l i mpa i red fa s ti ng gl ucos e l evel s (s ee Ta bl e 99-2).
Screening for complications: Al l pa ti ents wi th type 1 DM s houl d begi n s creeni ng for di a beti c compl i ca ti ons 5 yr a fter di a gnos i s . For pa ti ents wi th type
2 DM, s creeni ng begi ns a t di a gnos i s . Typi ca l s creeni ng for compl i ca ti ons i ncl udes
Foot exa mi na ti on
Fundus copi c exa mi na ti on
Uri ne tes ti ng for protei nuri a a nd mi croa l bumi nuri a
Mea s urement of s erum crea ti ni ne a nd l i pi d profi l e
Pa ti ents s houl d ha ve thei r feet exa mi ned a t l ea s t a nnua l l y for i mpa i red s ens e of pres s ure, vi bra ti on, pa i n, or tempera ture, whi ch i s cha ra cteri s ti c
of peri phera l neuropa thy. Pres s ure s ens e i s bes t tes ted wi th a monofi l a ment es thes i ometer (s ee Fi g. 99-1). The enti re foot, a nd es peci a l l y s ki n
benea th the meta ta rs a l hea ds , s houl d be exa mi ned for s ki n cra cki ng a nd s i gns of i s chemi a , s uch a s ul cera ti ons , ga ngrene, funga l na i l i nfecti ons ,
decea s ed pul s es , a nd ha i r l os s .
Fundus copi c exa mi na ti on s houl d be done by a n ophtha l mol ogi s t; the s creeni ng i nterva l i s controvers i a l but ra nges from a nnua l l y for pa ti ents
wi th es ta bl i s hed reti nopa thy to every 3 yr for thos e wi thout reti nopa thy on a t l ea s t one exa mi na ti on.
Spot or 24-h uri ne tes ti ng i s i ndi ca ted a nnua l l y to detect protei nuri a or mi croa l bumi nuri a , a nd s erum crea ti ni ne s houl d be mea s ured to a s s es s
rena l functi on.
Ma ny phys i ci a ns cons i der ba s el i ne el ectroca rdi ogra phy i mporta nt gi ven the ri s k of hea rt di s ea s e. Li pi d profi l e s houl d be checked a t l ea s t
a nnua l l y a nd more often when a bnorma l i ti es a re pres ent. BP s houl d be mea s ured a t every exa mi na ti on.
Treatment
Di et a nd exerci s e
For type 1 DM, i ns ul i n
For type 2 DM, ora l a nti hypergl ycemi cs , i ns ul i n, or both

Often ACE i nhi bi tors , s ta ti ns , a nd a s pi ri n to prevent compl i ca ti ons
Goals and methods: Trea tment i nvol ves control of hypergl ycemi a to rel i eve s ymptoms a nd prevent compl i ca ti ons whi l e mi ni mi zi ng hypogl ycemi c
epi s odes .
Goa l s for gl ycemi c control a re
Bl ood gl ucos e between 80 a nd 120 mg/dL (4.4 a nd 6.7 mmol /L) duri ng the da y
Bl ood gl ucos e between 100 a nd 140 mg/dL (5.6 a nd 7.8 mmol /L) a t bedti me
HbA1c l evel s < 7%
Gl ucos e l evel s a re typi ca l l y determi ned by home moni tori ng (s ee Moni tori ng: on p. 873). Thes e goa l s ma y be a djus ted for pa ti ents i n whom s tri ct
gl ucos e control ma y be i na dvi s a bl e, s uch a s the fra i l el derl y; pa ti ents wi th a s hort l i fe expecta ncy; pa ti ents who experi ence repea ted bouts of
hypogl ycemi a , es peci a l l y wi th hypogl ycemi c una wa renes s ; a nd pa ti ents who ca nnot communi ca te the pres ence of hypogl ycemi a s ymptoms (eg,
young chi l dren).
Key el ements for a l l pa ti ents a re pa ti ent educa ti on, di eta ry a nd exerci s e couns el i ng, a nd moni tori ng of gl ucos e control .
Al l pa ti ents wi th type 1 DM requi re i ns ul i n.
Pa ti ents wi th type 2 DM a nd mi l dl y el eva ted pl a s ma gl ucos e s houl d be pres cri bed a tri a l of di et a nd exerci s e, fol l owed by a s i ngl e ora l
a nti hypergl ycemi c drug i f l i fes tyl e cha nges a re i ns uffi ci ent, a ddi ti ona l ora l drugs a s needed (combi na ti on thera py), a nd i ns ul i n when 2 drugs a re
i neffecti ve for meeti ng recommended goa l s .
Pa ti ents wi th type 2 DM a nd more s i gni fi ca nt gl ucos e el eva ti ons a t di a gnos i s a re typi ca l l y pres cri bed l i fes tyl e cha nges a nd ora l a nti hypergl ycemi c
drugs s i mul ta neous l y.
Ins ul i n i s i ndi ca ted a s i ni ti a l thera py for women wi th type 2 DM who a re pregna nt a nd for pa ti ents who pres ent wi th a cute meta bol i c
decompens a ti on, s uch a s nonketoti c hyperos mol a r s yndrome (NKHS) or DKA. Pa ti ents wi th s evere hypergl ycemi a (pl a s ma gl ucos e > 400 mg/dL) ma y
res pond better to ora l thera py a fter gl ucos e l evel s a re norma l i zed wi th a bri ef peri od of i ns ul i n trea tment.
Pa ti ents wi th i mpa i red gl ucos e regul a ti on s houl d recei ve couns el i ng a ddres s i ng thei r ri s k of devel opi ng DM a nd the i mporta nce of l i fes tyl e
cha nges for preventi ng DM. They s houl d be moni tored cl os el y for devel opment of DM s ymptoms or el eva ted pl a s ma gl ucos e. Idea l fol l ow-up
i nterva l s ha ve not been determi ned, but a nnua l or bi a nnua l checks a re proba bl y a ppropri a te.
Patient education: Educa ti on a bout ca us es of DM, di et, exerci s e, drugs , s el f-moni tori ng wi th fi ngers ti ck tes ti ng, a nd the s ymptoms a nd s i gns of
hypogl ycemi a , hypergl ycemi a , a nd di a beti c compl i ca ti ons i s cruci a l to opti mi zi ng ca re. Mos t pa ti ents wi th type 1 DM ca n a l s o be ta ught how to
a djus t thei r i ns ul i n dos es . Educa ti on s houl d be rei nforced a t every phys i ci a n vi s i t a nd hos pi ta l i za ti on. Forma l di a betes educa ti on progra ms ,
genera l l y conducted by di a betes nurs es a nd nutri ti on s peci a l i s ts , a re often very effecti ve.
Diet: Adjus ti ng di et to i ndi vi dua l ci rcums ta nces ca n hel p pa ti ents control fl uctua ti ons i n thei r gl ucos e l evel a nd, for pa ti ents wi th type 2 DM, l os e
wei ght.
In genera l , a l l pa ti ents wi th DM need to be educa ted a bout a di et tha t i s l ow i n s a tura ted fa t a nd chol es terol a nd conta i ns modera te a mounts of
ca rbohydra te, prefera bl y from whol e gra i n s ources wi th hi gher fi ber content. Al though di eta ry protei n a nd fa t contri bute to ca l ori c i nta ke (a nd
thus , wei ght ga i n or l os s ), onl y ca rbohydra tes ha ve a di rect effect on bl ood gl ucos e l evel s . A l ow-ca rbohydra te, hi gh-fa t di et i mproves gl ucos e
control for s ome pa ti ents , but i ts l ong-term s a fety i s uncerta i n.
Pa ti ents wi th type 1 DM s houl d us e ca rbohydra te counti ng or the ca rbohydra te excha nge s ys tem to ma tch i ns ul i n dos e to ca rbohydra te i nta ke a nd
fa ci l i ta te phys i ol ogi c i ns ul i n repl a cement. "Counti ng" the a mount of ca rbohydra te i n the mea l i s us ed to ca l cul a te the prepra ndi a l i ns ul i n dos e.
In genera l , pa ti ents requi re 1 uni t of ra pi d-a cti ng i ns ul i n for ea ch 15 g of ca rbohydra te i n a mea l . Thi s a pproa ch requi res deta i l ed pa ti ent
educa ti on a nd i s mos t s ucces s ful when gui ded by a di eti ti a n experi enced i n worki ng wi th di a beti c pa ti ents . Some experts a dvi s e us e of the
gl ycemi c i ndex to del i nea te between ra pi d a nd s l owl y meta bol i zed ca rbohydra tes , a l though others bel i eve the i ndex a dds l i ttl e.
Pa ti ents wi th type 2 DM s houl d res tri ct ca l ori es , ea t regul a rl y, i ncrea s e fi ber i nta ke, a nd l i mi t i nta ke of refi ned ca rbohydra tes a nd s a tura ted fa ts .
Some experts a l s o recommend di eta ry protei n res tri cti on to 0.8 g/kg/da y to prevent progres s i on of ea rl y nephropa thy (s ee p. 2401). Nutri ti on
cons ul ta ti on s houl d compl ement phys i ci a n couns el i ng; the pa ti ent a nd the pers on who prepa res the pa ti ent's mea l s s houl d both be pres ent.
Exercise: Phys i ca l a cti vi ty s houl d i ncrea s e i ncrementa l l y to wha tever l evel a pa ti ent ca n tol era te. Some experts bel i eve tha t a erobi c exerci s e i s
better tha n i s ometri c exerci s e for wei ght l os s a nd protecti on from va s cul a r di s ea s e, but res i s ta nce tra i ni ng a l s o ca n i mprove gl ucos e control , a nd
a l l forms of exerci s e a re benefi ci a l .
Pa ti ents who experi ence hypogl ycemi c s ymptoms duri ng exerci s e s houl d be a dvi s ed to tes t thei r bl ood gl ucos e a nd i nges t ca rbohydra tes or l ower
thei r i ns ul i n dos e a s needed to get thei r gl ucos e s l i ghtl y a bove norma l jus t before exerci s e. Hypogl ycemi a duri ng vi gorous exerci s e ma y requi re
ca rbohydra te i nges ti on duri ng the workout peri od, typi ca l l y 5 to 15 g of s ucros e or a nother s i mpl e s uga r.
Pa ti ents wi th known or s us pected ca rdi ova s cul a r di s ea s e ma y benefi t from exerci s e s tres s tes ti ng before begi nni ng a n exerci s e progra m, whi l e
a cti vi ty goa l s ma y need to be modi fi ed for pa ti ents wi th di a beti c compl i ca ti ons s uch a s neuropa thy a nd reti nopa thy.
Monitoring: DM control ca n be moni tored by mea s uri ng bl ood l evel s of

Gl ucos e
HbA1c
Fructos a mi ne
Sel f-moni tori ng of whol e bl ood gl ucos e us i ng fi ngerti p bl ood, tes t s tri ps , a nd a gl ucos e meter i s mos t i mporta nt. It s houl d be us ed to hel p
pa ti ents a djus t di eta ry i nta ke a nd i ns ul i n a nd to hel p phys i ci a ns recommend a djus tments i n the ti mi ng a nd dos es of drugs .
Ma ny di fferent moni tori ng devi ces a re a va i l a bl e. Nea rl y a l l requi re tes t s tri ps a nd a mea ns for pri cki ng the s ki n a nd obta i ni ng a s a mpl e. Mos t
come wi th control s ol uti ons , whi ch s houl d be us ed peri odi ca l l y to veri fy proper meter ca l i bra ti on. Choi ce a mong devi ces i s us ua l l y ba s ed on
pa ti ent preferences for fea tures s uch a s ti me to res ul ts (us ua l l y 5 to 30 s ec), s i ze of di s pl a y pa nel (l a rge s creens ma y benefi t pa ti ents wi th poor
eyes i ght), a nd need for ca l i bra ti on. Meters tha t a l l ow for tes ti ng a t s i tes l es s pa i nful tha n fi ngerti ps (pa l m, forea rm, upper a rm, a bdomen, thi gh)
a re a l s o a va i l a bl e.
Conti nuous gl ucos e moni tori ng s ys tems us i ng a s ubcuta neous ca theter ca n provi de rea l -ti me res ul ts , i ncl udi ng a n a l a rm to wa rn of hypogl ycemi a ,
hypergl ycemi a , or ra pi dl y cha ngi ng gl ucos e l evel s . Such devi ces a re expens i ve a nd do not el i mi na te the need for fi ngers ti ck gl ucos e tes ti ng, but
they ma y be us eful for s el ected pa ti ents .
Pa ti ents wi th poor gl ucos e control a nd thos e gi ven a new drug or a new dos e of a currentl y us ed drug ma y be a s ked to s el f-moni tor 1 (us ua l l y
morni ng fa s ti ng) to 5 ti mes /da y, dependi ng on the pa ti ent's needs a nd a bi l i ti es a nd the compl exi ty of the trea tment regi men. Mos t pa ti ents
wi th type 1 DM benefi t from tes ti ng a t l ea s t 4 ti mes /da y.
HbA1c levels refl ect gl ucos e control over the precedi ng 2 to 3 mo a nd hence a s s es s control between phys i ci a n vi s i ts . HbA1c s houl d be a s s es s ed
qua rterl y i n pa ti ents wi th type 1 DM a nd a t l ea s t a nnua l l y i n pa ti ents wi th type 2 DM whos e pl a s ma gl ucos e s eems s ta bl e (more frequentl y when
control i s uncerta i n). Home tes ti ng ki ts a re us eful for pa ti ents who a re a bl e to fol l ow the tes ti ng i ns tructi ons ri gorous l y.
Control s ugges ted by HbA1C va l ues s ometi mes s eems to di ffer from tha t s ugges ted by da i l y gl ucos e rea di ngs beca us e of fa l s el y el eva ted or norma l
va l ues . Fa l s e el eva ti ons ma y occur wi th rena l i ns uffi ci ency (urea i nterferes wi th the a s s a y), l ow RBC turnover (a s occurs wi th i ron, fol a te, or
vi ta mi n B 12 defi ci ency a nemi a ), hi gh-dos e a s pi ri n, a nd hi gh bl ood a l cohol concentra ti ons . Fa l s el y norma l va l ues occur wi th i ncrea s ed RBC
turnover, a s occurs wi th hemol yti c a nemi a s a nd hemogl obi nopa thi es (eg, HbS, HbC) or duri ng trea tment of defi ci ency a nemi a s .
Fructosamine, whi ch i s mos tl y gl ycos yl a ted a l bumi n but a l s o compri s es other gl ycos yl a ted protei ns , refl ects gl ucos e control i n the previ ous 1 to 2
wk. Fructos a mi ne moni tori ng ma y be us ed duri ng i ntens i ve trea tment of DM a nd for pa ti ents wi th Hb va ri a nts or hi gh RBC turnover (whi ch ca us e
fa l s e HbA1c res ul ts ), but i t i s ma i nl y us ed i n res ea rch s etti ngs .
Urine glucose monitoring provi des a crude i ndi ca ti on of hypergl ycemi a a nd ca n be recommended onl y when bl ood gl ucos e moni tori ng i s i mpos s i bl e.
By contra s t, s el f-mea s urement of uri ne ketones i s recommended for pa ti ents wi th type 1 DM i f they experi ence s ymptoms , s i gns , or tri ggers of
ketoa ci dos i s , s uch a s na us ea or vomi ti ng, a bdomi na l pa i n, fever, col d or fl u-l i ke s ymptoms , or unus ua l s us ta i ned hypergl ycemi a (> 250 to 300
mg/dL) duri ng gl ucos e s el f-moni tori ng.
Insulin: Ins ul i n i s requi red for a l l pa ti ents wi th type 1 DM i f they become ketoa ci doti c wi thout i t; i t i s a l s o hel pful for ma na gement of ma ny
pa ti ents wi th type 2 DM. Ins ul i n repl a cement s houl d i dea l l y mi mi c -cel l functi on us i ng 2 i ns ul i n types to provi de ba s a l a nd pra ndi a l
requi rements (phys i ol ogi c repl a cement); thi s a pproa ch requi res cl os e a ttenti on to di et a nd exerci s e a s wel l a s to i ns ul i n ti mi ng a nd dos e. Mos t
i ns ul i n prepa ra ti ons a re now recombi na nt huma n, pra cti ca l l y el i mi na ti ng the once-common a l l ergi c rea cti ons to the drug when i t wa s extra cted
from a ni ma l s ources . Except for us e of regul a r i ns ul i n IV i n hos pi ta l i zed pa ti ents , i ns ul i n i s a dmi ni s tered s ubcuta neous l y. A number of a na l ogs ,
crea ted by modi fi ca ti ons of the huma n i ns ul i n mol ecul e tha t a l ter s ubcuta neous a bs orpti on ra tes , a re a va i l a bl e.
Ins ul i n types a re commonl y ca tegori zed by thei r ti me to ons et a nd dura ti on of a cti on (s ee
Ta bl e 99-3). However, thes e pa ra meters va ry wi thi n a nd a mong pa ti ents dependi ng on ma ny fa ctors (eg, s i te a nd techni que of i njecti on,
[Table 99-3. Ons et, Pea k, a nd Dura ti on of Acti on of Huma n Ins ul i n Prepa ra ti ons *]
a mount of s ubcuta neous fa t, bl ood fl ow a t the i njecti on s i te).
Ra pi d-a cti ng i ns ul i ns , i ncl udi ng l i s pro a nd a s pa rt, a re ra pi dl y a bs orbed beca us e revers a l of a n a mi no a ci d pa i r prevents the i ns ul i n mol ecul e
from a s s oci a ti ng i nto di mers a nd pol ymers . They begi n to reduce pl a s ma gl ucos e often wi thi n 15 mi n but ha ve s hort dura ti on of a cti on (< 4 h).
Thes e i ns ul i ns a re bes t us ed a t mea l ti me to control pos tpra ndi a l s pi kes i n pl a s ma gl ucos e.
Regul a r i ns ul i n i s s l i ghtl y s l ower i n ons et (30 to 60 mi n) tha n l i s pro a nd a s pa rt but l a s ts l onger (6 to 8 h). It i s the onl y form for IV us e.
Neutra l prota mi ne Ha gedorn (NPH, or i ns ul i n i s opha ne) i s i ntermedi a te-a cti ng; ons et of a cti on i s a bout 2 h a fter i njecti on, pea k effect i s 4 to 12 h
a fter i njecti on, a nd dura ti on of a cti on i s 18 to 26 h. Unl i ke NPH, i ns ul i n gl a rgi ne ha s no di s cerni bl e pea k of a cti on a nd provi des a s tea dy ba s a l
effect over 24 h. Combi na ti ons of NPH a nd regul a r i ns ul i n a nd of i ns ul i n l i s pro a nd l i s pro prota mi ne (a form of l i s pro modi fi ed to a ct l i ke NPH) a re
commerci a l l y a va i l a bl e i n premi xed prepa ra ti ons (s ee Ta bl e 99-3).
Di fferent i ns ul i n types ca n be dra wn i nto the s a me s yri nge for i njecti on but s houl d not be premi xed i n bottl es except by a ma nufa cturer. On
occa s i on, mi xi ng i ns ul i ns ma y a ffect ra tes of i ns ul i n a bs orpti on, produci ng va ri a bi l i ty of effect a nd ma ki ng gl ycemi c control l es s predi cta bl e,
es peci a l l y i f mi xed > 1 h before us e. Ins ul i n gl a rgi ne s houl d never be mi xed wi th a ny other i ns ul i n.
Ma ny prefi l l ed i ns ul i n pen devi ces a re a va i l a bl e a s a n a l terna ti ve to the conventi ona l vi a l a nd s yri nge method. Ins ul i n pens ma y be more
conveni ent for us e a wa y from home a nd ma y be prefera bl e for pa ti ents wi th l i mi ted vi s i on or ma nua l dexteri ty. Spri ng-l oa ded s el f-i njecti on
devi ces (for us e wi th a s yri nge) ma y be us eful for the occa s i ona l pa ti ent who i s fea rful of i njecti on, a nd s yri nge ma gni fi ers a re a va i l a bl e for
pa ti ents wi th l ow vi s i on.
Li s pro, a s pa rt, or regul a r i ns ul i n ca n a l s o be gi ven conti nuous l y us i ng a n i ns ul i n pump. Conti nuous s ubcuta neous i ns ul i n i nfus i on pumps ca n
el i mi na te the need for mul ti pl e da i l y i njecti ons , provi de ma xi ma l fl exi bi l i ty i n the ti mi ng of mea l s , a nd s ubs ta nti a l l y reduce va ri a bi l i ty i n gl ucos e
l evel s . Di s a dva nta ges i ncl ude cos t, mecha ni ca l fa i l ures l ea di ng to i nterrupti ons i n i ns ul i n s uppl y, a nd the i nconveni ence of wea ri ng a n externa l
devi ce. Frequent a nd meti cul ous s el f-moni tori ng a nd cl os e a ttenti on to pump functi on a re neces s a ry for s a fe a nd effecti ve us e of the i ns ul i n
pump.
Ol i gomeri c or l i pos oma l ora l forms a nd tra ns mucos a l (eg, i ntra na s a l , ora l s pra y) or tra ns derma l del i very s ys tems s how promi s e but requi re further
s tudy.
Complications of insulin treatment: Hypogl ycemi a i s the mos t common compl i ca ti on of i ns ul i n trea tment, occurri ng more often a s pa ti ents try to
a chi eve s tri ct gl ucos e control a nd a pproa ch nea r-normogl ycemi a . Symptoms of mi l d or modera te hypogl ycemi a i ncl ude hea da che, di a phores i s ,
pa l pi ta ti ons , l i ght-hea dednes s , bl urred vi s i on, a gi ta ti on, a nd confus i on. Symptoms of more s evere hypogl ycemi a i ncl ude s ei zures a nd l os s of
cons ci ous nes s . In ol der pa ti ents , hypogl ycemi a ma y ca us e s trokel i ke s ymptoms of a pha s i a or hemi pa res i s a nd i s more l i kel y to preci pi ta te s troke,
MI, a nd s udden dea th. Pa ti ents wi th type 1 DM wi th l ong dura ti on of di s ea s e ma y be una wa re of hypogl ycemi c epi s odes beca us e they no l onger
experi ence a utonomi c s ymptoms (hypogl ycemi a una wa renes s ).
Pa ti ents s houl d be ta ught to recogni ze s ymptoms of hypogl ycemi a , whi ch us ua l l y res pond ra pi dl y to the i nges ti on of s uga r, i ncl udi ng ca ndy, jui ce,
a nd gl ucos e ta bl ets . Typi ca l l y, 15 g of gl ucos e or s ucros e s houl d be i nges ted. Pa ti ents s houl d check thei r gl ucos e l evel s 15 mi n a fter gl ucos e or
s ucros e i nges ti on a nd i nges t a n a ddi ti ona l 15 g i f thei r gl ucos e l evel i s not > 80 mg/dL. For pa ti ents who a re uncons ci ous or una bl e to s wa l l ow,
hypogl ycemi a ca n be trea ted i mmedi a tel y wi th gl uca gon 1 mg s c or IM or a 50% dextros e s ol uti on 50 mL IV (25 g) fol l owed, i f neces s a ry, by IV
i nfus i on of a 5% or 10% dextros e s ol uti on to ma i nta i n a dequa te pl a s ma gl ucos e l evel s .
Hypergl ycemi a ma y fol l ow hypogl ycemi a ei ther beca us e too much s uga r wa s i nges ted or beca us e hypogl ycemi a ca us ed a s urge i n counterregul a tory hormones (gl uca gon, epi nephri ne, corti s ol , growth hormone). Too hi gh a bedti me i ns ul i n dos e ca n dri ve gl ucos e down a nd s ti mul a te a
counter-regul a tory res pons e, l ea di ng to morni ng hypergl ycemi a (Somogyi phenomenon). A more common ca us e of unexpl a i ned morni ng
hypergl ycemi a , however, i s a ri s e i n ea rl y morni ng growth hormone (da wn phenomenon). In thi s ca s e, the eveni ng i ns ul i n dos e s houl d be
i ncrea s ed, cha nged to a l onger-a cti ng prepa ra ti on, or i njected l a ter.
Hypoka l emi a ma y be ca us ed by i ntra cel l ul a r s hi fts of K due to i ns ul i n-i nduced s ti mul a ti on of the Na -K pump, but i t i s uncommon. Hypoka l emi a
more commonl y occurs i n a cute ca re s etti ngs where IV i ns ul i n i s us ed.
Loca l a l l ergi c rea cti ons a t the s i te of i ns ul i n i njecti ons a re ra re, es peci a l l y wi th the us e of huma n i ns ul i ns , but they ma y s ti l l occur i n pa ti ents
wi th l a tex a l l ergy beca us e of the na tura l rubber l a tex conta i ned i n vi a l s toppers . They ca n ca us e i mmedi a te pa i n or burni ng fol l owed by erythema ,
pruri tus , a nd i ndura ti on the l a tter s ometi mes pers i s t for da ys . Mos t rea cti ons s ponta neous l y di s a ppea r a fter weeks of conti nued i njecti on a nd
requi re no s peci fi c trea tment, a l though a nti hi s ta mi nes ma y provi de s ymptoma ti c rel i ef.
Genera l i zed a l l ergi c rea cti on i s extremel y ra re wi th huma n i ns ul i ns but ca n occur when i ns ul i n i s res ta rted a fter a l a ps e i n trea tment. Symptoms
devel op 30 mi n to 2 h a fter i njecti on a nd i ncl ude urti ca ri a , a ngi oedema , pruri tus , bronchos pa s m, a nd a na phyl a xi s . Trea tment wi th a nti hi s ta mi nes
often s uffi ces , but epi nephri ne a nd IV gl ucocorti coi ds ma y be needed. If i ns ul i n trea tment i s needed a fter a genera l i zed a l l ergi c rea cti on, s ki n
tes ti ng wi th a pa nel of puri fi ed i ns ul i n prepa ra ti ons a nd des ens i ti za ti on s houl d be done.
Loca l fa t a trophy or hypertrophy a t i njecti on s i tes i s rel a ti vel y ra re a nd i s thought to res ul t from a n i mmune rea cti on to a component of the i ns ul i n
prepa ra ti on. Ei ther ma y res ol ve by rota ti on of i njecti on s i tes .
Ins ul i n res i s ta nce occurs mos tl y i n pa ti ents wi th type 2 DM. The ca us es a re us ua l l y obes i ty a nd geneti c fa ctors . Ci rcul a ti ng a nti -i ns ul i n a nti bodi es
a re a ra re ca us e. Thi s type of i ns ul i n res i s ta nce ca n s ometi mes be trea ted by cha ngi ng i ns ul i n prepa ra ti ons (eg, from a ni ma l to huma n i ns ul i n)
a nd by a dmi ni s teri ng corti cos teroi ds i f neces s a ry.
Insulin regimens for type 1 DM: Regi mens ra nge from twi ce/da y s pl i t-mi xed (eg, s pl i t dos es of ra pi d- a nd i ntermedi a te-a cti ng i ns ul i ns ) to more
phys i ol ogi c ba s a l -bol us regi mens us i ng mul ti pl e da i l y i njecti ons (eg, s i ngl e fi xed [ba s a l ] dos e of l ong-a cti ng a nd va ri a bl e pra ndi a l [bol us ] dos es
of ra pi d-a cti ng i ns ul i n) or a n i ns ul i n pump. Intens i ve trea tment, defi ned a s gl ucos e moni tori ng 4 ti mes /da y a nd 3 i njecti ons /da y or conti nuous
i ns ul i n i nfus i on, i s more effecti ve tha n conventi ona l trea tment (1 to 2 i ns ul i n i njecti ons da i l y wi th or wi thout moni tori ng) for preventi ng di a beti c
reti nopa thy, nephropa thy, a nd neuropa thy. However, i ntens i ve thera py ma y res ul t i n more frequent epi s odes of hypogl ycemi a a nd wei ght ga i n a nd
i s genera l l y effecti ve onl y i n pa ti ents who a re a bl e a nd wi l l i ng to ta ke a n a cti ve rol e i n thei r s el f-ca re.
In genera l , mos t pa ti ents wi th type 1 DM ca n s ta rt wi th a tota l dos e of 0.2 to 0.8 uni ts of i ns ul i n/kg/da y. Obes e pa ti ents ma y requi re hi gher dos es .
Phys i ol ogi c repl a cement i nvol ves gi vi ng 40 to 60% of the da i l y i ns ul i n dos e a s a n i ntermedi a te- or l ong-a cti ng prepa ra ti on to cover ba s a l needs ,
wi th the rema i nder gi ven a s a ra pi d- or s hort-a cti ng prepa ra ti on to cover pos tpra ndi a l i ncrea s es . Thi s a pproa ch i s mos t effecti ve when the dos e of
ra pi d- or s hort-a cti ng i ns ul i n i s determi ned by a s l i di ng s ca l e tha t ta kes i nto a ccount prepra ndi a l bl ood gl ucos e a nd a nti ci pa ted mea l content.
Dos e ca n be a djus ted 1 to 2 uni ts for ea ch 50 mg/dL (2.7 mmol /L) a bove or bel ow ta rget gl ucos e l evel . Thi s phys i ol ogi c regi men a l l ows grea ter
freedom of l i fes tyl e beca us e pa ti ents ca n s ki p or ti me-s hi ft mea l s a nd ma i nta i n normogl ycemi a . However, no s peci fi c i ns ul i n regi men ha s proved
more effecti ve tha n others , a nd thes e recommenda ti ons a re for i ni ti a ti on of thera py; therea fter, choi ce of regi mens genera l l y res ts on phys i ol ogi c
res pons e a nd pa ti ent a nd phys i ci a n preferences .
Insulin regimens for type 2 DM: Regi mens for type 2 DM a l s o va ry. In ma ny pa ti ents , gl ucos e l evel s a re a dequa tel y control l ed wi th l i fes tyl e cha nges
or ora l drugs , but i ns ul i n s houl d be a dded when gl ucos e rema i ns i na dequa tel y control l ed by 2 ora l drugs . Al though uncommon, a dul t-ons et type
1 DM ma y be the ca us e. Ins ul i n s houl d repl a ce ora l drugs i n women who become pregna nt. The ra ti ona l e for combi na ti on thera py i s s tronges t for
us e of i ns ul i n wi th ora l bi gua ni des a nd i ns ul i n s ens i ti zers . Regi mens va ry from a s i ngl e da i l y i njecti on of l ong- or i ntermedi a te-a cti ng i ns ul i n
(us ua l l y a t bedti me) to the mul ti pl e-i njecti on regi men us ed by pa ti ents wi th type 1 DM. In genera l , the s i mpl es t effecti ve regi men i s preferred.
Beca us e of i ns ul i n res i s ta nce, s ome pa ti ents wi th type 2 DM requi re very l a rge dos es (> 2 uni ts /kg/da y). A common compl i ca ti on i s wei ght ga i n,
whi ch i s mos tl y a ttri buta bl e to reducti on i n l os s of gl ucos e i n uri ne a nd i mproved meta bol i c effi ci ency.
Oral antihyperglycemic drugs: Ora l a nti -hypergl ycemi c drugs (s ee
Ta bl es 99-4 a nd
99-5) a re the pri ma ry trea tment for type 2 DM, a l though i ns ul i n i s often a dded when 2 ora l drugs fa i l to provi de a dequa te gl ycemi c control . Ora l
a nti hypergl ycemi c drugs ma y
Enha nce pa ncrea ti c i ns ul i n s ecreti on (s ecreta gogues )
Sens i ti ze peri phera l ti s s ues to i ns ul i n (s ens i ti zers )
Impa i r GI a bs orpti on of gl ucos e
Drugs wi th di fferent mecha ni s ms of a cti on ma y be s ynergi s ti c.
Sulfonylureas (SUs ) a re i ns ul i n s ecreta gogues . They l ower pl a s ma gl ucos e by s ti mul a ti ng pa ncrea ti c -cel l i ns ul i n s ecreti on a nd ma y s econda ri l y
i mprove peri phera l a nd hepa ti c i ns ul i n s ens i ti vi ty by reduci ng gl ucos e toxi ci ty. Fi rs t-genera ti on drugs (s ee Ta bl e 99-4) a re more l i kel y to ca us e
a dvers e effects a nd a re us ed i nfrequentl y. Al l SUs promote hyperi ns ul i nemi a a nd wei ght ga i n of 2 to 5 kg, whi ch over ti me ma y potenti a te i ns ul i n
res i s ta nce a nd l i mi t thei r us eful nes s . Al l a l s o ca n ca us e hypogl ycemi a . Ri s k fa ctors i ncl ude a ge > 65, us e of l ong-a cti ng drugs (es peci a l l y
chl orpropa mi de, gl yburi de, or gl i pi zi de), erra ti c ea ti ng a nd exerci s e, a nd rena l or hepa ti c i ns uffi ci ency. Hypogl ycemi a ca us ed by l ong-a cti ng drugs
ma y l a s t for da ys a fter trea tment ces s a ti on, occa s i ona l l y ca us es perma nent neurol ogi c di s a bi l i ty, a nd ca n be fa ta l . For thes e rea s ons , s ome
phys i ci a ns hos pi ta l i ze hypogl ycemi c pa ti ents , es peci a l l y ol der ones . Chl orpropa mi de a l s o ca us es the s yndrome of i na ppropri a te ADH s ecreti on.
Mos t pa ti ents ta ki ng SUs a l one eventua l l y requi re a ddi ti ona l drugs to a chi eve normogl ycemi a , s ugges ti ng tha t SUs ma y exha us t -cel l functi on.
However, wors eni ng of i ns ul i n s ecreti on a nd i ns ul i n res i s ta nce i s proba bl y more a fea ture of DM i ts el f tha n of drugs us ed to trea t i t.
Short-acting insulin secretagogues (repa gl i ni de, na tegl i ni de) s ti mul a te i ns ul i n s ecreti on i n a ma nner s i mi l a r to SUs . They a re fa s ter a cti ng, however,
a nd ma y s ti mul a te i ns ul i n s ecreti on more duri ng mea l s tha n a t other ti mes . Thus , they ma y be es peci a l l y effecti ve for reduci ng pos tpra ndi a l
hypergl ycemi a a nd s eem to ha ve l ower ri s k of hypogl ycemi a . There ma y be s ome wei ght ga i n, a l though a ppa rentl y l es s tha n wi th SUs . Repa gl i ni de
s eems to be a s effecti ve a s SUs or metformi n i n l oweri ng gl ucos e l evel s . Na tegl i ni de ma y be s omewha t l es s effecti ve a nd therefore more
a ppropri a te for pa ti ents wi th mi l d hypergl ycemi a . Pa ti ents who ha ve not res ponded to other ora l drug cl a s s es (eg, SUs , metformi n) a re not l i kel y
to res pond to thes e drugs .
Biguanides l ower pl a s ma gl ucos e by decrea s i ng hepa ti c gl ucos e producti on (gl uconeogenes i s a nd gl ycogenol ys i s ). They a re cons i dered peri phera l
i ns ul i n s ens i ti zers , but thei r s ti mul a ti on of peri phera l gl ucos e upta ke ma y s i mpl y be a res ul t of reducti ons i n gl ucos e from thei r hepa ti c effects .
Bi gua ni des a l s o l ower l i pi d l evel s a nd ma y a l s o decrea s e GI nutri ent a bs orpti on, i ncrea s e -cel l s ens i ti vi ty to ci rcul a ti ng gl ucos e, a nd decrea s e
l evel s of pl a s mi nogen a cti va tor i nhi bi tor 1, thereby exerti ng a n a nti thromboti c effect. Metformi n i s the onl y bi gua ni de commerci a l l y a va i l a bl e i n
the US. It i s a t l ea s t a s effecti ve a s SUs i n reduci ng pl a s ma gl ucos e, ra rel y ca us es hypogl ycemi a , a nd ca n be s a fel y us ed wi th other drugs a nd
i ns ul i n. In a ddi ti on, metformi n does not ca us e wei ght ga i n a nd ma y even promote wei ght l os s by s uppres s i ng a ppeti te. However, the drug
commonl y ca us es GI a dvers e effects (eg, dys peps i a , di a rrhea ), whi ch for mos t peopl e recede wi th ti me. Les s commonl y, metformi n ca us es vi ta mi n
B 12 ma l a bs orpti on, but cl i ni ca l l y
[Table 99-4. Cha ra cteri s ti cs of Ora l Anti hypergl ycemi cs ]
s i gni fi ca nt a nemi a i s ra re. Contri buti on of metformi n to l i fe-threa teni ng l a cti c a ci dos i s i s controvers i a l , but the drug i s thought to be
contra i ndi ca ted i n pa ti ents a t ri s k of a ci demi a (i ncl udi ng thos e wi th rena l i ns uffi ci ency [crea ti ni ne 1.4 mg/dL], hea rt fa i l ure, hypoxi a or s evere
res pi ra tory di s ea s e, a l cohol i s m, other forms of meta bol i c a ci dos i s , or dehydra ti on). The drug s houl d be wi thhel d duri ng s urgery, a dmi ni s tra ti on of
IV contra s t, a nd a ny s eri ous i l l nes s . Ma ny peopl e recei vi ng metformi n monothera py eventua l l y requi re a n a ddi ti ona l drug.
Thiazolidinediones (TZDs ) decrea s e peri phera l i ns ul i n res i s ta nce (i ns ul i n s ens i ti zers ), but thei r s peci fi c mecha ni s ms of a cti on a re not wel l
unders tood. The drugs bi nd a nucl ea r receptor pri ma ri l y pres ent i n fa t cel l s (peroxi s ome-prol i fera tor-a cti va ted receptor- [PPAR-]) tha t i s i nvol ved
i n the tra ns cri pti on of genes tha t regul a te gl ucos e a nd l i pi d meta bol i s m. TZDs a l s o i ncrea s e HDL l evel s , l ower tri gl yceri des , a nd ma y ha ve a nti i nfl a mma tory a nd a nti -a theros cl eroti c effects . TZDs a re a s effecti ve a s SUs a nd metformi n i n reduci ng HbA1c. Beca us e the drug cl a s s i s rel a ti vel y
new, da ta on l ong-term s a fety a nd effecti venes s a re not a va i l a bl e. Though one TZD (trogl i ta zone) ca us ed a cute l i ver fa i l ure, currentl y a va i l a bl e
drugs ha ve not proven hepa totoxi c. Neverthel es s , peri odi c moni tori ng of l i ver functi on i s recommended. TZDs ma y ca us e peri phera l edema ,
es peci a l l y i n pa ti ents ta ki ng i ns ul i n, a nd ma y wors en hea rt fa i l ure i n s us cepti bl e pa ti ents . Wei ght ga i n, due to fl ui d retenti on a nd i ncrea s ed
a di pos e ti s s ue ma s s , i s common a nd ma y be s ubs ta nti a l (> 10 kg) i n s ome pa ti ents . Ra s i gl i ta zone ma y i ncrea s e ri s k of hea rt fa i l ure, a ngi na , MI,
s troke, a nd fra cture.
-Glucosidase inhibitors (AGIs ) competi ti vel y i nhi bi t i ntes ti na l enzymes tha t hydrol yze di eta ry ca rbohydra tes ; ca rbohydra tes a re di ges ted a nd
a bs orbed more s l owl y, thereby l oweri ng pos tpra ndi a l pl a s ma gl ucos e. AGIs a re l es s effecti ve tha n other ora l drugs i n reduci ng pl a s ma gl ucos e,
a nd pa ti ents often s top the drugs beca us e they ma y ca us e dys peps i a , fl a tul ence, a nd di a rrhea . But the drugs a re otherwi s e s a fe a nd ca n be us ed
i n combi na ti on wi th a l l other ora l drugs a nd wi th i ns ul i n.
Dipeptidyl peptidase-4 inhibitors (eg, s i ta gl i pti n, s a xa gl i pti n) bl ock gl uca gon-l i ke pepti de-1 (GLP-1) brea kdown by i nhi bi ti ng the enzyme di pepti dyl
pepti da s e-4 (DPP-4). Vi l da gl i pti n, a s i mi l a r drug, i s bei ng devel oped.
Injectable antihyperglycemic drugs: Injecta bl e a nti hypergl ycemi c drugs other tha n i ns ul i n a re the GLP-1 a goni s ts a nd the a myl i n a na l og, pra ml i nti de
(s ee Ta bl e 99-4). Thes e drugs a re us ed i n combi na ti on wi th other a nti hypergl ycemi cs .
GLP-1 agonists (eg, exena ti de [a n i ncreti n hormone], l i ra gl uti de) enha nce gl ucos e-dependent i ns ul i n s ecreti on a nd s l ow ga s tri c emptyi ng.
Exena ti de ma y a l s o reduce a ppeti te a nd promote wei ght l os s a nd s ti mul a te -cel l prol i fera ti on. It i s gi ven by i njecti on 5 or 10 g bi d before mea l s
a nd ma y be us ed i n combi na ti on wi th ora l a nti hypergl ycemi cs . Other GLP-1 a goni s ts , i ncl udi ng a l ong-a cti ng form of exena ti de, a re bei ng
devel oped,.
The amylin analog pra ml i nti de mi mi cs a myl i n, a pa ncrea ti c -cel l hormone tha t hel ps regul a te pos tpra ndi a l gl ucos e l evel s . Pra ml i nti de s uppres s es
pos tpra ndi a l gl uca gon s ecreti on, s l ows ga s tri c emptyi ng, a nd promotes s a ti ety. It i s gi ven by i njecti on a nd i s us ed i n combi na ti on wi th mea l ti me
i ns ul i n. Pa ti ents wi th type 1 DM a re gi ven 30 to 60 g s c before mea l s , a nd thos e wi th type 2 DM a re gi ven 120 g.
Other antihyperglycemic treatments: Tra ns pl a nta ti on of pa ncrea ti c or i s l et cel l s i s a n a l terna ti ve mea ns of i ns ul i n del i very; both techni ques
effecti vel y tra ns pl a nt i ns ul i n-produci ng
[Table 99-5. Combi na ti on Ora l Anti hypergl ycemi cs ]
-cel l s i nto i ns ul i n-defi ci ent (type 1) pa ti ents . Indi ca ti ons , ti s s ue s ources , procedures , a nd l i mi ta ti ons of both procedures a re di s cus s ed
el s ewhere (s ee p. 1138).
Other ora l a nti hypergl ycemi c drugs a re under i nves ti ga ti on. Thes e drugs i ncl ude PPAR- a nd PPAR- a goni s ts (ra ga gl i ta za r, tes a gl i ta za r); non-TZD
i ns ul i n s ens i ti zers , i ncl udi ng recombi na nt huma n i ns ul i n-l i ke growth fa ctor-1 (IGF-1); a nd phos phodi es tera s e i nhi bi tors , whi ch a ugment
pa ncrea ti c i ns ul i n s ecreti on.
Adjunctive treatments: Mea s ures to prevent or trea t compl i ca ti ons of DM a re cri ti ca l . ACE i nhi bi tors , a ngi otens i n II receptor bl ockers , or both a re
i ndi ca ted for pa ti ents wi th evi dence of ea rl y nephropa thy (mi croa l bumi nuri a or protei nuri a ), even i n the a bs ence of hypertens i on, a nd a re a good
choi ce for trea ti ng hypertens i on i n pa ti ents who ha ve DM a nd who ha ve not yet s hown rena l i mpa i rment.
ACE i nhi bi tors a l s o hel p prevent ca rdi ova s cul a r events i n pa ti ents wi th DM. As pi ri n 81 to 325 mg once/da y provi des ca rdi ova s cul a r protecti on a nd
s houl d be us ed by mos t a dul ts wi th DM i n the a bs ence of a s peci fi c contra i ndi ca ti on. Pa ti ents wi th type 2 DM tend to ha ve hi gh l evel s of
tri gl yceri des a nd s ma l l , dens e l ow-dens i ty l i poprotei ns (LDL) a nd l ow l evel s of HDL; they s houl d recei ve a ggres s i ve trea tment wi th the s a me
trea tment goa l s a s thos e of pa ti ents wi th known corona ry a rtery di s ea s e (LDL < 100 mg/dL [< 2.6 mmol /L], HDL > 40 mg/dL [> 1.1 mmol /L], a nd
tri gl yceri des < 150 mg/dL [< 1.7 mmol /L]s ee
Ta bl e 100-4 on p. 897).
Orl i s ta t, a n i ntes ti na l l i pa s e i nhi bi tor, reduces di eta ry fa t a bs orpti on; i t reduces s erum l i pi ds a nd hel ps promote wei ght l os s . Si butra mi ne, a
centra l l y a cti ng a norecti c drug, i s for s hort-term us e to promote wei ght l os s . Both of thes e drugs ma y be us eful i n s el ected pa ti ents a s pa rt of a
comprehens i ve wei ght l os s progra m. Surgi ca l trea tment for obes i ty, s uch a s ga s tri c ba ndi ng or bypa s s , a l s o l ea ds to wei ght l os s a nd i mproved
gl ucos e control i n pa ti ents who ha ve DM a nd a re una bl e to l os e wei ght through other mea ns .
Regul a r profes s i ona l podi a tri c ca re, i ncl udi ng tri mmi ng of toena i l s a nd ca l l us es , i s i mporta nt for pa ti ents wi th s ens ory l os s or ci rcul a tory
i mpa i rment. Such pa ti ents s houl d be a dvi s ed to i ns pect thei r feet da i l y for cra cks , fi s s ures , ca l l us es , corns , a nd ul cers . Feet s houl d be wa s hed
da i l y i n l ukewa rm wa ter, us i ng mi l d s oa p, a nd dri ed gentl y a nd thoroughl y. A l ubri ca nt (eg, l a nol i n) s houl d be a ppl i ed to dry, s ca l y s ki n.
Nonmedi ca ted foot powders s houl d be a ppl i ed to moi s t feet. Toena i l s s houl d be cut, prefera bl y by a podi a tri s t, s tra i ght a cros s a nd not too cl os e
to the s ki n. Adhes i ve pl a s ters a nd ta pe, ha rs h chemi ca l s , corn cures , wa ter bottl es , a nd el ectri c pa ds s houl d not be us ed on s ki n. Pa ti ents s houl d
cha nge s tocki ngs da i l y a nd not wea r cons tri cti ng cl othi ng (eg, ga rters , s ocks or s tocki ngs wi th ti ght el a s ti c tops ). Shoes s houl d fi t wel l , be wi detoed wi thout open heel s or toes , a nd be cha nged frequentl y. Speci a l s hoes s houl d be pres cri bed to reduce tra uma i f the foot i s deformed (eg,
previ ous toe a mputa ti on, ha mmer toe, buni on). Wa l ki ng ba refoot s houl d be a voi ded. Pa ti ents wi th neuropa thi c foot ul cers s houl d a voi d wei ght
bea ri ng unti l ul cers hea l . If they ca nnot, they s houl d wea r a ppropri a te orthoti c protecti on. Beca us e mos t pa ti ents wi th thes e ul cers ha ve l i ttl e or
no ma crova s cul a r occl us i ve di s ea s e, debri dement a nd a nti bi oti cs frequentl y res ul t i n good hea l i ng a nd ma y prevent ma jor s urgery (s ee p. 672).
After the ul cer ha s hea l ed, a ppropri a te i ns erts or s peci a l s hoes s houl d be pres cri bed. In refra ctory ca s es , es peci a l l y i f os teomyel i ti s i s pres ent,
s urgi ca l remova l of the meta ta rs a l hea d (the s ource of pres s ure) or a mputa ti on of the i nvol ved toe or tra ns meta ta rs a l a mputa ti on ma y be
requi red. A neuropa thi c joi nt ca n often be s a ti s fa ctori l y ma na ged wi th orthopedi c devi ces (eg, s hort l eg bra ces , mol ded s hoes , s ponge-rubber a rch
s upports , crutches , pros thes es ).
Al l pa ti ents wi th DM s houl d be va cci na ted a ga i ns t Streptococcus pneumoniae (once) a nd i nfl uenza vi rus (a nnua l l y).
Special Populations and Settings
The term bri ttl e di a betes ha s been us ed to refer to pa ti ents who ha ve dra ma ti c, recurrent s wi ngs i n gl ucos e l evel s , often for no a ppa rent rea s on.
However, thi s concept ha s no bi ol ogi c ba s i s a nd s houl d not be us ed. La bi l e pl a s ma gl ucos e l evel s a re more l i kel y to occur i n pa ti ents wi th type 1
DM beca us e endogenous i ns ul i n producti on i s compl etel y a bs ent a nd, i n s ome pa ti ents , counterregul a tory res pons e to hypogl ycemi a i s i mpa i red.
Other ca us es i ncl ude occul t i nfecti on, ga s tropa res i s (whi ch l ea ds to erra ti c a bs orpti on of di eta ry ca rbohydra tes ), a nd endocri nopa thi es (eg,
Addi s on's di s ea s e).
Pa ti ents wi th chroni c di ffi cul ty ma i nta i ni ng a ccepta bl e gl ucos e l evel s s houl d be eva l ua ted for s i tua ti ona l fa ctors tha t a ffect gl ucos e control . Such
fa ctors i ncl ude i na dequa te pa ti ent educa ti on or unders ta ndi ng tha t l ea ds to errors i n i ns ul i n a dmi ni s tra ti on, i na ppropri a te food choi ces , a nd
ps ychos oci a l s tres s tha t expres s es i ts el f i n erra ti c pa tterns of drug us e a nd food i nta ke.
The i ni ti a l a pproa ch i s to thoroughl y revi ew s el f-ca re techni ques , i ncl udi ng i ns ul i n prepa ra ti on a nd i njecti on a nd gl ucos e tes ti ng. Increa s ed
frequency of s el f-tes ti ng ma y revea l previ ous l y unrecogni zed pa tterns a nd provi des the pa ti ent wi th hel pful feedba ck. A thorough di eta ry hi s tory,
i ncl udi ng ti mi ng of mea l s , s houl d be ta ken to i denti fy potenti a l contri buti ons to poor control . Underl yi ng di s orders s houl d be rul ed out by
phys i ca l exa mi na ti on a nd a ppropri a te l a bora tory tes ts . For s ome i ns ul i n-trea ted pa ti ents , cha ngi ng to a more i ntens i ve regi men tha t a l l ows for
frequent dos e a djus tments (ba s ed on gl ucos e tes ti ng) i s hel pful . In s ome ca s es , the frequency of hypogl ycemi c a nd hypergl ycemi c epi s odes
di mi ni s hes over ti me even wi thout s peci fi c trea tment, s ugges ti ng l i fe ci rcums ta nces ma y contri bute to ca us a ti on.
Children: Chi l dren wi th type 1 DM requi re phys i ol ogi c i ns ul i n repl a cement a s do a dul ts , a nd s i mi l a r trea tment regi mens , i ncl udi ng i ns ul i n pumps ,
a re us ed. However, the ri s k of hypogl ycemi a , beca us e of unpredi cta bl e mea l a nd a cti vi ty pa tterns a nd l i mi ted a bi l i ty to report hypogl ycemi c
s ymptoms , ma y requi re modi fi ca ti on of trea tment goa l s . Mos t young chi l dren ca n be ta ught to a cti vel y pa rti ci pa te i n thei r own ca re, i ncl udi ng
gl ucos e tes ti ng a nd i ns ul i n i njecti ons . School pers onnel a nd other ca regi vers mus t be i nformed a bout the di s ea s e a nd i ns tructed a bout the
detecti on a nd trea tment of hypogl ycemi c epi s odes . Screeni ng for mi crova s cul a r compl i ca ti ons ca n genera l l y be deferred unti l a fter puberty.
Chi l dren wi th type 2 DM requi re the s a me a ttenti on to di et a nd wei ght control a nd recogni ti on a nd ma na gement of dys l i pi demi a a nd hypertens i on
a s do a dul ts . Mos t chi l dren wi th type 2 DM ha ve s evere obes i ty, s o l i fes tyl e modi fi ca ti on i s the corners tone of thera py. Chi l dren wi th mi l d
hypergl ycemi a genera l l y begi n trea tment wi th metformi n unl es s they ha ve ketos i s , rena l i ns uffi ci ency, or a nother contra i ndi ca ti on to metformi n
us e. Dos a ge i s 500 to 1000 mg bi d. If res pons e i s i ns uffi ci ent, a n i ns ul i n s ecreta gogue (s uch a s a SU or repa gl i ni de) or i ns ul i n ma y be a dded. TZDs
a re genera l l y a voi ded beca us e l ong-term s a fety i s unknown.
Adolescents: Gl ucos e control typi ca l l y deteri ora tes a s chi l dren wi th DM enter a dol es cence. Mul ti pl e fa ctors contri bute, i ncl udi ng puberta l a nd
i ns ul i n-i nduced wei ght ga i n; hormona l cha nges tha t decrea s e i ns ul i n s ens i ti vi ty; ps ychos oci a l fa ctors tha t l ea d to i ns ul i n nona dherence (eg,
mood a nd a nxi ety di s orders ); fa mi l y confl i ct, rebel l i on, a nd peer pres s ure; ea ti ng di s orders tha t l ea d to i ns ul i n omi s s i on a s a mea ns of
control l i ng wei ght; a nd experi menta ti on wi th ci ga rettes , a l cohol , a nd s ubs ta nce us e. For thes e rea s ons , s ome a dol es cents experi ence recurrent
epi s odes of hypergl ycemi a a nd DKA requi ri ng emergency depa rtment vi s i ts a nd hos pi ta l i za ti on.
Trea tment often i nvol ves i ntens i ve medi ca l s upervi s i on combi ned wi th ps ychos oci a l i nterventi ons (eg, mentori ng or s upport groups ), i ndi vi dua l or
fa mi l y thera py, a nd ps ychopha rma col ogy when i ndi ca ted. Pa ti ent educa ti on i s i mporta nt s o tha t a dol es cents ca n s a fel y enjoy the freedoms of
ea rl y a dul thood. Ra ther tha n judgi ng pers ona l choi ces a nd beha vi ors , provi ders mus t conti nua l l y rei nforce the need for ca reful gl ycemi c control ,
es peci a l l y frequent bl ood s uga r moni tori ng a nd us e of frequent, l ow-dos e, fa s t-a cti ng i ns ul i ns a s needed.
Hospitalization: Di a betes ca n be a pri ma ry rea s on for hos pi ta l i za ti on or ca n a ccompa ny other i l l nes s es tha t requi re i npa ti ent ca re. Al l di a beti c
pa ti ents wi th DKA, NKHS, or prol onged or s evere hypogl ycemi a s houl d be hos pi ta l i zed. Others wi th SU-i nduced hypogl ycemi a , poorl y control l ed
hypergl ycemi a , or a cute wors eni ng of di a beti c compl i ca ti ons ma y benefi t from bri ef hos pi ta l i za ti on, a s do chi l dren a nd a dol es cents wi th newons et di s ea s e. Control ma y wors en on di s cha rge when i ns ul i n regi mens devel oped i n control l ed i npa ti ent s etti ngs prove i na dequa te to the
uncontrol l ed condi ti ons outs i de the hos pi ta l .
When other i l l nes s es ma nda te hos pi ta l i za ti on, ma ny pa ti ents do wel l wi thout a ny cha nge i n drugs . However, gl ucos e control ma y prove di ffi cul t,
a nd i t i s often negl ected when other di s ea s es a re more a cute. Res tri cted phys i ca l a cti vi ty a nd a cute i l l nes s wors en hypergl ycemi a i n s ome
pa ti ents , wherea s di eta ry res tri cti ons a nd s ymptoms tha t a ccompa ny i l l nes s (eg, na us ea , vomi ti ng, di a rrhea , a norexi a ) preci pi ta te hypogl ycemi a
i n others es peci a l l y when a nti hypergl ycemi c drug dos es rema i n uncha nged. In a ddi ti on, i t ma y be di ffi cul t to control gl ucos e a dequa tel y i n
hos pi ta l i zed pa ti ents beca us e us ua l routi nes (eg, ti mi ng of mea l s , drugs , a nd procedures ) a re i nfl exi bl y ti med rel a ti ve to di a betes trea tment
regi mens . Inpa ti ents who a re a bl e to ea t ma y conti nue us ua l outpa ti ent regi mens ; others ma y be a ppropri a tel y trea ted wi th ba s a l i ns ul i n wi thout
or wi th s uppl ementa l s hort-a cti ng i ns ul i n. Sl i di ngs ca l e i ns ul i n s houl d not be the onl y i nterventi on to correct hypergl ycemi a ; i t i s rea cti ve ra ther
tha n proa cti ve, a nd no da ta s ugges t i t l ea ds to outcomes equi va l ent to or better tha n other a pproa ches . Longer-a cti ng i ns ul i ns s houl d be a djus ted
to prevent hypergl ycemi a ra ther tha n jus t us i ng s hort-a cti ng i ns ul i ns to correct i t.
Inpa ti ent hypergl ycemi a wors ens s hort-term prognos i s for ma ny a cute condi ti ons , mos t nota bl y s troke a nd a cute MI, a nd often prol ongs hos pi ta l
s ta y. Cri ti ca l i l l nes s ca us es i ns ul i n res i s ta nce a nd hypergl ycemi a even i n pa ti ents wi thout known DM. Ins ul i n i nfus i on to ma i nta i n pl a s ma
gl ucos e between 100 a nd 150 mg/dL (4.4 a nd 6.1 mmol /L) prevents a dvers e outcomes s uch a s orga n fa i l ure, ma y enha nce recovery from s troke, a nd
l ea ds to i mproved s urvi va l i n pa ti ents requi ri ng prol onged (> 5 da ys ) cri ti ca l ca re. Severel y i l l pa ti ents , es peci a l l y thos e recei vi ng gl ucocorti coi ds
or pres s ors , ma y need very hi gh dos es of i ns ul i n (> 5 to 10 uni ts /h) beca us e of i ns ul i n res i s ta nce. Ins ul i n i nfus i on s houl d a l s o be cons i dered for
pa ti ents recei vi ng TPN a nd for pa ti ents wi th type 1 DM who ca nnot i nges t a nythi ng ora l l y.
Surgery: The phys i ol ogi c s tres s of s urgery ca n i ncrea s e pl a s ma gl ucos e i n pa ti ents wi th DM a nd i nduce DKA i n thos e wi th type 1 DM. For type 1
pa ti ents , one ha l f to two thi rds of the us ua l morni ng dos e of i ntermedi a te-a cti ng i ns ul i n or 70 to 80% of the dos e of l ong-a cti ng i ns ul i n (gl a rgi ne
or detemi r) ca n be gi ven the morni ng before s urgery wi th a n IV i nfus i on of a 5% dextros e s ol uti on a t a ra te of 100 to 150 mL/h. Duri ng a nd a fter
s urgery, pl a s ma gl ucos e (a nd ketones i f hypergl ycemi a s ugges ts the need) s houl d be mea s ured a t l ea s t every 2 h. Gl ucos e i nfus i on i s conti nued
(moni tori ng i s done a t 2- to 4-h i nterva l s ), a nd regul a r or s hort-a cti ng i ns ul i n i s gi ven s c q 4 to 6 h a s needed to ma i nta i n the pl a s ma gl ucos e l evel
between 100 a nd 200 mg/dL (5.55 a nd 11.01 mmol /L) unti l the pa ti ent ca n be s wi tched to ora l feedi ngs a nd res ume the us ua l i ns ul i n regi men.
Addi ti ona l dos es of i ntermedi a te- or l ong-a cti ng i ns ul i n s houl d be gi ven i f there i s a s ubs ta nti a l del a y (> 24 h) i n res umi ng the us ua l regi men.
Thi s a pproa ch ma y a l s o be us ed for i ns ul i n-trea ted pa ti ents wi th type 2 DM, but frequent mea s urement of ketones ma y be omi tted.
Some phys i ci a ns prefer to wi thhol d s c i ns ul i n on the da y of s urgery a nd to gi ve i ns ul i n by IV i nfus i on. One a pproa ch i s to a dd 6 to 10 uni ts of
regul a r i ns ul i n to 1 L of 5% dextros e i n 0.9% s a l i ne s ol uti on or wa ter i nfus ed i ni ti a l l y a t 100 to 150 mL/h on the morni ng of s urgery ba s ed on the
pl a s ma gl ucos e l evel . Al terna ti vel y, s epa ra te i ns ul i n (1 to 2 uni ts /h) a nd dextros e (75 to 125 mL/h of 5% dextros e) i nfus i ons ma y be us ed a nd a l l ow
for ea s i er ti tra ti on. Ins ul i n a ds orpti on onto IV tubi ng ca n l ea d to i ncons i s tent effects , whi ch ca n be mi ni mi zed by prefl us hi ng the IV tubi ng wi th
i ns ul i n s ol uti on. Ins ul i n i nfus i on i s conti nued through recovery, wi th i ns ul i n a djus ted ba s ed on the pl a s ma gl ucos e l evel s obta i ned i n the
recovery room a nd a t 1- to 2-h i nterva l s therea fter.
Mos t pa ti ents wi th type 2 DM who a re trea ted wi th ora l a nti hypergl ycemi c drugs ma i nta i n a ccepta bl e gl ucos e l evel s when fa s ti ng a nd ma y not
requi re i ns ul i n i n the peri opera ti ve peri od. Mos t ora l drugs , i ncl udi ng SUs a nd metformi n, s houl d be wi thhel d on the da y of s urgery, a nd pl a s ma
gl ucos e l evel s s houl d be mea s ured preopera ti vel y a nd pos topera ti vel y a nd every 6 h whi l e pa ti ents recei ve IV fl ui ds . Ora l drugs ma y be res umed
when pa ti ents a re a bl e to ea t, but metformi n s houl d be wi thhel d unti l norma l rena l functi on i s confi rmed 48 h a fter s urgery.
Prevention
Type 1: No trea tments defi ni tel y prevent the ons et or progres s i on of type 1 DM. Aza thi opri ne, corti cos teroi ds , a nd cycl os pori ne i nduce remi s s i on of
ea rl y type 1 DM i n s ome pa ti ents , pres uma bl y through s uppres s i on of a utoi mmune -cel l des tructi on. However, toxi ci ty a nd the need for l i fel ong
trea tment l i mi t thei r us e. In a few pa ti ents , s hort-term trea tment wi th a nti -CD3 monocl ona l a nti bodi es reduces i ns ul i n requi rements for a t l ea s t
the fi rs t yea r of recent-ons et di s ea s e by s uppres s i ng a utoi mmune T-cel l res pons e.
Type 2: Type 2 DM us ua l l y ca n be prevented wi th l i fes tyl e modi fi ca ti on. Wei ght l os s of a s l i ttl e a s 7% of ba s el i ne body wei ght, combi ned wi th
modera te-i ntens i ty phys i ca l a cti vi ty (eg, wa l ki ng 30 mi n/da y), ma y reduce the i nci dence of DM i n hi gh-ri s k peopl e by > 50%. Metformi n a nd
a ca rbos e ha ve a l s o been s hown to reduce the ri s k of DM i n pa ti ents wi th i mpa i red gl ucos e regul a ti on. TZDs ma y a l s o be protecti ve, perha ps by
i nduci ng PPAR- a cti vi ty but requi re further s tudy before they ca n be recommended for routi ne preventi ve us e.
Complications: Ri s k of DM compl i ca ti ons ca n be decrea s ed by s tri ct control of pl a s ma gl ucos e, defi ned a s HbA1c < 7%, a nd by control of hypertens i on
a nd l i pi d l evel s (s ee pp. 2069 a nd 896). Speci fi c mea s ures for preventi on of progres s i on of compl i ca ti ons once detected a re des cri bed under
Compl i ca ti ons (s ee p. 868) a nd Trea tment (s ee p. 871).
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. DKA occurs
mostly in type 1 diabetes mellitus (DM). It causes nausea, vomiting, and abdominal pain and can progress to cerebral edema, coma, and death. DKA is diagnosed
by detection of hyperketonemia and anion gap metabolic acidosis in the presence of hyperglycemia. Treatment involves volume expansion, insulin replacement,
and prevention of hypokalemia.
DKA i s mos t common a mong pa ti ents wi th type 1 DM a nd devel ops when i ns ul i n l evel s a re i ns uffi ci ent to meet the body's ba s i c meta bol i c
requi rements . DKA i s the fi rs t ma ni fes ta ti on of type 1 DM i n a mi nori ty of pa ti ents . Ins ul i n defi ci ency ca n be a bs ol ute (eg, duri ng l a ps es i n the
a dmi ni s tra ti on of exogenous i ns ul i n) or rel a ti ve (eg, when us ua l i ns ul i n dos es do not meet meta bol i c needs duri ng phys i ol ogi c s tres s ). Common
phys i ol ogi c s tres s es tha t ca n tri gger DKA i ncl ude a cute i nfecti on (pa rti cul a rl y pneumoni a a nd UTI), MI, s troke, pa ncrea ti ti s , a nd tra uma . Drugs
i mpl i ca ted i n ca us i ng DKA i ncl ude corti cos teroi ds , thi a zi de di ureti cs , a nd s ympa thomi meti cs . DKA i s l es s common i n type 2 DM, but i t ma y occur i n
s i tua ti ons of unus ua l phys i ol ogi c s tres s .
Pathophysiology
Ins ul i n defi ci ency ca us es the body to meta bol i ze tri gl yceri des a nd mus cl e i ns tea d of gl ucos e for energy. Serum l evel s of gl ycerol a nd free fa tty
a ci ds (FFAs ) ri s e beca us e of unres tra i ned l i pol ys i s , a s does a l a ni ne beca us e of mus cl e ca ta bol i s m. Gl ycerol a nd a l a ni ne provi de s ubs tra te for
hepa ti c gl uconeogenes i s , whi ch i s s ti mul a ted by the exces s of gl uca gon tha t a ccompa ni es i ns ul i n defi ci ency. Gl uca gon a l s o s ti mul a tes
mi tochondri a l convers i on of FFAs i nto ketones . Ins ul i n norma l l y bl ocks ketogenes i s by i nhi bi ti ng the tra ns port of FFA deri va ti ves i nto the
mi tochondri a l ma tri x, but ketogenes i s proceeds i n the a bs ence of i ns ul i n. The ma jor ketoa ci ds produced, a cetoa ceti c a ci d a nd -hydroxybutyri c
a ci d, a re s trong orga ni c a ci ds tha t crea te meta bol i c a ci dos i s . Acetone deri ved from the meta bol i s m of a cetoa ceti c a ci d a ccumul a tes i n s erum a nd
i s s l owl y di s pos ed of by res pi ra ti on.
Hypergl ycemi a due to i ns ul i n defi ci ency ca us es a n os moti c di ures i s tha t l ea ds to ma rked uri na ry l os s es of wa ter a nd el ectrol ytes . Uri na ry
excreti on of ketones obl i ga tes a ddi ti ona l l os s es of Na a nd K. Serum Na ma y fa l l from na tri ures i s or ri s e due to excreti on of l a rge vol umes of free
wa ter. K i s a l s o l os t i n l a rge qua nti ti es , s ometi mes > 300 mEq/24 h. Des pi te a s i gni fi ca nt tota l body defi ci t of K, i ni ti a l s erum K i s typi ca l l y norma l
or el eva ted beca us e of the extra cel l ul a r mi gra ti on of K i n res pons e to a ci dos i s . K l evel s genera l l y fa l l further duri ng trea tment a s i ns ul i n thera py
dri ves K i nto cel l s . If s erum K i s not moni tored a nd repl a ced a s needed, l i fe-threa teni ng hypoka l emi a ma y devel op.
Symptoms and Signs
Symptoms a nd s i gns of DKA i ncl ude thos e of hypergl ycemi a (s ee p. 868) wi th the a ddi ti on of na us ea , vomi ti ng, a ndpa rti cul a rl y i n chi l dren
a bdomi na l pa i n. Letha rgy a nd s omnol ence a re s ymptoms of more s evere decompens a ti on. Pa ti ents ma y be hypotens i ve a nd ta chyca rdi c from
dehydra ti on a nd a ci dos i s ; they ma y brea the ra pi dl y a nd deepl y to compens a te for a ci demi a (Kus s ma ul 's res pi ra ti ons ). They ma y a l s o ha ve frui ty
brea th due to exha l ed a cetone. Fever i s not a s i gn of DKA i ts el f a nd, i f pres ent, s i gni fi es underl yi ng i nfecti on. In the a bs ence of ti mel y trea tment,
DKA progres s es to coma a nd dea th.
Acute cerebra l edema , a compl i ca ti on i n a bout 1% of DKA pa ti ents , occurs pri ma ri l y i n chi l dren a nd l es s often i n a dol es cents a nd young a dul ts .
Hea da che a nd fl uctua ti ng l evel of cons ci ous nes s hera l d thi s compl i ca ti on i n s ome pa ti ents , but res pi ra tory a rres t i s the i ni ti a l ma ni fes ta ti on i n
others . The ca us e i s not wel l unders tood but ma y be rel a ted to too-ra pi d reducti ons i n s erum os mol a l i ty or to bra i n i s chemi a . It i s mos t l i kel y to
occur i n chi l dren < 5 yr when DKA i s the i ni ti a l ma ni fes ta ti on of DM. Chi l dren wi th the hi ghes t BUN a nd l owes t Pa CO2 a t pres enta ti on s eem to be a t
grea tes t ri s k. Del a ys i n correcti on of hypona tremi a a nd the us e of HCO3 duri ng DKA trea tment a re a ddi ti ona l ri s k fa ctors .
Diagnosis
Arteri a l pH
Serum ketones
Ca l cul a ti on of a ni on ga p
In pa ti ents s us pected of ha vi ng DKA, s erum el ectrol ytes , BUN a nd crea ti ni ne, gl ucos e, ketones , a nd os mol a ri ty s houl d be mea s ured. Uri ne s houl d
be tes ted for ketones . Pa ti ents who a ppea r s i gni fi ca ntl y i l l a nd thos e wi th pos i ti ve ketones s houl d ha ve ABG mea s urement. DKA i s di a gnos ed by
a n a rteri a l pH < 7.30 wi th a n a ni on ga p > 12 (s ee Si deba r 98-1 on p. 858) a nd s erum ketones i n the pres ence of hypergl ycemi a . A pres umpti ve
di a gnos i s ca n be ma de when uri ne gl ucos e a nd ketones a re s trongl y pos i ti ve. Uri ne tes t s tri ps a nd s ome a s s a ys for s erum ketones ma y
underes ti ma te the degree of ketos i s beca us e they detect a cetoa ceti c a nd not -hydroxybutyri c a ci d, whi ch i s us ua l l y the predomi na nt ketoa ci d.
Symptoms a nd s i gns of a tri ggeri ng i l l nes s s houl d be purs ued wi th a ppropri a te s tudi es (eg, cul tures , i ma gi ng s tudi es ). Adul ts s houl d ha ve a n ECG
to s creen for a cute MI a nd to hel p determi ne the s i gni fi ca nce of a bnorma l i ti es i n s erum K.
Other l a bora tory a bnorma l i ti es i ncl ude hypona tremi a , el eva ted s erum crea ti ni ne, a nd el eva ted s erum os mol a ri ty. Hypergl ycemi a ma y ca us e
di l uti ona l hypona tremi a , s o mea s ured s erum Na i s corrected by a ddi ng 1.6 mEq/L for ea ch 100 mg/dL el eva ti on of s erum gl ucos e over 100 mg/dL. To
i l l us tra te, for a pa ti ent wi th s erum Na of 124 mEq/L a nd gl ucos e of 600 mg/dL, a dd 1.6 ([600-100]/100) = 8 mEq/L to 124 for a corrected s erum Na of
132 mEq/L. As a ci dos i s i s corrected, s erum K drops . An i ni ti a l K l evel < 4.5 mEq/L i ndi ca tes ma rked K depl eti on a nd requi res i mmedi a te K
s uppl ementa ti on. Serum a myl a s e a nd l i pa s e a re often el eva ted, even i n the a bs ence of pa ncrea ti ti s (whi ch ma y be pres ent i n a l cohol i c DKA
pa ti ents a nd i n thos e wi th coexi s ti ng hypertri gl yceri demi a ).
Prognosis
Morta l i ty ra tes for DKA a re between 1 a nd 10%. Shock or coma on a dmi s s i on i ndi ca tes a wors e prognos i s . Ma i n ca us es of dea th a re ci rcul a tory
col l a ps e, hypoka l emi a , a nd i nfecti on. Among chi l dren wi th cerebra l edema , 57% recover compl etel y, 21% s urvi ve wi th neurol ogi c s equel a e, a nd
21% di e.
Treatment
IV 0.9% s a l i ne
Correcti on of a ny hypoka l emi a
IV i ns ul i n (a s l ong a s s erum K i s 3.3 mEq/L)
Ra rel y IV Na HCO3 (i f pH < 7 a fter 1 h of trea tment)
The mos t urgent goa l s a re ra pi d i ntra va s cul a r vol ume repl eti on, correcti on of hypergl ycemi a a nd a ci dos i s , a nd preventi on of hypoka l emi a .
Identi fi ca ti on of preci pi ta ti ng fa ctors i s a l s o i mporta nt. Trea tment s houl d occur i n i ntens i ve ca re s etti ngs beca us e cl i ni ca l a nd l a bora tory
a s s es s ments a re i ni ti a l l y needed every hour or every other hour wi th a ppropri a te a djus tments i n trea tment.
Intra va s cul a r vol ume s houl d be res tored ra pi dl y to ra i s e BP a nd ens ure gl omerul a r perfus i on; once i ntra va s cul a r vol ume i s res tored, rema i ni ng
tota l body wa ter defi ci ts a re corrected more s l owl y, typi ca l l y over a bout 24 h. Ini ti a l vol ume repl eti on i n a dul ts i s typi ca l l y a chi eved wi th ra pi d IV
i nfus i on of 1 to 3 L of 0.9% s a l i ne s ol uti on, fol l owed by s a l i ne i nfus i ons a t 1 L/h or fa s ter a s needed to ra i s e BP, correct hypergl ycemi a , a nd keep
uri ne fl ow a dequa te. Adul ts wi th DKA typi ca l l y need a mi ni mum of 3 L of s a l i ne over the fi rs t 5 h. When BP i s s ta bl e a nd uri ne fl ow a dequa te,
norma l s a l i ne i s repl a ced by 0.45% s a l i ne. When pl a s ma gl ucos e fa l l s to < 250 mg/dL, IV fl ui d s houl d be cha nged to 5% dextros e i n 0.45% s a l i ne.
For chi l dren, fl ui d defi ci ts a re es ti ma ted a t 60 to 100 mL/kg body wei ght. Ma i ntena nce fl ui ds (for ongoi ng l os s es ) mus t a l s o be provi ded (s ee p.
2808). Ini ti a l fl ui d thera py s houl d be 0.9% s a l i ne (20 mL/kg) over 1 to 2 h, fol l owed by 0.45% s a l i ne once BP i s s ta bl e a nd uri ne output a dequa te.
The rema i ni ng fl ui d defi ci t s houl d be repl a ced over 36 h, typi ca l l y requi ri ng a ra te (i ncl udi ng ma i ntena nce fl ui ds ) of a bout 2 to 4 mL/kg/h,
dependi ng on the degree of dehydra ti on.
Hypergl ycemi a i s corrected by gi vi ng regul a r i ns ul i n 0.15 uni t/kg IV bol us i ni ti a l l y, fol l owed by conti nuous IV i nfus i on of 0.1 uni t/kg/h i n 0.9%
s a l i ne s ol uti on. Insulin should be withheld until serum K is 3.3 mEq/L (s ee p. 886). Ins ul i n a ds orpti on onto IV tubi ng ca n l ea d to i ncons i s tent effects ,
whi ch ca n be mi ni mi zed by prefl us hi ng the IV tubi ng wi th i ns ul i n s ol uti on. If pl a s ma gl ucos e does not fa l l by 50 to 75 mg/dL i n the fi rs t hour,
i ns ul i n dos es s houl d be doubl ed. Chi l dren s houl d be gi ven a conti nuous IV i ns ul i n i nfus i on of 0.1 uni t/kg/h or hi gher wi th or wi thout a bol us .
Ketones s houl d begi n to cl ea r wi thi n hours i f i ns ul i n i s gi ven i n s uffi ci ent dos es . However, cl ea ra nce of ketones ma y s eem to l a g beca us e of
convers i on of -hydroxybutyra te to a cetoa ceta te (whi ch i s the "ketone" mea s ured i n mos t hos pi ta l l a bora tori es ) a s a ci dos i s res ol ves . Serum pH
a nd HCO3 l evel s s houl d a l s o qui ckl y i mprove, but res tora ti on of a norma l s erum HCO3 l evel ma y ta ke 24 h. Ra pi d correcti on of pH by HCO3
a dmi ni s tra ti on ma y be cons i dered i f pH rema i ns < 7 a fter a bout a n hour of i ni ti a l fl ui d res us ci ta ti on, but HCO3 i s a s s oci a ted wi th devel opment of
a cute cerebra l edema (pri ma ri l y i n chi l dren) a nd s houl d not be us ed routi nel y. If us ed, onl y modes t pH el eva ti on s houl d be a ttempted (ta rget pH
of a bout 7.1), wi th dos es of 50 to 100 mEq over 30 to 60 mi n, fol l owed by repea t mea s urement of a rteri a l pH a nd s erum K.
When pl a s ma gl ucos e becomes 250 to 300 mg/dL (13.88 to 16.65 mmol /L) i n a dul ts , 5% dextros e s houl d be a dded to IV fl ui ds to reduce the ri s k of
hypogl ycemi a . Ins ul i n dos a ge ca n then be reduced (mi ni mum 1 to 2 uni ts /h), but the conti nuous IV i nfus i on of regul a r i ns ul i n s houl d be
ma i nta i ned unti l the a ni on ga p ha s na rrowed a nd bl ood a nd uri ne a re cons i s tentl y nega ti ve for ketones . Ins ul i n repl a cement ma y then be
s wi tched to regul a r i ns ul i n 5 to 10 uni ts s c q 4 to 6 h. When the pa ti ent i s s ta bl e a nd a bl e to ea t, a typi ca l s pl i t-mi xed or ba s a l -bol us i ns ul i n
regi men i s begun. IV i ns ul i n s houl d be conti nued for 1 to 4 h a fter the i ni ti a l dos e of s c i ns ul i n i s gi ven. Chi l dren s houl d conti nue to recei ve 0.05
uni t/kg/h i ns ul i n i nfus i on unti l s c i ns ul i n i s i ni ti a ted a nd pH i s > 7.3.
Hypoka l emi a preventi on requi res repl a cement of 20 to 30 mEq K i n ea ch l i ter of IV fl ui d to keep s erum K between 4 a nd 5 mEq/L. If s erum K i s < 3.3
mEq/L, i ns ul i n s houl d be wi thhel d a nd K gi ven a t 40 mEq/h unti l s erum K i s 3.3 mEq/L; i f s erum K i s > 5 mEq/L, K s uppl ementa ti on ca n be
wi thhel d. Ini ti a l l y norma l or el eva ted s erum K mea s urements ma y refl ect s hi fts from i ntra cel l ul a r s tores i n res pons e to a ci demi a a nd bel i e the
true K defi ci ts tha t a l mos t a l l DKA pa ti ents ha ve. Ins ul i n repl a cement ra pi dl y s hi fts K i nto cel l s , s o l evel s s houl d be checked hourl y or every other
hour i n the i ni ti a l s ta ges of trea tment. Hypophos pha temi a often devel ops duri ng trea tment of DKA, but phos pha te repl eti on i s of uncl ea r benefi t
i n mos t ca s es . If i ndi ca ted (eg, i f rha bdomyol ys i s , hemol ys i s , or neurol ogi c deteri ora ti on occurs ), K phos pha te 1 to 2 mmol /kg of phos pha te, ca n be
i nfus ed over 6 to 12 h. If K phos pha te i s gi ven, the s erum Ca l evel us ua l l y decrea s es a nd s houl d be moni tored.
Trea tment of s us pected cerebra l edema i s hyperventi l a ti on, corti cos teroi ds , a nd ma nni tol , but thes e mea s ures a re often i neffecti ve a fter the
ons et of res pi ra tory a rres t.
Nonketotic Hyperosmolar Syndrome
(Hyperos mol a r Hypergl ycemi c Sta te)
Nonketotic hyperosmolar syndrome (NKHS) is a metabolic complication of diabetes mellitus (DM) characterized by hyperglycemia, extreme dehydration,
hyperosmolar plasma, and altered consciousness. It most often occurs in type 2 DM, often in the setting of physiologic stress. NKHS is diagnosed by severe
hyperglycemia and serum hyperosmolarity and absence of significant ketosis. Treatment is IV saline solution and insulin. Complications include coma, seizures,
and death.
NKHS i s a compl i ca ti on of type 2 DM a nd ha s a morta l i ty ra te of up to 40%. It us ua l l y devel ops a fter a peri od of s ymptoma ti c hypergl ycemi a i n
whi ch fl ui d i nta ke i s i na dequa te to prevent extreme dehydra ti on due to hypergl ycemi a -i nduced os moti c di ures i s . The preci pi ta ti ng fa ctor ma y be a
coexi s ti ng a cute i nfecti on, drugs tha t i mpa i r gl ucos e tol era nce (gl ucocorti coi ds ) or i ncrea s e fl ui d l os s (di ureti cs ), medi ca l nona dherence, or other
medi ca l condi ti ons . Serum ketones a re not pres ent beca us e the a mounts of i ns ul i n pres ent i n mos t pa ti ents wi th type 2 DM a re a dequa te to
s uppres s ketogenes i s . Beca us e s ymptoms of a ci dos i s a re not pres ent, mos t pa ti ents endure a s i gni fi ca ntl y l onger peri od of os moti c dehydra ti on
before pres enta ti on, a nd thus pl a s ma gl ucos e (> 600 mg/dL [> 33 mmol /L]) a nd os mol a ri ty (> 320 mOs m/L) a re typi ca l l y much hi gher tha n i n
di a beti c ketoa ci dos i s (DKA).
Symptoms and Signs

The pri ma ry s ymptom of NKHS i s a l tered cons ci ous nes s va ryi ng from confus i on or di s ori enta ti on to coma , us ua l l y a s a res ul t of extreme
dehydra ti on wi th or wi thout prerena l a zotemi a , hypergl ycemi a , a nd hyperos mol a ri ty. In contra s t to DKA, foca l or genera l i zed s ei zures a nd
tra ns i ent hemi pl egi a ma y occur.
Diagnosis
Bl ood gl ucos e l evel
Serum os mol a ri ty
Genera l l y, NKHS i s i ni ti a l l y s us pected when a ma rkedl y el eva ted gl ucos e l evel i s found i n a fi ngers ti ck s peci men obta i ned i n the cours e of a
workup of a l tered menta l s ta tus . If mea s urements ha ve not a l rea dy been obta i ned, mea s urement of s erum el ectrol ytes , BUN a nd crea ti ni ne,
gl ucos e, ketones , a nd os mol a ri ty s houl d be done. Uri ne s houl d be tes ted for ketones . Serum K l evel s a re us ua l l y norma l , but Na ma y be l ow or
hi gh dependi ng on vol ume defi ci ts . BUN a nd s erum crea ti ni ne l evel s a re ma rkedl y i ncrea s ed. Arteri a l pH i s us ua l l y > 7.3, but occa s i ona l l y mi l d
meta bol i c a ci dos i s devel ops due to l a cta te a ccumul a ti on.
The a vera ge fl ui d defi ci t i s 10 L, a nd a cute ci rcul a tory col l a ps e i s a common ca us e of dea th. Wi des prea d thrombos i s i s a frequent fi ndi ng on
a utops y, a nd i n s ome ca s es bl eedi ng ma y occur a s a cons equence of di s s emi na ted i ntra va s cul a r coa gul a ti on. Other compl i ca ti ons i ncl ude
a s pi ra ti on pneumoni a , a cute rena l fa i l ure, a nd a cute res pi ra tory di s tres s s yndrome.
Treatment
IV 0.9% s a l i ne
Correcti on of a ny hypoka l emi a
IV i ns ul i n (a s l ong a s s erum K i s 3.3 mEq/L)
Trea tment i s 0.9% s a l i ne s ol uti on 1 L IV over 30 mi n, then a t 1 L/h to ra i s e BP a nd i mprove ci rcul a ti on a nd uri ne output. It ca n be repl a ced by 0.45%
s a l i ne when BP becomes norma l a nd pl a s ma gl ucos e rea ches 300 mg/dL. The ra te of i nfus i on of IV fl ui ds s houl d be a djus ted dependi ng on BP,
ca rdi a c s ta tus , a nd the ba l a nce between fl ui d i nput a nd output.
Ins ul i n i s gi ven a t 0.15 uni t/kg IV bol us fol l owed by a 0.1 uni t/kg/h i nfus i on a fter the fi rs t l i ter of s a l i ne ha s been i nfus ed. Hydra ti on a l one ca n
s ometi mes preci pi tous l y decrea s e pl a s ma gl ucos e, s o i ns ul i n dos e ma y need to be reduced. A too-qui ck reducti on i n os mol a l i ty ca n l ea d to
cerebra l edema . Occa s i ona l pa ti ents wi th i ns ul i n-res i s ta nt type 2 DM wi th NKHS requi re l a rger i ns ul i n dos es . Once pl a s ma gl ucos e rea ches 200 to
250 mg/dL, i ns ul i n i nfus i on s houl d be reduced to ba s a l l evel s (1 to 2 uni ts /h) unti l rehydra ti on i s compl ete a nd the pa ti ent i s a bl e to ea t. Addi ti on
of 5% dextros e i nfus i on ma y occa s i ona l l y be needed to a voi d hypogl ycemi a . After recovery from the a cute epi s ode, pa ti ents a re us ua l l y s wi tched
to a djus ted dos es of s c i ns ul i n. Mos t pa ti ents ca n res ume us i ng ora l a nti hypergl ycemi c drugs once thei r condi ti on i s s ta bl e.
K repl a cement i s s i mi l a r to DKA: 40 mEq/h for s erum K < 3.3 mEq/L; 20 to 30 mEq/h for s erum K between 3.3 a nd 4.9 mEq/L; a nd none for s erum K 5
mEq/L.
Alcoholic Ketoacidosis
Alcoholic ketoacidosis is a metabolic complication of alcohol use and starvation characterized by hyperketonemia and anion gap metabolic acidosis without
significant hyperglycemia. Alcoholic ketoacidosis causes nausea, vomiting, and abdominal pain. Diagnosis is by history and findings of ketoacidosis without
hyperglycemia. Treatment is IV saline solution and dextrose infusion.
Al cohol i c ketoa ci dos i s i s a ttri buted to the combi ned effects of a l cohol a nd s ta rva ti on on gl ucos e meta bol i s m.
Pathophysiology
Al cohol di mi ni s hes hepa ti c gl uconeogenes i s a nd l ea ds to decrea s ed i ns ul i n s ecreti on, i ncrea s ed l i pol ys i s , i mpa i red fa tty a ci d oxi da ti on, a nd
s ubs equent ketogenes i s . Counter-regul a tory hormones a re i ncrea s ed a nd ma y further i nhi bi t i ns ul i n s ecreti on. Pl a s ma gl ucos e l evel s a re us ua l l y
l ow or norma l , but mi l d hypergl ycemi a s ometi mes occurs .
Symptoms and Signs
Typi ca l l y, a n a l cohol bi nge l ea ds to vomi ti ng a nd the ces s a ti on of a l cohol or food i nta ke for 24 h. Duri ng thi s peri od of s ta rva ti on, vomi ti ng
conti nues a nd a bdomi na l pa i n devel ops , l ea di ng the pa ti ent to s eek medi ca l a ttenti on. Pa ncrea ti ti s ma y occur.
Diagnosis
Ca l cul a ti on of a ni on ga p
Excl us i on of other di s orders
Di a gnos i s requi res a hi gh i ndex of s us pi ci on; s i mi l a r s ymptoms i n a n a l cohol i c pa ti ent ma y res ul t from a cute pa ncrea ti ti s , metha nol or ethyl ene
gl ycol poi s oni ng, or di a beti c ketoa ci dos i s (DKA). In pa ti ents s us pected of ha vi ng a l cohol i c ketoa ci dos i s s erum el ectrol ytes (i ncl udi ng Mg), BUN
a nd crea ti ni ne, gl ucos e, ketones , a myl a s e, l i pa s e, a nd os mol a ri ty s houl d be mea s ured. Uri ne s houl d be tes ted for ketones . Pa ti ents who a ppea r
s i gni fi ca ntl y i l l a nd thos e wi th pos i ti ve ketones s houl d proba bl y ha ve ABG a nd s erum l a cta te mea s urement. The a bs ence of hypergl ycemi a ma kes
DKA i mproba bl e. Thos e wi th mi l d hypergl ycemi a ma y ha ve underl yi ng di a betes mel l i tus , whi ch ma y be recogni zed by el eva ted l evel s of
gl ycos yl a ted Hb (HbA1c). Typi ca l l a bora tory fi ndi ngs i ncl ude a hi gh a ni on ga p meta bol i c a ci dos i s , ketonemi a , a nd l ow l evel s of K, Mg, a nd P.
Detecti on of a ci dos i s ma y be compl i ca ted by concurrent meta bol i c a l ka l os i s due to vomi ti ng, res ul ti ng i n a rel a ti vel y norma l pH; the ma i n cl ue i s
the el eva ted a ni on ga p. If hi s tory does not rul e out toxi c a l cohol i nges ti on a s a ca us e of the el eva ted a ni on ga p, s erum metha nol a nd ethyl ene
gl ycol l evel s s houl d be obta i ned. Ca oxa l a te crys ta l s i n the uri ne a l s o s ugges ts ethyl ene gl ycol poi s oni ng. La cti c a ci d l evel s a re often el eva ted
beca us e of hypoperfus i on a nd the a l tered ba l a nce of reducti on a nd oxi da ti on rea cti ons i n the l i ver.
Treatment
IV thi a mi n a nd other vi ta mi ns pl us Mg
IV 5% dextros e i n 0.9% s a l i ne
Trea tment begi ns wi th a n IV i nfus i on of 5% dextros e i n 0.9% s a l i ne s ol uti on, preceded by thi a mi n 100 mg IV to prevent devel opment of Werni cke's
encepha l opa thy or Kors a koff's ps ychos i s . Ini ti a l IV fl ui ds s houl d conta i n a dded wa ter-s ol ubl e vi ta mi ns a nd Mg, wi th K repl a cement a s requi red.
Ketoa ci dos i s a nd GI s ymptoms us ua l l y res pond ra pi dl y. Us e of i ns ul i n i s a ppropri a te onl y i f there i s a ny ques ti on of a typi ca l DKA or i f
hypergl ycemi a > 300 mg/dL devel ops .
Hypoglycemia
Hypoglycemia unrelated to exogenous insulin therapy is an uncommon clinical syndrome characterized by low plasma glucose level, symptomatic sympathetic
nervous system stimulation, and CNS dysfunction. Many drugs and disorders cause it. Diagnosis requires blood tests done at the time of symptoms or during a 72h fast. Treatment is provision of glucose combined with treatment of the underlying disorder.
Mos t commonl y, s ymptoma ti c hypogl ycemi a i s a compl i ca ti on of drug trea tment of di a betes mel l i tus (DM). Ora l a nti hypergl ycemi cs or i ns ul i n ma y
be i nvol ved.
Symptoma ti c hypogl ycemi a unrel a ted to trea tment of DM i s rel a ti vel y ra re, i n pa rt beca us e the body ha s extens i ve counter-regul a tory mecha ni s ms
to compens a te for l ow bl ood gl ucos e l evel s . Gl uca gon a nd epi nephri ne l evel s s urge i n res pons e to a cute hypogl ycemi a a nd s eem to be the fi rs t
l i ne of defens e. Corti s ol a nd growth hormone l evel s a l s o i ncrea s e a cutel y a nd a re i mporta nt i n the recovery from prol onged hypogl ycemi a . The
thres hol d for rel ea s e of thes e hormones i s us ua l l y a bove tha t for hypogl ycemi c s ymptoms .
Etiology
Ca us es of phys i ol ogi c hypogl ycemi a ca n be cl a s s i fi ed a s
Rea cti ve (pos tpra ndi a l ) or fa s ti ng
Ins ul i n-medi a ted or non-i ns ul i n-medi a ted
Drug-i nduced or nondrug-i nduced
Ins ul i n-medi a ted ca us es i ncl ude exogenous a dmi ni s tra ti on of i ns ul i n or a n i ns ul i n s ecreta gogue a nd i ns ul i n-s ecreti ng tumors (i ns ul i noma s ). A
hel pful pra cti ca l cl a s s i fi ca ti on i s ba s ed on cl i ni ca l s ta tus : whether hypogl ycemi a occurs i n pa ti ents who a ppea r hea l thy or i l l . Wi thi n thes e
ca tegori es , ca us es of hypogl ycemi a ca n be di vi ded i nto drug-i nduced a nd other ca us es . Ps eudohypogl ycemi a occurs when proces s i ng of bl ood
s peci mens i n untrea ted tes t tubes i s del a yed a nd cel l s , s uch a s RBCs a nd l eukocytes (es peci a l l y i f i ncrea s ed, a s i n l eukemi a or pol ycythemi a ),
cons ume gl ucos e. Fa cti ti ous hypogl ycemi a i s true hypogl ycemi a i nduced by nonthera peuti c a dmi ni s tra ti on of s ul fonyl urea s or i ns ul i n.
Symptoms and Signs
The s urge i n a utonomi c a cti vi ty i n res pons e to l ow pl a s ma gl ucos e ca us es s wea ti ng, na us ea , wa rmth, a nxi ety, tremul ous nes s , pa l pi ta ti ons , a nd
pos s i bl y hunger a nd pa res thes i a s . Ins uffi ci ent gl ucos e s uppl y to the bra i n ca us es hea da che, bl urred or doubl e vi s i on, confus i on, di ffi cul ty
s pea ki ng, s ei zures , a nd coma . In control l ed s etti ngs , a utonomi c s ymptoms begi n a t or benea th a pl a s ma gl ucos e l evel of a bout 60 mg/dL (3.33
mmol /L), wherea s CNS s ymptoms occur a t or bel ow a gl ucos e l evel of a bout 50 mg/dL (2.78 mmol /L). However, s ymptoms s ugges ti ve of
hypogl ycemi a a re fa r more common tha n the condi ti on i ts el f. Mos t peopl e wi th gl ucos e l evel s a t thes e thres hol ds ha ve no s ymptoms , a nd mos t
peopl e wi th s ymptoms s ugges ti ve of hypogl ycemi a ha ve norma l gl ucos e concentra ti ons .
Diagnosis
Bl ood gl ucos e l evel correl a ted wi th cl i ni ca l fi ndi ngs
Res pons e to dextros e (or other s uga r) a dmi ni s tra ti on
Someti mes 72-h fa s t
Someti mes i ns ul i n, C-pepti de, a nd proi ns ul i n l evel s
In pri nci pl e, di a gnos i s requi res veri fi ca ti on tha t a l ow pl a s ma gl ucos e l evel (< 50 mg/dL [< 2.78 mmol /L]) exi s ts a t the ti me hypogl ycemi c s ymptoms
occur a nd tha t the s ymptoms a re res pons i ve to dextros e a dmi ni s tra ti on. If a pra cti ti oner i s pres ent when s ymptoms occur, bl ood s houl d be s ent
for gl ucos e tes ti ng. If gl ucos e i s norma l , hypogl ycemi a i s rul ed out a nd no further tes ti ng i s needed. If gl ucos e i s a bnorma l l y l ow, s erum i ns ul i n, Cpepti de, a nd proi ns ul i n mea s ured from the s a me tube ca n di s ti ngui s h i ns ul i n-medi a ted from non-i ns ul i n-medi a ted a nd fa cti ti ous from
phys i ol ogi c hypogl ycemi a a nd ca n obvi a te the need for further tes ti ng. Ins ul i n growth fa ctor 2 (IGF-2) l evel s ma y hel p i denti fy non-i s l et cel l (IGF-2
s ecreti ng) tumors , whi ch a re a n unus ua l ca us e of hypogl ycemi a .

In pra cti ce, however, i t i s unus ua l tha t pra cti ti oners a re pres ent when pa ti ents experi ence s ymptoms s ugges ti ve of hypogl ycemi a . Home gl ucos e
meters a re unrel i a bl e for qua nti fyi ng hypogl ycemi a , a nd there a re no cl ea r gl ycos yl a ted Hb (HbA1c) thres hol ds tha t di s ti ngui s h l ong-term
hypogl ycemi a from normogl ycemi a . So the need for more extens i ve di a gnos ti c tes ti ng i s ba s ed on the proba bi l i ty tha t a n underl yi ng di s order tha t
coul d ca us e hypogl ycemi a exi s ts gi ven a pa ti ent's cl i ni ca l a ppea ra nce a nd coexi s ti ng i l l nes s es .
A 72-h fa s t done i n a control l ed s etti ng i s the s ta nda rd for di a gnos i s . Pa ti ents dri nk onl y nonca l ori c, nonca ffei na ted bevera ges , a nd pl a s ma
gl ucos e i s mea s ured a t ba s el i ne, whenever s ymptoms occur, a nd q 4 to 6 h or q 1 to 2 h i f gl ucos e fa l l s bel ow 60 mg/dL (3.3 mmol /L). Serum i ns ul i n,
C-pepti de, a nd proi ns ul i n s houl d be mea s ured a t ti mes of hypogl ycemi a to di s ti ngui s h endogenous from exogenous (fa cti ti ous ) hypogl ycemi a .
The fa s t i s termi na ted a t 72 h i f the pa ti ent ha s experi enced no s ymptoms a nd gl ucos e rema i ns norma l , s ooner i f gl ucos e decrea s es to 45 mg/dL
( 2.5 mmol /L) i n the pres ence of hypogl ycemi c s ymptoms . End-of-fa s t mea s urements i ncl ude -hydroxybutyra te (whi ch s houl d be l ow i n
i ns ul i noma ), s erum s ul fonyl urea to detect drug-i nduced hypogl ycemi a , a nd pl a s ma gl ucos e a fter IV gl uca gon i njecti on to detect a n i ncrea s e
cha ra cteri s ti c of i ns ul i noma . Sens i ti vi ty, s peci fi ci ty, a nd predi cti ve va l ues for detecti ng hypogl ycemi a by thi s protocol ha ve not been reported.
There i s no defi ni ti ve l ower l i mi t of gl ucos e tha t unequi voca l l y defi nes pa thol ogi c hypogl ycemi a duri ng a 72-h fa s t. Norma l women tend to ha ve
l ower fa s ti ng gl ucos e l evel s tha n men a nd ma y ha ve gl ucos e l evel s a s l ow a s 30 mg/dL wi thout s ymptoms . If s ymptoma ti c hypogl ycemi a ha s not
occurred by 72 h, the pa ti ent s houl d exerci s e vi gorous l y for a bout 30 mi n. If hypogl ycemi a s ti l l does not occur, i ns ul i noma i s es s enti a l l y excl uded
a nd further tes ti ng i s genera l l y not i ndi ca ted.
Treatment
Ora l s uga r or IV dextros e
Someti mes pa rentera l gl uca gon
Immedi a te trea tment of hypogl ycemi a i nvol ves provi s i on of gl ucos e. Pa ti ents a bl e to ea t or dri nk ca n dri nk jui ces , s ucros e wa ter, or gl ucos e
s ol uti ons ; ea t ca ndy or other foods ; or chew on gl ucos e ta bl ets when s ymptoms occur. Infa nts a nd younger chi l dren ma y be gi ven 10% dextros e
s ol uti on 2 to 5 mL/kg IV bol us . Adul ts a nd ol der chi l dren una bl e to ea t or dri nk ca n be gi ven gl uca gon 0.5 (< 20 kg) or 1 mg ( 20 kg) s c or IM or 50%
dextros e 50 to 100 mL IV bol us , wi th or wi thout a conti nuous i nfus i on of 5 to 10% dextros e s ol uti on s uffi ci ent to res ol ve s ymptoms . The effi ca cy of
gl uca gon depends on the s i ze of hepa ti c gl ycogen s tores ; gl uca gon ha s l i ttl e effect on pl a s ma gl ucos e i n pa ti ents who ha ve been fa s ti ng or who
a re hypogl ycemi c for l ong peri ods .
Underl yi ng di s orders ca us i ng hypogl ycemi a mus t a l s o be trea ted. Is l et cel l a nd non-i s l et cel l tumors mus t fi rs t be l oca l i zed, then removed by
enucl ea ti on or pa rti a l pa ncrea tectomy; a bout 6% recur wi thi n 10 yr. Di a zoxi de a nd octreoti de ca n be us ed to control s ymptoms whi l e the pa ti ent i s
a wa i ti ng s urgery or when a pa ti ent refus es or i s not a ca ndi da te for a procedure. Is l et cel l hypertrophy i s mos t often a di a gnos i s of excl us i on a fter
a n i s l et cel l tumor i s s ought but not i denti fi ed. Drugs tha t ca us e hypogl ycemi a , i ncl udi ng a l cohol , mus t be s topped. Trea tment of heredi ta ry a nd
endocri ne di s orders ; hepa ti c, rena l , a nd hea rt fa i l ure; a nd s eps i s a nd s hock a re des cri bed el s ewhere.
Chapter 100. Lipid Disorders

Introduction
Li pi ds a re fa ts tha t a re ei ther a bs orbed from food or s ynthes i zed by the l i ver. Tri gl yceri des (TGs ) a nd chol es terol contri bute mos t to di s ea s e,
a l though a l l l i pi ds a re phys i ol ogi ca l l y i mporta nt. The pri ma ry functi on of TGs i s to s tore energy i n a di pocytes a nd mus cl e cel l s ; chol es terol i s a
ubi qui tous cons ti tuent of cel l membra nes , s teroi ds , bi l e a ci ds , a nd s i gna l i ng mol ecul es . Al l l i pi ds a re hydrophobi c a nd mos tl y i ns ol ubl e i n bl ood,
s o they requi re tra ns port wi thi n hydrophi l i c, s pheri ca l s tructures ca l l ed l i poprotei ns , whi ch pos s es s s urfa ce protei ns (a poprotei ns , or
a pol i poprotei ns ) tha t a re cofa ctors a nd l i ga nds for l i pi d-proces s i ng enzymes (s ee
Ta bl e 100-1). Li poprotei ns a re cl a s s i fi ed by s i ze a nd dens i ty (defi ned a s the ra ti o of l i pi d to protei n) a nd a re i mporta nt beca us e hi gh l evel s of
l ow-dens i ty l i poprotei ns (LDL) a nd l ow l evel s of hi gh-dens i ty l i poprotei ns (HDL) a re ma jor ri s k fa ctors for a theros cl eroti c hea rt di s ea s e (s ee p.
2081).
Physiology
Pa thwa y defects i n l i poprotei n s ynthes i s , proces s i ng, a nd cl ea ra nce ca n l ea d to a ccumul a ti on of a therogeni c l i pi ds i n pl a s ma a nd endothel i um.
Exogenous (dietary) lipid metabolism: Over 95% of di eta ry l i pi ds a re TGs ; the res t a re phos phol i pi ds , free fa tty a ci ds (FFAs ), chol es terol (pres ent i n
foods a s es teri fi ed chol es terol ), a nd fa t-s ol ubl e vi ta mi ns . Di eta ry TGs a re di ges ted i n the s toma ch a nd duodenum i nto monogl yceri des (MGs ) a nd
FFAs by ga s tri c l i pa s e, emul s i fi ca ti on from vi gorous s toma ch peri s ta l s i s , a nd pa ncrea ti c l i pa s e. Di eta ry chol es terol es ters a re de-es teri fi ed i nto
free chol es terol by thes e s a me mecha ni s ms . MGs , FFAs , a nd free chol es terol a re then s ol ubi l i zed i n the i ntes ti ne by bi l e a ci d mi cel l es , whi ch
s huttl e them to i ntes ti na l vi l l i for a bs orpti on. Once a bs orbed i nto the enterocyte, they a re rea s s embl ed i nto TGs a nd pa cka ged wi th chol es terol
i nto chyl omi crons , the l a rges t l i poprotei ns .
[Table 100-1. Ma jor Apoprotei ns a nd Enzymes Importa nt to Li pi d Meta bol i s m]
Chylomicrons tra ns port di eta ry TGs a nd chol es terol from wi thi n enterocytes through l ympha ti cs i nto the ci rcul a ti on. In the ca pi l l a ri es of a di pos e
a nd mus cl e ti s s ue, a poprotei n C-II (a po C-II) on the chyl omi cron a cti va tes endothel i a l l i poprotei n l i pa s e (LPL) to convert 90% of chyl omi cron TG to
fa tty a ci ds a nd gl ycerol , whi ch a re ta ken up by a di pocytes a nd mus cl e cel l s for energy us e or s tora ge. Chol es terol -ri ch chyl omi cron remna nts then
ci rcul a te ba ck to the l i ver, where they a re cl ea red i n a proces s medi a ted by a poprotei n E (a po E).
Endogenous lipid metabolism: Li poprotei ns s ynthes i zed by the l i ver tra ns port endogenous TGs a nd chol es terol . Li poprotei ns ci rcul a te through the
bl ood conti nuous l y unti l the TGs they conta i n a re ta ken up by peri phera l ti s s ues or the l i poprotei ns thems el ves a re cl ea red by the l i ver. Fa ctors
tha t s ti mul a te hepa ti c l i poprotei n s ynthes i s genera l l y l ea d to el eva ted pl a s ma chol es terol a nd TG l evel s .
Very-low-density lipoproteins (VLDL) conta i n a poprotei n B-100 (a po B), a re s ynthes i zed i n the l i ver, a nd tra ns port TGs a nd chol es terol to peri phera l
ti s s ues . VLDL i s the wa y the l i ver exports exces s TGs deri ved from pl a s ma FFA a nd chyl omi cron remna nts ; VLDL s ynthes i s i ncrea s es wi th i ncrea s es
i n i ntra hepa ti c FFA, s uch a s occur wi th hi gh-fa t di ets a nd when exces s a di pos e ti s s ue rel ea s es FFAs di rectl y i nto the ci rcul a ti on (eg, i n obes i ty,
uncontrol l ed di a betes mel l i tus ). Apo C-II on the VLDL s urfa ce a cti va tes endothel i a l LPL to brea k down TGs i nto FFAs a nd gl ycerol , whi ch a re ta ken
up by cel l s .
Intermediate-density lipoproteins (IDL) a re the product of LPL proces s i ng of VLDL a nd chyl omi crons . IDL a re chol es terol -ri ch VLDL a nd chyl omi cron
remna nts tha t a re ei ther cl ea red by the l i ver or meta bol i zed by hepa ti c l i pa s e i nto LDL, whi ch reta i ns a po B.
Low-density lipoproteins (LDL), the products of VLDL a nd IDL meta bol i s m, a re the mos t chol es terol -ri ch of a l l l i poprotei ns . About 40 to 60% of a l l LDL
a re cl ea red by the l i ver i n a proces s medi a ted by a po B a nd hepa ti c LDL receptors . The res t a re ta ken up by ei ther hepa ti c LDL or nonhepa ti c nonLDL (s ca venger) receptors . Hepa ti c LDL receptors a re down-regul a ted by del i very of chol es terol to the l i ver by chyl omi crons a nd by i ncrea s ed di eta ry
s a tura ted fa t; they ca n be up-regul a ted by decrea s ed di eta ry fa t a nd chol es terol . Nonhepa ti c s ca venger receptors , mos t nota bl y on ma cropha ges ,
ta ke up exces s oxi di zed ci rcul a ti ng LDL not proces s ed by hepa ti c receptors . Monocytes ri ch i n oxi di zed LDL mi gra te i nto the s ubendothel i a l s pa ce
a nd become ma cropha ges ; thes e ma cropha ges then ta ke up more oxi di zed LDL a nd form foa m cel l s wi thi n a theros cl eroti c pl a ques (s ee p. 2081).
There a re 2 forms of LDL: l a rge, buoya nt a nd s ma l l , dens e LDL. Sma l l , dens e LDL i s es peci a l l y ri ch i n chol es terol es ters , a s s oci a ted wi th meta bol i c
di s turba nces s uch a s hypertri gl yceri demi a a nd i ns ul i n res i s ta nce, a nd es peci a l l y a therogeni c. The i ncrea s ed a therogeni ci ty of s ma l l , dens e LDL
deri ves from l es s effi ci ent hepa ti c LDL receptor bi ndi ng, l ea di ng to prol onged ci rcul a ti on a nd expos ure to endothel i um a nd i ncrea s ed oxi da ti on.
High-density lipoproteins (HDL) a re i ni ti a l l y chol es terol -free l i poprotei ns tha t a re s ynthes i zed i n both enterocytes a nd the l i ver. HDL meta bol i s m i s
compl ex, but HDL's overa l l rol e i s to obta i n chol es terol from peri phera l ti s s ues a nd other l i poprotei ns a nd tra ns port i t to where i t i s needed mos t
other cel l s , other l i poprotei ns (us i ng chol es teryl es ter tra ns fer protei n [CETP]), a nd the l i ver (for cl ea ra nce). Its overa l l effect i s a nti -a therogeni c.
Effl ux of free chol es terol from cel l s i s medi a ted by ATP-bi ndi ng ca s s ette tra ns porter A1 (ABCA1), whi ch combi nes wi th a poprotei n A-I (a po A-I) to
produce na s cent HDL. Free chol es terol i n na s cent HDL i s then es teri fi ed by the enzyme l eci thi n-chol es terol a cyl tra ns fera s e (LCAT), produci ng
ma ture HDL. Bl ood HDL l evel s ma y not compl etel y repres ent revers e chol es terol tra ns port.
Lipoprotein (a) [Lp (a)] i s LDL tha t conta i ns a poprotei n(a ), cha ra cteri zed by 5 cys tei ne-ri ch regi ons ca l l ed kri ngl es . One of thes e regi ons i s
homol ogous wi th pl a s mi nogen a nd i s thought to competi ti vel y i nhi bi t fi bri nol ys i s a nd thus predi s pos e to thrombus . The Lp(a ) ma y a l s o di rectl y
promote a theros cl eros i s . The meta bol i c pa thwa ys of Lp(a ) producti on a nd cl ea ra nce a re not wel l cha ra cteri zed, but l evel s i ncrea s e i n pa ti ents
wi th di a beti c nephropa thy.
Dyslipidemia
(Hyperl i pi demi a )
Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein level that contributes to the development of
atherosclerosis. Causes may be primary (genetic) or secondary. Diagnosis is by measuring plasma levels of total cholesterol, TGs, and individual lipoproteins.
Treatment is dietary changes, exercise, and lipid-lowering drugs.
There i s no na tura l cutoff between norma l a nd a bnorma l l i pi d l evel s beca us e l i pi d mea s urements a re conti nuous . A l i nea r rel a ti on proba bl y
exi s ts between l i pi d l evel s a nd ca rdi ova s cul a r ri s k, s o ma ny peopl e wi th "norma l " chol es terol l evel s benefi t from a chi evi ng s ti l l l ower l evel s .
Cons equentl y, there a re no numeri c defi ni ti ons of dys l i pi demi a ; the term i s a ppl i ed to l i pi d l evel s for whi ch trea tment ha s proved benefi ci a l .
Proof of benefi t i s s tronges t for l oweri ng el eva ted l ow-dens i ty l i poprotei n (LDL) l evel s . In the overa l l popul a ti on, evi dence i s l es s s trong for a
benefi t from l oweri ng el eva ted TG a nd i ncrea s i ng l ow hi gh-dens i ty l i poprotei n (HDL) l evel s , i n pa rt beca us e el eva ted TG a nd l ow HDL l evel s a re
more predi cti ve of ca rdi ova s cul a r ri s k i n women tha n i n men.
HDL l evel s do not a l wa ys predi ct ca rdi ova s cul a r ri s k. For exa mpl e, hi gh HDL l evel s ca us ed by s ome geneti c di s orders ma y not protect a ga i ns t
ca rdi ova s cul a r di s orders , a nd l ow HDL l evel s ca us ed by s ome geneti c di s orders ma y not i ncrea s e the ri s k of ca rdi ova s cul a r di s orders . Al though
HDL l evel s predi ct ca rdi ova s cul a r ri s k i n the overa l l popul a ti on, the i ncrea s ed ri s k ma y be ca us ed by other fa ctors , s uch a s a ccompa nyi ng l i pi d a nd
meta bol i c a bnorma l i ti es , ra ther tha n the HDL l evel i ts el f.
Classification
Dys l i pi demi a s were tra di ti ona l l y cl a s s i fi ed by pa tterns of el eva ti on i n l i pi ds a nd l i poprotei ns (Fredri cks on phenotypes ee
Ta bl e 100-2). A more pra cti ca l s ys tem ca tegori zes dys l i pi demi a s a s pri ma ry or s econda ry a nd cha ra cteri zes them by i ncrea s es i n chol es terol onl y
(pure or i s ol a ted hyperchol es terol emi a ), i ncrea s es i n TGs onl y (pure or i s ol a ted hypertri gl yceri demi a ), or i ncrea s es i n both chol es terol a nd TGs
(mi xed or combi ned hyperl i pi demi a s ). Thi s s ys tem does not ta ke i nto a ccount s peci fi c l i poprotei n a bnorma l i ti es (eg, l ow HDL or hi gh LDL) tha t ma y
contri bute to di s ea s e des pi te norma l chol es terol a nd TG l evel s .
Etiology
Pri ma ry (geneti c) ca us es a nd s econda ry (l i fes tyl e a nd other) ca us es contri bute to dys l i pi demi a s i n va ryi ng degrees . For exa mpl e, i n fa mi l i a l
combi ned hyperl i pi demi a , expres s i on ma y occur onl y i n the pres ence of s i gni fi ca nt s econda ry ca us es .
Primary causes: Pri ma ry ca us es a re s i ngl e or mul ti pl e gene muta ti ons tha t res ul t i n ei ther overproducti on or defecti ve cl ea ra nce of TG a nd LDL
chol es terol , or i n underproducti on or exces s i ve cl ea ra nce of HDL (s ee
Ta bl e 100-3). Pri ma ry di s orders , the mos t common ca us e of dys l i pi demi a i n chi l dren, do not ca us e a l a rge percenta ge of ca s es i n a dul ts . The
na mes of ma ny refl ect a n ol d nomencl a ture i n whi ch l i poprotei ns were detected a nd di s ti ngui s hed by how they s epa ra ted i nto (HDL) a nd (LDL)
ba nds on el ectrophoreti c gel s .
[Table 100-2. Li poprotei n Pa tterns (Fredri cks on Phenotypes )]
Secondary causes: Seconda ry ca us es contri bute to mos t ca s es of dys l i pi demi a i n a dul ts . The mos t i mporta nt s econda ry ca us e i n devel oped
countri es i s a s edenta ry l i fes tyl e wi th exces s i ve di eta ry i nta ke of s a tura ted fa t, chol es terol , a nd tra ns fa ts . Tra ns fa ts a re pol yuns a tura ted or
monouns a tura ted fa tty a ci ds to whi ch hydrogen a toms ha ve been a dded; they a re commonl y us ed i n ma ny proces s ed foods a nd a re a s a therogeni c
a s s a tura ted fa t. Other common s econda ry ca us es i ncl ude di a betes mel l i tus , a l cohol overus e, chroni c ki dney di s ea s e, hypothyroi di s m, pri ma ry
bi l i a ry ci rrhos i s a nd other chol es ta ti c l i ver di s ea s es , a nd drugs , s uch a s thi a zi des , -bl ockers , reti noi ds , hi ghl y a cti ve a nti retrovi ra l a gents ,
es trogen a nd proges ti ns , a nd gl ucocorti coi ds .
Diabetes i s a n es peci a l l y s i gni fi ca nt s econda ry ca us e beca us e pa ti ents tend to ha ve a n a therogeni c combi na ti on of hi gh TGs ; hi gh s ma l l , dens e
LDL fra cti ons ; a nd l ow HDL (di a beti c dys l i pi demi a , hypertri gl yceri demi c hypera po B). Pa ti ents wi th type 2 di a betes a re es peci a l l y a t ri s k. The
combi na ti on ma y be a cons equence of obes i ty, poor control of di a betes , or both, whi ch ma y i ncrea s e ci rcul a ti ng free fa tty a ci ds (FFAs ), l ea di ng to
i ncrea s ed hepa ti c very-l ow-dens i ty l i poproti en (VLDL) producti on. TG-ri ch VLDL then tra ns fers TG a nd chol es terol to LDL a nd HDL, promoti ng
forma ti on of TG-ri ch, s ma l l , dens e LDL a nd cl ea ra nce of TG-ri ch HDL. Di a beti c dys l i pi demi a i s often exa cerba ted by the i ncrea s ed ca l ori c i nta ke
a nd phys i ca l i na cti vi ty tha t cha ra cteri ze the l i fes tyl es of s ome pa ti ents wi th type 2 di a betes . Women wi th di a betes ma y be a t s peci a l ri s k of
ca rdi a c di s ea s e from thi s form.
[Table 100-3. Geneti c (Pri ma ry) Dys l i pi demi a s ]
Symptoms and Signs
Dys l i pi demi a i ts el f us ua l l y ca us es no s ymptoms but ca n l ea d to s ymptoma ti c va s cul a r di s ea s e, i ncl udi ng corona ry a rtery di s ea s e (CAD) a nd
peri phera l a rteri a l di s ea s e. Hi gh l evel s of TGs (> 1000 mg/dL [> 11.3 mmol /L]) ca n ca us e a cute pa ncrea ti ti s . Hi gh l evel s of LDL ca n ca us e eyel i d
xa nthel a s ma s ; a rcus cornea e; a nd tendi nous xa nthoma s a t the Achi l l es , el bow, a nd knee tendons a nd over meta ca rpopha l a ngea l joi nts . Pa ti ents
wi th the homozygous form of fa mi l i a l hyperchol es terol emi a ma y ha ve the a bove fi ndi ngs pl us pl a na r or cuta neous xa nthoma s . Pa ti ents wi th
s evere el eva ti ons of TGs ca n ha ve erupti ve xa nthoma s over the trunk, ba ck, el bows , buttocks , knees , ha nds , a nd feet. Pa ti ents wi th the ra re
dys beta l i poprotei nemi a ca n ha ve pa l ma r a nd tuberous xa nthoma s .
Severe hypertri gl yceri demi a (> 2000 mg/dL [> 22.6 mmol /L]) ca n gi ve reti na l a rteri es a nd vei ns a crea my whi te a ppea ra nce (l i pemi a reti na l i s ).
Extremel y hi gh l i pi d l evel s a l s o gi ve a l a ctes cent (mi l ky) a ppea ra nce to bl ood pl a s ma . Symptoms ca n i ncl ude pa res thes i a s , dyps nea , a nd
confus i on.
Diagnosis
Serum l i pi d profi l e (mea s ured tota l chol es terol , TG, a nd HDL chol es terol a nd ca l cul a ted LDL chol es terol a nd VLDL)
Dys l i pi demi a i s s us pected i n pa ti ents wi th cha ra cteri s ti c phys i ca l fi ndi ngs or compl i ca ti ons of dys l i pi demi a (eg, a theros cl eroti c di s ea s e). Pri ma ry
l i pi d di s orders a re s us pected when pa ti ents ha ve phys i ca l s i gns of dys l i pi demi a , ons et of prema ture a theros cl eroti c di s ea s e (a t < 60 yr), a fa mi l y
hi s tory of a theros cl eroti c di s ea s e, or s erum chol es terol > 240 mg/dL (> 6.2 mmol /L). Dys l i pi demi a i s di a gnos ed by mea s uri ng s erum l i pi ds . Routi ne
mea s urements (l i pi d profi l e) i ncl ude tota l chol es terol (TC), TGs , HDL chol es terol , a nd LDL chol es terol .
Lipid profile measurement: TC, TGs , a nd HDL chol es terol a re mea s ured di rectl y; TC a nd TG va l ues refl ect chol es terol a nd TGs i n a l l ci rcul a ti ng
l i poprotei ns , i ncl udi ng chyl omi crons , VLDL, i ntermedi a te-dens i ty l i poprotei n (IDL), LDL, a nd HDL. TC va l ues va ry by 10% a nd TGs by up to 25% da y-toda y even i n the a bs ence of a di s order. TC a nd HDL chol es terol ca n be mea s ured i n the non-fa s ti ng s ta te, but mos t pa ti ents s houl d ha ve a l l l i pi ds
mea s ured whi l e fa s ti ng for ma xi mum a ccura cy a nd cons i s tency.

Tes ti ng s houl d be pos tponed unti l a fter res ol uti on of a cute i l l nes s , beca us e TGs i ncrea s e a nd chol es terol l evel s decrea s e i n i nfl a mma tory s ta tes .
Li pi d profi l es ca n va ry for a bout 30 da ys a fter a n a cute MI; however, res ul ts obta i ned wi thi n 24 h a fter MI a re us ua l l y rel i a bl e enough to gui de
i ni ti a l l i pi d-l oweri ng thera py.
LDL chol es terol va l ues a re mos t often ca l cul a ted a s the a mount of chol es terol not conta i ned i n HDL a nd VLDL. VLDL i s es ti ma ted by TG 5 beca us e
the chol es terol concentra ti on i n VLDL pa rti cl es i s us ua l l y one fi fth of the tota l l i pi d i n the pa rti cl e. Thus , LDL chol es terol = TC - [HDL chol es terol +
(TGs 5)] (Fri edewa l d formul a ). Thi s ca l cul a ti on i s va l i d onl y when TGs a re < 400 mg/dL a nd pa ti ents a re fa s ti ng, beca us e ea ti ng i ncrea s es TGs .
The ca l cul a ted LDL chol es terol va l ue i ncorpora tes mea s ures of a l l non-HDL, nonchyl omi cron chol es terol , i ncl udi ng tha t i n IDL a nd l i poprotei n (a )
[Lp(a )]. LDL ca n a l s o be mea s ured di rectl y us i ng pl a s ma ul tra centri fuga ti on, whi ch s epa ra tes chyl omi crons a nd VLDL fra cti ons from HDL a nd LDL,
a nd by a n i mmunoa s s a y method. Di rect mea s urement ma y be us eful i n s ome pa ti ents wi th el eva ted TGs , but thes e di rect mea s urements a re not
routi nel y neces s a ry. The rol e of a poprotei n B tes ti ng i s under s tudy beca us e va l ues refl ect a l l non-HDL chol es terol (i n VLDL, VLDL remna nts , IDL,
a nd LDL) a nd ma y be more predi cti ve of CAD ri s k tha n LDL a l one.
Other tests: Pa ti ents wi th prema ture a theros cl eroti c ca rdi ova s cul a r di s ea s e, ca rdi ova s cul a r di s ea s e wi th norma l or nea r-norma l l i pi d l evel s , or
hi gh LDL l evel s refra ctory to drug thera py s houl d proba bl y ha ve Lp(a ) l evel s mea s ured. Lp(a ) l evel s ma y a l s o be di rectl y mea s ured i n pa ti ents wi th
borderl i ne hi gh LDL chol es terol l evel s to determi ne whether drug thera py i s wa rra nted. C-rea cti ve protei n a nd homocys tei ne mea s urement ma y be
cons i dered i n the s a me popul a ti ons .
Secondary causes: Tes ts for s econda ry ca us es of dys l i pi demi a i ncl udi ng mea s urements of fa s ti ng gl ucos e, l i ver enzymes , crea ti ni ne, thyroi ds ti mul a ti ng hormone (TSH), a nd uri na ry protei ns houl d be done i n mos t pa ti ents wi th newl y di a gnos ed dys l i pi demi a a nd when a component of
the l i pi d profi l e ha s i nexpl i ca bl y cha nged for the wors e.
Screening: A fa s ti ng l i pi d profi l e (TC, TGs , HDL chol es terol , a nd ca l cul a ted LDL chol es terol ) s houl d be obta i ned i n a l l a dul ts 20 yr a nd s houl d be
repea ted every 5 yr. Li pi d mea s urement s houl d be a ccompa ni ed by a s s es s ment of other ca rdi ova s cul a r ri s k fa ctors , defi ned a s
Di a betes mel l i tus
Ci ga rette us e
Hypertens i on
Fa mi l y hi s tory of CAD i n a ma l e 1s t-degree rel a ti ve before a ge 55 or a fema l e 1s t-degree rel a ti ve before a ge 65
A defi ni te a ge a fter whi ch pa ti ents no l onger requi re s creeni ng ha s not been es ta bl i s hed, but evi dence s upports s creeni ng of pa ti ents i nto thei r
80s , es peci a l l y i n the pres ence of a theros cl eroti c ca rdi ova s cul a r di s ea s e.
Indi ca ti ons for s creeni ng pa ti ents < 20 yr a re a theros cl eroti c ri s k fa ctors , s uch a s di a betes , hypertens i on, ci ga rette s moki ng, a nd obes i ty;
prema ture CAD i n a pa rent, gra ndpa rent, or s i bl i ng; or a chol es terol l evel > 240 mg/dL (> 6.2 mmol /L) or known dys l i pi demi a i n a pa rent. If
i nforma ti on on rel a ti ves i s una va i l a bl e, a s i n the ca s e of a dopted chi l dren, s creeni ng i s a t the di s creti on of the hea l th ca re pra cti ti oner.
Pa ti ents wi th a n extens i ve fa mi l y hi s tory of hea rt di s ea s e s houl d a l s o be s creened by mea s uri ng Lp(a ) l evel s .
Treatment
Ri s k a s s es s ment by expl i ci t cri teri a
Li fes tyl e cha nges (eg, exerci s e, di eta ry modi fi ca ti on)
For hi gh LDL chol es terol , s ta ti ns , s ometi mes bi l e a ci d s eques tra nts , ezeti mi be, a nd other mea s ures
For hi gh TG or l ow HDL chol es terol , ni a ci n, fi bra tes , a nd s ometi mes other mea s ures
General principles: Trea tment i s i ndi ca ted for a l l pa ti ents wi th ca rdi ova s cul a r di s ea s e (s econda ry preventi on) a nd for s ome wi thout (pri ma ry
preventi on). The Na ti ona l Ins ti tutes of Hea l th's Na ti ona l Chol es terol Educa ti on Progra m (NCEP) Adul t Trea tment Pa nel III (ATPIII) gui del i nes a re
the mos t common reference for deci di ng whi ch a dul ts s houl d be trea ted (s ee
Ta bl es 100-4 a nd
100-5). The gui del i nes focus pri ma ri l y on reduci ng el eva ted LDL chol es terol l evel s a nd s econda ri l y on trea ti ng hi gh TGs , l ow HDL, a nd meta bol i c
s yndrome (s ee p. 64). An a l terna te trea tment gui de (the Sheffi el d ta bl e) us es TC:HDL ra ti os combi ned wi th pres ence of CAD ri s k fa ctors to predi ct
ca rdi ova s cul a r ri s k, but thi s a pproa ch proba bl y l ea ds to undertrea tment.
Trea tment of chi l dren i s controvers i a l ; di eta ry cha nges ma y be di ffi cul t to i mpl ement, a nd no da ta s ugges t tha t l oweri ng l i pi d l evel s i n chi l dhood
effecti vel y prevents hea rt di s ea s e i n a dul thood. Moreover, the s a fety a nd effecti venes s of l ong-term l i pi d-l oweri ng trea tment a re ques ti ona bl e.
Neverthel es s , the Ameri ca n Aca demy of Pedi a tri cs (AAP) recommends trea tment for s ome chi l dren who ha ve el eva ted LDL chol es terol l evel s .
Trea tment opti ons depend on the s peci fi c l i pi d a bnorma l i ty, a l though di fferent l i pi d a bnorma l i ti es often coexi s t. In s ome pa ti ents , a s i ngl e
a bnorma l i ty ma y requi re s evera l thera pi es ; i n others , a s i ngl e trea tment ma y be a dequa te for s evera l a bnorma l i ti es . Trea tment s houl d a l wa ys
i ncl ude trea tment of hypertens i on a nd di a betes , s moki ng ces s a ti on, a nd i n pa ti ents
[Table 100-4. Na ti ona l Chol es terol Educa ti on Progra m Adul t Trea tment Pa nel III Approa ch to Dys l i pi demi a s ]
wi th a 10-yr ri s k of MI or dea th from CAD of 10% (a s determi ned from the Fra mi ngha m ta bl es s ee
Ta bl es 100-6 a nd
100-7), l ow-dos e da i l y a s pi ri n. In genera l , trea tment opti ons for men a nd women a re the s a me.
Elevated LDL cholesterol: In adults, ATPIII gui del i nes recommend trea tment for thos e wi th a ny of the fol l owi ng:
El eva ted LDL chol es terol l evel s a nd a hi s tory of CAD
Condi ti ons tha t confer a ri s k of future ca rdi a c events s i mi l a r to tha t of CAD i ts el f (CAD equi va l ents , defi ned a s di a betes mel l i tus , a bdomi na l
a orti c a neurys m, peri phera l a rteri a l di s ea s e, a nd s ymptoma ti c ca roti d a rtery di s ea s e)
2 CAD ri s k fa ctors
ATPIII gui del i nes recommend tha t thes e pa ti ents ha ve LDL chol es terol l evel s l owered to < 100 mg/dL, but a ccumul a ti ng evi dence
[Table 100-5. Ncep Adul t Trea tment Pa nel III Gui del i nes for Trea tment of Hyperl i pi demi a ]
s ugges ts tha t thi s ta rget ma y be too hi gh a nd a ta rget LDL chol es terol < 70 mg/dL i s a n opti on for pa ti ents a t very hi gh ri s k (eg, pa ti ents wi th known
CAD a nd di a betes , other poorl y control l ed ri s k fa ctors , meta bol i c s yndrome, or a cute corona ry s yndrome). When drugs a re us ed, a dos e provi di ng a t
l ea s t a 30 to 40% decrea s e i n LDL chol es terol i s des i ra bl e (s ee
Ta bl e 100-8).
For children, the AAP recommends di eta ry trea tment for chi l dren wi th LDL chol es terol > 110 mg/dL. Drug thera py i s recommended for chi l dren > 8 yr
a nd wi th ei ther of the fol l owi ng:
Poor res pons e to di eta ry thera py, LDL chol es terol 190 mg/dL, a nd no fa mi l y hi s tory of prema ture ca rdi ova s cul a r di s ea s e
LDL chol es terol 160 mg/dL a nd a fa mi l y hi s tory of prema ture ca rdi ova s cul a r di s ea s e or 2 ri s k fa ctors for prema ture ca rdi ova s cul a r di s ea s e
Chi l dhood ri s k fa ctors bes i des fa mi l y hi s tory a nd di a betes i ncl ude ci ga rette s moki ng, hypertens i on, l ow HDL chol es terol (< 35 mg/dL), obes i ty, a nd
phys i ca l i na cti vi ty.
Trea tment opti ons to l ower LDL chol es terol i n a l l a ge groups i ncl ude l i fes tyl e cha nges (di et a nd exerci s e), drugs , di eta ry s uppl ements , procedura l
i nterventi ons , a nd experi menta l thera pi es . Ma ny of thes e opti ons a re a l s o effecti ve for trea ti ng other l i pi d a bnorma l i ti es . Exerci s e l owers LDL
chol es terol i n s ome peopl e; i t i s a l s o es s enti a l to ma i nta i n i dea l body wei ght. Di eta ry cha nges a nd exerci s e s houl d be the i ni ti a l a pproa ch
whenever fea s i bl e.
Lifestyle changes ca n i nvol ve di et a nd exerci s e. Di eta ry cha nges i ncl ude decrea s i ng i nta ke of s a tura ted fa ts a nd chol es terol ; i ncrea s i ng the
proporti on of di eta ry fi ber, a nd compl ex ca rbohydra tes ; a nd ma i nta i ni ng i dea l body wei ght. Referra l to a di eti ti a n i s often us eful , es peci a l l y for
ol der peopl e. The l ength
[Table 100-6. Fra mi ngha m Ri s k Ta bl es for Men]
of ti me for whi ch l i fes tyl e cha nges s houl d be a ttempted before begi nni ng l i pi d-l oweri ng drugs i s controvers i a l . In pa ti ents a t a vera ge or l ow
ca rdi ova s cul a r ri s k, 3 to 6 mo i s rea s ona bl e. Genera l l y, 2 to 3 vi s i ts wi th a pa ti ent over 2 to 3 mo a re s uffi ci ent to a s s es s moti va ti on a nd
a dherence.
Drugs a re the next s tep when l i fes tyl e cha nges a re not effecti ve. However, for pa ti ents wi th extremel y el eva ted LDL chol es terol (> 200 mg/dL [> 5.2
mmol /L]) a nd thos e a t hi gh ca rdi ova s cul a r ri s k, drug thera py s houl d a ccompa ny di et a nd exerci s e from the s ta rt.
Statins a re the drugs a nd pos s i bl y trea tment of choi ce for LDL chol es terol reducti on; they demons tra bl y reduce ca rdi ova s cul a r morta l i ty. Sta ti ns
i nhi bi t hydroxymethyl gl uta ryl CoA reducta s e, a key enzyme i n chol es terol s ynthes i s , l ea di ng to up-regul a ti on of LDL receptors a nd i ncrea s ed LDL
cl ea ra nce. They reduce LDL chol es terol by up to 60% a nd produce s ma l l i ncrea s es i n HDL a nd modes t decrea s es i n TGs . Sta ti ns a l s o s eem to
decrea s e i ntra a rteri a l i nfl a mma ti on, s ys temi c i nfl a mma ti on, or both by s ti mul a ti ng producti on of endothel i a l ni tri c oxi de a nd ma y ha ve other
benefi ci a l effects . Advers e effects a re uncommon but i ncl ude l i ver enzyme el eva ti ons a nd myos i ti s or rha bdomyol ys i s . Mus cl e toxi ci ty wi thout
enzyme el eva ti on ha s a l s o been reported. Advers e effects a re more common a mong ol der pa ti ents , pa ti ents wi th s evera l di s orders , a nd pa ti ents
ta ki ng s evera l drugs . In s ome pa ti ents , cha ngi ng from one s ta ti n to a nother or l oweri ng the dos e rel i eves the probl em. Mus cl e toxi ci ty s eems to be
mos t common when s ome of the s ta ti ns a re us ed wi th drugs tha t i nhi bi t cytochrome P3A4 (eg, ma crol i de a nti bi oti cs , a zol e a nti funga l s ,
cycl os pori ne) a nd wi th fi bra tes , es peci a l l y gemfi brozi l . Properti es of s ta ti ns di ffer
[Table 100-7. Fra mi ngha m Ri s k Ta bl es for Women]
s l i ghtl y by drug, a nd the choi ce of drug s houl d be ba s ed on pa ti ent cha ra cteri s ti cs , LDL chol es terol l evel , a nd provi der di s creti on (s ee Ta bl e 100-8).
Bile acid sequestrants bl ock i ntes ti na l bi l e a ci d rea bs orpti on, forci ng up-regul a ti on of hepa ti c LDL receptors to recrui t ci rcul a ti ng chol es terol for bi l e
s ynthes i s . They a re proved to reduce ca rdi ova s cul a r morta l i ty. Bi l e a ci d s eques tra nts a re us ua l l y us ed wi th s ta ti ns or wi th ni coti ni c a ci d (s ee p.
903) to a ugment LDL chol es terol reducti on a nd a re the drugs of choi ce for chi l dren a nd women who a re or a re pl a nni ng to become pregna nt. Bi l e
a ci d s eques tra nts a re s a fe, but thei r us e i s l i mi ted by a dvers e effects of bl oa ti ng, na us ea , cra mpi ng, a nd cons ti pa ti on. They ma y a l s o i ncrea s e
TGs , s o thei r us e i s contra i ndi ca ted i n pa ti ents wi th hypertri gl yceri demi a . Chol es tyra mi ne a nd col es ti pol , but not col es evel a m, i nterfere wi th
a bs orpti on of other drugs nota bl y thi a zi des , -bl ockers , wa rfa ri n, di goxi n, a nd thyroxi nea n effect tha t ca n be decrea s ed by a dmi ni s tra ti on 4 h
before or 1 h a fter other drugs .
Cholesterol absorption inhibitors, s uch a s ezeti mi be, i nhi bi t i ntes ti na l a bs orpti on of chol es terol a nd phytos terol . Ezeti mi be us ua l l y l owers LDL
chol es terol by 15 to 20% a nd ca us es s ma l l i ncrea s es i n HDL a nd a mi l d decrea s e i n TGs . Ezeti mi be ca n be us ed a s monothera py i n pa ti ents
i ntol era nt to s ta ti ns or a dded to s ta ti ns for pa ti ents on ma xi mum dos es wi th pers i s tent LDL chol es terol el eva ti on. Advers e effects a re i nfrequent.
Dietary supplements tha t l ower LDL chol es terol l evel s i ncl ude fi ber s uppl ements a nd commerci a l l y a va i l a bl e ma rga ri nes a nd other products
conta i ni ng pl a nt s terol s (s i tos terol a nd ca mpes terol ) or s ta nol s . The l a tter reduce LDL chol es terol by up to 10% wi thout a ffecti ng HDL or TGs by
competi ti vel y di s pl a ci ng chol es terol from i ntes ti na l mi cel l es .
[Table 100-8. Li pi d-Loweri ng Drugs ]
Procedural approaches a re res erved for pa ti ents wi th s evere hyperl i pi demi a (LDL chol es terol > 300 mg/dL) tha t i s refra ctory to conventi ona l thera py,
s uch a s occurs wi th fa mi l i a l hyperchol es terol emi a . Opti ons i ncl ude LDL a pheres i s (i n whi ch LDL i s removed by extra corporea l pl a s ma excha nge),
i l ea l bypa s s (to bl ock rea bs orpti on of bi l e a ci ds ), l i ver tra ns pl a nta ti on (whi ch tra ns pl a nts LDL receptors ), a nd portoca va l s hunti ng (whi ch
decrea s es LDL producti on by unknown mecha ni s ms ). LDL a pheres i s i s the procedure of choi ce i n mos t i ns ta nces when ma xi ma l l y tol era ted thera py
fa i l s to l ower LDL a dequa tel y. Apheres i s i s a l s o the us ua l thera py i n pa ti ents wi th the homozygous form of fa mi l i a l hyperchol es terol emi a who
ha ve l i mi ted or no res pons e to drug thera py.
Future therapies to reduce LDL i ncl ude peroxi s ome prol i fera tor-a cti va ted receptor a goni s ts tha t ha ve thi a zol i di nedi one-l i ke a nd fi bra te-l i ke
properti es , LDL-receptor a cti va tors , LPL a cti va tors , a nd recombi na nt a po E. Chol es terol va cci na ti on (to i nduce a nti -LDL a nti bodi es a nd ha s ten LDL
cl ea ra nce from s erum) a nd gene tra ns fer a re conceptua l l y a ppea l i ng thera pi es tha t a re under s tudy but yea rs a wa y from bei ng a va i l a bl e for us e.
Elevated TGs: Though i t i s uncl ea r whether el eva ted TGs i ndependentl y contri bute to ca rdi ova s cul a r di s ea s e, they a re a s s oci a ted wi th mul ti pl e
meta bol i c a bnorma l i ti es tha t contri bute to CAD (eg, di a betes , meta bol i c s yndrome). Cons ens us i s emergi ng tha t l oweri ng el eva ted TGs i s
benefi ci a l (s ee Ta bl e 100-4). No ta rget goa l s exi s t, but l evel s < 150 mg/dL (< 1.7 mmol /L) a re genera l l y cons i dered des i ra bl e. No gui del i nes
s peci fi ca l l y a ddres s trea tment of el eva ted TGs i n chi l dren.
The overall treatment strategy i s to fi rs t i mpl ement l i fes tyl e cha nges , i ncl udi ng exerci s e, wei ght l os s , a nd a voi da nce of concentra ted di eta ry s uga r
a nd a l cohol . Inta ke of 2 to 4 s ervi ngs /wk of ma ri ne fi s h hi gh i n -3 fa tty a ci ds ma y be effecti ve, but the a mount of -3 fa tty a ci ds i s often l ower
tha n needed; s uppl ements ma y be hel pful . In pa ti ents wi th di a betes , gl ucos e l evel s s houl d be ti ghtl y control l ed. If thes e mea s ures a re
i neffecti ve, l i pi d-l oweri ng drugs s houl d be cons i dered. Pa ti ents wi th very hi gh TGs s houl d begi n drug thera py a t di a gnos i s to more qui ckl y reduce
the ri s k of a cute pa ncrea ti ti s .
Fibrates reduce TGs by a bout 50%. They s eem to s ti mul a te endothel i a l LPL, l ea di ng to i ncrea s ed fa tty a ci d oxi da ti on i n the l i ver a nd mus cl e a nd
decrea s ed hepa ti c VLDL s ynthes i s . They a l s o i ncrea s e HDL by up to 20%. Fi bra tes ca n ca us e GI a dvers e effects , i ncl udi ng dys peps i a , a bdomi na l
pa i n, a nd el eva ted l i ver enzymes . They uncommonl y ca us e chol el i thi a s i s . Fi bra tes ma y potenti a te mus cl e toxi ci ty when us ed wi th s ta ti ns a nd
potenti a te the effects of wa rfa ri n.
Nicotinic acid ma y a l s o be us eful (s ee bel ow).
Statins ca n be us ed i n pa ti ents wi th TGs < 500 mg/dL i f LDL chol es terol el eva ti ons a re a l s o pres ent; s ta ti ns ma y reduce both LDL chol es terol a nd
TGs through reducti on of VLDL. If onl y TGs a re el eva ted, fi bra tes a re the drug of choi ce.
Omega-3 fatty acids i n hi gh dos es (1 to 6 g/da y of ei cos a penta enoi c a ci d [EPA] a nd docos a hexa enoi c a ci d [DHA]) ca n be effecti ve i n reduci ng TGs .
The -3 fa tty a ci ds EPA a nd DHA a re the a cti ve i ngredi ents i n ma ri ne fi s h oi l or -3 ca ps ul es . Advers e effects i ncl ude eructa ti on a nd di a rrhea .
Thes e ma y be decrea s ed by gi vi ng the fi s h oi l ca ps ul es wi th mea l s i n di vi ded dos es (eg, bi d or ti d). Omega -3 fa tty a ci ds ca n be a us eful a djunct to
other thera pi es .
Low HDL: Trea tment to i ncrea s e HDL chol es terol l evel s ma y decrea s e ri s k of dea th, but da ta a re l i mi ted. ATPIII gui del i nes defi ne l ow HDL
chol es terol a s < 40 mg/dL [< 1.04 mmol /L]; the gui del i nes do not s peci fy a n HDL chol es terol ta rget l evel a nd recommend i nterventi ons to ra i s e HDL
chol es terol onl y a fter LDL chol es terol ta rgets ha ve been rea ched. Trea tments for LDL chol es terol a nd TG reducti on often i ncrea s e HDL chol es terol ,
a nd the 3 objecti ves ca n s ometi mes be a chi eved s i mul ta neous l y. No gui del i nes s peci fi ca l l y a ddres s trea tment of l ow HDL chol es terol i n chi l dren.
Trea tment i ncl udes lifestyle changes s uch a s a n i ncrea s e i n exerci s e a nd wei ght l os s . Al cohol ra i s es HDL chol es terol but i s not routi nel y
recommended a s a thera py beca us e of i ts ma ny other a dvers e effects . Drugs a re us eful when l i fes tyl e cha nges a l one a re i ns uffi ci ent.
Nicotinic acid (niacin) i s the mos t effecti ve drug for i ncrea s i ng HDL. Its mecha ni s m of a cti on i s unknown, but i t s eems to both i ncrea s e HDL
producti on a nd i nhi bi t HDL cl ea ra nce; i t ma y a l s o mobi l i ze chol es terol from ma cropha ges . Ni a ci n a l s o decrea s es TGs a nd, i n dos es of 1500 to 2000
mg/da y, reduces LDL chol es terol . Ni a ci n ca us es fl us hi ng, pruri tus , a nd na us ea ; premedi ca ti on wi th l ow-dos e a s pi ri n ma y prevent thes e a dvers e
effects . Extended-rel ea s e prepa ra ti ons ca us e fl us hi ng l es s often. However, mos t OTC s l ow-rel ea s e prepa ra ti ons a re not recommended; a n
excepti on i s pol ygel control l ed-rel ea s e ni a ci n. Ni a ci n ca n ca us e l i ver enzyme el eva ti ons a nd occa s i ona l l y l i ver fa i l ure, i ns ul i n res i s ta nce, a nd
hyperuri cemi a a nd gout. It ma y a l s o i ncrea s e homocys tei ne l evel s . In pa ti ents wi th a vera ge LDL chol es terol a nd bel ow-a vera ge HDL chol es terol
l evel s , ni a ci n combi ned wi th s ta ti n trea tment ma y be effecti ve i n preventi ng ca rdi ova s cul a r di s orders .
Fibrates i ncrea s e HDL. Infus i on of recombi na nt HDL (eg, a poprotei n A-1 Mi l a no, a n HDL va ri a nt i n whi ch a cys tei ne i s s ubs ti tuted for a n a rgi ni ne a t
pos i ti on 173 a l l owi ng for di mer forma ti on) s eems promi s i ng a s a trea tment for a theros cl eros i s but requi res further s tudy.
Elevated Lp(a): The upper l i mi t of norma l for Lp(a ) i s a bout 30 mg/dL (0.8 mmol /L), but va l ues i n Afri ca n Ameri ca ns run hi gher. Few da ta exi s t to
gui de the trea tment of el eva ted Lp(a ) or to es ta bl i s h trea tment effi ca cy. Ni a ci n i s the onl y drug tha t di rectl y decrea s es Lp(a ); i t ca n l ower Lp(a ) by
20% a t hi gher dos es . The us ua l a pproa ch i n pa ti ents wi th el eva ted Lp(a ) i s to l ower LDL chol es terol a ggres s i vel y.
Secondary causes: Trea tment of di a beti c dys l i pi demi a s houl d a l wa ys i nvol ve l i fes tyl e cha nges , wi th s ta ti ns to reduce LDL chol es terol , fi bra tes to
decrea s e TGs , or both drugs . Metformi n l owers TGs , whi ch ma y be a rea s on to choos e i t over other ora l a nti hypergl ycemi c drugs when trea ti ng
di a betes . Some thi a zol i di nedi ones (TZDs ) i ncrea s e both HDL chol es terol a nd LDL chol es terol (proba bl y the l es s a therogeni c l a rge, buoya nt type of
LDL). Some TZDs a l s o decrea s e TGs . Thes e a nti hypergl ycemi c drugs s houl d not be chos en over l i pi d-l oweri ng drugs to trea t l i pi d a bnorma l i ti es i n
di a beti c pa ti ents but ma y be us eful a djuncts . Pa ti ents wi th very hi gh TG l evel s a nd l es s tha n opti ma l l y control l ed di a betes ma y ha ve better
res pons e to i ns ul i n tha n to ora l a nti hypergl ycemi c drugs .
Trea tment of dys l i pi demi a i n pa ti ents wi th hypothyroi di s m, rena l di s ea s e, l i ver di s ea s e, or a combi na ti on of thes e di s orders i nvol ves trea ti ng the
underl yi ng di s orders pri ma ri l y a nd l i pi d a bnorma l i ti es s econda ri l y. Abnorma l l i pi d l evel s i n pa ti ents wi th l ow-norma l thyroi d functi on (hi ghnorma l TSH l evel s ) i mprove wi th hormone repl a cement. Reduci ng the dos a ge of or s toppi ng drugs tha t ca us e l i pi d a bnorma l i ti es s houl d be
cons i dered.
Monitoring treatment: Li pi d l evel s s houl d be moni tored peri odi ca l l y a fter s ta rti ng trea tment. No da ta s upport s peci fi c moni tori ng i nterva l s , but
mea s uri ng l i pi d l evel s 2 to 3 mo a fter s ta rti ng or cha ngi ng thera pi es a nd once or twi ce yea rl y a fter l i pi d l evel s a re s ta bi l i zed i s common pra cti ce.
Des pi te the l ow i nci dence of l i ver a nd mus cl e toxi ci ty wi th s ta ti n us e (0.5 to 2% of a l l us ers ), current recommenda ti ons a re for ba s el i ne
mea s urements of l i ver a nd mus cl e enzyme l evel s a t the begi nni ng of trea tment. Ma ny pra cti ti oners obta i n a t l ea s t one a ddi ti ona l s et of l i ver
enzyme mea s urements 4 to 12 wk a fter begi nni ng trea tment a nd a nnua l l y therea fter. Sta ti n thera py ca n be conti nued unl es s l i ver enzymes
i ncrea s e to > 3 ti mes the upper l i mi t of norma l . Mus cl e enzyme l evel s need not be checked regul a rl y unl es s pa ti ents devel op mya l gi a s or other
mus cl e s ymptoms . If s ta ti n-i nduced mus cl e da ma ge i s s us pected, s ta ti n us e i s s topped a nd CK ma y be mea s ured. When mus cl e s ymptoms
s ubs i de, a l ower dos e or a di fferent s ta ti n ca n be tri ed.
Elevated High-Density Lipoprotein Levels
Elevated high-density lipoprotein (HDL) level is HDL cholesterol > 80 mg/dL (> 2.1 mmol/L).
El eva ted HDL chol es terol l evel s us ua l l y correl a te wi th decrea s ed ca rdi ova s cul a r ri s k; however, hi gh HDL chol es terol l evel s ca us ed by s ome geneti c
di s orders ma y not protect a ga i ns t ca rdi ova s cul a r di s ea s e, proba bl y beca us e of a ccompa nyi ng l i pi d a nd meta bol i c a bnorma l i ti es .
Pri ma ry ca us es a re s i ngl e or mul ti pl e geneti c muta ti ons tha t res ul t i n overproducti on or decrea s ed cl ea ra nce of HDL. Seconda ry ca us es of hi gh HDL
chol es terol i ncl ude a l l of the fol l owi ng:
Chroni c a l cohol i s m wi thout ci rrhos i s
Pri ma ry bi l i a ry ci rrhos i s
Hyperthyroi di s m
Drugs (eg, corti cos teroi ds , i ns ul i n, phenytoi n)
The unexpected fi ndi ng of hi gh HDL chol es terol i n pa ti ents not ta ki ng l i pi d-l oweri ng drugs s houl d prompt a di a gnos ti c eva l ua ti on for a s econda ry
ca us e wi th mea s urements of AST, ALT, a nd thyroi d-s ti mul a ti ng hormone; a nega ti ve eva l ua ti on s ugges ts a pos s i bl e pri ma ry ca us e.
Cholesteryl ester transfer protein (CETP) deficiency i s a ra re a utos oma l reces s i ve di s order ca us ed by a CETP gene muta ti on. CETP fa ci l i ta tes tra ns fer of
chol es terol es ters from HDL to other l i poprotei ns , a nd CETP defi ci ency a ffects l ow-dens i ty l i poprotei n (LDL) chol es terol a nd s l ows HDL cl ea ra nce.
Affected pa ti ents di s pl a y no s ymptoms or s i gns but ha ve HDL chol es terol > 150 mg/dL. Protecti on from ca rdi ova s cul a r di s orders ha s not been
proved. No trea tment i s neces s a ry.
Familial hyperalphalipoproteinemia i s a n a utos oma l domi na nt condi ti on ca us ed by va ri ous uni denti fi ed a nd known geneti c muta ti ons , i ncl udi ng
thos e tha t ca us e a poprotei n A-I overproducti on a nd a poprotei n C-III va ri a nts . The di s order i s us ua l l y di a gnos ed i nci denta l l y when pl a s ma HDL
chol es terol l evel s a re > 80 mg/dL. Affected pa ti ents ha ve no other s ymptoms or s i gns . No trea tment i s neces s a ry.
Hypolipidemia
Hypolipidemia is a decrease in plasma lipoprotein caused by primary (genetic) or secondary factors. It is usually asymptomatic and diagnosed incidentally on
routine lipid screening. Treatment of secondary hypolipidemia involves treating underlying disorders. Treatment of primary hypolipidemia is often unnecessary,
but patients with some genetic disorders require high-dose vitamin E and dietary supplementation of fats and other fat-soluble vitamins.
Etiology
Hypol i pi demi a i s defi ned a s a tota l chol es terol (TC) < 120 mg/dL (< 3.1 mmol /L) or l ow-dens i ty l i poprotei n (LDL) chol es terol < 50 mg/dL (< 0.13
mmol /L). Seconda ry ca us es a re fa r more common tha n pri ma ry ca us es a nd i ncl ude a l l of the fol l owi ng:
Hyperthyroi di s m
Chroni c i nfecti ons a nd other i nfl a mma tory s ta tes
Hema tol ogi c a nd other ca ncers
Undernutri ti on (i ncl udi ng tha t a ccompa nyi ng chroni c a l cohol us e)
Ma l a bs orpti on
The unexpected fi ndi ng of l ow chol es terol or l ow LDL chol es terol i n a pa ti ent not ta ki ng a l i pi d-l oweri ng drug s houl d prompt a di a gnos ti c
eva l ua ti on, i ncl udi ng mea s urements of AST, ALT, a nd thyroi d-s ti mul a ti ng hormone; a nega ti ve eva l ua ti on s ugges ts a pos s i bl e pri ma ry ca us e.
There a re 3 pri ma ry di s orders i n whi ch s i ngl e or mul ti pl e geneti c muta ti ons res ul t i n underproducti on or i ncrea s ed cl ea ra nce of LDL.
Abetalipoproteinemia (Bassen-Kornzweig syndrome): Thi s a utos oma l reces s i ve condi ti on i s ca us ed by muta ti ons i n the gene for mi cros oma l
tri gl yceri de (TG) tra ns fer protei n, a protei n cri ti ca l to chyl omi cron a nd very-l ow-dens i ty l i poprotei n (VLDL) forma ti on. Di eta ry fa t ca nnot be
a bs orbed, a nd l i poprotei ns i n both meta bol i c pa thwa ys a re vi rtua l l y a bs ent from s erum; TC i s typi ca l l y < 45 mg/dL (< 1.16 mmol /L), TGs a re < 20
mg/dL (< 0.23 mmol /L), a nd LDL i s undetecta bl e. The condi ti on i s often fi rs t noti ced i n i nfa nts wi th fa t ma l a bs orpti on, s tea torrhea , a nd fa i l ure to
thri ve. Intel l ectua l di s a bi l i ty ma y res ul t. Beca us e vi ta mi n E i s di s tri buted to peri phera l ti s s ues vi a VLDL a nd LDL, mos t a ffected peopl e eventua l l y
devel op s evere vi ta mi n E defi ci ency. Symptoms a nd s i gns i ncl ude vi s ua l cha nges from s l ow reti na l degenera ti on, s ens ory neuropa thy, pos teri or
col umn s i gns , a nd cerebel l a r s i gns of dys metri a , a ta xi a , a nd s pa s ti ci ty, whi ch ca n eventua l l y l ea d to dea th. RBC a ca nthocytos i s i s a di s ti ngui s hi ng
fea ture on bl ood s mea r. Di a gnos i s i s ma de by the a bs ence of a poprotei n B (a po B) i n pl a s ma ; i ntes ti na l bi ops i es s how l a ck of mi cros oma l
tra ns fer protei n. Trea tment i s wi th hi gh dos es (100 to 300 mg/kg once/da y) of vi ta mi n E wi th s uppl ementa ti on of di eta ry fa t a nd other fa t-s ol ubl e
vi ta mi ns . The prognos i s i s poor.
Hypobetalipoproteinemia: Hypobeta l i poprotei nemi a i s a n a utos oma l domi na nt or codomi na nt condi ti on ca us ed by muta ti ons i n the gene codi ng for
a po B. Heterozygous pa ti ents ha ve trunca ted a po B, l ea di ng to ra pi d LDL cl ea ra nce. Heterozygous pa ti ents ma ni fes t no s ymptoms or s i gns except
for TC < 120 mg/dL a nd LDL chol es terol < 80 mg/dL. TGs a re norma l . Homozygous pa ti ents ha ve ei ther s horter trunca ti ons , l ea di ng to l ower l i pi d
l evel s (TC < 80 mg/dL, LDL chol es terol < 20 mg/dL), or a bs ent a po B s ynthes i s , l ea di ng to s ymptoms a nd s i gns of a beta l i poprotei nemi a . Di a gnos i s
i s by fi ndi ng l ow l evel s of LDL chol es terol a nd a po B; hypobeta l i poprotei nemi a a nd a beta l i poprotei nemi a a re di s ti ngui s hed from one a nother by
fa mi l y hi s tory. Peopl e who a re heterozygous a nd peopl e who a re homozygous wi th l ow but detecta bl e LDL chol es terol requi re no trea tment.
Trea tment of peopl e who a re homozygous wi th no LDL i s the s a me a s for a beta l i poprotei nemi a .
Chylomicron retention disease: Chyl omi cron retenti on di s ea s e i s a very ra re a utos oma l reces s i ve condi ti on ca us ed by a n unknown muta ti on l ea di ng
to defi ci ent a po B s ecreti on from enterocytes . Chyl omi cron s ynthes i s i s a bs ent, but VLDL s ynthes i s rema i ns i nta ct. Affected i nfa nts ha ve fa t
ma l a bs orpti on, s tea torrhea , a nd fa i l ure to thri ve a nd ma y devel op neurol ogi c di s orders s i mi l a r to thos e i n a beta l i poprotei nemi a . Di a gnos i s i s by
i ntes ti na l bi ops y of pa ti ents wi th l ow chol es terol l evel s a nd a bs ence of pos tpra ndi a l chyl omi crons . Trea tment i s s uppl ementa ti on of fa t a nd
fa ts ol ubl e vi ta mi ns .
Chapter 101. Amyloidosis

Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of various insoluble proteins. These proteins may accumulate
locally, causing relatively few symptoms, or widely, involving multiple organs and causing severe multiorgan failure. Amyloidosis can be primary or be secondary
to various infectious, inflammatory, or malignant conditions. Rarely, it results from any of several inherited metabolic defects. Diagnosis is by biopsy of affected
tissue. Treatment varies with the type of amyloidosis.
Amyl oi d depos i ts ma y be formed from a t l ea s t 18 di fferent protei ns , i ncl udi ng i mmunogl obul i n fra gments . Amyl oi d depos i ts a re meta bol i ca l l y
i nert but i nterfere phys i ca l l y wi th orga n s tructure a nd functi on. Al l s ta i n pos i ti ve wi th Congo red dye, s ta i n pi nk wi th hema toxyl i n a nd eos i n, a nd
ha ve a ppl e-green bi refri ngence under pol a ri zed l i ght a fter Congo red s ta i ni ng. Amyl oi d depos i ts ha ve a fi bri l l a r, us ua l l y ri gi d, a nd nonbra nchi ng
ul tra s tructure. They form a -pl ea ted s heet tha t ca n be s een by x-ra y di ffra cti on. In a ddi ti on to the fi bri l l a r a myl oi d protei n, the depos i ts a l s o
conta i n s erum a myl oi d P component a nd gl ycos a mi nogl yca ns . On gros s i ns pecti on, a ffected orga ns a ppea r wa xy a nd tra ns l ucent.
Etiology
There a re 3 ma jor s ys temi c forms of a myl oi dos i s : pri ma ry, s econda ry, a nd fa mi l i a l . Al s o, there a re 2 ma jor l oca l i zed forms , A (a s s oci a ted wi th
Al zhei mer's di s ea s e) a nd AIAPP (whi ch occurs i n the pa ncrea s of pa ti ents wi th type 2 di a betes ), a s wel l a s s evera l mi s cel l a neous forms (eg, A 2 mi crogl obul i n a s s oci a ted wi th chroni c hemodi a l ys i s ).
Primary amyloidosis (AL): AL i s a monocl ona l pl a s ma cel l di s order i n whi ch the a bnorma l protei n i s a n i mmunogl obul i n, us ua l l y a l i ght cha i n
fra gment (Bence Jones protei n) but occa s i ona l l y a hea vy cha i n fra gment (AH a myl oi dos i s ). Thes e cha i ns ei ther ha ve a n a berra nt s tructure or a re
proces s ed a bnorma l l y s o tha t s ome form i ns ol ubl e depos i ts . Common s i tes for depos i ti on i ncl ude the s ki n, nerves , hea rt, GI tra ct (i ncl udi ng
tongue), ki dneys , l i ver, s pl een, a nd bl ood ves s el s . A mi l d pl a s ma cytos i s occurs i n the bone ma rrow, whi ch i s s ugges ti ve of mul ti pl e myel oma , but
mos t pa ti ents do not ha ve true mul ti pl e myel oma (wi th l yti c bone l es i ons , rena l tubul a r ca s ts , a nd a nemi a ). However, a bout 10 to 20% of pa ti ents
wi th mul ti pl e myel oma a l s o devel op a myl oi dos i s .
Secondary amyloidosis (AA): Thi s form ca n occur s econda ry to s evera l i nfecti ous , i nfl a mma tory, a nd ma l i gna nt (eg, rena l cel l ca rci noma s a nd others )
condi ti ons a nd i s ca us ed by the degra da ti on of the a cute-pha s e rea cta nt s erum a myl oi d A (SAA). Common ca us a ti ve i nfecti ons i ncl ude TB,
bronchi ecta s i s , os teomyel i ti s , a nd l epros y. Infl a mma tory condi ti ons i ncl ude RA, juveni l e i di opa thi c a rthri ti s (formerl y juveni l e RA), Crohn's
di s ea s e, a nd fa mi l i a l Medi terra nea n fever. Infl a mma tory cytoki nes (eg, IL-1, tumor necros i s fa ctor, IL-6) tha t a re produced i n thes e di s orders ca us e
i ncrea s ed hepa ti c producti on of the precurs or protei n SAA, whi ch ci rcul a tes i n the s erum.
AA a myl oi dos i s s hows a predi l ecti on for the s pl een, l i ver, ki dneys , a drena l s , a nd l ymph nodes . The l i ver, s pl een, a nd ki dneys a re often enl a rged,
fi rm, a nd rubbery. Invol vement of the hea rt a nd peri phera l or a utonomi c nerves i s ra re. However, no orga n s ys tem i s s pa red, a nd va s cul a r
i nvol vement ma y be wi des prea d.
Familial amyloidosis: The fa mi l i a l form res ul ts from a ccumul a ti on of a muta ted vers i on of a pl a s ma protei n (mos t commonl y tra ns thyreti n [TTR],
hence ATTR). Nea rl y a l l of the a bnorma l protei n i s produced by the l i ver. Over 80 muta ti ons of the gene for TTR ha ve been i denti fi ed, a l l i nheri ted
i n a n a utos oma l domi na nt pa ttern.
Age a t ons et of s ymptoms i s hi ghl y va ri a bl e, ra ngi ng from the teens to the 70s . ATTR a myl oi dos i s ca us es peri phera l s ens ory a nd motor neuropa thy,
often wi th a n a utonomi c neuropa thy. Ca rpa l tunnel s yndrome i s common. La ter i n the i l l nes s , ca rdi ova s cul a r a nd rena l i nvol vement occurs .
Vi treous a bnorma l i ti es ma y a l s o devel op.
Other very ra re heredi ta ry a myl oi dos es res ul t from muta ti ons of other phys i ol ogi c protei ns , i ncl udi ng a pol i poprotei n A-1, l ys ozyme, fi bri nogen,
gel s ol i n, a nd cys ta ti n C. Thes e a myl oi dos es ha ve va ri ous s ys temi c a nd l oca l i zed effects .
A 2 -microglobulin (dialysis-related) amyloidosis: Thi s form occurs i n pa ti ents wi th chroni c rena l fa i l ure who ha ve been on hemodi a l ys i s or peri tonea l
di a l ys i s for l ong peri ods , us ua l l y > 8 yr. The a myl oi d depos i ts cons i s t of 2 -mi crogl obul i n, a component of the cl a s s I ma jor hi s tocompa ti bi l i ty
compl ex, whi ch i s norma l l y cl ea red by the ki dneys but ca nnot be removed by di a l ys i s membra nes . Depos i ts preferenti a l l y occur i n a nd a round
bones a nd joi nts a nd i n the ca rpa l tunnel a nd ha ve been found i n the GI tra ct a nd i n other orga ns .
A -protein amyloidosis: Thi s form occurs i n pa ti ents wi th Al zhei mer's di s ea s e. Al though the exa ct rol e of a myl oi d depos i ts i s uncl ea r, the neuri ti c
pl a ques cha ra cteri s ti c of Al zhei mer's di s ea s e conta i n a myl oi d depos i ts cons i s ti ng of a -protei n fra gment of -a myl oi d precurs or protei n (a
tra ns membra ne gl ycoprotei n). The -protei n fra gment i s s ometi mes compl exed wi th a pol i poprotei n E. Wi thi n the pl a ques , nonfi bri l l a r forms of
the protei n a re i ntermi xed wi th fi bri l l a r a myl oi d forms .
-Protei n a myl oi d depos i ti on ma y a l s o occur a round cerebra l bl ood ves s el s , whi ch i s thought to be a ca us e of nonhypertens i ve cerebra l
hemorrha ge (cerebra l a myl oi d a ngi opa thy). The a ngi opa thy ma y occur s pora di ca l l y or a s a heredi ta ry s yndrome (Dutch heredi ta ry cerebra l
hemorrha ge).
Symptoms and Signs
Symptoms a nd s i gns a re nons peci fi c a nd rel a te to the orga n or s ys tem a ffected. Symptoms i n AA a myl oi dos i s a re often obs cured by the underl yi ng
di s ea s e.
When the ki dneys a re a ffected, nephroti c s yndrome i s the mos t s tri ki ng ea rl y ma ni fes ta ti on. Ini ti a l l y, onl y s l i ght protei nuri a ma y occur; l a ter, the
di s ti ncti ve s ymptom compl ex devel ops wi th a na s a rca , hypoprotei nemi a , a nd ma s s i ve protei nuri a .
Hepa ti c i nvol vement ca us es pa i nl es s hepa tomega l y, whi ch ma y be ma s s i ve (l i ver wei ght > 7 kg). Except for occa s i ona l el eva ti on of a l ka l i ne
phos pha ta s e, l i ver functi on tes ts rema i n norma l . Ja undi ce i s ra re. Occa s i ona l l y, porta l hypertens i on devel ops , wi th res ul ti ng es opha gea l va ri ces
a nd a s ci tes .
Ca rdi a c i nvol vement ca us es a res tri cti ve ca rdi omyopa thy, eventua l l y l ea di ng to hea rt fa i l ure. Ca rdi omega l y a nd va ri ous degrees of hea rt bl ock or
a rrhythmi a ma y occur.
Peri phera l neuropa thy, wi th pa res thes i a s of the fi ngers a nd toes , i s a common pres enti ng ma ni fes ta ti on i n AL a nd ATTR a myl oi dos es . Autonomi c
neuropa thy ma y ca us e orthos ta ti c hypotens i on, erecti l e dys functi on, s wea ti ng a bnorma l i ti es , a nd GI moti l i ty di s turba nces .
Rheuma tol ogi c s ymptoms i n pa ti ents wi th A 2 -mi crogl obul i n a myl oi dos i s i ncl ude ca rpa l tunnel s yndrome a nd chroni c pa i n i n the s houl der, wri s t,
a nd fi ngers . Pa thol ogi c fra ctures , pa rti cul a rl y of the humerus a nd femur, ma y occur.
GI a myl oi d ma y ca us e moti l i ty a bnorma l i ti es of the es opha gus a nd s ma l l a nd l a rge i ntes ti nes . Ga s tri c a tony, ma l a bs orpti on, bl eedi ng, or ps eudoobs tructi on ma y a l s o occur. Ma crogl os s i a i s common i n AL a myl oi dos es .
A fi rm, s ymmetri c, nontender goi ter res embl i ng tha t found i n Ha s hi moto's thyroi di ti s ma y res ul t from a myl oi dos i s of the thyroi d gl a nd. Lung
i nvol vement (mos tl y i n AL a myl oi dos i s ) ca n be cha ra cteri zed by foca l pul mona ry nodul es , tra cheobronchi a l l es i ons , or di ffus e a l veol a r depos i ts . In
s evera l heredi ta ry a myl oi dos es , a myl oi d vi treous opa ci ti es a nd bi l a tera l s ca l l oped pupi l l a ry ma rgi ns devel op.
Diagnosis
Bi ops y
Amyl oi dos i s i s s us pected cl i ni ca l l y but ca n be di a gnos ed onl y by bi ops y. Subcuta neous a bdomi na l fa t pa d a s pi ra ti on a nd bi ops y of recta l mucos a
a re the bes t a pproa ches . Other us eful bi ops y s i tes a re the gi ngi va , s ki n, nerves , ki dneys , a nd l i ver. Ti s s ue s ecti ons a re s ta i ned wi th Congo red dye
a nd exa mi ned wi th a pol a ri zi ng mi cros cope for cha ra cteri s ti c bi refri ngence. Is otopi ca l l y l a bel ed s erum AP (i n whi ch AP repres ents the penta gona l
component of a myl oi d) ca n be us ed i n a s ci nti gra phi c tes t to confi rm the di a gnos i s .
Prognosis
Prognos i s depends on the type of a myl oi dos i s a nd the orga n s ys tem i nvol ved. AL a myl oi dos i s wi th mul ti pl e myel oma ha s the poores t prognos i s :
dea th wi thi n 1 yr i s common. Untrea ted ATTR a myl oi dos es a re fa ta l wi thi n 10 to 15 yr. Prognos i s i n other fa mi l i a l a myl oi dos es va ri es . In genera l ,
rena l or ca rdi a c i nvol vement i n pa ti ents wi th a ny type of a myl oi dos i s i s of pa rti cul a r concern.
Prognos i s i n AA a myl oi dos i s depends on s ucces s ful trea tment of the underl yi ng di s order, a l though ra re pa ti ents undergo s ponta neous regres s i on
of the a myl oi d depos i ts wi thout s uch trea tment.
Treatment
Symptom rel i ef
Someti mes ki dney tra ns pl a nta ti on
Someti mes chemothera py for AL a myl oi dos i s
Ma na gement i s genera l l y s ymptoma ti c, a l though trea tment of the underl yi ng di s order ca n s ometi mes a rres t a myl oi dos i s . In pa ti ents wi th rena l
a myl oi d, ki dney tra ns pl a nta ti on provi des l ong-term s urvi va l compa ra bl e to tha t i n other rena l di s ea s es , a l though morta l i ty i s hi gher i n the ea rl y
yea rs . Amyl oi d ul ti ma tel y recurs i n a donor ki dney, but s evera l reci pi ents ha ve done very wel l a nd ha ve s urvi ved up to 10 yr. Hea rt tra ns pl a nta ti on
ha s been s ucces s ful i n ca reful l y s el ected pa ti ents wi th AL a myl oi dos i s a nd s evere ca rdi a c i nvol vement.
Pa ti ents wi th AL a myl oi dos i s a re often trea ted wi th chemothera py. A common protocol us es mel pha l a n 0.075 mg/kg po bi d a nd predni s one 0.2
mg/kg po qi d. Mel pha l a n wi th a utol ogous s tem cel l tra ns pl a nta ti on a chi eves good s hort-term s ucces s a nd a ppa rent cures i n s ome ca s es .
In pa ti ents wi th ATTR a myl oi dos i s , l i ver tra ns pl a nta ti onwhi ch removes the s i te of s ynthes i s of the muta nt protei ni s very effecti ve.
For AA a myl oi dos i s wi th fa mi l i a l Medi terra nea n fever, col chi ci ne 0.6 mg po once/da y or bi d i s effecti ve. Underl yi ng i nfecti ons i n pa ti ents wi th AA
a myl oi dos i s of i nfecti ous ori gi n mus t be trea ted a ggres s i vel y. Trea tment of a myl oi d res ul ti ng from ca ncer (eg, rena l cel l ca rci noma ) i s di rected a t
the ca ncer.
Chapter 102. Carcinoid Tumors

Introduction
Ca rci noi d tumors devel op from neuroendocri ne cel l s i n the GI tra ct (90%s ee p. 191), pa ncrea s , a nd pul mona ry bronchi (s ee p. 2013). More tha n
95% of a l l GI ca rci noi ds ori gi na te i n onl y 3 s i tes : the a ppendi x, i l eum, a nd rectum. Al though ca rci noi ds a re often beni gn or onl y l oca l l y i nva s i ve,
thos e a ffecti ng the i l eum a nd bronchus a re frequentl y ma l i gna nt.
Ca rci noi ds ca n be endocri nol ogi ca l l y i nert or produce va ri ous hormones . The mos t common endocri nol ogi c s yndrome i s ca rci noi d s yndrome;
however, mos t pa ti ents wi th ca rci noi ds do not devel op ca rci noi d s yndrome. The l i kel i hood tha t a tumor wi l l be endocri nol ogi ca l l y a cti ve va ri es
wi th i ts s i te of ori gi n, bei ng hi ghes t for tumors ori gi na ti ng i n the i l eum a nd proxi ma l col on (40 to 50%). The l i kel i hood i s l ower wi th bronchi a l
ca rci noi ds , l ower s ti l l wi th a ppendi cea l ca rci noi ds , a nd es s enti a l l y zero wi th recta l ca rci noi ds .
Endocri nol ogi ca l l y i nert ca rci noi ds a re s us pected beca us e of thei r s ymptoms a nd s i gns (eg, pa i n, l umi na l bl eedi ng, GI obs tructi on). They ca n be
detected by a ngi ogra phy, CT, or MRI. Sma l l -bowel ca rci noi ds ma y exhi bi t fi l l i ng defects or other a bnorma l i ti es on ba ri um x-ra ys . Defi ni ti ve
di a gnos i s i s ma de hi s tol ogi ca l l y a fter bi ops y or res ecti on.
Endocri nol ogi ca l l y a cti ve ca rci noi ds a re di a gnos ed a nd trea ted a s des cri bed bel ow.
Carcinoid Syndrome
Carcinoid syndrome develops in some people with carcinoid tumors and is characterized by cutaneous flushing, abdominal cramps, and diarrhea. Right-sided
valvular heart disease may develop after several years. The syndrome results from vasoactive substances (including serotonin, bradykinin, histamine,
prostaglandins, polypeptide hormones) secreted by the tumor, which is typically a metastatic intestinal carcinoid. Diagnosis is clinical and by demonstrating
increased urinary 5-hydroxyindoleacetic acid. Tumor localization may require a radionuclide scan or laparotomy. Treatment of symptoms is with somatostatin or
octreotide, but surgical removal is done where possible; chemotherapy may be used for malignant tumors.
Etiology
Endocri nol ogi ca l l y a cti ve tumors of the di ffus e peri phera l endocri ne or pa ra cri ne s ys tem produce va ri ous a mi nes a nd pol ypepti des wi th
corres pondi ng s ymptoms a nd s i gns , i ncl udi ng ca rci noi d s yndrome. Ca rci noi d s yndrome i s us ua l l y due to endocri nol ogi ca l l y a cti ve ma l i gna nt
tumors tha t devel op from neuroendocri ne cel l s (mos tl y i n the i l eum) a nd produce s erotoni n. It ca n, however, occur from tumors el s ewhere i n the
GI tra ct (pa rti cul a rl y the a ppendi x a nd rectum), pa ncrea s , bronchi , or, ra rel y, the gona ds . Ra rel y, certa i n hi ghl y ma l i gna nt tumors (eg, oa t cel l
ca rci noma of the l ung, pa ncrea ti c i s l et cel l ca rci noma , medul l a ry thyroi d ca rci noma ) a re res pons i bl e.
An i ntes ti na l ca rci noi d does not us ua l l y ca us e the s yndrome unl es s hepa ti c meta s ta s es ha ve occurred, beca us e meta bol i c products rel ea s ed by
the tumor a re ra pi dl y des troyed by bl ood a nd l i ver enzymes i n the porta l ci rcul a ti on (eg, s erotoni n by hepa ti c monoa mi ne oxi da s e). Hepa ti c
meta s ta s es , however, rel ea s e meta bol i c products vi a the hepa ti c vei ns di rectl y i nto the s ys temi c ci rcul a ti on. Meta bol i c products rel ea s ed by
pri ma ry pul mona ry a nd ova ri a n ca rci noi ds bypa s s the porta l route a nd ma y s i mi l a rl y i nduce s ymptoms . Ra re i ntes ti na l ca rci noi ds wi th onl y i ntra a bdomi na l s prea d ca n dra i n di rectl y i nto the s ys temi c ci rcul a ti on or the l ympha ti cs a nd ca us e s ymptoms .
Pathophysiology
Serotoni n a cts on s mooth mus cl e to ca us e di a rrhea , col i c, a nd ma l a bs orpti on. Hi s ta mi ne a nd bra dyki ni n, through thei r va s odi l a tor effects , ca us e
fl us hi ng. The rol e of pros ta gl a ndi ns a nd va ri ous pol ypepti de hormones , whi ch ma y be produced by pa ra cri ne cel l s , a wa i ts further i nves ti ga ti on;
el eva ted huma n chori oni c gona dotropi n a nd pa ncrea ti c pol ypepti de l evel s a re occa s i ona l l y pres ent wi th ca rci noi ds .
Ma ny pa ti ents devel op ri ght-s i ded endoca rdi a l fi bros i s , l ea di ng to pul mona ry s tenos i s a nd tri cus pi d regurgi ta ti on. Left hea rt l es i ons , whi ch ha ve
been reported wi th bronchi a l ca rci noi ds , a re ra re beca us e s erotoni n i s des troyed duri ng pa s s a ge through the l ungs .
Symptoms and Signs
The mos t common (a nd often ea rl i es t) s i gn i s a n uncomforta bl e fl us hi ng, typi ca l l y of the hea d a nd neck, often preci pi ta ted by emoti ona l s tres s or
the i nges ti on of food, hot bevera ges , or a l cohol . Stri ki ng s ki n col or cha nges ma y occur, ra ngi ng from pa l l or or erythema to a vi ol a ceous hue.
Abdomi na l cra mps wi th recurrent di a rrhea occur a nd a re often the pa ti ent's ma jor compl a i nt. Ma l a bs orpti on s yndrome ma y occur. Pa ti ents wi th
va l vul a r l es i ons ma y ha ve a hea rt murmur. A few pa ti ents ha ve a s thma ti c wheezi ng, a nd s ome ha ve decrea s ed l i bi do a nd erecti l e dys functi on;
pel l a gra devel ops ra rel y.
Diagnosis
Uri na ry 5-hydroxyi ndol ea ceti c a ci d (5-HIAA)
Serotoni n-s ecreti ng ca rci noi ds a re s us pected ba s ed on thei r s ymptoms a nd s i gns . Di a gnos i s i s confi rmed by demons tra ti ng i ncrea s ed uri na ry
excreti on of the s erotoni n meta bol i te 5-HIAA. To a voi d fa l s e-pos i ti ve res ul ts , cl i ni ci a ns do the tes t a fter the pa ti ent ha s a bs ta i ned from s erotoni nconta i ni ng foods (eg, ba na na s , toma toes , pl ums , a voca dos , pi nea ppl es , eggpl a nt, wa l nuts ) for 3 da ys . Certa i n drugs , i ncl udi ng gua i fenes i n,
methoca rba mol , a nd phenothi a zi nes , a l s o i nterfere wi th the tes t a nd s houl d be s topped tempora ri l y before tes ti ng. On the 3rd da y, a 24-h uri ne
s a mpl e i s col l ected for a s s a y. Norma l excreti on of 5-HIAA i s < 10 mg/da y (< 52 mol /da y); i n pa ti ents wi th ca rci noi d s yndrome, excreti on i s us ua l l y
> 50 mg/da y (> 260 mol /da y).
Provoca ti ve tes ts wi th Ca gl ucona te, ca techol a mi nes , penta ga s tri n, or a l cohol ha ve been us ed to i nduce fl us hi ng. Thes e tes ts ma y be hel pful when
the di a gnos i s i s i n doubt, but they mus t be done wi th ca re. Loca l i za ti on of the tumor i nvol ves the s a me techni ques us ed to l oca l i ze a
nonfuncti oni ng ca rci noi d (s ee p. 907) but ma y requi re extens i ve eva l ua ti on, s ometi mes i ncl udi ng l a pa rotomy. A s ca n wi th ra di onucl i de-l a bel ed
s oma tos ta ti n receptor l i ga nd i ndi um-111 pentetreoti de or wi th i odi ne-123 meta i odobenzyl gua ni di ne ma y s how meta s ta s es .
Other condi ti ons tha t ma ni fes t wi th fl us hi ng a nd tha t coul d, therefore, be confus ed wi th ca rci noi d s yndrome s houl d be excl uded. In pa ti ents i n
whom 5-HIAA excreti on i s not i ncrea s ed, di s orders tha t i nvol ve s ys temi c a cti va ti on of ma s tocytes (eg, s ys temi c ma s tocytos i s wi th i ncrea s ed uri na ry
l evel s of hi s ta mi ne meta bol i tes a nd i ncrea s ed s erum trypta s e l evel ) a nd i di opa thi c a na phyl a xi s ma y be res pons i bl e. Addi ti ona l ca us es of
fl us hi ng i ncl ude menopa us e, etha nol i nges ti on, drugs s uch a s ni a ci n, a nd certa i n tumors (eg, vi poma s , rena l cel l ca rci noma , medul l a ry thyroi d
ca rci noma ).
Prognosis
Des pi te meta s ta ti c di s ea s e, thes e tumors a re s l ow growi ng, a nd s urvi va l of 10 to 15 yr i s not unus ua l .
Treatment
Octreoti de for s ymptoms
Res ecti on of pri ma ry l ung ca rci noi ds i s often cura ti ve. For pa ti ents wi th hepa ti c meta s ta s es , s urgery i s onl y di a gnos ti c or pa l l i a ti ve, a nd ra di a ti on
thera py i s uns ucces s ful , i n pa rt beca us e of the poor tol era nce of norma l hepa ti c ti s s ue to ra di a ti on. No effecti ve chemothera peuti c regi men ha s
been es ta bl i s hed, but s treptozoci n wi th 5-fl uoroura ci l i s mos t wi del y us ed, s ometi mes wi th doxorubi ci n.
Certa i n s ymptoms , i ncl udi ng fl us hi ng, ha ve been rel i eved by s oma tos ta ti n (whi ch i nhi bi ts rel ea s e of mos t hormones ) wi thout l oweri ng uri na ry 5HIAA or ga s tri n. Numerous s tudi es ha ve s ugges ted good res ul ts wi th octreoti de, a l ong-a cti ng a na l og of s oma tos ta ti n. Octreoti de i s the drug of
choi ce for control l i ng di a rrhea a nd fl us hi ng. Ca s e reports i ndi ca te tha t ta moxi fen ha s been effecti ve i nfrequentl y; l eukocyte i nterferon (IFN-) ha s
tempora ri l y rel i eved s ymptoms .
Fl us hi ng a l s o ca n be trea ted wi th phenothi a zi nes (eg, prochl orpera zi ne 5 to 10 mg or chl orproma zi ne 25 to 50 mg po q 6 h). Hi s ta mi ne 2 bl ockers
ma y a l s o be us ed. Phentol a mi ne (a n -bl ocker) 5 to 15 mg IV ha s prevented experi menta l l y i nduced fl us hes . Corti cos teroi ds (eg, predni s one 5 mg
po q 6 h) ma y be us eful for s evere fl us hi ng ca us ed by bronchi a l ca rci noi ds .
Di a rrhea ma y be control l ed by codei ne phos pha te 15 mg po q 4 to 6 h, ti ncture of opi um 0.6 mL po q 6 h, l opera mi de 4 mg po a s a l oa di ng dos e a nd
2 mg a fter ea ch l oos e bowel to a ma xi mum of 16 mg/da y, di phenoxyl a te 5 mg po qi d, or peri phera l s erotoni n a nta goni s ts s uch a s cyprohepta di ne 4
to 8 mg po q 6 h or methys ergi de 1 to 2 mg po qi d.
Ni a ci n a nd a dequa te protei n i nta ke a re needed to prevent pel l a gra , beca us e di eta ry tryptopha n i s di verted to s erotoni n by the tumor. Enzyme
i nhi bi tors tha t prevent the convers i on of 5-hydroxytryptopha n to s erotoni n i ncl ude methyl dopa 250 to 500 mg po q 6 h a nd phenoxybenza mi ne 10
mg/da y.
Chapter 103. Multiple Endocrine Neoplasia Syndromes

Introduction
(Fa mi l i a l Endocri ne Adenoma tos i s ; Mul ti pl e Endocri ne Adenoma tos i s )
The mul ti pl e endocri ne neopl a s i a (MEN) s yndromes compri s e 3 geneti ca l l y di s ti nct fa mi l i a l di s ea s es i nvol vi ng a denoma tous hyperpl a s i a a nd
ma l i gna nt tumors i n s evera l endocri ne gl a nds . Cl i ni ca l fea tures depend on the gl a ndul a r el ements i nvol ved.
Ea ch s yndrome i s i nheri ted a s a n a utos oma l domi na nt tra i t wi th a hi gh degree of penetra nce, va ri a bl e expres s i vi ty, a nd producti on of s eemi ngl y
unrel a ted effects by a s i ngl e muta nt gene. The s peci fi c muta ti on i s not a l wa ys known.
Symptoms a nd s i gns devel op a t a ny a ge. Proper ma na gement i ncl udes ea rl y i denti fi ca ti on of a ffected i ndi vi dua l s wi thi n a ki ndred a nd s urgi ca l
remova l of the tumors when pos s i bl e. Al though thes e s yndromes a re genera l l y cons i dered cl i ni ca l l y di s ti nct, s i gni fi ca nt overl a p exi s ts (s ee
Ta bl e 103-1).
Multiple Endocrine Neoplasia, Type 1
(Mul ti pl e Endocri ne Adenoma tos i s , Type I; Wermer's Syndrome)
Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by tumors
[Table 103-1. Condi ti ons As s oci a ted wi th Men Syndromes ]
of the parathyroid glands, pancreatic islet cells, and pituitary gland. Clinical features most commonly include hyperparathyroidism and asymptomatic
hypercalcemia. Genetic screening is used to detect carriers. Diagnosis is by hormonal and imaging tests. Tumors are surgically removed when possible.
MEN 1 i s proba bl y ca us ed by a n i na cti va ti ng muta ti on of the tumor s uppres s or gene tha t encodes the tra ns cri pti on fa ctor meni n; ma ny muta ti ons
of thi s gene ma y be res pons i bl e.
About 40% of MEN 1 ca s es i nvol ve tumors of a l l 3 a ffected gl a nds the pa ra thyroi ds , pa ncrea s , a nd pi tui ta ry. Al mos t a ny combi na ti on of the tumors
a nd s ymptom compl exes outl i ned bel ow i s pos s i bl e. A pa ti ent wi th a MEN 1 gene muta ti on a nd one of the MEN 1 tumors i s a t ri s k of devel opi ng
a ny of the other tumors l a ter on. Age a t ons et ra nges from 4 to 81 yr, but pea k i nci dence occurs i n the 20s i n women a nd 30s i n men. Women a re
a ffected twi ce a s often a s men.
Symptoms and Signs
The cl i ni ca l fea tures depend on the gl a ndul a r el ements a ffected (s ee Ta bl e 103-1).
Parathyroid: Hyperpa ra thyroi di s m i s pres ent i n 90% of pa ti ents . As ymptoma ti c hyperca l cemi a i s the mos t common ma ni fes ta ti on: a bout 25% of
pa ti ents ha ve evi dence of nephrol i thi a s i s or nephroca l ci nos i s . In contra s t to s pora di c ca s es of hyperpa ra thyroi di s m, di ffus e hyperpl a s i a or
mul ti pl e a denoma s a re more common tha n s ol i ta ry a denoma s .
Pancreas: Pa ncrea ti c i s l et cel l tumors occur i n 60 to 70% of pa ti ents . Tumors a re us ua l l y mul ti centri c. Mul ti pl e a denoma s or di ffus e i s l et cel l
hyperpl a s i a commonl y occurs ; s uch tumors ma y a ri s e from the s ma l l bowel ra ther tha n the pa ncrea s . About 30% of tumors a re ma l i gna nt a nd ha ve
l oca l or di s ta nt meta s ta s es . Ma l i gna nt i s l et cel l tumors due to MEN 1 s yndrome often ha ve a more beni gn cours e tha n do s pora di ca l l y occurri ng
ma l i gna nt i s l et cel l tumors .
About 40% of i s l et cel l tumors ori gi na te from a cel l , s ecrete i ns ul i n (i ns ul i noma ), a nd ca n ca us e fa s ti ng hypogl ycemi a . -Cel l tumors a re more
common a mong pa ti ents < 40. About 60% of i s l et cel l tumors ori gi na te from non--cel l el ements a nd tend to occur i n pa ti ents > 40. Non--cel l
tumors a re s omewha t more l i kel y to be ma l i gna nt.
Mos t i s l et cel l tumors s ecrete pa ncrea ti c pol ypepti de, the cl i ni ca l s i gni fi ca nce of whi ch i s unknown. Ga s tri n i s s ecreted by ma ny non--cel l tumors
(i ncrea s ed ga s tri n s ecreti on i n MEN 1 a l s o often ori gi na tes from the duodenum). Increa s ed ga s tri n s ecreti on i ncrea s es ga s tri c a ci d, whi ch ma y
i na cti va te pa ncrea ti c l i pa s e, l ea di ng to di a rrhea a nd s tea torrhea . Increa s ed ga s tri n s ecreti on a l s o l ea ds to pepti c ul cers i n > 50% of MEN 1
pa ti ents . Us ua l l y the ul cers a re mul ti pl e or a typi ca l i n l oca ti on, a nd often bl eed, perfora te, or become obs tructed. Pepti c ul cer di s ea s e ma y be
i ntra cta bl e a nd compl i ca ted (Zol l i nger-El l i s on s yndromes ee p. 200). Among pa ti ents pres enti ng wi th Zol l i nger-El l i s on s yndrome, 20 to 60% ha ve
MEN 1.
A s evere s ecretory di a rrhea ca n devel op a nd ca us e fl ui d a nd el ectrol yte depl eti on wi th non--cel l tumors . Thi s compl ex, referred to a s the wa tery
di a rrhea , hypoka l emi a , a nd a chl orhydri a s yndrome (WDHA; pa ncrea ti c chol era s ee p. 201), ha s been a s cri bed to va s oa cti ve i ntes ti na l
pol ypepti de, a l though other i ntes ti na l hormones or s ecreta gogues (i ncl udi ng pros ta gl a ndi ns ) ma y contri bute. Hypers ecreti on of gl uca gon,
s oma tos ta ti n, chromogra ni n, or ca l ci toni n, ectopi c s ecreti on of ACTH (ca us i ng Cus hi ng's s yndrome), a nd hypers ecreti on of growth hormonerel ea s i ng hormone (ca us i ng a cromega l y) s ometi mes occur i n non--cel l tumors . Al l of thes e a re ra re i n MEN 1.
Nonfuncti oni ng pa ncrea ti c tumors a l s o occur i n pa ti ents wi th MEN 1 a nd ma y be the mos t common type of pa ncrea toduodena l tumor i n MEN 1. The
s i ze of the nonfuncti oni ng tumor correl a tes wi th ri s k of meta s ta s i s a nd dea th.
Pituitary: Pi tui ta ry tumors occur i n 15 to 42% of MEN 1 pa ti ents . From 25 to 90% a re prol a cti noma s . About 25% of pi tui ta ry tumors s ecrete growth
hormone or growth hormone a nd prol a cti n. Exces s prol a cti n ma y ca us e ga l a ctorrhea (s ee p. 770), a nd exces s growth hormone ca us es a cromega l y
cl i ni ca l l y i ndi s ti ngui s ha bl e from s pora di ca l l y occurri ng a cromega l y. About 3% of tumors s ecrete ACTH, ca us i ng Cus hi ng's di s ea s e. Mos t of the
rema i nder a re nonfuncti ona l . Loca l tumor expa ns i on ma y ca us e vi s ua l di s turba nce, hea da che, a nd hypopi tui ta ri s m. Pi tui ta ry tumors i n MEN 1
pa ti ents a ppea r to be l a rger a nd beha ve more a ggres s i vel y tha n s pora di c pi tui ta ry tumors .
Other manifestations: Adenoma s a nd a denoma tous hyperpl a s i a of the thyroi d a nd a drena l gl a nds occurs occa s i ona l l y i n MEN 1 pa ti ents . Hormone
s ecreti on i s ra rel y a l tered a s a res ul t, a nd the s i gni fi ca nce of thes e a bnorma l i ti es i s uncerta i n. Ca rci noi d tumors , pa rti cul a rl y thos e deri ved from
the embryol ogi c foregut, occur i n i s ol a ted ca s es . Mul ti pl e s ubcuta neous a nd vi s cera l l i poma s , a ngi ofi broma s , a nd col l a genoma s ma y a l s o occur.
Diagnosis
Cl i ni ca l eva l ua ti on for other tumors of the tri a d
Serum Ca , pa ra thyroi d hormone (PTH), ga s tri n, a nd prol a cti n l evel s
Tumor l oca l i za ti on wi th MRI, CT, or s ci nti gra phy
Geneti c tes ti ng
Pa ti ents wi th tumors of the pa ra thyroi ds , pa ncrea s , or pi tui ta ry, pa rti cul a rl y thos e wi th a fa mi l y hi s tory of endocri nopa thy, s houl d undergo cl i ni ca l
s creeni ng for other tumors of MEN 1. Such s creeni ng i ncl udes the fol l owi ng:
As ki ng a bout s ymptoms of pepti c ul cer di s ea s e, di a rrhea , nephrol i thi a s i s , hypogl ycemi a , a nd hypopi tui ta ri s m
Exa mi ni ng for vi s ua l fi el d defects , ga l a ctorrhea i n women, a nd fea tures of a cromega l y a nd s ubcuta neous l i poma s
Mea s uri ng l evel s of s erum Ca , i nta ct PTH, ga s tri n, a nd prol a cti n
Addi ti ona l l a bora tory or ra di ol ogi c tes ts s houl d be done i f thes e s creeni ng tes ts s ugges t a n endocri ne a bnorma l i ty rel a ted to MEN 1. An i ns ul i ns ecreti ng -cel l tumor of the pa ncrea s i s di a gnos ed by detecti ng fa s ti ng hypogl ycemi a wi th a n el eva ted pl a s ma i ns ul i n l evel .
A ga s tri n-s ecreti ng non--cel l tumor of the pa ncrea s or duodenum i s di a gnos ed by el eva ted ba s a l pl a s ma ga s tri n l evel s , a n exa ggera ted ga s tri n
res pons e to i nfus ed Ca , a nd a pa ra doxi ca l ri s e i n ga s tri n l evel a fter i nfus i on of s ecreti n. An el eva ted ba s a l l evel of pa ncrea ti c pol ypepti de or
ga s tri n or a n exa ggera ted res pons e of thes e hormones to a s ta nda rd mea l ma y be the ea rl i es t s i gn of pa ncrea ti c i nvol vement. CT or MRI ca n hel p
l oca l i ze tumors . Beca us e thes e tumors a re often s ma l l a nd di ffi cul t to l oca l i ze, other i ma gi ng tes ts (eg, s oma tos ta ti n receptor s ci nti gra phy,
endos copi c ul tra s onogra phy, i ntra opera ti ve ul tra s onogra phy) ma y be neces s a ry.
Acromega l y i s di a gnos ed by el eva ted growth hormone l evel s tha t a re not s uppres s ed by gl ucos e a dmi ni s tra ti on a nd by el eva ted l evel s of s erum
i ns ul i n-l i ke growth fa ctor 1.
In pa ti ents wi th 2 or more endocri ne a bnorma l i ti es rel a ted to MEN 1 who a re not from a known MEN 1 ki ndred (i ndex ca s e), di rect DNA s equenci ng
of the MEN 1 gene i denti fi es a s peci fi c muta ti on i n 80 to 90%. If a n i ndex ca s e i s i denti fi ed, 1s t-degree rel a ti ves s houl d cons i der geneti c
s creeni ng. Ea rl y pres ymptoma ti c s creeni ng of fa mi l y members of MEN 1 pa ti ents ha s not been s hown to reduce morbi di ty or morta l i ty; a nnua l
cl i ni ca l a nd bi ochemi ca l s creeni ng ma y thus be prefera bl e i n thi s group.
Treatment
Surgi ca l exci s i on when pos s i bl e
Drug ma na gement of hormone exces s
Trea tment of pa ra thyroi d a nd pi tui ta ry l es i ons i s pri ma ri l y s urgi ca l , a l though prol a cti noma i s us ua l l y ma na ged wi th dopa mi ne a goni s ts . Is l et cel l
tumors a re more di ffi cul t to ma na ge beca us e the l es i ons a re often s ma l l a nd di ffi cul t to fi nd a nd mul ti pl e l es i ons a re common. If a s i ngl e tumor
ca nnot be found, tota l pa ncrea tectomy ma y be requi red for a dequa te control of hyperi ns ul i ni s m. Di a zoxi de ma y be a us eful a djunct i n trea ti ng
hypogl ycemi a . Streptozoci n a nd other cytotoxi c drugs ma y a mel i ora te s ymptoms by reduci ng tumor burden.
The trea tment of ga s tri n-s ecreti ng non--cel l tumors i s compl ex. Loca l i za ti on a nd remova l of the tumor s houl d be a ttempted. If l oca l i za ti on i s
i mpos s i bl e, a proton pump i nhi bi tor frequentl y produces s ymptoma ti c rel i ef from pepti c ul cer di s ea s e. Wi th the a va i l a bi l i ty of thes e drugs ,
ga s trectomy i s ra rel y requi red.
Octreoti de, a s oma tos ta ti n a na l og, ca n bl ock hormone s ecreti on from nonga s tri n-s ecreti ng pa ncrea ti c tumors a nd i s wel l tol era ted, pa rti cul a rl y i f
gi ven a s a l ong-a cti ng prepa ra ti on a dmi ni s tered every 4 wk. Pa l l i a ti ve trea tments for meta s ta ti c pa ncrea ti c tumors i ncl ude hepa ti c a rtery
embol i za ti on a nd i nterferon a l fa (i n combi na ti on wi th octreoti de).
Multiple Endocrine Neoplasia, Type 2A
(MEN 2; Mul ti pl e Endocri ne Adenoma tos i s , Type 2; Si ppl e's Syndrome)
Multiple endocrine neoplasia, type 2A (MEN 2A) is a hereditary syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma,
hyperparathyroidism, and occasionally cutaneous lichen amyloidosis. Clinical features depend on the glandular elements affected. Familial medullary thyroid
carcinoma is a distinct variant of MEN 2A. Diagnosis involves genetic testing. Hormonal and imaging tests help locate the tumors, which are removed surgically
when possible.
Muta ti ons i n the RET proto-oncogene on chromos ome 10 ha ve been i denti fi ed i n MEN 2A, MEN 2B, a nd fa mi l i a l medul l a ry thyroi d ca rci noma
(FMTC). The RET protei n i s a receptor tyros i ne ki na s e; MEN 2A a nd FMTC muta ti ons res ul t i n a cti va ti on of certa i n i ntra cel l ul a r pa thwa ys .
Symptoms and Signs
Cl i ni ca l fea tures depend on the type of tumor pres ent (Ta bl e 103-1).
Thyroid: Al mos t a l l pa ti ents ha ve medul l a ry thyroi d ca rci noma (MTCs ee p. 790). The tumor us ua l l y devel ops duri ng chi l dhood a nd begi ns wi th
thyroi d pa ra fol l i cul a r C-cel l hyperpl a s i a . Tumors a re frequentl y mul ti centri c.
Adrenal: Pheochromocytoma us ua l l y ori gi na tes i n the a drena l gl a nds . Pheochromocytoma occurs i n 40 to 50% of pa ti ents wi thi n a MEN 2A ki ndred,
a nd i n s ome ki ndreds pheochromocytoma a ccounts for 30% of dea ths . In contra s t to s pora di c pheochromocytoma (s ee p. 801), the fa mi l i a l va ri ety
wi thi n MEN 2A begi ns wi th a drena l medul l a ry hyperpl a s i a a nd i s mul ti centri c a nd bi l a tera l i n > 50% of ca s es . Extra -a drena l pheochromocytoma s
a re ra re. Pheochromocytoma s a re a l mos t a l wa ys beni gn, but s ome tend to recur l oca l l y.
Pheochromocytoma s tha t occur wi th MEN 2A (a nd 2B) us ua l l y produce epi nephri ne di s proporti ona tel y to norepi nephri ne, i n contra s t to s pora di c
ca s es .
Hypertens i ve cri s i s s econda ry to pheochromocytoma i s a common ma ni fes ta ti on. Hypertens i on i n MEN 2A pa ti ents wi th pheochromocytoma i s
more often pa roxys ma l tha n s us ta i ned, i n contra s t to the us ua l s pora di c ca s e. Pa ti ents wi th pheochromocytoma s ma y ha ve pa roxys ma l
pa l pi ta ti ons , a nxi ety, hea da ches , or s wea ti ng; ma ny a re a s ymptoma ti c.
Parathyroid: Ten to 20% of pa ti ents ha ve evi dence of hyperpa ra thyroi di s m (whi ch ma y be l ong-s ta ndi ng), wi th hyperca l cemi a , nephrol i thi a s i s ,
nephroca l ci nos i s , or rena l fa i l ure. Hyperpa ra thyroi di s m frequentl y i nvol ves mul ti pl e gl a nds a s ei ther di ffus e hyperpl a s i a or mul ti pl e a denoma s ,
a nd mi l d a bnorma l i ti es i n pa ra thyroi d functi on ma y a l s o be pres ent i n MEN 2A.
Other manifestations: Cuta neous l i chen a myl oi dos i s , a pruri ti c, s ca l y, pa pul a r s ki n l es i on, l oca ted i n the i nters ca pul a r regi on or on extens or
s urfa ces , occurs i n s ome MEN 2A ki ndreds . Increa s ed i nci dence of Hi rs chs prung's di s ea s e ha s been reported i n chi l dren i n a t l ea s t one MEN 2A
ki ndred.
Diagnosis
Geneti c tes ti ng
Serum Ca , pa ra thyroi d hormone, a nd pl a s ma free meta nephri ne or uri na ry ca techol a mi ne l evel s i n a ffected pa ti ents
Pheochromocytoma l oca l i za ti on wi th MRI or CT
Ma ny ca s es a re i denti fi ed duri ng s creeni ng of fa mi l y members of known ca s es . MEN 2A s houl d a l s o be s us pected i n pa ti ents wi th bi l a tera l
pheochromocytoma or a t l ea s t 2 of i ts cha ra cteri s ti c endocri ne ma ni fes ta ti ons . The di a gnos i s ca n be confi rmed wi th geneti c tes ti ng. Al though onl y
25% of MTC ca s es a re fa mi l i a l , geneti c tes ti ng of peopl e wi th a ppa rent s pora di c MTC s houl d be cons i dered i f pa ti ents a re < 35 yr, tumors a re
bi l a tera l or mul ti centri c, or a fa mi l y hi s tory i s s us pected.
Beca us e pheochromocytoma ma y be a s ymptoma ti c, i ts excl us i on ma y be di ffi cul t (s ee p. 802). The mos t s ens i ti ve tes ts a re pl a s ma free
meta nephri nes a nd fra cti ona ted uri na ry ca techol a mi nes (pa rti cul a rl y epi nephri ne). CT or MRI i s us eful i n l oca l i zi ng the pheochromocytoma or
es ta bl i s hi ng the pres ence of bi l a tera l l es i ons .
Hyperpa ra thyroi di s m i s di a gnos ed by hyperca l cemi a , hypophos pha temi a , a nd i ncrea s ed pa ra thyroi d hormone l evel .
Screening: Geneti c s creeni ng of fa mi l y members of MEN 2A pa ti ents i s now the di a gnos ti c tes t of choi ce; the a va i l a bi l i ty of s uch tes ti ng ha s ma de
bi ochemi ca l s creeni ng for ea rl y MTC l a rgel y obs ol ete. Among a ffected fa mi l y members , a nnua l s creeni ng for hyperpa ra thyroi di s m a nd
pheochromocytoma s houl d begi n i n ea rl y chi l dhood a nd conti nue i ndefi ni tel y. Screeni ng for hyperpa ra thyroi di s m i s wi th mea s urement of s erum
Ca . Screeni ng for pheochromocytoma i ncl udes ques ti ons a bout s ymptoms , mea s urement of BP, a nd l a bora tory tes ti ng.
Treatment
Surgi ca l exci s i on of i denti fi ed tumors
Prophyl a cti c thyroi dectomy
In pa ti ents pres enti ng wi th pheochromocytoma a nd ei ther MTC or hyperpa ra thyroi di s m, the pheochromocytoma s houl d be removed fi rs t; even i f
a s ymptoma ti c, i t grea tl y i ncrea s es ri s k of other s urgeri es . Once MTC ha s meta s ta s i zed, chemothera py a nd ra di a ti on thera py a re l a rgel y i neffecti ve
i n l engtheni ng s urvi va l but ma y s l ow di s ea s e progres s i on. Ra di oi mmunothera py ha s i mproved s urvi va l i n i ni ti a l s tudi es .
Once geneti c tes ti ng i denti fi es a chi l d a s ha vi ng a RET muta ti on, prophyl a cti c thyroi dectomy i s recommended, genera l l y when the chi l d i s between
4 a nd 6 yr; thi s potenti a l l y fa ta l condi ti on ca n be cured or prevented by ea rl y thyroi dectomy.
Multiple Endocrine Neoplasia, Type 2B
(MEN 3; Mucos a l Neuroma Syndrome; Mul ti pl e Endocri ne Adenoma tos i s , Type 2B)
Multiple endocrine neoplasia, type 2B (MEN 2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple
mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus. Symptoms depend on the glandular elements present. Diagnosis and
treatment are the same as for MEN 2A.
Ni nety-fi ve percent of MEN 2B ca s es res ul t from a s i ngl e a mi no a ci d s ubs ti tuti on i n the RET protei n. More tha n 50% a re de novo muta ti ons a nd
thus s eem to be s pora di c ra ther tha n fa mi l i a l .
Symptoms and Signs
Symptoms a nd s i gns refl ect the gl a ndul a r a bnorma l i ti es pres ent (s ee Ta bl e 103-1). About 50% of pa ti ents ha ve the compl ete s yndrome wi th
mucos a l neuroma s , pheochromocytoma s , a nd medul l a ry thyroi d ca rci noma (MTC). Fewer tha n 10% ha ve neuroma s a nd pheochromocytoma s a l one,
wherea s the rema i ni ng pa ti ents ha ve neuroma s a nd medul l a ry ca rci noma of the thyroi d wi thout pheochromocytoma .
Often, mucos a l neuroma s a re the ea rl i es t s i gn, a nd they occur i n mos t or a l l pa ti ents . Neuroma s a ppea r a s s ma l l gl i s teni ng bumps on the l i ps ,
tongue, a nd bucca l mucos a . The eyel i ds , conjuncti va e, a nd cornea s a l s o commonl y devel op neuroma s . Thi ckened eyel i ds a nd di ffus el y
hypertrophi ed l i ps a re cha ra cteri s ti c. GI a bnorma l i ti es rel a ted to a l tered moti l i ty (cons ti pa ti on, di a rrhea , a nd, occa s i ona l l y, mega col on) a re
common a nd thought to res ul t from di ffus e i ntes ti na l ga ngl i oneuroma tos i s . Pa ti ents ma y ha ve a ma rfa noi d ha bi tus . Skel eta l a bnorma l i ti es of the
s pi ne (l ordos i s , kyphos i s , s col i os i s ), pes ca vus , a nd ta l i pes equi nova rus a re common.
MTC a nd pheochromocytoma res embl e the corres pondi ng di s orders i n MEN 2A s yndrome; both tend to be bi l a tera l a nd mul ti centri c. MTC, however,
tends to be pa rti cul a rl y a ggres s i ve i n MEN 2B a nd ma y be pres ent i n very young chi l dren.
Al though the neuroma s , fa ci a l cha ra cteri s ti cs , a nd GI di s orders a re pres ent a t a n ea rl y a ge, the s yndrome ma y not be recogni zed unti l MTC or
pheochromocytoma ma ni fes ts i n l a ter l i fe.
Diagnosis
Geneti c tes ti ng
Pl a s ma free meta nephri ne or uri na ry ca techol a mi ne l evel s
Pheochromocytoma l oca l i za ti on wi th MRI or CT
MEN 2B i s s us pected i n pa ti ents wi th a fa mi l y hi s tory of MEN 2B, pheochromocytoma , mul ti pl e mucos a l neuroma s , or MTC. Geneti c tes ti ng i s hi ghl y
a ccura te a nd i s done i n 1s t-degree rel a ti ves a nd a ny s ymptoma ti c fa mi l y members of MEN 2B pa ti ents .
Pheochromocytoma ma y be s us pected cl i ni ca l l y a nd i s confi rmed by mea s uri ng pl a s ma free meta nephri nes or uri na ry ca techol a mi nes (s ee p. 802).
La bora tory tes ti ng for MTC ma y be done (s ee p. 790). MRI or CT i s us ed to s ea rch for pheochromocytoma s a nd MTC.
Treatment
Surgi ca l exci s i on of i denti fi ed tumors
Prophyl a cti c thyroi dectomy
Affected pa ti ents s houl d ha ve tota l thyroi dectomy a s s oon a s the di a gnos i s i s es ta bl i s hed. Pheochromocytoma , i f pres ent, s houl d be removed
before thyroi dectomy i s done. Gene ca rri ers s houl d undergo prophyl a cti c thyroi dectomy i n i nfa ncy or ea rl y chi l dhood.
9 - Hematology and Oncology

Chapter 104. Approach to the Patient With Anemia
Introduction
Red bl ood cel l (RBC) producti on (erythropoi es i s ) ta kes pl a ce i n the bone ma rrow under the control of the hormone erythropoi eti n (EPO).
Juxta gl omerul a r cel l s i n the ki dney produce EPO i n res pons e to decrea s ed O2 del i very (a s i n a nemi a a nd hypoxi a ) a nd i ncrea s ed l evel s of
a ndrogens . In a ddi ti on to EPO, RBC producti on requi res a dequa te s uppl i es of s ubs tra tes , ma i nl y i ron, vi ta mi n B 12 , a nd fol a te. Vi ta mi n B 12 a nd
fol a te a re di s cus s ed i n Ch. 4; i ron i s di s cus s ed on pp. 53 a nd 924.
RBCs become s enes cent a fter a bout 120 da ys . They then l os e thei r cel l membra nes a nd a re l a rgel y cl ea red from the ci rcul a ti on by the pha gocyti c
cel l s of the s pl een, l i ver, a nd bone ma rrow. Hb i s broken down i n thes e cel l s a nd i n hepa tocytes pri ma ri l y by the heme oxygena s e s ys tem wi th
cons erva ti on (a nd s ubs equent reuti l i za ti on) of i ron, degra da ti on of heme to bi l i rubi n through a s eri es of enzyma ti c s teps , a nd reuti l i za ti on of
protei n. Ma i ntena nce of a s tea dy number of RBCs requi res da i l y renewa l of 1/120 of the cel l s ; i mma ture RBCs (reti cul ocytes ) a re conti nua l l y
rel ea s ed a nd cons ti tute 0.5 to 1.5% of the peri phera l RBC popul a ti on.
Low l evel s of a ndrogens l ea di ng to decrea s ed EPO l evel s i n women a nd gi rl s a nd i n el derl y pa ti ents ca n predi s pos e to a nemi a , a s does the
decl i ne i n the ca pa ci ty of bone ma rrow to produce RBCs . Wi th a gi ng, Hb a nd Hct decrea s e s l i ghtl y, but not bel ow norma l va l ues . In women, other
fa ctors tha t frequentl y contri bute to l ower l evel s of RBCs i ncl ude cumul a ti ve mens trua l bl ood l os s a nd i ncrea s ed dema nd for i ron due to mul ti pl e
pregna nci es .
Etiology of Anemia
Anemi a i s a decrea s e i n the number of RBCs , Hct, or Hb content.
The RBC ma s s repres ents the ba l a nce between producti on a nd des tructi on or l os s of RBCs . Thus , a nemi a ca n res ul t from one or more of 3 ba s i c
mecha ni s ms (s ee
Ta bl e 104-1):
[Table 104-1. Cl a s s i fi ca ti on of Anemi a by Ca us e]
Bl ood l os s
Defi ci ent erythropoi es i s
Exces s i ve hemol ys i s (RBC des tructi on)
Blood loss ca n be a cute or chroni c. Anemi a does not devel op unti l s evera l hours a fter a cute bl ood l os s , when i nters ti ti a l fl ui d di ffus es i nto the
i ntra va s cul a r s pa ce a nd di l utes the rema i ni ng RBC ma s s . Duri ng the fi rs t few hours , however, l evel s of pol ymorphonucl ea r gra nul ocytes , pl a tel ets ,
a nd, i n s evere hemorrha ge, i mma ture WBCs a nd normobl a s ts ma y ri s e. Chroni c bl ood l os s res ul ts i n a nemi a i f l os s i s more ra pi d tha n ca n be
repl a ced or, more commonl y, i f a ccel era ted erythropoi es i s depl etes body i ron s tores (s ee p. 924).
Deficient erythropoiesis (s ee p. 924) ha s myri a d ca us es . Compl ete ces s a ti on of erythropoi es i s res ul ts i n a decl i ne i n RBCs of a bout 7 to 10%/wk
(1%/da y). Impa i red erythropoi es i s , even i f not s uffi ci ent to decrea s e the numbers of RBCs , often ca us es a bnorma l RBC s i ze a nd s ha pe.
Excessive hemolysis (s ee p. 934) ca n be ca us ed by i ntri ns i c a bnorma l i ti es of RBCs or by extri ns i c fa ctors , s uch a s the pres ence of a nti bodi es on thei r
s urfa ce, tha t l ea d to thei r ea rl y des tructi on. An enl a rged s pl een s eques ters a nd des troys RBCs more ra pi dl y tha n norma l . Some ca us es of
hemol ys i s deform a s wel l a s des troy RBCs . Exces s i ve hemol ys i s does not norma l l y decrea s e reti cul ocyte producti on unl es s i ron or other es s enti a l
nutri ents a re depl eted.
Evaluation of Anemia
Anemi a i s not a di a gnos i s ; i t i s a ma ni fes ta ti on of a n underl yi ng di s order. Thus , even mi l d, a s ymptoma ti c a nemi a s houl d be i nves ti ga ted s o tha t
the pri ma ry probl em ca n be di a gnos ed a nd trea ted.
Acute or chroni c bl ood l os s i s the fi rs t cons i dera ti on. The di a gnos i s us ua l l y i s ba s ed on hi s tory, exa mi na ti on, a nd a s tool tes t for occul t bl ood.
Further tes ti ng for occul t bl eedi ng i s s ometi mes neces s a ry.
If bl ood l os s i s not detected, l a bora tory tes ti ng i s us ua l l y done to determi ne whether a nemi a i s due to defi ci ent RBC producti on or exces s i ve
hemol ys i s .
History
The hi s tory s houl d a ddres s ri s k fa ctors for pa rti cul a r a nemi a s , s ymptoms of a nemi a i ts el f, a nd s ymptoms tha t refl ect the underl yi ng di s order.
Anemi a ha s ma ny ri s k fa ctors . For exa mpl e, a vega n di et predi s pos es to vi ta mi n B 12 defi ci ency a nemi a , wherea s a l cohol i s m i ncrea s es the ri s k of
fol a te defi ci ency a nemi a . A number of hemogl obi nopa thi es a re i nheri ted, a nd certa i n drugs predi s pos e to hemol ys i s . Ca ncer, rheuma ti c
di s orders , a nd chroni c i nfl a mma tory di s orders ca n s uppres s bone ma rrow a cti vi ty or enl a rge the s pl een.
The s ymptoms of a nemi a a re nei ther s ens i ti ve nor s peci fi c a nd do not hel p di fferenti a te between types of a nemi a s . Symptoms refl ect
compens a tory res pons es to ti s s ue hypoxi a a nd us ua l l y devel op when Hb fa l l s to < 7 g/dL. However, they ma y devel op a t hi gher Hb l evel s i n
pa ti ents wi th l i mi ted ca rdi opul mona ry res erve or i n whom the a nemi a devel oped very ra pi dl y. Symptoms s uch a s wea knes s , s eei ng s pots , fa ti gue,
drows i nes s , a ngi na , s yncope, a nd dys pnea on exerti on ca n i ndi ca te a nemi a . Verti go, hea da che, pul s a ti l e ti nni tus , a menorrhea , l os s of l i bi do, a nd
GI compl a i nts ma y a l s o occur. Hea rt fa i l ure or s hock ca n devel op i n pa ti ents wi th s evere ti s s ue hypoxi a or hypovol emi a .
Certa i n s ymptoms ma y s ugges t the ca us e of the a nemi a . For exa mpl e, mel ena , epi s ta xi s , hema tochezi a , hema temes i s , or menorrha gi a i ndi ca tes
bl eedi ng. Ja undi ce a nd da rk uri ne, i n the a bs ence of l i ver di s ea s e, s ugges t hemol ys i s . Wei ght l os s ma y s ugges t ca ncer. Di ffus e s evere bone or
ches t pa i n ma y s ugges t s i ckl e cel l di s ea s e, a nd s tocki ng-gl ove pa res thes i a s ma y s ugges t vi ta mi n B 12 or fol a te defi ci ency.
Compl ete phys i ca l exa mi na ti on i s neces s a ry. Si gns of a nemi a i ts el f a re nei ther s ens i ti ve nor s peci fi c; however, pa l l or i s common wi th s evere
a nemi a .
Si gns of underl yi ng di s orders a re often more di a gnos ti ca l l y a ccura te tha n a re s i gns of a nemi a . Heme-pos i ti ve s tool i denti fi es GI bl eedi ng.
Hemorrha gi c s hock (eg, hypotens i on, ta chyca rdi a , pa l l or, ta chypnea , di a phores i s , confus i ons ee p. 2292) ma y res ul t from a cute bl eedi ng. Ja undi ce
ma y s ugges t hemol ys i s . Spl enomega l y ma y occur wi th hemol ys i s , hemogl obi nopa thy, connecti ve ti s s ue di s ea s e, myel oprol i fera ti ve di s order,
i nfecti on, or ca ncer. Peri phera l neuropa thy s ugges ts vi ta mi n B 12 defi ci ency. Abdomi na l di s tenti on i n a pa ti ent wi th bl unt tra uma s ugges ts a cute
hemorrha ge. Petechi a e devel op i n thrombocytopeni a or pl a tel et dys functi on. Fever a nd hea rt murmurs s ugges t i nfecti ous endoca rdi ti s , a pos s i bl e
ca us e of hemol ys i s . Ra rel y, hi gh-output hea rt fa i l ure devel ops a s a compens a tory res pons e to a nemi a -i nduced ti s s ue hypoxi a .
Testing
CBC wi th WBC a nd pl a tel ets
RBC i ndi ces a nd morphol ogy
Reti cul ocyte count
Peri phera l s mea r
Someti mes bone ma rrow a s pi ra ti on a nd bi ops y
La bora tory eva l ua ti on begi ns wi th a CBC, i ncl udi ng WBC a nd pl a tel et counts , RBC i ndi ces a nd morphol ogy (MCV, MCH, MCHC, RBC vol ume
di s tri buti on wi dth [RDW]), a nd exa mi na ti on of the peri phera l s mea r. Reti cul ocyte count demons tra tes how wel l the bone ma rrow compens a tes for
the a nemi a . Subs equent tes ts a re s el ected on the ba s i s of thes e res ul ts a nd on the cl i ni ca l pres enta ti on. Recogni ti on of genera l di a gnos ti c
pa tterns ca n expedi te the di a gnos i s (s ee
Ta bl e 104-2).
The automated CBC di rectl y mea s ures Hb, RBC count, a nd MCV (a mea s ure of RBC s i ze). Hct (a mea s ure of the percenta ge of bl ood ma de up of RBCs ),
MCH (a mea s ure of the Hb content i n i ndi vi dua l RBCs ), a nd MCHC (a mea s ure of the Hb l evel i n i ndi vi dua l RBCs ) a re ca l cul a ted va l ues . The
di a gnos ti c cri teri on for a nemi a i n men i s Hb < 14 g/dL, Hct < 42%, or RBC < 4.5 mi l l i on/L; for women, Hb < 12 g/dL, Hct < 37%, or RBC < 4 mi l l i on/L. For
i nfa nts , norma l va l ues va ry wi th a ge, neces s i ta ti ng us e of a ge-rel a ted ta bl es . RBC popul a ti ons a re termed mi crocyti c (s ma l l cel l s ) i f MCV i s < 80 fL,
a nd ma crocyti c (l a rge cel l s ) i f MCV i s > 100 fL. However, beca us e reti cul ocytes a re a l s o l a rger tha n ma ture red cel l s , l a rge numbers of reti cul ocytes
ca n el eva te the MCV a nd not repres ent a n a l tera ti on of RBC producti on. Automa ted techni ques ca n a l s o determi ne the degree of va ri a ti on i n RBC
s i ze, expres s ed a s the RDW. A hi gh RDW ma y be the onl y i ndi ca ti on of s i mul ta neous mi crocyti c a nd ma crocyti c di s orders (or s i mul ta neous
mi crocytos i s a nd reti cul ocytos i s ); s uch a pa ttern ma y res ul t i n a norma l MCV, whi ch mea s ures onl y the mea n va l ue. The term hypochromi a refers to
RBC popul a ti ons i n whi ch MCH i s < 27 pg/RBC or MCHC i s < 30%. RBC popul a ti ons wi th norma l MCH a nd MCHC va l ues a re normochromi c.
The RBC indices ca n hel p i ndi ca te the mecha ni s m of a nemi a a nd na rrow the number of pos s i bl e ca us es . Mi crocyti c i ndi ces occur wi th a l tered heme
or gl obi n s ynthes i s . The mos t common ca us es a re i ron defi ci ency, tha l a s s emi a , a nd rel a ted Hb-s ynthes i s defects . In s ome pa ti ents wi th a nemi a
of chroni c di s ea s e, the MCV i s mi crocyti c or borderl i ne mi crocyti c. Ma crocyti c i ndi ces occur wi th i mpa i red DNA s ynthes i s (eg, due to vi ta mi n B 12 or
fol a te defi ci enci es or chemothera peuti c drugs s uch a s hydroxyurea a nd a nti fol a te a gents ) a nd i n a l cohol i s m beca us e of a bnorma l i ti es of the cel l
membra ne. Acute bl eedi ng ma y bri efl y produce ma crocyti c i ndi ces beca us e of the rel ea s e of l a rge young reti cul ocytes . Normocyti c i ndi ces occur i n
a nemi a s res ul ti ng from defi ci ent EPO or i na dequa te res pons e to i t (hypoprol i fera ti ve a nemi a s ). Hemorrha ge, before i ron defi ci ency devel ops ,
us ua l l y res ul ts i n normocyti c a nd normochromi c a nemi a unl es s the number of l a rge reti cul ocytes i s exces s i ve.
The peripheral smear i s hi ghl y s ens i ti ve for exces s i ve RBC producti on a nd hemol ys i s . It i s more a ccura te tha n a utoma ted technol ogi es for
recogni ti on of a l tered RBC s tructure, thrombocytopeni a , nucl ea ted RBCs , or i mma ture gra nul ocytes a nd ca n detect other a bnorma l i ti es (eg, ma l a ri a
a nd other pa ra s i tes , i ntra cel l ul a r RBC or gra nul ocyte i ncl us i ons ) tha t ca n occur des pi te norma l a utoma ted bl ood cel l counts . RBC i njury ma y be
i denti fi ed by fi ndi ng RBC fra gments , porti ons of di s rupted cel l s (s chi s tocytes ), or evi dence of s i gni fi ca nt membra ne a l tera ti ons from ova l -s ha ped
cel l s (ova l ocytes ) or s pherocyti c cel l s . Ta rget cel l s (thi n RBCs wi th a centra l dot of Hb) a re RBCs wi th i ns uffi ci ent Hb or exces s cel l membra ne (eg,
due to hemogl obi nopa thi es or l i ver di s orders ). The peri phera l s mea r ca n a l s o revea l va ri a ti on i n RBC s ha pe (poi ki l ocytos i s ) a nd s i ze
(a ni s ocytos i s ).
The reticulocyte count i s expres s ed a s the percenta ge of reti cul ocytes (norma l ra nge, 0.5 to 1.5%) or a s the a bs ol ute reti cul ocyte count (norma l ra nge,
50,000 to 150,000/L). Hi gher va l ues i ndi ca te exces s i ve producti on, or reti cul ocytos i s ; i n the pres ence of a nemi a , reti cul ocytos i s s ugges ts exces s i ve
RBC des tructi on. Low numbers i n the pres ence of a nemi a i ndi ca te decrea s ed RBC producti on. The reti cul ocyte res pons e ca n us ua l l y be es ti ma ted
ba s ed on the number of bl ue-s ta i ned cel l s found when the peri phera l s mea r i s s ta i ned wi th a s upra vi ta l s ta i n; thi s es ti ma tes ma kes a
reti cul ocyte count, whi ch requi res fl ow cytometry or a l a rge a mount of ti me, unneces s a ry.
Bone marrow aspiration and biopsy provi de di rect obs erva ti on a nd a s s es s ment of RBC precurs ors . The pres ence of a bnorma l ma tura ti on (dys poi es i s )
of bl ood cel l s a nd the a mount, di s tri buti on, a nd cel l ul a r pa ttern of i ron content ca n be a s s es s ed. Bone ma rrow a s pi ra ti on a nd bi ops y a re done to
di a gnos e the fol l owi ng condi ti ons :
Unexpl a i ned a nemi a s
Other cytopeni a s
Unexpl a i ned l eukocytos i s

[Table 104-2. Cha ra cteri s ti cs of Common Anemi a s ]
Thrombocytos i s
Sus pected l eukemi a , mul ti pl e myel oma , or myel ophthi s i s
Cytogeneti c a nd mol ecul a r a na l ys es ca n be done on a s pi ra te ma teri a l i n hema topoi eti c or other tumors or i n s us pected congeni ta l l es i ons of RBC
precurs ors (eg, Fa nconi 's a nemi a ). Fl ow cytometry ca n be done i n s us pected l ymphoprol i fera ti ve or myel oprol i fera ti ve s ta tes to defi ne the
i mmunophenotype. Bone ma rrow a s pi ra ti on a nd bi ops y a re not techni ca l l y di ffi cul t a nd do not pos e s i gni fi ca nt ri s k of morbi di ty. Thes e
procedures a re s a fe a nd hel pful when hema tol ogi c di s ea s e i s s us pected. Both us ua l l y ca n be done a s a s i ngl e procedure. Beca us e bi ops y
requi res a dequa te bone depth, the s a mpl e i s us ua l l y ta ken from the pos teri or (or, l es s commonl y, a nteri or) i l i a c cres t. If onl y a s pi ra ti on i s
neces s a ry, the s ternum ma y be us ed.
Serum bi l i rubi n a nd LDH ca n s ometi mes hel p di fferenti a te between hemol ys i s a nd bl ood l os s ; both a re el eva ted i n hemol ys i s a nd norma l i n
bl ood l os s . Other tes ts a re di s cus s ed under s peci fi c a nemi a s a nd bl eedi ng di s orders (s ee p. 921).
Treatment of Anemia
When pos s i bl e, the ca us e of the a nemi a i s trea ted. When the Hb fa l l s da ngerous l y l ow (eg, < 7 g/dL for pa ti ents wi thout ca rdi opul mona ry
i ns uffi ci ency or hi gher for pa ti ents wi th i t), RBC tra ns fus i on tempora ri l y i ncrea s es O2 -ca rryi ng ca pa ci ty. RBC tra ns fus i on s houl d be res erved for
pa ti ents
Wi th or a t hi gh ri s k of ca rdi opul mona ry s ymptoms
Wi th a cti ve, uncontrol l a bl e bl ood l os s
Wi th s ome form of hypoxi c or i s chemi c end-orga n fa i l ure (eg, neurol ogi c i s chemi c s ymptoms , a ngi na , ta chyca rdi a i n pa ti ents wi th underl yi ng
hea rt fa i l ure or s evere COPD)
Tra ns fus i on procedures a nd bl ood components a re di s cus s ed i n Ch. 121.
Chapter 105. Anemias Caused by Deficient Erythropoiesis

Introduction
Anemi a (a decrea s e i n the number of RBCs , Hb content, or Hct) ca n res ul t from decrea s ed RBC producti on (erythropoi es i s ), i ncrea s ed RBC
des tructi on, or bl ood l os s . Anemi a s due to decrea s ed erythropoi es i s a re recogni zed by reti cul ocytopeni a , whi ch i s us ua l l y evi dent on the
peri phera l s mea r (s ee p. 921). The RBC i ndi ces , ma i nl y the MCV, na rrow the di fferenti a l di a gnos i s of defi ci ent erythropoi es i s a nd determi ne wha t
further tes ti ng i s neces s a ry.
Microcytic anemias res ul t from defi ci ent or defecti ve heme or gl obi n s ynthes i s . Mi crocyti c a nemi a s i ncl ude i ron defi ci ency a nemi a s , i ron-tra ns port
defi ci ency a nemi a s , i ron-uti l i za ti on a nemi a s (i ncl udi ng s ome s i derobl a s ti c a nemi a s a nd l ea d poi s oni ng), a nd tha l a s s emi a s (whi ch a l s o ca us e
hemol ys i s s ee p. 946). Pa ti ents wi th mi crocyti c a nemi a s typi ca l l y requi re tes ti ng of i ron s tores (s ee bel ow).
Normocytic anemias res ul t from pri ma ry bone ma rrow fa i l ure. They a re us ua l l y cha ra cteri zed by a norma l RBC di s tri buti on wi dth (RDW) a nd
normochromi c i ndi ces . The mecha ni s ms i nvol ved a re hypoprol i fera ti on (defi ci ency of or i na dequa te res pons e to erythropoi eti n [EPO]), hypopl a s i a
(i n a pl a s ti c a nemi a ), myel ophthi s i s , a nd myel odys pl a s i a .
Macrocytic anemias res ul t mos t often from i mpa i red DNA s ynthes i s , a s occurs wi th defi ci enci es of vi ta mi n B 12 or fol a te.
Some a nemi a s ha ve va ri a bl e fi ndi ngs on the peri phera l s mea r. Anemi a of chroni c di s ea s e ma y be mi crocyti c or normocyti c. Anemi a s due to
myel odys pl a s ti c s yndromes ma y be mi crocyti c, normocyti c, or ma crocyti c. Trea tment of defi ci ent RBC producti on depends on the ca us e; however,
s ti mul a ti on of erythropoi es i s wi th huma n recombi na nt EPO often i s hel pful i n the a nemi a due to rena l fa i l ure. Beca us e erythropoi es i s i ncrea s es
the i ron requi rement, s uppl ementa l i ron i s hel pful when a dmi ni s teri ng a ny trea tment tha t a i ms to i ncrea s e erythropoi es i s .
Iron Deficiency Anemia
(Anemi a of Chroni c Bl ood Los s ; Chl oros i s )
Iron deficiency is the most common cause of anemia and usually results from blood loss. Symptoms are usually nonspecific. RBCs tend to be microcytic and
hypochromic, and iron stores are low as shown by low serum ferritin and low serum iron levels with high serum total iron binding capacity. If the diagnosis is
made, occult blood loss is suspected. Treatment involves iron replacement and treatment of the cause of blood loss.
Pathophysiology
Iron i s di s tri buted i n a cti ve meta bol i c a nd s tora ge pool s . Tota l body i ron i s a bout 3.5 g i n hea l thy men a nd 2.5 g i n women; the di fference rel a tes
to women's s ma l l er body s i ze, l ower a ndrogen l evel s , a nd dea rth of s tored i ron beca us e of i ron l os s due to mens es a nd pregna ncy. The
di s tri buti on of body i ron i n a n a vera ge ma n i s Hb, 2100 mg; ferri ti n, 700 mg (i n cel l s a nd pl a s ma ); hemos i deri n, 300 mg (i n cel l s ); myogl obi n, 200
mg; ti s s ue (heme a nd nonheme) enzymes , 150 mg; a nd tra ns port-i ron compa rtment, 3 mg.
Iron absorption: Iron i s a bs orbed i n the duodenum a nd upper jejunum. Abs orpti on of i ron i s determi ned by the type of i ron mol ecul e a nd by wha t
other s ubs ta nces a re i nges ted. Iron a bs orpti on i s bes t when food conta i ns heme i ron (mea t). Di eta ry nonheme i ron mus t be reduced to the
ferrous s ta te a nd rel ea s ed from food bi nders by ga s tri c s ecreti ons . Nonheme i ron a bs orpti on i s reduced by other food i tems (eg, vegeta bl e fi ber
phyta tes a nd pol yphenol s ; tea ta nna tes , i ncl udi ng phos phoprotei ns ; bra n) a nd certa i n a nti bi oti cs (eg, tetra cycl i ne). As corbi c a ci d i s the onl y
common food el ement known to i ncrea s e nonheme i ron a bs orpti on.
The a vera ge Ameri ca n di et, whi ch conta i ns 6 mg of el ementa l i ron/kca l of food, i s a dequa te for i ron homeos ta s i s . Of a bout 15 mg/da y of di eta ry
i ron, a dul ts a bs orb onl y 1 mg, whi ch i s the a pproxi ma te a mount l os t da i l y by cel l des qua ma ti on from the s ki n a nd i ntes ti nes . In i ron depl eti on,
a bs orpti on i ncrea s es , a l though the exa ct s i gna l i ng mecha ni s m i s not known; however, a bs orpti on ra rel y i ncrea s es to > 6 mg/da y unl es s
s uppl ementa l i ron i s a dded. Chi l dren ha ve a grea ter need for i ron a nd a ppea r to a bs orb more to meet thi s need.
Iron transport and usage: Iron from i ntes ti na l mucos a l cel l s i s tra ns ferred to tra ns ferri n, a n i ron-tra ns port protei n s ynthes i zed i n the l i ver; tra ns ferri n
ca n tra ns port i ron from cel l s (i ntes ti na l , ma cropha ges ) to s peci fi c receptors on erythrobl a s ts , pl a centa l cel l s , a nd l i ver cel l s . For heme s ynthes i s ,
tra ns ferri n tra ns ports i ron to the erythrobl a s t mi tochondri a , whi ch i ns ert the i ron i nto protoporphyri n for i t to become heme. Tra ns ferri n (pl a s ma
ha l f-l i fe, 8 da ys ) i s extruded for reuti l i za ti on. Synthes i s of tra ns ferri n i ncrea s es wi th i ron defi ci ency but decrea s es wi th a ny type of chroni c
di s ea s e.
Iron storage and recycling: Iron not us ed for erythropoi es i s i s tra ns ferred by tra ns ferri n, a n i ron-tra ns porti ng protei n, to the s tora ge pool ; i ron i s
s tored i n 2 forms , ferri ti n a nd hemos i deri n. The mos t i mporta nt i s ferri ti n (a heterogeneous group of protei ns s urroundi ng a n i ron core), whi ch i s a
s ol ubl e a nd a cti ve s tora ge fra cti on l oca ted i n the l i ver (i n hepa tocytes ), bone ma rrow, a nd s pl een (i n ma cropha ges ); i n RBCs ; a nd i n s erum. Iron
s tored i n ferri ti n i s rea di l y a va i l a bl e for a ny body requi rement. Ci rcul a ti ng (s erum) ferri ti n l evel pa ra l l el s the s i ze of the body s tores (1 ng/mL = 8
mg of i ron i n the s tora ge pool ). The 2nd s tora ge pool of i ron i s i n hemos i deri n, whi ch i s rel a ti vel y i ns ol ubl e a nd i s s tored pri ma ri l y i n the l i ver (i n
Kupffer cel l s ) a nd i n bone ma rrow (i n ma cropha ges ).
Beca us e i ron a bs orpti on i s s o l i mi ted, the body recycl es a nd cons erves i ron. Tra ns ferri n gra s ps a nd recycl es a va i l a bl e i ron from a gi ng RBCs
undergoi ng pha gocytos i s by mononucl ea r pha gocytes . Thi s mecha ni s m provi des a bout 97% of the da i l y i ron needed (a bout 25 mg of i ron). Wi th
a gi ng, i ron s tores tend to i ncrea s e beca us e i ron el i mi na ti on i s s l ow.
Iron deficiency: Defi ci ency devel ops i n s ta ges . In the fi rs t s ta ge, i ron requi rement exceeds i nta ke, ca us i ng progres s i ve depl eti on of bone ma rrow
i ron s tores . As s tores decrea s e, a bs orpti on of di eta ry i ron i ncrea s es i n compens a ti on. Duri ng l a ter s ta ges , defi ci ency i mpa i rs RBC s ynthes i s ,
ul ti ma tel y ca us i ng a nemi a .
Severe a nd prol onged i ron defi ci ency a l s o ma y ca us e dys functi on of i ron-conta i ni ng cel l ul a r enzymes .
Etiology
Beca us e i ron i s poorl y a bs orbed, di eta ry i ron ba rel y meets the da i l y requi rement for mos t peopl e. Even s o, peopl e who ea t a typi ca l Wes tern di et
a re unl i kel y to become i ron defi ci ent s ol el y a s a res ul t of di eta ry defi ci ency. However, even modes t l os s es , i ncrea s ed requi rements , or decrea s ed
i nta ke rea di l y ca us es i ron defi ci ency.
Blood loss i s a l mos t a l wa ys the ca us e. In men, the mos t frequent ca us e i s chroni c occul t bl eedi ng, us ua l l y from the GI tra ct. In premenopa us a l
women, cumul a ti ve mens trua l bl ood l os s (mea n, 0.5 mg i ron/da y) i s a common ca us e. Another pos s i bl e ca us e of bl ood l os s i n men a nd women i s
chroni c i ntra va s cul a r hemol ys i s (s ee p. 934) when the a mount of i ron rel ea s ed duri ng hemol ys i s exceeds the ha ptogl obi n-bi ndi ng ca pa ci ty.
Vi ta mi n C defi ci ency ca n contri bute to i ron defi ci ency a nemi a by ca us i ng ca pi l l a ry fra gi l i ty, hemol ys i s , a nd bl eedi ng.
Increased iron requirement ma y contri bute to i ron defi ci ency. From bi rth to a ge 2 a nd duri ng a dol es cence, when ra pi d growth requi res a l a rge i ron
i nta ke, di eta ry i ron often i s i na dequa te. Duri ng pregna ncy, the feta l i ron requi rement i ncrea s es the ma terna l i ron requi rement (mea n, 0.5 to 0.8
mg/da ys ee Anemi a i n Pregna ncy on p. 2634) des pi te the a bs ence of mens es . La cta ti on a l s o i ncrea s es the i ron requi rement (mea n, 0.4 mg/da y).
Decreased iron absorption ca n res ul t from ga s trectomy a nd upper s ma l l -bowel ma l a bs orpti on s yndromes . Ra rel y, a bs orpti on i s decrea s ed by di eta ry
depri va ti on from undernutri ti on.
Symptoms and Signs
Mos t s ymptoms of i ron defi ci ency a re due to a nemi a . Such s ymptoms i ncl ude fa ti gue, l os s of s ta mi na , s hortnes s of brea th, wea knes s , di zzi nes s ,
a nd pa l l or. Fa ti gue a l s o ma y res ul t from dys functi on of i ron-conta i ni ng cel l ul a r enzymes .
In a ddi ti on to the us ua l ma ni fes ta ti ons of a nemi a , s ome uncommon s ymptoms occur i n s evere i ron defi ci ency. Pa ti ents ma y ha ve pi ca , a n
a bnorma l cra vi ng to ea t s ubs ta nces (eg, i ce, di rt, pa i nt). Other s ymptoms of s evere defi ci ency i ncl ude gl os s i ti s , chei l os i s , conca ve na i l s
(koi l onychi a ), a nd, ra rel y, dys pha gi a ca us ed by a pos tcri coi d es opha gea l web (Pl ummer-Vi ns on s yndrome).
Diagnosis
CBC, s erum i ron, i ron-bi ndi ng ca pa ci ty, a nd s erum ferri ti n
Ra rel y bone ma rrow exa mi na ti on
Iron defi ci ency a nemi a i s s us pected i n pa ti ents wi th chroni c bl ood l os s or mi crocyti c a nemi a , pa rti cul a rl y i f pi ca i s pres ent. In s uch pa ti ents , CBC,
s erum i ron a nd i ron-bi ndi ng ca pa ci ty, a nd s erum ferri ti n a re obta i ned.
Iron a nd i ron-bi ndi ng ca pa ci ty (or tra ns ferri n) a re us ua l l y both mea s ured beca us e thei r rel a ti ons hi p i s i mporta nt. Va ri ous tes ts exi s t; the ra nge of
norma l va l ues rel a tes to the tes t us ed. In genera l , norma l s erum i ron i s 75 to 150 g/dL (13 to 27 mol /L) for men a nd 60 to 140 g/dL (11 to 25
mol /L) for women; tota l i ron-bi ndi ng ca pa ci ty i s 250 to 450 g/dL (45 to 81 mol /L). Serum i ron l evel i s l ow i n i ron defi ci ency a nd i n ma ny chroni c
di s ea s es a nd i s el eva ted i n hemol yti c di s orders a nd i n i ron-overl oa d s yndromes (s ee p. 1032). Pa ti ents ta ki ng ora l i ron ma y ha ve norma l s erum
i ron des pi te a defi ci ency; i n s uch ci rcums ta nces , a va l i d tes t requi res ces s a ti on of i ron thera py for 24 to 48 h. The i ron-bi ndi ng ca pa ci ty i ncrea s es
i n i ron defi ci ency. Serum tra ns ferri n receptor l evel s refl ect the a mount of RBC precurs ors a va i l a bl e for a cti ve prol i fera ti on; l evel s a re s ens i ti ve a nd
s peci fi c. The ra nge of norma l i s 3.0 to 8.5 g/mL. Level s i ncrea s e i n ea rl y i ron defi ci ency a nd wi th i ncrea s ed erythropoi es i s .
Serum ferri ti n l evel s cl os el y correl a te wi th tota l body i ron s tores . The ra nge of norma l i n mos t l a bora tori es i s 30 to 300 ng/mL, a nd the mea n i s 88
ng/mL i n men a nd 49 ng/mL i n women. Low l evel s (< 12 ng/mL) a re s peci fi c for i ron defi ci ency. However, ferri ti n i s a n a cute-pha s e rea cta nt, a nd
l evel s i ncrea s e i n i nfl a mma tory a nd neopl a s ti c di s orders , s o ferri ti n ma y a l s o be el eva ted i n ca s es of l i ver i njury (eg, hepa ti ti s ) a nd i n s ome
tumors (es peci a l l y a cute l eukemi a , Hodgki n l ymphoma , a nd GI tra ct tumors ).
The mos t s ens i ti ve a nd s peci fi c cri teri on for i ron-defi ci ent erythropoi es i s i s a bs ent bone ma rrow s tores of i ron, a l though a bone ma rrow
exa mi na ti on i s ra rel y needed.
Stages of iron deficiency: La bora tory tes t res ul ts hel p s ta ge i ron defi ci ency a nemi a .
Sta ge 1 i s cha ra cteri zed by decrea s ed bone ma rrow i ron s tores ; Hb a nd s erum i ron rema i n norma l , but s erum ferri ti n l evel fa l l s to < 20 ng/mL. The
compens a tory i ncrea s e i n i ron a bs orpti on ca us es a n i ncrea s e i n i ron-bi ndi ng ca pa ci ty (tra ns ferri n l evel ).
Duri ng s ta ge 2, erythropoi es i s i s i mpa i red. Al though the tra ns ferri n l evel i s i ncrea s ed, the s erum i ron l evel decrea s es ; tra ns ferri n s a tura ti on
decrea s es . Erythropoi es i s i s i mpa i red when s erum i ron fa l l s to < 50 g/dL (< 9 mol /L) a nd tra ns ferri n s a tura ti on to < 16%. The s erum ferri ti n
receptor l evel ri s es (> 8.5 mg/L).
Duri ng s ta ge 3, a nemi a wi th norma l -a ppea ri ng RBCs a nd i ndi ces devel ops .
Duri ng s ta ge 4, mi crocytos i s a nd then hypochromi a devel op.
Duri ng s ta ge 5, i ron defi ci ency a ffects ti s s ues , res ul ti ng i n s ymptoms a nd s i gns .
Di a gnos i s of i ron defi ci ency a nemi a prompts cons i dera ti on of i ts ca us e, us ua l l y bl eedi ng. Pa ti ents wi th obvi ous bl ood l os s (eg, women wi th
menorrha gi a ) ma y requi re no further tes ti ng. Men a nd pos tmenopa us a l women wi thout obvi ous bl ood l os s s houl d undergo eva l ua ti on of the GI
tra ct, beca us e a nemi a ma y be the onl y i ndi ca ti on of a n occul t GI ca ncer. Ra rel y, chroni c epi s ta xi s or GU bl eedi ng i s underes ti ma ted by the pa ti ent
a nd requi res eva l ua ti on i n pa ti ents wi th norma l GI s tudy res ul ts .
Other microcytic anemias: Iron defi ci ency a nemi a mus t be di fferenti a ted from other mi crocyti c a nemi a s (s ee
Ta bl e 105-1). If tes ts excl ude i ron defi ci ency i n pa ti ents wi th mi crocyti c a nemi a , then a nemi a of chroni c di s ea s e, s tructura l Hb a bnorma l i ti es (eg,
hemogl obi nopa thi es ), a nd congeni ta l RBC membra ne a bnorma l i ti es a re cons i dered. Cl i ni ca l fea tures , Hb s tudi es (eg, Hb el ectrophores i s a nd Hb
A2 ), a nd geneti c tes ti ng (eg, for -tha l a s s emi a ) ma y hel p di s ti ngui s h thes e enti ti es .
[Table 105-1. Di fferenti a l Di a gnos i s of Mi crocyti c Anemi a Due to Decrea s ed RBC Producti on]
Treatment
Ora l s uppl ementa l i ron
Ra rel y pa rentera l i ron
Iron thera py wi thout purs ui t of the ca us e i s poor pra cti ce; the bl eedi ng s i te s houl d be s ought even i n ca s es of mi l d a nemi a .
Iron ca n be provi ded by va ri ous i ron s a l ts (eg, ferrous s ul fa te, gl ucona te, fuma ra te) or s a ccha ra ted i ron po 30 mi n before mea l s (food or a nta ci ds
ma y reduce a bs orpti on). A typi ca l i ni ti a l dos e i s 60 mg of el ementa l i ron (eg, a s 325 mg of ferrous s ul fa te) gi ven once/da y or bi d. La rger dos es a re
l a rgel y una bs orbed but i ncrea s e a dvers e effects es peci a l l y. As corbi c a ci d ei ther a s a pi l l (500 mg) or a s ora nge jui ce when ta ken wi th i ron
enha nces i ron a bs orpti on wi thout i ncrea s i ng ga s tri c di s tres s . Pa rentera l i ron ca us es the s a me thera peuti c res pons e a s ora l i ron but ca n ca us e
a dvers e effects , s uch a s a na phyl a ctoi d rea cti ons , s erum s i cknes s , thrombophl ebi ti s , a nd pa i n. It i s res erved for pa ti ents who do not tol era te or
who wi l l not ta ke ora l i ron or for pa ti ents who s tea di l y l os e l a rge a mounts of bl ood beca us e of ca pi l l a ry or va s cul a r di s orders (eg, heredi ta ry
hemorrha gi c tel a ngi ecta s i a ). The dos e of pa rentera l i ron i s determi ned by a hema tol ogi s t. Ora l or pa rentera l i ron thera py s houl d conti nue for 6
mo a fter correcti on of Hb l evel s to repl eni s h ti s s ue s tores .
The res pons e to trea tment i s a s s es s ed by s eri a l Hb mea s urements unti l norma l RBC va l ues a re a chi eved. Hb ri s es l i ttl e for 2 wk but then ri s es 0.7
to 1 g/wk unti l nea r norma l , a t whi ch ti me ra te of i ncrea s e ta pers . Anemi a s houl d be corrected wi thi n 2 mo. A s ubnorma l res pons e s ugges ts
conti nued hemorrha ge, underl yi ng i nfecti on or ca ncer, i ns uffi ci ent i ron i nta ke, or, very ra rel y, ma l a bs orpti on of ora l i ron.
Sideroblastic Anemias
Sideroblastic anemias are iron-utilization anemias that are usually part of a myelodysplastic syndrome, causing a normocytic-normochromic anemia with high
RBC distribution width or a microcytic-hypochromic anemia, particularly with increased serum iron and ferritin and transferrin saturation.
Si derobl a s ti c a nemi a s a re a mong the a nemi a s cha ra cteri zed by i na dequa te ma rrow uti l i za ti on of i ron for Hb s ynthes i s des pi te the pres ence of
a dequa te or i ncrea s ed a mounts of i ron (i ron-uti l i za ti on a nemi a s ). Other i ron-uti l i za ti on a nemi a s i ncl ude s ome hemogl obi nopa thi es , pri ma ri l y
tha l a s s emi a s (s ee p. 946). Si derobl a s ti c a nemi a s a re cha ra cteri zed by the pres ence of pol ychroma tophi l i c, s ti ppl ed, ta rgeted RBCs (s i derocytes ).
Si derobl a s ti c a nemi a s a re genera l l y pa rt of a myel odys pl a s ti c s yndrome but ma y be heredi ta ry or ma y occur s econda ry to drugs (eg,
chl ora mpheni col , cycl os eri ne, i s oni a zi d, pyra zi na mi de) or toxi ns (i ncl udi ng etha nol a nd l ea d). Pyri doxi ne defi ci ency ca n l ea d to s i derobl a s ti c
a nemi a . Defi ci ent reti cul ocyte producti on, i ntra medul l a ry dea th of RBCs , a nd bone ma rrow erythroi d hyperpl a s i a (a nd dys pl a s i a ) occur. Al though
hypochromi c RBCs a re produced, other RBCs ma y be l a rge, produci ng normochromi c i ndi ces ; i f s o, va ri a ti on i n RBC s i ze (di morphi s m) us ua l l y
produces a hi gh RBC di s tri buti on wi dth (RDW).
Si derobl a s ti c a nemi a i s s us pected i n pa ti ents wi th mi crocyti c a nemi a or a hi gh RDW a nemi a , pa rti cul a rl y wi th i ncrea s ed s erum i ron, s erum
ferri ti n, a nd tra ns ferri n s a tura ti on (s ee Iron Defi ci ency Anemi a on p. 924). The peri phera l s mea r s hows RBC di morphi s m. RBCs ma y a ppea r
s ti ppl ed. Bone ma rrow exa mi na ti on i s neces s a ry a nd revea l s erythroi d hyperpl a s i a . Iron s ta i ni ng revea l s the pa thognomoni c i ron-engorged
pa ra nucl ea r mi tochondri a i n devel opi ng RBCs (ri nged s i derobl a s ts ). Other fea tures of myel odys pl a s i a , s uch a s chromos oma l a bnorma l i ti es , a re
frequentl y evi dent. Serum l ea d i s mea s ured i f s i derobl a s ti c a nemi a ha s a n unknown ca us e.
El i mi na ti on of a toxi n or drug (es peci a l l y a l cohol ) ca n l ea d to recovery. Ra rel y, congeni ta l ca s es res pond to pyri doxi ne 50 mg po ti d, but
i ncompl etel y. Pyri doxi ne defi ci ency i s corrected by vi ta mi n B 6 s uppl ementa ti on.
Anemia of Chronic Disease
(Iron-Reuti l i za ti on Anemi a )
Anemia of chronic disease is a multifactorial anemia often coexistent with iron deficiency. Diagnosis generally requires the presence of chronic infection,
inflammation, or cancer; microcytic or marginal normocytic anemia; and values for serum transferrin receptor and serum ferritin that are between those typical
for iron deficiency and sideroblastic anemia. Treatment is to reverse the underlying disorder or, if the disorder is irreversible, to give erythropoietin.
Worl dwi de, a nemi a of chroni c di s ea s e i s the 2nd mos t common a nemi a . Ea rl y on, the RBCs a re normocyti c; wi th ti me they become mi crocyti c. The
ma jor i s s ue i s tha t the ma rrow erythroi d ma s s fa i l s to expa nd a ppropri a tel y i n res pons e to a nemi a .
Etiology
Thi s type of a nemi a wa s thought to occur a s pa rt of a chroni c di s order, mos t often i nfecti on, i nfl a mma tory di s ea s e (es peci a l l y RA), or ca ncer;
however, the s a me proces s a ppea rs to begi n a cutel y duri ng vi rtua l l y a ny i nfecti on or i nfl a mma ti on. Three pa thophys i ol ogi c mecha ni s ms ha ve
been i denti fi ed:
Sl i ghtl y s hortened RBC s urvi va l occurs vi a unknown mecha ni s ms i n pa ti ents wi th ca ncer or chroni c gra nul oma tous i nfecti ons .
Erythropoi es i s i s i mpa i red beca us e of decrea s es i n both erythropoi eti n (EPO) producti on a nd ma rrow res pons i venes s to EPO.
Intra cel l ul a r i ron meta bol i s m i s i mpa i red.
Reti cul oendothel i a l cel l s reta i n i ron from s enes cent RBCs , ma ki ng i ron una va i l a bl e for Hb s ynthes i s . There i s thus a fa i l ure to compens a te for the
a nemi a wi th i ncrea s ed RBC producti on. Ma cropha ge-deri ved cytoki nes (eg, IL-1, tumor necros i s fa ctor-, i nterferon-) i n pa ti ents wi th i nfecti ons ,
i nfl a mma tory s ta tes , a nd ca ncer ca us e or contri bute to the decrea s e i n EPO producti on a nd the i mpa i red i ron meta bol i s m.
Diagnosis
Symptoms a nd s i gns of underl yi ng di s order
CBC a nd s erum i ron, ferri ti n, tra ns ferri n, a nd tra ns ferri n receptor
Cl i ni ca l fi ndi ngs a re us ua l l y thos e of the underl yi ng di s order (i nfecti on, i nfl a mma ti on, or ca ncer). Anemi a of chroni c di s ea s e i s s us pected i n
pa ti ents wi th mi crocyti c or ma rgi na l normocyti c a nemi a wi th chroni c i nfecti on, i nfl a mma ti on, or ca ncer. If a nemi a of chroni c di s ea s e i s s us pected,
s erum i ron, tra ns ferri n, tra ns ferri n receptor, a nd s erum ferri ti n a re mea s ured. Hb us ua l l y i s > 8 g/dL unl es s a n a ddi ti ona l mecha ni s m contri butes
to a nemi a (s ee a l s o Ta bl e 105-1). If i ron defi ci ency i s pres ent i n a ddi ti on to a nemi a of chroni c di s ea s e, s erum ferri ti n genera l l y rema i ns < 100
ng/mL, a nd, i f there i s i nfecti on, i nfl a mma ti on, or ca ncer, a ferri ti n l evel of s l i ghtl y < 100 ng/mL s ugges ts tha t i ron defi ci ency i s s uperi mpos ed on
a nemi a of chroni c di s ea s e. However, beca us e s erum ferri ti n ma y be fa l s el y el eva ted a s a n a cute-pha s e rea cta nt, the s erum tra ns ferri n receptor
mea s urement ma y better di fferenti a te i ron defi ci ency from a nemi a of chroni c di s ea s e when s erum ferri ti n i s > 100 ng/mL.
Treatment
Recombi na nt EPO a nd i ron s uppl ements
Trea ti ng the underl yi ng di s order i s mos t i mporta nt. Beca us e the a nemi a i s genera l l y mi l d, tra ns fus i ons us ua l l y a re not requi red, a nd recombi na nt
EPO ma y be offered. Beca us e both reduced producti on of a nd ma rrow res i s ta nce to EPO occur, the EPO dos e ma y need to be 150 to 300 uni ts /kg s c 3
ti mes /wk. A good res pons e i s l i kel y i f a fter 2 wk of thera py Hb ha s i ncrea s ed > 0.5 g/dL a nd s erum ferri ti n i s < 400 ng/mL. Iron s uppl ements (s ee p.
927) a re requi red to ens ure a n a dequa te res pons e to EPO. However, ca reful moni tori ng of Hb res pons e i s needed beca us e a dvers e effects (eg,
venous thromboembol i s m, MI, dea th) ma y occur when Hb ri s es to > 12 g/dL.
Hypoproliferative Anemias
Hypoproliferative anemias result from deficient erythropoietin (EPO) or a diminished response to it; they tend to be normocytic and normochromic. Renal,
metabolic, and endocrine disorders are common causes. Treatment includes measures to correct the underlying disorder and sometimes EPO.
Hypoprol i fera ti on i s a common mecha ni s m i n a nemi a s of rena l di s ea s e, hypometa bol i c or endocri ne defi ci ency s ta tes (eg, hypothyroi di s m,
hypopi tui ta ri s m), a nd protei n depri va ti on. The mecha ni s m a ppea rs to be a rel a ti ve or a bs ol ute decrea s ed producti on of EPO. In hypometa bol i c
s ta tes , the bone ma rrow ma y a l s o fa i l to res pond to EPO.
Anemia of renal disease: The defi ci ency i n rena l producti on of EPO a nd the s everi ty of a nemi a correl a te wi th the extent of rena l dys functi on; a nemi a
occurs when crea ti ni ne cl ea ra nce i s < 45 mL/mi n. Rena l gl omerul a r l es i ons (eg, from a myl oi dos i s , di a beti c nephropa thy) genera l l y res ul t i n the
mos t s evere a nemi a for thei r degree of excretory fa i l ure.
The term a nemi a of rena l di s ea s e refers onl y to tha t ca us ed by decrea s ed EPO, but other mecha ni s ms ma y i ncrea s e i ts s everi ty. In uremi a , mi l d
hemol ys i s i s common; i ts ba s i s i s uncerta i n. Les s common i s RBC fra gmenta ti on (tra uma ti c hemol yti c a nemi a ), whi ch occurs when the
renova s cul a r endothel i um i s i njured (eg, i n ma l i gna nt hypertens i on, membra noprol i fera ti ve gl omerul onephri ti s , pol ya rteri ti s nodos a , or a cute
corti ca l necros i s ). Tra uma ti c hemol ys i s i n chi l dren ca n be a n a cute, s ometi mes fa ta l i l l nes s ca l l ed hemol yti c-uremi c s yndrome (s ee p. 961).
Di a gnos i s i s ba s ed on demons tra ti on of rena l i ns uffi ci ency a nd normocyti c a nemi a , peri phera l reti cul ocytopeni a , a nd a pa uci ty of erythroi d
hyperpl a s i a for the degree of a nemi a . RBC fra gmenta ti on on the peri phera l s mea r, pa rti cul a rl y i f there i s thrombocytopeni a , s ugges ts
s i mul ta neous tra uma ti c hemol ys i s .
Thera py i s di rected a t i mprovi ng rena l functi on a nd i ncrea s i ng RBC producti on. If rena l functi on returns to norma l , a nemi a i s s l owl y corrected. In
pa ti ents recei vi ng l ong-term di a l ys i s , EPO, begi nni ng wi th 50 to 100 uni ts /kg IV or s c 3 ti mes /wk wi th i ron s uppl ements , i s the trea tment of choi ce.
In a l mos t a l l ca s es , ma xi mum i ncrea s es i n RBCs a re rea ched by 8 to 12 wk. Reduced dos es of EPO (a bout one ha l f the i nducti on dos e) ca n then be
gi ven 1 to 3 ti mes /wk. Tra ns fus i ons a re ra rel y neces s a ry. Ca reful moni tori ng of the res pons e i s needed to a voi d a dvers e effects when Hb i ncrea s es
to > 12 g/dL.
Other hypoproliferative anemias: Cl i ni ca l a nd l a bora tory fi ndi ngs of other hypoprol i fera ti ve normochromi c-normocyti c a nemi a s a re mi l der but
otherwi s e mi mi c thos e of the a nemi a of rena l di s ea s e. The mecha ni s m of the a nemi a of protei n depl eti on ma y be genera l hypometa bol i s m.
Hypometa bol i s m ma y di mi ni s h the ma rrow res pons e to EPO. Protei n's rol e i n hema topoi es i s i s uncl ea r.
Aplastic Anemia
(Hypopl a s ti c Anemi a )
Aplastic anemia is a normocytic-normochromic anemia that results from a loss of blood cell precursors, causing hypoplasia of bone marrow, RBCs, WBCs, and
platelets. Symptoms result from severe anemia, thrombocytopenia (petechiae, bleeding), or leukopenia (infections). Diagnosis requires demonstration of
peripheral pancytopenia and the absence of cell precursors in bone marrow. Treatment is equine antithymocyte globulin and cyclosporine. Erythropoietin,
granulocyte-macrophage colony-stimulating factor, and bone marrow transplantation may also be useful.
The term a pl a s ti c a nemi a commonl y i mpl i es a pa nhypopl a s i a of the ma rrow wi th a s s oci a ted l eukopeni a a nd thrombocytopeni a . In contra s t, pure
RBC a pl a s i a i s res tri cted to the erythroi d cel l l i ne. Al though both di s orders a re uncommon, a pl a s ti c a nemi a i s more common.
Etiology
True a pl a s ti c a nemi a (mos t common i n a dol es cents a nd young a dul ts ) i s i di opa thi c i n a bout one ha l f of ca s es . Recogni zed ca us es a re chemi ca l s
(eg, benzene, i norga ni c a rs eni c), ra di a ti on, a nd drugs (eg, a nti neopl a s ti c drugs , a nti bi oti cs , NSAIDs , a nti convul s a nts , a ceta zol a mi de, gol d s a l ts ,
peni ci l l a mi ne, qui na cri ne). The mecha ni s m i s unknown, but s el ecti ve (perha ps geneti c) hypers ens i ti vi ty a ppea rs to be the ba s i s .
Fanconi's anemia i s a very ra re, fa mi l i a l form of a pl a s ti c a nemi a wi th bone a bnorma l i ti es , mi crocepha l y, hypogona di s m, a nd brown pi gmenta ti on of
s ki n. It occurs i n chi l dren wi th a bnorma l chromos omes . Fa nconi 's a nemi a i s often i na ppa rent unti l s ome i l l nes s (es peci a l l y a n a cute i nfecti on or
i nfl a mma tory di s order) s upervenes , ca us i ng peri phera l cytopeni a s . Wi th cl ea ri ng of the s uperveni ng i l l nes s , peri phera l va l ues return to norma l
des pi te reduced ma rrow ma s s .
Pure RBC aplasia ma y be a cute a nd revers i bl e. Acute erythrobl a s topeni a i s a bri ef di s a ppea ra nce of RBC precurs ors from the bone ma rrow duri ng
va ri ous a cute vi ra l i l l nes s es (pa rti cul a rl y huma n pa rvovi rus i nfecti on), es peci a l l y i n chi l dren. The a nemi a l a s ts l onger tha n the a cute i nfecti on.
Chroni c pure RBC a pl a s i a ha s been a s s oci a ted wi th hemol yti c di s orders , thymoma s , a nd a utoi mmune mecha ni s ms a nd, l es s often, wi th drugs (eg,
tra nqui l i zers , a nti convul s a nts ), toxi ns (orga ni c phos pha tes ), ri bofl a vi n defi ci ency, a nd chroni c l ymphocyti c l eukemi a . A ra re congeni ta l form,
Di a mond-Bl a ckfa n a nemi a , us ua l l y occurs duri ng i nfa ncy but ha s a l s o been reported i n a dul thood. Di a mond-Bl a ckfa n a nemi a i s a s s oci a ted wi th
bony a bnorma l i ti es of the thumbs or di gi ts a nd s hort s ta ture.
Symptoms and Signs
Al though ons et of a pl a s ti c a nemi a us ua l l y i s i ns i di ous , often occurri ng over weeks or months a fter expos ure to a toxi n, occa s i ona l l y i t i s a cute.
Si gns va ry wi th the s everi ty of the pa ncytopeni a . Symptoms a nd s i gns of a nemi a (eg, pa l l or) us ua l l y a re s evere.
Severe thrombocytopeni a ma y ca us e petechi a e, ecchymos i s , a nd bl eedi ng from the gums , i nto the conjuncti va e, or other ti s s ues . Agra nul ocytos i s
commonl y ca us es l i fe-threa teni ng i nfecti ons . Spl enomega l y i s a bs ent unl es s i nduced by tra ns fus i on hemos i deros i s . Symptoms of pure RBC
a pl a s i a a re genera l l y mi l der a nd rel a te to the degree of the a nemi a or to the underl yi ng di s order.
Diagnosis
CBC
Bone ma rrow exa mi na ti on
Apl a s ti c a nemi a i s s us pected i n pa ti ents , pa rti cul a rl y young pa ti ents , wi th pa ncytopeni a (eg, WBC < 1500/L, pl a tel ets < 50,000/L). Pure RBC
a pl a s i a (i ncl udi ng Di a mond-Bl a ckfa n a nemi a ) i s s us pected i n pa ti ents wi th bony a bnorma l i ti es a nd normocyti c a nemi a but norma l WBC a nd
pl a tel et counts . If ei ther di a gnos i s i s s us pected, bone ma rrow exa mi na ti on i s done.
In a pl a s ti c a nemi a , RBCs a re normochromi cnormocyti c (s ometi mes ma rgi na l l y ma crocyti c). The WBC count reducti on occurs chi efl y i n the
gra nul ocytes . Pl a tel ets a re often fa r bel ow 50,000/L. Reti cul ocytes a re decrea s ed or a bs ent. Serum i ron i s el eva ted. The bone ma rrow i s a cel l ul a r.
In pure RBC a pl a s i a , normocyti c a nemi a , reti cul ocytopeni a , a nd el eva ted s erum i ron a re pres ent, but WBC a nd pl a tel et counts a re norma l . Bone
ma rrow cel l ul a ri ty a nd ma tura ti on ma y be norma l except for a bs ence of erythroi d precurs ors .
Treatment
Equi ne a nti thymocyte gl obul i n, corti cos teroi ds , a nd cycl os pori ne
Someti mes hema topoi eti c cel l tra ns pl a nta ti on
Someti mes cytoki nes
Someti mes s urgery i n thymoma -a s s oci a ted RBC a pl a s i a
In a pl a s ti c a nemi a , trea tment of choi ce i s equi ne a nti thymocyte gl obul i n (ATG) 10 to 20 mg/kg di l uted i n 500 mL s a l i ne a nd i nfus ed IV over 4 to 6 h
once/da y for 10 cons ecuti ve da ys . Shorter regi mens a re a l s o us ed. About 60% of pa ti ents res pond to ATG. Al l ergi c rea cti ons a nd s erum s i cknes s
ma y occur; s ome experts a dvoca te s ki n tes ti ng (to i denti fy a l l ergy to hors e s erum) a nd concomi ta nt corti cos teroi ds (predni s one 40 mg/m 2 po
once/da y begi nni ng on da y 7 for 10 da ys or unti l s ymptoms s ubs i de). Cycl os pori ne (5 to 10 mg/kg po once/da y) i s a s effecti ve a s ATG a nd produces
res pons es i n a bout 50% of pa ti ents who do not res pond to ATG, s ugges ti ng tha t i ts mecha ni s m of a cti on i s di fferent. Combi ned ATG a nd
cycl os pori ne i s a l s o effecti ve. If a pl a s ti c a nemi a i s very s evere or fa i l s to res pond to ATG a nd cycl os pori ne, bone ma rrow tra ns pl a nta ti on or
trea tment wi th cytoki nes (erythropoi eti n, gra nul ocyte col ony-s ti mul a ti ng fa ctor, or gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor) ma y be
effecti ve.
Hema topoi eti c s tem cel l tra ns pl a nta ti on ma y hel p younger pa ti ents (pa rti cul a rl y pa ti ents < 30) but requi res a n i denti ca l twi n or a n HLAcompa ti bl e s i bl i ng. At di a gnos i s , s i bl i ngs a re eva l ua ted for HLA compa ti bi l i ty. Beca us e tra ns fus i ons pos e a ri s k to s ubs equent tra ns pl a nta ti on,
bl ood products a re us ed onl y when es s enti a l .
Pure RBC a pl a s i a ha s been s ucces s ful l y ma na ged wi th i mmunos uppres s a nts (predni s one, cycl os pori ne, or cycl ophos pha mi de), es peci a l l y when a n
a utoi mmune mecha ni s m i s s us pected. Beca us e pa ti ents wi th thymoma -a s s oci a ted pure RBC a pl a s i a i mprove a fter thymectomy, CT i s us ed to s eek
the pres ence of s uch a l es i on, a nd s urgery i s cons i dered.
Myelophthisic Anemia
Myelophthisic anemia is a normocytic-normochromic anemia that occurs when normal marrow space is infiltrated and replaced by nonhematopoietic or abnormal
cells. Causes include tumors, granulomatous disorders, and lipid storage diseases. Marrow fibrosis often occurs. Splenomegaly may develop. Characteristic
changes in peripheral blood include anisocytosis, poikilocytosis, and excessive numbers of RBC and WBC precursors. Diagnosis usually requires bone marrow
biopsy. Treatment is supportive and includes measures directed at the underlying disorder.
Des cri pti ve terms us ed i n thi s a nemi a ca n be confus i ng. Myel ofi bros i s , whi ch i s repl a cement of ma rrow by fi brous ti s s ue ba nds , ma y be i di opa thi c
(pri ma ry) or s econda ry. True myel ofi bros i s i s a s tem cel l defect i n whi ch the fi bros i s i s s econda ry to other hema topoi eti c i ntra medul l a ry events .
Myel os cl eros i s i s new bone forma ti on tha t s ometi mes a ccompa ni es myel ofi bros i s . Myel oi d meta pl a s i a refers to extra medul l a ry hema topoi es i s
i n the l i ver, s pl een, or l ymph nodes tha t ma y a ccompa ny myel ophthi s i s due to a ny ca us e. An ol d term, a gnogeni c myel oi d meta pl a s i a , i ndi ca tes
pri ma ry myel ofi bros i s wi th or wi thout myel oi d meta pl a s i a .
Etiology
The mos t common ca us e i s repl a cement of bone ma rrow by meta s ta ti c ca ncer (mos t often, brea s t or pros ta te; l es s often, ki dney, l ung, a drena l , or
thyroi d); extra medul l a ry hema topoi es i s tends to be modes t. Other ca us es i ncl ude myel oprol i fera ti ve di s orders (es peci a l l y l a te-s ta ge or s pent
pol ycythemi a vera ), gra nul oma tous di s ea s es , a nd (l i pi d) s tora ge di s ea s es . Myel ofi bros i s ca n occur i n a l l of thes e.
Fa ctors tha t ma y contri bute to decrea s ed RBC producti on i ncl ude a decrea s ed a mount of functi oni ng hema topoi eti c ti s s ue, di s ordered meta bol i s m
rel a ted to the underl yi ng di s order, a nd, i n s ome ca s es , erythropha gocytos i s . Extra medul l a ry hema topoi es i s or di s rupti on of the ma rrow s i nus oi ds
ca us es rel ea s e of i mma ture cel l s . Abnorma l l y s ha ped RBCs often res ul t i n i ncrea s ed RBC des tructi on.
Symptoms and Signs
Myel oi d meta pl a s i a ma y res ul t i n s pl enomega l y, pa rti cul a rl y i n pa ti ents wi th s tora ge di s ea s es . In s evere ca s es , s ymptoms of a nemi a a nd of the
underl yi ng di s order ma y be pres ent. Ma s s i ve s pl enomega l y ca n ca us e a bdomi na l pres s ure, ea rl y s a ti ety, a nd l eft upper qua dra nt a bdomi na l pa i n;
hepa tomega l y ma y be pres ent. Hepa tos pl enomega l y i s ra re wi th myel ofi bros i s from ma l i gna nt tumors .
Diagnosis
CBC, RBC i ndi ces , reti cul ocyte count, a nd peri phera l s mea r
Myel ophthi s i c a nemi a i s s us pected i n pa ti ents wi th normocyti c a nemi a , pa rti cul a rl y when s pl enomega l y or a potenti a l underl yi ng di s order i s
pres ent. If i t i s s us pected, a peri phera l s mea r s houl d be obta i ned, beca us e a l eukoerythrobl a s ti c pa ttern (i mma ture myel oi d cel l s a nd nucl ea ted
RBCs , s uch a s normobl a s ts i n the s mea r) s ugges ts myel ophthi s i c a nemi a . Anemi a , us ua l l y modera tel y s evere, i s cha ra cteri s ti ca l l y normocyti c but
ma y be s l i ghtl y ma crocyti c. RBC morphol ogy ma y s how extreme va ri a ti on (a ni s ocytos i s a nd poi ki l ocytos i s ) i n s i ze a nd s ha pe. The WBC count ma y
va ry. The pl a tel et count i s often l ow, a nd pl a tel ets a re often l a rge a nd bi za rre i n s ha pe. Reti cul ocytos i s often occurs ; i t ma y be ca us ed by
prema ture rel ea s e of reti cul ocytes from the ma rrow or extra medul l a ry s i tes a nd thus does not a l wa ys i ndi ca te i ncrea s ed bl ood regenera ti on.
Al though exa mi na ti on of peri phera l bl ood ca n be s ugges ti ve, di a gnos i s us ua l l y requi res bone ma rrow exa mi na ti on. Indi ca ti ons i ncl ude a
l eukoerythrobl a s ti c pa ttern a nd unexpl a i ned s pl enomega l y. The ma rrow ma y be di ffi cul t to a s pi ra te; ma rrow trephi ne bi ops y i s us ua l l y requi red.
Fi ndi ngs va ry a ccordi ng to the underl yi ng di s order. Erythropoi es i s i s norma l or i ncrea s ed i n s ome ca s es . However, the l i fe s pa n of RBCs i s often
reduced. Hema topoi es i s ma y be pres ent i n the s pl een a nd l i ver.
X-ra ys , i f obta i ned i nci denta l l y, ma y di s cl os e bony l es i ons (myel os cl eros i s ) cha ra cteri s ti c of l ong-s ta ndi ng myel ofi bros i s or other os s eous cha nges
(i e, os teobl a s ti c or l yti c l es i ons of a tumor), s ugges ti ng the ca us e of a nemi a .
Treatment
Tra ns fus i ons a nd corti cos teroi ds
Hydroxyurea
Pos s i bl y tha l i domi de
The underl yi ng di s order i s trea ted. In i di opa thi c ca s es , ma na gement i s s upporti ve. Erythropoi eti n (20,000 to 40,000 uni ts s c once/wk or twi ce/wk)
a nd corti cos teroi ds (eg, predni s one 10 to 30 mg po once/da y) ha ve been us ed, but onl y modes t res pons es ha ve been obs erved. Hydroxyurea (500
mg po once/da y or once every other da y) decrea s es s pl een s i ze a nd norma l i zes RBC va l ues i n ma ny pa ti ents , but the res pons e requi res 6 to 12 mo
of trea tment. Tha l i domi de (50 to 100 mg po once/da y i n the eveni ng) ma y provi de modes t res pons es , but i t i ncrea s es the ri s k of thrombos i s a nd
ca us es fa ti gue, whi ch ca n be s evere.
Megaloblastic Macrocytic Anemias
Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly RBCs.
Diagnosis is usually based on a CBC and peripheral smear, which may show a macrocytic anemia with anisocytosis and poikilocytosis, large oval RBCs (macroovalocytes), hypersegmented neutrophils, and reticulocytopenia. Treatment is directed at the underlying disorder.
Ma crocytes a re enl a rged RBCs (i e, MCV > 100 fL/cel l ). Ma crocyti c RBCs occur i n a va ri ety of cl i ni ca l ci rcums ta nces , ma ny unrel a ted to the
mega l obl a s tos i s a nd the res ul ta nt a nemi a . Ma crocytos i s ma y be due to mega l obl a s ts or other enl a rged RBCs (s ee Si deba r 105-1). Mega l obl a s ts
a re l a rge nucl ea ted RBC precurs ors wi th noncondens ed chroma ti n. Mega l obl a s tos i s precedes ma crocyti c a nemi a .
Etiology
The mos t common ca us e of mega l obl a s ti c s ta tes i s defi ci ency or defecti ve uti l i za ti on of vi ta mi n B 12 (s ee p. 37) or fol a te (s ee p. 29). Other ca us es
i ncl ude drugs (genera l l y a nti neopl a s ti cs or i mmunos uppres s a nts ) tha t i nterfere wi th DNA s ynthes i s a nd ra re meta bol i c di s orders (eg, heredi ta ry
oroti c a ci duri a ); s ome ca s es a re of unknown eti ol ogy.
Pathophysiology
Mega l obl a s ti c s ta tes res ul t from defecti ve DNA s ynthes i s . RNA s ynthes i s conti nues , res ul ti ng i n a l a rge cel l wi th a l a rge nucl eus . Al l cel l l i nes
ha ve dys poi es i s , i n whi ch cytopl a s mi c ma turi ty i s grea ter tha n nucl ea r ma turi ty; thi s dys poi es i s produces mega l obl a s ts i n the ma rrow before they
a ppea r i n the peri phera l bl ood. Dys poi es i s res ul ts i n i ntra medul l a ry cel l dea th, ma ki ng erythropoi es i s i neffecti ve a nd ca us i ng i ndi rect
hyperbi l i rubi nemi a a nd hyperuri cemi a . Beca us e dys poi es i s a ffects a l l cel l l i nes , reti cul ocytopeni a a nd, duri ng l a ter s ta ges , l eukopeni a a nd
thrombocytopeni a devel op. La rge, ova l RBCs (ma cro-ova l ocytes ) enter the ci rcul a ti on. Hypers egmenta ti on of pol ymorphonucl ea r neutrophi l s i s
common; the mecha ni s m of thei r producti on i s unknown.
Symptoms and Signs
Anemi a devel ops i ns i di ous l y a nd ma y not ca us e s ymptoms unti l i t i s s evere. Defi ci enci es of vi ta mi n B 12 ma y ca us e neurol ogi c ma ni fes ta ti ons ,
i ncl udi ng peri phera l neuropa thy, dementi a , a nd s uba cute combi ned degenera ti on. Fol a te defi ci ency ma y a l s o ca us e di a rrhea a nd gl os s i ti s . Ma ny
pa ti ents wi th fol a te defi ci ency a ppea r wa s ted, pa rti cul a rl y wi th tempora l wa s ti ng.
Diagnosis
CBC, RBC i ndi ces , reti cul ocyte count, a nd peri phera l s mea r
Someti mes bone ma rrow exa mi na ti on
Mega l obl a s ti c a nemi a i s s us pected i n a nemi c pa ti ents wi th ma crocyti c i ndi ces . Di a gnos i s i s us ua l l y ba s ed on peri phera l s mea r. When ful l y
devel oped, the a nemi a i s ma crocyti c, wi th MCV > 100 fL/cel l . The s mea r s hows ma cro-ova l ocytos i s , a ni s ocytos i s , a nd poi ki l ocytos i s . The RBC
di s tri buti on wi dth (RDW) i s hi gh. Howel l -Jol l y bodi es (res i dua l fra gments of the nucl eus ) a re common. Reti cul ocytopeni a i s pres ent.
Hypers egmenta ti on of the gra nul ocytes devel ops ea rl y; neutropeni a devel ops l a ter. Thrombocytopeni a i s often pres ent i n s evere ca s es , a nd
pl a tel ets ma y be bi za rre i n s i ze a nd s ha pe. If the di a gnos i s i s ques ti ona bl e, a bone ma rrow exa mi na ti on ma y be needed.
Treatment
Before trea tment, the ca us e mus t be i denti fi ed. Defi ci ency of vi ta mi n B 12 or fol a te i s s us pected i f mega l obl a s ti c a nemi a i s recogni zed; thes e
di s orders a re i ndi s ti ngui s ha bl e on the ba s i s of peri phera l bl ood a nd bone ma rrow fi ndi ngs , s o vi ta mi n B 12 a nd fol a te l evel s a re requi red (s ee pp.
30 a nd 39).
Sidebar 105-1 Nonmegaloblastic Macrocytosis

Mos t ma crocyti c (i e, MCV > 100 fL/cel l ) a nemi a s a re mega l obl a s ti c. Nonmega l obl a s ti c ma crocytos i s occurs i n va ri ous cl i ni ca l s ta tes , not a l l of
whi ch a re unders tood. Anemi a commonl y occurs i n pa ti ents wi th ma crocytos i s but us ua l l y res ul ts from mecha ni s ms i ndependent of ma crocytos i s .
Ma crocytos i s due to exces s RBC membra ne occurs i n pa ti ents wi th chroni c l i ver di s ea s e when chol es terol es teri fi ca ti on i s defecti ve. Ma crocytos i s
wi th a n MCV of a bout 100 to 105 fL/cel l ca n occur wi th chroni c a l cohol us e i n the a bs ence of fol a te defi ci ency. Mi l d ma crocytos i s ca n occur i n
a pl a s ti c a nemi a , es peci a l l y a s recovery occurs . Ma crocytos i s i s a l s o common i n myel odys pl a s i a . Beca us e RBC membra ne mol di ng occurs i n the
s pl een a fter cel l rel ea s e from the ma rrow, RBCs ma y be s l i ghtl y ma crocyti c a fter s pl enectomy, a l though thes e cha nges a re not a s s oci a ted wi th
a nemi a .
Nonmega l obl a s ti c ma crocytos i s i s s us pected i n pa ti ents wi th ma crocyti c a nemi a s when tes ti ng excl udes vi ta mi n B 12 a nd fol a te defi ci enci es . The
ma cro-ova l ocytes on peri phera l s mea r a nd the i ncrea s ed RBC di s tri buti on wi dth tha t a re typi ca l of cl a s s i c mega l obl a s ti c a nemi a ma y be a bs ent. If
nonmega l obl a s ti c ma crocytos i s i s unexpl a i ned cl i ni ca l l y (eg, by the pres ence of a pl a s ti c a nemi a , chroni c l i ver di s ea s e, or a l cohol us e) or i f
myel odys pl a s i a i s s us pected, bone ma rrow exa mi na ti on a nd cytogeneti c a na l ys i s a re done to excl ude myel odys pl a s i a . In nonmega l obl a s ti c
ma crocytos i s , the ma rrow i s not mega l obl a s ti c, but i n myel odys pl a s i a a nd a dva nced l i ver di s ea s e there a re mega l obl a s toi d RBC precurs ors wi th
dens e nucl ea r chroma ti n tha t di ffer from the us ua l fi ne fi bri l l a r pa ttern i n mega l obl a s ti c a nemi a s .
Trea tment depends on the ca us e. For trea tment of fol a te a nd vi ta mi n B 12 defi ci enci es , s ee pp. 30 a nd 39. Drugs ca us i ng mega l obl a s ti c s ta tes ma y
need to be el i mi na ted or gi ven i n reduced dos es .
Myelodysplasia and Iron-Transport Deficiency Anemia
In myel odys pl a s ti c s yndrome (s ee p. 1014), a nemi a i s commonl y promi nent. The a nemi a ca n be mi crocyti c or normochromi c-normocyti c, us ua l l y
wi th a di morphi c (l a rge a nd s ma l l ) popul a ti on of ci rcul a ti ng cel l s . Bone ma rrow exa mi na ti on s hows decrea s ed erythroi d a cti vi ty, mega l obl a s toi d
a nd dys pl a s ti c cha nges , a nd, s ometi mes , i ncrea s ed numbers of ri nged s i derobl a s ts . Trea tment i s the s a me a s for s i derobl a s ti c a nemi a s (s ee p.
928).
Iron-tra ns port defi ci ency a nemi a (a tra ns ferri nemi a ) i s exceedi ngl y ra re. It occurs when i ron ca nnot move from s tora ge s i tes (eg, mucos a l cel l s ,
l i ver) to the erythropoi eti c precurs ors . The pres umed mecha ni s m i s a bs ence of tra ns ferri n or pres ence of a defecti ve tra ns ferri n mol ecul e. In
a ddi ti on to a nemi a , hemos i deros i s of l ymphoi d ti s s ue, es peci a l l y a l ong the GI tra ct, i s promi nent.
Chapter 106. Anemias Caused by Hemolysis

Introduction
At the end of thei r norma l l i fe s pa n (a bout 120 da ys ), RBCs a re removed from the ci rcul a ti on. Hemol ys i s i nvol ves prema ture des tructi on a nd hence
a s hortened RBC l i fe s pa n (< 120 da ys ). Anemi a res ul ts when bone ma rrow producti on ca n no l onger compens a te for the s hortened RBC s urvi va l ;
thi s condi ti on i s termed hemol yti c a nemi a . If the ma rrow ca n compens a te, the condi ti on i s termed compens a ted hemol yti c a nemi a .
Etiology
Hemol ys i s ca n res ul t from di s orders extri ns i c to the RBC or from i ntri ns i c RBC a bnorma l i ti es (s ee
Ta bl e 106-1).
Disorders extrinsic to the RBC: Mos t extri ns i c di s orders a re a cqui red; the RBCs a re norma l a nd tra ns fus ed cel l s a s wel l a s a utol ogous cel l s a re
des troyed. Di s orders extri ns i c to the RBC i ncl ude reti cul oendothel i a l hypera cti vi ty (hypers pl eni s ms ee p. 985), i mmunol ogi c a bnorma l i ti es (eg,
a utoi mmune hemol yti c a nemi a , i s oi mmune hemol yti c a nemi a ), mecha ni ca l i njury (tra uma ti c hemol yti c a nemi a ), a nd certa i n i nfecti ons . Infecti ous
orga ni s ms ma y ca us e hemol yti c a nemi a through the di rect a cti on of toxi ns (eg, from Clostridium perfringens, - or -hemol yti c s treptococci ,
meni ngococci ) or by i nva s i on a nd des tructi on of RBC by the orga ni s m (eg, Plasmodium s p, Bartonella s p).
Intrinsic RBC abnormalities: Defects i ntri ns i c to the RBC tha t ca n ca us e hemol ys i s i nvol ve one or more components or functi ons of the RBC: the
membra ne, cel l meta bol i s m, a nd the Hb. Abnorma l i ti es i ncl ude heredi ta ry a nd a cqui red cel l membra ne di s orders (eg, s pherocytos i s ), di s orders of
RBC meta bol i s m (eg, G6PD defi ci ency), a nd hemogl obi nopa thi es (eg, s i ckl e cel l di s ea s es , tha l a s s emi a s ). Qua nti ta ti ve a nd functi ona l
a bnorma l i ti es of certa i n RBC membra ne protei ns (- a nd -s pectri n, protei n 4.1, F-a cti n, a nkyri n) ca us e hemol yti c a nemi a s .
Pathophysiology
Hemol ys i s ma y be a cute, chroni c, or epi s odi c. Chroni c hemol ys i s ma y be compl i ca ted by a pl a s ti c cri s i s (tempora ry fa i l ure of erythropoi es i s ),
us ua l l y ca us ed by a n i nfecti on, often pa rvovi rus . Hemol ys i s ca n be extra va s cul a r, i ntra va s cul a r, or both.
[Table 106-1. Hemol yti c Anemi a s ]
Normal RBC processing: Senes cent RBCs l os e membra ne a nd a re cl ea red from the ci rcul a ti on l a rgel y by the pha gocyti c cel l s of the s pl een, l i ver, bone
ma rrow, a nd reti cul oendothel i a l s ys tem. Hb i s broken down i n thes e cel l s pri ma ri l y by the heme oxygena s e s ys tem. The i ron i s cons erved a nd
reuti l i zed, a nd heme i s degra ded to bi l i rubi n, whi ch i s conjuga ted i n the l i ver to bi l i rubi n gl ucuroni de a nd excreted i n the bi l e.
Extravascular hemolysis: Mos t pa thol ogi c hemol ys i s i s extra va s cul a r a nd occurs when da ma ged or a bnorma l RBCs a re cl ea red from the ci rcul a ti on by
cel l s of the s pl een, l i ver, a nd bone ma rrow s i mi l a r to the proces s by whi ch s enes cent RBCs a re removed. The s pl een us ua l l y contri butes to
hemol ys i s by des troyi ng mi l dl y a bnorma l RBCs or cel l s coa ted wi th wa rm a nti bodi es . An enl a rged s pl een ma y s eques ter even norma l RBCs .
Severel y a bnorma l RBCs or RBCs coa ted wi th col d a nti bodi es or compl ement (C3) a re des troyed wi thi n the ci rcul a ti on a nd i n the l i ver, whi ch
(beca us e of i ts l a rge bl ood fl ow) ca n remove da ma ged cel l s effi ci entl y.
Intravascular hemolysis: Intra va s cul a r hemol ys i s i s a n i mporta nt rea s on for prema ture RBC des tructi on a nd us ua l l y occurs when the cel l membra ne
ha s been s everel y da ma ged by a ny of a number of di fferent mecha ni s ms , i ncl udi ng a utoi mmune phenomena , di rect tra uma (eg, ma rch
hemogl obi nuri a ), s hea r s tres s (eg, defecti ve mecha ni ca l hea rt va l ves ), a nd toxi ns (eg, cl os tri di a l toxi ns , venomous s na ke bi te).
Intra va s cul a r hemol ys i s res ul ts i n hemogl obi nemi a when the a mount of Hb rel ea s ed i nto pl a s ma exceeds the Hb-bi ndi ng ca pa ci ty of the pl a s ma bi ndi ng protei n ha ptogl obi n, a gl obul i n norma l l y pres ent i n concentra ti ons of a bout 1.0 g/L i n pl a s ma . Wi th hemogl obi nemi a , unbound Hb di mers
a re fi l tered i nto the uri ne a nd rea bs orbed by rena l tubul a r cel l s ; hemogl obi nuri a res ul ts when rea bs orpti ve ca pa ci ty i s exceeded. Iron i s
embedded i n hemos i deri n wi thi n the tubul a r cel l s ; s ome of the i ron i s a s s i mi l a ted for reuti l i za ti on a nd s ome rea ches the uri ne when the tubul a r
cel l s s l ough.
Consequences of hemolysis: Unconjuga ted (i ndi rect) hyperbi l i rubi nemi a a nd ja undi ce occur when the convers i on of Hb to bi l i rubi n exceeds the l i ver's
ca pa ci ty to conjuga te a nd excrete bi l i rubi n (s ee p. 270). Bi l i rubi n ca ta bol i s m ca us es i ncrea s ed s tercobi l i n i n the s tool a nd urobi l i nogen i n the
uri ne a nd s ometi mes chol el i thi a s i s .
The bone ma rrow res ponds to the exces s l os s of RBCs by a ccel era ti ng producti on a nd rel ea s e of RBCs , res ul ti ng i n a reti cul ocytos i s .
Symptoms and Signs
Sys temi c ma ni fes ta ti ons res embl e thos e of other a nemi a s a nd i ncl ude pa l l or, fa ti gue, di zzi nes s , a nd pos s i bl e hypotens i on. Hemol yti c cri s i s
(a cute, s evere hemol ys i s ) i s uncommon; i t ma y be a ccompa ni ed by chi l l s , fever, pa i n i n the ba ck a nd a bdomen, pros tra ti on, a nd s hock. Severe
hemol ys i s ca n ca us e ja undi ce a nd s pl enomega l y. Hemogl obi nuri a ca us es red or reddi s h-brown uri ne.
Diagnosis
Peri phera l s mea r, reti cul ocyte count, s erum bi l i rubi n, LDH, a nd ALT
Someti mes , mea s urement of uri na ry hemos i deri n a nd s erum ha ptogl obi n
Ra rel y, mea s urement of RBC s urvi va l us i ng a ra di oa cti ve l a bel
Hemol ys i s i s s us pected i n pa ti ents wi th a nemi a a nd reti cul ocytos i s , pa rti cul a rl y i f s pl enomega l y or a nother pos s i bl e ca us e i s recogni zed. If
hemol ys i s i s s us pected, peri phera l s mea r i s exa mi ned a nd s erum bi l i rubi n, LDH, a nd ALT a re mea s ured. If res ul ts of thes e tes ts a re i nconcl us i ve,
uri na ry hemos i deri n a nd s erum ha ptogl obi n a re mea s ured.
Abnorma l i ti es of RBC morphol ogy a re s el dom di a gnos ti c but often s ugges t the pres ence a nd ca us e of hemol ys i s (s ee
Ta bl e 106-2).
[Table 106-2. RBC Morphol ogi c Cha nges i n Hemol yti c Anemi a s ]
Other s ugges ti ve fi ndi ngs i ncl ude i ncrea s ed l evel s of s erum LDH a nd i ndi rect bi l i rubi n wi th a norma l ALT, a nd the pres ence of uri na ry
urobi l i nogen. Intra va s cul a r hemol ys i s i s s ugges ted by RBC fra gments (s chi s tocytes ) on the peri phera l s mea r a nd by decrea s ed s erum ha ptogl obi n
l evel s ; however, ha ptogl obi n l evel s ca n decrea s e beca us e of hepa tocel l ul a r dys functi on a nd ca n i ncrea s e beca us e of s ys temi c i nfl a mma ti on.
Intra va s cul a r hemol ys i s i s a l s o s ugges ted by uri na ry hemos i deri n. Uri na ry Hb, l i ke hema turi a a nd myogl obi nuri a , produces a pos i ti ve benzi di ne
rea cti on on di ps ti ck tes ti ng; i t ca n be di fferenti a ted from hema turi a by the a bs ence of RBCs on mi cros copi c uri ne exa mi na ti on. Free Hb ma y ma ke
pl a s ma reddi s h brown, noti cea bl e often i n centri fuged bl ood; myogl obi n does not.
Al though hemol ys i s ca n us ua l l y be i denti fi ed by thes e s i mpl e cri teri a , the defi ni ti ve di a gnos i s i s demons tra ti on of decrea s ed RBC s urvi va l ,
prefera bl y wi th a ra di oa cti ve l a bel , s uch a s ra di ochromi um ( 51 Cr). The mea s ured s urvi va l of ra di ol a bel ed RBCs ca n es ta bl i s h hemol ys i s a nd a l s o
i denti fy the s i tes of s eques tra ti on by us i ng body s urfa ce counti ng. Thi s procedure i s ra rel y requi red, however.
Once hemol ys i s ha s been i denti fi ed, the s peci fi c di s order i s s ought. One a pproa ch to na rrowi ng the di fferenti a l di a gnos i s i n hemol yti c a nemi a s
i s to cons i der ri s k fa ctors (eg, geogra phi c l oca ti on, geneti cs , underl yi ng di s order), exa mi ne the pa ti ent for s pl enomega l y, a nd do a di rect
a nti gl obul i n (Coombs ') tes t a nd peri phera l s mea r; mos t hemol yti c a nemi a s produce a bnorma l i ti es i n one of thes e va ri a bl es tha t ca n di rect further
tes ti ng. Other l a bora tory tes ts tha t ca n hel p di s cern the ca us es of hemol ys i s i ncl ude the fol l owi ng:
Qua nti ta ti ve Hb el ectrophores i s
RBC enzyme a s s a ys
Fl ow cytometry
Col d a ggl uti ni ns
Os moti c fra gi l i ty
Al though s ome tes ts ca n hel p di fferenti a te i ntra va s cul a r from extra va s cul a r hemol ys i s , ma ki ng the di s ti ncti on i s s ometi mes di ffi cul t. Duri ng
i ncrea s ed RBC des tructi on, both types a re commonl y i nvol ved, a l though to di fferi ng degrees .
Treatment
Trea tment depends on the s peci fi c mecha ni s m of hemol ys i s .
Hemogl obi nuri a a nd hemos i deri nuri a ma y neces s i ta te i ron-repl a cement thera py. Corti cos teroi ds a re hel pful i n the i ni ti a l trea tment of wa rm
a nti body a utoi mmune hemol ys i s . Long-term tra ns fus i on thera py ma y ca us e exces s i ve i ron a ccumul a ti on, neces s i ta ti ng chel a ti on thera py.
Spl enectomy i s benefi ci a l i n s ome s i tua ti ons , pa rti cul a rl y when s pl eni c s eques tra ti on i s the ma jor ca us e of RBC des tructi on. If pos s i bl e,
s pl enectomy i s del a yed unti l 2 wk a fter va cci na ti on wi th pneumococca l , Haemophilus influenzae, a nd meni ngococca l va cci nes . In col d a ggl uti ni n
di s ea s e, the pa ti ent i s kept wa rm. Fol a te repl a cement i s needed for pa ti ents wi th ongoi ng l ong-term hemol ys i s .
Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemia is caused by autoantibodies that react with RBCs at temperatures 37 C (warm antibody hemolytic anemia) or < 37 C (cold
agglutinin disease). Hemolysis is usually extravascular. The direct antiglobulin (Coombs') test establishes the diagnosis and may suggest the cause. Treatment
depends on the cause and may include corticosteroids, splenectomy, IV immune globulin, immunosuppressants, avoidance of blood transfusions, and withdrawal
of drugs.
Etiology
Warm antibody hemolytic anemia: Wa rm a nti body hemol yti c a nemi a i s the mos t common form of a utoi mmune hemol yti c a nemi a (AIHA); i t i s more
common a mong women. Autoa nti bodi es i n wa rm a nti body hemol yti c a nemi a genera l l y rea ct a t tempera tures 37 C. They ma y occur
s ponta neous l y or i n a s s oci a ti on wi th certa i n di s orders (SLE, l ymphoma , chroni c l ymphocyti c l eukemi a ). Some drugs (eg, -methyl dopa , l evodopa
s ee
Ta bl e 106-3) s ti mul a te producti on of a utoa nti bodi es a ga i ns t Rh a nti gens (-methyl dopa -type of AIHA). Other drugs s ti mul a te producti on of
a utoa nti bodi es a ga i ns t the a nti bi oti c-RBC-membra ne compl ex a s pa rt of a tra ns i ent ha pten mecha ni s m; the ha pten ma y be s ta bl e (eg, hi gh-dos e
peni ci l l i n, cepha l os pori ns ) or uns ta bl e (eg, qui ni di ne, s ul fona mi des ).
In wa rm a nti body hemol yti c a nemi a , hemol ys i s occurs pri ma ri l y i n the s pl een. It i s often s evere a nd ca n be fa ta l . Mos t of the a utoa nti bodi es i n
wa rm a nti body hemol yti c a nemi a a re IgG. Mos t a re pa na ggl uti ni ns a nd ha ve l i mi ted s peci fi ci ty.
Cold agglutinin disease: Col d a ggl uti ni n di s ea s e (col d a nti body di s ea s e) i s ca us ed by a utoa nti bodi es tha t rea ct a t tempera tures < 37 C. It s ometi mes
occurs wi th i nfecti ons
[Table 106-3. Drugs tha t Ca us e Wa rm Anti body Hemol yti c Anemi a ]
(es peci a l l y mycopl a s ma l pneumoni a s or i nfecti ous mononucl eos i s ) a nd l ymphoprol i fera ti ve s ta tes ; a bout one ha l f of ca s es a re i di opa thi c, whi ch
i s the common form i n ol der a dul ts . Infecti ons tend to ca us e a cute di s ea s e, wherea s i di opa thi c di s ea s e tends to be chroni c. The hemol ys i s occurs
l a rgel y i n the extra va s cul a r mononucl ea r pha gocyte s ys tem of the l i ver. The a nemi a i s us ua l l y mi l d (Hb > 7.5 g/dL). Autoa nti bodi es i n col d
a ggl uti ni n di s ea s e a re us ua l l y IgM. The hi gher the tempera ture (i e, the cl os er to norma l body tempera ture) a t whi ch thes e a nti bodi es rea ct wi th
the RBC, the grea ter the hemol ys i s .
Paroxysmal cold hemoglobinuria: Pa roxys ma l col d hemogl obi nuri a (PCH; Dona th-La nds tei ner s yndrome) i s a ra re type of col d a ggl uti ni n di s ea s e.
Hemol ys i s res ul ts from expos ure to col d, whi ch ma y even be l oca l i zed (eg, from dri nki ng col d wa ter, from wa s hi ng ha nds i n col d wa ter). An IgG
a utohemol ys i n bi nds to RBCs a t l ow tempera tures a nd ca us es i ntra va s cul a r hemol ys i s a fter wa rmi ng. It occurs mos t often a fter a nons peci fi c vi ra l
i l l nes s or i n otherwi s e hea l thy pa ti ents , a l though i t occurs i n s ome pa ti ents wi th congeni ta l or a cqui red s yphi l i s . The s everi ty a nd ra pi di ty of
devel opment of the a nemi a va ri es a nd ma y be ful mi na nt.
Symptoms and Signs
Symptoms of wa rm a nti body hemol yti c a nemi a tend to be due to the a nemi a . If the di s order i s s evere, fever, ches t pa i n, s yncope, or hea rt fa i l ure
ma y occur. Mi l d s pl enomega l y i s typi ca l .
Col d a ggl uti ni n di s ea s e ma ni fes ts a s a n a cute or chroni c hemol yti c a nemi a . Other cryopa thi c s ymptoms or s i gns ma y be pres ent (eg, a crocya nos es ,
Ra yna ud's s yndrome, col d-a s s oci a ted occl us i ve cha nges ). Symptoms of PCH ma y i ncl ude s evere pa i n i n the ba ck a nd l egs , hea da che, vomi ti ng,
di a rrhea , a nd pa s s a ge of da rk brown uri ne; hepa tos pl enomega l y ma y be pres ent.
Diagnosis
As s a ys for hemol yti c a nemi a (eg, peri phera l s mea r, reti cul ocyte count; s ometi mes uri na ry hemos i deri n, s erum ha ptogl obi n)
Di rect a nti gl obul i n tes t
AIHA i s s us pected i n pa ti ents wi th hemol yti c a nemi a , pa rti cul a rl y i f s ymptoms a re s evere or other s ugges ti ve s ymptoms a re pres ent. Routi ne
l a bora tory tes ts genera l l y s ugges t extra va s cul a r hemol ys i s (eg, hemos i deri nuri a i s a bs ent; ha ptogl obi n l evel s a re nea r norma l ) unl es s a nemi a i s
s udden a nd s evere or PCH i s the ca us e. Spherocytos i s a nd a hi gh MCHC a re typi ca l .
AIHA i s di a gnos ed by detecti on of a utoa nti bodi es wi th the di rect a nti gl obul i n (di rect Coombs ') tes t. Anti gl obul i n s erum i s a dded to wa s hed RBCs
from the pa ti ent; a ggl uti na ti on i ndi ca tes the pres ence of i mmunogl obul i n or compl ement (C) bound to the RBCs . Genera l l y IgG i s pres ent i n wa rm
a nti body hemol yti c a nemi a , a nd C3 (C3b a nd C3d) i n col d a nti body di s ea s e. The tes t i s 98% s ens i ti ve for AIHA; fa l s e-nega ti ve res ul ts ca n occur i f
a nti body dens i ty i s very l ow or i f the a utoa nti bodi es a re IgA or IgM. In genera l , the i ntens i ty of the di rect a nti gl obul i n tes t correl a tes wi th the
number of mol ecul es of IgG or C3 bound to the RBC a nd, roughl y, wi th the ra te of hemol ys i s . A compl ementa ry tes t cons i s ts of mi xi ng the pa ti ent's
pl a s ma wi th norma l RBCs to determi ne whether s uch a nti bodi es a re free i n the pl a s ma (the i ndi rect a nti gl obul i n [i ndi rect Coombs '] tes t). A
pos i ti ve i ndi rect a nti gl obul i n tes t a nd a nega ti ve di rect tes t genera l l y i ndi ca te a n a l l oa nti body ca us ed by pregna ncy, pri or tra ns fus i ons , or l ecti n
cros s -rea cti vi ty ra ther tha n i mmune hemol ys i s . Even i denti fi ca ti on of a wa rm a nti body does not defi ne hemol ys i s , beca us e 1/10,000 hea l thy bl ood
donors ha s a pos i ti ve tes t res ul t.
Once AIHA ha s been i denti fi ed by the Coombs ' tes t, tes ti ng s houl d di fferenti a te between wa rm a nti body hemol yti c a nemi a a nd col d a ggl uti ni n
di s ea s e a s wel l a s the mecha ni s m res pons i bl e for wa rm a nti body hemol yti c a nemi a . Thi s determi na ti on ca n often be ma de by obs ervi ng the
pa ttern of the di rect a nti gl obul i n rea cti on. Three pa tterns a re pos s i bl e:
The rea cti on i s pos i ti ve wi th a nti -IgG a nd nega ti ve wi th a nti -C3. Thi s pa ttern i s common i n i di opa thi c AIHA a nd i n the drug-a s s oci a ted or methyl dopa -type of AIHA, us ua l l y wa rm a nti body hemol yti c a nemi a .
The rea cti on i s pos i ti ve wi th a nti -IgG a nd a nti -C3. Thi s pa ttern i s common i n pa ti ents wi th SLE a nd i di opa thi c AIHA, us ua l l y wa rm a nti body
hemol yti c a nemi a , a nd i s ra re i n drug-a s s oci a ted ca s es .
The rea cti on i s pos i ti ve wi th a nti -C3 but nega ti ve wi th a nti -IgG. Thi s pa ttern occurs i n col d a ggl uti ni n di s ea s e. It i s uncommon i n i di opa thi c AIHA,
wa rm a nti body hemol yti c a nemi a , when the IgG a nti body i s of l ow a ffi ni ty, i n s ome drug-a s s oci a ted ca s es , a nd i n PCH.
Other s tudi es ca n s ugges t the ca us e of AIHA but a re not defi ni ti ve. In col d a ggl uti ni n di s ea s e, RBCs cl ump on the peri phera l s mea r, a nd
a utoma ted cel l counts often revea l a n i ncrea s ed MCV a nd s puri ous l y l ow Hb due to s uch cl umpi ng; ha nd wa rmi ng of the tube a nd recounti ng
res ul t i n va l ues s i gni fi ca ntl y cl os er to norma l . Wa rm a nti body hemol yti c a nemi a ca n often be di fferenti a ted from col d a ggl uti ni n di s ea s e by the
tempera ture a t whi ch the di rect a nti gl obul i n tes t i s pos i ti ve; a tes t tha t i s pos i ti ve a t tempera tures 37 C i ndi ca tes wa rm a nti body hemol yti c
a nemi a , wherea s a tes t tha t i s pos i ti ve a t l ower tempera tures i ndi ca tes col d a ggl uti ni n di s ea s e.
If PCH i s s us pected, the Dona th-La nds tei ner tes t, whi ch i s s peci fi c for PCH, s houl d be done. Tes ti ng for s yphi l i s i s recommended.
Treatment
For drug-i nduced wa rm a nti body hemol yti c a nemi a , drug wi thdra wa l , s ometi mes IV i mmune gl obul i n
For i di opa thi c wa rm a nti body hemol yti c a nemi a , corti cos teroi ds
For col d a ggl uti ni n di s ea s e, a voi da nce of col d
Trea tment depends on the s peci fi c mecha ni s m of the hemol ys i s .
Warm antibody hemolytic anemias: In drug-i nduced wa rm a nti body hemol yti c a nemi a s , drug wi thdra wa l decrea s es the ra te of hemol ys i s . Wi th methyl dopa -type AIHA, hemol ys i s us ua l l y cea s es wi thi n 3 wk; however, a pos i ti ve Coombs ' tes t ma y pers i s t for > 1 yr. Wi th ha pten-medi a ted AIHA,
hemol ys i s cea s es when the drug i s cl ea red from the pl a s ma . Corti cos teroi ds ha ve onl y l i ttl e effect i n drug-i nduced hemol ys i s ; i nfus i ons of
i mmune gl obul i n ma y be more effecti ve.
Corti cos teroi ds (eg, predni s one 1 mg/kg po once/da y or hi gher dos es ) a re the trea tment of choi ce i n i di opa thi c wa rm a nti body AIHA. In very s evere
hemol ys i s , a n i ni ti a l l oa di ng dos e of 100 to 200 mg i s recommended. Mos t pa ti ents ha ve a n excel l ent res pons e, whi ch i n a bout one thi rd i s
s us ta i ned a fter 12 to 20 wk of thera py. When s ta bl e RBC va l ues a re a chi eved, corti cos teroi ds a re ta pered s l owl y. In pa ti ents who rel a ps e a fter
corti cos teroi d ces s a ti on or who a re not hel ped by corti cos teroi ds , s pl enectomy i s done. About one thi rd to one ha l f of pa ti ents ha ve a s us ta i ned
res pons e a fter s pl enectomy. In ca s es of ful mi na nt hemol ys i s , pl a s ma excha nge ha s been us ed. For l es s s evere but uncontrol l ed hemol ys i s ,
i mmune gl obul i n i nfus i ons ha ve provi ded tempora ry control . Long-term ma na gement wi th i mmunos uppres s a nts (i ncl udi ng cycl os pori ne) ha s been
effecti ve i n pa ti ents i n whom corti cos teroi ds a nd s pl enectomy ha ve been i neffecti ve.
The pres ence of pa na ggl uti na ti ng a nti bodi es i n wa rm a nti body hemol yti c a nemi a ma kes cros s -ma tchi ng of donor bl ood di ffi cul t. In a ddi ti on,
tra ns fus i ons often s uperi mpos e a n a l l oa nti body on the a utoa nti body, a ccel era ti ng hemol ys i s . Thus , tra ns fus i ons s houl d be a voi ded whenever
pos s i bl e. When neces s a ry, they s houl d be gi ven onl y i n s ma l l a l i quots (100 to 200 mL over 1 to 2 h, wi th moni tori ng for hemol ys i s ).
Cold agglutinin disease: Trea tment i s l a rgel y s upporti ve i n a cute ca s es , beca us e the a nemi a ma y be s el f-l i mi ted. In chroni c ca s es , trea tment of the
underl yi ng di s order often control s the a nemi a . However, i n i di opa thi c chroni c ca s es , mi l d a nemi a (Hb, 9 to 10 g/dL) ma y pers i s t for l i fe. Avoi da nce
of col d expos ure i s often hel pful . Spl enectomy i s of no va l ue. Immunos uppres s a nts ha ve onl y modes t effecti venes s . Tra ns fus i ons s houl d be gi ven
s pa ri ngl y, wi th the bl ood wa rmed through a n on-l i ne wa rmer. Beca us e the a utol ogous RBCs ha ve a l rea dy s urvi ved the a utoa nti bodi es , a utol ogous
cel l s urvi va l i s better tha n tha t of tra ns fus ed cel l s , l i mi ti ng the effi ca cy of tra ns fus i on.
In PCH, thera py cons i s ts of s tri ct a voi da nce of expos ure to col d. Spl enectomy i s of no va l ue. Immunos uppres s a nts ha ve been effecti ve but s houl d
be res tri cted to pa ti ents wi th progres s i ve or i di opa thi c ca s es . Trea tment of concomi ta nt s yphi l i s ma y cure PCH.
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by intravascular hemolysis and hemoglobinuria, the latter accentuated during sleep.
Leukopenia, thrombocytopenia, and episodic crises are common. Diagnosis requires flow cytometry. Treatment is supportive.
PNH i s mos t common a mong men i n thei r 20s , but i t occurs i n both s exes a nd a t a ny a ge.
Etiology
PNH i s a n a cqui red geneti c muta ti on res ul ti ng i n a membra ne defect i n s tem cel l s a nd thei r progeny, i ncl udi ng RBCs , WBCs , a nd pl a tel ets . It
res ul ts i n unus ua l s ens i ti vi ty to norma l (C3) i n the pl a s ma , l ea di ng to ongoi ng i ntra va s cul a r hemol ys i s of RBCs a nd di mi ni s hed ma rrow producti on
of WBCs a nd pl a tel ets . The defect i s a mi s s i ng gl ycos yl -phos pha ti dyl i nos i tol a nchor for membra ne protei ns ca us ed by a n a bnorma l i ty of the PIG-A
gene, whi ch i s l oca ted on the X chromos ome.
Pathophysiology
Protra cted uri na ry Hb l os s ma y res ul t i n i ron defi ci ency. Pa ti ents a re s trongl y predi s pos ed to both venous a nd a rteri a l thrombi , i ncl udi ng the BuddChi a ri s yndrome. Thrombi a re commonl y fa ta l . Some pa ti ents wi th PNH devel op a pl a s ti c a nemi a , a nd s ome wi th a pl a s ti c a nemi a devel op PNH.
Cri s es ma y be preci pi ta ted by i nfecti on, i ron us e, va cci na ti on, or mens trua ti on. Abdomi na l a nd l umba r pa i n a nd s ymptoms of s evere a nemi a ma y
occur; gros s hemogl obi nuri a a nd s pl enomega l y a re common.
Diagnosis
Fl ow cytometry
Pos s i bl y a ci d hemol ys i s tes t (Ha m's tes t)
PNH i s s us pected i n pa ti ents who ha ve typi ca l s ymptoms of a nemi a or unexpl a i ned normocyti c a nemi a wi th i ntra va s cul a r hemol ys i s , pa rti cul a rl y i f
l eukopeni a or thrombocytopeni a i s pres ent. Hi s tori ca l l y, i f PNH wa s s us pected, the s uga r-wa ter tes t wa s us ua l l y the fi rs t tes t done; i t rel i es on
enha nced hemol ys i s of C3-dependent s ys tems i n i s otoni c s ol uti ons of l ow i oni c s trength, i s s i mpl e to do, a nd i s s ens i ti ve. However, the tes t i s
nons peci fi c; pos i ti ve res ul ts requi re confi rma ti on by further tes ti ng. The mos t s ens i ti ve a nd s peci fi c tes t i s determi na ti on of the a bs ence of
s peci fi c RBC or WBC membra ne protei ns (CD59 a nd CD55) by fl ow cytometry. An a l terna ti ve i s the a ci d hemol ys i s tes t (Ha m's tes t). Hemol ys i s
us ua l l y occurs i f bl ood i s a ci di fi ed wi th HCl , i ncuba ted for 1 h, a nd centri fuged. Bone ma rrow exa mi na ti on i s not neces s a ry but, i f done to excl ude
other di s orders , us ua l l y s hows ma rrow hypopl a s i a . Gros s hemogl obi nuri a i s common duri ng cri s es , a nd the uri ne ma y conta i n hemos i deri n.
Treatment
Pos s i bl y monocl ona l a nti body
Trea tment i s l a rgel y s ymptoma ti c. However, a new monocl ona l a nti body tha t i s a termi na l compl ement i nhi bi tor, ecul i zuma b, ha s reduced
tra ns fus i on requi rements , thromboembol i s m, a nd s ymptoms . Supporti ve mea s ures i ncl ude corti cos teroi ds , a ndrogen hormones , i ron a nd fol a te
s uppl ementa ti on, a nd s ometi mes tra ns fus i ons a nd s tem cel l tra ns pl a nta ti on. Empi ri c us e of corti cos teroi ds (eg, predni s one 20 to 40 mg po
once/da y) control s s ymptoms a nd s ta bi l i zes RBC va l ues i n > 50% of pa ti ents . Androgeni c hormones a nd recombi na nt erythropoi eti n to s ti mul a te
hema topoi es i s ha ve been us ed i n s ome pa ti ents . Genera l l y, tra ns fus i ons a re res erved for cri s es . Tra ns fus i ons conta i ni ng pl a s ma (a nd C3) s houl d
be a voi ded. Wa s hi ng RBCs wi th s a l i ne before tra ns fus i on i s no l onger neces s a ry. Hepa ri n fol l owed by wa rfa ri n ma y be requi red for thrombos es
but s houl d be us ed ca uti ous l y. Ora l i ron a nd fol a te s uppl ements ma y be neces s a ry. Mos t ca s es ca n be ma na ged by thes e s upporti ve mea s ures for
yea rs to deca des . Al l ogeni c s tem cel l tra ns pl a nta ti on ha s been s ucces s ful i n a s ma l l number of ca s es .
Traumatic Hemolytic Anemia
(Mi croa ngi opa thi c Hemol yti c Anemi a )
Traumatic hemolytic anemia is intravascular hemolysis caused by excessive shear or turbulence in the circulation.
Tra uma ma y ori gi na te outs i de the ves s el , a s i n s kel eta l i mpa ct, eg, repeti ti ve foot s tri ki ng (ma rch hemogl obi nuri a ) or from ka ra te or bongo
pl a yi ng; wi thi n the hea rt a cros s a pres s ure gra di ent, a s i n ca l ci fi c a orti c s tenos i s or wi th fa ul ty a orti c va l ve pros thes es ; i n a rteri ol es , a s i n s evere
(es peci a l l y ma l i gna nt) hypertens i on, s ome ma l i gna nt tumors , or pol ya rteri ti s nodos a ; or i n end a rteri ol es , often a cros s fi bri n depos i ts , a s i n
thromboti c thrombocytopeni c purpura a nd di s s emi na ted i ntra va s cul a r coa gul a ti on. The tra uma ca us es odd-s ha ped RBC fra gments (eg, tri a ngl es ,
hel met s ha pes ) ca l l ed s chi s tocytes i n the peri phera l bl ood; thei r a ppea ra nce on the peri phera l s mea r i s di a gnos ti c. The s ma l l s chi s tocytes ca us e
l ow MCV a nd hi gh RBC di s tri buti on wi dth (the l a tter refl ecti ng the a ni s ocytos i s ).
Trea tment a ddres s es the underl yi ng proces s . Iron defi ci ency a nemi a occa s i ona l l y i s s uperi mpos ed on the hemol ys i s a s a res ul t of chroni c
hemos i deri nuri a a nd, when pres ent, res ponds to i ron-repl a cement thera py.
Hereditary Spherocytosis and Hereditary Elliptocytosis
Hereditary spherocytosis and hereditary elliptocytosis are congenital RBC membrane disorders. Symptoms, generally milder in hereditary elliptocytosis, include
variable degrees of anemia, jaundice, and splenomegaly. Diagnosis requires demonstration of increased RBC osmotic fragility and a negative direct antiglobulin
test. Rarely, patients < 45 yr with symptomatic disease require splenectomy.
Heredi ta ry s pherocytos i s (chroni c fa mi l i a l i cterus ; congeni ta l hemol yti c ja undi ce; fa mi l i a l s pherocytos i s ; s pherocyti c a nemi a ) i s a n a utos oma l
domi na nt di s ea s e wi th va ri a bl e gene penetra nce. It i s cha ra cteri zed by hemol ys i s of s pheroi da l RBCs a nd a nemi a .
Heredi ta ry el l i ptocytos i s (ova l ocytos i s ) i s a ra re a utos oma l domi na nt di s order i n whi ch RBCs a re ova l or el l i pti ca l . Hemol ys i s i s us ua l l y a bs ent or
s l i ght, wi th l i ttl e or no a nemi a ; s pl enomega l y i s often pres ent.
Pathophysiology
Al tera ti ons i n membra ne protei ns ca us e the RBC a bnorma l i ti es i n both di s orders . In heredi ta ry s pherocytos i s , the cel l membra ne s urfa ce a rea i s
decrea s ed di s proporti ona tel y to the i ntra cel l ul a r content. The decrea s ed s urfa ce a rea of the cel l i mpa i rs the fl exi bi l i ty needed for the cel l to
tra vers e the s pl een's mi croci rcul a ti on, ca us i ng i ntra s pl eni c hemol ys i s . In heredi ta ry el l i ptocytos i s , geneti c muta ti ons res ul t i n wea knes s of the
cytos kel eton of the cel l , l ea di ng to deforma ti on of the cel l . The a bnorma l l y s ha ped RBCs a re ta ken up a nd des troyed by the s pl een.
Symptoms and Signs
Symptoms a nd s i gns of heredi ta ry s pherocytos i s a re us ua l l y mi l d, a nd the a nemi a ma y be s o wel l compens a ted tha t i t i s not recogni zed unti l a n
i ntercurrent vi ra l i l l nes s tra ns i entl y decrea s es RBC producti on, s i mul a ti ng a n a pl a s ti c cri s i s . However, thes e epi s odes a re s el f-l i mi ted, res ol vi ng
wi th res ol uti on of the i nfecti on. Modera te ja undi ce a nd s ymptoms of a nemi a a re pres ent i n s evere ca s es . Spl enomega l y i s a l mos t i nva ri a bl e but
onl y ra rel y ca us es a bdomi na l di s comfort. Hepa tomega l y ma y be pres ent. Chol el i thi a s i s (pi gment s tones ) i s common a nd ma y be the pres enti ng
s ymptom. Congeni ta l s kel eta l a bnorma l i ti es (eg, tower-s ha ped s kul l , pol yda ctyl i s m) occa s i ona l l y occur. Al though us ua l l y one or more fa mi l y
members ha ve ha d s ymptoms , s evera l genera ti ons ma y be s ki pped beca us e of va ri a ti ons i n the degree of gene penetra nce.
Cl i ni ca l fea tures of heredi ta ry el l i ptocytos i s a re s i mi l a r to thos e of heredi ta ry s pherocytos i s but tend to be mi l der.
Diagnosis
RBC fra gi l i ty a s s a y, RBC a utohemol ys i s a s s a y, a nd di rect a nti gl obul i n tes t
Thes e di s orders a re s us pected i n pa ti ents wi th unexpl a i ned hemol ys i s , pa rti cul a rl y i f s pl enomega l y, a fa mi l y hi s tory of s i mi l a r ma ni fes ta ti ons , or
s ugges ti ve RBC i ndi ces a re pres ent. Beca us e RBCs a re s pheroi da l a nd the MCV i s norma l , the mea n corpus cul a r di a meter i s bel ow norma l , a nd
RBCs res embl e mi cros pherocytes . MCHC i s i ncrea s ed. Reti cul ocytos i s of 15 to 30% a nd l eukocytos i s a re common.
If thes e di s orders a re s us pected, the RBC os moti c fra gi l i ty tes t (whi ch mi xes RBCs wi th va ryi ng concentra ti ons of s a l i ne), the RBC a utohemol ys i s
tes t (whi ch mea s ures the a mount of s ponta neous hemol ys i s occurri ng a fter 48 h of s teri l e i ncuba ti on), a nd, to rul e out s pherocytos i s due to
a utoi mmune hemol yti c a nemi a , the di rect a nti gl obul i n (Coombs ') tes t a re done. RBC fra gi l i ty i s cha ra cteri s ti ca l l y i ncrea s ed, but i n mi l d ca s es , i t
ma y be norma l unl es s s teri l e defi bri na ted bl ood i s fi rs t i ncuba ted a t 37 C for 24 h. RBC a utohemol ys i s i s i ncrea s ed a nd ca n be corrected by the
a ddi ti on of gl ucos e. The di rect a nti gl obul i n tes t res ul ts a re nega ti ve.
Treatment
Someti mes s pl enectomy
Spl enectomy, a fter a ppropri a te va cci na ti on, i s the onl y s peci fi c trea tment for ei ther di s order but i s ra rel y needed. It i s i ndi ca ted i n pa ti ents < 45 yr
wi th Hb pers i s tentl y < 10 g/dL, ja undi ce or bi l i a ry col i c, or pers i s tent a pl a s ti c cri s i s . If the ga l l bl a dder ha s s tones or other evi dence of chol es ta s i s ,
i t s houl d be removed duri ng s pl enectomy. Al though s pherocytos i s pers i s ts a fter s pl enectomy, the cel l s s urvi ve l onger i n the ci rcul a ti on. Us ua l l y,
s ymptoms res ol ve a nd a nemi a a nd reti cul ocytos i s decrea s e. However, RBC fra gi l i ty rema i ns hi gh.
Stomatocytosis and Anemia Caused by Hypophosphatemia
Stomatocytosis (presence of cup- or bowl-shaped RBCs) and hypophosphatemia are RBC membrane abnormalities causing hemolytic anemia.
Stomatocytosis: Stoma tocytos i s i s a ra re condi ti on of RBCs i n whi ch a mouth-l i ke or s l i tl i ke pa ttern repl a ces the norma l centra l zone of pa l l or.
Thes e cel l s a re a s s oci a ted wi th congeni ta l a nd a cqui red hemol yti c a nemi a . The s ymptoms res ul t from the a nemi a .
The ra re congeni ta l s toma tocytos i s , whi ch s hows a utos oma l domi na nt i nheri ta nce, ca us es a s evere hemol yti c a nemi a pres enti ng very ea rl y i n l i fe.
The RBC membra ne i s hyperpermea bl e to monova l ent ca ti ons (Na a nd K); movement of di va l ent ca ti ons a nd a ni ons i s norma l . About 20 to 30% of
ci rcul a ti ng RBCs a re s toma tocyti c; RBC fra gi l i ty i s i ncrea s ed, a s i s a utohemol ys i s wi th i ncons ta nt correcti on wi th gl ucos e. Spl enectomy a mel i ora tes
a nemi a i n s ome ca s es .
Acqui red s toma tocytos i s wi th hemol yti c a nemi a occurs pri ma ri l y wi th recent exces s i ve a l cohol i nges ti on. Stoma tocytes i n the peri phera l bl ood
a nd hemol ys i s di s a ppea r wi thi n 2 wk of a l cohol wi thdra wa l .
Anemia caused by hypophosphatemia: RBC pl i a bi l i ty va ri es a ccordi ng to i ntra cel l ul a r ATP l evel s . Beca us e the s erum phos pha te concentra ti on a ffects
RBC ATP l evel s , s erum phos pha te l evel < 0.5 mg/dL (< 0.16 mmol /L) depl etes RBC ATP; the compl ex meta bol i c s equel a e of hypophos pha temi a a l s o
i ncl ude 2,3-di phos phogl yceri c a ci d depl eti on, a s hi ft to the l eft i n the O2 di s s oci a ti on curve, decrea s ed gl ucos e uti l i za ti on, a nd i ncrea s ed l a cta te
producti on. The res ul ta nt ri gi d, nonyi el di ng RBCs a re s us cepti bl e to i njury i n the ca pi l l a ry ci rcul a tory bed, l ea di ng to hemol ys i s a nd s ma l l , s pheres ha ped RBCs (mi cros pherocytos i s ).
Severe hypophos pha temi a ma y occur i n a l cohol wi thdra wa l , di a betes mel l i tus , refeedi ng a fter s ta rva ti on, the recovery (di ureti c) pha s e a fter
s evere burns , hypera l i menta ti on, s evere res pi ra tory a l ka l os i s , a nd i n uremi c pa ti ents recei vi ng di a l ys i s who a re ta ki ng a nta ci ds . Phos pha te
s uppl ements prevent or revers e the a nemi a a nd a re cons i dered for pa ti ents a t ri s k of or who ha ve hypophos pha temi a .
Embden-Meyerhof Pathway Defects
Embden-Meyerhof pathway defects are autosomal recessive RBC metabolic disorders that cause hemolytic anemia.
Pyruva te ki na s e defi ci ency i s one s uch enzyme defect. In a l l of thes e pa thwa y defects , hemol yti c a nemi a occurs onl y i n homozygotes , a nd the exa ct
mecha ni s m of hemol ys i s i s unknown. Spherocytes a re a bs ent, but s ma l l numbers of i rregul a rl y s ha ped s pheres ma y be pres ent. In genera l , a s s a ys
of ATP a nd di phos phogl ycera te hel p i denti fy a ny meta bol i c defect a nd l oca l i ze the defecti ve s i tes for further a na l ys i s . There i s no s peci fi c thera py
for thes e hemol yti c a nemi a s , a l though mos t pa ti ents requi re no trea tment other tha n s uppl ementa l fol a te 1 mg po once/da y duri ng a cute
hemol ys i s . Hemol ys i s a nd a nemi a pers i s t a fter s pl enectomy, a l though s ome i mprovement ma y occur, pa rti cul a rl y i n pa ti ents wi th pyruva te ki na s e
defi ci ency.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in blacks that can result in hemolysis after acute illnesses or
intake of oxidant drugs (including salicylates and sulfonamides). Diagnosis is based on assay for G6PD, although tests are often falsely negative during acute
hemolysis. Treatment is supportive.
The onl y i mporta nt defect i n the hexos e monophos pha te s hunt pa thwa y i s ca us ed by G6PD defi ci ency. Over 100 muta nt forms of the enzyme ha ve
been i denti fi ed. Cl i ni ca l l y, the mos t common form i s the drug-s ens i ti ve va ri ety. Thi s X-l i nked di s order i s ful l y expres s ed i n ma l es a nd homozygous
fema l es a nd i s va ri a bl y expres s ed i n heterozygous fema l es . Thi s defect occurs i n a bout 10% of bl a ck ma l es a nd i n < 10% of bl a ck fema l es i n the US
a nd i n l ower frequenci es a mong peopl e wi th a nces tors from the Medi terra nea n ba s i n (eg, Ita l i a ns , Greeks , Ara bs , Sepha rdi c Jews ).
Pathophysiology
G6PD defi ci ency reduces energy a va i l a bl e to ma i nta i n the i ntegri ty of the red cel l membra ne, whi ch s hortens RBC s urvi va l .
Hemol ys i s s el ecti vel y a ffects ol der RBCs a mong a ffected bl a cks a nd a mong mos t a ffected whi tes . Hemol ys i s occurs commonl y a fter fever, a cute
vi ra l a nd ba cteri a l i nfecti ons , a nd di a beti c a ci dos i s . Les s commonl y, hemol ys i s occurs a fter expos ure to drugs or to other s ubs ta nces tha t produce
peroxi de a nd ca us e oxi da ti on of Hb a nd RBC membra nes . Thes e drugs a nd s ubs ta nces i ncl ude pri ma qui ne, s a l i cyl a tes , s ul fona mi des , ni trofura ns ,
phena ceti n, na phtha l ene, s ome vi ta mi n K deri va ti ves , da ps one, phena zopyri di ne, na l i di xi c a ci d, methyl ene bl ue, a nd, i n s ome whi tes , fa va bea ns .
Whether conti nued us e of the offendi ng drug l ea ds to a compens a ted hemol yti c s ta te or l etha l hemol ys i s depends on the degree of G6PD
defi ci ency a nd the oxi da nt potenti a l of the drug. Chroni c congeni ta l hemol ys i s (wi thout drug us e) occurs i n s ome whi tes . Beca us e ol der cel l s a re
s el ecti vel y des troyed i n bl a cks , hemol ys i s i s us ua l l y s el f-l i mi ted, a ffecti ng < 25% of RBC ma s s ; i n whi tes , the defi ci ency i s more s evere, a nd
profound hemol ys i s ma y l ea d to hemogl obi nuri a a nd a cute rena l fa i l ure.
Diagnosis
G6PD a s s a y
The di a gnos i s i s cons i dered i n pa ti ents wi th a cute hemol ys i s , pa rti cul a rl y bl a ck ma l es . G6PD a s s a y i s done. Anemi a , ja undi ce, a nd reti cul ocytos i s
devel op duri ng hemol ys i s . Hei nz bodi es , pos s i bl y pa rti cl es of dea d cytopl a s m or dena tured Hb, ma y be vi s i bl e ea rl y duri ng the hemol yti c epi s ode
but do not pers i s t i n pa ti ents wi th a n i nta ct s pl een beca us e they a re removed by i t. A s peci fi c di a gnos ti c cl ue i s the pres ence i n the peri phera l
bl ood of RBCs tha t a ppea r to ha ve ha d one or more bi tes (1-m wi de) ta ken from the cel l peri phery (bi te cel l s ), pos s i bl y a s a res ul t of Hei nz body
remova l by the s pl een. Ma ny s creeni ng tes ts a re a va i l a bl e. However, duri ng a nd i mmedi a tel y a fter a hemol yti c epi s ode, tes ts ma y yi el d fa l s enega ti ve res ul ts beca us e of des tructi on of the ol der, more defi ci ent RBCs a nd the pres ence of reti cul ocytes ri ch i n G6PD. Speci fi c enzyme a s s a ys
a re the bes t di a gnos ti c tes ts .
Treatment
Duri ng a cute hemol ys i s , trea tment i s s upporti ve; tra ns fus i ons a re ra rel y needed. Pa ti ents a re a dvi s ed to a voi d drugs or s ubs ta nces tha t i ni ti a te
hemol ys i s .
Sickle Cell Disease
(Hb S Di s ea s e)
Sickle cell disease (a hemoglobinopathysee Sidebar 106-1) causes a chronic hemolytic anemia occurring almost exclusively in blacks, caused by homozygous
inheritance of Hb S. Sickle-shaped RBCs clog capillaries, causing organ ischemia. Acute exacerbations (crises) may develop frequently. Infection, bone marrow
aplasia, or lung involvement (acute chest syndrome) can develop acutely and be fatal. Normocytic hemolytic anemia is characteristic. Diagnosis requires Hb
electrophoresis. Crises are treated with analgesics and other supportive measures. Transfusions are occasionally required. Vaccines against bacterial infections,
prophylactic antibiotics, and aggressive treatment of infections prolong survival. Hydroxyurea may decrease the frequency of crises.
Homozygotes (a bout 0.3% of bl a cks i n the US) ha ve s i ckl e cel l a nemi a ; heterozygotes (8 to 13% of bl a cks ) a re typi ca l l y not a nemi c.
Pathophysiology
In Hb S, va l i ne i s s ubs ti tuted for gl uta mi c a ci d i n the 6th a mi no a ci d of the cha i n. Oxygena ted Hb S i s much l es s s ol ubl e tha n oxygena ted Hb A; i t
forms a s emi s ol i d gel tha t ca us es RBCs to deform i n a s i ckl e s ha pe a t s i tes of l ow PO2 . Di s torted, i nfl exi bl e RBCs a dhere to va s cul a r endothel i um
a nd pl ug s ma l l a rteri ol es a nd ca pi l l a ri es , whi ch l ea ds to i nfa rcti on. Venous pl uggi ng predi s pos es to thrombos es . Beca us e s i ckl ed RBCs a re
fra gi l e, the mecha ni ca l tra uma of ci rcul a ti on ca us es hemol ys i s . Chroni c compens a tory ma rrow hypera cti vi ty deforms the bones .
Acute exacerbations: Acute exa cerba ti ons (cri s es ) occur i ntermi ttentl y, often for no known rea s on. In s ome ca s es , fever, vi ra l i nfecti on, or l oca l
tra uma a ppea rs to preci pi ta te a cri s i s .
Sidebar 106-1 Hemoglobinopathies

Hb mol ecul es cons i s t of pol ypepti de cha i ns whos e chemi ca l s tructure i s geneti ca l l y control l ed. The norma l a dul t Hb mol ecul e (Hb A) cons i s ts of 2
pa i rs of cha i ns des i gna ted a nd . Norma l bl ood a l s o conta i ns a 2.5% concentra ti on of Hb A2 (compos ed of a nd cha i ns ). Feta l Hb (Hb F,
whi ch ha s cha i ns i n the pl a ce of cha i ns ) gra dua l l y decrea s es , pa rti cul a rl y i n the fi rs t months of l i fe, unti l i t ma kes up < 2% of tota l Hb i n a dul ts
(s ee Hemogl obi nopa thi es on p. 2636). Hb F concentra ti on i ncrea s es i n certa i n di s orders of Hb s ynthes i s a nd i n a pl a s ti c a nd myel oprol i fera ti ve
s ta tes .
Some hemogl obi nopa thi es res ul t i n a nemi a s tha t a re s evere i n pa ti ents who a re homozygous but mi l d i n pa ti ents who a re heterozygous . Some
pa ti ents a re heterozygous for 2 s uch a bnorma l i ti es a nd ha ve a nemi a wi th cha ra cteri s ti cs of both tra i ts .
Di fferent Hbs , a s di s ti ngui s hed by el ectrophoreti c mobi l i ty, a re a l pha beti ca l l y des i gna ted i n order of di s covery (eg, A, B, C), a l though the fi rs t
a bnorma l Hb, s i ckl e cel l Hb, wa s des i gna ted Hb S. Structura l l y di fferent Hbs wi th the s a me el ectrophoreti c mobi l i ty a re na med for the ci ty or
l oca ti on i n whi ch they were di s covered (eg, Hb S Memphi s , Hb C Ha rl em). Sta nda rd des cri pti on of a pa ti ent's Hb compos i ti on pl a ces the Hb of
grea tes t concentra ti on fi rs t (eg, AS i n s i ckl e cel l tra i t).
In the US, i mporta nt a nemi a s a re ca us ed by defecti ve s ynthes i s of Hb S or Hb C a nd the tha l a s s emi a s , a nd i mmi gra ti on of Southea s t As i a ns ha s
ma de Hb E di s ea s e common.
Pa i nful cri s i s i s the mos t common type; i t i s ca us ed by i s chemi a a nd i nfa rcti on, typi ca l l y of the bones , but a l s o of the s pl een, l ung, or ki dney.
Apl a s ti c cri s i s occurs when ma rrow erythropoi es i s s l ows duri ng a cute i nfecti on (es peci a l l y vi ra l ), duri ng whi ch a n a cute erythrobl a s topeni a ma y
occur.
Acute ches t s yndrome res ul ts from pul mona ry mi crova s cul a r occl us i on a nd i s a common ca us e of dea th, wi th morta l i ty ra tes of up to 10%. It occurs
i n a l l a ge groups but i s mos t common i n chi l dhood. Repea ted epi s odes predi s pos e to chroni c pul mona ry hypertens i on.
In chi l dren, a cute s eques tra ti on of s i ckl ed cel l s i n the s pl een ma y occur, exa cerba ti ng a nemi a .
Pri a pi s m, a s eri ous compl i ca ti on tha t ca n ca us e erecti l e dys functi on, i s mos t common i n young men.
Complications: Long-term cons equences i ncl ude i mpa i red growth a nd devel opment. Increa s ed s us cepti bi l i ty to i nfecti on, pa rti cul a rl y pneumococca l
a nd Salmonella i nfecti ons (i ncl udi ng Salmonella os teomyel i ti s ), a l s o res ul ts . Thes e i nfecti ons a re es peci a l l y common i n ea rl y chi l dhood a nd ca n be
ra pi dl y fa ta l .
Other cons equences i ncl ude i s chemi c s troke, CNS va s cul i ti s , a va s cul a r necros i s of the hi ps , rena l concentra ti ng defects , rena l fa i l ure, hea rt
fa i l ure, a nd pul mona ry fi bros i s .
Symptoms and Signs
Mos t s ymptoms occur onl y i n pa ti ents who a re homozygous a nd res ul t from a nemi a a nd va s o-occl us i ve events res ul ti ng i n ti s s ue i s chemi a a nd
i nfa rcti on. Anemi a i s us ua l l y s evere but va ri es hi ghl y a mong pa ti ents ; mi l d ja undi ce a nd pa l l or a re common.
Pa ti ents ma y be poorl y devel oped a nd often ha ve a rel a ti vel y s hort trunk wi th l ong extremi ti es a nd a tower-s ha ped s kul l . Hepa tos pl enomega l y i s
common i n chi l dren, but beca us e of repea ted i nfa rcti ons a nd s ubs equent fi bros i s (a utos pl enectomy), the s pl een i n a dul ts i s commonl y very
s ma l l . Ca rdi omega l y a nd s ys tol i c ejecti on (fl ow) murmurs a re common. Chol el i thi a s i s a nd chroni c punched-out ul cers a round the a nkl es a re
common.
Pa i nful cri s i s ca us es s evere pa i n i n l ong bones (eg, preti bi a l pa i n), the ha nds a nd feet (eg, ha nd-foot s yndrome), a nd joi nts . Joi nt pa i n ma y res ul t
from hema rthros i s or a va s cul a r necros i s of the femora l hea d. Severe a bdomi na l pa i n ma y devel op wi th or wi thout vomi ti ng a nd, when due to
s i ckl i ng i ts el f, i s us ua l l y a ccompa ni ed by ba ck a nd joi nt pa i n.
Acute ches t s yndrome i s cha ra cteri zed by s udden ons et of fever, ches t pa i n, a nd pul mona ry i nfi l tra tes . The i nfi l tra tes begi n i n the l ower l obes , a re
bi l a tera l i n one thi rd of ca s es , a nd ma y be a ccompa ni ed by pl eura l effus i on. It ma y fol l ow ba cteri a l pneumoni a . Hypoxemi a ma y devel op ra pi dl y,
ca us i ng dys pnea .
Heterozygotes: Pa ti ents who a re heterozygous (Hb AS) do not experi ence hemol ys i s , pa i nful cri s es , or thromboti c compl i ca ti ons except pos s i bl y
duri ng hypoxi c condi ti ons (eg, a t hi gh a l ti tudes , duri ng s udden decompres s i on i n a i rpl a nes ). However, rha bdomyol ys i s a nd s udden dea th ma y
occur duri ng s us ta i ned, exha us ti ng exerci s e. Impa i red a bi l i ty to concentra te uri ne (hypos thenuri a ) i s common. Uni l a tera l hema turi a (by unknown
mecha ni s ms a nd us ua l l y from the l eft ki dney) ca n occur but i s s el f-l i mi ted. Typi ca l rena l pa pi l l a ry necros i s ca n occur but i s l es s common tha n
a mong homozygous pa ti ents .
Diagnosis
DNA tes ti ng (prena ta l di a gnos i s )
Sol ubi l i ty tes ti ng
Hb el ectrophores i s (or thi n-l a yer i s oel ectri c focus i ng)
The type of tes ti ng done depends on the a ge of the pa ti ent. DNA tes ti ng ca n be us ed for prena ta l di a gnos i s or to confi rm a di a gnos i s of the s i ckl e
cel l genotype. Screeni ng of neona tes i s a va i l a bl e i n mos t US s ta tes a nd i nvol ves Hb el ectrophores i s . Screeni ng a nd di a gnos i s i n chi l dren a nd
a dul ts i nvol ve exa mi na ti on of the peri phera l s mea r, Hb s ol ubi l i ty tes ti ng, a nd Hb el ectrophores i s .
Prenatal screening: The s ens i ti vi ty of prena ta l di a gnos i s ha s been grea tl y i mproved wi th the a va i l a bi l i ty of the PCR techni que. It i s recommended for
fa mi l i es a t ri s k for s i ckl e cel l (eg, coupl es wi th medi ca l or fa mi l y hi s tori es of a nemi a or of s ugges ti ve ethni c ba ckground). DNA s a mpl es ca n be
obta i ned by chori oni c vi l l us s a mpl i ng a t 8 to 10 wk ges ta ti on. Amni oti c fl ui d ca n a l s o be tes ted a t 14 to 16 wk. Di a gnos i s i s i mporta nt for geneti c
couns el i ng.
Newborn screening: Uni vers a l tes ti ng i s currentl y recommended a nd i s frequentl y one of a ba ttery of newborn s creeni ng tes ts . To di s ti ngui s h
between Hbs F, S, A, a nd C, the recommended tes ts a re Hb el ectrophores i s us i ng cel l ul os e a ceta te or a ci d ci tra te a ga r, thi n-l a yer i s oel ectri c
focus i ng, or Hb fra cti ona ti on by hi gh performa nce l i qui d chroma togra phy (HPLC). Repea t tes ti ng a t a ge 3 to 6 mo ma y be neces s a ry for confi rma ti on.
Sol ubi l i ty tes ti ng for Hb S i s unrel i a bl e duri ng the fi rs t few months of l i fe.
Screening and diagnosis of children and adults: Pa ti ents wi th a fa mi l y hi s tory of s i ckl e cel l di s ea s e or tra i t s houl d be s creened wi th peri phera l s mea r,
Hb s ol ubi l i ty tes ti ng, a nd Hb el ectrophores i s .
Pa ti ents wi th s ymptoms or s i gns s ugges ti ng the di s order or i ts compl i ca ti ons (eg, poor growth, a cute a nd unexpl a i ned bone pa i n, a s epti c necros i s
of the femora l hea d, unexpl a i ned hema turi a ), a nd bl a ck pa ti ents wi th normocyti c a nemi a (pa rti cul a rl y i f hemol ys i s i s pres ent) requi re l a bora tory
tes ts for hemol yti c a nemi a (s ee p. 936), Hb el ectrophores i s , a nd exa mi na ti on of RBCs for s i ckl i ng. If s i ckl e cel l di s ea s e i s pres ent, RBC count i s
us ua l l y between 2 a nd 3 mi l l i on/L wi th Hb reduced proporti ona tel y; cel l s a re normocyti c (mi crocytos i s s ugges ts a concomi ta nt -tha l a s s emi a ).
Nucl ea ted RBCs frequentl y a ppea r i n the peri phera l bl ood, a nd reti cul ocytos i s 10% i s common. Dry-s ta i ned s mea rs ma y s how s i ckl ed RBCs
(cres cent-s ha ped, often wi th el onga ted or poi nted ends ).
The homozygous s ta te i s di fferenti a ted from other s i ckl e hemogl obi nopa thi es by el ectrophores i s s howi ng onl y Hb S wi th a va ri a bl e a mount of Hb
F. The heterozygote i s di fferenti a ted by the pres ence of more Hb A tha n Hb S on el ectrophores i s . Hb S mus t be di s ti ngui s hed from other Hb wi th a
s i mi l a r el ectrophoreti c pa ttern by s howi ng the pa thognomoni c RBC morphol ogy.
Bone ma rrow exa mi na ti on i s not us ed for di a gnos i s . If i t i s done to di fferenti a te other a nemi a s , i t s hows hyperpl a s i a , wi th normobl a s ts
predomi na ti ng; bone ma rrow ma y become a pl a s ti c duri ng s i ckl i ng or s evere i nfecti ons . ESR, i f done to excl ude other di s orders (eg, juveni l e RA
ca us i ng ha nd a nd foot pa i n), i s l ow. Inci denta l fi ndi ngs on s kel eta l x-ra ys ma y i ncl ude wi deni ng of the di pl oi c s pa ces of the s kul l a nd a s un-ra y
a ppea ra nce of the di pl oi c tra becul a ti ons . The l ong bones often s how corti ca l thi nni ng, i rregul a r dens i ti es , a nd new bone forma ti on wi thi n the
medul l a ry ca na l . Unexpl a i ned hema turi a , even a mong pa ti ents not s us pected of ha vi ng s i ckl e cel l di s ea s e, s houl d prompt cons i dera ti on of s i ckl e
cel l tra i t.
Evaluation of exacerbations: If pa ti ents wi th known s i ckl e cel l di s ea s e ha ve a cute exa cerba ti ons , i ncl udi ng pa i n, fever, or other s ymptoms of
i nfecti on, a pl a s ti c cri s i s i s cons i dered a nd CBC a nd reti cul ocyte count a re done. Reti cul ocyte count < 1% s ugges ts a pl a s ti c cri s i s , pa rti cul a rl y when
Hb decrea s es bel ow the pa ti ent's us ua l l evel . In a pa i nful cri s i s wi thout a pl a s i a , WBC count ri s es , often wi th a s hi ft to the l eft, pa rti cul a rl y duri ng
ba cteri a l i nfecti on. Pl a tel et count us ua l l y i ncrea s es . If mea s ured, s erum bi l i rubi n i s us ua l l y el eva ted (eg, 2 to 4 mg/dL [34 to 68 mol /L]), a nd uri ne
ma y conta i n urobi l i nogen.
In pa ti ents wi th ches t pa i n or di ffi cul ty brea thi ng, a cute ches t s yndrome a nd pul mona ry embol i s m a re cons i dered; ches t x-ra y a nd pul s e oxi metry
a re neces s a ry. Hypoxemi a or pul mona ry pa renchyma l i nfi l tra tes on ches t x-ra y s ugges t a cute ches t s yndrome or pneumoni a . Hypoxemi a wi thout
pul mona ry i nfi l tra tes s ugges ts pul mona ry embol i s m.
In pa ti ents wi th fever, i nfecti on a nd a cute ches t s yndrome a re cons i dered; cul tures , ches t x-ra y, a nd other a ppropri a te di a gnos ti c tes ts a re done.
Prognosis
The l i fe s pa n of homozygous pa ti ents ha s s tea di l y i ncrea s ed to > 50 yr. Common ca us es of dea th a re a cute ches t s yndrome, i ntercurrent i nfecti ons ,
pul mona ry embol i , i nfa rcti on of a vi ta l orga n, a nd rena l fa i l ure.
Treatment
Broa d-s pectrum a nti bi oti cs (for i nfecti on)
Ana l ges i cs a nd IV hydra ti on (for va s ooccl us i ve pa i n cri s i s )
Someti mes tra ns fus i ons

Immuni za ti ons , fol a te s uppl ementa ti on, a nd hydroxyurea (for hea l th ma i ntena nce)
Trea tment i ncl udes regul a r hea l th ma i ntena nce mea s ures a s wel l a s s peci fi c trea tment of the compl i ca ti ons a s they a ri s e. Compl i ca ti ons a re
trea ted s upporti vel y. No effecti ve i n vi vo a nti -s i ckl i ng drug i s a va i l a bl e. Spl enectomy i s va l uel es s . Stem cel l tra ns pl a nta ti on ha s been cura ti ve i n a
s ma l l number of pa ti ents but ha s a 5 to 10% morta l i ty ra te a nd s o i s not commonl y done. Gene thera py offers hope for a cure, but i t i s s ti l l under
s tudy.
Indi ca ti ons for hos pi ta l i za ti on i ncl ude s us pected s eri ous (i ncl udi ng s ys temi c) i nfecti on, a pl a s ti c cri s i s , a cute ches t s yndrome, a nd, often,
i ntra cta bl e pa i n or the need for tra ns fus i on. Fever a l one ma y not be a rea s on to hos pi ta l i ze. However, pa ti ents who a ppea r a cutel y i l l a nd ha ve a
tempera ture > 38C s houl d be a dmi tted s o tha t cul tures ca n be obta i ned from mul ti pl e a rea s a nd IV a nti bi oti cs ca n be gi ven.
Antibiotics: Pa ti ents wi th s us pected s eri ous ba cteri a l i nfecti ons or a cute ches t s yndrome requi re broa d-s pectrum a nti bi oti cs i mmedi a tel y.
Analgesics: Pa i nful cri s es a re ma na ged wi th l i bera l a dmi ni s tra ti on of a na l ges i cs , us ua l l y opi oi ds . IV morphi ne (conti nuous or bol us ) i s effecti ve
a nd s a fe; meperi di ne i s a voi ded. Al though dehydra ti on contri butes to s i ckl i ng a nd ma y preci pi ta te cri s es , i t i s uncl ea r whether vi gorous hydra ti on
i s hel pful duri ng cri s es . Neverthel es s , ma i nta i ni ng norma l i ntra va s cul a r vol ume ha s been a ma i ns ta y of thera py. Duri ng cri s es , pa i n a nd fever ma y
pers i s t for a s l ong a s 5 da ys .
Transfusion: Tra ns fus i on i s gi ven i n ma ny s i tua ti ons i n whi ch i ts effi ca cy ha s not been demons tra ted. However, routi ne tra ns fus i on thera py i s
i ndi ca ted for preventi on of recurrent cerebra l thrombos i s , es peci a l l y i n chi l dren. Tra ns fus i on i s us ua l l y done when Hb i s < 5 g/dL. Speci fi c
i ndi ca ti ons i ncl ude a cute s pl eni c s eques tra ti on, a pl a s ti c cri s es , ca rdi opul mona ry s ymptoms or s i gns (eg, hi gh-output hea rt fa i l ure, hypoxemi a
wi th PO2 < 65 mm Hg), preopera ti ve us e, pri a pi s m, a nd l i fe-threa teni ng events tha t woul d benefi t from i mproved O2 del i very (eg, s eps i s , s evere
i nfecti on, a cute ches t s yndrome, s troke, a cute orga n i s chemi a ). Tra ns fus i on i s not hel pful duri ng a n uncompl i ca ted pa i nful cri s i s ; however, i t ma y
brea k a cycl e of cl os el y s pa ced pa i nful cri s es . Tra ns fus i on ma y be needed i n pregna ncy.
Pa rti a l excha nge tra ns fus i on i s us ua l l y preferred to s i mpl e tra ns fus i on i f routi ne or mul ti pl e tra ns fus i ons a re neces s a ry. It ca n be done wi th
modern a pheres i s ma chi nes . If the i ni ti a l Hb i s l ow (< 7 g/dL), thi s proces s ca nnot be i ni ti a ted before fi rs t tra ns fus i ng red cel l s . Pa rti a l excha nge
tra ns fus i on mi ni mi zes i ron a ccumul a ti on a nd hypervi s cos i ty.
Health maintenance: For l ong-term ma na gement the fol l owi ng i nterventi ons ha ve reduced morta l i ty, pa rti cul a rl y duri ng chi l dhood:
Pneumococca l , Haemophilus influenzae, a nd meni ngococca l va cci nes
Ea rl y i denti fi ca ti on a nd trea tment of s eri ous ba cteri a l i nfecti ons
Prophyl a cti c a nti bi oti cs , i ncl udi ng conti nuous prophyl a xi s wi th ora l peni ci l l i n from a ge 4 mo to 6 yr
Us e of hydroxyurea a nd fol a te s uppl ementa ti on
Suppl ementa l fol a te, 1 mg po once/da y, i s us ua l l y pres cri bed.
Hydroxyurea , by i ncrea s i ng Hb F a nd thereby reduci ng s i ckl i ng, decrea s es pa i nful cri s es (by 50%) a nd decrea s es a cute ches t s yndrome a nd
tra ns fus i on requi rements . The dos e of hydroxyurea i s va ri a bl e a nd i s a djus ted to i ncrea s e Hb F. Hydroxyurea ma y be more effecti ve when
combi ned wi th erythropoi eti n (eg, 40,000 to 60,000 uni ts /wk). However, hydroxyurea i s a l eukemogen a nd ca us es neutropeni a a nd
thrombocytopeni a . It i s a l s o a tera togen a nd s houl d not be gi ven to fema l es of chi l d-bea ri ng a ge.
Erythropoi eti n us e i n pa ti ents wi th a nemi a unrel a ted to chemothera py ha s been a s s oci a ted wi th i ncrea s ed frequency of venous thromboembol i c
events a nd ca rdi opul mona ry compl i ca ti ons (eg, MI); i t i s genera l l y not hel pful i n pa ti ents wi th s i ckl e cel l di s ea s e.
Hemoglobin C Disease
Hemoglobin C disease is a hemoglobinopathy (see Sidebar 106-1) that causes symptoms similar to those of sickle cell disease, but milder.
Of bl a cks i n the US, 2 to 3% ha ve the tra i t, whi ch i s a s ymptoma ti c. Symptoms i n homozygotes a re us ua l l y s i mi l a r to thos e of s i ckl e cel l di s ea s e, but
mi l der. However, the a bdomi na l cri s es of s i ckl e cel l di s ea s e do not occur, a nd the s pl een i s us ua l l y enl a rged. Spl eni c s eques tra ti on i s pos s i bl e.
Hemogl obi n C di s ea s e i s s us pected i n a l l pa ti ents wi th a fa mi l y hi s tory a nd i n bl a ck pa ti ents wi th cl i ni ca l fea tures s ugges ti ng s i ckl e cel l di s ea s e,
pa rti cul a rl y i n a dul ts wi th s pl enomega l y. The a nemi a i s us ua l l y mi l d but ca n be modera tel y s evere. The s mea r i s normocyti c, wi th 30 to 100%
ta rget cel l s , s pherocytes , a nd, ra rel y, crys ta l -conta i ni ng RBCs . Nucl ea ted RBCs ma y be pres ent. The RBCs do not s i ckl e. On el ectrophores i s , the Hb i s
type C. In heterozygotes , the onl y l a bora tory a bnorma l i ty i s centra l l y ta rgeted RBCs .
No s peci fi c trea tment i s recommended. Anemi a us ua l l y i s not s evere enough to requi re bl ood tra ns fus i on.
Hemoglobin S-C Disease
Hemoglobin S-C disease is a hemoglobinopathy (see Sidebar 106-1) that causes symptoms similar to those of sickle cell disease, but milder.
Beca us e 10% of bl a cks ca rry the Hb S tra i t, the heterozygous S-C combi na ti on i s more common tha n homozygous Hb C di s ea s e. The a nemi a i n Hb SC di s ea s e i s mi l der tha n the a nemi a i n s i ckl e cel l di s ea s e; s ome pa ti ents even ha ve norma l Hb l evel s . Mos t s ymptoms a re thos e of s i ckl e cel l
di s ea s e, but s ymptoms a re us ua l l y l es s frequent a nd l es s s evere. However, gros s hema turi a , reti na l hemorrha ges , a nd a s epti c necros i s of the
femora l hea d a re common. Hb S-C di s ea s e i s s us pected i n pa ti ents whos e cl i ni ca l fea tures s ugges t s i ckl e cel l di s ea s e or whos e RBCs
demons tra te s i ckl i ng. Sta i ned bl ood s mea rs s how ta rget cel l s a nd a ra re s i ckl e cel l . Si ckl i ng i s i denti fi ed i n a s i ckl i ng prepa ra ti on, a nd Hb
el ectrophores i s es ta bl i s hes the di a gnos i s . Trea tment ca n be s i mi l a r to tha t of s i ckl e cel l di s ea s e but i s determi ned by s everi ty of s ymptoms .
Hemoglobin E Disease
Homozygous Hb E disease (a hemoglobinopathysee Sidebar 106-1) causes a mild hemolytic anemia, usually without splenomegaly.
Hb E i s the 3rd mos t preva l ent Hb worl dwi de (a fter Hb A a nd Hb S), pri ma ri l y i n bl a ck a nd Southea s t As i a n (> 15% i nci dence of homozygous
di s ea s e) popul a ti ons , a l though ra rel y i n Chi nes e popul a ti ons . Heterozygotes (Hb AE) a re a s ymptoma ti c. Pa ti ents heterozygous for Hb E a nd tha l a s s emi a ha ve a hemol yti c di s ea s e more s evere tha n S-tha l a s s emi a or homozygous Hb E di s ea s e a nd us ua l l y ha ve s pl enomega l y.
In heterozygotes (Hb AE), routi ne l a bora tory tes t res ul ts of peri phera l bl ood a re norma l . In homozygotes , a mi l d mi crocyti c a nemi a wi th promi nent
ta rget cel l s exi s ts . Di a gnos i s of Hb E di s orders i s by Hb el ectrophores i s . Trea tment i n homozygous pa ti ents wi th s evere di s ea s e us ua l l y i nvol ves
chroni c tra ns fus i ons .
Thalassemias
(Medi terra nea n Anemi a ; Tha l a s s emi a Ma jor a nd Mi nor)
Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective Hb synthesis. They are particularly common in people of
Mediterranean, African, and Southeast Asian ancestry. Symptoms and signs result from anemia, hemolysis, splenomegaly, bone marrow hyperplasia, and, if there
have been multiple transfusions, iron overload. Diagnosis is based on genetic tests and quantitative Hb analysis. Treatment for severe forms may include
transfusion, splenectomy, chelation, and stem cell transplantation.
Pathophysiology
Tha l a s s emi a (a hemogl obi nopa thys ee Si deba r 106-1) i s a mong the mos t common i nheri ted di s orders of Hb producti on. It res ul ts from
unba l a nced Hb s ynthes i s ca us ed by decrea s ed producti on of a t l ea s t one gl obi n pol ypepti de cha i n (, , , ).
-Tha l a s s emi a res ul ts from decrea s ed producti on of -pol ypepti de cha i ns . Inheri ta nce i s a utos oma l : Heterozygotes a re ca rri ers a nd ha ve
a s ymptoma ti c mi l d to modera te mi crocyti c a nemi a (tha l a s s emi a mi nor); homozygotes (-tha l a s s emi a ma jor, or Cool ey's a nemi a ) devel op s evere
a nemi a a nd bone ma rrow hypera cti vi ty. --Tha l a s s emi a i s a l es s common form of -tha l a s s emi a i n whi ch -cha i n a s wel l a s -cha i n producti on i s
i mpa i red a nd whi ch a l s o ha s heterozygous a nd homozygous s ta tes .
-Tha l a s s emi a , whi ch res ul ts from decrea s ed producti on of -pol ypepti de cha i ns , ha s a more compl ex i nheri ta nce pa ttern, beca us e geneti c
control of -cha i n s ynthes i s i nvol ves 2 pa i rs of genes (4 genes ). Heterozygotes for a s i ngl e gene defect (-tha l a s s emi a -2 [s i l ent]) a re us ua l l y
cl i ni ca l l y norma l . Heterozygotes wi th defects i n 2 of the 4 genes (-tha l a s s emi a -1 [tra i t]) tend to devel op mi l d to modera te mi crocyti c a nemi a but
no s ymptoms . Defects i n 3 of the 4 genes more s everel y i mpa i rs -cha i n producti on, res ul ti ng i n the forma ti on of tetra mers of exces s cha i ns (Hb
H) or, i n i nfa ncy, cha i ns (Ba rt's Hb). Defects i n a l l 4 genes a re a l etha l condi ti on i n utero, beca us e Hb tha t l a cks cha i ns does not tra ns port O2 . In
bl a cks , the gene frequency for -tha l a s s emi a i s a bout 25%; onl y 10% ha ve defects i n more tha n 2 genes .
Symptoms and Signs
Cl i ni ca l fea tures of tha l a s s emi a s a re s i mi l a r but va ry i n s everi ty. -Tha l a s s emi a ma jor ma ni fes ts by a ge 1 to 2 yr wi th s ymptoms of s evere a nemi a
a nd tra ns fus i ona l a nd a bs orpti ve i ron overl oa d. Pa ti ents a re ja undi ced, a nd l eg ul cers a nd chol el i thi a s i s occur (a s i n s i ckl e cel l a nemi a ).
Spl enomega l y, often ma s s i ve, i s common. Spl eni c s eques tra ti on ma y devel op, a ccel era ti ng des tructi on of tra ns fus ed norma l RBCs . Bone ma rrow
hypera cti vi ty ca us es thi ckeni ng of the cra ni a l bones a nd ma l a r emi nences . Long bone i nvol vement predi s pos es to pa thol ogi c fra ctures a nd
i mpa i rs growth, pos s i bl y del a yi ng or preventi ng puberty. Iron depos i ts i n hea rt mus cl e ma y ca us e hea rt fa i l ure. Hepa ti c s i deros i s i s typi ca l ,
l ea di ng to functi ona l i mpa i rment a nd ci rrhos i s . Pa ti ents wi th Hb H di s ea s e often ha ve s ymptoma ti c hemol yti c a nemi a a nd s pl enomega l y.
Diagnosis
Eva l ua ti on for hemol yti c a nemi a i f s us pected
El ectrophores i s
DNA tes ti ng (prena ta l di a gnos i s )
Tha l a s s emi a s a re s us pected i n pa ti ents wi th a fa mi l y hi s tory, s ugges ti ve s ymptoms or s i gns , or mi crocyti c hemol yti c a nemi a . If tha l a s s emi a s a re
s us pected, l a bora tory tes ts for mi crocyti c a nd hemol yti c a nemi a s a nd qua nti ta ti ve Hb s tudi es a re done. Serum bi l i rubi n, i ron, a nd ferri ti n l evel s
a re i ncrea s ed.
In -tha l a s s emi a ma jor, a nemi a i s s evere, often wi th Hb 6 g/dL. RBC count i s el eva ted rel a ti ve to Hb beca us e the cel l s a re very mi crocyti c. The
bl ood s mea r i s vi rtua l l y di a gnos ti c, wi th ma ny nucl ea ted erythrobl a s ts ; ta rget cel l s ; s ma l l , pa l e RBCs ; a nd puncta te a nd di ffus e ba s ophi l i a .
In qua nti ta ti ve Hb s tudi es , el eva ti on of Hb A2 i s di a gnos ti c for -tha l a s s emi a mi nor. In -tha l a s s emi a ma jor, Hb F i s us ua l l y i ncrea s ed, s ometi mes
to a s much a s 90%, a nd Hb A2 i s us ua l l y el eva ted to > 3%. The percenta ges of Hb F a nd Hb A2 a re genera l l y norma l i n -tha l a s s emi a s , a nd the
di a gnos i s of s i ngl e or doubl e gene defect tha l a s s emi a s ma y be ca rri ed out wi th newer geneti c tes ts a nd often i s one of excl us i on of other ca us es
of mi crocyti c a nemi a . Hb H di s ea s e ca n be di a gnos ed by demons tra ti ng the fa s t-mi gra ti ng Hb H or Ba rt's fra cti ons on Hb el ectrophores i s . The
s peci fi c mol ecul a r defect ca n be cha ra cteri zed but does not a l ter the cl i ni ca l a pproa ch. Recombi na nt DNA a pproa ches of gene ma ppi ng
(pa rti cul a rl y the PCR) ha ve become s ta nda rd for prena ta l di a gnos i s a nd geneti c couns el i ng.
If bone ma rrow exa mi na ti on i s done for a nemi a (eg, to excl ude other ca us es ), i t s hows ma rked erythroi d hyperpl a s i a . X-ra ys done for other
rea s ons i n pa ti ents wi th -tha l a s s emi a ma jor s how cha nges due to chroni c bone ma rrow hypera cti vi ty. The s kul l ma y s how corti ca l thi nni ng,
wi dened di pl oi c s pa ce, a s un-ra y a ppea ra nce of the tra becul a e, a nd a gra nul a r or ground-gl a s s a ppea ra nce. The l ong bones ma y s how corti ca l
thi nni ng, ma rrow s pa ce wi deni ng, a nd a rea s of os teoporos i s . The vertebra l bodi es ma y ha ve a gra nul a r or ground-gl a s s a ppea ra nce. The
pha l a nges ma y a ppea r recta ngul a r or bi convex.
Prognosis
Li fe expecta ncy i s norma l for peopl e wi th -tha l a s s emi a mi nor or -tha l a s s emi a mi nor. The outl ook for peopl e wi th Hb H di s ea s e va ri es . Li fe
expecta ncy i s decrea s ed i n peopl e wi th -tha l a s s emi a ma jor; onl y s ome l i ve to puberty or beyond.
Treatment
Someti mes s pl enectomy
Someti mes RBC tra ns fus i on a nd chel a ti on thera py
Ra rel y a l l ogenei c s tem cel l tra ns pl a nta ti on
Peopl e wi th - a nd -tha l a s s emi a mi nor requi re no trea tment. Spl enectomy ma y be hel pful i f Hb H di s ea s e ca us es s evere a nemi a or
s pl enomega l y.
Chi l dren wi th -tha l a s s emi a ma jor s houl d recei ve a s few tra ns fus i ons a s pos s i bl e to a voi d i ron overl oa d. However, s uppres s i on of a bnorma l
hema topoi es i s by peri odi c RBC tra ns fus i on ma y be va l ua bl e i n s everel y a ffected pa ti ents . To prevent or del a y i ron overl oa d, exces s (tra ns fus i ona l )
i ron mus t be removed (eg, vi a chroni c i ron-chel a ti on thera py). Spl enectomy ma y hel p decrea s e tra ns fus i on requi rements for pa ti ents wi th
s pl enomega l y. Al l ogenei c s tem cel l tra ns pl a nta ti on ha s been s ucces s ful , but the requi rement for a hi s tocompa ti bl e ma tch, morta l i ty a nd
morbi di ty of the procedure, a nd l i fel ong requi rement for i mmunos uppres s i on ha ve l i mi ted i ts us eful nes s .
Hemoglobin S--Thalassemia Disease
Hemoglobin S--thalassemia disease is a hemoglobinopathy (see Sidebar 106-1) that causes symptoms similar to those of sickle cell disease, but milder.
Beca us e of the i ncrea s ed frequency of both Hb S a nd -tha l a s s emi a genes i n s i mi l a r popul a ti on groups , i nheri ta nce of both defects i s rel a ti vel y
common. Cl i ni ca l l y, the di s order ca us es s ymptoms of modera te a nemi a a nd s i gns of s i ckl e cel l a nemi a , whi ch a re us ua l l y l es s frequent a nd l es s
s evere tha n thos e of s i ckl e cel l di s ea s e. Mi l d to modera te mi crocyti c a nemi a i s us ua l l y pres ent a l ong wi th s ome s i ckl ed RBCs on s ta i ned bl ood
s mea rs . Di a gnos i s requi res qua nti ta ti ve Hb s tudi es . The Hb A2 i s > 3%. Hb S predomi na tes on el ectrophores i s , a nd Hb A i s decrea s ed or a bs ent.
Hb F i ncrea s e i s va ri a bl e. Trea tment, i f neces s a ry, i s the s a me a s for s i ckl e cel l di s ea s e.
Chapter 107. Neutropenia and Lymphocytopenia

Introduction
Leukopeni a i s a reducti on i n the ci rcul a ti ng WBC count to < 4000/L. It i s us ua l l y cha ra cteri zed by a reduced number of ci rcul a ti ng neutrophi l s ,
a l though a reduced number of l ymphocytes , monocytes , eos i nophi l s , or ba s ophi l s ma y a l s o contri bute. Thus , i mmune functi on i s genera l l y grea tl y
decrea s ed.
Neutropeni a i s a reducti on i n bl ood neutrophi l count to < 1500/L i n whi tes a nd < 1200/L i n bl a cks . It i s more s eri ous when a ccompa ni ed by
monocytopeni a a nd l ymphocytopeni a . Lymphocytopeni a , i n whi ch the tota l number of l ymphocytes i s < 1000/L i n a dul ts , i s not a l wa ys refl ected i n
the tota l WBC count, beca us e l ymphocytes a ccount for onl y 20 to 40% of the count.
Neutropenia
(Agra nul ocytos i s ; Gra nul ocytopeni a )
Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of
infection may be muted, but fever is present during most serious infections. Diagnosis is by WBC count, but evaluation requires identification of the cause. If
fever is present, infection is presumed, and immediate, empiric broad-spectrum antibiotics are necessary. Treatment with granulocyte-macrophage colonystimulating factor or granulocyte colony-stimulating factor is sometimes helpful.
Neutrophi l s (gra nul ocytes ) a re the body's ma i n defens e a ga i ns t ba cteri a l a nd funga l i nfecti ons . When neutropeni a i s pres ent, the i nfl a mma tory
res pons e to s uch i nfecti ons i s i neffecti ve. Norma l l ower l i mi t of the neutrophi l count (tota l WBC % neutrophi l s a nd ba nds ) i s 1500/L i n whi tes
a nd i s s omewha t l ower i n bl a cks (a bout 1200/L).
Severi ty of neutropeni a rel a tes to the rel a ti ve ri s k of i nfecti on:
Mi l d (1000 to 1500/L)
Modera te (500 to 1000/L)
Severe (< 500/L)
When neutrophi l counts fa l l to < 500/L, endogenous mi crobi a l fl ora (eg, i n the mouth or gut) ca n ca us e i nfecti ons . If the count fa l l s to < 200/L,
i nfl a mma tory res pons e ma y be nonexi s tent. Acute, s evere neutropeni a , pa rti cul a rl y i f a nother fa ctor (eg, ca ncer) a l s o i mpa i rs the i mmune s ys tem,
predi s pos i ng to ra pi dl y fa ta l i nfecti ons . The i ntegri ty of the s ki n a nd mucous membra nes , the va s cul a r s uppl y to ti s s ue, a nd the nutri ti ona l s ta tus
of the pa ti ent a l s o i nfl uence the ri s k of i nfecti ons .
The mos t frequentl y occurri ng pyogeni c i nfecti ons i n pa ti ents wi th profound neutropeni a a re
Cel l ul i ti s
Li ver a bs ces s es
Furuncul os i s
Pneumoni a
Septi cemi a
Va s cul a r ca theters a nd other puncture s i tes confer extra ri s k of s ki n i nfecti ons ; the mos t common ba cteri a l ca us es a re coa gul a s e-nega ti ve
s ta phyl ococci a nd Staphylococcus aureus. Stoma ti ti s , gi ngi vi ti s , peri recta l i nfl a mma ti on, col i ti s , s i nus i ti s , pa ronychi a , a nd oti ti s medi a often occur.
Pa ti ents wi th prol onged neutropeni a a fter bone ma rrow tra ns pl a nta ti on or chemothera py a nd pa ti ents recei vi ng hi gh dos es of corti cos teroi ds a re
predi s pos ed to funga l i nfecti ons .
Etiology
Acute neutropeni a (occurri ng over hours to a few da ys ) ca n devel op from ra pi d neutrophi l us e or des tructi on or from i mpa i red producti on. Chroni c
neutropeni a (l a s ti ng months to yea rs ) us ua l l y a ri s es from reduced producti on or exces s i ve s pl eni c s eques tra ti on.
Neutropeni a a l s o ma y be cl a s s i fi ed a s due to a n i ntri ns i c defect i n ma rrow myel oi d cel l s or a s s econda ry (due to fa ctors extri ns i c to ma rrow
myel oi d cel l s s ee
Ta bl e 107-1).
Neutropenia caused by intrinsic defects in myeloid cells or their precursors: Thi s type of neutropeni a i s uncommon, but when pres ent, the mos t common
ca us es i ncl ude
Chroni c i di opa thi c neutropeni a
Congeni ta l neutropeni a
Cycl i c neutropeni a i s a ra re congeni ta l gra nul ocytopoi eti c di s order, us ua l l y tra ns mi tted i n a n a utos oma l domi na nt fa s hi on. It i s cha ra cteri zed by
regul a r, peri odi c os ci l l a ti ons i n the number of peri phera l neutrophi l s . The mea n os ci l l a tory peri od i s 21 3 da ys .
Severe congeni ta l neutropeni a (Kos tma nn's s yndrome) i s a ra re di s order tha t occurs s pora di ca l l y i n the US a nd i s cha ra cteri zed by a n a rres t i n
myel oi d ma tura ti on a t the promyel ocyte s ta ge of the bone ma rrow, res ul ti ng i n a n a bs ol ute neutrophi l count of < 200/L.
Chroni c i di opa thi c neutropeni a i s a group of uncommon, poorl y unders tood di s orders i nvol vi ng s tem cel l s commi tted to the myel oi d s eri es ; RBC
a nd pl a tel et precurs ors a re una ffected. The s pl een i s not enl a rged. Chroni c beni gn neutropeni a i s a type of chroni c i di opa thi c neutropeni a i n
whi ch the res t of the i mmune s ys tem a ppea rs to rema i n i nta ct; even wi th neutrophi l counts < 200/L, s eri ous i nfecti ons us ua l l y do not occur,
proba bl y beca us e neutrophi l s a re s ometi mes produced i n a dequa te qua nti ti es i n res pons e to i nfecti on.
Neutropeni a ca n a l s o res ul t from bone ma rrow fa i l ure due to ra re s yndromes (eg, ca rti l a ge-ha i r hypopl a s i a , Chedi a k-Hi ga s hi s yndrome,
dys kera tos i s congeni ta , gl ycogen s tora ge di s ea s e type IB, Shwa chma n-Di a mond s yndrome). Neutropeni a i s a l s o a promi nent fea ture of
myel odys pl a s i a (s ee p. 1014), where i t ma y be a ccompa ni ed by mega l obl a s toi d fea tures i n the bone ma rrow, a nd of a pl a s ti c a nemi a (s ee p. 929)
a nd ca n occur i n dys ga mma gl obul i nemi a a nd pa roxys ma l nocturna l hemogl obi nemi a .
Secondary neutropenia: Seconda ry neutropeni a ca n res ul t from us e of certa i n drugs , bone ma rrow i nfi l tra ti on or repl a cement, certa i n i nfecti ons , or
i mmune rea cti ons . The mos t common ca us es i ncl ude
Drugs
Infecti ons
Ma rrow i nfi l tra ti ve proces s es
[Table 107-1. Cl a s s i fi ca ti on of Neutropeni a s ]
Drug-i nduced neutropeni a i s one of the mos t common ca us es of neutropeni a . Drugs ca n decrea s e neutrophi l producti on through toxi c,
i di os yncra ti c, or hypers ens i ti vi ty mecha ni s ms or i ncrea s e peri phera l neutrophi l des tructi on through i mmune mecha ni s ms . Onl y the toxi c
mecha ni s m (eg, wi th phenothi a zi nes ) produces dos e-rel a ted neutropeni a . Idi os yncra ti c rea cti ons a re unpredi cta bl e a nd occur wi th a wi de va ri ety
of drugs , i ncl udi ng a l terna ti ve medi ci ne prepa ra ti ons or extra cts , a nd toxi ns . Hypers ens i ti vi ty rea cti ons a re ra re a nd occa s i ona l l y i nvol ve
a nti convul s a nts (eg, phenytoi n, phenoba rbi ta l ). Thes e rea cti ons ma y l a s t for onl y a few da ys or for months or yea rs . Often, hepa ti ti s , nephri ti s ,
pneumoni ti s , or a pl a s ti c a nemi a a ccompa ni es hypers ens i ti vi ty-i nduced neutropeni a . Immune-medi a ted drug-i nduced neutropeni a , thought to
a ri s e from drugs tha t a ct a s ha ptens to s ti mul a te a nti body forma ti on, us ua l l y pers i s ts for a bout 1 wk a fter the drug i s s topped. It ma y res ul t from
a mi nopyri ne, propyl thi oura ci l , peni ci l l i n, or other a nti bi oti cs . Severe dos e-rel a ted neutropeni a occurs predi cta bl y a fter cytotoxi c ca ncer drugs or
ra di a ti on thera py s uppres s es bone ma rrow producti on.
Neutropeni a due to i neffecti ve bone ma rrow producti on ca n occur i n mega l obl a s ti c a nemi a s ca us ed by vi ta mi n B 12 or fol a te defi ci ency. Us ua l l y,
ma crocyti c a nemi a a nd s ometi mes mi l d thrombocytopeni a devel op s i mul ta neous l y.
Bone ma rrow i nfi l tra ti on by l eukemi a , myel oma , l ymphoma , or meta s ta ti c s ol i d tumors (eg, brea s t, pros ta te) ca n i mpa i r neutrophi l producti on.
Tumor-i nduced myel ofi bros i s ma y further exa cerba te neutropeni a . Myel ofi bros i s ca n a l s o occur from gra nul oma tous i nfecti ons , Ga ucher's
di s ea s e, a nd ra di a ti on thera py. Hypers pl eni s m of a ny ca us e ca n l ea d to modera te neutropeni a , thrombocytopeni a , a nd a nemi a .
Infecti ons ca n ca us e neutropeni a by i mpa i ri ng neutrophi l producti on or by i nduci ng i mmune des tructi on or ra pi d us e of neutrophi l s . Seps i s i s a
pa rti cul a rl y s eri ous ca us e. Neutropeni a tha t occurs wi th common chi l dhood vi ra l di s ea s es devel ops duri ng the fi rs t 1 to 2 da ys of i l l nes s a nd ma y
pers i s t for 3 to 8 da ys . Tra ns i ent neutropeni a ma y a l s o res ul t from vi rus - or endotoxemi a -i nduced redi s tri buti on of neutrophi l s from the ci rcul a ti ng
to the ma rgi na l pool . Al cohol ma y contri bute to neutropeni a by i nhi bi ti ng the neutrophi l i c res pons e of the ma rrow duri ng s ome i nfecti ons (eg,
pneumococca l pneumoni a ).
Chroni c s econda ry neutropeni a often a ccompa ni es HIV i nfecti on beca us e of i mpa i red producti on of neutrophi l s a nd a ccel era ted des tructi on of
neutrophi l s by a nti bodi es . Autoi mmune neutropeni a s ma y be a cute, chroni c, or epi s odi c. They ma y i nvol ve a nti bodi es di rected a ga i ns t ci rcul a ti ng
neutrophi l s or neutrophi l precurs or cel l s . Mos t pa ti ents wi th a utoi mmune neutropeni a ha ve a n underl yi ng a utoi mmune di s order or
l ymphoprol i fera ti ve di s order (eg, SLE, Fel ty's s yndrome).
Symptoms and Signs
Neutropeni a i s a s ymptoma ti c unti l i nfecti on devel ops . Fever i s often the onl y i ndi ca ti on of i nfecti on. Foca l s ymptoms ma y devel op but a re often
s ubtl e. Pa ti ents wi th drug-i nduced neutropeni a due to hypers ens i ti vi ty ma y ha ve a fever, ra s h, a nd l ympha denopa thy from the hypers ens i ti vi ty.
Some pa ti ents wi th chroni c beni gn neutropeni a a nd neutrophi l counts < 200/L do not experi ence ma ny s eri ous i nfecti ons . Pa ti ents wi th cycl i c
neutropeni a or s evere congeni ta l neutropeni a tend to ha ve epi s odes of ora l ul cers , s toma ti ti s , or pha ryngi ti s a nd l ymph node enl a rgement duri ng
s evere chroni c neutropeni a . Pneumoni a s a nd s epti cemi a often occur.
Diagnosis
Cl i ni ca l s us pi ci on (repea ted or unus ua l i nfecti ons )
Confi rma tory CBC wi th di fferenti a l
Eva l ua ti on for i nfecti on wi th cul tures a nd i ma gi ng
Identi fi ca ti on of mecha ni s m a nd ca us e of neutropeni a
Neutropeni a i s s us pected i n pa ti ents wi th frequent, s evere, or unus ua l i nfecti ons or i n pa ti ents a t ri s k (eg, thos e recei vi ng cytotoxi c drugs or
ra di a ti on thera py). Confi rma ti on i s by CBC wi th di fferenti a l .
Evaluation for infection: The fi rs t pri ori ty i s to determi ne whether a n i nfecti on i s pres ent. Beca us e i nfecti on ma y be s ubtl e, phys i ca l exa mi na ti on
s ys tema ti ca l l y a s s es s es the mos t common pri ma ry s i tes of i nfecti on: mucos a l s urfa ces , s uch a s the a l i menta ry tra ct (gums , pha rynx, a nus ); l ungs ;
a bdomen; uri na ry tra ct; s ki n a nd fi ngerna i l s ; veni puncture s i tes ; a nd va s cul a r ca theters .
If neutropeni a i s a cute, l a bora tory eva l ua ti on mus t proceed ra pi dl y.
Cul tures a re the ma i ns ta y of eva l ua ti on. At l ea s t 2 s ets of ba cteri a l a nd funga l bl ood cul tures a re obta i ned from a l l febri l e pa ti ents ; i f a n
i ndwel l i ng IV ca theter i s pres ent, cul tures a re obta i ned from the l umen a nd from a s epa ra te peri phera l vei n. Pers i s tent or chroni c dra i na ge
ma teri a l i s a l s o cul tured for fungi a nd a typi ca l mycoba cteri a . Ski n l es i ons a re a s pi ra ted or bi ops i ed for cytol ogy a nd cul ture. Sa mpl es for
uri na l ys i s a nd uri ne cul tures a re obta i ned from a l l pa ti ents . If di a rrhea i s pres ent, s tool i s eva l ua ted for enteri c ba cteri a l pa thogens a nd
Clostridium difficile toxi ns .
Ima gi ng s tudi es a re hel pful . Ches t x-ra ys a re done on a l l pa ti ents . CT s ca n of the pa ra -na s a l s i nus es ma y be hel pful i f s ymptoms or s i gns of
s i nus i ti s (eg, pos i ti ona l hea da che, upper tooth or ma xi l l a ry pa i n, fa ci a l s wel l i ng, na s a l di s cha rge) a re pres ent. CT s ca n of the a bdomen i s us ua l l y
done i f s ymptoms (eg, pa i n) or hi s tory (eg, recent s urgery) s ugges ts a n i ntra -a bdomi na l i nfecti on.
Identification of cause: Next, mecha ni s m a nd ca us e of neutropeni a a re determi ned. The hi s tory a ddres s es a l l drugs , other prepa ra ti ons , a nd
pos s i bl e toxi n expos ure or i nges ti on. Phys i ca l exa mi na ti on a ddres s es the pres ence of s pl enomega l y a nd s i gns of other underl yi ng di s order (eg,
a rthri ti s , l ympha denopa thy).
The mos t i mporta nt tes t i s bone ma rrow exa mi na ti on, whi ch determi nes whether neutropeni a i s due to decrea s ed ma rrow producti on or i s
s econda ry to i ncrea s ed des tructi on or us e of the cel l s (determi ned by norma l or i ncrea s ed producti on of the cel l s ). Bone ma rrow ma y a l s o i ndi ca te
the s peci fi c ca us e of the neutropeni a (eg, a pl a s ti c a nemi a , myel ofi bros i s , l eukemi a ). Addi ti ona l ma rrow s tudi es (eg, cytogeneti c a na l ys i s ; s peci a l
s ta i ns a nd fl ow cytometry for detecti ng l eukemi a , other ma l i gna nt di s orders , a nd i nfecti ons ) a re obta i ned.
Further tes ti ng for the ca us e of neutropeni a ma y be neces s a ry, dependi ng on the di a gnos es s us pected. In pa ti ents a t ri s k of defi ci ency, l evel s of
fol a te a nd vi ta mi n B 12 a re determi ned. Tes ti ng for the pres ence of a nti neutrophi l a nti bodi es i s done i f i mmune neutropeni a i s s us pected.
Di fferenti a ti on between neutropeni a ca us ed by certa i n a nti bi oti cs a nd i nfecti on ca n s ometi mes be di ffi cul t. The WBC count jus t before the s ta rt of
a nti bi oti c trea tment us ua l l y refl ects the cha nge i n bl ood count due to the i nfecti on.
Pa ti ents who ha ve ha d chroni c neutropeni a s i nce i nfa ncy a nd a hi s tory of recurrent fevers a nd chroni c gi ngi vi ti s ha ve WBC counts wi th di fferenti a l
done 3 ti mes /wk for 6 wk, s o tha t peri odi ci ty s ugges ti ve of cycl i c neutropeni a ca n be eva l ua ted. Pl a tel et a nd reti cul ocyte counts a re done
s i mul ta neous l y. Eos i nophi l s , reti cul ocytes , a nd pl a tel ets frequentl y cycl e s ynchronous l y wi th the neutrophi l s , wherea s monocytes a nd
l ymphocytes ma y cycl e out of pha s e.
Treatment
Trea tment of a s s oci a ted condi ti ons (eg, i nfecti ons , s toma ti ti s )
Someti mes a nti bi oti c prophyl a xi s
Myel oi d growth fa ctors
Di s conti nua ti on of s us pected eti ol ogi c a gent (eg, drug)
Ra rel y s pl enectomy
Acute neutropenia: Sus pected i nfecti ons a re a l wa ys trea ted i mmedi a tel y. If fever or hypotens i on i s pres ent, s eri ous i nfecti on i s a s s umed, a nd
empi ri c, hi gh-dos e, broa d-s pectrum a nti bi oti cs a re gi ven IV. Regi men s el ecti on i s ba s ed on the mos t l i kel y i nfecti ng orga ni s ms , the a nti mi crobi a l
s us cepti bi l i ty of pa thogens a t tha t pa rti cul a r i ns ti tuti on, a nd the regi men's potenti a l toxi ci ty. Beca us e of the ri s k of crea ti ng res i s ta nt orga ni s ms ,
va ncomyci n i s us ed onl y i f gra m-pos i ti ve orga ni s ms res i s ta nt to other drugs a re s us pected.
Indwel l i ng va s cul a r ca theters ca n us ua l l y rema i n i n pl a ce even i f ba cteremi a i s s us pected or documented, but remova l i s cons i dered i f i nfecti ons
i nvol ve S. aureus or Bacillus, Corynebacterium, or Candida s p or i f bl ood cul tures a re pers i s tentl y pos i ti ve des pi te a ppropri a te a nti bi oti cs . Infecti ons
ca us ed by coa gul a s e-nega ti ve s ta phyl ococci genera l l y res ol ve wi th a nti mi crobi a l thera py a l one. Indwel l i ng Fol ey ca theters ca n a l s o predi s pos e to
i nfecti ons i n thes e pa ti ents , a nd cha nge or remova l of the ca theter s houl d be cons i dered for pers i s tent uri na ry i nfecti ons .
If cul tures a re pos i ti ve, a nti bi oti c thera py i s a djus ted to the res ul ts of s ens i ti vi ty tes ts . If a pa ti ent deferves ces wi thi n 72 h, a nti bi oti cs a re
conti nued for a t l ea s t 7 da ys a nd unti l the pa ti ent ha s no s ymptoms or s i gns of i nfecti on. When neutropeni a i s tra ns i ent (s uch a s tha t fol l owi ng
myel os uppres s i ve chemothera py), a nti bi oti c thera py i s us ua l l y conti nued unti l the neutrophi l count i s > 500/L; however, s toppi ng a nti mi crobi a l s
ca n be cons i dered i n s el ected pa ti ents wi th pers i s tent neutropeni a , es peci a l l y thos e i n whom s ymptoms a nd s i gns of i nfl a mma ti on ha ve
res ol ved, i f cul tures rema i n nega ti ve.
Fever tha t pers i s ts > 72 h des pi te a nti bi oti c thera py s ugges ts a nonba cteri a l ca us e, i nfecti on wi th a res i s ta nt s peci es , a s uperi nfecti on wi th a 2nd
ba cteri a l s peci es , i na dequa te s erum or ti s s ue l evel s of the a nti bi oti cs , or l oca l i zed i nfecti on, s uch a s a n a bs ces s . Neutropeni c pa ti ents wi th
pers i s tent fever a re rea s s es s ed every 2 to 4 da ys wi th phys i ca l exa mi na ti on, cul tures , a nd ches t x-ra y. If the pa ti ent i s wel l except for the pres ence
of fever, the i ni ti a l a nti bi oti c regi men ca n be conti nued. If the pa ti ent i s deteri ora ti ng, a l tera ti on of the a nti mi crobi a l regi men i s cons i dered.
Funga l i nfecti ons a re the mos t l i kel y ca us e of pers i s tent fevers a nd deteri ora ti on. Anti funga l thera py (eg, wi th a zol e, echi noca ndi n, or pol yene
drug) i s a dded empi ri ca l l y i f unexpl a i ned fever pers i s ts a fter 4 da ys of broa d-s pectrum a nti bi oti c thera py. If fever pers i s ts a fter 3 wk of empi ri c
thera py (i ncl udi ng 2 wk of a nti funga l thera py) a nd the neutropeni a ha s res ol ved, then s toppi ng a l l a nti mi crobi a l s i s cons i dered a nd the ca us e of
fever reeva l ua ted.
Antibiotic prophylaxis i n a febri l e neutropeni c pa ti ents rema i ns controvers i a l . Tri methopri m/s ul fa methoxa zol e (TMP/SMX) prevents Pneumocystis
jirovecii pneumoni a i n neutropeni c a nd nonneutropeni c pa ti ents wi th a s s oci a ted i mpa i red cel l -medi a ted i mmuni ty. Al s o, TMP/SMX ma y prevent
ba cteri a l i nfecti ons i n pa ti ents expected to be profoundl y neutropeni c for > 1 wk. The di s a dva nta ges of TMP/SMX prophyl a xi s i ncl ude a dvers e
effects , potenti a l myel os uppres s i on, a nd devel opment of res i s ta nt ba cteri a a nd ora l ca ndi di a s i s . Anti funga l prophyl a xi s i s not routi nel y
recommended for neutropeni c pa ti ents , but pa ti ents a t hi gh ri s k of devel opi ng funga l i nfecti ons (eg, a fter bone ma rrow tra ns pl a nta ti on a nd a fter
recei vi ng hi gh dos es of corti cos teroi ds ) ma y benefi t.
Myeloid growth factors (gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor [GM-CSF] a nd gra nul ocyte col ony-s ti mul a ti ng fa ctor [G-CSF]) a re now
wi del y us ed to i ncrea s e the neutrophi l count a nd to prevent i nfecti ons i n pa ti ents wi th s evere neutropeni a (eg, a fter bone ma rrow
tra ns pl a nta ti on a nd i ntens i ve ca ncer chemothera py). They a re expens i ve. However, i f the ri s k of febri l e neutropeni a i s 30% (a s a s s es s ed by
neutrophi l count < 500 L, pres ence of i nfecti on duri ng a previ ous cycl e of chemothera py, a s s oci a ted comorbi d di s ea s e, or a ge > 75), growth fa ctors
a re i ndi ca ted. In genera l , mos t cl i ni ca l benefi t occurs when the growth fa ctor i s a dmi ni s tered begi nni ng a bout 24 h a fter compl eti on of
chemothera py. Pa ti ents wi th neutropeni a ca us ed by a n i di os yncra ti c drug rea cti on ma y a l s o benefi t from myel oi d growth fa ctors , pa rti cul a rl y i f a
del a yed recovery i s a nti ci pa ted. The dos e for G-CSF i s 5 g/kg s c once/da y; for GM-CSF, 250 g/m 2 s c once/da y.
Gl ucocorti coi ds , a na bol i c s teroi ds , a nd vi ta mi ns do not s ti mul a te neutrophi l producti on but ca n a ffect di s tri buti on a nd des tructi on. If a cute
neutropeni a i s s us pected to be drug or toxi n i nduced, a l l potenti a l l y eti ol ogi c a gents a re s topped. If neutropeni a devel ops duri ng trea tment wi th
a drug known to i nduce l ow counts (eg, chl ora mpheni col ), then s wi tchi ng to a n a l terna ti ve a nti bi oti c ma y be hel pful .
Sa l i ne or hydrogen peroxi de ga rgl es every few hours , a nes theti c l ozenges (benzoca i ne 15 mg q 3 or 4 h), or chl orhexi di ne mouth ri ns es (1%
s ol uti on) bi d or ti d ma y rel i eve the di s comfort of s toma ti ti s wi th oropha ryngea l ul cera ti ons . Ora l or es opha gea l ca ndi di a s i s i s trea ted wi th
nys ta ti n (400,000 to 600,000 uni ts ora l ri ns e qi d; s wa l l owed i f es opha gi ti s i s pres ent) or wi th s ys temi c a nti funga l drugs (eg, fl ucona zol e). A
s emi s ol i d or l i qui d di et ma y be neces s a ry duri ng a cute s toma ti ti s or es opha gi ti s to mi ni mi ze di s comfort.
Chronic neutropenia: Neutrophi l producti on i n congeni ta l , cycl i c, a nd i di opa thi c neutropeni a ca n be i ncrea s ed wi th a dmi ni s tra ti on of G-CSF 1 to 10
g/kg s c once/da y. Effecti venes s ca n be ma i nta i ned wi th da i l y or i ntermi ttent G-CSF for months or yea rs . Long-term G-CSF ha s a l s o been us ed i n
other pa ti ents wi th chroni c neutropeni a , i ncl udi ng thos e wi th myel odys pl a s i a , HIV, a nd a utoi mmune di s orders . In genera l , neutrophi l counts
i ncrea s e, a l though cl i ni ca l benefi ts a re l es s cl ea r, es peci a l l y for pa ti ents who do not ha ve s evere neutropeni a . For pa ti ents wi th a utoi mmune
di s orders or who ha ve ha d a n orga n tra ns pl a nt, cycl os pori ne ca n a l s o be benefi ci a l .
In s ome pa ti ents wi th a ccel era ted neutrophi l des tructi on ca us ed by a utoi mmune di s orders , corti cos teroi ds (genera l l y, predni s one 0.5 to 1.0 mg/kg
po once/da y) i ncrea s e bl ood neutrophi l s . Thi s i ncrea s e often ca n be ma i nta i ned wi th a l terna te-da y G-CSF thera py.
Spl enectomy i ncrea s es the neutrophi l count i n s ome pa ti ents wi th s pl enomega l y a nd s pl eni c s eques tra ti on of neutrophi l s (eg, Fel ty's s yndrome,
ha i ry cel l l eukemi a ). However, s pl enectomy s houl d be res erved for pa ti ents wi th s evere neutropeni a (i e, < 500/L) a nd s eri ous probl ems wi th
i nfecti ons i n whom other trea tments ha ve fa i l ed. Pa ti ents s houl d be va cci na ted a ga i ns t i nfecti ons ca us ed by Streptococcus pneumoniae, Neisseria
meningitidis, a nd Haemophilus influenzae before a nd a fter s pl enectomy beca us e s pl enectomy predi s pos es pa ti ents to i nfecti on by enca ps ul a ted
orga ni s ms .
Lymphocytopenia
Lymphocytopenia is a total lymphocyte count of < 1000/L in adults or < 3000/L in children < 2 yr. Sequelae include opportunistic infections and an increased risk
of malignant and autoimmune disorders. If the CBC reveals lymphocytopenia, testing for immunodeficiency and analysis of lymphocyte subpopulations should
follow. Treatment is directed at the underlying disorder.
The norma l l ymphocyte count i n a dul ts i s 1000 to 4800/L; i n chi l dren < 2 yr, 3000 to 9500/L. At a ge 6 yr, the l ower l i mi t of norma l i s 1500/L. Both B
a nd T cel l s a re pres ent i n the peri phera l bl ood; a bout 75% of the l ymphocytes a re T cel l s a nd 25% B cel l s . Beca us e l ymphocytes a ccount for onl y 20
to 40% of the tota l WBC count, l ymphocytopeni a ma y go unnoti ced when WBC count i s checked wi thout a di fferenti a l .
Al mos t 65% of bl ood T cel l s a re CD4+ (hel per) T cel l s . Mos t pa ti ents wi th l ymphocytopeni a ha ve a reduced a bs ol ute number of T cel l s , pa rti cul a rl y
i n the number of CD4+ T cel l s . The a vera ge number of CD4+ T cel l s i n a dul t bl ood i s 1100/L (ra nge, 300 to 1300/L), a nd the a vera ge number of cel l s
of the other ma jor T-cel l s ubgroup, CD8+ (s uppres s or) T cel l s , i s 600/L (ra nge, 100 to 900/L).
Etiology
Lymphocytopeni a ca n be a cqui red or i nheri ted.
Acquired lymphocytopenia ca n occur wi th a number of other di s orders (s ee
Ta bl e 107-2). The mos t common ca us es i ncl ude
Protei n-energy undernutri ti on
AIDS
Protei n-energy undernutri ti on i s the mos t common ca us e worl dwi de. AIDS i s the mos t common i nfecti ous di s ea s e ca us i ng l ymphocytopeni a , whi ch
a ri s es from des tructi on of CD4+ T cel l s i nfected wi th HIV. Lymphocytopeni a ma y a l s o refl ect i mpa i red l ymphocyte producti on a ri s i ng from
des tructi on of thymi c or l ymphoi d a rchi tecture. In a cute vi remi a due to HIV or other vi rus es , l ymphocytes ma y undergo a ccel era ted des tructi on from
a cti ve i nfecti ons wi th the vi rus , ma y be tra pped i n the s pl een or l ymph nodes , or ma y mi gra te to the res pi ra tory tra ct.
Inherited lymphocytopenia (s ee Ta bl e 107-2) mos t commonl y res ul ts from
Severe combi ned i mmunodefi ci ency di s order
Wi s kott-Al dri ch s yndrome
It ma y occur wi th i nheri ted i mmunodefi ci ency di s orders (s ee Ch. 126) a nd di s orders tha t i nvol ve i mpa i red l ymphocyte producti on. Other i nheri ted
di s orders , s uch a s Wi s kott-Al dri ch s yndrome, a denos i ne dea mi na s e defi ci ency, a nd puri ne nucl eos i de phos phoryl a s e defi ci ency, ma y i nvol ve
a ccel era ted T-cel l des tructi on. In ma ny di s orders , a nti body producti on i s a l s o defi ci ent.
Ia trogeni c l ymphocytopeni a i s ca us ed by cytotoxi c chemothera py, ra di a ti on thera py, or the a dmi ni s tra ti on of a nti l ymphocyte gl obul i n (or other
l ymphocyte a nti bodi es ). Long-term trea tment for ps ori a s i s us i ng ps ora l en a nd ul tra vi ol et i rra di a ti on ma y des troy T cel l s . Gl ucocorti coi ds ca n
i nduce l ymphocyte des tructi on.
Lymphocytopeni a ma y occur wi th a utoi mmune di s ea s es s uch a s SLE, RA, mya s theni a gra vi s , a nd protei n-l os i ng enteropa thy.
Symptoms and Signs
Lymphocytopeni a per s e genera l l y ca us es no s ymptoms . However, fi ndi ngs of a n a s s oci a ted di s order ma y i ncl ude a bs ent or di mi ni s hed
[Table 107-2. Ca us es of Lymphocytopeni a ]
tons i l s or l ymph nodes , i ndi ca ti ve of cel l ul a r i mmunodefi ci ency; s ki n a bnorma l i ti es , s uch a s a l opeci a , eczema , pyoderma , or tel a ngi ecta s i a ;
evi dence of hema tol ogi c di s ea s e, s uch a s pa l l or, petechi a e, ja undi ce, or mouth ul cers ; a nd genera l i zed l ympha denopa thy a nd s pl enomega l y,
whi ch ma y s ugges t HIV i nfecti on.
Lymphocytopeni c pa ti ents experi ence recurrent i nfecti ons or devel op i nfecti ons wi th unus ua l orga ni s ms . Pneumocystis jirovecii, cytomega l ovi rus ,
rubeol a , a nd va ri cel l a pneumoni a s often a re fa ta l . Lymphocytopeni a i s a l s o a ri s k fa ctor for ca ncer a nd for a utoi mmune di s orders .
Diagnosis
Cl i ni ca l s us pi ci on (repea ted or unus ua l i nfecti ons )
CBC wi th di fferenti a l
Mea s urement of l ymphocyte s ubpopul a ti ons a nd i mmunogl obul i n l evel s
Lymphocytopeni a i s s us pected i n pa ti ents wi th recurrent vi ra l , funga l , or pa ra s i ti c i nfecti ons but i s us ua l l y detected i nci denta l l y on a CBC. P.
jirovecii, cytomega l ovi rus , rubeol a , or va ri cel l a pneumoni a s wi th l ymphocytopeni a s ugges t i mmunodefi ci ency. Lymphocyte s ubpopul a ti ons a re
mea s ured i n l ymphocytopeni c pa ti ents . Mea s urements of i mmunogl obul i n l evel s s houl d a l s o be done to eva l ua te a nti body producti on. Pa ti ents
wi th a hi s tory of recurrent i nfecti ons undergo compl ete l a bora tory eva l ua ti on for i mmunodefi ci ency (s ee p. 1095), even i f i ni ti a l s creeni ng tes ts a re
norma l .
Treatment
Someti mes IV i mmune gl obul i n
Pos s i bl y s tem cel l tra ns pl a nta ti on
Lymphocytopeni a us ua l l y remi ts wi th remova l of the underl yi ng fa ctor or s ucces s ful trea tment of the underl yi ng di s order i n the a cqui red
l ymphocytopeni a s . Intra venous i mmune gl obul i n i s i ndi ca ted i f pa ti ents ha ve chroni c IgG defi ci ency, l ymphocytopeni a , a nd recurrent i nfecti ons .
Hema topoi eti c s tem cel l tra ns pl a nta ti on ca n be cons i dered for a l l pa ti ents wi th congeni ta l i mmunodefi ci enci es a nd ma y be cura ti ve (s ee p. 1132).
Chapter 108. Thrombocytopenia and Platelet Dysfunction

Introduction
Pl a tel ets a re cel l fra gments tha t functi on i n the cl otti ng s ys tem. Thrombopoi eti n, pri ma ri l y produced i n the l i ver i n res pons e to decrea s ed
numbers of bone ma rrow mega ka ryocytes a nd ci rcul a ti ng pl a tel ets , s ti mul a tes the bone ma rrow to s ynthes i ze pl a tel ets from mega ka ryocytes .
Pl a tel ets ci rcul a te for 7 to 10 da ys . About one thi rd a re a l wa ys tra ns i entl y s eques tered i n the s pl een. The pl a tel et count i s norma l l y 140,000 to
440,000/L. However, the count ca n va ry s l i ghtl y a ccordi ng to mens trua l cycl e pha s e, decrea s e duri ng nea r-term pregna ncy (ges ta ti ona l
thrombocytopeni a ), a nd i ncrea s e i n res pons e to i nfl a mma tory cytoki nes (s econda ry, or rea cti ve, thrombocytos i s ). Pl a tel ets a re eventua l l y
des troyed, pri ma ri l y by the s pl een.
Platelet disorders i ncl ude
An a bnorma l i ncrea s e i n pl a tel ets (thrombocythemi a , a myel oprol i fera ti ve di s orders ee p. 997)
A decrea s e i n pl a tel ets (thrombocytopeni a )
Pl a tel et dys functi on
Any of thes e condi ti ons , even thos e i n whi ch pl a tel ets a re i ncrea s ed, ma y ca us e defecti ve forma ti on of hemos ta ti c pl ugs a nd bl eedi ng.
The ri s k of bl eedi ng i s i nvers el y proporti ona l to the pl a tel et count. When the pl a tel et count i s < 50,000/L, mi nor bl eedi ng occurs ea s i l y a nd the
ri s k of ma jor bl eedi ng i ncrea s es . Counts between 20,000 a nd 50,000/L predi s pos e to bl eedi ng wi th tra uma , even mi nor tra uma ; wi th counts <
20,000/L, s ponta neous bl eedi ng ma y occur; wi th counts < 5000/L, s evere s ponta neous bl eedi ng i s more l i kel y. However, pa ti ents wi th counts <
10,000/L ma y be a s ymptoma ti c for yea rs .
Etiology
Thrombocytopenia: Ca us es of thrombocytopeni a ca n be cl a s s i fi ed by mecha ni s m (s ee
Ta bl e 108-1) a nd i ncl ude fa i l ed pl a tel et producti on, i ncrea s ed s pl eni c s eques tra ti on of pl a tel ets wi th norma l pl a tel et s urvi va l , i ncrea s ed pl a tel et
des tructi on or cons umpti on (both i mmunol ogi c a nd noni mmunol ogi c ca us es ), di l uti on of pl a tel ets , a nd a combi na ti on of thes e mecha ni s ms .
[Table 108-1. Cl a s s i fi ca ti on of Thrombocytopeni a ]
Increa s ed s pl eni c s eques tra ti on i s s ugges ted by s pl enomega l y.
A l a rge number of drugs ma y ca us e thrombocytopeni a (s ee p. 960), typi ca l l y by tri ggeri ng i mmunol ogi c des tructi on.
Overa l l , the mos t common s peci fi c ca us es of thrombocytopeni a i ncl ude
Ges ta ti ona l thrombocytopeni a
Drug-i nduced thrombocytopeni a due to i mmune-medi a ted pl a tel et des tructi on (commonl y qui ni ne, tri methopri m/s ul fa methoxa zol e)
Drug-i nduced thrombocytopeni a due to dos e-dependent bone ma rrow s uppres s i on (by chemothera peuti c a gents )
Thrombocytopeni a a ccompa nyi ng s ys temi c i nfecti on
Immune thrombocytopeni c purpura (ITP)
Platelet dysfunction: Pl a tel et dys functi on ma y s tem from a n i ntri ns i c pl a tel et defect or from a n extri ns i c fa ctor tha t a l ters the functi on of norma l
pl a tel ets . Dys functi on ma y be heredi ta ry or a cqui red. Heredi ta ry di s orders of pl a tel et functi on cons i s t of von Wi l l ebra nd's di s ea s e, the mos t
common heredi ta ry hemorrha gi c di s ea s e, a nd heredi ta ry i ntri ns i c pl a tel et di s orders (s ee p. 957), whi ch a re much l es s common. Acqui red di s orders
of pl a tel et functi on (s ee p. 957) a re commonl y due to di s ea s es a s wel l a s to a s pi ri n a nd other drugs .
Symptoms and Signs
Pl a tel et di s orders res ul t i n a typi ca l pa ttern of bl eedi ng:
Mul ti pl e petechi a e i n the s ki n (typi ca l l y mos t evi dent on the l ower l egs )
Sca ttered s ma l l ecchymos es a t s i tes of mi nor tra uma
Mucos a l bl eedi ng (epi s ta xi s , bl eedi ng i n the GI a nd GU tra cts , va gi na l bl eedi ng)
Exces s i ve bl eedi ng a fter s urgery
Hea vy GI bl eedi ng a nd bl eedi ng i nto the CNS ma y be l i fe threa teni ng. However, bl eedi ng i nto ti s s ues (eg, deep vi s cera l hema toma s or
hema rthros es ) does not occur wi th thrombocytopeni a , whi ch ca us es i mmedi a te, s uperfi ci a l bl eedi ng; ti s s ue bl eedi ng (often del a yed for up to a
da y a fter tra uma ) s ugges ts a coa gul a ti on di s order (eg, hemophi l i a ).
Diagnosis
Cl i ni ca l pres enta ti on of petechi a e a nd mucos a l bl eedi ng
CBC wi th pl a tel ets , coa gul a ti on s tudi es , peri phera l bl ood s mea r
Someti mes bone ma rrow a s pi ra ti on
Someti mes von Wi l l ebra nd's a nti gen a nd fa ctor a cti vi ty s tudi es
Pl a tel et di s orders a re s us pected i n pa ti ents wi th petechi a e a nd mucos a l bl eedi ng. A CBC wi th pl a tel et count, coa gul a ti on s tudi es , a nd a
peri phera l bl ood s mea r a re obta i ned. Exces s i ve pl a tel ets a nd thrombocytopeni a a re di a gnos ed from the pl a tel et count; coa gul a ti on s tudi es a re
norma l unl es s there i s a s i mul ta neous coa gul opa thy. In pa ti ents wi th a norma l CBC, pl a tel et count, a nd INR a nd norma l or onl y s l i ghtl y prol onged
PTT, pl a tel et dys functi on i s s us pected.
Thrombocytopenia: In pa ti ents wi th thrombocytopeni a , the peri phera l s mea r ma y s ugges t the ca us e (s ee
Ta bl e 108-2). If the s mea r s hows a bnorma l i ti es other tha n thrombocytopeni a , s uch a s nucl ea ted RBCs or a bnorma l or i mma ture WBCs , bone
ma rrow a s pi ra ti on i s i ndi ca ted. Bone ma rrow a s pi ra ti on revea l s the number a nd a ppea ra nce of mega ka ryocytes a nd i s the defi ni ti ve tes t for ma ny
di s orders ca us i ng ma rrow fa i l ure. However, norma l number a nd a ppea ra nce of mega ka ryocytes does not a l wa ys i ndi ca te norma l pl a tel et
producti on. For exa mpl e, i n pa ti ents wi th i mmune thrombocytopeni c purpura , pl a tel et producti on i s frequentl y decrea s ed, or not a ppropri a tel y
i ncrea s ed, des pi te the norma l a ppea ra nce of mega ka ryocytes . If the bone ma rrow i s norma l but the s pl een i s enl a rged, i ncrea s ed s pl eni c
s eques tra ti on i s the l i kel y ca us e of thrombocytopeni a ; i f the bone ma rrow i s norma l a nd the s pl een i s not enl a rged, exces s pl a tel et des tructi on i s
the l i kel y ca us e. Mea s urement of a nti pl a tel et a nti bodi es i s not cl i ni ca l l y us eful . HIV tes ti ng i s done i n pa ti ents a t ri s k of HIV i nfecti on.
Suspected platelet dysfunction: In pa ti ents wi th pl a tel et dys functi on, a drug ca us e i s s us pected i f s ymptoms bega n onl y a fter pa ti ents s ta rted ta ki ng
a potenti a l l y ca us a ti ve drug. A heredi ta ry ca us e i s s us pected i f there i s a l i fel ong hi s tory of ea s y brui s i ng a nd bl eedi ng a fter tooth extra cti ons or
s urgery. In the ca s e of a s us pected heredi ta ry ca us e, von Wi l l ebra nd's a nti gen a nd fa ctor a cti vi ty s tudi es a re obta i ned. Pl a tel et dys functi on ca us ed
by s ys temi c di s orders i s typi ca l l y mi l d a nd of mi nor cl i ni ca l i mporta nce. In thes e pa ti ents , the ca us a ti ve s ys temi c di s order i s the cl i ni ca l concern,
a nd hema tol ogi c tes ts a re unneces s a ry.
[Table 108-2. Peri phera l Bl ood Fi ndi ngs i n Thrombocytopeni c Di s orders ]
Treatment
Avoi da nce of drugs tha t i mpa i r pl a tel et functi on
Ra rel y pl a tel et tra ns fus i ons
In pa ti ents wi th thrombocytopeni a or pl a tel et dys functi on, drugs tha t further i mpa i r pl a tel et functi on, pa rti cul a rl y a s pi ri n a nd other NSAIDs ,
s houl d not be gi ven. Pa ti ents who a re a l rea dy ta ki ng s uch drugs s houl d cons i der a l terna ti ve drugs , s uch a s a ceta mi nophen, or s i mpl y s top us i ng
them.
Pa ti ents ma y requi re pl a tel et tra ns fus i on, but tra ns fus i ons a re gi ven onl y i n l i mi ted s i tua ti ons (s ee p. 1039). Prophyl a cti c tra ns fus i ons a re us ed
s pa ri ngl y beca us e they ma y l os e thei r effecti venes s wi th repea ted us e due to the devel opment of pl a tel et a l l oa nti bodi es . In pl a tel et dys functi on
or thrombocytopeni a ca us ed by decrea s ed producti on, tra ns fus i ons a re res erved for pa ti ents wi th a cti ve bl eedi ng or s evere thrombocytopeni a (eg,
pl a tel et count < 10,000/L). In thrombocytopeni a ca us ed by pl a tel et des tructi on, tra ns fus i ons a re res erved for l i fe-threa teni ng or CNS bl eedi ng.
Acquired Platelet Dysfunction
Acquired platelet dysfunction, which is common, may result from aspirin, other NSAIDs, or systemic disorders.
Acqui red a bnorma l i ti es of pl a tel et functi on a re very common. Ca us es i ncl ude
Drugs
Sys temi c di s orders
Ca rdi opul mona ry bypa s s
Acqui red pl a tel et dys functi on i s s us pected a nd di a gnos ed when a n i s ol a ted prol onga ti on of bl eedi ng ti me i s obs erved a nd other pos s i bl e
di a gnos es ha ve been el i mi na ted. Pl a tel et a ggrega ti on s tudi es a re unneces s a ry.
Drugs: As pi ri n a nd other NSAIDs , whi ch a re very commonl y us ed drugs , ma y i nduce pl a tel et dys functi on. Someti mes thi s effect i s i nci denta l (eg,
when the drugs a re us ed to rel i eve pa i n a nd i nfl a mma ti on) a nd s ometi mes thera peuti c (eg, when a s pi ri n i s us ed for preventi on of s troke or
corona ry thrombos i s ). Other thera peuti c a nti pl a tel et drugs i ncl ude cl opi dogrel , ti cl opi di ne, a nd the gl ycoprotei n IIb/IIIa i nhi bi tors .
As pi ri n a nd NSAIDs prevent cycl ooxygena s e-medi a ted producti on of thromboxa ne A2 . Thi s effect ca n l a s t 5 to 7 da ys . As pi ri n modes tl y prol ongs
bl eedi ng ti me i n hea l thy peopl e but ma y ma rkedl y prol ong bl eedi ng ti me i n pa ti ents wi th underl yi ng pl a tel et dys functi on or a s evere coa gul a ti on
di s turba nce (eg, pa ti ents recei vi ng hepa ri n, pa ti ents wi th s evere hemophi l i a ).
Systemic disorders: Ma ny di s orders (eg, myel oprol i fera ti ve a nd myel odys pl a s ti c di s orders , uremi a , ma crogl obul i nemi a a nd mul ti pl e myel oma ,
ci rrhos i s , SLE) ca n i mpa i r pl a tel et functi on.
Uremi a ma y prol ong bl eedi ng vi a unknown mecha ni s ms . If bl eedi ng i s obs erved cl i ni ca l l y, bl eedi ng ti me ma y be corrected tra ns i entl y wi th
vi gorous di a l ys i s , cryopreci pi ta te a dmi ni s tra ti on, or des mopres s i n i nfus i on. If i ndi ca ted for trea tment of a nemi a , RBC count ca n be i ncrea s ed by
tra ns fus i on or by gi vi ng erythropoi eti n; thi s proces s a l s o s hortens the bl eedi ng ti me.
Cardiopulmonary bypass: Pl a tel ets ma y become dys functi ona l , prol ongi ng the bl eedi ng ti me a s bl ood ci rcul a tes through a pump oxygena tor duri ng
ca rdi opul mona ry bypa s s . The mecha ni s m a ppea rs to be a cti va ti on of fi bri nol ys i s on the pl a tel et s urfa ce wi th res ul ta nt l os s of the gl ycoprotei n IbIX bi ndi ng s i te for von Wi l l ebra nd's fa ctor. Rega rdl es s of pl a tel et count, pa ti ents who bl eed exces s i vel y a fter ca rdi opul mona ry bypa s s a nd who
ha ve a l ong bl eedi ng ti me a re tra ns fus ed wi th pl a tel ets . Gi vi ng a proti ni n (a protea s e i nhi bi tor tha t neutra l i zes pl a s mi n a cti vi ty) duri ng bypa s s
ma y pres erve pl a tel et functi on, prevent prol onga ti on of bl eedi ng ti me, a nd reduce the need for tra ns fus i on.
Hereditary Intrinsic Platelet Disorders
Hereditary intrinsic platelet disorders are rare and produce lifelong bleeding tendencies. Diagnosis is confirmed by platelet aggregation tests. Platelet transfusion
is necessary to control serious bleeding.
Norma l hemos ta s i s requi res pl a tel et a dhes i on a nd a cti va ti on.
Adhesion (i e, of pl a tel ets to expos ed va s cul a r s ubendothel i um) requi res von Wi l l ebra nd's fa ctor (VWF) a nd the pl a tel et gl ycoprotei n Ib-IX compl ex.
Activation promotes pl a tel et a ggrega ti on a nd fi bri nogen bi ndi ng a nd requi res the pl a tel et gl ycoprotei n IIb-IIIa compl ex. Acti va ti on i nvol ves
rel ea s e of a denos i ne di phos pha te (ADP) from pl a tel et s tora ge gra nul es a nd convers i on of a ra chi doni c a ci d to thromboxa ne A2 vi a a
cycl ooxygena s e-medi a ted rea cti on.
Heredi ta ry i ntri ns i c pl a tel et di s orders ca n i nvol ve defects i n a ny of thes e s ubs tra tes a nd s teps . Thes e di s orders a re s us pected i n pa ti ents wi th
l i fel ong bl eedi ng di s orders who ha ve norma l pl a tel et counts a nd coa gul a ti on s tudy res ul ts . Di a gnos i s us ua l l y i s ba s ed on pl a tel et a ggrega ti on
tes ts ; however, pl a tel et a ggrega ti on tes ts a re not qua nti ta ti ve, a nd i nterpreta ti on of res ul ts i s often i nconcl us i ve (s ee
Ta bl e 108-3).
Disorders of adhesion: Berna rd-Soul i er s yndrome i s a ra re a utos oma l reces s i ve di s order. It i mpa i rs pl a tel et a dhes i on vi a a defect i n the gl ycoprotei n
Ib-IX compl ex. Bl eedi ng ma y be s evere. Pl a tel ets a re unus ua l l y l a rge. They do not a ggrega te wi th ri s toceti n but a ggrega te norma l l y wi th ADP,
col l a gen, a nd epi nephri ne.
La rge pl a tel ets a s s oci a ted wi th functi ona l a bnorma l i ti es a l s o occur i n the Ma y-Heggl i n a noma l y, a thrombocytopeni c di s order wi th a bnorma l
WBCs , a nd i n the Chedi a k-Hi ga s hi s yndrome (s ee p. 1101).
Pl a tel et tra ns fus i on i s neces s a ry to control s eri ous bl eedi ng.
Disorders of activation: Di s orders of a mpl i fi ca ti on of pl a tel et a cti va ti on a re the mos t common heredi ta ry i ntri ns i c pl a tel et di s orders a nd produce
mi l d bl eedi ng. They ma y res ul t from decrea s ed ADP i n the pl a tel et gra nul es (s tora ge pool defi ci ency), from a n i na bi l i ty to genera te thromboxa ne
A2 from a ra chi doni c a ci d, or from a n i na bi l i ty of pl a tel ets to a ggrega te i n res pons e to thromboxa ne A2 . Pl a tel et a ggrega ti on tes ts revea l i mpa i red
a ggrega ti on a fter expos ure to col l a gen, epi nephri ne, a nd l ow l evel s of ADP a nd norma l a ggrega ti on a fter expos ure to hi gh l evel s of ADP. The s a me
pa ttern ca n res ul t from us e of NSAIDs or a s pi ri n, the effect of whi ch ca n pers i s t for s evera l da ys . Therefore, pl a tel et a ggrega ti on tes ts s houl d not
be done i n pa ti ents who ha ve recentl y ta ken thes e drugs .
Thromba s theni a (Gl a nzma nn di s ea s e) i s a ra re a utos oma l reces s i ve di s order ca us i ng a defect i n the pl a tel et gl ycoprotei n IIb-IIIa compl ex;
pl a tel ets ca nnot a ggrega te. Pa ti ents ma y experi ence s evere mucos a l bl eedi ng (eg, nos ebl eeds tha t s top onl y a fter na s a l pa cki ng a nd tra ns fus i ons
of pl a tel et concentra tes ). The di a gnos i s i s s ugges ted by a fi ndi ng of s i ngl e pl a tel ets wi thout a ggrega tes on a peri phera l bl ood s mea r obta i ned
from a fi nger s ti ck. It i s confi rmed by the fi ndi ng tha t pl a tel ets fa i l to a ggrega te wi th epi nephri ne, col l a gen, or even hi gh l evel s of ADP but do
a ggrega te tra ns i entl y wi th ri s toceti n. Pl a tel et tra ns fus i on i s neces s a ry to control s eri ous bl eedi ng.
Immune Thrombocytopenic Purpura
(Idi opa thi c Thrombocytopeni c Purpura )
Immune thrombocytopenic purpura (ITP) is a bleeding disorder caused by thrombocytopenia not associated with a systemic disease. Typically, it is chronic in
adults but is usually acute and self-limited in children. Spleen size is normal. Diagnosis requires that other disorders be excluded through selective tests.
Treatment includes corticosteroids, splenectomy, and immunosuppressants and thrombopoietic-mimetic drugs. For life-threatening bleeding, platelet
transfusions, IV corticosteroids, and IV immune globulin are required.
ITP us ua l l y res ul ts from devel opment of a n a utoa nti body di rected a ga i ns t a s tructura l pl a tel et a nti gen. In chi l dhood ITP, the a utoa nti body ma y be
tri ggered by bi ndi ng of vi ra l a nti gen to mega ka ryocytes .
Symptoms and Signs
The s ymptoms a nd s i gns a re petechi a e, purpura , a nd mucos a l bl eedi ng. Gros s GI bl eedi ng a nd hema turi a a re uncommon. The
[Table 108-3. Res ul ts of Aggrega ti on Tes ts i n Heredi ta ry Di s orders of Pl a tel et Functi on]
s pl een i s of norma l s i ze unl es s i t i s enl a rged by a coexi s ti ng chi l dhood vi ra l i nfecti on.
Diagnosis
CBC wi th pl a tel ets , peri phera l bl ood s mea r
Someti mes bone ma rrow a s pi ra ti on
Excl us i on of other thrombocytopeni c di s orders
ITP i s s us pected i n pa ti ents wi th i s ol a ted thrombocytopeni a (i e, otherwi s e norma l CBC a nd peri phera l bl ood s mea r). Beca us e ma ni fes ta ti ons of
ITP a re nons peci fi c, other ca us es of i s ol a ted thrombocytopeni a (eg, drugs , a l cohol , l ymphoprol i fera ti ve di s orders , s ys temi c i l l nes s ) need to be
excl uded by cl i ni ca l eva l ua ti on a nd a ppropri a te tes ti ng. Typi ca l l y, pa ti ents ha ve coa gul a ti on s tudi es , l i ver functi on tes ts (i ncl udi ng tes ti ng for
hepa ti ti s C), a nd, beca us e HIV-a s s oci a ted thrombocytopeni a ma y be otherwi s e i ndi s ti ngui s ha bl e from ITP, HIV tes ti ng. Tes ti ng for a nti pl a tel et
a nti bodi es does not a i d di a gnos i s or trea tment.
Bone ma rrow exa mi na ti on i s not requi red to ma ke the di a gnos i s but i s done i f bl ood counts or bl ood s mea r revea l s a bnorma l i ti es i n a ddi ti on to
thrombocytopeni a , when cl i ni ca l fea tures a re not typi ca l , a nd i n pa ti ents > 60 yr (beca us e myel odys pl a s i a i s more common i n ol der pa ti ents ). In
pa ti ents wi th ITP, bone ma rrow exa mi na ti on revea l s norma l or pos s i bl y i ncrea s ed numbers of mega ka ryocytes i n a n otherwi s e norma l bone
ma rrow s a mpl e.
Prognosis
Chi l dren typi ca l l y recover s ponta neous l y, even from s evere thrombocytopeni a , i n s evera l weeks to months .
In a dul ts , s ponta neous remi s s i on i s ra re. However, s ome ha ve mi l d a nd s ta bl e di s ea s e (i e, pl a tel et counts > 30,000/L); s uch ca s es ma y be more
common tha n previ ous l y thought, ma ny bei ng di s covered by the a utoma ted pl a tel et counti ng now routi nel y done wi th CBC. Others ha ve s i gni fi ca nt,
s ymptoma ti c thrombocytopeni a , a l though l i fe-threa teni ng bl eedi ng a nd dea th a re ra re.
Treatment
Ora l corti cos teroi ds
Spl enectomy
Ri tuxi ma b
Someti mes thrombopoi eti c-mi meti c drugs
Someti mes other i mmunos uppres s a nts
For s evere bl eedi ng, IV i mmune gl obul i n, IV corti cos teroi ds , or pl a tel et tra ns fus i ons
Adul ts us ua l l y a re gi ven a n ora l corti cos teroi d (eg, predni s one 1 mg/kg once/da y) i ni ti a l l y. In pa ti ents who res pond, the pl a tel et count ri s es to
norma l wi thi n 2 to 6 wk. The corti cos teroi d dos a ge i s then ta pered. An a l terna ti ve corti cos teroi d regi men i s dexa metha s one 40 mg po once/da y for
4 da ys . However, mos t pa ti ents do not res pond a dequa tel y or rel a ps e a s the corti cos teroi d i s ta pered. Spl enectomy ca n a chi eve a compl ete
remi s s i on i n a bout two thi rds of thes e pa ti ents but i s us ua l l y res erved for thos e wi th s evere thrombocytopeni a , bl eedi ng, or both; i t ma y not be
a ppropri a te for thos e wi th mi l d di s ea s e. Ri tuxi ma b (375 mg/m 2 IV once/wk for 4 wk) ma y be us ed i n pa ti ents who do not res pond to s pl enectomy
or i n pa ti ents who a re not ca ndi da tes for s pl enectomy.
Beca us e other trea tments ma y not be effecti ve for pa ti ents wi th ITP refra ctory to corti cos teroi ds a nd s pl enectomy a nd beca us e ITP often ha s a
beni gn na tura l hi s tory, a ddi ti ona l trea tments ma y not be i ndi ca ted unl es s the pl a tel et count i s < 10,000 to 20,000/L a nd a cti ve bl eedi ng i s
pres ent. In thes e pa ti ents , thrombopoi eti n-mi meti c drugs , s uch a s romi pl os ti m 1 to 5 g/kg s c once/wk a nd el trombopa g 50 to 75 mg po once/da y,
ma y be us ed.
About 75 to 80% of pa ti ents res pond to thrombopoi eti n-mi meti c drugs even a fter fa i l ure of mul ti pl e previ ous trea tments . However, thes e drugs a re
us ed for ma i ntena nce thera py ra ther tha n i nducti on of remi s s i on a nd need to be a dmi ni s tered conti nuous l y to ma i nta i n the pl a tel et count >
50,000/L. More i ntens i ve i mmunos uppres s i on ma y be requi red wi th drugs s uch a s cycl ophos pha mi de a nd a za thi opri ne i n pa ti ents unres pons i ve
to other drugs who ha ve s evere, s ymptoma ti c thrombocytopeni a .
Trea tment of chi l dren i s us ua l l y s upporti ve, beca us e mos t chi l dren s ponta neous l y recover. Even a fter months or yea rs of thrombocytopeni a , mos t
chi l dren ha ve s ponta neous remi s s i ons . If mucos a l bl eedi ng occurs , corti cos teroi ds or IV i mmune gl obul i n i s gi ven. Ini ti a l us e of corti cos teroi ds
a nd IV i mmune gl obul i n i s controvers i a l , beca us e they i ncrea s e pl a tel et count but ma y not i mprove cl i ni ca l outcome. Spl enectomy i s ra rel y done
i n chi l dren. However, i f thrombocytopeni a i s s evere a nd s ymptoma ti c for > 6 mo, then s pl enectomy i s effecti ve.
In chi l dren or a dul ts wi th ITP a nd l i fe-threa teni ng bl eedi ng, ra pi d pha gocyti c bl ocka de i s a ttempted by gi vi ng IV i mmune gl obul i n 1 g/kg once/da y
for 1 to 2 da ys . Thi s trea tment us ua l l y ca us es the pl a tel et count to ri s e wi thi n 2 to 4 da ys , but the count rema i ns hi gh onl y for 2 to 4 wk. Hi gh-dos e
methyl predni s ol one (1 g IV once/da y for 3 da ys ) i s l es s expens i ve tha n IV i mmune gl obul i n a nd i s ea s i er to a dmi ni s ter but ma y not be a s effecti ve.
Pa ti ents wi th ITP a nd l i fe-threa teni ng bl eedi ng a re a l s o gi ven pl a tel et tra ns fus i ons . Pl a tel et tra ns fus i ons a re not us ed prophyl a cti ca l l y.
Ora l corti cos teroi ds or IV i mmune gl obul i n ma y a l s o be gi ven when a tra ns i ent i ncrea s e of the pl a tel et count i s requi red for tooth extra cti ons ,
chi l dbi rth, s urgery, or other i nva s i ve procedures .
Thrombocytopenia Due to Splenic Sequestration
Increa s ed s pl eni c pl a tel et s eques tra ti on ca n occur i n va ri ous di s orders tha t ca us e s pl enomega l y. Seques tra ti on i s expected i n pa ti ents wi th
conges ti ve s pl enomega l y ca us ed by a dva nced ci rrhos i s . The pl a tel et count us ua l l y i s > 30,000/L unl es s the di s order ca us i ng the s pl enomega l y
a l s o i mpa i rs pl a tel et producti on (eg, i n myel ofi bros i s wi th myel oi d meta pl a s i a ). Pl a tel ets a re rel ea s ed from the s pl een by epi nephri ne a nd
therefore ma y be a va i l a bl e a t a ti me of s tres s . Therefore, thrombocytopeni a ca us ed onl y by s pl eni c s eques tra ti on does not ca us e bl eedi ng.
Spl enectomy corrects the thrombocytopeni a but i s not i ndi ca ted unl es s s evere thrombocytopeni a from s i mul ta neous ma rrow fa i l ure i s pres ent.
Thrombocytopenia: Other Causes
Platelet destruction can develop because of immunologic causes (HIV infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or
nonimmunologic causes (sepsis, acute respiratory distress syndrome). Manifestations are petechiae, purpura, and mucosal bleeding. Laboratory findings depend
on the cause. The history may be the only suggestion of the diagnosis. Treatment is correction of the underlying disorder.
Acute respiratory distress syndrome: Pa ti ents wi th a cute res pi ra tory di s tres s s yndrome ma y devel op noni mmunol ogi c thrombocytopeni a , pos s i bl y
s econda ry to depos i ti on of pl a tel ets i n the pul mona ry ca pi l l a ry bed.
Blood transfusions: Pos ttra ns fus i on purpura ca us es i mmunol ogi c pl a tel et des tructi on i ndi s ti ngui s ha bl e from i mmune thrombocytopeni c purpura
(ITP), except for a hi s tory of a bl ood tra ns fus i on wi thi n the precedi ng 7 to 10 da ys . The pa ti ent, us ua l l y a woma n, l a cks a pl a tel et a nti gen (PLA-1)
pres ent i n mos t peopl e. Tra ns fus i on wi th PLA-1-pos i ti ve pl a tel ets s ti mul a tes forma ti on of a nti -PLA-1 a nti bodi es , whi ch (by a n unknown
mecha ni s m) ca n rea ct wi th the pa ti ent's PLA-1-nega ti ve pl a tel ets . Severe thrombocytopeni a res ul ts , ta ki ng 2 to 6 wk to s ubs i de.
Connective tissue and lymphoproliferative disorders: Connecti ve ti s s ue (eg, SLE) or l ymphoprol i fera ti ve di s orders ca n ca us e i mmunol ogi c
thrombocytopeni a . Corti cos teroi ds a nd s pl enectomy a re often effecti ve.
Drug-induced immunologic destruction: Commonl y us ed drugs tha t occa s i ona l l y i nduce thrombocytopeni a i ncl ude
Qui ni ne
Tri methopri m/s ul fa methoxa zol e
Gl ycoprotei n IIb/IIIa i nhi bi tors (a bci xi ma b, epti fi ba ti de, ti rofi ba n)
Hydrochl orothi a zi de
Ca rba ma zepi ne
Aceta mi nophen
Chl orpropa mi de
Ra ni ti di ne
Ri fa mpi n
Va ncomyci n
Drug-i nduced thrombocytopeni a occurs typi ca l l y by ca us i ng a n i mmune rea cti on i n whi ch drug bound to the pl a tel et crea tes a new a nd "forei gn"
a nti gen. Thi s di s order i s i ndi s ti ngui s ha bl e from ITP except for the hi s tory of drug i nges ti on. When the drug i s s topped, the pl a tel et count typi ca l l y
begi ns to i ncrea s e wi thi n 1 to 2 da ys a nd recovers to norma l wi thi n 7 da ys .
Up to 5% of pa ti ents recei vi ng unfra cti ona ted hepa ri n devel op thrombocytopeni a , whi ch ma y occur even wi th very-l ow-dos e hepa ri n (eg, us ed i n
fl us hes to keep IV or a rteri a l l i nes open). The mecha ni s m i s us ua l l y i mmunol ogi c. Bl eedi ng ca n occur, but more commonl y pl a tel ets cl ump
exces s i vel y, ca us i ng ves s el obs tructi on, l ea di ng to pa ra doxi ca l a rteri a l a nd venous thrombos es , whi ch ma y be l i fe threa teni ng (eg,
thromboembol i c occl us i on of l i mb a rteri es , s troke, a cute MI). Hepa ri n s houl d be s topped i n a ny pa ti ent who becomes thrombocytopeni c or whos e
pl a tel et count decrea s es by more tha n 50%. Beca us e 5 da ys of hepa ri n i s s uffi ci ent to trea t venous thrombos i s a nd beca us e mos t pa ti ents begi n
ora l a nti coa gul a nts s i mul ta neous l y wi th hepa ri n, s toppi ng hepa ri n i s us ua l l y s a fe. Low mol wt hepa ri n (LMWH) ma y be l es s i mmunogeni c tha n
unfra cti ona ted hepa ri n. However, LMWH i s not us eful i f hepa ri n-i nduced thrombocytopeni a ha s a l rea dy devel oped, beca us e mos t a nti bodi es
cros s -rea ct wi th LMWH.
Infections: HIV infection ma y ca us e i mmunol ogi c thrombocytopeni a i ndi s ti ngui s ha bl e from ITP except for the a s s oci a ti on wi th HIV. The pl a tel et
count ma y i ncrea s e wi th gl ucocorti coi ds , whi ch a re often wi thhel d unl es s the pl a tel et count fa l l s to < 20,000/L, beca us e thes e drugs ma y further
depres s i mmune functi on. The pl a tel et count a l s o us ua l l y i ncrea s es a fter trea tment wi th a nti vi ra l drugs .
Other infections s uch a s s ys temi c vi ra l i nfecti ons (eg, Eps tei n-Ba rr vi rus , cytomega l ovi rus ), ri cketts i a l i nfecti ons (eg, Rocky Mounta i n s potted fever),
a nd ba cteri a l s eps i s a re typi ca l l y a s s oci a ted wi th thrombocytopeni a .
Pregnancy: Mi l d thrombocytopeni a , typi ca l l y a s ymptoma ti c, occurs l a te i n ges ta ti on i n a bout 5% of norma l pregna nci es (ges ta ti ona l
thrombocytopeni a ); i t i s us ua l l y mi l d (pl a tel et counts < 70,000/L a re ra re), requi res no trea tment, a nd res ol ves a fter del i very. However, s evere
thrombocytopeni a ma y devel op i n pregna nt women wi th preecl a mps i a a nd the HELLP s yndrome (hemol ys i s , el eva ted l i ver functi on tes ts , a nd l ow
pl a tel ets s ee p. 2670); s uch women typi ca l l y requi re i mmedi a te del i very, a nd pl a tel et tra ns fus i on i s cons i dered i f pl a tel et count i s < 20,000/L (or
< 50,000/L i f del i very i s to be ces a rea n).
Sepsis: Seps i s often ca us es noni mmunol ogi c thrombocytopeni a tha t pa ra l l el s the s everi ty of the i nfecti on. The thrombocytopeni a ha s mul ti pl e
ca us es : di s s emi na ted i ntra va s cul a r coa gul a ti on, forma ti on of i mmune compl exes tha t ca n a s s oci a te wi th pl a tel ets , a cti va ti on of compl ement, a nd
depos i ti on of pl a tel ets on da ma ged endothel i a l s urfa ces .
Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome
Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are acute, fulminant disorders characterized by thrombocytopenia and
microangiopathic hemolytic anemia. Other manifestations may include alterations in level of consciousness and renal failure. Diagnosis requires demonstrating
characteristic laboratory test abnormalities, including Coombs'-negative hemolytic anemia. Treatment is plasma exchange and corticosteroids in adults and
supportive care (sometimes including hemodialysis) in children.
Pathophysiology
TTP a nd HUS i nvol ve noni mmunol ogi c pl a tel et des tructi on. Loos e s tra nds of von Wi l l ebra nd's fa ctor (VWF) or fi bri n a re depos i ted i n mul ti pl e
s ma l l ves s el s a nd da ma ge pa s s i ng pl a tel ets a nd RBCs , ca us i ng s i gni fi ca nt thrombocytopeni a a nd a nemi a . Pl a tel ets a re a l s o des troyed wi thi n
mul ti pl e s ma l l thrombi . Mul ti pl e orga ns devel op bl a nd pl a tel et-VWF thrombi (wi thout the ves s el wa l l gra nul ocyti c i nfi l tra ti on cha ra cteri s ti c of
va s cul i ti s ) l oca l i zed pri ma ri l y to a rteri oca pi l l a ry juncti ons , des cri bed a s thromboti c mi croa ngi opa thy. The bra i n, hea rt, a nd ki dneys a re pa rti cul a rl y
l i kel y to be a ffected.
TTP a nd HUS di ffer ma i nl y i n the rel a ti ve degree of rena l fa i l ure. Typi ca l l y, di s orders i n a dul ts a re des cri bed a s TTP a nd a re l es s l i kel y to i nvol ve
rena l fa i l ure. HUS i s us ed to des cri be the di s order i n chi l dren, whi ch typi ca l l y i nvol ves rena l fa i l ure.
Etiology
Children: Mos t ca s es fol l ow a cute hemorrha gi c col i ti s res ul ti ng from Shiga toxi n-produci ng ba cteri a (eg, Escherichia coli O157:H7, s ome s tra i ns of
Shigella dysenteriae).
Adults: Ma ny ca s es a re i di opa thi c. Known ca us es a nd a s s oci a ti ons i ncl ude
Drugs : Qui ni ne (mos t common), i mmunos uppres s a nts , a nd ca ncer chemothera py drugs (eg, cycl os pori ne, mi tomyci n C)
Pregna ncy (often i ndi s ti ngui s ha bl e from s evere preecl a mps i a or ecl a mps i a )
Ra rel y, hemorrha gi c col i ti s due to Escherichia coli O157:H7
A predi s pos i ng fa ctor i n ma ny pa ti ents i s congeni ta l or a cqui red defi ci ency of the pl a s ma enzyme ADAMTS13, whi ch cl ea ves VWF a nd thus
el i mi na tes a bnorma l l y l a rge VWF mul ti mers tha t ca n ca us e pl a tel et thrombi .
Symptoms and Signs
Ma ni fes ta ti ons of i s chemi a devel op wi th va ryi ng s everi ty i n mul ti pl e orga ns . Thes e ma ni fes ta ti ons i ncl ude wea knes s , confus i on a nd coma ,
a bdomi na l pa i n, na us ea , vomi ti ng, di a rrhea , a nd a rrhythmi a s ca us ed by myoca rdi a l da ma ge. Chi l dren us ua l l y ha ve a prodrome of vomi ti ng,
a bdomi na l pa i n, a nd di a rrhea (frequentl y bl oody). Fever ma y occur, but hi gh fever wi th chi l l s does not occur i n TTP or HUS a nd s ugges ts s eps i s . The
cl i ni ca l s yndromes of TTP a nd HUS a re i ndi s ti ngui s ha bl e, except tha t neurol ogi c s ymptoms a re l es s common wi th HUS.
Diagnosis
CBC wi th pl a tel ets , peri phera l bl ood s mea r, Coombs ' tes t
Excl us i on of other thrombocytopeni c di s orders
TTP-HUS i s s us pected i n pa ti ents wi th s ugges ti ve s ymptoms , thrombocytopeni a , a nd a nemi a . If the di s order i s s us pected, uri na l ys i s , peri phera l
bl ood s mea r, reti cul ocyte count, s erum LDH, rena l functi on tes ts , s erum bi l i rubi n (di rect a nd i ndi rect), a nd Coombs ' tes t a re done. The di a gnos i s i s
s ugges ted by:
Thrombocytopeni a a nd a nemi a
Fra gmented RBCs on the bl ood s mea r (hel met cel l s , tri a ngul a r RBCs , di s torted-a ppea ri ng RBCs ; thes e cha nges des cri be mi croa ngi opa thi c
hemol ys i s )
Evi dence of hemol ys i s (fa l l i ng Hb l evel , pol ychroma s i a , el eva ted reti cul ocyte count, el eva ted s erum LDH)
Nega ti ve di rect a nti gl obul i n (Coombs ') tes t
Otherwi s e unexpl a i ned thrombocytopeni a a nd mi croa ngi opa thi c hemol yti c a nemi a a re s uffi ci ent evi dence for a pres umpti ve di a gnos i s .
Causes: Al though ca us es (eg, qui ni ne s ens i ti vi ty) or a s s oci a ti ons (eg, pregna ncy) a re cl ea r i n s ome pa ti ents , i n mos t pa ti ents TTP-HUS a ppea rs
s uddenl y a nd s ponta neous l y wi thout a ppa rent ca us e. TTP-HUS i s often i ndi s ti ngui s ha bl e, even wi th rena l bi ops y, from s yndromes tha t ca us e
i denti ca l thromboti c mi croa ngi opa thi es (eg, preecl a mps i a , s ys temi c s cl eros i s , a ccel era ted hypertens i on, a cute rena l a l l ogra ft rejecti on).
Tes ti ng for ADAMTS13 a cti vi ty i s a ppropri a te i n pa ti ents wi th s us pected TTP-HUS, except i n chi l dren who ha ve typi ca l di a rrhea -a s s oci a ted HUS.
Al though the res ul ts of ADAMTS13 tes ti ng do not a ffect i ni ti a l trea tment, res ul ts a re i mporta nt prognos ti ca l l y.
Stool tes ti ng (s peci fi c cul ture for E. coli O157:H7 or Shiga toxi n a s s a y) i s done i n chi l dren wi th di a rrhea a nd a l s o a dul ts who ha d a prodrome of
bl oody di a rrhea ; however, the orga ni s m a nd toxi n ma y ha ve cl ea red by the ti me of pres enta ti on.
Treatment
Pl a s ma excha nge a nd corti cos teroi ds i n a dul ts
Typi ca l di a rrhea -a s s oci a ted HUS i n chi l dren ca us ed by enterohemorrha gi c i nfecti on us ua l l y s ponta neous l y remi ts a nd i s trea ted wi th s upporti ve
ca re a nd not pl a s ma excha nge; over ha l f of pa ti ents requi re rena l di a l ys i s . In other ca s es , untrea ted TTP-HUS i s a l mos t a l wa ys fa ta l . Wi th pl a s ma
excha nge, however, > 85% of pa ti ents recover compl etel y.
Pl a s ma excha nge i s conti nued da i l y unti l evi dence of di s ea s e a cti vi ty ha s s ubs i ded, a s i ndi ca ted by a norma l pl a tel et count, whi ch ma y be s evera l
da ys to ma ny weeks . Adul ts wi th TTP a re a l s o gi ven corti cos teroi ds . In pa ti ents wi th recurrence when pl a s ma excha nge i s s topped or i n pa ti ents
wi th rel a ps es , more i ntens i ve i mmunos uppres s i on wi th ri tuxi ma b ma y be effecti ve. Mos t pa ti ents experi ence onl y a s i ngl e epi s ode of TTP-HUS.
However, rel a ps es occur i n a bout 40% of pa ti ents who ha ve a s evere defi ci ency of ADAMTS13 a cti vi ty ca us ed by a n a utoa nti body i nhi bi tor. Pa ti ents
mus t be eva l ua ted qui ckl y i f s ymptoms s ugges ti ve of a rel a ps e devel op.
Von Willebrand's Disease
Von Willebrand's disease (VWD) is a hereditary deficiency of von Willebrand's factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually mild.
Screening tests show a normal platelet count and, possibly, a slightly prolonged PTT. Diagnosis is based on low levels of VWF antigen and abnormal ristocetin
cofactor activity. Treatment involves control of bleeding with replacement therapy (cryoprecipitate or pasteurized intermediate-purity factor VIII concentrate) or
desmopressin.
VWF i s s ynthes i zed a nd s ecreted by va s cul a r endothel i um to form pa rt of the peri va s cul a r ma tri x. VWF promotes the pl a tel et a dhes i on pha s e of
hemos ta s i s by bi ndi ng wi th a receptor on the pl a tel et s urfa ce membra ne (gl ycoprotei n Ib/IX), whi ch connects the pl a tel ets to the ves s el wa l l . VWF
i s a l s o requi red to ma i nta i n norma l pl a s ma fa ctor VIII l evel s . Level s of VWF ca n tempora ri l y i ncrea s e i n res pons e to s tres s , exerci s e, pregna ncy,
i nfl a mma ti on, or i nfecti on.
VWD i s cl a s s i fi ed i nto 3 types :
Type 1: a qua nti ta ti ve defi ci ency of VWF, whi ch i s the mos t common form a nd i s a n a utos oma l domi na nt di s order
Type 2: a qua l i ta ti ve i mpa i rment i n s ynthes i s of VWF tha t ca n res ul t from va ri ous geneti c a bnorma l i ti es a nd i s a n a utos oma l domi na nt di s order
Type 3: a ra re a utos oma l reces s i ve di s order i n whi ch homozygotes ha ve no detecta bl e VWF
Al though VWD, l i ke hemophi l i a A, i s a heredi ta ry di s order tha t ma y, when s evere, ca us e fa ctor VIII defi ci ency, the defi ci ency i s us ua l l y onl y
modera te.
Symptoms and Signs
Bl eedi ng ma ni fes ta ti ons a re mi l d to modera te a nd i ncl ude ea s y brui s i ng, mucos a l bl eedi ng, bl eedi ng from s ma l l s ki n cuts tha t ma y s top a nd s ta rt
over hours , s ometi mes i ncrea s ed mens trua l bl eedi ng, a nd a bnorma l bl eedi ng a fter s urgi ca l procedures (eg, tooth extra cti on, tons i l l ectomy).
Pl a tel ets functi on wel l enough tha t petechi a e a nd purpura do not occur.
Diagnosis
Tota l pl a s ma VWF a nti gen, VWF functi on, a nd pl a s ma fa ctor VIII l evel
VWD i s s us pected i n pa ti ents wi th bl eedi ng di s orders , pa rti cul a rl y thos e wi th a fa mi l y hi s tory of the di s order. Screeni ng coa gul a ti on tes ts revea l a
norma l pl a tel et count, norma l INR, a nd s ometi mes a s l i ghtl y prol onged PTT. Bl eedi ng ti me ma y be prol onged, but thi s tes t ha s poor reproduci bi l i ty
a nd i s of l i mi ted va l ue. Di a gnos i s requi res mea s uri ng tota l pl a s ma VWF a nti gen, VWF functi on a s determi ned by the a bi l i ty of pl a s ma to s upport
a ggl uti na ti on of norma l pl a tel ets by ri s toceti n (ri s toceti n cofa ctor a cti vi ty), a nd pl a s ma fa ctor VIII l evel . Sti mul i tha t tempora ri l y i ncrea s e VWF
l evel s ca n ca us e fa l s e-nega ti ve res ul ts i n mi l d VWD; tes ts ma y need to be repea ted.
In the common (type 1) form of VWD, res ul ts a re concorda nt; i e, VWF a nti gen, VWF functi on, a nd pl a s ma fa ctor VIII l evel a re equa l l y depres s ed.
The degree of depres s i on va ri es from a bout 15 to 60% of norma l a nd determi nes the s everi ty of a pa ti ent's a bnorma l bl eedi ng. Level s of VWF
a nti gen ca n a l s o be a s l ow a s 40% of norma l i n hea l thy peopl e wi th type O bl ood.
Type 2 va ri a nts a re s us pected i f tes ts a re di s corda nt, i e, VWF a nti gen i s hi gher tha n expected for the degree of a bnorma l i ty i n ri s toceti n cofa ctor
a cti vi ty. (VWF a nti gen i s hi gher tha n expected beca us e the VWF defect i n type 2 i s qua l i ta ti ve, not qua nti ta ti ve.) Di a gnos i s i s confi rmed by
demons tra ti ng a reduced concentra ti on of l a rge VWF mul ti mers on a ga ros e gel el ectrophores i s . Four di fferent type 2 va ri a nts a re recogni zed,
di s ti ngui s hed by di fferent functi ona l a bnorma l i ti es of the VWF mol ecul e.
Pa ti ents wi th type 3 VWD ha ve no detecta bl e VWF a nd a ma rked defi ci ency of fa ctor VIII.
Treatment
VWF repl a cement when neces s a ry
Pa ti ents a re trea ted onl y i f they a re a cti vel y bl eedi ng or a re undergoi ng a n i nva s i ve procedure (eg, s urgery, denta l extra cti on). Trea tment i nvol ves
repl a cement of VWF by i nfus i on of pa s teuri zed i ntermedi a te-puri ty fa ctor VIII concentra tes , whi ch conta i n components of VWF. Thes e concentra tes
a re vi ra l l y i na cti va ted a nd therefore do not tra ns mi t HIV i nfecti on or hepa ti ti s . Beca us e they do not ca us e tra ns fus i on-tra ns mi tted i nfecti ons ,
thes e concentra tes a re preferred to the previ ous l y us ed cryopreci pi ta te. Hi gh-puri ty fa ctor VIII concentra tes a re prepa red by i mmunoa ffi ni ty
chroma togra phy a nd conta i n no VWF.
Des mopres s i n i s a n a na l og of a nti di ureti c hormone (va s opres s i n) tha t s ti mul a tes rel ea s e of VWF i nto the pl a s ma a nd ma y i ncrea s e l evel s of
fa ctor VIII. Des mopres s i n ca n be hel pful for type 1 VWD but i s us ua l l y of no va l ue i n other types a nd ma y even be ha rmful i n s ome. To ens ure
a dequa te res pons e to the drug, phys i ci a ns gi ve pa ti ents a tes t dos e a nd mea s ure the res pons e of VWF a nti gen. Des mopres s i n 0.3 g/kg gi ven i n
50 mL of 0.9% s a l i ne s ol uti on IV over 15 to 30 mi n ma y ena bl e pa ti ents to undergo mi nor procedures (eg, tooth extra cti on, mi nor s urgery) wi thout
needi ng repl a cement thera py. If a repl a cement product i s needed, des mopres s i n ma y reduce the requi red dos e. One dos e of des mopres s i n i s
effecti ve for a bout 8 to 10 h. About 48 h mus t el a ps e for new s tores of VWF to a ccumul a te, permi tti ng a 2nd i njecti on of des mopres s i n to be a s
effecti ve a s the i ni ti a l dos e.
Chapter 109. Hemostasis

Introduction
Hemos ta s i s , the a rres t of bl eedi ng from a n i njured bl ood ves s el , requi res the combi ned a cti vi ty of va s cul a r, pl a tel et, a nd pl a s ma fa ctors .
Regul a tory mecha ni s ms counterba l a nce the tendency of cl ots to form. Hemos ta ti c a bnorma l i ti es ca n l ea d to exces s i ve bl eedi ng or thrombos i s .
Vascular Factors
Va s cul a r fa ctors reduce bl ood l os s from tra uma through l oca l va s ocons tri cti on (a n i mmedi a te rea cti on to i njury) a nd compres s i on of i njured
ves s el s by extra va s a ti on of bl ood i nto s urroundi ng ti s s ues . Ves s el wa l l i njury tri ggers the a tta chment a nd a cti va ti on of pl a tel ets a nd producti on of
fi bri n; pl a tel ets a nd fi bri n combi ne to form a cl ot.
Platelet Factors
Va ri ous mecha ni s ms , i ncl udi ng endothel i a l cel l ni tri c oxi de a nd pros ta cycl i n, promote bl ood fl ui di ty by preventi ng pl a tel et s ta s i s a nd di l a ti ng
i nta ct bl ood ves s el s . Thes e medi a tors a re no l onger produced when the va s cul a r endothel i um i s di s rupted. Under thes e condi ti ons , pl a tel ets
a dhere to the da ma ged i nti ma a nd form a ggrega tes . Ini ti a l pl a tel et a dhes i on i s to von Wi l l ebra nd's fa ctor (VWF), previ ous l y s ecreted by
endothel i a l cel l s i nto the s ubendothel i um. VWF bi nds to receptors on the pl a tel et s urfa ce membra ne (gl ycoprotei n Ib/IX). Pl a tel ets a nchored to
the ves s el wa l l undergo a cti va ti on. Duri ng a cti va ti on, pl a tel ets rel ea s e medi a tors from s tora ge gra nul es , i ncl udi ng a denos i ne di phos pha te (ADP).
Other bi ochemi ca l cha nges res ul ti ng from a cti va ti on i ncl ude hydrol ys i s of membra ne phos phol i pi ds , i nhi bi ti on of a denyl a te cycl a s e, mobi l i za ti on
of i ntra cel l ul a r Ca , a nd phos phoryl a ti on of i ntra cel l ul a r protei ns . Ara chi doni c a ci d i s converted to thromboxa ne A2 ; thi s rea cti on requi res
cycl ooxygena s e a nd i s i nhi bi ted i rrevers i bl y by a s pi ri n a nd revers i bl y by ma ny NSAIDs . ADP, thromboxa ne A2 , a nd other medi a tors i nduce a cti va ti on
a nd a ggrega ti on of a ddi ti ona l pl a tel ets on the i njured endothel i um. Another receptor i s a s s embl ed on the pl a tel et s urfa ce membra ne from
gl ycoprotei ns IIb a nd IIIa . Fi bri nogen bi nds to the gl ycoprotei n IIb/IIIa compl exes of a dja cent pl a tel ets , connecti ng them i nto a ggrega tes .
Pl a tel ets provi de s urfa ces for the a s s embl y a nd a cti va ti on of coa gul a ti on compl exes a nd the genera ti on of thrombi n. Thrombi n converts
fi bri nogen to fi bri n. Fi bri n s tra nds bi nd a ggrega ted pl a tel ets to hel p s ecure the pl a tel et-fi bri n hemos ta ti c pl ug.
Plasma Factors
Pl a s ma coa gul a ti on fa ctors i ntera ct to produce thrombi n, whi ch converts fi bri nogen to fi bri n. Ra di a ti ng from a nd a nchori ng the hemos ta ti c pl ug,
fi bri n s trengthens the cl ot.
In the i ntri ns i c pa thwa y, fa ctor XII, hi gh mol wt ki ni nogen, preka l l i krei n, a nd a cti va ted fa ctor XI (fa ctor XIa ) i ntera ct to produce fa ctor IXa from fa ctor
IX. Fa ctor IXa then combi nes wi th fa ctor VIIIa a nd procoa gul a nt phos phol i pi d (pres ent on the s urfa ce of a cti va ted pl a tel ets a nd ti s s ue cel l s ) to
form a compl ex tha t a cti va tes fa ctor X. In the extri ns i c pa thwa y, fa ctor VIIa a nd ti s s ue fa ctor di rectl y a cti va te fa ctor X (the fa ctor VIIa /ti s s ue fa ctor
compl ex a l s o a cti va tes fa ctor IXs ee
Fi g. 109-1 a nd
Ta bl e 109-1).
[Fig. 109-1. Pa thwa ys i n bl ood coa gul a ti on.]
[Table 109-1. Components of Bl ood Coa gul a ti on Rea cti ons ]
Acti va ti on of the i ntri ns i c or extri ns i c pa thwa y a cti va tes the common pa thwa y, res ul ti ng i n forma ti on of the fi bri n cl ot. Three s teps a re i nvol ved i n
common pa thwa y a cti va ti on:
1. A prothrombi n a cti va tor i s produced on the s urfa ce of a cti va ted pl a tel ets a nd ti s s ue cel l s . The a cti va tor i s a compl ex of a n enzyme, fa ctor Xa , a nd
2 cofa ctors , fa ctor Va a nd procoa gul a nt phos phol i pi d.
2. The prothrombi n a cti va tor cl ea ves prothrombi n i nto thrombi n a nd a nother fra gment.
3. Thrombi n i nduces the genera ti on of fi bri n pol ymers from fi bri nogen. Thrombi n a l s o a cti va tes fa ctor XIII, a n enzyme tha t ca ta l yzes forma ti on of
s tronger bonds between a dja cent fi bri n monomers , a s wel l a s fa ctor VIII a nd fa ctor XI.
Ca 2+ i ons a re needed i n mos t thrombi n-genera ti ng rea cti ons (Ca 2+-chel a ti ng a gents [eg, ci tra te, ethyl enedi a mi netetra a ceti c a ci d] a re us ed i n vi tro
a s a nti coa gul a nts ). Vi ta mi n K-dependent cl otti ng fa ctors (fa ctors II, VII, IX, a nd X) ca nnot bi nd norma l l y to phos phol i pi d s urfa ces through Ca 2+
bri dges a nd functi on i n bl ood coa gul a ti on when s ynthes i zed i n the a bs ence of vi ta mi n K.
Al though the coa gul a ti on pa thwa ys a re hel pful i n unders ta ndi ng mecha ni s ms a nd l a bora tory eva l ua ti on of coa gul a ti on di s orders , i n vi vo
coa gul a ti on i s predomi na ntl y vi a the extri ns i c pa thwa y. Peopl e wi th heredi ta ry defi ci enci es of fa ctor XII, hi gh mol wt ki ni nogen, or preka l l i krei n
ha ve no bl eedi ng a bnorma l i ty. Peopl e wi th heredi ta ry fa ctor XI defi ci ency ha ve a mi l d to modera te bl eedi ng di s order. In vi vo, fa ctor XI (a n i ntri ns i c
pa thwa y fa ctor) i s a cti va ted when a s ma l l a mount of thrombi n i s genera ted. Fa ctor IX ca n be a cti va ted both by fa ctor XIa a nd fa ctor VIIa /ti s s ue
fa ctor compl exes .
In vi vo, i ni ti a ti on of the extri ns i c pa thwa y occurs when i njury to bl ood ves s el s bri ngs bl ood i nto conta ct wi th the ti s s ue fa ctor on membra nes of
cel l s wi thi n a nd a round the ves s el wa l l s . Thi s conta ct wi th ti s s ue fa ctor genera tes fa ctor VIIa /ti s s ue fa ctor compl exes tha t a cti va te fa ctor X a nd
fa ctor IX. Fa ctor IXa , combi ned wi th i ts cofa ctor, fa ctor VIIIa , on phos phol i pi d membra ne s urfa ces genera tes a ddi ti ona l fa ctor Xa . Fa ctor X
a cti va ti on by both fa ctor VIIa /ti s s ue fa ctor a nd fa ctor IXa /VIIIa compl exes i s requi red for norma l hemos ta s i s . Thi s requi rement for fa ctors VIII a nd
IX expl a i ns why hemophi l i a type A (defi ci ency of fa ctor VIII) or type B (defi ci ency of fa ctor IX) res ul ts i n bl eedi ng, des pi te a n i nta ct extri ns i c
coa gul a ti on pa thwa y i ni ti a ted by fa ctor VIIa /ti s s ue fa ctor compl exes .
Regulatory Mechanisms
Severa l i nhi bi tory mecha ni s ms prevent a cti va ted coa gul a ti on rea cti ons from a mpl i fyi ng uncontrol l a bl y, ca us i ng extens i ve l oca l thrombos i s or
di s s emi na ted i ntra va s cul a r coa gul a ti on. Thes e mecha ni s ms i ncl ude i na cti va ti on of procoa gul a nt enzymes , fi bri nol ys i s , a nd hepa ti c cl ea ra nce of
a cti va ted cl otti ng fa ctors .
Inactivation of coagulation factors: Pl a s ma protea s e i nhi bi tors (a nti thrombi n, ti s s ue fa ctor pa thwa y i nhi bi tor, 2 -ma crogl obul i n, hepa ri n cofa ctor II)
i na cti va te coa gul a ti on enzymes . Anti thrombi n i nhi bi ts thrombi n, fa ctor Xa , fa ctor XIa , a nd fa ctor IXa . Hepa ri n enha nces a nti thrombi n a cti vi ty.
Two vi ta mi n K-dependent protei ns , protei n C a nd protei n S, form a compl ex tha t i na cti va tes fa ctors VIIIa a nd Va by proteol ys i s . Thrombi n, when
bound to a receptor on endothel i a l cel l s (thrombomodul i n), a cti va tes protei n C. Acti va ted protei n C, i n combi na ti on wi th protei n S a nd
phos phol i pi d cofa ctors , proteol yzes a nd i na cti va tes fa ctors VIIIa a nd Va .
Fibrinolysis: Fi bri n depos i ti on a nd l ys i s mus t be ba l a nced to ma i nta i n a nd remol d the hemos ta ti c s ea l duri ng repa i r of a n i njured ves s el wa l l . The
fi bri nol yti c s ys tem di s s ol ves fi bri n by mea ns of pl a s mi n, a proteol yti c enzyme. Fi bri nol ys i s i s a cti va ted by pl a s mi nogen a cti va tors rel ea s ed from
va s cul a r endothel i a l cel l s . Pl a s mi nogen a cti va tors a nd pl a s mi nogen (from pl a s ma ) bi nd to fi bri n, a nd pl a s mi nogen a cti va tors cl ea ve pl a s mi nogen
i nto pl a s mi n (s ee
Fi g. 109-2). Pl a s mi n then proteol yzes fi bri n i nto s ol ubl e fi bri n degra da ti on products tha t a re s wept a wa y i n the ci rcul a ti on.
There a re s evera l pl a s mi nogen a cti va tors :
Tissue plasminogen activator (tPA), from endothel i a l cel l s , i s a poor a cti va tor when
[Fig. 109-2. Fi bri nol yti c pa thwa y.]
free i n s ol uti on but a n effi ci ent a cti va tor when bound to fi bri n i n proxi mi ty to pl a s mi nogen.
Urokinase exi s ts i n s i ngl e-cha i n a nd doubl e-cha i n forms wi th di fferent functi ona l properti es . Si ngl e-cha i n uroki na s e ca nnot a cti va te free
pl a s mi nogen but, l i ke tPA, ca n rea di l y a cti va te pl a s mi nogen bound to fi bri n. A tra ce concentra ti on of pl a s mi n cl ea ves s i ngl e-cha i n to doubl echa i n uroki na s e, whi ch a cti va tes pl a s mi nogen i n s ol uti on a s wel l a s pl a s mi nogen bound to fi bri n. Epi thel i a l cel l s tha t l i ne excretory pa s s a ges
(eg, rena l tubul es , ma mma ry ducts ) s ecrete uroki na s e, whi ch i s the phys i ol ogi c a cti va tor of fi bri nol ys i s i n thes e cha nnel s .
Streptokinase, a ba cteri a l product not norma l l y found i n the body, i s a nother potent pl a s mi nogen a cti va tor.
Streptoki na s e, uroki na s e, a nd recombi na nt tPA (a l tepl a s e) ha ve a l l been us ed thera peuti ca l l y to i nduce fi bri nol ys i s i n pa ti ents wi th a cute
thromboti c di s orders .
Regulation of fibrinolysis: Fi bri nol ys i s i s regul a ted by pl a s mi nogen a cti va tor i nhi bi tors (PAIs ) a nd pl a s mi n i nhi bi tors tha t s l ow fi bri nol ys i s . PAI-1, the
mos t i mporta nt PAI, i na cti va tes tPA a nd uroki na s e a nd i s rel ea s ed from va s cul a r endothel i a l cel l s a nd a cti va ted pl a tel ets . The pri ma ry pl a s mi n
i nhi bi tor i s 2 -a nti pl a s mi n, whi ch qui ckl y i na cti va tes free pl a s mi n es ca pi ng from cl ots . Some 2 -a nti pl a s mi n i s a l s o cros s -l i nked to fi bri n by the
a cti on of fa ctor XIIIa duri ng cl otti ng. Thi s cros s -l i nki ng ma y prevent exces s i ve pl a s mi n a cti vi ty wi thi n cl ots . tPA a nd uroki na s e a re ra pi dl y cl ea red by
the l i ver, whi ch i s a nother mecha ni s m of preventi ng exces s i ve fi bri nol ys i s .
Excessive Bleeding
Unus ua l or exces s i ve bl eedi ng ma y be i ndi ca ted by s evera l di fferent s i gns a nd s ymptoms . Pa ti ents ma y pres ent wi th unexpl a i ned nos ebl eeds
(epi s ta xi s ), exces s i ve or prol onged mens trua l bl ood fl ow (menorrha gi a ), or prol onged bl eedi ng a fter mi nor cuts , tooth brus hi ng or fl os s i ng, or
tra uma . Other pa ti ents ma y ha ve unexpl a i ned s ki n l es i ons , i ncl udi ng petechi a e (s ma l l i ntra derma l or mucos a l hemorrha ges ), purpura (a rea s of
mucos a l or s ki n hemorrha ge l a rger tha n petechi a e), ecchymos es (brui s es ), or tel a ngi ecta s i a s (di l a ted s ma l l ves s el s vi s i bl e on s ki n or mucos a ).
Some cri ti ca l l y i l l pa ti ents ma y s uddenl y bl eed from va s cul a r punctures or s ki n l es i ons a nd ha ve s evere hemorrha ge from thes e s i tes or from the
GI or GU tra ct. In s ome pa ti ents , a l a bora tory tes t a bnorma l i ty s ugges ti ng the s us cepti bi l i ty to exces s i ve bl eedi ng i s found i nci denta l l y.
Etiology
Exces s i ve bl eedi ng ca n res ul t from s evera l mecha ni s ms (s ee
Ta bl e 109-2), i ncl udi ng the fol l owi ng:
Pl a tel et di s orders
Coa gul a ti on di s orders
Defects i n bl ood ves s el s
Pl a tel et di s orders ma y i nvol ve a n a bnorma l number of pl a tel ets (typi ca l l y too few pl a tel ets , a l though a n extremel y el eva ted pl a tel et count ma y be
a s s oci a ted ei ther wi th thrombos i s or wi th exces s i ve bl eedi ng), defecti ve pl a tel et functi on, or both. Coa gul a ti on di s orders ma y be a cqui red or
heredi ta ry.
Overa l l , the mos t common ca us es of exces s i ve bl eedi ng i ncl ude
Severe thrombocytopeni a
Exces s i ve a nti coa gul a ti on wi th wa rfa ri n or hepa ri n
Li ver di s ea s e (i na dequa te producti on of coa gul a ti on fa ctors )
Evaluation
History: History of present illness s houl d determi ne the bl eedi ng s i tes , the a mount a nd dura ti on of bl eedi ng, a nd the rel a ti ons hi p of bl eedi ng to a ny
pos s i bl e preci pi ta ti ng fa ctors .
Review of systems s houl d s peci fi ca l l y query a bout bl eedi ng from s i tes other tha n thos e vol unteered (eg, pa ti ents compl a i ni ng of ea s y brui s i ng
s houl d be ques ti oned a bout frequent nos ebl eeds , gum bl eedi ng whi l e tooth brus hi ng, mel ena , hemoptys i s , bl ood i n s tool or uri ne). Pa ti ents
s houl d be a s ked a bout s ymptoms of pos s i bl e ca us es , i ncl udi ng a bdomi na l pa i n a nd di a rrhea (GI i l l nes s ); joi nt pa i n (connecti ve ti s s ue di s orders );
a nd a menorrhea a nd morni ng s i cknes s (pregna ncy).
Past medical history s houl d s eek known s ys temi c condi ti ons a s s oci a ted wi th defects i n pl a tel ets or coa gul a ti on, pa rti cul a rl y
Severe i nfecti on, ca ncer, ci rrhos i s , HIV i nfecti on, pregna ncy, SLE, or uremi a
Pri or exces s i ve or unus ua l bl eedi ng or tra ns fus i ons
Fa mi l y hi s tory of exces s i ve bl eedi ng
Drug hi s tory s houl d be revi ewed, pa rti cul a rl y us e of hepa ri n, wa rfa ri n, a s pi ri n, a nd NSAIDs .
Physical examination: Vi ta l s i gns a nd genera l a ppea ra nce ca n i ndi ca te hypovol emi a
[Table 109-2. Some Ca us es of Exces s i ve Bl eedi ng]
(ta chyca rdi a , hypotens i on, pa l l or, di a phores i s ) or i nfecti on (fever, ta chyca rdi a , hypotens i on wi th s eps i s ).
The s ki n a nd mucous membra nes (nos e, mouth, va gi na ) a re exa mi ned for petechi a e, purpura , a nd tel a ngi ecta s i a s . GI bl eedi ng ca n often be
i denti fi ed by di gi ta l recta l exa mi na ti on. Si gns of bl eedi ng i n deeper ti s s ues ma y i ncl ude tendernes s duri ng movement a nd l oca l s wel l i ng, mus cl e
hema toma s , a nd, for i ntra cra ni a l bl eedi ng, confus i on, s ti ff neck, foca l neurol ogi c a bnorma l i ti es , or a combi na ti on of thes e fi ndi ngs .
Cha ra cteri s ti c fi ndi ngs of a l cohol a bus e or l i ver di s ea s e a re a s ci tes , s pl enomega l y (s econda ry to porta l hypertens i on), a nd ja undi ce.
Si gns of hypovol emi a or hemorrha gi c s hock
Pregna ncy or recent del i very
Si gns of i nfecti on or s eps i s
Interpretation of findings: Bl eedi ng i n a pa ti ent ta ki ng wa rfa ri n, es peci a l l y i f there ha s been a recent i ncrea s e i n dos e, i s l i kel y due to the drug.
Tel a ngi ecta s i a s on the fa ce, l i ps , ora l or na s a l mucos a , a nd ti ps of the fi ngers a nd toes i n a pa ti ent wi th a pos i ti ve fa mi l y hi s tory of exces s i ve
bl eedi ng i s l i kel y heredi ta ry hemorrha gi c tel a ngi ecta s i a .
Bl eedi ng from s uperfi ci a l s i tes , i ncl udi ng s ki n a nd mucous membra nes , s ugges ts a qua nti ta ti ve or qua l i ta ti ve defect i n pl a tel ets or a defect i n
bl ood ves s el s (eg, a myl oi dos i s ).
Bl eedi ng i nto deep ti s s ues (eg, hema rthros es , mus cl e hema toma s , retroperi tonea l hemorrha ge) s ugges ts a defect i n coa gul a ti on (coa gul opa thy).
A fa mi l y hi s tory of exces s i ve bl eedi ng s ugges ts a n i nheri ted coa gul opa thy (eg, hemophi l i a ), a qua l i ta ti ve pl a tel et di s order, a type of von
Wi l l ebra nd's di s ea s e (VWD), or heredi ta ry hemorrha gi c tel a ngi ecta s i a . Abs ence of a known fa mi l y hi s tory does not, however, excl ude a n i nheri ted
di s order of hemos ta s i s .
Bl eedi ng i n a pa ti ent who i s pregna nt or ha s recentl y del i vered, who i s i n s hock, or who ha s a s eri ous i nfecti on s ugges ts di s s emi na ted
i ntra va s cul a r coa gul a ti on (DIC).
Bl oody di a rrhea a nd thrombocytopeni a i n a chi l d wi th fever a nd GI s ymptoms s ugges t the hemol yti c-uremi c s yndrome (HUS), whi ch i s often
a s s oci a ted wi th i nfecti on by Escherichia coli O157:H7.
In a chi l d, a pa l pa bl e, purpuri c ra s h on the extens or s urfa ces of the extremi ti es s ugges ts Henoch-Schonl ei n purpura , pa rti cul a rl y i f a ccompa ni ed
by fever, pol ya rthra l gi a , or GI s ymptoms .
Pa ti ents wi th known a l cohol a bus e or l i ver di s ea s e ma y ha ve coa gul opa thy, s pl enomega l y, or thrombocytopeni a .
In pa ti ents wi th a hi s tory of IV drug a bus e, HIV i nfecti on s houl d be cons i dered.
Testing: Mos t pa ti ents requi re l a bora tory eva l ua ti on (s ee
Ta bl e 109-3). The i ni ti a l tes ts a re
CBC wi th pl a tel et count
Peri phera l bl ood s mea r
PT a nd PTT
Screeni ng tes ts eva l ua te the components of hemos ta s i s , i ncl udi ng the number of ci rcul a ti ng pl a tel ets a nd the pl a s ma coa gul a ti on pa thwa ys . The
mos t common s creeni ng tes ts for bl eedi ng di s orders a re the pl a tel et count, PT, a nd PTT. If res ul ts a re a bnorma l , a s peci fi c tes t ca n us ua l l y
pi npoi nt the defect. Determi na ti on of the l evel of fi bri n degra da ti on products mea s ures i n vi vo a cti va ti on of fi bri nol ys i s .
[Table 109-3. La bora tory Tes ts of Hemos ta s i s by Pha s e]
Prothrombin time (PT) s creens for a bnorma l i ti es i n the extri ns i c a nd common pa thwa ys of coa gul a ti on (pl a s ma fa ctors VII, X, V, prothrombi n, a nd
fi bri nogen). The PT i s reported a s the i nterna ti ona l norma l i zed ra ti o (INR), whi ch refl ects the ra ti o of the pa ti ent's PT to the l a bora tory's control
va l ue; the INR control s for di fferences i n rea gents a mong di fferent l a bora tori es . Beca us e commerci a l rea gents a nd i ns trumenta ti on va ry wi del y,
ea ch l a bora tory determi nes i ts own norma l ra nge for PT a nd PTT; a typi ca l norma l ra nge for the PT i s between 10 a nd 13 s ec. An INR > 1.5 or a PT 3
s ec l onger tha n a l a bora tory's norma l control va l ue i s us ua l l y a bnorma l a nd requi res further eva l ua ti on. The INR i s va l ua bl e i n s creeni ng for
a bnorma l coa gul a ti on i n va ri ous a cqui red condi ti ons (eg, vi ta mi n K defi ci ency, l i ver di s ea s e, DIC). It i s a l s o us ed to moni tor thera py wi th the ora l
vi ta mi n K a nta goni s t, wa rfa ri n.
Partial thromboplastin time (PTT) s creens pl a s ma for a bnorma l i ti es i n fa ctors of the i ntri ns i c a nd common pa thwa ys (preka l l i krei n; hi gh mol wt
ki ni nogen; fa ctors XII, XI, IX, VIII, X, a nd V; prothrombi n; fi bri nogen). The PTT tes ts for defi ci enci es of a l l cl otti ng fa ctors except fa ctor VII (mea s ured
by the PT) a nd fa ctor XIII. A typi ca l norma l ra nge i s 28 to 34 s ec. A norma l res ul t i ndi ca tes tha t a t l ea s t 30% of a l l coa gul a ti on fa ctors i n the pa thwa y
a re pres ent i n the pl a s ma . Hepa ri n prol ongs the PTT, a nd the PTT i s often us ed to moni tor hepa ri n thera py. Inhi bi tors tha t prol ong the PTT i ncl ude
a n a utoa nti body a ga i ns t fa ctor VIII (s ee pp. 977 a nd 979) a nd a nti bodi es a ga i ns t protei n-phos phol i pi d compl exes (l upus a nti coa gul a nts ee pp.
973 a nd 979).
Prolongation of PT or PTT ma y refl ect
Fa ctor defi ci ency
Pres ence of a n i nhi bi tor of a component of the coa gul a ti on pa thwa y
The PT a nd PTT do not become prol onged unti l one or more of the cl otti ng fa ctors tes ted a re a bout 70% defi ci ent. For determi ni ng i f prol onga ti on
refl ects a defi ci ency of one or more cl otti ng fa ctor or the pres ence of a n i nhi bi tor, the tes t i s repea ted a fter mi xi ng the pa ti ent's pl a s ma wi th
norma l pl a s ma i n a 1:1 ra ti o. Beca us e thi s mi xture provi des a bout 50% of norma l l evel s of a l l coa gul a ti on fa ctors , fa i l ure of the mi xture to correct
a l mos t compl etel y the prol onga ti on s ugges ts the pres ence of a n i nhi bi tor i n pa ti ent pl a s ma .
The previ ous l y us ed bl eedi ng ti me tes t i s of doubtful rel i a bi l i ty.
Normal results on i ni ti a l tes ts excl ude ma ny bl eedi ng di s orders . The ma i n excepti ons a re VWD a nd heredi ta ry hemorrha gi c tel a ngi ecta s i a . VWD i s
a common enti ty i n whi ch the a s s oci a ted defi ci ency of fa ctor VIII i s frequentl y i ns uffi ci ent to prol ong the PTT. Pa ti ents who ha ve norma l i ni ti a l tes t
res ul ts , a l ong wi th s ymptoms or s i gns of bl eedi ng a nd a pos i ti ve fa mi l y hi s tory, s houl d be tes ted for VWD by mea s uri ng pl a s ma von Wi l l ebra nd's
fa ctor (VWF) a nti gen, ri s toceti n cofa ctor a cti vi ty (a n i ndi rect tes t for l a rge VWF mul ti mers ), a nd fa ctor VIII l evel s .
If thrombocytopenia i s pres ent, the peri phera l bl ood s mea r often s ugges ts the ca us e (s ee
Ta bl e 108-2). If the s mea r i s norma l , pa ti ents s houl d be tes ted for HIV. If the res ul t of the HIV tes t i s nega ti ve a nd the pa ti ent i s not pregna nt a nd
ha s not ta ken a drug known to ca us e pl a tel et des tructi on, then i di opa thi c thrombocytopeni c purpura i s l i kel y. If there a re s i gns of hemol ys i s
(fra gmented RBCs on s mea r, decrea s i ng Hb l evel ), thromboti c thrombocytopeni c purpura (TTP) or HUS i s s us pected, a l though s ometi mes other
hemol yti c di s orders ca n ca us e thes e fi ndi ngs . HUS occurs i n chi l dren wi th hemorrha gi c col i ti s . The Coombs ' tes t i s nega ti ve i n TTP a nd HUS. If the
CBC a nd peri phera l bl ood s mea r demons tra te other cytopeni a s or a bnorma l WBCs , a hema tol ogi c a bnorma l i ty a ffecti ng mul ti pl e cel l types i s
s us pected, a nd a bone ma rrow a s pi ra ti on or bi ops y i s neces s a ry for di a gnos i s .
Prolonged PTT with normal platelets and PT s ugges ts hemophi l i a A or B. Fa ctor VIII a nd IX a s s a ys a re i ndi ca ted. Inhi bi tors tha t prol ong the PTT i ncl ude
a n a utoa nti body a ga i ns t fa ctor VIII a nd a nti bodi es a ga i ns t protei n-phos phol i pi d compl exes (l upus a nti coa gul a nt). Such i nhi bi tors a re s us pected
when a prol onged PTT does not correct upon 1:1 mi xi ng wi th norma l pl a s ma .
Prolonged PT with normal platelets and PTT s ugges ts fa ctor VII defi ci ency. Congeni ta l fa ctor VII defi ci ency i s ra re; however, the s hort ha l f-l i fe of fa ctor
VII i n pl a s ma ca us es fa ctor VII to decrea s e to l ow l evel s more ra pi dl y tha n other vi ta mi n K-dependent coa gul a ti on fa ctors (eg, i n pa ti ents gi ven
wa rfa ri n a nti coa gul a ti on or i n pa ti ents wi th i nci pi ent l i ver di s ea s e).
Prolonged PT and PTT with thrombocytopenia s ugges t DIC, es peci a l l y i n a s s oci a ti on wi th obs tetri c compl i ca ti ons , s eps i s , ca ncer, or s hock.
Confi rma ti on i s by fi ndi ng el eva ted l evel s of D-di mers (or fi bri n degra da ti on products ) a nd decrea s i ng pl a s ma fi bri nogen l evel s on s eri a l tes ti ng.
Prol onged PT or PTT wi th norma l pl a tel et count occurs wi th l i ver di s ea s e or vi ta mi n K defi ci ency or duri ng a nti coa gul a ti on wi th wa rfa ri n or
unfra cti ona ted hepa ri n. Li ver di s ea s e i s s us pected ba s ed on hi s tory a nd i s confi rmed by fi ndi ng el eva ti on of s erum a mi notra ns fera s es a nd
bi l i rubi n; hepa ti ti s tes ti ng i s recommended.
Imaging tests a re often requi red to detect occul t bl eedi ng i n pa ti ents wi th bl eedi ng di s orders . For exa mpl e, hea d CT s houl d be done i n pa ti ents
wi th s evere hea da ches , hea d i njuri es , or i mpa i rment of cons ci ous nes s ; a nd a bdomi na l CT i n pa ti ents wi th a bdomi na l pa i n or other fi ndi ngs
compa ti bl e wi th i ntra peri tonea l or retroperi tonea l hemorrha ge.
Treatment
Trea tment i s di rected a t the underl yi ng di s order a nd a t a ny hypovol emi a . For i mmedi a te trea tment of bl eedi ng due to a coa gul opa thy tha t ha s not
yet been di a gnos ed, fres h frozen pl a s ma , whi ch conta i ns a l l coa gul a ti on fa ctors , s houl d be i nfus ed pendi ng defi ni ti ve eva l ua ti on.
Key Points
DIC s houl d be s us pected i n pa ti ents wi th s eps i s , s hock, or compl i ca ti ons of pregna ncy or del i very.
Drug ca us es a re common, pa rti cul a rl y mi l d pl a tel et dys functi on ca us ed by a s pi ri n or NSAIDs .

Ea s y brui s i ng wi th no other cl i ni ca l ma ni fes ta ti ons a nd norma l l a bora tory tes t res ul ts i s proba bl y beni gn.
Chapter 110. Thrombotic Disorders

Introduction
In hea l thy peopl e, homeos ta ti c ba l a nce exi s ts between procoa gul a nt (cl otti ng) forces a nd a nti coa gul a nt a nd fi bri nol yti c forces (s ee Ch. 109).
Numerous geneti c, a cqui red, a nd envi ronmenta l fa ctors ca n ti p the ba l a nce i n fa vor of coa gul a ti on, l ea di ng to the pa thol ogi c forma ti on of thrombi
i n vei ns (eg, deep venous thrombos i s [DVT]), a rteri es (eg, MI, i s chemi c s troke), or ca rdi a c cha mbers . Thrombi ca n obs truct bl ood fl ow a t the s i te of
forma ti on or deta ch a nd embol i ze to bl ock a di s ta nt bl ood ves s el (eg, pul mona ry embol i s m, embol i c s troke).
Etiology
Genetic defects tha t i ncrea s e the propens i ty for venous thromboembol i s m i ncl ude
Fa ctor V Lei den muta ti on, whi ch ca us es res i s ta nce to a cti va ted protei n C (APC)
Prothrombi n 20210 gene muta ti on
Defi ci ency of protei n C, protei n S, protei n Z, or a nti thrombi n
Acquired defects a l s o predi s pos e to venous a nd a rteri a l thrombos i s (s ee
Ta bl e 110-1).
Other di s orders a nd envi ronmenta l fa ctors ca n i ncrea s e the ri s k of thrombos i s , es peci a l l y i f a geneti c a bnorma l i ty i s a l s o pres ent.
Diagnosis
Di a gnos es a re s umma ri zed el s ewhere i n THE MANUAL s peci fi c to the l oca ti on of the thrombus .
Predisposing factors: Predi s pos i ng fa ctors s houl d a l wa ys be cons i dered. In s ome ca s es , the condi ti on i s cl i ni ca l l y obvi ous (eg, recent s urgery or
tra uma , prol onged i mmobi l i za ti on, ca ncer, genera l i zed a theros cl eros i s ). If no predi s pos i ng fa ctor i s rea di l y a ppa rent, further eva l ua ti on s houl d
be conducted i n pa ti ents wi th
Fa mi l y hi s tory of venous thrombos i s
More tha n one epi s ode of venous thrombos i s
Venous or a rteri a l thrombos i s before a ge 50
Unus ua l s i tes of venous thrombos i s (eg, ca vernous s i nus , mes enteri c vei ns )
As ma ny a s ha l f of a l l pa ti ents wi th s ponta neous DVT ha ve a geneti c predi s pos i ti on.
[Table 110-1. Acqui red Ca us es of Thromboembol i s m]
Tes ti ng for predi s pos i ng congeni ta l fa ctors i ncl udes mea s urements of the qua nti ty of a cti vi ty of na tura l a nti coa gul a nt mol ecul es i n pl a s ma a nd
tes ts for s peci fi c gene defects . Tes ti ng begi ns wi th a group of s creeni ng tes ts , fol l owed (i f neces s a ry) by s peci fi c a s s a ys .
Treatment
Trea tment i s s umma ri zed el s ewhere i n THE MANUAL s peci fi c to the l oca ti on of the thrombus .
Factor V Resistance to Activated Protein C
APC (i n compl ex wi th protei n S) degra des fa ctors Va a nd VIIIa , thus i nhi bi ti ng coa gul a ti on. Any of s evera l muta ti ons to fa ctor V ma ke i t res i s ta nt to
i na cti va ti on by APC, i ncrea s i ng the tendency for thrombos i s . Fa ctor V Lei den i s the mos t common of thes e muta ti ons . Homozygous muta ti ons
i ncrea s e the ri s k of thrombos i s more tha n do heterozygous muta ti ons .
Fa ctor V Lei den a s a s i ngl e gene defect i n Europea n popul a ti ons i s pres ent i n a bout 5%, but i t ra rel y occurs i n na ti ve As i a n or Afri ca n popul a ti ons .
It i s pres ent i n 20 to 60% of pa ti ents wi th s ponta neous venous thrombos i s .
Di a gnos i s i s ba s ed on a functi ona l pl a s ma coa gul a ti on a s s a y (the fa i l ure of pa ti ent pl a s ma PTT to become prol onged i n the pres ence of s na ke
venom-a cti va ted pa ti ent protei n C) a nd on mol ecul a r a na l ys i s of the fa ctor V gene.
Trea tment, i f neces s a ry, i nvol ves a nti coa gul a ti on wi th hepa ri n fol l owed by wa rfa ri n.
Protein C Deficiency
Protei n C i s a vi ta mi n K-dependent protei n, a s a re coa gul a ti on fa ctors VII, IX, a nd X, prothrombi n, a nd protei ns S a nd Z. Beca us e APC degra des
fa ctors Va a nd VIIIa , APC i s a na tura l pl a s ma a nti coa gul a nt. Decrea s ed protei n C from geneti c or a cqui red ca us es promotes venous thrombos i s .
Heterozygous defi ci ency of pl a s ma protei n C ha s a preva l ence of 0.2 to 0.5%; a bout 75% of peopl e wi th thi s defect experi ence a venous
thromboembol i s m (50% by a ge 50). Homozygous or doubl y heterozygous defi ci ency ca us es neona ta l purpura ful mi na ns , i e, s evere neona ta l
di s s emi na ted i ntra va s cul a r coa gul a ti on (DIC). Acqui red decrea s es occur i n pa ti ents wi th l i ver di s ea s e or DIC, duri ng ca ncer chemothera py
(i ncl udi ng L-a s pa ra gi na s e a dmi ni s tra ti on), a nd duri ng wa rfa ri n thera py.
Di a gnos i s i s ba s ed on a nti geni c a nd functi ona l pl a s ma a s s a ys .
Pa ti ents wi th s ymptoma ti c thrombos i s requi re a nti coa gul a ti on wi th hepa ri n or l ow mol wt hepa ri n, fol l owed by wa rfa ri n; us e of the vi ta mi n K
a nta goni s t, wa rfa ri n, a s i ni ti a l thera py occa s i ona l l y ca us es thromboti c s ki n i nfa rcti on by l oweri ng vi ta mi n K-dependent protei n C l evel s before a
thera peuti c decrea s e ha s occurred i n mos t vi ta mi n K-dependent cl otti ng fa ctors . Neona ta l purpura ful mi na ns i s fa ta l wi thout repl a cement of
protei n C (us i ng norma l pl a s ma or puri fi ed concentra te) a nd a nti coa gul a ti on wi th hepa ri n.
Protein S Deficiency
Protei n S, a vi ta mi n K-dependent protei n, i s a cofa ctor for APC-medi a ted cl ea va ge of fa ctors Va a nd VIIIa . Heterozygous defi ci ency of pl a s ma
protei n S predi s pos es to venous thrombos i s a nd i s s i mi l a r to protei n C defi ci ency i n geneti c tra ns mi s s i on, preva l ence, l a bora tory tes ti ng,
trea tment, a nd preca uti ons . Homozygous defi ci ency of protei n S ca n ca us e neona ta l purpura ful mi na ns tha t i s cl i ni ca l l y i ndi s ti ngui s ha bl e from
tha t ca us ed by homozygous defi ci ency of protei n C. Acqui red defi ci enci es of protei n S (a nd protei n C) occur duri ng DIC a nd wa rfa ri n thera py a nd
a fter L-a s pa ra gi na s e a dmi ni s tra ti on.
Di a gnos i s i s ba s ed on a nti geni c a s s a ys of tota l or free pl a s ma protei n S. (Free protei n S i s the form unbound to C4 bi ndi ng protei n.)
Protein Z Deficiency
Protei n Z, a nother vi ta mi n K-dependent protei n, functi ons a s a cofa ctor to down-regul a te coa gul a ti on by formi ng a compl ex wi th the pl a s ma
protei n, Z-dependent protea s e i nhi bi tor (ZPI). The compl ex i na cti va tes fa ctors Xa , XI, a nd IX on phos phol i pi ds s urfa ces . The cons equence of ei ther
protei n Z or ZPI defi ci ency i n the pa thophys i ol ogy of thrombos i s a nd feta l l os s i s unres ol ved; however, ei ther defect ma y ma ke thrombos i s more
l i kel y i f a n a ffected pa ti ent a l s o ha s a nother congeni ta l coa gul a ti on a bnorma l i ty (eg, fa ctor V Lei den). Qua nti fi ca ti on of protei n Z a nd ZPI i s done
i n res ea rch l a bora tori es by pl a s ma el ectrophores i s a nd i mmunobl otti ng. It i s not yet known whether a nti coa gul a nt thera py or prophyl a xi s i s
i ndi ca ted i n protei n Z or ZPI defi ci ency.
Antithrombin Deficiency
Anti thrombi n i s a protei n tha t i nhi bi ts thrombi n a nd fa ctors Xa , IXa , a nd XIa . Heterozygous defi ci ency of pl a s ma a nti thrombi n ha s a preva l ence of
a bout 0.2 to 0.4%; a bout ha l f of thos e a ffected devel op venous thrombos es . Homozygous defi ci enci es a re proba bl y l etha l to the fetus i n utero.
Acqui red defi ci enci es occur i n pa ti ents wi th DIC, l i ver di s ea s e, or nephroti c s yndrome a nd duri ng hepa ri n or L-a s pa ra gi na s e thera py.
La bora tory tes ti ng i nvol ves qua nti fi ca ti on of pl a s ma i nhi bi ti on of thrombi n i n the pres ence of hepa ri n.
Ora l wa rfa ri n i s us ed for prophyl a xi s a ga i ns t venous thromboembol i s m.
Prothrombin 20210 Gene Mutation
A muta ti on of the prothrombi n 20210 gene res ul ts i n i ncrea s ed pl a s ma prothrombi n l evel s a nd i ncrea s es the ri s k of venous thromboembol i s m.
Trea tment, i f neces s a ry, i nvol ves a nti coa gul a ti on wi th hepa ri n fol l owed by wa rfa ri n.
Antiphospholipid Antibody Syndrome
(Anti -Ca rdi ol i pi n Anti bodi es ; Lupus Anti coa gul a nt)
The a nti phos phol i pi d a nti body s yndrome cons i s ts of thrombos i s a nd (i n pregna ncy) feta l demi s e a s s oci a ted wi th va ri ous a utoi mmune a nti bodi es
di rected a ga i ns t one or more phos phol i pi d-bi ndi ng protei ns (eg, 2 -gl ycoprotei n I, prothrombi n, a nnexi n). Thes e protei ns norma l l y bi nd to
phos phol i pi d membra ne cons ti tuents a nd protect them from exces s i ve coa gul a ti on a cti va ti on. The a utoa nti bodi es di s pl a ce the protecti ve
protei ns a nd, thus , produce procoa gul a nt endothel i a l cel l s urfa ces a nd ca us e a rteri a l or venous thrombos es . In vi tro cl otti ng tes ts ma y
pa ra doxi ca l l y be prol onged beca us e the a nti protei n/phos phol i pi d a nti bodi es i nterfere wi th coa gul a ti on fa ctor a s s embl y a nd a cti va ti on on the
phos phol i pi d components a dded to pl a s ma to i ni ti a te the tes ts . The l upus a nti coa gul a nt i s a n a nti phos phol i pi d a utoa nti body tha t bi nds to
protei n-phos phol i pi d compl exes . It wa s i ni ti a l l y recogni zed i n pa ti ents wi th SLE, but thes e pa ti ents now a ccount for a mi nori ty of pa ti ents wi th
the a utoa nti body.
The l upus a nti coa gul a nt i s s us pected i f the PTT i s prol onged a nd does not correct i mmedi a tel y upon 1:1 mi xi ng wi th norma l pl a s ma but does
return to norma l upon the a ddi ti on of a n exces s i ve qua nti ty of phos phol i pi ds (done by the hema tol ogy l a bora tory). Anti phos phol i pi d a nti bodi es
i n pa ti ent pl a s ma a re mea s ured by i mmunoa s s a ys of IgG a nd IgM a nti bodi es tha t bi nd to phos phol i pi d-2 -gl ycoprotei n I compl exes on mi croti ter
pl a tes .
Hepa ri n, wa rfa ri n, a nd a s pi ri n ha ve been us ed for prophyl a xi s a nd trea tment.
Hyperhomocysteinemia
Hyperhomocys tei nemi a ma y predi s pos e to a rteri a l thrombos i s a nd venous thromboembol i s m, pos s i bl y beca us e of i njury to va s cul a r endothel i a l
cel l s . Pl a s ma homocys tei ne l evel s a re el eva ted 10-fol d i n homozygous cys ta thi oni ne -s yntha s e defi ci ency. Mi l der el eva ti ons occur i n
heterozygous defi ci ency a nd i n other a bnorma l i ti es of fol a te meta bol i s m, i ncl udi ng methyl tetra hydrofol a te dehydrogena s e defi ci ency. However,
by fa r the mos t common ca us es of hyperhomocys tei nemi a a re a cqui red defi ci enci es of fol a te, vi ta mi n B 12 , or vi ta mi n B 6 .
The di a gnos i s i s es ta bl i s hed by mea s uri ng pl a s ma homocys tei ne l evel s .
Pl a s ma homocys tei ne l evel s ma y be norma l i zed by di eta ry s uppl ementa ti on wi th fol i c a ci d, vi ta mi n B 12 , or vi ta mi n B 6 (pyri doxi ne) a l one or i n
combi na ti on; however, i t i s not cl ea r tha t thi s thera py reduces the ri s k of a rteri a l or venous thrombos i s .
Chapter 111. Coagulation Disorders

Introduction
Abnorma l bl eedi ng ca n res ul t from di s orders of the coa gul a ti on s ys tem (s ee p. 963), of pl a tel ets , or of bl ood ves s el s . Di s orders of coa gul a ti on ca n
be a cqui red or heredi ta ry. The ma jor ca us es of a cqui red coa gul a ti on di s orders a re vi ta mi n K defi ci ency (s ee p. 46), l i ver di s ea s e, di s s emi na ted
i ntra va s cul a r coa gul a ti on, a nd devel opment of ci rcul a ti ng a nti coa gul a nts . Severe l i ver di s ea s e (eg, ci rrhos i s , ful mi na nt hepa ti ti s , a cute fa tty l i ver
of pregna ncy) ma y di s turb hemos ta s i s by i mpa i ri ng cl otti ng fa ctor s ynthes i s . Beca us e a l l coa gul a ti on fa ctors a re ma de i n the l i ver, both the PT a nd
PTT a re el eva ted i n s evere l i ver di s orders . (PT res ul ts a re typi ca l l y reported a s INR.) Occa s i ona l l y, decompens a ted l i ver di s ea s e a l s o ca us es
exces s i ve fi bri nol ys i s a nd bl eedi ng due to decrea s ed hepa ti c s ynthes i s of 2 -a nti pl a s mi n.
The mos t common heredi ta ry di s order of hemos ta s i s i s von Wi l l ebra nd's di s ea s e (s ee p. 962). The mos t common heredi ta ry coa gul a ti on di s orders
a re the hemophi l i a s .
Disseminated Intravascular Coagulation
(Cons umpti on Coa gul opa thy; Defi bri na ti on Syndrome)
Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process,
increased platelet aggregation and coagulation factor consumption occur. DIC that evolves slowly (over weeks or months) causes primarily venous thrombotic
and embolic manifestations; DIC that evolves rapidly (over hours or days) causes primarily bleeding. Severe, rapidly evolving DIC is diagnosed by demonstrating
thrombocytopenia, an elevated PTT and PT, increased levels of plasma D-dimer (or serum fibrin degradation products), and a decreasing plasma fibrinogen level.
Treatment includes correction of the cause and replacement of platelets, coagulation factors (in fresh frozen plasma), and fibrinogen (in cryoprecipitate) to control
severe bleeding. Heparin is used as therapy (or prophylaxis) in patients with slowly evolving DIC who have (or are at risk of) venous thromboembolism.
Etiology
DIC us ua l l y res ul ts from expos ure of ti s s ue fa ctor to bl ood, i ni ti a ti ng the coa gul a ti on ca s ca de (s ee
Fi g. 109-2). DIC occurs i n the fol l owi ng cl i ni ca l ci rcums ta nces :
Compl i ca ti ons of obs tetri cs (eg, a brupti o pl a centa e, s a l i ne-i nduced thera peuti c a borti on, reta i ned dea d fetus or products of concepti on,
a mni oti c fl ui d embol i s m): Pl a centa l ti s s ue wi th ti s s ue fa ctor a cti vi ty enters or i s expos ed to the ma terna l ci rcul a ti on.
Infecti on, pa rti cul a rl y wi th gra m-nega ti ve orga ni s ms : Gra m-nega ti ve endotoxi n ca us es genera ti on or expos ure of ti s s ue fa ctor a cti vi ty i n
pha gocyti c, endothel i a l , a nd ti s s ue cel l s .
Ca ncer, pa rti cul a rl y muci n-s ecreti ng a denoca rci noma s of the pa ncrea s a nd pros ta te a nd a cute promyel ocyti c l eukemi a : Tumor cel l s expres s or
rel ea s e ti s s ue fa ctor.
Shock due to a ny condi ti on tha t ca us es i s chemi c ti s s ue i njury a nd rel ea s e of ti s s ue fa ctor
Les s common ca us es of DIC i ncl ude s evere ti s s ue da ma ge from hea d tra uma , burns , fros tbi te, or guns hot wounds ; compl i ca ti ons of pros ta te
s urgery tha t a l l ow pros ta ti c ma teri a l wi th ti s s ue fa ctor a cti vi ty (a l ong wi th pl a s mi nogen a cti va tors ) to enter the ci rcul a ti on; venomous s na ke bi tes
i n whi ch enzymes enter the ci rcul a ti on, a cti va te one or s evera l coa gul a ti on fa ctors , a nd ei ther genera te thrombi n or di rectl y convert fi bri nogen to
fi bri n; profound i ntra va s cul a r hemol ys i s ; a nd a orti c a neurys ms or ca vernous hema ngi oma s (Ka s a ba ch-Merri tt s yndrome) a s s oci a ted wi th ves s el
wa l l da ma ge a nd a rea s of bl ood s ta s i s .
Pathophysiology
Slowly evolving DIC pri ma ri l y ca us es venous thromboembol i c ma ni fes ta ti ons (eg, deep venous thrombos i s , pul mona ry embol i s m), a l though
occa s i ona l l y ca rdi a c va l ve vegeta ti ons occur; a bnorma l bl eedi ng i s uncommon.
Severe, rapidly evolving DIC, i n contra s t, ca us es thrombocytopeni a a nd depl eti on of pl a s ma cl otti ng fa ctors a nd fi bri nogen, whi ch ca us e bl eedi ng.
Bl eedi ng i nto orga ns , a l ong wi th mi crova s cul a r thrombos es , ma y ca us e dys functi on a nd fa i l ure i n mul ti pl e orga ns . Del a yed di s s ol uti on of fi bri n
pol ymers by fi bri nol ys i s ma y res ul t i n the mecha ni ca l di s rupti on of RBCs , produci ng s chi s tocytes a nd mi l d i ntra va s cul a r hemol ys i s (s ee p. 961).
Symptoms and Signs
In s l owl y evol vi ng DIC, s ymptoms of venous thrombos i s (s ee p. 2224) a nd pul mona ry embol i s m (s ee p. 1908) ma y be pres ent.
In s evere, ra pi dl y evol vi ng DIC, s ki n puncture s i tes (eg, IV or a rteri a l punctures ) bl eed pers i s tentl y, ecchymos es form a t s i tes of pa rentera l
i njecti ons , a nd s eri ous GI bl eedi ng ma y occur.
Diagnosis
Pl a tel et count, PT, PTT, pl a s ma fi bri nogen, pl a s ma D-di mer
DIC i s s us pected i n pa ti ents wi th unexpl a i ned bl eedi ng or venous thromboembol i s m, es peci a l l y i f a predi s pos i ng condi ti on exi s ts . If DIC i s
s us pected, pl a tel et count, PT, PTT, pl a s ma fi bri nogen l evel , a nd pl a s ma D-di mer l evel (a n i ndi ca ti on of i n vi vo fi bri n depos i ti on a nd degra da ti on)
a re obta i ned.
Sl owl y evol vi ng DIC produces mi l d thrombocytopeni a , a norma l to mi ni ma l l y prol onged PT (res ul ts a re typi ca l l y reported a s INR) a nd PTT, a norma l
or modera tel y reduced fi bri nogen l evel , a nd a n i ncrea s ed pl a s ma D-di mer l evel . Beca us e va ri ous di s orders s ti mul a te i ncrea s ed s ynthes i s of
fi bri nogen a s a n a cute-pha s e rea cta nt, a decl i ni ng fi bri nogen l evel on 2 cons ecuti ve mea s urements ca n hel p ma ke the di a gnos i s of DIC. Ini ti a l
PTT va l ues i n s l owl y evol vi ng DIC ma y a ctua l l y be s horter tha n norma l , proba bl y beca us e of the pres ence of a cti va ted coa gul a ti on fa ctors i n the
pl a s ma .
Severe, ra pi dl y evol vi ng DIC res ul ts i n more s evere thrombocytopeni a , more prol onged PT a nd PTT, a ra pi dl y decl i ni ng pl a s ma fi bri nogen l evel , a nd
a hi gh pl a s ma D-di mer l evel .
A fa ctor VIII l evel ca n s ometi mes be hel pful i f s evere, a cute DIC mus t be di fferenti a ted from ma s s i ve hepa ti c necros i s , whi ch ca n ca us e s i mi l a r
a bnorma l i ti es i n coa gul a ti on s tudi es . The fa ctor VIII l evel i s el eva ted i n hepa ti c necros i s , beca us e fa ctor VIII i s ma de i n hepa tocytes a nd
rel ea s ed a s they a re des troyed; fa ctor VIII i s reduced i n DIC beca us e of the thrombi n-i nduced genera ti on of a cti va ted protei n C, whi ch proteol ys es
fa ctor VIII.
Treatment
Pos s i bl y repl a cement thera py (eg, pl a tel ets , cryopreci pi ta te, fres h frozen pl a s ma , na tura l a nti coa gul a nts )
Someti mes hepa ri n
Immedi a te correcti on of the ca us e i s the pri ori ty (eg, broa d-s pectrum a nti bi oti c trea tment of s us pected gra m-nega ti ve s eps i s , eva cua ti on of the
uterus i n a brupti o pl a centa e). If trea tment i s effecti ve, DIC s houl d s ubs i de qui ckl y. If bl eedi ng i s s evere, a djuncti ve repl a cement thera py i s
i ndi ca ted, cons i s ti ng of pl a tel et concentra tes to correct thrombocytopeni a ; cryopreci pi ta te to repl a ce fi bri nogen a nd fa ctor VIII; a nd fres h frozen
pl a s ma to i ncrea s e l evel s of other cl otti ng fa ctors a nd na tura l a nti coa gul a nts (a nti thrombi n, protei ns C, S, a nd Z). The effecti venes s of i nfus i on of
concentra tes of a nti thrombi n or a cti va ted protei n C i n s evere, ra pi dl y evol vi ng DIC i s unres ol ved.
Hepa ri n i s us eful i n the trea tment of s l owl y evol vi ng DIC wi th venous thrombos i s or pul mona ry embol i s m. Hepa ri n us ua l l y i s not i ndi ca ted i n
ra pi dl y evol vi ng DIC wi th bl eedi ng or bl eedi ng ri s k, except i n women wi th a reta i ned dea d fetus a nd evol vi ng DIC wi th a progres s i ve decrea s e i n
pl a tel ets , fi bri nogen, a nd coa gul a ti on fa ctors . In thes e pa ti ents , hepa ri n i s a dmi ni s tered for s evera l da ys to control DIC, i ncrea s e fi bri nogen a nd
pl a tel et l evel s , a nd decrea s e exces s i ve coa gul a ti on fa ctor cons umpti on. Hepa ri n i s then s topped a nd the uterus eva cua ted.
Hemophilia
Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the
probability and severity of bleeding. Bleeding into deep tissues or joints usually develops within hours of trauma. The diagnosis is suspected in a patient with an
elevated PTT and normal PT and platelet count; it is confirmed by specific factor assays. Treatment includes replacement of the deficient factor if acute bleeding
is suspected, confirmed, or likely to develop (eg, before surgery).
Hemophi l i a A (fa ctor VIII defi ci ency), whi ch a ffects a bout 80% of pa ti ents wi th hemophi l i a , a nd hemophi l i a B (fa ctor IX defi ci ency) ha ve i denti ca l
cl i ni ca l ma ni fes ta ti ons , s creeni ng tes t a bnorma l i ti es , a nd X-l i nked geneti c tra ns mi s s i on. Speci fi c fa ctor a s s a ys a re requi red to di s ti ngui s h the
two.
Etiology
Hemophi l i a i s a n i nheri ted di s order tha t res ul ts from muta ti ons , del eti ons , or i nvers i ons a ffecti ng a fa ctor VIII or fa ctor IX gene. Beca us e thes e
genes a re l oca ted on the X chromos ome, hemophi l i a a ffects ma l es a l mos t excl us i vel y. Da ughters of men wi th hemophi l i a a re obl i ga te ca rri ers ,
but s ons a re norma l . Ea ch s on of a ca rri er ha s a 50% cha nce of ha vi ng hemophi l i a , a nd ea ch da ughter ha s a 50% cha nce of bei ng a ca rri er.
Pathophysiology
Norma l hemos ta s i s requi res > 30% of norma l fa ctor VIII a nd IX l evel s . Mos t pa ti ents wi th hemophi l i a ha ve l evel s < 5%. Ca rri ers us ua l l y ha ve l evel s
of a bout 50%; ra rel y, ra ndom i na cti va ti on of thei r norma l X chromos ome i n ea rl y embryoni c l i fe res ul ts i n a ca rri er ha vi ng fa ctor VIII or IX l evel s of <
30%.
Mos t pa ti ents wi th hemophi l i a who were trea ted wi th pl a s ma concentra tes i n the ea rl y 1980s were i nfected wi th HIV due to conta mi na ted fa ctor
concentra tes . Occa s i ona l pa ti ents devel oped i mmune thrombocytopeni a s econda ry to HIV i nfecti on, whi ch exa cerba ted bl eedi ng.
Symptoms and Signs
Pa ti ents wi th hemophi l i a bl eed i nto ti s s ues (eg, hema rthros es , mus cl e hema toma s , retroperi tonea l hemorrha ge). The bl eedi ng ma y be
i mmedi a te or occur s l owl y, dependi ng on the extent of tra uma a nd pl a s ma l evel of fa ctor VIII or IX. Pa i n often occurs a s bl eedi ng commences ,
s ometi mes before other s i gns of bl eedi ng devel op. Chroni c or recurrent hema rthros es ca n l ea d to s ynovi ti s a nd a rthropa thy. Even a tri vi a l bl ow to
the hea d ca n ca us e i ntra cra ni a l bl eedi ng. Bl eedi ng i nto the ba s e of the tongue ca n ca us e l i fe-threa teni ng a i rwa y compres s i on.
Severe hemophi l i a (fa ctor VIII or IX l evel < 1% of norma l ) ca us es s evere bl eedi ng throughout l i fe, us ua l l y begi nni ng s oon a fter bi rth (eg, s ca l p
hema toma a fter del i very or exces s i ve bl eedi ng a fter ci rcumci s i on). Modera te hemophi l i a (fa ctor l evel s 1 to 5% of norma l ) us ua l l y ca us es bl eedi ng
a fter mi ni ma l tra uma . In mi l d hemophi l i a (fa ctor l evel s 5 to 25% of norma l ), exces s i ve bl eedi ng ma y occur a fter s urgery or denta l extra cti on.
Diagnosis
Pl a tel et count, PT, PTT, fa ctor VIII a nd IX a s s a ys
Someti mes von Wi l l ebra nd's fa ctor a cti vi ty a nd a nti gen a nd mul ti mer compos i ti on
Hemophi l i a i s s us pected i n pa ti ents wi th recurrent bl eedi ng, unexpl a i ned hema rthros es , or a prol onga ti on of the PTT. If hemophi l i a i s s us pected,
PTT, PT, pl a tel et count, a nd fa ctor VIII a nd IX a s s a ys a re obta i ned. In hemophi l i a , the PTT i s prol onged, but the PT a nd pl a tel et count a re norma l .
Fa ctor VIII a nd IX a s s a ys determi ne the type a nd s everi ty of the hemophi l i a . Beca us e fa ctor VIII l evel s ma y a l s o be reduced i n von Wi l l ebra nd's
di s ea s e (VWD), von Wi l l ebra nd's fa ctor (VWF) a cti vi ty, a nti gen, a nd mul ti mer compos i ti on a re mea s ured i n pa ti ents wi th newl y di a gnos ed
hemophi l i a A, pa rti cul a rl y i f the di s order i s mi l d a nd a fa mi l y hi s tory i ndi ca tes tha t both ma l e a nd fema l e fa mi l y members a re a ffected.
Determi ni ng i f a fema l e i s a true ca rri er of hemophi l i a A i s s ometi mes pos s i bl e by mea s uri ng the fa ctor VIII l evel . Si mi l a rl y, mea s uri ng the fa ctor
IX l evel often i denti fi es a ca rri er of hemophi l i a B. PCR a na l ys i s of DNA tha t compri s es the fa ctor VIII gene, a va i l a bl e a t s peci a l i zed centers , ca n be
us ed for di a gnos i s of the hemophi l i a A ca rri er s ta te a nd for prena ta l di a gnos i s of hemophi l i a A by chori oni c vi l l us s a mpl i ng a t 12 wk or
a mni ocentes i s a t 16 wk. Thes e procedures ca rry a 0.5 to 1% ri s k of mi s ca rri a ge.
After repea ted expos ure to fa ctor VIII repl a cement, a bout 15 to 35% of pa ti ents wi th hemophi l i a A devel op fa ctor VIII i s oa nti bodi es
(a l l oa nti bodi es ) tha t i nhi bi t the coa gul a nt a cti vi ty of a ny a ddi ti ona l fa ctor VIII i nfus ed. Pa ti ents s houl d be s creened for i s oa nti bodi es (eg, by
mea s uri ng the degree of PTT s horteni ng i mmedi a tel y a fter mi xi ng the pa ti ent's pl a s ma wi th a n equa l vol ume of norma l pl a s ma , a nd then by
repea ti ng the mea s urement a fter i ncuba ti on for 1 h), es peci a l l y before a n el ecti ve procedure tha t requi res repl a cement thera py. If i s oa nti bodi es
a re pres ent, thei r ti ters ca n be mea s ured by determi ni ng the extent of fa ctor VIII i nhi bi ti on by s eri a l di l uti ons of pa ti ent pl a s ma .
Treatment
Repl a cement of defi ci ent fa ctor
Someti mes a nti fi bri nol yti cs
If s ymptoms s ugges t bl eedi ng, trea tment s houl d begi n i mmedi a tel y, even before di a gnos ti c tes ts a re compl eted. For exa mpl e, trea tment for
hea da che tha t mi ght i ndi ca te i ntra cra ni a l hemorrha ge s houl d begi n before a CT s ca n i s compl eted.
Repl a cement of the defi ci ent fa ctor i s the pri ma ry trea tment. In hemophi l i a A, the fa ctor VIII l evel s houl d be ra i s ed tra ns i entl y to
About 30% of norma l to prevent bl eedi ng a fter denta l extra cti on or to a bort a n i nci pi ent joi nt hemorrha ge
50% of norma l i f s evere joi nt or IM bl eedi ng i s a l rea dy evi dent
100% of norma l before ma jor s urgery or i f bl eedi ng i s i ntra cra ni a l , i ntra ca rdi a c, or otherwi s e l i fe threa teni ng
Repea ted i nfus i ons a t 50% of the i ni ti a l ca l cul a ted dos e s houl d then be gi ven every 8 to 12 h to keep trough l evel s a bove 50% for 7 to 10 da ys a fter
ma jor s urgery or l i fe-threa teni ng hemorrha ge. Ea ch uni t/kg of fa ctor VIII i ncrea s es the fa ctor VIII l evel by a bout 2%. Thus , to i ncrea s e the l evel from
0% to 50%, a bout 25 uni ts /kg a re requi red.
Fa ctor VIII ca n be gi ven a s puri fi ed fa ctor VIII concentra te, whi ch i s deri ved from mul ti pl e donors . It undergoes vi ra l i na cti va ti on, but i na cti va ti on
ma y not el i mi na te pa rvovi rus or hepa ti ti s A. Recombi na nt fa ctor VIII i s free of vi rus es a nd i s us ua l l y preferred unl es s pa ti ents a re a l rea dy
s eropos i ti ve for HIV or for hepa ti ti s B or C vi rus .
In hemophi l i a B, fa ctor IX ca n be gi ven a s a puri fi ed or recombi na nt vi ra l -i na cti va ted product every 24 h. The ta rget l evel s of fa ctor correcti on a re
the s a me a s i n hemophi l i a A. However, to a chi eve thes e l evel s , the dos e mus t be hi gher tha n i n hemophi l i a A beca us e fa ctor IX i s s ma l l er tha n
fa ctor VIII a nd, i n contra s t to VIII, ha s a n extens i ve extra va s cul a r di s tri buti on.
Fres h frozen pl a s ma conta i ns fa ctors VIII a nd IX. However, unl es s pl a s ma excha nge i s done, s uffi ci ent whol e pl a s ma us ua l l y ca nnot be gi ven to
pa ti ents wi th s evere hemophi l i a to ra i s e fa ctor VIII or IX to l evel s tha t prevent or control bl eedi ng. Fres h frozen pl a s ma s houl d, therefore, be us ed
onl y i f ra pi d repl a cement thera py i s neces s a ry a nd fa ctor concentra te i s una va i l a bl e or the pa ti ent ha s a coa gul opa thy tha t i s not yet defi ned
preci s el y.
In pa ti ents wi th hemophi l i a who devel op a fa ctor VIII i nhi bi tor, trea tment i s bes t a ccompl i s hed us i ng recombi na nt fa ctor VIIa i n repea ted hi gh
dos es (eg, 90 g/kg).
Adjuncti ve thera pi es ma y i ncl ude des mopres s i n or a n a nti fi bri nol yti c drug. As des cri bed for VWD (s ee p. 963), des mopres s i n ma y tempora ri l y ra i s e
fa ctor VIII l evel s . The pa ti ent's res pons e s houl d be tes ted before des mopres s i n i s us ed thera peuti ca l l y. Its us e a fter mi nor tra uma or before
el ecti ve denta l s urgery ma y obvi a te repl a cement thera py. Des mopres s i n s houl d be us ed onl y for pa ti ents wi th mi l d hemophi l i a A (ba s a l fa ctor
VIII l evel s 5%) who ha ve demons tra ted res pons i venes s .
An a nti fi bri nol yti c a gent (-a mi noca proi c a ci d 2.5 to 4 g po qi d for 1 wk or tra nexa mi c a ci d 1.0 to 1.5 g po ti d or qi d for 1 wk) s houl d be gi ven to
prevent l a te bl eedi ng a fter denta l extra cti on or other oropha ryngea l mucos a l tra uma (eg, tongue l a cera ti on).
Prevention
Pa ti ents s houl d a voi d a s pi ri n a nd NSAIDs (both i nhi bi t pl a tel et functi on). Regul a r denta l ca re i s es s enti a l s o tha t tooth extra cti ons a nd other
denta l s urgery ca n be a voi ded. Drugs s houl d be gi ven ora l l y or IV; IM i njecti ons ca n ca us e hema toma s . Pa ti ents wi th hemophi l i a s houl d be
va cci na ted a ga i ns t hepa ti ti s B.
Coagulation Disorders Caused by Circulating Anticoagulants
Ci rcul a ti ng a nti coa gul a nts a re us ua l l y a utoa nti bodi es tha t neutra l i ze s peci fi c cl otti ng fa ctors i n vi vo (eg, a n a utoa nti body a ga i ns t fa ctor VIII or
fa ctor V) or i nhi bi t protei n-bound phos phol i pi d i n vi tro. Occa s i ona l l y, the l a tter type of a utoa nti body ca us es bl eedi ng i n vi vo by bi ndi ng
prothrombi n.
Ci rcul a ti ng a nti coa gul a nts s houl d be s us pected i n pa ti ents wi th exces s i ve bl eedi ng combi ned wi th ei ther a prol onged PTT or PT tha t does not
correct when the tes t i s repea ted wi th a 1:1 mi xture of norma l pl a s ma a nd the pa ti ent's pl a s ma .
Anti phos phol i pi d a nti bodi es (s ee p. 975) typi ca l l y ca us e thrombos i s . However, i n a s ubs et of pa ti ents , the a nti bodi es bi nd to prothrombi nphos phol i pi d compl exes a nd i nduce hypoprothrombi nemi a a nd bl eedi ng.
Factor VIII Anticoagulants
Is oa nti bodi es to fa ctor VIII devel op i n a bout 15 to 35% of pa ti ents wi th s evere hemophi l i a A a s a compl i ca ti on of repea ted expos ure to norma l
fa ctor VIII mol ecul es duri ng repl a cement thera py (s ee p. 978). Fa ctor VIII a utoa nti bodi es a l s o a ri s e occa s i ona l l y i n pa ti ents wi thout hemophi l i a ,
eg, i n pos tpa rtum women a s a ma ni fes ta ti on of a n underl yi ng s ys temi c a utoi mmune di s order or of tra ns i entl y di s ordered i mmune regul a ti on, or
i n el derl y pa ti ents wi thout overt evi dence of other underl yi ng di s orders . Pa ti ents wi th a fa ctor VIII a nti coa gul a nt ca n devel op l i fe-threa teni ng
hemorrha ge.
Pl a s ma conta i ni ng a fa ctor VIII a nti body ha s a prol onged PTT tha t does not correct when norma l pl a s ma or a nother s ource of fa ctor VIII i s a dded i n
a 1:1 mi xture to the pa ti ent's pl a s ma . Tes ti ng i s done i mmedi a tel y a fter mi xture a nd a ga i n a fter i ncuba ti on.
Thera py wi th cycl ophos pha mi de a nd corti cos teroi ds ma y s uppres s a utoa nti body producti on i n pa ti ents wi thout hemophi l i a . In pos tpa rtum
women, the a utoa nti bodi es ma y di s a ppea r s ponta neous l y. Ma na gement of a cute hemorrha ge i n pa ti ents wi th hemophi l i a who ha ve fa ctor VIII
i s oa nti bodi es or a utoa nti bodi es i s by recombi na nt fa ctor VIIa (s ee a bove).
Uncommon Hereditary Coagulation Disorders
Mos t heredi ta ry coa gul a ti on di s orders other tha n hemophi l i a a re ra re a utos oma l reces s i ve condi ti ons tha t ca us e di s ea s e onl y i n homozygous
peopl e (s ee
Ta bl e 111-1). Fa ctor XI defi ci ency i s uncommon i n the genera l popul a ti on but common i n des cenda nts of Europea n Jews (gene frequency a bout 5 to
9%). Bl eedi ng typi ca l l y occurs a fter s i gni fi ca nt i njuri es , i ncl udi ng tra uma or s urgery, i n peopl e who a re homozygotes or compound heterozygotes .
Severe defi ci ency of 2 -a nti pl a s mi n (1 to 3% of norma l ), the ma jor phys i ol ogi c i nhi bi tor of pl a s mi n, ca n a l s o ca us e bl eedi ng. Di a gnos i s
[Table 111-1. Screeni ng La bora tory Tes t Res ul ts i n Inheri ted Defects i n Bl ood Coa gul a ti on]
i s ba s ed on a s peci fi c 2 -a nti pl a s mi n a s s a y. -Ami noca proi c a ci d or tra nexa mi c a ci d i s us ed to control or prevent a cute bl eedi ng. Heterozygous
peopl e wi th 2 -a nti pl a s mi n l evel s of 40 to 60% of norma l ca n occa s i ona l l y experi ence exces s i ve s urgi ca l bl eedi ng i f s econda ry fi bri nol ys i s i s
extens i ve (eg, i n pa ti ents who ha ve ha d open pros ta tectomy).
Chapter 112. Bleeding Due to Abnormal Blood Vessels

Introduction
Bl eedi ng ma y res ul t from a bnorma l i ti es i n pl a tel ets , coa gul a ti on fa ctors , or bl ood ves s el s . Va s cul a r bl eedi ng di s orders res ul t from defects i n
bl ood ves s el s , typi ca l l y ca us i ng petechi a e, purpura , a nd brui s i ng but s el dom l ea di ng to s eri ous bl ood l os s . Bl eedi ng ma y res ul t from defi ci enci es
of va s cul a r a nd peri va s cul a r col l a gen i n Ehl ers -Da nl os s yndrome a nd i n other ra re heredi ta ry connecti ve ti s s ue di s orders (eg, ps eudoxa nthoma
el a s ti cum, os teogenes i s i mperfecta , Ma rfa n s yndromes ee p. 2908). Hemorrha ge ma y be a promi nent fea ture of s curvy (s ee p. 40) or of HenochSchonl ei n purpura , a hypers ens i ti vi ty va s cul i ti s common duri ng chi l dhood (s ee p. 321). In va s cul a r bl eedi ng di s orders , tes ts of hemos ta s i s a re
us ua l l y norma l . Di a gnos i s i s cl i ni ca l .
Autoerythrocyte Sensitization
(Ga rdner-Di a mond Syndrome)
Autoerythrocyte sensitization is a rare disorder affecting women. It is characterized by local pain and burning preceding painful ecchymoses that occur primarily
on the extremities.
Autoerythrocyte s ens i ti za ti on typi ca l l y occurs i n whi te women who a re experi enci ng emoti ona l s tres s or who ha ve concomi ta nt ps ychol ogi c i l l nes s .
Epi s odes of ecchymos i s a re pa i nful a nd ca n occur s ponta neous l y or a fter tra uma or s urgery. Brui s i ng ca n occur on di fferent s i tes of the body from
where the tra uma occurs . Tes ts of the coa gul a ti on s ys tem a re norma l .
In women wi th a utoerythrocyte s ens i ti za ti on, i ntra derma l i njecti on of 0.1 mL of a utol ogous RBCs or RBC s troma ma y res ul t i n pa i n, s wel l i ng, a nd
i ndura ti on a t the i njecti on s i te. Thi s res ul t s ugges ts tha t es ca pe of RBCs i nto the ti s s ues i s i nvol ved i n the pa thogenes i s of the l es i on. However,
mos t pa ti ents a l s o ha ve a s s oci a ted s evere ps ychoneuroti c s ymptoms . In a ddi ti on, ps ychogeni c fa ctors , s uch a s s el f-i nduced purpura , s eem rel a ted
to the pa thogenes i s of the s yndrome i n s ome pa ti ents .
Di a gnos i s i s ba s ed on exa mi na ti on of the s i te of i ntra derma l i njecti on of a utol ogous RBCs a nd of a s epa ra te control i njecti on s i te (wi thout RBCs )
24 to 48 h a fter i njecti on. Excori a ti on, whi ch ca n compl i ca te the tes t's i nterpreta ti on, i s prevented by ma ki ng both s i tes di ffi cul t for the pa ti ent to
rea ch. Trea tment i s ps ychi a tri c i nterventi on a nd thera py.
Dysproteinemias Causing Vascular Purpura
Conditions that cause an abnormal protein content in the blood, typically in the form of immunoglobulins, can affect vascular fragility and lead to purpura.
Amyloidosis (s ee p. 905) ca us es a myl oi d depos i ti on wi thi n ves s el s i n the s ki n a nd s ubcuta neous ti s s ues , whi ch ma y i ncrea s e va s cul a r fra gi l i ty,
produci ng purpura . In s ome pa ti ents , coa gul a ti on fa ctor X i s a ds orbed by a myl oi d a nd becomes defi ci ent, but thi s defi ci ency i s us ua l l y not the
ca us e of bl eedi ng. Peri orbi ta l purpura or a purpuri c ra s h tha t devel ops i n a nonthrombocytopeni c pa ti ent a fter gentl e s troki ng of the s ki n s ugges ts
a myl oi dos i s .
Cryoglobulinemia produces i mmunogl obul i ns tha t preci pi ta te when pl a s ma i s cool ed (i e, cryogl obul i ns ) whi l e fl owi ng through the s ki n a nd
s ubcuta neous ti s s ues of the extremi ti es . Monocl ona l i mmunogl obul i ns formed i n Wa l dens trom's ma crogl obul i nemi a or i n mul ti pl e myel oma
(s ee p. 1029) occa s i ona l l y beha ve a s cryogl obul i ns , a s ma y mi xed IgMI-gG i mmune compl exes formed i n s ome chroni c i nfecti ous di s ea s es , mos t
commonl y hepa ti ti s C. Cryogl obul i nemi a ca n l ea d to s ma l l -ves s el va s cul i ti s , whi ch ca n ca us e purpura . Cryogl obul i ns ca n be detected by l a bora tory
tes ti ng.
Hypergammaglobulinemic purpura i s a va s cul i ti c purpura tha t pri ma ri l y a ffects women. Recurrent crops of s ma l l , pa l pa bl e purpuri c l es i ons devel op
on the l ower l egs . Thes e l es i ons l ea ve s ma l l res i dua l brown s pots . Ma ny pa ti ents ha ve ma ni fes ta ti ons of a n underl yi ng i mmunol ogi c di s order
(eg, Sjogren's s yndrome, SLE). The di a gnos ti c fi ndi ng i s a pol ycl ona l i ncrea s e i n IgG (broa d-ba s ed or di ffus e hyperga mma gl obul i nemi a on s erum
protei n el ectrophores i s ).
Hyperviscosity syndrome (s ee p. 1027) res ul ti ng from a ma rkedl y el eva ted pl a s ma IgM concentra ti on ma y a l s o res ul t i n purpura a nd other forms of
a bnorma l bl eedi ng (eg, profus e epi s ta xi s ) i n pa ti ents wi th Wa l dens trom's ma crogl obul i nemi a .
Hereditary Hemorrhagic Telangiectasia
(Rendu-Os l er-Weber Syndrome)
Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women.
Symptoms and Signs
The mos t cha ra cteri s ti c l es i ons a re s ma l l red-to-vi ol et tel a ngi ecta ti c l es i ons on the fa ce, l i ps , ora l a nd na s a l mucos a , a nd ti ps of the fi ngers a nd
toes (s ee
Pl a te 56). Si mi l a r l es i ons ma y be pres ent throughout the mucos a of the GI tra ct, res ul ti ng i n recurrent GI bl eedi ng. Pa ti ents ma y experi ence
recurrent, profus e nos ebl eeds . Some pa ti ents ha ve pul mona ry a rteri ovenous fi s tul a s . Thes e fi s tul a s ma y ca us e s i gni fi ca nt ri ght-to-l eft s hunts ,
whi ch ca n res ul t i n dys pnea , fa ti gue, cya nos i s , or pol ycythemi a . However, the fi rs t s i gn of thei r pres ence ma y be a bra i n a bs ces s , tra ns i ent
i s chemi c a tta ck, or s troke a s a res ul t of i nfected or noni nfected embol i . Cerebra l or s pi na l a rteri ovenous ma l forma ti ons occur i n s ome fa mi l i es
a nd ma y ca us e s uba ra chnoi d hemorrha ge, s ei zures , or pa ra pl egi a .
Diagnosis
Someti mes endos copy or a ngi ogra phy
Di a gnos i s i s ba s ed on the fi ndi ng of cha ra cteri s ti c a rteri ovenous ma l forma ti ons on the fa ce, mouth, nos e, a nd di gi ts . Endos copy or a ngi ogra phy i s
s ometi mes needed, however. La bora tory fi ndi ngs a re us ua l l y norma l except for i ron defi ci ency a nemi a i n mos t pa ti ents .
Screening: If a fa mi l y hi s tory of pul mona ry or cerebra l a rteri ovenous ma l forma ti ons exi s ts , s creeni ng a t puberty a nd a t the end of a dol es cence wi th
pul mona ry CT or cerebra l MRI i s recommended.
Treatment
Someti mes l a s er a bl a ti on, s urgi ca l res ecti on, or embol othera py
Suppl ementa l i ron thera py
Pos s i bl y bl ood tra ns fus i ons
Trea tment for mos t pa ti ents i s s upporti ve, but a cces s i bl e tel a ngi ecta s es (eg, i n the nos e or GI tra ct vi a endos copy) ma y be trea ted wi th l a s er
a bl a ti on. Arteri ovenous fi s tul a s ma y be trea ted by s urgi ca l res ecti on or embol othera py. Repea ted bl ood tra ns fus i ons ma y be needed; therefore,
i mmuni za ti on wi th hepa ti ti s B va cci ne i s i mporta nt. Mos t pa ti ents requi re conti nuous i ron thera py to repl a ce i ron l os t i n repea ted mucos a l
bl eedi ng; s ome pa ti ents requi re pa rentera l i ron (s ee Iron Defi ci ency Anemi a on p. 924). Trea tment wi th drugs tha t i nhi bi t fi bri nol ys i s , s uch a s
a mi noca proi c a ci d, ma y be benefi ci a l .
Purpura Simplex
(Ea s y Brui s i ng)
Purpura simplex is increased bruising that results from vascular fragility.
Purpura s i mpl ex i s extremel y common. The ca us e a nd mecha ni s m a re unknown; i t ma y repres ent a heterogeneous group of di s orders or merel y a
va ri a ti on of norma l .
The di s order us ua l l y a ffects women. Brui s es devel op on the thi ghs , buttocks , a nd upper a rms i n peopl e wi thout known tra uma . The hi s tory us ua l l y
revea l s no other a bnorma l bl eedi ng, but ea s y brui s i ng ma y be pres ent i n fa mi l y members . Seri ous bl eedi ng does not occur. The pl a tel et count a nd
tes ts of pl a tel et functi on, bl ood coa gul a ti on, a nd fi bri nol ys i s a re norma l .
No drug prevents the brui s i ng; pa ti ents a re often a dvi s ed to a voi d a s pi ri n a nd a s pi ri n-conta i ni ng drugs , but there i s no evi dence tha t brui s i ng i s
rel a ted to or wors ened by thei r us e. Pa ti ents s houl d be rea s s ured tha t the condi ti on i s not s eri ous .
Senile Purpura
Senile purpura causes ecchymoses and results from increased vessel fragility due to connective tissue damage to the dermis caused by chronic sun exposure and
aging.
Seni l e purpura typi ca l l y a ffects el derl y pa ti ents a s thei r derma l ti s s ues a trophy a nd bl ood ves s el s become more fra gi l e. Pa ti ents devel op
pers i s tent da rk purpl e ecchymos es , whi ch a re cha ra cteri s ti ca l l y confi ned to the extens or s urfa ces of the ha nds a nd forea rms . New l es i ons a ppea r
wi thout known tra uma a nd then res ol ve over s evera l da ys , l ea vi ng a browni s h di s col ora ti on ca us ed by depos i ts of hemos i deri n; thi s di s col ora ti on
ma y cl ea r over weeks to months or ma y be perma nent. The s ki n a nd s ubcuta neous ti s s ue of the i nvol ved a rea often a ppea r thi nned a nd a trophi c.
No trea tment ha s tens l es i on res ol uti on or i s needed. Al though cos meti ca l l y di s pl ea s i ng, the di s order ha s no hea l th cons equences .
Chapter 113. Spleen Disorders

Introduction
By s tructure a nd functi on the s pl een i s l i ke 2 orga ns . The whi te pul p, cons i s ti ng of peri a rteri a l l ympha ti c s hea ths a nd germi na l centers , a cts a s a n
i mmune orga n. The red pul p, cons i s ti ng of ma cropha ges a nd gra nul ocytes l i ni ng va s cul a r s pa ces (the cords a nd s i nus oi ds ), a cts a s a pha gocyti c
orga n.
The whi te pul p i s a s i te of producti on a nd ma tura ti on of B a nd T cel l s . B cel l s i n the s pl een genera te protecti ve humora l a nti bodi es ; i n certa i n
a utoi mmune di s orders (eg, i mmune thrombocytopeni c purpura [ITP], Coombs '-pos i ti ve i mmune hemol yti c a nemi a s ), i na ppropri a te a utoa nti bodi es
to ci rcul a ti ng bl ood el ements a l s o ma y be s ynthes i zed.
The red pul p removes a nti body-coa ted ba cteri a , s enes cent or defecti ve RBCs , a nd a nti body-coa ted bl ood cel l s (a s ma y occur i n i mmune cytopeni a s
s uch a s ITP, Coombs '-pos i ti ve hemol yti c a nemi a s , a nd s ome neutropeni a s ). The red pul p a l s o s erves a s a res ervoi r for bl ood el ements , es peci a l l y
WBCs a nd pl a tel ets . Duri ng i ts cul l i ng a nd pi tti ng of RBCs , the s pl een removes i ncl us i on bodi es , s uch a s Hei nz bodi es (preci pi ta tes of i ns ol ubl e
gl obi n), Howel l -Jol l y bodi es (nucl ea r fra gments ), a nd whol e nucl ei ; thus , a fter s pl enectomy or i n the functi ona l l y hypos pl eni c s ta te, RBCs wi th
thes e i ncl us i ons a ppea r i n the peri phera l ci rcul a ti on. Hema topoi es i s norma l l y occurs i n the red pul p onl y duri ng feta l l i fe. Beyond feta l l i fe,
hema topoi es i s ma y occur i f i njury to bone ma rrow (eg, by fi bros i s or tumors ) a l l ows hema topoi eti c s tem cel l s to ci rcul a te a nd repopul a te the
a dul t s pl een (s ee Pri ma ry Myel ofi bros i s on p. 999 a nd Myel odys pl a s ti c Syndrome on p. 1014).
Splenomegaly
Spl enomega l y i s a l mos t a l wa ys s econda ry to other di s orders . Its ca us es a re myri a d, a s a re the ma ny pos s i bl e wa ys of cl a s s i fyi ng them (s ee
Ta bl e 113-1). In tempera te cl i ma tes , the mos t common ca us es a re
Myel oprol i fera ti ve di s orders
Lymphoprol i fera ti ve di s orders
Stora ge di s ea s es (eg, Ga ucher's di s ea s e)
Connecti ve ti s s ue di s orders
In the tropi cs , the mos t common ca us es a re
Infecti ous di s ea s es (eg, ma l a ri a , ka l a -a za r)
If s pl enomega l y i s ma s s i ve (s pl een pa l pa bl e 8 cm bel ow the cos ta l ma rgi n), the ca us e i s us ua l l y chroni c l ymphocyti c l eukemi a , non-Hodgki n
l ymphoma , chroni c myel ocyti c l eukemi a , pol ycythemi a vera , myel ofi bros i s wi th myel oi d meta pl a s i a , or ha i ry cel l l eukemi a .
Spl enomega l y ca n l ea d to cytopeni a (s ee Hypers pl eni s m on p. 985).
Evaluation
History: At pres enta ti on, mos t of the s ymptoms res ul t from the underl yi ng di s order. However, s pl enomega l y i ts el f ma y ca us e ea rl y s a ti ety by
encroa chment of the enl a rged s pl een on the s toma ch. Ful l nes s a nd l eft upper qua dra nt a bdomi na l pa i n a re a l s o pos s i bl e. Severe pa i n s ugges ts
s pl eni c i nfa rcti on. Recurrent i nfecti ons , s ymptoms of a nemi a , or bl eedi ng ma ni fes ta ti ons s ugges t cytopeni a a nd pos s i bl e hypers pl eni s m.
Physical examination: The s ens i ti vi ty for detecti on of ul tra s ound-documented s pl eni c enl a rgement i s 60 to 70% for pa l pa ti on a nd 60 to 80% for
percus s i on. Up to 3% of norma l ,
[Table 113-1. Common Ca us es of Spl enomega l y*]
thi n, peopl e ha ve a pa l pa bl e s pl een. Al s o, a pa l pa bl e l eft upper qua dra nt ma s s ma y i ndi ca te a probl em other tha n a n enl a rged s pl een.
Other hel pful s i gns i ncl ude a s pl eni c fri cti on rub tha t s ugges ts s pl eni c i nfa rcti on a nd epi ga s tri c a nd s pl eni c brui ts tha t s ugges t conges ti ve
s pl enomega l y. Genera l i zed a denopa thy ma y s ugges t a myel oprol i fera ti ve, l ymphoprol i fera ti ve, i nfecti ous , or a utoi mmune di s order.
Testing: If confi rma ti on of s pl enomega l y i s neces s a ry beca us e the exa mi na ti on i s equi voca l , ul tra s onogra phy i s the tes t of choi ce beca us e of i ts
a ccura cy a nd l ow cos t. CT a nd MRI ma y provi de more deta i l of the orga n's cons i s tency. MRI i s es peci a l l y us eful i n detecti ng porta l or s pl eni c vei n
thrombos es . Nucl ea r s ca nni ng i s a ccura te a nd ca n i denti fy a cces s ory s pl eni c ti s s ue but i s expens i ve a nd cumbers ome to do.
Speci fi c ca us es s ugges ted cl i ni ca l l y s houl d be confi rmed by a ppropri a te tes ti ng (s ee el s ewhere i n THE MANUAL). If no ca us e i s s ugges ted, the
hi ghes t pri ori ty i s excl us i on of occul t i nfecti on, beca us e ea rl y trea tment a ffects the outcome of i nfecti on more tha n i t does mos t other ca us es of
s pl enomega l y. Tes ti ng s houl d be thorough i n a rea s of hi gh geogra phi c preva l ence of i nfecti on or i f the pa ti ent a ppea rs to be i l l . CBC, bl ood
cul tures , a nd bone ma rrow exa mi na ti on a nd cul ture s houl d be cons i dered. If the pa ti ent i s not i l l , ha s no s ymptoms bes i des thos e due to
s pl enomega l y, a nd ha s no ri s k fa ctors for i nfecti on, the extent of tes ti ng i s controvers i a l but proba bl y i ncl udes CBC, peri phera l bl ood s mea r, l i ver
functi on tes ts , a nd a bdomi na l CT. Fl ow cytometry of peri phera l bl ood i s i ndi ca ted i f l ymphoma i s s us pected.
Speci fi c peri phera l bl ood fi ndi ngs ma y s ugges t underl yi ng di s orders (eg, l ymphocytos i s i n chroni c l ymphocyti c l eukemi a ; l eukocytos i s a nd
i mma ture forms i n other l eukemi a s ). Exces s i ve ba s ophi l s , eos i nophi l s , or nucl ea ted or tea rdrop RBCs s ugges t myel oprol i fera ti ve di s orders .
Cytopeni a s s ugges t hypers pl eni s m. Spherocytos i s s ugges ts hypers pl eni s m or heredi ta ry s pherocytos i s . Li ver functi on tes t res ul ts a re di ffus el y
a bnorma l i n conges ti ve s pl enomega l y wi th ci rrhos i s ; a n i s ol a ted el eva ti on of s erum a l ka l i ne phos pha ta s e s ugges ts hepa ti c i nfi l tra ti on, a s i n
myel oprol i fera ti ve a nd l ymphoprol i fera ti ve di s orders a nd mi l i a ry TB.
Some other tes ts ma y be us eful , even i n a s ymptoma ti c pa ti ents . Serum protei n el ectrophores i s i denti fyi ng a monocl ona l ga mmopa thy or
decrea s ed i mmunogl obul i ns s ugges t l ymphoprol i fera ti ve di s orders or a myl oi dos i s ; di ffus e hyperga mma gl obul i nemi a s ugges ts chroni c i nfecti on
(eg, ma l a ri a , ka l a -a za r, brucel l os i s , TB) or ci rrhos i s wi th conges ti ve s pl enomega l y, s a rcoi dos i s , or connecti ve ti s s ue di s orders . El eva ti on of s erum
uri c a ci d s ugges ts a myel oprol i fera ti ve or l ymphoprol i fera ti ve di s order. El eva ti on of WBC a l ka l i ne phos pha ta s e s ugges ts a myel oprol i fera ti ve
di s order, wherea s decrea s ed l evel s s ugges t chroni c myel ocyti c l eukemi a .
If tes ti ng revea l s no a bnorma l i ti es other tha n s pl enomega l y, the pa ti ent s houl d be reeva l ua ted a t i nterva l s of 6 to 12 mo or when new s ymptoms
devel op.
Treatment
Trea tment i s di rected a t the underl yi ng di s order. The enl a rged s pl een i ts el f needs no trea tment unl es s s evere hypers pl eni s m i s pres ent. Pa ti ents
wi th pa l pa bl e or very l a rge s pl eens proba bl y s houl d a voi d conta ct s ports to decrea s e the ri s k of s pl eni c rupture.
Hypersplenism
Hypersplenism is cytopenia caused by splenomegaly.
Hypers pl eni s m i s a s econda ry proces s tha t ca n a ri s e from s pl enomega l y of a l mos t a ny ca us e (s ee Ta bl e 113-1). Spl enomega l y i ncrea s es the
s pl een's mecha ni ca l fi l teri ng a nd des tructi on of RBCs a nd often of WBCs a nd pl a tel ets . Compens a tory bone ma rrow hyperpl a s i a occurs i n thos e
cel l l i nes tha t a re reduced i n the ci rcul a ti on.
Symptoms and Signs
Spl enomega l y i s the ha l l ma rk; s pl een s i ze correl a tes wi th the degree of a nemi a . The s pl een ca n be expected to extend a bout 2 cm benea th the
cos ta l ma rgi n for ea ch 1-g decrea s e i n Hb. Other cl i ni ca l fi ndi ngs us ua l l y res ul t from the underl yi ng di s order.
Diagnosis
Hypers pl eni s m i s s us pected i n pa ti ents wi th s pl enomega l y a nd a nemi a or cytopeni a s . Eva l ua ti on i s s i mi l a r to tha t of s pl enomega l y (s ee p. 984).
Unl es s other mecha ni s ms coexi s t to compound thei r s everi ty, a nemi a a nd other cytopeni a s a re modes t a nd a s ymptoma ti c (eg, pl a tel et counts ,
50,000 to 100,000/L; WBC counts , 2500 to 4000/L wi th norma l WBC di fferenti a l count). RBC morphol ogy i s genera l l y norma l except for occa s i ona l
s pherocytos i s . Reti cul ocytos i s i s us ua l .
Treatment
Pos s i bl y s pl eni c a bl a ti on (s pl enectomy or ra di a ti on thera py)
Va cci na ti on for s pl enectomi zed pa ti ents
Trea tment i s di rected a t the underl yi ng di s order. However, i f hypers pl eni s m i s the onl y s eri ous ma ni fes ta ti on of the di s order (eg, Ga ucher's
di s ea s e), s pl eni c a bl a ti on by s pl enectomy or ra di a ti on thera py ma y be i ndi ca ted (s ee
Ta bl e 113-2). Beca us e the i nta ct s pl een protects a ga i ns t s eri ous i nfecti ons wi th enca ps ul a ted ba cteri a , s pl enectomy s houl d be a voi ded whenever
pos s i bl e, a nd pa ti ents undergoi ng s pl enectomy requi re va cci na ti on a ga i ns t i nfecti ons ca us ed by Streptococcus pneumoniae, Neisseria meningitidis,
a nd Haemophilus influenzae. After s pl enectomy, pa ti ents a re pa rti cul a rl y s us cepti bl e to s evere s eps i s . Pa ti ents who devel op fever s houl d recei ve
empi ri c a nti bi oti cs .
Splenic Injury
Splenic injury usually results from blunt abdominal trauma.
Si gni fi ca nt i mpa ct (eg, motor vehi cl e cra s h) ca n da ma ge the s pl een, a s ca n penetra ti ng tra uma (eg, kni fe wound, guns hot wound). Spl eni c
enl a rgement a s a res ul t of ful mi na nt Eps tei n-Ba rr vi ra l di s ea s e (i nfecti ous mononucl eos i s or pos ttra ns pl a nt Eps tei n-Ba rr vi rus -medi a ted
ps eudol ymphoma ) predi s pos es to i njury wi th mi ni ma l tra uma or even s ponta neous l y. Spl eni c i njuri es ra nge from s ubca ps ul a r hema toma s a nd
s ma l l ca ps ul a r l a cera ti ons to deep pa renchyma l l a cera ti ons , crus h i njury, a nd a vul s i on from the pedi cl e.
[Table 113-2. Indi ca ti ons for Spl enectomy or Ra di a ti on Thera py i n Hypers pl eni s m]
The ma i n i mmedi a te cons equence i s hemorrha ge i nto the peri tonea l ca vi ty. The a mount of hemorrha ge ma y be s ma l l or l a rge, dependi ng on the
na ture a nd degree of i njury. Ma ny s ma l l l a cera ti ons , pa rti cul a rl y i n chi l dren, cea s e bl eedi ng s ponta neous l y. La rger i njuri es hemorrha ge
extens i vel y, often ca us i ng hemorrha gi c s hock. A s pl eni c hema toma s ometi mes ruptures , us ua l l y i n the fi rs t few da ys , a l though rupture ca n occur
from hours to even months a fter i njury.
Symptoms and Signs
The ma ni fes ta ti ons of ma jor hemorrha ge, i ncl udi ng hemorrha gi c s hock, a bdomi na l pa i n, a nd di s tenti on, a re us ua l l y cl i ni ca l l y obvi ous . Les s er
hemorrha ge ca us es l eft upper qua dra nt a bdomi na l pa i n, whi ch s ometi mes ra di a tes to the s houl der. Pa ti ents wi th unexpl a i ned l eft upper
qua dra nt pa i n, pa rti cul a rl y i f there i s evi dence of hypovol emi a or s hock, s houl d be a s ked a bout recent tra uma .
Diagnosis
The di a gnos i s i s confi rmed wi th CT i n s ta bl e pa ti ents a nd wi th beds i de (poi nt of ca re) ul tra s onogra phy or expl ora tory l a pa rotomy i n uns ta bl e
pa ti ents .
Treatment
Trea tment ha s tra di ti ona l l y been s pl enectomy. However, s pl enectomy s houl d be a voi ded i f pos s i bl e, pa rti cul a rl y i n chi l dren, to a voi d the
res ul ti ng perma nent s us cepti bi l i ty to ba cteri a l i nfecti ons . Mos t s ma l l , a nd s ome modera tes i zed l a cera ti ons i n s ta bl e pa ti ents (pa rti cul a rl y
chi l dren) a re ma na ged wi th hos pi ta l obs erva ti on a nd s ometi mes tra ns fus i on ra ther tha n s urgery. When s urgery i s needed, the s pl een ca n be
s urgi ca l l y repa i red i n a few ca s es , but s pl enectomy i s s ti l l the ma i n s urgi ca l trea tment.
Chapter 114. Eosinophilic Disorders

Introduction
Eos i nophi l s a re gra nul ocytes deri ved from the s a me progeni tor cel l s a s monocytes ma cropha ges , neutrophi l s , a nd ba s ophi l s . The preci s e
functi ons of eos i nophi l s a re unknown. Al though they a re pha gocyti c, eos i nophi l s a re l es s effi ci ent tha n neutrophi l s i n ki l l i ng i ntra cel l ul a r
ba cteri a . And a l though eos i nophi l i a commonl y a ccompa ni es hel mi nthi c i nfecti ons a nd eos i nophi l s a re toxi c to hel mi nths i n vi tro, there i s no
di rect evi dence tha t they ki l l pa ra s i tes i n vi vo. Eos i nophi l s ma y modul a te i mmedi a te hypers ens i ti vi ty rea cti ons by degra di ng or i na cti va ti ng
medi a tors rel ea s ed by ma s t cel l s , s uch a s hi s ta mi ne, l eukotri enes (whi ch ma y ca us e va s ocons tri cti on a nd bronchocons tri cti on),
l ys ophos phol i pi ds , a nd hepa ri n. Prol onged eos i nophi l i a ma y res ul t i n ti s s ue da ma ge by mecha ni s ms tha t a re not ful l y unders tood.
Eos i nophi l gra nul es conta i n ma jor ba s i c protei n a nd eos i nophi l ca ti oni c protei n tha t a re toxi c to s evera l pa ra s i tes a nd to ma mma l i a n cel l s . Thes e
protei ns bi nd hepa ri n a nd neutra l i ze i ts a nti coa gul a nt a cti vi ty. Eos i nophi l -deri ved neurotoxi n ca n s everel y da ma ge myel i na ted neurons .
Eos i nophi l peroxi da s e, whi ch di ffers s i gni fi ca ntl y from peroxi da s e of other gra nul ocytes , genera tes oxi di zi ng ra di ca l s i n the pres ence of hydrogen
peroxi de a nd a ha l i de. Cha rcot-Leyden crys ta l s a re pri ma ri l y compos ed of phos phol i pa s e B a nd a re l oca ted i n s putum, ti s s ues , a nd s tool i n
di s orders i n whi ch there i s eos i nophi l i a (eg, a s thma , eos i nophi l i c pneumoni a ).
The norma l peri phera l bl ood eos i nophi l count i s < 350/L, wi th di urna l l evel s tha t va ry i nvers el y wi th pl a s ma corti s ol l evel s ; the pea k occurs a t
ni ght a nd the trough i n the morni ng. The eos i nophi l count ca n decrea s e wi th s tres s , wi th us e of -bl ockers or corti cos teroi ds , a nd s ometi mes wi th
ba cteri a l or vi ra l i nfecti ons . The count ca n i ncrea s e wi th a l l ergi c di s orders , wi th certa i n i nfecti ons (typi ca l l y pa ra s i ti c), a nd from numerous other
ca us es (s ee bel ow). The ci rcul a ti ng ha l f-l i fe of eos i nophi l s i s 6 to 12 h, wi th mos t eos i nophi l s res i di ng i n ti s s ues (eg, the upper res pi ra tory a nd GI
tra cts , s ki n, uterus ).
Eos i nophi l producti on a ppea rs to be regul a ted by T cel l s through the s ecreti on of the hema topoi eti c growth fa ctors gra nul ocyte-ma cropha ge
col ony-s ti mul a ti ng fa ctor (GM-CSF), i nterl euki n-3 (IL-3), a nd i nterl euki n-5 (IL-5). Al though GM-CSF a nd IL-3 a l s o i ncrea s e the producti on of other
myel oi d cel l s , IL-5 i ncrea s es eos i nophi l producti on excl us i vel y.
Eosinophilia
Eosinophilia is defined as a peripheral blood eosinophil count > 450/L. Causes and associated disorders are myriad but often represent an allergic reaction or
parasitic infection. Diagnosis involves selective testing directed at clinically suspected causes. Treatment is directed at the cause.
Eos i nophi l i a ha s fea tures of a n i mmune res pons e: a n a gent s uch a s Trichinella spiralis i nvokes a pri ma ry res pons e wi th rel a ti vel y l ow l evel s of
eos i nophi l s , wherea s repea ted expos ures res ul t i n a n a ugmented or s econda ry eos i nophi l i c res pons e. Severa l compounds rel ea s ed by ma s t cel l s
a nd ba s ophi l s i nduce IgE-medi a ted eos i nophi l producti on. Such s ubs ta nces i ncl ude eos i nophi l chemota cti c fa ctor of a na phyl a xi s , l eukotri ene B4,
compl ement compl ex (C5-C6-C7), a nd hi s ta mi ne (over a na rrow ra nge of concentra ti on).
Eos i nophi l i a i ts el f does not ca us e s ymptoms . However, occa s i ona l l y pa ti ents wi th very s evere eos i nophi l i a (eg, eos i nophi l counts of > 100,000/L),
us ua l l y wi th eos i nophi l i c l eukemi a , devel op compl i ca ti ons of hyperl eukocytos i s (s ee p. 990).
Etiology
Eos i nophi l i a ma y be pri ma ry (i e, cl ona l prol i fera ti on of eos i nophi l s a s s oci a ted wi th hema tol ogi c di s orders s uch a s l eukemi a s a nd
myel oprol i fera ti ve di s orders ), s econda ry to (or a s s oci a ted wi th) numerous nonhema tol ogi c di s orders (s ee
Ta bl e 114-1), or i di opa thi c (i f other ca us es ca nnot be i denti fi ed).
The most common cause i n the US i s
Al l ergi c or a topi c di s orders (typi ca l l y res pi ra tory or derma tol ogi c)
Other common ca us es i ncl ude
Infecti ons (typi ca l l y pa ra s i ti c)
Certa i n tumors (hema tol ogi c or s ol i d, beni gn or ma l i gna nt)
Al mos t a ny pa ra s i ti c i nva s i on of ti s s ues ca n el i ci t eos i nophi l i a , but protozoa a nd noni nva s i ve meta zoa us ua l l y do not.
Of the tumors , Hodgki n l ymphoma ma y el i ci t ma rked eos i nophi l i a , wherea s eos i nophi l i a i s l es s common i n non-Hodgki n l ymphoma , chroni c
myel ocyti c l eukemi a , a nd
[Table 114-1. Importa nt Di s orders a nd Trea tments As s oci a ted wi th Eos i nophi l i a ]
a cute l ymphobl a s ti c l eukemi a . Ova ri a n ca ncer i s the mos t commonl y a s s oci a ted s ol i d tumor.
The pul mona ry i nfi l tra tes wi th eos i nophi l i a s yndrome compri s es a s pectrum of cl i ni ca l ma ni fes ta ti ons cha ra cteri zed by peri phera l eos i nophi l i a
a nd eos i nophi l i c pul mona ry i nfi l tra tes (s ee p. 1953) but i s us ua l l y of unknown ca us e.
Pa ti ents wi th eos i nophi l i c drug rea cti ons ma y be a s ymptoma ti c or ha ve va ri ous s yndromes , i ncl udi ng i nters ti ti a l nephri ti s , s erum s i cknes s ,
chol es ta ti c ja undi ce, hypers ens i ti vi ty va s cul i ti s , a nd i mmunobl a s ti c l ympha denopa thy. Severa l hundred pa ti ents were reported to ha ve devel oped
a n eos i nophi l i a -mya l gi a s yndrome a fter ta ki ng L-tryptopha n for s eda ti on or ps ychotropi c s upport. Thi s s yndrome wa s proba bl y ca us ed by a
conta mi na nt ra ther tha n by L-tryptopha n. The s ymptoms (s evere mus cl e pa i n, tenos ynovi ti s , mus cl e edema , ra s h) l a s ted weeks to months , a nd
s evera l dea ths occurred.
Evaluation
The number of pos s i bl e ca us es a nd a s s oci a ted di s orders i s very l a rge. Common ca us es (eg, a l l ergi c, i nfecti ous , neopl a s ti c di s orders ) s houl d be
cons i dered fi rs t, but even they a re often di ffi cul t to i denti fy; a thorough hi s tory a nd phys i ca l exa mi na ti on a re a l wa ys requi red.
History: The ques ti ons mos t l i kel y to be hel pful perta i n to the fol l owi ng:
Tra vel (s ugges ti ng pos s i bl e pa ra s i te expos ure)
Al l ergi es
Drug us e
Us e of herba l products a nd di eta ry s uppl ements , i ncl udi ng L-tryptopha n
Sys temi c s ymptoms (eg, fever, wei ght l os s , mya l gi a s , a rthra l gi a s , ra s hes , l ympha denopa thy)
Sys temi c s ymptoms s ugges t tha t a mi nor a l l ergi c or drug ca us e i s l es s l i kel y, a nd a deta i l ed eva l ua ti on for a n i nfecti ous , neopl a s ti c, connecti ve
ti s s ue, or other s ys temi c di s order s houl d be done. Other i mporta nt pa rts of the hi s tory i ncl ude fa mi l y hi s tory of bl ood dys cra s i a s (eg, pl a s ma cel l
di s orders ) a nd a compl ete revi ew of s ys tems , i ncl udi ng s ymptoms of a l l ergi c, pul mona ry, ca rdi a c, GI, a nd neurol ogi c dys functi on.
Physical examination: Genera l phys i ca l exa mi na ti on i s done, i ncl udi ng the hea rt, s ki n, a nd neurol ogi c a nd pul mona ry s ys tems . Certa i n phys i ca l
fi ndi ngs ma y s ugges t ca us es or a s s oci a ted di s orders . Exa mpl es i ncl ude ra s h (a l l ergi c, derma tol ogi c, or va s cul i ti c di s orders ), a bnorma l l ung
fi ndi ngs (a s thma , l ung i nfecti ons , or s yndromes of pul mona ry i nfi l tra ti on wi th eos i nophi l i a ), a nd genera l i zed l ympha denopa thy or s pl enomega l y
(myel oprol i fera ti ve di s orders or ca ncer).
Testing: Eos i nophi l i a i s typi ca l l y recogni zed when CBC i s done for other rea s ons . Addi ti ona l tes ti ng often i ncl udes the fol l owi ng:
Stool ova a nd pa ra s i te tes ti ng
Other tes ts to detect orga n da ma ge or for s peci fi c ca us es ba s ed on cl i ni ca l fi ndi ngs
When the CBC i ndi ca tes eos i nophi l i a , a n a bs ol ute eos i nophi l count i s ra rel y needed.
In genera l , i f a drug or a l l ergi c ca us e i s not cl i ni ca l l y s us pected, 3 s tool s peci mens s houl d be exa mi ned for ova a nd pa ra s i tes ; however, nega ti ve
fi ndi ngs do not rul e out a pa ra s i ti c ca us e (eg, tri chi nos i s requi res a mus cl e bi ops y; vi s cera l l a rva mi gra ns a nd fi l a ri a l i nfecti ons requi re other
ti s s ue bi ops i es ; duodena l a s pi ra tes ma y be needed to excl ude s peci fi c pa ra s i tes , eg, Strongyloides s ps ee p. 1350).
Other s peci fi c di a gnos ti c tes ts a re determi ned by the cl i ni ca l fi ndi ngs (pa rti cul a rl y tra vel hi s tory) a nd ma y i ncl ude ches t x-ra y, uri na l ys i s , l i ver a nd
ki dney functi on tes ts , a nd s erol ogi c tes ts for pa ra s i ti c a nd connecti ve ti s s ue di s ea s es . If pa ti ents ha ve genera l i zed l ympha denopa thy,
s pl enomega l y, or s ys temi c s ymptoms , bl ood tes ts a re done; a n el eva ted s erum vi ta mi n B 12 l evel , l ow WBC a l ka l i ne phos pha ta s e l evel , or
a bnorma l i ti es on the peri phera l bl ood s mea r s ugges t a n underl yi ng myel oprol i fera ti ve di s order, i n whi ch ca s e a bone ma rrow a s pi ra te a nd
bi ops y wi th cytogeneti c s tudi es ma y be hel pful . Al s o, i f routi ne eva l ua ti on does not revea l a ca us e, tes ts a re done to detect orga n da ma ge.
Tes ti ng ca n i ncl ude s ome of the tes ts previ ous l y menti oned a s wel l a s LDH a nd l i ver functi on tes ts (s ugges ti ng l i ver da ma ge or pos s i bl y a
myel oprol i fera ti ve di s order), echoca rdi ogra m, a nd pul mona ry functi on tes ts .
Treatment
Corti cos teroi d trea tment of hypereos i nophi l i c s yndrome i s di s cus s ed on p.
992.
Drugs known to be a s s oci a ted wi th eos i nophi l i a a re s topped. Other i denti fi ed ca us es a re trea ted.
If no ca us e i s detected, the pa ti ent i s fol l owed for compl i ca ti ons . A bri ef tri a l wi th l ow-dos e corti cos teroi ds ma y l ower the eos i nophi l count i f
eos i nophi l i a i s s econda ry (eg, to a l l ergy, connecti ve ti s s ue di s orders , or pa ra s i ti c i nfecti on) ra ther tha n pri ma ry. Such a tri a l i s i ndi ca ted i f
eos i nophi l i a i s pers i s tent a nd progres s i ve i n the a bs ence of a trea ta bl e ca us e.
Hypereosinophilic Syndrome
(Idi opa thi c Hypereos i nophi l i c Syndrome)
Hypereosinophilic syndrome (HES) is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction
directly related to eosinophilia in the absence of parasitic, allergic, or other causes of eosinophilia. Symptoms are myriad, depending on which organs are
dysfunctional. Diagnosis involves excluding other causes of eosinophilia and bone marrow and genetic tests. Treatment usually begins with prednisone and, in
one common subtype, includes imatinib.
HES i s tra di ti ona l l y defi ned by peri phera l bl ood eos i nophi l i a > 1500/L pers i s ti ng 6 mo. HES wa s previ ous l y cons i dered to be i di opa thi c but i s
now known to res ul t from va ri ous di s orders , s ome of whi ch ha ve known ca us es . One l i mi ta ti on of the tra di ti ona l defi ni ti on i s tha t i t does not
i ncl ude thos e pa ti ents wi th s ome of the s a me a bnorma l i ti es (eg, geneti c defects ) tha t a re known ca us es of HES a nd who do not ful fi l l the
tra di ti ona l HES di a gnos ti c cri teri a for degree or dura ti on of eos i nophi l i a . Another l i mi ta ti on i s tha t s ome pa ti ents wi th eos i nophi l i a a nd orga n
da ma ge tha t cha ra cteri ze HES requi re trea tment ea rl i er tha n the 6 mo neces s a ry to confi rm the tra di ti ona l di a gnos ti c cri teri a .
HES i s ra re, ha s a n unknown preva l ence, a nd mos t often a ffects peopl e a ge 20 through 50. Onl y s ome pa ti ents wi th prol onged eos i nophi l i a
devel op orga n dys functi on tha t cha ra cteri zes hypereos i nophi l i c s yndrome. Al though a ny orga n ma y be i nvol ved, the hea rt, l ungs , s pl een, s ki n, a nd
nervous s ys tem a re typi ca l l y a ffected. Ca rdi a c i nvol vement often ca us es morbi di ty a nd morta l i ty.
Subtypes: There a re two broa d s ubtypes (s ee
Ta bl e 114-2):
Myel oprol i fera ti ve va ri a nt
Lymphoprol i fera ti ve va ri a nt
The myeloproliferative variant i s often a s s oci a ted wi th a s ma l l i nters ti ti a l del eti on i n chromos ome 4 a nd the FIPILI/PDGFRA-a s s oci a ted fus i on gene
(refl ecti ng tyros i ne ki na s e a cti vi ty tha t ca n tra ns form hema topoi eti c cel l s ). Pa ti ents often ha ve
Spl enomega l y
Thrombocytopeni a
Anemi a
El eva ted s erum vi ta mi n B 12 l evel s
Hypogra nul a r or va cuol a ted eos i nophi l s
Myel ofi bros i s
[Table 114-2. Subtypes of Hypereos i nophi l i c Syndrome]
Pa ti ents wi th thi s s ubtype often devel op endomyoca rdi a l fi bros i s a nd ma y ra rel y devel op a cute myel oi d or l ymphobl a s ti c l eukemi a . Pa ti ents wi th
the FIPILI/PDGFRA-a s s oci a ted fus i on gene a re more often ma l es a nd ma y be res pons i ve to i ma ti ni b.
The lymphoproliferative variant i s a s s oci a ted wi th a cl ona l popul a ti on of T cel l s wi th a berra nt phenotype. Pa ti ents more often ha ve
Angi oedema , s ki n a bnorma l i ti es , or both
Hyperga mma gl obul i nemi a (es peci a l l y IgE)
Ci rcul a ti ng i mmune compl exes (s ometi mes wi th s erum s i cknes s )
They a l s o more often res pond fa vora bl y to corti cos teroi ds a nd occa s i ona l l y devel op T-cel l l ymphoma .
Other HES variants i ncl ude chroni c eos i nophi l i c l eukemi a , Gl ei ch's s yndrome (cycl i ca l eos i nophi l i a a nd a ngi oedema ), fa mi l i a l hypereos i nophi l i c
s yndrome ma pped to 5q 31-33, a nd other orga n-s peci fi c s yndromes . Hyperl eukocytos i s ma y occur i n pa ti ents wi th eos i nophi l i c l eukemi a a nd very
hi gh eos i nophi l counts (eg, > 100,000 cel l s /L). Eos i nophi l s ca n form a ggrega tes tha t occl ude s ma l l bl ood ves s el s , ca us i ng ti s s ue i s chemi a a nd
mi croi nfa rcti ons . Common ma ni fes ta ti ons i ncl ude bra i n or l ung hypoxi a (eg, encepha l opa thy, dys pnea or res pi ra tory fa i l ure).
Symptoms and Signs
Symptoms a re di vers e a nd depend on whi ch orga ns a re dys functi ona l (s ee Ta bl e 114-3).
Occa s i ona l l y, pa ti ents wi th very s evere eos i nophi l i a (eg, eos i nophi l counts of > 100,000/L) devel op compl i ca ti ons of hyperl eukocytos i s , s uch a s
ma ni fes ta ti ons of bra i n or l ung hypoxi a (eg, encepha l opa thy, dys pnea or res pi ra tory fa i l ure).
Diagnosis
Excl us i on of s econda ry eos i nophi l i a
Tes ts to i denti fy orga n da ma ge
Bone ma rrow exa mi na ti on wi th cytogeneti cs
Eva l ua ti on for HES s houl d be cons i dered i n pa ti ents who ha ve peri phera l bl ood eos i nophi l i a > 1500/L pres ent on more tha n one occa s i on tha t i s
unexpl a i ned, pa rti cul a rl y when there a re ma ni fes ta ti ons of orga n da ma ge. Tes ti ng to excl ude di s orders ca us i ng eos i nophi l i a s houl d be done (s ee
p. 990). Further eva l ua ti on s houl d i ncl ude bl ood chemi s tri es (i ncl udi ng l i ver enzymes , crea ti ne ki na s e, rena l functi on, a nd troponi n), ECG;
echoca rdi ogra phy; pul mona ry functi on tes ts ; a nd CT of the ches t, a bdomen, a nd pel vi s . Bone ma rrow a s pi ra te a nd bi ops y wi th fl ow cytometry,
cytogeneti cs , a nd revers e tra ns cri pta s e-PCR or fl uores cence i n s i tu hybri di za ti on (FISH) i s done to i denti fy the FIPILI/PDGFRA-a s s oci a ted fus i on
gene a nd other pos s i bl e ca us es of eos i nophi l i a (eg, BCR-ABL a bnorma l i ti es cha ra cteri s ti c of chroni c myel ogenous l eukemi a ).
Prognosis
Dea th us ua l l y res ul ts from orga n, pa rti cul a rl y hea rt, dys functi on. Ca rdi a c i nvol vement
[Table 114-3. Abnorma l i ti es i n Pa ti ents wi th Hypereos i nophi l i c Syndrome]
i s not predi cted by the degree or dura ti on of eos i nophi l i a . Prognos i s va ri es dependi ng on res pons e to thera py. Res pons e to i ma ti ni b i mproves the
prognos i s a mong pa ti ents wi th the FIPILI/PDGFRA-a s s oci a ted fus i on gene. Current thera py ha s i mproved prognos i s .
Treatment
Corti cos teroi ds for hypereos i nophi l i a a nd often for ongoi ng trea tment of orga n da ma ge
Ima ti ni b for pa ti ents wi th the FIPILI/PDGFRA-a s s oci a ted fus i on gene
Supporti ve thera py
Trea tments i ncl ude i mmedi a te thera py, defi ni ti ve thera pi es (trea tments di rected a t the di s order i ts el f), a nd s upporti ve thera pi es .
Immediate therapy: For pa ti ents wi th very s evere eos i nophi l i a , compl i ca ti ons of hyperl eukocytos i s , or both (us ua l l y pa ti ents wi th eos i nophi l i c
l eukemi a ), hi gh-dos e IV corti cos teroi ds (eg, predni s one 1 mg/kg or equi va l ent) s houl d be i ni ti a ted a s s oon a s pos s i bl e. If the eos i nophi l count i s
much l ower (eg, by 50%) a fter 24 h, corti cos teroi d dos e ca n be repea ted da i l y; i f not, a n a l terna ti ve trea tment (eg, vi ncri s ti ne, i ma ti ni b,
l euka pheres i s ) i s begun.
Definitive therapy: Pa ti ents wi th the FIPILI/PDGFRA-a s s oci a ted fus i on gene a re us ua l l y trea ted wi th i ma ti ni b a nd, pa rti cul a rl y i f hea rt da ma ge i s
s us pected, corti cos teroi ds . If i ma ti ni b i s i neffecti ve or poorl y tol era ted, a nother tyros i ne ki na s e i nhi bi tor (eg, da s a ti ni b, ni l oti ni b, s ora feni b) ca n
be us ed, or a l l ogeni c hema topoi eti c s tem cel l tra ns pl a nta ti on ca n be tri ed.
Pa ti ents wi thout the FIPILI/PDGFRA-a s s oci a ted fus i on gene, even i f a s ymptoma ti c, a re often gi ven one dos e of predni s one 60 mg (or 1 mg/kg) po to
determi ne corti cos teroi d res pons i venes s (i e, a decrea s e i n the eos i nophi l count). In pa ti ents wi th s ymptoms or orga n da ma ge, predni s one i s
conti nued a t the s a me dos e for 2 wk, then ta pered. Pa ti ents wi thout s ymptoms a nd orga n da ma ge a re moni tored for a t l ea s t 6 mo for thes e
compl i ca ti ons . If corti cos teroi ds ca nnot be ea s i l y ta pered, a corti cos teroi d-s pa ri ng drug (eg, hydroxyurea , i nterferon a l fa ) ca n be us ed.
Supportive therapy: Supporti ve drug thera py a nd s urgery ma y be requi red for ca rdi a c ma ni fes ta ti ons (eg, i nfi l tra ti ve ca rdi omyopa thy, va l vul a r
l es i ons , hea rt fa i l ure). Thromboti c compl i ca ti ons ma y requi re the us e of a nti pl a tel et drugs (eg, a s pi ri n, cl opi dogrel , ti cl opi di ne); a nti coa gul a ti on
i s i ndi ca ted i f a l eft ventri cul a r mura l thrombus i s pres ent or i f tra ns i ent i s chemi c a tta cks pers i s t des pi te us e of a s pi ri n.
Chapter 115. Histiocytic Syndromes

Introduction
The hi s ti ocyti c s yndromes a re cl i ni ca l l y heterogeneous di s orders tha t res ul t from a n a bnorma l prol i fera ti on of hi s ti ocytes ei ther monocytema cropha ges (a nti gen-proces s i ng cel l s ) or dendri ti c cel l s (a nti gen-pres enti ng cel l s ). Cl a s s i fyi ng thes e di s orders i s di ffi cul t (s ee
Ta bl e 115-1) a nd ha s cha nged over ti me a s a n unders ta ndi ng of the bi ol ogy of thes e cel l s ha s evol ved.
Langerhans' Cell Histiocytosis
(See a l s o p. 1963.)
Langerhans' cell histiocytosis (LCH) is a proliferation of dendritic mononuclear cells with infiltration into organs locally or diffusely. Most cases occur in children.
Manifestations may include lung infiltrates; bone lesions; rashes; and hepatic, hematopoietic, and endocrine dysfunction. Diagnosis is based on biopsy. Factors
predicting a poor prognosis include age < 2 yr and dissemination, particularly involving the hematopoietic
[Table 115-1. Some Hi s ti ocyti c Syndromes ]
system, liver, lungs, or a combination. Treatments include supportive measures and chemotherapy or local treatment with surgery or radiation therapy as
indicated by the extent of disease.
LCH i s a dendri ti c cel l di s order. It ca n ca us e di s ti nct cl i ni ca l s yndromes tha t ha ve been hi s tori ca l l y des cri bed a s eos i nophi l i c gra nul oma , Ha ndSchul l er-Chri s ti a n di s ea s e, a nd Letterer-Si we di s ea s e. Beca us e thes e s yndromes ma y be va ri ed ma ni fes ta ti ons of the s a me underl yi ng di s order
a nd beca us e mos t pa ti ents wi th LCH ha ve ma ni fes ta ti ons of more tha n one of thes e s yndromes , the des i gna ti ons of the s epa ra te s yndromes a re
now mos tl y of hi s tori ca l s i gni fi ca nce. Es ti ma tes of the preva l ence of LCH va ry wi del y (eg, from a bout 1:50,000 to 1:200,000).
In LCH, a bnorma l l y prol i fera ti ng dendri ti c cel l s i nfi l tra te one or more orga ns . Bone, s ki n, teeth, gi ngi va l ti s s ue, ea rs , endocri ne orga ns , l ungs , l i ver,
s pl een, l ymph nodes , a nd bone ma rrow ma y be i nvol ved. Orga ns ma y be a ffected by i nfi l tra ti on, ca us i ng dys functi on, or by compres s i on from
a dja cent enl a rged s tructures . In a bout ha l f of pa ti ents , more tha n one orga n i s i nvol ved.
Symptoms and Signs
Symptoms a nd s i gns va ry cons i dera bl y dependi ng on whi ch orga ns a re i nfi l tra ted. The s yndromes a re des cri bed by thei r hi s tori ca l des i gna ti ons ,
but few pa ti ents pres ent wi th cl a s s i c ma ni fes ta ti ons .
Eosinophilic granuloma: Sol i ta ry or mul ti foca l eos i nophi l i c gra nul oma (60 to 80% of LCH ca s es ) occurs predomi na ntl y i n ol der chi l dren a nd young
a dul ts , us ua l l y by a ge 30; i nci dence pea ks between a ges 5 a nd 10 yr. Les i ons mos t frequentl y i nvol ve bone, often wi th pa i n, the i na bi l i ty to bea r
wei ght, or both a nd wi th overl yi ng tender (s ometi mes wa rm) s wel l i ng.
Hand-Schuller-Christian disease: Thi s s yndrome (15 to 40% of LCH ca s es ) occurs i n chi l dren a ged 2 to 5 yr a nd i n s ome ol der chi l dren a nd a dul ts . Thi s
s ys temi c di s order cl a s s i ca l l y i nvol ves the fl a t bones of the s kul l , ri bs , pel vi s , s ca pul a , or a combi na ti on. Long bones a nd l umbos a cra l vertebra e
a re l es s frequentl y i nvol ved; the wri s ts , ha nds , knees , feet, a nd cervi ca l vertebra e a re ra rel y i nvol ved. In cl a s s i c ca s es , pa ti ents ha ve
exophtha l mos ca us ed by orbi ta l tumor ma s s . Ra rel y, vi s i on l os s or s tra bi s mus i s ca us ed by opti c nerve or orbi ta l mus cl e i nvol vement. Tooth l os s
ca us ed by a pi ca l a nd gi ngi va l i nfi l tra ti on i s common i n ol der pa ti ents .
Chroni c oti ti s medi a a nd oti ti s externa due to i nvol vement of the ma s toi d a nd petrous porti ons of the tempora l bone wi th pa rti a l obs tructi on of
the a udi tory ca na l a re fa i rl y common. Di a betes i ns i pi dus , the l a s t component of the cl a s s i c tri a d tha t i ncl udes fl a t bone i nvol vement a nd
exophtha l mos , a ffects 5 to 50% of pa ti ents , wi th hi gher percenta ges i n chi l dren who ha ve s ys temi c di s ea s e a nd i nvol vement of the orbi t a nd s kul l .
Up to 40% of chi l dren wi th s ys temi c di s ea s e ha ve s hort s ta ture. Hyperprol a cti nemi a a nd hypogona di s m ca n res ul t from hypotha l a mi c i nfi l tra ti on.
Letterer-Siwe disease: Thi s s yndrome (10% of LCH ca s es ), a s ys temi c di s order, i s the mos t s evere form of LCH. Typi ca l l y, a chi l d < 2 yr pres ents wi th a
s ca l y s eborrhei c, eczema toi d, s ometi mes purpuri c ra s h i nvol vi ng the s ca l p, ea r ca na l s , a bdomen, a nd i nter-tri gi nous a rea s of the neck a nd fa ce.
Denuded s ki n ma y fa ci l i ta te mi crobi a l i nva s i on, l ea di ng to s eps i s . Frequentl y, there i s ea r dra i na ge, l ympha denopa thy, hepa tos pl enomega l y,
a nd, i n s evere ca s es , hepa ti c dys functi on wi th hypoprotei nemi a a nd di mi ni s hed s ynthes i s of cl otti ng fa ctors . Anorexi a , i rri ta bi l i ty, fa i l ure to thri ve,
a nd pul mona ry ma ni fes ta ti ons (eg, cough, ta chypnea , pneumothora x) ma y a l s o occur. Si gni fi ca nt a nemi a a nd s ometi mes neutropeni a occur;
thrombocytopeni a i s of gra ve prognos ti c s i gni fi ca nce. Pa rents frequentl y report precoci ous erupti on of teeth, when i n fa ct the gums a re recedi ng to
expos e i mma ture denti ti on. Pa ti ents ma y a ppea r a bus ed or negl ected.
Diagnosis
Bi ops y
LCH i s s us pected i n pa ti ents (pa rti cul a rl y young pa ti ents ) wi th unexpl a i ned pul mona ry i nfi l tra tes , bone l es i ons , or ocul a r or cra ni ofa ci a l
a bnorma l i ti es ; a nd i n chi l dren < 2 yr wi th typi ca l ra s hes or s evere, unexpl a i ned mul ti orga n di s ea s e.
X-ra ys a re often done beca us e of pres enti ng s ymptoms . Bone l es i ons a re us ua l l y s ha rpl y ma rgi na ted, a nd round or ova l , wi th a bevel ed edge
gi vi ng the a ppea ra nce of depth. However, s ome l es i ons a re ra di ogra phi ca l l y i ndi s ti ngui s ha bl e from Ewi ng's s a rcoma , os teogeni c s a rcoma , other
beni gn a nd ma l i gna nt condi ti ons , or os teomyel i ti s .
Di a gnos i s i s ba s ed on bi ops y. La ngerha ns ' cel l s a re us ua l l y promi nent, except i n ol der l es i ons . Thes e cel l s a re i denti fi ed by a pa thol ogi s t
experi enced i n the di a gnos i s of LCH a ccordi ng to thei r i mmunohi s tochemi ca l cha ra cteri s ti cs , whi ch i ncl ude cel l s urfa ce CD 1a a nd S-100. Once
di a gnos i s i s es ta bl i s hed, the extent of di s ea s e mus t be determi ned by a ppropri a te i ma gi ng a nd l a bora tory s tudi es .
Prognosis
Prognos i s i s good for pa ti ents wi th both of the fol l owi ng:

Di s ea s e res tri cted to s ki n, l ymph nodes , or bone
Age > 2 yr
Wi th trea tment, a l mos t a l l s uch pa ti ents s urvi ve.
Morbi di ty a nd morta l i ty a re i ncrea s ed i n pa ti ents wi th mul ti orga n i nvol vement, pa rti cul a rl y thos e wi th
Age < 2 yr
Invol vement of the hema topoi eti c s ys tem, l i ver, l ungs , or s pl een
Wi th trea tment, the overa l l s urvi va l ra te for pa ti ents wi th mul ti orga n di s ea s e i s a bout 80%. Dea th i s more l i kel y a mong a t-ri s k pa ti ents who do
not res pond to i ni ti a l thera py. Di s ea s e recurrence i s common. A chroni c remi tti ng a nd exa cerba ti ng cours e ma y occur, pa rti cul a rl y a mong a dul ts .
Treatment
Supporti ve ca re
Someti mes hormone repl a cement thera py for hypopi tui ta ri s m
Chemothera py for mul ti orga n i nvol vement
Someti mes s urgery or ra di a ti on thera py (us ua l l y for s i ngl e bone i nvol vement)
Beca us e thes e s yndromes a re ra re a nd compl ex, pa ti ents a re us ua l l y referred to i ns ti tuti ons experi enced i n the trea tment of LCH. Genera l
s upporti ve ca re i s es s enti a l a nd ma y i ncl ude s crupul ous hygi ene to l i mi t ea r, cuta neous , a nd denta l l es i ons . Debri dement or res ecti on of s everel y
a ffected gi ngi va l ti s s ue l i mi ts ora l i nvol vement. Seborrhea -l i ke derma ti ti s of the s ca l p ma y di mi ni s h wi th us e of a s el eni um-ba s ed s ha mpoo
twi ce/wk. If s ha mpooi ng i s i neffecti ve, topi ca l corti cos teroi ds a re us ed i n s ma l l a mounts a nd bri efl y i n s ma l l a rea s .
Pa ti ents wi th s ys temi c di s ea s e a re moni tored for potenti a l chroni c di s a bi l i ti es , s uch a s cos meti c or functi ona l orthopedi c a nd cuta neous
di s orders a nd neurotoxi ci ty a s wel l a s for ps ychol ogi c probl ems tha t ma y requi re ps ychos oci a l s upport.
Ma ny pa ti ents requi re hormone repl a cement for di a betes i ns i pi dus or other ma ni fes ta ti ons of hypopi tui ta ri s m.
Chemothera py i s i ndi ca ted for pa ti ents wi th mul ti orga n i nvol vement. Protocol s s pons ored by the Hi s ti ocyte Soci ety a re us ed; trea tment protocol s
va ry a ccordi ng to the ri s k ca tegory. Al mos t a l l pa ti ents wi th a good res pons e to thera py ca n s top trea tment. Protocol s for poor res ponders a re
under s tudy.
Loca l s urgery or ra di a ti on thera py i s us ed for di s ea s e i nvol vi ng a s i ngl e bone a nd, ra rel y, when mul ti pl e l es i ons or mul ti pl e bones a re i nvol ved.
Ea s i l y a cces s i bl e l es i ons i n noncri ti ca l l oca ti ons undergo s urgi ca l curetta ge. Surgery s houl d be a voi ded when i t ma y res ul t i n s i gni fi ca nt cos meti c
deformi ti es , orthopedi c deformi ti es , or l os s of functi on. Ra di a ti on thera py i nvol vi ng mega vol ta ge equi pment ma y be gi ven to pa ti ents a t ri s k of
s kel eta l deformi ty, vi s ua l l os s s econda ry to exophtha l mos , pa thol ogi c fra ctures , vertebra l col l a ps e, a nd s pi na l cord i njury or to pa ti ents wi th
s evere pa i n. Dos es of ra di a ti on a re cons i dera bl y l es s tha n thos e us ed to trea t ca ncer. Surgery a nd ra di a ti on thera py s houl d be done by s peci a l i s ts
experi enced i n trea ti ng LCH.
Pa ti ents wi th mul ti orga n di s ea s e tha t progres s es des pi te s ta nda rd thera py us ua l l y res pond to more a ggres s i ve chemothera py. Pa ti ents who do
not res pond to s a l va ge chemothera py ma y undergo bone ma rrow tra ns pl a nta ti on, experi menta l chemothera py, or i mmunos uppres s i ve or other
i mmunomodul a tory thera py.
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder causing immune dysfunction in infants and young children. Many patients have an
underlying immune disorder, although in some patients the underlying disorder is not known. Manifestations may include lymphadenopathy,
hepatosplenomegaly, fever, and neurologic abnormalities. Diagnosis is by specific clinical and testing (genetic) criteria. Treatment is usually with chemotherapy
and, in refractory cases or in cases with a genetic cause, hematopoietic stem cell transplantation.
HLH i s cha ra cteri zed by
Hi gh l evel s of cytoki nes (eg, IL-1, IL-2; TNF-; i nterferon [INF]-; s ol ubl e IL-6, IL-10, IL-12; gra nul ocyte-ma cropha ge col ony s ti mul a ti ng fa ctor [GMCSF])
Uncontrol l ed prol i fera ti on a nd a cti va ti on of cytotoxi c T cel l s , na tura l ki l l er cel l s , a nd ma cropha ges i n mul ti pl e ti s s ues
Certa i n a s pects of i mmune functi on, s uch a s na tura l ki l l er cel l a nd cytotoxi c T-cel l a cti vi ty, a re a bnorma l .
HLH i s uncommon. It a ffects mos tl y i nfa nts < 18 mo. HLH ca n be
Fa mi l i a l (pri ma ry)
Acqui red (s econda ry)
In both forms , geneti c a bnorma l i ti es , cl i ni ca l ma ni fes ta ti ons , a nd outcomes tend to be s i mi l a r. Acqui red HLH ca n be a s s oci a ted wi th other
i mmune di s orders (eg, l eukemi a s , l ymphoma s , SLE, RA, pol ya rteri ti s nodos a , s a rcoi dos i s , progres s i ve s ys temi c s cl eros i s , Sjogren's s yndrome,
Ka wa s a ki di s ea s e) a nd ca n occur i n ki dney or l i ver tra ns pl a nt reci pi ents . Acqui red HLH ma y be s econda ry to other di s orders or to
i mmunos uppres s i ve regi mens us ed to trea t them or pos s i bl y to i nfecti ons .
Symptoms and Signs
Common ea rl y ma ni fes ta ti ons i ncl ude fever, hepa tomega l y, s pl enomega l y, ra s h, l ympha denopa thy, a nd neurol ogi c a bnorma l i ti es (eg, s ei zures ,
reti na l hemorrha ges , a ta xi a , a l tered cons ci ous nes s or coma ). Bone l es i ons ma y occur, a nd cl i ni ca l ma ni fes ta ti ons ma y mi mi c chi l d a bus e.
Diagnosis
Speci fi c cl i ni ca l a nd tes ti ng cri teri a
HLH i s s us pected i n chi l dren wi th unexpl a i ned recurrent i nfecti ons a nd typi ca l l a bora tory a bnorma l i ti es (cytopeni a s , coa gul opa thy, a bnorma l l i ver
functi on tes t res ul ts , hi gh s erum ferri ti n l evel s ) or wi th typi ca l s ymptoms a nd s i gns .
Di a gnos i s requi res the pres ence of > 5 of the fol l owi ng cri teri a :
Fever (pea k tempera ture of > 38.5C for > 7 da ys )
Spl enomega l y (s pl een pa l pa bl e > 3 cm bel ow cos ta l ma rgi n)
Cytopeni a i nvol vi ng > 2 cel l l i nes (Hb < 9 g/dL, a bs ol ute neutrophi l count < 100/L, pl a tel ets < 100,000/L)
Hypertri gl yceri demi a (fa s ti ng tri gl yceri des > 2.0 mmol /L or > 3 s ta nda rd devi a ti ons [SD] more tha n norma l va l ue for a ge) or hypofi bri nogenemi a
(fi bri nogen < 1.5 g/L or > 3 SD l es s tha n norma l va l ue for a ge)
Hemopha gocytos i s (i n bi ops y s a mpl es of bone ma rrow, s pl een, or l ymph nodes )
Low or a bs ent na tura l ki l l er cel l a cti vi ty
Serum ferri ti n > 500 g/L pl us el eva ted s ol ubl e IL-2 (CD25) l evel s (> 2400 U/mL or very hi gh for a ge)
Beca us e s ome of thes e tes ts ma y not be wi del y a va i l a bl e a nd HLH i s uncommon, pa ti ents a re us ua l l y referred to s peci a l i zed centers for
eva l ua ti on.
Treatment
Hema topoi eti c s tem cel l tra ns pl a nta ti on a nd chemothera py
Trea tment s houl d be s ta rted i f the di s order i s s us pected, even i f not a l l di a gnos ti c cri teri a a re ful fi l l ed. Pa ti ents a re us ua l l y trea ted by a pedi a tri c
hema tol ogi s t a nd i n a referra l center experi enced i n trea ti ng pa ti ents wi th HLH. Dependi ng on the pres ence of fa ctors s uch a s a fa mi l y hi s tory of
HLH, coexi s ti ng i nfecti ons , a nd demons tra ted i mmune s ys tem defects , trea tment ca n i nvol ve combi na ti ons of hema topoi eti c s tem cel l
tra ns pl a nta ti on, dexa metha s one, cycl os pori ne, etopos i de, a nd methotrexa te.
Rosai-Dorfman Disease
(Si nus Hi s ti ocytos i s Wi th Ma s s i ve Lympha denopa thy)
Rosai-Dorfman disease is a rare disorder characterized by accumulation of histiocytes and massive lymphadenopathy, particularly in the neck and head.
Ros a i -Dorfma n di s ea s e i s mos t common a mong pa ti ents < 20 yr, pa rti cul a rl y bl a cks . Ca us e i s unknown.
The mos t common pres enti ng s ymptoms a re fever a nd ma s s i ve, pa i nl es s cervi ca l a denopa thy. Other noda l s i tes , i ncl udi ng the medi a s ti num,
retroperi toneum, a xi l l a e, a nd i ngui na l regi on, ma y be i nvol ved, a s ma y the na s a l ca vi ty, s a l i va ry gl a nd ti s s ue, other regi ons of the hea d a nd neck,
a nd CNS. Other ma ni fes ta ti ons ma y i ncl ude l yti c bone l es i ons , pul mona ry nodul es , a nd ra s h. The bone ma rrow a nd s pl een a re typi ca l l y s pa red.
La bora tory tes ti ng us ua l l y s hows l eukocytos i s , pol ycl ona l hyperga mma gl obul i nemi a , hypochromi c or normocyti c a nemi a , a nd el eva ted ESR.
The di s order commonl y res ol ves wi thout trea tment. Trea tment i s uncerta i n; chemothera py ha s been tri ed.
Chapter 116. Myeloproliferative Disorders

Introduction
The myel oprol i fera ti ve di s orders a re cha ra cteri zed by a bnorma l prol i fera ti on of one or more hema topoi eti c cel l l i nes or connecti ve ti s s ue
el ements . They i ncl ude
Es s enti a l thrombocythemi a
Pri ma ry myel ofi bros i s
Pol ycythemi a vera
Chroni c myel ocyti c l eukemi a (s ee p. 1012)
Es s enti a l thrombocythemi a , pri ma ry myel ofi bros i s , a nd pol ycythemi a vera a re Phi l a del phi a chromos ome-nega ti ve myel oprol i fera ti ve di s orders .
Myel oprol i fera ti ve di s orders , pa rti cul a rl y chroni c myel ocyti c l eukemi a , s ometi mes l ea d to a cute l eukemi a ; s ome hema tol ogi s ts a l s o cl a s s i fy
hypereos i nophi l i c s yndrome a nd ma s tocytos i s a s myel oprol i fera ti ve di s orders . However, mos t experts a rgue tha t thes e di s orders a re s uffi ci entl y
di fferent a nd omi t them.
Ea ch di s order i s i denti fi ed a ccordi ng to i ts predomi na nt fea ture or s i te of prol i fera ti on (s ee
Ta bl e 116-1). Des pi te overl a p, ea ch di s order ha s a s omewha t typi ca l cons tel l a ti on of cl i ni ca l fea tures , l a bora tory fi ndi ngs , a nd cours e. Al though
prol i fera ti on of one cel l l i ne ma y domi na te the cl i ni ca l pi cture, ea ch di s order i s typi ca l l y ca us ed by cl ona l prol i fera ti on of a pl uri potent s tem cel l ,
ca us i ng va ryi ng degrees of a bnorma l prol i fera ti on of RBC, WBC, a nd pl a tel et precurs ors i n the bone ma rrow. Thi s a bnorma l cl one does not,
however, produce bone ma rrow fi brobl a s ts , whi ch ca n prol i fera te i n pol ycl ona l rea cti ve fa s hi on.
An a bnorma l i ty of a tyros i ne ki na s e ca l l ed JAK2, i nvol ved i n the bone ma rrow res pons e to erythropoi eti n, contri butes to the ca us e of pol ycythemi a
vera a nd ca us es a hi gh proporti on of ca s es of es s enti a l thrombocythemi a a nd myel ofi bros i s .
[Table 116-1. Cl a s s i fi ca ti on of Myel oprol i fera ti ve Di s orders ]
Essential Thrombocythemia
(Es s enti a l Thrombocytos i s ; Pri ma ry Thrombocythemi a )
Essential thrombocythemia (ET) is characterized by an increased platelet count, megakaryocytic hyperplasia, and a hemorrhagic or thrombotic tendency.
Symptoms and signs may include weakness, headaches, paresthesias, bleeding, splenomegaly, and erythromelalgia with digital ischemia. Diagnosis is based on a
platelet count > 450,000/L, normal RBC mass or normal Hct in the presence of adequate iron stores, absence of myelofibrosis, the Philadelphia chromosome (or
BCR-ABL rearrangement), and any other disorder that could cause thrombocytosis. Treatment is controversial but may include aspirin. Patients > 60 yr and those
with previous thromboses and transient ischemic attacks require cytotoxic drugs to decrease risk of thromboses. Data suggest that risk of thrombosis does not
correlate with platelet count, although anecdotal experience suggests otherwise.
Pathophysiology
ET i s a typi ca l l y cl ona l a bnorma l i ty of a mul ti potent hema topoi eti c s tem cel l . However, s ome women who ful fi l l di a gnos ti c cri teri a for ET ha ve
pol ycl ona l hema topoi es i s . ET us ua l l y occurs wi th bi moda l pea ks of between a ges 50 a nd 70 yr a nd a s epa ra te pea k a mong young fema l es .
Pl a tel et producti on i s i ncrea s ed. Pl a tel et s urvi va l i s us ua l l y norma l , a l though i t ma y decrea s e due to s pl eni c s eques tra ti on a nd i n pa ti ents wi th
erythromel a l gi a wi th di gi ta l i s chemi a .
In el derl y pa ti ents wi th a theros cl eros i s , i ncrea s ed pl a tel ets ma y l ea d to s eri ous bl eedi ng or, more commonl y, thrombos i s . Thrombos i s i s the
ma jor ca us e of morbi di ty a nd morta l i ty. Recent s tudi es i ndi ca te tha t a n el eva ted l eukocyte count i s a ma jor i ndependent ri s k fa ctor for
thrombos es . Al though a necdota l l y (a nd i ntui ti vel y), el eva ted pl a tel et count ma y i ncrea s e the ri s k of thrombos i s , one s tudy found a n i nvers e
rel a ti ons hi p between a bs ol ute pl a tel et count a nd thromboti c ri s k. Bl eedi ng i s more l i kel y wi th extreme thrombocytos i s (i e, > 1.5 mi l l i on
pl a tel ets /L) due to a n a cqui red von Wi l l ebra nd's fa ctor defi ci ency.
Symptoms and Signs
Common s ymptoms a re
Wea knes s
Hemorrha ge
Gout
Ocul a r mi gra i nes
Pa res thes i a s of the ha nds a nd feet
Thrombos i s ma y ca us e s ymptoms i n the a ffected s i te (eg, neurol ogi c defi ci ts wi th s troke or tra ns i ent i s chemi c a tta ck, l eg pa i n, s wel l i ng or both
wi th l ower extremi ty thrombos i s , ches t pa i n a nd dys pnea wi th pul mona ry embol i s m). Bl eedi ng i s us ua l l y mi l d a nd ma ni fes ts a s epi s ta xi s , ea s y
brui s a bi l i ty, or GI bl eedi ng. Di gi ta l i s chemi a ma y occur, a nd s pl enomega l y (us ua l l y not extendi ng > 3 cm bel ow the l eft cos ta l ma rgi n) occurs i n <
50% of pa ti ents . Hepa tomega l y ma y ra rel y occur. In pregna nt pa ti ents , thrombos i s ma y ca us e recurrent s ponta neous a borti ons .
Diagnosis
CBC a nd peri phera l bl ood s mea r
Cytogeneti c s tudi es
Pos s i bl y bone ma rrow exa mi na ti on
ET s houl d be cons i dered i n pa ti ents i n whom common rea cti ve ca us es (s ee p. 999) a re excl uded. If ET i s s us pected, CBC, peri phera l bl ood s mea r,
a nd cytogeneti c s tudi es , i ncl udi ng Phi l a del phi a chromos ome or BCR-ABL a s s a y, s houl d be done. Some a uthori ti es recommend bone ma rrow
exa mi na ti on, but a l though cl a s s i c ET morphol ogi c a bnorma l i ti es ha ve been des cri bed, the di a gnos ti c va l ue of bone ma rrow exa mi na ti on i s not
es ta bl i s hed. The pl a tel et count ca n be > 1,000,000/L but ma y be a s l ow a s 450,000/L. Pl a tel et count ma y decrea s e s ponta neous l y duri ng
pregna ncy. The peri phera l s mea r ma y s how pl a tel et a ggrega tes , gi a nt pl a tel ets , a nd mega ka ryocyte fra gments . The bone ma rrow s hows
mega ka ryocyti c hyperpl a s i a , wi th a n a bunda nce of pl a tel ets bei ng rel ea s ed. Bone ma rrow i ron i s pres ent. To di s ti ngui s h from other
myel oprol i fera ti ve di s orders tha t produce thrombocytos i s , the di a gnos i s of ET requi res a norma l Hct, MCV, a nd i ron s tudi es ; a bs ence of the
Phi l a del phi a chromos ome a nd BCR-ABL tra ns l oca ti on; a nd a bs ence of tea rdrop-s ha ped RBCs ; there ma y be s i gni fi ca nt i ncrea s e i n bone ma rrow
fi bros i s (pres ent i n i di opa thi c myel ofi bros i s ). The JAK2V617F muta ti on occurs i n a bout 50% of pa ti ents , a nd a s ma l l mi nori ty of ET pa ti ents ha s
a cqui red s oma ti c thrombopoi eti n receptor gene muta ti ons (c-mpl).
Prognosis
Li fe expecta ncy i s nea r norma l . Al though s ymptoms a re common, the cours e of the di s ea s e i s often beni gn. Seri ous a rteri a l a nd venous thromboti c
compl i ca ti ons a re ra re but ca n be l i fe-threa teni ng. Leukemi c tra ns forma ti on occurs i n < 2% of pa ti ents but ma y i ncrea s e a fter expos ure to cytotoxi c
thera py, es peci a l l y a l kyl a ti ng a gents .
Treatment
As pi ri n
Pl a tel et-l oweri ng drugs (eg, hydroxyurea , a na grel i de)
Ra rel y pl a tel etpheres i s
For mi l d va s omotor s ymptoms (eg, hea da che, mi l d di gi ta l i s chemi a , erythromel a l gi a ) a nd to decrea s e the ri s k of thrombos i s i n l ow-ri s k pa ti ents ,
a s pi ri n 81 mg po once/da y ma y be s uffi ci ent. Al s o, mos t pregna nt pa ti ents a re gi ven a s pi ri n. Us e i n l ow-ri s k pa ti ents i s a ccepta bl e but not da ta proven.
Beca us e prognos i s i s often good, potenti a l l y toxi c drugs tha t l ower the pl a tel et count s houl d be us ed s pa ri ngl y. Genera l l y a greed i ndi ca ti ons for
s uch thera py a re
Previ ous thrombos es or tra ns i ent i s chemi c a tta ck
Age > 60 yr
Other i ndi ca ti ons a re controvers i a l . Pa ti ents wi th s i gni fi ca nt bl eedi ng a nd extreme thrombocytos i s (hi gh-ri s k pa ti ents ) ma y need thera py to l ower
the pl a tel et count. It i s uncl ea r whether a s ymptoma ti c pa ti ents < 60 yr need pl a tel et-l oweri ng drugs . Myel os uppres s i ve drugs to l ower pl a tel et
count i ncl ude a na grel i de, i nterferon a l fa -2b, a nd hydroxyurea (s ometi mes wi th l ow-dos e a s pi ri n). Hydroxyurea i s genera l l y cons i dered the drug of
choi ce, a l though s ome cl i ni ci a ns prefer a na grel i de. Beca us e a na grel i de a nd hydroxyurea cros s the pl a centa , they a re not us ed duri ng pregna ncy;
i nterferon a l fa -2b ca n be us ed i n pregna nt women when neces s a ry.
Dos a ge a nd moni tori ng a re des cri bed i n the trea tment of pol ycythemi a vera (s ee p. 1000). The conventi ona l a i m of thera py i s a pl a tel et count <
450,000/L wi thout s i gni fi ca nt cl i ni ca l toxi ci ty or s uppres s i on of other bone ma rrow el ements ; however, thi s goa l needs to be reeva l ua ted i n vi ew
of recent da ta s ugges ti ng a n i nvers e rel a ti ons hi p between pl a tel et count a nd thromboti c ri s k.
Plateletpheresis ha s been us ed i n ra re pa ti ents wi th s eri ous hemorrha ge a nd recurrent thrombos i s or before emergency s urgery to i mmedi a tel y
reduce the pl a tel et count; thi s procedure, however, i s ra rel y neces s a ry. Due to the l ong ha l f-l i fe of pl a tel ets (7 da ys ), hydroxyurea a nd a na grel i de
do not provi de a n i mmedi a te effect.
Thrombocytosis
(Seconda ry Thrombocythemi a )
Thrombocytos i s ca n devel op s econda ry to
Chroni c i nfl a mma tory di s orders , eg, RA, i nfl a mma tory bowel di s ea s e, TB, s a rcoi dos i s , Wegener's gra nul oma tos i s
Acute i nfecti on
Hemorrha ge
Iron defi ci ency
Hemol ys i s
Ca ncer (pa rti cul a rl y Hodgki n l ymphoma , non-Hodgki n l ymphoma )

Spl enectomy
Myel oprol i fera ti ve a nd hema tol ogi c di s orders (eg, pol ycythemi a vera , chroni c myel ocyti c l eukemi a , s i derobl a s ti c a nemi a , myel odys pl a s i a [5qs yndrome], i di opa thi c myel odys pl a s i a )
There a re a l s o congeni ta l fa mi l i a l thrombocytos es s uch a s thos e due to thrombopoi eti n a nd thrombopoi eti n receptor gene muta ti ons .
Pl a tel et functi on i s us ua l l y norma l . Unl i ke ET, thrombocytos i s does not i ncrea s e the ri s k of thromboti c or hemorrha gi c compl i ca ti ons unl es s
pa ti ents ha ve s evere a rteri a l di s ea s e or prol onged i mmobi l i ty. Wi th s econda ry thrombocytos i s , the pl a tel et count i s us ua l l y < 1,000,000/L, a nd
the ca us e ma y be obvi ous from the hi s tory a nd phys i ca l exa mi na ti on (perha ps wi th confi rma tory tes ti ng). CBC a nd peri phera l bl ood s mea r s houl d
hel p s ugges t i ron defi ci ency or hemol ys i s . If a ca us e i s not obvi ous , eva l ua ti on for a myel oprol i fera ti ve di s order s houl d be cons i dered.
Trea tment of the underl yi ng di s order us ua l l y returns the pl a tel et count to norma l .
Primary Myelofibrosis
(Agnogeni c Myel oi d Meta pl a s i a ; Myel ofi bros i s wi th Myel oi d Meta pl a s i a )
Primary myelofibrosis (PMF) is a chronic, usually idiopathic disorder characterized by bone marrow fibrosis, splenomegaly, and anemia with immature and
teardrop-shaped RBCs. Diagnosis requires bone marrow examination and exclusion of other conditions that can cause myelofibrosis (secondary myelofibrosis).
Treatment is usually supportive.
Pathophysiology
Myel ofi bros i s i s exces s i ve bone ma rrow fi bros i s a nd l os s of hema topoi eti c cel l s , wi th s ubs equent ma rked i ncrea s e i n extra medul l a ry
hema topoi es i s (pri ma ri l y i n the l i ver a nd s pl een, whi ch enl a rge s i gni fi ca ntl y). Myel ofi bros i s ma y be pri ma ry or s econda ry to a number of
hema tol ogi c, ma l i gna nt, a nd nonma l i gna nt condi ti ons (s ee
Ta bl e 116-2).
PMF i s more common tha n s econda ry myel ofi bros i s a nd res ul ts from neopl a s ti c tra ns forma ti on of a mul ti potent bone ma rrow s tem cel l . Thes e
PMF progeny cel l s s ti mul a te bone ma rrow fi brobl a s ts (whi ch a re not pa rt of the neopl a s ti c tra ns forma ti on) to s ecrete exces s i ve col l a gen. The pea k
i nci dence of PMF i s between 50 a nd 70 yr.
In PMF, l a rge numbers of nucl ea ted RBCs (normobl a s ts ) a nd gra nul ocytes a re rel ea s ed i nto the ci rcul a ti on (l eukoerythrobl a s tos i s ). Serum LDH
l evel i s often el eva ted. Bone ma rrow fa i l ure eventua l l y occurs , wi th cons equent a nemi a a nd thrombocytopeni a . Ra pi dl y
[Table 116-2. Condi ti ons As s oci a ted wi th Myel ofi bros i s ]
progres s i ve, chemothera py-i ncura bl e a cute l eukemi a devel ops i n a bout 10% of pa ti ents .
Ma l i gna nt or a cute myel ofi bros i s , a n unus ua l va ri a nt, ha s a more ra pi dl y progres s i ve downhi l l cours e; thi s va ri a nt ma y a ctua l l y be a true
mega ka ryocyti c l eukemi a .
Symptoms and Signs
In ma ny pa ti ents , myel ofi bros i s i s a s ymptoma ti c. Other pa ti ents ha ve s ymptoms of a nemi a , s pl enomega l y, or, i n l a ter s ta ges , genera l ma l a i s e,
wei ght l os s , fever, or s pl eni c i nfa rcti on. Hepa tomega l y occurs i n a s i gni fi ca nt proporti on of pa ti ents . Lympha denopa thy i s ra re.
Diagnosis
PMF s houl d be s us pected i n pa ti ents wi th s pl enomega l y, s pl eni c i nfa rcti on, a nemi a , or unexpl a i ned el eva ti ons i n LDH. If the di s order i s
s us pected, CBC s houl d be done a nd peri phera l bl ood morphol ogy a nd bone ma rrow s houl d be exa mi ned, i ncl udi ng cytogeneti c tes ti ng. If
myel ofi bros i s i s detected on bone ma rrow exa mi na ti on (eg, by i ncrea s ed fi brobl a s ts a nd col l a gen a s detected by reti cul i n s ta i ni ng,
os teos cl eros i s ), other di s orders a s s oci a ted wi th myel ofi bros i s (s ee Ta bl e 116-2) s houl d be excl uded by a ppropri a te cl i ni ca l a nd l a bora tory
eva l ua ti on.
Anemi a i s typi ca l l y pres ent a nd us ua l l y i ncrea s es over ti me. Bl ood cel l morphol ogy i s va ri a bl e. RBCs a re poi ki l ocyti c. Reti cul ocytos i s a nd
pol ychroma tophi l i a ma y be pres ent; tea rdrop-s ha ped RBCs (da cryocytes ) a re cha ra cteri s ti c morphol ogi c fea tures . Nucl ea ted RBCs a nd neutrophi l
precurs ors a re typi ca l l y pres ent i n peri phera l bl ood. WBC counts a re us ua l l y i ncrea s ed but a re hi ghl y va ri a bl e; a l ow WBC count tends to i ndi ca te a
poor prognos i s . Neutrophi l s a re us ua l l y i mma ture, a nd myel obl a s ts ma y be pres ent, even i n the a bs ence of a cute l eukemi a . Pl a tel et counts
i ni ti a l l y ma y be hi gh, norma l , or decrea s ed; however, thrombocytopeni a tends to s upervene a s the di s order progres s es .
If di a gnos i s i s di ffi cul t, CD34+ cel l count on peri phera l bl ood ca n be done. Level s a re much hi gher i n pa ti ents wi th PMF.
Bone ma rrow a s pi ra ti on i s us ua l l y dry. Beca us e demons tra ti on of bone ma rrow fi bros i s i s requi red a nd fi bros i s ma y not be uni forml y di s tri buted,
bi ops y s houl d be repea ted a t a di fferent s i te i f the fi rs t bi ops y i s nondi a gnos ti c.
Prognosis
The medi a n s urvi va l i s 5 yr from ons et, but va ri a ti on i s wi de; s ome pa ti ents ha ve a ra pi dl y progres s i ng di s order wi th s hort s urvi va l a nd s ome ha ve
a del a y i n i ni ti a l di a gnos i s . Unfa vora bl e prognos ti c ma rkers i ncl ude Hb < 10 g/dL, hi s tory of tra ns fus i ons , l eukocytos i s a nd l eukopeni a , a nd
pl a tel et count < 100,000/L. Pa ti ents i n the l ea s t fa vora bl e ri s k group us ua l l y s urvi ve < 1 yr. No trea tment revers es or control s the underl yi ng
proces s except for a l l ogenei c s tem cel l tra ns pl a nt.
Treatment
Symptoma ti c thera py
Someti mes a l l ogenei c s tem cel l tra ns pl a nta ti on
Trea tment i s di rected a t s ymptoms a nd compl i ca ti ons . Androgens , s pl enectomy, chemothera py, a nd s pl eni c embol i za ti on a nd ra di a ti on thera py
ha ve been us ed for pa l l i a ti on. For pa ti ents wi th l ow erythropoi eti n l evel s rel a ti ve to the degree of a nemi a , erythropoi eti n ma y i ncrea s e Hct
s uffi ci entl y; otherwi s e, RBC tra ns fus i on ma y be neces s a ry. For younger pa ti ents wi th a dva nced di s ea s e, a l l ogenei c s tem cel l tra ns pl a nta ti on
s houl d be cons i dered. Nonmyel oa bl a ti ve a l l ogenei c s tem cel l tra ns pl a nta ti on ha s been s ucces s ful l y us ed even i n ol der pa ti ents ; however, i t i s
us ua l l y l i mi ted to pa ti ents < 65 yr.
Inhi bi tors of the JAK pa thwa y a ppea r to ha ve a s i gni fi ca nt effect on s pl enomega l y a nd a bnorma l peri phera l hema tol ogi c a bnorma l i ti es . Thes e
drugs a re i n ea rl y tri a l s .
Polycythemia Vera
(Pri ma ry Pol ycythemi a )
Polycythemia vera (PV) is an idiopathic chronic myeloproliferative disorder characterized by an increase in RBC mass, which often manifests as an increased Hct.
There is an increased risk of thrombosis and, rarely, acute leukemia and myelofibrotic transformation. Hepatosplenomegaly may also occur. Diagnosis is made by
CBC, testing for JAK2 mutations, and clinical criteria. Treatment involves low-dose aspirin for all patients and myelosuppressive drugs for high-risk patients;
phlebotomy, once standard, is now controversial.
PV i s the mos t common of the myel oprol i fera ti ve di s orders ; i nci dence i n the US i s es ti ma ted to be 1.9/100,000, wi th i nci dence i ncrea s i ng wi th a ge.
PV ma y be s l i ghtl y more common i n men. The mea n a ge a t di a gnos i s i s a round 60 yr. PV i s very ra re i n chi l dren.
Pathophysiology
PV i nvol ves i ncrea s ed producti on of a l l cel l l i nes , i ncl udi ng RBCs , WBCs , a nd pl a tel ets . Thus , PV i s s ometi mes ca l l ed a pa nmyel os i s beca us e of
el eva ti ons of a l l 3 peri phera l bl ood components . Increa s ed producti on confi ned to the RBC l i ne i s termed erythrocytos i s ; erythrocytos i s ma y occur
wi th PV but i s more commonl y due to other ca us es (s econda ry erythrocytos i s s ee p. 1003). In PV, RBC producti on proceeds i ndependentl y of
erythropoi eti n l evel s .
Extra medul l a ry hema topoi es i s ma y occur i n the s pl een, l i ver, a nd other s i tes tha t ha ve the potenti a l for bl ood cel l forma ti on. Peri phera l bl ood
cel l turnover i ncrea s es . Eventua l l y, progres s i on to a s pent-pha s e ma y occur, wi th a phenotype i ndi s ti ngui s ha bl e from pri ma ry myel ofi bros i s .
Tra ns forma ti on to a cute l eukemi a i s ra re, a l though the ri s k i s i ncrea s ed wi th expos ure to a l kyl a ti ng a gents a nd ra di oa cti ve phos phorus , whi ch
s houl d onl y be us ed ra rel y, i f ever.
Complications: In PV, bl ood vol ume expa nds a nd hypervi s cos i ty devel ops . Pa ti ents a re prone to devel op thrombos i s . Thrombos i s ca n occur i n mos t
bl ood ves s el s , res ul ti ng i n s troke, tra ns i ent i s chemi c a tta cks , deep venous thrombos i s , MI, reti na l a rtery or vei n occl us i on, s pl eni c i nfa rcti on
(often wi th a fri cti on rub), or Budd-Chi a ri s yndrome (s ee p. 261). Previ ous l y, mos t experts bel i eved hypervi s cos i ty wa s the predi s pos i ng fa ctor for
thrombos i s . Newer s tudi es s ugges t tha t ri s k of thrombos i s ma y be pri ma ri l y rel a ted to the degree of l eukocytos i s . However, thi s hypothes i s ha s
yet to be confi rmed i n dedi ca ted, pros pecti ve tri a l s .
Pl a tel ets ma y functi on a bnorma l l y, predi s pos i ng to i ncrea s ed bl eedi ng. Increa s ed cel l turnover ma y ca us e hyperuri cemi a , i ncrea s i ng the ri s k of
gout a nd ura te ki dney s tones .
Genetic basis: Cl ona l hema topoi es i s i s a ha l l ma rk of PV, s ugges ti ng tha t a muta ti on of hema topoi eti c s tem cel l s i s the ca us e of prol i fera ti on. The
JAK2 V617F muta ti on (or one of s evera l other ra rer JAK2 muta ti ons ) i s pres ent i n vi rtua l l y a l l pa ti ents wi th PV. However, one or more other di s ea s ei ni ti a ti ng muta ti ons a l mos t certa i nl y exi s t. Thes e muta ti ons l ea d to s us ta i ned a cti va ti on of the JAK2 protei n, whi ch ca us es exces s cel l producti on,
i ndependent of erythropoi eti n l evel s .
Symptoms and Signs
PV i ts el f i s often a s ymptoma ti c. Occa s i ona l l y, i ncrea s ed red cel l vol ume a nd vi s cos i ty produce wea knes s , hea da che, l i ght-hea dednes s , vi s ua l
di s turba nces , fa ti gue, a nd dys pnea . Pruri tus often occurs , pa rti cul a rl y a fter a hot ba th. The fa ce ma y be red a nd the reti na l vei ns engorged. The
pa l ms a nd feet ma y be red, wa rm, a nd pa i nful , s ometi mes wi th di gi ta l i s chemi a (erythromel a l gi a ). Hepa tomega l y i s common, a nd > 75% of
pa ti ents ha ve s pl enomega l y (whi ch ma y be ma s s i ve).
Thrombos i s ma y ca us e s ymptoms i n the a ffected s i te (eg, neurol ogi c defi ci ts wi th s troke or tra ns i ent i s chemi c a tta ck, l eg pa i n, s wel l i ng or both
wi th l ower extremi ty thrombos i s , uni l a tera l vi s i on l os s wi th reti na l va s cul a r occl us i on).
Bl eedi ng (typi ca l l y GI) occurs i n a bout 10% of pa ti ents .
Hypermeta bol i s m ca n ca us e l ow-gra de fevers a nd wei ght l os s a nd s ugges ts progres s i on to s pent-pha s e pol ycythemi a , whi ch i s cl i ni ca l l y
i ndi s ti ngui s ha bl e from pri ma ry myel ofi bros i s .
Diagnosis
CBC
Tes ti ng for JAK2 muta ti ons
Someti mes bone ma rrow exa mi na ti on a nd s erum erythropoi eti n l evel
Us e of WHO cri teri a
PV i s often fi rs t s us pected beca us e of a n a bnorma l CBC (eg, Hb > 18.5 g/dL i n men or > 16.5 g/dL i n women), but i t mus t be cons i dered i n pa ti ents
wi th s ugges ti ve s ymptoms , pa rti cul a rl y Budd-Chi a ri s yndrome (however, s ome pa ti ents devel op Budd-Chi a ri s yndrome before the Hct i ncrea s es ).
Neutrophi l s a nd pl a tel ets a re often, but not i nva ri a bl y, i ncrea s ed; i n pa ti ents wi th onl y el eva ted Hb, PV ma y be pres ent, but s econda ry
erythrocytos i s , a more common ca us e of el eva ted Hb, mus t fi rs t be cons i dered (s ee p. 1003). PV s houl d a l s o be cons i dered i n the ra re pa ti ent wi th
a norma l Hb l evel but mi crocytos i s a nd evi dence of i ron defi ci ency; thi s combi na ti on of fi ndi ngs ca n occur wi th i ron-l i mi ted hema topoi es i s , whi ch
i s a ha l l ma rk of s ome ca s es of PV.
New WHO cri teri a for di a gnos i s ha ve been es ta bl i s hed (s ee
Ta bl e 116-3). Thus , pa ti ents s us pected of ha vi ng PV typi ca l l y s houl d ha ve tes ti ng for JAK2 muta ti ons ; bone ma rrow exa mi na ti on i s not a l wa ys
neces s a ry.
When done, bone ma rrow typi ca l l y s hows pa nmyel os i s , l a rge a nd cl umped mega ka ryocytes , a nd s ometi mes reti cul i n fi bers . However, no bone
ma rrow fi ndi ngs a bs ol utel y di fferenti a te between PV a nd other di s orders of exces s i ve erythrocytos i s , s uch a s congeni ta l fa mi l i a l pol ycythemi a .
[Table 116-3. WHO Cri teri a for Di a gnos i s of Pol ycythemi a Vera *]
Pa ti ents wi th PV typi ca l l y ha ve l ow or l ow-norma l s erum erythropoi eti n l evel s . El eva ted l evel s s ugges t s econda ry erythrocytos i s .
Someti mes i n vi tro tes ti ng for endogenous erythroi d col ony forma ti on i s done (erythroi d progeni tors from peri phera l bl ood or bone ma rrow from
pa ti ents wi th PV, unl i ke thos e from hea l thy peopl e, ca n form erythroi d cel l s i n cul ture wi thout the a ddi ti on of erythropoi eti n).
RBC ma s s determi na ti on wi th chromi um-l a bel ed RBCs ca n hel p di fferenti a te between true a nd rel a ti ve pol ycythemi a a nd ca n a l s o hel p to
di fferenti a te between PV a nd other myel oprol i fera ti ve di s orders . However, thi s tes t i s techni ca l l y di ffi cul t a nd i s us ua l l y not done due to i ts
l i mi ted a va i l a bi l i ty a nd the fa ct i t ha s been s ta nda rdi zed onl y a t s ea l evel .
Nons peci fi c l a bora tory a bnorma l i ti es tha t ma y occur i n PV i ncl ude el eva ted vi ta mi n B 12 a nd B 12 -bi ndi ng ca pa ci ty, hyperuri cemi a a nd
hyperuri cos uri a (pres ent i n 30% of pa ti ents ), i ncrea s ed expres s i on of PRV-1 gene i n l eukocytes , a nd decrea s ed expres s i on of C-mpl (the receptor
for thrombopoi eti n) i n mega ka ryocytes a nd pl a tel ets . Thes e tes ts a re not needed for di a gnos i s .
Prognosis
Genera l l y, PV i s a s s oci a ted wi th a s hortened l i fe s pa n. Medi a n s urvi va l for a l l pa ti ents i s a round 8 to 15 yr, a l though ma ny pa ti ents l i ve much
l onger. Thrombos i s i s the mos t common ca us e of dea th, fol l owed by compl i ca ti ons of myel ofi bros i s a nd devel opment of l eukemi a .
Treatment
As pi ri n thera py
Pos s i bl y phl ebotomy
Pos s i bl y myel os uppres s i ve thera py
Beca us e PV i s the onl y form of erythrocytos i s for whi ch myel os uppres s i ve thera py ma y be i ndi ca ted, a ccura te di a gnos i s i s cri ti ca l . Thera py mus t be
i ndi vi dua l i zed a ccordi ng to a ge, s ex, medi ca l s ta tus , cl i ni ca l ma ni fes ta ti ons , a nd hema tol ogi c fi ndi ngs . Pa ti ents a re cl a s s i fi ed a s hi gh-ri s k or l owri s k. Hi gh-ri s k pa ti ents a re > 60 yr a nd ha ve a hi s tory of thrombos i s or tra ns i ent i s chemi c a tta cks or both.
Aspirin: As pi ri n (81 to 100 mg po once/da y) reduces the i nci dence of thromboti c compl i ca ti ons . Thus , pa ti ents undergoi ng phl ebotomy a l one or
phl ebotomy a nd myel os uppres s i on s houl d be gi ven a s pi ri n unl es s contra i ndi ca ted. Hi gher dos es of a s pi ri n a re a s s oci a ted wi th a n una ccepta bl y
i ncrea s ed ri s k of bl eedi ng.
Phlebotomy: Phl ebotomy ha s been the ma i ns ta y of thera py for hi gh- a nd l ow-ri s k pa ti ents beca us e experts bel i eved i t decrea s ed the ri s k of
thrombos i s . However, us e of phl ebotomy i s now controvers i a l beca us e recent s tudi es s ugges t tha t the Hct l evel ma y not correl a te wi th ri s k of
thrombos i s , a nd s ome cl i ni ci a ns no l onger a dhere to the s tri ct phl ebotomy gui del i nes . However, thi s i s s ue requi res further s tudy, a nd phl ebotomy
ma y s ti l l be cons i dered for a ny pa ti ent. In a mi nori ty of pa ti ents wi th s ymptoma ti c rubor a nd hypervi s cos i ty s ymptoms , phl ebotomy ca n be
thera peuti c. Common thres hol ds for phl ebotomy a re Hct > 45% i n men a nd > 42% i n women. Ini ti a l l y, 300 to 500 mL of bl ood a re removed every
other da y. Les s bl ood i s removed (i e, 200 to 300 mL twi ce/wk) from el derl y pa ti ents a nd from pa ti ents wi th ca rdi a c or cerebrova s cul a r di s orders .
Once the Hct i s bel ow the thres hol d va l ue, i t i s checked monthl y a nd ma i nta i ned a t thi s l evel by a ddi ti ona l phl ebotomi es a s needed. If neces s a ry,
i ntra va s cul a r vol ume ca n be ma i nta i ned wi th crys ta l l oi d or col l oi d s ol uti ons .
Myelosuppressive therapy: Myel os uppres s i ve thera py i s i ndi ca ted for hi gh-ri s k pa ti ents .
Radioactive phosphorus ( 32 P) ha s l ong been us ed a s a trea tment for PV. It ha s a s ucces s ra te of 80 to 90%. Remi s s i on ma y l a s t 6 mo to s evera l yea rs .
Ra di oa cti ve phos phorus i s wel l tol era ted a nd requi res fewer fol l ow-up vi s i ts once the di s order i s control l ed. However, ra di oa cti ve phos phorus i s
a s s oci a ted wi th a n i ncrea s ed i nci dence of a cute l eukemi c tra ns forma ti on, a nd the l eukemi a tha t devel ops a fter thi s thera py i s often res i s ta nt to
i nducti on chemothera py a nd i s never cura bl e. Thus , us e of ra di oa cti ve phos phorus requi res ca reful pa ti ent s el ecti on (eg, us ed onl y for pa ti ents
who a re expected to di e of other di s orders wi thi n 5 yr). It s houl d be us ed ra rel y; ma ny cl i ni ci a ns do not us e i t a t a l l .
Hydroxyurea, whi ch i nhi bi ts the enzyme ri bonucl eos i de di phos pha te reducta s e, i s a l s o us ed to a chi eve myel os uppres s i on. It ha s not been cl ea rl y
s hown to be l eukemogeni c; however, the pos s i bi l i ty of l eukemi c convers i on, a l though s ma l l , does exi s t. Hydroxyurea i s s ta rted a t a dos e of 500 to
1000 mg po once/da y. Pa ti ents a re moni tored wi th a weekl y CBC. When a s tea dy s ta te i s a chi eved, the i nterva l between CBCs i s l engthened to 2 wk
a nd then to 4 wk. If the WBC count fa l l s to < 4000/L or the pl a tel et count to < 100,000/L, hydroxyurea i s wi thhel d a nd rei ns ti tuted a t 50% of the
dos e when thos e va l ues norma l i ze. It i s rea s ona bl e to ti tra te the hydroxyurea dos e to a chi eve a nea r-norma l Hct, a l though there i s no evi dence
tha t ti tra ti on i s benefi ci a l . It i s l i kel y tha t norma l i za ti on of the WBC count i s more i mporta nt, but thi s theory ha s not been demons tra ted
pros pecti vel y. There i s no evi dence tha t norma l i za ti on of the pl a tel et count i s neces s a ry, a nd s ome cl i ni ci a ns do not i ncrea s e the hydroxyurea
dos e a s l ong a s the pl a tel et count i s < 1.5 mi l l i on/L. Acute toxi ci ty i s i nfrequent; occa s i ona l l y pa ti ents devel op a ra s h, GI s ymptoms , fever, na i l
cha nges , a nd s ki n ul cers , whi ch ma y requi re s toppi ng hydroxyurea .
Interferon alfa-2b ha s been us ed i f hydroxyurea does not control bl ood counts or i s not tol era ted. However, pegyl a ted i nterferon a l fa -2b i s us ua l l y
wel l tol era ted. Thi s drug a ffects the di s ea s e a t the mol ecul a r l evel wi th rel a ti vel y l ow toxi ci ty.
Al kyl a ti ng a gents a re l eukemogeni c a nd s houl d be a voi ded.
Severa l i nhi bi tors of the JAK2 pa thwa y a re currentl y i n cl i ni ca l tri a l s , pri ma ri l y i n pa ti ents wi th a dva nced myel ofi bros i s .
Treatment of complications: Hyperuri cemi a s houl d be trea ted wi th a l l opuri nol 300 mg po once/da y i f i t ca us es s ymptoms or i f pa ti ents a re recei vi ng
s i mul ta neous myel os uppres s i ve thera py. Pruri tus ma y be ma na ged wi th a nti hi s ta mi nes but i s often di ffi cul t to control ; myel os uppres s i on often i s
mos t effecti ve. Chol es tyra mi ne 4 g po ti d, cyprohepta di ne 4 mg po ti d to qi d, ci meti di ne 300 mg po qi d, or pa roxeti ne 20 to 40 mg po once/da y ma y
be s ucces s ful . After ba thi ng, the s ki n s houl d be dri ed gentl y. As pi ri n rel i eves s ymptoms of erythromel a l gi a ; hi gher dos es ma y be requi red but
cl ea rl y i ncrea s e the ri s k of hemorrha ge.
Secondary Erythrocytosis
(Seconda ry Pol ycythemi a )
Secondary erythrocytosis is erythrocytosis that develops secondary to circulating erythropoiesis-stimulating substances.
In s econda ry erythrocytos i s , onl y the RBC l i ne i s i ncrea s ed.
Common causes of s econda ry erythrocytos i s i ncl ude
Smoki ng
Chroni c a rteri a l hypoxemi a
Tumors (tumor-a s s oci a ted erythrocytos i s )
Less common ca us es i ncl ude certa i n congeni ta l di s orders s uch a s
Hi gh O2 -a ffi ni ty hemogl obi nopa thi es
Erythropoi eti n receptor muta ti ons
Chuva s h pol ycythemi a (i n whi ch a muta ti on i n the VHL gene a ffects the hypoxi a -s ens i ng pa thwa y)
Prol i ne hydroxyl a s e 2 a nd hypoxi a -i nduci bl e fa ctor 2 (HIF-2) muta ti ons
Spuri ous erythrocytos i s ma y occur wi th hemoconcentra ti on (eg, from burns , di a rrhea , di ureti cs ).
In pa ti ents who s moke, revers i bl e erythrocytos i s res ul ts ma i nl y from ti s s ue hypoxi a due to el eva ti on of bl ood ca rboxyhemogl obi n concentra ti on;
l evel s often norma l i ze wi th s moki ng ces s a ti on.
Pa ti ents wi th chroni c hypoxemi a (a rteri a l Hb O2 concentra ti on < 92%), typi ca l l y due to l ung di s ea s e, ri ght-to-l eft i ntra ca rdi a c s hunts , rena l
tra ns pl a nta ti on, prol onged expos ure to hi gh a l ti tudes (s ee p. 3275), or hypoventi l a ti on s yndromes , often devel op erythrocytos i s . The pri ma ry
trea tment i s to a l l evi a te the underl yi ng condi ti on, but O2 thera py ma y hel p, a nd s ome degree of phl ebotomy ma y decrea s e vi s cos i ty a nd a l l evi a te
s ymptoms . Beca us e i n s ome ca s es the el eva ted Hct i s phys i ol ogi c, phl ebotomy ma y ca us e ha rm beca us e i t decrea s es ti s s ue oxygena ti on.
Tumor-a s s oci a ted erythrocytos i s ca n occur when rena l tumors , cys ts , hepa toma s , cerebel l a r hema ngi obl a s toma s , or uteri ne l ei omyoma s s ecrete
erythropoi eti n. Remova l of the l es i on ma y be cura ti ve.
Hi gh O2 -a ffi ni ty hemogl obi nopa thi es a re very ra re. Thi s di a gnos i s i s s ugges ted by a fa mi l y hi s tory of erythrocytos i s ; i t i s es ta bl i s hed by mea s uri ng
the P50 (the pa rti a l pres s ure of O2 a t whi ch Hb becomes 50% s a tura ted) a nd, i f pos s i bl e, determi ni ng the compl ete oxyhemogl obi n di s s oci a ti on
curve. Sta nda rd Hb el ectrophores i s ma y be norma l a nd ca nnot rel i a bl y excl ude thi s ca us e of erythrocytos i s .
Evaluation: Tes ts done when erythrocytos i s i s pres ent i ncl ude
Arteri a l O2 s a tura ti on
Serum erythropoi eti n l evel s

P50
A l ow or l ow-norma l s erum erythropoi eti n l evel s ugges ts PV. Pa ti ents wi th hypoxi a -i nduced erythrocytos i s ha ve a n el eva ted l evel or
i na ppropri a tel y norma l l evel for thei r el eva ted Hct. Pa ti ents wi th tumor-a s s oci a ted erythrocytos i s typi ca l l y ha ve el eva ted erythropoi eti n l evel s .
Pa ti ents wi th el eva ted erythropoi eti n l evel s or mi cros copi c hema turi a s houl d undergo a bdomi na l i ma gi ng, CNS i ma gi ng, or both to s eek a rena l
l es i on or other tumor s ource of erythropoi eti n.
P50 mea s ures the a ffi ni ty of Hb for O2 ; a norma l res ul t excl udes a hi gh-a ffi ni ty Hb (a fa mi l i a l a bnorma l i ty) a s the ca us e of erythrocytos i s .
Chapter 117. Leukemias

Introduction
The l eukemi a s a re ca ncers of the WBCs i nvol vi ng bone ma rrow, ci rcul a ti ng WBCs , a nd orga ns s uch a s the s pl een a nd l ymph nodes .
Etiology
Ri s k of devel opi ng mos t l eukemi a s i ncrea s es wi th
Hi s tory of expos ure to i oni zi ng ra di a ti on (eg, pos t-a tom bomb i n Na ga s a ki a nd Hi ros hi ma ) or to chemi ca l s (eg, benzene)
Pri or trea tment wi th certa i n a nti neopl a s ti c drugs , pa rti cul a rl y proca rba zi ne, ni tros urea s (cycl ophos pha mi de, mel pha l a n), a nd
epi podophyl l otoxi ns (etopos i de, teni pos i de)
Infecti on wi th a vi rus (eg, huma n T-l ymphotrophi c vi rus 1 a nd 2, Eps tei n-Ba rr vi rus )
Chromos oma l tra ns l oca ti ons
Preexi s ti ng condi ti ons , i ncl udi ng i mmunodefi ci ency di s orders , chroni c myel oprol i fera ti ve di s orders , a nd chromos oma l di s orders (eg, Fa nconi 's
a nemi a , Bl oom s yndrome, a ta xi a -tel a ngi ecta s i a , Down s yndrome, i nfa nti l e X-l i nked a ga mma gl obul i nemi a )
Pathophysiology
Ma l i gna nt tra ns forma ti on us ua l l y occurs a t the pl uri potent s tem cel l l evel , a l though i t s ometi mes i nvol ves a commi tted s tem cel l wi th more
l i mi ted ca pa ci ty for di fferenti a ti on. Abnorma l prol i fera ti on, cl ona l expa ns i on, a nd di mi ni s hed a poptos i s (progra mmed cel l dea th) l ea d to
repl a cement of norma l bl ood el ements wi th ma l i gna nt cel l s .
Ma ni fes ta ti ons of l eukemi a a re due to s uppres s i on of norma l bl ood cel l forma ti on a nd orga n i nfi l tra ti on by l eukemi c cel l s . Inhi bi tory fa ctors
produced by l eukemi c cel l s a nd repl a cement of ma rrow s pa ce ma y s uppres s norma l hema topoi es i s , wi th ens ui ng a nemi a , thrombocytopeni a , a nd
gra nul ocytopeni a . Orga n i nfi l tra ti on res ul ts i n enl a rgement of the l i ver, s pl een, a nd l ymph nodes , wi th occa s i ona l ki dney a nd gona da l
i nvol vement. Meni ngea l i nfi l tra ti on res ul ts i n cl i ni ca l fea tures a s s oci a ted wi th i ncrea s i ng i ntra cra ni a l pres s ure (eg, cra ni a l nerve pa l s i es ).
Classification
Leukemi a s were ori gi na l l y termed a cute or chroni c ba s ed on l i fe expecta ncy but now a re cl a s s i fi ed a ccordi ng to cel l ul a r ma turi ty.
Acute leukemias cons i s t of predomi na ntl y i mma ture, poorl y di fferenti a ted cel l s (us ua l l y bl a s t forms ). Acute l eukemi a s a re di vi ded i nto l ymphocyti c
(ALL) a nd myel ocyti c (AML) types , whi ch ma y be further s ubdi vi ded by the French-Ameri ca n-Bri ti s h (FAB) cl a s s i fi ca ti on (s ee
Ta bl e 117-1).
Chronic leukemias ha ve more ma ture cel l s tha n do a cute l eukemi a s . Chroni c l eukemi a s a re des cri bed a s l ymphocyti c (CLL) or myel ocyti c (CMLs ee
Ta bl e 117-2).
Myelodysplastic syndromes i nvol ve progres s i ve bone ma rrow fa i l ure but wi th a n i ns uffi ci ent proporti on of bl a s t cel l s (< 30%) for ma ki ng a defi ni te
di a gnos i s of AML; 40 to 60% of ca s es evol ve i nto AML.
A leukemoid reaction i s ma rked gra nul ocyti c l eukocytos i s (i e, WBC > 30,000/L) produced by norma l bone ma rrow i n res pons e to s ys temi c i nfecti on or
ca ncer. Al though not a neopl a s ti c di s order, a l eukemoi d rea cti on wi th a very hi gh WBC count ma y requi re tes ti ng to di s ti ngui s h i t from CML (s ee p.
1012).
Acute Leukemia
Acute l eukemi a occurs when a hema topoi eti c s tem cel l undergoes ma l i gna nt tra ns forma ti on i nto a pri mi ti ve, undi fferenti a ted cel l wi th a bnorma l
l ongevi ty. Thes e l ymphocytes (a cute l ymphocyti c l eukemi a [ALL]) or myel oi d cel l s (a cute myel ocyti c l eukemi a [AML]) prol i fera te a bnorma l l y,
repl a ci ng norma l ma rrow ti s s ue a nd hema topoi eti c cel l s a nd i nduci ng a nemi a , thrombocytopeni a , a nd gra nul ocytopeni a . Beca us e they a re bl oodborne, they ca n i nfi l tra te va ri ous orga ns a nd s i tes , i ncl udi ng the l i ver, s pl een, l ymph nodes , CNS, ki dneys , a nd gona ds .
Symptoms and Signs
Symptoms ha ve us ua l l y been pres ent for onl y da ys to weeks before di a gnos i s . Di s rupted hema topoi es i s l ea ds to the mos t common pres enti ng
s ymptoms (a nemi a , i nfecti on, ea s y brui s i ng a nd bl eedi ng). Other pres enti ng s ymptoms a nd s i gns a re us ua l l y nons peci fi c (eg, pa l l or, fa ti gue, fever,
ma l a i s e, wei ght l os s , ta chyca rdi a , ches t pa i n) a nd a re a ttri buta bl e to a nemi a a nd a hypermeta bol i c s ta te. The ca us e of fever often i s not found,
a l though gra nul ocytopeni a ma y l ea d to a ra pi dl y progres s i ng a nd potenti a l l y l i fe-threa teni ng ba cteri a l i nfecti on. Bl eedi ng i s us ua l l y ma ni fes ted
by petechi a e, ea s y brui s i ng, epi s ta xi s , bl eedi ng gums , or mens trua l i rregul a ri ty. Hema turi a a nd GI bl eedi ng a re uncommon. Bone ma rrow a nd
peri os tea l i nfi l tra ti on ma y ca us e bone a nd joi nt pa i n, es peci a l l y i n chi l dren wi th ALL. Ini ti a l CNS i nvol vement or l eukemi c meni ngi ti s (ma ni fes ti ng
a s hea da ches , vomi ti ng, i rri ta bi l i ty, cra ni a l nerve pa l s i es , s ei zures , a nd pa pi l l edema ) i s uncommon. Extra medul l a ry i nfi l tra ti on by l eukemi c cel l s
ma y ca us e
[Table 117-1. French-Ameri ca n-Bri ti s h (FAB) Cl a s s i fi ca ti on of Acute Leukemi a s ]
[Table 117-2. Fi ndi ngs a t Di a gnos i s i n the Mos t Common Leukemi a s ]
l ympha denopa thy, s pl enomega l y, hepa tomega l y, a nd l eukemi a cuti s (a ra i s ed, nonpruri ti c ra s h).
Diagnosis
Hi s tochemi ca l s tudi es , cytogeneti cs , i mmunophenotypi ng, a nd mol ecul a r bi ol ogy s tudi es
Ima gi ng
CBC a nd peri phera l s mea r a re the fi rs t tes ts done; pa ncytopeni a a nd peri phera l bl a s ts s ugges t a cute l eukemi a . Bl a s t cel l s i n the peri phera l s mea r
ma y a pproa ch 90%, unl es s the WBC count i s ma rkedl y decrea s ed. Al though the di a gnos i s ca n us ua l l y be ma de from the peri phera l s mea r, bone
ma rrow exa mi na ti on (a s pi ra ti on or needl e bi ops y) s houl d a l wa ys be done. Bl a s t cel l s i n the bone ma rrow a re between 20 a nd 95%. Apl a s ti c
a nemi a , vi ra l i nfecti ons s uch a s i nfecti ous mononucl eos i s , a nd vi ta mi n B 12 a nd fol a te defi ci ency s houl d be cons i dered i n the di fferenti a l
di a gnos i s of s evere pa ncytopeni a . Leukemoi d rea cti ons to i nfecti ous di s ea s e (s uch a s TB) ca n ma ni fes t a s hi gh bl a s t counts .
Hi s tochemi ca l s tudi es , cytogeneti cs , i mmunophenotypi ng, a nd mol ecul a r bi ol ogy s tudi es hel p di s ti ngui s h the bl a s ts of ALL from thos e of AML or
other di s ea s e proces s es . Speci fi c B-cel l , T-cel l , a nd myel oi d-a nti gen monocl ona l a nti bodi es , together wi th fl ow cytometry, a re very hel pful i n
cl a s s i fyi ng ALL vs AML, whi ch i s cri ti ca l for trea tment.
Other l a bora tory fi ndi ngs ma y i ncl ude hyperuri cemi a , hyperphos pha temi a , hyperka l emi a or hypoka l emi a , el eva ted s erum hepa ti c tra ns a mi na s es
or LDH, hypogl ycemi a , a nd hypoxi a . Lumba r puncture a nd hea d CT s ca n a re done i n pa ti ents wi th CNS s ymptoms , B-cel l ALL, hi gh WBC count, or hi gh
LDH. Ches t x-ra y i s done; i f a medi a s ti na l ma s s i s pres ent, CT ma y be done. CT, MRI, or a bdomi na l ul tra s onogra phy ma y hel p a s s es s s pl enomega l y
or l eukemi a i nfi l tra ti on of other orga ns .
Prognosis
Cure i s a rea l i s ti c goa l for both ALL a nd AML, es peci a l l y i n younger pa ti ents . Prognos i s i s wors e i n i nfa nts a nd the el derl y a nd i n thos e wi th
hepa ti c or rena l dys functi on, CNS i nvol vement, myel odys pl a s i a , or a hi gh WBC count (> 25,000/L). Survi va l i n untrea ted a cute l eukemi a genera l l y i s
3 to 6 mo. Prognos i s va ri es a ccordi ng to ka ryotype.
Treatment
Chemothera py
Supporti ve ca re
The goa l of trea tment i s compl ete remi s s i on, i ncl udi ng res ol uti on of a bnorma l cl i ni ca l fea tures , res tora ti on of norma l bl ood counts a nd norma l
hema topoi es i s wi th < 5% bl a s t cel l s , a nd el i mi na ti on of the l eukemi c cl one. Al though ba s i c pri nci pl es i n trea ti ng ALL a nd AML a re s i mi l a r, the
drug regi mens di ffer. The compl ex na ture of pa ti ents ' cl i ni ca l s i tua ti ons a nd the a va i l a bl e trea tment protocol s neces s i ta te a n experi enced tea m.
Whenever pos s i bl e, pa ti ents s houl d be trea ted a t s peci a l i zed medi ca l centers , pa rti cul a rl y duri ng cri ti ca l pha s es (eg, remi s s i on i nducti on).
Supportive care: Supporti ve ca re i s s i mi l a r i n the a cute l eukemi a s a nd ma y i ncl ude
Tra ns fus i ons
Anti bi oti cs or a nti funga l drugs
Hydra ti on a nd uri ne a l ka l i ni za ti on
Ps ychol ogi c s upport
Transfusions of pl a tel ets , RBCs , a nd gra nul ocytes a re a dmi ni s tered a s needed to pa ti ents wi th bl eedi ng, a nemi a , a nd neutropeni a , res pecti vel y.
Prophyl a cti c pl a tel et tra ns fus i on i s done when pl a tel ets fa l l to < 10,000/L; a hi gher thres hol d (20,000/L) i s us ed for pa ti ents wi th the tri a d of
fever, di s s emi na ted i ntra va s cul a r coa gul a ti on, a nd mucos i ti s s econda ry to chemothera py. Anemi a (Hb < 8 g/dL) i s trea ted wi th pa cked RBC
tra ns fus i ons . Gra nul ocyte tra ns fus i ons ma y hel p neutropeni c pa ti ents wi th gra m-nega ti ve or other s eri ous s eps i s but ha ve no proven benefi t a s
prophyl a xi s .
Antimicrobials a re often needed beca us e i nfecti ons a re s eri ous i n neutropeni c, i mmunos uppres s ed pa ti ents a nd ca n progres s qui ckl y wi thout the
us ua l cl i ni ca l evi dence. After a ppropri a te s tudi es a nd cul tures ha ve been done, both febri l e a nd a febri l e pa ti ents wi th neutrophi l counts < 500/L
s houl d begi n broa d-s pectrum ba cteri ci da l a nti bi oti c trea tment tha t i s effecti ve a ga i ns t gra m-pos i ti ve a nd gra m-nega ti ve orga ni s ms (eg,
cefta zi di me, i mi penem, ci l a s ta ti n). Funga l i nfecti ons , es peci a l l y pneumoni a s , a re becomi ng more common a nd a re di ffi cul t to di a gnos e; empi ri c
a nti funga l drugs s houl d be gi ven i f a nti ba cteri a l thera py i s not effecti ve wi thi n 72 h. In pa ti ents wi th refra ctory pneumoni ti s , Pneumocystis jirovecii
i nfecti on or a vi ra l i nfecti on s houl d be s us pected a nd confi rmed by bronchos copy a nd bronchoa l veol a r l a va ge a nd trea ted a ppropri a tel y. Empi ri c
thera py wi th tri methopri m/s ul fa methoxa zol e (TMP/SMX), a mphoteri ci n B, a nd a cycl ovi r or other a na l ogs , often wi th gra nul ocyte tra ns fus i ons , i s
often neces s a ry. In pa ti ents wi th drug-i nduced i mmunos uppres s i on a t ri s k of opportuni s ti c i nfecti ons , TMP/SMX i s gi ven to prevent P. jirovecii
pneumoni a .
Hydration (twi ce the da i l y ma i ntena nce vol ume), uri ne a l ka l i ni za ti on (pH 7 to 8), a nd el ectrol yte moni tori ng ca n prevent the hyperuri cemi a ,
hyperphos pha temi a , a nd hyperka l emi a (tumor l ys i s s yndromes ee p. 1075) ca us ed by the ra pi d l ys i s of l eukemi c cel l s duri ng i ni ti a l thera py
(pa rti cul a rl y i n ALL). Hyperuri cemi a ca n be mi ni mi zed by gi vi ng a l l opuri nol (a xa nthi ne oxi da s e i nhi bi tor) or ra s buri ca s e (a recombi na nt ura teoxi da s e enzyme) before s ta rti ng chemothera py to reduce the convers i on of xa nthi ne to uri c a ci d.
Psychologic support ma y hel p pa ti ents a nd thei r fa mi l i es wea ther the s hock of i l l nes s a nd the ri gors of trea tment for a potenti a l l y l i fe-threa teni ng
condi ti on.
Acute Lymphocytic Leukemia
(Acute Lymphobl a s ti c Leukemi a )
ALL is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally
differentiated, long-lived hematopoietic progenitor cell results in a high circulating number of blasts, replacement of normal marrow by malignant cells, and the
potential for leukemic infiltration of the CNS and abdominal organs. Symptoms include fatigue, pallor, infection, and easy bruising and bleeding. Examination of
peripheral smear and bone marrow is usually diagnostic. Treatment typically includes combination chemotherapy to achieve remission, intrathecal chemotherapy
for CNS prophylaxis and/or cerebral irradiation for intracerebral leukemic infiltration, consolidation chemotherapy with or without stem cell transplantation, and
maintenance chemotherapy for 1 to 3 yr to avoid relapse.
Two thi rds of a l l ALL ca s es occur i n chi l dren, wi th a pea k i nci dence a t a ge 2 to 5 yr; ALL i s the mos t common ca ncer i n chi l dren a nd the 2nd mos t
common ca us e of dea th i n chi l dren < 15 yr. A 2nd ri s e i n i nci dence occurs a fter a ge 45.
Prognosis
Prognos ti c fa ctors hel p determi ne trea tment protocol a nd i ntens i ty.
Favorable prognostic factors a re
Age 3 to 7 yr
WBC count < 25,000/L
French-Ameri ca n-Bri ti s h (FAB) L1 morphol ogy
Leukemi c cel l ka ryotype wi th > 50 chromos omes a nd t(12;21)
No CNS di s ea s e a t di a gnos i s
Unfavorable factors a re
A l eukemi c cel l ka ryotype wi th chromos omes tha t a re norma l i n number but a bnorma l i n morphol ogy (ps eudodi pl oi d)
Pres ence of the Phi l a del phi a (Ph) chromos ome t(9;22)
Increa s ed a ge i n a dul ts
B-cel l i mmunophenotype wi th s urfa ce or cytopl a s mi c i mmunogl obul i n
Rega rdl es s of prognos ti c fa ctors , the l i kel i hood of i ni ti a l remi s s i on i s 95% i n chi l dren a nd 70 to 90% i n a dul ts . About 75% of chi l dren a nd 30 to
40% of a dul ts ha ve conti nuous di s ea s e-free s urvi va l for 5 yr a nd a ppea r cured. Ima ti ni b i mproves outcome i n pa ti ents wi th Ph chromos omepos i ti ve ALL. Mos t i nves ti ga tory protocol s s el ect pa ti ents wi th poor prognos ti c fa ctors for more i ntens e thera py, beca us e the i ncrea s ed ri s k of a nd
toxi ci ty from trea tment a re outwei ghed by the grea ter ri s k of trea tment fa i l ure l ea di ng to dea th.
Treatment
Chemothera py
Someti mes s tem cel l tra ns pl a nta ti on or ra di a ti on thera py
The 4 genera l pha s es of chemothera py for ALL i ncl ude
Remi s s i on i nducti on
CNS prophyl a xi s
Pos tremi s s i on cons ol i da ti on or i ntens i fi ca ti on
Ma i ntena nce
Induction therapy: The goa l i s to i nduce remi s s i on. Severa l regi mens empha s i ze ea rl y i ntroducti on of a n i ntens i ve mul ti drug regi men. Remi s s i on
ca n be i nduced wi th da i l y ora l predni s one a nd weekl y IV vi ncri s ti ne wi th the a ddi ti on of a n a nthra cycl i ne or a s pa ra gi na s e. Other drugs a nd
combi na ti ons tha t ma y be i ntroduced ea rl y i n trea tment a re cyta ra bi ne a nd etopos i de a s wel l a s cycl ophos pha mi de. In s ome regi mens ,
i ntermedi a te-dos e or hi gh-dos e IV methotrexa te i s gi ven wi th l eucovori n res cue. The combi na ti ons a nd thei r dos a ges a re modi fi ed a ccordi ng to
the pres ence of ri s k fa ctors . Ima ti ni b ca n be a dded to the drug regi men i n pa ti ents wi th Ph chromos ome-pos i ti ve ALL.
CNS prophylaxis: An i mporta nt s i te of l eukemi c i nfi l tra ti on i s the meni nges ; prophyl a xi s a nd trea tment ma y i ncl ude hi gh-dos e i ntra theca l
methotrexa te, cytos i ne a ra bi nos i de, a nd corti cos teroi ds . Cra ni a l nerve or whol e-bra i n i rra di a ti on ma y be neces s a ry a nd i s often us ed for pa ti ents
a t hi gh ri s k of CNS di s ea s e (eg, hi gh WBC count, hi gh s erum LDH, B-cel l phenotype) but ha s been us ed l es s often i n recent yea rs .
Consolidation therapy: The goa l of cons ol i da ti on i s to prevent l eukemi c regrowth. Cons ol i da ti on thera py us ua l l y l a s ts a few months a nd combi nes
drugs tha t ha ve di fferent mecha ni s ms of a cti on tha n drugs us ed i n i nducti on regi mens . Al l ogenei c s tem cel l tra ns pl a nta ti on i s recommended a s
cons ol i da ti on of Ph chromos ome-pos i ti ve ALL or i n 2nd or l a ter rel a ps es or remi s s i ons .
Maintenance therapy: Mos t regi mens i ncl ude ma i ntena nce thera py wi th methotrexa te a nd merca ptopuri ne. Thera py dura ti on i s us ua l l y 2 1/2 to 3 yr
but ma y be s horter wi th regi mens tha t a re more i ntens i ve i n ea rl i er pha s es a nd for B-cel l (L3) ca s es . For pa ti ents i n conti nuous compl ete
remi s s i on for 2 1/2 yr, the ri s k of rel a ps e a fter thera py ces s a ti on i s a bout 20%, us ua l l y wi thi n 1 yr. Thus , when thera py ca n be s topped, mos t
pa ti ents a re cured.
Relapse: Leukemi c cel l s ma y rea ppea r i n the bone ma rrow, the CNS, or the tes tes . Bone ma rrow rel a ps e i s pa rti cul a rl y omi nous . Al though a new
round of chemothera py ma y i nduce a 2nd remi s s i on i n 80 to 90% of chi l dren (30 to 40% of a dul ts ), s ubs equent remi s s i ons tend to be bri ef. Onl y a
few pa ti ents wi th l a te bone ma rrow rel a ps es a chi eve l ong di s ea s e-free 2nd remi s s i ons or cure.
If a n HLA-ma tched s i bl i ng i s a va i l a bl e, s tem cel l tra ns pl a nta ti on offers the grea tes t hope of l ong-term remi s s i on or cure (s ee p. 1132). Cel l s from
other rel a ti ves or ma tched, unrel a ted donors a re s ometi mes us ed. Tra ns pl a nta ti on i s ra rel y us ed for pa ti ents > 65 yr beca us e i t i s much l es s l i kel y
to be s ucces s ful a nd beca us e a dvers e effects a re much more l i kel y to be fa ta l .
When rel a ps e i nvol ves the CNS, trea tment i ncl udes i ntra theca l methotrexa te (wi th or wi thout cyta ra bi ne or corti cos teroi ds ) twi ce weekl y unti l a l l
s i gns di s a ppea r. Mos t regi mens i ncl ude s ys temi c rei nducti on chemothera py beca us e of the l i kel i hood of s ys temi c s prea d of bl a s t cel l s . The rol e
of conti nued i ntra theca l drug us e or CNS i rra di a ti on i s uncl ea r.
Tes ti cul a r rel a ps e ma y be evi denced cl i ni ca l l y by pa i nl es s fi rm s wel l i ng of the tes ti s or ma y be i denti fi ed on bi ops y. If uni l a tera l tes ti cul a r
i nvol vement i s cl i ni ca l l y evi dent, the a ppa rentl y uni nvol ved tes ti s s houl d undergo bi ops y. Trea tment i s by i rra di a ti on of the i nvol ved tes ti s a nd
a dmi ni s tra ti on of s ys temi c rei nducti on thera py a s for i s ol a ted CNS rel a ps e.
Acute Myelocytic Leukemia
(Acute Myel ogenous Leukemi a ; Acute Myel oi d Leukemi a )
In AML, malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating
numbers of immature blood forms and replacement of normal marrow by malignant cells. Symptoms include fatigue, pallor, easy bruising and bleeding, fever,
and infection; symptoms of leukemic infiltration are present in only about 5% of patients (often as skin manifestations). Examination of peripheral smear and
bone marrow is diagnostic. Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell
transplantation) to avoid relapse.
The i nci dence of AML i ncrea s es wi th a ge; i t i s the more common a cute l eukemi a i n a dul ts , wi th a medi a n a ge of ons et of 50 yr. AML ma y occur a s a
s econda ry ca ncer a fter chemothera py or i rra di a ti on for a di fferent type of ca ncer.
AML ha s a number of s ubtypes tha t a re di s ti ngui s hed from ea ch other by morphol ogy, i mmunophenotype, a nd cytochemi s try. Fi ve cl a s s es a re
des cri bed, ba s ed on predomi na nt cel l type, i ncl udi ng myel oi d, myel oi d-monocyti c, monocyti c, erythroi d, a nd mega ka ryocyti c.
Acute promyelocytic leukemia (APL) i s a pa rti cul a rl y i mporta nt s ubtype, repres enti ng 10 to 15% of a l l ca s es of AML, s tri ki ng a younger a ge group
(medi a n a ge 31 yr) a nd pa rti cul a r ethni ci ty (Hi s pa ni cs ), i n whi ch the pa ti ent commonl y pres ents wi th a coa gul a ti on di s order.
Prognosis
Remi s s i on i nducti on ra tes ra nge from 50 to 85%. Long-term di s ea s e-free s urvi va l reportedl y occurs i n 20 to 40% of pa ti ents a nd i ncrea s es to 40 to
50% i n younger pa ti ents trea ted wi th s tem cel l tra ns pl a nta ti on.
Prognos ti c fa ctors hel p determi ne trea tment protocol a nd i ntens i ty; pa ti ents wi th s trongl y nega ti ve prognos ti c fea tures a re us ua l l y gi ven more
i ntens e forms of thera py, beca us e the potenti a l benefi ts a re thought to jus ti fy the i ncrea s ed trea tment toxi ci ty. The mos t i mporta nt prognos ti c
fa ctor i s the l eukemi a cel l ka ryotype. The s peci fi c chromos oma l rea rra ngements of the di fferent forms of AML ca n a ffect the outcome. Three l evel s
of outcome ha ve been i denti fi ed: fa vora bl e, i ntermedi a te, a nd poor. Pa ti ents who ha ve the cytogeneti cs t(8;21), t(15;17), a nd i nv(16) typi ca l l y ha ve
a fa vora bl e res pons e to thera py, remi s s i on dura ti on, a nd s urvi va l . Pa ti ents wi th a norma l ka ryotype ha ve a n i ntermedi a te prognos i s , a nd pa ti ents
wi th a poor prognos i s a re thos e wi th a del eti on of chromos ome 5 or 7, tri s omy 8, or a ka ryotype wi th > 3 a bnorma l i ti es . Other nega ti ve fa ctors
i ncl ude i ncrea s i ng a ge, a precedi ng myel odys pl a s ti c pha s e, s econda ry l eukemi a , hi gh WBC count, a nd a bs ence of Auer rods . The FAB or WHO
cl a s s i fi ca ti on a l one does not predi ct res pons e.
Treatment
Chemothera py (i nducti on a nd cons ol i da ti on)
Someti mes s tem cel l tra ns pl a nta ti on
Induction therapy: Ini ti a l thera py a ttempts to i nduce remi s s i on a nd di ffers mos t from ALL i n tha t AML res ponds to fewer drugs . The ba s i c i nducti on
regi men i ncl udes cyta ra bi ne by conti nuous IV i nfus i on or hi gh dos es for 5 to 7 da ys ; da unorubi ci n or i da rubi ci n i s gi ven IV for 3 da ys duri ng thi s
ti me. Some regi mens i ncl ude 6-thi ogua ni ne, etopos i de, vi ncri s ti ne, a nd predni s one, but thei r contri buti on i s uncl ea r. Trea tment us ua l l y res ul ts i n
s i gni fi ca nt myel os uppres s i on, wi th i nfecti on or bl eedi ng; there i s s i gni fi ca nt l a tency before ma rrow recovery. Duri ng thi s ti me, meti cul ous
preventi ve a nd s upporti ve ca re i s vi ta l (s ee p. 1007).
In APL a nd s ome other ca s es of AML, di s s emi na ted i ntra va s cul a r coa gul a ti on (DIC) ma y be pres ent on di a gnos i s a nd ma y wors en a s l eukemi c cel l
l ys i s rel ea s es procoa gul a nt. In APL wi th the tra ns l oca ti on t(15;17), a l l -trans-reti noi c a ci d corrects the DIC i n 2 to 5 da ys ; combi ned wi th
da unorubi ci n or i da rubi ci n, thi s regi men ca n i nduce remi s s i on i n 80 to 90% of pa ti ents a nd bri ng a bout l ong-term s urvi va l i n 65 to 70%. Ars eni c
tri oxi de i s a l s o very a cti ve i n APL.
Consolidation therapy: After remi s s i on, ma ny regi mens i nvol ve a pha s e of i ntens i fi ca ti on wi th the s a me drugs us ed for i nducti on or wi th other drugs .
Hi gh-dos e cyta ra bi ne regi mens ma y l engthen remi s s i on dura ti on, pa rti cul a rl y when gi ven a s cons ol i da ti on i n pa ti ents < 60 yr. CNS prophyl a xi s
us ua l l y i s not gi ven, beca us e wi th better s ys temi c di s ea s e control , CNS l eukemi a i s a l es s frequent compl i ca ti on. In AML pa ti ents who ha ve ha d
cons ol i da ti on, ma i ntena nce thera py ha s no demons tra ted rol e.
Relapse: Pa ti ents who ha ve not res ponded to trea tment a nd younger pa ti ents who a re i n remi s s i on but who a re a t hi gh ri s k of rel a ps e (genera l l y
i denti fi ed by certa i n chromos oma l a bnorma l i ti es ) ma y be gi ven hi gh-dos e chemothera py a nd s tem cel l tra ns pl a nta ti on. Extra medul l a ry s i tes a re
i nfrequentl y i nvol ved i n i s ol a ted rel a ps e. When rel a ps e occurs , a ddi ti ona l chemothera py for pa ti ents una bl e to undergo s tem cel l
tra ns pl a nta ti on i s l es s effecti ve a nd often poorl y tol era ted. Another cours e of chemothera py i s mos t effecti ve i n younger pa ti ents a nd i n pa ti ents
whos e i ni ti a l remi s s i on l a s ted > 1 yr. Gemtuzuma b ozoga mi ci n, a recombi na nt monocl ona l a nti body combi ned wi th a cytotoxi c drug, i s effecti ve i n
s ome pa ti ents a fter rel a ps e ha s occurred, but l ong-term benefi ts ha ve not been determi ned.
Chronic Leukemia
Chroni c l eukemi a us ua l l y ma ni fes ts a s a bnorma l l eukocytos i s wi th or wi thout cytopeni a i n a n otherwi s e a s ymptoma ti c pers on. Fi ndi ngs a nd
ma na gement di ffer s i gni fi ca ntl y between chroni c l ymphocyti c l eukemi a (CLL) a nd chroni c myel ocyti c l eukemi a (CML).
Chronic Lymphocytic Leukemia
(Chroni c Lympha ti c Leukemi a )
The most common type of leukemia in the Western world, CLL involves mature-appearing defective neoplastic lymphocytes (almost always B cells) with an
abnormally long life span. The peripheral blood, bone marrow, spleen, and lymph nodes undergo leukemic infiltration. Symptoms may be absent or may include
lymphadenopathy, splenomegaly, hepatomegaly, and nonspecific symptoms attributable to anemia (fatigue, malaise). Diagnosis is by examination of peripheral
smear and bone marrow aspirate. Treatment, delayed until symptoms develop, is aimed at lengthening life and decreasing symptoms and may involve
chlorambucil or fludarabine, prednisone, and cyclophosphamide or doxorubicin or both. Monoclonal antibodies, such as alemtuzumab and rituximab, are
increasingly being used. Palliative radiation therapy is reserved for patients whose lymphadenopathy or splenomegaly interferes with other organs.
Inci dence of CLL i ncrea s es wi th a ge; 75% of ca s es a re di a gnos ed i n pa ti ents > 60 yr. CLL i s twi ce a s common i n men. Al though the ca us e i s
unknown, s ome ca s es a ppea r to ha ve a heredi ta ry component. CLL i s ra re i n Ja pa n a nd Chi na a nd does not s eem to i ncrea s e a mong Ja pa nes e
expa tri a tes i n the US, s ugges ti ng a geneti c fa ctor. CLL i s more common a mong Jews of Ea s tern Europea n des cent.
Pathophysiology
In a bout 98% of ca s es , CD5+ B cel l s undergo ma l i gna nt tra ns forma ti on, wi th l ymphocytes i ni ti a l l y a ccumul a ti ng i n the bone ma rrow a nd then
s prea di ng to l ymph nodes a nd other l ymphoi d ti s s ues , eventua l l y i nduci ng s pl enomega l y a nd hepa tomega l y. As CLL progres s es , a bnorma l
hema topoi es i s res ul ts i n a nemi a , neutropeni a , thrombocytopeni a , a nd decrea s ed i mmunogl obul i n producti on. Ma ny pa ti ents devel op
hypoga mma gl obul i nemi a a nd i mpa i red a nti body res pons e, perha ps rel a ted to i ncrea s ed T-s uppres s or cel l a cti vi ty. Pa ti ents ha ve i ncrea s ed
s us cepti bi l i ty to a utoi mmune di s ea s e cha ra cteri zed by i mmunohemol yti c a nemi a s (us ua l l y Coombs ' tes t-pos i ti ve) or thrombocytopeni a a nd a
modes t i ncrea s e i n ri s k of devel opi ng other ca ncers .
In 2 to 3% of ca s es , the cl ona l expa ns i on i s T cel l i n type, a nd even thi s group ha s a s ubtype (eg, l a rge gra nul a r l ymphocytes wi th cytopeni a s ).
In a ddi ti on, other chroni c l eukemi c pa tterns ha ve been ca tegori zed under CLL:
Prol ymphocyti c l eukemi a
Leukemi c pha s e of cuta neous T-cel l l ymphoma (i e, Seza ry s yndrome)
Ha i ry cel l l eukemi a
Lymphoma l eukemi a (i e, l eukemi c cha nges tha t occur i n a dva nced s ta ges of ma l i gna nt l ymphoma )
Di fferenti a ti on of thes e s ubtypes from typi ca l CLL i s us ua l l y s tra i ghtforwa rd.
Symptoms and Signs
Ons et i s us ua l l y i ns i di ous ; CLL i s often di a gnos ed i nci denta l l y duri ng routi ne bl ood tes ts or through eva l ua ti on of a s ymptoma ti c
l ympha denopa thy. Symptoma ti c pa ti ents us ua l l y ha ve nons peci fi c compl a i nts of fa ti gue, a norexi a , wei ght l os s , dys pnea on exerti on, or a s ens e of
a bdomi na l ful l nes s (s econda ry to a n enl a rged s pl een). Ini ti a l fi ndi ngs i ncl ude genera l i zed l ympha denopa thy a nd mi ni ma l -to-modera te
hepa tomega l y a nd s pl enomega l y. Wi th progres s i ve di s ea s e, there ma y be pa l l or due to a nemi a . Ski n i nfi l tra ti on, ei ther ma cul opa pul a r or di ffus e,
ma y be a fea ture of T-cel l CLL. Hypoga mma gl obul i nemi a a nd gra nul ocytopeni a i n l a te CLL ma y predi s pos e to ba cteri a l , vi ra l , a nd funga l i nfecti on,
es peci a l l y pneumoni a . Herpes zos ter i s common a nd us ua l l y derma tomi c.
Diagnosis
CBC a nd peri phera l s mea r
Immunophenotypi ng
CLL i s confi rmed by exa mi ni ng the peri phera l s mea r a nd bone ma rrow; the ha l l ma rk i s s us ta i ned, a bs ol ute peri phera l l ymphocytos i s (> 5000/L)
a nd i ncrea s ed l ymphocytes (> 30%) i n the bone ma rrow. Di fferenti a l di a gnos i s i s s i mpl i fi ed by i mmunophenotypi ng. Other fi ndi ngs a t di a gnos i s
ma y i ncl ude hypoga mma gl obul i nemi a (< 15% of ca s es ) a nd, ra rel y, el eva ted LDH. Onl y 10% of pa ti ents pres ent wi th modera te a nemi a (s ometi mes
i mmunohemol yti c), thrombocytopeni a , or both. A monocl ona l s erum i mmunogl obul i n s pi ke of the s a me type ma y be found on the l eukemi c cel l
s urfa ce i n 2 to 4% of ca s es .
Cl i ni ca l s ta gi ng i s us eful for prognos i s a nd trea tment. Two common a pproa ches a re Ra i a nd Bi net s ta gi ng, pri ma ri l y ba s ed on hema tol ogi c
cha nges a nd extent of di s ea s e (s ee
Ta bl e 117-3).
Prognosis
The medi a n s urvi va l of pa ti ents wi th B-cel l CLL or i ts compl i ca ti ons i s a bout 7 to 10 yr. Pa ti ents i n Ra i s ta ge 0 to II a t di a gnos i s ma y s urvi ve for 5 to
20 yr wi thout trea tment. Pa ti ents i n Ra i s ta ge III or IV a re more l i kel y to di e wi thi n 3 to 4 yr of di a gnos i s . Progres s i on to bone ma rrow fa i l ure i s
us ua l l y a s s oci a ted wi th s hort s urvi va l . Pa ti ents wi th CLL a re more l i kel y to devel op a s econda ry ca ncer, es peci a l l y s ki n ca ncer.
Treatment
Symptom a mel i ora ti on
Supporti ve ca re
Al though CLL i s progres s i ve, s ome pa ti ents ma y be a s ymptoma ti c for yea rs ; thera py i s not i ndi ca ted unti l progres s i on or s ymptoms occur. Cure
us ua l l y i s not pos s i bl e, s o trea tment a ttempts to a mel i ora te s ymptoms a nd prol ong l i fe. Supporti ve ca re i ncl udes tra ns fus i on of pa cked RBCs or
erythropoi eti n i njecti ons for a nemi a ; pl a tel et tra ns fus i ons for bl eedi ng a s s oci a ted wi th thrombocytopeni a ; a nd a nti mi crobi a l s for ba cteri a l ,
funga l , or vi ra l i nfecti ons . Beca us e neutropeni a a nd a ga mma gl obul i nemi a l i mi t ba cteri a l ki l l i ng, a nti bi oti c thera py s houl d be ba cteri ci da l .
Thera peuti c i nfus i ons of -gl obul i n s houl d be cons i dered i n pa ti ents wi th hypoga mma gl obul i nemi a a nd repea ted or refra ctory i nfecti ons or, for
prophyl a xi s , when 2 s evere i nfecti ons occur wi thi n 6 mo.
[Table 117-3. Cl i ni ca l Sta gi ng of Chroni c Lymphocyti c Leukemi a ]
Speci fi c thera py i ncl udes
Chemothera py
Corti cos teroi ds
Monocl ona l a nti body thera py
Thes e moda l i ti es ma y a l l evi a te s ymptoms but ha ve not been proven to prol ong s urvi va l . Overtreatment is more dangerous than under-treatment.
Chemotherapy: Chemothera py ma y be i ns ti tuted i n res pons e to the a dvent of s ymptoma ti c di s ea s e, i ncl udi ng cons ti tuti ona l s ymptoms (fever, ni ght
s wea ts , extreme fa ti gue, wei ght l os s ); s i gni fi ca nt hepa tomega l y, s pl enomega l y, or l ympha denopa thy; l ymphocytos i s > 100,000/L; a nd i nfecti ons
a ccompa ni ed by a nemi a , neutropeni a , or thrombocytopeni a . Al kyl a ti ng drugs , es peci a l l y chl ora mbuci l , a l one or wi th corti cos teroi ds , ha ve l ong
been the us ua l thera py for B-cel l CLL. However, fl uda ra bi ne i s more effecti ve. Combi na ti on chemothera py wi th fl uda ra bi ne, cycl ophos pha mi de,
a nd ri tuxi ma b more often i nduces compl ete remi s s i ons . It a l s o l engthens remi s s i on dura ti on a nd prol ongs s urvi va l . Interferon a l fa ,
deoxycoformyci n, a nd 2-chl orodeoxya denos i ne a re hi ghl y effecti ve for ha i ry cel l l eukemi a . Pa ti ents wi th prol ymphocyti c l eukemi a a nd l ymphoma
l eukemi a us ua l l y requi re mul ti drug chemothera py a nd often res pond onl y pa rti a l l y.
Corticosteroids: Immunohemol yti c a nemi a a nd thrombocytopeni a a re i ndi ca ti ons for corti cos teroi ds . Predni s one 1 mg/kg po once/da y ma y
occa s i ona l l y res ul t i n s tri ki ng, ra pi d i mprovement i n pa ti ents wi th a dva nced CLL, a l though res pons e i s often bri ef. The meta bol i c compl i ca ti ons
a nd i ncrea s i ng ra te a nd s everi ty of i nfecti ons wa rra nt ca uti on i n i ts prol onged us e. Predni s one us ed wi th fl uda ra bi ne i ncrea s es the ri s k of
Pneumocystis jirovecii a nd Listeria i nfecti ons .
Monoclonal antibody therapy: Ri tuxi ma b i s the fi rs t monocl ona l a nti body us ed i n the s ucces s ful trea tment of l ymphoi d ca ncers . The pa rti a l res pons e
ra te wi th conventi ona l dos es i n CLL i s 10 to 15%. In previ ous l y untrea ted pa ti ents , the res pons e ra te i s 75%, wi th 20% of pa ti ents a chi evi ng
compl ete remi s s i on. Al emtuzuma b ha s a 33% res pons e ra te i n previ ous l y trea ted pa ti ents refra ctory to fl uda ra bi ne a nd a 75 to 80% res pons e ra te
i n previ ous l y untrea ted pa ti ents . More probl ems wi th i mmunos uppres s i on occur wi th a l emtuzuma b tha n wi th ri tuxi ma b. Ri tuxi ma b ha s been
combi ned wi th fl uda ra bi ne a nd wi th fl uda ra bi ne a nd cycl ophos pha mi de; thes e combi na ti ons ha ve ma rkedl y i mproved the compl ete remi s s i on
ra te i n both previ ous l y trea ted a nd untrea ted pa ti ents . Al emtuzuma b i s now bei ng combi ned wi th ri tuxi ma b a nd wi th chemothera py to trea t
mi ni ma l res i dua l di s ea s e a nd ha s effecti vel y cl ea red bone ma rrow i nfi l tra ti on. Rea cti va ti on of cytomega l ovi rus a nd other opportuni s ti c i nfecti ons
ha s occurred wi th a l emtuzuma b.
Radiation therapy: Loca l i rra di a ti on ma y be gi ven to a rea s of l ympha denopa thy or l i ver a nd s pl een i nvol vement for tra ns i ent s ymptoma ti c
pa l l i a ti on. Tota l body i rra di a ti on i n s ma l l dos es i s occa s i ona l l y s ucces s ful .
Chronic Myelocytic Leukemia
(Chroni c Gra nul ocyti c Leukemi a ; Chroni c Myel ogenous Leukemi a ; Chroni c Myel oi d Leukemi a )
CML occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of immature
granulocytes. Initially asymptomatic, CML progression is insidious, with a nonspecific "benign" stage (malaise, anorexia, weight loss) eventually giving way to
accelerated or blast phases with more ominous signs, such as splenomegaly, pallor, easy bruising and bleeding, fever, lymphadenopathy, and skin changes.
Peripheral smear, bone marrow aspirate, and demonstration of Philadelphia chromosome are diagnostic. Treatment is with imatinib, which significantly improves
response and probably prolongs survival. The curative potential of imatinib is undefined. Myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation,
and interferon alfa are also used.
CML a ccounts for a bout 15% of a l l a dul t l eukemi a s . CML ca n s tri ke a t a ny a ge, a l though i t i s uncommon before a ge 10, a nd the medi a n a ge a t
di a gnos i s i s 45 to 55. CML ma y occur i n ei ther s ex.
Pathophysiology
Mos t ca s es of CML a ppea r to be i nduced by a tra ns l oca ti on known a s the Phi l a del phi a (Ph) chromos ome, whi ch i s demons tra bl e i n 95% of
pa ti ents . It i s a reci proca l tra ns l oca ti on t(9;22) i n whi ch a pi ece of chromos ome 9 conta i ni ng the oncogene c-abl i s tra ns l oca ted to chromos ome 22
a nd fus ed to the gene BCR. The fus i on gene BCR-ABL i s i mporta nt i n the pa thogenes i s a nd expres s i on of CML a nd res ul ts i n the producti on of a
s peci fi c tyros i ne ki na s e. CML ens ues when a n a bnorma l pl uri potent hema topoi eti c progeni tor cel l i ni ti a tes exces s i ve producti on of gra nul ocytes ,
pri ma ri l y i n the bone ma rrow but a l s o i n extra medul l a ry s i tes (eg, s pl een, l i ver). Al though gra nul ocyte producti on predomi na tes , the neopl a s ti c
cl one i ncl udes RBC, mega ka ryocyte, monocyte, a nd even s ome T a nd B cel l s . Norma l s tem cel l s a re reta i ned a nd ca n emerge a fter drug
s uppres s i on of the CML cl one.
CML ha s 3 pha s es :
Chronic phase: An i ni ti a l i ndol ent peri od tha t ma y l a s t months to yea rs
Accelerated myeloproliferative phase: Trea tment fa i l ure, wors eni ng a nemi a , a nd progres s i ve thrombocytopeni a
Terminal phase: Bl a s t cri s i s ; bl a s t cel l tumors pos s i bl y devel opi ng i n extra medul l a ry s i tes (eg, bone, CNS, l ymph nodes , s ki n)
The termi na l pha s e l ea ds to ful mi na nt compl i ca ti ons res embl i ng thos e of a cute l eukemi a , i ncl udi ng s eps i s a nd bl eedi ng. Some pa ti ents progres s
di rectl y from the chroni c to the bl a s t pha s e.
Symptoms and Signs
Pa ti ents a re often a s ymptoma ti c ea rl y on, wi th i ns i di ous ons et of nons peci fi c s ymptoms (eg, fa ti gue, wea knes s , a norexi a , wei ght l os s , fever, ni ght
s wea ts , a s ens e of a bdomi na l ful l nes s ), whi ch ma y prompt eva l ua ti on. Ini ti a l l y, pa l l or, bl eedi ng, ea s y brui s i ng, a nd l ympha denopa thy a re
unus ua l , but modera te or occa s i ona l l y extreme s pl enomega l y i s common (60 to 70% of ca s es ). Wi th di s ea s e progres s i on, s pl enomega l y ma y
i ncrea s e, a nd pa l l or a nd bl eedi ng occur. Fever, ma rked l ympha denopa thy, a nd ma cul opa pul a r s ki n i nvol vement a re omi nous devel opments .
Diagnosis
CBC a nd peri phera l s mea r
Cytogeneti c s tudi es (Ph chromos ome)
CML i s mos t frequentl y di a gnos ed by a CBC obta i ned i nci denta l l y or duri ng eva l ua ti on of s pl enomega l y. Gra nul ocyte count i s el eva ted, us ua l l y <
50,000/L i n a s ymptoma ti c pa ti ents a nd 200,000/L to 1,000,000/L i n s ymptoma ti c pa ti ents , a nd pl a tel et count i s norma l or modera tel y i ncrea s ed.
Hb l evel i s us ua l l y > 10 g/dL.
Peri phera l s mea r ma y hel p di fferenti a te CML from l eukocytos i s of other eti ol ogy. In CML, peri phera l s mea r s hows predomi na ntl y i mma ture
gra nul ocytes a nd a bs ol ute eos i nophi l i a a nd ba s ophi l i a , a l though i n pa ti ents wi th WBC counts < 50,000/L, i mma ture gra nul ocytes ma y be
uncommon. Leukocytos i s i n pa ti ents wi th myel ofi bros i s i s us ua l l y a s s oci a ted wi th nucl ea ted RBCs , tea rdrop-s ha ped RBCs , a nemi a , a nd
thrombocytopeni a . Myel oi d l eukemoi d rea cti ons res ul ti ng from ca ncer or i nfecti on a re not often a s s oci a ted wi th a bs ol ute eos i nophi l i a a nd
ba s ophi l i a .
The l eukocyte a l ka l i ne phos pha ta s e s core i s us ua l l y l ow i n CML a nd i ncrea s ed i n l eukemoi d rea cti ons . Bone ma rrow exa mi na ti on s houl d be done
to eva l ua te the ka ryotype a s wel l a s cel l ul a ri ty (us ua l l y i ncrea s ed) a nd extent of myel ofi bros i s .
Di a gnos i s i s confi rmed by pres ence of the Ph chromos ome on cytogeneti c or mol ecul a r s tudi es , a l though i t i s a bs ent i n 5% of pa ti ents .
Duri ng the a ccel era ted pha s e of di s ea s e, a nemi a a nd thrombocytopeni a us ua l l y devel op. Ba s ophi l s ma y i ncrea s e, a nd gra nul ocyte ma tura ti on
ma y be defecti ve. The proporti on of i mma ture cel l s a nd the l eukocyte a l ka l i ne phos pha ta s e s core ma y i ncrea s e. In the bone ma rrow,
myel ofi bros i s ma y devel op a nd s i derobl a s ts ma y be s een on mi cros copy. Evol uti on of the neopl a s ti c cl one ma y be a s s oci a ted wi th devel opment
of new a bnorma l ka ryotypes , often a n extra chromos ome 8 or i s ochromos ome 17.
Further evol uti on ma y l ea d to a bl a s t cri s i s wi th myel obl a s ts (60% of pa ti ents ), l ymphobl a s ts (30%), a nd mega ka ryocytobl a s ts (10%). In 80% of
thes e pa ti ents , a ddi ti ona l chromos oma l a bnorma l i ti es occur frequentl y.
Prognosis
Wi th i ma ti ni b, s urvi va l i s > 90% a t 5 yr a fter di a gnos i s . Before i ma ti ni b wa s us ed, wi th trea tment 5 to 10% of pa ti ents di ed wi thi n 2 yr of di a gnos i s ;
10 to 15% di ed ea ch yea r therea fter. Medi a n s urvi va l wa s 4 to 7 yr. Mos t (90%) dea ths fol l ow a bl a s t cri s i s or a n a ccel era ted pha s e of the di s ea s e.
Medi a n s urvi va l a fter bl a s t cri s i s i s a bout 3 to 6 mo but ca n be up to 12 mo wi th remi s s i on.
Ph chromos ome-nega ti ve CML a nd chroni c myel omonocyti c l eukemi a ha ve a wors e prognos i s tha n Ph chromos ome-pos i ti ve CML. Thei r cl i ni ca l
beha vi ors res embl e a myel odys pl a s ti c s yndrome (s ee p. 1014).
Treatment
A tyros i ne ki na s e i nhi bi tor, s ometi mes wi th chemothera py
Someti mes s tem cel l tra ns pl a nta ti on
Except when s tem cel l tra ns pl a nta ti on i s s ucces s ful , trea tment i s not cura ti ve; however, s urvi va l ca n be prol onged by trea tment wi th i ma ti ni b.
Ima ti ni b a nd s evera l newer drugs i nhi bi t the s peci fi c tyros i ne ki na s e tha t res ul ts from the BCR-ABL gene product. It i s dra ma ti ca l l y effecti ve i n
a chi evi ng compl ete cl i ni ca l a nd cytogeneti c remi s s i ons of Ph chromos ome-pos i ti ve CML a nd i s cl ea rl y s uperi or to other regi mens (eg, i nterferon
wi th or wi thout cytos i ne a ra bi nos i de). Ima ti ni b a l s o i s s uperi or to other trea tments i n the a ccel era ted a nd bl a s t pha s es . In bl a s t cri s i s ,
combi na ti ons of chemothera py wi th i ma ti ni b ha ve a hi gher res pons e ra te tha n does thera py wi th ei ther a pproa ch a l one. Trea tment tol era nce i s
excel l ent. The hi gh l evel of dura bl e compl ete remi s s i ons a s s oci a ted wi th i ma ti ni b thera py ha s l ed to the pros pect of cure of the di s ea s e.
Ol der chemothera py regi mens a re res erved for BCR-ABL-nega ti ve pa ti ents , pa ti ents who rel a ps e a fter recei vi ng i ma ti ni b, a nd pa ti ents i n bl a s t
cri s i s . The ma i n a gents a re bus ul fa n, hydroxyurea , a nd i nterferon. Hydroxyurea i s ea s i es t to ma na ge a nd ha s the fewes t a dvers e effects . The
s ta rti ng dos a ge i s genera l l y 500 to 1000 mg po bi d. Bl ood counts s houl d be done every 1 to 2 wk a nd the dos a ge a djus ted a ccordi ngl y. Bus ul fa n
often ca us es unexpected genera l myel os uppres s i on, a nd i nterferon ca us es a fl u-l i ke s yndrome tha t often i s una ccepta bl e to pa ti ents . The ma i n
benefi t of thes e thera pi es i s reducti on i n di s tres s i ng s pl enomega l y a nd a denopa thy a nd control of the tumor burden to reduce the i nci dence of
tumor l ys i s a nd gout. None of thes e thera pi es prol ongs medi a n s urvi va l > 1 yr compa red wi th untrea ted pa ti ents ; thus , reducti on i n s ymptoms i s
the ma jor goa l , a nd thera py i s not conti nued when pa ti ents ha ve s i gni fi ca nt toxi c s ymptoms .
Al l ogenei c s tem cel l tra ns pl a nta ti on ca n be us eful for pa ti ents refra ctory to frontl i ne thera py.
Al though s pl eni c ra di a ti on i s ra rel y us ed, i t ma y be hel pful i n refra ctory ca s es of CML or i n pa ti ents wi th termi na l di s ea s e a nd ma rked
s pl enomega l y. Tota l dos a ge us ua l l y ra nges from 6 to 10 Gy del i vered i n fra cti ons of 0.25 to 2 Gy/da y. Trea tment s houl d begi n wi th very l ow dos es
a nd ca reful eva l ua ti on of the WBC count. Res pons e i s us ua l l y di s a ppoi nti ng.
Spl enectomy ma y a l l evi a te a bdomi na l di s comfort, l es s en thrombocytopeni a , a nd rel i eve tra ns fus i on requi rements when s pl enomega l y ca nnot be
control l ed wi th chemothera py or i rra di a ti on. Spl enectomy does not pl a y a s i gni fi ca nt rol e duri ng the chroni c pha s e of CML.
Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) involves a group of disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular bone
marrow, and a high risk of conversion to acute myelocytic leukemia (AML). Symptoms are referable to the specific cell line most affected and may include
fatigue, weakness, pallor (secondary to anemia), increased infections and fever (secondary to neutropenia), and increased bleeding and bruising (secondary to
thrombocytopenia). Diagnosis is by blood count, peripheral smear, and bone marrow aspiration. Treatment with 5-azacytidine may help; if AML supervenes, it is
treated per the usual protocols.
Pathophysiology
MDS i s a group of di s orders , often termed prel eukemi a , refra ctory a nemi a s , Phi l a del phi a chromos ome-nega ti ve chroni c myel ocyti c l eukemi a ,
chroni c myel omonocyti c l eukemi a , or a gnogeni c myel oi d meta pl a s i a , res ul ti ng from a s oma ti c muta ti on of hema topoi eti c precurs ors . Eti ol ogy i s
often unknown, but ri s k i s i ncrea s ed wi th expos ure to benzene, ra di a ti on, a nd chemothera peuti c a gents (pa rti cul a rl y l ong or i ntens e regi mens
a nd thos e i nvol vi ng a l kyl a ti ng a gents a nd epi podophyl l otoxi ns ).
MDS i s cha ra cteri zed by cl ona l prol i fera ti on of hema topoi eti c cel l s , i ncl udi ng erythroi d, myel oi d, a nd mega ka ryocyti c forms . The bone ma rrow i s
norma l or hypercel l ul a r, a nd i neffecti ve hema topoi es i s ca n ca us e a nemi a (mos t common), neutropeni a , thrombocytopeni a , or a combi na ti on. The
di s ordered cel l producti on i s a l s o a s s oci a ted wi th morphol ogi c cel l ul a r a bnorma l i ti es i n bone ma rrow a nd bl ood. Extra medul l a ry hema topoi es i s
ma y occur, l ea di ng to hepa tomega l y a nd s pl enomega l y. Myel ofi bros i s i s occa s i ona l l y pres ent a t di a gnos i s or ma y devel op duri ng the cours e of
MDS. Cl a s s i fi ca ti on i s by bl ood a nd bone ma rrow fi ndi ngs (s ee
Ta bl e 117-4). The MDS cl one i s uns ta bl e a nd tends to progres s to AML.
Symptoms and Signs
Symptoms tend to refl ect the mos t a ffected cel l l i ne a nd ma y i ncl ude pa l l or, wea knes s , a nd fa ti gue (a nemi a ); fever a nd i nfecti ons (neutropeni a );
a nd i ncrea s ed brui s i ng, petechi a e, epi s ta xi s , a nd mucos a l bl eedi ng (thrombocytopeni a ). Spl enomega l y a nd hepa tomega l y a re common. Symptoms
ma y a l s o be refera bl e to other underl yi ng di s orders ; eg, i n el derl y pa ti ents wi th preexi s ti ng ca rdi ova s cul a r di s orders , a nemi a from MDS ma y
exa cerba te a ngi na l pa i n.
Diagnosis
CBC
MDS i s s us pected i n pa ti ents (es peci a l l y the el derl y) wi th refra ctory a nemi a , l eukopeni a , or thrombocytopeni a . Cytopeni a s s econda ry to
congeni ta l di s orders , vi ta mi n defi ci enci es , or drug a dvers e effects mus t be rul ed out. Di a gnos i s
[Table 117-4. Myel odys pl a s ti c Syndrome Bone Ma rrow Fi ndi ngs a nd Survi va l ]
i s by exa mi ni ng peri phera l bl ood a nd bone ma rrow a nd i denti fyi ng morphol ogi c a bnorma l i ti es i n 10 to 20% of cel l s of a pa rti cul a r l i nea ge.
Anemi a i s the mos t common fea ture, a s s oci a ted us ua l l y wi th ma crocytos i s a nd a ni s ocytos i s . Wi th a utoma ti c cel l counters , thes e cha nges a re
i ndi ca ted by a n i ncrea s ed MCV a nd RBC di s tri buti on wi dth. Some degree of thrombocytopeni a i s us ua l ; on peri phera l s mea r, pl a tel ets va ry i n s i ze,
a nd s ome a ppea r hypogra nul a r. The WBC count ma y be norma l , i ncrea s ed, or decrea s ed. Neutrophi l cytopl a s mi c gra nul a ri ty i s a bnorma l , wi th
a ni s ocytos i s a nd va ri a bl e numbers of gra nul es . Eos i nophi l s a l s o ma y ha ve a bnorma l gra nul a ri ty. Ps eudo Pel ger-Huet cel l s (hypos egmented
neutrophi l s ) ma y be s een. Monocytos i s i s cha ra cteri s ti c of the chroni c myel omonocyti c l eukemi a s ubgroup, a nd i mma ture myel oi d cel l s ma y occur
i n the l es s wel l di fferenti a ted s ubgroups . The cytogeneti c pa ttern i s us ua l l y a bnorma l , wi th one or more cl ona l cytogeneti c a bnorma l i ti es often
i nvol vi ng chromos omes 5 or 7.
Prognosis
Prognos i s depends grea tl y on cl a s s i fi ca ti on a nd on a ny a s s oci a ted di s order. Pa ti ents wi th refra ctory a nemi a or refra ctory a nemi a wi th
s i derobl a s ts a re l es s l i kel y to progres s to the more a ggres s i ve forms a nd ma y di e of unrel a ted ca us es .
Treatment
Symptom a mel i ora ti on
Supporti ve ca re
Aza ci ti di ne rel i eves s ymptoms , decrea s es the ra te of tra ns forma ti on to l eukemi a a nd the need for tra ns fus i ons , a nd proba bl y i mproves s urvi va l .
Other thera py i s s upporti ve, i ncl udi ng RBC tra ns fus i ons a s i ndi ca ted, pl a tel et tra ns fus i ons for bl eedi ng, a nd a nti bi oti c thera py for ba cteri a l
i nfecti on. Deoxya za ci ti di ne, a hypomethyl a ti ng a gent, i s s ometi mes effecti ve, even i n pa ti ents who do not res pond to a za ci ti di ne. In s ome
pa ti ents , erythropoi eti n to s upport RBC needs , gra nul ocyte col ony-s ti mul a ti ng fa ctor to ma na ge s evere s ymptoma ti c gra nul ocytopeni a , a nd, when
a va i l a bl e, thrombopoi eti n for s evere thrombocytopeni a ca n s erve a s i mporta nt hema topoi eti c s upport but ha ve not i ncrea s ed s urvi va l . Al l ogenei c
s tem cel l tra ns pl a nta ti on i s us eful , a nd nona bl a ti ve a l l ogenei c bone ma rrow tra ns pl a nta ti ons a re now bei ng s tudi ed for pa ti ents > 50 yr.
Res pons e of MDS to chemothera py us ed for AML i s s i mi l a r to tha t of AML, a fter a ge a nd ka ryotype a re cons i dered.
Chapter 118. Lymphomas

Introduction
Lymphoma s a re a heterogeneous group of tumors a ri s i ng i n the reti cul oendothel i a l a nd l ympha ti c s ys tems . The ma jor types a re Hodgki n
l ymphoma a nd non-Hodgki n l ymphoma (NHLs ee
Ta bl e 118-1).
Lymphoma s were once thought to be a bs ol utel y di s ti nct from l eukemi a s . However, better unders ta ndi ng of cel l ma rkers a nd tool s wi th whi ch to
eva l ua te thos e ma rkers now s how tha t the di fferenti a ti on between thes e 2 ca ncers i s often va gue. The noti on tha t l ymphoma i s rel a ti vel y
res tri cted to the l ympha ti c s ys tem a nd l eukemi a s to the bone ma rrow, a t l ea s t i n ea rl y s ta ges , i s a l s o not a l wa ys true.
Hodgkin Lymphoma
(Hodgki n's Di s ea s e)
Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen,
liver, and bone marrow. Symptoms include painless lymphadenopathy, sometimes with fever, night sweats, unintentional weight loss, pruritus, splenomegaly,
and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is curative in about 75% of cases and consists of chemotherapy with or without radiation
therapy.
In the US, a bout 8000 new ca s es of Hodgki n l ymphoma a re di a gnos ed a nnua l l y. The ma l e:fema l e ra ti o i s 1.4:1. Hodgki n l ymphoma i s ra re before
a ge 10 a nd i s mos t common between a ges 15 a nd 40; a 2nd pea k occurs i n peopl e > 50 to 60.
Pathophysiology
Hodgki n l ymphoma res ul ts from the cl ona l tra ns forma ti on of cel l s of B-cel l ori gi n, gi vi ng ri s e to pa thognomi c bi nucl ea ted Reed-Sternberg cel l s .
The ca us e i s unknown, but geneti c s us cepti bi l i ty a nd envi ronmenta l a s s oci a ti ons (eg, occupa ti on, s uch a s woodworki ng; hi s tory of trea tment wi th
phenytoi n, ra di a ti on thera py, or chemothera py; i nfecti on wi th Eps tei n-Ba rr vi rus , Mycobacterium tuberculosis, herpes vi rus type 6, HIV) pl a y a rol e.
Ri s k i s s l i ghtl y i ncrea s ed i n peopl e wi th certa i n types of i mmunos uppres s i on (eg, pos ttra ns pl a nt pa ti ents ta ki ng i mmunos uppres s a nts ); i n peopl e
wi th congeni ta l i mmunodefi ci ency s ta tes (eg, a ta xi a -tel a ngi ecta s i a , Kl i nefel ter's s yndrome, Chedi a k-Hi ga s hi s yndrome, Wi s kott-Al dri ch
s yndrome); a nd i n peopl e wi th certa i n a utoi mmune di s orders (RA, cel i a c s prue, Sjogren's s yndrome, SLE).
[Table 118-1. Compa ri s on of Hodgki n Lymphoma a nd Non-Hodgki n Lymphoma ]
Mos t pa ti ents a l s o devel op a s l owl y progres s i ve defect i n cel l -medi a ted i mmuni ty (T-cel l functi on) tha t, i n a dva nced di s ea s e, contri butes to
common ba cteri a l a nd unus ua l funga l , vi ra l , a nd protozoa l i nfecti ons . Humora l i mmuni ty (a nti body producti on) i s depres s ed i n a dva nced di s ea s e.
Dea th often res ul ts from s eps i s .
Symptoms and Signs
Mos t pa ti ents pres ent wi th pa i nl es s cervi ca l a denopa thy. Al though the mecha ni s m i s uncl ea r, pa i n ma y occur i n di s ea s ed a rea s i mmedi a tel y a fter
dri nki ng a l cohol i c bevera ges , thereby provi di ng a n ea rl y i ndi ca ti on of the di a gnos i s .
Other ma ni fes ta ti ons devel op a s the di s ea s e s prea ds through the reti cul oendothel i a l s ys tem, genera l l y to conti guous s i tes . Intens e pruri tus ma y
occur ea rl y. Cons ti tuti ona l s ymptoms i ncl ude fever, ni ght s wea ts , a nd uni ntenti ona l wei ght l os s (> 10% of body wei ght i n previ ous 6 mo), whi ch
ma y s i gni fy i nvol vement of i nterna l l ymph nodes (medi a s ti na l or retroperi tonea l ), vi s cera (l i ver), or bone ma rrow. Spl enomega l y i s often pres ent;
hepa tomega l y ma y be pres ent. Pel -Ebs tei n fever (a few da ys of hi gh fever regul a rl y a l terna ti ng wi th a few da ys to s evera l weeks of norma l or
bel ow-norma l tempera ture) occa s i ona l l y occurs . Ca chexi a i s common a s di s ea s e a dva nces .
Bone i nvol vement i s often a s ymptoma ti c but ma y produce vertebra l os teobl a s ti c l es i ons (i vory vertebra e) a nd, ra rel y, pa i n wi th os teol yti c l es i ons
a nd compres s i on fra cture. Intra cra ni a l , ga s tri c, a nd cuta neous l es i ons a re ra re a nd when pres ent s ugges t HIV-a s s oci a ted Hodgki n l ymphoma .
Loca l compres s i on by tumor ma s s es often ca us es s ymptoms , i ncl udi ng
Ja undi ce s econda ry to i ntra hepa ti c or extra hepa ti c bi l e duct obs tructi on
Leg edema s econda ry to l ympha ti c obs tructi on i n the pel vi s or groi n
Severe dys pnea a nd wheezi ng s econda ry to tra cheobronchi a l compres s i on
Lung ca vi ta ti on or a bs ces s s econda ry to i nfi l tra ti on of l ung pa renchyma , whi ch ma y s i mul a te l oba r cons ol i da ti on or bronchopneumoni a
Epi dura l i nva s i on tha t compres s es the s pi na l cord ma y res ul t i n pa ra pl egi a . Horner's s yndrome a nd l a ryngea l pa ra l ys i s ma y res ul t when enl a rged
l ymph nodes compres s the cervi ca l s ympa theti c a nd recurrent l a ryngea l nerves . Neura l gi c pa i n fol l ows nerve root compres s i on.
Diagnosis
Ches t x-ra y
CT of ches t, a bdomen, a nd pel vi s
CBC, ESR, a l ka l i ne phos pha ta s e, LDH, l i ver functi on tes ts , a l bumi n, Ca , BUN, a nd crea ti ni ne
Lymph node bi ops y
Bone ma rrow bi ops y

Pos s i bl y PET for s ta gi ng, bone s ca nni ng i f bone pa i n i s pres ent, or MRI i f neurol ogi c s ymptoms a re pres ent
Hodgki n l ymphoma i s us ua l l y s us pected i n pa ti ents wi th pa i nl es s l ympha denopa thy or medi a s ti na l a denopa thy detected on routi ne ches t x-ra y.
Si mi l a r l ympha denopa thy ca n res ul t from i nfecti ous mononucl eos i s , toxopl a s mos i s , cytomega l ovi rus i nfecti on, non-Hodgki n l ymphoma , or
l eukemi a . Si mi l a r ches t x-ra y fi ndi ngs ca n res ul t from l ung ca ncer, s a rcoi dos i s , or TB (for eva l ua ti on of a medi a s ti na l ma s s , s ee p.
1994).
A ches t x-ra y i s obta i ned i f not a l rea dy done. X-ra y i s us ua l l y fol l owed by l ymph node bi ops y i f fi ndi ngs a re confi rmed on CT or PET s ca n of the
ches t. If onl y medi a s ti na l nodes a re enl a rged, medi a s ti nos copy or Cha mberl a i n procedure (a l i mi ted l eft a nteri or thora cos tomy a l l owi ng bi ops y of
medi a s ti na l l ymph nodes i na cces s i bl e by cervi ca l medi a s ti nos copy) ma y be i ndi ca ted. CT-gui ded bi ops y ma y a l s o be cons i dered, but res ul ts of
fi ne-needl e a s pi ra ti on a re often i na ccura te, s o l ymph node bi ops y i s preferred. CBC, ESR, a l ka l i ne phos pha ta s e, a nd rena l a nd l i ver functi on tes ts
a re genera l l y done. Other tes ts a re done dependi ng on fi ndi ngs (eg, MRI for s ymptoms of cord compres s i on, bone s ca n for eva l ua ti on of bone
pa i n).
Bi ops y revea l s Reed-Sternberg cel l s (l a rge bi nucl ea ted cel l s ) i n a cha ra cteri s ti ca l l y heterogeneous cel l ul a r i nfi l tra te cons i s ti ng of hi s ti ocytes ,
l ymphocytes , monocytes , pl a s ma cel l s , a nd eos i nophi l s . Cl a s s i c Hodgki n l ymphoma ha s 4 hi s topa thol ogi c s ubtypes (s ee
Ta bl e 118-2); there i s a l s o a l ymphocyte-predomi na nt type. Certa i n a nti gens on Reed-Sternberg cel l s ma y hel p di fferenti a te Hodgki n l ymphoma
from non-Hodgki n l ymphoma , a nd cl a s s i c Hodgki n l ymphoma from the l ymphocyte-predomi na nt type.
Other tes t res ul ts ma y be a bnorma l but a re nondi a gnos ti c. CBC ma y s how s l i ght pol ymorphonucl ea r l eukocytos i s . Lymphocytopeni a ma y occur ea rl y
a nd become pronounced wi th a dva nced di s ea s e. Eos i nophi l i a i s pres ent i n a bout 20% of pa ti ents , a nd thrombocytos i s ma y be pres ent. Anemi a ,
often mi crocyti c, us ua l l y devel ops wi th a dva nced di s ea s e. In a dva nced a nemi a , defecti ve i ron reuti l i za ti on i s cha ra cteri zed by l ow s erum i ron, l ow
i ron-bi ndi ng ca pa ci ty, a nd i ncrea s ed bone ma rrow i ron. Pa ncytopeni a i s occa s i ona l l y ca us ed by bone ma rrow i nva s i on, us ua l l y by the l ymphocytedepl eted type. Hypers pl eni s m (s ee p. 985) ma y a ppea r i n pa ti ents wi th ma rked s pl enomega l y. El eva ted s erum a l ka l i ne phos pha ta s e l evel s ma y
be pres ent, but el eva ti ons do not a l wa ys i ndi ca te bone ma rrow or l i ver i nvol vement. Increa s es i n l eukocyte a l ka l i ne phos pha ta s e, s erum
ha ptogl obi n, ESR, a nd other a cute-pha s e rea cta nts us ua l l y refl ect a cti ve di s ea s e.
Staging: After di a gnos i s , s ta ge i s determi ned to gui de thera py. The commonl y us ed Ann Arbor s ta gi ng s ys tem (s ee
Ta bl e 118-3) i ncorpora tes s ymptoms ; phys i ca l exa mi na ti on fi ndi ngs ; res ul ts of i ma gi ng tes ts , i ncl udi ng ches t x-ra y, CT of the ches t, a bdomen, a nd
pel vi s ; a nd uni l a tera l bone ma rrow bi ops y. La pa rotomy i s not requi red for s ta gi ng. Other
[Table 118-2. Hi s topa thol ogi c Subtypes of Hodgki n Lymphoma (WHO Cl a s s i fi ca ti on)]
s ta gi ng tes ts ma y i ncl ude PET s ca n a nd ca rdi a c a nd pul mona ry functi on tes ts i n a nti ci pa ti on of thera py. The Cots wol d modi fi ca ti ons of the Ann
Arbor s ta gi ng s ys tem i ncorpora te the prognos ti c i mpl i ca ti ons of tumor bul ki nes s a nd numerous di s ea s e s i tes .
Des i gna ti on of the l etter A to a ny s ta ge mea ns tha t no s ys temi c s ymptoms a re bei ng experi enced. Des i gna ti on of the l etter B mea ns tha t a t l ea s t
one s ys temi c s ymptom i s experi enced. The pres ence of s ymptoms correl a tes wi th res pons e to trea tment.
Prognosis
In cl a s s i c Hodgki n l ymphoma , di s ea s e-free s urvi va l 5 yr a fter thera py i s cons i dered a cure. Rel a ps e i s very ra re a fter 5 yr. Chemothera py wi th or
wi thout ra di a ti on thera py a chi eves cure i n 70 to 80% of pa ti ents . Increa s ed potenti a l for rel a ps e depends on ma ny fa ctors , i ncl udi ng ma l e s ex, a ge
> 45 yr, i nvol vement of mul ti pl e extra noda l s i tes , a nd pres ence of cons ti tuti ona l s ymptoms a t di a gnos i s . Pa ti ents who do not a chi eve compl ete
remi s s i on or who rel a ps e wi thi n 12 mo ha ve a poor prognos i s .
Treatment
Chemothera py
Surgery
Someti mes hema topoi eti c s tem cel l tra ns pl a nta ti on
The choi ce of trea tment moda l i ty i s compl ex a nd depends on the preci s e s ta ge of di s ea s e. Before trea tment, men s houl d be offered s perm
ba nki ng, a nd women s houl d di s cus s ferti l i ty opti ons wi th thei r oncol ogi s ts .
Sta ge IA, IIA, IB, or IIB di s ea s e i s genera l l y trea ted wi th a n a bbrevi a ted chemothera py regi men of doxorubi ci n (Adri a myci n), bl eomyci n, vi nbl a s ti ne,
a nd da ca rba zi ne (ABVD) pl us ra di a ti on thera py or wi th l onger-cours e chemothera py a l one. Such trea tment cures a bout 80% of pa ti ents . In pa ti ents
wi th bul ky medi a s ti na l di s ea s e, chemothera py ma y be of l onger dura ti on or of a di fferent type, a nd ra di a ti on thera py i s us ed routi nel y.
Sta ge IIIA di s ea s e i s us ua l l y trea ted wi th ABVD combi na ti on chemothera py. Invol ved fi el d i rra di a ti on i s a l s o s ometi mes a dded. Cure ra tes of 75 to
80% ha ve been a chi eved.
[Table 118-3. Cots wol d Modi fi ca ti on of Ann Arbor Sta gi ng of Hodgki n Lymphoma a nd Non-Hodgki n Lymphoma ]
Sta ge IIIB di s ea s e requi res ABVD combi na ti on chemothera py typi ca l l y a l one but s ometi mes wi th i nvol ved fi el d i rra di a ti on. Survi va l ra tes ra nge
from 70 to 80%.
For s ta ge IVA a nd IVB di s ea s e, ABVD combi na ti on chemothera py i s the s ta nda rd regi men, produci ng compl ete remi s s i on i n 70 to 80% of pa ti ents ; >
50% rema i n di s ea s e-free a t 5 yr. Other effecti ve drugs i ncl ude ni tros ourea s , i fos fa mi de, ci s pl a ti n or ca rbopl a ti n, a nd etopos i de. A promi s i ng new
drug combi na ti on, Sta nford V, i s a 12-wk regi men tha t i ncorpora tes i nvol ved fi el d i rra di a ti on for cons ol i da ti on.
Autol ogous tra ns pl a nta ti on us i ng peri phera l s tem cel l products s houl d be cons i dered for a l l phys i ol ogi ca l l y el i gi bl e pa ti ents wi th rel a ps ed or
refra ctory Hodgki n l ymphoma who res pond to s a l va ge chemothera py.
Complications of treatment: Chemothera py wi th mechl oretha mi ne, vi ncri s ti ne (Oncovi n), proca rba zi ne, a nd predni s one (MOPP) a nd MOPP-l i ke
regi mens i ncrea s es the ri s k of l eukemi a , whi ch genera l l y devel ops a fter > 3 yr. Both chemothera py a nd ra di a ti on thera py i ncrea s e the ri s k of
ma l i gna nt s ol i d tumors (eg, brea s t, GI, l ung, s oft ti s s ue). Medi a s ti na l ra di a ti on i ncrea s es the ri s k of corona ry a theros cl eros i s . Brea s t ca ncer ri s k i s
i ncrea s ed i n women begi nni ng a bout 7 yr a fter they ha ve recei ved ra di a ti on trea tment to a dja cent noda l regi ons .
Posttreatment surveillance: Routi ne tes ti ng i s done to i denti fy recurrence. For a s chedul e of pos ttrea tment s urvei l l a nce, s ee
Ta bl e 118-4.
[Table 118-4. Hodgki n Lymphoma Pos ttrea tment Survei l l a nce]
Non-Hodgkin Lymphomas
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites,
including lymph nodes, bone marrow, the spleen, the liver, and the GI tract. Presenting symptoms usually include peripheral lymphadenopathy. However, some
patients present without lymphadenopathy but with abnormal lymphocytes in circulation. Compared with Hodgkin lymphoma, there is a greater likelihood of
disseminated disease at the time of diagnosis. Diagnosis is usually based on lymph node or bone marrow biopsy or both. Treatment involves radiation therapy,
chemotherapy, or both. Stem cell transplantation is usually reserved for salvage therapy after incomplete remission or relapse.
NHL i s more common tha n Hodgki n l ymphoma . It i s the 6th mos t common ca ncer i n the US; a bout 65,000 new ca s es a re di a gnos ed a nnua l l y i n a l l
a ge groups . However, NHL i s not one di s ea s e but ra ther a ca tegory of l ymphocyte ca ncers . Inci dence i ncrea s es wi th a ge (medi a n a ge, 50 yr).
Etiology
The ca us e of NHL i s unknown, a l though, a s wi th the l eukemi a s , s ubs ta nti a l evi dence s ugges ts a vi ra l ca us e (eg, huma n T-cel l l eukemi a -l ymphoma
vi rus , Eps tei n-Ba rr vi rus , hepa ti ti s C vi rus , HIV). Ri s k fa ctors for NHL i ncl ude i mmunodefi ci ency (s econda ry to pos ttra ns pl a nt i mmunos uppres s i on,
AIDS, pri ma ry i mmune di s orders , s i cca s yndrome, RA), Helicobacter pylori i nfecti on, certa i n chemi ca l expos ures , a nd previ ous trea tment for Hodgki n
l ymphoma . NHL i s the 2nd mos t common ca ncer i n HIV-i nfected pa ti ents (s ee p. 1457), a nd s ome AIDS pa ti ents pres ent wi th l ymphoma . C-myc gene
rea rra ngements a re cha ra cteri s ti c of s ome AIDS-a s s oci a ted l ymphoma s .
Pathophysiology
Mos t (80 to 85%) NHLs a ri s e from B cel l s ; the rema i nder a ri s e from T cel l s or na tura l ki l l er cel l s . Ei ther precurs or or ma ture cel l s ma y be i nvol ved.
Overl a p exi s ts between l eukemi a a nd NHL beca us e both i nvol ve prol i fera ti on of l ymphocytes or thei r precurs ors . A l eukemi a -l i ke pi cture wi th
peri phera l l ymphocytos i s a nd bone ma rrow i nvol vement ma y be pres ent i n up to 50% of chi l dren a nd i n a bout 20% of a dul ts wi th s ome types of
NHL. Di fferenti a ti on ca n be di ffi cul t, but genera l l y pa ti ents wi th more extens i ve noda l i nvol vement (es peci a l l y medi a s ti na l ), fewer ci rcul a ti ng
a bnorma l cel l s , a nd fewer bl a s t forms i n the ma rrow (< 25%) a re cons i dered to ha ve l ymphoma . A promi nent l eukemi c pha s e i s l es s common i n
a ggres s i ve l ymphoma s , except Burki tt's a nd l ymphobl a s ti c l ymphoma s .
Hypoga mma gl obul i nemi a ca us ed by a progres s i ve decrea s e i n i mmunogl obul i n producti on occurs i n 15% of pa ti ents a nd ma y predi s pos e to
s eri ous ba cteri a l i nfecti on.
Classification
Pa thol ogi c cl a s s i fi ca ti on of NHLs conti nues to evol ve, refl ecti ng new i ns i ghts i nto the cel l s of ori gi n a nd the bi ol ogi c ba s es of thes e
heterogeneous di s ea s es . The WHO cl a s s i fi ca ti on (s ee
Ta bl e 118-5) i s va l ua bl e beca us e i t i ncorpora tes i mmunophenotype, genotype, a nd cytogeneti cs ,
[Table 118-5. Subtypes of Non-Hodgki n Lymphoma (WHO Cl a s s i fi ca ti on)]
but numerous other s ys tems exi s t (eg, Lyon cl a s s i fi ca ti on). Among the mos t i mporta nt new l ymphoma s recogni zed by the WHO s ys tem a re mucos a a s s oci a ted l ymphoi d tumors (MALTs ee p. 133); ma ntl e cel l l ymphoma (previ ous l y di ffus e s ma l l cl ea ved cel l l ymphoma ); a nd a na pl a s ti c l a rge cel l
l ymphoma , a heterogeneous di s order wi th 75% of ca s es of T-cel l ori gi n, 15% of B-cel l ori gi n, a nd 10% uncl a s s i fi ed. However, des pi te the pl ethora
of enti ti es , trea tment i s often s i mi l a r except i n certa i n T-cel l l ymphoma s .
Lymphoma s a re commonl y a l s o ca tegori zed a s i ndol ent or a ggres s i ve. Indol ent l ymphoma s a re s l owl y progres s i ve a nd res pons i ve to thera py but
a re not cura bl e wi th s ta nda rd a pproa ches . Aggres s i ve l ymphoma s a re ra pi dl y progres s i ve but res pons i ve to thera py a nd often cura bl e.
In chi l dren, NHL i s a l mos t a l wa ys a ggres s i ve. Fol l i cul a r a nd other i ndol ent l ymphoma s a re very ra re. The trea tment of thes e a ggres s i ve l ymphoma s
(Burki tt's , di ffus e l a rge B cel l , a nd l ymphobl a s ti c l ymphoma ) pres ents s peci a l concerns , i ncl udi ng GI tra ct i nvol vement (pa rti cul a rl y i n the termi na l
i l eum); meni ngea l s prea d (requi ri ng CSF prophyl a xi s or trea tment); a nd other s a nctua ry s i tes of i nvol vement (eg, tes tes , bra i n). In a ddi ti on, wi th
thes e potenti a l l y cura bl e l ymphoma s , trea tment a dvers e effects a s wel l a s outcome mus t be cons i dered, i ncl udi ng l a te ri s ks of s econda ry ca ncer,
ca rdi ores pi ra tory s equel a e, ferti l i ty pres erva ti on, a nd devel opmenta l cons equences . Current res ea rch i s focus ed on thes e a rea s a s wel l a s on the
mol ecul a r events a nd predi ctors of l ymphoma i n chi l dren.
Symptoms and Signs
Ma ny pa ti ents pres ent wi th a s ymptoma ti c peri phera l l ympha denopa thy. Enl a rged l ymph nodes a re rubbery a nd di s crete a nd l a ter become ma tted.
Di s ea s e i s l oca l i zed i n s ome pa ti ents , but mos t pa ti ents ha ve s evera l a rea s of i nvol vement. Medi a s ti na l a nd retroperi tonea l l ympha denopa thy
ma y ca us e pres s ure s ymptoms on va ri ous orga ns . Extra noda l s i tes ma y domi na te cl i ni ca l l y (eg, ga s tri c i nvol vement ca n s i mul a te GI ca rci noma ;
i ntes ti na l l ymphoma ma y ca us e a ma l a bs orpti on s yndrome; HIV pa ti ents who devel op NHL often pres ent wi th CNS i nvol vement).
The s ki n a nd bones a re i ni ti a l l y i nvol ved i n 15% of pa ti ents wi th a ggres s i ve l ymphoma a nd i n 7% of thos e wi th i ndol ent l ymphoma . Occa s i ona l l y,
pa ti ents wi th extens i ve a bdomi na l or thora ci c di s ea s e devel op chyl ous a s ci tes or pl eura l effus i on beca us e of l ympha ti c obs tructi on. Wei ght l os s ,
fever, ni ght s wea ts , a nd a s theni a i ndi ca te di s s emi na ted di s ea s e. Pa ti ents ma y ha ve hepa tomega l y a nd s pl enomega l y a s wel l .
Two probl ems a re common i n NHL but ra re i n Hodgki n l ymphoma : Conges ti on a nd edema of the fa ce a nd neck from pres s ure on the s uperi or vena
ca va (s uperi or vena ca va or s uperi or medi a s ti na l s yndrome) ma y occur. Al s o, ureters ma y be compres s ed by retroperi tonea l or pel vi c l ymph nodes
or both; thi s compres s i on ma y i nterfere wi th uri na ry fl ow a nd ca us e s econda ry rena l fa i l ure.
Anemi a i s i ni ti a l l y pres ent i n a bout 33% of pa ti ents a nd eventua l l y devel ops i n mos t. It ma y be ca us ed by bl eedi ng from GI l ymphoma , wi th or
wi thout l ow pl a tel et l evel s ; hemol ys i s from hypers pl eni s m or Coombs '-pos i ti ve hemol yti c a nemi a ; bone ma rrow i nfi l tra ti on from l ymphoma ; or
ma rrow s uppres s i on from chemothera py or ra di a ti on thera py.
The a cute i l l nes s of a dul t T-cel l l eukemi a -l ymphoma (a s s oci a ted wi th huma n T-l ymphotrophi c vi rus 1 [HTLV-1]) ha s a ful mi na ti ng cl i ni ca l cours e
wi th s ki n i nfi l tra tes , l ympha denopa thy, hepa tos pl enomega l y, a nd l eukemi a . The l eukemi c cel l s a re ma l i gna nt T cel l s , ma ny wi th convol uted
nucl ei . Hyperca l cemi a often devel ops , rel a ted to humora l fa ctors ra ther tha n to di rect bone i nva s i on.
Pa ti ents wi th a na pl a s ti c l a rge cel l l ymphoma ha ve ra pi dl y progres s i ve s ki n l es i ons , a denopa thy, a nd vi s cera l l es i ons . Thi s di s ea s e ma y be
mi s ta ken for Hodgki n l ymphoma or meta s ta ti c undi fferenti a ted ca rci noma .
Diagnosis
Ches t x-ra y
CT of ches t, a bdomen, a nd pel vi s (pos s i bl y i ntegra ted PET-CT)
CBC, ESR, a l ka l i ne phos pha ta s e, LDH, l i ver functi on tes ts , a l bumi n, Ca , BUN, crea ti ni ne, el ectrol ytes , a nd uri c a ci d
HIV, hepa ti ti s B vi rus , a nd hepa ti ti s C vi rus tes ti ng
Lymph node a nd bone ma rrow bi ops y
MRI of s pi ne i f neurol ogi c s ymptoms a re pres ent
As wi th Hodgki n l ymphoma , NHL i s us ua l l y s us pected i n pa ti ents wi th pa i nl es s l ympha denopa thy or when medi a s ti na l a denopa thy i s detected on
routi ne ches t x-ra y. Pa i nl es s l ympha denopa thy ca n a l s o res ul t from i nfecti ous mononucl eos i s , toxopl a s mos i s , cytomega l ovi rus i nfecti on, pri ma ry
HIV i nfecti on, or l eukemi a . Si mi l a r ches t x-ra y fi ndi ngs ca n res ul t from l ung ca rci noma , s a rcoi dos i s , or TB. Les s commonl y, pa ti ents pres ent a fter a
fi ndi ng of peri phera l l ymphocytos i s on CBC done for nons peci fi c s ymptoms . In s uch ca s es , the di fferenti a l di a gnos i s i ncl udes l eukemi a , Eps tei nBa rr vi rus i nfecti on, a nd Dunca n's s yndrome (X-l i nked l ymphoprol i fera ti ve s yndrome).
Ches t x-ra y i s obta i ned i f not done previ ous l y, a nd a l ymph node bi ops y i s done i f l ympha denopa thy i s confi rmed on CT or PET s ca n. If onl y
medi a s ti na l nodes a re enl a rged, pa ti ents requi re CT-gui ded needl e bi ops y or medi a s ti nos copy. Us ua l l y, tes ts s houl d i ncl ude CBC, a l ka l i ne
phos pha ta s e, rena l a nd l i ver functi on tes ts , LDH, a nd uri c a ci d. Other tes ts a re done dependi ng on fi ndi ngs (eg, MRI for s ymptoms of s pi na l cord
compres s i on or CNS a bnorma l i ti es ).
Hi s tol ogi c cri teri a on bi ops y i ncl ude des tructi on of norma l l ymph node a rchi tecture a nd i nva s i on of the ca ps ul e a nd a dja cent fa t by cha ra cteri s ti c
neopl a s ti c cel l s . Immunophenotypi ng s tudi es to determi ne the cel l of ori gi n a re of grea t va l ue i n i denti fyi ng s peci fi c s ubtypes a nd hel pi ng defi ne
prognos i s a nd ma na gement; thes e s tudi es a l s o ca n be done on peri phera l cel l s . Demons tra ti on of the l eukocyte common a nti gen CD45 by
i mmunoperoxi da s e rul es out meta s ta ti c ca ncer, whi ch i s often i n the di fferenti a l di a gnos i s of "undi fferenti a ted" ca ncers . The tes t for l eukocyte
common a nti gen, mos t s urfa ce ma rker s tudi es , a nd gene rea rra ngement (to document B-cel l or T-cel l cl ona l i ty) ca n be done on fi xed ti s s ues .
Cytogeneti cs a nd fl ow cytometry requi re fres h ti s s ue.
Staging: Al though l oca l i zed NHL does occur, the di s ea s e i s typi ca l l y di s s emi na ted when fi rs t recogni zed. Sta gi ng procedures i ncl ude CT of the ches t,
a bdomen, a nd pel vi s ; PET; a nd bone ma rrow bi ops y. The fi na l s ta gi ng of NHL (s ee Ta bl e 118-3) i s s i mi l a r to tha t of Hodgki n l ymphoma a nd i s
ba s ed on cl i ni ca l a nd pa thol ogi c fi ndi ngs .
Prognosis
Pa ti ents wi th T-cel l l ymphoma s genera l l y ha ve a wors e prognos i s tha n do thos e wi th B-cel l types , a l though newer i ntens i ve trea tment regi mens
ma y l es s en thi s di fference. Prognos i s for ea ch NHL va ri a nt i s rel a ted to di fferences i n tumor cel l bi ol ogy.
Survi va l a l s o va ri es wi th other fa ctors . The Interna ti ona l Prognos ti c Index (IPI) i s frequentl y us ed i n a ggres s i ve l ymphoma s . It cons i ders 5 ri s k
fa ctors :
Age > 60
Poor performa nce s ta tus (ca n be mea s ured us i ng the Ea s tern Coopera ti ve Oncol ogy Group tool )
El eva ted LDH
> 1 extra noda l s i te
Sta ge III or IV di s ea s e
Outcome i s wors e wi th a n i ncrea s i ng number of ri s k fa ctors . Survi va l , a s determi ned by IPI fa ctor, ha s i mproved wi th the a ddi ti on of ri tuxi ma b to
the s ta nda rd chemothera peuti c regi men. Pa ti ents i n the hi ghes t ri s k groups (pa ti ents wi th 4 or 5 ri s k fa ctors ) now ha ve a 50% 5-yr s urvi va l . Low-ri s k
pa ti ents wi thout a ny of the ri s k fa ctors ha ve a very hi gh cure ra te. A modi fi ed IPI (fol l i cul a r l ymphoma IPI [FLIPI]) i s bei ng us ed i n fol l i cul a r
l ymphoma s a nd i n di ffus e l a rge B-cel l l ymphoma (revi s ed IPI [R-IPI]).
Treatment
Chemothera py, ra di a ti on thera py, or both
Someti mes a nti -CD20 monocl ona l a nti body
Someti mes hema topoi eti c s tem cel l tra ns pl a nta ti on
Trea tment va ri es cons i dera bl y wi th cel l type, whi ch a re too numerous to permi t deta i l ed di s cus s i on. Genera l i za ti ons ca n be ma de rega rdi ng
l oca l i zed vs a dva nced di s ea s e a nd a ggres s i ve vs i ndol ent forms . Burki tt's l ymphoma (s ee bel ow) a nd mycos i s fungoi des (s ee p. 1024) a re
di s cus s ed s epa ra tel y.
Localized disease (stages I and II): Pa ti ents wi th i ndol ent l ymphoma s ra rel y pres ent wi th l oca l i zed di s ea s e, but when they do, regi ona l ra di a ti on
thera py ma y offer l ong-term control . However, rel a ps es ma y occur > 10 yr a fter ra di a ti on thera py.
About one ha l f of pa ti ents wi th a ggres s i ve l ymphoma s pres ent wi th l oca l i zed di s ea s e, for whi ch combi na ti on chemothera py, wi th or wi thout
regi ona l ra di a ti on, i s us ua l l y cura ti ve. Pa ti ents wi th l ymphobl a s ti c l ymphoma s or Burki tt's l ymphoma , even i f a ppa rentl y l oca l i zed, mus t recei ve
i ntens i ve combi na ti on chemothera py wi th meni ngea l prophyl a xi s . Trea tment ma y requi re ma i ntena nce chemothera py (l ymphobl a s ti c), but cure i s
expected.
Advanced disease (stages III and IV): For i ndol ent l ymphoma s , trea tment va ri es cons i dera bl y. A wa tch-a nd-wa i t a pproa ch, trea tment wi th a s i ngl e
a l kyl a ti ng drug, or 2- or 3-drug regi mens ma y be us ed. Cri teri a cons i dered i n s el ecti ng ma na gement opti ons i ncl ude a ge, genera l hea l th,
di s tri buti on of di s ea s e, tumor bul k, hi s tol ogy, a nd a nti ci pa ted benefi ts of thera py. The B-cel l s peci fi c a nti -CD20 a nti body ri tuxi ma b a nd other
bi ol ogi c res pons e modi fi ers a ppea r to be of benefi t; one of thes e drugs ca n be combi ned wi th chemothera py or a dmi ni s tered a s s i ngl e thera py.
Ra di ol a bel ed-a nti body thera py i s a l s o va l ua bl e.
In pa ti ents wi th the a ggres s i ve B-cel l l ymphoma s (eg, di ffus e l a rge B cel l ), the s ta nda rd drug combi na ti on i s ri tuxi ma b pl us cycl ophos pha mi de,
hydroxyda unorubi ci n (doxorubi ci n), vi ncri s ti ne, predni s one (R-CHOP). Compl ete di s ea s e regres s i on i s expected i n 70% of pa ti ents , dependi ng on
the IPI ca tegory. More tha n 70% of compl ete res ponders a re cured, a nd rel a ps es > 2 yr a fter trea tment cea s es a re ra re.
As cure ra tes ha ve i mproved wi th the us e of R-CHOP, a utol ogous tra ns pl a nta ti on i s res erved for pa ti ents wi th rel a ps ed or refra ctory a ggres s i ve Bcel l l ymphoma s , s ome younger pa ti ents wi th ma ntl e cel l l ymphoma , a nd s ome pa ti ents wi th a ggres s i ve T-cel l l ymphoma s .
Lymphoma relapse: The fi rs t rel a ps e a fter i ni ti a l chemothera py i s a l mos t a l wa ys trea ted wi th a utol ogous s tem cel l tra ns pl a nta ti on. Pa ti ents
us ua l l y s houl d be 70 yr or i n equi va l ent hea l th a nd ha ve res pons i ve di s ea s e, good performa nce s ta tus , a s ource of unconta mi na ted s tem cel l s ,
a nd a n a dequa te number of CD34+ s tem cel l s (ha rves ted from peri phera l bl ood or bone ma rrow). Cons ol i da ti on myel oa bl a ti ve thera py ma y
i ncl ude chemothera py wi th or wi thout i rra di a ti on. Pos ttrea tment i mmunothera py (eg, ri tuxi ma b, va cci na ti on, IL-2) i s bei ng s tudi ed.
An a l l ogenei c tra ns pl a nt i s the dona ti on of s tem cel l s from a compa ti bl e donor (brother, s i s ter, or ma tched unrel a ted donor). The s tem cel l s ha ve
a 2-fol d effect: recons ti tuti ng norma l bl ood counts a nd provi di ng a pos s i bl e gra ft-vs -tumor effect.
In a ggres s i ve l ymphoma , a cure ma y be expected i n 30 to 50% of el i gi bl e pa ti ents undergoi ng myel oa bl a ti ve thera py.
In i ndol ent l ymphoma s , cure wi th a utol ogous tra ns pl a nta ti on rema i ns uncerta i n, a l though remi s s i on ma y be s uperi or to tha t wi th s econda ry
pa l l i a ti ve thera py a l one. Reduced i ntens i ty a l l otra ns pl a nta ti on a ppea rs to offer a potenti a l l y cura ti ve opti on i n s ome pa ti ents wi th i ndol ent
l ymphoma .
The morta l i ty ra te of pa ti ents undergoi ng myel oa bl a ti ve tra ns pl a nta ti on ha s decrea s ed dra ma ti ca l l y to 2 to 5% for mos t a utol ogous procedures
a nd to < 15% for mos t a l l ogenei c procedures .
Complications of treatment: A l a te s equel a of s ta nda rd a nd hi gh-dos e chemothera py i s the occurrence of 2nd tumors , es peci a l l y myel odys pl a s i a s
a nd a cute myel ogenous l eukemi a . Chemothera py combi ned wi th ra di a ti on thera py i ncrea s es thi s ri s k, a l though i ts i nci dence i s s ti l l onl y a bout
3%.
Burkitt's Lymphoma
Burkitt's lymphoma is a B-cell lymphoma occurring primarily in children. Endemic (African), sporadic (non-African), and immunodeficiency-related forms exist.
Burki tt's l ymphoma i s endemi c i n centra l Afri ca a nd cons ti tutes 30% of chi l dhood l ymphoma s i n the US. The form endemi c to Afri ca often
ma ni fes ts a s enl a rgement of the ja w or fa ci a l bones . In non-Afri ca n Burki tt's l ymphoma , a bdomi na l di s ea s e predomi na tes , often a ri s i ng i n the
regi on of the i l eoceca l va l ve or the mes entery. The ki dneys , ova ri es , or brea s ts ma y be i nvol ved a s wel l , a nd i n a dul ts , di s ea s e ma y be bul ky a nd
genera l i zed, often wi th ma s s i ve i nvol vement of l i ver, s pl een, a nd bone ma rrow. CNS i nvol vement i s often pres ent a t di a gnos i s or wi th rel a ps i ng
l ymphoma .
Burki tt's l ymphoma i s the mos t ra pi dl y growi ng huma n tumor, a nd pa thol ogy revea l s a hi gh mi toti c ra te, a monocl ona l prol i fera ti on of B cel l s , a nd
a "s ta rry-s ky" pa ttern of beni gn ma cropha ges tha t ha ve engul fed a poptoti c ma l i gna nt l ymphocytes . There i s a di s ti ncti ve geneti c tra ns l oca ti on
i nvol vi ng the C-myc gene on chromos ome 8 a nd the i mmunogl obul i n hea vy cha i n of chromos ome 14. The di s ea s e i s cl os el y a s s oci a ted wi th
Eps tei n-Ba rr vi rus i nfecti on i n endemi c l ymphoma ; however, i t i s uncerta i n whether Eps tei n-Ba rr vi rus pl a ys a n eti ol ogi c rol e. Burki tt's l ymphoma
occurs frequentl y i n pa ti ents wi th AIDS a nd ma y be a n AIDS-defi ni ng di s ea s e.
Diagnosis
Di a gnos i s i s ba s ed on bi ops y of l ymph node or ti s s ue from a nother s us pected di s ea s e s i te. Sta gi ng i ncl udes CT of the ches t, a bdomen, a nd pel vi s ,
bone ma rrow bi ops y, CSF cytol ogy, a nd PET s ca n.
Treatment
Intens i ve chemothera py
Trea tment mus t be i ni ti a ted ra pi dl y a nd s ta gi ng s tudi es mus t be expedi ted beca us e of ra pi d tumor growth. An i ntens i ve a l terna ti ng regi mencycl ophos pha mi de, vi ncri s ti ne, doxorubi ci n, methotrexa te, i fos fa mi de, etopos i de, a nd cyta ra bi ne (CODOX-M/IVAC)-res ul ts i n a cure ra te of > 90%
for chi l dren a nd a dul ts . Meni ngea l prophyl a xi s i s es s enti a l . Wi th trea tment, tumor l ys i s s yndrome (s ee p. 1075) i s common, a nd pa ti ents mus t
recei ve IV hydra ti on, a l l opuri nol or ra s buri ca s e, a l ka l i ni za ti on, a nd cl os e a ttenti on to el ectrol ytes (pa rti cul a rl y K a nd Ca ).
If the pa ti ent pres ents wi th bowel obs tructi on s econda ry to tumor a nd the tumor i s compl etel y res ected a t i ni ti a l di a gnos ti c-thera peuti c
l a pa rotomy, then a ggres s i ve thera py i s s ti l l i ndi ca ted. Sa l va ge thera py for trea tment fa i l ures i s genera l l y uns ucces s ful , unders cori ng the
i mporta nce of very a ggres s i ve i ni ti a l thera py.
Mycosis Fungoides
Mycosis fungoides is an uncommon chronic T-cell lymphoma primarily affecting the skin and occasionally the internal organs.
Mycos i s fungoi des i s ra re compa red wi th Hodgki n l ymphoma a nd NHL. Unl i ke mos t other l ymphoma s , i t i s i ns i di ous i n ons et, s ometi mes
a ppea ri ng a s a chroni c, pruri ti c ra s h tha t i s di ffi cul t to di a gnos e. It begi ns foca l l y but ma y s prea d to i nvol ve mos t of the s ki n. Les i ons a re
pl a quel i ke but ma y become nodul a r or ul cera ted. Eventua l l y, s ys temi c i nvol vement of l ymph nodes , l i ver, s pl een, a nd l ungs occurs , res ul ti ng i n the
a dvent of s ymptoms , whi ch i ncl ude fever, ni ght s wea ts , a nd uni ntenti ona l wei ght l os s .
Diagnosis
Ski n bi ops y
For s ta gi ng, bone ma rrow bi ops y a nd CT of ches t, a bdomen, a nd pel vi s
Di a gnos i s i s ba s ed on s ki n bi ops y, but hi s tol ogy ma y be equi voca l ea rl y i n the cours e beca us e of i ns uffi ci ent qua nti ti es of l ymphoma cel l s . The
ma l i gna nt cel l s a re ma ture T cel l s (T4+, T11+, T12+). Cha ra cteri s ti c Pa utri er's mi croa bs ces s es a re pres ent i n the epi dermi s . In s ome ca s es , a
l eukemi c pha s e ca l l ed Seza ry s yndrome i s cha ra cteri zed by the a ppea ra nce of ma l i gna nt T cel l s wi th s erpenti ne nucl ei i n the peri phera l bl ood.
Once mycos i s fungoi des ha s been confi rmed, the s ta ge (s ee Ta bl e 118-3) i s determi ned by CT s ca n of the ches t, a bdomen, a nd pel vi s a nd by bone
ma rrow bi ops y for bl ood or l ymph node i nvol vement. PET s ca n ma y a l s o be us ed for s us pected vi s cera l i nvol vement.
Prognosis
Mos t pa ti ents a re > 50 yr a t di a gnos i s ; a vera ge l i fe expecta ncy i s 7 to 10 yr a fter di a gnos i s , even wi thout trea tment. However, s urvi va l ra tes va ry
ma rkedl y dependi ng on s ta ge a t di a gnos i s . Pa ti ents who recei ve trea tment for s ta ge IA di s ea s e ha ve a l i fe expecta ncy a na l ogous to tha t of s i mi l a r
peopl e wi thout mycos i s fungoi des . Pa ti ents who recei ve trea tment for s ta ge IIB di s ea s e s urvi ve for a bout 3 yr. Pa ti ents trea ted for s ta ge III
di s ea s e s urvi ve a n a vera ge of 4 to 6 yr. Pa ti ents trea ted for s ta ge IVA or IVB di s ea s e (extra -cuta neous di s ea s e) s urvi ve < 1.5 yr.
Treatment
Ra di a ti on thera py, topi ca l chemothera py, photothera py, or topi ca l corti cos teroi ds
Someti mes s ys temi c chemothera py
El ectron bea m ra di a ti on thera py, i n whi ch mos t of the energy i s a bs orbed i n the fi rs t 5 to 10 mm of ti s s ue, a nd topi ca l ni trogen mus ta rd ha ve
proved hi ghl y effecti ve. Pl a ques ma y a l s o be trea ted wi th s unl i ght a nd topi ca l corti cos teroi ds . Sys temi c trea tment wi th a l kyl a ti ng drugs a nd fol i c
a ci d a nta goni s ts produces tra ns i ent tumor regres s i on, but s ys temi c trea tment i s pri ma ri l y us ed when other thera pi es ha ve fa i l ed, a fter rel a ps e, or
i n pa ti ents wi th documented extra noda l or extra cuta neous di s ea s e. Extra corporea l photothera py wi th a chemos ens i ti ve drug ha s s hown modes t
s ucces s . The a denos i ne dea mi na s e i nhi bi tors fl uda ra bi ne a nd 2-chl orodeoxya denos i ne s how promi s e.
Chapter 119. Plasma Cell Disorders

Introduction
(Dys protei nemi a s ; Monocl ona l Ga mmopa thi es ; Pa ra protei nemi a s ; Pl a s ma Cel l Dys cra s i a s )
Pl a s ma cel l di s orders a re a di vers e group of di s orders of unknown eti ol ogy cha ra cteri zed by the di s proporti ona te prol i fera ti on of one cl one of B
cel l s a nd the pres ence of a s tructura l l y a nd el ectrophoreti ca l l y homogeneous (monocl ona l ) i mmunogl obul i n or pol ypepti de s ubuni t i n s erum,
uri ne, or both.
Patiology
(For s tructura l fea tures a nd cl a s s i fi ca ti on of the i mmunogl obul i ns , s ee p. 1083.)
After devel opi ng i n the bone ma rrow, undi fferenti a ted B cel l s enter peri phera l l ymphoi d ti s s ues , s uch a s l ymph nodes , s pl een, a nd Peyer's
pa tches . Here, they begi n to di fferenti a te i nto cel l s , ea ch of whi ch ca n res pond to a l i mi ted number of a nti gens . After encounteri ng the
a ppropri a te a nti gen, s ome B cel l s undergo cl ona l prol i fera ti on i nto pl a s ma cel l s . Ea ch cl ona l pl a s ma cel l l i ne i s commi tted to s ynthes i zi ng one
s peci fi c i mmunogl obul i n a nti body tha t cons i s ts of 2 i denti ca l hea vy cha i ns (ga mma [], mu [], a l pha [], del ta [], or eps i l on []) a nd 2 i denti ca l
l i ght cha i ns (ka ppa [] or l a mbda []). A s l i ght exces s of l i ght cha i ns i s norma l l y produced, a nd uri na ry excreti on of s ma l l a mounts of free
pol ycl ona l l i ght cha i ns ( 40 mg/24 h) i s norma l .
Pl a s ma cel l di s orders a re of unknown eti ol ogy a nd a re cha ra cteri zed by the di s proporti ona te prol i fera ti on of one cl one. The res ul t i s a
corres pondi ng i ncrea s e i n the s erum l evel of i ts product, the monocl ona l i mmunogl obul i n protei n (M-protei n).
M-protei ns ma y cons i s t of both hea vy a nd l i ght cha i ns or of onl y one type of cha i n. Some s how a nti body a cti vi ty, whi ch ma y ca us e a utoi mmune
da ma ge of orga ns , pa rti cul a rl y the ki dneys . When M-protei ns a re produced, producti on of other i mmunogl obul i ns i s commonl y reduced, a nd
i mmuni ty ma y become i mpa i red. M-protei n ma y coa t pl a tel ets , i na cti va te cl otti ng fa ctors , i ncrea s e bl ood vi s cos i ty, a nd ca us e bl eedi ng by other
mecha ni s ms . M-protei ns ma y a l s o produce s econda ry a myl oi dos i s . The cl ona l cel l s ca n i nfi l tra te bone ma tri x or ma rrow, wi th res ul ta nt
os teoporos i s , hyperca l cemi a , a nemi a , or pa ncytopeni a .
Pl a s ma cel l di s orders ca n va ry from a s ymptoma ti c, s ta bl e condi ti ons (i n whi ch onl y the protei n i s pres ent) to progres s i ve ca ncers (eg, mul ti pl e
myel oma for cl a s s i fi ca ti on, s ee
Ta bl e 119-1). Ra rel y, tra ns i ent pl a s ma cel l di s orders occur i n pa ti ents wi th drug hypers ens i ti vi ty (s ul fona mi de, phenytoi n, a nd peni ci l l i n), wi th
pres umed vi ra l i nfecti ons , a nd a fter hea rt or tra ns pl a nt s urgery.
Pl a s ma cel l di s orders ma y be s us pected beca us e of cl i ni ca l ma ni fes ta ti ons , fi ndi ngs duri ng eva l ua ti on of a nemi a , or a n i nci denta l fi ndi ng of
el eva ted s erum protei n or protei nuri a tha t l ea ds to further eva l ua ti on wi th s erum or uri ne protei n el ectrophores i s . El ectrophores i s detects Mprotei n, whi ch i s further eva l ua ted wi th i mmunofi xa ti on el ectrophores i s for i denti fi ca ti on of hea vy a nd l i ght cha i n cl a s s es .
Heavy Chain Diseases
Heavy chain diseases are neoplastic plasma cell disorders characterized by overproduction of monoclonal immunoglobulin heavy chains. Symptoms, diagnosis,
and treatment vary according to the specific disorder.
Hea vy cha i n di s ea s es a re pl a s ma cel l di s orders tha t a re genera l l y ma l i gna nt. In mos t pl a s ma cel l di s orders , M-protei ns a re s tructura l l y s i mi l a r to
norma l a nti body mol ecul es . In contra s t, i n hea vy cha i n di s ea s es , i ncompl ete monocl ona l i mmunogl obul i ns (true pa ra protei ns ) a re produced. They
cons i s t of onl y hea vy cha i n components (ei ther , , , or ) wi thout l i ght cha i ns ( hea vy cha i n di s ea s e ha s not been des cri bed). Mos t hea vy cha i n
protei ns a re fra gments of thei r norma l counterpa rts wi th i nterna l del eti ons of va ri a bl e l ength; thes e del eti ons a ppea r to res ul t from s tructura l
muta ti ons . The cl i ni ca l pi cture i s more l i ke l ymphoma tha n mul ti pl e myel oma . Hea vy cha i n di s ea s es a re cons i dered i n pa ti ents wi th cl i ni ca l
ma ni fes ta ti ons s ugges ti ng l ymphoprol i fera ti ve di s orders .
IgA Heavy Chain Disease
(-Cha i n Di s ea s e)
IgA heavy chain disease is the most common heavy chain disease and is similar to Mediterranean lymphoma (immunoproliferative small intestinal disease).
IgA hea vy cha i n di s ea s e us ua l l y a ppea rs between a ges 10 a nd 30 a nd i s geogra phi ca l l y
[Table 119-1. Cl a s s i fi ca ti on of Pl a s ma Cel l Di s orders ]
concentra ted i n the Mi ddl e Ea s t. The ca us e ma y be a n a berra nt i mmune res pons e to a pa ra s i te or other mi croorga ni s m. Vi l l ous a trophy a nd
pl a s ma cel l i nfi l tra ti on of the jejuna l mucos a a re us ua l l y pres ent a nd, s ometi mes , i nfi l tra ti on of the mes enteri c l ymph nodes . The peri phera l
l ymph nodes , bone ma rrow, l i ver, a nd s pl een us ua l l y a re not i nvol ved. A res pi ra tory tra ct form of the di s ea s e ha s been reported ra rel y. Os teol yti c
l es i ons do not occur.
Al mos t a l l pa ti ents pres ent wi th di ffus e a bdomi na l l ymphoma a nd ma l a bs orpti on. Serum protei n el ectrophores i s i s norma l i n ha l f of ca s es ;
often, there i s a n i ncrea s ed 2 a nd fra cti on or a decrea s ed fra cti on. Di a gnos i s requi res the detecti on of a monocl ona l cha i n on
i mmunofi xa ti on el ectrophores i s . Thi s cha i n i s s ometi mes found i n concentra ted uri ne. If i t ca nnot be found i n s erum or uri ne, bi ops y i s requi red.
The a bnorma l protei n ca n s ometi mes be detected i n i ntes ti na l s ecreti ons . The i ntes ti na l cel l ul a r i nfi l tra te ma y be pl eomorphi c a nd not overtl y
ma l i gna nt. Bence Jones protei nuri a i s a bs ent.
The cours e i s hi ghl y va ri a bl e: Some pa ti ents di e i n 1 to 2 yr, wherea s others ha ve remi s s i ons tha t l a s t ma ny yea rs , pa rti cul a rl y a fter trea tment wi th
corti cos teroi ds , cytotoxi c drugs , a nd broa d-s pectrum a nti bi oti cs .
IgG Heavy Chain Disease

IgG heavy chain disease is generally similar to an aggressive malignant lymphoma but is occasionally asymptomatic and benign.
IgG hea vy cha i n di s ea s e occurs pri ma ri l y i n el derl y men but ca n occur i n chi l dren. As s oci a ted chroni c di s orders i ncl ude RA, Sjogren's s yndrome, SLE,
TB, mya s theni a gra vi s , hypereos i nophi l i c s yndrome, a utoi mmune hemol yti c a nemi a , a nd thyroi di ti s . Reducti ons i n norma l i mmunogl obul i n l evel s
occur. Lyti c bone l es i ons a re uncommon. Amyl oi dos i s s ometi mes devel ops .
Common ma ni fes ta ti ons i ncl ude l ympha denopa thy a nd hepa tos pl enomega l y, fever, a nd recurri ng i nfecti ons . Pa l a ta l edema occurs i n a bout one
fourth of pa ti ents .
The CBC ma y s how a nemi a , l eukopeni a , thrombocytopeni a , eos i nophi l i a , a nd ci rcul a ti ng a typi ca l l ymphocytes or pl a s ma cel l s . Di a gnos i s requi res
demons tra ti on by i mmunofi xa ti on of free monocl ona l hea vy cha i n fra gments of IgG i n s erum a nd uri ne. Of a ffected pa ti ents , one ha l f ha ve
monocl ona l s erum components > 1 g/dL (often broa d a nd heterogeneous ), a nd one ha l f ha ve protei nuri a > 1 g/24 h. Al though hea vy cha i n protei ns
ma y i nvol ve a ny IgG s ubcl a s s , the G3 s ubcl a s s i s es peci a l l y common. Bone ma rrow or l ymph node bi ops y, done i f other tes ts a re not di a gnos ti c,
revea l s va ri a bl e hi s topa thol ogy.
The medi a n s urvi va l wi th a ggres s i ve di s ea s e i s a bout 1 yr. Dea th us ua l l y res ul ts from ba cteri a l i nfecti on or progres s i ve ma l i gna ncy. Al kyl a ti ng
drugs , vi ncri s ti ne, or corti cos teroi ds , a nd ra di a ti on thera py ma y yi el d tra ns i ent remi s s i ons .
IgM Heavy Chain Disease
IgM heavy chain disease, which is rare, produces a clinical picture similar to chronic lymphocytic leukemia or other lymphoproliferative disorders.
IgM hea vy cha i n di s ea s e mos t often a ffects a dul ts > 50 yr. Vi s cera l orga n i nvol vement (s pl een, l i ver, a bdomi na l l ymph nodes ) i s common, but
extens i ve peri phera l l ympha denopa thy i s not. Pa thol ogi c fra ctures a nd a myl oi dos i s ma y occur. Serum protei n el ectrophores i s us ua l l y i s norma l or
s hows hypoga mma gl obul i nemi a . Bence Jones protei nuri a (type ) i s pres ent i n 10 to 15% of pa ti ents .
Di a gnos i s us ua l l y requi res bone ma rrow exa mi na ti on; va cuol a ted pl a s ma cel l s a re pres ent i n two thi rds of pa ti ents a nd, when pres ent, a re
vi rtua l l y pa thognomoni c. Dea th ca n occur i n a few months or i n ma ny yea rs . The us ua l ca us e of dea th i s uncontrol l a bl e prol i fera ti on of chroni c
l ymphocyti c l eukemi a cel l s .
Trea tment depends on the pa ti ent's condi ti on but ma y cons i s t of a l kyl a ti ng a gents pl us corti cos teroi ds or ma y be s i mi l a r to trea tment of the
l ymphoprol i fera ti ve di s order tha t i t mos t cl os el y res embl es .
Macroglobulinemia
(Pri ma ry Ma crogl obul i nemi a ; Wa l dens trom's Ma crogl obul i nemi a )
Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity,
bleeding, recurring infections, and generalized adenopathy. Diagnosis requires bone marrow examination and demonstration of M-protein. Treatment includes
plasmapheresis as needed for hyperviscosity, and systemic therapy with alkylating drugs, corticosteroids, nucleoside analogs, or monoclonal antibodies.
Ma crogl obul i nemi a , a n uncommon B-cel l ca ncer, i s cl i ni ca l l y more s i mi l a r to a l ymphoma tous di s ea s e tha n to myel oma a nd other pl a s ma cel l
di s orders . Ca us e i s unknown. Men a re a ffected more often tha n women; medi a n a ge i s 65.
After myel oma , ma crogl obul i nemi a i s the 2nd mos t common ma l i gna nt di s order a s s oci a ted wi th a monocl ona l ga mmopa thy. Exces s i ve a mounts of
IgM M-protei ns ca n a l s o a ccumul a te i n other di s orders , ca us i ng ma ni fes ta ti ons s i mi l a r to ma crogl obul i nemi a . Sma l l monocl ona l IgM components
a re pres ent i n the s era of a bout 5% of pa ti ents wi th B-cel l non-Hodgki n l ymphoma ; thi s ci rcums ta nce i s termed ma crogl obul i nemi c l ymphoma .
Addi ti ona l l y, IgM M-protei ns a re occa s i ona l l y pres ent i n pa ti ents wi th chroni c l ymphocyti c l eukemi a or other l ymphoprol i fera ti ve di s orders .
Cl i ni ca l ma ni fes ta ti ons of ma crogl obul i nemi a ma y be due to the l a rge a mount of hi gh mol wt monocl ona l IgM protei ns ci rcul a ti ng i n pl a s ma , but
mos t pa ti ents do not devel op probl ems rel a ted to hi gh IgM l evel s . Some of thes e protei ns a re a nti bodi es di rected towa rd a utol ogous IgG
(rheuma toi d fa ctors ) or I a nti gens (col d a ggl uti ni ns ). About 10% a re cryogl obul i ns . Seconda ry a myl oi dos i s occurs i n 5% of pa ti ents .
Symptoms and Signs
Mos t pa ti ents a re a s ymptoma ti c, but ma ny pres ent wi th ma ni fes ta ti ons of hypervi s cos i ty s yndrome: fa ti gue, wea knes s , s ki n a nd mucos a l
bl eedi ng, vi s ua l di s turba nces , hea da che, s ymptoms of peri phera l neuropa thy, a nd other cha ngi ng neurol ogi c ma ni fes ta ti ons . An i ncrea s ed
pl a s ma vol ume ca n preci pi ta te hea rt fa i l ure. Col d s ens i ti vi ty, Ra yna ud's s yndrome, or recurri ng ba cteri a l i nfecti ons ma y occur.
Exa mi na ti on ma y di s cl os e l ympha denopa thy, hepa tos pl enomega l y, a nd purpura . Ma rked engorgement a nd l oca l i zed na rrowi ng of reti na l vei ns ,
whi ch res embl e s a us a ge l i nks , s ugges ts hypervi s cos i ty s yndrome. Reti na l hemorrha ges , exuda tes , mi croa neurys ms , a nd pa pi l l edema occur i n l a te
s ta ges .
Diagnosis
CBC wi th pl a tel ets , RBC i ndi ces , a nd peri phera l bl ood s mea r
Serum protei n el ectrophores i s fol l owed by s erum a nd uri ne i mmunofi xa ti on
Serum vi s cos i ty a s s a y
Someti mes l ymph node bi ops y
Ma crogl obul i nemi a i s s us pected i n pa ti ents wi th s ymptoms of hypervi s cos i ty or other typi ca l s ymptoms , pa rti cul a rl y i f a nemi a i s pres ent.
However, i t i s often di a gnos ed i nci denta l l y when protei n el ectrophores i s revea l s a n M-protei n tha t proves to be IgM by i mmunofi xa ti on.
La bora tory eva l ua ti on i ncl udes tes ts us ed to eva l ua te pl a s ma cel l di s orders (s ee Mul ti pl e Myel oma on p. 1029) a s wel l a s mea s urement of
cryogl obul i ns , rheuma toi d fa ctor, a nd col d a ggl uti ni ns ; coa gul a ti on s tudi es ; a nd di rect Coombs ' tes t.
Modera te normocyti c, normochromi c a nemi a , ma rked roul ea u forma ti on, a nd a very hi gh ESR a re typi ca l . Leukopeni a , rel a ti ve l ymphocytos i s , a nd
thrombocytopeni a occa s i ona l l y occur. Cryogl obul i ns , rheuma toi d fa ctor, or col d a ggl uti ni ns ma y be pres ent. If col d a ggl uti ni ns a re pres ent, the
di rect Coombs ' tes t us ua l l y i s pos i ti ve. Va ri ous coa gul a ti on a nd pl a tel et functi on a bnorma l i ti es ma y occur. Res ul ts of routi ne bl ood s tudi es ma y
be s puri ous i f cryogl obul i nemi a or ma rked hypervi s cos i ty i s pres ent. Norma l i mmunogl obul i ns a re decrea s ed i n one ha l f of pa ti ents .
Immunofi xa ti on el ectrophores i s of concentra ted uri ne frequentl y s hows a monocl ona l l i ght cha i n (us ua l l y ), but gros s Bence Jones protei nuri a i s
unus ua l . Bone ma rrow s tudi es s how a va ri a bl e i ncrea s e i n pl a s ma cel l s , l ymphocytes , pl a s ma cytoi d l ymphocytes , a nd ma s t cel l s . Peri odi c a ci dSchi ff-pos i ti ve ma teri a l ma y be pres ent i n l ymphoi d cel l s . Lymph node bi ops y, done i f bone ma rrow exa mi na ti on i s norma l , i s frequentl y
i nterpreted a s di ffus e wel l -di fferenti a ted or pl a s ma cyti c l ymphocyti c l ymphoma . Serum vi s cos i ty i s mea s ured to confi rm s us pected hypervi s cos i ty
a nd when pres ent i s us ua l l y > 4.0 (norma l , 1.4 to 1.8).
Treatment
Pl a s ma pheres i s (when hypervi s cos i ty i s pres ent)
Al kyl a ti ng drugs , nucl eos i de a na l ogs , monocl ona l a nti bodi es (ri tuxi ma b), or a combi na ti on
Pos s i bl y bortezomi b, tha l i domi de, or l ena l i domi de
The cours e i s va ri a bl e, wi th a medi a n s urvi va l of 7 to 10 yr. Age > 60 yr, a nemi a , a nd cryogl obul i nemi a predi ct s horter s urvi va l .
Often, pa ti ents requi re no trea tment for ma ny yea rs . If hypervi s cos i ty i s pres ent, i ni ti a l trea tment i s pl a s ma pheres i s , whi ch ra pi dl y revers es
bl eedi ng a s wel l a s neurol ogi c a bnorma l i ti es . Pl a s ma pheres i s often needs to be repea ted.
Long-term trea tment wi th ora l a l kyl a ti ng drugs ma y be i ndi ca ted for pa l l i a ti on, but bone ma rrow toxi ci ty ca n occur. Nucl eos i de a na l ogs
(fl uda ra bi ne a nd 2-chl orodeoxya denos i ne) produce res pons es i n l a rge numbers of newl y di a gnos ed pa ti ents . Ri tuxi ma b ca n reduce tumor burden
wi thout s uppres s i ng norma l hema topoi es i s . However, duri ng the fi rs t s evera l months , IgM l evel s ma y i ncrea s e, requi ri ng pl a s ma pheres i s . The
protea s ome i nhi bi tor bortezomi b a nd the i mmunomodul a ti ng a gents tha l i domi de a nd l ena l i domi de a re a l s o effecti ve i n thi s ca ncer.
Monoclonal Gammopathy of Undetermined Significance
Monoclonal gammopathy of undetermined significance (MGUS) is the production of M-protein by noncancerous plasma cells in the absence of other
manifestations typical of multiple myeloma.
The i nci dence of MGUS i ncrea s es wi th a ge, from 1% of peopl e a ged 25 yr to > 5% of peopl e > 70 yr. MGUS ma y occur i n a s s oci a ti on wi th other
di s orders (s ee Ta bl e 119-1), i n whi ch ca s e M-protei ns ma y be a nti bodi es produced i n l a rge a mounts i n res pons e to protra cted a nti geni c s ti mul i .
MGUS us ua l l y i s a s ymptoma ti c, but peri phera l neuropa thy ca n occur. Al though mos t ca s es a re i ni ti a l l y beni gn, up to 25% (1%/yr) progres s to
myel oma or a rel a ted B-cel l di s order, s uch a s ma crogl obul i nemi a , a myl oi dos i s , or l ymphoma .
Di a gnos i s i s us ua l l y s us pected when M-protei n i s i nci denta l l y detected i n bl ood or uri ne duri ng a routi ne exa mi na ti on. On l a bora tory eva l ua ti on,
M-protei n i s pres ent i n l ow l evel s i n s erum (< 3 g/dL) or uri ne (< 300 mg/24 h). MGUS i s di fferenti a ted from other pl a s ma cel l di s orders beca us e Mprotei n l evel s rema i n rel a ti vel y s ta bl e over ti me a nd l yti c bone l es i ons , a nemi a , a nd rena l dys functi on a re a bs ent. However, pa ti ents s how
enha nced bone l os s a nd a hi gher ra te of fra ctures . Thus , ba s el i ne eva l ua ti on wi th a s kel eta l s urvey a nd bone dens i tometry s houl d be done. Bone
ma rrow s hows onl y mi l d pl a s ma cytos i s (< 10% of nucl ea ted cel l s ).
No a nti neopl a s ti c trea tment i s recommended. However, recent s tudi es s ugges t tha t MGUS pa ti ents wi th a s s oci a ted bone l os s (os teopeni a or
os teoporos i s ) ma y benefi t from trea tment wi th bi s phos phona tes . Pa ti ents s houl d be eva l ua ted for progres s i on of di s ea s e every 6 to 12 mo wi th
cl i ni ca l exa mi na ti on a nd s erum a nd uri ne protei n el ectrophores i s .
Multiple Myeloma
(Myel oma tos i s ; Pl a s ma Cel l Myel oma )
Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations
include bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Diagnosis requires demonstration of M-protein (sometimes present in
urine and not serum) and either lytic bone lesions, light-chain proteinuria, or excessive plasma cells in bone marrow. A bone marrow biopsy is usually needed.
Specific treatment includes conventional chemotherapy with the addition of bortezomib, lenalidomide, thalidomide, corticosteroids, and high-dose melphalan
followed by autologous peripheral blood stem cell transplantation.
The i nci dence of mul ti pl e myel oma i s 2 to 4/100,000. Ma l e:fema l e ra ti o i s 1.6:1, a nd the medi a n a ge i s a bout 65 yr. Preva l ence i n bl a cks i s twi ce
tha t i n whi tes . Eti ol ogy i s unknown, a l though chromos oma l a nd geneti c fa ctors , ra di a ti on, a nd chemi ca l s ha ve been s ugges ted.
Pathophysiology
The M-protei n produced by the ma l i gna nt pl a s ma cel l s i s IgG i n a bout 55% of myel oma pa ti ents a nd IgA i n a bout 20%; of pa ti ents produci ng ei ther
IgG or IgA, 40% a l s o ha ve Bence Jones protei nuri a , whi ch i s free monocl ona l or l i ght cha i ns i n the uri ne. In 15 to 20% of pa ti ents , pl a s ma cel l s
s ecrete onl y Bence Jones protei n. IgD myel oma a ccounts for a bout 1% of ca s es .
Di ffus e os teoporos i s or di s crete os teol yti c l es i ons devel op, us ua l l y i n the pel vi s , s pi ne, ri bs , a nd s kul l . Les i ons a re ca us ed by bone repl a cement
by expa ndi ng pl a s ma cytoma s or by cytoki nes tha t a re s ecreted by ma l i gna nt pl a s ma cel l s tha t a cti va te os teocl a s ts a nd s uppres s os teobl a s ts . The
os teol yti c l es i ons a re us ua l l y mul ti pl e; occa s i ona l l y, they a re s ol i ta ry i ntra medul l a ry ma s s es . Enha nced bone l os s ma y a l s o l ea d to
hyperca l cemi a . Extra os s eous s ol i ta ry pl a s ma cytoma s a re unus ua l but ma y occur i n a ny ti s s ue, es peci a l l y i n the upper res pi ra tory tra ct.
Rena l fa i l ure (myel oma ki dney) occurs i n ma ny pa ti ents a t di a gnos i s or duri ng the cours e of the di s order due to ma ny ca us es , mos t commonl y
from depos i ti on of l i ght cha i ns i n the di s ta l tubul es a nd hyperca l cemi a . Pa ti ents a l s o often devel op a nemi a us ua l l y from ki dney di s ea s e or
s uppres s i on of erythropoi es i s by ca ncer cel l s .
Sus cepti bi l i ty to ba cteri a l i nfecti on ma y occur i n s ome pa ti ents . Vi ra l i nfecti ons , es peci a l l y herpes i nfecti ons , a re i ncrea s i ngl y occurri ng a s a
res ul t of newer trea tment moda l i ti es . Seconda ry a myl oi dos i s (s ee p. 906) occurs i n 10% of myel oma pa ti ents , mos t often i n pa ti ents wi th Bence
Jones protei nuri a of -type.
Va ri a nt expres s i ons of mul ti pl e myel oma occur (s ee
Ta bl e 119-2).
[Table 119-2. Va ri a nt Expres s i ons of Mul ti pl e Myel oma ]
Symptoms and Signs
Pers i s tent bone pa i n (es peci a l l y i n the ba ck or thora x), rena l fa i l ure, a nd recurri ng ba cteri a l i nfecti ons a re the mos t common probl ems on
pres enta ti on, but ma ny pa ti ents a re i denti fi ed when routi ne l a bora tory tes ts s how a n el eva ted tota l protei n l evel i n the bl ood or s how
protei nuri a . Pa thol ogi c fra ctures a re common, a nd vertebra l col l a ps e ma y l ea d to s pi na l cord compres s i on a nd pa ra pl egi a . Symptoms of a nemi a
predomi na te or ma y be the s ol e rea s on for eva l ua ti on i n s ome pa ti ents , a nd a few pa ti ents ha ve ma ni fes ta ti ons of hypervi s cos i ty s yndrome (s ee
p. 1027). Peri phera l neuropa thy, ca rpa l tunnel s yndrome, a bnorma l bl eedi ng, a nd s ymptoms of hyperca l cemi a (eg, pol ydi ps i a ) a re common.
Pa ti ents ma y a l s o pres ent wi th rena l fa i l ure. Lympha denopa thy a nd hepa tos pl enomega l y a re unus ua l .
Diagnosis
CBC wi th pl a tel ets , peri phera l bl ood s mea r, ESR, a nd chemi s try pa nel (BUN, crea ti ni ne, Ca , uri c a ci d, LDH)
Serum a nd uri ne protei n el ectrophores i s fol l owed by i mmunofi xa ti on
X-ra ys (s kel eta l s urvey)
Mul ti pl e myel oma i s s us pected i n pa ti ents > 40 yr wi th pers i s tent unexpl a i ned bone pa i n, pa rti cul a rl y a t ni ght or a t res t, other typi ca l s ymptoms ,
or unexpl a i ned l a bora tory a bnorma l i ti es , s uch a s el eva ted bl ood protei n or uri na ry protei n, hyperca l cemi a , rena l i ns uffi ci ency, or a nemi a .
La bora tory eva l ua ti on i ncl udes routi ne bl ood tes ts , protei n el ectrophores i s , x-ra ys , a nd bone ma rrow exa mi na ti on.
Routi ne bl ood tes ts i ncl ude CBC, ESR, a nd chemi s try pa nel . Anemi a i s pres ent i n 80% of pa ti ents , us ua l l y normocyti c-normochromi c a nemi a wi th
forma ti on of roul ea u, whi ch a re cl us ters of 3 to 12 RBCs tha t occur i n s ta cks . WBC a nd pl a tel et counts a re us ua l l y norma l . ESR us ua l l y i s > 100
mm/h; BUN, s erum crea ti ni ne, LDH, a nd s erum uri c a ci d a re frequentl y el eva ted. Ani on ga p i s s ometi mes l ow. Hyperca l cemi a i s pres ent a t
di a gnos i s i n a bout 10% of pa ti ents .
Protei n el ectrophores i s i s done on a s erum s a mpl e a nd on a uri ne s a mpl e concentra ted from a 24-h col l ecti on to qua nti fy the a mount of uri na ry
M-protei n. Serum el ectrophores i s i denti fi es M-protei n i n a bout 80 to 90% of pa ti ents . The rema i ni ng 10 to 20% a re us ua l l y pa ti ents wi th onl y free
monocl ona l l i ght cha i ns (Bence Jones protei n) or IgD. They a l mos t a l wa ys ha ve M-protei n detected by uri ne protei n el ectrophores i s .
Immunofi xa ti on el ectrophores i s ca n i denti fy the i mmunogl obul i n cl a s s of the M-protei n a nd ca n often detect l i ght-cha i n protei n i f s erum
i mmuno-el ectrophores i s i s fa l s el y nega ti ve; i mmunofi xa ti on el ectrophores i s i s done even when the s erum tes t i s nega ti ve i f mul ti pl e myel oma i s
s trongl y s us pected. Li ght-cha i n a na l ys i s wi th del i nea ti on of a nd ra ti os hel ps confi rm the di a gnos i s . Li ght-cha i n a na l ys i s ca n a l s o be us ed to
moni tor effi ca cy of thera py a nd provi de prognos ti c da ta . Serum l evel of 2 -mi crogl obul i n i s mea s ured i f di a gnos i s i s confi rmed or very l i kel y; i t
frequentl y i s el eva ted, a nd a l bumi n ma y be decrea s ed. A new i nterna ti ona l s ta gi ng s ys tem us es the l evel s of s erum a l bumi n a nd 2 mi crogl obul i n to i ndi ca te s everi ty of di s ea s e a nd s ubs equent prognos i s .
X-ra ys i ncl ude a s kel eta l s urvey. Punched-out l yti c l es i ons or di ffus e os teoporos i s i s pres ent i n 80% of ca s es . Ra di onucl i de bone s ca ns us ua l l y a re
not hel pful . MRI ca n provi de more deta i l a nd i s obta i ned i f s peci fi c s i tes of pa i n or neurol ogi c s ymptoms a re pres ent.
Bone ma rrow a s pi ra ti on a nd bi ops y a re done a nd revea l s heets or cl us ters of pl a s ma cel l s ; myel oma i s di a gnos ed when > 10% of the cel l s a re of
thi s type. However, bone ma rrow i nvol vement i s pa tchy; therefore, s ome s a mpl es from pa ti ents wi th myel oma ma y s how < 10% pl a s ma cel l s . Sti l l ,
the number of pl a s ma cel l s i n bone ma rrow i s ra rel y norma l . Pl a s ma cel l morphol ogy does not correl a te wi th the cl a s s of i mmunogl obul i n
s ynthes i zed. Chromos oma l s tudi es on bone ma rrow ma y revea l s peci fi c ka ryotypi c a bnorma l i ti es i n pl a s ma cel l s a s s oci a ted wi th di fferences i n
s urvi va l .
In pa ti ents wi thout s erum M protei n, myel oma i s i ndi ca ted by Bence Jones protei nuri a > 300 mg/24 h, os teol yti c l es i ons (wi thout evi dence of
meta s ta ti c ca ncer or gra nul oma tous di s ea s e), a nd s heets or cl us ters of pl a s ma cel l s i n the bone ma rrow.
Prognosis
The di s ea s e i s progres s i ve a nd i ncura bl e, but medi a n s urvi va l ha s recentl y i mproved to > 5 yr a s a res ul t of a dva nces i n trea tment. Unfa vora bl e
prognos ti c s i gns a t di a gnos i s a re l ower s erum a l bumi n a nd hi gher 2 -mi crogl obul i n l evel s . Pa ti ents pres enti ng wi th rena l fa i l ure a l s o do poorl y
unl es s ki dney functi on i mproves wi th thera py.
Beca us e mul ti pl e myel oma i s ul ti ma tel y fa ta l , pa ti ents a re l i kel y to benefi t from di s cus s i ons of end-of-l i fe ca re tha t i nvol ve thei r doctors a nd
a ppropri a te fa mi l y a nd fri ends . Poi nts for di s cus s i on ma y i ncl ude a dva nce di recti ves , the us e of feedi ng tubes , a nd pa i n rel i ef.
Treatment
Chemothera py for s ymptoma ti c pa ti ents
Tha l i domi de, bortezomi b, or l ena l i domi de wi th corti cos teroi ds a nd/or chemothera py
Pos s i bl y ma i ntena nce thera py
Pos s i bl y ra di a ti on thera py
Trea tment of compl i ca ti ons (a nemi a , hyperca l cemi a , rena l i ns uffi ci ency, i nfecti ons , s kel eta l l es i ons )
Trea tment of myel oma ha s i mproved i n the pa s t deca de, a nd l ong-term s urvi va l i s a rea s ona bl e thera peuti c ta rget. Thera py i nvol ves di rect
trea tment of ma l i gna nt cel l s i n s ymptoma ti c pa ti ents a nd the trea tment of the compl i ca ti ons . As ymptoma ti c pa ti ents proba bl y do not benefi t from
trea tment, whi ch i s us ua l l y wi thhel d unti l s ymptoms or compl i ca ti ons devel op. However, pa ti ents wi th evi dence of l yti c l es i ons or bone l os s
(os teopeni a or os teoporos i s ) s houl d be trea ted wi th monthl y i nfus i ons of zol edroni c a ci d or pa mi drona te to reduce the ri s k of s kel eta l
compl i ca ti ons .
Treatment of malignant cells: Unti l recentl y, conventi ona l chemothera py cons i s ted onl y of ora l mel pha l a n a nd predni s one gi ven i n cycl es of 4 to 6 wk
wi th monthl y eva l ua ti on of res pons e. Recent s tudi es s how s uperi or outcome wi th the a ddi ti on of ei ther bortezomi b or tha l i domi de. Other
chemothera peuti c drugs , i ncl udi ng other a l kyl a ti ng drugs (eg, cycl ophos pha mi de, doxorubi ci n a nd i ts newer a na l og l i pos oma l pegyl a ted
doxorubi ci n) a l s o a re more effecti ve when combi ned wi th tha l i domi de or bortezomi b. Ma ny other pa ti ents a re effecti vel y trea ted wi th bortezomi b,
tha l i domi de, or l ena l i domi de pl us gl ucocorti coi ds a nd/or chemothera py.
Chemothera py res pons e i s i ndi ca ted by decrea s es i n s erum or uri ne M-protei n, i ncrea s es i n RBCs , a nd i mprovement i n rena l functi on a mong
pa ti ents pres enti ng wi th ki dney fa i l ure.
Autol ogous peri phera l bl ood s tem cel l tra ns pl a nta ti on ma y be cons i dered for pa ti ents who ha ve a dequa te ca rdi a c, hepa ti c, pul mona ry, a nd rena l
functi on, pa rti cul a rl y thos e whos e di s ea s e i s s ta bl e or res pons i ve a fter s evera l cycl es of i ni ti a l thera py. Al l ogenei c s tem cel l tra ns pl a nta ti on a fter
nonmyel oa bl a ti ve chemothera py (eg, l ow-dos e cycl ophos pha mi de a nd fl uda ra bi ne) or l ow-dos e ra di a ti on thera py ca n produce myel oma -free
s urvi va l of 5 to 10 yr i n s ome pa ti ents . However, a l l ogenei c s tem cel l tra ns pl a nta ti on rema i ns experi menta l beca us e of the hi gh morbi di ty a nd
morta l i ty from gra ft vs . hos t di s ea s e.
In rel a ps ed or refra ctory myel oma , combi na ti ons of bortezomi b, tha l i domi de, or i ts newer a na l og l ena l i domi de wi th chemothera py or
corti cos teroi ds ma y be us ed. Thes e drugs a re us ua l l y combi ned wi th other effecti ve drugs tha t the pa ti ent ha s not yet been trea ted wi th, a l though
pa ti ents wi th prol onged remi s s i ons ma y res pond to retrea tment wi th the s a me regi men tha t l ed to the remi s s i on.
Ma i ntena nce thera py ha s been tri ed wi th nonchemothera peuti c drugs , i ncl udi ng i nterferon a l fa , whi ch prol ongs remi s s i on but does not i mprove
s urvi va l a nd i s a s s oci a ted wi th s i gni fi ca nt a dvers e effects . Fol l owi ng a res pons e to corti cos teroi d-ba s ed regi mens , corti cos teroi ds a l one a re
effecti ve a s a ma i ntena nce trea tment. Tha l i domi de ma y a l s o be effecti ve a s a ma i ntena nce trea tment, a nd s tudi es a re eva l ua ti ng ma i ntena nce
thera py wi th bortezomi b a nd l ena l i domi de a mong pa ti ents who ha ve res ponded to thes e drugs a l one or i n combi na ti on thera peuti c regi mens .
Treatment of complications: In a ddi ti on to di rect trea tment of ma l i gna nt cel l s , thera py mus t a l s o be di rected a t compl i ca ti ons , whi ch i ncl ude
a nemi a , hyperca l cemi a , rena l i ns uffi ci ency, i nfecti ons , a nd s kel eta l l es i ons .
Anemia ca n be trea ted wi th recombi na nt erythropoi eti n (40,000 uni ts s c once/wk) i n pa ti ents whos e a nemi a i s i na dequa tel y rel i eved by
chemothera py. If a nemi a ca us es ca rdi ova s cul a r or s i gni fi ca nt s ys temi c s ymptoms , pa cked RBCs a re tra ns fus ed. Pl a s ma pheres i s i s i ndi ca ted i f
hypervi s cos i ty devel ops (s ee p. 1027).
Hypercalcemia i s trea ted wi th s a l ures i s , IV bi s phos phona tes , a nd s ometi mes wi th predni s one. Mos t pa ti ents do not requi re a l l opuri nol . However,
a l l opuri nol i s i ndi ca ted for pa ti ents wi th hi gh l evel s of s erum uri c a ci d or hi gh tumor burden a nd a hi gh ri s k of tumor l ys i s s yndrome wi th
trea tment.
Renal compromise ca n be a mel i ora ted wi th a dequa te hydra ti on. Even pa ti ents wi th prol onged, ma s s i ve Bence Jones protei nuri a ( 10 to 30 g/da y)
ma y ha ve i nta ct rena l functi on i f they ma i nta i n uri ne output > 2000 mL/da y. Dehydra ti on combi ned wi th hi gh-os mol a r IV contra s t ma y preci pi ta te
a cute ol i guri c rena l fa i l ure i n pa ti ents wi th Bence Jones protei nuri a .
Infection i s more l i kel y duri ng chemothera py-i nduced neutropeni a . In a ddi ti on, i nfecti ons wi th the herpes zos ter vi rus a re occurri ng more
frequentl y i n pa ti ents trea ted wi th newer a nti myel oma drugs . Documented ba cteri a l i nfecti ons s houl d be trea ted wi th a nti bi oti cs ; however,
prophyl a cti c us e of a nti bi oti cs i s not routi nel y recommended. Prophyl a cti c us e of a nti vi ra l drugs ma y be i ndi ca ted for pa ti ents recei vi ng s peci fi c
drugs . Prophyl a cti c IV i mmune gl obul i n ma y reduce the ri s k of i nfecti on but i s genera l l y res erved for pa ti ents wi th recurri ng i nfecti ons .
Pneumococca l a nd i nfl uenza va cci nes a re i ndi ca ted to prevent i nfecti on.
Skeletal lesions requi re mul ti pl e s upporti ve mea s ures . Ma i ntena nce of a mbul a ti on a nd s uppl ementa l Ca a nd vi ta mi n D hel p pres erve bone
dens i ty. Ana l ges i cs a nd pa l l i a ti ve dos es of ra di a ti on thera py (18 to 24 Gy) ca n rel i eve bone pa i n. However, ra di a ti on thera py ma y i mpa i r the
pa ti ent's a bi l i ty to recei ve cytotoxi c dos es of s ys temi c chemothera py. Mos t pa ti ents , es peci a l l y thos e wi th l yti c l es i ons a nd genera l i zed
os teoporos i s or os teopeni a , s houl d recei ve a monthl y IV bi s phos phona te (ei ther pa mi drona te or zol edroni c a ci d). Bi s phos phona tes reduce
s kel eta l compl i ca ti ons a nd l es s en bone pa i n a nd ma y ha ve a n a nti tumor effect.
Chapter 120. Iron Overload

Introduction
(Hemos i deros i s ; Hemochroma tos i s )
(For i ron poi s oni ng, s ee p. 3341.)
Iron (Fe) i n exces s of bodi l y needs i s depos i ted i n ti s s ues :
Hemos i deros i s i s foca l depos i ti on of i ron tha t does not ca us e ti s s ue da ma ge.
Hemochroma tos i s (i ron overl oa d) i s a typi ca l l y s ys temi c proces s i n whi ch i ron depos i ti on ca n ca us e ti s s ue da ma ge.
Iron overl oa d ma y res ul t from pri ma ry hemochroma tos i s (a geneti c di s order of i ron meta bol i s m), from exces s ora l i nta ke or a bs orpti on of i ron, or
from repea ted bl ood tra ns fus i ons . Morbi di ty i s ma i nl y due to i ron a ccumul a ti on i n the endocri ne orga ns (es peci a l l y the pa ncrea s , gona ds , a nd
pi tui ta ry), l i ver, a nd hea rt.
Hemosiderosis
Hemosiderosis is focal deposition of iron that does not cause tissue damage.
Foca l hemos i deros i s ca n res ul t from hemorrha ge wi thi n a n orga n. Iron l i bera ted from extra va s a ted RBCs i s depos i ted wi thi n tha t orga n, a nd
s i gni fi ca nt hemos i deri n depos i ts ma y eventua l l y devel op. Occa s i ona l l y, i ron l os s from ti s s ue hemorrha ge ca us es i ron defi ci ency a nemi a , beca us e
i ron i n ti s s ues ca nnot be reus ed.
Us ua l l y the l ungs a re a ffected, a nd the ca us e us ua l l y i s recurrent pul mona ry hemorrha ge, ei ther i di opa thi c (eg, Goodpa s ture's s yndrome) or due
to chroni c pul mona ry hypertens i on (eg, from pri ma ry pul mona ry hypertens i on, pul mona ry fi bros i s , s evere mi tra l s tenos i s ).
Another common s i te of a ccumul a ti on i s the ki dneys , where hemos i deros i s ca n res ul t from extens i ve i ntra va s cul a r hemol ys i s (s ee p. 934). Free Hb
i s fi l tered a t the gl omerul us , res ul ti ng i n i ron depos i ti on i n the ki dneys . The rena l pa renchyma i s not da ma ged, but s evere hemos i deri nuri a ma y
res ul t i n i ron defi ci ency.
Primary Hemochromatosis
(Heredi ta ry Hemochroma tos i s )
Primary hemochromatosis is a genetic disorder characterized by excessive iron accumulation that results in tissue damage. Manifestations can include
constitutional symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Diagnosis is by serum ferritin level and gene assay.
Treatment is usually with serial phlebotomies.
Etiology
Unti l recentl y, the ca us e i n vi rtua l l y a l l pa ti ents wi th pri ma ry hemochroma tos i s wa s thought to be a muta ti on of the HFE gene. Recentl y, other
ca us es ha ve been i denti fi ed; di fferent muta ti ons ca us i ng pri ma ry hemochroma tos i s occur i n ferroporti n di s ea s e, juveni l e hemochroma tos i s ,
neona ta l hemochroma tos i s (neona ta l i ron s tora ge di s ea s e), hypotra ns ferri nemi a , a nd a cerul opl a s mi nemi a . Al though thes e types va ry ma rkedl y
i n a ge of ons et, cl i ni ca l cons equences of i ron overl oa d a re the s a me i n a l l .
More tha n 80% of HFE-rel a ted hemochroma tos i s i s ca us ed by the homozygous C282Y or C282Y/H63D compound heterozygote muta ti on. The di s order
i s a utos oma l reces s i ve, wi th a homozygous frequency of 1:200 a nd a heterozygous frequency of 1:8 i n peopl e of northern Europea n a nces try. It i s
uncommon a mong bl a cks a nd ra re a mong peopl e of As i a n a nces try. Of pa ti ents wi th cl i ni ca l hemochroma tos i s , 83% a re homozygous . However, for
unknown rea s ons , phenotypi c (cl i ni ca l ) di s ea s e i s much l es s common tha n predi cted by the frequency of the gene (i e, ma ny homozygous peopl e
do not ma ni fes t the di s order).
Pathophysiology
Norma l tota l body i ron content i s a bout 2.5 g i n women a nd 3.5 g i n men. Beca us e s ymptoms ma y be del a yed unti l i ron a ccumul a ti on i s exces s i ve,
hemochroma tos i s ma y not be recogni zed unti l tota l body i ron content i s > 10 g, or often s evera l ti mes grea ter. In women, cl i ni ca l ma ni fes ta ti ons
a re uncommon before menopa us e beca us e i ron l os s due to mens es (a nd s ometi mes pregna ncy a nd chi l dbi rth) tends to offs et i ron a ccumul a ti on.
The mecha ni s m for i ron overl oa d i s i ncrea s ed i ron a bs orpti on from the GI tra ct, l ea di ng to chroni c depos i ti on of i ron i n the ti s s ues . Hepci di n, a
l i ver-deri ved pepti de, i s the cri ti ca l control mecha ni s m for i ron a bs orpti on. Hepci di n, a l ong wi th the norma l HFE gene, prevents exces s i ve i ron
a bs orpti on a nd s tora ge i n norma l peopl e.
In genera l , ti s s ue i njury a ppea rs to res ul t from rea cti ve free hydroxyl ra di ca l s genera ted when i ron depos i ti on i n ti s s ues ca ta l yzes thei r forma ti on.
Other mecha ni s ms ma y a ffect pa rti cul a r orga ns (eg, s ki n hyperpi gmenta ti on ca n res ul t from i ncrea s ed mel a ni n a s wel l a s i ron a ccumul a ti on).
Symptoms and Signs
The cl i ni ca l cons equences of i ron overl oa d a re the s a me rega rdl es s of the eti ol ogy a nd pa thophys i ol ogy of the overl oa d.
Hi s tori ca l l y, experts bel i eved tha t s ymptoms di d not devel op unti l s i gni fi ca nt orga n da ma ge ha d occurred. However, orga n da ma ge i s s l ow a nd
s ubtl e, a nd fa ti gue a nd nons peci fi c cons ti tuti ona l s ymptoms often occur ea rl y.
Other s ymptoms rel a te to the orga ns wi th the l a rges t i ron depos i ts (s ee
Ta bl e 120-1). In men, the i ni ti a l s ymptoms ma y be hypogona di s m a nd erecti l e dys functi on ca us ed by gona da l i ron depos i ti on. Gl ucos e i ntol era nce
or di a betes mel l i tus i s a nother common i ni ti a l pres enta ti on. Some pa ti ents pres ent wi th hypothyroi di s m.
Li ver di s ea s e i s the mos t common compl i ca ti on a nd ma y progres s to ci rrhos i s ; 20 to 30% of pa ti ents wi th ci rrhos i s devel op hepa tocel l ul a r
ca rci noma . Li ver di s ea s e i s the mos t common ca us e of dea th. Ca rdi omyopa thy wi th hea rt fa i l ure i s the 2nd mos t common fa ta l compl i ca ti on.
Hyperpi gmenta ti on (bronze di a betes ) i s common, a s i s s ymptoma ti c a rthropa thy.
[Table 120-1. Common Ma ni fes ta ti ons of Pri ma ry Hemochroma tos i s ]
Diagnosis
Serum ferri ti n l evel
Geneti c tes ti ng
Symptoms a nd s i gns ma y be nons peci fi c, s ubtl e, a nd of gra dua l ons et, s o tha t i ndex of s us pi ci on s houl d be hi gh. Pri ma ry hemochroma tos i s s houl d
be s us pected when typi ca l ma ni fes ta ti ons , pa rti cul a rl y combi na ti ons of s uch ma ni fes ta ti ons , rema i n unexpl a i ned a fter routi ne eva l ua ti on.
Al though a ny fa mi l y hi s tory i s a more s peci fi c cl ue, i t i s not us ua l l y pres ent.
Serum ferri ti n mea s urement i s the s i mpl es t a nd mos t di rect i ni ti a l tes t. El eva ted l evel s (> 200 ng/mL i n women or > 300 ng/mL i n men) a re us ua l l y
pres ent i n pri ma ry hemochroma tos i s but ca n res ul t from other a bnorma l i ti es , s uch a s i nfl a mma tory l i ver di s orders (eg, chroni c vi ra l hepa ti ti s ,
nona l cohol i c s tea tohepa ti ti s , a l cohol i c l i ver di s ea s e), ca ncer, certa i n s ys temi c i nfl a mma tory di s orders (eg, RA, hemopha gocyti c
l ymphohi s ti ocytos i s ), or obes i ty. Further tes ti ng i s done i f ferri ti n l evel i s a bnorma l ; tes ti ng i ncl udes s erum i ron (us ua l l y > 300 mg/dL) a nd i ron
bi ndi ng ca pa ci ty (tra ns ferri n s a tura ti on; l evel s us ua l l y > 50%). Gene a s s a y i s di a gnos ti c of pri ma ry hemochroma tos i s ca us ed by HFE gene
muta ti ons . Other types of pri ma ry hemochroma tos i s (eg, ferroporti n di s ea s e, juveni l e hemochroma tos i s , neona ta l hemochroma tos i s , tra ns ferri n
defi ci ency, cerul opl a s mi n defi ci ency) a re s us pected i n very ra re i ns ta nces i n whi ch ferri ti n a nd i ron bl ood tes ts i ndi ca te i ron overl oa d a nd geneti c
tes ti ng i s nega ti ve for the HFE gene muta ti on, pa rti cul a rl y i n younger pa ti ents . Confi rma ti on of thes e di a gnos es i s evol vi ng.
Beca us e the pres ence of ci rrhos i s a ffects prognos i s , a l i ver bi ops y i s commonl y done a nd ti s s ue i ron content i s mea s ured (when a va i l a bl e). Hi ghi ntens i ty MRI i s a noni nva s i ve a l terna ti ve for es ti ma ti ng hepa ti c i ron content tha t i s becomi ng i ncrea s i ngl y a ccura te.
Screeni ng i s requi red for fi rs t-degree rel a ti ves of peopl e wi th pri ma ry hemochroma tos i s by mea s uri ng s erum ferri ti n l evel s a nd tes ti ng for the
282Y/H63D gene.
Treatment
Phl ebotomy
Trea tment i s i ndi ca ted for pa ti ents wi th cl i ni ca l ma ni fes ta ti ons , el eva ted s erum ferri ti n l evel s (pa rti cul a rl y l evel s > 1000 ng/mL), or el eva ted
tra ns ferri n s a tura ti on. As ymptoma ti c pa ti ents need onl y peri odi c (eg, yea rl y) cl i ni ca l eva l ua ti on a nd mea s urement of s erum i ron, ferri ti n, a nd
tra ns ferri n s a tura ti on.
Phl ebotomy i s the s i mpl es t a nd mos t effecti ve method to remove exces s i ron. It del a ys progres s i on of fi bros i s to ci rrhos i s , s ometi mes even
revers i ng ci rrhoti c cha nges , a nd prol ongs s urvi va l , but i t does not prevent hepa tocel l ul a r ca rci noma . About 500 mL of bl ood (a bout 250 mg of i ron)
i s removed weekl y unti l s erum i ron l evel s a re norma l a nd tra ns ferri n s a tura ti on i s < 50%. Weekl y phl ebotomy ma y be needed for ma ny months (eg,
i f 250 mg Fe a re removed per week, 40 wk wi l l be requi red to remove 10 g Fe). When i ron l evel s a re norma l , phl ebotomi es ca n be i ntermi ttent to
ma i nta i n tra ns ferri n s a tura ti on a t < 30%.
Di a betes , ca rdi omyopa thy, erecti l e dys functi on, a nd other s econda ry ma ni fes ta ti ons a re trea ted a s i ndi ca ted.
Pa ti ents s houl d fol l ow a ba l a nced di et; i t i s not neces s a ry to res tri ct cons umpti on of i ron-conta i ni ng foods (eg, red mea t, l i ver). Al cohol s houl d be
cons umed onl y i n modera ti on beca us e i t ca n i ncrea s e i ron a bs orpti on a nd, i n hi gh a mounts , i ncrea s es the ri s k of ci rrhos i s .
Ferroportin Disease
Ferroporti n di s ea s e occurs l a rgel y i n peopl e of s outhern Europea n a nces try. It res ul ts from a n a utos oma l domi na nt muta ti on i n the SLC 40 A1 gene.
It ma ni fes ts i n the fi rs t deca de of l i fe a s i ncrea s ed s erum ferri ti n l evel s wi th l ow or norma l tra ns ferri n s a tura ti on; progres s i ve s a tura ti on of
tra ns ferri n occurs when pa ti ents a re i n thei r 20s a nd 30s . Cl i ni ca l ma ni fes ta ti ons a re mi l der tha n i n HFE di s ea s e, wi th modes t l i ver di s ea s e a nd
mi l d a nemi a . Tol era nce to vi gorous phl ebotomy i s poor; s eri a l moni tori ng of Hb l evel a nd tra ns ferri n s a tura ti on i s requi red.
Juvenile Hemochromatosis
Juveni l e hemochroma tos i s i s a ra re a utos oma l reces s i ve di s order ca us ed by muta ti ons i n the HJV gene tha t a ffect the tra ns cri pti on protei n
hemojuvel i n. It often ma ni fes ts i n a dol es cents . Symptoms a nd s i gns i ncl ude progres s i ve hepa tomega l y a nd hypogona dotropi c hypogona di s m.
Ferri ti n l evel s a re > 1000 ng/mL, a nd tra ns ferri n s a tura ti on i s > 90%.
Transferrin and Ceruloplasmin Deficiency
(Hypotra ns ferri nemi a /Atra ns ferri nemi a ; Acerul opl a s mi nemi a )
In tra ns ferri n defi ci ency, a bs orbed i ron tha t enters the porta l s ys tem not bound to tra ns ferri n i s depos i ted i n the l i ver. Subs equent i ron tra ns fer to
s i tes of RBC producti on i s reduced beca us e of tra ns ferri n defi ci ency.
In cerul opl a s mi n defi ci ency, l a ck of ferroxi da s e ca us es defecti ve convers i on of Fe 2+ to Fe 3+; s uch convers i on i s neces s a ry for bi ndi ng to tra ns ferri n.
Defecti ve tra ns ferri n bi ndi ng i mpa i rs the movement of i ron from i ntra cel l ul a r s tores to pl a s ma tra ns port, res ul ti ng i n a ccumul a ti on of i ron i n
ti s s ues .
Di a gnos i s i s ba s ed on mea s urement of s erum tra ns ferri n (i e, i ron-bi ndi ng ca pa ci ty) a nd cerul opl a s mi n l evel s (s ee Inheri ted Copper Toxi ci ty on p.
51). Trea tment i s experi menta l ; eg, i ron chel a tors ma y be better tol era ted tha n phl ebotomy beca us e pa ti ents typi ca l l y ha ve a nemi a .
Transferrin Receptor 2 Mutation
Muta ti ons i n tra ns ferri n receptor 2, a protei n tha t a ppea rs to control s a tura ti on of tra ns ferri n, ca n ca us e a ra re a utos oma l reces s i ve form of
hemochroma tos i s . Symptoms a nd s i gns a re s i mi l a r to HFE hemochroma tos i s .
Secondary Iron Overload
(Seconda ry Hemochroma tos i s )
Secondary iron overload results from excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of
erythropoiesis. Diagnosis is with serum iron studies. Treatment is usually by iron chelation.
Etiology
Seconda ry i ron overl oa d typi ca l l y occurs i n pa ti ents who ha ve
Hemogl obi nopa thi es (eg, s i ckl e cel l di s ea s e, tha l a s s emi a , s i derobl a s ti c a nemi a s )
Congeni ta l hemol yti c a nemi a s
Myel odys pl a s i a
Iron overl oa d res ul ts from the fol l owi ng mecha ni s ms :
Increa s ed i ron a bs orpti on (whi ch occurs , for unknown rea s ons , wi th i neffecti ve erythropoi es i s )
Exogenous i ron gi ven to trea t the a nemi a
Repea ted bl ood tra ns fus i ons (ea ch uni t of bl ood provi des a bout 250 mg of i ron; ti s s ue depos i ti on becomes s i gni fi ca nt when more tha n a bout 40
uni ts of bl ood a re tra ns fus ed)
Pa ti ents wi th hemogl obi nopa thi es a nd congeni ta l hemol yti c a nemi a s now typi ca l l y l i ve i nto a dul thood, s o compl i ca ti ons of i ron overl oa d a re now
common. In s uch pa ti ents , i ron overl oa d i nvol vi ng the hea rt, the l i ver, a nd endocri ne orga ns ha s become a common ca us e of dea th, but s urvi va l
ca n be prol onged by i ron remova l .
Diagnosis
Pa ti ents wi th i neffecti ve erythropoi es i s s houl d be eva l ua ted for s econda ry i ron overl oa d, whi ch i s di a gnos ed by mea s uri ng s erum ferri ti n, s erum
i ron, a nd tra ns ferri n s a tura ti on.
Treatment
Us ua l l y i ron chel a ti on wi th defera s i rox or deferoxa mi ne
Some pa ti ents ca n be trea ted wi th phl ebotomy a nd gi ven erythropoi eti n to ma i nta i n erythropoi es i s . However, beca us e i t wors ens a nemi a ,
phl ebotomy i s not recommended for ma ny pa ti ents (eg, thos e wi th Hb l evel < 10 g/dL, thos e who a re tra ns fus i on dependent, a nd thos e who
devel op s ymptoms of a nemi a a fter phl ebotomy). Trea tment i n thes e pa ti ents i s i ron chel a ti on. The goa l of trea tment i s a tra ns ferri n s a tura ti on of
< 50%.
Deferoxamine i s the drug tra di ti ona l l y us ed for i ron chel a ti on thera py. It i s gi ven by a s l ow s ubcuta neous i nfus i on overni ght through a porta bl e
pump for 5 to 7 ni ghts /wk or vi a 24-h IV i nfus i on. Dos e i s 1 to 2 g i n a dul ts a nd 20 to 40 mg/kg i n chi l dren. However, thi s thera py i s compl ex to
a dmi ni s ter a nd requi res a n unus ua l ti me commi tment from pa ti ents , res ul ti ng i n a hi gh ra te of nona dherence. Importa nt a dvers e effects i ncl ude
hypotens i on, GI di s turba nces , a nd a na phyl a xi s (a cutel y) a nd vi s i on a nd hea ri ng l os s (wi th chroni c us e).
Deferasirox, a n ora l chel a ti ng a gent, i s a n effecti ve a nd i ncrea s i ngl y us ed a l terna ti ve to deferoxa mi ne. Defera s i rox reduces i ron l evel s a nd
prevents or del a ys ons et of compl i ca ti ons of i ron overl oa d. Ini ti a l dos e i s 20 mg/kg po once/da y. Pa ti ents a re moni tored monthl y wi th dos e
i ncrea s es of up to 30 mg/kg once/da y. Trea tment ca n be i nterrupted when s erum ferri ti n i s < 500 ng/mL. Advers e effects (whi ch occur i n a bout 10%
of pa ti ents ) ca n i ncl ude na us ea , a bdomi na l pa i n, di a rrhea , a nd ra s h. Li ver a nd ki dney functi on ma y become a bnorma l ; l i ver a nd ki dney functi on
tes ts s houl d be done peri odi ca l l y (eg, monthl y, s ometi mes more frequentl y for hi gh-ri s k pa ti ents ).
Chapter 121. Transfusion Medicine

Introduction
More tha n 29 mi l l i on uni ts of bl ood components a re tra ns fus ed yea rl y i n the US, from a bout 8 mi l l i on vol unteer donors . Al though tra ns fus i on i s
proba bl y s a fer tha n ever, ri s k (a nd the publ i c's percepti on of ri s k) ma nda tes i nformed cons ent whenever pra cti ca l .
Blood Collection
In the US, the col l ecti on, s tora ge, a nd tra ns port of bl ood a nd i ts components a re s ta nda rdi zed a nd regul a ted by the FDA, the AABB, a nd s ometi mes
s ta te or l oca l hea l th a uthori ti es . Donor s creeni ng i ncl udes a n extens i ve ques ti onna i re a nd hea l th i ntervi ew; mea s urement of tempera ture, hea rt
ra te, a nd BP; a nd Hb determi na ti on. Some potenti a l donors a re deferred ei ther tempora ri l y or perma nentl y (s ee
Ta bl e 121-1). Cri teri a for deferra l protect pros pecti ve donors from pos s i bl e i l l effects of dona ti on a nd reci pi ents from di s ea s e. Dona ti ons a re
l i mi ted to once every 56 da ys . Wi th ra re excepti ons , bl ood donors a re unpa i d.
In s ta nda rd bl ood dona ti on, a bout 450 mL of whol e bl ood i s col l ected i n a pl a s ti c ba g conta i ni ng a n a nti coa gul a nt pres erva ti ve. Whol e bl ood or
pa cked RBCs pres erved wi th ci tra te-phos pha te-dextros e-a deni ne ma y be s tored for 35 da ys . Pa cked RBCs ma y be s tored for 42 da ys i f a n a deni nedextros e-s a l i ne s ol uti on i s a dded.
[Table 121-1. Some Rea s ons for Bl ood Dona ti on Deferra l or Deni a l ]
Autol ogous dona ti on, whi ch i s us e of the pa ti ent's own bl ood, i s the preferred method of tra ns fus i on when condi ti ons permi t. In the 2 to 3 wk
precedi ng el ecti ve s urgery, up to 3 or 4 uni ts of whol e bl ood or pa cked RBCs a re col l ected, a nd the pa ti ent i s gi ven i ron s uppl ements . Speci a l
bl ood s a l va ge procedures a re a l s o a va i l a bl e for col l ecti ng a nd a utotra ns fus i ng bl ood s hed a fter tra uma a nd duri ng s urgery.
Pretransfusion Testing
Donor bl ood tes ti ng i ncl udes ABO a nd Rh 0 (D) a nti gen typi ng, a nti body s creeni ng, a nd tes ti ng for i nfecti ous di s ea s e ma rkers (s ee
Ta bl e 121-2).
Compa ti bi l i ty tes ti ng tes ts the reci pi ent's RBCs for a nti gens A, B, a nd Rh 0 (D); s creens the reci pi ent's pl a s ma for a nti bodi es a ga i ns t other RBC
a nti gens ; a nd i ncl udes a cros s -ma tch to ens ure tha t the reci pi ent's pl a s ma i s compa ti bl e wi th a nti gens on donor RBCs . Compa ti bi l i ty tes ti ng i s
done before a tra ns fus i on; however, i n a n emergency, tes ti ng i s done a fter rel ea s i ng bl ood from the bl ood ba nk. It ca n a l s o hel p i n di a gnos i ng
tra ns fus i on rea cti ons .
ABO typi ng of donor a nd reci pi ent bl ood i s done to prevent tra ns fus i on of i ncompa ti bl e RBCs (s ee
Fi g. 121-1). As a rul e, bl ood for tra ns fus i on s houl d be of the s a me ABO type a s tha t of the reci pi ent. In urgent s i tua ti ons or when the correct ABO
type i s i n doubt or unknown, type O Rh-nega ti ve pa cked RBCs (not whol e bl oods ee p. 1040 for Acute Hemol yti c Tra ns fus i on Rea cti on), whi ch
conta i ns nei ther A nor B a nti gens , ma y be us ed for pa ti ents of a ny ABO type.
Rh typi ng determi nes whether the Rh fa ctor Rh 0 (D) i s pres ent on (Rh-pos i ti ve) or a bs ent from (Rh-nega ti ve) the RBCs . Rh-nega ti ve pa ti ents s houl d
a l wa ys recei ve Rh-nega ti ve bl ood except i n l i fe-threa teni ng emergenci es when Rh-nega ti ve bl ood i s una va i l a bl e. Rh-pos i ti ve pa ti ents ma y recei ve
Rh-pos i ti ve or Rh-nega ti ve bl ood. Occa s i ona l l y, RBCs from s ome Rh-pos i ti ve peopl e rea ct wea kl y on s ta nda rd Rh typi ng (wea k D, or D u, pos i ti ve),
but thes e peopl e a re s ti l l cons i dered Rh-pos i ti ve.
Anti body s creeni ng for unexpected a nti -RBC a nti bodi es i s routi nel y done on bl ood from pros pecti ve reci pi ents a nd prena ta l l y on ma terna l
s peci mens . Unexpected a nti -RBC a nti bodi es a re s peci fi c for RBC bl ood group a nti gens other tha n A a nd B [eg, Rh 0 (D), Kel l (K), Duffy (Fy)]. Ea rl y
detecti on i s i mporta nt, beca us e s uch a nti bodi es ca n ca us e s eri ous
[Table 121-2. Infecti ous Di s ea s e Tra ns mi s s i on Tes ti ng]
[Fig. 121-1. Compa ti bl e RBC types .]
hemol yti c tra ns fus i on rea cti ons or hemol yti c di s ea s e of the newborn (s ee p. 2784), a nd they ma y grea tl y compl i ca te compa ti bi l i ty tes ti ng a nd
del a y procurement of compa ti bl e bl ood.
Indi rect a nti gl obul i n tes ti ng (the i ndi rect Coombs ' tes t) i s us ed to s creen for unexpected a nti -RBC a nti bodi es . Thi s tes t ma y be pos i ti ve i n the
pres ence of a n unexpected bl ood group a nti body or when free (non-RBC-a tta ched) a nti body i s pres ent i n a utoi mmune hemol yti c a nemi a s (s ee p.
936). Rea gent RBCs a re mi xed wi th the pa ti ent's s erum, i ncuba ted, wa s hed, tes ted wi th a nti huma n gl obul i n, a nd obs erved for a ggl uti na ti on. Once
a n a nti body i s detected, i ts s peci fi ci ty i s determi ned. Knowi ng the s peci fi ci ty of the a nti body i s hel pful for a s s es s i ng i ts cl i ni ca l s i gni fi ca nce,
s el ecti ng compa ti bl e bl ood, a nd ma na gi ng hemol yti c di s ea s e of the newborn.
Di rect a nti gl obul i n tes ti ng (the di rect Coombs ' tes t) detects a nti bodi es tha t ha ve coa ted the pa ti ent's RBCs i n vi vo. It i s us ed when i mmunemedi a ted hemol ys i s i s s us pected. Pa ti ents ' RBCs a re di rectl y tes ted wi th a nti huma n gl obul i n a nd obs erved for a ggl uti na ti on. A pos i ti ve res ul t, i f
correl a ted wi th cl i ni ca l fi ndi ngs , s ugges ts a utoi mmune hemol yti c a nemi a , drug-i nduced hemol ys i s , a tra ns fus i on rea cti on, or hemol yti c di s ea s e of
the newborn.
Anti body ti tra ti on i s done when a cl i ni ca l l y s i gni fi ca nt, unexpected a nti -RBC a nti body i s i denti fi ed i n the s erum of a pregna nt woma n or i n a
pa ti ent wi th col d a utoi mmune hemol yti c a nemi a (s ee p. 936). The ma terna l a nti body ti ter correl a tes fa i rl y wel l wi th the s everi ty of hemol yti c
di s ea s e i n the i ncompa ti bl e fetus a nd i s often us ed to gui de trea tment i n hemol yti c di s ea s e of the newborn a l ong wi th ul tra s onogra phy a nd
a mni oti c fl ui d s tudy.
The a ddi ti on of a cros s -ma tch to ABO/Rh typi ng a nd a nti body s creeni ng i ncrea s es detecti on of i ncompa ti bi l i ty by onl y 0.01%. If the reci pi ent ha s a
cl i ni ca l l y s i gni fi ca nt a nti -RBC a nti body, donor bl ood i s res tri cted to RBC uni ts nega ti ve for the corres pondi ng a nti gen; further tes ti ng for
compa ti bi l i ty i s done by combi ni ng reci pi ent s erum, donor RBCs , a nd a nti huma n gl obul i n. In reci pi ents wi thout cl i ni ca l l y s i gni fi ca nt a nti -RBC
a nti bodi es , a n i mmedi a te s pi n cros s -ma tch, whi ch omi ts the a nti gl obul i n pha s e, confi rms ABO compa ti bi l i ty.
Emergency tra ns fus i on i s done when not enough ti me (genera l l y < 60 mi n) i s a va i l a bl e for thorough compa ti bi l i ty tes ti ng beca us e the pa ti ent i s i n
hemorrha gi c s hock. When ti me permi ts (a bout 10 mi n i s needed), ABO/Rh type-s peci fi c bl ood ma y be gi ven. In more urgent ci rcums ta nces , type O
RBCs a re tra ns fus ed i f the ABO type i s uncerta i n, a nd Rh-nega ti ve bl ood i s gi ven i f the Rh type i s uncerta i n.
"Type a nd s creen" ma y be reques ted i n ci rcums ta nces not l i kel y to requi re tra ns fus i on, a s i n el ecti ve s urgery. The pa ti ent's bl ood i s typed for
ABO/Rh a nti gens a nd s creened for a nti bodi es . If a nti bodi es a re a bs ent a nd the pa ti ent needs bl ood, ABO/Rh type s peci fi c or compa ti bl e RBCs ma y
be rel ea s ed wi thout the a nti gl obul i n pha s e of the cros s -ma tch. If a n unexpected a nti body i s pres ent, ful l tes ti ng i s requi red.
Blood Products
Whol e bl ood ca n provi de i mproved O2 -ca rryi ng ca pa ci ty, vol ume expa ns i on, a nd repl a cement of cl otti ng fa ctors a nd wa s previ ous l y recommended
for ra pi d ma s s i ve bl ood l os s . However, beca us e component thera py i s equa l l y effecti ve a nd i s a more effi ci ent us e of dona ted bl ood, whol e bl ood
i s not genera l l y a va i l a bl e i n the US.
RBCs: Pa cked RBCs a re ordi na ri l y the component of choi ce wi th whi ch to i ncrea s e Hb. Indi ca ti ons depend on the pa ti ent. O2 -ca rryi ng ca pa ci ty ma y
be a dequa te wi th Hb l evel s a s l ow a s 7 g/L i n hea l thy pa ti ents , but tra ns fus i on ma y be i ndi ca ted wi th hi gher Hb l evel s i n pa ti ents wi th decrea s ed
ca rdi opul mona ry res erve or ongoi ng bl eedi ng. One uni t of RBCs i ncrea s es a n a vera ge a dul t's Hb by a bout 1 g/dL, a nd the Hct by a bout 3% a bove the
pretra ns fus i on Hct va l ue. When onl y vol ume expa ns i on i s requi red, other fl ui ds ca n be us ed concurrentl y or s epa ra tel y. In pa ti ents wi th mul ti pl e
bl ood group a nti bodi es or wi th a nti bodi es to hi gh-frequency RBC a nti gens , ra re frozen RBCs a re us ed.
Wa s hed RBCs a re free of a l mos t a l l tra ces of pl a s ma , mos t WBCs , a nd pl a tel ets . They a re genera l l y gi ven to pa ti ents who ha ve s evere rea cti ons to
pl a s ma (eg, s evere a l l ergi es , pa roxys ma l nocturna l hemogl obi nuri a , or IgA i mmuni za ti on). In IgA-i mmuni zed pa ti ents , bl ood col l ected from IgAdefi ci ent donors ma y be prefera bl e for tra ns fus i on.
WBC-depl eted RBCs a re prepa red wi th s peci a l fi l ters tha t remove 99.99% of WBCs . They a re i ndi ca ted for pa ti ents who ha ve experi enced
nonhemol yti c febri l e tra ns fus i on rea cti ons , for excha nge tra ns fus i ons , for pa ti ents who requi re cytomega l ovi rus -nega ti ve bl ood tha t i s
una va i l a bl e, a nd pos s i bl y for the preventi on of pl a tel et a l l oi mmuni za ti on.
Fresh frozen plasma: Fres h frozen pl a s ma (FFP) i s a n unconcentra ted s ource of a l l cl otti ng fa ctors wi thout pl a tel ets . Indi ca ti ons i ncl ude correcti on of
bl eedi ng s econda ry to fa ctor defi ci enci es for whi ch s peci fi c fa ctor repl a cements a re una va i l a bl e, mul ti fa ctor defi ci ency s ta tes (eg, ma s s i ve
tra ns fus i on, di s s emi na ted i ntra va s cul a r coa gul a ti on [DIC], l i ver fa i l ure), a nd urgent wa rfa ri n revers a l , a l though prothrombi n compl ex concentra te
(PCC) s houl d be the fi rs t choi ce i f a va i l a bl e. FFP ca n s uppl ement RBCs when whol e bl ood i s una va i l a bl e for excha nge tra ns fus i on. FFP s houl d not
be us ed s i mpl y for vol ume expa ns i on.
Cryoprecipitate: Cryopreci pi ta te i s a concentra te prepa red from FFP. Ea ch concentra te us ua l l y conta i ns a bout 80 uni ts ea ch of fa ctor VIII a nd von
Wi l l ebra nd's fa ctor a nd a bout 250 mg of fi bri nogen. It a l s o conta i ns fi bronecti n a nd fa ctor XIII. Al though ori gi na l l y us ed for hemophi l i a a nd von
Wi l l ebra nd's di s ea s e, cryopreci pi ta te i s currentl y us ed a s a s ource of fi bri nogen i n a cute DIC wi th bl eedi ng, trea tment of uremi c bl eedi ng,
ca rdi othora ci c s urgery (fi bri n gl ue), obs tetri c emergenci es s uch a s a brupti o pl a centa e a nd HELLP (hemol ys i s , el eva ted l i ver enzymes , a nd l ow
pl a tel et count) s yndrome, a nd ra re fa ctor XIII defi ci ency. In genera l , i t s houl d not be us ed for other i ndi ca ti ons .
WBCs: Gra nul ocytes ma y be tra ns fus ed when s eps i s occurs i n a pa ti ent wi th profound pers i s tent neutropeni a (WBCs < 500/L) who i s unres pons i ve
to a nti bi oti cs . Gra nul ocytes mus t be gi ven wi thi n 24 h of ha rves t; however, tes ti ng for HIV, hepa ti ti s , huma n T-cel l l ymphotropi c vi rus , a nd s yphi l i s
ma y not be compl eted before i nfus i on. Beca us e of i mproved a nti bi oti c thera py a nd drugs tha t s ti mul a te gra nul ocyte producti on duri ng
chemothera py, gra nul ocytes a re s el dom us ed.
Immune globulins: Rh i mmune gl obul i n (RhIg), gi ven IM or IV, prevents devel opment of ma terna l Rh a nti bodi es tha t ca n res ul t from fetoma terna l
hemorrha ge. The s ta nda rd dos e of i ntra mus cul a r RhIg (300 g) mus t be gi ven to a n Rh-nega ti ve mother i mmedi a tel y a fter a borti on or del i very (l i ve
or s ti l l born) unl es s the i nfa nt i s Rh 0 (D) a nd D u nega ti ve or the mother's s erum a l rea dy conta i ns a nti -Rh 0 (D). If fetoma terna l hemorrha ge i s > 30 mL,
a l a rger dos e i s needed. If hemorrha ge of thi s a mount i s s us pected, tes ti ng of the vol ume of fetoma terna l hemorrha ge begi ns wi th the s creeni ng
ros ette tes t, whi ch, i f pos i ti ve, i s fol l owed by a qua nti ta ti ve tes t (eg, Kl ei ha uer-Betke). RhIg i s gi ven IV onl y when IM a dmi ni s tra ti on i s
contra i ndi ca ted (eg, i n pa ti ents wi th coa gul opa thy).
Other i mmune gl obul i ns a re a va i l a bl e for pos texpos ure prophyl a xi s for pa ti ents expos ed to a number of i nfecti ous di s ea s es , i ncl udi ng
cytomega l ovi rus , hepa ti ti s A a nd B, mea s l es , ra bi es , res pi ra tory s yncyti a l vi rus , rubel l a , teta nus , s ma l l pox, a nd va ri cel l a (for us a ge, s ee under
s peci fi c di s ea s e).
Platelets: Pl a tel et concentra tes a re us ed to prevent bl eedi ng i n a s ymptoma ti c s evere thrombocytopeni a (pl a tel et count < 10,000/L), for bl eedi ng
pa ti ents wi th l es s s evere thrombocytopeni a (pl a tel et count < 50,000/L), for bl eedi ng pa ti ents wi th pl a tel et dys functi on due to a nti pl a tel et drugs
but wi th norma l pl a tel et count, for pa ti ents recei vi ng ma s s i ve tra ns fus i on tha t ca us es di l uti ona l thrombocytopeni a , a nd s ometi mes before
i nva s i ve s urgery, pa rti cul a rl y wi th extra corporea l ci rcul a ti on for > 2 h (whi ch often ma kes pl a tel ets dys functi ona l ). One pl a tel et concentra te uni t
i ncrea s es the pl a tel et count by a bout 10,000/L, a nd a dequa te hemos ta s i s i s a chi eved wi th a pl a tel et count of a bout 10,000/L i n a pa ti ent
wi thout compl i ca ti ng condi ti ons a nd a bout 50,000/L for thos e undergoi ng s urgery. Therefore, 4 to 6 uni ts of ra ndom donor pl a tel et concentra tes
a re commonl y us ed i n a dul ts .
Pl a tel et concentra tes a re i ncrea s i ngl y bei ng prepa red by a utoma ted devi ces tha t ha rves t the pl a tel ets (or other cel l s ) a nd return unneeded
components (eg, RBCs , pl a s ma ) to the donor. Thi s procedure, ca l l ed cyta pheres i s , provi des enough pl a tel ets from a s i ngl e dona ti on (equi va l ent to
6 ra ndom pl a tel et uni ts ) for tra ns fus i on to a n a dul t, whi ch, beca us e i t mi ni mi zes i nfecti ous a nd i mmunogeni c ri s ks , i s preferred to mul ti pl e donor
tra ns fus i ons i n certa i n condi ti ons .
Certa i n pa ti ents ma y not res pond to pl a tel et tra ns fus i ons , pos s i bl y beca us e of s pl eni c s eques tra ti on or pl a tel et cons umpti on due to HLA or
pl a tel et-s peci fi c a nti gen a l l oi mmuni za ti on. Thes e pa ti ents ma y res pond to mul ti pl e ra ndom donor pl a tel ets (beca us e of grea ter l i kel i hood tha t
s ome uni ts a re HLA compa ti bl e), pl a tel ets from fa mi l y members , or ABO-or HLA-ma tched pl a tel ets . Al l oi mmuni za ti on ma y be mi ti ga ted by
tra ns fus i ng WBC-depl eted RBCs a nd WBC-depl eted pl a tel et concentra tes .
Other products: Irra di a ted bl ood products a re us ed to prevent gra ft-vs -hos t di s ea s e i n pa ti ents a t ri s k (s ee p. 1042). Bl ood s ubs ti tutes a re bei ng
devel oped tha t us e i nert chemi ca l s or Hb s ol uti ons to ca rry a nd del i ver O2 to ti s s ues . Perfl uoroca rbons a re chemi ca l l y a nd bi ol ogi ca l l y i na cti ve
a nd a re ca pa bl e of di s s ol vi ng O2 a nd CO2 under pres s ure. Beca us e perfl uoroca rbons a re not wa ter mi s ci bl e, they a re prepa red a s emul s i ons . They
a re undergoi ng pha s e II a nd III cl i ni ca l tri a l s . Hb-ba s ed O2 ca rri er s ol uti ons a re undergoi ng pha s e III cl i ni ca l tri a l s i n the US. Hb, huma n or bovi ne,
i s chemi ca l l y modi fi ed, produci ng a s ol uti on ca pa bl e of O2 tra ns port. Thes e s ol uti ons ca n be s tored a t room tempera ture for up to 2 yr, ma ki ng
them a ttra cti ve for tra ns port to the s i te of tra uma or to the ba ttl efi el d. However, both perfl uoroca rbons a nd Hb-ba s ed O2 ca rri ers a re cl ea red from
pl a s ma wi thi n 24 h.
Hema topoi eti c progeni tor cel l s (s tem cel l s ) from a utol ogous or a l l ogeni c donors ca n be tra ns fus ed a s a wa y of recons ti tuti ng hema topoi eti c
functi on (pa rti cul a rl y i mmune functi on) i n pa ti ents undergoi ng myel oa bl a ti ve or myel otoxi c thera py (s ee p. 1132).
Technique of Transfusion
CAUTION: Before transfusion is started, the patient's wristband, blood unit label, and compatibility test report must be checked at the bedside to ensure that the
blood component is the one intended for the recipient.
Us e of a n 18-ga uge (or l a rger) needl e prevents mecha ni ca l da ma ge to a nd hemol ys i s of RBCs . A s ta nda rd fi l ter s houl d a l wa ys be us ed for i nfus i on
of a ny bl ood component. Onl y 0.9% s a l i ne IV s houl d be a l l owed i nto the bl ood ba g or i n the s a me tubi ng wi th bl ood. Hypotoni c s ol uti ons l ys e
RBCs , a nd the Ca i n Ri nger's l a cta te ca n ca us e cl otti ng.
Tra ns fus i on of 1 uni t of bl ood or bl ood component s houl d be compl eted by 4 h; l onger dura ti on i ncrea s es the ri s k of ba cteri a l growth. If
tra ns fus i on mus t be gi ven s l owl y beca us e of hea rt fa i l ure or hypervol emi a , uni ts ma y be di vi ded i nto s ma l l er a l i quots i n the bl ood ba nk. For
chi l dren, 1 uni t of bl ood ca n be provi ded i n s ma l l s teri l e a l i quots us ed over s evera l da ys , thereby mi ni mi zi ng expos ure to mul ti pl e donors .
Cl os e obs erva ti on i s i mporta nt, pa rti cul a rl y duri ng the fi rs t 15 mi n, a nd i ncl udes recordi ng tempera ture, BP, pul s e, a nd res pi ra tory ra te. Peri odi c
obs erva ti on conti nues throughout a nd a fter the tra ns fus i on, duri ng whi ch fl ui d s ta tus i s a s s es s ed. The pa ti ent i s kept covered a nd wa rm to
prevent chi l l s , whi ch ma y be i nterpreted a s a tra ns fus i on rea cti on. El ecti ve tra ns fus i ons a t ni ght a re di s coura ged.
Complications of Transfusion
The mos t common compl i ca ti ons of tra ns fus i on a re febri l e nonhemol yti c a nd chi l l -ri gor rea cti ons . The mos t s eri ous compl i ca ti ons a re
tra ns fus i on-rel a ted a cute l ung i njury a nd a cute hemol yti c rea cti on due to ABO i ncompa ti bl e tra ns fus i on, whi ch ha ve very hi gh morta l i ty ra tes .
Ea rl y recogni ti on of s ymptoms s ugges ti ve of a tra ns fus i on rea cti on a nd prompt reporti ng to the bl ood ba nk a re es s enti a l . The mos t common
s ymptoms a re chi l l s , ri gors , fever, dys pnea , l i ght-hea dednes s , urti ca ri a , i tchi ng, a nd fl a nk pa i n. If a ny of thes e s ymptoms (other tha n l oca l i zed
urti ca ri a a nd i tchi ng) occur, the tra ns fus i on s houl d be s topped i mmedi a tel y a nd the IV l i ne kept open wi th norma l s a l i ne. The rema i nder of the
bl ood product a nd cl otted a nd a nti coa gul a ted s a mpl es of the pa ti ent's bl ood s houl d be s ent to the bl ood ba nk for i nves ti ga ti on. NOTE: The unit in
question should not be restarted, and transfusion of any previously issued unit should not be initiated. Further tra ns fus i on s houl d be del a yed unti l the ca us e
of the rea cti on i s known, unl es s the need i s urgent, i n whi ch ca s e type O Rh-nega ti ve RBCs s houl d be us ed.
Hemol ys i s of donor or reci pi ent RBCs (us ua l l y the former) duri ng or a fter tra ns fus i on ca n res ul t from ABO/Rh i ncompa ti bi l i ty, pl a s ma a nti bodi es ,
or hemol yzed or fra gi l e RBCs (eg, by overwa rmi ng s tored bl ood or conta ct wi th hypotoni c IV s ol uti ons ). Hemol ys i s i s mos t common a nd mos t s evere
when i ncompa ti bl e donor RBCs a re hemol yzed by a nti body i n the reci pi ent's pl a s ma . Hemol yti c rea cti ons ma y be a cute (wi thi n 24 h) or del a yed
(from 1 to 14 da ys ).
Acute hemolytic transfusion reaction (AHTR): About 20 peopl e di e yea rl y i n the US from AHTR. AHTR us ua l l y res ul ts from reci pi ent pl a s ma a nti bodi es
to donor RBC a nti gens . ABO i ncompa ti bi l i ty i s the mos t common ca us e of AHTR. Anti bodi es a ga i ns t bl ood group a nti gens other tha n ABO ca n a l s o
ca us e AHTR. Mi s l a bel i ng the reci pi ent's pretra ns fus i on s a mpl e a t col l ecti on or fa i l i ng to ma tch the i ntended reci pi ent wi th the bl ood product
i mmedi a tel y before tra ns fus i on i s the us ua l ca us e, not l a bora tory error.
Hemol ys i s i s i ntra va s cul a r, ca us i ng hemogl obi nuri a wi th va ryi ng degrees of a cute rena l fa i l ure a nd pos s i bl y di s s emi na ted i ntra va s cul a r
coa gul a ti on (DIC). The s everi ty of AHTR depends on the degree of i ncompa ti bi l i ty, the a mount of bl ood gi ven, the ra te of a dmi ni s tra ti on, a nd the
i ntegri ty of the ki dneys , l i ver, a nd hea rt. An a cute pha s e us ua l l y devel ops wi thi n 1 h of i ni ti a ti on of tra ns fus i on, but i t ma y occur l a ter duri ng the
tra ns fus i on or i mmedi a tel y a fterwa rd. Ons et i s us ua l l y a brupt. The pa ti ent ma y compl a i n of di s comfort a nd a nxi ety. Dys pnea , fever, chi l l s , fa ci a l
fl us hi ng, a nd s evere pa i n ma y occur, es peci a l l y i n the l umba r a rea . Shock ma y devel op, ca us i ng a ra pi d, feebl e pul s e; col d, cl a mmy s ki n; l ow BP;
a nd na us ea a nd vomi ti ng. Ja undi ce ma y fol l ow a cute hemol ys i s .
If AHTR occurs whi l e the pa ti ent i s under genera l a nes thes i a , the onl y s ymptom ma y be hypotens i on, uncontrol l a bl e bl eedi ng from i nci s i on s i tes
a nd mucous membra nes ca us ed by a n a s s oci a ted DIC, or da rk uri ne tha t refl ects hemogl obi nuri a .
If AHTR i s s us pected, one of the fi rs t s teps i s to recheck the s a mpl e a nd pa ti ent i denti fi ca ti ons . Di a gnos i s i s confi rmed by mea s uri ng uri na ry Hb,
s erum LDH, bi l i rubi n, a nd ha ptogl obi n. Intra va s cul a r hemol ys i s produces free Hb i n the pl a s ma a nd uri ne; ha ptogl obi n l evel s a re very l ow.
Hyperbi l i rubi nemi a ma y fol l ow.
After the a cute pha s e, the degree of a cute rena l fa i l ure determi nes the prognos i s . Di ures i s a nd a decrea s i ng BUN us ua l l y portend recovery.
Perma nent rena l i ns uffi ci ency i s unus ua l . Prol onged ol i guri a a nd s hock a re poor prognos ti c s i gns .
If AHTR i s s us pected, the tra ns fus i on s houl d be s topped a nd s upporti ve trea tment begun. The goa l of i ni ti a l thera py i s to a chi eve a nd ma i nta i n
a dequa te BP a nd rena l bl ood fl ow wi th IV 0.9% s a l i ne a nd furos emi de. IV s a l i ne i s gi ven to ma i nta i n uri ne output of 100 mL/h for 24 h. The i ni ti a l
furos emi de dos e i s 40 to 80 mg (1 to 2 mg/kg i n chi l dren), wi th l a ter dos es a djus ted to ma i nta i n uri na ry fl ow > 100 mL/h duri ng the fi rs t da y.
Anti hypertens i ve drugs mus t be a dmi ni s tered wi th ca uti on. Pres s or drugs tha t decrea s e rena l bl ood fl ow (eg, epi nephri ne, norepi nephri ne, hi ghdos e dopa mi ne) a re contra i ndi ca ted. If a pres s or drug i s neces s a ry, dopa mi ne 2 to 5 g/kg/mi n i s us ua l l y a dmi ni s tered.
A nephrol ogi s t s houl d be cons ul ted a s ea rl y a s pos s i bl e, pa rti cul a rl y i f no di ureti c res pons e occurs wi thi n a bout 2 to 3 h a fter i ni ti a ti ng thera py,
whi ch ma y i ndi ca te a cute tubul a r necros i s . Further fl ui d a nd di ureti c thera py ma y be contra i ndi ca ted, a nd ea rl y di a l ys i s ma y be hel pful .
Delayed hemolytic transfusion reaction: Occa s i ona l l y, a pa ti ent who ha s been s ens i ti zed to a n RBC a nti gen ha s very l ow a nti body l evel s a nd nega ti ve
pretra ns fus i on tes ts . After tra ns fus i on wi th RBCs bea ri ng thi s a nti gen, a pri ma ry or a na mnes ti c res pons e ma y res ul t (us ua l l y i n 1 to 4 wk) a nd
ca us e a del a yed hemol yti c tra ns fus i on rea cti on. Del a yed hemol yti c tra ns fus i on rea cti on us ua l l y does not ma ni fes t a s dra ma ti ca l l y a s AHTR.
Pa ti ents ma y be a s ymptoma ti c or ha ve a s l i ght fever. Ra rel y, s evere s ymptoms occur. Us ua l l y, onl y des tructi on of the tra ns fus ed RBCs (wi th the
a nti gen) occurs , res ul ti ng i n a fa l l i ng Hct a nd a s l i ght ri s e i n LDH a nd bi l i rubi n. Beca us e del a yed hemol yti c tra ns fus i on rea cti on i s us ua l l y mi l d
a nd s el f-l i mi ted, i t i s often uni denti fi ed, a nd the cl i ni ca l cl ue ma y be a n unexpl a i ned drop i n Hb to the pretra ns fus i on l evel occurri ng 1 to 2 wk
pos ttra ns fus i on. Severe rea cti ons a re trea ted s i mi l a rl y to a cute rea cti ons .
Febrile nonhemolytic transfusion reaction: Febri l e rea cti on ma y occur wi thout hemol ys i s . Anti bodi es di rected a ga i ns t WBC HLA from otherwi s e
compa ti bl e donor bl ood a re one pos s i bl e ca us e. Thi s ca us e i s mos t common i n mul ti tra ns fus ed or mul ti pa rous pa ti ents . Cytoki nes rel ea s ed from
WBCs duri ng s tora ge, pa rti cul a rl y i n pl a tel et concentra tes , a re a nother pos s i bl e ca us e.
Cl i ni ca l l y, febri l e rea cti ons cons i s t of a tempera ture i ncrea s e of 1 C, chi l l s , a nd s ometi mes hea da che a nd ba ck pa i n. Si mul ta neous s ymptoms of
a l l ergi c rea cti on a re common. Beca us e fever a nd chi l l s a l s o hera l d a s evere hemol yti c tra ns fus i on rea cti on, a l l febri l e rea cti ons mus t be
i nves ti ga ted a s for AHTR, a s wi th a ny tra ns fus i on rea cti on.
Mos t febri l e rea cti ons a re trea ted s ucces s ful l y wi th a ceta mi nophen a nd, i f neces s a ry, di phenhydra mi ne (s ee p. 1042). Pa ti ents s houl d a l s o be
trea ted (eg, wi th a ceta mi nophen) before future tra ns fus i ons . If a reci pi ent ha s experi enced more tha n one febri l e rea cti on, s peci a l
l eukoreducti on fi l ters a re us ed duri ng future tra ns fus i ons ; mos t hos pi ta l s us e pres tora ge, l eukoreduced bl ood components .
Allergic reactions: Al l ergi c rea cti ons to a n unknown component i n donor bl ood a re common, us ua l l y due to a l l ergens i n donor pl a s ma or, l es s often,
to a nti bodi es from a n a l l ergi c donor. Thes e rea cti ons a re us ua l l y mi l d, wi th urti ca ri a , edema , occa s i ona l di zzi nes s , a nd hea da che duri ng or
i mmedi a tel y a fter the tra ns fus i on. Si mul ta neous fever i s common. Les s frequentl y, dys pnea , wheezi ng, a nd i nconti nence ma y occur, i ndi ca ti ng a
genera l i zed s pa s m of s mooth mus cl e. Ra rel y, a na phyl a xi s occurs , pa rti cul a rl y i n IgA-defi ci ent reci pi ents .
In a pa ti ent wi th a hi s tory of a l l ergi es or a n a l l ergi c tra ns fus i on rea cti on, a n a nti hi s ta mi ne ma y be gi ven prophyl a cti ca l l y jus t before or a t the
begi nni ng of the tra ns fus i on (eg, di phenhydra mi ne 50 mg po or IV). NOTE: Drugs must never be mixed with the blood. If a n a l l ergi c rea cti on occurs , the
tra ns fus i on i s s topped. An a nti hi s ta mi ne (eg, di phenhydra mi ne 50 mg IV) us ua l l y control s mi l d urti ca ri a a nd i tchi ng, a nd tra ns fus i on ma y be
res umed. However, a modera te a l l ergi c rea cti on (genera l i zed urti ca ri a or mi l d bronchos pa s m) requi res hydrocorti s one (100 to 200 mg IV), a nd a
s evere a na phyl a cti c rea cti on requi res a ddi ti ona l trea tment wi th epi nephri ne 0.5 mL of 1:1000 s ol uti on s c a nd 0.9% s a l i ne IV (s ee p. 1121) a l ong
wi th i nves ti ga ti on by the bl ood ba nk. Further tra ns fus i on s houl d not occur unti l the i nves ti ga ti on i s compl eted. Pa ti ents wi th s evere IgA defi ci ency
requi re tra ns fus i on of wa s hed RBCs , wa s hed pl a tel ets , a nd pl a s ma from a n IgA-defi ci ent donor.
Volume overload: The hi gh os moti c l oa d of bl ood products dra ws vol ume i nto the i ntra va s cul a r s pa ce over the cours e of hours , whi ch ca n ca us e
vol ume overl oa d i n s us cepti bl e pa ti ents (eg, thos e wi th ca rdi a c or rena l i ns uffi ci ency). RBCs s houl d be i nfus ed s l owl y. The pa ti ent s houl d be
obs erved a nd, i f s i gns of hea rt fa i l ure (eg, dys pnea , cra ckl es ) occur, the tra ns fus i on s houl d be s topped a nd trea tment for hea rt fa i l ure begun.
Typi ca l trea tment i s wi th a di ureti c s uch a s furos emi de 20 to 40 mg IV. Occa s i ona l l y, pa ti ents requi ri ng a hi gher vol ume of pl a s ma i nfus i on to
revers e a wa rfa ri n overdos e ma y be gi ven a l ow dos e of furos emi de s i mul ta neous l y; however, prothrombi n compl ex concentra te (PCC) s houl d be
the fi rs t choi ce for s uch pa ti ents . Pa ti ents a t hi gh ri s k of vol ume overl oa d (eg, thos e wi th hea rt fa i l ure or s evere rena l i ns uffi ci ency) a re trea ted
prophyl a cti ca l l y wi th a di ureti c (eg, furos emi de 20 to 40 mg IV).
Acute lung injury: Tra ns fus i on-rel a ted a cute l ung i njury i s a n i nfrequent compl i ca ti on ca us ed by a nti -HLA a nd/or a nti gra nul ocyte a nti bodi es i n
donor pl a s ma tha t a ggl uti na te a nd degra nul a te reci pi ent gra nul ocytes wi thi n the l ung. Acute res pi ra tory s ymptoms devel op, a nd ches t x-ra y ha s a
cha ra cteri s ti c pa ttern of nonca rdi ogeni c pul mona ry edema . Thi s compl i ca ti on i s the 2nd mos t common ca us e of tra ns fus i on-rel a ted dea th.
Inci dence i s one i n 5,000 to one i n 10,000, but ma ny ca s es a re mi l d. Mi l d to modera te tra ns fus i on-rel a ted a cute l ung i njury proba bl y i s commonl y
mi s s ed. Genera l s upporti ve thera py typi ca l l y l ea ds to recovery wi thout l ong-l a s ti ng s equel a e. Di ureti cs s houl d be a voi ded. Ca s es s houl d be
reported.
Altered oxygen affinity: Bl ood s tored for > 7 da ys ha s decrea s ed RBC 2,3-di phos phogl ycera te (DPG), a nd the 2,3-DPG i s a bs ent a fter > 10 da ys . Thi s
a bs ence res ul ts i n a n i ncrea s ed a ffi ni ty for O2 a nd s l ower O2 rel ea s e to the ti s s ues . There i s l i ttl e evi dence tha t 2,3-DPG defi ci ency i s cl i ni ca l l y
s i gni fi ca nt except i n excha nge tra ns fus i ons i n i nfa nts , i n s i ckl e cel l pa ti ents wi th a cute ches t s yndrome a nd s troke, a nd i n s ome pa ti ents wi th
s evere hea rt fa i l ure. After tra ns fus i on of RBCs , 2,3-DPG regenera tes wi thi n 12 to 24 h.
Graft-vs-host disease (GVHD): Tra ns fus i on-a s s oci a ted GVHD (s ee p. 1131) i s us ua l l y ca us ed by tra ns fus i on of products conta i ni ng i mmunocompetent
l ymphocytes to a n i mmunocompromi s ed hos t. The donor l ymphocytes a tta ck hos t ti s s ues . GVHD ca n occur occa s i ona l l y i n i mmunocompetent
pa ti ents i f they recei ve bl ood from a donor (us ua l l y a cl os e rel a ti ve) who i s homozygous for a n HLA ha pl otype for whi ch they a re heterozygous .
Symptoms a nd s i gns i ncl ude fever, ra s h (centri fuga l l y s prea di ng ra s h becomi ng erythroderma wi th bul l a e), vomi ti ng, wa tery a nd bl oody di a rrhea ,
l ympha denopa thy, a nd pa ncytopeni a due to bone ma rrow a pl a s i a . Ja undi ce a nd el eva ted l i ver enzymes a re a l s o common. GVHD occurs 4 to 30
da ys a fter tra ns fus i on a nd i s di a gnos ed ba s ed on cl i ni ca l s us pi ci on a nd s ki n a nd bone ma rrow bi ops i es . GVHD ha s > 90% morta l i ty beca us e no
s peci fi c trea tment i s a va i l a bl e.
Preventi on of GVHD i s wi th i rra di a ti on (to da ma ge DNA of the donor l ymphocytes ) of a l l tra ns fus ed bl ood products . It i s done i f the reci pi ent i s
i mmunocompromi s ed (eg, pa ti ents wi th congeni ta l i mmune defi ci ency s yndromes , hema tol ogi c ca ncers , or hema topoi eti c s tem cel l tra ns pl a nts ;
neona tes ), i f donor bl ood i s obta i ned from a 1s t-degree rel a ti ve, or when HLA-ma tched components , excl udi ng s tem cel l s , a re tra ns fus ed.
Trea tment wi th corti cos teroi ds a nd other i mmunos uppres s a nts , i ncl udi ng thos e us ed for s ol i d orga n tra ns pl a nta ti on, i s not a n i ndi ca ti on for
bl ood i rra di a ti on.

Complications of massive transfusion: Ma s s i ve tra ns fus i on i s tra ns fus i on of a vol ume of bl ood grea ter tha n or equa l to one bl ood vol ume i n 24 h (eg,
10 uni ts i n a 70-kg a dul t). When a pa ti ent recei ves s tored bl ood i n s uch l a rge vol ume, the pa ti ent's own bl ood ma y be, i n effect, "wa s hed out." In
ci rcums ta nces uncompl i ca ted by prol onged hypotens i on or DIC, di l uti ona l thrombocytopeni a i s the mos t l i kel y compl i ca ti on. Pl a tel ets i n s tored
whol e bl ood a re not functi ona l . Cl otti ng fa ctors (except fa ctor VIII) us ua l l y rema i n s uffi ci ent. Mi crova s cul a r bl eedi ng (a bnorma l oozi ng a nd
conti nued bl eedi ng from ra w a nd cut s urfa ces ) ma y res ul t. Fi ve to 8 uni ts (1 uni t/10 kg) of pl a tel et concentra tes a re us ua l l y enough to correct s uch
bl eedi ng i n a n a dul t. Fres h frozen pl a s ma a nd cryopreci pi ta te ma y be needed.
Hypothermi a due to ra pi d tra ns fus i on of l a rge a mounts of col d bl ood ca n ca us e a rrhythmi a s or ca rdi a c a rres t. Hypothermi a i s a voi ded by us i ng a n
IV s et wi th a hea t-excha nge devi ce tha t gentl y wa rms bl ood. Other mea ns of wa rmi ng bl ood (eg, mi crowa ve ovens ) a re contra i ndi ca ted beca us e of
potenti a l RBC da ma ge a nd hemol ys i s .
Ci tra te a nd K toxi ci ti es genera l l y a re not of concern even i n ma s s i ve tra ns fus i on; however, toxi ci ti es of both ma y be a mpl i fi ed i n the pres ence of
hypothermi a . Pa ti ents wi th l i ver fa i l ure ma y ha ve di ffi cul ty meta bol i zi ng ci tra te. Hypoca l cemi a ca n res ul t but ra rel y neces s i ta tes trea tment (whi ch
i s 10 mL of a 10% s ol uti on of Ca gl ucona te IV di l uted i n 100 mL D 5 W, gi ven over 10 mi n). Pa ti ents wi th rena l fa i l ure ma y ha ve el eva ted K i f
tra ns fus ed wi th bl ood s tored for > 1 wk (K a ccumul a ti on i s us ua l l y i ns i gni fi ca nt i n bl ood s tored for < 1 wk). Mecha ni ca l hemol ys i s duri ng
tra ns fus i on ma y i ncrea s e K. Hypoka l emi a ma y occur a bout 24 h a fter tra ns fus i on of ol der RBCs (> 3 wk), whi ch ta ke up K.
Infectious complications: Ba cteri a l conta mi na ti on of pa cked RBCs occurs ra rel y, pos s i bl y due to i na dequa te a s epti c techni que duri ng col l ecti on or to
tra ns i ent a s ymptoma ti c donor ba cteremi a . Refri gera ti on of RBCs us ua l l y l i mi ts ba cteri a l growth except for cryophi l i c orga ni s ms s uch a s Yersinia s p,
whi ch ma y produce da ngerous l evel s of endotoxi n. Al l RBC uni ts a re i ns pected before i s s ue for ba cteri a l growth, whi ch i s i ndi ca ted by a col or
cha nge. Beca us e pl a tel et concentra tes a re s tored a t room tempera ture, they ha ve grea ter potenti a l for ba cteri a l growth a nd endotoxi n producti on
i f conta mi na ted. To mi ni mi ze growth, s tora ge i s l i mi ted to 5 da ys . The ri s k of ba cteri a l conta mi na ti on of pl a tel ets i s 1:2500. Therefore, pl a tel ets
a re routi nel y tes ted for ba cteri a .
Ra rel y, s yphi l i s i s tra ns mi tted i n fres h bl ood or pl a tel ets . Stori ng bl ood for 96 h a t 4 to 10 C ki l l s the s pi rochete. Al though federa l regul a ti ons
requi re a s erol ogi c tes t for s yphi l i s on donor bl ood, i nfecti ve donors a re s eronega ti ve ea rl y i n the di s ea s e. Reci pi ents of i nfected uni ts ma y
devel op the cha ra cteri s ti c s econda ry ra s h.
Hepa ti ti s ma y occur a fter tra ns fus i on of a ny bl ood product. The ri s k ha s been reduced by vi ra l i na cti va ti on through hea t trea tment of s erum
a l bumi n a nd pl a s ma protei ns a nd by the us e of recombi na nt fa ctor concentra tes . Tes ts for hepa ti ti s a re requi red for a l l donor bl ood (s ee Ta bl e
121-2). The es ti ma ted ri s k of hepa ti ti s B i s 1:200,000; of hepa ti ti s C, 1:2.6 mi l l i on. Beca us e i ts tra ns i ent vi remi c pha s e a nd concomi ta nt cl i ni ca l
i l l nes s l i kel y precl ude bl ood dona ti on, hepa ti ti s A (i nfecti ous hepa ti ti s ) i s not a s i gni fi ca nt ca us e of tra ns fus i on-a s s oci a ted hepa ti ti s .
HIV i nfecti on i n the US i s a l mos t enti rel y HIV-1, a l though HIV-2 i s a l s o of concern. Tes ti ng for a nti bodi es to both s tra i ns i s requi red. Nucl ei c a ci d
tes ti ng for HIV-1 a nti gen a nd HIV-1 p24 a nti gen tes ti ng a re a l s o requi red. Addi ti ona l l y, bl ood donors a re a s ked a bout beha vi ors tha t ma y put them
a t hi gh ri s k of HIV i nfecti on. HIV-0 ha s not been i denti fi ed a mong bl ood donors . The es ti ma ted ri s k of HIV tra ns mi s s i on due to tra ns fus i on i s 1:2.6
mi l l i on.
Cytomega l ovi rus (CMV) ca n be tra ns mi tted by WBCs i n tra ns fus ed bl ood. It i s not tra ns mi tted through fres h frozen pl a s ma . Beca us e CMV does not
ca us e di s ea s e i n i mmunocompetent reci pi ents , routi ne a nti body tes ti ng of donor bl ood i s not requi red. However, CMV ma y ca us e s eri ous or fa ta l
di s ea s e i n i mmunocompromi s ed pa ti ents , who s houl d proba bl y recei ve CMV-nega ti ve bl ood products tha t ha ve been provi ded by CMV a nti bodynega ti ve donors or by bl ood depl eted of WBCs by fi l tra ti on.
Huma n T-cel l l ymphotropi c vi rus 1 (HTLV-1), whi ch ca n ca us e a dul t T-cel l l ymphoma /l eukemi a , HTLV-1-a s s oci a ted myel opa thy, a nd tropi ca l s pa s ti c
pa ra pa res i s , ca us es pos ttra ns fus i on s eroconvers i on i n s ome reci pi ents . Al l donor bl ood i s tes ted for HTLV-1 a nd HTLV-2 a nti bodi es . The
es ti ma ted ri s k of fa l s e-nega ti ve res ul ts on tes ti ng of donor bl ood i s 1:641,000.
Creutzfel dt-Ja kob di s ea s e ha s never been reported to be tra ns mi tted by tra ns fus i on, but current pra cti ce precl udes dona ti on from a pers on who
ha s recei ved huma n-deri ved growth hormone or a dura ma ter tra ns pl a nt or who ha s a fa mi l y member wi th Creutzfel dt-Ja kob di s ea s e. New va ri a nt
Creutzfel dt-Ja kob di s ea s e (ma d cow di s ea s e) ha s not been tra ns mi tted by bl ood tra ns fus i on. However, donors who ha ve s pent s i gni fi ca nt ti me i n
the Uni ted Ki ngdom a nd s ome other pa rts of Europe ma y be perma nentl y deferred from dona ti on (s ee Ta bl e 121-1).
Ma l a ri a i s tra ns mi tted ea s i l y through i nfected RBCs . Ma ny donors a re una wa re tha t they ha ve ma l a ri a , whi ch ma y be l a tent a nd tra ns mi s s i bl e for
10 to 15 yr. Stora ge does not render bl ood s a fe. Pros pecti ve donors mus t be a s ked a bout ma l a ri a or whether they ha ve been i n a regi on where i t i s
preva l ent. Donors who ha ve ha d a di a gnos i s of ma l a ri a or who a re i mmi gra nts , refugees , or ci ti zens from countri es i n whi ch ma l a ri a i s cons i dered
endemi c a re deferred for 3 yr; tra vel ers to endemi c countri es a re deferred for 1 yr.
Ba bes i os i s ha s ra rel y been tra ns mi tted by tra ns fus i on.
Therapeutic Apheresis
Thera peuti c a pheres i s i ncl udes pl a s ma excha nge a nd cyta pheres i s , whi ch a re genera l l y tol era ted by hea l thy donors . However, ma ny mi nor a nd a
few ma jor ri s ks exi s t. Ins erti on of the l a rge IV ca theters neces s a ry for a pheres i s ca n ca us e compl i ca ti ons (eg, bl eedi ng, i nfecti on, pneumothora x).
Ci tra te a nti coa gul a nt ma y decrea s e s erum i oni zed Ca . Repl a cement of pl a s ma wi th a noncol l oi da l s ol uti on (eg, s a l i ne) s hi fts fl ui d from the
i ntra va s cul a r s pa ce. Col l oi da l repl a cement s ol uti ons do not repl a ce IgG a nd coa gul a ti on fa ctors .
Mos t compl i ca ti ons ca n be ma na ged wi th cl os e a ttenti on to the pa ti ent a nd ma ni pul a ti on of the procedure, but s ome s evere rea cti ons a nd a few
dea ths ha ve occurred.
Plasma exchange: Thera peuti c pl a s ma excha nge removes pl a s ma components from bl ood. A bl ood cel l s epa ra tor extra cts the pa ti ent's pl a s ma a nd
returns RBCs a nd pl a tel ets i n pl a s ma or a pl a s ma -repl a ci ng fl ui d; for thi s purpos e, 5% a l bumi n i s preferred to fres h frozen pl a s ma (except for
pa ti ents wi th thromboti c thrombocytopeni c purpura ) beca us e i t ca us es fewer rea cti ons a nd tra ns mi ts no i nfecti ons . Thera peuti c pl a s ma excha nge
res embl es di a l ys i s but, i n a ddi ti on, ca n remove protei n-bound toxi c s ubs ta nces . A one-vol ume excha nge removes a bout 66% of s uch components .
To be of benefi t, pl a s ma excha nge s houl d be us ed for di s ea s es i n whi ch the pl a s ma conta i ns a known pa thogeni c s ubs ta nce, a nd pl a s ma
excha nge s houl d remove thi s s ubs ta nce more ra pi dl y tha n the body produces i t. For exa mpl e, i n ra pi dl y progres s i ve a utoi mmune di s orders ,
pl a s ma excha nge ma y be us ed to remove exi s ti ng ha rmful pl a s ma components (eg, cryogl obul i ns , a nti gl omerul a r ba s ement membra ne
a nti bodi es ) whi l e i mmunos uppres s i ve or cytotoxi c drugs s uppres s thei r future producti on.
There a re numerous i ndi ca ti ons (s ee
Ta bl e 121-3). The frequency of pl a s ma excha nge, the vol ume to be removed, the repl a cement fl ui d, a nd other va ri a bl es a re i ndi vi dua l i zed.
[Table 121-3. Indi ca ti ons for Pl a s ma Excha nge Accordi ng to the Ameri ca n Soci ety for Apheres i s ]
Low dens i ty l i poprotei n chol es terol ca n be removed by pl a s ma excha nge wi th a recentl y i mpl emented fi l tra ti on method. Compl i ca ti ons of pl a s ma
excha nge a re s i mi l a r to thos e of thera peuti c cyta pheres i s .
Cytapheresis: Thera peuti c cyta pheres i s removes cel l ul a r components from bl ood, returni ng pl a s ma . It i s mos t often us ed to remove defecti ve RBCs
a nd s ubs ti tute norma l ones i n pa ti ents wi th s i ckl e cel l a nemi a who ha ve the fol l owi ng condi ti ons : a cute ches t s yndrome, s troke, pregna ncy, or
frequent, s evere s i ckl e cel l cri s es . Cyta pheres i s a chi eves Hb S l evel s of < 30% wi thout the ri s k of i ncrea s ed vi s cos i ty tha t ca n occur beca us e of
i ncrea s ed Hct wi th s i mpl e tra ns fus i on.
Thera peuti c cyta pheres i s ma y a l s o be us ed to reduce s evere thrombocytos i s or l eukocytos i s (cytoreducti on) i n a cute or chroni c l eukemi a when
there i s ri s k of hemorrha ge, thrombos i s , or pul mona ry or cerebra l compl i ca ti ons of extreme l eukocytos i s (l eukos ta s i s ). Cyta pheres i s i s effecti ve i n
thrombocytos i s beca us e pl a tel ets a re not repl a ced a s ra pi dl y a s WBCs . One or 2 procedures ma y reduce pl a tel et counts to s a fe l evel s . Thera peuti c
WBC remova l (l euka pheres i s ) ca n remove ki l ogra ms of buffy coa t i n a few procedures , a nd i t often rel i eves l eukos ta s i s a nd s pl enomega l y.
However, the reducti on i n WBC count i ts el f ma y be mi l d a nd onl y tempora ry.
Other us es of cyta pheres i s i ncl ude col l ecti on of peri phera l bl ood s tem cel l s for a utol ogous or a l l ogenei c bone ma rrow recons ti tuti on (a n
a l terna ti ve to bone ma rrow tra ns pl a nta ti on) a nd col l ecti on of l ymphocytes for us e i n i mmune modul a ti on ca ncer thera py (a dopti ve
i mmunothera py).
Chapter 122. Overview of Cancer

Introduction
Ca ncer i s a n unregul a ted prol i fera ti on of cel l s due to l os s of norma l control s , res ul ti ng i n unregul a ted growth, l a ck of di fferenti a ti on, l oca l ti s s ue
i nva s i on, a nd, often, meta s ta s i s . Ca ncer ca n devel op i n a ny ti s s ue or orga n a t a ny a ge. There i s often evi dence of a n i mmune res pons e to tumors ,
but the rol e of the i mmune s ys tem i n preventi ng a nd trea ti ng ca ncer i s s ti l l uncerta i n.
Ma ny ca ncers a re cura bl e i f detected a t a n ea rl y s ta ge, a nd l ong-term remi s s i on i s often pos s i bl e i n l a ter s ta ges . However, cure i s not a l wa ys
pos s i bl e a nd i s not a ttempted i n s ome a dva nced ca s es i n whi ch pa l l i a ti ve ca re provi des better qua l i ty of l i fe tha n a ggres s i ve trea tment,
pa rti cul a rl y i n the el derl y or i n pa ti ents wi th underl yi ng comorbi d di s orders .
Cellular and Molecular Basis of Cancer
Cellular Kinetics
Genera ti on ti me i s the ti me requi red for a qui es cent cel l to compl ete a cycl e i n cel l di vi s i on (s ee
Fi g. 122-1) a nd gi ve ri s e to 2 da ughter cel l s . Ma l i gna nt cel l s us ua l l y ha ve a s horter genera ti on ti me tha n nonma l i gna nt cel l s from the s a me ti s s ue,
a nd there us ua l l y a re a s ma l l er percenta ge of cel l s i n G 0 (res ti ng pha s e). Ini ti a l exponenti a l tumor growth i s fol l owed by a pl a tea u pha s e when
cel l dea th nea rl y equa l s the ra te of forma ti on of da ughter cel l s . The s l owi ng i n growth ra te i s l i kel y rel a ted to exha us ti on of the s uppl y of
nutri ents a nd O2 for the ra pi dl y expa ndi ng
[Fig. 122-1. The cel l cycl e.]
tumor. Sma l l tumors ha ve a grea ter percenta ge of a cti vel y di vi di ng cel l s tha n do l a rge tumors .
Cel l ul a r ki neti cs of pa rti cul a r tumors i s a n i mporta nt cons i dera ti on i n the des i gn of a nti neopl a s ti c drug regi mens a nd ma y i nfl uence the dos i ng
s chedul es a nd ti mi ng i nterva l s of trea tment. Ma ny a nti neopl a s ti c drugs a re effecti ve onl y i f cel l s a re a cti vel y di vi di ng, a nd s ome drugs work onl y
duri ng a s peci fi c pha s e of the cel l cycl e a nd thus requi re prol onged a dmi ni s tra ti on to ca tch di vi di ng cel l s duri ng the pha s e of ma xi ma l s ens i ti vi ty.
Tumor Growth and Metastasis
As a tumor grows , nutri ents a re provi ded by di rect di ffus i on from the ci rcul a ti on. Loca l growth i s fa ci l i ta ted by enzymes (eg, protea s es ) tha t des troy
a dja cent ti s s ues . As tumor vol ume i ncrea s es , tumor a ngi ogenes i s fa ctors a re produced to promote forma ti on of the va s cul a r s uppl y requi red for
further tumor growth.
Al mos t from i ncepti on, a tumor ma y s hed cel l s i nto the ci rcul a ti on. From a ni ma l model s , i t i s es ti ma ted tha t a 1-cm tumor s heds > 1 mi l l i on
cel l s /24 h i nto the venous ci rcul a ti on. Al though mos t ci rcul a ti ng tumor cel l s di e a s a res ul t of i ntra va s cul a r tra uma , a n occa s i ona l cel l ma y a dhere
to the va s cul a r endothel i um a nd penetra te i nto s urroundi ng ti s s ues , genera ti ng i ndependent tumors (meta s ta s es ) a t di s ta nt s i tes . Meta s ta ti c
tumors grow i n much the s a me ma nner a s pri ma ry tumors a nd ma y s ubs equentl y gi ve ri s e to other meta s ta s es .
Experi ments s ugges t tha t through ra ndom muta ti on, a s ubs et of cel l s i n the pri ma ry tumor ma y a cqui re the a bi l i ty to i nva de a nd mi gra te to di s ta nt
s i tes , res ul ti ng i n meta s ta s i s .
Molecular Abnormalities
Geneti c muta ti ons a re res pons i bl e for the genera ti on of ca ncer cel l s . Thes e muta ti ons a l ter the qua nti ty or functi on of protei n products tha t
regul a te cel l growth a nd di vi s i on a nd DNA repa i r. Two ma jor ca tegori es of muta ted genes a re oncogenes a nd tumor s uppres s or genes .
Oncogenes: Thes e a re a bnorma l forms of norma l genes (proto-oncogenes ) tha t regul a te va ri ous a s pects of cel l growth. Muta ti on of thes e genes
ma y res ul t i n di rect a nd conti nuous s ti mul a ti on of the pa thwa ys (eg, i ntra cel l ul a r s i gna l tra ns ducti on pa thwa ys , tra ns cri pti on fa ctors , s ecreted
growth fa ctors ) tha t control cel l ul a r growth a nd di vi s i on, DNA repa i r, a ngi ogenes i s , a nd other phys i ol ogi c proces s es .
There a re > 100 known oncogenes tha t ma y contri bute to huma n neopl a s ti c tra ns forma ti on. For exa mpl e, the ra s gene encodes the Ra s protei n,
whi ch regul a tes cel l di vi s i on. Muta ti ons ma y res ul t i n the i na ppropri a te a cti va ti on of the Ra s protei n, l ea di ng to uncontrol l ed cel l growth a nd
di vi s i on. In fa ct, the Ra s protei n i s a bnorma l i n a bout 25% of huma n ca ncers . Other oncogenes ha ve been i mpl i ca ted i n s peci fi c ca ncers . Thes e
i ncl ude
Her2/neu (brea s t ca ncer)
BCR-ABL (chroni c myel ocyti c l eukemi a , B-cel l a cute l ymphocyti c l eukemi a )
C-myc (Burkett's l ymphoma )
N-myc (s ma l l cel l l ung ca ncer, neurobl a s toma )
Speci fi c oncogenes ma y ha ve i mporta nt i mpl i ca ti ons for di a gnos i s , thera py, a nd prognos i s (s ee i ndi vi dua l di s cus s i ons under the s peci fi c ca ncer
type).
Oncogenes typi ca l l y res ul t from a cqui red s oma ti c cel l muta ti ons s econda ry to poi nt muta ti ons (eg, from chemi ca l ca rci nogens ), gene a mpl i fi ca ti on
(eg, a n i ncrea s e i n the number of copi es of a norma l gene), or tra ns l oca ti ons . Occa s i ona l l y, muta ti on of genes res ul ts i n i nheri ta nce of a ca ncer
predi s pos i ti on, a s i n the i nheri ta nce of BRCA1 or BRCA2 i n fa mi l i es wi th a hi gh i nci dence of brea s t or ova ri a n ca ncer.
Tumor suppressor genes: Genes s uch a s the p53 gene pl a y a rol e i n norma l cel l di vi s i on a nd DNA repa i r a nd a re cri ti ca l for detecti ng i na ppropri a te
growth s i gna l s i n cel l s . If thes e genes , a s a res ul t of i nheri ted or a cqui red muta ti ons , become una bl e to functi on, geneti c muta ti ons i n other
genes ca n proceed unchecked, l ea di ng to neopl a s ti c tra ns forma ti on.

As wi th mos t genes , 2 a l l el es a re pres ent tha t encode for ea ch tumor s uppres s or gene. A defecti ve copy of one gene ma y be i nheri ted, l ea vi ng onl y
one functi ona l a l l el e for the i ndi vi dua l tumor s uppres s or gene. If a muta ti on i s a cqui red i n the other a l l el e, the norma l protecti ve mecha ni s ms of
the tumor s uppres s or gene a re l os t, a nd dys functi on of other protei n products or DNA da ma ge ma y es ca pe unregul a ted, l ea di ng to ca ncer. For
exa mpl e, the reti nobl a s toma (RB) gene encodes for the protei n Rb, whi ch regul a tes the cel l cycl e by s toppi ng DNA repl i ca ti on. Muta ti ons i n the RB
gene fa mi l y occur i n ma ny huma n ca ncers , a l l owi ng a ffected cel l s to di vi de conti nuous l y.
Another i mporta nt regul a tory protei n, p53, prevents repl i ca ti on of da ma ged DNA i n norma l cel l s a nd promotes cel l dea th (a poptos i s ) i n cel l s wi th
a bnorma l DNA. Ina cti ve or a l tered p53 a l l ows cel l s wi th a bnorma l DNA to s urvi ve a nd di vi de. Muta ti ons a re pa s s ed to da ughter cel l s , conferri ng a
hi gh proba bi l i ty of neopl a s ti c tra ns forma ti on. The p53 gene i s defecti ve i n ma ny huma n ca ncers . As wi th oncogenes , muta ti on of tumor s uppres s or
genes s uch a s p53 or RB i n germ cel l l i nes ma y res ul t i n verti ca l tra ns mi s s i on a nd a hi gher i nci dence of ca ncer i n offs pri ng.
Chromosomal abnormalities: Gros s chromos oma l a bnorma l i ti es (s ee p. 2997) ca n occur through del eti on, tra ns l oca ti on, or dupl i ca ti on. If thes e
a l tera ti ons a cti va te or i na cti va te genes tha t res ul t i n a prol i fera ti ve a dva nta ge over norma l cel l s , then a tumor ma y devel op. Chromos oma l
a bnorma l i ti es occur i n certa i n huma n ca ncers (s ee
Ta bl e 122-1). In s ome congeni ta l di s ea s es (Bl oom s yndrome, Fa nconi 's a nemi a , Down s yndrome), DNA repa i r proces s es a re defecti ve a nd
chromos omes brea k ea s i l y, putti ng chi l dren a t hi gh ri s k of devel opi ng a cute l eukemi a a nd l ymphoma s .
Other influences: Mos t ca ncers l i kel y i nvol ve s evera l of the mecha ni s ms des cri bed a bove tha t l ea d to neopl a s ti c convers i on. For exa mpl e, the
devel opment of tumor i n fa mi l i a l pol ypos i s ta kes pl a ce through a s equence of geneti c events : epi thel i um hyperprol i fera ti on (l os s of a s uppres s or
gene on chromos ome 5), ea rl y a denoma (cha nge i n DNA methyl a ti on), i ntermedi a te a denoma (overa cti vi ty of the ras oncogene), l a te a denoma
(l os s of a s uppres s or gene on chromos ome 18), a nd fi na l l y, ca ncer (l os s of a gene on chromos ome 17). Further geneti c cha nges ma y be requi red for
meta s ta s i s .
Telomeres a re nucl eoprotei n compl exes tha t ca p the ends of chromos omes a nd ma i nta i n thei r i ntegri ty. In norma l ti s s ue, tel omere s horteni ng
(whi ch occurs wi th a gi ng) res ul ts i n a fi ni te l i mi t i n cel l di vi s i on. The enzyme tel omera s e provi des for tel omere s ynthes i s a nd ma i ntena nce; thus
tel omera s e ma y potenti a l l y a l l ow for cel l ul a r i mmorta l i ty. Acti va ti on of tel omera s e i n tumors a l l ows conti nuous prol i fera ti on of tumors .
Environmental Factors
Infections: Vi rus es contri bute to the pa thogenes i s of huma n ca ncers (s ee
Ta bl e 122-2). Pa thogenes i s ma y occur through the i ntegra ti on of vi ra l geneti c el ements i nto the hos t DNA. Thes e new genes a re expres s ed by the
hos t; they ma y a ffect cel l growth or di vi s i on or di s rupt norma l hos t genes requi red for control of cel l growth a nd di vi s i on. Al terna ti vel y, vi ra l
i nfecti on ma y res ul t i n i mmune dys functi on, l ea di ng to decrea s ed i mmune s urvei l l a nce for ea rl y tumors .
Ba cteri a ma y a l s o ca us e ca ncer. Helicobacter pylori i nfecti on i ncrea s es the ri s k of
[Table 122-1. Huma n Ca ncers As s oci a ted wi th Chromos oma l Abnorma l i ti es ]
[Table 122-2. Ca ncer-As s oci a ted Vi rus es ]
s evera l ki nds of ca ncer (ga s tri c a denoca rci noma , ga s tri c l ymphoma , mucos a -a s s oci a ted l ymphoi d ti s s ue [MALT] l ymphoma ).
Pa ra s i tes of s ome types ca n l ea d to ca ncer. Schistosoma haematobium ca us es chroni c i nfl a mma ti on a nd fi bros i s of the bl a dder, whi ch ma y l ea d to
ca ncer. Opisthorchis sinensis ha s been l i nked to ca rci noma of the pa ncrea s a nd bi l e ducts .
Radiation: Ul tra vi ol et ra di a ti on ma y i nduce s ki n ca ncer (eg, ba s a l a nd s qua mous cel l ca rci noma , mel a noma ) by da ma gi ng DNA. Thi s DNA da ma ge
cons i s ts of forma ti on of thymi di ne di mers , whi ch ma y es ca pe repa i r beca us e of i nherent defects i n DNA repa i r (eg, xeroderma pi gmentos um) or
through ra re, ra ndom events .
Ioni zi ng ra di a ti on i s a l s o ca rci nogeni c. For exa mpl e, s urvi vors of the a tomi c bomb expl os i ons i n Hi ros hi ma a nd Na ga s a ki ha ve a hi gher-tha nexpected i nci dence of l eukemi a a nd other ca ncers . Si mi l a rl y, the previ ous us e of x-ra ys to trea t nonma l i gna nt di s ea s e (a cne, thymi c or a denoi d
enl a rgement, a nd a nkyl os i ng s pondyl i ti s ) res ul ted i n hi gher ra tes of a cute a nd chroni c l eukemi a s , Hodgki n a nd non-Hodgki n l ymphoma s , mul ti pl e
myel oma , a pl a s ti c a nemi a termi na ti ng i n a cute nonl ymphocyti c l eukemi a , myel ofi bros i s , mel a noma , a nd thyroi d ca ncer. Us e of x-ra ys i n
di a gnos ti c i ma gi ng s tudi es i s thought to i ncrea s e ri s k of ca ncer (s ee p.
3402). Indus tri a l expos ure (eg, to ura ni um by mi ne workers ) i s l i nked to devel opment of l ung ca ncer a fter a 15- to 20-yr l a tency. Long-term expos ure
to occupa ti ona l i rra di a ti on or to i nterna l l y depos i ted thori um di oxi de predi s pos es peopl e to a ngi os a rcoma s a nd a cute nonl ymphocyti c l eukemi a .
Expos ure to the ra di oa cti ve ga s ra don, whi ch i s rel ea s ed from s oi l , i ncrea s es the ri s k of l ung ca ncer. Norma l l y, ra don di s pers es ra pi dl y i nto the
a tmos phere a nd ca us es no ha rm. However, when a bui l di ng i s pl a ced on s oi l wi th hi gh ra don content, ra don ca n a ccumul a te wi thi n the bui l di ng,
s ometi mes produci ng s uffi ci entl y hi gh l evel s i n the a i r to ca us e ha rm. In expos ed peopl e who a l s o s moke, the ri s k of l ung ca ncer i s further
i ncrea s ed.
Drugs and chemicals: Es trogens i n ora l contra cepti ves ma y s l i ghtl y i ncrea s e the ri s k of brea s t ca ncer, but thi s ri s k decrea s es over ti me. Es trogen a nd
proges ti n us ed for hormone repl a cement thera py a l s o i ncrea s e the ri s k of brea s t ca ncer. Di ethyl s ti l bes trol (DES) i ncrea s es the ri s k of brea s t
ca ncer i n women who took the drug a nd i ncrea s es the ri s k of va gi na l ca rci noma i n da ughters of thes e women who were expos ed before bi rth.
Long-term us e of a na bol i c s teroi ds ma y i ncrea s e the ri s k of l i ver ca ncer. Trea tment of ca ncer wi th chemothera py drugs a nd wi th ra di a ti on thera py
i ncrea s es the ri s k of devel opi ng a s econd ca ncer.
Chemi ca l ca rci nogens ca n i nduce gene muta ti ons a nd res ul t i n uncontrol l ed growth a nd tumor forma ti on (s ee
Ta bl e 122-3). Other s ubs ta nces , ca l l ed co-ca rci nogens , ha ve l i ttl e or no i nherent ca rci nogeni c potency but enha nce the ca rci nogeni c effect of
a nother a gent when expos ed s i mul ta neous l y.
Dietary substances: Certa i n s ubs ta nces cons umed i n the di et ca n i ncrea s e the ri s k of ca ncer. For i ns ta nce, a di et hi gh i n fa t ha s been l i nked to a n
i ncrea s ed ri s k of col on, brea s t, a nd pos s i bl y pros ta te ca ncer. Peopl e who dri nk l a rge a mounts of a l cohol a re a t much hi gher ri s k of devel opi ng
es opha gea l ca ncer. A di et hi gh i n s moked a nd pi ckl ed foods or i n ba rbecued mea ts i ncrea s es the ri s k of devel opi ng s toma ch ca ncer. Peopl e who
a re overwei ght or obes e ha ve a hi gher ri s k of ca ncer of the brea s t, endometri um, col on, ki dneys , a nd es opha gus .
Physical factors: Chroni c s ki n i rri ta ti on l ea ds to chroni c derma ti ti s a nd, i n ra re ca s es , to s qua mous cel l ca rci noma . Thi s occurrence i s pres uma bl y
due to ra ndom muta ti ons tha t occur more frequentl y beca us e of the i ncrea s ed cel l turnover.
Immunologic Disorders
Immune s ys tem dys functi on a s a res ul t of i nheri ted geneti c muta ti on, a cqui red di s orders , a gi ng, or i mmunos uppres s a nts i nterferes wi th
[Table 122-3. Common Chemi ca l Ca rci nogens ]
norma l i mmune s urvei l l a nce of ea rl y tumors a nd res ul ts i n hi gher ra tes of ca ncer. Known ca ncer-a s s oci a ted i mmune di s orders i ncl ude
Ata xi a -tel a ngi ecta s i a (a cute l ymphocyti c l eukemi a [ALL], bra i n tumors , ga s tri c ca ncer)
Wi s kott-Al dri ch s yndrome (l ymphoma , ALL)
X-l i nked a ga mma gl obul i nemi a (l ymphoma , ALL)
Immune defi ci ency s econda ry to i mmunos uppres s a nts or HIV i nfecti on (l a rge cel l l ymphoma , Ka pos i 's s a rcoma )
Rheuma tol ogi c condi ti ons , s uch a s SLE, RA, a nd Sjogren's s yndrome (B-type l ymphoma )
Genera l i mmune di s orders (l ymphoreti cul a r neopl a s i a )
Cancer Diagnosis
A di a gnos i s of ca ncer ma y be s us pected ba s ed on hi s tory a nd phys i ca l exa mi na ti on but requi res confi rma ti on by tumor bi ops y a nd hi s topa thol ogi c
exa mi na ti on.
A compl ete hi s tory a nd phys i ca l exa mi na ti on ma y revea l unexpected cl ues to ea rl y ca ncer.
History
Phys i ci a ns mus t be a wa re of predi s pos i ng fa ctors a nd mus t s peci fi ca l l y a s k a bout fa mi l i a l ca ncer, envi ronmenta l expos ure (i ncl udi ng s moki ng
hi s tory), a nd pri or or pres ent i l l nes s es (eg, a utoi mmune di s orders , previ ous i mmunos uppres s i ve thera py, hepa ti ti s B or hepa ti ti s C, HIV i nfecti on,
a bnorma l Pa pa ni col a ou tes t, huma n pa pi l l oma vi rus i nfecti on). Symptoms s ugges ti ng occul t ca ncer ca n i ncl ude
Fa ti gue
Wei ght l os s
Fevers
Ni ght s wea ts
Cough
Hemoptys i s
Hema temes i s
Hema tochezi a
Cha nge i n bowel ha bi ts
Pers i s tent pa i n
Physical examination
Pa rti cul a r a ttenti on s houl d be pa i d to s ki n, l ymph nodes , l ungs , brea s ts , a bdomen, a nd tes tes . Pros ta te, recta l , a nd va gi na l exa mi na ti ons a re a l s o
i mporta nt. Fi ndi ngs hel p di rect further tes ti ng, i ncl udi ng x-ra ys a nd bi ops i es .
Testing
Tes ts i ncl ude i ma gi ng tes ts , s erum tumor ma rkers , a nd bi ops y.
Imaging tests often i ncl ude pl a i n x-ra ys , ul tra s onogra phy, CT, a nd MRI. Thes e tes ts a s s i s t i n i denti fyi ng a bnorma l i ti es , determi ni ng qua l i ti es of a
ma s s (s ol i d or cys ti c), provi di ng di mens i ons , a nd es ta bl i s hi ng rel a ti ons hi p to s urroundi ng s tructures , whi ch ma y be i mporta nt i f s urgery or bi ops y
i s bei ng cons i dered.
Serum tumor markers ma y offer corrobora ti ng evi dence i n pa ti ents wi th fi ndi ngs s ugges ti ve of a s peci fi c ca ncer (s ee p. 1058). Wi th s ome excepti ons
(eg, pros ta te-s peci fi c a nti gen [PSA]), thes e ma rkers do not ha ve enough s ens i ti vi ty a nd s peci fi ci ty to be us ed for s creeni ng. They a re the mos t
us eful i n detecti ng ea rl y rel a ps e a nd moni tori ng res pons e to thera py. Us eful exa mpl es i ncl ude
-Fetoprotei n (hepa tocel l ul a r ca rci noma , tes ti cul a r ca rci noma )
Ca rci noembryoni c a nti gen (col on ca ncer)
-huma n chori oni c gona dotropi n (chori oca rci noma , tes ti cul a r ca rci noma )
Serum i mmunogl obul i ns (mul ti pl e myel oma )
DNA probes (eg, bcr probe to i denti fy a chromos ome 22 a l tera ti on i n chroni c myel ogenous l eukemi a )
CA 125 (ova ri a n ca ncer)
CA 27-29 (brea s t ca ncer)
PSA (pros ta te ca ncer)
Biopsy to confi rm the di a gnos i s a nd ti s s ue of ori gi n i s a l mos t a l wa ys requi red when ca ncer i s s us pected or detected. The choi ce of bi ops y s i te i s
us ua l l y determi ned by ea s e of a cces s a nd degree of i nva s i venes s . If l ympha denopa thy i s pres ent, fi ne-needl e or core bi ops y ma y yi el d the tumor
type; i f nondi a gnos ti c, open bi ops y i s done. Other bi ops y routes i ncl ude bronchos copy for ea s i l y a cces s i bl e medi a s ti na l or centra l pul mona ry
tumors , percuta neous l i ver bi ops y i f l i ver l es i ons a re pres ent, a nd CT- or ul tra s ound-gui ded bi ops y. If thes e procedures a re not s ui ta bl e, open
bi ops y ma y be neces s a ry.
Grading i s a hi s tol ogi c mea s ure of tumor a ggres s i venes s a nd provi des i mporta nt prognos ti c i nforma ti on. It i s determi ned by exa mi ni ng the bi ops y
s peci men. Gra de i s ba s ed on the morphol ogi c a ppea ra nce of tumor cel l s , i ncl udi ng the a ppea ra nce of the nucl ei , cytopl a s m, a nd nucl eol i ;
frequency of mi tos es ; a nd a mount of necros i s . For ma ny ca ncers , gra di ng s ca l es ha ve been devel oped.
Molecular tests s uch a s chromos oma l a na l ogs , fl uores cent i n s i tu hybri di za ti on (FISH), PCR, a nd cel l s urfa ce a nti gens (eg, i n l ymphoma s , l eukemi a s )
del i nea te the ori gi n of meta s ta ti c ca ncers ori gi na ti ng from a n unknown pri ma ry ca ncer or a s s i s t i n recogni zi ng chemothera py res i s ta nce (eg, i n
a cute myel ogenous l eukemi a ).
Staging
Once a hi s tol ogi c di a gnos i s i s ma de, s ta gi ng (i e, determi na ti on of the extent of di s ea s e) hel ps determi ne trea tment deci s i ons a nd prognos i s .
Cl i ni ca l s ta gi ng us es da ta from the hi s tory, phys i ca l exa mi na ti on, i ma gi ng tes ts , l a bora tory tes ts , a nd bi ops y of bone ma rrow, l ymph nodes , or
other s i tes of s us pected di s ea s e. For s ta gi ng of s peci fi c neopl a s ms , s ee deta i l s i n the orga n-rel eva nt cha pter.
Imaging tests: Ima gi ng tes ts , es peci a l l y CT a nd MRI, ca n detect meta s ta s es to bra i n, l ungs , or a bdomi na l vi s cera , i ncl udi ng the a drena l gl a nds ,
retroperi tonea l l ymph nodes , l i ver, a nd s pl een. MRI (wi th ga dol i ni um contra s t) i s the procedure of choi ce for recogni ti on a nd eva l ua ti on of bra i n
tumors , both pri ma ry a nd meta s ta ti c. PET s ca nni ng i s i ncrea s i ngl y bei ng us ed to determi ne the meta bol i c a cti vi ty of a s us pect l ymph node or ma s s .
Integra ted PET-CT ca n be va l ua bl e, es peci a l l y i n l ung, hea d a nd neck, a nd brea s t ca ncer a nd i n l ymphoma .
Ul tra s onogra phy ca n be us ed to s tudy orbi ta l , thyroi d, ca rdi a c, peri ca rdi a l , hepa ti c, pa ncrea ti c, rena l , a nd retroperi tonea l a rea s . It ma y gui de
percuta neous bi ops i es a nd di fferenti a te rena l cel l ca rci noma from a beni gn rena l cys t.
Nucl ea r s ca ns ca n i denti fy s evera l types of meta s ta s es . Bone s ca ns i denti fy a bnorma l bone growth (i e, os teobl a s ti c a cti vi ty) before i t i s vi s i bl e on
pl a i n x-ra y. Thus , thi s techni que i s us el es s i n neopl a s ms tha t a re purel y l yti c (eg, mul ti pl e myel oma ); routi ne bone x-ra ys a re the s tudy of choi ce i n
s uch di s ea s es .
Laboratory tests: Serum chemi s tri es a nd enzymes ma y hel p s ta gi ng. El eva ted l i ver enzyme (a l ka l i ne phos pha ta s e, LDH, ALT) l evel s s ugges t the
pres ence of l i ver meta s ta s es . El eva ted a l ka l i ne phos pha ta s e a nd s erum Ca ma y be the fi rs t evi dence of bone meta s ta s es . El eva ted BUN or
crea ti ni ne l evel s ma y i ndi ca te a n obs tructi ve uropa thy s econda ry to a pel vi c ma s s , i ntra rena l obs tructi on from tubul a r preci pi ta ti on of myel oma
protei n, or uri c a ci d nephropa thy from l ymphoma or other ca ncers . El eva ted uri c a ci d l evel s often occur i n myel oprol i fera ti ve a nd
l ymphoprol i fera ti ve di s orders .
Invasive tests: Medi a s ti nos copy (s ee p. 1863) i s es peci a l l y va l ua bl e i n the s ta gi ng of non-s ma l l cel l l ung ca ncer. When medi a s ti na l l ymph node
i nvol vement i s found, pa ti ents do not us ua l l y benefi t from thora cotomy a nd l ung res ecti on but ma y benefi t from chemora di a ti on a nd s ubs equent
tumor res ecti on.
Bone ma rrow a s pi ra ti on a nd bi ops y a re es peci a l l y us eful i n detecti ng meta s ta s es from ma l i gna nt l ymphoma a nd s ma l l cel l l ung ca ncer, a nd thei r
rol e i n brea s t a nd pros ta te ca ncer s ta gi ng i s expa ndi ng. Bone ma rrow bi ops y i s pos i ti ve a t di a gnos i s i n 50 to 70% of pa ti ents wi th ma l i gna nt
l ymphoma (l ow a nd i ntermedi a te gra de) a nd i n 15 to 18% of pa ti ents wi th s ma l l cel l l ung ca ncer. Bone ma rrow bi ops y s houl d be done i n pa ti ents
wi th hema tol ogi c a bnorma l i ti es (i e, a nemi a , thrombocytopeni a , pa ncytopeni a ) tha t ca nnot be expl a i ned by other mecha ni s ms .
Bi ops y of regi ona l l ymph nodes i s pa rt of the eva l ua ti on of mos t tumors , s uch a s brea s t, l ung, or col on ca ncers .
Cancer Screening
Ca ncer ca n s ometi mes be detected i n a s ymptoma ti c pa ti ents vi a regul a r phys i ca l exa mi na ti ons a nd s creeni ng tes ts .
Phys i ca l exa mi na ti ons for ca ncers of the thyroi d, ora l ca vi ty, s ki n, l ymph nodes , tes tes , pros ta te, a nd ova ri es s houl d a l s o be done duri ng routi ne
medi ca l ca re.
Screeni ng tes ts a re done i n a s ymptoma ti c pa ti ents a t ri s k. The ra ti ona l e i s tha t ea rl y di a gnos i s ma y decrea s e ca ncer morta l i ty by detecti ng ca ncer
a t a n ea rl y a nd cura bl e s ta ge. Ea rl y detecti on ma y a l l ow for l es s ra di ca l thera py a nd reduce cos ts . Ri s ks , however, i ncl ude fa l s e-pos i ti ve res ul ts ,
whi ch neces s i ta te confi rma tory tes ts (eg, bi ops y, endos copy) tha t ca n l ea d to a nxi ety, s i gni fi ca nt morbi di ty, a nd s i gni fi ca nt cos ts ; a nd fa l s enega ti ve res ul ts , whi ch ma y gi ve a mi s ta ken s ens e of s ecuri ty, ca us i ng pa ti ents to i gnore s ubs equent s ymptoms .
Screeni ng for ca ncer s houl d be done i n the fol l owi ng ci rcums ta nces :
When di s ti nct hi gh-ri s k groups ca n be i denti fi ed (eg, peopl e wi th certa i n i nfecti ons , expos ures , or beha vi ors )
When the di s order ha s a n a s ymptoma ti c peri od duri ng whi ch trea tment woul d a l ter outcome
When the morbi di ty of the di s order i s s i gni fi ca nt
When a n i nterventi on i s a va i l a bl e tha t i s a ccepta bl e a nd effecti ve a t cha ngi ng the na tura l hi s tory of the di s order
The s creeni ng tes ts thems el ves s houl d s a ti s fy the fol l owi ng cri teri a :
Cos t a nd conveni ence a re rea s ona bl e.
Res ul ts a re rel i a bl e a nd reproduci bl e.
Sens i ti vi ty a nd s peci fi ci ty a re a dequa te.
The pos i ti ve predi cti ve va l ue (proba bi l i ty tha t a pers on wi th a pos i ti ve tes t res ul t ha s or wi l l devel op a di s order or condi ti ons ee p. 3391) i s
hi gh i n the popul a ti on s creened, a nd few fa l s e-nega ti ve res ul ts occur.
The tes t or procedure i s a ccepta bl e to pa ti ents .
Recommended s creeni ng s chedul es a re cons ta ntl y evol vi ng ba s ed on ongoi ng s tudi es (s ee
Ta bl e 122-4).
Clinical Sequelae of Cancer
Ca ncer ma y l ea d to pa i n, wei ght l os s , neuropa thy, na us ea , fa ti gue, s ei zures , or obs tructi on of vi s cera l orga ns . Dea th typi ca l l y occurs a s a res ul t of
fa i l ure of one or more orga n s ys tems .
Pain i n pa ti ents wi th meta s ta ti c ca ncer frequentl y res ul ts from bone meta s ta s es , nerve or pl exus i nvol vement, or pres s ure exerted by a tumor ma s s
or effus i on. Aggres s i ve pa i n ma na gement i s es s enti a l i n the trea tment of ca ncer a nd for ma i ntena nce of qua l i ty of l i fe (s ee p. 1623).
Cardiac tamponade ca n res ul t from ma l i gna nt peri ca rdi a l effus i on a nd often occurs preci pi tous l y. The mos t common ca us es a re brea s t ca ncer, l ung
ca ncer, a nd l ymphoma . The precedi ng effus i on ma y ca us e i l l -defi ned ches t pa i n or pres s ure tha t i s wors e when pa ti ents a re s upi ne a nd better
when they a re s i tti ng up (s ee p. 2203). Pa ti ents wi th ta mpona de ma y experi ence s i gns a nd s ymptoms of decrea s ed ca rdi a c output (eg, di zzi nes s or
s yncope). On phys i ca l exa mi na ti on, hea rt s i gns ma y be muffl ed a nd a fri cti on rub a nd pul s us pa ra doxus ma y be pres ent. X-ra y ma y s how a gl obul a r
ca rdi a c s i l houette. Peri ca rdi ocentes i s s houl d be done for di a gnos ti c a nd thera peuti c purpos es , a nd a pl europeri ca rdi a l wi ndow or
peri ca rdi ectomy s houl d be cons i dered.
Pleural effusions s houl d be dra i ned i f s ymptoma ti c a nd moni tored for rea ccumul a ti on. If the effus i on rea ccumul a tes ra pi dl y, thora cos tomy tube
dra i na ge (s ee p. 1866) a nd s cl eros i ng a gents or repea ted ca theter dra i na ge s houl d be cons i dered. Pa l l i a ti ve s urgi ca l pl eurectomy ca n be us ed for
refra ctory effus i ons i n a dva nced ma l i gna nt di s ea s e.
Spinal cord compression (s ee p. 1810) ca n res ul t from ca ncer s prea d to the vertebra e a nd requi res i mmedi a te s urgery or ra di a ti on thera py. Symptoms
ma y i ncl ude ba ck pa i n, l ower extremi ty pa res thes i a s , a nd bowel a nd bl a dder
[Table 122-4. Screeni ng Procedures i n Avera ge-Ri s k As ymptoma ti c Peopl e a s Recommended by the Ameri ca n Ca ncer Soci ety*]
dys functi on. Di a gnos i s i s confi rmed by CT or MRI.
Clots in the veins of the l ower extremi ti es often ca us e compl i ca ti ons i n ca ncer pa ti ents . Tumors produce procoa gul a nts , s uch a s ti s s ue fa ctors ,
l ea di ng to exces s cl ot forma ti on, pa rti cul a rl y i n a fter s urgery. Anti coa gul a nts ma y be neces s a ry to prevent pul mona ry embol i .
Metabolic and immune consequences of ca ncer ca n i ncl ude hyperca l cemi a , hyperuri cemi a , i ncrea s ed ACTH producti on, a nti bodi es tha t produce
neurol ogi c dys functi on, hemol yti c a nemi a , a nd ma ny other compl i ca ti ons .
Metastatic Carcinoma of Unknown Primary Origin
A pa ti ent i s cons i dered to ha ve ca rci noma of unknown pri ma ry ori gi n when a tumor i s detected a t one or more meta s ta ti c s i tes a nd routi ne
eva l ua ti on fa i l s to i denti fy a pri ma ry tumor. Meta s ta ti c ca rci noma of unknown pri ma ry ori gi n cons ti tutes up to 7% of a l l ca ncers a nd pos es a
thera peuti c di l emma , beca us e ca ncer trea tment i s typi ca l l y di rected a t the s peci fi c pri ma ry ti s s ue type.
The mos t common ca us a ti ve pri ma ry tumors a re thos e of the tes tes , l ungs , col on a nd rectum, a nd pa ncrea s . Exa mi na ti on of thes e a rea s s houl d be
thorough.
Types of tes ti ng us ed to hel p s peci fy the pri ma ry s i te i ncl ude

La bora tory tes ti ng
Ima gi ng tes ts
Immunocytochemi ca l a nd i mmunoperoxi da s e s ta i ni ng
Ti s s ue a na l ys i s
La bora tory tes ts s houl d i ncl ude a CBC, uri na l ys i s , s tool exa mi na ti on for occul t bl ood, a nd s erum chemi s tri es (i ncl udi ng pros ta te-s peci fi c a nti gen
a s s a ys i n ma l es ).
Ima gi ng s houl d be l i mi ted to a ches t x-ra y, a bdomi na l CT, a nd ma mmogra phy. An upper GI s eri es a nd ba ri um enema s houl d be done i f bl ood i s
pres ent i n the s tool .
Increa s i ng numbers of i mmunocytochemi ca l s ta i ns ca n be us ed to tes t a va i l a bl e ca ncerous ti s s ue to hel p determi ne the pri ma ry ti s s ue s i te. In
a ddi ti on, i mmunoperoxi da s e s ta i ni ng for i mmunogl obul i n, gene rea rra ngement s tudi es , a nd el ectron mi cros copy hel p di a gnos e l a rge cel l
l ymphoma , wherea s i mmunoperoxi da s e s ta i ni ng for -fetoprotei n or -huma n chori oni c gona dotropi n ma y s ugges t germ cel l tumors . Ti s s ue
a na l ys i s for es trogen a nd proges terone receptors hel ps i denti fy brea s t ca ncer, a nd i mmunoperoxi da s e s ta i ni ng for pros ta te-s peci fi c a nti gen hel ps
i denti fy pros ta te ca ncer.
Even i f a preci s e hi s tol ogi c di a gnos i s ca nnot be ma de, one cons tel l a ti on of fi ndi ngs ma y s ugges t a n ori gi n. Poorl y di fferenti a ted ca rci noma s nea r
or a t mi dl i ne regi ons of the medi a s ti num or retroperi toneum i n young or mi ddl e-a ged ma l es s houl d be cons i dered germ cel l neopl a s ms even i n
the a bs ence of a tes ti cul a r ma s s . Pa ti ents wi th thi s type of ca rci noma s houl d be trea ted wi th a ci s pl a ti n-ba s ed regi men, beca us e nea rl y 50% of
s uch pa ti ents experi ence l ong di s ea s e-free i nterva l s . For mos t other unknown pri ma ry ca ncers , the res pons es to thi s regi men a nd to other
mul ti drug chemothera py regi mens a re modes t a nd of bri ef dura ti on (eg, medi a n s urvi va l < 1 yr).
Paraneoplastic Syndromes
Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastasis.
Al though the pa thogenes i s rema i ns uncl ea r, thes e s ymptoms ma y be s econda ry to s ubs ta nces s ecreted by the tumor or ma y be a res ul t of
a nti bodi es di rected a ga i ns t tumors tha t cros s -rea ct wi th other ti s s ue. Symptoms ma y occur i n a ny orga n or phys i ol ogi c s ys tem. Up to 20% of ca ncer
pa ti ents experi ence pa ra neopl a s ti c s yndromes , but often thes e s yndromes a re unrecogni zed.
The mos t common ca ncers a s s oci a ted wi th pa ra neopl a s ti c s yndromes i ncl ude
Lung ca rci noma (mos t common)
Rena l ca rci noma
Hepa tocel l ul a r ca rci noma
Leukemi a s
Lymphoma s
Brea s t tumors
Ova ri a n tumors
Neura l ca ncers
Ga s tri c ca ncers
Pa ncrea ti c ca ncers
Succes s ful trea tment i s bes t obta i ned by control l i ng the underl yi ng ca ncer, but s ome s ymptoms ca n be pa l l i a ted wi th s peci fi c drugs (eg,
cyprohepta di ne for ca rci noi d s yndrome, bi s phos phona tes a nd corti cos teroi ds for hyperca l cemi a ).
General paraneoplastic symptoms: Pa ti ents wi th ca ncer often experi ence fever, ni ght s wea ts , a norexi a , a nd ca chexi a . Thes e s ymptoms ma y a ri s e from
rel ea s e of cytoki nes i nvol ved i n the i nfl a mma tory or i mmune res pons e or from medi a tors i nvol ved i n tumor cel l dea th, s uch a s tumor necros i s
fa ctor-. Al tera ti ons i n l i ver functi on a nd s teroi dogenes i s ma y a l s o contri bute.
Cutaneous paraneoplastic syndromes: Pa ti ents ma y experi ence ma ny s ki n s ymptoms .
Itching i s the mos t common cuta neous s ymptom experi enced by pa ti ents wi th ca ncer (eg, l eukemi a , l ymphoma s ) a nd ma y res ul t from
hypereos i nophi l i a .
Flushing ma y a l s o occur a nd i s l i kel y rel a ted to tumor-genera ted ci rcul a ti ng va s oa cti ve s ubs ta nces (eg, pros ta gl a ndi ns ).
Pigmented skin lesions, or kera tos es , ma y a ppea r, i ncl udi ng a ca nthos i s ni gri ca ns (GI ca ncer), genera l i zed dermi c mel a nos i s (l ymphoma , mel a noma ,
hepa tocel l ul a r ca rci noma ), Bowen's di s ea s e (l ung, GI, GU ca ncer), a nd l a rge mul ti pl e s eborrhei c kera tos es , i e, Les er-Trel a t s i gns (l ymphoma , GI
ca ncer). Secreti on of mel a ni n precurs ors from tumors ma y promote forma ti on of thes e l es i ons .
Ichthyosis, or des qua ma ti on of the extens or s urfa ce of the extremi ti es , ma y a l s o occur.
Hypertrichosis ma y ma ni fes t a s s udden a ppea ra nce of coa rs e ha i r on the fa ce a nd ea rs tha t res ol ves a fter res ecti on or trea tment of the tumor.
Al terna ti vel y, a l opeci a ma y occur wi th certa i n tumor types . The mecha ni s m by whi ch a l opeci a occurs i s not cl ea r.
Necrotizing migrating erythema ma y occur wi th gl uca gonoma s .
Subcutaneous adipose nodular necrosis ma y res ul t from rel ea s e of proteol yti c enzymes from va ri ous pa ncrea ti c tumors .
Herpes zoster ma y res ul t from rea cti va ti on of l a tent vi rus i n pa ti ents wi th i mmune s ys tem depres s i on or dys functi on.
Endocrine paraneoplastic syndromes: The endocri ne s ys tem i s often a ffected by pa ra neopl a s ti c s yndromes .
Cushing's syndrome (corti s ol exces s , l ea di ng to hypergl ycemi a , hypoka l emi a , hypertens i on, centra l obes i ty, moon fa ci es ) ma y res ul t from ectopi c
producti on of ACTH or ACTH-l i ke mol ecul es , mos t often wi th s ma l l cel l ca ncer of the l ung.
Abnormalities in water and electrolyte balance, i ncl udi ng hypona tremi a , ma y res ul t from producti on of ADH a nd pa ra thyroi d hormone-l i ke hormones
from s ma l l cel l a nd non-s ma l l cel l l ung ca ncer.
Hypoglycemia ma y res ul t from producti on of i ns ul i n-l i ke growth fa ctors or i ns ul i n producti on by pa ncrea ti c i s l et cel l tumors or
hema ngi operi cytoma s .
Hypertension ma y res ul t from a bnorma l epi nephri ne a nd norepi nephri ne s ecreti on (pheochromocytoma s ) or from corti s ol exces s (ACTH-s ecreti ng
tumors ).
Other ectopically produced hormones i ncl ude pa ra thyroi d hormone-rel a ted pepti de (PTHRPfrom s qua mous cel l l ung ca ncer, hea d a nd neck ca ncer,
bl a dder ca ncer), ca l ci toni n (from brea s t ca ncer, s ma l l cel l l ung ca ncer, a nd medul l a ry thyroi d ca rci noma ), a nd thyroi d-s ti mul a ti ng hormone (from
ges ta ti ona l chori oca rci noma ). PTHRP ca us es hyperca l cemi a a nd i ts a s s oci a ted s ymptoms (pol yuri a , dehydra ti on, cons ti pa ti on, mus cl e wea knes s );
ca l ci toni n ca us es a fa l l i n the s erum Ca l evel , wi th contra cti ons a nd ca rdi a c a rrhythmi a s .
GI paraneoplastic syndromes: Wa tery di a rrhea wi th s ubs equent dehydra ti on a nd el ectrol yte i mba l a nces ma y res ul t from tumor-rel a ted s ecreti on of
pros ta gl a ndi ns or va s oa cti ve i ntes ti na l pepti de. Impl i ca ted tumors i ncl ude pa ncrea ti c i s l et cel l tumors a nd others . Protei n-l os i ng enteropa thi es
ma y res ul t from tumor ma s s i nfl a mma ti on, pa rti cul a rl y wi th l ymphoma s .
Hematologic paraneoplastic syndromes: Pa ti ents wi th ca ncer ma y devel op pure RBC a pl a s i a , a nemi a of chroni c di s ea s e, l eukocytos i s (l eukemoi d
rea cti on), thrombocytos i s , eos i nophi l i a , ba s ophi l i a , a nd di s s emi na ted i ntra va s cul a r coa gul a ti on. In a ddi ti on, i di opa thi c thrombocytopeni c
purpura a nd a Coombs '-pos i ti ve hemol yti c a nemi a ca n compl i ca te the cours e of l ymphoi d ca ncers a nd Hodgki n l ymphoma . Erythrocytos i s ma y occur
i n va ri ous ca ncers , es peci a l l y rena l ca ncers a nd hepa toma s , due to ectopi c producti on of erythropoi eti n or erythropoi eti n-l i ke s ubs ta nces , a nd
monocl ona l ga mmopa thi es ma y s ometi mes be pres ent.
Demons tra ted mecha ni s ms of hema tol ogi c a bnorma l i ti es i ncl ude tumor-genera ted s ubs ta nces tha t mi mi c or bl ock norma l endocri ne s i gna l s for
hema tol ogi c l i ne devel opment a nd genera ti on of a nti bodi es tha t cros s -rea ct wi th receptors or cel l l i nes .
Neurologic paraneoplastic syndromes: Severa l types of peri phera l neuropa thy a re a mong the neurol ogi c pa ra neopl a s ti c s yndromes . Cerebel l a r
s yndromes a nd other centra l neurol ogi c pa ra neopl a s ti c s yndromes a l s o occur.
Peripheral neuropathy i s the mos t common neurol ogi c pa ra neopl a s ti c s yndrome. It i s us ua l l y a di s ta l s ens ori motor pol yneuropa thy tha t ca us es mi l d
motor wea knes s , s ens ory l os s , a nd a bs ent di s ta l refl exes . The s yndrome i s i ndi s ti ngui s ha bl e from tha t a ccompa nyi ng ma ny chroni c i l l nes s es .
Subacute sensory neuropathy i s a more s peci fi c but ra re peri phera l neuropa thy. Dors a l root ga ngl i a degenera ti on a nd progres s i ve s ens ory l os s wi th
a ta xi a but l i ttl e motor wea knes s devel op; the di s order ma y be di s a bl i ng. Anti -Hu, a n a utoa nti body, i s found i n the s erum of s ome pa ti ents wi th
l ung ca ncer. There i s no trea tment.
Guillain-Barre syndrome, a nother peri phera l neuropa thy, i s more common i n pa ti ents wi th Hodgki n l ymphoma tha n i n the genera l popul a ti on.
Eaton-Lambert syndrome i s a n i mmune-medi a ted, mya s theni a -l i ke s yndrome wi th wea knes s us ua l l y a ffecti ng the l i mbs a nd s pa ri ng ocul a r a nd
bul ba r mus cl es . It i s pre-s yna pti c, res ul ti ng from i mpa i red rel ea s e of a cetyl chol i ne from nerve termi na l s . An IgG a nti body i s i nvol ved. The
s yndrome ca n precede, occur wi th, or devel op a fter the di a gnos i s of ca ncer. It occurs mos t commonl y i n men wi th i ntra thora ci c tumors (70% ha ve
s ma l l or oa t cel l l ung ca rci noma ). Symptoms a nd s i gns i ncl ude fa ti ga bi l i ty, wea knes s , pa i n i n proxi ma l l i mb mus cl es , peri phera l pa res thes i a s , dry
mouth, erecti l e dys functi on, a nd ptos i s . Deep tendon refl exes a re reduced or l os t. The di a gnos i s i s confi rmed by fi ndi ng a n i ncrementa l res pons e
to repeti ti ve nerve s ti mul a ti on: Ampl i tude of the compound mus cl e a cti on potenti a l i ncrea s es > 200% a t ra tes > 10 Hz. Trea tment i s fi rs t di rected a t
the underl yi ng ca ncer a nd s ometi mes i nduces remi s s i on. Gua ni di ne (i ni ti a l l y 125 mg po qi d, gra dua l l y i ncrea s ed to a ma xi mum of 35 mg/kg),
whi ch fa ci l i ta tes a cetyl chol i ne rel ea s e, often l es s ens s ymptoms but ma y depres s bone ma rrow a nd l i ver functi on. Corti cos teroi ds a nd
pl a s ma pheres i s benefi t s ome pa ti ents .
Subacute cerebellar degeneration ca us es progres s i ve bi l a tera l l eg a nd a rm a ta xi a , dys a rthri a , a nd s ometi mes verti go a nd di pl opi a . Neurol ogi c s i gns
ma y i ncl ude dementi a wi th or wi thout bra i n s tem s i gns , ophtha l mopl egi a , nys ta gmus , a nd extens or pl a nta r s i gns , wi th promi nent dys a rthri a a nd
a rm i nvol vement. Cerebel l a r degenera ti on us ua l l y progres s es over weeks to months , often ca us i ng profound di s a bi l i ty. Cerebel l a r degenera ti on
ma y precede the di s covery of the ca ncer by weeks to yea rs . Anti -Yo, a ci rcul a ti ng a utoa nti body, i s found i n the s erum or CSF of s ome pa ti ents ,
es peci a l l y women wi th brea s t or ova ri a n ca ncer. MRI or CT ma y s how cerebel l a r a trophy, es peci a l l y l a te i n the di s ea s e. Cha ra cteri s ti c pa thol ogi c
cha nges i ncl ude wi des prea d l os s of Purki nje cel l s a nd l ymphocyti c cuffi ng of deep bl ood ves s el s . CSF occa s i ona l l y ha s mi l d l ymphocyti c
pl eocytos i s . Trea tment i s nons peci fi c, but s ome i mprovement ma y fol l ow s ucces s ful ca ncer thera py.
Opsoclonus (s ponta neous cha oti c eye movements ) i s a ra re cerebel l a r s yndrome tha t ma y a ccompa ny chi l dhood neurobl a s toma . It i s a s s oci a ted
wi th cerebel l a r a ta xi a a nd myocl onus of the trunk a nd extremi ti es . Anti -Ri , a ci rcul a ti ng a utoa nti body, ma y be pres ent. The s yndrome often
res ponds to corti cos teroi ds a nd trea tment of the ca ncer.
Subacute motor neuronopathy i s a ra re di s order ca us i ng pa i nl es s l ower motor neuron wea knes s of upper a nd l ower extremi ti es , us ua l l y i n pa ti ents
wi th Hodgki n l ymphoma or other l ymphoma s . Anteri or horn cel l s degenera te. Sponta neous i mprovement us ua l l y occurs .
Subacute necrotizing myelopathy i s a ra re s yndrome i n whi ch ra pi d a s cendi ng s ens ory a nd motor l os s occurs i n gra y a nd whi te ma tter of the s pi na l
cord, l ea di ng to pa ra pl egi a . MRI hel ps rul e out epi dura l compres s i on from meta s ta ti c tumora much more common ca us e of ra pi dl y progres s i ve
s pi na l cord dys functi on i n pa ti ents wi th ca ncer. MRI ma y s how necros i s i n the s pi na l cord.
Encephalitis ma y occur a s a pa ra neopl a s ti c s yndrome, ta ki ng s evera l di fferent forms , dependi ng on the a rea of the bra i n i nvol ved. Gl oba l
encepha l i ti s ha s been propos ed to expl a i n the encepha l opa thy tha t occurs mos t commonl y i n s ma l l cel l l ung ca ncer. Li mbi c encepha l i ti s i s
cha ra cteri zed by a nxi ety a nd depres s i on, l ea di ng to memory l os s , a gi ta ti on, confus i on, ha l l uci na ti ons , a nd beha vi ora l a bnorma l i ti es . Anti -Hu
a nti bodi es , di rected a ga i ns t RNA bi ndi ng protei ns , ma y be pres ent i n the s erum a nd s pi na l fl ui d. MRI ma y di s cl os e a rea s of i ncrea s ed contra s t
upta ke a nd edema .
Renal paraneoplastic syndrome: Membra nous gl omerul onephri ti s ma y occur i n pa ti ents wi th col on ca ncer, ova ri a n ca ncer, a nd l ymphoma a s a res ul t
of ci rcul a ti ng i mmune compl exes .
Rheumatologic paraneoplastic syndromes: Rheuma tol ogi c di s orders medi a ted by a utoi mmune rea cti ons ca n a l s o be a ma ni fes ta ti on of
pa ra neopl a s ti c s yndromes .
Arthropathies (rheuma ti c pol ya rthri ti s , pol ymya l gi a ) or s ys temi c s cl eros i s ma y devel op i n pa ti ents wi th hema tol ogi c ca ncers or wi th ca ncers of the
col on, pa ncrea s , or pros ta te. Sys temi c s cl eros i s or SLE ma y a l s o devel op i n pa ti ents wi th l ung a nd gynecol ogi c ca ncers .
Hypertrophic osteoarthropathy i s promi nent wi th certa i n l ung ca ncers a nd ma ni fes ts a s pa i nful s wel l i ng of the joi nts (knees , a nkl es , wri s ts , el bows ,
meta ca rpopha l a ngea l joi nts ) wi th effus i on a nd s ometi mes fi ngerti p cl ubbi ng.
Secondary amyloidosis ma y occur wi th myel oma , l ymphoma s , or rena l cel l ca rci noma s .
Dermatomyositis a nd, to a l es s er degree, polymyositis (s ee p. 299) a re thought to be more common i n pa ti ents wi th ca ncer, es peci a l l y i n thos e > 50
yr. Typi ca l l y, proxi ma l mus cl e wea knes s i s progres s i ve wi th pa thol ogi ca l l y demons tra bl e mus cl e i nfl a mma ti on a nd necros i s . A dus ky,
erythema tous butterfl y ra s h wi th a hel i otrope hue ma y devel op on the cheeks wi th peri orbi ta l edema . Corti cos teroi ds ma y be hel pful .
Chapter 123. Tumor Immunology

Introduction
Tumor recogni ti on i s a compl ex, cha l l engi ng probl em for the i mmune s ys tem, whi ch mus t di s ti ngui s h proper cel l ul a r growth a nd orga ni za ti on from
neopl a s ti c tra ns forma ti on. Thi s proces s i nvol ves recogni ti on of tumor a nti gens by effector cel l s a nd i nducti on of i mmuni ty. The devel opment of
tumors des pi te the pres ence of a nti gens , the s i gni fi ca nce of i mmune recogni ti on i n the pa thogenes i s of tumors , a nd the potenti a l for thera peuti c
a ugmenta ti on of i mmune res pons es rema i n the s ubject of i ntens e i nves ti ga ti on.
Tumor Antigens
Ma ny tumor cel l s produce a nti gens , whi ch ma y be rel ea s ed i n the bl oods trea m or rema i n on the cel l s urfa ce. Anti gens ha ve been i denti fi ed i n
mos t of the huma n ca ncers , i ncl udi ng Burki tt's l ymphoma , neurobl a s toma , ma l i gna nt mel a noma , os teos a rcoma , rena l cel l ca rci noma , brea s t
ca rci noma , pros ta te ca ncer, l ung ca rci noma s , a nd col on ca ncer. A key rol e of the i mmune s ys tem i s detecti on of thes e a nti gens to permi t
s ubs equent ta rgeti ng for era di ca ti on. However, des pi te thei r forei gn s tructure, the i mmune res pons e to tumor a nti gens va ri es a nd i s often
i ns uffi ci ent to prevent tumor growth.
Tumor-a s s oci a ted a nti gens (TAAs ) a re rel a ti vel y res tri cted to tumor cel l s , wherea s tumor-s peci fi c a nti gens (TSAs ) a re uni que to tumor cel l s . TSAs
a nd TAAs typi ca l l y a re porti ons of i ntra cel l ul a r mol ecul es expres s ed on the cel l s urfa ce a s pa rt of the ma jor hi s tocompa ti bi l i ty compl ex.
Sugges ted mecha ni s ms of ori gi n for tumor a nti gens i ncl ude
Introducti on of new geneti c i nforma ti on from a vi rus (eg, huma n pa pi l l oma vi rus E6 a nd E7 protei ns i n cervi ca l ca ncer)
Al tera ti on of oncogenes or tumor s uppres s or genes by ca rci nogens , whi ch ei ther genera te a novel protei n s equence di rectl y or i nduce
a ccumul a ti on of protei ns tha t a re norma l l y not expres s ed or a re expres s ed a t very l ow l evel s (eg, ras, p53)
Abnorma l l y hi gh l evel s of protei ns tha t norma l l y a re pres ent a t s ubs ta nti a l l y l ower l evel s (eg, pros ta te-s peci fi c a nti gens , mel a noma -a s s oci a ted
a nti gens ) or tha t a re expres s ed onl y duri ng embryoni c devel opment (ca rci noembryoni c a nti gens )
Uncoveri ng of a nti gens norma l l y buri ed i n the cel l membra ne beca us e of defecti ve membra ne homeos ta s i s i n tumor cel l s
Rel ea s e of a nti gens norma l l y s eques tered wi thi n the cel l or i ts orga nel l es when tumor cel l s di e
Host Response to Tumors
The i mmune res pons e to forei gn a nti gens cons i s ts of humora l (eg, a nti bodi es ) a nd cel l ul a r mecha ni s ms . Mos t humora l res pons es ca nnot prevent
tumor growth. However, effector cel l s , s uch a s T cel l s , ma cropha ges , a nd na tura l ki l l er cel l s , ha ve rel a ti vel y effecti ve tumori ci da l a bi l i ti es . Effector
cel l a cti vi ty i s i nduced by cel l s tha t pres ent tumor-s peci fi c a nti gens (TSAs ) or tumor-a s s oci a ted a nti gens (TAAs ) on thei r s urfa ce (thes e cel l s a re
ca l l ed a nti gen-pres enti ng cel l s ) a nd i s s upported by cytoki nes (eg, i nterl euki ns , i nterferons s ee p. 1084). Des pi te the a cti vi ty of effector cel l s ,
hos t i mmunorea cti vi ty ma y fa i l to control tumor occurrence a nd growth.
Cellular Immunity
The T cell i s the pri ma ry cel l res pons i bl e for di rect recogni ti on a nd ki l l i ng of tumor cel l s . T cel l s ca rry out i mmunol ogi c s urvei l l a nce, then
prol i fera te a nd des troy newl y tra ns formed tumor cel l s a fter recogni zi ng TAAs . The T-cel l res pons e to tumors i s modul a ted by other cel l s of the
i mmune s ys tem; s ome cel l s requi re the pres ence of humora l a nti bodi es di rected a ga i ns t the tumor cel l s (a nti body-dependent cel l ul a r
cytotoxi ci ty) to i ni ti a te the i ntera cti ons tha t l ea d to the dea th of tumor cel l s . In contra s t, s uppres s or T cel l s i nhi bi t the i mmune res pons e a ga i ns t
tumors .
Cytotoxic T lymphocytes (CTLs ) recogni ze a nti gens on ta rget cel l s a nd l ys e thes e cel l s . Thes e a nti gens ma y be cel l s urfa ce protei ns or ma y be
i ntra cel l ul a r protei ns (eg, TAAs ) tha t a re expres s ed on the s urfa ce i n combi na ti on wi th cl a s s I ma jor hi s tocompa ti bi l i ty compl ex (MHC) mol ecul es .
Tumor-s peci fi c CTLs ha ve been found wi th neurobl a s toma s ; ma l i gna nt mel a noma s ; s a rcoma s ; a nd ca rci noma s of the col on, brea s t, cervi x,
endometri um, ova ry, tes ti s , na s opha rynx, a nd ki dney.
Natural killer (NK) cells a re a nother popul a ti on of effector cel l s wi th tumori ci da l a cti vi ty. In contra s t to CTLs , NK cel l s l a ck the receptor for a nti gen
detecti on but ca n s ti l l recogni ze norma l cel l s i nfected wi th vi rus es or tumor cel l s . Thei r tumori ci da l a cti vi ty i s termed na tura l beca us e i t i s not
i nduced by a s peci fi c a nti gen. The mecha ni s m by whi ch NK cel l s di s cri mi na te between norma l a nd a bnorma l cel l s i s under s tudy. Evi dence
s ugges ts tha t cl a s s I MHC mol ecul es on the s urfa ce of norma l cel l s i nhi bi t NK cel l s a nd prevent l ys i s . Thus , the decrea s ed l evel of cl a s s I mol ecul e
expres s i on cha ra cteri s ti c of ma ny tumor cel l s ma y a l l ow a cti va ti on of NK cel l s a nd s ubs equent tumor l ys i s .
Macrophages ca n ki l l s peci fi c tumor cel l s when a cti va ted by a combi na ti on of fa ctors , i ncl udi ng l ymphoki nes (s ol ubl e fa ctors produced by T cel l s )
a nd i nterferon. They a re l es s effecti ve tha n T-cel l -medi a ted cytotoxi c mecha ni s ms . Under certa i n ci rcums ta nces , ma cropha ges ma y pres ent TAAs to
T cel l s a nd s ti mul a te tumor-s peci fi c i mmune res pons e.
Dendritic cells a re dedi ca ted a nti gen-pres enti ng cel l s pres ent i n ba rri er ti s s ues (eg, s ki n, l ymph nodes ). They pl a y a centra l rol e i n i ni ti a ti on of
tumor-s peci fi c i mmune res pons e. Thes e cel l s ta ke up tumor-a s s oci a ted protei ns , proces s them, a nd pres ent TAAs to T cel l s to s ti mul a te the CTL
res pons e a ga i ns t tumor. The pres ence of dendri ti c cel l s i n tumor ti s s ues correl a tes wi th i mproved prognos i s .
Lymphokines produced by i mmune cel l s s ti mul a te growth or i nduce a cti vi ti es of other i mmune cel l s . Such l ymphoki nes i ncl ude IL-2, a l s o known a s
T-cel l growth fa ctor, a nd the i nterferons . IL-12 i s produced by dendri ti c cel l s a nd s peci fi ca l l y i nduces CTLs , thereby enha nci ng a nti tumor i mmune
res pons es .
Regulatory T cells a re norma l l y pres ent i n the body a nd hel p prevent a utoi mmune rea cti ons . They a re produced duri ng the a cti ve pha s e of i mmune
res pons es to pa thogens a nd l i mi t the s trong i mmune res pons e tha t coul d da ma ge the hos t. Accumul a ti on of thes e cel l s i n ca ncers i nhi bi ts
a nti tumor i mmune res pons es .

Myeloid-derived suppressor cells cons i s t of i mma ture myel oi d cel l s a nd thei r precurs ors . Thes e cel l s a ccumul a te i n l a rge numbers i n ca ncers a nd
potentl y s uppres s i mmune res pons es .
Humoral Immunity
In contra s t to T-cel l cytotoxi c i mmuni ty, humora l a nti bodi es do not a ppea r to confer s i gni fi ca nt protecti on a ga i ns t tumor growth. Mos t a nti bodi es
ca nnot recogni ze TAAs . Rega rdl es s , humora l a nti bodi es tha t rea ct wi th tumor cel l s i n vi tro ha ve been detected i n the s era of pa ti ents wi th va ri ous
tumors , i ncl udi ng Burki tt's l ymphoma ; ma l i gna nt mel a noma ; os teos a rcoma ; neurobl a s toma ; a nd ca rci noma s of the l ung, brea s t, a nd GI tra ct.
Cytotoxi c a nti bodi es a re di rected a ga i ns t s urfa ce a nti gens of tumor cel l s . Thes e a nti bodi es ca n exert a nti -tumor effects through compl ement
fi xa ti on or by s ervi ng a s a fl a g for des tructi on of tumor cel l s by T cel l s (a nti body-dependent cel l -medi a ted cytotoxi ci ty). Another popul a ti on of
humora l a nti bodi es , ca l l ed enha nci ng a nti bodi es (bl ocki ng a nti bodi es ), ma y a ctua l l y fa vor ra ther tha n i nhi bi t tumor growth. The mecha ni s ms a nd
rel a ti ve i mporta nce of s uch i mmunol ogi c enha ncement a re not wel l unders tood.
Failure of Host Defenses
Al though ma ny tumors a re el i mi na ted by the i mmune s ys tem (a nd thus a re never detected), others conti nue to grow des pi te the pres ence of TAAs .
Severa l mecha ni s ms ha ve been propos ed to expl a i n thi s defi ci ent hos t res pons e to the TAA, i ncl udi ng the fol l owi ng:
Speci fi c i mmunol ogi c tol era nce to TAAs i n a proces s tha t i nvol ves a nti gen-pres enti ng cel l s a nd s uppres s or T cel l s , pos s i bl y s econda ry to
prena ta l expos ure to the a nti gen
Suppres s i on of i mmune res pons e by chemi ca l , phys i ca l , or vi ra l a gents (eg, hel per T-cel l des tructi on by HIV)
Suppres s i on of the i mmune res pons e by cytotoxi c drugs or ra di a ti on
Suppres s i on of the i mmune res pons e by the tumor i ts el f through va ri ous compl ex a nd l a rgel y uncha ra cteri zed mecha ni s ms tha t ca us e va ri ous
probl ems i ncl udi ng decrea s ed T, B, a nd a nti gen-pres enti ng cel l functi on, decrea s ed IL-2 producti on, a nd i ncrea s ed ci rcul a ti ng s ol ubl e IL-2
receptors (whi ch bi nd a nd hence i na cti va te IL-2)
Tumor Immunodiagnosis
Tumor-a s s oci a ted a nti gens (TAAs ) ca n hel p di a gnos e va ri ous tumors a nd s ometi mes determi ne the res pons e to thera py or recurrence. An i dea l
tumor ma rker woul d be rel ea s ed onl y from tumor ti s s ue, be s peci fi c for a gi ven tumor type, be detecta bl e a t l ow l evel s of tumor cel l burden, ha ve
a di rect rel a ti ons hi p to the tumor cel l burden, a nd be pres ent i n a l l pa ti ents wi th the tumor. However, a l though mos t tumors rel ea s e detecta bl e
a nti geni c ma cromol ecul es i nto the ci rcul a ti on, no tumor ma rker ha s a l l the requi s i te cha ra cteri s ti cs to provi de enough s peci fi ci ty or s ens i ti vi ty to
be us ed i n ea rl y di a gnos i s or ma s s ca ncer s creeni ng progra ms .
Carcinoembryonic antigen (CEA) i s a protei n-pol ys a ccha ri de compl ex pres ent i n col on ca rci noma s a nd i n norma l feta l i ntes ti ne, pa ncrea s , a nd l i ver.
Bl ood l evel s a re el eva ted i n pa ti ents wi th col on ca rci noma , but the s peci fi ci ty i s rel a ti vel y l ow beca us e pos i ti ve res ul ts a l s o occur i n hea vy
ci ga rette s mokers a nd i n pa ti ents wi th ci rrhos i s , ul cera ti ve col i ti s , a nd other ca ncers (eg, brea s t, pa ncrea s , bl a dder, ova ry, cervi x). Moni tori ng CEA
l evel s ma y be us eful for detecti ng ca ncer recurrence a fter tumor exci s i on i f the pa ti ent i ni ti a l l y ha d a n el eva ted CEA a nd for refi ni ng es ti ma tes of
prognos i s by s ta ge.
-Fetoprotein, a norma l product of feta l l i ver cel l s , i s a l s o pres ent i n the s era of pa ti ents wi th pri ma ry hepa toma , nons emi noma tous germ cel l
tumors , a nd, frequentl y, ova ri a n or tes ti cul a r embryona l ca rci noma . Level s a re s ometi mes us eful for es ti ma ti ng prognos i s or, l es s often, for
di a gnos i s .
Subunit of human chorionic gonadotropin (-hCG), mea s ured by i mmunoa s s a y, i s the ma jor cl i ni ca l ma rker i n women wi th ges ta ti ona l trophobl a s ti c
neopl a s i a (GTN)a di s ea s e s pectrum tha t i ncl udes hyda ti di form mol e, nonmeta s ta ti c GTN, a nd meta s ta ti c GTN (s ee a l s o p. 2574)a nd i n a bout
two thi rds of men wi th tes ti cul a r embryona l ca rci noma or chori oca rci noma . The s ubuni t i s mea s ured beca us e i t i s s peci fi c for hCG. Thi s ma rker i s
pres ent i n l ow l evel s i n hea l thy peopl e. Level s a re el eva ted duri ng pregna ncy.
Prostate-specific antigen (PSA), a gl ycoprotei n l oca ted i n ducta l epi thel i a l cel l s of the pros ta te gl a nd, ca n be detected i n l ow concentra ti ons i n the
s era of hea l thy men. Us i ng a n a ppropri a te upper l i mi t of norma l , a s s a ys wi th monocl ona l a nti bodi es detect el eva ted s erum l evel s of PSA i n a bout
90% of pa ti ents wi th a dva nced pros ta te ca ncer, even i n the a bs ence of defi ned meta s ta ti c di s ea s e. It i s more s ens i ti ve tha n pros ta ti c a ci d
phos pha ta s e. However, beca us e PSA i s el eva ted i n other condi ti ons (eg, beni gn pros ta ti c hypertrophy, pros ta ti ti s , recent GU tra ct i ns trumenta ti on),
i t i s l es s s peci fi c. PSA ca n be us ed to moni tor recurrence a fter pros ta ti c ca rci noma ha s been di a gnos ed a nd trea ted.
CA 125 i s cl i ni ca l l y us eful for s creeni ng, di a gnos i ng, a nd moni tori ng thera py for ova ri a n ca ncer, a l though a ny peri tonea l i nfl a mma tory proces s a nd
s ome other ca ncers ca n i ncrea s e l evel s .
2 -Microglobulin i s often el eva ted i n mul ti pl e myel oma a nd i n s ome l ymphoma s . Its pri ma ry us e i s i n prognos i s .
CA 19-9 wa s ori gi na l l y devel oped to detect col orecta l ca ncer but proved more s ens i ti ve for pa ncrea ti c ca ncer. It i s pri ma ri l y us ed to judge the
res pons e to trea tment i n pa ti ents wi th a dva nced pa ncrea ti c ca ncers . CA 19-9 ca n a l s o be el eva ted i n other GI ca ncers , pa rti cul a rl y ca ncer of the
bi l e ducts , a nd s ome beni gn bi l e duct a nd chol es ta ti c di s orders .
CA 15-3 a nd CA 27-29 a re el eva ted i n mos t pa ti ents wi th meta s ta ti c brea s t ca ncer. Level s ma y a l s o be el eva ted i n other condi ti ons . Thes e ma rkers
a re pri ma ri l y us ed to moni tor the res pons e to thera py.
Chromogranin A i s us ed a s a ma rker for ca rci noi d a nd other neuroendocri ne tumors . Sens i ti vi ty a nd s peci fi ci ty for neuroendocri ne tumors ca n
exceed 75%, a nd di a gnos ti c a ccura cy i s hi gher wi th di ffus e tha n wi th l oca l i zed tumors . Level s ca n be el eva ted i n other ca ncers , s uch a s l ung a nd
pros ta te, a nd s ome beni gn di s orders (eg, pri ma ry hypertens i on, chroni c ki dney di s ea s e, chroni c a trophi c ga s tri ti s ).
Thyroglobulin i s produced by the thyroi d a nd ma y be el eva ted wi th va ri ous thyroi d di s orders . It i s pri ma ri l y us ed a fter compl ete thyroi dectomy to
detect recurrent thyroi d ca ncer a nd to moni tor the res pons e to trea tment i n meta s ta ti c thyroi d ca ncer.
TA-90 i s a hi ghl y i mmunogeni c s ubuni t of a uri na ry tumor-a s s oci a ted a nti gen tha t i s pres ent i n 70% of mel a noma s , s oft-ti s s ue s a rcoma s , a nd
ca rci noma s of the brea s t, col on, a nd l ung. Some s tudi es ha ve s hown tha t TA-90 l evel s ca n a ccura tel y predi ct s urvi va l a nd the pres ence of
s ubcl i ni ca l di s ea s e a fter s urgery for mel a noma .
Immunotherapy
A number of i mmunol ogi c i nterventi ons , both pa s s i ve a nd a cti ve, ca n be di rected a ga i ns t tumor cel l s .
Passive Cellular Immunotherapy
In pa s s i ve cel l ul a r i mmunothera py, s peci fi c effector cel l s a re di rectl y i nfus ed a nd a re not i nduced or expa nded wi thi n the pa ti ent.
Lymphokine-activated killer (LAK) cells a re produced from the pa ti ent's endogenous T cel l s , whi ch a re extra cted a nd grown i n a cel l cul ture s ys tem by
expos i ng them to the l ymphoki ne IL-2. The prol i fera ted LAK cel l s a re then returned to the pa ti ent's bl oods trea m. Ani ma l s tudi es ha ve s hown tha t
LAK cel l s a re more effecti ve a ga i ns t ca ncer cel l s tha n a re the ori gi na l endogenous T cel l s , pres uma bl y beca us e of thei r grea ter number. Cl i ni ca l
tri a l s of LAK cel l s i n huma ns a re ongoi ng.
Tumor-infiltrating lymphocytes (TILs) ma y ha ve grea ter tumori ci da l a cti vi ty tha n LAK cel l s . Thes e cel l s a re grown i n cul ture i n a ma nner s i mi l a r to LAK
cel l s . However, the progeni tor cel l s cons i s t of T cel l s tha t a re i s ol a ted from res ected tumor ti s s ue. Thi s proces s theoreti ca l l y provi des a l i ne of T
cel l s tha t ha s grea ter tumor s peci fi ci ty tha n thos e obta i ned from the bl oods trea m. Recent cl i ni ca l s tudi es ha ve s hown hi ghl y promi s i ng res ul ts .
Concomi ta nt us e of i nterferon enha nces the expres s i on of ma jor hi s tocompa ti bi l i ty compl ex (MHC) a nti gens a nd tumor-a s s oci a ted a nti gens (TAAs )
on tumor cel l s , thereby a ugmenti ng the ki l l i ng of tumor cel l s by the i nfus ed effector cel l s .
However, remi s s i ons us i ng unmodi fi ed TILs ha ve been i nfrequent. A new a pproa ch us i ng T cel l s geneti ca l l y modi fi ed to expres s receptors tha t
recogni ze TAAs wi th hi gh s peci fi ci ty to tumor cel l s i s under s tudy a nd ma y provi de s i gni fi ca nt cl i ni ca l benefi t.
Passive Humoral Immunotherapy
Admi ni s tra ti on of exogenous a nti bodi es cons ti tutes pa s s i ve humora l i mmunothera py. Anti l ymphocyte s erum ha s been us ed i n the trea tment of
chroni c l ymphocyti c l eukemi a a nd i n T-cel l a nd B-cel l l ymphoma s , res ul ti ng i n tempora ry decrea s es i n l ymphocyte counts or l ymph node s i ze.
Monocl ona l a nti tumor a nti bodi es ma y a l s o be conjuga ted wi th toxi ns (eg, ri ci n, di phtheri a ) or wi th ra di oi s otopes s o tha t the a nti bodi es del i ver
thes e toxi c a gents s peci fi ca l l y to the tumor cel l s . Another techni que i nvol ves bi s peci fi c a nti bodi es , or l i nka ge of one a nti body tha t rea cts wi th the
tumor cel l to a s econd a nti body tha t rea cts wi th a cytotoxi c effector cel l . Thi s techni que bri ngs the effector cel l i n cl os e oppos i ti on to the tumor
cel l , res ul ti ng i n i ncrea s ed tumori ci da l a cti vi ty. However, thes e techni ques a re i n ea rl y s ta ges of tes ti ng; thus , potenti a l cl i ni ca l benefi ts a re
uncerta i n.
Active Specific Immunotherapy
Induci ng cel l ul a r i mmuni ty (i nvol vi ng cytotoxi c T cel l s ) i n a hos t tha t fa i l ed to s ponta neous l y devel op a n effecti ve res pons e genera l l y i nvol ves
methods to enha nce pres enta ti on of tumor a nti gens to hos t effector cel l s . Cel l ul a r i mmuni ty ca n be i nduced to s peci fi c, very wel l -defi ned
a nti gens . Severa l techni ques ca n be us ed to s ti mul a te a hos t res pons e; thes e techni ques ma y i nvol ve gi vi ng pepti des , DNA, or tumor cel l s (from
the hos t or a nother pa ti ent). Pepti des a nd DNA a re often gi ven us i ng a nti gen-pres enti ng cel l s (dendri ti c cel l s ). Thes e dendri ti c cel l s ca n a l s o be
geneti ca l l y modi fi ed to s ecrete a ddi ti ona l i mmune-res pons e s ti mul a nts (eg, gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor [GM-CSF]).
Peptide-based vaccines us e pepti des from defi ned TAAs . An i ncrea s i ng number of TAAs ha ve been i denti fi ed a s the ta rget of T cel l s i n ca ncer
pa ti ents a nd a re bei ng tes ted i n cl i ni ca l tri a l s . Recent da ta i ndi ca te tha t res pons es a re mos t potent i f TAAs a re del i vered us i ng dendri ti c cel l s .
Thes e cel l s a re obta i ned from the pa ti ent, l oa ded wi th the des i red TAA, a nd then rei ntroduced i ntra derma l l y; they s ti mul a te endogenous T cel l s
to res pond to the TAA. The pepti des a l s o ca n be del i vered by co-a dmi ni s tra ti on wi th i mmunogeni c a djuva nts .
DNA vaccines us e recombi na nt DNA tha t encodes a s peci fi c (defi ned) a nti geni c protei n. The DNA i s i ncorpora ted i nto vi rus es tha t a re i njected
di rectl y i nto pa ti ents or, more often, i ntroduced i nto dendri ti c cel l s obta i ned from the pa ti ents , whi ch a re then i njected ba ck i nto them. The DNA
expres s es the ta rget a nti gen whi ch tri ggers or enha nces pa ti ents ' i mmune res pons e.
Autochthonous tumor cells (cel l s ta ken from the hos t) ha ve been rei ntroduced to the hos t a fter us e of ex vi vo techni ques (eg, i rra di a ti on,
neura mi ni da s e trea tment, ha pten conjuga ti on, hybri di za ti on wi th other cel l l i nes ) to reduce thei r ma l i gna nt potenti a l a nd i ncrea s e thei r
a nti geni c a cti vi ty. Someti mes the tumor cel l s a re geneti ca l l y modi fi ed to produce i mmunos ti mul a tory mol ecul es (i ncl udi ng cytoki nes s uch a s GMCSF or IL-2, cos ti mul a tory mol ecul es s uch a s B7-1, a nd a l l ogenei c cl a s s I MHC mol ecul es ); thi s modi fi ca ti on hel ps a ttra ct effector mol ecul es a nd
enha nces s ys temi c tumor ta rgeti ng. Cl i ni ca l tri a l s wi th GM-CSF-modi fi ed tumor cel l s ha ve produced encoura gi ng prel i mi na ry res ul ts .
Allogeneic tumor cells (cel l s ta ken from other pa ti ents ) ha ve been us ed i n pa ti ents wi th a cute l ymphocyti c l eukemi a a nd a cute myel obl a s ti c
l eukemi a . Remi s s i on i s i nduced by i ntens i ve chemothera py a nd ra di a ti on thera py. Then, i rra di a ted a l l ogenei c tumor cel l s tha t ha ve been
modi fi ed ei ther geneti ca l l y or chemi ca l l y to i ncrea s e thei r i mmunogeni c potenti a l a re i njected i nto the pa ti ent. Someti mes pa ti ents a re a l s o
gi ven ba ci l l e Ca l mette-Gueri n (BCG) va cci ne or other a djuva nts (s ee p. 1061) to enha nce the i mmune res pons e a ga i ns t the tumor. Prol onged
remi s s i ons or i mproved rei nducti on ra tes ha ve been reported i n s ome s eri es but not i n mos t.
A novel a pproa ch to ca ncer trea tment combi ni ng i mmunothera py a nd conventi ona l chemothera py ha s s hown s ome s ucces s (vs hi s tori c control s ) i n
nonra ndomi zed pha s e I a nd pha s e II cl i ni ca l tri a l s i nvol vi ng va ri ous ca ncers , types of va cci nes , a nd chemothera py.
Nonspecific Immunotherapy
Interferons (IFN-, -, -) a re gl ycoprotei ns tha t ha ve a nti tumor a nd a nti vi ra l a cti vi ty. Dependi ng on dos e, i nterferons ma y ei ther enha nce or
decrea s e cel l ul a r a nd humora l i mmune functi ons . Interferons a l s o i nhi bi t di vi s i on a nd certa i n s yntheti c proces s es i n a va ri ety of cel l s . Cl i ni ca l
tri a l s ha ve i ndi ca ted tha t i nterferons ha ve a nti tumor a cti vi ty i n va ri ous ca ncers , i ncl udi ng ha i ry cel l l eukemi a , chroni c myel ocyti c l eukemi a , AIDSa s s oci a ted Ka pos i 's s a rcoma , non-Hodgki n l ymphoma , mul ti pl e myel oma , a nd ova ri a n ca rci noma . However, i nterferons ma y ha ve s i gni fi ca nt
a dvers e effects , s uch a s fever, ma l a i s e, l eukopeni a , a l opeci a , a nd mya l gi a s .
Certa i n bacterial adjuvants (BCG a nd deri va ti ves , ki l l ed s us pens i ons of Corynebacterium parvum) ha ve tumori ci da l properti es . They ha ve been us ed
wi th or wi thout a dded tumor a nti gen to trea t a va ri ety of ca ncers , us ua l l y a l ong wi th i ntens i ve chemothera py or ra di a ti on thera py. For exa mpl e,
di rect i njecti on of BCG i nto ca ncerous ti s s ues ha s res ul ted i n regres s i on of mel a noma a nd prol onga ti on of di s ea s e-free i nterva l s i n s uperfi ci a l
bl a dder ca rci noma s a nd ma y hel p prol ong drug-i nduced remi s s i on i n a cute myel obl a s ti c l eukemi a , ova ri a n ca rci noma , a nd non-Hodgki n
l ymphoma .
Chapter 124. Principles of Cancer Therapy

Introduction
Curi ng ca ncer requi res el i mi na ti ng a l l ca ncer cel l s . The ma jor moda l i ti es of thera py a re
Surgery a nd ra di a ti on thera py (for l oca l a nd l oca l -regi ona l di s ea s e)
Chemothera py (for s ys temi c di s ea s e) Other i mporta nt methods i ncl ude
Hormona l thera py (for s el ected ca ncers , eg, pros ta te, brea s t, endometri um)
Immunothera py (monocl ona l a nti bodi es , i nterferons , a nd other bi ol ogi c res pons e modi fi ers a nd tumor va cci nes s ee p. 1059)
Di fferenti a ti ng a gents s uch a s reti noi ds
Ta rgeted a gents tha t expl oi t the growi ng knowl edge of cel l ul a r a nd mol ecul a r bi ol ogy
Overa l l trea tment s houl d be coordi na ted a mong a ra di a ti on oncol ogi s t, s urgeon, a nd medi ca l oncol ogi s t, where a ppropri a te. Choi ce of moda l i ti es
cons ta ntl y evol ves , a nd numerous control l ed res ea rch tri a l s conti nue. When a va i l a bl e a nd a ppropri a te, cl i ni ca l tri a l pa rti ci pa ti on s houl d be
cons i dered a nd di s cus s ed wi th pa ti ents .
Va ri ous terms a re us ed to des cri be the res pons e to trea tment (s ee
Ta bl e 124-1). The di s ea s e-free i nterva l often s erves a s a n i ndi ca tor of cure a nd va ri es wi th ca ncer type. For exa mpl e, l ung, col on, bl a dder, a nd
tes ti cul a r ca ncers a re us ua l l y cured i f a 5-yr di s ea s e-free i nterva l occurs . However, brea s t ca ncer ma y recur even a fter 5 yr; thus a 10-yr di s ea s e-free
i nterva l i s more i ndi ca ti ve of cure.
Trea tment deci s i ons s houl d wei gh the l i kel i hood of a dvers e effects a ga i ns t the l i kel i hood of benefi t; thes e deci s i ons requi re fra nk
communi ca ti on a nd pos s i bl y the i nvol vement of a mul ti di s ci pl i na ry ca ncer tea m. Pa ti ent preferences for how to l i ve out the end of l i fe s houl d be
es ta bl i s hed ea rl y i n the cours e of ca ncer
[Table 124-1. Defi ni ng Res pons e to Ca ncer Trea tment]
trea tment des pi te the di ffi cul ti es of di s cus s i ng dea th a t s uch a s ens i ti ve ti me (s ee p. 3471).
Modalities of Cancer Therapy
Trea tment of ca ncer ca n i nvol ve a ny of s evera l moda l i ti es :
Surgery
Chemothera py
Often, moda l i ti es a re combi ned to crea te a progra m tha t i s a ppropri a te for the pa ti ent a nd i s ba s ed on pa ti ent a nd tumor cha ra cteri s ti cs a s wel l
a s pa ti ent preferences .
Survi va l ra tes wi th the di fferent moda l i ti es , a l one a nd i n combi na ti on, a re l i s ted for s el ected ca ncers (s ee
Ta bl e 124-2).
Surgery
Surgery i s the ol des t form of effecti ve ca ncer thera py. It ma y be us ed a l one or i n combi na ti on wi th other moda l i ti es .
Fa ctors tha t i ncrea s e opera ti ve ri s k i n ca ncer pa ti ents i ncl ude
Age
Comorbi d condi ti ons
Debi l i ta ti on due to ca ncer
Pa ra neopl a s ti c s yndromes (l es s commons ee p. 1054)
Ca ncer pa ti ents often ha ve poor nutri ti on due to a norexi a a nd the ca ta bol i c i nfl uences of tumor growth, a nd thes e fa ctors ma y i nhi bi t or s l ow
recovery from s urgery. Pa ti ents ma y be neutropeni c or thrombocytopeni c or ma y ha ve cl otti ng di s orders ; thes e condi ti ons i ncrea s e the ri s k of
s eps i s a nd hemorrha ge. Therefore, preopera ti ve a s s es s ment i s pa ra mount (s ee p. 3445).
[Table 124-2. 5-yr Di s ea s e-Free Survi va l Ra tes by Ca ncer Thera py]
Primary tumor resection: If a pri ma ry tumor ha s not meta s ta s i zed, s urgery ma y be cura ti ve. Es ta bl i s hi ng a compl ete ma rgi n of norma l ti s s ue a round
the pri ma ry tumor i s cri ti ca l for the s ucces s of pri ma ry tumor res ecti on. Intra opera ti ve exa mi na ti on of frozen ti s s ue s ecti ons by a pa thol ogi s t ma y
be needed, wi th i mmedi a te res ecti on of a ddi ti ona l ti s s ue i f ma rgi ns a re pos i ti ve for tumor cel l s . However, frozen ti s s ue exa mi na ti on i s i nferi or to
exa mi na ti on of proces s ed a nd s ta i ned ti s s ue. La ter revi ew of ma rgi n ti s s ue ma y prove the need for wi der res ecti on.
Surgi ca l res ecti on for pri ma ry tumor wi th l oca l s prea d ma y a l s o requi re remova l of i nvol ved regi ona l l ymph nodes , res ecti on of a n i nvol ved
a dja cent orga n, or en bl oc res ecti on. Survi va l ra tes wi th s urgery a l one a re l i s ted for s el ected ca ncers (s ee Ta bl e 124-2).
When the pri ma ry tumor ha s s prea d i nto a dja cent norma l ti s s ues extens i vel y, s urgery ma y be del a yed s o tha t other moda l i ti es (eg, chemothera py,
ra di a ti on thera py) ca n be us ed to reduce the s i ze of the requi red res ecti on.
Resection of metastases: Wi th regi ona l l ymph node meta s ta s es , nons urgi ca l moda l i ti es ma y be the bes t i ni ti a l trea tments , a s i n l oca l l y a dva nced
l ung ca ncer or hea d a nd neck ca ncer. Si ngl e meta s ta s es , es peci a l l y thos e i n the l ung, ca n s ometi mes be res ected wi th a rea s ona bl e ra te of cure.
Pa ti ents wi th a l i mi ted number of meta s ta s es , pa rti cul a rl y to the l i ver, bra i n, or l ungs , ma y benefi t from s urgi ca l res ecti on of both the pri ma ry a nd
meta s ta ti c tumor. For exa mpl e, i n col on ca ncer wi th l i ver meta s ta s es , res ecti on produces 5-yr s urvi va l ra tes of 30 to 40% i f < 4 hepa ti c l es i ons exi s t
a nd i f a dequa te tumor ma rgi ns ca n be obta i ned.
Cytoreduction: Cytoreducti on (s urgi ca l res ecti on to reduce tumor burden) i s often a n opti on when remova l of a l l tumor ti s s ue i s i mpos s i bl e, a s i n
mos t ca s es of ova ri a n ca ncer. Cytoreducti on ma y i ncrea s e the s ens i ti vi ty of the rema i ni ng ti s s ue to other trea tment moda l i ti es through
mecha ni s ms tha t a re not enti rel y cl ea r. Cytoreducti on ha s yi el ded fa vora bl e res ul ts i n pedi a tri c s ol i d tumors a nd i n ova ri a n ca ncer.
Palliative surgery: Surgery to rel i eve s ymptoms a nd pres erve qua l i ty of l i fe ma y be a rea s ona bl e a l terna ti ve when cure i s unl i kel y or when a n
a ttempt a t cure produces a dvers e effects tha t a re una ccepta bl e to the pa ti ent. Tumor res ecti on ma y be i ndi ca ted to control pa i n, to reduce the ri s k
of hemorrha ge, or to rel i eve obs tructi on of a vi ta l orga n (eg, i ntes ti ne, uri na ry tra ct). Nutri ti ona l s uppl ementa ti on wi th a feedi ng ga s tros tomy or
jejunos tomy tube ma y be neces s a ry i f proxi ma l obs tructi on exi s ts .
Reconstructive surgery: Recons tructi ve s urgery ma y i mprove a pa ti ent's comfort or qua l i ty of l i fe a fter tumor res ecti on (eg, brea s t recons tructi on a fter
ma s tectomy).
Radiation Therapy
Ra di a ti on thera py ca n cure ma ny ca ncers (s ee Ta bl e 124-2), pa rti cul a rl y thos e tha t a re l oca l i zed or tha t ca n be compl etel y encompa s s ed wi thi n the
ra di a ti on fi el d. Ra di a ti on thera py wi th s urgery (for hea d a nd neck, l a ryngea l , or uteri ne ca ncer) or wi th chemothera py a nd s urgery (for s a rcoma s or
brea s t, es opha gea l , l ung, or recta l ca ncers ) i mproves cure ra tes a nd a l l ows for more l i mi ted s urgery a s compa red wi th tra di ti ona l s urgi ca l
res ecti on.
Ra di a ti on thera py ca n provi de s i gni fi ca nt pa l l i a ti on when cure i s not pos s i bl e:
For bra i n tumors : Prol ongs pa ti ent functi oni ng
For ca ncers tha t compres s the s pi na l cord: Prevents progres s i on of neurol ogi c defi ci ts
For s uperi or vena ca va s yndromes : Rel i eves venous obs tructi on
For pa i nful bone l es i ons : Us ua l l y rel i eves s ymptoms
Ra di a ti on ca nnot des troy ma l i gna nt cel l s wi thout des troyi ng s ome norma l cel l s a s wel l . Therefore, the ri s k to norma l ti s s ue mus t be wei ghed
a ga i ns t the potenti a l ga i n i n trea ti ng the ma l i gna nt cel l s . The fi na l outcome of a dos e of ra di a ti on depends on numerous fa ctors , i ncl udi ng
Na ture of the del i vered ra di a ti on (mode, ti mi ng, vol ume, dos e)
Properti es of the tumor (cel l cycl e pha s e, oxygena ti on, mol ecul a r properti es , overa l l s ens i ti vi ty to ra di a ti on)
In genera l , ca ncer cel l s a re s el ecti vel y da ma ged beca us e of thei r hi gh meta bol i c ra te. Norma l ti s s ue repa i rs i ts el f more effecti vel y, res ul ti ng i n
grea ter net des tructi on of tumor.
Importa nt cons i dera ti ons i n the us e of ra di a ti on thera py i ncl ude the fol l owi ng:
Trea tment ti mi ng (cri ti ca l )
Dos e fra cti ona ti on (cri ti ca l )
Norma l ti s s ue i n or a dja cent to the propos ed ra di a ti on fi el d
Ta rget vol ume
Confi gura ti on of ra di a ti on bea ms
Dos e di s tri buti on
Moda l i ty a nd energy mos t s ui ted to the pa ti ent's s i tua ti on
Trea tment i s ta i l ored to ta ke a dva nta ge of the cel l ul a r ki neti cs of tumor growth, wi th the a i m of ma xi mi zi ng da ma ge to the tumor whi l e
mi ni mi zi ng da ma ge to norma l ti s s ues .
Ra di a ti on thera py s es s i ons begi n wi th the preci s e pos i ti oni ng of the pa ti ent. Foa m ca s ts or pl a s ti c ma s ks a re often cons tructed to ens ure exa ct
repos i ti oni ng for s eri a l trea tments . La s er-gui ded s ens ors a re us ed. Typi ca l cours es cons i s t of l a rge da i l y dos es gi ven over 3 wk for pa l l i a ti ve
trea tment or s ma l l er dos es gi ven once/da y 5 da ys /wk for 6 to 8 wk for cura ti ve trea tment.
Types of radiation therapy: There a re s evera l di fferent types of ra di a ti on thera py.
External beam radiation therapy ca n be done wi th photons (ga mma ra di a ti on), el ectrons , or protons . Ga mma ra di a ti on us i ng a l i nea r a ccel era tor i s
the mos t common type of ra di a ti on thera py. The ra di a ti on dos e to a dja cent norma l ti s s ue ca n be l i mi ted by conforma l technol ogy, whi ch reduces
s ca tter a t the fi el d ma rgi ns . El ectron bea m ra di a ti on thera py produces l i ttl e ti s s ue penetra ti on a nd i s bes t for s ki n or s uperfi ci a l ca ncers .
Di fferent energi es of el ectrons a re us ed ba s ed on the des i red depth of penetra ti on a nd type of tumor. Proton thera py, a l though l i mi ted i n
a va i l a bi l i ty, ca n provi de s ha rp ma rgi ns a nd i s pa rti cul a rl y us eful for tumors of the eye, the ba s e of the bra i n, a nd the s pi ne.
Stereotactic radiation therapy i s ra di o-s urgery wi th preci s e s tereota cti c l oca l i za ti on of a tumor to del i ver a s i ngl e hi gh dos e or mul ti pl e, fra cti ona ted
dos es to a s ma l l i ntra cra ni a l or other ta rget. Adva nta ges i ncl ude compl ete tumor a bl a ti on where conventi ona l s urgery woul d not be pos s i bl e a nd
mi ni ma l a dvers e effects . Di s a dva nta ges i ncl ude l i mi ta ti ons i nvol vi ng the s i ze of the a rea tha t ca n be trea ted a nd the potenti a l da nger to a dja cent
ti s s ues beca us e of the hi gh dos e of ra di a ti on. In a ddi ti on, i t ca nnot be us ed i n a l l a rea s of the body. Pa ti ents mus t be i mmobi l i zed a nd the a rea
kept compl etel y s ti l l .
Brachytherapy i nvol ves pl a cement of ra di oa cti ve s eeds i nto the tumor bed i ts el f (eg, i n the pros ta te or cervi x). Typi ca l l y, pl a cement i s gui ded by CT
or ul tra s onogra phy. Bra chythera py a chi eves hi gher effecti ve ra di a ti on dos es over a l onger peri od tha n coul d be a ccompl i s hed by us e of
fra cti ona ted, externa l i rra di a ti on.
Systemic radioactive isotopes ca n di rect ra di a ti on to ca ncer i n orga ns tha t ha ve s peci fi c receptors for upta ke of the i s otope (i e, ra di oa cti ve i odi ne for
thyroi d ca ncer) or when the ra di onucl i de i s a tta ched to a monocl ona l a nti body (eg, tos i tumoma b pl us i odi ne-131 tos i tumoma b for non-Hodgki n
l ymphoma ). Is otopes ca n a l s o a ccompl i s h pa l l i a ti on of genera l i zed bony meta s ta s es (i e, ra di os tronti um for pros ta te ca ncer).
Other a gents or s tra tegi es , pa rti cul a rl y chemothera py, ca n s ens i ti ze tumor ti s s ue to the del i vered ra di a ti on a nd i ncrea s e effi ca cy.
Adverse effects: Ra di a ti on ca n da ma ge a ny i nterveni ng norma l ti s s ue.
Acute adverse effects depend on the a rea recei vi ng ra di a ti on a nd ma y i ncl ude
Letha rgy
Fa ti gue
Mucos i ti s
Derma tol ogi c ma ni fes ta ti ons (erythema , pruri tus , des qua ma ti on)
Es opha gi ti s
Pneumoni ti s
Hepa ti ti s
GI s ymptoms (na us ea , vomi ti ng, di a rrhea , tenes mus )
GU s ymptoms (frequency, urgency, dys uri a )
Cytopeni a s
Ea rl y detecti on a nd ma na gement of thes e a dvers e effects i s i mporta nt not onl y for the pa ti ent's comfort a nd qua l i ty of l i fe but a l s o to ens ure
conti nuous trea tment; prol onged i nterrupti on ca n a l l ow for tumor regrowth.
Late complications ca n i ncl ude ca ta ra cts , kera ti ti s , a nd reti na l da ma ge i f the eye i s i n the trea tment fi el d; hypopi tui ta ri s m; xeros tomi a ;
hypothyroi di s m; pneumoni ti s ; peri ca rdi ti s ; es opha gea l s tri cture; hepa ti ti s ; ul cers ; ga s tri ti s ; nephri ti s ; s teri l i ty; a nd mus cul a r contra ctures .
Ra di a ti on tha t rea ches norma l ti s s ue ca n l ea d to poor hea l i ng of the ti s s ues i f further procedures or s urgery i s neces s a ry. For exa mpl e, ra di a ti on
to the hea d a nd neck i mpa i rs recovery from denta l procedures (eg, res tora ti on, extra cti on) a nd thus s houl d be a dmi ni s tered onl y a fter a l l
neces s a ry denta l work ha s been done.
Ra di a ti on thera py ca n i ncrea s e the ri s k of devel opi ng other ca ncers , pa rti cul a rl y l eukemi a s a nd ca ncers of the thyroi d or brea s t. Pea k i nci dence
occurs 5 to 10 yr a fter expos ure a nd depends on the pa ti ent's a ge a t the ti me of trea tment. For exa mpl e, ches t i rra di a ti on for Hodgki n l ymphoma i n
a dol es cent gi rl s l ea ds to a hi gher ri s k of brea s t ca ncer tha n does the s a me trea tment for pos ta dol es cent women.
Chemotherapy
The i dea l chemothera peuti c drug woul d ta rget a nd des troy onl y ca ncer cel l s . Onl y a few s uch drugs exi s t. Common chemothera peuti c drugs a nd
thei r a dvers e effects a re des cri bed (s ee
Ta bl e 124-3).
The mos t common routes of a dmi ni s tra ti on a re IV a nd ora l . Frequent dos i ng for extended
[Table 124-3. Commonl y Us ed Anti neopl a s ti c Drugs ]
peri ods ma y neces s i ta te s ubcuta neous l y i mpl a nted venous a cces s devi ces (centra l or peri phera l ), mul ti l umen externa l ca theters , or peri phera l l y
i ns erted centra l ca theters .

Drug res i s ta nce ca n occur to chemothera py. Identi fi ed mecha ni s ms i ncl ude overexpres s i on of ta rget genes , muta ti on of ta rget genes , drug
i na cti va ti on by tumor cel l s , defecti ve a poptos i s i n tumor cel l s , a nd l os s of receptors for hormona l a gents . One of the bes t cha ra cteri zed
mecha ni s ms i s overexpres s i on of the MDR-1 gene, a cel l membra ne tra ns porter tha t ca us es effl ux of certa i n drugs (eg, vi nca a l ka l oi ds , ta xa nes ,
a nthra cycl i nes ). Attempts to a l ter MDR-1 functi on a nd thus prevent drug res i s ta nce ha ve been uns ucces s ful .
Cytotoxic drugs: Tra di ti ona l cytotoxi c chemothera py, whi ch da ma ges cel l DNA, ki l l s ma ny norma l cel l s i n a ddi ti on to ca ncer cel l s . Anti meta bol i tes ,
s uch a s 5-fl uoroura ci l a nd methotrexa te, a re cel l cycl e-s peci fi c a nd ha ve no l i nea r dos e-res pons e rel a ti ons hi p. In contra s t, other
chemothera peuti c drugs (eg, DNA cros s -l i nkers , a l s o known a s a l kyl a ti ng a gents ) ha ve a l i nea r dos e-res pons e rel a ti ons hi p, produci ng more tumor
ki l l i ng a s wel l a s more toxi ci ty a t hi gher dos es . At thei r hi ghes t dos es , DNA cros s -l i nkers ma y produce bone ma rrow a pl a s i a , neces s i ta ti ng bone
ma rrow tra ns pl a nta ti on to res tore bone ma rrow functi on.
Si ngl e-drug chemothera py ma y cure s el ected ca ncers (eg, chori oca rci noma , ha i ry cel l l eukemi a ). More commonl y, mul ti drug regi mens i ncorpora ti ng
drugs wi th di fferent mecha ni s ms of a cti on a nd di fferent toxi ci ti es a re us ed to i ncrea s e the tumor cel l ki l l , reduce dos e-rel a ted toxi ci ty, a nd
decrea s e the proba bi l i ty of drug res i s ta nce. Thes e regi mens ca n provi de s i gni fi ca nt cure ra tes (eg, i n a cute l eukemi a , tes ti cul a r ca ncer, Hodgki n
l ymphoma , non-Hodgki n l ymphoma , a nd, l es s commonl y, s ol i d tumors s uch a s s ma l l cel l l ung ca ncer a nd na s opha ryngea l ca ncer). Mul ti drug
regi mens typi ca l l y a re gi ven a s repeti ti ve cycl es of a fi xed combi na ti on of drugs . The i nterva l between cycl es s houl d be the s hortes t one tha t
a l l ows for recovery of norma l ti s s ue. Conti nuous i nfus i on ma y i ncrea s e cel l ki l l wi th s ome cel l cycl e-s peci fi c drugs (eg, 5-fl uoroura ci l ).
For ea ch pa ti ent, the proba bi l i ty of s i gni fi ca nt toxi ci ti es s houl d be wei ghed a ga i ns t the l i kel i hood of benefi t. End-orga n functi on s houl d be
a s s es s ed before chemothera peuti c drugs wi th orga n-s peci fi c toxi ci ti es a re us ed (eg, echoca rdi ogra phy before doxorubi ci n us e). Dos e modi fi ca ti on
or excl us i on of certa i n drugs ma y be neces s a ry i n pa ti ents wi th chroni c l ung di s ea s e (eg, bl eomyci n), rena l fa i l ure (eg, methotrexa te), or hepa ti c
dys functi on (eg, ta xa nes ).
Des pi te thes e preca uti ons , a dvers e effects commonl y res ul t from cytotoxi c chemothera py. The norma l ti s s ues mos t commonl y a ffected a re thos e
wi th the hi ghes t i ntri ns i c turnover ra te: bone ma rrow, ha i r fol l i cl es , a nd the GI epi thel i um.
Ima gi ng (eg, CT, MRI, PET) i s frequentl y done a fter 2 to 3 cycl es of thera py to eva l ua te res pons e to trea tment. Thera py conti nues i f there i s a cl ea r
res pons e. If the tumor progres s es des pi te thera py, the regi men i s often a mended or s topped. If the di s ea s e rema i ns s ta bl e wi th trea tment a nd
the pa ti ent ca n tol era te thera py, then a deci s i on to conti nue i s rea s ona bl e wi th the unders ta ndi ng tha t the di s ea s e wi l l eventua l l y progres s .
Hormonal therapy: Hormona l thera py us es hormone a goni s ts or a nta goni s ts to i nfl uence the cours e of ca ncer. It ma y be us ed a l one or i n
combi na ti on wi th other trea tment moda l i ti es .
Hormona l thera py i s pa rti cul a rl y us eful i n pros ta te ca ncer, whi ch grows i n res pons e to a ndrogens . Other ca ncers wi th hormone receptors on thei r
cel l s (eg, brea s t, endometri um) ca n often be pa l l i a ted by hormone a nta goni s t thera py or hormone a bl a ti on.
Us e of predni s one, a gl ucocorti cos teroi d, i s a l s o cons i dered hormona l thera py. It i s frequentl y us ed to trea t tumors deri ved from the i mmune
s ys tem (l ymphoma s , l ymphocyti c l eukemi a s , mul ti pl e myel oma ).
Biologic response modifiers: Interferons a re protei ns s ynthes i zed by cel l s of the i mmune s ys tem a s a phys i ol ogi c i mmune protecti ve res pons e to
forei gn a nti gens (vi rus es , ba cteri a , other forei gn cel l s ). In pha rma col ogi c a mounts , they ca n pa l l i a te s ome ca ncers , i ncl udi ng ha i ry cel l l eukemi a ,
chroni c myel ocyti c l eukemi a , l oca l l y a dva nced mel a noma , meta s ta ti c rena l cel l ca ncer, a nd Ka pos i 's s a rcoma . Si gni fi ca nt toxi c effects of i nterferon
i ncl ude fa ti gue, depres s i on, na us ea , l eukopeni a , chi l l s a nd fever, a nd mya l gi a s .
Interl euki ns , pri ma ri l y the l ymphoki ne IL-2 produced by a cti va ted T cel l s , ca n be us ed i n meta s ta ti c mel a noma s a nd ca n provi de modes t pa l l i a ti on
i n rena l cel l ca ncer.
Differentiating drugs: Thes e drugs i nduce di fferenti a ti on i n ca ncer cel l s . Al l -trans-reti noi c a ci d ha s been hi ghl y effecti ve i n trea ti ng a cute
promyel ocyti c l eukemi a . Other drugs i n thi s cl a s s i ncl ude a rs eni c compounds a nd the hypomethyl a ti ng a gents a za cyti di ne a nd deoxya za cyti di ne.
When us ed a l one, thes e drugs ha ve onl y tra ns i ent effects , but thei r rol e i n preventi on a nd i n combi na ti on wi th cytotoxi c drugs i s promi s i ng.
Antiangiogenesis drugs: Sol i d tumors produce growth fa ctors tha t form new bl ood ves s el s neces s a ry to s upport ongoi ng tumor growth. Severa l drugs
tha t i nhi bi t thi s proces s a re a va i l a bl e. Tha l i domi de i s a nti a ngi ogeni c, a mong i ts ma ny effects . Beva ci zuma b, a monocl ona l a nti body to va s cul a r
endothel i a l growth fa ctor (VEGF), i s effecti ve a ga i ns t rena l ca ncers a nd col on ca ncer. VEGF receptor i nhi bi tors a re a l s o a ffecti ve i n rena l ca ncer,
hepa tocel l ul a r ca ncers , a nd GI s troma l tumors .
Signal transduction inhibitors: Ma ny epi thel i a l tumors pos s es s muta ti ons tha t a cti va te s i gna l i ng pa thwa ys tha t ca us e thei r conti nuous prol i fera ti on
a nd fa i l ure to di fferenti a te. Thes e muta ted pa thwa ys i ncl ude growth fa ctor receptors a nd the downs trea m protei ns tha t tra ns mi t mes s a ges to the
cel l nucl eus from growth fa ctor receptors on the cel l s urfa ce. Three s uch drugs , i ma ti ni b (a n i nhi bi tor of the BCR-ABL tyros i ne ki na s e i n chroni c
myel ocyti c l eukemi a ) a nd erl oti ni b a nd gefi ti ni b (i nhi bi tors of the epi derma l growth fa ctor receptor), a re now i n routi ne cl i ni ca l us e. Other
i nhi bi tors of thes e s i gna l i ng pa thwa ys a re under s tudy.
Monoclonal antibodies: Monocl ona l a nti bodi es di rected a ga i ns t uni que tumor a nti gens ha ve s ome effi ca cy a ga i ns t neopl a s ti c ti s s ue (s ee a l s o p.
1060). Tra s tuzuma b, a n a nti body di rected a ga i ns t a protei n ca l l ed Her-2 or Erb-B2, pl us chemothera py ha s s hown benefi t i n meta s ta ti c brea s t
ca ncer. Anti bodi es a ga i ns t CD a nti gens expres s ed on neopl a s ti c cel l s , s uch a s CD20 a nd CD33, a re us ed to trea t pa ti ents wi th non-Hodgki n
l ymphoma (ri tuxi ma b, a nti -CD20 a nti body) a nd a cute myel ocyti c l eukemi a (gemtuzuma b, a n a nti body l i nked to a potent toxi n).
The effecti venes s of monocl ona l a nti bodi es ma y be i ncrea s ed by l i nki ng them to ra di oa cti ve nucl i de. One s uch drug, i bri tumoma b, i s us ed to trea t
non-Hodgki n l ymphoma .
Multimodality and Adjuvant Chemotherapy
In s ome tumors wi th a hi gh l i kel i hood of rel a ps e des pi te opti ma l i ni ti a l s urgery or ra di a ti on thera py, rel a ps e ma y be prevented by a ddi ti on of
a djuva nt chemothera py. Increa s i ngl y, combi ned-moda l i ty thera py (eg, ra di a ti on thera py, chemothera py, s urgery) i s us ed. It ma y permi t orga ns pa ri ng procedures a nd pres erve orga n functi on.
Adjuvant therapy: Adjuva nt thera py i s s ys temi c chemothera py or ra di a ti on thera py gi ven to era di ca te res i dua l occul t tumor a fter i ni ti a l s urgery.
Pa ti ents who ha ve a hi gh ri s k of recurrence ma y benefi t from i ts us e. Genera l cri teri a a re ba s ed on degree of l oca l extens i on of the pri ma ry tumor,
pres ence of pos i ti ve l ymph nodes , a nd certa i n morphol ogi c or bi ol ogi c cha ra cteri s ti cs of i ndi vi dua l ca ncer cel l s . Adjuva nt thera py ha s i ncrea s ed
di s ea s e-free s urvi va l a nd cure ra te i n brea s t a nd i n col orecta l ca ncer.
Neoadjuvant therapy: Neoa djuva nt thera py i s chemothera py, ra di a ti on thera py, or both gi ven before s urgi ca l res ecti on. Thi s trea tment ma y enha nce
res ecta bi l i ty a nd pres erve l oca l orga n functi on. For exa mpl e, when thi s thera py i s us ed i n hea d a nd neck, es opha gea l , or recta l ca ncer, a s ma l l er
s ubs equent res ecti on ma y be pos s i bl e. Another a dva nta ge of neoa djuva nt thera py i s i n a s s es s i ng res pons e to trea tment; i f the pri ma ry tumor
does not res pond, mi crometa s ta s es a re unl i kel y to be era di ca ted, a nd a n a l terna te regi men s houl d be cons i dered. Neoa djuva nt thera py ma y
obs cure the true pa thol ogi c s ta ge of the ca ncer by a l teri ng tumor s i ze a nd ma rgi ns a nd converti ng hi s tol ogi ca l l y pos i ti ve nodes to nega ti ve,
compl i ca ti ng cl i ni ca l s ta gi ng. The us e of neoa djuva nt thera py ha s i mproved s urvi va l i n i nfl a mma tory a nd l oca l l y a dva nced brea s t, s ta ge IIIA l ung,
na s opha ryngea l , a nd bl a dder ca ncers .
Bone Marrow Transplantation
Bone ma rrow or s tem cel l tra ns pl a nta ti on i s a n i mporta nt component of the trea tment of otherwi s e refra ctory l ymphoma s , l eukemi a s , a nd
mul ti pl e myel oma (for a n i n-depth di s cus s i on of thi s topi c, s ee p. 1132).
Gene Therapy
Geneti c modul a ti on i s under i ntens e i nves ti ga ti on. Stra tegi es i ncl ude the us e of a nti s ens e thera py, s ys temi c vi ra l vector tra ns fecti on, DNA
i njecti on i nto tumors , geneti c modul a ti on of res ected tumor cel l s to i ncrea s e thei r i mmunogeni ci ty, a nd a l tera ti on of i mmune cel l s to enha nce
thei r a nti tumor res pons e.
Management of Adverse Effects
Pa ti ents bei ng trea ted for ca ncer frequentl y experi ence a dvers e effects . Ma na gi ng thes e effects i mproves qua l i ty of l i fe.
Nausea and Vomiting
Na us ea a nd vomi ti ng a re commonl y experi enced by ca ncer pa ti ents a nd ma y res ul t from the ca ncer i ts el f (eg, pa ra neopl a s ti c s yndromes ) or from
i ts trea tment (eg, chemothera py, ra di a ti on thera py to the bra i n or a bdomen). However, refra ctory na us ea a nd vomi ti ng s houl d prompt further
i nves ti ga ti on, i ncl udi ng ba s i c l a bora tory tes ti ng (el ectrol ytes , l i ver functi on tes ts , l i pa s e) a nd x-ra ys to i nves ti ga te pos s i bl e bowel obs tructi on or
i ntra cra ni a l meta s ta s es .
Serotonin-receptor antagonists a re the mos t effecti ve drugs but a re a l s o the mos t expens i ve. Vi rtua l l y no toxi ci ty occurs wi th gra ni s etron a nd
onda ns etron a s i de from hea da che a nd orthos ta ti c hypotens i on. A 0.15-mg/kg dos e of onda ns etron or a 10-g/kg dos e of gra ni s etron i s gi ven IV 30
mi n before chemothera py. Dos es of onda ns etron ca n be repea ted 4 a nd 8 h a fter the fi rs t dos e. The effi ca cy a ga i ns t hi ghl y emetogeni c drugs , s uch
a s the pl a ti num compl exes , ca n be i mproved wi th co-a dmi ni s tra ti on of dexa metha s one (8 mg IV gi ven 30 mi n before chemothera py wi th repea t
dos es of 4 mg IV q 8 h).
A substance P/neurokinin-1 antagonist, a prepi ta nt, ca n l i mi t na us ea a nd vomi ti ng res ul ti ng from hi ghl y emetogeni c chemothera py. Dos a ge i s 125 mg
po 1 h before chemothera py on da y 1, then 80 mg po 1 h before chemothera py on da ys 2 a nd 3.
Other tra di ti ona l a nti emeti cs , i ncl udi ng phenothi a zi nes (eg, prochl orpera zi ne 10 mg IV q 8 h, prometha zi ne 12.5 to 25 mg po or IV q 8 h) a nd
metocl opra mi de (10 mg po or IV gi ven 30 mi n before chemothera py wi th repea ted dos es q 6 to 8 h), a re a l terna ti ves res tri cted to pa ti ents wi th
mi l d to modera te na us ea a nd vomi ti ng.
Dronabinol (-9-tetrahydrocannabinol [THC]) i s a n a l terna ti ve trea tment for na us ea a nd vomi ti ng ca us ed by chemothera py. THC i s the pri nci pa l
ps ychoa cti ve component of ma ri jua na . Its mecha ni s m of a nti emeti c a cti on i s unknown, but ca nna bi noi ds bi nd to opi oi d receptors i n the forebra i n
a nd ma y i ndi rectl y i nhi bi t the vomi ti ng center. Drona bi nol i s a dmi ni s tered i n dos es of 5 mg/m 2 po 1 to 3 h before chemothera py, wi th repea ted
dos es q 2 to 4 h a fter the s ta rt of chemothera py (ma xi mum of 4 to 6 dos es /da y). However, i t ha s va ri a bl e ora l bi oa va i l a bi l i ty, i s not effecti ve for
i nhi bi ti ng the na us ea a nd vomi ti ng of pl a ti num-ba s ed chemothera py regi mens , a nd ha s s i gni fi ca nt a dvers e effects (eg, drows i nes s , orthos ta ti c
hypotens i on, dry mouth, mood cha nges , vi s ua l a nd ti me s ens e a l tera ti ons ). Smoki ng ma ri jua na ma y be more effecti ve. Ma ri jua na for thi s purpos e
ca n be obta i ned l ega l l y i n s ome s ta tes . It i s us ed l es s commonl y beca us e of ba rri ers to a va i l a bi l i ty a nd beca us e ma ny pa ti ents ca nnot tol era te
s moki ng.
Benzodiazepines, s uch a s l ora zepa m (1 to 2 mg po or IV gi ven 10 to 20 mi n before chemothera py wi th repea ted dos es q 4 to 6 h prn), a re s ometi mes
hel pful for refra ctory or a nti ci pa tory na us ea a nd vomi ti ng.
Cytopenias
Anemi a , l eukopeni a , a nd thrombocytopeni a ma y devel op duri ng chemothera py or ra di a ti on thera py.
Anemia: Cl i ni ca l s ymptoms a nd decrea s ed effi ca cy of ra di a ti on thera py us ua l l y occur a t Hct l evel s of < 30% or Hb l evel s < 10 g/dL, s ooner i n pa ti ents
wi th corona ry a rtery di s ea s e or peri phera l va s cul a r di s ea s e. Recombi na nt erythropoi eti n thera py ma y be s ta rted when Hb fa l l s to < 10 mg/dL,
dependi ng on s ymptoms . In genera l , 150 to 300 uni ts /kg s c 3 ti mes /wk (a conveni ent a dul t dos e i s 10,000 uni ts ) i s effecti ve a nd reduces the need
for tra ns fus i ons . Longer-a cti ng formul a ti ons of erythropoi eti n requi re l es s frequent dos i ng (da rbepoeti n a l fa 2.25 to 4.5 g/kg s c q 1 to 2 wk).
Unneces s a ry us e of erythropoi eti n s houl d be a voi ded. Pa cked RBC tra ns fus i ons ma y be needed to rel i eve a cute ca rdi ores pi ra tory s ymptoms .
Thrombocytopenia: A pl a tel et count < 10,000/mL, es peci a l l y wi th bl eedi ng, requi res tra ns fus i on of pl a tel et concentra tes . Sma l l mol ecul es tha t
mi mi c thrombopoi eti n a re a va i l a bl e but a re not commonl y us ed i n ca ncer trea tment.
Leukocyte depl eti on of tra ns fus ed bl ood products ma y prevent a l l oi mmuni za ti on to pl a tel ets a nd s houl d be us ed i n pa ti ents who a re expected to
need pl a tel et tra ns fus i ons duri ng mul ti pl e cours es of chemothera py or for ca ndi da tes for bone ma rrow or s tem cel l tra ns pl a nta ti on. Leukocyte
depl eti on a l s o l owers the proba bi l i ty of cytomega l ovi rus bei ng tra ns ferred to the pa ti ent through WBCs . Ga mma i rra di a ti on of bl ood products to
i na cti va te l ymphocytes a nd prevent tra ns fus i on-i nduced gra ft-vs -hos t di s ea s e i s a l s o i ndi ca ted i n pa ti ents undergoi ng s everel y
i mmunos uppres s i ve chemothera py.
Neutropenia: Neutropeni a (s ee a l s o p. 948), us ua l l y defi ned by a n a bs ol ute neutrophi l count < 500/L, predi s pos es to i mmedi a te l i fe-threa teni ng
i nfecti on.
Afebri l e pa ti ents wi th neutropeni a requi re cl os e outpa ti ent fol l ow-up for detecti on of fever a nd s houl d be i ns tructed to a voi d conta ct wi th s i ck
peopl e or a rea s frequented by l a rge numbers of peopl e (eg, s hoppi ng ma l l s , a i rports ). Al though mos t pa ti ents do not requi re a nti bi oti cs , pa ti ents
wi th s evere i mmunos uppres s i on (i e, concomi ta nt T-cel l depl eti on or l os s of functi on) and l eukopeni a a re s ometi mes gi ven
tri methopri m/s ul fa methoxa zol e (one doubl e-s trength ta bl et/da y) a s prophyl a xi s for Pneumocystis jiroveci. In tra ns pl a nt pa ti ents or others recei vi ng
hi gh-dos e chemothera py, a nti vi ra l prophyl a xi s (a cycl ovi r 800 mg po bi d or 400 mg IV q 12 h) s houl d be cons i dered i f s erol ogi c tes ts a re pos i ti ve for
herpes s i mpl ex vi rus .
Fever > 38 C i n a pa ti ent wi th neutropeni a i s a n emergency. Eva l ua ti on s houl d i ncl ude i mmedi a te ches t x-ra y a nd cul tures of bl ood, s putum, uri ne,
s tool , a nd a ny s us pect s ki n l es i ons . Exa mi na ti on i ncl udes pos s i bl e a bs ces s s i tes (eg, s ki n, ea rs ), s ki n a nd mucos a for pres ence of herpeti c
l es i ons , reti na for va s cul a r l es i ons s ugges ti ve of meta s ta ti c i nfecti on, a nd ca theter s i tes . Recta l exa mi na ti on a nd us e of a recta l thermometer a re
a voi ded i f pos s i bl e i n neutropeni c pa ti ents beca us e of the ri s k of ba cteremi a .
Febri l e neutropeni c pa ti ents s houl d recei ve broa d-s pectrum a nti bi oti cs chos en on the ba s i s of the mos t l i kel y s ource. Typi ca l regi mens i ncl ude
cefepi me or cefta zi di me 2 g IV q 8 h i mmedi a tel y a fter s a mpl es for cul ture a re obta i ned. If di ffus e pul mona ry i nfi l tra tes a re pres ent, s putum
s houl d be tes ted for P. jirovecii, a nd i f pos i ti ve, a ppropri a te thera py s houl d be s ta rted. If fever res ol ves wi thi n 72 h a fter s ta rti ng empi ri c
a nti bi oti cs , then a nti bi oti cs a re conti nued unti l the a bs ol ute neutrophi l count i s > 500/L. If fever conti nues for 120 h, a nti funga l drugs s houl d be
a dded to trea t pos s i bl e funga l ca us es . Re-a s s es s ment for occul t i nfecti on (often i ncl udi ng CT of the ches t a nd a bdomen) s houl d be underta ken a t
thi s ti me.
In s el ected pa ti ents wi th neutropeni a rel a ted to chemothera py, es peci a l l y a fter hi gh-dos e chemothera py, gra nul ocyte col ony-s ti mul a ti ng fa ctor
(G-CSF) or gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor (GM-CSF) ma y be s ta rted to s horten the l eukopeni c peri od. GCSF 5 g/kg s c once/da y
up to 14 da ys a nd l onger-a cti ng forms (eg, pegfi l gra s ti m 6 mg s c s i ngl e dos e once per chemothera py cycl e) ma y be us ed to a ccel era te WBC recovery.
Thes e drugs s houl d not be a dmi ni s tered i n the fi rs t 24 h a fter chemothera py, a nd for pegfi l gra s ti m, a t l ea s t 14 da ys s houl d el a ps e unti l the next
pl a nned chemothera py dos e. Thes e drugs a re begun a t the ons et of fever or s eps i s or, i n a febri l e pa ti ents , when neutrophi l counts fa l l to <
500/L.
Ma ny centers us e outpa ti ent trea tment of s el ected l ow-ri s k pa ti ents wi th fever a nd neutropeni a . Ca ndi da tes mus t not ha ve hypotens i on, a l tered
menta l s ta tus , res pi ra tory di s tres s , uncontrol l ed pa i n, or s eri ous comorbi d i l l nes s es , s uch a s di a betes , hea rt di s ea s e, or hyperca l cemi a . The
regi men i n s uch ca s es requi res da i l y fol l ow-up a nd often i nvol ves vi s i ti ng nurs e s ervi ces a nd home a nti bi oti c i nfus i on. Some regi mens i nvol ve
ora l a nti bi oti cs , s uch a s ci profl oxa ci n 750 mg po bi d pl us a moxi ci l l i n/cl a vul a na te 875 mg po bi d or 500 mg po ti d. If no defi ned i ns ti tuti ona l
progra m for fol l ow-up a nd trea tment of neutropeni c fever i s a va i l a bl e i n a n outpa ti ent s etti ng, then hos pi ta l i za ti on i s requi red.
Gastrointestinal Effects
Oral lesions: Ora l l es i ons , s uch a s ul cers , i nfecti ons , a nd i nfl a mma ti on, a re common.
Ora l ca ndi di a s i s ca n be trea ted wi th nys ta ti n ora l s us pens i on 5 to 10 mL qi d, cl otri ma zol e troches 10 mg qi d, or fl ucona zol e 100 mg po once/da y.
Mucos i ti s from ra di a ti on thera py ca n ca us e pa i n a nd precl ude s uffi ci ent ora l i nta ke, l ea di ng to undernutri ti on a nd wei ght l os s . Ri ns es wi th
a na l ges i cs a nd topi ca l a nes theti cs (2% vi s cous l i doca i ne, 5 to 10 mL q 2 h or other commerci a l l y a va i l a bl e mi xtures ) before mea l s , a bl a nd di et
wi thout ci trus food or jui ces , a nd a voi da nce of tempera ture extremes ma y a l l ow pa ti ents to ea t a nd ma i nta i n wei ght. If not, a feedi ng tube ma y be
hel pful i f the s ma l l i ntes ti ne i s functi ona l . For s evere mucos i ti s a nd di a rrhea or a n a bnorma l l y functi oni ng i ntes ti ne, pa rentera l a l i menta ti on
ma y be needed.
Diarrhea: Di a rrhea from pel vi c ra di a ti on thera py or from chemothera py ca n be a l l evi a ted wi th a nti di a rrhea l drugs a s needed (ka ol i n/pecti n
s us pens i on 60 to 120 mL regul a r s trength, or 30 to 60 mL concentra te, po a t fi rs t s i gn of di a rrhea a nd a fter ea ch l oos e s tool or prn; l opera mi de 2 to
4 mg po; or di phenoxyl a te/a tropi ne 1 to 2 ta bl ets po). Pa ti ents who underwent a bdomi na l s urgery or recei ved broa d-s pectrum a nti bi oti cs wi thi n
the precedi ng 3 mo s houl d undergo s tool tes ti ng for Clostridium difficile.
Constipation: Cons ti pa ti on ma y res ul t from opi oi d us e. A s ti mul a nt l a xa ti ve s uch a s s enna 2 to 6 ta bl ets po a t bedti me or bi s a codyl 10 mg po a t
bedti me s houl d be i ni ti a ted when repea ted opi oi d us e i s a nti ci pa ted. Es ta bl i s hed cons ti pa ti on ca n be trea ted wi th va ri ous drugs (eg, bi s a codyl 5
to 10 mg po q 12 to 24 h, mi l k of ma gnes i a 15 to 30 mL po a t bedti me, l a ctul os e 15 to 30 mL q 12 to 24 h, Mg ci tra te 250 to 500 mL po once). Enema s
a nd s uppos i tori es s houl d be a voi ded i n pa ti ents wi th neutropeni a or thrombocytopeni a .
Anorexia: Appeti te ma y decrea s e s econda ry to ca ncer trea tment or to a pa ra neopl a s ti c s yndrome. Corti cos teroi ds (dexa metha s one 4 mg po
once/da y, predni s one 5 to 10 mg po once/da y) a nd meges trol a ceta te 400 to 800 mg once/da y a re mos t effecti ve. However, the pri ma ry benefi ts a re
va ri a bl y i ncrea s ed a ppeti te a nd wei ght ga i n, not i mproved s urvi va l or qua l i ty of l i fe.
Pain
Pa i n s houl d be a nti ci pa ted a nd a ggres s i vel y trea ted (s ee a l s o p. 1623). Us e of mul ti pl e drug cl a s s es ma y provi de better pa i n control wi th fewer or
l es s s evere a dvers e effects tha n s i ngl e drug cl a s s es . NSAIDs s houl d be a voi ded i n pa ti ents wi th thrombocytopeni a . Opi oi ds a re the ma i ns ta y of
trea tment, gi ven a round the cl ock i n genera l l y effi ci ent dos es , wi th s uppl ementa l dos es gi ven for occa s i ona l wors e pa i n. If the ora l route i s
una va i l a bl e, fenta nyl i s gi ven tra ns derma l l y. Anti emeti cs a nd prophyl a cti c bowel regi mens a re often needed wi th opi oi ds .
Neuropa thi c pa i n ca n be trea ted wi th ga ba penti n; the dos e requi red i s hi gh (up to 3.6 g/da y) but mus t be s ta rted l ow a nd then i ncrea s ed over a
few weeks . Al terna ti vel y, a tri cycl i c a nti depres s a nt (eg, nortri ptyl i ne 25 to 75 mg po a t bedti me) ma y be tri ed.
Us eful nondrug trea tments for pa i n i ncl ude foca l ra di a ti on thera py, nerve bl ocka de, a nd s urgery.
Depression
Depres s i on i s often overl ooked. It ma y occur i n res pons e to the di s ea s e (i ts s ymptoms a nd fea red cons equences ), a dvers e effects of the
trea tments , or both. Pa ti ents recei vi ng i nterferon ca n devel op depres s i on a s a n a dvers e effect. Al s o, a l opeci a a s a n a dvers e effect of ra di a ti on
thera py or chemothera py ca n contri bute to depres s i on. Fra nk di s cus s i on of a pa ti ent's fea rs ca n often rel i eve a nxi ety; depres s i on ca n often be
trea ted effecti vel y (s ee p. 1538).
Tumor Lysis Syndrome
Tumor l ys i s s yndrome ma y occur s econda ry to rel ea s e of i ntra cel l ul a r components i nto the bl oods trea m a s a res ul t of tumor cel l dea th a fter
chemothera py. It occurs ma i nl y i n a cute l eukemi a s a nd non-Hodgki n l ymphoma s but ca n a l s o occur i n other hema tol ogi c ca ncers a nd,
uncommonl y, a fter trea tment of s ol i d tumors . It s houl d be s us pected i n pa ti ents wi th a l a rge tumor burden who devel op a cute rena l fa i l ure a fter
i ni ti a l trea tment.
The di a gnos i s i s confi rmed by s ome combi na ti on of the fol l owi ng fi ndi ngs :
Rena l fa i l ure
Hypoca l cemi a (< 8 mg/dL)
Hyperuri cemi a (> 15 mg/dL)
Hyperphos pha temi a (> 8 mg/dL)
Al l opuri nol (200 to 400 mg/m 2 once/da y, ma xi mum 600 mg/da y) a nd norma l s a l i ne IV to a chi eve uri ne output > 2 L/da y s houl d be i ni ti a ted wi th
cl os e l a bora tory a nd ca rdi a c moni tori ng. Pa ti ents who ha ve a ca ncer wi th ra pi d cel l turnover s houl d recei ve a l l opuri nol for a t l ea s t 2 da ys before
a nd duri ng chemothera py; for pa ti ents wi th hi gh cel l burden, thi s regi men ca n be conti nued for 10 to 14 da ys a fter thera py. Al l s uch pa ti ents
s houl d recei ve vi gorous IV hydra ti on to es ta bl i s h a di ures i s of a t l ea s t 100 mL/h pri or to trea tment. Al though s ome phys i ci a ns a dvoca te Na HCO3 IV
to a l ka l i ni ze the uri ne a nd i ncrea s e s ol ubi l i za ti on of uri c a ci d, a l ka l i ni za ti on ma y promote Ca phos pha te depos i ti on i n pa ti ents wi th
hyperphos pha temi a , a nd a pH of a bout 7 s houl d be a voi ded. Al terna ti vel y, ra s buri ca s e, a n enzyme tha t oxi di zes uri c a ci d to a l l a ntoi n (a more
s ol ubl e mol ecul e), ma y be us ed to prevent tumor l ys i s . The dos e i s 0.15 to 0.2 mg/kg IV over 30 mi n once/da y for 5 to 7 da ys , typi ca l l y i ni ti a ted 4 to
24 h before the fi rs t chemothera py trea tment. Advers e effects ma y i ncl ude a na phyl a xi s , hemol ys i s , hemogl obi nuri a , a nd methemogl obi nemi a .
Cachexia
Ca chexi a i s wa s ti ng of both a di pos e a nd s kel eta l mus cl e. It occurs i n ma ny condi ti ons a nd i s common wi th ma ny ca ncers when remi s s i on or
control fa i l s . Some ca ncers , es peci a l l y pa ncrea ti c a nd ga s tri c ca ncers , ca us e profound ca chexi a . Affected pa ti ents ma y l os e 10 to 20% of body
wei ght. Men tend to experi ence wors e ca chexi a wi th ca ncer tha n do women. Nei ther tumor s i ze nor the extent of meta s ta ti c di s ea s e predi cts the
degree of ca chexi a . Ca chexi a i s a s s oci a ted wi th reduced res pons e to chemothera py, poor functi ona l performa nce, a nd i ncrea s ed morta l i ty.
The pri ma ry ca us e of ca chexi a i s not a norexi a or decrea s ed ca l ori c i nta ke. Ra ther, thi s compl ex meta bol i c condi ti on i nvol ves i ncrea s ed ti s s ue
ca ta bol i s m. Protei n s ynthes i s i s decrea s ed a nd degra da ti on i ncrea s ed. Ca chexi a i s medi a ted by certa i n cytoki nes , es peci a l l y tumor necros i s
fa ctor-, IL-1b, a nd IL-6, whi ch a re produced by tumor cel l s a nd hos t cel l s i n the ti s s ue ma s s . The ATP-ubi qui ti n-protea s e pa thwa y pl a ys a rol e a s
wel l .
Ca chexi a i s ea s y to recogni ze, pri ma ri l y by wei ght l os s , whi ch i s mos t a ppa rent wi th l os s of tempora l i s mus cl e ma s s i n the fa ce. The l os s of
s ubcuta neous fa t i ncrea s es the ri s k of pres s ure ul cers over bony promi nences .
Treatment
Trea tment i nvol ves trea tment of the ca ncer. If the ca ncer ca n be control l ed or cured, rega rdl es s of moda l i ty, ca chexi a res ol ves .
Addi ti ona l ca l ori c s uppl ementa ti on does not rel i eve ca chexi a . Any wei ght ga i n i s us ua l l y mi ni ma l a nd i s l i kel y to cons i s t of a di pos e ti s s ue ra ther
tha n mus cl e. Nei ther functi on nor prognos i s i s i mproved. Thus , i n mos t ca checti c pa ti ents wi th ca ncer, hi gh-ca l ori e s uppl ementa ti on i s not
recommended, a nd pa rentera l nutri ti ona l s upport i s not i ndi ca ted, except i n s i tua ti ons where ora l i nta ke of a dequa te nutri ti on i s i mpos s i bl e.
However, other trea tments ca n mi ti ga te ca chexi a a nd i mprove functi on. Corti cos teroi ds i ncrea s e a ppeti te a nd ma y i mprove a s ens e of wel l -bei ng
but do l i ttl e to i ncrea s e body wei ght. Li kewi s e, ca nna bi noi ds (ma ri jua na , drona bi nol ) i ncrea s e a ppeti te but not wei ght. Proges togens , s uch a s
meges trol a ceta te, 40 mg po bi d or ti d, ma y i ncrea s e both a ppeti te a nd body wei ght. Drugs to a l ter cytoki ne producti on a nd effects a re bei ng
s tudi ed.
Incurable Cancer
Even i n ca s es of i ncura bl e ca ncer, pa l l i a ti ve or experi menta l thera py ma y i mprove qua l i ty a nd extent of l i fe. But i n ma ny ca s es , phys i ci a ns mus t
res i s t the urge to a dmi ni s ter a rel a ti vel y i neffecti ve chemothera py drug. A better choi ce i s to di s cus s the l i kel y res ul ts of s uch trea tments a nd to
s et rea l i s ti c goa l s wi th the pa ti ent. A pa ti ent's deci s i on to forgo ca ncer trea tment mus t be res pected. Another a l terna ti ve i s the cl i ni ca l tri a l , the
ri s ks a nd benefi ts of whi ch des erve di s cus s i on.

Rega rdl es s of prognos i s , qua l i ty of l i fe i n ca ncer pa ti ents ma y i mprove wi th nutri ti ona l s upport, effecti ve pa i n ma na gement, other s ymptoma ti c
pa l l i a ti ve ca re, a nd ps ychi a tri c a nd s oci a l s upport of the pa ti ent a nd fa mi l y. Above a l l , pa ti ents mus t know tha t the cl i ni ca l tea m wi l l rema i n
i nvol ved a nd a cces s i bl e for s upporti ve ca re, rega rdl es s of the prognos i s . Hos pi ce or other rel a ted end-of-l i fe ca re progra ms a re i mporta nt pa rts of
ca ncer trea tment. For more i nforma ti on perta i ni ng to pa ti ents wi th i ncura bl e di s ea s e, s ee Ch. 353.
10 - Immunology; Allergic Disorders

Chapter 125. Biology of the Immune System
Introduction
The i mmune s ys tem di s ti ngui s hes s el f from nons el f a nd el i mi na tes potenti a l l y ha rmful nons el f mol ecul es a nd cel l s from the body. The i mmune
s ys tem a l s o ha s the ca pa ci ty to recogni ze a nd des troy a bnorma l cel l s tha t deri ve from hos t ti s s ues (s ee p. 1057). Any mol ecul e ca pa bl e of bei ng
recogni zed by the i mmune s ys tem i s cons i dered a n a nti gen (Ag).
The s ki n, cornea , a nd mucos a of the res pi ra tory, GI, a nd GU tra cts form a phys i ca l ba rri er tha t i s the body's fi rs t l i ne of defens e. Some of thes e
ba rri ers a l s o i nvol ve i mmune functi ons a nd other a cti ve defens es :
Outer, kera ti ni zed epi dermi s : Kera ti nocytes i n the s ki n s ecrete a nti mi crobi a l pepti des (defens i ns ), a nd s eba ceous a nd s wea t gl a nds s ecrete
mi crobe-i nhi bi ti ng s ubs ta nces (eg, l a cti c a ci d, fa tty a ci ds ). Al s o, ma ny i mmune cel l s (eg, ma s t cel l s , i ntra epi thel i a l l ymphocytes , Ag-s a mpl i ng
La ngerha ns ' cel l s ) res i de i n the s ki n.
Mucos a of the res pi ra tory, GI, a nd GU tra cts : The mucus conta i ns a nti mi crobi a l s ubs ta nces , s uch a s l ys ozyme, l a ctoferri n, a nd s ecretory IgA
a nti body (SIgA).
Brea chi ng of a na tomi c ba rri ers ca n tri gger 2 types of i mmune res pons e: i nna te a nd a cqui red. Ma ny mol ecul a r components (eg, compl ement,
cytoki nes , a cute pha s e protei ns ) pa rti ci pa te i n both i nna te a nd a cqui red i mmuni ty.
Innate immunity: Inna te (na tura l ) i mmuni ty does not requi re pri or expos ure to a n Ag (i e, memory) to be effecti ve. Thus , i t ca n res pond i mmedi a tel y
to a n i nva der. However, i t recogni zes ma i nl y Ag mol ecul es tha t a re broa dl y di s tri buted ra ther tha n s peci fi c to one orga ni s m or cel l . Components
i ncl ude
Pha gocyti c cel l s
Ag-pres enti ng cel l s
Na tura l ki l l er (NK) cel l s
Pol ymorphonucl ea r l eukocytes
Pha gocyti c cel l s (neutrophi l s a nd monocytes i n bl ood, ma cropha ges a nd dendri ti c cel l s i n ti s s ues ) i nges t a nd des troy i nva di ng Ags . Atta ck by
pha gocyti c cel l s ca n be fa ci l i ta ted when Ags a re coa ted wi th a nti body (Ab), whi ch i s produced a s pa rt of a cqui red i mmuni ty. Ag-pres enti ng cel l s
(ma cropha ges , dendri ti c cel l s ) pres ent fra gments of i nges ted Ags to T cel l s (whi ch a re pa rt of a cqui red i mmuni ty). Na tura l ki l l er cel l s ki l l vi rus i nfected cel l s a nd s ome tumor cel l s . Certa i n pol ymorphonucl ea r l eukocytes (eos i nophi l s , ba s ophi l s , ma s t cel l s ) rel ea s e i nfl a mma tory medi a tors .
Acquired immunity: Acqui red (a da pti ve) i mmuni ty requi res pri or expos ure to a n Ag a nd thus ta kes ti me to devel op a fter the i ni ti a l encounter wi th a
new i nva der. Therea fter, res pons e i s qui ck. The s ys tem remembers pa s t expos ures a nd i s Ag-s peci fi c. Components i ncl ude
T cel l s
B cel l s
Acqui red i mmuni ty deri ved from certa i n T-cel l res pons es i s ca l l ed cel l -medi a ted i mmuni ty. Immuni ty deri ved from B-cel l res pons es i s ca l l ed
humora l i mmuni ty beca us e B cel l s s ecrete s ol ubl e Ag-s peci fi c Ab. B cel l s a nd T cel l s work together to des troy i nva ders . Some of thes e cel l s do not
di rectl y des troy i nva ders but i ns tea d ena bl e other WBCs to recogni ze a nd des troy i nva ders .
Immune Response
Succes s ful i mmune defens e requi res a cti va ti on, regul a ti on, a nd res ol uti on of the i mmune res pons e.
Activation: The i mmune s ys tem i s a cti va ted when a forei gn Ag i s recogni zed by ci rcul a ti ng Abs or cel l s urfa ce receptors . Thes e receptors ma y be
hi ghl y s peci fi c (Ab expres s ed on B cel l s or T-cel l receptors ) or broa dl y s peci fi c (eg, pa ttern-recogni ti on receptors s uch a s Tol l -l i ke, ma nnos e, a nd
s ca venger receptors on dendri ti c a nd other cel l s ). Broa dl y s peci fi c receptors recogni ze common mi crobi a l pa thogen-a s s oci a ted mol ecul a r pa tterns
i n l i ga nds , s uch a s gra m-nega ti ve l i popol ys a ccha ri de, gra m-pos i ti ve pepti dogl yca ns , ba cteri a l fl a gel l i n, unmethyl a ted cytos i ne-gua nos i ne
di nucl eoti des (CpG moti fs ), a nd vi ra l doubl e-s tra nded RNA. Acti va ti on ma y a l s o occur when Ab-Ag a nd compl ement-mi croorga ni s m compl exes bi nd
to s urfa ce receptors for the crys ta l l i za bl e fra gment (Fc) regi on of IgG (FcR) a nd for C3b a nd i C3b.
Once recogni zed, a n Ag, Ag-Ab compl ex, or compl ement-mi croorga ni s m compl ex i s pha gocytos ed. Mos t mi croorga ni s ms a re ki l l ed a fter they a re
pha gocytos ed, but others (eg, mycoba cteri a ) i nhi bi t the pha gocyte's a bi l i ty to ki l l them once they a re engul fed. In s uch ca s es , T cel l -deri ved
cytoki nes , pa rti cul a rl y i nterferon- (IFN-), s ti mul a te the pha gocyte to produce l yti c enzymes a nd other mi crobi ci da l ma cropha ge products , whi ch
ki l l the mi croorga ni s m.
Unl es s Ag i s ra pi dl y pha gocytos ed a nd enti rel y degra ded (a n uncommon event), the a cqui red i mmune res pons e i s recrui ted. Thi s res pons e begi ns
i n the s pl een for ci rcul a ti ng Ag, i n regi ona l l ymph nodes for ti s s ue Ag, a nd i n mucos a -a s s oci a ted l ymphoi d ti s s ues (eg, tons i l s , a denoi ds , Peyer's
pa tches ) for mucos a l Ag. For exa mpl e, La ngerha ns ' dendri ti c cel l s i n the s ki n pha gocytos e Ag a nd mi gra te to l oca l l ymph nodes ; there, pepti des
deri ved from the Ag a re expres s ed on the cel l s urfa ce wi thi n cl a s s II ma jor hi s tocompa ti bi l i ty compl ex (MHC) mol ecul es , whi ch pres ent the pepti de
to CD4 hel per T (TH ) cel l s . When the TH cel l enga ges the MHC-pepti de compl ex a nd recei ves va ri ous cos ti mul a tory s i gna l s , i t i s a cti va ted to expres s
receptors for the cytoki ne IL-2 a nd s ecretes s evera l cytoki nes . Ea ch s ubs et of TH cel l s s ecretes di fferent s ubs ta nces , whi ch effect di fferent i mmune
res pons e (s ee p. 1081).
Cl a s s II MHC mol ecul es pres ent pepti des deri ved from extra cel l ul a r (exogenous ) Ag to CD4 TH cel l s ; i n contra s t, cl a s s I MHC mol ecul es pres ent
pepti des deri ved from i ntra cel l ul a r (endogenous ) Ag (eg, vi rus es ) to CD8 cytotoxi c T cel l s . The a cti va ted cytotoxi c T cel l then ki l l s the i nfected cel l .
Regulation: The i mmune res pons e mus t be regul a ted to prevent overwhel mi ng da ma ge to the hos t (eg, a na phyl a xi s , wi des prea d ti s s ue
des tructi on). Regul a tory T cel l s (mos t of whi ch expres s Foxp3 tra ns cri pti on fa ctor) hel p control the i mmune res pons e vi a s ecreti on of
i mmunos uppres s i ve cytoki nes , s uch a s IL-10 a nd tra ns formi ng growth fa ctor- (TGF-), or vi a a poorl y defi ned cel l conta ct mecha ni s m. Thes e
regul a tory cel l s hel p prevent a utoi mmune res pons es a nd proba bl y hel p res ol ve ongoi ng res pons es to nons el f Ag.
Resolution: The i mmune res pons e res ol ves when Ag i s s eques tered a nd el i mi na ted from the body. Wi thout s ti mul a ti on by Ag, cytoki ne s ecreti on
cea s es , a nd a cti va ted cytotoxi c T cel l s undergo a poptos i s . Apoptos i s ta gs a cel l for i mmedi a te pha gocytos i s , whi ch prevents s pi l l -a ge of the
cel l ul a r contents a nd devel opment of s ubs equent i nfl a mma ti on. T a nd B cel l s tha t ha ve di fferenti a ted i nto memory cel l s a re s pa red thi s fa te.
Wi th a gi ng, the i mmune s ys tem becomes l es s effecti ve i n the fol l owi ng wa ys :
The i mmune s ys tem becomes l es s a bl e to di s ti ngui s h s el f from nons el f, ma ki ng a utoi mmune di s orders more common.
Ma cropha ges des troy ba cteri a , ca ncer cel l s , a nd other Ag more s l owl y, pos s i bl y contri buti ng to the i ncrea s ed i nci dence of ca ncer a mong the
el derl y.
T cel l s res pond l es s qui ckl y to Ag.
There a re fewer l ymphocytes tha t ca n res pond to new Ag.
The a gi ng body produces l es s compl ement i n res pons e to ba cteri a l i nfecti ons .
Les s Ab i s produced i n res pons e to Ag, a nd Ab i s l es s a bl e to a tta ch to Ag, pos s i bl y contri buti ng to the i ncrea s ed i nci dence of pneumoni a ,
i nfl uenza , i nfecti ous endoca rdi ti s , a nd teta nus a nd the i ncrea s ed ri s k of dea th due to thes e di s orders a mong the el derl y. Thes e cha nges ma y
a l s o pa rtl y expl a i n why va cci nes a re l es s effecti ve i n the el derl y.
Components of the Immune System
The i mmune s ys tem cons i s ts of cel l ul a r a nd mol ecul a r components tha t work together to des troy a nti gens (Ags ).
Antigen-Presenting Cells
Al though s ome Ags ca n s ti mul a te the i mmune res pons e di rectl y, T cel l -dependent a cqui red i mmune res pons es typi ca l l y requi re a nti genpres enti ng cel l s (APCs ) to pres ent Ag-deri ved pepti des wi thi n ma jor hi s tocompa ti bi l i ty compl ex (MHC) mol ecul es . Intra cel l ul a r Ag (eg, vi rus es ) ca n
be proces s ed a nd pres ented to CD8 cytotoxi c T cel l s by a ny nucl ea ted cel l beca us e a l l nucl ea ted cel l s expres s cl a s s I MHC mol ecul es . However,
extra cel l ul a r Ag mus t be proces s ed i nto pepti des a nd compl exed wi th s urfa ce cl a s s II MHC mol ecul es on profes s i ona l APCs to be recogni zed by
CD4 hel per T (TH ) cel l s . The fol l owi ng cel l s cons ti tuti vel y expres s cl a s s II MHC mol ecul es a nd therefore a ct a s profes s i ona l APCs :
B cel l s
Monocytes
Ma cropha ges
Dendri ti c cel l s
Monocytes i n the ci rcul a ti on a re precurs ors to ti s s ue ma cropha ges . Monocytes mi gra te i nto ti s s ues , where over a bout 8 h, they devel op i nto
ma cropha ges under the i nfl uence of ma cropha ge col ony-s ti mul a ti ng fa ctor (M-CSF), s ecreted by va ri ous cel l types (eg, endothel i a l cel l s ,
fi brobl a s ts ). At i nfecti on s i tes , a cti va ted T cel l s s ecrete cytoki nes (eg, i nterferon- [IFN-]) tha t i nduce producti on of ma cropha ge mi gra ti on
i nhi bi tory fa ctor, preventi ng ma cropha ges from l ea vi ng.
Macrophages a re a cti va ted by IFN- a nd gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor (GM-CSF). Acti va ted ma cropha ges ki l l i ntra cel l ul a r
orga ni s ms a nd s ecrete IL-1 a nd tumor necros i s fa ctor- (TNF-). Thes e cytoki nes potenti a te the s ecreti on of IFN- a nd GM-CSF a nd i ncrea s e the
expres s i on of a dhes i on mol ecul es on endothel i a l cel l s , fa ci l i ta ti ng l eukocyte i nfl ux a nd des tructi on of pa thogens .
Dendritic cells a re pres ent i n the s ki n (a s La ngerha ns ' cel l s ), l ymph nodes , a nd ti s s ues throughout the body. Dendri ti c cel l s i n the s ki n a ct a s
s enti nel APCs , ta ki ng up Ag, then tra vel to l oca l l ymph nodes where they ca n a cti va te T cel l s . Fol l i cul a r dendri ti c cel l s a re a di s ti nct l i nea ge, do not
expres s cl a s s II MHC mol ecul es , a nd therefore do not pres ent Ag to TH cel l s . However, they ha ve receptors for the crys ta l l i za bl e fra gment (Fc)
regi on of IgG a nd for compl ement, whi ch ena bl e them to bi nd wi th i mmune compl exes a nd pres ent the compl ex to B cel l s i n germi na l centers of
s econda ry l ymphoi d orga ns .
Polymorphonuclear Leukocytes
Pol ymorphonucl ea r (PMN) l eukocytes , a l s o ca l l ed gra nul ocytes beca us e thei r cytopl a s m conta i ns gra nul es , i ncl ude
Neutrophi l s
Eos i nophi l s
Ba s ophi l s
Ma s t cel l s
Al l , except for ma s t cel l s , occur i n the ci rcul a ti on, a nd a l l ha ve mul ti l obed nucl ei . Ma s t cel l s a re ti s s ue-ba s ed a nd functi ona l l y s i mi l a r to
ci rcul a ti ng bl ood ba s ophi l s .
Neutrophils cons ti tute 40 to 70% of tota l WBCs ; they a re a fi rs t l i ne of defens e a ga i ns t i nfecti on. Ma ture neutrophi l s ha ve a ha l f-l i fe of a bout 2 to 3
da ys . Duri ng a cute i nfl a mma tory res pons es (eg, to i nfecti on), neutrophi l s , dra wn by chemota cti c fa ctors a nd a l erted by the expres s i on of a dhes i on
mol ecul es on bl ood ves s el endothel i um, l ea ve the ci rcul a ti on a nd enter ti s s ues . Thei r purpos e i s to pha gocytos e a nd di ges t pa thogens .
Mi croorga ni s ms a re ki l l ed when pha gocytos i s genera tes l yti c enzymes a nd rea cti ve O2 compounds (eg, s uperoxi de, hypochl orous a ci d) a nd tri ggers
rel ea s e of gra nul e contents (eg, defens i ns , protea s es , ba cteri ci da l permea bi l i ty-i ncrea s i ng protei n, l a ctoferri n, a nd l ys ozymes ). DNA a nd hi s tones
a re a l s o rel ea s ed, a nd they, wi th gra nul e contents s uch a s el a s ta s e, genera te fi bers i n the s urroundi ng ti s s ues ; the fi bers ma y fa ci l i ta te ki l l i ng by
tra ppi ng ba cteri a a nd focus i ng enzyme a cti vi ty.
Eosinophils cons ti tute up to 5% of WBCs . They ta rget orga ni s ms too l a rge to be engul fed; they ki l l by s ecreti ng toxi c s ubs ta nces (eg, rea cti ve O2
compounds s i mi l a r to thos e produced i n neutrophi l s ), ma jor ba s i c protei n (whi ch i s toxi c to pa ra s i tes ), eos i nophi l ca ti oni c protei n, a nd s evera l
enzymes . Eos i nophi l s a re a l s o a ma jor s ource of i nfl a mma tory medi a tors (eg, pros ta gl a ndi ns , l eukotri enes , pl a tel et-a cti va ti ng fa ctor, ma ny
cytoki nes ).
Basophils cons ti tute < 5% of WBCs a nd s ha re s evera l cha ra cteri s ti cs wi th ma s t cel l s , a l though the 2 cel l types ha ve di s ti nct l i nea ges . Both ha ve
hi gh-a ffi ni ty receptors for IgE ca l l ed FcRI. When thes e cel l s encounter certa i n Ags , the bi va l ent IgE mol ecul es bound to the receptors become
cros s -l i nked, tri ggeri ng cel l degra nul a ti on wi th rel ea s e of preformed i nfl a mma tory medi a tors (eg, hi s ta mi ne, pl a tel et-a cti va ti ng fa ctor) a nd
genera ti on of newl y s ynthes i zed medi a tors (eg, l eukotri enes , pros ta gl a ndi ns , thromboxa nes ).
Mast cells occur i n di fferent ti s s ues of the body. Mucos a l ma s t cel l gra nul es conta i n trypta s e a nd chondroi ti n s ul fa te; connecti ve ti s s ue ma s t cel l
gra nul es conta i n trypta s e, chyma s e, a nd hepa ri n. By rel ea s i ng thes e medi a tors , ma s t cel l s pl a y a key rol e i n genera ti ng protecti ve a cute
i nfl a mma tory res pons es ; ba s ophi l s a nd ma s t cel l s a re the s ource of type I hypers ens i ti vi ty rea cti ons a s s oci a ted wi th a topi c a l l ergy (s ee p. 1113).
Degra nul a ti on ca n be tri ggered by cros s -l i nki ng of IgE receptors or by the a na phyl a toxi n compl ement fra gments C3a a nd C5a .
Cytotoxic Leukocytes
Cytotoxi c l eukocytes i ncl ude
Na tura l ki l l er cel l s
Lymphoki ne-a cti va ted ki l l ers
Natural killer (NK) cells: Typi ca l NK cel l s cons ti tute 5 to 15% of peri phera l bl ood mononucl ea r cel l s . They ha ve a round nucl eus a nd gra nul a r
cytopl a s m a nd i nduce a poptos i s i n i nfected or a bnorma l cel l s by a number of pa thwa ys . As cel l s of the i nna te res pons e, they l a ck a nti gen-s peci fi c
receptors a nd i mmunol ogi c memory. NK cel l s a re bes t cha ra cteri zed by CD2+, CD3-, CD4-, CD8+, CD16+(a receptor for IgG-Fc), a nd CD56+ s urfa ce
ma rkers .
Typi ca l NK cel l s a re thought to be i mporta nt for tumor s urvei l l a nce. NK cel l s expres s both a cti va ti ng a nd i nhi bi tory receptors . The a cti va ti ng
receptors on NK cel l s ca n recogni ze numerous l i ga nds on ta rget cel l s (eg, MHC cl a s s I-rel a ted cha i n A [MICA] a nd cha i n B [MICB]); the i nhi bi tory
receptors on NK cel l s recogni ze MHC cl a s s I mol ecul es . NK cel l s ca n ki l l thei r ta rget onl y when there i s no s trong s i gna l from i nhi bi tory receptors .
MHC cl a s s I mol ecul es (norma l l y expres s ed on nucl ea ted cel l s ) therefore prevent des tructi on of cel l s ; thei r a bs ence i ndi ca tes tha t the cel l i s
i nfected wi th certa i n vi rus es tha t i nhi bi t MHC expres s i on or ha s l os t MHC expres s i on beca us e ca ncer ha s cha nged the cel l .
NK cel l s ca n a l s o s ecrete s evera l cytoki nes (eg, IFN-, IL-1, TNF-); they a re a ma jor s ource of IFN-. By s ecreti ng IFN-, NK cel l s ca n i nfl uence the
a cqui red i mmune s ys tem by promoti ng di fferenti a ti on of type 1 hel per T (TH 1) cel l s a nd i nhi bi ti ng tha t of type 2 (TH 2) cel l s .
Lymphokine-activated killers (LAK): Some l eukocytes devel op i nto potent l ymphoki ne-a cti va ted ki l l ers , ca pa bl e of ki l l i ng a wi de s pectrum of tumor
ta rget cel l s a nd a bnorma l l ymphocytes (eg, i nfected wi th certa i n vi rus es ). Thes e cel l s a re a phenomenon ra ther tha n a uni que s ubs et of cel l s . LAK
precurs ors a re heterogeneous but ca n be cl a s s i fi ed pri ma ri l y a s NK-l i ke (mos t common) or T-cel l -l i ke.
Lymphocytes
The 2 ma i n types of l ymphocytes a re
B cel l s (whi ch ma ture i n bone ma rrow)
T cel l s (whi ch ma ture i n the thymus )
They a re morphol ogi ca l l y i ndi s ti ngui s ha bl e but ha ve di fferent i mmune functi ons . They ca n be di s ti ngui s hed by Ag-s peci fi c s urfa ce receptors a nd
mol ecul es ca l l ed cl us ters of di fferenti a ti on (CDs ), whos e pres ence a nd a bs ence defi ne s ome s ubs ets . More tha n 300 CDs ha ve been i denti fi ed
(for further i nforma ti on on CD Ags , s ee the Huma n Cel l Di fferenti a ti on Mol ecul es web s i te a t www.hl da 8.org/). Ea ch l ymphocyte recogni zes a
s peci fi c Ag vi a s urfa ce receptors .
B cells: About 5 to 15% of l ymphocytes i n the bl ood a re B cel l s ; they a re a l s o pres ent i n the s pl een, l ymph nodes , a nd mucos a -a s s oci a ted l ymphoi d
ti s s ues . B cel l s ca n pres ent Ag to T cel l s , but thei r pri ma ry functi on i s to devel op i nto pl a s ma cel l s , whi ch ma nufa cture a nd s ecrete a nti bodi es
(Abs s ee p. 1083).
After ra ndom rea rra ngement of the genes tha t encode i mmunogl obul i n (Ig), B cel l s ha ve the potenti a l to recogni ze a n a l mos t l i mi tl es s number of
uni que Ags . Gene rea rra ngement occurs i n progra mmed s teps i n the bone ma rrow duri ng B-cel l devel opment. The proces s s ta rts wi th a commi tted
s tem cel l , conti nues through pro-B a nd pre-B cel l s ta ges , a nd res ul ts i n a n i mma ture B cel l . If a n i mma ture B cel l i ntera cts wi th Ag, i t ma y become
i na cti va ted (tol era nt) or be el i mi na ted (by a poptos i s ). Imma ture B cel l s tha t a re not i na cti va ted or el i mi na ted ma y conti nue to devel op i nto
ma ture na i ve B cel l s , l ea ve the ma rrow, a nd enter peri phera l l ymphoi d orga ns , where they ma y encounter Ag. Thei r res pons e to Ag ha s 2 s ta ges :
Primary immune response: When ma ture na i ve B cel l s fi rs t encounter Ag, they become l ymphobl a s ts , undergo cl ona l prol i fera ti on, a nd
di fferenti a te i nto memory cel l s , whi ch ca n res pond to the s a me Ag i n the future, or i nto ma ture Ab-s ecreti ng pl a s ma cel l s . After fi rs t expos ure,
there i s a l a tent peri od of da ys before Ab i s produced. Then, onl y IgM i s produced. After tha t, wi th the hel p of T cel l s , B cel l s ca n further
rea rra nge thei r Ig genes a nd s wi tch to producti on of IgG, IgA, or IgE. Thus , a fter fi rs t expos ure, the res pons e i s s l ow a nd provi des l i mi ted
protecti ve i mmuni ty.
Secondary (anamnestic or booster) immune response: When memory B a nd TH cel l s a re reexpos ed to the Ag, the memory B cel l s ra pi dl y prol i fera te,
di fferenti a te i nto ma ture pl a s ma cel l s , a nd promptl y produce l a rge a mounts of Ab (chi efl y IgG beca us e of a T cel l -i nduced i s otype s wi tch). The
Ab i s rel ea s ed i nto the bl ood a nd other ti s s ues , where i t ca n rea ct wi th Ag. Thus , a fter reexpos ure, the i mmune res pons e i s fa s ter a nd more
effecti ve.
T cells: T cel l s devel op from bone ma rrow s tem cel l s tha t tra vel to the thymus , where they go through ri gorous s el ecti on. There a re 3 ma i n types of T
cel l :
Hel per
Regul a tory
Cytotoxi c
In s el ecti on, T cel l s tha t rea ct to s el f Ag pres ented by s el f MHC mol ecul es or to s el f MHC mol ecul es (rega rdl es s of the Ag pres ented) a re
el i mi na ted by a poptos i s . Onl y T cel l s tha t ca n recogni ze nons el f Ag compl exed to s el f MHC mol ecul es s urvi ve; they l ea ve the thymus for peri phera l
bl ood a nd l ymphoi d ti s s ues .
Mos t ma ture T cel l s expres s ei ther CD4 or CD8 a nd ha ve a n Ag-bi ndi ng, Ig-l i ke s urfa ce receptor ca l l ed the T-cel l receptor (TCR). Genes tha t encode
the TCR, l i ke Ig genes , a re rea rra nged, res ul ti ng i n defi ned s peci fi ci ty a nd a ffi ni ty for the Ag pepti de di s pl a yed i n the MHC mol ecul e of a n APC. As
for B cel l s , the number of T-cel l s peci fi ci ti es i s a l mos t l i mi tl es s .
For T cel l s to be a cti va ted, the TCR mus t enga ge wi th Ag-MHC. Cos ti mul a tory a cces s ory mol ecul es mus t a l s o i ntera ct; otherwi s e, the T cel l becomes
a nergi c or di es by a poptos i s . Some a cces s ory mol ecul es (eg, CTLA-4) i nhi bi t previ ous l y a cti va ted T cel l s a nd thus da mpen the i mmune res pons e.
Helper T (TH) cells a re us ua l l y CD4 but ma y be CD8. They di fferenti a te from TH 0 cel l s i nto one of the fol l owi ng:
TH 1 cel l s : In genera l , TH 1 cel l s promote cel l -medi a ted i mmuni ty vi a cytotoxi c T cel l s a nd ma cropha ges .
TH 2 cel l s : TH 2 cel l s promote Ab producti on by B cel l s (humora l i mmuni ty).
TH 17 cel l s : TH 17 cel l s promote ti s s ue i nfl a mma ti on.
Ea ch cel l type s ecretes s evera l cytoki nes (s ee
Ta bl e 125-1). Di fferent pa tterns of cytoki ne producti on i denti fy other TH -cel l functi ona l phenotypes .
The di s ti ncti on between the di fferent TH cel l s i s cl i ni ca l l y rel eva nt. For exa mpl e, a TH 1 res pons e domi na tes i n tubercul oi d l epros y, a nd a TH 2
res pons e domi na tes i n l eproma tous l epros y. A TH 1 res pons e i s cha ra cteri s ti c of certa i n a utoi mmune di s orders (eg, type 1 di a betes , mul ti pl e
s cl eros i s ), a nd a TH 2 res pons e promotes IgE producti on a nd devel opment of a l l ergi c di s orders , a s wel l a s hel ps B cel l s produce a utoa nti bodi es i n
s ome a utoi mmune di s orders (eg, Gra ves ' di s ea s e, mya s theni a gra vi s ). TH 17 cel l s , vi a thei r rol e i n i nfl a mma ti on, ma y a l s o contri bute to
a utoi mmune di s orders .
Regulatory T cells medi a te s uppres s i on of i mmune res pons es . The proces s i nvol ves functi ona l s ubs ets of CD4 T cel l s tha t ei ther s ecrete cytoki nes
wi th i mmunos uppres s i ve properti es or s uppres s the i mmune res pons e by poorl y defi ned mecha ni s ms tha t requi re cel l -to-cel l conta ct. Some
regul a tory T cel l s expres s the CD8 T-cel l phenotype.
[Table 125-1. Functi ons of T Cel l s ]
Cytotoxic T (TC) cells a re us ua l l y CD8 but ma y be CD4; they a re vi ta l for el i mi na ti ng i ntra cel l ul a r pa thogens , es peci a l l y vi rus es . TC cel l s pl a y a rol e i n
orga n tra ns pl a nt rejecti on.
TC-cel l devel opment i nvol ves 3 pha s es :
A precurs or cel l tha t, when a ppropri a tel y s ti mul a ted, ca n di fferenti a te i nto a TC cel l
An effector cel l tha t ha s di fferenti a ted a nd ca n ki l l i ts a ppropri a te ta rget
A memory cel l tha t i s qui es cent (no l onger s ti mul a ted) but i s rea dy to become a n effector when res ti mul a ted by the ori gi na l Ag-MHC combi na ti on
Ful l y a cti va ted TC cel l s , l i ke NK cel l s , ca n ki l l a n i nfected ta rget cel l by i nduci ng a poptos i s .
TC cel l s ma y be
Syngenei c: Genera ted i n res pons e to s el f (a utol ogous ) cel l s modi fi ed by vi ra l i nfecti on or other forei gn protei ns
Al l ogenei c: Genera ted i n res pons e to cel l s tha t expres s forei gn MHC products (eg, i n orga n tra ns pl a nta ti on when the donor's MHC mol ecul es
di ffer from the reci pi ent's ) Some TC cel l s ca n di rectl y recogni ze forei gn MHC (di rect pa thwa y); others ma y recogni ze fra gments of forei gn MHC
pres ented by s el f MHC mol ecul es of the tra ns pl a nt reci pi ent (i ndi rect pa thwa y).
NK T cells a re a di s ti nct s ubs et of T cel l s . Acti va ted NK T cel l s s ecrete IL-4 a nd IFN- a nd ma y hel p regul a te i mmune res pons es .
Antibodies
Abs a ct a s the Ag receptor on the s urfa ce of B cel l s a nd, i n res pons e to Ag, a re s ubs equentl y s ecreted by pl a s ma cel l s . Abs recogni ze s peci fi c
confi gura ti ons (epi topes , or a nti geni c determi na nts ) on the s urfa ces of Ags (eg, protei ns , pol ys a ccha ri des , nucl ei c a ci ds ). Abs a nd Ags fi t ti ghtl y
together beca us e thei r s ha pe a nd other s urfa ce properti es (eg, cha rge) a re compl ementa ry. The s a me Ab mol ecul e ca n cros s -rea ct wi th rel a ted Ags
i f thei r epi topes a re s i mi l a r enough to thos e of the ori gi na l Ag.
Structure: Abs cons i s t of 4 pol ypepti de cha i ns (2 i denti ca l hea vy cha i ns a nd 2 i denti ca l l i ght cha i ns ) joi ned by di s ul fi de bonds to produce a Y
confi gura ti on (s ee
Fi g. 125-1). The hea vy a nd l i ght cha i ns a re di vi ded i nto a va ri a bl e (V) regi on a nd a cons ta nt (C) regi on.
V regions a re l oca ted a t the a mi no-termi na l ends of the Y a rms ; they a re ca l l ed va ri a bl e beca us e the a mi no a ci ds they conta i n a re di fferent i n
di fferent Abs . The a mi no a ci ds pres ent determi ne the s peci fi ci ty of the Ig. Hyperva ri a bl e regi ons wi thi n the V regi ons conta i n i di otypi c
determi na nts , to whi ch certa i n na tura l (a nti -i di otype) Abs ca n bi nd; thi s bi ndi ng ma y hel p regul a te B-cel l res pons es . A B cel l ca n s wi tch the Ig
hea vy cha i n i s otype i t produces , but i t reta i ns i ts hea vy cha i n V regi on a nd the enti re l i ght-cha i n, thereby reta i ni ng a nti geni c s peci fi ci ty.
[Fig. 125-1. B-cel l receptor.]
The C region conta i ns a rel a ti vel y cons ta nt s equence of a mi no a ci ds tha t i s di s ti ncti ve for ea ch Ig i s otype.
The a mi no-termi na l (va ri a bl e) end of the Ab bi nds to Ag to form a n Ab-Ag compl ex. The Ag-bi ndi ng (Fa b) porti on of Ig cons i s ts of a l i ght cha i n a nd
a fra gment of a hea vy cha i n a nd conta i ns the V regi on of the Ig mol ecul e (i e, the combi ni ng s i tes ). The crys ta l l i za bl e fra gment (Fc) conta i ns mos t
of the C regi on of the hea vy cha i ns ; Fc i s res pons i bl e for compl ement a cti va ti on a nd bi nds to Fc receptors on cel l s .
Antibody classes: Anti bodi es a re di vi ded i nto 5 cl a s s es :
IgM
IgG
IgA
IgD
IgE
The cl a s s es a re defi ned by thei r type of hea vy cha i n ( for IgM, for IgG, for IgA, for IgE, a nd for IgD); there a re a l s o 2 types of l i ght cha i ns (
a nd ). Ea ch of the 5 Ig cl a s s es ca n bea r ei ther or l i ght cha i ns .
IgM i s the fi rs t Ab formed a fter expos ure to new Ag. It ha s 5 Y-s ha ped mol ecul es (10 hea vy cha i ns a nd 10 l i ght cha i ns ), l i nked by a s i ngl e joi ni ng (J)
cha i n. IgM ci rcul a tes pri ma ri l y i n the i ntra va s cul a r s pa ce; i t compl exes wi th a nd a ggl uti na tes Ag a nd ca n a cti va te compl ement, thereby fa ci l i ta ti ng
pha gocytos i s . Is ohema ggl uti ni ns a nd ma ny Abs to gra m-nega ti ve ba cteri a a re IgM. Monomeri c IgM a cts a s a s urfa ce Ag receptor on B cel l s .
IgG i s the mos t preva l ent Ig i s otype i n s erum a nd i s pres ent a l s o i n i ntra va s cul a r a nd extra va s cul a r s pa ces . It coa ts Ag to a cti va te compl ement a nd
fa ci l i ta te pha gocytos i s by neutrophi l s a nd ma cropha ges . IgG i s the pri ma ry ci rcul a ti ng Ig produced a fter reexpos ure to Ag (s econda ry i mmune
res pons e) a nd i s the predomi na nt i s otype conta i ned i n commerci a l -gl obul i n products . IgG protects a ga i ns t ba cteri a , vi rus es , a nd toxi ns ; i t i s the
onl y Ig i s otype tha t cros s es the pl a centa .
There a re 4 s ubcl a s s es of IgG: IgG1, IgG2, IgG3, a nd IgG4. They a re numbered i n des cendi ng order of s erum concentra ti on. IgG s ubcl a s s es di ffer
functi ona l l y ma i nl y i n thei r a bi l i ty to a cti va te compl ement; IgG1 a nd IgG3 a re mos t effi ci ent, IgG2 i s l es s effi ci ent, a nd IgG4 i s i neffi ci ent. IgG1 a nd
IgG3 a re effi ci ent medi a tors of Ab-dependent cel l ul a r cytotoxi ci ty; IgG4 a nd IgG2 a re l es s s o.
IgA occurs a t mucos a l s urfa ces , i n s erum, a nd i n s ecreti ons (s a l i va ; tea rs ; res pi ra tory, GU, a nd GI tra ct s ecreti ons ; col os trum), where i t provi des a n
ea rl y a nti ba cteri a l a nd a nti vi ra l defens e. J cha i n l i nks IgA i nto a di mer to form s ecretory IgA. Secretory IgA i s s ynthes i zed by pl a s ma cel l s i n the
s ubepi thel i a l regi ons of the GI a nd res pi ra tory tra cts .
IgD i s coexpres s ed wi th IgM on the s urfa ce of na i ve B cel l s . Whether thes e 2 cl a s s es functi on di fferentl y on the s urfa ce of the B cel l a nd, i f s o, how
di fferentl y a re uncl ea r. They ma y s i mpl y be a n exa mpl e of mol ecul a r degenera cy. Serum IgD l evel s a re very l ow, a nd the functi on of ci rcul a ti ng IgD
i s unknown.
IgE i s pres ent i n l ow l evel s i n s erum a nd i n res pi ra tory a nd GI mucous s ecreti ons . IgE bi nds wi th hi gh a ffi ni ty to receptors pres ent i n hi gh l evel s on
ma s t cel l s a nd ba s ophi l s a nd to a l es s er extent on s evera l other hema topoi eti c cel l s , i ncl udi ng dendri ti c cel l s . If Ag bri dges 2 IgE mol ecul es
bound to the ma s t cel l or ba s ophi l s urfa ce, the cel l s degra nul a te, rel ea s i ng chemi ca l medi a tors tha t ca us e a n i nfl a mma tory res pons e. IgE l evel s
a re el eva ted i n a topi c di s orders (eg, a l l ergi c or extri ns i c a s thma , ha y fever, a topi c derma ti ti s ) a nd pa ra s i ti c i nfecti ons .
Acute Phase Reactants
Acute pha s e rea cta nts a re pl a s ma protei ns whos e l evel s dra ma ti ca l l y i ncrea s e i f i nfecti on or ti s s ue da ma ge occurs . Mos t dra ma ti ca l l y i ncrea s ed
a re C-rea cti ve protei n a nd ma nnos e-bi ndi ng l ecti n (whi ch fi x compl ement a nd a ct a s ops oni ns ), the tra ns port protei n 1 -a ci d gl ycoprotei n, a nd
s erum a myl oi d P component. Ma ny a cute pha s e rea cta nts a re ma de i n the l i ver. Col l ecti vel y, they ma y hel p l i mi t ti s s ue i njury, enha nce hos t
res i s ta nce to i nfecti on, a nd promote ti s s ue repa i r a nd res ol uti on of i nfl a mma ti on.
Cytokines
Cytoki nes a re pol ypepti des s ecreted by i mmune a nd other cel l s when the cel l i ntera cts wi th a s peci fi c Ag, endotoxi n, or other cytoki nes . Ma i n
ca tegori es i ncl ude
IFNs (IFN-, IFN-, IFN-)
TNFs (TNF-, l ymphotoxi n-, l ymphotoxi n-)
ILs
Chemoki nes
TGFs
Hema topoi eti c col ony-s ti mul a ti ng fa ctors (CSFs )
Al though l ymphocyte i ntera cti on wi th a s peci fi c Ag tri ggers cytoki ne s ecreti on, cytoki nes thems el ves a re not Ag-s peci fi c; thus , they bri dge i nna te
a nd a cqui red i mmuni ty a nd genera l l y i nfl uence the ma gni tude of i nfl a mma tory or i mmune res pons es . They a ct s equenti a l l y, s ynergi s ti ca l l y, or
a nta goni s ti ca l l y. They ma y a ct i n a n a utocri ne or pa ra cri ne ma nner.
Cytoki nes del i ver thei r s i gna l s vi a cel l s urfa ce receptors . For exa mpl e, the IL-2 receptor cons i s ts of 3 cha i ns : , , a nd . The receptor's a ffi ni ty for IL2 i s hi gh i f a l l 3 cha i ns a re expres s ed, i ntermedi a te i f onl y the a nd cha i ns a re expres s ed, or l ow i f onl y the cha i n i s expres s ed. Muta ti ons or
del eti on of the cha i n i s the ba s i s for X-l i nked s evere combi ned i mmunodefi ci ency (s ee p. 1106).
Chemoki nes i nduce chemota xi s a nd mi gra ti on of l eukocytes . There a re 4 s ubs ets , defi ned by the number of i nterveni ng a mi no a ci ds between the
fi rs t 2 cys tei ne res i dues i n the mol ecul e. Chemoki ne receptors (CCR5 on memory T cel l s , monocytes /ma cropha ges , a nd dendri ti c cel l s ; CXCR4 on
res ti ng T cel l s ) a ct a s core-ceptors for entry of HIV i nto cel l s .
Human Leukocyte Antigen System
The huma n l eukocyte a nti gen (HLA) s ys tem, the ma jor hi s tocompa ti bi l i ty compl ex (MHC) i n huma ns , i s control l ed by genes l oca ted on chromos ome
6. It encodes cel l s urfa ce mol ecul es s peci a l i zed to pres ent a nti geni c pepti des to the T-cel l receptor (TCR) on T cel l s . MHC mol ecul es tha t pres ent
a nti gen (Ag) a re di vi ded i nto 2 ma i n cl a s s es .
Class I MHC molecules a re pres ent on the s urfa ce of a l l nucl ea ted cel l s a nd pl a tel ets . Thes e pol ypepti des cons i s t of a hea vy cha i n bound to a 2 mi crogl obul i n mol ecul e. The hea vy cha i n cons i s ts of 2 pepti de-bi ndi ng doma i ns , a n Ig-l i ke doma i n, a nd a tra ns membra ne regi on wi th a
cytopl a s mi c ta i l . The hea vy cha i n of the cl a s s I mol ecul e i s encoded by genes a t HLA-A, HLA-B, a nd HLA-C l oci . Lymphocytes tha t expres s CD8
mol ecul es rea ct wi th cl a s s I MHC mol ecul es . Thes e l ymphocytes often ha ve a cytotoxi c functi on, requi ri ng them to be ca pa bl e of recogni zi ng a ny
i nfected cel l . Al l nucl ea ted cel l s expres s cl a s s I MHC mol ecul es a nd ca n thus a ct a s a nti gen-pres enti ng cel l s for CD8 T cel l s (CD8 bi nds to the
nonpol ymorphi c pa rt of the cl a s s I hea vy cha i n). Some cl a s s I MHC genes encode noncl a s s i ca l MHC mol ecul es , s uch a s HLA-G (whi ch ma y pl a y a
rol e i n protecti ng the fetus from the ma terna l i mmune res pons e) a nd HLA-E (whi ch pres ents pepti des to certa i n receptors on na tura l ki l l er cel l s ).
Class II MHC molecules a re us ua l l y pres ent onl y on profes s i ona l Ag-pres enti ng cel l s (B cel l s , ma cropha ges , dendri ti c cel l s , La ngerha ns ' cel l s ), thymi c
epi thel i um, a nd a cti va ted (but not res ti ng) T cel l s ; mos t nucl ea ted cel l s ca n be i nduced to expres s cl a s s II MHC mol ecul es by i nterferon (IFN)-.
Cl a s s II MHC mol ecul es cons i s t of 2 pol ypepti de ( a nd ) cha i ns ; ea ch cha i n ha s a pepti de-bi ndi ng doma i n, a n Ig-l i ke doma i n, a nd a
tra ns membra ne regi on wi th a cytopl a s mi c ta i l . Both pol ypepti de cha i ns a re encoded by genes i n the HLA-DP, -DQ, or -DR regi on of chromos ome 6.
Lymphocytes rea cti ve to cl a s s II mol ecul es expres s CD4 a nd a re often hel per T cel l s .
The MHC cl a s s III regi on of the genome encodes s evera l mol ecul es i mporta nt i n i nfl a mma ti on; they i ncl ude compl ement components C2, C4, a nd
fa ctor B; tumor necros i s fa ctor (TNF)-; l ymphotoxi n-; l ymphotoxi n-; a nd 3 hea t s hock protei ns .
Indi vi dua l a l l el es of the cl a s s I a nd II l oci i n the HLA s ys tem a re gi ven s ta nda rd des i gna ti ons (eg, HLA-A1, -B5, -Cw1, -DR1). Al l el es defi ned by DNA
s equenci ng a re na med to i denti fy the gene a nd to gi ve ea ch a l l el e a uni que number compos ed of the HLA l ocus , a n a s teri s k, 2 numbers
repres enti ng the s erol ogi c equi va l ent of the Ag, a nd 2 numbers repres enti ng the s peci fi c a l l el e (eg, A*0201, DRB1*0103, DQA1*0102). Someti mes
a nother number i s a dded to i denti fy a di fferent s ubtype.
Some di s orders a re l i nked to s peci fi c HLA a l l el es (eg, ps ori a s i s to HLA-Cw6, a nkyl os i ng s pondyl i ti s a nd rea cti ve a rthri ti s to HLA-B27, na rcol eps y to
HLA-DR2 a nd HLA-DQB1*0602, type 1 di a betes mel l i tus to HLA-DQ2 a nd HLA-DQ8, mul ti pl e s cl eros i s to HLA-DR2, RA to HLA-DRB1).
Complement System
The compl ement s ys tem i s a n enzyme ca s ca de tha t hel ps defend a ga i ns t i nfecti on. Ma ny compl ement protei ns occur i n s erum a s i na cti ve enzyme
precurs ors (zymogens ); others res i de on cel l s urfa ces . The compl ement s ys tem bri dges i nna te a nd a cqui red i mmuni ty by
Augmenti ng a nti body (Ab) res pons es a nd i mmunol ogi c memory

Lys i ng forei gn cel l s
Cl ea ri ng i mmune compl exes a nd a poptoti c cel l s
Compl ement components ha ve ma ny bi ol ogi c functi ons (eg, s ti mul a ti on of chemota xi s , tri ggeri ng of ma s t cel l degra nul a ti on i ndependent of IgE).
Complement activation: There a re 3 pa thwa ys of compl ement a cti va ti on (s ee
Fi g. 125-2):
Cl a s s i ca l
Lecti n
Al terna ti ve
Cl a s s i ca l pa thwa y components a re l a bel ed wi th a C a nd a number (eg, C1, C3), ba s ed on the order i n whi ch they were i denti fi ed. Al terna ti ve
pa thwa y components a re often l ettered (eg, fa ctor B, fa ctor D) or na med (eg, properdi n).
Classical pathway a cti va ti on i s Ab-dependent, occurri ng when C1 i ntera cts wi th Ag-IgM or a ggrega ted Ag-IgG compl exes , or Ab-i ndependent,
occurri ng when pol ya ni ons (eg, hepa ri n, prota mi ne, DNA a nd RNA from a poptoti c cel l s ), gra m-nega ti ve ba cteri a , or bound C-rea cti ve protei n rea cts
di rectl y wi th C1. Thi s pa thwa y i s regul a ted by C1 i nhi bi tor (C1-INH). Heredi ta ry a ngi oedema i s due to a geneti c defi ci ency of C1-INH.
Lectin pathway a cti va ti on i s Ab-i ndependent; i t occurs when ma nnos e-bi ndi ng l ecti n (MBL), a s erum protei n, bi nds to ma nnos e or fructos e groups
on ba cteri a l cel l wa l l s , yea s t wa l l s , or vi rus es . Thi s pa thwa y otherwi s e res embl es the cl a s s i ca l pa thwa y s tructura l l y a nd functi ona l l y.
Alternate pathway a cti va ti on occurs when components of mi crobi a l cel l s urfa ces (eg, yea s t wa l l s , ba cteri a l cel l wa l l l i popol ys a ccha ri de [endotoxi n])
or Ig (eg, nephri ti c fa ctor, a ggrega ted IgA) cl ea ve s ma l l a mounts of C3. Thi s pa thwa y i s regul a ted by properdi n, fa ctor H, a nd deca y-a ccel era ti ng
fa ctor.
The 3 a cti va ti on pa thwa ys converge i nto a fi na l common pa thwa y when C3 converta s e cl ea ves C3 i nto C3a a nd C3b (s ee Fi g. 125-2). C3 cl ea va ge ma y
res ul t i n forma ti on of the membra ne a tta ck compl ex (MAC), the cytotoxi c component of the compl ement s ys tem. MAC ca us es l ys i s of forei gn cel l s .
Biologic activities: Compl ement components ha ve other i mmune functi ons tha t a re medi a ted by compl ement receptors (CR) on va ri ous cel l s .
CR1 (CD35) promotes pha gocytos i s a nd hel ps cl ea r i mmune compl exes .
CR2 (CD21) regul a tes Ab producti on by B cel l s a nd i s the Eps tei n-Ba rr vi rus receptor.
CR3 (CD11b/CD18), CR4 (CD11c/CD18), a nd C1q receptors pl a y a rol e i n pha gocytos i s .
C3a , C5a , a nd C4a (wea kl y) ha ve a na phyl a toxi n a cti vi ty: They ca us e ma s t cel l degra nul a ti on, l ea di ng to i ncrea s ed va s cul a r permea bi l i ty a nd
s mooth mus cl e contra cti on.
[Fig. 125-2. Compl ement a cti va ti on pa thwa ys .]
C3b a cts a s a n ops oni n by coa ti ng mi croorga ni s ms a nd thereby enha nci ng thei r pha gocytos i s .
C3d enha nces Ab producti on by B cel l s .
C5a i s a neutrophi l chemoa ttra cta nt; i t regul a tes neutrophi l a nd monocyte a cti vi ti es a nd ma y ca us e a ugmented a dherence of cel l s ,
degra nul a ti on a nd rel ea s e of i ntra cel l ul a r enzymes from gra nul ocytes , producti on of toxi c oxygen meta bol i tes , a nd i ni ti a ti on of other cel l ul a r
meta bol i c events .
Immunotherapeutics
Immunothera peuti c a gents us e or modi fy i mmune mecha ni s ms . Us e of thes e a gents i s ra pi dl y evol vi ng; new cl a s s es , new a gents , a nd new us es of
current a gents a re certa i n to be devel oped. A number of di fferent cl a s s es of i mmunothera peuti c a gents ha ve been devel oped (s ee
Ta bl e 125-2):
Monocl ona l a nti bodi es
Fus i on protei ns
Sol ubl e cytoki ne receptors
Recombi na nt cytoki nes
Sma l l -mol ecul e mi meti cs
Monoclonal antibodies: Monocl ona l a nti bodi es (mAbs ) a re ma nufa ctured i n vi tro to recogni ze s peci fi c ta rgeted Ags ; they a re us ed to trea t s ol i d a nd
hema topoi eti c tumors a nd i nfl a mma tory di s orders . The mAbs tha t a re currentl y i n cl i ni ca l us e i ncl ude
Muri ne
Chi meri c
Huma ni zed
Murine mAbs a re produced by i njecti ng a mous e wi th a n Ag, ha rves ti ng i ts s pl een to obta i n pl a s ma cel l s tha t a re produci ng Ab s peci fi c to tha t Ag,
fus i ng thos e cel l s wi th i mmorta l mous e myel oma cel l s , growi ng thes e hybri doma cel l s (eg, i n cel l cul ture), a nd ha rves ti ng
[Table 125-2. Some Immunothera peuti c Agents i n Cl i ni ca l Us e*]
the Ab. Al though mous e a nti bodi es a re s i mi l a r to huma n a nti bodi es , cl i ni ca l us e of muri ne mAbs i s l i mi ted beca us e they i nduce huma n a nti mous e Ab producti on, ca n ca us e i mmune compl ex s erum s i cknes s (a type III hypers ens i ti vi ty rea cti on), a nd a re ra pi dl y cl ea red. An excepti on i s
muromona b-CD3 (OKT3), whi ch effecti vel y prevents a cute rejecti on of s ol i d orga n tra ns pl a nts ; i t i s typi ca l l y gi ven onl y once or twi ce to a pa ti ent
recei vi ng other i mmunos uppres s a nts (s ee p. 1128).
To mi ni mi ze the probl ems due to us e of pure mous e Ab, res ea rchers ha ve us ed recombi na nt DNA techni ques to crea te monocl ona l Abs tha t a re
pa rt huma n a nd pa rt mous e. Dependi ng on the proporti on of the Ab mol ecul e tha t i s huma n, the res ul ta nt product i s termed chi meri c or
huma ni zed. In both ca s es , the proces s us ua l l y begi ns a s a bove wi th producti on of mous e hybri doma cel l s tha t ma ke Ab to the des i red Ag. Then
the DNA for s ome or a l l of the va ri a bl e porti on of the mous e Ab i s merged wi th DNA for huma n i mmunogl obul i n. The res ul ta nt DNA i s pl a ced i n a
ma mma l i a n cel l cul ture, whi ch then expres s es the res ul ta nt gene, produci ng the des i red Ab. If the mous e gene for the whol e va ri a bl e regi on i s
s pl i ced next to the huma n cons ta nt regi on, the product i s termed "chi meri c"; i f onl y pa rts of the mous e gene for the bi ndi ng porti on of the va ri a bl e
regi on a re us ed, the product, termed "huma ni zed," i s even more huma n.
Chi meri c mAbs a cti va te Ag-pres enti ng cel l s (APCs ) a nd T cel l s more effecti vel y tha n muri ne mAbs but ca n s ti l l i nduce producti on of huma n a nti chi meri c Ab.
Huma ni zed mAbs a ga i ns t va ri ous a nti gens (Ags ) ha ve been a pproved for the trea tment of col orecta l a nd brea s t ca ncer, l eukemi a , a l l ergy,
a utoi mmune di s ea s e, tra ns pl a nt rejecti on, a nd res pi ra tory s yncyti a l vi rus i nfecti on.
Fusion proteins: Thes e hybri d protei ns a re crea ted by l i nki ng together the gene s equences encodi ng a l l or pa rt of 2 di fferent protei ns to genera te a
chi meri c pol ypepti de tha t i ncorpora tes des i ra bl e a ttri butes from the pa rent mol ecul es (eg, a cel l ta rgeti ng component combi ned wi th a cel l toxi n).
The ci rcul a ti ng ha l f-l i fe of thera peuti c protei ns ca n a l s o often be i mproved by fus i ng them to a nother protei n tha t na tura l l y ha s a l onger s erum
ha l f-l i fe (eg, the Fc regi on of IgG).
Soluble cytokine receptors: Sol ubl e vers i ons of cytoki ne receptors a re us ed a s thera peuti c rea gents . They ca n bl ock the a cti on of cytoki nes by bi ndi ng
wi th them before they a tta ch to thei r norma l cel l s urfa ce receptor.
Eta nercept, a fus i on protei n, cons i s ts of 2 i denti ca l cha i ns from the receptor for CD120b tumor necros i s fa ctor (TNF)-. Thi s a gent thus bl ocks TNF-
a nd i s us ed to trea t RA refra ctory to other trea tments , a nkyl os i ng s pondyl i ti s , ps ori a ti c a rthri ti s , a nd pl a que ps ori a s i s .
Sol ubl e IL receptors (eg, thos e for IL-1, IL-2, IL-4, IL-5, a nd IL-6) a re bei ng devel oped for trea tment of i nfl a mma tory a nd a l l ergi c di s orders a nd
ca ncer.
Recombinant cytokines: Col ony-s ti mul a ti ng fa ctors (CSF), s uch a s erythropoi eti n, gra nul ocyte CSF (G-CSF), a nd gra nul ocyte-ma cropha ge CSF (GM-CSF),
a re us ed i n pa ti ents undergoi ng chemothera py or tra ns pl a nta ti on for hema tol ogi c di s orders a nd ca ncers (s ee Ta bl e 125-2). Interferon- (IFN-)
a nd IFN- a re us ed to trea t ca ncer, i mmunodefi ci ency di s orders , a nd vi ra l i nfecti ons ; IFN- i s us ed to trea t rel a ps i ng mul ti pl e s cl eros i s . Ma ny other
cytoki nes a re bei ng s tudi ed.
Ana ki nra , us ed to trea t RA, i s a recombi na nt, s l i ghtl y modi fi ed form of the na tura l l y occurri ng IL-1R a nta goni s t; thi s drug a tta ches to the IL-1
receptor a nd thus prevents bi ndi ng of IL-1, but unl i ke IL-1, i t does not a cti va te the receptor.
Cel l s expres s i ng cytoki ne receptors ca n be ta rgeted by modi fi ed vers i ons of the rel eva nt cytoki ne (eg, deni l euki n di fti tox, whi ch i s a fus i on protei n
conta i ni ng s equences from IL-2 a nd from di phtheri a toxi n). Deni l euki n i s us ed i n cuta neous T-cel l l ymphoma to ta rget the toxi n to cel l s expres s i ng
the CD25 component of the IL-2 receptor.
Small-molecule mimetics: Sma l l l i nea r pepti des , cycl i ci zed pepti des , a nd s ma l l orga ni c mol ecul es ha ve been devel oped a s a goni s ts or a nta goni s ts
for va ri ous a ppl i ca ti ons . Screeni ng l i bra ri es of pepti des a nd orga ni c compounds ca n i denti fy potenti a l mi meti cs (eg, a goni s ts for receptors for
erythropoi eti n, thrombopoi eti n, a nd G-CSF).
Chapter 126. Immunodeficiency Disorders

Introduction
Immunodefi ci ency di s orders i ncrea s e s us cepti bi l i ty to i nfecti on. They ma y be s econda ry or pri ma ry; s econda ry i s more common.
Secondary immunodeficiencies: Ca us es i ncl ude s ys temi c di s orders (eg, di a betes , undernutri ti on, HIV i nfecti on) a nd i mmunos uppres s i ve trea tments
(eg, chemothera py, ra di a ti on thera pys ee
Ta bl e 126-1). Seconda ry i mmunodefi ci ency a l s o occurs a mong cri ti ca l l y i l l , ol der, or hos pi ta l i zed pa ti ents . Prol onged s eri ous i l l nes s ma y i mpa i r
i mmune res pons es ; i mpa i rment i s often revers i bl e i f the underl yi ng i l l nes s res ol ves .
Immunodefi ci ency ca n res ul t from l os s of s erum protei ns (pa rti cul a rl y IgG a nd a l bumi n) through the ki dneys i n nephroti c s yndrome, through s ki n
i n s evere burns or derma ti ti s , or through the GI tra ct i n enteropa thy. Enteropa thy ma y a l s o l ea d to l ymphocyte l os s , res ul ti ng i n l ymphopeni a .
Thes e di s orders ca n mi mi c Ba nd T-cel l defects . Trea tment focus es on the underl yi ng di s order; a di et hi gh i n medi um-cha i n tri gl yceri des ma y
decrea s e l os s of Igs a nd l ymphocytes from the GI tra ct a nd be rema rka bl y benefi ci a l .
Primary immunodeficiencies: Thes e di s orders a re geneti ca l l y determi ned; they ma y occur a l one or a s pa rt of a s yndrome. More tha n 200 ha ve been
des cri bed, a nd heterogenei ty wi thi n ea ch di s order ma y be cons i dera bl e. The mol ecul a r ba s i s for a bout 80% i s known.
[Table 126-1. Ca us es of Seconda ry Immunodefi ci ency]
[
Table 126-2. Some Drugs tha t Ca us e Immunos uppres s i on]
Pri ma ry i mmunodefi ci enci es typi ca l l y ma ni fes t duri ng i nfa ncy a nd chi l dhood a s a bnorma l l y frequent (recurrent) or unus ua l i nfecti ons . About 70%
of pa ti ents a re < 20 yr a t ons et; beca us e tra ns mi s s i on i s often X-l i nked, 60% a re ma l e. Overa l l i nci dence of s ymptoma ti c di s ea s e i s a bout 1/280
peopl e.
Pri ma ry i mmunodefi ci enci es a re cl a s s i fi ed by the ma i n component of the i mmune s ys tem tha t i s defi ci ent, a bs ent, or defecti ve (s ee
Ta bl e 126-3):
B cel l s (or Ig)
T cel l s
Na tura l ki l l er cel l s (very ra re)
Pha gocyti c cel l s
Compl ement protei ns
As more mol ecul a r defects a re defi ned, cl a s s i fyi ng i mmunodefi ci enci es by thei r mol ecul a r defects wi l l be more a ppropri a te.
B-cell defects ca us i ng Ig a nd a nti body defi ci enci es a ccount for 50 to 60% of pri ma ry i mmunodefi ci enci es . Serum Ig a nd a nti body ti ters decrea s e,
predi s pos i ng to i nfecti ons wi th enca ps ul a ted gra m-pos i ti ve ba cteri a . The mos t common B-cel l di s order i s s el ecti ve IgA defi ci ency.
T-cell disorders a ccount for a bout 5 to 10% of pri ma ry i mmunodefi ci enci es a nd predi s pos e to i nfecti on by vi rus es , Pneumocystis jirovecii, fungi , other
opportuni s ti c orga ni s ms , a nd ma ny common pa thogens . T-cel l di s orders a l s o ca us e Ig defi ci enci es beca us e the B- a nd T-cel l i mmune s ys tems a re
i nterdependent. The mos t common T-cel l di s orders a re Di George s yndrome, ZAP-70 defi ci ency, X-l i nked l ymphoprol i fera ti ve s yndrome, a nd chroni c
mucocuta neous ca ndi di a s i s (s ee p. 1102).
Combined B- and T-cell defects a ccount for a bout 20% of pri ma ry i mmunodefi ci enci es . The mos t i mporta nt form i s s evere combi ned
i mmunodefi ci ency (SCID). In s ome forms of combi ned i mmunodefi ci ency (eg, puri ne nucl eos i de phos phoryl a s e defi ci ency), Ig l evel s a re norma l or
el eva ted, but beca us e of i na dequa te T-cel l functi on, a nti body forma ti on i s i mpa i red.
Natural killer cell defects a re very ra re a nd ma y predi s pos e to vi ra l i nfecti ons a nd tumors .
Phagocytic cell defects a ccount for 10 to 15% of pri ma ry i mmunodefi ci enci es ; the a bi l i ty of pha gocyti c cel l s (eg, monocytes , ma cropha ges ,
gra nul ocytes s uch a s neutrophi l s a nd eos i nophi l s ) to ki l l pa thogens i s i mpa i red. Cuta neous s ta phyl ococca l a nd gra m-nega ti ve i nfecti ons a re
cha ra cteri s ti c. The mos t common pha gocyti c cel l defects a re chroni c gra nul oma tous di s ea s e, l eukocyte a dhes i on defi ci ency, a nd Chedi a k-Hi ga s hi
s yndrome.
Complement deficiencies a re ra re ( 2%); they i ncl ude i s ol a ted defi ci enci es of compl ement components or i nhi bi tors a nd ma y be heredi ta ry or
a cqui red. Heredi ta ry defi ci enci es a re a utos oma l reces s i ve except for defi ci enci es of C1 i nhi bi tor, whi ch i s a utos oma l domi na nt, a nd properdi n,
whi ch i s X-l i nked. The defi ci enci es res ul t i n defecti ve ops oni za ti on, pha gocytos i s , a nd l ys i s of pa thogens a nd i n defecti ve cl ea ra nce of a nti gena nti body compl exes . Recurrent i nfecti on, due to defecti ve ops oni za ti on, a nd a utoi mmune di s orders (eg, SLE, gl omerul onephri ti s ), due to defecti ve
cl ea ra nce of a nti gen-a nti body compl exes (s ee Ta bl e 126-3), a re the mos t s eri ous cons equences . One of thes e defi ci enci es ca us es heredi ta ry
a ngi oedema .
Primary immunodeficiency syndromes a re geneti ca l l y determi ned i mmunodefi ci enci es wi th i mmune a nd noni mmune defects . Noni mmune
ma ni fes ta ti ons a re often more ea s i l y recogni zed tha n thos e of the i mmunodefi ci ency. Exa mpl es a re a ta xi a -tel a ngi ecta s i a , ca rti l a ge-ha i r
hypopl a s i a , Di George s yndrome, hyper-IgE s yndrome, a nd Wi s kott-Al dri ch s yndrome.
Some decrea s e i n i mmuni ty occurs wi th a gi ng. For exa mpl e, i n the el derl y, the thymus
[Table 126-3. Pri ma ry Immunodefi ci ency Di s orders ]
tends to produce fewer na i ve T cel l s ; thus , fewer T cel l s a re a va i l a bl e to res pond to new a nti gens . The number of T cel l s does not decrea s e
(beca us e of ol i gocl ona l i ty), but thes e cel l s ca n recogni ze onl y a l i mi ted number of a nti gens .
Si gna l tra ns ducti on (tra ns mi s s i on of a nti gen-bi ndi ng s i gna l a cros s the cel l membra ne i nto the cel l ) i s i mpa i red, ma ki ng T cel l s l es s l i kel y to
res pond to a nti gens . Al s o, hel per T cel l s ma y be l es s l i kel y to s i gna l B cel l s to produce a nti bodi es .
The number of neutrophi l s does not decrea s e, but thes e cel l s become l es s effecti ve i n pha gocytos i s a nd mi crobi ci da l a cti on.
Undernutri ti on, common a mong the el derl y, i mpa i rs i mmune res pons es . Ca , zi nc, a nd vi ta mi n E a re pa rti cul a rl y i mporta nt to i mmuni ty. Ri s k of Ca
defi ci ency i s i ncrea s ed i n the el derl y, pa rtl y beca us e wi th a gi ng, the i ntes ti ne becomes l es s a bl e to a bs orb Ca . Al s o, the el derl y ma y not i nges t
enough Ca i n thei r di et. Zi nc defi ci ency i s very common a mong the i ns ti tuti ona l i zed el derl y a nd homebound pa ti ents .
Approach to the Patient With Suspected Immunodeficiency
Immunodefi ci ency typi ca l l y ma ni fes ts a s recurrent i nfecti ons . However, more l i kel y ca us es of recurrent i nfecti ons i n chi l dren a re repea ted
expos ures to i nfecti on a t da y ca re or s chool (i nfa nts a nd chi l dren ma y norma l l y ha ve up to 10 res pi ra tory i nfecti ons /yr), a nd more l i kel y ca us es i n
chi l dren a nd a dul ts a re i na dequa te dura ti on of a nti bi oti c trea tment, res i s ta nt orga ni s ms , a nd other di s orders tha t predi s pos e to i nfecti on (eg,
congeni ta l hea rt defects , a l l ergi c rhi ni ti s , uretera l or urethra l s tenos i s , i mmoti l e ci l i a s yndrome, a s thma , cys ti c fi bros i s , s evere derma ti ti s ).
Immunodefi ci ency s houl d be s us pected when recurrent i nfecti ons a re the fol l owi ng:
Severe
Compl i ca ted
In mul ti pl e l oca ti ons
Res i s ta nt to trea tment
Ca us ed by unus ua l orga ni s ms
Ini ti a l l y, i nfecti ons due to i mmunodefi ci ency a re typi ca l l y upper a nd l ower res pi ra tory tra ct i nfecti ons (eg, s i nus i ti s , bronchi ti s , pneumoni a ) a nd
ga s troenteri ti s , but they ma y be s eri ous ba cteri a l i nfecti ons (eg, meni ngi ti s , s eps i s ).
Immunodefi ci ency s houl d a l s o be s us pected i n i nfa nts or young chi l dren wi th chroni c di a rrhea a nd fa i l ure to thri ve, es peci a l l y when the di a rrhea
i s ca us ed by unus ua l vi rus es (eg, a denovi rus ) or fungi (eg, Cryptosporidium s p). Other s i gns i ncl ude s ki n l es i ons (eg, eczema , wa rts , a bs ces s es ,
pyoderma , a l opeci a ), ora l or es opha gea l thrus h, ora l ul cers , a nd peri odonti ti s .
Les s common ma ni fes ta ti ons i ncl ude s evere vi ra l i nfecti on wi th herpes s i mpl ex or va ri cel l a zos ter vi rus a nd CNS probl ems (eg, chroni c
encepha l i ti s , del a yed devel opment, s ei zure di s order). Frequent us e of a nti bi oti cs ma y ma s k ma ny of the common s ymptoms a nd s i gns .
Immunodefi ci ency s houl d be cons i dered pa rti cul a rl y i n pa ti ents wi th i nfecti ons a nd a n a utoi mmune di s order (eg, hemol yti c a nemi a ,
thrombocytopeni a ).
Evaluation
Hi s tory a nd phys i ca l exa mi na ti on a re hel pful but mus t be s uppl emented by i mmune functi on tes ti ng. Prena ta l tes ti ng i s a va i l a bl e for ma ny
di s orders a nd i s i ndi ca ted i f there i s a fa mi l y hi s tory of i mmunodefi ci ency a nd the muta ti on ha s been i denti fi ed i n fa mi l y members .
History: Cl i ni ci a ns s houl d determi ne whether pa ti ents ha ve a hi s tory of ri s k fa ctors for i nfecti on or of s ymptoms a nd ri s k fa ctors for s econda ry
i mmunodefi ci ency di s orders . Fa mi l y hi s tory i s very i mporta nt.
Age when recurrent i nfecti ons bega n i s i mporta nt. Ons et of i nfecti ons before a ge 12 mo s ugges ts combi ned B- a nd T-cel l defects or a B-cel l defect,
whi ch becomes evi dent when ma terna l a nti bodi es a re di s a ppea ri ng (a t a bout a ge 6 mo). In genera l , the ea rl i er the a ge a t ons et i n chi l dren, the
more s evere the i mmunodefi ci ency. Often, certa i n other pri ma ry i mmunodefi ci enci es (eg, common va ri a bl e i mmunodefi ci ency [CVID]) do not
ma ni fes t unti l a dul thood.
Certa i n i nfecti ons s ugges t certa i n i mmunodefi ci ency di s orders (s ee
Ta bl e 126-4); however, no i nfecti on i s s peci fi c to a ny one di s order, a nd certa i n common i nfecti ons (eg, res pi ra tory vi ra l or ba cteri a l i nfecti ons )
occur i n ma ny.
Physical examination: Pa ti ents wi th i mmunodefi ci ency ma y or ma y not a ppea r chroni ca l l y i l l . Ma cul a r ra s hes , ves i cl es , pyoderma , eczema ,
petechi a e, a l opeci a , or tel a ngi ecta s i a ma y be evi dent.
Cervi ca l l ymph nodes a nd a denoi d a nd tons i l l a r ti s s ue a re typi ca l l y very s ma l l or a bs ent i n X-l i nked a ga mma gl obul i nemi a , X-l i nked hyper-IgM
s yndrome, s evere combi ned i mmunodefi ci ency (SCID), a nd other T-cel l i mmunodefi ci enci es des pi te a hi s tory of recurrent i nfecti ons . In certa i n
other i mmunodefi ci enci es (eg, chroni c gra nul oma tous di s ea s e), l ymph nodes of the hea d a nd neck ma y be enl a rged a nd s uppura ti ve.
Tympa ni c membra nes ma y be s ca rred or perfora ted. The nos tri l s ma y be crus ted, i ndi ca ti ng purul ent na s a l di s cha rge. Chroni c cough i s common, a s
a re l ung cra ckl es , es peci a l l y i n a dul ts wi th CVID. The l i ver a nd s pl een a re often enl a rged i n pa ti ents wi th CVID or chroni c gra nul oma tous di s ea s e.
Mus cl e ma s s a nd fa t depos i ts of the buttocks a re decrea s ed. In i nfa nts , s ki n a round the a nus ma y brea k down beca us e of chroni c di a rrhea .
Neurol ogi c exa mi na ti on ma y detect del a yed devel opmenta l mi l es tones or a ta xi a .

Other cha ra cteri s ti c fi ndi ngs tenta ti vel y s ugges t a cl i ni ca l di a gnos i s (s ee
Ta bl e 126-5).
Initial testing: If a s peci fi c s econda ry i mmunodefi ci ency di s order i s s us pected cl i ni ca l l y, tes ti ng s houl d focus on tha t di s order (eg, di a betes , HIV
i nfecti on, cys ti c fi bros i s , pri ma ry ci l i a ry dys ki nes i a ).
Tes ts a re needed to confi rm a di a gnos i s of i mmunodefi ci ency (s ee
Ta bl e 126-6). Ini ti a l s creeni ng tes ts s houl d i ncl ude
CBC wi th ma nua l di fferenti a l
Qua nti ta ti ve Ig mea s urements
Anti body ti ters
Ski n tes ti ng for del a yed hypers ens i ti vi ty
[Table 126-4. Some Cl ues i n Pa ti ent Hi s tory to Type of Immunodefi ci ency]
If res ul ts a re norma l , i mmunodefi ci ency (es peci a l l y Ig defi ci ency) ca n be excl uded. If res ul ts a re a bnorma l , further tes ts i n s peci a l i zed
l a bora tori es a re needed to i denti fy s peci fi c defi ci enci es . If chroni c i nfecti ons a re objecti vel y documented, i ni ti a l a nd s peci fi c tes ts ma y be done
s i mul ta neous l y.
CBC ca n detect a bnorma l i ti es i n one or more cel l types (eg, WBCs , pl a tel ets ) cha ra cteri s ti c of s peci fi c di s orders . However, ma ny a bnorma l i ti es a re
tra ns i ent ma ni fes ta ti ons of i nfecti on, drug us e, or other fa ctors ; thus , a bnorma l i ti es s houl d be confi rmed a nd fol l owed.
Neutropenia (a bs ol ute neutrophi l count < 1200 cel l s /L) ma y be congeni ta l or cycl i c or ma y occur i n a pl a s ti c a nemi a .
Lymphopenia (l ymphocytes < 2000/L a t bi rth, < 4500/L a t a ge 9 mo, or < 1000/L i n ol der chi l dren or a dul ts ) s ugges ts a T-cel l di s order beca us e
70% of ci rcul a ti ng l ymphocytes a re T cel l s .
Leukocytosis tha t pers i s ts between i nfecti ons ma y occur i n l eukocyte a dhes i on defi ci ency.
Thrombocytopenia i n ma l e i nfa nts s ugges ts Wi s kott-Al dri ch s yndrome.
Anemia ma y s ugges t a nemi a of chroni c di s ea s e or a utoi mmune hemol yti c a nemi a , whi ch ma y occur i n CVID a nd other i mmunodefi ci enci es .
Peripheral blood smear s houl d be exa mi ned for Howel l -Jol l y bodi es a nd other unus ua l RBC forms , whi ch s ugges t pri ma ry a s pl eni a or i mpa i red
s pl eni c functi on. Gra nul ocytes ma y ha ve morphol ogi c a bnorma l i ti es (eg, gi a nt gra nul es i n Chedi a k-Hi ga s hi s yndrome).
Quantitative serum Ig levels a re mea s ured. Low s erum l evel s of IgG, IgM, or IgA s ugges t a nti body defi ci ency, but res ul ts mus t be compa red wi th
thos e of a ge-ma tched control s . An IgG l evel < 200 mg/dL us ua l l y i ndi ca tes s i gni fi ca nt a nti body defi ci ency, a l though s uch l evel s ma y occur i n
protei n-l os i ng enteropa thi es or nephroti c s yndrome.
IgM antibodies ca n be a s s es s ed by mea s uri ng i s ohema ggl uti ni n ti ters (a nti -A, a nti -B). Al l pa ti ents except i nfa nts < 6 mo a nd peopl e wi th bl ood
type AB ha ve na tura l a nti bodi es a t
[Table 126-5. Cha ra cteri s ti c Cl i ni ca l Fi ndi ngs i n Some Pri ma ry Immunodefi ci ency Di s orders ]
a ti ter of 1:8 (a nti -A) or 1:4 (a nti -B). Anti bodi es to bl ood groups A a nd B a nd to s ome ba cteri a l pol ys a ccha ri des a re s el ecti vel y defi ci ent i n
certa i n di s orders (eg, Wi s kott-Al dri ch s yndrome, compl ete IgG2 defi ci ency).
IgG antibody ti ters ca n be a s s es s ed i n i mmuni zed pa ti ents by mea s uri ng a nti body ti ters before a nd a fter a dmi ni s tra ti on of va cci ne a nti gens
(Haemophilus influenzae type B, teta nus , di phtheri a , conjuga ted or nonconjuga ted pneumococca l , a nd meni ngococca l a nti gens ); a l es s -tha ntwofol d i ncrea s e i n ti ter a t 2 to 3 wk s ugges ts a nti body defi ci ency rega rdl es s of Ig l evel s . Na tura l a nti bodi es (eg, a nti s treptol ys i n O, heterophi l
a nti bodi es ) ma y a l s o be mea s ured.
[Table 126-6. Ini ti a l a nd Addi ti ona l La bora tory Tes ts for Immunodefi ci ency]
Wi th skin testing, mos t i mmunocompetent a dul ts , i nfa nts , a nd chi l dren rea ct to 0.1 mL of Candida albicans extra ct (1:100 for i nfa nts a nd 1:1000 for
ol der chi l dren a nd a dul ts ) i njected i ntra derma l l y. Pos i ti ve rea cti vi ty, defi ned a s erythema a nd i ndura ti on > 5 mm a t 24, 48, a nd 72 h, excl udes a Tcel l di s order. La ck of res pons e does not confi rm i mmunodefi ci ency i n pa ti ents wi th no previ ous expos ure to Candida.
Ches t x-ra y ma y be us eful i n s ome i nfa nts ; a n a bs ent thymi c s ha dow s ugges ts a T-cel l di s order, es peci a l l y i f the x-ra y i s obta i ned before ons et of
i nfecti on or other s tres s es tha t ma y s hri nk the thymus . La tera l pha ryngea l x-ra y ma y s how a bs ence of a denoi da l ti s s ue.
Additional testing: If cl i ni ca l fi ndi ngs or i ni ti a l tes ts s ugges t a s peci fi c di s order of i mmune cel l or compl ement functi on, other tes ts a re i ndi ca ted.
If pa ti ents ha ve recurrent i nfecti ons a nd l ymphopeni a , l ymphocyte phenotypi ng us i ng fl ow cytometry a nd monocl ona l a nti bodi es to T, B, a nd
na tura l ki l l er (NK) cel l s i s i ndi ca ted to check for l ymphocyte defi ci ency. If T cel l s a re l ow or a bs ent, i nvi tro mi togen s ti mul a ti on s tudi es a re done to
a s s es s T-cel l functi on. If MHC a nti gen defi ci ency i s s us pected, s erol ogi c (not mol ecul a r) HLA typi ng i s i ndi ca ted.
If pha gocyti c cel l defects a re s us pected, a fl ow cytometri c res pi ra tory burs t a s s a y ca n detect whether O2 ra di ca l s a re produced duri ng pha gocytos i s ;
no producti on i s cha ra cteri s ti c of chroni c gra nul oma tous di s ea s e.
If the type or pa ttern of i nfecti ons s ugges ts compl ement defi ci ency, the s erum di l uti on requi red to l ys e 50% of a nti body-coa ted RBCs (CH50) i s
mea s ured. Thi s tes t detects compl ement component defi ci enci es i n the cl a s s i ca l or a l terna ti ve compl ement a cti va ti on pa thwa y but does not
i ndi ca te whi ch component i s a bnorma l .
If exa mi na ti on or s creeni ng tes ts detect a bnorma l i ti es s ugges ti ng l ymphocyte or pha gocyti c cel l defects , other tes ts ca n more preci s el y
cha ra cteri ze s peci fi c di s orders (s ee
Ta bl e 126-7).
Prenatal diagnosis: An i ncrea s i ng number of pri ma ry i mmunodefi ci ency di s orders ca n be di a gnos ed prena ta l l y us i ng chori oni c vi l l us s a mpl i ng,
cul tured a mni oti c cel l s , or feta l bl ood s a mpl i ng, but thes e tes ts a re us ed onl y when a muta ti on i n fa mi l y members ha s a l rea dy been i denti fi ed
(s ee p. 2602). X-l i nked a ga mma gl obul i nemi a , Wi s kott-Al dri ch s yndrome, a ta xi a -tel a ngi ecta s i a , X-l i nked l ymphoprol i fera ti ve s yndrome, a l l forms of
SCID, a nd a l l forms of chroni c gra nul oma tous di s ea s e ca n be detected. Sex determi na ti on by ul tra s onogra phy ca n be us ed to excl ude X-l i nked
di s orders .
Prognosis
Prognos i s depends on the pri ma ry i mmunodefi ci ency di s order. Mos t pa ti ents wi th a n Ig or a compl ement defi ci ency ha ve a good prognos i s wi th a
nea r-norma l l i fe expecta ncy i f they a re di a gnos ed ea rl y, a re trea ted a ppropri a tel y, a nd ha ve no coexi s ti ng chroni c di s orders (eg, pul mona ry
di s orders s uch a s bronchi ecta s i s ). Other i mmunodefi ci ent pa ti ents (eg, thos e wi th a pha gocyti c cel l defect or combi ned i mmunodefi ci enci es , s uch
a s Wi s kott-Al dri ch s yndrome or a ta xi a -tel a ngi ecta s i a ) ha ve a gua rded prognos i s ; mos t requi re i ntens i ve a nd frequent trea tment. Some
i mmunodefi ci ent pa ti ents (eg, thos e wi th SCID) di e duri ng
[Table 126-7. Adva nced La bora tory Tes ts for Immunodefi ci ency]
i nfa ncy unl es s i mmuni ty i s provi ded through tra ns pl a nta ti on. Al l forms of SCID coul d be di a gnos ed a t bi rth i f a WBC count a nd ma nua l di fferenti a l
of cord or peri phera l bl ood were routi nel y done i n neona tes . Sus pi ci on for SCID, a true pedi a tri c emergency, mus t be hi gh beca us e prompt
di a gnos i s i s es s enti a l for s urvi va l . If done before pa ti ents rea ch a ge 3 mo, tra ns pl a nta ti on of bone ma rrow or s tem cel l s from a ma tched or ha l fma tched (ha pl oi denti ca l ) rel a ti ve i s l i fes a vi ng i n 95%.
Treatment
Va cci nes a nd a voi da nce of expos ure to i nfecti on
Anti bi oti cs a nd s ometi mes s urgery
Repl a cement of mi s s i ng i mmune components
Trea tment genera l l y i nvol ves preventi ng i nfecti on, ma na gi ng a cute i nfecti on, a nd repl a ci ng mi s s i ng i mmune components when pos s i bl e.
Infection prevention: Infecti on ca n be prevented by a dvi s i ng pa ti ents to a voi d envi ronmenta l expos ures a nd gi vi ng l i ve-vi rus va cci nes (va ri cel l a ,
rota vi rus , mea s l es , mumps , rubel l a ). Pa ti ents a t ri s k of s eri ous i nfecti ons (eg, thos e wi th SCID, chroni c gra nul oma tous di s ea s e, Wi s kott-Al dri ch
s yndrome, or a s pl eni a ) or a s peci fi c i nfecti on (eg, wi th Pneumocystis jirovecii i n pa ti ents wi th T-cel l di s orders ) ca n be gi ven prophyl a cti c a nti bi oti cs
(eg, 5 mg/kg tri methopri m/s ul fa methoxa zol e po bi d).
To prevent gra ft-vs -hos t di s ea s e a fter tra ns fus i ons , cl i ni ci a ns s houl d us e bl ood products from cytomega l ovi rus -nega ti ve donors ; the products
s houl d be fi l tered to remove WBCs a nd i rra di a ted (15 to 30 Gy).
Management of acute infection: After a ppropri a te cul tures a re obta i ned, a nti bi oti cs tha t ta rget l i kel y ca us es s houl d be gi ven promptl y. Someti mes
s urgery (eg, to dra i n a bs ces s es ) i s needed. Us ua l l y, s el f-l i mi ted vi ra l i nfecti ons ca us e s evere pers i s tent di s ea s e i n i mmunocompromi s ed
pa ti ents . Anti vi ra l s (eg, a ma nta di ne, ri ma nta di ne, os el ta mi vi r, or za na mi vi r for i nfl uenza ; a cycl ovi r for herpes s i mpl ex a nd va ri cel l a -zos ter
i nfecti ons ; ri ba vi ri n for res pi ra tory s yncyti a l vi rus or pa ra i nfl uenza 3 i nfecti ons ) ma y be l i fes a vi ng.
Replacement of missing immune components: Such repl a cement hel ps prevent i nfecti on. Thera pi es us ed i n more tha n one pri ma ry i mmunodefi ci ency
di s order i ncl ude the fol l owi ng:
IV immune globulin (IVIG) i s effecti ve repl a cement thera py i n mos t forms of a nti body defi ci ency. The us ua l dos e i s 400 mg/kg once/mo; trea tment
i s begun a t a l ow i nfus i on ra te. Some pa ti ents need hi gher or more frequent dos es . IVIG 800 mg/kg once/mo hel ps s ome a nti body-defi ci ent
pa ti ents who do not res pond wel l to conventi ona l dos es , pa rti cul a rl y thos e wi th a chroni c l ung di s order. Hi gh-dos e IVIG a i ms to keep IgG
trough l evel s i n the norma l ra nge (> 500 mg/dL). IVIG ma y a l s o be gi ven by s l ow s c i nfus i ons a t weekl y i nterva l s .
Hematopoietic stem cell transplantation us i ng bone ma rrow, cord bl ood, or a dul t peri phera l bl ood s tem cel l s i s effecti ve for l etha l T-cel l a nd other
i mmunodefi ci enci es . Pretra ns pl a nta ti on chemothera py i s unneces s a ry i n pa ti ents wi thout T cel l s (eg, thos e wi th SCID). However, pa ti ents wi th
i nta ct T-cel l functi on or pa rti a l T-cel l defi ci enci es (eg, Wi s kott-Al dri ch s yndrome, combi ned i mmunodefi ci ency wi th i na dequa te but not a bs ent
T-cel l functi on) requi re pretra ns pl a nta ti on chemothera py to ens ure gra ft a ccepta nce. When a ma tched s i bl i ng donor i s una va i l a bl e,
ha pl oi denti ca l bone ma rrow from a pa rent ca n be us ed. In s uch ca s es , ma ture T cel l s tha t ca us e gra ft-vs -hos t di s ea s e mus t be ri gorous l y
depl eted from pa renta l ma rrow before i t i s gi ven. Umbi l i ca l cord bl ood from a n HLA-ma tched s i bl i ng ca n a l s o be us ed a s a s ource of s tem cel l s .
In s ome ca s es , bone ma rrow or umbi l i ca l cord bl ood from a ma tched unrel a ted donor ca n be us ed, but a fter tra ns pl a nta ti on,
i mmunos uppres s a nts a re requi red to prevent gra ft-vs -hos t di s ea s e, a nd thei r us e del a ys res tora ti on of i mmuni ty.
Retrovi ra l vector gene thera py ha s been s ucces s ful i n a few pa ti ents wi th X-l i nked a nd ADA-defi ci ent SCID, but thi s trea tment i s not wi del y us ed
beca us e s ome pa ti ents wi th X-l i nked SCID devel oped l eukemi a .
Ataxia-Telangiectasia
Ataxia-telangiectasia results from a T-cell defect and causes progressive cerebellar ataxia, oculocutaneous telangiectasias, and recurrent sinopulmonary
infections.
Inheri ta nce i s a utos oma l -reces s i ve. Ata xi a -tel a ngi ecta s i a i s ca us ed by muta ti ons i n the gene tha t encodes a ta xi a -tel a ngi ecta s i a -muta ted (ATM)
protei n. ATM protei n ma y be i mporta nt i n mi togeni c s i gna l tra ns ducti on, mei oti c recombi na ti on, a nd cel l cycl e control .
Age a t ons et of neurol ogi c s ymptoms a nd evi dence of i mmunodefi ci ency va ry. Ata xi a us ua l l y devel ops when chi l dren begi n to wa l k. Progres s i on of
neurol ogi c s ymptoms l ea ds to s evere di s a bi l i ty. Speech becomes s l urred, choreoa thetoi d movements a nd nys ta gmus devel op, a nd mus cl e
wea knes s us ua l l y progres s es to mus cl e a trophy. Tel a ngi ecta s i a s ma y not a ppea r unti l a ge 4 to 6 yr; they a re mos t promi nent on the bul ba r
conjuncti va e, ea rs , a ntecubi ta l a nd popl i tea l fos s a e, a nd s i des of the neck. Recurrent s i nopul mona ry i nfecti ons l ea d to recurrent pneumoni a ,
bronchi ecta s i s , a nd chroni c res tri cti ve pul mona ry di s ea s e. Pa ti ents often l a ck IgA a nd IgE a nd ha ve a progres s i ve T-cel l defect. Certa i n endocri ne
a bnorma l i ti es (eg, gona da l dys genes i s , tes ti cul a r a trophy, di a betes mel l i tus ) ma y occur.
Frequency of ca ncer (es peci a l l y l eukemi a , bra i n tumors , a nd ga s tri c ca ncer) i s hi gh, a nd frequency of chromos ome brea ks , cons i s tent wi th a defect
i n DNA repa i r, i s i ncrea s ed. Serum 1 -fetoprotei n i s us ua l l y el eva ted.
Diagnosis
Cl i ni ca l fi ndi ngs of cerebel l a r a ta xi a (pa rti cul a rl y when tel a ngi ecta s i a s a re pres ent), l ow l evel s of IgA, a nd hi gh l evel s of s erum1 -fetoprotei n
s ugges t the di a gnos i s . Di a gnos i s i s confi rmed by i denti fyi ng muta ti ons on both a l l el es of the gene for ATM protei n.
Treatment
Trea tment wi th a nti bi oti cs or IV i mmune gl obul i n ma y hel p, but no trea tment i s effecti ve for the CNS a bnorma l i ti es . Thus , neurol ogi c deteri ora ti on
progres s es , ca us i ng dea th, us ua l l y by a ge 30.
Chediak-Higashi Syndrome
Chediak-Higashi syndrome is characterized by impaired lysis of phagocytized bacteria, resulting in recurrent bacterial respiratory and other infections and
oculocutaneous albinism.
Chedi a k-Hi ga s hi s yndrome i s ra re. Inheri ta nce i s a utos oma l reces s i ve. The s yndrome i s ca us ed by a muta ti on i n a gene tha t regul a tes
i ntra cel l ul a r protei n tra ffi cki ng. Gi a nt l ys os oma l gra nul es devel op i n neutrophi l s a nd other cel l s (eg, mel a nocytes , neura l Schwa nn cel l s ). The
a bnorma l l ys os omes ca nnot fus e wi th pha gos omes , s o i nges ted ba cteri a ca nnot be l ys ed norma l l y.
Cl i ni ca l fi ndi ngs i ncl ude ocul ocuta neous a l bi ni s m a nd s us cepti bi l i ty to recurrent res pi ra tory a nd other i nfecti ons . In a bout 85% of pa ti ents , a n
a ccel era ted pha s e occurs , ca us i ng fever, ja undi ce, hepa tos pl enomega l y, l ympha denopa thy, pa ncytopeni a , bl eedi ng di a thes i s , a nd neurol ogi c
cha nges . Once the a ccel era ted pha s e occurs , the s yndrome i s us ua l l y fa ta l wi thi n 30 mo.
A peri phera l bl ood s mea r i s exa mi ned for gi a nt gra nul es i n neutrophi l s a nd other cel l s ; a bone ma rrow s mea r i s exa mi ned for gi a nt i ncl us i on
bodi es i n l eukocyte precurs or cel l s .
Tra ns pl a nta ti on of unfra cti ona ted HLA-i denti ca l bone ma rrow a fter pretra ns pl a nta ti on cytoreducti ve chemothera py ma y be cura ti ve.
Chronic Granulomatous Disease
Chronic granulomatous disease is characterized by WBCs that cannot produce activated O2 compounds and by defects in phagocytic cell microbicidal function.
Manifestations include recurrent infections; multiple granulomatous lesions of the lungs, liver, lymph nodes, and GI and GU tract; abscesses; lymphadenitis;
hypergammaglobulinemia; elevated ESR; and anemia. Diagnosis is by assessing O2 radical production in WBCs via a flow cytometric respiratory burst assay.
Treatment is with antibiotics, antifungal drugs, and interferon-; granulocyte transfusions may be needed.
More tha n 50% of ca s es of chroni c gra nul oma tous di s ea s e (CGD) a re i nheri ted a s a n X-l i nked reces s i ve tra i t a nd thus occur onl y i n ma l es ; i n the
res t, i nheri ta nce i s a utos oma l reces s i ve. In CGD, WBCs do not produce hydrogen peroxi de, s uperoxi de, a nd other a cti va ted O2 compounds beca us e
ni coti na mi de a deni ne di nucl eoti de phos pha te oxi da s e a cti vi ty i s defi ci ent. Pha gocyti c cel l mi crobi ci da l functi on i s defecti ve; thus , ba cteri a a nd
fungi a re not ki l l ed des pi te norma l pha gocytos i s .
Symptoms and Signs
CGD us ua l l y begi ns wi th recurrent a bs ces s es duri ng ea rl y chi l dhood, but i n a few pa ti ents , ons et i s del a yed unti l the ea rl y teens . Typi ca l
pa thogens a re ca ta l a s e-produci ng orga ni s ms (eg, Staphylococcus aureus; Escherichia coli; Serratia, Klebsiella, a nd Pseudomonas s p; fungi ). Aspergillus
i nfecti ons a re the l ea di ng ca us e of dea th.
Mul ti pl e gra nul oma tous l es i ons occur i n the l ungs , l i ver, l ymph nodes , a nd GI a nd GU tra ct (ca us i ng obs tructi on). Suppura ti ve l ympha deni ti s ,
hepa tos pl enomega l y, pneumoni a , a nd hema tol ogi c evi dence of chroni c i nfecti on a re common. Ski n, l ymph node, l ung, l i ver, a nd peri a na l
a bs ces s es ; s toma ti ti s ; a nd os teomyel i ti s a l s o occur. Growth ma y be del a yed.
Diagnosis
Di a gnos i s i s by a fl ow cytometri c res pi ra tory burs t a s s a y to detect O2 ra di ca l producti on. The tes t ca n a l s o i denti fy fema l e ca rri ers of the X-l i nked
form. Hyperga mma gl obul i nemi a a nd a nemi a ca n occur; ESR i s el eva ted.
Treatment
Prophyl a cti c a nti bi oti cs , s ometi mes i ncl udi ng a nti funga l s
Someti mes i nterferon (IFN)-
For s evere i nfecti ons , gra nul ocyte tra ns fus i ons or bone ma rrow tra ns pl a nta ti on
Trea tment i s conti nuous prophyl a cti c a nti bi oti cs , pa rti cul a rl y tri methopri m/s ul fa methoxa zol e 160/800 mg po bi d a l one or wi th cepha l exi n 500 mg
po q 8 h. Ora l a nti funga l s a re gi ven a s pri ma ry prophyl a xi s or a re a dded i f funga l i nfecti ons occur even once; mos t us eful a re i tra cona zol e po q 12
h (100 mg for pa ti ents < 13 yr; 200 mg for thos e 13 yr or wei ghi ng > 50 kg), vori cona zol e po q 12 h (100 mg for thos e wei ghi ng < 40 kg; 200 mg for
thos e wei ghi ng 40 kg), or pos a cona zol e (400 mg bi d). IFN- ma y reduce s everi ty a nd frequency of i nfecti ons . Us ua l dos e i s 50 g/m 2 s c 3 ti mes /wk.
Gra nul ocyte tra ns fus i ons ca n be l i fes a vi ng when i nfecti ons a re s evere. When preceded by pretra ns pl a nta ti on chemothera py, HLA-i denti ca l s i bl i ng
bone ma rrow tra ns pl a nta ti on ma y be s ucces s ful .
Chronic Mucocutaneous Candidiasis
Chronic mucocutaneous candidiasis is persistent or recurrent candidal infection due to T-cell defects.
Inheri ta nce i s a utos oma l domi na nt or reces s i ve. Pa ti ents ha ve cuta neous a nergy to Candida, a bs ent prol i fera ti ve res pons es to Candida a nti gen (but
norma l prol i fera ti ve res pons es to mi togens ), a nd i nta ct a nti body res pons e to Candida a nd other a nti gens . Ca ndi di a s i s recurs or pers i s ts , us ua l l y
begi nni ng duri ng i nfa ncy but s ometi mes duri ng ea rl y a dul thood. Li fe s pa n i s not a ffected.
Pa ti ents wi th the reces s i ve form (a utoi mmune pol yendocri nopa thy-ca ndi dos i s -ectoderma l dys trophy) devel op endocri ne di s orders (eg,
hypopa ra thyroi di s m, a drena l i ns uffi ci ency, hypogona di s m, thyroi d di s ea s e, di a betes ), a nd hepa ti ti s .
Thrus h i s common, a s a re i nfecti ons of the s ca l p, s ki n, na i l s , a nd GI a nd va gi na l mucos a . Severi ty va ri es . Na i l s ma y be thi ckened, cra cked, a nd
di s col ored, wi th edema a nd erythema of the s urroundi ng peri ungua l ti s s ue, res embl i ng cl ubbi ng. Ski n l es i ons a re crus ted, pus tul a r,
erythema tous , a nd hyperkera toti c. Sca l p l es i ons ma y res ul t i n s ca rri ng a l opeci a . Infa nts often pres ent wi th refra ctory thrus h, ca ndi da l di a per
derma ti ti s , or both.
Diagnosis
Di a gnos i s i s ba s ed on the pres ence of recurrent ca ndi da l s ki n or mucos a l l es i ons when no other known ca us es of ca ndi da l i nfecti on (eg,
di a betes , a nti bi oti c us e) a re pres ent. Ca ndi da l l es i ons a re confi rmed by other tes ts (eg, pota s s i um hydroxi de wet mount of s cra pi ngs ).
Treatment
Anti funga l drugs
Us ua l l y, the i nfecti ons ca n be control l ed wi th a topi ca l a nti funga l . However, l ong-term trea tment wi th a s ys temi c a nti funga l drug (eg,
a mphoteri ci n B, fl ucona zol e, ketocona zol e) ma y be needed. Topi ca l a nti funga l s a re us ua l l y i neffecti ve. Someti mes a n i mmunomodul a tor (eg,
tra ns fer fa ctor) i s a l s o us ed.
Common Variable Immunodeficiency
Common variable immunodeficiency (acquired or adult-onset hypogammaglobulinemia) is characterized by low immunoglobulin (Ig) levels with phenotypically
normal B cells that can proliferate but do not develop into Ig-producing cells.
Common va ri a bl e i mmunodefi ci ency (CVID) i ncl udes s evera l di fferent mol ecul a r defects , but i n mos t pa ti ents , the mol ecul a r defect i s unknown.
CVID i s cl i ni ca l l y s i mi l a r to X-l i nked a ga mma gl obul i nemi a i n the types of i nfecti ons tha t devel op, but ons et tends to be l a ter, even i n a dul thood.
T-cel l i mmuni ty ma y be i mpa i red i n s ome pa ti ents . Autoi mmune di s orders (eg, SLE, Addi s on's di s ea s e, thyroi di ti s , RA, a l opeci a a rea ta ,
a utoi mmune thrombocytopeni a , a utoi mmune hemol yti c or perni ci ous a nemi a ) ca n occur, a s ca n ma l a bs orpti on, nodul a r l ymphoi d hyperpl a s i a of
the GI tra ct, l ymphoi d i nters ti ti a l pneumoni a , s pl enomega l y, a nd bronchi ecta s i s . Ga s tri c ca rci noma a nd l ymphoma occur i n 10% of pa ti ents .
Diagnosis
Mea s urement of s erum Ig a nd a nti body ti ters
Fl ow cytometry
Serum protei n el ectrophores i s
Di a gnos i s i s s ugges ted by fa mi l i a l cl us teri ng of a utoi mmune di s orders a nd i s confi rmed by mea s uri ng s erum Ig a nd a nti body ti ters to protei n a nd
pol ys a ccha ri de va cci ne a nti gens . If ei ther mea s urement i s l ow, B-cel l qua nti fi ca ti on by fl ow cytometry i s i ndi ca ted to di s ti ngui s h CVID from Xl i nked a ga mma gl obul i nemi a , mul ti pl e myel oma , a nd chroni c l ymphocyti c l eukemi a . Serum protei n el ectrophores i s i s i ndi ca ted to s creen for
monocl ona l ga mmopa thi es (eg, myel oma ), whi ch ma y be a s s oci a ted wi th reduced l evel s of other Ig i s otypes . If pa ti ents a re trea ted wi th IV
i mmune gl obul i n (IVIG) before tes ti ng, s erol ogi c tes ts ha ve no va l ue beca us e the a nti bodi es a re from the IVIG.
Treatment
Trea tment cons i s ts of IVIG 400 mg/kg once/mo a nd a nti bi oti cs a s needed to trea t i nfecti on. Ri tuxi ma b or a corti cos teroi d ma y be requi red to trea t
a utoi mmune di s orders .

DiGeorge Syndrome
DiGeorge syndrome is thymic and parathyroid hypoplasia or aplasia leading to T-cell immunodeficiency and hypoparathyroidism.
Di George s yndrome res ul ts from gene del eti ons i n the Di George chromos oma l regi on a t 22q11, muta ti ons i n genes a t chromos ome 10p13, a nd
muta ti ons i n other unknown genes , whi ch ca us e dys embryogenes i s of s tructures tha t devel op from pha ryngea l pouches duri ng the 8th wk of
ges ta ti on. Mos t ca s es a re s pora di c; boys a nd gi rl s a re equa l l y a ffected. Di -George s yndrome ma y be pa rti a l (s ome T-cel l functi on exi s ts ) or
compl ete (T-cel l functi on i s a bs ent).
Infa nts ha ve l ow-s et ea rs , mi dl i ne fa ci a l cl efts , a s ma l l recedi ng ma ndi bl e, hypertel ori s m, a s hortened phi l trum, a nd a congeni ta l hea rt di s order.
They a l s o ha ve thymi c a nd pa ra thyroi d hypopl a s i a or a pl a s i a , ca us i ng T-cel l defi ci ency a nd hypopa ra thyroi di s m. Recurrent i nfecti ons begi n s oon
a fter bi rth, but the degree of i mmunodefi ci ency va ri es cons i dera bl y, a nd T-cel l functi on ma y i mprove s ponta neous l y. Hypoca l cemi c teta ny a ppea rs
wi thi n 24 to 48 h of bi rth.
Prognos i s often depends on s everi ty of the hea rt di s order.
Diagnosis
Immune functi on a s s es s ment
Pa ra thyroi d functi on a s s es s ment
Chromos ome a na l ys i s
Di a gnos i s i s ba s ed on cl i ni ca l fi ndi ngs . An a bs ol ute l ymphocyte count i s done, fol l owed by B- a nd T-cel l counts i f l eukopeni a i s detected; bl ood
tes ts to eva l ua te T-cel l a nd pa ra thyroi d functi on a re done. A l a tera l ches t x-ra y ma y hel p eva l ua te thymi c s ha dow. Fl uores cent i n s i tu hybri di za ti on
(FISH) tes ti ng ca n detect the chromos oma l del eti on i n the 22q11 regi on; s ta nda rd chromos oma l tes ts to check for other a bnorma l i ti es ma y a l s o be
done. Ca rdi a c ca theteri za ti on ma y be needed to i denti fy hea rt defects .
Treatment
In pa rti a l Di George s yndrome, hypopa ra thyroi di s m i s trea ted wi th Ca a nd vi ta mi n D s uppl ementa ti on; l ong-term s urvi va l i s not a ffected. Compl ete
Di George s yndrome i s fa ta l wi thout trea tment, whi ch i s tra ns pl a nta ti on of cul tured thymus ti s s ue.
Hyper-IgE Syndrome
Hyper-IgE (Buckley) syndrome is combined Band T-cell immunodeficiency characterized by recurrent staphylococcal abscesses of the skin, lungs, joints, and
viscera.
Inheri ta nce i s a utos oma l domi na nt wi th i ncompl ete penetra nce; i t i s ca us ed by muta ti ons i n the STAT3 (s i gna l tra ns ducer a nd a cti va tor of
tra ns cri pti on 3) gene.
Hyper-IgE s yndrome s ta rts duri ng i nfa ncy. It typi ca l l y ca us es recurrent s ta phyl ococca l a bs ces s es of the s ki n, l ungs , joi nts , a nd vi s cera wi th
pul mona ry pneuma tocel es a nd a pruri ti c eos i nophi l i c derma ti ti s . Pa ti ents ha ve coa rs e fa ci a l fea tures , del a yed s heddi ng of ba by teeth,
os teopeni a , a nd recurrent fra ctures . Al l ha ve ti s s ue a nd bl ood eos i nophi l i a a nd very hi gh IgE l evel s (> 1000 IU/mL [> 2400 g/L]).
Di a gnos i s i s s us pected ba s ed on s ymptoms a nd confi rmed by mea s urement of s erum IgE l evel s . Geneti c tes ti ng ca n i denti fy the a bnorma l gene.
Trea tment cons i s ts of l i fel ong conti nuous a nti s ta phyl ococca l a nti bi oti cs (eg, di cl oxa ci l l i n, cepha l exi n).
Hyper-IgM Syndrome
Hyper-IgM syndrome is an Ig deficiency characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum Igs, resulting in
susceptibility to bacterial infections.
Hyper-IgM s yndrome ma y be X-l i nked or a utos oma l . Mos t ca s es a re ca us ed by muta ti ons i n a gene tha t i s l oca ted on the X chromos ome; thi s gene
encodes a protei n (CD154, or CD40 l i ga nd) on the s urfa ces of a cti va ted hel per T cel l s . In the pres ence of cytoki nes , norma l CD40 l i ga nd i ntera cts
wi th B cel l s a nd thus s i gna l s them to s wi tch from produci ng IgM to produci ng IgA, IgG, or IgE.
In X-l i nked hyper-IgM s yndrome, T cel l s l a ck functi ona l CD40 l i ga nd a nd ca nnot s i gna l B cel l s to s wi tch. Thus , B cel l s produce onl y IgM; IgM l evel s
ma y be norma l or el eva ted. Pa ti ents wi th thi s form ma y ha ve s evere neutropeni a a nd often pres ent duri ng i nfa ncy wi th Pneumocystis jirovecii
pneumoni a . Otherwi s e, cl i ni ca l pres enta ti on i s s i mi l a r to tha t of X-l i nked a ga mma gl obul i nemi a a nd i ncl udes recurrent pyogeni c ba cteri a l
s i nopul mona ry i nfecti ons duri ng the fi rs t 2 yr of l i fe. Sus cepti bi l i ty to Cryptosporidium i nfecti ons ma y be i ncrea s ed. Lymphoi d ti s s ue i s very s ma l l
beca us e germi na l centers a re mi s s i ng. Ma ny pa ti ents di e before puberty, a nd thos e who l i ve l onger often devel op ci rrhos i s or B-cel l l ymphoma s .
At l ea s t 4 a utos oma l reces s i ve forms i nvol ve a B-cel l defect. In 2 of thes e forms (defi ci ency of a cti va ti on-i nduced cyti di ne dea mi na s e or ura ci l DNA
gl ycos yl a s e [UNG]), s erum IgM l evel s a re much hi gher tha n i n the X-l i nked form; l ymphoi d hyperpl a s i a (i ncl udi ng l ympha denopa thy, s pl enomega l y,
a nd tons i l l a r hypertrophy) i s pres ent, a nd a utoi mmune di s orders ma y be pres ent.
Diagnosis
Di a gnos i s i s cl i ni ca l a nd by detecti ng norma l or el eva ted s erum IgM l evel s a nd l ow l evel s or a bs ence of other Igs .
Treatment
Trea tment i s IV i mmune gl obul i n 400 mg/kg once/mo. For the X-l i nked form, gra nul ocyte col ony-s ti mul a ti ng fa ctor i s a l s o gi ven a s needed for
neutropeni a , a nd beca us e prognos i s i s poor, bone ma rrow tra ns pl a nta ti on i s preferred i f a n HLA-i denti ca l s i bl i ng donor i s a va i l a bl e.
IgA Deficiency
IgA deficiency is an IgA level < 10 mg/dL with normal IgG and IgM levels. It is the most common primary immunodeficiency. Many patients are asymptomatic,
but some develop recurrent infections and autoimmune disorders. Some patients develop common variable immunodeficiency, and some remit spontaneously.
Diagnosis is by measuring serum Igs. Treatment is avoidance of blood products that contain IgA; antibiotics are given as needed.
IgA defi ci ency a ffects up to 1/333 peopl e. Tra ns mi s s i on i s a utos oma l domi na nt wi th i ncompl ete penetra nce. IgA defi ci ency i s commonl y
a s s oci a ted wi th certa i n HLA ha pl otypes , a nd ra re a l l el es or del eti ons of genes i n the ma jor hi s tocompa ti bi l i ty compl ex (MHC) cl a s s III regi on (s ee
p. 1085) a re common. IgA defi ci ency a l s o occurs i n s i bl i ngs of chi l dren wi th common va ri a bl e i mmunodefi ci ency (CVID) a nd evol ves i nto CVID i n
s ome pa ti ents . Us e of drugs s uch a s phenytoi n, s ul fa s a l a zi ne, col l oi da l gol d a nd D-peni ci l l a mi ne ma y l ea d to IgA defi ci ency i n geneti ca l l y
s us cepti bl e pa ti ents .
Symptoms and Signs
Ma ny pa ti ents a re a s ymptoma ti c; others ha ve recurrent s i nopul mona ry i nfecti ons , di a rrhea , a l l ergi es , or a utoi mmune di s orders (eg, cel i a c or
i nfl a mma tory bowel di s ea s e, SLE, chroni c a cti ve hepa ti ti s ). Anti -IgA a nti bodi es ma y devel op a fter expos ure to IgA i n tra ns fus i ons ; a na phyl a cti c
rea cti ons to IV i mmune gl obul i n (IVIG) a nd other bl ood products tha t conta i n IgA ma y occur.
Diagnosis
Mea s urement of s erum Ig l evel s a nd a nti body ti ters
Di a gnos i s i s s us pected i n pa ti ents who ha ve recurrent i nfecti ons (i ncl udi ng gi a rdi a s i s ); a na phyl a cti c tra ns fus i on rea cti ons ; or a fa mi l y hi s tory of
CVID, IgA defi ci ency, or a utoi mmune di s orders or who a re ta ki ng drugs tha t l ea d to IgA defi ci ency. Di a gnos i s i s confi rmed by a s erum IgA l evel < 10
mg/dL wi th norma l IgG a nd IgM l evel s a nd norma l a nti body ti ters i n res pons e to va cci ne a nti gens .
Prognosis
A few IgA-defi ci ent pa ti ents devel op CVID over ti me; others i mprove s ponta neous l y. Prognos i s i s wors e i f a n a utoi mmune di s order devel ops .
Treatment
Avoi da nce of bl ood products tha t conta i n IgA
Anti bi oti cs a s needed
Trea tment i s a voi da nce of bl ood products tha t conta i n IgA beca us e even tra ce a mounts ca n el i ci t a n a nti -IgA-medi a ted a na phyl a cti c rea cti on. If
RBC tra ns fus i on i s needed, onl y wa s hed RBCs or frozen bl ood ca n be us ed.
Anti bi oti cs a re gi ven a s needed for ba cteri a l i nfecti ons of the ea rs , s i nus es , l ungs , or GI or GU tra ct.
IVIG i s contra i ndi ca ted beca us e ma ny pa ti ents ha ve a nti bodi es to IgA a nd beca us e IVIG i s > 99% IgG, whi ch pa ti ents do not need. Pa ti ents a re
a dvi s ed to wea r a n i denti fi ca ti on bra cel et to prevent i na dvertent pl a s ma or IVIG a dmi ni s tra ti on, whi ch coul d l ea d to a na phyl a xi s .
Leukocyte Adhesion Deficiency
Leukocyte adhesion deficiency results from an adhesion molecule defect that causes granulocyte and lymphocyte dysfunction and recurrent soft-tissue infections.
Inheri ta nce i s a utos oma l reces s i ve. Leukocyte a dhes i on defi ci ency i s ca us ed by defi ci ency of a dhes i ve gl ycoprotei ns on the s urfa ces of WBCs ;
thes e gl ycoprotei ns fa ci l i ta te cel l ul a r i ntera cti ons , cel l a tta chment to bl ood ves s el wa l l s , cel l movement, a nd i ntera cti on wi th compl ement
fra gments . Defi ci enci es i mpa i r the a bi l i ty of gra nul ocytes (a nd l ymphocytes ) to mi gra te out of the i ntra va s cul a r compa rtment, to enga ge i n
cytotoxi c rea cti ons , a nd to pha gocytos e ba cteri a . Severi ty of di s ea s e correl a tes wi th degree of defi ci ency.
Severel y a ffected i nfa nts ha ve recurrent or progres s i ve necroti c s oft-ti s s ue i nfecti ons wi th s ta phyl ococca l a nd gra m-nega ti ve ba cteri a ,
peri odonti ti s , poor wound hea l i ng, l eukocytos i s , a nd del a yed (> 3 wk) umbi l i ca l cord deta chment. WBC counts rema i n hi gh even between
i nfecti ons . Infecti ons become i ncrea s i ngl y di ffi cul t to control .
Diagnosis
Di a gnos i s i s by detecti ng a bs ence or s evere defi ci ency of a dhes i ve gl ycoprotei ns on the s urfa ce of WBCs us i ng monocl ona l a nti bodi es (eg, a nti CD11, a nti -CD18) a nd fl ow cytometry. Leukocytos i s on CBC i s common but nons peci fi c.
Treatment
Mos t pa ti ents di e by a ge 5 unl es s trea ted s ucces s ful l y wi th bone ma rrow tra ns pl a nta ti on, but modera tel y a ffected pa ti ents s urvi ve i nto young
a dul thood.
Trea tment i s wi th a nti bi oti cs , often gi ven conti nuous l y. Gra nul ocyte tra ns fus i ons ca n a l s o hel p. Bone ma rrow tra ns pl a nta ti on i s the onl y effecti ve
trea tment a nd ca n be cura ti ve.
Severe Combined Immunodeficiency
Severe combined immunodeficiency is characterized by absent T cells and a low, high, or normal number of B cells and natural killer cells. Most infants develop
opportunistic infections within the first 3 mo of life. Diagnosis is by detecting lymphopenia, absence or a very low number of T cells, and impaired lymphocyte
proliferative responses to mitogens. Patients must be kept in a protected environment; definitive treatment is bone marrow stem cell transplantation.
Severe combi ned i mmunodefi ci ency (SCID) i s ca us ed by muta ti ons i n a ny one of a t l ea s t 12 di fferent genes . Al l but one type a re a utos oma l
reces s i ve defects , s o for the i nfa nt to be a ffected wi th SCID, the s a me gene mus t be muta ted on both chromos omes . There a re 4 di fferent
a bnorma l l ymphocyte phenotypes . In a l l forms of SCID, T cel l s a re a bs ent (T-); the number of B cel l s a nd na tura l ki l l er (NK) cel l s ma y be l ow or
none (B-; NK-) or hi gh or norma l (B+; NK+), dependi ng on the form of SCID. However, B cel l s , even when norma l i n number, ca nnot functi on beca us e
T cel l s a re a bs ent.
The mos t common form i s X-l i nked. It a ffects the IL-2 receptor cha i n (a component of a t l ea s t 6 cytoki ne receptors ) a nd thus ca us es s evere
di s ea s e; phenotype i s T- B+ NK-. The 2nd mos t common form res ul ts from a denos i ne dea mi na s e (ADA) defi ci ency, whi ch l ea ds to a poptos i s of
precurs ors for B, T, a nd NK cel l s ; phenotype i s T- B- NK-. The next mos t common form res ul ts from IL-7 receptor -cha i n defi ci ency; phenotype i s TB+ NK+.
Symptoms and Signs
By a ge 6 mo, mos t i nfa nts wi th SCID devel op ca ndi di a s i s , pers i s tent vi ra l i nfecti ons , Pneumocystis jirovecii pneumoni a , a nd di a rrhea , l ea di ng to
fa i l ure to thri ve. Some ha ve gra ft-vs -hos t di s ea s e due to ma terna l l ymphocytes or bl ood tra ns fus i ons . Other i nfa nts pres ent a t a ge 6 to 12 mo.
Exfol i a ti ve derma ti ti s ma y devel op a s pa rt of Omenn's s yndrome, one form of SCID. ADA defi ci ency ma y ca us e bone a bnorma l i ti es . The thymus i s
extremel y s ma l l , a nd l ymphoi d ti s s ue ma y be decrea s ed or a bs ent.
Al l forms of SCID a re fa ta l duri ng i nfa ncy unl es s they a re di a gnos ed a nd trea ted ea rl y.
Diagnosis
Hi s tory of pers i s tent i nfecti ons
Mi togen a nd va cci ne a nti gen s ti mul a ti on a s s a ys
Tes ts to determi ne type of SCID
SCID i s s us pected i n i nfa nts wi th a hi s tory of pers i s tent i nfecti ons . CBC, i ncl udi ng a bs ol ute WBC count a nd di fferenti a l , i s done; Ig l evel s a re
mea s ured. Res pons es to mi togens a nd to s ta nda rd va cci ne a nti gens a re determi ned to eva l ua te WBC a nd a nti body functi on. Ches t x-ra ys to
eva l ua te the thymus a re not neces s a ry for di a gnos i s .
The di s order i s di a gnos ed i n pa ti ents wi th the fol l owi ng:
Lymphopeni a
A l ow number of or no T cel l s
Abs ent l ymphocyte prol i fera ti ve res pons es to mi togens
Other tes ts a re done to determi ne the type of SCID. ADA a nd puri ne nucl eos i de phos phoryl a s e l evel s i n WBCs , RBCs , a nd fi brobl a s ts a re mea s ured.
X-i na cti va ti on tes ts ma y be done to determi ne whether SCID i s X-l i nked.
Treatment
IV i mmune gl obul i n (IVIG)
Anti bi oti cs
Bone ma rrow s tem cel l tra ns pl a nta ti on
Someti mes ADA i njecti ons or gene thera py
Pa ti ents mus t be kept i n revers e i s ol a ti on. Trea tment wi th IVIG a nd a nti bi oti cs , i ncl udi ng P. jirovecii prophyl a xi s , i s hel pful but not cura ti ve.
In 90 to 100% of i nfa nts wi th SCID or i ts va ri a nts , bone ma rrow s tem cel l tra ns pl a nta ti on from a n HLA-i denti ca l , mi xed l eukocyte cul ture-ma tched
s i bl i ng res tores i mmuni ty. When a n HLA-i denti ca l s i bl i ng i s not a va i l a bl e, ha pl oi denti ca l bone ma rrow from a pa rent tha t i s ri gorous l y depl eted
of T cel l s ca n be us ed. If SCID i s di a gnos ed by a ge 3 mo, the s urvi va l ra te a fter tra ns pl a nta ti on wi th ei ther type of bone ma rrow i s 96%.
Pretra ns pl a nta ti on chemothera py i s unneces s a ry beca us e pa ti ents do not ha ve T cel l s a nd therefore ca nnot reject a gra ft.
Pa ti ents wi th ADA defi ci ency who do not recei ve a bone ma rrow gra ft ma y be trea ted wi th i njecti ons of pol yethyl ene gl ycol -modi fi ed bovi ne ADA
once or twi ce/wk. Gene thera py ha s been s ucces s ful i n X-l i nked SCID but ha s ca us ed T-cel l l eukemi a s , precl udi ng i ts us e. Gene thera py ha s a l s o
been s ucces s ful i n ADA-defi ci ent SCID, a nd no pos ttrea tment l eukemi a s or l ymphoma s ha ve been reported.
Transient Hypogammaglobulinemia of Infancy
Transient hypogammaglobulinemia of infancy is a temporary decrease in serum IgG and sometimes IgA and other Ig isotypes to levels below age-appropriate
normal values.
In tra ns i ent hypoga mma gl obul i nemi a of i nfa ncy, IgG l evel s conti nue to be l ow a fter the phys i ol ogi c fa l l i n ma terna l IgG a t a bout a ge 3 to 6 mo.
The condi ti on ra rel y l ea ds to s i gni fi ca nt i nfecti ons a nd i s not thought to be a true i mmunodefi ci ency.
Di a gnos i s i s ba s ed on l ow s erum Ig l evel s a nd tes ts s howi ng tha t a nti body producti on i n res pons e to va cci ne a nti gens (eg, teta nus , di phtheri a ) i s
norma l . Thus , thi s condi ti on ca n be di s ti ngui s hed from perma nent forms of hypoga mma gl obul i nemi a , i n whi ch s peci fi c a nti bodi es to va cci ne
a nti gens a re not produced.
IV i mmunogl obul i n i s unneces s a ry. Thi s condi ti on ma y pers i s t for months to a few yea rs but us ua l l y res ol ves .
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome results from a combined B- and T-cell defect and is characterized by recurrent infection, atopic dermatitis, and thrombocytopenia.
Inheri ta nce i s X-l i nked reces s i ve. Wi s kott-Al dri ch s yndrome i s ca us ed by muta ti ons i n the gene tha t encodes the Wi s kott-Al dri ch s yndrome protei n
(WASP), a cytopl a s mi c protei n neces s a ry for norma l B- a nd T-cel l s i gna l i ng. Beca us e B- a nd T-cel l functi ons a re i mpa i red, i nfecti ons wi th pyogeni c
ba cteri a a nd opportuni s ti c orga ni s ms , pa rti cul a rl y vi rus es a nd Pneumocystis jirovecii, devel op.
The fi rs t ma ni fes ta ti ons a re often hemorrha gi c (us ua l l y bl oody di a rrhea ), fol l owed by recurrent res pi ra tory i nfecti ons , eczema , a nd
thrombocytopeni a . Ca ncers , es peci a l l y Eps tei n-Ba rr vi rus l ymphoma s a nd a cute l ymphobl a s ti c l eukemi a , devel op i n a bout 10% of pa ti ents > 10 yr.
Diagnosis
Di a gnos i s i s ba s ed on tes ts s howi ng i mpa i red a nti body res pons es to pol ys a ccha ri de a nti gens , cuta neous a nergy, pa rti a l T-cel l i mmunodefi ci ency,
el eva ted IgE a nd IgA l evel s , l ow IgM l evel s , a nd l ow or norma l IgG l evel s . Anti bodi es to pol ys a ccha ri de a nti gens (eg, bl ood group a nti gens A a nd
B) ma y be s el ecti vel y defi ci ent. Pl a tel ets a re s ma l l a nd defecti ve, a nd s pl eni c des tructi on of pl a tel ets i s i ncrea s ed, ca us i ng thrombocytopeni a .
Muta ti on a na l ys i s ma y be us ed.
Treatment
Trea tment i s s pl enectomy, conti nuous a nti bi oti cs , IV i mmunogl obul i n, a nd bone ma rrow tra ns pl a nta ti on. Wi thout tra ns pl a nta ti on, mos t pa ti ents
di e by a ge 15; however, s ome pa ti ents s urvi ve i nto a dul thood.
X-linked Agammaglobulinemia
(Bruton's Di s ea s e)
X-linked agammaglobulinemia is characterized by low levels or absence of Igs and absent B cells, leading to recurrent infections with encapsulated bacteria.
X-l i nked a ga mma gl obul i nemi a res ul ts from muta ti ons i n a gene on the X chromos ome tha t encodes Bruton tyros i ne ki na s e (Btk). Btk i s es s enti a l
for B-cel l devel opment a nd ma tura ti on; wi thout i t, there a re no B cel l s a nd hence no a nti bodi es . As a res ul t, ma l e i nfa nts ha ve very s ma l l tons i l s
a nd do not devel op l ymph nodes ; they ha ve recurrent pyogeni c l ung, s i nus , a nd s ki n i nfecti ons wi th enca ps ul a ted ba cteri a (eg, Streptococcus
pneumoniae, Haemophilus influenzae). Pa ti ents a re a l s o s us cepti bl e to pers i s tent CNS i nfecti ons res ul ti ng from l i ve-a ttenua ted ora l pol i o va cci ne
a nd from echovi rus es a nd coxs a cki evi rus es ; thes e i nfecti ons ca n a l s o ma ni fes t a s progres s i ve derma tomyos i ti s wi th or wi thout encepha l i ti s .
Wi th ea rl y di a gnos i s a nd a ppropri a te trea tment, prognos i s i s good unl es s CNS vi ra l i nfecti ons devel op.
Diagnosis
Low Ig l evel s a nd a bs ent B cel l s
Di a gnos i s i s by detecti ng l ow IgG l evel s (< 100 mg/dL) a nd a bs ent B cel l s (< 1% CD19+ cel l s vi a fl ow cytometry). Tra ns i ent neutropeni a ma y a l s o be
pres ent. If the muta ti on ha s been i denti fi ed i n fa mi l y members , muta ti ona l a na l ys i s of chori oni c vi l l us , a mni ocentes i s , or percuta neous umbi l i ca l
cord bl ood s a mpl es ca n provi de prena ta l di a gnos i s .
Treatment
Trea tment i s IV i mmune gl obul i n 400 mg/kg once/mo. Prompt us e of a dequa te a nti bi oti cs for ea ch i nfecti on i s cruci a l ; bronchi ecta s i s requi res
conti nuous rota ti on of a nti bi oti cs .
X-linked Lymphoproliferative Syndrome
(Dunca n's Syndrome)
X-linked lymphoproliferative syndrome results from a T-cell and natural killer cell defect and is characterized by an abnormal response to Epstein-Barr virus
infection, leading to liver failure, immunodeficiency, lymphoma, fatal lymphoproliferative disease, or bone marrow aplasia.
X-l i nked l ymphoprol i fera ti ve s yndrome i s ca us ed by muta ti ons i n a gene on the X chromos ome tha t encodes a T a nd na tura l ki l l er (NK) cel l -
s peci fi c protei n ca l l ed SAP. Wi thout SAP, l ymphocytes prol i fera te unchecked i n res pons e to Eps tei n-Ba rr vi rus (EBV) i nfecti on, a nd NK cel l s do not
functi on.
The s yndrome i s us ua l l y a s ymptoma ti c unti l EBV i nfecti on devel ops . Then, mos t pa ti ents devel op ful mi na ti ng or fa ta l i nfecti ous mononucl eos i s
wi th l i ver fa i l ure (ca us ed by cytotoxi c T cel l s tha t rea ct to EBV-i nfected B or other ti s s ue cel l s ); s urvi vors of i ni ti a l i nfecti on devel op B-cel l
l ymphoma s , a pl a s ti c a nemi a , hypoga mma gl obul i nemi a (res embl i ng tha t i n common va ri a bl e i mmunodefi ci ency), or a combi na ti on.
Diagnosis
Di a gnos ti c fi ndi ngs i n pa ti ents tha t s urvi ve i ni ti a l EBV i nfecti on i ncl ude hypoga mma gl obul i nemi a , decrea s ed a nti body res pons es to a nti gens
(pa rti cul a rl y to EBV nucl ea r a nti gen), i mpa i red T-cel l prol i fera ti ve res pons es to mi togens , decrea s ed NK-cel l functi on, a nd a n i nverted CD4:CD8
ra ti o. Geneti c di a gnos i s by muta ti on a na l ys i s i s pos s i bl e before EBV i nfecti on a nd s ymptoms devel op.
Treatment
About 75% of pa ti ents di e by a ge 10, a nd a l l di e by a ge 40 unl es s bone ma rrow tra ns pl a nta ti on i s done. Tra ns pl a nta ti on i s cura ti ve i f done before
EBV i nfecti on or other di s orders become i rrevers i bl e, res ul ti ng i n dea th.
ZAP-70 Deficiency
ZAP-70 (-associated protein 70) deficiency is impaired T-cell activation caused by a signaling defect.
ZAP-70 i s i mporta nt i n T-cel l s i gna l i ng a nd i n T-cel l s el ecti on i n the thymus . ZAP-70 defi ci ency ca us es T-cel l a cti va ti on defects .
Pa ti ents who ha ve ZAP-70 defi ci ency pres ent duri ng i nfa ncy or ea rl y chi l dhood wi th recurrent i nfecti ons s i mi l a r to thos e i n s evere combi ned
i mmunodefi ci ency (SCID); however, they l i ve l onger, a nd the defi ci ency ma y not be di a gnos ed unti l they a re s evera l yea rs ol d. Pa ti ents ha ve
norma l , l ow, or el eva ted s erum Ig l evel s a nd norma l or el eva ted numbers of ci rcul a ti ng CD4 T cel l s but es s enti a l l y no CD8 T cel l s . Thei r CD4 T cel l s
do not res pond to mi togens or a l l ogenei c cel l s i n vi tro a nd do not produce cytotoxi c T cel l s . In contra s t, na tura l ki l l er cel l a cti vi ty i s norma l .
Di a gnos i s i s s i mi l a r to tha t for SCID.
The di s order i s fa ta l unl es s trea ted by bone ma rrow tra ns pl a nta ti on.
Chapter 127. Allergic and Other Hypersensitivity Disorders

Introduction
Al l ergi c a nd other hypers ens i ti vi ty di s orders a re exa ggera ted or i na ppropri a te i mmune rea cti ons .
Classification
The Gel l a nd Coombs cl a s s i fi ca ti on del i nea tes 4 types of hypers ens i ti vi ty rea cti on. Hypers ens i ti vi ty di s orders often i nvol ve more tha n 1 type.
Type I: Type I rea cti ons (i mmedi a te hypers ens i ti vi ty) a re IgE-medi a ted. Anti gen bi nds to IgE (whi ch i s bound to ti s s ue ma s t cel l s a nd bl ood
ba s ophi l s ), tri ggeri ng rel ea s e of preformed medi a tors (eg, hi s ta mi ne, protea s es , chemota cti c fa ctors ) a nd s ynthes i s of other medi a tors (eg,
pros ta gl a ndi ns , l eukotri enes , pl a tel et-a cti va ti ng fa ctor, cytoki nes ). Thes e medi a tors ca us e va s odi l a ti on, i ncrea s ed ca pi l l a ry permea bi l i ty, mucus
hypers ecreti on, s mooth mus cl e s pa s m, a nd ti s s ue i nfi l tra ti on wi th eos i nophi l s , type 2 hel per T cel l s (TH 2), a nd other i nfl a mma tory cel l s . Type I
rea cti ons underl i e a topi c di s orders (eg, a l l ergi c a s thma , rhi ni ti s , conjuncti vi ti s ) a nd l a tex a nd s ome food a l l ergi es .
Type II: Type II rea cti ons res ul t when a nti body bi nds to cel l ul a r or ti s s ue a nti gens or to a mol ecul e coupl ed to a cel l or ti s s ue. The a nti gena nti body compl ex a cti va tes cel l s tha t pa rti ci pa te i n a nti body-dependent cel l -medi a ted cytotoxi ci ty (eg, NK cel l s , eos i nophi l s , ma cropha ges ),
compl ement, or both. The res ul t i s cel l a nd ti s s ue da ma ge. Di s orders i nvol vi ng type II rea cti ons i ncl ude hypera cute gra ft rejecti on of a n orga n
tra ns pl a nt, Coombs '-pos i ti ve hemol yti c a nemi a s , Ha s hi moto's thyroi di ti s , a nd a nti gl omerul a r ba s ement membra ne di s ea s e (eg, Goodpa s ture's
s yndrome).
Type III: Type III rea cti ons ca us e a cute i nfl a mma ti on i n res pons e to ci rcul a ti ng a nti gen-a nti body i mmune compl exes depos i ted i n ves s el s or
ti s s ue. Thes e compl exes ca n a cti va te the compl ement s ys tem or bi nd to a nd a cti va te certa i n i mmune cel l s , res ul ti ng i n rel ea s e of i nfl a mma tory
medi a tors . Cons equences of i mmune compl ex forma ti on depend i n pa rt on the rel a ti ve proporti ons of a nti gen a nd a nti body i n the i mmune
compl ex. Ea rl y, there i s exces s a nti gen wi th s ma l l a nti gen-a nti body compl exes , whi ch do not a cti va te compl ement. La ter, when a nti gen a nd
a nti body a re more ba l a nced, i mmune compl exes a re l a rger a nd tend to be depos i ted i n va ri ous ti s s ues (gl omerul i , bl ood ves s el s ), ca us i ng
s ys temi c rea cti ons . The i s otype of i nduced a nti bodi es cha nges , a nd gl ycos yl a ti on of the compl ex's components contri butes to the cl i ni ca l
res pons e. Type III di s orders i ncl ude s erum s i cknes s , SLE, RA, l eukocytocl a s ti c va s cul i ti s , cryogl obul i nemi a , hypers ens i ti vi ty pneumoni ti s ,
bronchopul mona ry a s pergi l l os i s , a nd s evera l types of gl omerul onephri ti s .
Type IV: Type IV rea cti ons (del a yed hypers ens i ti vi ty) a re T cel l -medi a ted. There a re 4 s ubtypes ba s ed on the T-cel l s ubpopul a ti on i nvol ved:
IVa : Type 1 hel per T cel l s
IVb: Type 2 hel per T cel l s
IVc: Cytotoxi c T cel l s
IVd: IL-8-s ecreti ng T cel l s
Thes e cel l s , s ens i ti zed a fter conta ct wi th a s peci fi c a nti gen, a re a cti va ted by reexpos ure to the a nti gen; they da ma ge ti s s ue by di rect toxi c effects
or through rel ea s e of cytoki nes , whi ch a cti va te eos i nophi l s , monocytes a nd ma cropha ges , neutrophi l s , or ki l l er cel l s dependi ng on type. Di s orders
i nvol vi ng type IV rea cti ons i ncl ude conta ct derma ti ti s (eg, poi s on i vy), hypers ens i ti vi ty pneumoni ti s , a l l ogra ft rejecti on, TB, a nd ma ny forms of drug
hypers ens i ti vi ty.
Autoimmune disorders: Immune s ys tem rea cti ons di rected a ga i ns t i ntri ns i c body components ca n l ea d to a utoi mmune di s ea s e (s ee
Ta bl e 127-1).
Angioedema
Angioedema is edema of the deep dermis and subcutaneous tissues. It is caused by exposure to drug, venom, dietary, or extracted allergens. The main symptom
is diffuse, painful swelling that can be severe. Diagnosis is by examination. Treatment is elimination or avoidance of the allergen and H 1 blockers.
Acute a ngi oedema i s es s enti a l l y a na phyl a xi s of the s ubcuta neous ti s s ues . It i s s ometi mes a ccompa ni ed by urti ca ri a (l oca l whea l s a nd erythema
i n the s ki ns ee p. 639); the two ha ve s i mi l a r ca us es (eg, drug, venom, di eta ry, or extra cted a l l ergens ). Al s o, a ngi oedema i s pa thogeneti ca l l y
rel a ted to urti ca ri a , whi ch occurs a t the epi derma l -derma l juncti on.
Chroni c (> 6 wk) a ngi oedema i s ra rel y IgE-medi a ted a nd i s more di ffi cul t to expl a i n. Ca us e i s us ua l l y unknown (i di opa thi c), but chroni c i nges ti on
of a n uns us pected drug or chemi ca l (eg, peni ci l l i n i n mi l k, a nonpres cri pti on drug, pres erva ti ves , other food a ddi ti ves ) i s s ometi mes the ca us e. A
few ca s es a re heredi ta ry (s ee p. 1112).
Symptoms and Signs
Angi oedema ma y be s l i ghtl y pruri ti c or nonpruri ti c. It i s cha ra cteri zed by l oca l l y di ffus e a nd pa i nful s oft-ti s s ue s wel l i ng tha t ma y be a s ymmetri c,
es peci a l l y on the eyel i ds , l i ps (s ee
Pl a te 57), fa ce, a nd tongue but a l s o on the ba ck of ha nds or feet a nd on the geni ta l s . Edema of the upper a i rwa ys ma y ca us e res pi ra tory di s tres s ,
a nd the s tri dor ma y be mi s ta ken for a s thma . Compl ete a i rwa y obs tructi on ma y occur.
Diagnosis
The ca us e i s often obvi ous , a nd di a gnos ti c tes ts a re s el dom requi red beca us e rea cti ons a re s el f-l i mi ted a nd nonrecurrent. No tes t i s pa rti cul a rl y
us eful . Erythropoi eti c protoporphyri a ma y mi mi c a l l ergi c forms of a ngi oedema a nd ca n be di s ti ngui s hed by mea s uri ng bl ood a nd feca l porphyri ns
(s ee p. 817).
Treatment
Ora l predni s one
Someti mes s c epi nephri ne
Someti mes IV a nti hi s ta mi nes
[Table 127-1. Puta ti ve Autommune Di s orders ]
For a cute a ngi oedema , trea tment i s removi ng or a voi di ng the a l l ergen a nd rel i evi ng s ymptoms (eg, wi th H 1 bl ockers s ee p.
1116 a nd Ta bl e 127-2). Predni s one 30 to 40 mg po once/da y i s i ndi ca ted for more s evere rea cti ons . Topi ca l corti cos teroi ds a re us el es s . If a ca us e i s
not obvi ous , a l l nones s enti a l drugs s houl d be s topped. Pha ryngea l or l a ryngea l a ngi oedema requi res epi nephri ne 0.3 mL of a 1:1000 s ol uti on s c. It
ma y be s uppl emented wi th a n IV a nti -hi s ta mi ne (eg, di phenhydra mi ne 50 to 100 mg). Long-term trea tment ma y i nvol ve H 1 a nd H 2 bl ockers a nd
occa s i ona l l y corti cos teroi ds .
[Table 127-2. Ora l H 1 Bl ockers ]
Hereditary Angioedema
Hereditary angioedema is caused by deficiency or dysfunction of C1 inhibitor, a protein that regulates the classical complement activation pathway (see p. 1085).
Heredi ta ry a ngi oedema ha s 2 types :
Type 1 (85%): C1 i nhi bi tor i s defi ci ent.
Type 2 (15%): C1 i nhi bi tor ma l functi ons .
Inheri ta nce i s a utos oma l domi na nt. C1 i nhi bi tor defi ci ency ma y a l s o be a cqui red: when compl ement i s cons umed i n neopl a s ti c di s orders (eg, Bcel l l ymphoma ), when C1 i nhi bi tor a utoa nti body i s produced i n monocl ona l ga mmopa thy, or, ra rel y, when the a utoa nti body i s produced i n other
di s orders (eg, SLE, derma tomyos i ti s ). Atta cks ca n be preci pi ta ted by mi l d tra uma (eg, denta l work, tongue pi erci ng), vi ra l i l l nes s , col d expos ure,
pregna ncy, or i nges ti on of certa i n foods or ma y be a ggra va ted by emoti ona l s tres s .
Symptoms a nd s i gns a re s i mi l a r to thos e of a ngi oedema except tha t edema progres s es unti l compl ement components ha ve been cons umed; the
GI tra ct i s often i nvol ved, ca us i ng na us ea , vomi ti ng, col i c, a nd s i gns of i ntes ti na l obs tructi on. Other common a na tomi c l oca ti ons i ncl ude the s ki n
a nd the l a rynx. Epi s odes of s wel l i ng a re s el f-l i mi ted; however, l a ryngea l i nvol vement ca n l ea d to dea th.
Diagnosis
Mea s urement of compl ement protei n l evel s
Di a gnos i s i s ba s ed on detecti on of l ow l evel s of C2 a nd C4, norma l l evel s of C1q (a fra gment of C1), a nd decrea s ed C1 i nhi bi tor functi on. In type 1,
C1 i nhi bi tor protei n l evel s a re l ow; i n type 2, l evel s a re norma l or i ncrea s ed. In a cqui red C1 i nhi bi tor defi ci ency, C1q l evel s a re l ow.
Treatment
Attenua ted a ndrogens
Symptoma ti c trea tments
Attenua ted a ndrogens (eg, s ta nozol ol 2 mg po ti d, da na zol 200 mg po ti d) a re us ed to s ti mul a te hepa ti c C1 i nhi bi tor s ynthes i s . Thi s trea tment ma y
be l es s effecti ve for the a cqui red form. Some experts a dvoca te gi vi ng fres h frozen pl a s ma i mmedi a tel y before denta l or medi ca l procedures to
prevent a tta cks , but thi s a pproa ch coul d theoreti ca l l y provoke a n a tta ck by provi di ng s ubs tra te for a ngi oedema .
Puri fi ed C1 i nhi bi tor a nd recombi na nt C1 i nhi bi tor a re bei ng devel oped for a cute trea tment. Corti cos teroi ds a nd a nti hi s ta mi nes a re not effecti ve.
Epi nephri ne ca n be of tra ns i ent benefi t i n ca s es of a i rwa y i nvol vement. Symptoma ti c rel i ef ca n be provi ded by a na l ges i cs , a nti emeti cs , a nd fl ui d
repl a cement.
Atopic and Allergic Disorders
Type I hypers ens i ti vi ty rea cti ons underl i e a l l a topi c a nd ma ny a l l ergi c di s orders . The terms a topy a nd a l l ergy a re often us ed i ntercha ngea bl y but
a re di fferent:
Atopy i s a n exa ggera ted IgE-medi a ted i mmune res pons e; a l l a topi c di s orders a re type I hypers ens i ti vi ty di s orders .
Allergy i s a ny exa ggera ted i mmune res pons e to a forei gn a nti gen rega rdl es s of mecha ni s m.
Thus , a l l a topi c di s orders a re cons i dered a l l ergi c, but ma ny a l l ergi c di s orders (eg, hypers ens i ti vi ty pneumoni ti s ) a re not a topi c. Al l ergi c di s orders
a re the mos t common di s orders a mong peopl e.
Atopi c di s orders mos t commonl y a ffect the nos e, eyes , s ki n, a nd l ungs . Thes e di s orders i ncl ude a topi c derma ti ti s , conta ct derma ti ti s , urti ca ri a
(s ee p. 639), a ngi oedema (whi ch ma y be pri ma ry s ki n di s orders or s ymptoms of s ys temi c di s orders ), l a tex a l l ergy (s ee Si deba r 127-1), a l l ergi c l ung
di s orders (eg, a s thma , a l l ergi c bronchopul mona ry a s pergi l l os i s , hypers ens i ti vi ty pneumoni ti s ), a nd a l l ergi c rea cti ons to venomous s ti ngs .
Etiology
Compl ex geneti c, envi ronmenta l , a nd s i te-s peci fi c fa ctors contri bute to devel opment of a l l ergi es .
Genetic factors ma y be i nvol ved, a s s ugges ted by fa mi l i a l i nheri ta nce of di s ea s e, a s s oci a ti on between a topy a nd s peci fi c HLA l oci , a nd
pol ymorphi s ms of s evera l genes , i ncl udi ng thos e for the hi gh-a ffi ni ty IgE receptor -cha i n, IL-4 receptor -cha i n, IL-4, IL-13, CD14, di pepti dyl pepti da s e 10 (DPP10), a nd a di s i ntegri n a nd meta l l oprotea s e doma i n 33 (ADAM33).
Environmental factors i ntera ct wi th geneti c fa ctors to ma i nta i n type 2 hel per T (TH 2) cel l i mmune res pons es , whi ch a cti va te eos i nophi l s a nd IgE
producti on a nd a re proa l l ergi c. Ea rl y chi l dhood expos ure to ba cteri a l a nd vi ra l i nfecti ons a nd endotoxi ns (eg, l i popol ys a ccha ri de) ma y norma l l y
s hi ft na ti ve TH 2-cel l res pons es to type 1 hel per T (TH 1)-cel l res pons es , whi ch s uppres s TH 2 cel l s a nd therefore di s coura ge a l l ergi c res pons es .
Regul a tory T (CD4+CD25+Foxp3+) cel l s (whi ch a re ca pa bl e of s uppres s i ng TH 2-cel l res pons es ) a nd IL-12-s ecreti ng dendri ti c cel l s (whi ch dri ve TH 1cel l res pons es ) a re perha ps a l s o i nvol ved. But trends i n devel oped countri es towa rd s ma l l er fa mi l i es wi th fewer chi l dren, cl ea ner i ndoor
envi ronments , a nd ea rl y us e of va cci na ti ons a nd a nti bi oti cs ma y depri ve chi l dren of expos ure to i nfecti ous a gents tha t dri ve a predomi na ntl y TH 1cel l res pons e; s uch trends ma y expl a i n the i ncrea s ed preva l ence of s ome a l l ergi c di s orders . Other fa ctors thought to contri bute to a l l ergy
devel opment i ncl ude chroni c a l l ergen expos ure a nd s ens i ti za ti on, di et, a nd envi ronmenta l pol l uta nts .
Sidebar 127-1 Latex Sensitivity

La tex s ens i ti vi ty i s a n exa ggera ted i mmune res pons e to wa ter-s ol ubl e protei ns i n l a tex products (eg, rubber gl oves , denta l da ms , condoms , tubi ng
for res pi ra tory equi pment, ca theters , enema ti ps wi th i nfl a ta bl e l a tex cuffs ), ca us i ng urti ca ri a , a ngi oedema , a nd a na phyl a xi s .
Rea cti ons to l a tex ma y be a cute (IgE-medi a ted) or del a yed (cel l -medi a ted). Acute rea cti ons ca us e urti ca ri a a nd a na phyl a xi s ; del a yed rea cti ons
ca us e derma ti ti s .
Di a gnos i s i s ba s ed on hi s tory. As s a ys for detecti ng IgE a nti -l a tex a nti bodi es a nd pa tch tes ts for detecti ng a nti -l a tex cel l ul a r i mmuni ty a re bei ng
devel oped, but none i s wel l -va l i da ted yet.
Trea tment i s a voi da nce of l a tex.
Site-specific factors i ncl ude a dhes i on mol ecul es i n bronchi a l epi thel i um a nd i n s ki n a nd mol ecul es i n the GI tra ct tha t di rect TH 2 cel l s to ta rget
ti s s ues .
Allergens: By defi ni ti on, a n a l l ergen i nduces IgE-medi a ted a nd TH 2-cel l i mmune res pons es . Al l ergi c tri ggers a re a l mos t a l wa ys l ow mol ecul a r
wei ght protei ns ; ma ny of them ca n be cons ti tuted a s a i rborne pa rti cl es .
Al l ergens tha t mos t commonl y ca us e a cute a nd chroni c a l l ergi c rea cti ons i ncl ude
Hous e dus t
Mi te feces
Ani ma l da nder
Pol l ens (tree, gra s s , weed)
Mol ds
Pathophysiology
When a l l ergen bi nds to IgE-s ens i ti zed ma s t cel l s a nd ba s ophi l s , hi s ta mi ne i s rel ea s ed from thei r i ntra cel l ul a r gra nul es . Ma s t cel l s a re wi del y
di s tri buted but a re mos t concentra ted i n s ki n, l ungs , a nd GI mucos a ; hi s ta mi ne fa ci l i ta tes i nfl a mma ti on a nd i s the pri ma ry medi a tor of cl i ni ca l
a topy. Phys i ca l di s rupti on of ti s s ue a nd va ri ous s ubs ta nces (eg, ti s s ue i rri ta nts , opi oi ds , s urfa ce-a cti ve a gents , compl ement components C3a a nd
C5a ) ca n tri gger hi s ta mi ne rel ea s e di rectl y, i ndependent of IgE.
Hi s ta mi ne ca us es the fol l owi ng:
Loca l va s odi l a ti on (ca us i ng erythema )
Increa s ed ca pi l l a ry permea bi l i ty a nd edema (produci ng a whea l )
Surroundi ng a rteri ol a r va s odi l a ti on medi a ted by neurona l refl ex mecha ni s ms (ca us i ng fl a re)
Sti mul a ti on of s ens ory nerves (ca us i ng i tchi ng)
Smooth mus cl e contra cti on i n the a i rwa ys (bronchocons tri cti on) a nd i n the GI tra ct (i ncrea s i ng GI moti l i ty)
Increa s ed s a l i va ry a nd bronchi a l gl a nd s ecreti ons
When rel ea s ed s ys temi ca l l y, hi s ta mi ne i s a potent a rteri ol a r di l a tor a nd ca n ca us e extens i ve peri phera l pool i ng of bl ood a nd hypotens i on;
cerebra l va s odi l a ti on ma y be a fa ctor i n va s cul a r hea da che. Hi s ta mi ne i ncrea s es ca pi l l a ry permea bi l i ty; the res ul ti ng l os s of pl a s ma a nd pl a s ma
protei ns from the va s cul a r s pa ce ca n wors en ci rcul a tory s hock. Thi s l os s tri ggers a compens a tory ca techol a mi ne s urge from a drena l chroma ffi n
cel l s .
Symptoms and Signs
Common s ymptoms i ncl ude rhi norrhea , s neezi ng, a nd na s a l conges ti on (upper res pi ra tory tra ct); wheezi ng a nd dys pnea (l ower res pi ra tory tra ct);
a nd i tchi ng (eyes a nd s ki n).
Si gns ma y i ncl ude na s a l turbi na te edema , s i nus pa i n duri ng pa l pa ti on, wheezi ng, conjuncti va l hyperemi a a nd edema , a nd s ki n l i cheni fi ca ti on.
Stri dor, wheezi ng, a nd s ometi mes hypotens i on a re l i fe-threa teni ng s i gns of a na phyl a xi s (s ee p. 1120). In s ome chi l dren, a na rrow a nd hi gh-a rched
pa l a te, na rrow chi n, a nd el onga ted ma xi l l a wi th overbi te (a l l ergi c fa ci es ) a re thought to be a s s oci a ted wi th chroni c a l l ergy.
Diagnosis
CBC a nd s erum IgE l evel s (nons peci fi c tes ts )
Ski n tes ti ng a nd ra di oa l l ergos orbent tes ti ng (s peci fi c tes ts )
Ra rel y, provoca ti ve tes ti ng
A thorough hi s tory i s genera l l y more rel i a bl e tha n tes ti ng or s creeni ng. Hi s tory s houl d i ncl ude
Ques ti ons a bout frequency a nd dura ti on of a tta cks a nd cha nges over ti me
Tri ggeri ng fa ctors i f i denti fi a bl e
Rel a ti on to s ea s ona l or s i tua ti ona l s etti ngs (eg, predi cta bl y occurri ng duri ng pol l en s ea s ons ; a fter expos ure to a ni ma l s , ha y, or dus t; duri ng
exerci s e; or i n pa rti cul a r pl a ces )
Fa mi l y hi s tory of s i mi l a r s ymptoms or of a topi c di s orders
Res pons es to a ttempted trea tments
Age a t ons et ma y be i mporta nt i n a s thma beca us e chi l dhood a s thma i s l i kel y to be a topi c a nd a s thma begi nni ng a fter a ge 30 i s not.
Nonspecific tests: Certa i n tes ts ca n s ugges t but not confi rm a n a l l ergi c ori gi n of s ymptoms .
CBC s houl d be ordered to detect eos i nophi l i a i n a l l pa ti ents except thos e ta ki ng corti cos teroi ds , whi ch reduce the eos i nophi l count. An eos i nophi l
di fferenti a l of 5 to 15% of tota l WBCs s ugges ts a topy but i s nons peci fi c; 16 to 40% ma y refl ect a topy or other condi ti ons (eg, drug hypers ens i ti vi ty,
ca ncer, a utoi mmune di s orders , pa ra s i ti c i nfecti on); a di fferenti a l of 50 to 90% a l mos t never occurs i n a topi c di s orders a nd i s more cha ra cteri s ti c of
hypereos i nophi l i c s yndrome or vi s cera l l a rva mi gra ns . Tota l WBC i s us ua l l y norma l .
Conjuncti va l or na s a l s ecreti ons or s putum ca n be exa mi ned for l eukocytes ; fi ndi ng a ny eos i nophi l s i ndi ca tes tha t TH 2-medi a ted a l l ergi c
i nfl a mma ti on i s l i kel y.
Serum IgE l evel s a re el eva ted i n a topi c di s orders but a re of l i ttl e hel p i n di a gnos i s beca us e they ma y a l s o be el eva ted i n pa ra s i ti c i nfecti ons ,
i nfecti ous mononucl eos i s , a utoi mmune di s orders , drug rea cti ons , i mmunodefi ci ency di s orders (hyper-IgE s yndromes ee p. 1104a nd Wi s kottAl dri ch s yndromes ee p. 1107), a nd i n s ome forms of mul ti pl e myel oma . IgE l evel s a re proba bl y mos t hel pful for fol l owi ng res pons e to thera py i n
a l l ergi c bronchopul mona ry a s pergi l l os i s (s ee p. 1887).
Specific tests: Ski n tes ti ng us es s ta nda rdi zed concentra ti ons of a nti gen i ntroduced di rectl y i nto s ki n a nd i s i ndi ca ted when a deta i l ed hi s tory a nd
phys i ca l exa mi na ti on do not i denti fy the ca us e a nd tri ggers for s ymptoms . Ski n tes ti ng ha s hi gher pos i ti ve predi cti ve va l ues for di a gnos i ng a l l ergi c
rhi nos i nus i ti s a nd conjuncti vi ti s tha n for di a gnos i ng a l l ergi c a s thma or food a l l ergy; nega ti ve predi cti ve va l ue for food a l l ergy i s hi gh. The mos t
commonl y us ed a nti gens a re pol l ens (tree, gra s s , weed), mol ds , hous e dus t mi tes , a ni ma l da nders a nd s era , i ns ect venom, foods , a nd -l a cta m
a nti bi oti cs . Choi ce of a nti gens to i ncl ude i s ba s ed on pa ti ent hi s tory a nd geogra phi c preva l ence.
Two s ki n tes t techni ques ca n be us ed
Percuta neous (pri ck)
Intra derma l
The pri ck tes t ca n detect mos t a l l ergi es . The i ntra derma l tes t i s more s ens i ti ve but l es s s peci fi c; i t ca n be us ed to eva l ua te s ens i ti vi ty to a l l ergens
wi th nega ti ve or equi voca l pri ck tes t res ul ts .
For the prick test, a drop of a nti gen extra ct i s pl a ced on the s ki n, whi ch i s then pri cked or punctured through the extra ct by tenti ng up the s ki n wi th
the ti p of a 27-ga uge needl e hel d a t a 20 a ngl e or wi th a commerci a l l y a va i l a bl e pri ck devi ce.
For the intradermal test, jus t enough extra ct to produce a 1- or 2-mm bl eb (typi ca l l y 0.02 mL) i s i njected i ntra derma l l y wi th a 0.5- or 1-mL s yri nge a nd
a 27-ga uge s hort-bevel needl e.
Pri ck a nd i ntra derma l s ki n tes ti ng s houl d i ncl ude the di l uent a l one a s a nega ti ve control a nd hi s ta mi ne (10 mg/mL for pri ck tes ts , 0.01 mL of a
1:1000 s ol uti on for i ntra derma l tes ts ) a s a pos i ti ve control . For pa ti ents who ha ve ha d a recent (< 1 yr) genera l i zed rea cti on to the tes t a nti gen,
tes ti ng begi ns wi th the s ta nda rd rea gent di l uted 100-fol d, then 10-fol d, a nd then the s ta nda rd concentra ti on. A tes t i s cons i dered pos i ti ve i f a
whea l a nd fl a re rea cti on occurs a nd whea l di a meter i s 3 to 5 mm grea ter tha n tha t of the nega ti ve control a fter 15 to 20 mi n. Fa l s e pos i ti ves occur
i n derma togra phi s m (a whea l a nd fl a re rea cti on provoked by s troki ng or s cra pi ng the s ki n). Fa l s e nega ti ves occur when a l l ergen extra cts ha ve
been s tored i ncorrectl y or a re outda ted. Certa i n drugs ca n a l s o i nterfere wi th res ul ts a nd s houl d be s topped a few da ys to a week before tes ti ng.
Thes e drugs i ncl ude OTC a nd pres cri pti on a nti hi s ta mi nes , tri cycl i c a nti depres s a nts , a nd monoa mi ne oxi da s e i nhi bi tors . Pa ti ents ta ki ng -bl ockers
s houl d not be tes ted.
Radioallergosorbent testing (RAST) detects the pres ence of a l l ergen-s peci fi c s erum IgE a nd i s i ndi ca ted when s ki n tes ti ng i s contra i ndi ca ted beca us e
of genera l i zed derma ti ti s , derma togra phi s m, hi s tory of a na phyl a xi s to the a l l ergen, or need to conti nue a nti hi s ta mi nes . A known a l l ergen i n the
form of a n i ns ol ubl e pol ymer-a l l ergen conjuga te i s mi xed wi th the s erum to be tes ted a nd wi th 125 I-l a bel ed a nti -IgE a nti body. Any a l l ergens peci fi c IgE i n the s erum bi nds the conjuga te a nd ca n be qua nti fi ed by mea s uri ng the 125 I-l a bel ed a nti body.
Provocative testing i nvol ves di rect expos ure of the mucos a e to a l l ergen a nd i s i ndi ca ted for pa ti ents who mus t document thei r rea cti on (eg, for
occupa ti ona l or di s a bi l i ty cl a i ms ) a nd s ometi mes for di a gnos i s of food a l l ergy.
Ophthalmic testing ha s no a dva nta ge over s ki n tes ti ng a nd i s ra rel y us ed.
Nasal and bronchial challenge a re pri ma ri l y res ea rch tool s , but bronchi a l cha l l enge i s s ometi mes us ed when the cl i ni ca l s i gni fi ca nce of a pos i ti ve
s ki n tes t i s uncl ea r or when no a nti gen extra cts a re a va i l a bl e (eg, for occupa ti on-rel a ted a s thma ).
Treatment
Remova l or a voi da nce of a l l ergi c tri ggers
Anti hi s ta mi nes
Ma s t cel l s ta bi l i zers
Anti -i nfl a mma tory corti cos teroi ds a nd l eukotri ene i nhi bi tors
Immunothera py (des ens i ti za ti on)
Environmental control: Remova l or a voi da nce of a l l ergi c tri ggers i s the pri ma ry trea tment for a l l ergy, a s wel l a s the pri ma ry preventi ve s tra tegy (s ee
Preventi on on p. 1117).
Antihistamines: Anti hi s ta mi nes bl ock receptors ; they do not a ffect hi s ta mi ne producti on or meta bol i s m. H 1 bl ockers a re a ma i ns ta y of trea tment for
a l l ergi c di s orders . H 2 bl ockers a re us ed pri ma ri l y for ga s tri c a ci d s uppres s i on a nd ha ve l i mi ted us eful nes s for a l l ergi c rea cti ons ; they ma y be
i ndi ca ted for certa i n a topi c di s orders , es peci a l l y chroni c urti ca ri a .
Ora l H 1 bl ockers rel i eve s ymptoms i n va ri ous a topi c a nd a l l ergi c di s orders (eg, s ea s ona l ha y fever, a l l ergi c rhi ni ti s , conjuncti vi ti s , urti ca ri a , other
derma tos es , mi nor rea cti ons to bl ood tra ns fus i on i ncompa ti bi l i ti es a nd to x-ra y ra di opa que dyes ); they a re l es s effecti ve for a l l ergi c
bronchocons tri cti on a nd va s odi l a ti on. Ons et of a cti on i s us ua l l y 15 to 30 mi n, wi th pea k effects i n 1 h; dura ti on of a cti on i s us ua l l y 3 to 6 h.
Ora l H 1 bl ockers a re cl a s s i fi ed a s s eda ti ng or nons eda ti ng (better thought of a s l es s s eda ti ng). Seda ti ng a nti hi s ta mi nes a re wi del y a va i l a bl e
wi thout pres cri pti on. Al l ha ve s i gni fi ca nt s eda ti ve a nd a nti chol i nergi c properti es ; they pos e pa rti cul a r probl ems for the el derl y a nd for pa ti ents
wi th gl a ucoma , beni gn pros ta ti c hyperpl a s i a , cons ti pa ti on, or dementi a . Nons eda ti ng (nona nti chol i nergi c) a nti hi s ta mi nes a re preferred except
when s eda ti ve effects ma y be thera peuti c (eg, for ni ghtti me rel i ef of a l l ergy, for s hort-term trea tment of i ns omni a i n a dul ts or na us ea i n younger
pa ti ents ). Anti chol i nergi c effects ma y a l s o pa rti a l l y jus ti fy us e of s eda ti ng a nti hi s ta mi nes to rel i eve rhi norrhea i n URIs .
Anti hi s ta mi ne s ol uti ons ma y be i ntra na s a l (a zel a s ti ne to trea t rhi ni ti s ) or ocul a r (a zel a s ti ne, emeda s ti ne, ketoti fen, l evoca ba s ti ne, or
ol opa ta di ne to trea t conjuncti vi ti s ). Topi ca l di phenhydra mi ne i s a va i l a bl e but s houl d not be us ed; i ts effi ca cy i s unproved, drug s ens i ti za ti on (i e,
a l l ergy) ma y occur, a nd a nti chol i nergi c toxi ci ty ca n devel op i n young chi l dren who a re s i mul ta neous l y ta ki ng ora l H 1 bl ockers .
Mast cell stabilizers: Thes e drugs (eg, cromol yn) bl ock the rel ea s e of medi a tors from ma s t cel l s ; they a re us ed when other drugs (eg, a nti hi s ta mi nes ,
topi ca l corti cos teroi ds ) a re i neffecti ve or not wel l tol era ted. Ocul a r forms (eg, l odoxa mi de, ol opa ta di ne, pemi rol a s t) a re a l s o a va i l a bl e.
Anti-inflammatory drugs: Corti cos teroi ds ca n be gi ven i ntra na s a l l y (s ee
Ta bl e 127-3) or ora l l y. Ora l corti cos teroi ds a re i ndi ca ted for s ys temi c a l l ergi c di s orders tha t a re s evere but s el f-l i mi ted (eg, s ea s ona l a s thma
fl a res , s evere wi des prea d conta ct derma ti ti s ) a nd for di s orders refra ctory to other mea s ures . NSAIDs a re typi ca l l y not us eful , wi th the excepti on of
topi ca l ketorol a c for a l l ergi c conjuncti vi ti s .
Leukotri ene modi fi ers a re i ndi ca ted for trea tment of mi l d pers i s tent a s thma (s ee p. 1881) a nd s ea s ona l a l l ergi c rhi ni ti s .
Anti -IgE a nti body (oma l i zuma b) i s i ndi ca ted for modera tel y pers i s tent or s evere a s thma refra ctory to s ta nda rd trea tment (s ee p. 1881).
Immunotherapy: Expos ure to a l l ergen i n gra dua l l y i ncrea s i ng dos es (hypos ens i ti za ti on or des ens i ti za ti on) vi a i njecti on or i n hi gh dos es
s ubl i ngua l l y ca n i nduce tol era nce
[Table 127-3. Inha l ed Na s a l Corti cos teroi ds a nd Ma s t Cel l Sta bi l i zers ]
a nd i s i ndi ca ted when a l l ergen expos ure ca nnot be a voi ded a nd drug trea tment i s i na dequa te. Mecha ni s m i s unknown but ma y i nvol ve i nducti on
of IgG a nti bodi es , whi ch compete wi th IgE for a l l ergen or bl ock IgE from bi ndi ng wi th ma s t cel l IgE receptors ; i nducti on of i nterferon-, IL-12, a nd
cytoki nes s ecreted by TH 1 cel l s ; or i nducti on of regul a tory T cel l s .
For ful l effect, i njecti ons mus t be gi ven monthl y. Dos e typi ca l l y s ta rts a t 0.1 to 1.0 bi ol ogi ca l l y a cti ve uni ts (BAU), dependi ng on i ni ti a l s ens i ti vi ty,
a nd i s i ncrea s ed weekl y or bi weekl y by 2 ti mes wi th ea ch i njecti on unti l a ma xi mum tol era ted concentra ti on i s rea ched; patients should be
observed for about 30 min postinjection during dose escalation because anaphylaxis may occur after injection. Ma xi mum dos e s houl d be gi ven q 4 to 6 wk
yea r-round; yea r-round trea tment i s better tha n pres ea s ona l or cos ea s ona l trea tment even for s ea s ona l a l l ergi es . Al l ergens us ed a re thos e tha t
typi ca l l y ca nnot be a voi ded: pol l ens , hous e dus t mi tes , mol ds , a nd venom of s ti ngi ng i ns ects . Ins ect venoms a re s ta nda rdi zed by wei ght; a typi ca l
s ta rti ng dos e i s 0.01 g, a nd us ua l ma i ntena nce dos e i s 100 to 200 g. Ani ma l da nder des ens i ti za ti on i s ordi na ri l y l i mi ted to pa ti ents who ca nnot
a voi d expos ure (eg, veteri na ri a ns , l a bora tory workers ), but there i s l i ttl e evi dence tha t i t i s us eful . Food des ens i ti za ti on i s not i ndi ca ted.
Des ens i ti za ti on for peni ci l l i n a nd certa i n other a nti bi oti cs a nd for forei gn (xenogenei c) s erum ca n be done (s ee p. 1120).
Advers e effects a re mos t commonl y rel a ted to overdos e, occa s i ona l l y vi a a n i na dvertent IM or IV i njecti on, a nd ra nge from mi l d cough or s neezi ng
to genera l i zed urti ca ri a , s evere a s thma , a na phyl a cti c s hock, a nd, ra rel y, dea th. They ca n be prevented by the fol l owi ng:
Increa s i ng the dos e i n s ma l l i ncrements
Repea ti ng or decrea s i ng the dos e i f l oca l rea cti on to the previ ous i njecti on i s l a rge ( 2.5 cm i n di a meter)
Reduci ng the dos e when a fres h extra ct i s us ed
Reduci ng the dos e of pol l en extra ct duri ng pol l en s ea s on i s recommended. Epi nephri ne, O2 , a nd res us ci ta ti on equi pment s houl d be i mmedi a tel y
a va i l a bl e for prompt trea tment of a na phyl a xi s .
Prevention
Al l ergi c tri ggers s houl d be removed or a voi ded. Stra tegi es i ncl ude the fol l owi ng:
Us i ng s yntheti c fi ber pi l l ows a nd i mpermea bl e ma ttres s covers
Frequentl y wa s hi ng bed s heets , pi l l owca s es , a nd bl a nkets i n hot wa ter
Removi ng uphol s tered furni ture, s oft toys , ca rpets , a nd pets
Hous e cl ea ni ng a nd extermi na ti on to el i mi na te cockroa ch expos ure
Us i ng dehumi di fi ers i n ba s ements a nd other poorl y a era ted, da mp rooms
Trea ti ng homes wi th hea t-s tea m
Us i ng hi gh-effi ci ency pa rti cul a te a i r (HEPA) va cuums a nd fi l ters
Avoi di ng food tri ggers
Li mi ti ng pets to certa i n rooms
Frequentl y cl ea ni ng cl oth furni ture a nd ca rpets
Adjuncti ve nona l l ergeni c tri ggers (eg, ci ga rette s moke, s trong odors , i rri ta ti ng fumes , a i r pol l uti on, col d tempera tures , hi gh humi di ty) s houl d a l s o
be a voi ded or control l ed when pos s i bl e.
Allergic Rhinitis
Allergic rhinitis is seasonal or perennial itching, sneezing, rhinorrhea, nasal congestion, and sometimes conjunctivitis, caused by exposure to pollens or other
allergens. Diagnosis is by history and skin testing. Treatment is with a combination of antihistamines, decongestants, nasal corticosteroids, and, for severe,
refractory cases, desensitization.
Al l ergi c rhi ni ti s ma y occur s ea s ona l l y (ha y fever) or throughout the yea r (perenni a l rhi ni ti s ). At l ea s t 25% of perenni a l rhi ni ti s i s nona l l ergi c.
Sea s ona l rhi ni ti s i s ca us ed by
Spring: Tree pol l ens (eg, oa k, el m, ma pl e, a l der, bi rch, juni per, ol i ve)
Summer: Gra s s pol l ens (eg, Bermuda , ti mothy, s weet verna l , orcha rd, Johns on) a nd weed pol l ens (eg, Rus s i a n thi s tl e, Engl i s h pl a nta i n)
Fall: Other weed pol l ens (eg, ra gweed)
Ca us es a l s o di ffer by regi on, a nd s ea s ona l rhi ni ti s i s occa s i ona l l y ca us ed by a i rborne funga l s pores . Perenni a l rhi ni ti s i s ca us ed by yea r-round
expos ure to i ndoor i nha l ed a l l ergens (eg, dus t mi tes , cockroa ches , a ni ma l da nder, mol d) or by s trong rea cti vi ty to pl a nt pol l ens i n s equenti a l
s ea s ons .
Al l ergi c rhi ni ti s a nd a s thma frequentl y coexi s t; whether rhi ni ti s a nd a s thma res ul t from the s a me a l l ergi c proces s (one-a i rwa y hypothes i s ) or
rhi ni ti s i s a di s crete a s thma tri gger i s uncl ea r.
Nona l l ergi c forms of perenni a l rhi ni ti s i ncl ude i nfecti ous , va s omotor, a trophi c, hormona l , drug-i nduced, a nd gus ta tory rhi ni ti s (s ee p. 478).
Symptoms and Signs
Pa ti ents ha ve i tchi ng (i n the nos e, eyes , or mouth), s neezi ng, rhi norrhea , a nd na s a l a nd s i nus obs tructi on. Si nus obs tructi on ma y ca us e fronta l
hea da ches ; s i nus i ti s i s a frequent compl i ca ti on. Coughi ng a nd wheezi ng ma y a l s o occur, es peci a l l y i f a s thma i s a l s o pres ent.
The mos t promi nent fea ture of perenni a l rhi ni ti s i s chroni c na s a l obs tructi on, whi ch, i n chi l dren, ca n l ea d to chroni c oti ti s medi a ; s ymptoms va ry
i n s everi ty throughout the yea r. Itchi ng i s l es s promi nent tha n i n s ea s ona l rhi ni ti s .
Si gns i ncl ude edema tous , bl ui s h-red na s a l turbi na tes , a nd, i n s ome ca s es of s ea s ona l rhi ni ti s , conjuncti va l i njecti on a nd eyel i d edema .
Diagnosis
Someti mes s ki n tes ti ng, RAST, or both
Al l ergi c rhi ni ti s ca n a l mos t a l wa ys be di a gnos ed ba s ed on hi s tory a l one. Di a gnos ti c tes ti ng i s not routi nel y needed unl es s pa ti ents do not
i mprove when trea ted empi ri ca l l y; for s uch pa ti ents , s ki n tes ts a re done to i denti fy a rea cti on to pol l ens (s ea s ona l ) or to dus t mi te, cockroa ch,
a ni ma l da nder, mol d, or other a nti gens (perenni a l ), whi ch ca n be us ed to gui de a ddi ti ona l trea tment. Occa s i ona l l y, s ki n tes t res ul ts a re
a mbi va l ent, or tes ti ng ca nnot be done (eg, beca us e pa ti ents a re ta ki ng drugs tha t i nterfere wi th res ul ts ); then, RAST i s done. Eos i nophi l i a
detected on na s a l s mea r pl us nega ti ve s ki n tes ts s ugges ts a s pi ri n s ens i ti vi ty or nona l l ergi c rhi ni ti s wi th eos i nophi l i a (NARES).
Di a gnos i s of i nfecti ous , va s omotor, a trophi c, hormona l , drug-i nduced, a nd gus ta tory rhi ni ti s i s us ua l l y ba s ed on hi s tory or thera peuti c tri a l s .
Treatment
Remova l or a voi da nce of a l l ergens for perenni a l rhi ni ti s
Anti hi s ta mi nes , deconges ta nts , na s a l corti cos teroi ds , or a combi na ti on
Someti mes i mmunothera py for s ea s ona l rhi ni ti s
Des ens i ti za ti on for s evere, refra ctory rhi ni ti s
Trea tment of s ea s ona l a nd perenni a l a l l ergi c rhi ni ti s i s genera l l y the s a me, a l though a ttempts a t envi ronmenta l control (eg, el i mi na ti ng dus t
mi tes a nd cockroa ches ) a re recommended for perenni a l rhi ni ti s .
The mos t effecti ve fi rs t-l i ne drug trea tments a re
Ora l a nti hi s ta mi nes pl us ora l deconges ta nts
Na s a l corti cos teroi ds wi th or wi thout ora l a nti hi s ta mi nes (s ee Ta bl e 127-3)
Les s effecti ve a l terna ti ves i ncl ude na s a l ma s t cel l s ta bi l i zers (eg, cromol yn) gi ven bi d to qi d, the na s a l H 1 bl ocker a zel a s ti ne 2 puffs once/da y, a nd
na s a l i pra tropi um 0.03% 2 puffs q 4 to 6 h, whi ch rel i eves rhi norrhea . Intra na s a l s a l i ne, often forgotten, hel ps mobi l i ze thi ck na s a l s ecreti ons a nd
hydra te na s a l mucous membra nes .
Immunothera py ma y be more effecti ve for s ea s ona l tha n for a l l ergi c perenni a l rhi ni ti s ; i t i s i ndi ca ted when s ymptoms a re s evere, a l l ergen ca nnot
be a voi ded, a nd drug trea tment i s i na dequa te.
Des ens i ti za ti on ma y be needed for s evere, refra ctory rhi ni ti s . Fi rs t a ttempts a t des ens i ti za ti on s houl d begi n s oon a fter the pol l en s ea s on ends to
prepa re for the next s ea s on; a dvers e rea cti ons i ncrea s e when des ens i ti za ti on i s s ta rted duri ng the pol l en s ea s on beca us e the pers on's a l l ergi c
i mmuni ty i s a l rea dy ma xi ma l l y s ti mul a ted.
Montel uka s t rel i eves a l l ergi c rhi ni ti s s ymptoms , but i ts rol e rel a ti ve to other trea tments i s uncerta i n. Anti -IgE a nti body i s under s tudy for
trea tment of a l l ergi c rhi ni ti s but wi l l proba bl y ha ve a l i mi ted rol e beca us e l es s expens i ve, effecti ve a l terna ti ves a re a va i l a bl e.
Trea tment of NARES i s na s a l corti cos teroi ds . Trea tment of a s pi ri n s ens i ti vi ty i s a s pi ri n a voi da nce, wi th des ens i ti za ti on a nd l eukotri ene bl ockers
a s needed. Na s a l pol yps ma y res pond to na s a l corti cos teroi ds .
Food Allergy
Food allergy is an exaggerated immune response to dietary proteins.
Food a l l ergy s houl d be di s ti ngui s hed from noni mmune rea cti ons to food (eg, l a ctos e i ntol era nce, i rri ta bl e bowel s yndrome, i nfecti ous
ga s troenteri ti s ) a nd rea cti ons to a ddi ti ves (eg, monos odi um gl uta ma te, meta bi s ul fi te, ta rtra zi ne) or food conta mi na nts (eg, l a tex dus t i n food
ha ndl ed by workers wea ri ng l a tex gl oves ), whi ch ca us e mos t food rea cti ons . Preva l ence of true food a l l ergy ra nges from < 1 to 3% a nd va ri es by
geogra phy a nd method of a s certa i nment; pa ti ents tend to confus e i ntol era nce wi th a l l ergy.
Etiology
Al mos t a ny food or food a ddi ti ve ca n ca us e a n a l l ergi c rea cti on, but the mos t common tri ggers i ncl ude
Infants and young children: Mi l k, s oy, eggs , pea nuts , a nd whea t
Older children and adults: Nuts a nd s ea food
Cros s -rea cti vi ty between food a nd nonfood a l l ergens exi s ts , a nd s ens i ti za ti on ma y occur nonentera l l y. For exa mpl e, pa ti ents wi th ora l a l l ergi es
(typi ca l l y, pruri tus , erythema , a nd edema of the mouth when frui ts a nd vegeta bl es a re ea ten) ma y ha ve been s ens i ti zed by pol l en expos ure;
chi l dren wi th pea nut a l l ergy ma y ha ve been s ens i ti zed by topi ca l crea ms conta i ni ng pea nut oi l us ed to trea t ra s hes . Ma ny pa ti ents who a re
a l l ergi c to l a tex a re a l s o a l l ergi c to ba na na s , ki wi s , a voca does , or a combi na ti on.
In genera l , food a l l ergy i s medi a ted by IgE, T cel l s , or both. IgE-medi a ted a l l ergy (eg, urti ca ri a , a s thma , a na phyl a xi s ) i s a cute i n ons et, us ua l l y
devel ops duri ng i nfa ncy, a nd occurs mos t often i n peopl e wi th a s trong fa mi l y hi s tory of a topy. T cel l -medi a ted a l l ergy (eg, di eta ry protei n
ga s troenteropa thi es , cel i a c di s ea s e) ma ni fes ts gra dua l l y a nd i s chroni c. Al l ergi es medi a ted by both IgE a nd T cel l s (eg, a topi c derma ti ti s ,
eos i nophi l i c ga s troenteropa thy) tend to be del a yed i n ons et or chroni c.
Eosinophilic gastroenteropathy: Thi s unus ua l di s order ca us es pa i n, cra mps , a nd di a rrhea wi th bl ood eos i nophi l i a , eos i nophi l i c i nfi l tra tes i n the gut,
protei n-l os i ng enteropa thy, a nd a hi s tory of a topi c di s orders . Eos i nophi l i c es opha gi ti s s ometi mes a ccompa ni es eos i nophi l i c ga s troenteropa thy.
Ini ti a l l y, i t ma y ca us e dys pha gi a a nd dys moti l i ty or, i n chi l dren, feedi ng i ntol era nce a nd a bdomi na l pa i n.
Symptoms and Signs
Symptoms a nd s i gns va ry by a l l ergen, mecha ni s m, a nd pa ti ent a ge. The mos t common ma ni fes ta ti on i n i nfa nts i s a topi c derma ti ti s a l one or wi th
GI s ymptoms (na us ea , vomi ti ng, di a rrhea ). Chi l dren us ua l l y outgrow thes e ma ni fes ta ti ons a nd rea ct i ncrea s i ngl y to i nha l ed a l l ergens , wi th
s ymptoms of a s thma a nd rhi ni ti s ; thi s progres s i on i s ca l l ed a topi c ma rch. By a ge 10 yr, pa ti ents ra rel y ha ve res pi ra tory s ymptoms a fter the
a l l ergeni c food i s ea ten, even though s ki n tes ts rema i n pos i ti ve. If a topi c derma ti ti s pers i s ts or a ppea rs i n ol der chi l dren or a dul ts , i ts a cti vi ty
s eems l a rgel y i ndependent of IgE-medi a ted a l l ergy, even though a topi c pa ti ents wi th extens i ve derma ti ti s ha ve much hi gher s erum IgE l evel s tha n
thos e who a re free of derma ti ti s .
When food a l l ergy pers i s ts i n ol der chi l dren a nd a dul ts , rea cti ons tend to be more s evere (eg, expl os i ve urti ca ri a , a ngi oedema , even a na phyl a xi s ).
In a few pa ti ents , food (es peci a l l y whea t a nd cel ery) tri ggers a na phyl a xi s onl y i f they exerci s e s oon a fterwa rd; mecha ni s m i s unknown. A few
pa ti ents ha ve food-i nduced or a ggra va ted mi gra i ne, confi rmed by bl i nded ora l cha l l enge. Occa s i ona l l y, chei l i ti s , a phtha e, pyl oros pa s m, s pa s ti c
cons ti pa ti on, pruri tus a ni , a nd peri a na l eczema a re a ttri buted to food a l l ergy.
Diagnosis
Ski n tes ti ng or RAST
Tri a l el i mi na ti on di et (a l one or a fter s ki n tes ti ng or RAST)
Severe food a l l ergy i s us ua l l y obvi ous i n a dul ts . When i t i s not a nd when i t occurs i n chi l dren (us ua l l y), di a gnos i s ma y be di ffi cul t, a nd the
di s order mus t be di fferenti a ted from functi ona l GI probl ems .
If a food rea cti on i s s us pected, the rel a ti ons hi p of s ymptoms to foods i s a s s es s ed by s ki n tes ti ng or IgE-s peci fi c RAST. A pos i ti ve tes t does not
confi rm a cl i ni ca l l y rel eva nt a l l ergy, but a nega ti ve tes t excl udes i t. If a s ki n tes t i s pos i ti ve, the tes ted food i s el i mi na ted from the di et; i f
s ymptoms a re rel i eved, the pa ti ent i s reexpos ed to the food (prefera bl y i n a doubl e-bl i nd tes t) to s ee whether s ymptoms recur.
Al terna ti ves to s ki n tes ti ng i ncl ude el i mi na ti ng foods the pa ti ent s us pects of ca us i ng s ymptoms a nd pres cri bi ng a di et tha t cons i s ts of rel a ti vel y
nona l l ergeni c foods a nd tha t el i mi na tes common food a l l ergens (s ee
Ta bl e 127-4). No foods or fl ui ds ma y be cons umed other tha n thos e s peci fi ed. Pure products mus t a l wa ys be us ed. Ma ny commerci a l l y prepa red
products a nd mea l s conta i n a n undes i red food i n l a rge a mounts (eg, commerci a l rye brea d conta i ns whea t fl our) or i n tra ces a s fl a vori ng or
thi ckeners , a nd determi ni ng whether a n undes i red food i s pres ent ma y be di ffi cul t.
If no i mprovement occurs a fter 1 wk, a nother di et s houl d be tri ed. If s ymptoms a re rel i eved, one new food i s a dded a nd ea ten i n l a rge a mounts for
> 24 h or unti l s ymptoms recur. Al terna ti vel y, s ma l l a mounts of the food to be tes ted a re ea ten i n the cl i ni ci a n's pres ence, a nd the pa ti ent's
rea cti ons obs erved. Aggra va ti on or recrudes cence of s ymptoms a fter a ddi ti on of a new food i s the bes t evi dence of a l l ergy.
Treatment
Food el i mi na ti on di et
Someti mes ora l cromol yn
Someti mes corti cos teroi ds for eos i nophi l i c enteropa thy
[Table 127-4. Al l owa bl e Foods i n El i mi na ti on Di ets *]
Trea tment cons i s ts of el i mi na ti ng the food tha t tri ggers the a l l ergi c rea cti on. Thus , di a gnos i s a nd trea tment overl a p. When a s s es s i ng a n
el i mi na ti on di et's effect, cl i ni ci a ns mus t cons i der tha t food s ens i ti vi ti es ma y di s a ppea r s ponta neous l y.
Ora l des ens i ti za ti on (by fi rs t el i mi na ti ng the a l l ergeni c food for a ti me, then gi vi ng s ma l l a mounts a nd i ncrea s i ng them da i l y) i s not effecti ve nor
i s us e of s ubl i ngua l drops of food extra cts . Anti hi s ta mi nes a re of l i ttl e va l ue except i n a cute genera l rea cti ons wi th urti ca ri a a nd a ngi oedema .
Ora l cromol yn ha s been us ed wi th a ppa rent s ucces s . Prol onged corti cos teroi d trea tment i s hel pful for s ymptoma ti c eos i nophi l i c enteropa thy.
Anaphylaxis
Anaphylaxis is an acute, life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing
antigen. Symptoms include stridor, dyspnea, wheezing, and hypotension. Diagnosis is clinical. Bronchospasm and upper airway edema are treated with inhaled or
injected -agonists and sometimes endotracheal intubation. Hypotension requires IV fluids and vasopressors.
Etiology
Ana phyl a xi s i s typi ca l l y tri ggered by
Drugs (eg, -l a cta m a nti bi oti cs , i ns ul i n, s treptoki na s e, a l l ergen extra cts )
Foods (eg, nuts , eggs , s ea food)
Protei ns (eg, teta nus a nti toxi n, bl ood tra ns fus i ons )
Ani ma l venoms
La tex
Pea nut a nd l a tex a l l ergens ma y be a i rborne. Hi s tory of a topy does not i ncrea s e ri s k of a na phyl a xi s but i ncrea s es ri s k of dea th when a na phyl a xi s
occurs .
Pathophysiology
Intera cti on of a nti gen wi th IgE on ba s ophi l s a nd ma s t cel l s tri ggers rel ea s e of hi s ta mi ne, l eukotri enes , a nd other medi a tors tha t ca us e di ffus e
s mooth mus cl e contra cti on (bronchocons tri cti on, vomi ti ng, di a rrhea ) a nd va s odi l a ti on wi th pl a s ma l ea ka ge.
Anaphylactoid reactions: Thes e rea cti ons a re cl i ni ca l l y i ndi s ti ngui s ha bl e from a na phyl a xi s but do not i nvol ve IgE a nd do not requi re pri or
s ens i ti za ti on. They occur vi a di rect s ti mul a ti on of ma s t cel l s or vi a i mmune compl exes tha t a cti va te compl ement. The mos t common tri ggers a re
i odi na ted ra di ogra phi c ra di opa que dye, a s pi ri n, other NSAIDs , opi oi ds , bl ood tra ns fus i ons , Ig, a nd exerci s e.
Symptoms and Signs
Symptoms typi ca l l y i nvol ve the s ki n, upper or l ower a i rwa ys , ca rdi ova s cul a r s ys tem, or GI tra ct. One or more a rea s ma y be a ffected, a nd s ymptoms
do not neces s a ri l y progres s , a l though ea ch pa ti ent typi ca l l y ma ni fes ts the s a me rea cti on to s ubs equent expos ure.
Symptoms ra nge from mi l d to s evere a nd i ncl ude fl us hi ng, pruri tus , s neezi ng, rhi norrhea , na us ea , a bdomi na l cra mps , di a rrhea , s ens e of choki ng
or dys pnea , pa l pi ta ti ons , a nd di zzi nes s .
Si gns i ncl ude hypotens i on, ta chyca rdi a , urti ca ri a , a ngi oedema , wheezi ng, cya nos i s , a nd s yncope. Shock ca n devel op wi thi n mi nutes , a nd pa ti ents
ma y experi ence s ei zures , become unres pons i ve, a nd di e. Ca rdi ova s cul a r col l a ps e ca n occur wi thout res pi ra tory or other s ymptoms .
Diagnosis
Di a gnos i s i s cl i ni ca l . Ri s k of ra pi d progres s i on to s hock l ea ves no ti me for tes ti ng, a l though mi l d equi voca l ca s es ca n be confi rmed by mea s uri ng
24-h uri na ry l evel s of N-methyl hi s ta mi ne or s erum l evel s of trypta s e.
Treatment
Epi nephri ne gi ven i mmedi a tel y
Someti mes i ntuba ti on
IV fl ui ds a nd va s opres s ors for hypotens i on
Anti hi s ta mi nes
Inha l ed -a goni s ts for bronchocons tri cti on
Epi nephri ne i s the corners tone of trea tment a nd s houl d be gi ven i mmedi a tel y. It ca n be gi ven s c or IM (us ua l dos e i s 0.3 to 0.5 mL of a 1:1000
s ol uti on i n a dul ts or 0.01 mL/kg i n chi l dren, repea ted every 10 to 30 mi n); ma xi ma l a bs orpti on occurs when the drug i s gi ven IM i n the l a tera l thi gh.
Pa ti ents wi th ca rdi ova s cul a r col l a ps e or s evere a i rwa y obs tructi on ma y be gi ven epi nephri ne IV i n a s i ngl e dos e (3 to 5 mL of a 1:10,000 s ol uti on
over 5 mi n) or by conti nuous dri p (1 mg i n 250 mL 5% D/W for a concentra ti on of 4 g/mL, s ta rti ng a t 1 g/mi n up to 4 g/mi n [15 to 60 mL/h]).
Epi nephri ne ma y a l s o be gi ven by s ubl i ngua l i njecti on (0.5 mL of 1:1000 s ol uti on) or through a n endotra chea l tube (3 to 5 mL of a 1:10,000 s ol uti on
di l uted to 10 mL wi th s a l i ne). A 2nd i njecti on of epi nephri ne s c ma y be needed. Gl uca gon 1-mg bol us fol l owed by 1-mg/h i nfus i on s houl d be us ed
i n pa ti ents ta ki ng ora l -bl ockers , whi ch a ttenua te the effect of epi nephri ne.
Pa ti ents who ha ve s tri dor a nd wheezi ng unres pons i ve to epi nephri ne s houl d be gi ven O2 a nd be i ntuba ted. Ea rl y i ntuba ti on i s recommended
beca us e wa i ti ng for a res pons e to epi nephri ne ma y a l l ow upper a i rwa y edema to progres s s uffi ci entl y to prevent endotra chea l i ntuba ti on a nd
requi re cri cothyrotomy.
Hypotens i on ca n us ua l l y be trea ted wi th 1 to 2 L (20 to 40 mL/kg i n chi l dren) of i s otoni c IV fl ui ds (eg, 0.9% s a l i ne). Hypotens i on refra ctory to fl ui ds
a nd IV epi nephri ne ma y requi re va s opres s ors (eg, dopa mi ne 5 g/kg/mi n).
Anti hi s ta mi nes both H 1 bl ockers (eg, di phenhydra mi ne 50 to 100 mg IV) a nd H 2 bl ockers (eg, ci meti di ne 300 mg IV)s houl d be gi ven q 6 h unti l
s ymptoms res ol ve. Inha l ed -a goni s ts a re us eful for ma na gi ng bronchocons tri cti on; a l buterol 5 to 10 mg by conti nuous nebul i za ti on ca n be gi ven.
Corti cos teroi ds ha ve no proven rol e but ma y hel p prevent l a te-pha s e rea cti on i n 4 to 8 h; methyl predni s ol one 125 mg IV i ni ti a l l y i s a dequa te.
Prevention
Pri ma ry preventi on i s a voi da nce of known tri ggers . Des ens i ti za ti on i s us ed for a l l ergen tri ggers tha t ca nnot rel i a bl y be a voi ded (eg, i ns ect s ti ngs ).
Pa ti ents wi th pa s t rea cti ons to ra di opa que dye s houl d not be reexpos ed; when expos ure i s a bs ol utel y neces s a ry, pa ti ents a re gi ven 3 dos es of
predni s one 50 mg po q 6 h, s ta rti ng 18 h before the procedure, a nd di phenhydra mi ne 50 mg po 1 h before the procedure; however, no evi dence
s upports the effi ca cy of thi s a pproa ch (s ee a l s o p. 3404).
Pa ti ents wi th a n a na phyl a cti c rea cti on to i ns ect s ti ngs , foods , or other known s ubs ta nces s houl d wea r a n a l ert bra cel et a nd ca rry a prefi l l ed
epi nephri ne s yri nge (conta i ni ng 0.3 mg for a dul ts a nd 0.15 mg for chi l dren) for prompt s el f-trea tment a fter expos ure.
Autoimmune Disorders
In a utoi mmune di s orders , the i mmune s ys tem produces a nti bodi es to a n endogenous a nti gen. It ma y i nvol ve the fol l owi ng hypers ens i ti vi ty
rea cti ons :
Type II: Anti body-coa ted cel l s , l i ke a ny s i mi l a rl y coa ted forei gn pa rti cl e, a cti va te the compl ement s ys tem (s ee p. 1085), res ul ti ng i n ti s s ue i njury.
Type III: The mecha ni s m of i njury i nvol ves depos i ti on of a nti body-a nti gen compl exes .
Type IV: Injury i s T-cel l -medi a ted.
For s peci fi c a utoi mmune di s orders , s ee el s ewhere i n THE MANUAL a nd a l s o Ta bl e 127-1.
Etiology
Severa l mecha ni s ms ma y a ccount for the body's a tta ck on i ts el f.
Autoa nti gens ma y become i mmunogeni c beca us e they a re a l tered chemi ca l l y, phys i ca l l y, or bi ol ogi ca l l y. Certa i n chemi ca l s ca n coupl e wi th body
protei ns , ma ki ng them i mmunogeni c (a s i n conta ct derma ti ti s ). Drugs ca n produce s evera l a utoi mmune rea cti ons by bi ndi ng cova l entl y to s erum or
ti s s ue protei ns (s ee bel ow). Photos ens i ti vi ty exempl i fi es phys i ca l l y i nduced a utoi mmuni ty: Ul tra vi ol et l i ght a l ters s ki n protei n, to whi ch the
pa ti ent becomes a l l ergi c. In a ni ma l model s , pers i s tent i nfecti on wi th a n RNA vi rus tha t combi nes wi th hos t ti s s ues a l ters a utoa nti gens
bi ol ogi ca l l y, res ul ti ng i n a n a utoi mmune di s order res embl i ng SLE.
Anti bodi es produced i n res pons e to a forei gn a nti gen ma y cros s -rea ct wi th norma l a utoa nti gens (eg, cros s -rea cti on between s treptococca l M
protei n a nd huma n hea rt mus cl e).
Norma l l y, potenti a l l y pa thol ogi c a utoi mmune rea cti ons a re a voi ded beca us e of the i mmunol ogi c tol era nce mecha ni s ms of cl ona l del eti on a nd
cl ona l a nergy. Any a utorea cti ve l ymphocytes not control l ed by thes e mecha ni s ms a re us ua l l y res tra i ned by Foxp3+ regul a tory T cel l s . A regul a tory Tcel l defect ma y a ccompa ny a ny of thes e mecha ni s ms for a utoi mmuni ty. Anti -i di otype a nti bodi es (a nti bodi es to the a nti gen-combi ni ng s i te of
other a nti bodi es ) ma y i nterfere wi th regul a ti on of a nti body a cti vi ty.
Geneti c fa ctors pl a y a rol e. Rel a ti ves of pa ti ents wi th a utoi mmune di s orders often ha ve the s a me type of a utoa nti bodi es , a nd i nci dence of
a utoi mmune di s orders i s hi gher i n i denti ca l tha n i n fra terna l twi ns . Mos t a utoi mmune di s orders ha ve a pol ygeni c eti ol ogy, a nd a l l el i c va ri a nts
wi thi n the HLA gene l ocus nea rl y a l wa ys contri bute. Women a re a ffected more often tha n men. In geneti ca l l y predi s pos ed peopl e, envi ronmenta l
fa ctors ma y provoke di s ea s e (eg, certa i n drugs ca n tri gger hemol yti c a nemi a i n pa ti ents wi th G6PD defi ci ency).
Drug Hypersensitivity
Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include skin rash, anaphylaxis, and serum sickness.
Diagnosis is clinical; skin testing is occasionally useful. Treatment is drug discontinuation, antihistamines (for symptoms), and sometimes desensitization.
Drug hypers ens i ti vi ty mus t be di s ti ngui s hed from toxi c a nd a dvers e effects tha t ma y be expected from the drug a nd from probl ems due to drug
i ntera cti ons (s ee p. 3167).
Pathophysiology
Some protei n a nd l a rge pol ypepti de drugs (eg, i ns ul i n, thera peuti c a nti bodi es ) ca n di rectl y s ti mul a te a nti body producti on. However, mos t drugs
a ct a s ha ptens , bi ndi ng cova l entl y to s erum or cel l -bound protei ns , i ncl udi ng pepti des embedded i n ma jor hi s tocompa ti bi l i ty compl ex (MHC)
mol ecul es . The bi ndi ng ma kes the protei n i mmunogeni c, s ti mul a ti ng a nti drug a nti body producti on, T-cel l res pons es a ga i ns t the drug, or both.
Ha ptens ma y a l s o bi nd di rectl y to the MHC II mol ecul e, di rectl y a cti va ti ng T cel l s . When meta bol i zed, proha ptens become ha ptens ; eg, peni ci l l i n
i ts el f i s not a nti geni c, but i ts ma i n degra da ti on product, benzyl peni ci l l oi c a ci d, ca n combi ne wi th ti s s ue protei ns to form benzyl peni ci l l oyl (BPO), a
ma jor a nti geni c determi na nt. Some drugs bi nd a nd s ti mul a te T-cel l receptors (TCR) di rectl y; the cl i ni ca l s i gni fi ca nce of nonha pten TCR bi ndi ng i s
bei ng determi ned.
How pri ma ry s ens i ti za ti on occurs a nd how the i mmune s ys tem i s i ni ti a l l y i nvol ved i s uncl ea r, but once a drug s ti mul a tes a n i mmune res pons e,
cros s -rea cti ons wi thi n a nd between drug cl a s s es ca n occur. For exa mpl e, peni ci l l i n-s ens i ti ve pa ti ents a re hi ghl y l i kel y to rea ct to s emi s yntheti c
peni ci l l i ns (eg, a moxi ci l l i n, ca rbeni ci l l i n, ti ca rci l l i n), a nd a bout 10% rea ct to cepha l os pori ns , whi ch ha ve a s i mi l a r -l a cta m s tructure. However,
s ome a ppa rent cros s -rea cti ons (eg, between s ul fona mi de a nti bi oti cs a nd nona nti bi oti cs ) a re due to a predi s pos i ti on to a l l ergi c rea cti ons ra ther
tha n to s peci fi c i mmune cros s -rea cti vi ty. Al s o, not every a ppa rent rea cti on i s a l l ergi c; for exa mpl e, a moxi ci l l i n ca us es a ra s h tha t i s not i mmunemedi a ted a nd does not precl ude future us e of the drug.
Symptoms and Signs
Symptoms a nd s i gns va ry by pa ti ent a nd drug, a nd a s i ngl e drug ma y ca us e di fferent rea cti ons i n di fferent pa ti ents . The mos t s eri ous i s
a na phyl a xi s ; exa nthema (eg, morbi l l i form erupti on), urti ca ri a , a nd fever a re common. Fi xed drug rea cti ons a re uncommon.
Some di s ti nct cl i ni ca l s yndromes exi s t.
Serum sickness: Thi s rea cti on typi ca l l y occurs 7 to 10 da ys a fter expos ure a nd ca us es fever, a rthra l gi a s , a nd ra s h. Mecha ni s m i nvol ves druga nti body compl exes a nd compl ement a cti va ti on. Some pa ti ents ha ve fra nk a rthri ti s , edema , or GI s ymptoms . Symptoms a re s el f-l i mi ted, l a s ti ng
1 to 2 wk. -La cta m a nd s ul fona mi de a nti bi oti cs , i ron-dextra n, a nd ca rba ma zepi ne a re mos t commonl y i mpl i ca ted.
Hemolytic anemia: Thi s di s order ma y devel op when a n a nti body-drug-RBC i ntera cti on occurs or when a drug (eg, methyl dopa ) a l ters the RBC
membra ne, uncoveri ng a n a nti gen tha t i nduces a utoa nti body producti on.
Pulmonary effects: Some drugs i nduce res pi ra tory s ymptoms , deteri ora ti on i n pul mona ry functi on, a nd other pul mona ry cha nges (s ee p. 1952).
Renal effects: Tubul oi nters ti ti a l nephri ti s i s the mos t common a l l ergi c rena l rea cti on (s ee p. 2414); methi ci l l i n, a nti mi crobi a l s , a nd ci meti di ne a re
commonl y i mpl i ca ted.
Other autoimmune phenomena: Hydra l a zi ne a nd proca i na mi de ca n ca us e a n SLE-l i ke s yndrome. The s yndrome i s rel a ti vel y beni gn, s pa ri ng the
ki dneys a nd CNS; the a nti nucl ea r a nti body tes t i s pos i ti ve. Peni ci l l a mi ne ca n ca us e SLE a nd other a utoi mmune di s orders (eg, mya s theni a
gra vi s ).
Diagnosis
Pa ti ent's report of a rea cti on s oon a fter ta ki ng a drug
Ski n tes ti ng
Someti mes drug provoca ti on tes ti ng
Someti mes di rect a nd i ndi rect a nti gl obul i n a s s a ys
Drug hypers ens i ti vi ty i s s ugges ted when a rea cti on occurs wi thi n mi nutes to hours a fter drug a dmi ni s tra ti on. However, ma ny pa ti ents report a pa s t
rea cti on of uncerta i n na ture. In s uch ca s es , i f there i s no equi va l ent s ubs ti tute (eg, when peni ci l l i n i s needed to trea t s yphi l i s ), tes ti ng s houl d be
cons i dered.
Skin testing: Tes ts for i mmedi a te-type (IgE-medi a ted) hypers ens i ti vi ty hel p i denti fy rea cti ons to -l a cta m a nti bi oti cs , forei gn (xenogenei c) s erum,
a nd s ome va cci nes a nd pol ypepti de hormones . However, typi ca l l y, onl y 10 to 20% of pa ti ents who report a peni ci l l i n a l l ergy ha ve a pos i ti ve
rea cti on on s ki n tes ts . Al s o, for mos t drugs (i ncl udi ng cepha l os pori ns ), s ki n tes ts a re unrel i a bl e a nd, beca us e they detect onl y IgE-medi a ted
rea cti ons , do not predi ct the occurrence of morbi l l i form erupti ons , hemol yti c a nemi a , or nephri ti s .
Peni ci l l i n s ki n tes ti ng i s needed i f pa ti ents wi th a hi s tory of a n i mmedi a te hypers ens i ti vi ty rea cti on mus t ta ke a peni ci l l i n. BPO-pol yl ys i ne
conjuga te a nd peni ci l l i n G a re us ed wi th hi s ta mi ne a nd s a l i ne a s control s . The pri ck tes t (s ee p. 1115) i s us ed fi rs t. If pa ti ents ha ve a hi s tory of a
s evere expl os i ve rea cti on, rea gents s houl d be di l uted 100-fol d for i ni ti a l tes ti ng. If pri ck tes ts a re nega ti ve, i ntra derma l tes ti ng ma y fol l ow. If s ki n
tes ts a re pos i ti ve, trea ti ng pa ti ents wi th peni ci l l i n ma y i nduce a n a na phyl a cti c rea cti on. If tes ts a re nega ti ve, a s eri ous rea cti on i s l es s l i kel y but
not excl uded. Al though the peni ci l l i n s ki n tes t ha s not i nduced de novo s ens i ti vi ty i n pa ti ents , pa ti ents s houl d us ua l l y be tes ted onl y i mmedi a tel y
before es s enti a l peni ci l l i n thera py i s begun.
For xenogenei c s erum s ki n tes ti ng, pa ti ents who a re not a topi c a nd who ha ve not recei ved xenogenei c (eg, hors e) s erum previ ous l y s houl d fi rs t be
gi ven a pri ck tes t wi th a 1:10 di l uti on; i f thi s tes t i s nega ti ve, 0.02 mL of a 1:1000 di l uti on i s i njected i ntra derma l l y. A whea l > 0.5 cm i n di a meter
devel ops wi thi n 15 mi n i n s ens i ti ve pa ti ents . Al l pa ti ents who ma y ha ve recei ved s erum previ ous l ywhether or not they rea cteda nd thos e wi th
a s us pected a l l ergi c hi s tory s houl d be tes ted fi rs t wi th a 1:1000 di l uti on. A nega ti ve res ul t rul es out the pos s i bi l i ty of a na phyl a xi s but does not
predi ct i nci dence of s ubs equent s erum s i cknes s .
Other testing: For drug provoca ti on tes ti ng, a drug s us pected of ca us i ng a hypers ens i ti vi ty rea cti on i s gi ven i n es ca l a ti ng dos es to preci pi ta te the
rea cti on. Thi s tes t i s proba bl y s a fe a nd effecti ve i f done i n a control l ed s etti ng.
Tes ts for hema tol ogi c drug rea cti ons i ncl ude di rect a nd i ndi rect a nti gl obul i n tes ts (s ee p.
937). Tes ts for other s peci fi c drug hypers ens i ti vi ty (eg, ra di oa l l ergos orbent tes ti ng [RAST], hi s ta mi ne rel ea s e, ba s ophi l or ma s t cel l degra nul a ti on,
l ymphocyte tra ns forma ti on) a re unrel i a bl e or experi menta l .
Prognosis
Hypers ens i ti vi ty decrea s es wi th ti me. IgE a nti bodi es a re pres ent i n 90% of pa ti ents 1 yr a fter a n a l l ergi c rea cti on but i n onl y a bout 20 to 30% a fter
10 yr. Pa ti ents who ha ve a na phyl a cti c rea cti ons a re more l i kel y to reta i n a nti bodi es to the ca us a ti ve drug l onger. Peopl e wi th drug a l l ergi es s houl d
be ta ught a bout a voi di ng the drug a nd s houl d ca rry i denti fi ca ti on or a n a l ert bra cel et. Cha rts s houl d a l wa ys be a ppropri a tel y ma rked.
Treatment
Drug di s conti nua ti on
Supporti ve trea tment (eg, a nti hi s ta mi nes , corti cos teroi ds , epi nephri ne)
Someti mes des ens i ti za ti on
Trea tment i s s toppi ng the i mpl i ca ted drug; mos t s ymptoms a nd s i gns cl ea r wi thi n a few da ys a fter the drug i s s topped.
Symptoma ti c a nd s upporti ve trea tment for a cute rea cti ons ma y i ncl ude a nti hi s ta mi nes for pruri tus , NSAIDs for a rthra l gi a s , corti cos teroi ds for
s evere rea cti ons (eg, exfol i a ti ve derma ti ti s , bronchos pa s m), a nd epi nephri ne for a na phyl a xi s . Condi ti ons s uch a s drug fever, a nonpruri ti c s ki n
ra s h, or mi l d orga n s ys tem rea cti ons requi re no trea tment (for trea tment of s peci fi c cl i ni ca l rea cti ons , s ee el s ewhere i n THE MANUAL).
Desensitization: Ra pi d des ens i ti za ti on ma y be neces s a ry i f s ens i ti vi ty ha s been es ta bl i s hed a nd i f trea tment i s es s enti a l a nd no a l terna ti ve exi s ts .
If pos s i bl e, des ens i ti za ti on s houl d be done i n col l a bora ti on wi th a n a l l ergi s t. The procedure s houl d not be a ttempted i n pa ti ents who ha ve ha d
Stevens -Johns on s yndrome. Whenever des ens i ti za ti on i s us ed, O2 , epi nephri ne, a nd res us ci ta ti on equi pment mus t be a va i l a bl e for prompt
trea tment of a na phyl a xi s .
Des ens i ti za ti on i s ba s ed on i ncrementa l dos i ng of the a nti gen every 30 mi n, begi nni ng wi th a mi nute dos e to i nduce s ubcl i ni ca l a na phyl a xi s
before expos ure to thera peuti c dos es . Thi s procedure depends on cons ta nt pres ence of drug i n the s erum a nd s o mus t not be i nterrupted;
des ens i ti za ti on i s i mmedi a tel y fol l owed by ful l thera peuti c dos es . Hypers ens i ti vi ty typi ca l l y returns 24 to 48 h a fter trea tment i s s topped. Mi nor
rea cti ons (eg, i tchi ng, ra s h) a re common duri ng des ens i ti za ti on.
For peni ci l l i n, ora l or IV regi mens ca n be us ed; s c or IM regi mens a re not recommended. If onl y the i ntra derma l s ki n tes t i s pos i ti ve, 100 uni ts (or
g)/mL IV i n a 50-mL ba g (5000 uni ts tota l ) s houl d be gi ven very s l owl y a t fi rs t. If no s ymptoms a ppea r, fl ow ra te ca n be i ncrea s ed gra dua l l y unti l
the ba g i s empty, a fter 20 to 30 mi n. The procedure i s then repea ted wi th concentra ti ons of 1,000 uni ts /mL a nd 10,000 uni ts /mL, fol l owed by the ful l
thera peuti c dos e. If a ny a l l ergi c s ymptoms devel op, fl ow ra te s houl d be s l owed, a nd pa ti ents a re gi ven a ppropri a te drug trea tment (s ee a bove). If
the pri ck tes t for peni ci l l i n wa s pos i ti ve or pa ti ents ha ve ha d a s evere a na phyl a cti c rea cti on, the s ta rti ng dos e s houl d be l ower.
Ora l peni ci l l i n des ens i ti za ti on begi ns wi th 100 uni ts (or g); dos es a re doubl ed every 15 mi n up to 400,000 uni ts (dos e 13). Then, the drug i s gi ven
pa rentera l l y, a nd i f s ymptoms occur, they a re rel i eved wi th a ppropri a te a nti -a na phyl a cti c drugs .
For a l l ergi es to tri methopri m-s ul fa methoxa zol e a nd va ncomyci n, regi mens s i mi l a r to thos e for peni ci l l i n ca n be us ed.
If a s ki n tes t to xenogenei c s erum i s pos i ti ve, ri s k of a na phyl a xi s i s hi gh. If s erum trea tment i s es s enti a l , des ens i ti za ti on mus t precede i t. Ski n
tes ts , us i ng wea k concentra ti ons prepa red by s eri a l di l uti on, a re us ed to determi ne the a ppropri a te s ta rti ng dos e for des ens i ti za ti on (i e, the
concentra ti on tha t produces a nega ti ve or onl y a wea k rea cti on). 0.1 mL of thi s s ol uti on i s i njected s c or s l owl y IV; the IV route, a l though not
s ta nda rd, gi ves the cl i ni ci a n control over concentra ti on a nd ra te of del i very. If no rea cti on occurs i n 15 mi n, the dos e i s doubl ed every 15 mi n unti l
1 mL of undi l uted s erum i s gi ven. Thi s dos e i s repea ted IM, a nd i f no rea cti on occurs i n a nother 15 mi n, the ful l dos e ca n be gi ven. If a rea cti on
occurs , trea tment ma y s ti l l be pos s i bl e; the dos e i s reduced, a n a nti hi s ta mi ne i s gi ven a s for a cute urti ca ri a , a nd the dos e i s then i ncrea s ed by
s ma l l er i ncrements .
Mastocytosis
Mastocytosis is mast cell infiltration of skin or other tissues and organs. Symptoms result mainly from mediator release and include pruritus, flushing, and
dyspepsia due to gastric hypersecretion. Diagnosis is by skin or bone marrow biopsy or both. Treatment is with antihistamines and control of any underlying
disorder.
Ma s tocytos i s i s a group of di s orders cha ra cteri zed by prol i fera ti on of ma s t cel l s a nd i nfi l tra ti on of the s ki n, other orga ns , or both. Pa thol ogy
res ul ts ma i nl y from rel ea s e of ma s t cel l medi a tors , i ncl udi ng hi s ta mi ne, hepa ri n, l eukotri enes , a nd va ri ous i nfl a mma tory cytoki nes . Hi s ta mi ne
ca us es ma ny s ymptoms , i ncl udi ng ga s tri c s ymptoms , but other medi a tors a l s o contri bute. Si gni fi ca nt orga n i nfi l tra ti on ma y ca us e orga n
dys functi on. Medi a tor rel ea s e ma y be tri ggered by phys i ca l touch, exerci s e, a l cohol , NSAIDs , opi oi ds , i ns ect s ti ngs , or foods .
Eti ol ogy i n ma ny pa ti ents i nvol ves a n a cti va ti ng muta ti on (D816V) i n the gene codi ng for the s tem cel l fa ctor receptor c-ki t, pres ent on ma s t cel l s .
Classification
Ma s tocytos i s ma y be cuta neous or s ys temi c.
Cutaneous mastocytosis: Thi s type typi ca l l y occurs i n chi l dren. Mos t pa ti ents pres ent wi th urti ca ri a pi gmentos a , a l oca l or di ffus el y di s tri buted
s a l mon or brown ma cul opa pul a r s ki n ra s h ca us ed by mul ti pl e s ma l l ma s t cel l col l ecti ons . Les s common a re di ffus e cuta neous ma s tocytos i s ,
whi ch i s s ki n i nfi l tra ti on wi thout di s crete l es i ons , a nd ma s tocytoma , whi ch i s a l a rge (1 to 5 cm) s ol i ta ry col l ecti on of ma s t cel l s .
Systemic mastocytosis: Thi s type mos t commonl y occurs i n a dul ts a nd i s cha ra cteri zed by mul ti foca l bone ma rrow l es i ons ; i t often i nvol ves other
orga ns , mos t commonl y the s ki n, l ymph nodes , l i ver, s pl een, or GI tra ct. Sys temi c ma s tocytos i s i s cl a s s i fi ed a s
Indol ent ma s tocytos i s , wi th no orga n dys functi on a nd a good prognos i s
Ma s tocytos i s a s s oci a ted wi th other hema tol ogi c di s orders (eg, myel oprol i fera ti ve di s orders , myel odys pl a s i a , l ymphoma )
Aggres s i ve ma s tocytos i s , cha ra cteri zed by i mpa i red orga n functi on
Ma s t cel l l eukemi a , wi th > 20% ma s t cel l s i n bone ma rrow, no s ki n l es i ons , mul ti orga n fa i l ure, a nd a poor prognos i s
Symptoms and Signs
Ski n i nvol vement i s often pruri ti c. Stroki ng or rubbi ng s ki n l es i ons ca us es urti ca ri a a nd erythema a round the l es i on (Da ri er's s i gn); thi s rea cti on
di ffers from derma togra phi s m, whi ch i nvol ves norma l s ki n.
Sys temi c s ymptoms ca n occur wi th a ny form. The mos t common i s fl us hi ng; the mos t dra ma ti c i s a na phyl a ctoi d rea cti on wi th s yncope a nd s hock.
Other s ymptoms i ncl ude epi ga s tri c pa i n due to pepti c ul cer di s ea s e, na us ea , vomi ti ng, chroni c di a rrhea , a rthra l gi a s , bone pa i n, a nd
neurops ychi a tri c cha nges (eg, i rri ta bi l i ty, depres s i on, mood l a bi l i ty). Hepa ti c a nd s pl eni c i nfi l tra ti on ma y ca us e porta l hypertens i on wi th res ul ta nt
a s ci tes .
Diagnosis
Ski n l es i on bi ops y a nd s ometi mes bone ma rrow bi ops y
Di a gnos i s i s s ugges ted by cl i ni ca l pres enta ti on. Di a gnos i s i s confi rmed by bi ops y of s ki n l es i ons a nd s ometi mes of bone ma rrow. Mul ti foca l ,
dens e i nfi l tra tes of ma s t cel l s a re pres ent.
Tes ts ma y be done to rul e out di s orders tha t ca us e s i mi l a r s ymptoms (a na phyl a xi s , pheochromocytoma , ca rci noi d s yndrome, a nd Zol l i nger-El l i s on
s yndrome). Serum ga s tri n l evel i s us eful to rul e out Zol l i nger-El l i s on s yndrome i n pa ti ents wi th ul cer s ymptoms ; uri na ry excreti on of 5hydroxyi ndol ea ceti c a ci d (5-HIAA) i s mea s ured to rul e out ca rci noi d i n pa ti ents wi th fl us hi ng.
If the di a gnos i s i s uncerta i n, l evel s of ma s t cel l medi a tors a nd thei r meta bol i tes (eg, uri na ry N-methyl hi s ta mi ne a nd N-methyl i mi da zol e a ceti c
a ci d) ma y be mea s ured i n pl a s ma a nd uri ne; el eva ted l evel s s upport the di a gnos i s of ma s tocytos i s . The l evel of trypta s e (a ma rker of ma s t cel l
degra nul a ti on) i s el eva ted i n s ys temi c ma s tocytos i s but i s typi ca l l y norma l i n cuta neous ma s tocytos i s . A bone s ca n, GI workup, a nd i denti fi ca ti on
of the D816V c-kit muta ti on ca n a l s o be hel pful i n ca s es where the di a gnos i s requi res confi rma ti on.
Treatment
For cuta neous ma s tocytos i s , H 1 bl ockers a nd pos s i bl y ps ora l en pl us ul tra vi ol et l i ght or topi ca l corti cos teroi ds
For s ys temi c ma s tocytos i s , H 1 a nd H 2 bl ockers a nd s ometi mes cromol yn
For a ggres s i ve forms , i nterferon a l fa -2b, corti cos teroi ds , or s pl enectomy
Cutaneous mastocytosis: H 1 bl ockers a re effecti ve for s ymptoms . Chi l dren wi th cuta neous forms requi re no a ddi ti ona l trea tment beca us e mos t ca s es
res ol ve s ponta neous l y. Adul ts wi th cuta neous forms ma y be trea ted wi th ps ora l en pl us ul tra vi ol et l i ght or wi th topi ca l corti cos teroi ds once/da y or
bi d. Ma s tocytoma us ua l l y i nvol utes s ponta neous l y a nd requi res no trea tment. Cuta neous forms ra rel y progres s to s ys temi c di s ea s e i n chi l dren but
ma y do s o i n a dul ts .
Systemic mastocytosis: Al l pa ti ents s houl d be trea ted wi th H 1 a nd H 2 bl ockers . As pi ri n control s fl us hi ng but ma y enha nce l eukotri ene producti on,
thereby contri buti ng to ma s t cel l -rel a ted s ymptoms ; i t s houl d not be gi ven to chi l dren beca us e Reye's s yndrome i s a ri s k. Cromol yn 200 mg po qi d
(100 mg qi d for chi l dren 2 to 12 yr; not to exceed 40 mg/kg/da y) ma y hel p by preventi ng ma s t cel l degra nul a ti on. No trea tment ca n reduce the
number of ti s s ue ma s t cel l s . Ketoti fen 2 to 4 mg po bi d i s i ncons i s tentl y effecti ve.
In pa ti ents wi th a n a ggres s i ve form, i nterferon a l fa -2b 4 mi l l i on uni ts s c once/wk to a ma xi mum of 3 mi l l i on uni ts /da y i nduces regres s i on of bone
l es i ons . Corti cos teroi ds (eg, predni s one 40 to 60 mg po once/da y for 2 to 3 wk) ma y be requi red. Spl enectomy ma y i mprove s urvi va l .
Cytotoxi c drugs (eg, da unomyci n, etopos i de, 6-merca ptopuri ne) ma y be i ndi ca ted for trea tment of ma s t cel l l eukemi a , but effi ca cy i s unproved.
Ima ti ni b (a tyros i ne ki na s e receptor i nhi bi tor) ma y be us eful i n s ome pa ti ents but i s i neffecti ve i n pa ti ents wi th the D816V c-kit muta ti on.
Mi dos ta uri n (a 2nd-genera ti on tyros i ne ki na s e receptor i nhi bi tor) i s under s tudy i n s uch pa ti ents .
Chapter 128. Transplantation

Introduction
Tra ns pl a nts ma y be the pa ti ent's own ti s s ue (a utogra fts ; eg, bone, bone ma rrow, a nd s ki n gra fts ), geneti ca l l y i denti ca l (s yngenei c) donor ti s s ue
(i s ogra fts ), geneti ca l l y di s s i mi l a r donor ti s s ue (a l l ogra fts , or homogra fts ), or, ra rel y, gra fts from a di fferent s peci es (xenogra fts , or heterogra fts ).
Tra ns pl a nted ti s s ue ma y be cel l s (a s for hema topoi eti c s tem cel l [HSC], l ymphocyte, a nd pa ncrea ti c i s l et cel l tra ns pl a nts ), pa rts or s egments of a n
orga n (a s for hepa ti c or pul mona ry l oba r tra ns pl a nts a nd s ki n gra fts ), or enti re orga ns (a s for hea rt tra ns pl a nts ).
Ti s s ues ma y be gra fted to a n a na tomi ca l l y norma l s i te (orthotopi c; eg, hea rt tra ns pl a nts ) or a bnorma l s i te (heterotopi c; eg, a ki dney tra ns pl a nted
i nto the i l i a c fos s a ). Al mos t a l wa ys , tra ns pl a nta ti on i s done to i mprove pa ti ent s urvi va l . However, s ome procedures (eg, ha nd, l a rynx, tongue, a nd
fa ci a l tra ns pl a nta ti on) a ttempt to i mprove qua l i ty of l i fe but jeopa rdi ze qua nti ty of l i fe a nd thus a re controvers i a l .
Wi th ra re excepti ons , cl i ni ca l tra ns pl a nta ti on us es a l l ogra fts from l i vi ng rel a ted, l i vi ng unrel a ted, or decea s ed donors . Li vi ng donors a re often
us ed for ki dney a nd HSC tra ns pl a nts a nd i ncrea s i ngl y for s egmenta l l i ver, pa ncrea s , a nd l ung tra ns pl a nts . Us e of decea s ed-donor orga ns (from
hea rt-bea ti ng or non-hea rt-bea ti ng donors ) ha s hel ped reduce the di s pa ri ty between orga n dema nd a nd s uppl y; however, dema nd s ti l l fa r
exceeds s uppl y, a nd the number of pa ti ents wa i ti ng for orga n tra ns pl a nts conti nues to grow.
Al l a l l ogra ft reci pi ents a re a t ri s k of gra ft rejecti on; the reci pi ent's i mmune s ys tem recogni zes the gra ft a s forei gn a nd s eeks to des troy i t.
Reci pi ents of gra fts conta i ni ng i mmune cel l s a re a t ri s k of gra ft-vs -hos t di s ea s e. Ri s k of thes e compl i ca ti ons i s mi ni mi zed by pretra ns pl a nta ti on
s creeni ng a nd i mmunos uppres s i ve thera py duri ng a nd a fter tra ns pl a nta ti on.
Organ distribution: Al l oca ti on depends on di s ea s e s everi ty for s ome orga ns (l i ver, hea rt) a nd on di s ea s e s everi ty, ti me on the wa i ti ng l i s t, or both
for others (ki dney, l ung, bowel ). In the US a nd Puerto Ri co, orga ns a re a l l oca ted fi rs t a mong 12 geogra phi c regi ons , then a mong l oca l Orga n
Procurement Orga ni za ti ons . If no reci pi ent i n the fi rs t regi on i s s ui ta bl e, orga ns a re rea l l oca ted to reci pi ents i n other regi ons .
Pretransplantation Screening
Before the ri s k a nd expens e of tra ns pl a nta ti on a re underta ken a nd s ca rce donor orga ns a re commi tted, phys i ci a ns s creen potenti a l reci pi ents for
medi ca l a nd nonmedi ca l fa ctors tha t ma y a ffect the l i kel i hood of s ucces s .
Tissue compatibility: In pretra ns pl a nta ti on s creeni ng, reci pi ents a nd donors a re tes ted for huma n l eukocyte a nti gen (HLA) a nd ABO a nti gens , a nd
reci pi ents a re tes ted for pres ens i ti za ti on to donor a nti gens . HLA ti s s ue typi ng i s mos t i mporta nt for ki dney a nd the mos t common types of HSC
tra ns pl a nta ti on. Hea rt, l i ver, pa ncrea s , a nd l ung tra ns pl a nta ti on typi ca l l y occurs qui ckl y, often before HLA ti s s ue typi ng ca n be compl eted, s o the
rol e of ma tchi ng for thes e orga ns i s l es s wel l es ta bl i s hed.
HLA ti s s ue typi ng of peri phera l bl ood or l ymph node l ymphocytes i s us ed to ma tch the mos t i mporta nt known determi na nts of hi s tocompa ti bi l i ty
i n the donor a nd reci pi ent. More tha n 1250 a l l el es determi ne 6 HLA a nti gens (HLA-A, -B, -C, -DP, -DQ, -DR), s o ma tchi ng i s a cha l l enge; eg, i n the US,
onl y 2 of 6 a nti gens on a vera ge a re ma tched i n ki dney donors a nd reci pi ents . Ma tchi ng of a s ma ny HLA a nti gens a s pos s i bl e s i gni fi ca ntl y i mproves
functi ona l s urvi va l of gra fts from l i vi ng rel a ted ki dney a nd HSC donors ; HLA ma tchi ng of gra fts from unrel a ted donors a l s o i mproves s urvi va l ,
a l though much l es s s o beca us e of mul ti pl e undetected hi s tocompa ti bi l i ty di fferences . Better i mmunos uppres s i ve thera py ha s expa nded
el i gi bi l i ty for tra ns pl a nta ti on; HLA mi s ma tches no l onger a utoma ti ca l l y di s qua l i fy pa ti ents for tra ns pl a nta ti on.
ABO compa ti bi l i ty a nd HLA compa ti bi l i ty a re i mporta nt for gra ft s urvi va l . ABO mi s ma tches ca n preci pi ta te hypera cute rejecti on of hi ghl y va s cul a r
gra fts (eg, ki dney, hea rt), whi ch ha ve ABO a nti gens on the endothel i a l s urfa ces . Pres ens i ti za ti on to HLA a nd ABO a nti gens res ul ts from pri or bl ood
tra ns fus i ons , tra ns pl a nta ti ons , or pregna nci es a nd ca n be detected wi th s erol ogy tes ts or, more commonl y, wi th a l ymphocytotoxi c tes t us i ng the
reci pi ent's s erum a nd donor's l ymphocytes i n the pres ence of compl ement. A pos i ti ve cros s -ma tch i ndi ca tes tha t the reci pi ent's s erum conta i ns
a nti bodi es di rected a ga i ns t ABO or cl a s s I HLA a nti gens i n the donor; i t i s a n a bs ol ute contra i ndi ca ti on to tra ns pl a nta ti on, except pos s i bl y i n
i nfa nts (up to a ge 14 mo) who ha ve not yet produced i s ohema ggl uti ni ns . Hi gh-dos e IV i mmune gl obul i n ha s been us ed to s uppres s HLA
a nti bodi es a nd fa ci l i ta te tra ns pl a nta ti on, but l ong-term outcomes a re unknown. A nega ti ve cros s -ma tch does not gua ra ntee s a fety; when ABO
a nti gens a re compa ti bl e but not i denti ca l (eg, donor O a nd reci pi ent A, B, or AB), hemol ys i s i s a potenti a l compl i ca ti on due to a nti body producti on
by tra ns pl a nted (pa s s enger) donor l ymphocytes .
Al though ma tchi ng for HLA a nd ABO a nti gens genera l l y i mproves gra ft s urvi va l , nonwhi te pa ti ents a re di s a dva nta ged beca us e they ma y ha ve
di fferent HLA pol ymorphi s ms from whi te donors , a hi gher ra te of pres ens i ti za ti on to HLA a nti gens , a nd a hi gher i nci dence of bl ood types O a nd B.
Infection: Donor a nd reci pi ent expos ure to common i nfecti ous pa thogens a nd a cti ve i nfecti ons mus t be detected before tra ns pl a nta ti on to
mi ni mi ze ri s k of tra ns mi tti ng i nfecti on from the donor a nd ri s k of wors eni ng or rea cti va ti ng exi s ti ng i nfecti on i n the reci pi ent (due to us e of
i mmunos uppres s a nts ). Thi s s creeni ng us ua l l y i ncl udes the hi s tory; s erol ogi c tes ts for cytomega l ovi rus (CMV), Eps tei n-Ba rr vi rus (EBV), herpes
s i mpl ex vi rus (HSV), va ri cel l a zos ter vi rus (VZV), hepa ti ti s B a nd C vi rus es , HIV, a nd Wes t Ni l e vi rus (i f expos ure i s s us pected); a nd tubercul i n s ki n
tes ti ng. Pos i ti ve fi ndi ngs ma y requi re pos t-tra ns pl a nta ti on a nti vi ra l trea tment (eg, for CMV i nfecti on or hepa ti ti s B) or contra i ndi ca te
tra ns pl a nta ti on (eg, i f HIV wi th AIDS i s detected).
Contraindications to transplantation: Abs ol ute contra i ndi ca ti ons to tra ns pl a nta ti on i ncl ude a cti ve i nfecti on a nd ca ncer (except hepa tocel l ul a r
ca rci noma confi ned to the l i ver a nd certa i n neuroendocri ne tumors ).
Rel a ti ve contra i ndi ca ti ons i ncl ude a ge > 65, poor functi ona l or nutri ti ona l s ta tus (i ncl udi ng s evere obes i ty), HIV i nfecti on, a nd mul ti orga n
i ns uffi ci ency. Ps ychol ogi c a nd s oci a l fa ctors a l s o pl a y a rol e i n s ucces s of tra ns pl a nta ti on. For exa mpl e, peopl e who a bus e drugs or who a re
ps ychol ogi ca l l y uns ta bl e a re l es s l i kel y to fi rml y a dhere to the neces s a ry l i fel ong regi men of trea tments a nd fol l ow-up vi s i ts . El i gi bi l i ty deci s i ons
for pa ti ents wi th rel a ti ve contra i ndi ca ti ons di ffer by medi ca l center. Immunos uppres s a nts a re s a fe a nd effecti ve for HIV-pos i ti ve tra ns pl a nt
reci pi ents .
Immunosuppression
Immunos uppres s a nts control gra ft rejecti on a nd a re pri ma ri l y res pons i bl e for the s ucces s of tra ns pl a nta ti on. However, they s uppres s a l l i mmune
res pons es a nd contri bute to ma ny pos t-tra ns pl a nta ti on compl i ca ti ons , i ncl udi ng dea th due to overwhel mi ng i nfecti on. Except when HLA-i denti ca l
tra ns pl a nts a re us ed, i mmunos uppres s a nts mus t us ua l l y be conti nued l ong a fter tra ns pl a nta ti on, but i ni ti a l l y hi gh dos es ca n be reduced a few
weeks a fter the procedure, a nd l ow dos es ca n be conti nued i ndefi ni tel y unl es s rejecti on occurs .
Corticosteroids: A hi gh dos e i s us ua l l y gi ven a t the ti me of tra ns pl a nta ti on, then i s reduced gra dua l l y to a ma i ntena nce dos e, whi ch i s gi ven
i ndefi ni tel y. Severa l months a fter tra ns pl a nta ti on, corti cos teroi ds ca n be gi ven on a l terna te da ys ; thi s regi men hel ps prevent growth res tri cti on i n
chi l dren. If rejecti on occurs , hi gh dos es a re rei ns ti tuted.
Calcineurin inhibitors (CNIs): Thes e drugs (cycl os pori ne, ta crol i mus ) bl ock T-cel l tra ns cri pti on proces s es requi red for producti on of cytoki nes , thereby
s el ecti vel y i nhi bi ti ng T-cel l prol i fera ti on a nd a cti va ti on.
Cyclosporine i s the mos t commonl y us ed drug i n hea rt a nd l ung tra ns pl a nta ti on. It ca n be gi ven a l one but i s us ua l l y gi ven wi th other drugs (eg,
a za thi opri ne, predni s one), s o tha t l ower, l es s toxi c dos es ca n be us ed. The i ni ti a l dos e i s reduced to a ma i ntena nce dos e s oon a fter
tra ns pl a nta ti on. The drug i s meta bol i zed by the cytochrome P-450 3A enzyme, a nd bl ood l evel s a re a ffected by ma ny other drugs . The mos t s eri ous
a dvers e effect i s nephrotoxi ci ty; cycl os pori ne ca us es va s ocons tri cti on of a fferent (pregl omerul a r) a rteri ol es , l ea di ng to gl omerul a r a ppa ra tus
da ma ge, refra ctory gl omerul a r hypoperfus i on, a nd, eventua l l y, chroni c rena l fa i l ure. Al s o, B-cel l l ymphoma s a nd pol ycl ona l B-cel l
l ymphoprol i fera ti on occur more often i n pa ti ents recei vi ng hi gh dos es of cycl os pori ne or combi na ti ons of cycl os pori ne a nd other
i mmunos uppres s a nts di rected a t T cel l s , pos s i bl y beca us e of a n a s s oci a ti on wi th EBV. Other a dvers e effects i ncl ude di a betes , hepa totoxi ci ty,
refra ctory hypertens i on, i ncrea s ed i nci dence of other tumors , a nd l es s s eri ous effects (eg, gum hypertrophy, hi rs uti s m). Serum cycl os pori ne l evel s
do not correl a te wi th effecti venes s or toxi ci ty.
Tacrolimus i s the mos t commonl y us ed drug i n ki dney, l i ver, pa ncrea s , a nd s ma l l -bowel tra ns pl a nta ti on. Ta crol i mus ma y be s ta rted a t the ti me of
tra ns pl a nta ti on or da ys a fter the procedure. Dos i ng s houl d be gui ded by bl ood l evel s , whi ch a re i nfl uenced by the s a me drug i ntera cti ons a s for
cycl os pori ne. Ta crol i mus ma y be us eful when cycl os pori ne i s i neffecti ve or ha s i ntol era bl e a dvers e effects . Advers e effects of ta crol i mus a re
s i mi l a r to thos e of cycl os pori ne except ta crol i mus i s more prone to i nduce di a betes ; gum hypertrophy a nd hi rs uti s m a re l es s common.
Lymphoprol i fera ti ve di s orders s eem to occur more often i n pa ti ents ta ki ng ta crol i mus , even weeks a fter tra ns pl a nta ti on. If they occur, ta crol i mus
s houl d be s topped a nd cycl os pori ne or a nother i mmunos uppres s i ve drug s ubs ti tuted.
Purine metabolism inhibitors: Exa mpl es a re a za thi opri ne a nd mycophenol a te mofeti l .
Azathioprine, a n a nti meta bol i te, i s us ua l l y s ta rted a t the ti me of tra ns pl a nta ti on. Mos t pa ti ents tol era te i t i ndefi ni tel y. The mos t s eri ous a dvers e
effects a re bone ma rrow depres s i on a nd, ra rel y, hepa ti ti s . Aza thi opri ne i s often us ed wi th l ow dos es of cycl os pori ne.
Mycophenolate mofetil (MMF), a prodrug meta bol i zed to mycophenol i c a ci d, revers i bl y i nhi bi ts i nos i ne monophos pha te dehydrogena s e, a n enzyme
i n the gua ni ne nucl eoti de pa thwa y tha t i s ra te-l i mi ti ng i n l ymphocyte prol i fera ti on. MMF i s gi ven wi th cycl os pori ne (or ta crol i mus ) a nd
corti cos teroi ds to pa ti ents wi th a ki dney, hea rt, or l i ver tra ns pl a nt. The mos t common a dvers e effects a re l eukopeni a , na us ea , vomi ti ng, a nd
di a rrhea .
Rapamycins: Thes e drugs (s i rol i mus , everol i mus ) bl ock a key regul a tory ki na s e i n l ymphocytes , res ul ti ng i n a rres t of the cel l cycl e a nd i n i nhi bi ti on
of l ymphocyte res pons e to cytoki ne s ti mul a ti on.
Sirolimus i s typi ca l l y gi ven wi th cycl os pori ne a nd corti cos teroi ds a nd ma y be us eful for pa ti ents wi th rena l i ns uffi ci ency. Advers e effects i ncl ude
hyperl i pi demi a , i mpa i red wound hea l i ng, a nd bone ma rrow depres s i on wi th l eukopeni a , thrombocytopeni a , a nd a nemi a .
Everolimus i s typi ca l l y us ed to prevent hea rt tra ns pl a nt rejecti on; a dvers e effects a re s i mi l a r to thos e of s i rol i mus .
Immunosuppressive Igs: Exa mpl es a re a nti l ymphocyte gl obul i n (ALG) a nd a nti thymocyte gl obul i n (ATG). Both a re fra cti ons of a ni ma l a nti s era
di rected a ga i ns t huma n cel l s : l ymphocytes (ALG) or thymus cel l s (ATG). ALG a nd ATG s uppres s cel l ul a r i mmuni ty whi l e pres ervi ng humora l
i mmuni ty. They a re us ed wi th other i mmunos uppres s a nts to a l l ow thos e drugs to be us ed i n l ower, l es s toxi c dos es . Us e of ALG or ATG to control
a cute epi s odes of rejecti on i mproves gra ft s urvi va l ra tes ; us e a t the ti me of tra ns pl a nta ti on ma y decrea s e rejecti on i nci dence a nd a l l ow CNIs to be
s ta rted l a ter, thereby reduci ng toxi ci ty. Us e of hi ghl y puri fi ed s erum fra cti ons ha s grea tl y reduced i nci dence of a dvers e effects (eg, a na phyl a xi s ,
s erum s i cknes s , a nti gen-a nti body-i nduced gl omerul onephri ti s ).
Monoclonal antibodies (mAbs): mAbs di rected a ga i ns t T cel l s provi de a hi gher concentra ti on of a nti -T-cel l a nti bodi es a nd fewer i rrel eva nt s erum
protei ns tha n do ALG a nd ATG. OKT3 i nhi bi ts T-cel l receptor (TCR)-a nti gen bi ndi ng, res ul ti ng i n i mmunos uppres s i on. OKT3 i s us ed pri ma ri l y to
control epi s odes of a cute rejecti on; i t ma y a l s o be us ed a t the ti me of tra ns pl a nta ti on to reduce i nci dence or del a y ons et of rejecti on epi s odes .
However, benefi ts of prophyl a cti c us e mus t be wei ghed a ga i ns t a dvers e effects , whi ch i ncl ude s evere CMV i nfecti on a nd devel opment of
neutra l i zi ng a nti bodi es ; thes e effects precl ude us i ng OKT3 for a n a ctua l rejecti on epi s ode. Wi th fi rs t us e, OKT3 bi nds to the TCR-CD3 compl ex,
a cti va ti ng the cel l a nd tri ggeri ng rel ea s e of cytoki nes , whi ch ca us e a s yndrome of fevers , ri gors , mya l gi a s , a rthra l gi a s , na us ea , vomi ti ng, a nd
di a rrhea . Pretrea tment wi th corti cos teroi ds , a nti pyreti cs , a nd a nti hi s ta mi nes ca n a mel i ora te thes e s ymptoms . The fi rs t-dos e rea cti on l es s
commonl y i ncl udes ches t pa i n, dys pnea , a nd wheezi ng, pos s i bl y due to compl ement a cti va ti on. Repea ted us e i s a s s oci a ted wi th i ncrea s ed
i nci dence of EBV-i nduced B-cel l l ymphoprol i fera ti ve di s orders . Ra rel y, a s epti c meni ngi ti s a nd hemol yti c uremi c s yndrome occur.
Anti -IL-2 receptor monocl ona l a nti bodi es i nhi bi t T-cel l prol i fera ti on by bl ocki ng the effect of IL-2, s ecreted by a cti va ted T cel l s . Ba s i l i xi ma b a nd
da cl i zuma b, 2 huma ni zed a nti -IL-2 receptor a nti bodi es , a re i ncrea s i ngl y bei ng us ed to trea t a cute rejecti on of ki dney, l i ver, a nd s ma l l -bowel
tra ns pl a nts ; they a re a l s o us ed a s a djunct i mmunos uppres s i ve thera py a t the ti me of tra ns pl a nta ti on. The onl y a dvers e effect reported i s
a na phyl a xi s . Al s o, experi ence wi th IL-2 receptor a nti bodi es i s l i mi ted, a nd a n i ncrea s ed ri s k of l ymphoprol i fera ti ve di s orders ca nnot be excl uded.
Irradiation: Irra di a ti on of a gra ft, l oca l reci pi ent ti s s ues , or both ca n be us ed to trea t ki dney tra ns pl a nt rejecti on epi s odes when other trea tment
(eg, corti cos teroi ds a nd ATG) i s i neffecti ve. Tota l l ympha ti c i rra di a ti on i s experi menta l but a ppea rs to s a fel y s uppres s cel l ul a r i mmuni ty, a t fi rs t by
s ti mul a ti on of s uppres s or T cel l s a nd l a ter pos s i bl y by cl ona l del eti on of s peci fi c a nti gen-rea cti ve cel l s .
Future therapies: Protocol s a nd a gents to i nduce gra ft a nti gen-s peci fi c tol era nce wi thout s uppres s i ng other i mmune res pons es a re bei ng s ought.
Two s tra tegi es a re promi s i ng:
Bl ocka de of T-cel l cos ti mul a tory pa thwa ys us i ng a cytotoxi c T l ymphocyte-a s s oci a ted a nti gen 4 (CTLA-4)-IgG1 fus i on protei n
Inducti on of chi meri s m (coexi s tence of donor a nd reci pi ent i mmune cel l s i n whi ch gra ft ti s s ue i s recogni zed a s s el f) us i ng nonmyel oa bl a ti ve
pretra ns pl a nta ti on trea tment (eg, wi th cycl ophos pha mi de, thymi c i rra di a ti on, ATG, a nd cycl os pori ne) to i nduce tra ns i ent T-cel l depl eti on,
engra ftment of donor HSCs , a nd s ubs equent tol era nce of s ol i d orga n tra ns pl a nts from the s a me donor
Post-transplantation Complications
Compl i ca ti ons i ncl ude the fol l owi ng:
Rejecti on
Infecti on
Ca ncer
Rejection: Rejecti on of s ol i d orga ns ma y be hypera cute, a ccel era ted, a cute, or chroni c (l a te). Thes e ca tegori es overl a p s omewha t i n ti mi ng but ca n
be di s ti ngui s hed hi s topa thol ogi ca l l y. Symptoms va ry by orga n (s ee
Ta bl e 128-1).
Hyperacute rejection occurs wi thi n 48 h of tra ns pl a nta ti on a nd i s ca us ed by preexi s ti ng compl ement-fi xi ng a nti bodi es to gra ft a nti gens
(pres ens i ti za ti on). It ha s become ra re (1%) a s pretra ns pl a nta ti on s creeni ng ha s i mproved. Hypera cute rejecti on i s cha ra cteri zed by s ma l l -ves s el
thrombos i s a nd gra ft i nfa rcti on. No trea tment i s effecti ve except gra ft remova l .
Accelerated rejection occurs 3 to 5 da ys a fter tra ns pl a nta ti on a nd i s ca us ed by preexi s ti ng noncompl ement-fi xi ng a nti bodi es to gra ft a nti gens .
Accel era ted rejecti on i s a l s o ra re. It i s cha ra cteri zed hi s topa thol ogi ca l l y by cel l ul a r i nfi l tra te wi th or wi thout va s cul a r cha nges . Trea tment i s wi th
hi gh-dos e pul s e corti cos teroi ds or, i f va s cul a r cha nges occur, a nti l ymphocyte prepa ra ti ons . Pl a s ma pheres i s , whi ch ma y cl ea r ci rcul a ti ng
a nti bodi es more ra pi dl y, ha s been us ed.
Acute rejection i s gra ft des tructi on a fter tra ns pl a nta ti on a nd i s ca us ed by a T cel l -medi a ted del a yed hypers ens i ti vi ty rea cti on to a l l ogra ft
hi s tocompa ti bi l i ty a nti gens . It a ccounts for a bout one ha l f of a l l rejecti on epi s odes tha t occur wi thi n 10 yr. Acute rejecti on i s cha ra cteri zed by
mononucl ea r cel l ul a r i nfi l tra ti on, wi th va ryi ng degrees of hemorrha ge, edema , a nd necros i s . Va s cul a r i ntegri ty i s us ua l l y ma i nta i ned, a l though
va s cul a r endothel i um a ppea rs to be a pri ma ry ta rget. Acute rejecti on i s often revers ed by i ntens i fyi ng i mmunos uppres s i ve thera py (eg, wi th pul s e
corti cos teroi ds , ALG, or both). After rejecti on
[Table 128-1. Si gns of Tra ns pl a nt Rejecti on by Ca tegory]
revers a l , s everel y da ma ged pa rts of the gra ft hea l by fi bros i s , the rema i nder of the gra ft functi ons norma l l y, i mmunos uppres s a nt dos es ca n be
reduced to very l ow l evel s , a nd the a l l ogra ft ca n s urvi ve for l ong peri ods .
Chronic rejection i s gra ft dys functi on, often wi thout fever, typi ca l l y occurri ng months to yea rs a fter tra ns pl a nta ti on but s ometi mes wi thi n weeks .
Ca us es a re mul ti pl e a nd i ncl ude ea rl y a nti body-medi a ted rejecti on, peri procedura l i s chemi a a nd reperfus i on i njury, drug toxi ci ty, i nfecti on, a nd
va s cul a r fa ctors (eg, hypertens i on, hyperl i pi demi a ). Chroni c rejecti on a ccounts for mos t of the other one ha l f of a l l rejecti on epi s odes .
Prol i fera ti on of neoi nti ma cons i s ti ng of s mooth mus cl e cel l s a nd extra cel l ul a r ma tri x (tra ns pl a nta ti on a theros cl eros i s ) gra dua l l y a nd eventua l l y
occl udes ves s el l umi na , res ul ti ng i n pa tchy i s chemi a a nd fi bros i s of the gra ft. Chroni c rejecti on progres s es i ns i di ous l y des pi te
i mmunos uppres s i ve thera py; no es ta bl i s hed trea tments exi s t.
Infection: Immunos uppres s a nts , s econda ry i mmunodefi ci enci es tha t a ccompa ny orga n fa i l ure, a nd s urgery ma ke tra ns pl a nt pa ti ents more
vul nera bl e to i nfecti ons . Ra rel y, a tra ns pl a nted orga n i s the s ource of i nfecti on (eg, CMV).
The mos t common s i gn i s fever, often wi thout l oca l i zi ng s i gns . Fever ca n a l s o be a s ymptom of a cute rejecti on but i s us ua l l y a ccompa ni ed by s i gns
of gra ft dys functi on. If thes e s i gns a re a bs ent, the a pproa ch i s s i mi l a r to tha t for other FUO (s ee p. 1157); ti mi ng of s ymptoms a nd s i gns a fter
tra ns pl a nta ti on hel ps na rrow the di fferenti a l di a gnos i s .
In the fi rs t month a fter tra ns pl a nta ti on, mos t i nfecti ons a re ca us ed by the s a me hos pi ta l -a cqui red ba cteri a a nd fungi tha t i nfect other s urgi ca l
pa ti ents (eg, Pseudomonas s p ca us i ng pneumoni a , gra m-pos i ti ve ba cteri a ca us i ng wound i nfecti ons ). The grea tes t concern wi th ea rl y i nfecti on i s
tha t orga ni s ms ca n i nfect a gra ft or i ts va s cul a r s uppl y a t s uture s i tes , ca us i ng mycoti c a neurys ms or dehi s cence.
Opportuni s ti c i nfecti ons occur 1 to 6 mo a fter tra ns pl a nta ti on (for trea tment, s ee el s ewhere i n The Ma nua l ). Infecti ons ma y be ba cteri a l (eg,
l i s teri os i s , noca rdi os i s ), vi ra l (eg, due to CMV, EBV, VZV, or hepa ti ti s B or C vi rus ), funga l (eg, a s pergi l l os i s , cryptococcos i s , Pneumocystis jirovecii
i nfecti on), or pa ra s i ti c (eg, s trongyl oi di a s i s , toxopl a s mos i s , trypa nos omi a s i s , l ei s hma ni a s i s ).
Ri s k of i nfecti on returns to ba s el i ne for a bout 80% of pa ti ents a fter 6 mo. About 10% devel op compl i ca ti ons of ea rl y i nfecti ons , s uch a s vi ra l
i nfecti on of the gra ft, meta s ta ti c i nfecti on (eg, CMV reti ni ti s , col i ti s ), or vi rus -i nduced ca ncers (eg, hepa ti ti s a nd hepa tocel l ul a r ca rci noma , huma n
pa pi l l oma vi rus a nd ba s a l cel l ca rci noma ). Others devel op chroni c rejecti on, requi re hi gh dos es of i mmunos uppres s a nts (5 to 10%), a nd rema i n a t
hi gh ri s k of opportuni s ti c i nfecti ons i ndefi ni tel y.
After tra ns pl a nta ti on, mos t pa ti ents a re gi ven a nti mi crobi a l s to reduce ri s k of i nfecti on. Choi ce of drug depends on i ndi vi dua l ri s k a nd type of
tra ns pl a nta ti on; regi mens i ncl ude tri methopri m/s ul fa methoxa zol e 80/400 mg po once/da y for 4 to 12 mo to prevent P. jirovecii i nfecti on or to
prevent UTIs i n ki dney tra ns pl a nt pa ti ents . Neutropeni c pa ti ents a re s ometi mes gi ven qui nol one a nti bi oti cs (eg, l evofl oxa ci n 500 mg po or IV
once/da y) to prevent i nfecti on wi th gra m-nega ti ve orga ni s ms . Ina cti va ted va cci nes ca n be s a fel y gi ven pos t-tra ns pl a nta ti on; ri s ks due to l i ve-
a ttenua ted va cci nes mus t be ba l a nced a ga i ns t thei r potenti a l benefi ts , es peci a l l y for pa ti ents ta ki ng l ow dos es of i mmunos uppres s a nts .
Renal disorders: GFR decrea s es 30 to 50% duri ng the fi rs t 6 mo a fter s ol i d orga n tra ns pl a nta ti on i n 15 to 20% of pa ti ents . They us ua l l y a l s o devel op
hypertens i on. Inci dence i s grea tes t for reci pi ents of s ma l l -bowel tra ns pl a nts (21%) a nd l ea s t for reci pi ents of hea rt-l ung tra ns pl a nts (7%).
Nephrotoxi c a nd di a betogeni c effects of CNIs a re the mos t i mporta nt contri butor, but peri procedura l rena l i ns ul ts , pretra ns pl a nta ti on rena l
i ns uffi ci ency, hepa ti ti s C i nfecti on, a nd us e of other nephrotoxi c drugs a l s o contri bute. After the i ni ti a l decrea s e, GFR typi ca l l y s ta bi l i zes or
decrea s es more s l owl y; nonethel es s , morta l i ty ri s k qua drupl es unl es s s ubs equent ki dney tra ns pl a nta ti on i s done. Rena l i ns uffi ci ency a fter
tra ns pl a nta ti on ma y be prevented by ea rl y wea ni ng from CNIs , but a s a fe mi ni mum dos e ha s not been determi ned.
Cancer: Long-term i mmunos uppres s i on i ncrea s es i nci dence of vi rus -i nduced ca ncer, es peci a l l y s qua mous a nd ba s a l cel l ca rci noma ,
l ymphoprol i fera ti ve di s orders (ma i nl y B-cel l non-Hodgki n l ymphoma ), a nogeni ta l (i ncl udi ng cervi ca l ) ca ncer, a nd Ka pos i 's s a rcoma . Trea tment i s
s i mi l a r to tha t of ca ncer i n noni mmunos uppres s ed pa ti ents ; reducti on or i nterrupti on of i mmunos uppres s i on i s not us ua l l y requi red for l ow-gra de
tumors but i s recommended for more a ggres s i ve tumors a nd l ymphoma s .
Tra ns fus i on of pa rti a l l y HLA-ma tched cytotoxi c T cel l s i s under s tudy a s a pos s i bl e trea tment for s ome forms of l ymphoprol i fera ti ve di s orders .
Other complications: Immunos uppres s a nts (es peci a l l y corti cos teroi ds a nd CNIs ) i ncrea s e bone res orpti on a nd ri s k of os teoporos i s for pa ti ents who
a re a t ri s k before tra ns pl a nta ti on (eg, beca us e of reduced phys i ca l a cti vi ty, toba cco a nd a l cohol us e, or a preexi s ti ng rena l di s order). Al though not
routi ne, us e of vi ta mi n D, bi s phos phona tes , or other a nti res orpti ve drugs a fter tra ns pl a nta ti on ma y pl a y a rol e i n preventi on.
Fa i l ure to grow, pri ma ri l y a s a cons equence of chroni c corti cos teroi d us e, i s a concern i n chi l dren. Growth fa i l ure ca n be mi ti ga ted by ta peri ng
corti cos teroi ds to the mi ni mum dos e tha t does not l ea d to gra ft rejecti on.
Sys temi c a theros cl eros i s ca n res ul t from hyperl i pi demi a due to us e of CNIs a nd corti cos teroi ds ; i t typi ca l l y occurs i n ki dney tra ns pl a nt reci pi ents >
15 yr pos t-tra ns pl a nta ti on.
Gra ft vs hos t di s ea s e (GVHD) occurs when donor T cel l s rea ct a ga i ns t reci pi ent's s el f-a nti gens . GVHD pri ma ri l y a ffects hema topoi eti c s tem cel l
reci pi ents (s ee p. 1132) but ma y a l s o a ffect l i ver a nd s ma l l -bowel tra ns pl a nt reci pi ents .
Heart Transplantation
Hea rt tra ns pl a nta ti on i s a n opti on for pa ti ents who ha ve end-s ta ge hea rt fa i l ure, corona ry a rtery di s ea s e (CAD), a rrhythmi a s , hypertrophi c
ca rdi omyopa thy, or congeni ta l hea rt di s ea s e a nd who rema i n a t ri s k of dea th a nd ha ve i ntol era bl e s ymptoms des pi te opti ma l us e of drugs a nd
medi ca l devi ces . Tra ns pl a nta ti on ma y a l s o be i ndi ca ted for pa ti ents who ca nnot be wea ned from tempora ry ca rdi a c-a s s i s t devi ces a fter MI or
nontra ns pl a nt ca rdi a c s urgery a nd for pa ti ents wi th ca rdi a c s equel a e of a l ung di s order requi ri ng l ung tra ns pl a nta ti on. The onl y a bs ol ute
contra i ndi ca ti on i s pul mona ry hypertens i on; rel a ti ve contra i ndi ca ti ons i ncl ude orga n i ns uffi ci ency (eg, pul mona ry, rena l , hepa ti c) a nd l oca l or
s ys temi c i nfi l tra ti ve di s orders (eg, ca rdi a c s a rcoma , a myl oi dos i s ).
Al l dona ted hea rts come from bra i n-dea d donors , who mus t be < 60 a nd ha ve norma l ca rdi a c a nd pul mona ry functi on a nd no hi s tory of CAD or
other hea rt di s orders . Donor a nd reci pi ent mus t ha ve compa ti bl e ABO bl ood type a nd hea rt s i ze. About 25% of el i gi bl e reci pi ents di e before a
donor orga n becomes a va i l a bl e. Left ventri cul a r a s s i s t devi ces a nd a rti fi ci a l hea rts provi de i nteri m hemodyna mi c s upport for pa ti ents wa i ti ng for
a tra ns pl a nt. However, i f l eft i n pl a ce too l ong, thes e devi ces put the reci pi ent a t hi gh ri s k of s eps i s , devi ce fa i l ure, a nd thromboembol i s m.
Procedure
Donor hea rts a re pres erved by hypothermi c s tora ge. They mus t be tra ns pl a nted wi thi n 4 to 6 h. The reci pi ent i s pl a ced on a bypa s s pump, a nd the
reci pi ent hea rt i s removed, pres ervi ng the pos teri or ri ght a tri a l wa l l i n s i tu. The donor hea rt i s then tra ns pl a nted orthotopi ca l l y wi th a orti c,
pul mona ry a rtery, a nd pul mona ry vei n a na s tomos es ; a s i ngl e a na s tomos i s joi ns the reta i ned pos teri or a tri a l wa l l to tha t of the donor orga n.
Immunos uppres s i ve regi mens va ry but a re s i mi l a r to thos e for ki dney or l i ver tra ns pl a nta ti on (eg, a nti -IL-2 receptor monocl ona l a nti bodi es , a
ca l ci neuri n i nhi bi tor, corti cos teroi ds ). About 50 to 80% of pa ti ents ha ve a t l ea s t 1 epi s ode of rejecti on (a vera ge 2 to 3); mos t pa ti ents a re
a s ymptoma ti c, but a bout 5% devel op l eft ventri cl e dys functi on or a tri a l a rrhythmi a s . Inci dence of a cute rejecti on pea ks a t 1 mo, decrea s es over the
next 5 mo, a nd l evel s off by 1 yr. Ri s k fa ctors for rejecti on i ncl ude younger a ge, fema l e reci pi ent, fema l e or bl a ck donor, a nd HLA mi s ma tchi ng.
Cytomega l ovi rus (CMV) i nfecti on ma y a l s o i nfl uence ri s k.
Beca us e gra ft da ma ge ca n be i rrevers i bl e a nd ca ta s trophi c, s urvei l l a nce endomyoca rdi a l bi ops y i s us ua l l y done once/yr; degree a nd di s tri buti on
of mononucl ea r cel l i nfi l tra te a nd pres ence of myocyte i njury i n s peci mens i s determi ned. Di fferenti a l di a gnos i s i ncl udes peri opera ti ve i s chemi a ,
CMV i nfecti on, a nd i di opa thi c B-cel l i nfi l tra ti on (Qui l ty l es i ons ). Mi l d rejecti on (gra de 1) wi thout detecta bl e cl i ni ca l s equel a e requi res no
trea tment; modera te or s evere rejecti on (gra des 2 to 4) or mi l d rejecti on wi th cl i ni ca l s equel a e i s trea ted wi th corti cos teroi ds a nd a nti thymocyte
gl obul i n or OKT3 a s needed.
The ma i n compl i ca ti on i s ca rdi a c a l l ogra ft va s cul opa thy, a form of a theros cl eros i s tha t di ffus el y na rrows or obl i tera tes ves s el l umi na (i n 25% of
pa ti ents ). Its ca us e i s proba bl y mul ti fa ctori a l a nd rel a tes to donor a ge, col d a nd reperfus i on i s chemi a , dys l i pi demi a , i mmunos uppres s a nts ,
chroni c rejecti on, a nd vi ra l i nfecti on (a denovi rus i n chi l dren, CMV i n a dul ts ). For ea rl y detecti on, s urvei l l a nce s tres s tes ti ng or corona ry
a ngi ogra phy wi th or wi thout i ntra va s cul a r ul tra s onogra phy i s often done a t the ti me of endomyoca rdi a l bi ops y. Trea tment i s a ggres s i ve l i pi d
l oweri ng (s ee p. 896) a nd di l ti a zem; everol i mus 1.5 mg po bi d ma y be preventi ve.
Prognosis
Survi va l ra tes a t 1 yr a re 85%, a nd a nnua l morta l i ty therea fter i s a bout 4%. Pretra ns pl a nta ti on predi ctors of 1-yr morta l i ty i ncl ude need for
preopera ti ve venti l a ti on or l eft ventri cul a r a s s i s t devi ces , ca chexi a , fema l e reci pi ent or donor, a nd di a gnos es other tha n hea rt fa i l ure or CAD. Pos ttra ns pl a nta ti on predi ctors i ncl ude el eva ted C-rea cti ve protei n a nd troponi n l evel s .
Ca us e of dea th wi thi n 1 yr i s mos t often a cute rejecti on a nd i nfecti on; ca us e a fter 1 yr i s mos t often ca rdi a c a l l ogra ft va s cul opa thy or a
l ymphoprol i fera ti ve di s order. Prognos i s of reci pi ents a l i ve a t > 1 yr i s excel l ent; exerci s e ca pa ci ty rema i ns bel ow norma l but i s s uffi ci ent for da i l y
a cti vi ti es a nd ma y i ncrea s e over ti me wi th s ympa theti c rei nnerva ti on. More tha n 95% of pa ti ents rea ch New York Hea rt As s oci a ti on cl a s s I ca rdi a c
s ta tus , a nd > 70% return to ful l -ti me empl oyment.
Hematopoietic Stem Cell Transplantation
Hema topoi eti c s tem cel l (HSC) tra ns pl a nta ti on i s a ra pi dl y evol vi ng techni que tha t offers a potenti a l cure for hema tol ogi c ca ncers (l eukemi a s ,
l ymphoma s , myel oma ) a nd other hema tol ogi c di s orders (eg, pri ma ry i mmunodefi ci ency, a pl a s ti c a nemi a , myel odys pl a s i a ). HSC tra ns pl a nta ti on
ma y be a utol ogous or a l l ogenei c; bone ma rrow, peri phera l bl ood, or umbi l i ca l cord s tem cel l s ma y be us ed. Peri phera l bl ood ha s l a rgel y repl a ced
bone ma rrow a s a s ource of s tem cel l s , es peci a l l y i n a utol ogous HSC tra ns pl a nta ti on, beca us e s tem cel l ha rves t i s ea s i er a nd neutrophi l a nd
pl a tel et counts recover fa s ter. Umbi l i ca l cord HSC tra ns pl a nta ti on ha s been res tri cted ma i nl y to chi l dren beca us e the number of s tem cel l s i s l ow.
There a re no contra i ndi ca ti ons to a utol ogous HSC tra ns pl a nta ti on. Contra i ndi ca ti ons to a l l ogenei c HSC tra ns pl a nta ti on a re rel a ti ve a nd i ncl ude
a ge > 50, previ ous HSC tra ns pl a nta ti on, a nd s i gni fi ca nt comorbi di ti es . Al l ogenei c HSC tra ns pl a nta ti on i s l i mi ted ma i nl y by l a ck of hi s tocompa ti bl e
donors . An HLA-i denti ca l s i bl i ng donor i s i dea l , fol l owed by a n HLA-ma tched s i bl i ng donor. Beca us e onl y one fourth of pa ti ents ha ve s uch a
s i bl i ng donor, mi s ma tched rel a ted or ma tched unrel a ted donors (i denti fi ed through i nterna ti ona l regi s tri es ) a re often us ed. However, l ong-term
di s ea s e-free s urvi va l ra tes ma y be l ower tha n thos e wi th HLA-i denti ca l s i bl i ng donors . The techni que for umbi l i ca l cord HSC tra ns pl a nta ti on i s
s ti l l bei ng defi ned, but HLA-ma tchi ng i s proba bl y uni mporta nt.
Procedure
For bone ma rrow s tem cel l ha rves t, 700 to 1500 mL (ma xi mum 15 mL/kg) of ma rrow i s a s pi ra ted from the donor's pos teri or i l i a c cres ts ; l oca l or
genera l a nes thes i a i s us ed. For peri phera l bl ood ha rves t, the donor i s trea ted wi th recombi na nt growth fa ctors (gra nul ocyte col ony-s ti mul a ti ng
fa ctor or gra nul ocyte-ma cropha ge col ony-s ti mul a ti ng fa ctor) to s ti mul a te prol i fera ti on a nd mobi l i za ti on of s tem cel l s , wi th s ta nda rd phl ebotomy 4
to 6 da ys a fterwa rd. Fl uores cence-a cti va ted cel l s orti ng i s us ed to i denti fy a nd s epa ra te s tem cel l s from other cel l s .
Stem cel l s a re then i nfus ed over 1 to 2 h through a l a rge-bore centra l venous ca theter. In HSC tra ns pl a nta ti on for ca ncer, the reci pi ent fi rs t i s gi ven
a condi ti oni ng regi men (eg, cycl ophos pha mi de 60 mg/kg IV once/da y for 2 da ys wi th tota l body i rra di a ti on, bus ul fa n 1 mg/kg po qi d for 4 da ys pl us
cycl ophos pha mi de wi thout tota l body i rra di a ti on) to i nduce remi s s i on a nd s uppres s the i mmune s ys tem s o tha t the gra ft ca n be a ccepted. Si mi l a r
regi mens a re us ed for a l l ogenei c HSC tra ns pl a nta ti on, even when ca ncer i s not the i ndi ca ti on, to reduce i nci dence of rejecti on a nd rel a ps e, but
not for a utol ogous HSC tra ns pl a nta ti on. Nonmyel oa bl a ti ve condi ti oni ng regi mens ma y reduce morbi di ty a nd morta l i ty ri s ks a nd ma y be us eful for
el derl y pa ti ents , pa ti ents wi th comorbi di ti es , a nd pa ti ents s us cepti bl e to a gra ft-vs -tumor effect (eg, thos e wi th mul ti pl e myel oma ).
After tra ns pl a nta ti on, reci pi ents a re gi ven col ony-s ti mul a ti ng fa ctors to s horten dura ti on of pos t-tra ns pl a nta ti on l eukopeni a , prophyl a cti c a nti i nfecti ve drugs (s ee p. 1130), a nd, i n a l l ogenei c HSC tra ns pl a nta ti on, up to 6 mo of prophyl a cti c i mmunos uppres s a nts (typi ca l l y methotrexa te a nd
cycl os pori ne) to prevent donor T cel l s from rea cti ng a ga i ns t reci pi ent ma jor hi s tocompa ti bi l i ty compl ex mol ecul es (gra ft-vs -hos t di s ea s e [GVHD]).
Broa d-s pectrum a nti bi oti cs a re us ua l l y wi thhel d unl es s fever devel ops . Engra ftment typi ca l l y occurs 10 to 20 da ys a fter HSC tra ns pl a nta ti on
(ea rl i er wi th peri phera l bl ood s tem cel l s ) a nd i s defi ned by a n a bs ol ute neutrophi l count > 500 106 /L.
Ma jor early complications (< 100 da ys ) i ncl ude
Fa i l ure to engra ft
Rejecti on
Acute GVHD
Fa i l ure to engra ft a nd rejecti on a ffect < 5% of pa ti ents a nd ma ni fes t a s pers i s tent pa ncytopeni a or i rrevers i bl e decl i ne i n bl ood counts . Trea tment
i s corti cos teroi ds for s evera l weeks .
Acute GVHD occurs i n reci pi ents of a l l ogenei c HSC tra ns pl a nts , 40% of HLA-ma tched s i bl i ng gra ft reci pi ents , a nd 80% of unrel a ted donor gra ft
reci pi ents . It ca us es fever, ra s h, hepa ti ti s wi th hyperbi l i rubi nemi a , vomi ti ng, di a rrhea , a bdomi na l pa i n (whi ch ma y progres s to i l eus ), a nd wei ght
l os s . Ri s k fa ctors i ncl ude HLA a nd s ex mi s ma tchi ng; unrel a ted donor; ol der a ge of reci pi ent, donor, or both; donor pres ens i ti za ti on; a nd
i na dequa te GVHD prophyl a xi s . Di a gnos i s i s obvi ous by hi s tory a nd phys i ca l exa mi na ti on; trea tment i s methyl predni s ol one 2 mg/kg IV once/da y,
i ncrea s ed to 10 mg/kg i f there i s no res pons e wi thi n 5 da ys .
Ma jor later complications i ncl ude
Chroni c GVHD
Di s ea s e rel a ps e
Chroni c GVHD ma y occur by i ts el f, devel op from a cute GVHD, or occur a fter res ol uti on of a cute GVHD. It typi ca l l y occurs 4 to 7 mo a fter HSC
tra ns pl a nta ti on (ra nge 2 mo to 2 yr). Chroni c GVHD occurs i n reci pi ents of a l l ogenei c HSC tra ns pl a nts , a bout 35 to 50% of HLA-ma tched s i bl i ng gra ft
reci pi ents , a nd 60 to 70% of unrel a ted donor gra ft reci pi ents . It a ffects pri ma ri l y the s ki n (eg, l i chenoi d ra s h, s cl eroderma ) a nd mucous membra nes
(eg, kera toconjuncti vi ti s s i cca , peri odonti ti s , orogeni ta l l i chenoi d rea cti ons ), but i t a l s o a ffects the GI tra ct a nd l i ver. Immunodefi ci ency i s a
pri ma ry fea ture; bronchi ol i ti s obl i tera ns s i mi l a r to tha t a fter l ung tra ns pl a nta ti on ca n a l s o devel op. Ul ti ma tel y, 20 to 40% di e of GVHD; morta l i ty
ra te i s hi gher wi th more s evere rea cti ons . Trea tment ma y not be neces s a ry for s ki n a nd mucous membra ne di s ea s e; trea tment of more extens i ve
di s ea s e i s s i mi l a r to tha t of a cute GVHD. T-cel l depl eti on of a l l ogenei c donor gra fts us i ng monocl ona l a nti bodi es or mecha ni ca l s epa ra ti on
reduces i nci dence a nd s everi ty of GVHD but a l s o el i mi na tes a gra ft-vs -tumor effect tha t ma y enha nce s tem cel l prol i fera ti on a nd engra ftment a nd
reduce di s ea s e rel a ps e ra tes . Rel a ps e ra tes wi th a utol ogous HSC tra ns pl a nta ti on a re hi gher for thi s rea s on a nd beca us e ci rcul a ti ng tumor cel l s
ma y be tra ns pl a nted. Ex vi vo tumor cel l purgi ng before a utol ogous tra ns pl a nta ti on i s under s tudy.
In pa ti ents wi thout chroni c GVHD, a l l i mmunos uppres s i on ca n be s topped 6 mo a fter HSC tra ns pl a nta ti on; thus , l a te compl i ca ti ons a re ra re i n
thes e pa ti ents .
Prognosis
Prognos i s va ri es by i ndi ca ti on a nd procedure. Overa l l , di s ea s e rel a ps e occurs i n 40 to 75% of reci pi ents of a utol ogous HSC tra ns pl a nts a nd i n 10 to
40% of reci pi ents of a l l ogenei c HSC tra ns pl a nts . Succes s (ca ncer-free bone ma rrow) ra tes a re 30 to 40% for pa ti ents wi th rel a ps ed, chemothera pys ens i ti ve l ymphoma a nd 20 to 50% for pa ti ents wi th a cute l eukemi a i n remi s s i on; compa red wi th chemothera py a l one, HSC tra ns pl a nta ti on
i mproves s urvi va l of pa ti ents wi th mul ti pl e myel oma . Succes s ra tes a re l ow for pa ti ents wi th more a dva nced di s ea s e or wi th res pons i ve s ol i d
ca ncers (eg, brea s t ca ncer, germ cel l tumors ). Rel a ps e ra tes a re reduced i n pa ti ents wi th GVHD, but overa l l morta l i ty ra tes a re i ncrea s ed i f GVHD i s
s evere. Intens i ve prepa ra ti ve regi mens , effecti ve GVHD prophyl a xi s , cycl os pori ne-ba s ed regi mens , a nd i mproved s upporti ve ca re (eg, a nti bi oti cs ,
herpes vi rus a nd cytomega l ovi rus prophyl a xi s ) ha ve i ncrea s ed l ong-term di s ea s e-free s urvi va l a fter HSC tra ns pl a nta ti on.
Kidney Transplantation
Ki dney tra ns pl a nta ti on i s the mos t common type of s ol i d orga n tra ns pl a nta ti on; the pri ma ry i ndi ca ti on i s end-s ta ge rena l fa i l ure. Abs ol ute
contra i ndi ca ti ons i ncl ude comorbi di ti es tha t coul d compromi s e gra ft s urvi va l (eg, s evere hea rt di s orders , ca ncer), whi ch ca n be detected vi a
thorough s creeni ng. Rel a ti ve contra i ndi ca ti ons i ncl ude poorl y control l ed di a betes , whi ch ca n l ea d to rena l fa i l ure. Pa ti ents i n thei r 60s ma y be
tra ns pl a nt ca ndi da tes i f they a re otherwi s e hea l thy a nd functi ona l l y i ndependent wi th good s oci a l s upport, i f they ha ve a rea s ona bl y l ong l i fe
expecta ncy, a nd i f tra ns pl a nta ti on i s l i kel y to s ubs ta nti a l l y i mprove functi on a nd qua l i ty of l i fe beyond s i mpl y freei ng them from di a l ys i s . Pa ti ents
wi th type 1 di a betes ma y be ca ndi da tes for s i mul ta neous pa ncrea s -ki dney or pa ncrea s -a fter-ki dney tra ns pl a nta ti on.
More tha n one ha l f of dona ted ki dneys come from previ ous l y hea l thy, bra i n-dea d peopl e. About one thi rd of thes e ki dneys a re ma rgi na l , wi th
phys i ol ogi c or procedure-rel a ted da ma ge, but a re us ed beca us e dema nd i s s o grea t. The rema i ni ng dona ted ki dneys come from l i vi ng donors ;
beca us e of l i mi ted s uppl y, a l l ogra fts from ca reful l y s el ected l i vi ng unrel a ted donors a re bei ng i ncrea s i ngl y us ed. Li vi ng donors rel i nqui s h res erve
rena l ca pa ci ty, ma y put thems el ves a t ri s k of procedura l a nd l ong-term morbi di ty, a nd ma y ha ve ps ychol ogi c confl i cts a bout dona ti on; therefore,
they a re eva l ua ted for norma l bi l a tera l rena l functi on, a bs ence of s ys temi c di s ea s e, hi s tocompa ti bi l i ty, emoti ona l s ta bi l i ty, a nd a bi l i ty to gi ve
i nformed cons ent. Hypertens i on, di a betes , a nd ca ncer (except pos s i bl y CNS tumors ) us ua l l y precl ude ki dney dona ti on from l i vi ng donors .
Procedure
The donor ki dney i s removed duri ng a n open or l a pa ros copi c procedure, perfus ed wi th cool i ng s ol uti ons conta i ni ng rel a ti vel y l a rge concentra ti ons
of poorl y permea ti ng s ubs ta nces (eg, ma nni tol , heta s ta rch) a nd el ectrol yte concentra ti ons a pproxi ma ti ng i ntra cel l ul a r l evel s , then s tored i n a n
i ced s ol uti on. Ki dneys pres erved thi s wa y us ua l l y functi on wel l i f tra ns pl a nted wi thi n 48 h. Al though not commonl y us ed, conti nuous pul s a ti l e
hypothermi c perfus i on wi th a n oxygena ted, pl a s ma -ba s ed perfus a te ca n extend ex vi vo vi a bi l i ty up to 72 h.
Di a l ys i s ma y be requi red before tra ns pl a nta ti on to ens ure a rel a ti vel y norma l meta bol i c s ta te, but l i vi ng-donor a l l ogra fts a ppea r to s urvi ve better
i n reci pi ents who ha ve not begun l ong-term di a l ys i s before tra ns pl a nta ti on. Nephrectomy i s us ua l l y not requi red unl es s na ti ve ki dneys a re
i nfected. Whether tra ns fus i ons a re us eful for a nemi c pa ti ents a nti ci pa ti ng a n a l l ogra ft i s uncl ea r; tra ns fus i ons ca n s ens i ti ze pa ti ents to
a l l oa nti gens , but a l l ogra fts ma y s urvi ve better i n reci pi ents who recei ve tra ns fus i ons but do not become s ens i ti zed, pos s i bl y beca us e
tra ns fus i ons i nduce s ome form of tol era nce.
The tra ns pl a nted ki dney i s us ua l l y pl a ced i n the i l i a c fos s a . Rena l ves s el s a re a na s tomos ed to the i l i a c ves s el s , a nd the donor ureter i s
i mpl a nted i nto the bl a dder or a na s tomos ed to the reci pi ent ureter. Ves i couretera l refl ux occurs i n a bout 30% of reci pi ents but i s us ua l l y ha rml es s .
Immunos uppres s i ve regi mens va ry. Commonl y, ca l ci neuri n i nhi bi tors a re begun i mmedi a tel y a fter tra ns pl a nta ti on i n dos es ti tra ted to mi ni mi ze
toxi ci ty a nd rejecti on whi l e ma i nta i ni ng trough bl ood l evel s > 200 ng/mL. On the da y of tra ns pl a nta ti on, IV or ora l corti cos teroi ds a re a l s o gi ven;
dos e i s ta pered over the fol l owi ng 12 wk.
Des pi te us e of i mmunos uppres s a nts , a bout 20% of reci pi ents ha ve one or more rejecti on epi s odes wi thi n the fi rs t yea r a fter tra ns pl a nta ti on. Mos t
epi s odes a re proba bl y i ns i gni fi ca nt, s ubcl i ni ca l , a nd therefore never detected; however, they contri bute to l ong-term i ns uffi ci ency, gra ft fa i l ure, or
both. Si gns of rejecti on va ry by type (s ee Ta bl e 128-1).
Rejecti on ca n be di a gnos ed by percuta neous needl e bi ops y i f the di a gnos i s i s uncl ea r cl i ni ca l l y. Bi ops y ma y a l s o hel p di s ti ngui s h a nti bodymedi a ted from T-cel l -medi a ted rejecti on a nd i denti fy other common ca us es of gra ft i ns uffi ci ency or fa i l ure (eg, ca l ci neuri n i nhi bi tor toxi ci ty,
di a beti c or hypertens i ve nephropa thy, pol yoma vi rus type 1 i nfecti on). Adva nced tes ts tha t ma y i mprove a ccura cy of rejecti on di a gnos i s i ncl ude
mea s urement of uri na ry mRNA-encodi ng medi a tors of rejecti on a nd gene expres s i on profi l i ng of bi ops y s a mpl es us i ng DNA mi croa rra ys .
Chroni c a l l ogra ft nephropa thy refers to gra ft i ns uffi ci ency or fa i l ure 3 mo a fter tra ns pl a nta ti on. Mos t ca s es a re a ttri buta bl e to one or more of the
a bove ca us es . Some experts bel i eve the term s houl d be res erved to des cri be gra ft i ns uffi ci ency or fa i l ure when bi ops y s hows chroni c i nters ti ti a l
fi bros i s a nd tubul a r a trophy not a ttri buta bl e to a ny other ca us e.
Intens i fi ed i mmunos uppres s i ve thera py (eg, wi th hi gh-dos e pul s e corti cos teroi ds or a nti l ymphocyte gl obul i n) us ua l l y revers es a ccel era ted or
a cute rejecti on. If i mmunos uppres s a nts a re i neffecti ve, dos e i s ta pered a nd hemodi a l ys i s i s res umed unti l a s ubs equent tra ns pl a nt i s a va i l a bl e.
Nephrectomy of the tra ns pl a nted ki dney i s neces s a ry i f hema turi a , gra ft tendernes s , or fever devel ops a fter i mmunos uppres s a nts a re s topped.
Prognosis
Mos t rejecti on epi s odes a nd other compl i ca ti ons occur wi thi n 3 to 4 mo a fter tra ns pl a nta ti on; mos t pa ti ents then return to more norma l hea l th
a nd a cti vi ty but mus t ta ke ma i ntena nce dos es of i mmunos uppres s a nts i ndefi ni tel y.
At 1 yr, s urvi va l ra tes wi th l i vi ng-donor gra fts a re 98% for pa ti ents a nd 94% for gra fts ; ra tes wi th decea s ed-donor gra fts a re 94% a nd 88%,
res pecti vel y. Subs equent a nnua l gra ft l os s ra tes a re 3 to 5% wi th a l i vi ng-donor gra ft a nd 5 to 8% wi th a decea s ed-donor gra ft.
Among pa ti ents whos e gra ft s urvi ves the fi rs t yea r, one ha l f di e of other ca us es wi th the gra ft functi oni ng norma l l y; one ha l f devel op chroni c
a l l ogra ft nephropa thy wi th the gra ft ma l functi oni ng i n 1 to 5 yr. Ra tes of l a te fa i l ure a re hi gher for bl a cks tha n for whi tes .
Doppl er ul tra s onogra phi c mea s urement of pea k s ys tol i c a nd mi ni ma l end-di a s tol i c fl ow i n rena l s egmenta l a rteri es 3 mo a fter tra ns pl a nta ti on
ma y hel p a s s es s prognos i s , but the gol d s ta nda rd rema i ns s eri a l determi na ti on of s erum crea ti ni ne.
Liver Transplantation
Li ver tra ns pl a nta ti on i s the 2nd mos t common type of s ol i d orga n tra ns pl a nta ti on. Indi ca ti ons i ncl ude ci rrhos i s (70% of US tra ns pl a nts , 60 to 70%
of whi ch a re a ttri buted to hepa ti ti s C); ful mi na nt hepa ti c necros i s (a bout 8%); hepa tocel l ul a r ca rci noma (a bout 7%); bi l i a ry a tres i a a nd meta bol i c
di s orders , pri ma ri l y i n chi l dren (a bout 3% ea ch); a nd other chol es ta ti c (eg, pri ma ry s cl eros i ng chol a ngi ti s ) a nd nonchol es ta ti c (eg, a utoi mmune
hepa ti ti s ) di s orders (a bout 8%). For pa ti ents wi th hepa tocel l ul a r ca rci noma , tra ns pl a nta ti on i s i ndi ca ted for 1 tumor < 5 cm or up to 3 tumors < 3
cm (Mi l a n cri teri a ) a nd for s ome fi brol a mel l a r types . For pa ti ents wi th l i ver meta s ta s es , tra ns pl a nta ti on i s i ndi ca ted onl y for neuroendocri ne
tumors wi thout extra hepa ti c growth a fter remova l of the pri ma ry tumor.
Abs ol ute contra i ndi ca ti ons a re el eva ted i ntra cra ni a l pres s ure (> 40 mm Hg) or l ow cerebra l perfus i on pres s ure (< 60 mm Hg) i n pa ti ents wi th
ful mi na nt hepa ti c necros i s , s evere pul mona ry hypertens i on (mea n pul mona ry a rteri a l pres s ure > 50 mm Hg), s eps i s , a nd a dva nced or meta s ta ti c
hepa tocel l ul a r ca rci noma ; a l l of thes e condi ti ons l ea d to poor outcomes duri ng or a fter tra ns pl a nta ti on.
Nea rl y a l l dona ted l i vers come from s i ze-a nd ABO-ma tched decea s ed, hea rt-bea ti ng donors . Annua l l y, a bout 500 come from l i vi ng donors , who ca n
l i ve wi thout thei r ri ght l obe (i n a dul t-to-a dul t tra ns pl a nta ti on) or the l a tera l s egment of thei r l eft l obe (i n a dul t-to-chi l d tra ns pl a nta ti on).
Adva nta ges of l i vi ng dona ti on for the reci pi ent i ncl ude s horter wa i ti ng ti mes , s horter col d i s chemi c ti mes for expl a nted orga ns , a nd the a bi l i ty to
s chedul e tra ns pl a nta ti on to opti mi ze the pa ti ent's condi ti on. Di s a dva nta ges to the donor i ncl ude morta l i ty ri s k of 1/300 to 400 (compa red wi th
1/3300 i n l i vi ng-donor ki dney tra ns pl a nta ti on) a nd compl i ca ti ons (es peci a l l y bi l e l ea ka ge) i n up to one fourth, us ua l l y when res ecti on i s l oba r
(not s egmenta l ). Li vi ng donors a re a l s o a t ri s k of ps ychol ogi c coerci on. A few l i vers come from decea s ed, non-hea rt-bea ti ng donors .
Donor (decea s ed or l i vi ng) ri s k fa ctors for gra ft fa i l ure i n the reci pi ent i ncl ude a ge > 50; hepa ti c s tea tos i s ; el eva ted l i ver enzymes , bi l i rubi n, or
both; prol onged s ta y i n ICU; hypotens i on requi ri ng va s opres s ors ; a nd hyperna tremi a . Tra ns pl a nts from fema l e donors to ma l e reci pi ents ma y a l s o
i ncrea s e ri s k. But beca us e i mba l a nce between s uppl y a nd dema nd i s grea tes t for l i ver tra ns pl a nts (a nd i s growi ng beca us e preva l ence of
hepa ti ti s -i nduced ci rrhos i s i s i ncrea s i ng), l i vers from donors > 50 a nd wi th s hort col d i s chemi a ti mes , thos e wi th fa tty i nfi l tra ti on, a nd thos e wi th
vi ra l hepa ti ti s (for tra ns pl a nta ti on i nto reci pi ents wi th vi ra l hepa ti ti s -i nduced ci rrhos i s ) a re i ncrea s i ngl y bei ng us ed.
Addi ti ona l techni ques to i ncrea s e s uppl y i ncl ude s pl i t l i ver tra ns pl a nta ti on, i n whi ch decea s ed-donor l i vers a re di vi ded i nto ri ght a nd l eft l obes
or ri ght l obe a nd l eft l a tera l s egment (done i n or ex s i tu) a nd gi ven to 2 reci pi ents , a nd domi no tra ns pl a nta ti on, ra rel y i ndi ca ted, i n whi ch a
decea s ed-donor l i ver i s gi ven to a reci pi ent wi th a n i nfi l tra ti ve di s ea s e (eg, a myl oi dos i s ), a nd the expl a nted di s ea s ed l i ver i s gi ven to a n el derl y
reci pi ent who ca n benefi t from the di s ea s ed l i ver but i s not expected to l i ve l ong enough to experi ence a dvers e effects of tra ns pl a nt dys functi on.
Des pi te thes e i nnova ti ons , ma ny pa ti ents di e wa i ti ng for tra ns pl a nts . Li ver-a s s i s t devi ces (extra corporea l perfus i on of cul tured hepa tocyte
s us pens i ons or i mmorta l i zed hepa toma cel l l i nes ) a re us ed i n s ome centers to keep pa ti ents a l i ve unti l a l i ver i s a va i l a bl e or a cute dys functi on
res ol ves . For di s tri buti on of a va i l a bl e orga ns , pa ti ents on the na ti ona l wa i tl i s t a re gi ven a prognos ti c s core deri ved from crea ti ni ne, bi l i rubi n, a nd
INR mea s urements (for a dul ts ) or from a ge a nd s erum a l bumi n, bi l i rubi n, INR, a nd growth fa i l ure mea s urements (for chi l dren). For pa ti ents wi th
hepa tocel l ul a r ca rci noma , the s core i ncorpora tes tumor s i ze a nd wa i ti ng ti me (i ncrea s i ng wi th ea ch). Pa ti ents wi th hi gher s cores a re more l i kel y
to di e a nd a re gi ven hi gher pri ori ty for orga ns from ABO- a nd wei ght-ma tched donors .
Procedure
Decea s ed-donor l i vers a re removed a fter expl ora tory l a pa rotomy confi rms a bs ence of i ntra -a bdomi na l di s ea s e tha t woul d precl ude
tra ns pl a nta ti on. Li vi ng donors undergo l oba r or s egmenta l res ecti on. Expl a nted l i vers a re perfus ed a nd s tored i n a col d pres erva ti on s ol uti on for
up to 24 h before tra ns pl a nta ti on; i nci dence of gra ft nonfuncti on a nd i s chemi c-type bi l i a ry i njury i ncrea s es wi th prol onged s tora ge.
Reci pi ent hepa tectomy i s the mos t dema ndi ng pa rt of the procedure beca us e i t i s often done i n pa ti ents wi th porta l hypertens i on a nd
coa gul a ti on defects . Intra opera ti ve bl ood l os s ca n tota l > 100 uni ts i n ra re ca s es , but us e of a cel l s a ver ma chi ne a nd a utotra ns fus i on devi ces
reduce a l l ogenei c tra ns fus i on requi rements to a n a vera ge of 5 to 10 uni ts . After hepa tectomy, the s upra hepa ti c vena ca va of the donor gra ft i s
a na s tomos ed to the reci pi ent's vena ca va i n a n end-to-s i de fa s hi on ("pi ggy-ba ck" techni que). Donor a nd reci pi ent porta l vei ns , hepa ti c a rteri es ,
a nd bi l e ducts a re then a na s tomos ed. Wi th thi s techni que, a bypa s s pump i s not needed to ca rry porta l venous bl ood to the s ys temi c venous
ci rcui t. Heterotopi c pl a cement of the l i ver provi des a n a uxi l i a ry l i ver a nd obvi a tes s evera l techni ca l di ffi cul ti es , but outcomes ha ve been
di s coura gi ng, a nd thi s techni que i s s ti l l experi menta l .
Immunos uppres s i ve regi mens va ry. Commonl y, a nti -IL-2 receptor monocl ona l a nti bodi es a re gi ven on the da y of tra ns pl a nta ti on, wi th a
ca l ci neuri n i nhi bi tor (cycl os pori ne or ta crol i mus ), mycophenol a te mofeti l , a nd corti cos teroi ds . Except i n pa ti ents wi th a utoi mmune hepa ti ti s ,
corti cos teroi ds ca n be ta pered wi thi n weeks a nd often s topped a fter 3 to 4 mo. Compa red wi th other s ol i d orga n tra ns pl a nta ti on, l i ver
tra ns pl a nta ti on requi res the l owes t dos es of i mmunos uppres s a nts .
Li ver a l l ogra fts a re l es s a ggres s i vel y rejected tha n other orga n a l l ogra fts for unknown rea s ons ; hypera cute rejecti on occurs l es s frequentl y tha n
expected i n pa ti ents pres ens i ti zed to HLA or ABO a nti gens , a nd i mmunos uppres s a nts ca n often be ta pered rel a ti vel y qui ckl y a nd eventua l l y
s topped. Mos t epi s odes of a cute rejecti on a re mi l d a nd s el f-l i mi ted, occur i n the fi rs t 3 to 6 mo, a nd do not a ffect gra ft s urvi va l . Ri s k fa ctors
i ncl ude younger reci pi ent a ge, ol der donor a ge, grea ter HLA mi s ma tchi ng, l onger col d i s chemi a ti mes , a nd a utoi mmune di s orders ; wors e
nutri ti ona l s ta tus (eg, i n a l cohol i s m) a ppea rs protecti ve.
Symptoms a nd s i gns of rejecti on depend on the type of rejecti on (s ee Ta bl e 128-1). Symptoms of a cute rejecti on occur i n a bout 50% of pa ti ents ;
s ymptoms of chroni c rejecti on occur i n < 2%.
Di fferenti a l di a gnos i s of a cute rejecti on i ncl udes vi ra l hepa ti ti s (eg, cytomega l ovi rus or Eps tei n-Ba rr vi rus i nfecti on; recurrent hepa ti ti s B, C, or
both), ca l ci neuri n i nhi bi tor toxi ci ty, a nd chol es ta s i s . Rejecti on ca n be di a gnos ed by percuta neous needl e bi ops y i f the di a gnos i s i s uncl ea r
cl i ni ca l l y. Sus pected rejecti on i s trea ted wi th IV corti cos teroi ds ; a nti thymocyte gl obul i n a nd OKT3 a re opti ons when corti cos teroi ds a re i neffecti ve
(i n 10 to 20%). Retra ns pl a nta ti on i s tri ed when rejecti on i s refra ctory to i mmunos uppres s a nts .
Immunos uppres s i on contri butes to recurrence of vi ra l hepa ti ti s i n pa ti ents who ha d vi ra l hepa ti ti s -i nduced ci rrhos i s before tra ns pl a nta ti on.
Hepa ti ti s C recurs i n nea rl y a l l pa ti ents ; us ua l l y, vi remi a a nd i nfecti on a re cl i ni ca l l y s i l ent but ma y ca us e a cti ve hepa ti ti s a nd ci rrhos i s . Ri s k
fa ctors for cl i ni ca l l y s i gni fi ca nt rei nfecti on ma y be rel a ted to the reci pi ent (ol der a ge, HLA type, hepa tocel l ul a r ca rci noma ), donor (ol der a ge, fa tty
i nfi l tra ti on, prol onged i s chemi c ti me, l i vi ng donor), vi rus (hi gh vi ra l l oa d, genotype 1B, fa i l ure to res pond to i nterferon), or pos tprocedura l events
(i mmunos uppres s a nt dos es , a cute rejecti on trea ted wi th corti cos teroi ds or OKT3, cytomega l ovi rus i nfecti on). Sta nda rd trea tment (s ee p. 258) i s
onl y ma rgi na l l y effecti ve. Hepa ti ti s B recurs i n a l l but ha s been s ucces s ful l y ma na ged wi th hepa ti ti s B i mmune gl obul i n a nd l a mi vudi ne; coi nfecti on wi th hepa ti ti s D a ppea rs protecti ve a ga i ns t recurrence.
Ea rl y (wi thi n 2 mo) compl i ca ti ons of l i ver tra ns pl a nta ti on i ncl ude pri ma ry nonfuncti on i n 1 to 5%, bi l i a ry dys functi on (eg, i s chemi c a na s tomoti c
s tri ctures , bi l e l ea ka ge, ducta l obs tructi ons , l ea ka ge a round T-tube s i te) i n 15 to 20%, porta l vei n thrombos i s i n < 5%, hepa ti c a rtery thrombos i s i n
3 to 5% (es peci a l l y i n s ma l l chi l dren or pa ti ents ta ki ng s i rol i mus ), hepa ti c a rtery mycoti c or ps eudoa neurys m, a nd hepa ti c a rtery rupture. Typi ca l
s ymptoms i ncl ude fever, hypotens i on, a nd el eva ted l i ver functi on enzymes .
The mos t common l a te compl i ca ti ons a re i ntra hepa ti c or a na s tomoti c bi l e duct s tri ctures , whi ch produce s ymptoms of chol es ta s i s a nd chol a ngi ti s .
Stri ctures ca n s ometi mes be trea ted endos copi ca l l y or through percuta neous tra ns hepa ti c chol a ngi ogra phi c di l a ti on, s tenti ng, or both, but they
often ul ti ma tel y requi re retra ns pl a nta ti on.
Prognosis
At 1 yr, s urvi va l ra tes wi th l i vi ng-donor gra fts a re 90% for pa ti ents a nd 82% for gra fts ; ra tes wi th decea s ed-donor gra fts a re 86% a nd 82%,
res pecti vel y. Overa l l ra tes for pa ti ents a nd gra fts , res pecti vel y, a re 79% a nd 72% a t 3 yr a nd 73% a nd 65% a t 5 yr. Survi va l i s better for chroni c tha n
for a cute l i ver fa i l ure. Dea th a fter 1 yr i s ra re a nd a ttri buta bl e to a recurrent di s order (eg, ca ncer, hepa ti ti s ) ra ther tha n to pos t-tra ns pl a nta ti on
compl i ca ti ons .
Recurrent hepa ti ti s C i nfecti on l ea ds to ci rrhos i s i n 15 to 30% of pa ti ents by 5 yr. Hepa ti c di s orders wi th a n a utoi mmune component (eg, pri ma ry
bi l i a ry ci rrhos i s , pri ma ry s cl eros i ng chol a ngi ti s , a utoi mmune hepa ti ti s ) recur i n 20 to 30% by 5 yr.
Lung Transplantation
Lung tra ns pl a nta ti on i s a n opti on for pa ti ents who ha ve res pi ra tory i ns uffi ci ency or fa i l ure a nd who rema i n a t ri s k of dea th des pi te opti ma l
medi ca l trea tment. The mos t common i ndi ca ti ons a re COPD, i di opa thi c pul mona ry fi bros i s , cys ti c fi bros i s , 1 -a nti tryps i n defi ci ency, a nd pri ma ry
pul mona ry hypertens i on. Les s common i ndi ca ti ons i ncl ude i nters ti ti a l l ung di s orders (eg, s a rcoi dos i s ), bronchi ecta s i s , a nd congeni ta l hea rt
di s ea s e. Si ngl e a nd doubl e l ung procedures a re equa l l y a ppropri a te for mos t l ung di s orders wi thout ca rdi a c i nvol vement; the excepti on i s chroni c
di ffus e i nfecti on (eg, bronchi ecta s i s ), for whi ch doubl e l ung tra ns pl a nta ti on i s bes t. Hea rt-l ung tra ns pl a nta ti on i s i ndi ca ted for Ei s enmenger's
s yndrome a nd for a ny l ung di s order wi th s evere ventri cul a r dys functi on l i kel y to be i rrevers i bl e; cor pul mona l e i s not a n i ndi ca ti on beca us e i t
often revers es a fter l ung tra ns pl a nta ti on. Si ngl e a nd doubl e l ung procedures a re a bout equa l l y common a nd a re a t l ea s t 8 ti mes more common
tha n hea rt-l ung tra ns pl a nta ti on.
Rel a ti ve contra i ndi ca ti ons i ncl ude a ge (s i ngl e l ung reci pi ents mus t be < 65; doubl e l ung reci pi ents , < 60; a nd hea rt a nd l ung reci pi ents , < 55),
a cti ve ci ga rette s moki ng, previ ous thora ci c s urgery, a nd, for s ome cys ti c fi bros i s pa ti ents a nd a t s ome medi ca l centers , l ung i nfecti on wi th
res i s ta nt s tra i ns of Burkholderia cepacia, whi ch grea tl y i ncrea s es morta l i ty ri s k.
Nea rl y a l l dona ted l ungs a re from bra i n-dea d, hea rt-bea ti ng donors . Ra rel y, l i vi ng a dul t (us ua l l y pa rent-to-chi l d) l oba r tra ns pl a nta ti on i s done
when decea s ed-donor orga ns a re una va i l a bl e. Donors mus t be < 65 a nd never-s mokers a nd ha ve no a cti ve l ung di s order a s evi denced by
Oxygena ti on: Pa O2 /FIO2 (fra cti ona l i ns pi red O2 ) > 250 to 300, wi th Pa O2 i n mm Hg a nd FIO2 i n deci ma l fra cti on (eg, 0.5)
Lung compl i a nce: Pea k i ns pi ra tory pres s ure < 30 cm H 2 O a t ti da l vol ume (VT) 15 mL/kg a nd pos i ti ve end-expi ra tory pres s ure = 5 cm H 2 O
Gros s a ppea ra nce: Us i ng bronchos copy
Donor a nd reci pi ents mus t be s i ze-ma tched a na tomi ca l l y (by ches t x-ra y), phys i ol ogi ca l l y (by tota l l ung ca pa ci ty), or both.
Ti mi ng of referra l for tra ns pl a nta ti on s houl d be determi ned by fa ctors s uch a s
Degree of obs tructi ve defect: Forced expi ra tory vol ume i n 1 s ec (FEV1 ) < 25 to 30% predi cted i n pa ti ents wi th COPD, 1 -a nti tryps i n defi ci ency, or
cys ti c fi bros i s
Pa O2 < 55 mm Hg
Pa CO2 > 50 mm Hg
Ri ght a tri a l pres s ure > 10 mm Hg a nd pea k s ys tol i c pres s ure > 50 mm Hg for pa ti ents wi th pri ma ry pul mona ry hypertens i on
Progres s i on ra te of cl i ni ca l , ra di ogra phi c, or phys i ol ogi c di s ea s e
Procedure
The donor i s a nti coa gul a ted, a nd a col d crys ta l l oi d pres erva ti on s ol uti on conta i ni ng pros ta gl a ndi ns i s fl us hed through the pul mona ry a rteri es
i nto the l ungs . Donor orga ns a re cool ed wi th i ced s a l i ne s l us h i n s i tu or vi a ca rdi opul mona ry bypa s s , then removed. Prophyl a cti c a nti bi oti cs a re
often gi ven.
Single lung transplantation requi res pos terol a tera l thora cotomy. The na ti ve l ung i s removed, a nd the bronchus , pul mona ry a rtery, a nd pul mona ry
vei ns of the donor l ung a re a na s tomos ed to thei r res pecti ve cuffs . The bronchi a l a na s tomos i s requi res i ntus s us cepti on or wra ppi ng wi th
omentum or peri ca rdi um to fa ci l i ta te a dequa te hea l i ng. Adva nta ges i ncl ude a s i mpl er opera ti on, a voi da nce of ca rdi opul mona ry bypa s s a nd
s ys temi c a nti coa gul a ti on (us ua l l y), more fl exi bi l i ty concerni ng s i ze ma tchi ng, a nd a va i l a bi l i ty of the contra l a tera l l ung from the s a me donor for
a nother reci pi ent. Di s a dva nta ges i ncl ude the pos s i bi l i ty of venti l a ti on/perfus i on mi s ma tch between the na ti ve a nd tra ns pl a nt l ungs a nd the
pos s i bi l i ty of poor hea l i ng of the s i ngl e bronchi a l a na s tomos i s .
Double lung transplantation requi res s ternotomy or a nteri or tra ns vers e thora cotomy; the procedure i s s i mi l a r to 2 s equenti a l s i ngl e tra ns pl a nts . The
pri ma ry a dva nta ge i s defi ni ti ve remova l of a l l di s ea s ed ti s s ue. The di s a dva nta ge i s poor hea l i ng of the tra chea l a na s tomos i s .
Heart-lung transplantation requi res medi a n s ternotomy wi th ca rdi opul mona ry bypa s s . Aorti c, ri ght a tri a l , a nd tra chea l a na s tomos es a re requi red; the
tra chea i s a na s tomos ed i mmedi a tel y a bove the bi furca ti on. The pri ma ry a dva nta ges a re i mproved gra ft functi on a nd more dependa bl e hea l i ng of
the tra chea l a na s tomos i s beca us e of corona ry-bronchi a l col l a tera l s wi thi n the hea rt-l ung bl ock. Di s a dva nta ges i ncl ude l ong opera ti ve ti me wi th
the need for ca rdi opul mona ry bypa s s , the need for cl os e s i ze ma tchi ng, a nd us e of 3 donor orga ns by one reci pi ent.
Methyl predni s ol one IV i s often gi ven to reci pi ents before reperfus i on of the tra ns pl a nted l ung. A common i mmunos uppres s i ve regi men combi nes
a ca l ci neuri n i nhi bi tor (cycl os pori ne or ta crol i mus ), a puri ne meta bol i s m i nhi bi tor (a za thi opri ne or mycophenol a te mofeti l ), a nd
methyl predni s ol one. Prophyl a cti c a nti thymocyte gl obul i n (ATG) or OKT3 ma y a l s o be gi ven duri ng the fi rs t 2 wk a fter tra ns pl a nta ti on.
Corti cos teroi ds ma y be omi tted to fa ci l i ta te hea l i ng of the bronchi a l a na s tomos i s ; hi gher dos es of other drugs (eg, cycl os pori ne, a za thi opri ne) a re
s ubs ti tuted. Immunos uppres s a nts a re conti nued i ndefi ni tel y.
Rejecti on devel ops i n mos t pa ti ents des pi te i mmunos uppres s i ve thera py. Symptoms a nd s i gns a re s i mi l a r i n hypera cute, a cute, a nd chroni c forms
a nd i ncl ude fever, dys pnea , cough, decrea s ed Sa O2 , i nters ti ti a l i nfi l tra te on x-ra y, a nd a decrea s e i n FEV1 by > 10 to 15%. Hypera cute rejecti on mus t
be di s ti ngui s hed from ea rl y gra ft dys functi on ca us ed by i s chemi c i njury duri ng the tra ns pl a nta ti on procedure. Di a gnos i s i s confi rmed i f
bronchos copi c tra ns bronchi a l bi ops y s hows peri va s cul a r l ymphocyti c i nfi l tra ti on i n s ma l l ves s el s . IV corti cos teroi ds a re us ua l l y effecti ve.
Trea tment of recurrent or res i s ta nt ca s es va ri es a nd i ncl udes hi gher corti cos teroi d dos es , a eros ol i zed cycl os pori ne, ATG, a nd OKT3.
Chroni c rejecti on (a fter > 1 yr) occurs i n up to 50% of pa ti ents ; i t ta kes the form of obl i tera ti ve bronchi ol i ti s or, l es s commonl y, a theros cl eros i s .
Acute rejecti on ma y i ncrea s e ri s k of chroni c rejecti on. Pa ti ents wi th obl i tera ti ve bronchi ol i ti s pres ent wi th cough, dys pnea , a nd decrea s ed FEV1
wi th or wi thout phys i ca l a nd ra di ogra phi c evi dence of a n a i rwa y proces s . Di fferenti a l di a gnos i s i ncl udes pneumoni a . Di a gnos i s i s by
bronchos copy wi th bi ops y. No trea tment ha s proved effecti ve, but opti ons i ncl ude corti cos teroi ds , ATG or OKT3, i nha l ed cycl os pori ne, a nd
retra ns pl a nta ti on.
The mos t common s urgi ca l compl i ca ti on i s poor hea l i ng of the bronchi a l or tra chea l a na s tomos i s . Up to 20% of s i ngl e l ung reci pi ents devel op
bronchi a l s tenos i s tha t ca us es wheezi ng a nd a i rwa y obs tructi on; i t ca n be trea ted wi th di l a ti on or s tent pl a cement. Other s urgi ca l compl i ca ti ons
i ncl ude hoa rs enes s a nd di a phra gma ti c pa ra l ys i s , ca us ed by da ma ge to the recurrent l a ryngea l or phreni c nerves ; GI dys moti l i ty, ca us ed by da ma ge
to the thora ci c va gus nerve; a nd pneumothora x. Supra ventri cul a r a rrhythmi a s devel op i n s ome pa ti ents , proba bl y beca us e of conducti on cha nges
ca us ed by pul mona ry vei n-a tri a l s uturi ng.
Prognosis
At 1 yr, s urvi va l ra tes a re 84% wi th l i vi ng-donor gra fts a nd 83% wi th decea s ed-donor gra fts . At 5 yr, s urvi va l ra tes a re 34% wi th l i vi ng-donor gra fts
a nd 46% wi th decea s ed-donor gra fts . Morta l i ty ra te i s hi gher for pa ti ents wi th pri ma ry pul mona ry hypertens i on, i di opa thi c pul mona ry fi bros i s , or
s a rcoi dos i s a nd l ower for thos e wi th COPD or 1 -a nti tryps i n defi ci ency. Morta l i ty ra te i s hi gher for s i ngl e l ung tra ns pl a nta ti on tha n for doubl e.
Mos t common ca us es of dea th wi thi n 1 mo a re pri ma ry gra ft fa i l ure, i s chemi a a nd reperfus i on i njury, a nd i nfecti on (eg, pneumoni a ) excl udi ng
cytomega l ovi rus ; the mos t common ca us e between 1 mo a nd 1 yr i s i nfecti on; a nd a fter 1 yr, i t i s obl i tera ti ve bronchi ol i ti s . Morta l i ty ri s k fa ctors
i ncl ude cytomega l ovi rus mi s ma tchi ng (donor pos i ti ve, reci pi ent nega ti ve), huma n l eukocyte a nti gen (HLA-DR) mi s ma tchi ng, di a betes , a nd pri or
need for mecha ni ca l venti l a ti on or i notropi c s upport. Uncommonl y, the di s order recurs , pa rti cul a rl y i n s ome pa ti ents wi th a n i nters ti ti a l l ung
di s order. Exerci s e ca pa ci ty i s s l i ghtl y l i mi ted beca us e of a hyperventi l a tory res pons e.
Wi th hea rt-l ung tra ns pl a nta ti on, overa l l s urvi va l ra te a t 1 yr i s 60% for pa ti ents a nd gra fts .
Pancreas Transplantation
Pa ncrea s tra ns pl a nta ti on i s a form of pa ncrea ti c -cel l repl a cement tha t ca n res tore normogl ycemi a i n di a beti c pa ti ents . Beca us e the reci pi ent
excha nges ri s ks of i ns ul i n i njecti on for ri s ks of i mmunos uppres s i on, el i gi bi l i ty i s l i mi ted mos tl y to pa ti ents who ha ve type 1 di a betes wi th rena l
fa i l ure a nd who a re thus ca ndi da tes for ki dney tra ns pl a nta ti on; > 90% of pa ncrea s tra ns pl a nta ti ons i ncl ude tra ns pl a nta ti on of a ki dney. At ma ny
centers , fa i l ure of s ta nda rd trea tment a nd epi s odes of hypogl ycemi c una wa renes s a re a l s o el i gi bi l i ty cri teri a . Rel a ti ve contra i ndi ca ti ons i ncl ude
a ge > 55 a nd s i gni fi ca nt a theros cl eroti c ca rdi ova s cul a r di s ea s e, defi ned a s hi s tory of MI, corona ry a rtery bypa s s gra ft s urgery, percuta neous
corona ry i nterventi on, or a pos i ti ve s tres s tes t; thes e fa ctors dra ma ti ca l l y i ncrea s e peri opera ti ve ri s k.
Opti ons i ncl ude s i mul ta neous pa ncrea s -ki dney (SPK) tra ns pl a nta ti on; pa ncrea s -a fter-ki dney (PAK) tra ns pl a nta ti on; a nd pa ncrea s -a l one
tra ns pl a nta ti on. The a dva nta ges of SPK a re one-ti me expos ure to i nducti on i mmunos uppres s i on, potenti a l protecti on of the newl y tra ns pl a nted
ki dney from a dvers e effects of hypergl ycemi a , a nd the a bi l i ty to moni tor rejecti on i n the ki dney; the ki dney i s more prone to rejecti on tha n the
pa ncrea s , where rejecti on i s di ffi cul t to detect. The a dva nta ge of PAK i s the a bi l i ty to opti mi ze HLA ma tchi ng a nd ti mi ng of ki dney tra ns pl a nta ti on
us i ng a l i vi ng donor. Pa ncrea s -a l one tra ns pl a nta ti on offers a n a dva nta ge to pa ti ents who do not ha ve end-s ta ge rena l di s ea s e but ha ve other
s evere di a betes compl i ca ti ons , i ncl udi ng l a bi l e gl ucos e control .
Donors a re us ua l l y recentl y decea s ed pa ti ents who a re a ged 10 to 55 a nd ha ve no hi s tory of gl ucos e i ntol era nce or a l cohol a bus e. For SPK, the
pa ncrea s a nd ki dney come from the s a me donor, a nd the s a me res tri cti ons for ki dney dona ti on a ppl y (s ee p. 1133). A few (< 1%) s egmenta l
tra ns pl a nta ti ons from l i vi ng donors ha ve been done, but thi s procedure ha s s ubs ta nti a l ri s ks for the donor (eg, s pl eni c i nfa rcti on, a bs ces s ,
pa ncrea ti ti s , pa ncrea ti c l ea k a nd ps eudocys t, s econda ry di a betes ), whi ch l i mi t i ts wi des prea d us e.
Procedure
The donor i s a nti coa gul a ted, a nd a col d pres erva ti on s ol uti on i s fl us hed i nto the cel i a c a rtery. The pa ncrea s i s cool ed i n s i tu wi th i ced s a l i ne
s l us h, then removed en bl oc wi th the l i ver (for tra ns pl a nta ti on i nto a di fferent reci pi ent) a nd the 2nd porti on of the duodenum conta i ni ng the
a mpul l a of Va ter.
The donor pa ncrea s i s pos i ti oned i ntra peri tonea l l y a nd l a tera l l y i n the l ower a bdomen. In SPK, the pa ncrea s i s pl a ced i nto the ri ght l ower
qua dra nt of the reci pi ent's a bdomen a nd the ki dney i nto the l eft l ower qua dra nt. The na ti ve pa ncrea s i s l eft i n pl a ce. Ana s tomos es a re ma de
between the donor s pl eni c or s uperi or mes enteri c a rtery a nd reci pi ent i l i a c a rtery a nd between the donor porta l vei n a nd reci pi ent i l i a c vei n.
Thus , endocri ne s ecreti ons dra i n s ys temi ca l l y, ca us i ng hyperi ns ul i nemi a ; s ometi mes the pa ncrea ti c venous s ys tem i s a na s tomos ed to a porta l
vei n tri buta ry to re-crea te phys i ol ogi c condi ti ons , a l though thi s procedure i s more dema ndi ng a nd i ts benefi ts a re uncl ea r. The duodenum i s s ewn
to the bl a dder dome or to the jejunum for dra i na ge of exocri ne s ecreti ons .
Immunos uppres s i on regi mens va ry but typi ca l l y i ncl ude i mmunos uppres s i ve Igs , a ca l ci neuri n i nhi bi tor, a puri ne s ynthes i s i nhi bi tor, a nd
corti cos teroi ds , whi ch ca n be s l owl y ta pered over 12 mo. Des pi te a dequa te i mmunos uppres s i on, rejecti on devel ops i n 60 to 80% of pa ti ents ,
pri ma ri l y a ffecti ng exocri ne, not endocri ne, components . Compa red wi th ki dney tra ns pl a nta ti on a l one, SPK ha s a grea ter ri s k of rejecti on, a nd
rejecti on epi s odes tend to occur l a ter, to recur more often, a nd to be corti cos teroi d-res i s ta nt. Symptoms a nd s i gns a re nons peci fi c (s ee Ta bl e 1281).
After SPK a nd PAK, pa ncrea s rejecti on, i ndi ca ted by a n i ncrea s e i n s erum crea ti ni ne, a l mos t a l wa ys a ccompa ni es ki dney rejecti on. After pa ncrea s a l one tra ns pl a nta ti on, a s ta bl e uri na ry a myl a s e concentra ti on i n pa ti ents wi th uri na ry dra i na ge excl udes rejecti on; a decrea s e s ugges ts s ome
form of gra ft dys functi on but i s not s peci fi c to rejecti on. Ea rl y detecti on i s therefore di ffi cul t. Di a gnos i s i s confi rmed by ul tra s ound-gui ded
percuta neous or cys tos copi c tra ns duodena l bi ops y. Trea tment i s wi th a nti thymocyte gl obul i n.
Ea rl y compl i ca ti ons a ffect 10 to 15% of pa ti ents a nd i ncl ude wound i nfecti on a nd dehi s cence, gros s hema turi a , i ntra -a bdomi na l uri na ry l ea k,
refl ux pa ncrea ti ti s , recurrent UTI, s ma l l -bowel obs tructi on, a bdomi na l a bs ces s , a nd gra ft thrombos i s . La te compl i ca ti ons rel a te to uri na ry l os s of
pa ncrea ti c Na HCO3 -, ca us i ng vol ume depl eti on a nd non-a ni on ga p meta bol i c a ci dos i s . Hyperi ns ul i nemi a does not a ppea r to a dvers el y a ffect
gl ucos e or l i pi d meta bol i s m.
Prognosis
At 1 yr, 78% of gra fts s urvi ve, but > 90% of pa ti ents s urvi ve. Whether s urvi va l i s hi gher tha n tha t of pa ti ents wi thout tra ns pl a nta ti on i s uncl ea r;
however, the pri ma ry benefi ts of the procedure a re freedom from i ns ul i n thera py a nd s ta bi l i za ti on or a mel i ora ti on of ma ny di a beti c compl i ca ti ons
(eg, nephropa thy, neuropa thy). Gra ft s urvi va l i s 95% for SPK, 74% for PAK, a nd 76% for pa ncrea s -a l one tra ns pl a nta ti on. The ra te of i mmunol ogi c gra ft
l os s for PAK a nd pa ncrea s -a l one tra ns pl a nts i s hi gher, pos s i bl y beca us e s uch a tra ns pl a nted pa ncrea s l a cks a rel i a bl e moni tor of rejecti on; i n
contra s t, rejecti on a fter SPK ca n be moni tored us i ng es ta bl i s hed i ndi ca tors of rejecti on for the tra ns pl a nted ki dney.
Pancreatic Islet Cell Transplantation
Is l et cel l tra ns pl a nta ti on ha s theoreti ca l a dva nta ges over pa ncrea s tra ns pl a nta ti on; the mos t i mporta nt i s tha t the procedure i s l es s i nva s i ve. A
s econda ry a dva nta ge i s tha t i s l et cel l tra ns pl a nta ti on a ppea rs to hel p ma i nta i n normogl ycemi a i n pa ti ents who requi re tota l pa ncrea tectomy for
pa i n due to chroni c pa ncrea ti ti s . Neverthel es s , the procedure rema i ns experi menta l , a l though s tea dy i mprovement a ppea rs to be occurri ng.
Its di s a dva nta ges a re tha t tra ns pl a nted gl uca gon-s ecreti ng cel l s a re nonfuncti ona l (pos s i bl y compl i ca ti ng hypogl ycemi a ) a nd s evera l pa ncrea ta
a re us ua l l y requi red for a s i ngl e i s l et cel l reci pi ent (exa cerba ti ng di s pa ri ti es between gra ft s uppl y a nd dema nd a nd l i mi ti ng us e of the
procedure).
Indi ca ti ons a re the s a me a s thos e for pa ncrea s tra ns pl a nta ti on. Si mul ta neous i s l et cel l -ki dney tra ns pl a nta ti on ma y be des i ra bl e a fter the
techni que i s i mproved.
Procedure
A pa ncrea s i s removed from a bra i n-dea d donor; col l a gena s e i s i nfus ed i nto the pa ncrea ti c duct to s epa ra te i s l ets from pa ncrea ti c ti s s ue. A
puri fi ed i s l et cel l fra cti on i s i nfus ed percuta neous l y i nto the porta l vei n. Is l et cel l s tra vel i nto hepa ti c s i nus oi ds , where they l odge a nd s ecrete
i ns ul i n.
Res ul ts a re bes t when 2 ca da vers a re us ed, wi th ea ch s uppl yi ng 2 or 3 i nfus i ons of i s l et cel l s , fol l owed by a n i mmunos uppres s i ve regi men
cons i s ti ng of a n a nti -IL-2 receptor, monocl ona l a nti bodi es (da cl i zuma b), ta crol i mus , a nd s i rol i mus . Corti cos teroi ds a re not us ed.
Immunos uppres s i on mus t be conti nued l i fel ong or unti l i s l et cel l functi on cea s es .
Rejecti on i s poorl y defi ned but ca n be detected by deteri ora ti on i n bl ood gl ucos e control ; trea tment of rejecti on i s not es ta bl i s hed. Procedura l
compl i ca ti ons i ncl ude percuta neous hepa ti c puncture wi th bl eedi ng, porta l vei n thrombos i s , a nd porta l hypertens i on.
Succes s ful i s l et cel l tra ns pl a nta ti on ma i nta i ns s hort-term normogl ycemi a , but l ong-term outcomes a re unknown; a ddi ti ona l i njecti ons of i s l et
prepa ra ti ons ma y be neces s a ry to obta i n l onger-l a s ti ng i ns ul i n i ndependence.
Small-Bowel Transplantation
Sma l l -bowel tra ns pl a nta ti on i s i ndi ca ted for pa ti ents who ha ve ma l a bs orpti on beca us e of i ntes ti na l di s orders (eg, ga s tros chi s i s , Hi rs chs prung's
di s ea s e, a utoi mmune enteri ti s ) or i ntes ti na l res ecti on (eg, for mes enteri c thromboembol i s m or extens i ve Crohn's di s ea s e) a nd who a re a t hi gh
ri s k of dea th (us ua l l y due to congeni ta l enteropa thi es s uch a s mi crovi l l us i ncl us i on di s ea s e) or who devel op compl i ca ti ons of TPN (eg, l i ver
fa i l ure, recurrent s eps i s , tota l l os s of venous a cces s ). Pa ti ents wi th l oca l l y i nva s i ve tumors tha t ca us e obs tructi on, a bs ces s es , fi s tul a s , i s chemi a ,
or hemorrha ge (us ua l l y des moi d tumors a s s oci a ted wi th fa mi l i a l pol ypos i s ) a re a l s o ca ndi da tes .
Procedure
Procurement from a bra i n-dea d, bea ti ng-hea rt donor i s compl ex, pa rtl y beca us e the s ma l l bowel ca n be tra ns pl a nted a l one, wi th a l i ver, or wi th a
s toma ch, l i ver, duodenum, a nd pa ncrea s . The rol e of l i vi ng-rel a ted dona ti on for s ma l l -bowel a l l ogra fts ha s yet to be defi ned. Procedures va ry by
medi ca l center; i mmunos uppres s i ve regi mens a l s o va ry, but a typi ca l regi men i ncl udes a nti l ymphocyte gl obul i n for i nducti on, fol l owed by hi ghdos e ta crol i mus a nd mycophenol a te mofeti l for ma i ntena nce.
Weekl y endos copy i s i ndi ca ted to check for rejecti on. Symptoms a nd s i gns of rejecti on i ncl ude di a rrhea , fever, a nd a bdomi na l cra mpi ng.
Endos copi c fi ndi ngs i ncl ude mucos a l erythema , fri a bi l i ty, ul cera ti on, a nd exfol i a ti on; cha nges a re di s tri buted unevenl y, ma y be di ffi cul t to detect,
a nd ca n be di fferenti a ted from cytomega l ovi rus enteri ti s by vi ra l i ncl us i on bodi es . Bi ops y fi ndi ngs i ncl ude bl unted vi l l i a nd i nfl a mma tory
i nfi l tra tes i n the l a mi na propri a . Trea tment of a cute rejecti on i s hi gh-dos e corti cos teroi ds , a nti thymocyte gl obul i n, or both.
Prognosis
Surgi ca l compl i ca ti ons a ffect 50% of pa ti ents a nd i ncl ude a na s tomoti c l ea ks , bi l i a ry l ea ks a nd s tri ctures , hepa ti c a rtery thrombos i s , a nd chyl ous
a s ci tes . Nons urgi ca l compl i ca ti ons i ncl ude gra ft i s chemi a a nd gra ft-vs -hos t di s ea s e ca us ed by tra ns pl a nta ti on of gut-a s s oci a ted l ymphoi d ti s s ue.
At 3 yr, > 50% of gra fts wi th s ma l l -bowel tra ns pl a nta ti on a l one s urvi ve, but pa ti ent s urvi va l i s a round 65%. Wi th l i ver a nd s ma l l -bowel
tra ns pl a nta ti on, s urvi va l ra te i s l ower beca us e the procedure i s more extens i ve a nd the reci pi ent's condi ti on i s more s eri ous .
Tissue Transplantation
Skin allografts: Ski n a l l ogra fts a re us ed for pa ti ents wi th extens i ve burns or other condi ti ons ca us i ng ma s s i ve s ki n l os s . Al l ogra fts a re us ed to cover
broa d denuded a rea s a nd thus reduce fl ui d a nd protei n l os s es a nd di s coura ge i nva s i ve i nfecti on. The a l l ogra fts a re ul ti ma tel y rejected, but the
res ul ti ng denuded a rea s devel op wel l -va s cul a ri zed gra nul a ti ons onto whi ch a utogra fts from the pa ti ent's hea l ed s i tes ta ke rea di l y. Ski n cel l s ma y
be grown i n cul ture, then returned to a burned pa ti ent to hel p cover extens i ve burns ; a rti fi ci a l s ki n, compos ed of cul tured cel l s on a s yntheti c
underl a yer, ma y a l s o be us ed. Spl i t-thi cknes s s ki n gra fts a re us ed to a ccel era te hea l i ng of s ma l l wounds . A s ma l l pi ece of s ki n jus t a few
mi l l i meters thi ck i s ha rves ted, a nd the donor s ki n i s then l a i d onto the gra ft s i te.
Cartilage transplantation: Ca rti l a ge tra ns pl a nta ti on i s us ed for chi l dren wi th congeni ta l na s a l or ea r defects a nd a dul ts wi th s evere i njuri es or joi nt
des tructi on (eg, s evere os teoa rthri ti s ). Chondrocytes a re more res i s ta nt to rejecti on, pos s i bl y beca us e the s pa rs e popul a ti on of cel l s i n hya l i ne
ca rti l a ge i s protected from cel l ul a r a tta ck by the ca rti l a gi nous ma tri x a round them.
Bone transplantation: Bone tra ns pl a nta ti on i s us ed for recons tructi on of l a rge bony defects (eg, a fter ma s s i ve res ecti on of bone ca ncer). No vi a bl e
donor bone cel l s s urvi ve i n the reci pi ent, but dea d ma tri x from a l l ogra fts ca n s ti mul a te reci pi ent os teobl a s ts to recol oni ze the ma tri x a nd l a y
down new bone. Thi s ma tri x a cts a s s ca ffol di ng for bri dgi ng a nd s ta bi l i zi ng defects unti l new bone i s formed. Ca da veri c a l l ogra fts a re pres erved by
freezi ng to decrea s e i mmunogeni ci ty of the bone (whi ch i s dea d a t the ti me of i mpl a nta ti on) a nd by gl ycerol i za ti on to ma i nta i n chondrocyte
vi a bi l i ty. No pos ti mpl a nta ti on i mmunos uppres s i ve thera py i s us ed. Al though pa ti ents devel op a nti -HLA a nti bodi es , ea rl y fol l ow-up detects no
evi dence of ca rti l a ge degra da ti on.
Corneal transplantation: Cornea l tra ns pl a nta ti on i s di s cus s ed on p. 595.
Adrenal autografting: Adrena l a utogra fti ng by s tereota cti ca l l y pl a ci ng medul l a ry ti s s ue wi thi n the CNS ha s been reported to a l l evi a te s ymptoms i n
pa ti ents wi th Pa rki ns on's di s ea s e. Al l ogra fts of a drena l ti s s ue, es peci a l l y from feta l donors , ha ve a l s o been propos ed. Feta l ventra l
mes encepha l i c ti s s ue s tereota cti ca l l y i mpl a nted i n the puta men of pa ti ents wi th Pa rki ns on's di s ea s e ha s been reported to reduce ri gi di ty a nd
bra dyki nes i a . However, wi th the ethi ca l a nd pol i ti ca l deba tes a bout the propri ety of us i ng huma n feta l ti s s ue, a control l ed tri a l l a rge enough to
a dequa tel y a s s es s feta l neura l tra ns pl a nta ti on a ppea rs unl i kel y. Xenogra fts of endocri nol ogi ca l l y a cti ve cel l s from porci ne donors a re bei ng
tes ted.
Fetal thymus implants: Feta l thymus i mpl a nts obta i ned from s ti l l born i nfa nts ma y res tore i mmunol ogi c res pons i venes s i n chi l dren wi th thymi c
a pl a s i a a nd res ul ti ng a bnorma l devel opment of the l ymphoi d s ys tem. Beca us e the reci pi ent i s i mmunol ogi ca l l y unres pons i ve,
i mmunos uppres s i on i s not requi red; however, s evere gra ft-vs -hos t di s ea s e ma y occur.
11 - Infectious Diseases
Chapter 129. Biology of Infectious Disease
Introduction
A hea l thy pers on l i ves i n ha rmony wi th the mi crobi a l fl ora tha t hel ps protect i ts hos t from i nva s i on by pa thogens , us ua l l y defi ned a s
mi croorga ni s ms tha t ha ve the ca pa ci ty to ca us e di s ea s e. The mi crobi a l fl ora i s mos tl y ba cteri a a nd fungi a nd i ncl udes norma l res i dent fl ora ,
whi ch i s pres ent cons i s tentl y a nd promptl y rees ta bl i s hes i ts el f i f di s turbed, a nd tra ns i ent fl ora , whi ch ma y col oni ze the hos t for hours to weeks
but does not perma nentl y es ta bl i s h i ts el f. Orga ni s ms tha t a re norma l fl ora ca n occa s i ona l l y ca us e di s ea s e, es peci a l l y when defens es a re
di s rupted.
Tropi s ms (a ttra cti ons to certa i n ti s s ues ) determi ne whi ch body s i tes mi croorga ni s ms col oni ze. Norma l fl ora i s i nfl uenced by tropi s ms a nd ma ny
other fa ctors (eg, di et, hygi ene, s a ni ta ry condi ti ons , a i r pol l uti on). For exa mpl e, l a ctoba ci l l i a re common i n the i ntes ti nes of peopl e wi th a hi gh
i nta ke of da i ry products ; Haemophilus influenzae col oni zes the tra cheobronchi a l tree i n pa ti ents wi th COPD.
Host Defense Mechanisms
Hos t defens es tha t protect a ga i ns t i nfecti on i ncl ude na tura l ba rri ers (eg, s ki n, mucous membra nes ), nons peci fi c i mmune res pons es (eg,
pha gocyti c cel l s [neutrophi l s , ma cropha ges ] a nd thei r products ), a nd s peci fi c i mmune res pons es (eg, a nti bodi es , l ymphocytes ).
Natural Barriers
Skin: The s ki n us ua l l y ba rs i nva di ng mi croorga ni s ms unl es s i t i s phys i ca l l y di s rupted (eg, by i njury, IV ca theter, or s urgi ca l i nci s i on). Excepti ons
i ncl ude huma n pa pi l l oma vi rus , whi ch ca n i nva de norma l s ki n, ca us i ng wa rts , a nd s ome pa ra s i tes (eg, Schistosoma mansoni, Strongyloides stercoralis).
Mucous membranes: Ma ny mucous membra nes a re ba thed i n s ecreti ons tha t ha ve a nti mi crobi a l properti es (eg, cervi ca l mucus , pros ta ti c fl ui d, a nd
tea rs conta i ni ng l ys ozyme, whi ch s pl i ts the mura mi c a ci d l i nka ge i n ba cteri a l cel l wa l l s , es peci a l l y i n gra m-pos i ti ve orga ni s ms ). Loca l s ecreti ons
a l s o conta i n i mmunogl obul i ns , pri nci pa l l y IgG a nd s ecretory IgA, whi ch prevent mi croorga ni s ms from a tta chi ng to hos t cel l s .
Respiratory tract: The res pi ra tory tra ct ha s upper a i rwa y fi l ters . If i nva di ng orga ni s ms rea ch the tra cheobronchi a l tree, the mucoci l i a ry epi thel i um
tra ns ports them a wa y from the l ung. Coughi ng a l s o hel ps remove orga ni s ms . If the orga ni s ms rea ch the a l veol i , a l veol a r ma cropha ges a nd ti s s ue
hi s ti ocytes engul f them. However, thes e defens es ca n be overcome by l a rge numbers of orga ni s ms or by compromi s ed effecti venes s res ul ti ng from
a i r pol l uta nts (eg, ci ga rette s moke) or i nterference wi th protecti ve mecha ni s ms (eg, endotra chea l i ntuba ti on, tra cheos tomy).
GI tract: GI tra ct ba rri ers i ncl ude the a ci d pH of the s toma ch a nd the a nti ba cteri a l a cti vi ty of pa ncrea ti c enzymes , bi l e, a nd i ntes ti na l s ecreti ons .
Peri s ta l s i s a nd the norma l l os s of epi thel i a l cel l s remove mi croorga ni s ms . If peri s ta l s i s i s s l owed (eg, beca us e of drugs s uch a s bel l a donna or
opi um a l ka l oi ds ), thi s remova l i s del a yed a nd prol ongs s ome i nfecti ons , s uch a s s ymptoma ti c s hi gel l os i s . Compromi s ed GI defens e mecha ni s ms
ma y predi s pos e pa ti ents to pa rti cul a r i nfecti ons (eg, a chl orhydri a predi s pos es to s a l monel l os i s ). Norma l bowel fl ora ca n i nhi bi t pa thogens ;
a l tera ti on of thi s fl ora wi th a nti bi oti cs ca n a l l ow overgrowth of i nherentl y pa thogeni c mi croorga ni s ms (eg, Salmonella typhimurium) or
s uperi nfecti on wi th ordi na ri l y commens a l orga ni s ms (eg, Candida albicans).
GU tract: GU tra ct ba rri ers i ncl ude the l ength of the urethra (20 cm) i n men, the a ci d pH of the va gi na i n women, a nd the hypertoni c s ta te of the
ki dney medul l a . The ki dneys a l s o produce a nd excrete l a rge a mounts of Ta mm-Hors fa l l mucoprotei n, whi ch bi nds certa i n ba cteri a , fa ci l i ta ti ng
thei r ha rml es s excreti on.
Nonspecific Immune Responses
Cytoki nes (i ncl udi ng IL-1, IL-6, tumor necros i s fa ctor, i nterferon-) a re produced pri nci pa l l y by ma cropha ges a nd a cti va ted l ymphocytes a nd medi a te
a n a cute-pha s e res pons e tha t devel ops rega rdl es s of the i nci ti ng mi croorga ni s m (s ee a l s o p. 1084). The res pons e i nvol ves fever a nd i ncrea s ed
producti on of neutrophi l s by the bone ma rrow. Endothel i a l cel l s a l s o produce l a rge a mounts of IL-8, whi ch a ttra cts neutrophi l s .
The i nfl a mma tory res pons e di rects i mmune s ys tem components to i njury or i nfecti on s i tes a nd i s ma ni fes ted by i ncrea s ed bl ood s uppl y a nd
va s cul a r permea bi l i ty, whi ch a l l ows chemota cti c pepti des , neutrophi l s , a nd mononucl ea r cel l s to l ea ve the i ntra va s cul a r compa rtment. Mi crobi a l
s prea d i s l i mi ted by engul fment of mi croorga ni s ms by pha gocytes (eg, neutrophi l s , ma cropha ges ). Pha gocytes a re dra wn to mi crobes vi a
chemota xi s a nd engul f them, rel ea s i ng pha gocyti c l ys os oma l contents tha t hel p des troy mi crobes . Oxi da ti ve products s uch a s hydrogen peroxi de
a re genera ted by the pha gocytes a nd ki l l i nges ted mi crobes . When qua nti ta ti ve or qua l i ta ti ve defects i n neutrophi l s res ul t i n i nfecti on, the
i nfecti on i s us ua l l y prol onged a nd recurrent a nd res ponds s l owl y to a nti mi crobi a l drugs . Sta phyl ococci , gra m-nega ti ve orga ni s ms , a nd fungi a re
the pa thogens us ua l l y res pons i bl e.
Specific Immune Responses
After i nfecti on, the hos t ca n produce a va ri ety of a nti bodi es , compl ex gl ycoprotei ns known a s i mmunogl obul i ns tha t bi nd to s peci fi c mi crobi a l
a nti geni c ta rgets . Anti bodi es ca n hel p era di ca te the i nfecti ng orga ni s m by a ttra cti ng the hos t's WBCs a nd a cti va ti ng the compl ement s ys tem. The
compl ement s ys tem (s ee p. 1085) des troys cel l wa l l s , us ua l l y through the cl a s s i c pa thwa y. Compl ement ca n a l s o be a cti va ted on the s urfa ce of
s ome mi croorga ni s ms vi a the a l terna ti ve pa thwa y. Anti bodi es ca n a l s o promote the depos i ti on of s ubs ta nces known a s ops oni ns (eg, the
compl ement protei n C3b) on the s urfa ce of mi croorga ni s ms , whi ch hel ps promote pha gocytos i s . Ops oni za ti on i s i mporta nt for era di ca ti on of
enca ps ul a ted orga ni s ms s uch a s pneumococci a nd meni ngococci .
Factors Facilitating Microbial Invasion
Mi crobi a l i nva s i on ca n be fa ci l i ta ted by vi rul ence fa ctors , mi crobi a l a dherence, res i s ta nce to a nti mi crobi a l s , a nd defects i n hos t defens e
mecha ni s ms .
Virulence Factors
Vi rul ence fa ctors a s s i s t pa thogens i n i nva s i on a nd res i s ta nce of hos t defens es ; thes e fa ctors i ncl ude
Ca ps ul es
Enzymes
Toxi ns
Capsules: Some orga ni s ms (eg, certa i n s tra i ns of pneumococci , meni ngococci , type B Haemophilus influenzae) ha ve ca ps ul es tha t prevent ops oni c
a nti bodi es from bi ndi ng a nd thus a re more vi rul ent tha n nonenca ps ul a ted s tra i ns .
Enzymes: Ba cteri a l protei ns wi th enzyma ti c a cti vi ty (eg, protea s e, hya l uroni da s e, neura mi ni da s e, el a s ta s e, col l a gena s e) fa ci l i ta te l oca l ti s s ue
s prea d. Inva s i ve orga ni s ms (eg, Shigella flexneri, Yersinia enterocolitica) ca n penetra te a nd tra vers e i nta ct euka ryoti c cel l s , fa ci l i ta ti ng entry from
mucos a l s urfa ces .
Some ba cteri a (eg, Neisseria gonorrhoeae, H. influenzae, Proteus mirabilis, cl os tri di a l s peci es , Streptococcus pneumoniae) produce IgA-s peci fi c protea s es
tha t cl ea ve a nd i na cti va te s ecretory IgA on mucos a l s urfa ces .
Toxins: Orga ni s ms ma y rel ea s e toxi ns (ca l l ed exotoxi ns ), whi ch a re protei n mol ecul es tha t ma y ca us e the di s ea s e (eg, di phtheri a , chol era , teta nus ,
botul i s m) or i ncrea s e the s everi ty of the di s ea s e. Mos t toxi ns bi nd to s peci fi c ta rget cel l receptors . Wi th the excepti on of preformed toxi ns
res pons i bl e for food-borne i l l nes s es , toxi ns a re produced by orga ni s ms duri ng the cours e of i nfecti on.
Endotoxi n i s a l i popol ys a ccha ri de produced by gra m-nega ti ve ba cteri a a nd i s pa rt of the cel l wa l l . Endotoxi n tri ggers humora l enzyma ti c
mecha ni s ms i nvol vi ng the compl ement, cl otti ng, fi bri nol yti c, a nd ki ni n pa thwa ys a nd ca us es much of the morbi di ty i n gra m-nega ti ve s eps i s .
Other factors: Ma ny mi croorga ni s ms ha ve mecha ni s ms tha t i mpa i r a nti body producti on by i nduci ng s uppres s or cel l s , bl ocki ng a nti gen proces s i ng,
a nd i nhi bi ti ng l ymphocyte mi togenes i s .
Res i s ta nce to the l yti c effects of s erum compl ement confers vi rul ence. Among s peci es of N. gonorrhoeae, res i s ta nce predi s pos es to di s s emi na ted
ra ther tha n l oca l i zed i nfecti on.
Some orga ni s ms res i s t the oxi da ti ve s teps i n pha gocytos i s . For exa mpl e, Legionella a nd Listeria ei ther do not el i ci t or a cti vel y s uppres s the
oxi da ti ve s tep, wherea s other orga ni s ms produce enzymes (eg, ca ta l a s e, gl uta thi one reducta s e, or s uperoxi de di s muta s e) tha t mi ti ga te the
oxi da ti ve products .
Microbial Adherence
Adherence to s urfa ces hel ps mi croorga ni s ms es ta bl i s h a ba s e from whi ch to penetra te ti s s ues . Among the fa ctors tha t determi ne a dherence a re
a dhes i ns (mi crobi a l mol ecul es tha t medi a te a tta chment to a cel l ) a nd hos t receptors to whi ch the a dhes i ns bi nd. Hos t receptors i ncl ude cel l
s urfa ce s uga r res i dues a nd cel l s urfa ce protei ns (eg, fi bronecti n) tha t enha nce bi ndi ng of certa i n gra m-pos i ti ve orga ni s ms (eg, s ta phyl ococci ).
Other determi na nts of a dherence i ncl ude fi ne s tructures on certa i n ba cteri a l cel l s (eg, s treptococci ) ca l l ed fi bri l l a e, by whi ch s ome ba cteri a bi nd
to huma n epi thel i a l cel l s . Other ba cteri a , s uch a s Enteroba cteri a cea e (eg, Escherichia coli), ha ve s peci fi c a dhes i ve orga nel l es ca l l ed fi mbri a e or
pi l i . Fi mbri a e ena bl e the orga ni s m to a tta ch to a l mos t a l l huma n cel l s , i ncl udi ng neutrophi l s a nd epi thel i a l cel l s i n the GU tra ct, mouth, a nd
i ntes ti ne.
Biofilm: Bi ofi l m i s a s l i me l a yer tha t ca n form a round certa i n ba cteri a a nd confer res i s ta nce to pha gocytos i s a nd a nti bi oti cs . It devel ops a round
Pseudomonas aeruginosa i n the l ungs of pa ti ents wi th cys ti c fi bros i s a nd a round coa gul a s e-nega ti ve s ta phyl ococci on s yntheti c medi ca l devi ces ,
s uch a s IV ca theters , pros theti c va s cul a r gra fts , a nd s uture ma teri a l . Fa ctors tha t a ffect the l i kel i hood of bi ofi l m devel opi ng on s uch medi ca l
devi ces i ncl ude the ma teri a l 's roughnes s , chemi ca l compos i ti on, a nd hydrophobi ci ty.
Antimicrobial Resistance
Geneti c va ri a bi l i ty a mong mi crobes i s i nevi ta bl e. Us e of a nti mi crobi a l drugs eventua l l y s el ects for s urvi va l of s tra i ns tha t a re ca pa bl e of res i s ti ng
them.
In ma ny ca s es , res i s ta nt ba cteri a l s tra i ns ha ve a cqui red genes tha t a re encoded on pl a s mi ds or tra ns pos ons a nd tha t ena bl e the mi croorga ni s ms
to s ynthes i ze enzymes tha t
Modi fy or i na cti va te the a nti mi crobi a l a gent
Cha nge the ba cteri a l cel l 's a bi l i ty to a ccumul a te the a nti mi crobi a l a gent
Res i s t i nhi bi ti on by the a nti mi crobi a l a gent
Mi ni mi zi ng i na ppropri a te us e of a nti bi oti cs i s i mporta nt for publ i c hea l th. Res i s ta nce a mong ba cteri a i s di s cus s ed on p. 1184.
Defects in Host Defense Mechanisms
Two types of i mmune defi ci ency s ta tes a ffect the hos t's a bi l i ty to fi ght i nfecti on: Pri ma ry i mmune defi ci ency a nd s econda ry (a cqui red) i mmune
defi ci ency.
Primary immune deficiencies a re geneti c i n ori gi n; > 100 pri ma ry i mmune defi ci ency s ta tes ha ve been des cri bed. Mos t pri ma ry i mmune defi ci enci es
a re recogni zed duri ng i nfa ncy; however, up to 40% a re recogni zed duri ng a dol es cence or a dul thood.
Acquired immune deficiencies a re ca us ed by a nother di s ea s e (eg, ca ncer, HIV i nfecti on, chroni c di s ea s e) or by expos ure to a chemi ca l or drug tha t i s
toxi c to the i mmune s ys tem.
Mechanisms: Defects i n i mmune res pons es ma y i nvol ve
Cel l ul a r i mmuni ty
Humora l i mmuni ty
Pha gocyti c s ys tem
Compl ement s ys tem
Cel l ul a r defi ci enci es a re typi ca l l y T-cel l or combi ned i mmune defects . T cel l s contri bute to the ki l l i ng of i ntra cel l ul a r orga ni s ms ; thus , pa ti ents
wi th T-cel l defects ca n pres ent wi th opportuni s ti c i nfecti ons s uch a s Pneumocystis jirovecii or cryptococca l i nfecti ons . Chroni ci ty of thes e i nfecti ons
ca n l ea d to fa i l ure to thri ve, chroni c di a rrhea , a nd pers i s tent ora l ca ndi di a s i s .
Humora l defi ci enci es a re typi ca l l y ca us ed by the fa i l ure of B cel l s to ma ke functi oni ng i mmunogl obul i ns . Pa ti ents wi th thi s type of defect us ua l l y
ha ve i nfecti ons i nvol vi ng enca ps ul a ted orga ni s ms (eg, H. influenzae, s treptococci ). Pa ti ents ca n pres ent wi th poor growth, di a rrhea , a nd recurrent
s i nopul mona ry i nfecti ons .
A defect i n the pha gocyti c s ys tem a ffects the i mmedi a te i mmune res pons e to ba cteri a l i nfecti on a nd ca n res ul t i n devel opment of recurrent
a bs ces s es , s evere pneumoni a s , or del a yed umbi l i ca l cord s epa ra ti on.
Pri ma ry compl ement s ys tem defects a re pa rti cul a rl y ra re. Pa ti ents wi th thi s type of defect ma y pres ent wi th recurrent i nfecti ons wi th pyogeni c
ba cteri a (eg, enca ps ul a ted ba cteri a , Neisseria s p) a nd ha ve a n i ncrea s ed ri s k of a utoi mmune di s orders (eg, SLE).
Manifestations of Infection
Ma ni fes ta ti ons ma y be l oca l (eg, cel l ul i ti s , a bs ces s ) or s ys temi c, mos t often fever (s ee p. 1152). Ma ni fes ta ti ons ma y devel op i n mul ti pl e orga n
s ys tems . Severe, genera l i zed i nfecti ons ma y ha ve l i fe-threa teni ng ma ni fes ta ti ons (eg, s eps i s , s epti c s hocks ee p. 2299). Mos t ma ni fes ta ti ons
res ol ve wi th s ucces s ful trea tment of the underl yi ng i nfecti on.
Clinical: Mos t i nfecti ons i ncrea s e the pul s e ra te a nd body tempera ture, but others (eg, typhoi d fever, tul a remi a , brucel l os i s , dengue) ma y not
el eva te the pul s e ra te commens ura te wi th the degree of fever. Hypotens i on ca n res ul t from hypovol emi a or s epti c s hock. Hyperventi l a ti on a nd
res pi ra tory a l ka l os i s a re common.
Al tera ti ons i n s ens ori um (encepha l opa thy) ma y occur i n s evere i nfecti on rega rdl es s of whether CNS i nfecti on i s pres ent. Encepha l opa thy i s mos t
common a nd s eri ous i n the el derl y a nd ma y ca us e a nxi ety, confus i on, del i ri um, s tupor, s ei zures , a nd coma .
Hematologic: Infecti ous di s ea s es commonl y i ncrea s e the numbers of ma ture a nd i mma ture ci rcul a ti ng neutrophi l s . Mecha ni s ms i ncl ude
dema rgi na ti on a nd rel ea s e of i mma ture gra nul ocytes from bone ma rrow, IL-1- a nd IL-6-medi a ted rel ea s e of neutrophi l s from bone ma rrow, a nd
col ony-s ti mul a ti ng fa ctors el a bora ted by ma cropha ges , l ymphocytes , a nd other ti s s ues . Exa ggera ti on of thes e phenomena (eg, i n tra uma ,
i nfl a mma ti on, a nd s i mi l a r s tres s es ) ca n res ul t i n rel ea s e of exces s i ve numbers of i mma ture l eukocytes i nto the ci rcul a ti on (l eukemoi d rea cti on),
wi th l eukocyte counts up to 25 to 30 109 /L.
Convers el y, s ome i nfecti ons (eg, typhoi d fever, brucel l os i s ) commonl y ca us e neutropeni a . In overwhel mi ng, s evere i nfecti ons , profound
neutropeni a i s often a poor prognos ti c s i gn. Cha ra cteri s ti c morphol ogi c cha nges i n the neutrophi l s of s epti c pa ti ents i ncl ude Dohl e bodi es , toxi c
gra nul a ti ons , a nd va cuol i za ti on.
Anemi a ca n devel op des pi te a dequa te ti s s ue i ron s tores . If a nemi a i s chroni c, pl a s ma i ron a nd tota l i ron-bi ndi ng ca pa ci ty ma y be decrea s ed.
Seri ous i nfecti on, pa rti cul a rl y wi th gra m-nega ti ve orga ni s ms , ma y ca us e di s s emi na ted i ntra va s cul a r coa gul a ti on (DICs ee p. 976).
Other organ systems: Pul mona ry compl i a nce ma y decrea s e, progres s i ng to a cute res pi ra tory di s tres s s yndrome (ARDS) a nd res pi ra tory mus cl e
fa i l ure.
Rena l ma ni fes ta ti ons ra nge from mi ni ma l protei nuri a to a cute rena l fa i l ure, whi ch ca n res ul t from s hock a nd a cute tubul a r necros i s ,
gl omerul onephri ti s , or tubul oi nters ti ti a l di s ea s e.
Hepa ti c dys functi on, i ncl udi ng chol es ta ti c ja undi ce (often a poor prognos ti c s i gn) or hepa tocel l ul a r dys functi on, occurs wi th ma ny i nfecti ons , even
though the i nfecti on does not l oca l i ze to the l i ver. Upper GI bl eedi ng due to s tres s ul cera ti on ma y occur duri ng s eps i s .
Endocri nol ogi c dys functi ons i ncl ude i ncrea s ed producti on of thyroi d-s ti mul a ti ng hormone, va s opres s i n, i ns ul i n, a nd gl uca gon; brea kdown of
s kel eta l mus cl e protei ns a nd mus cl e wa s ti ng s econda ry to i ncrea s ed meta bol i c dema nds ; a nd bone demi nera l i za ti on. Hypogl ycemi a occurs
i nfrequentl y i n s eps i s , but a drena l i ns uffi ci ency s houl d be cons i dered i n pa ti ents wi th hypogl ycemi a a nd s eps i s . Hypergl ycemi a ma y be a n ea rl y
s i gn of i nfecti on i n di a beti cs .
Fever
Fever i s el eva ted body tempera ture (> 37.8 C ora l l y or > 38.2 C recta l l y) or a n el eva ti on a bove a pers on's known norma l da i l y va l ue. El eva ted body
tempera ture tha t i s not ca us ed by a res etti ng of the tempera ture s et poi nt i n the hypotha l a mus i s commonl y ca l l ed hyperthermi a . Ma ny pa ti ents
us e "fever" very l oos el y, often mea ni ng tha t they feel too wa rm, too col d, or s wea ty, but they ha ve not a ctua l l y mea s ured thei r tempera ture.
Symptoms a re due ma i nl y to the condi ti on ca us i ng the fever, a l though fever i ts el f ca n ca us e di s comfort.

Pathophysiology
Duri ng a 24-h peri od, tempera ture va ri es from l owes t l evel s i n the ea rl y morni ng to hi ghes t i n l a te a fternoon. Ma xi mum va ri a ti on i s a bout 0.6 C.
Body tempera ture i s determi ned by the ba l a nce between hea t producti on by ti s s ues , pa rti cul a rl y the l i ver a nd mus cl es , a nd hea t l os s from the
peri phery. Norma l l y, the hypotha l a mi c thermoregul a tory center ma i nta i ns the i nterna l tempera ture between 37 a nd 38 C. Fever res ul ts when
s omethi ng ra i s es the hypotha l a mi c s et poi nt, tri ggeri ng va s ocons tri cti on a nd s hunti ng of bl ood from the peri phery to decrea s e hea t l os s ;
s ometi mes s hi veri ng, whi ch i ncrea s es hea t producti on, i s i nduced. Thes e proces s es conti nue unti l the tempera ture of the bl ood ba thi ng the
hypotha l a mus rea ches the new s et poi nt. Res etti ng the hypotha l a mi c s et poi nt downwa rd (eg, wi th a nti pyreti c drugs ) i ni ti a tes hea t l os s through
s wea ti ng a nd va s odi l a ti on. The ca pa ci ty to genera te a fever i s reduced i n certa i n pa ti ents (eg, a l cohol i cs , the very ol d, the very young).
Pyrogens a re s ubs ta nces tha t ca us e fever. Exogenous pyrogens a re us ua l l y mi crobes or thei r products . The bes t s tudi ed a re the l i popol ys a ccha ri des
of gra m-nega ti ve ba cteri a (commonl y ca l l ed endotoxi ns ) a nd Staphylococcus aureus toxi n, whi ch ca us es toxi c s hock s yndrome. Exogenous pyrogens
us ua l l y ca us e fever by i nduci ng rel ea s e of endogenous pyrogens (eg, IL-1, tumor necros i s fa ctor [TNF], i nterferon-, IL-6), whi ch ra i s e the
hypotha l a mi c s et poi nt. Pros ta gl a ndi n E2 s ynthes i s a ppea rs to pl a y a cri ti ca l rol e.
Consequences of fever: Al though ma ny pa ti ents worry tha t fever i ts el f ca n ca us e ha rm, the modes t tra ns i ent core tempera ture el eva ti ons (i e, 38 to
40) ca us ed by mos t a cute i l l nes s es a re wel l tol era ted by hea l thy a dul ts . However, extreme tempera ture el eva ti on (typi ca l l y > 41 C) ma y be
da ma gi ng. Such el eva ti on i s more typi ca l of s evere envi ronmenta l hyperthermi a but s ometi mes res ul ts from expos ure to i l l i ci t drugs (eg, coca i ne,
phencycl i di ne), a nes theti cs , or a nti ps ychoti c drugs . At thi s tempera ture, protei n dena tura ti on occurs , a nd i nfl a mma tory cytoki nes tha t a cti va te the
i nfl a mma tory ca s ca de a re rel ea s ed. As a res ul t, cel l ul a r dys functi on occurs , l ea di ng to ma l functi on a nd ul ti ma tel y fa i l ure of mos t orga ns ; the
coa gul a ti on ca s ca de i s a l s o a cti va ted, l ea di ng to di s s emi na ted i ntra va s cul a r coa gul a ti on.
Beca us e fever ca n i ncrea s e the BMR by a bout 10 to 12% for every 1 C i ncrea s e over 37 C, fever ma y phys i ol ogi ca l l y s tres s a dul ts wi th preexi s ti ng
ca rdi a c or pul mona ry i ns uffi ci ency. Fever ca n a l s o wors en menta l s ta tus i n pa ti ents wi th dementi a .
Fever i n hea l thy chi l dren ca n ca us e febri l e s ei zures (s ee p. 2898).
Etiology
Ma ny di s orders ca n ca us e fever. They a re broa dl y ca tegori zed a s
Infecti ous (mos t common)
Neopl a s ti c
Infl a mma tory (i ncl udi ng rheuma ti c, nonrheuma ti c, a nd drug-rel a ted)
The ca us e of a n a cute (i e, dura ti on 4 da ys ) fever i n a dul ts i s hi ghl y l i kel y to be i nfecti ous . When pa ti ents pres ent wi th fever due to a
noni nfecti ous ca us e, the fever i s a l mos t a l wa ys chroni c or recurrent. Al s o, a n i s ol a ted, a cute febri l e event i n pa ti ents wi th a known i nfl a mma tory
or neopl a s ti c di s order i s s ti l l mos t l i kel y to be i nfecti ous . In hea l thy peopl e, a n a cute febri l e event i s unl i kel y to be the i ni ti a l ma ni fes ta ti on of a
chroni c i l l nes s .
Infectious causes: Vi rtua l l y a l l i nfecti ous i l l nes s es ca n ca us e fever. But overa l l , the mos t l i kel y ca us es a re
Upper a nd l ower res pi ra tory tra ct i nfecti ons
GI i nfecti ons
UTIs
Ski n i nfecti ons
Mos t a cute res pi ra tory tra ct a nd GI i nfecti ons a re vi ra l .
Speci fi c pa ti ent a nd externa l fa ctors a l s o i nfl uence whi ch ca us es a re mos t l i kel y.
Pa ti ent fa ctors i ncl ude hea l th s ta tus , a ge, occupa ti on, a nd ri s k fa ctors (eg, hos pi ta l i za ti on, recent i nva s i ve procedures , pres ence of IV or uri na ry
ca theters , us e of mecha ni ca l venti l a ti on).
Externa l fa ctors a re thos e tha t expos e pa ti ents to s peci fi c di s ea s es eg, through i nfected conta cts , l oca l outbrea ks , di s ea s e vectors (eg,
mos qui toes , ti cks ), a common vehi cl e (eg, food, wa ter), or geogra phi c l oca ti on (eg, res i dence i n or recent tra vel to a n endemi c a rea ).
Some ca us es a ppea r to predomi na te ba s ed on thes e fa ctors (s ee
Ta bl e 129-1).
Evaluation
Two genera l i s s ues a re i mporta nt i n the i ni ti a l eva l ua ti on of a cute fever:
Identi fyi ng a ny l oca l i zi ng s ymptoms (eg, hea da che, cough): Thes e s ymptoms hel p na rrow the ra nge of pos s i bl e ca us es . The l oca l i zi ng s ymptom
ma y be pa rt of the pa ti ent's chi ef compl a i nt or i denti fi ed onl y by s peci fi c ques ti oni ng.
Determi ni ng whether the pa ti ent i s s eri ous l y or chroni ca l l y i l l (pa rti cul a rl y i f s uch i l l nes s i s unrecogni zed): Ma ny ca us es of fever i n hea l thy
peopl e a re s el f-l i mi ted, a nd ma ny of the pos s i bl e vi ra l i nfecti ons a re di ffi cul t to di a gnos e s peci fi ca l l y. Li mi ti ng tes ti ng to the s eri ous l y or
chroni ca l l y i l l ca n hel p a voi d ma ny expens i ve, unneces s a ry, a nd often frui tl es s s ea rches .
History: History of present illness s houl d cover ma gni tude a nd dura ti on of fever a nd method us ed to ta ke the tempera ture. True ri gors (s evere,
s ha ki ng, teeth-cha tteri ng chi l l s not s i mpl y feel i ng col d) s ugges t fever due to i nfecti on but a re not otherwi s e s peci fi c. Pa i n i s a n i mporta nt cl ue to
the pos s i bl e s ource; the pa ti ent s houl d be a s ked a bout pa i n i n the ea rs , hea d, neck, teeth, throa t, ches t, a bdomen, fl a nk, rectum, mus cl es , a nd
joi nts .
Other l oca l i zi ng s ymptoms i ncl ude na s a l conges ti on a nd/or di s cha rge, cough, di a rrhea , a nd uri na ry s ymptoms (frequency, urgency, dys uri a ).
Pres ence of ra s h (i ncl udi ng na ture, l oca ti on, a nd ti me of ons et i n rel a ti on to other s ymptoms ) a nd l ympha denopa thy ma y hel p. Infected conta cts
a nd thei r di a gnos i s s houl d be i denti fi ed.
Review of systems s houl d i denti fy s ymptoms of chroni c i l l nes s , i ncl udi ng recurrent fevers , ni ght s wea ts , a nd wei ght l os s .
Past medical history s houl d pa rti cul a rl y cover the fol l owi ng:
Recent s urgery
Known di s orders tha t predi s pos e to i nfecti on (eg, HIV i nfecti on, di a betes , ca ncer, orga n tra ns pl a nta ti on, s i ckl e cel l di s ea s e, va l vul a r hea rt
di s orders pa rti cul a rl y i f a n a rti fi ci a l va l ve i s pres ent)
Other known di s orders tha t predi s pos e to fever (eg, rheuma tol ogi c di s orders , SLE, gout, s a rcoi dos i s , hyperthyroi di s m, ca ncer)
Ques ti ons to a s k a bout recent tra vel i ncl ude l oca ti on, ti me s i nce return, l oca l e (eg, i n ba ck country, onl y i n ci ti es ), va cci na ti ons recei ved before
tra vel , a nd a ny us e of prophyl a cti c a nti ma l a ri a l drugs (i f requi red).
Al l pa ti ents s houl d be a s ked a bout pos s i bl e expos ures (eg, vi a uns a fe food or wa ter, i ns ect bi tes , a ni ma l conta ct, or unprotected s ex).
Va cci na ti on hi s tory, pa rti cul a rl y a ga i ns t hepa ti ti s A a nd B a nd a ga i ns t orga ni s ms tha t ca us e meni ngi ti s , i nfl uenza , or pneumococca l i nfecti on,
s houl d be noted.
Drug hi s tory s houl d i ncl ude s peci fi c ques ti ons a bout the fol l owi ng:
Drugs known to ca us e fever (s ee Ta bl e 129-1)
Drugs tha t predi s pos e to i nfecti on (eg, corti cos teroi ds , a nti -TNF drugs , chemothera peuti c a nd a nti rejecti on drugs , other i mmunos uppres s a nts )
Il l i ci t us e of i njecti on drugs (predi s pos i ng to endoca rdi ti s , hepa ti ti s , s epti c pul mona ry embol i , a nd s ki n a nd s oft-ti s s ue i nfecti ons )
Physical examination: Phys i ca l exa mi na ti on begi ns wi th confi rma ti on of fever. Fever i s mos t a ccura tel y di a gnos ed by mea s uri ng recta l tempera ture.
Ora l tempera tures a re norma l l y a bout 0.6 C l ower a nd ma y be fa l s el y even l ower for ma ny rea s ons , s uch a s recent i nges ti on of a col d dri nk, mouth
brea thi ng, hyperventi l a ti on, a nd i na dequa te mea s urement ti me (up to s evera l mi nutes a re requi red wi th mercury thermometers ). Mea s urement
[Table 129-1. Some Ca us es of Acute Fever]
of tympa ni c membra ne tempera ture by i nfra red s ens or i s l es s a ccura te tha n recta l tempera ture.
Other vi ta l s i gns a re revi ewed for pres ence of ta chypnea , ta chyca rdi a , or hypotens i on.
For pa ti ents wi th l oca l i zi ng s ymptoms , exa mi na ti on proceeds a s di s cus s ed el s ewhere i n THE MANUAL. For febri l e pa ti ents wi thout l oca l i zi ng
s ymptoms , a compl ete exa mi na ti on i s neces s a ry beca us e cl ues to the di a gnos i s ma y be i n a ny orga n s ys tem.
The pa ti ent's genera l a ppea ra nce, i ncl udi ng a ny wea knes s , l etha rgy, confus i on, ca chexi a , a nd di s tres s , s houl d be noted.
Al l of the s ki n s houl d be i ns pected for ra s h, pa rti cul a rl y petechi a l or hemorrha gi c ra s h a nd a ny l es i ons or a rea s of erythema or bl i s teri ng
s ugges ti ng s ki n or s oft-ti s s ue i nfecti on. Axi l l a e a nd epi trochl ea r a nd i ngui na l a rea s s houl d be exa mi ned for a denopa thy. In hos pi ta l i zed pa ti ents ,
pres ence of a ny IVs , NGTs , uri na ry ca theters , a nd a ny other tubes or l i nes i ns erted i nto the body s houl d be noted. If pa ti ents ha ve ha d recent
s urgery, s urgi ca l s i tes s houl d be thoroughl y i ns pected.
For the hea d a nd neck exa mi na ti on, the fol l owi ng s houl d be done:
Tympa ni c membra nes : Exa mi ned for i nfecti on
Si nus es (fronta l a nd ma xi l l a ry): Percus s ed
Tempora l a rteri es : Pa l pa ted for tendernes s
Nos e: Ins pected for conges ti on a nd di s cha rge (cl ea r or purul ent)
Eyes : Ins pected for conjuncti vi ti s or i cterus
Fundi : Ins pected for Roth's s pots (s ugges ti ng endoca rdi ti s )
Oropha rynx a nd gi ngi va : Ins pected for i nfl a mma ti on or ul cera ti on (i ncl udi ng a ny l es i ons of ca ndi di a s i s , whi ch s ugges ts i mmunocompromi s e)
Neck: Fl exed to detect di s comfort, s ti ffnes s , or both, i ndi ca ti ng meni ngi s mus , a nd pa l pa ted for a denopa thy
The l ungs a re exa mi ned for cra ckl es or s i gns of cons ol i da ti on, a nd the hea rt i s a us cul ta ted for murmurs (s ugges ti ng pos s i bl e endoca rdi ti s ).
The a bdomen i s pa l pa ted for hepa tos pl enomega l y a nd tendernes s (s ugges ti ng i nfecti on).
The fl a nks a re percus s ed for tendernes s over the ki dneys (s ugges ti ng pyel onephri ti s ). A pel vi c exa mi na ti on i s done i n women to check for cervi ca l
moti on or a dnexa l tendernes s ; a geni ta l exa mi na ti on i s done i n men to check for urethra l di s cha rge a nd l oca l tendernes s .
The rectum i s exa mi ned for tendernes s a nd s wel l i ng, s ugges ti ng peri recta l a bs ces s (whi ch ma y be occul t i n i mmunos uppres s ed pa ti ents ).
Al l ma jor joi nts a re exa mi ned for s wel l i ng, erythema , a nd tendernes s (s ugges ti ng a joi nt i nfecti on or rheuma tol ogi c di s order). The ha nds a nd feet
a re i ns pected for s i gns of endoca rdi ti s , i ncl udi ng s pl i nter hemorrha ges under the na i l s , pa i nful erythema tous s ubcuta neous nodul es on the ti ps
of di gi ts (Os l er's nodes ), a nd nontender hemorrha gi c ma cul es on the pa l ms or s ol es (Ja newa y l es i ons ).
Al tered menta l s ta tus
Hea da che, s ti ff neck, or both
Petechi a l s ki n ra s h
Hypotens i on
Si gni fi ca nt ta chyca rdi a or ta chypnea
Tempera ture > 40 C or < 35 C
Recent tra vel to ma l a ri a -endemi c a rea
Recent us e of i mmunos uppres s a nts
Interpretation of findings: The degree of el eva ti on i n tempera ture us ua l l y does not predi ct the l i kel i hood or ca us e of i nfecti on. Fever pa ttern, once
thought to be s i gni fi ca nt, i s not.
Likelihood of serious illness i s cons i dered. If s eri ous i l l nes s i s s us pected, i mmedi a te a nd a ggres s i ve tes ti ng a nd often hos pi ta l a dmi s s i on a re
needed.
Red fl a g fi ndi ngs s trongl y s ugges t a s eri ous di s order. Hea da che, s ti ff neck, a nd petechi a l or purpuri c ra s h s ugges t meni ngi ti s . Ta chyca rdi a (beyond
the modes t el eva ti on norma l l y pres ent wi th fever) a nd ta chypnea , wi th or wi thout hypotens i on or menta l s ta tus cha nges , s ugges t s eps i s . Ma l a ri a
s houl d be s us pected i n pa ti ents who ha ve recentl y tra vel ed to a n endemi c a rea .
Immunocompromi s e, whether ca us ed by a known di s order or us e of i mmunos uppres s a nts or s ugges ted by exa mi na ti on fi ndi ngs (eg, wei ght l os s ,
ora l ca ndi di a s i s ), i s a l s o of concern, a s a re other known chroni c i l l nes s es , i njecti on drug us e, a nd hea rt murmur.
The el derl y, pa rti cul a rl y thos e i n nurs i ng homes , a re a t pa rti cul a r ri s k (s ee Geri a tri cs Es s enti a l s on p. 1157).
Localizing findings i denti fi ed by hi s tory or phys i ca l exa mi na ti on a re eva l ua ted a nd i nterpreted (s ee el s ewhere i n THE MANUAL). Other s ugges ti ve
fi ndi ngs i ncl ude genera l i zed a denopa thy a nd ra s h.
Generalized adenopathy ma y occur i n ol der chi l dren a nd younger a dul ts who ha ve a cute mononucl eos i s ; i t i s us ua l l y a ccompa ni ed by s i gni fi ca nt
pha ryngi ti s , ma l a i s e, a nd hepa tos pl enomega l y. Pri ma ry HIV i nfecti on or s econda ry s yphi l i s s houl d be s us pected i n pa ti ents wi th genera l i zed
a denopa thy, s ometi mes a ccompa ni ed by a rthra l gi a s , ra s h, or both. HIV i nfecti on devel ops 2 to 6 wk a fter expos ure (a l though pa ti ents ma y not
a l wa ys report unprotected s exua l conta ct or other ri s k fa ctors ). Seconda ry s yphi l i s i s us ua l l y preceded by a cha ncre, wi th s ys temi c s ymptoms
devel opi ng 4 to 10 wk l a ter.
Fever a nd ra s h ha ve ma ny i nfecti ous a nd drug ca us es . Petechi a l or purpuri c ra s h i s of pa rti cul a r concern; i t s ugges ts pos s i bl e meni ngococcemi a ,
Rocky Mounta i n s potted fever (pa rti cul a rl y i f the pa l ms or s ol es a re i nvol ved), a nd, l es s commonl y, s ome vi ra l i nfecti ons (eg, dengue fever,
hemorrha gi c fevers ). Other s ugges ti ve s ki n l es i ons i ncl ude the cl a s s i c erythema mi gra ns ra s h of Lyme di s ea s e, ta rget l es i ons of Stevens -Johns on
s yndrome, a nd the pa i nful , tender erythema of cel l ul i ti s a nd other ba cteri a l s oft-ti s s ue i nfecti ons . The pos s i bi l i ty of del a yed drug hypers ens i ti vi ty
(even a fter l ong peri ods of us e) s houl d be kept i n mi nd.
If no localizing findings are present, hea l thy peopl e wi th a cute fever a nd onl y nons peci fi c fi ndi ngs (eg, ma l a i s e, genera l i zed a ches ) mos t l i kel y ha ve a
s el f-l i mi ted vi ra l i l l nes s , unl es s a hi s tory of expos ure to i nfected conta cts (i ncl udi ng a new, unprotected s exua l conta ct), to di s ea s e vectors , or i n
a n endemi c a rea (i ncl udi ng recent tra vel ) s ugges ts otherwi s e.
Pa ti ents wi th s i gni fi ca nt underl yi ng di s orders a re more l i kel y to ha ve a n occul t ba cteri a l or pa ra s i ti c i nfecti on. Injecti on drug us ers a nd pa ti ents
wi th a pros theti c hea rt va l ve ma y ha ve endoca rdi ti s . Immunocompromi s ed pa ti ents a re predi s pos ed to i nfecti on ca us ed by certa i n
mi croorga ni s ms (s ee Ta bl e 129-1).
Drug fever (wi th or wi thout ra s h) i s a di a gnos i s of excl us i on, often requi ri ng a tri a l of s toppi ng the drug. One di ffi cul ty i s tha t i f a nti bi oti cs a re the
ca us e, the i l l nes s bei ng trea ted ma y a l s o ca us e fever. Someti mes a cl ue i s tha t the fever a nd ra s h begi n a fter cl i ni ca l i mprovement from the
i ni ti a l i nfecti on a nd wi thout wors eni ng or rea ppea ra nce of the ori gi na l s ymptoms (eg, i n a pa ti ent bei ng trea ted for pneumoni a , fever rea ppea rs
wi thout cough, dys pnea , or hypoxi a ).
Testing: Tes ti ng depends on whether l oca l i zed fi ndi ngs a re pres ent.
If localizing findings are present, tes ti ng i s gui ded by cl i ni ca l s us pi ci on a nd fi ndi ngs (s ee a l s o el s ewhere i n THE MANUAL), a s for the fol l owi ng:
Mononucl eos i s or HIV i nfecti on: Serol ogi c tes ti ng
Rocky Mounta i n s potted fever: Bi ops y of s ki n l es i ons to confi rm the di a gnos i s (a cute s erol ogi c tes ti ng i s unhel pful )
Ba cteri a l or funga l i nfecti on: Bl ood cul tures to detect pos s i bl e bl oods trea m i nfecti ons
Meni ngi ti s : Immedi a te l umba r puncture a nd IV a nti bi oti cs (hea d CT s houl d be done before l umba r puncture i f pa ti ents a re a t ri s k of bra i n
herni a ti on; IV a nti bi oti cs mus t be gi ven i mmedi a tel y a fter bl ood cul tures a re obta i ned a nd before hea d CT i s done)
Speci fi c di s orders ba s ed on expos ure (eg, to conta cts , to vectors , or i n endemi c a rea s ): Tes ti ng for thos e di s orders , pa rti cul a rl y a peri phera l
bl ood s mea r for ma l a ri a
If no localizing findings are present i n otherwi s e hea l thy pa ti ents a nd s eri ous i l l nes s i s not s us pected, pa ti ents ca n us ua l l y be obs erved a t home
wi thout tes ti ng. In mos t, s ymptoms res ol ve qui ckl y; the few who devel op worri s ome or l oca l i zi ng s ymptoms s houl d be reeva l ua ted a nd tes ted
ba s ed on the new fi ndi ngs .
If s eri ous i l l nes s i s s us pected i n pa ti ents who ha ve no l oca l i zi ng fi ndi ngs , tes ti ng i s needed. Pa ti ents wi th red fl a g fi ndi ngs s ugges ti ng s eps i s
requi re cul tures (uri ne a nd bl ood), ches t x-ra y, a nd eva l ua ti on for meta bol i c a bnorma l i ti es wi th mea s urement of s erum el ectrol ytes , gl ucos e, BUN,
crea ti ni ne, l a cta te, a nd l i ver enzymes . CBC i s typi ca l l y done, but s ens i ti vi ty a nd s peci fi ci ty for di a gnos i ng s eri ous ba cteri a l i nfecti on a re l ow.
However, WBC count i s i mporta nt prognos ti ca l l y for pa ti ents who ma y be i mmunos uppres s ed (i e, a l ow WBC count ma y be a s s oci a ted wi th a poor
prognos i s ).
Pa ti ents wi th certa i n underl yi ng di s orders ma y need tes ti ng even i f they ha ve no l oca l i zi ng fi ndi ngs a nd do not a ppea r s eri ous l y i l l . Beca us e of
the ri s k a nd deva s ta ti ng cons equences of endoca rdi ti s , febri l e i njecti on drug us ers a re us ua l l y a dmi tted to the hos pi ta l for s eri a l bl ood cul tures
a nd often echoca rdi ogra phy. Pa ti ents ta ki ng i mmunos uppres s a nts requi re CBC; i f neutropeni a i s pres ent, tes ti ng i s i ni ti a ted a nd ches t x-ra y i s
done, a s a re cul tures of bl ood, s putum, uri ne, s tool , a nd a ny s us pi ci ous s ki n l es i ons . Ma ny wi th neutropeni a a re a dmi tted to be gi ven IV
a nti bi oti cs , but certa i n pa ti ents ca n be s ent home provi ded da i l y fol l ow-up i s a va i l a bl e.
Febri l e el derl y pa ti ents often requi re tes ti ng (s ee Geri a tri cs Es s enti a l s on p. 1157).
Treatment
Speci fi c ca us es a re trea ted wi th a nti -i nfecti ve thera py; empi ri c a nti -i nfecti ve thera py i s requi red when s us pi ci on of s eri ous i nfecti on i s hi gh.
Whether fever due to i nfecti on s houl d be trea ted i s controvers i a l . Experi menta l evi dence, but not cl i ni ca l s tudi es , s ugges ts tha t fever enha nces
hos t defens es .
Fever s houl d proba bl y be trea ted i n certa i n pa ti ents a t pa rti cul a r ri s k, i ncl udi ng a dul ts wi th ca rdi a c or pul mona ry i ns uffi ci ency or wi th dementi a .
Drugs tha t i nhi bi t bra i n cycl ooxygena s e effecti vel y reduce fever:
Aceta mi nophen 650 to 1000 mg po q 6 h
Ibuprofen 400 to 600 mg po q 6 h
The da i l y dos e of a ceta mi nophen s houl d not exceed 4 g to a voi d toxi ci ty; pa ti ents s houl d be wa rned not to s i mul ta neous l y ta ke nonpres cri pti on
col d or fl u remedi es tha t conta i n a ceta mi nophen. Other NSAIDs (eg, a s pi ri n, na proxen) a re a l s o effecti ve a nti pyreti cs . Sa l i cyl a tes s houl d not be
us ed to trea t fever i n chi l dren wi th vi ra l i l l nes s es beca us e us e of s a l i cyl a tes ha s been a s s oci a ted wi th Reye's s yndrome.
If tempera ture i s 41 C, other cool i ng mea s ures (eg, eva pora ti ve cool i ng wi th tepi d wa ter mi s t, cool i ng bl a nkets ) s houl d a l s o be s ta rted.
In the fra i l el derl y, i nfecti on i s l es s l i kel y to ca us e fever, a nd even when el eva ted by i nfecti on, tempera ture ma y be l ower tha n the s ta nda rd
defi ni ti on of fever. Si mi l a rl y, other i nfl a mma tory s ymptoms , s uch a s foca l pa i n, ma y be l es s promi nent. Frequentl y, a l tera ti on of menta l s ta tus or
decl i ne i n da i l y functi oni ng ma y be the onl y other i ni ti a l ma ni fes ta ti ons of pneumoni a or UTI.
In s pi te of thei r l es s s evere ma ni fes ta ti ons of i l l nes s , the febri l e el derl y a re s i gni fi ca ntl y more l i kel y to ha ve a s eri ous ba cteri a l i l l nes s tha n a re
febri l e younger a dul ts . As i n younger a dul ts , the ca us e i s commonl y a res pi ra tory i nfecti on or UTI, but i n the el derl y, s ki n a nd s oft-ti s s ue i nfecti ons
a re a mong the top ca us es .
Foca l fi ndi ngs a re eva l ua ted a s for younger pa ti ents . But unl i ke younger pa ti ents , el derl y pa ti ents proba bl y requi re uri na l ys i s , uri ne cul ture, a nd
ches t x-ra y. Bl ood cul tures s houl d be done to excl ude s epti cemi a ; i f s epti cemi a i s s us pected or vi ta l s i gns a re a bnorma l , pa ti ents s houl d be
a dmi tted to the hos pi ta l .
Key Points
Mos t fevers i n hea l thy peopl e a re due to vi ra l res pi ra tory tra ct or GI i nfecti ons .
Loca l i zi ng s ymptoms gui de eva l ua ti on.
Underl yi ng chroni c di s orders , pa rti cul a rl y thos e i mpa i ri ng the i mmune s ys tem, mus t be cons i dered.
Fever of Unknown Origin
FUO i s body tempera ture 38.3 C recta l l y tha t does not res ul t from tra ns i ent a nd s el f-l i mi ted i l l nes s , ra pi dl y fa ta l i l l nes s , or di s orders wi th cl ea rcut l oca l i zi ng s ymptoms or s i gns or wi th a bnorma l i ti es on common tes ts s uch a s ches t x-ra y, uri na l ys i s , or bl ood cul tures .
FUO i s currentl y cl a s s i fi ed i nto 4 di s ti nct ca tegori es :
Classic FUO: Fever for 3 wk wi th no i denti fi ed ca us e a fter 3 da ys of hos pi ta l eva l ua ti on or 3 outpa ti ent vi s i ts
Nosocomial FUO: Fever i n hos pi ta l i zed pa ti ents recei vi ng a cute ca re a nd wi th no i nfecti on pres ent or i ncuba ti ng a t a dmi s s i on i f the di a gnos i s
rema i ns uncerta i n a fter 3 da ys of a ppropri a te eva l ua ti on, i ncl udi ng i ncuba ti on of mi crobi ol ogi c cul tures for 2 da ys
Neutropenic FUO: Fever i n pa ti ents who ha ve < 500 neutrophi l s /L or who a re expected to ha ve thi s l evel wi thi n 2 da ys i f the di a gnos i s rema i ns
uncerta i n a fter 3 da ys of a ppropri a te eva l ua ti on, i ncl udi ng i ncuba ti on of mi crobi ol ogi c cul tures for 2 da ys
HIV-associated FUO: Fever i n pa ti ents wi th confi rmed HIV i nfecti on for > 4 wk a s outpa ti ents or > 3 da ys a s i npa ti ents i f the di a gnos i s rema i ns
uncerta i n a fter 3 da ys of a ppropri a te eva l ua ti on, i ncl udi ng i ncuba ti on of mi crobi ol ogi c cul tures for 2 da ys
Etiology
Ca us es of FUO a re us ua l l y di vi ded i nto 4 ca tegori es (s ee
Ta bl e 129-2):
Infecti ous (25 to 50%)
Connecti ve ti s s ue di s orders (10 to 20%)
Neopl a s ti c (5 to 35%)
Mi s cel l a neous (15 to 25%)
Infecti ons a re the mos t common ca us e of FUO. In pa ti ents wi th HIV i nfecti on, opportuni s ti c i nfecti ons (eg, TB; i nfecti on by a typi ca l mycoba cteri a ,
di s s emi na ted fungi , or cytomega l ovi rus ) s houl d be s ought.
Common connecti ve ti s s ue di s orders i ncl ude SLE, RA, gi a nt cel l a rteri ti s , va s cul i ti s , a nd juveni l e RA of a dul ts .
The mos t common neopl a s ti c ca us es a re l ymphoma , l eukemi a , rena l cel l ca rci noma , hepa tocel l ul a r ca rci noma , a nd meta s ta ti c ca rci noma s .
However, the i nci dence of neopl a s ti c ca us es of FUO ha s been decrea s i ng, proba bl y beca us e ul tra s onogra phy a nd CT a re wi del y us ed duri ng i ni ti a l
eva l ua ti on.
[Table 129-2. Some Ca us es of FUO]
Importa nt mi s cel l a neous ca us es i ncl ude drug rea cti ons , deep venous thrombos i s , recurrent pul mona ry embol i , s a rcoi dos i s , i nfl a mma tory bowel
di s ea s e, a nd fa cti ti ous fever.
No ca us e of FUO i s i denti fi ed i n a bout 10% of a dul ts .
Evaluation
In puzzl i ng ca s es , s uch a s FUO, a s s umi ng tha t a l l i nforma ti on wa s ga thered or wa s ga thered a ccura tel y by previ ous cl i ni ci a ns i s us ua l l y a mi s ta ke.
Cl i ni ci a ns s houl d be a wa re of wha t pa ti ents previ ous l y reported (to res ol ve di s crepa nci es ) but s houl d not s i mpl y copy deta i l s of previ ous l y
recorded hi s tory (eg, fa mi l y hi s tory, s oci a l hi s tory). Ini ti a l errors of omi s s i on ha ve been perpetua ted through ma ny cl i ni ci a ns over ma ny da ys of
hos pi ta l i za ti on, ca us i ng much unneces s a ry tes ti ng. Even when i ni ti a l eva l ua ti on wa s thorough, pa ti ents often remember new deta i l s when
ques ti oni ng i s repea ted.
Convers el y, cl i ni ci a ns s houl d not i gnore previ ous tes t res ul ts a nd s houl d not repea t tes ts wi thout cons i deri ng how l i kel y res ul ts a re to be
di fferent (eg, beca us e the pa ti ent's condi ti on ha s cha nged, beca us e a di s order devel ops s l owl y).
History: Hi s tory a i ms to uncover foca l s ymptoms a nd fa cts (eg, tra vel , occupa ti on, fa mi l y hi s tory, expos ure to a ni ma l vectors , di eta ry hi s tory) tha t
s ugges t a ca us e.
History of present illness s houl d cover dura ti on a nd pa ttern (eg, i ntermi ttent, cons ta nt) of fever. Fever pa tterns us ua l l y ha ve l i ttl e or no s i gni fi ca nce
i n the di a gnos i s of FUO, a l though a fever tha t occurs every other da y (terti a n) or every 3rd da y (qua rta n) ma y s ugges t ma l a ri a i n pa ti ents wi th ri s k
fa ctors . Foca l pa i n often i ndi ca tes the l oca ti on (a l though not the ca us e) of the underl yi ng di s order. Cl i ni ci a ns s houl d a s k genera l l y, then
s peci fi ca l l y, a bout di s comfort i n ea ch body pa rt.
Review of systems s houl d i ncl ude nons peci fi c s ymptoms , s uch a s wei ght l os s , a norexi a , fa ti gue, ni ght s wea ts , a nd hea da ches . Al s o, s ymptoms of
connecti ve ti s s ue di s orders (eg, mya l gi a s , a rthra l gi a s , ra s hes ) a nd GI di s orders (eg, di a rrhea , s tea torrhea , a bdomi na l di s comfort) s houl d be
s ought.
Past medical history s houl d i ncl ude di s orders known to ca us e fever, s uch a s ca ncer, TB, connecti ve ti s s ue di s orders , a l cohol i c ci rrhos i s ,
i nfl a mma tory bowel di s ea s e, rheuma ti c fever, a nd hyperthyroi di s m. Cl i ni ci a ns s houl d note di s orders or fa ctors tha t predi s pos e to i nfecti on, s uch
a s i mmunocompromi s e (eg, due to di s orders s uch a s HIV i nfecti on, ca ncer, di a betes , or us e of i mmunos uppres s a nts ), s tructura l hea rt di s orders ,
uri na ry tra ct a bnorma l i ti es , opera ti ons , a nd i ns erti on of devi ces (eg, IV l i nes , pa cema kers , joi nt pros thes es ).
Drug hi s tory s houl d i ncl ude ques ti ons a bout s peci fi c drugs known to ca us e fever.
Soci a l hi s tory s houl d i ncl ude ques ti ons a bout ri s k fa ctors for i nfecti on s uch a s i njecti on drug us e, hi gh-ri s k s exua l pra cti ces (eg, unprotected s ex,
mul ti pl e pa rtners ), i nfected conta cts (eg, wi th TB), tra vel , a nd pos s i bl e expos ure to a ni ma l or i ns ect vectors . Ri s k fa ctors for ca ncer, i ncl udi ng
s moki ng, a l cohol us e, a nd occupa ti ona l expos ure to chemi ca l s , s houl d a l s o be i denti fi ed.
Fa mi l y hi s tory s houl d i ncl ude ques ti ons a bout i nheri ted ca us es of fever (eg, fa mi l i a l Medi terra nea n fever). Medi ca l records a re checked for
previ ous tes t res ul ts , pa rti cul a rl y thos e tha t effecti vel y rul e out certa i n di s orders .
Physical examination: The genera l a ppea ra nce, pa rti cul a rl y for ca chexi a , ja undi ce, a nd pa l l or, i s noted.
The s ki n i s thoroughl y i ns pected for foca l erythema (s ugges ti ng a s i te of i nfecti on) a nd ra s h (eg, ma l a r ra s h of SLE); i ns pecti on s houl d i ncl ude the
peri neum a nd feet, pa rti cul a rl y i n di a beti cs , who a re prone to i nfecti ons i n thes e a rea s . Cl i ni ci a ns s houl d a l s o check for cuta neous fi ndi ngs of
endoca rdi ti s , i ncl udi ng pa i nful erythema tous s ubcuta neous nodul es on the ti ps of di gi ts (Os l er's nodes ), nontender hemorrha gi c ma cul es on the
pa l ms or s ol es (Ja newa y l es i ons ), petechi a e, a nd s pl i nter hemorrha ges under the na i l s .
The enti re body (pa rti cul a rl y over the s pi ne, bones , joi nts , a bdomen, a nd thyroi d) i s pa l pa ted for a rea s of tendernes s , s wel l i ng, or orga nomega l y;
di gi ta l recta l exa mi na ti on a nd pel vi c exa mi na ti on a re i ncl uded. The teeth a re percus s ed for tendernes s (s ugges ti ng a pi ca l a bs ces s ). Duri ng
pa l pa ti on, a ny regi ona l or s ys temi c a denopa thy i s noted; eg, regi ona l a denopa thy i s cha ra cteri s ti c of ca t-s cra tch di s ea s e i n contra s t to the di ffus e
a denopa thy of l ymphoma .
The hea rt i s a us cul ta ted for murmurs (s ugges ti ng ba cteri a l endoca rdi ti s ) a nd rubs (s ugges ti ng peri ca rdi ti s due to a rheuma tol ogi c or i nfecti ous
di s order).
Someti mes key phys i ca l a bnorma l i ti es i n pa ti ents wi th FUO a re or s eem s o s ubtl e tha t repea ted phys i ca l exa mi na ti ons ma y be neces s a ry to
s ugges t ca us es (eg, by detecti ng new a denopa thy, hea rt murmurs , ra s h, or nodul a ri ty a nd wea k pul s a ti ons i n the tempora l a rtery).
Red flags: The fol l owi ng a re of pa rti cul a r concern:
Immunocompromi s e
Hea rt murmur
Pres ence of i ns erted devi ces (eg, IV l i nes , pa cema kers , joi nt pros thes es )
Recent tra vel to endemi c a rea s
Interpretation of findings: After a thorough hi s tory a nd phys i ca l exa mi na ti on, the fol l owi ng s cena ri os a re typi ca l :
Loca l i zi ng s ymptoms or s i gns tha t were not pres ent, not detected, or not ma na ged duri ng previ ous exa mi na ti ons a re di s covered. Thes e fi ndi ngs
a re i nterpreted a nd i nves ti ga ted a s i ndi ca ted (s ee Ta bl e 129-2).
More commonl y, eva l ua ti on detects onl y nons peci fi c fi ndi ngs tha t occur i n ma ny di fferent ca us es of FUO, but i t i denti fi es ri s k fa ctors tha t ca n
hel p gui de tes ti ng (eg, tra vel to a n endemi c a rea , expos ure to a ni ma l vectors ). Someti mes ri s k fa ctors a re l es s s peci fi c but ma y s ugges t a cl a s s
of i l l nes s ; eg, wei ght l os s wi thout a norexi a i s more cons i s tent wi th i nfecti on tha n ca ncer, whi ch us ua l l y ca us es a norexi a . Pos s i bl e ca us es
s houl d be i nves ti ga ted further.
In the mos t di ffi cul t s cena ri o, pa ti ents ha ve onl y nons peci fi c fi ndi ngs a nd no or mul ti pl e ri s k fa ctors , ma ki ng a l ogi ca l , s equenti a l a pproa ch to
tes ti ng es s enti a l . Ini ti a l tes ti ng i s us ed to na rrow the di a gnos ti c pos s i bi l i ti es a nd gui de s ubs equent tes ti ng.
Testing: Previ ous tes t res ul ts , pa rti cul a rl y for cul tures , a re revi ewed. Cul tures for s ome orga ni s ms ma y requi re a l ong ti me to become pos i ti ve.
As much a s pos s i bl e, cl i ni ca l i nforma ti on i s us ed to focus tes ti ng (s ee Ta bl e 129-2). For exa mpl e, hous ebound el derl y pa ti ents wi th hea da che
woul d not be tes ted for ti ck-borne i nfecti ons or ma l a ri a , but thos e di s orders s houl d be cons i dered i n younger tra vel ers who ha ve hi ked i n a n
endemi c a rea . El derl y pa ti ents requi re eva l ua ti on for gi a nt cel l a rteri ti s ; younger pa ti ents do not.
In a ddi ti on to s peci fi c tes ti ng, the fol l owi ng s houl d us ua l l y be done:
ESR
Seri a l bl ood cul tures (i dea l l y before a nti mi crobi a l thera py)
HIV a nti body tes t, RNA concentra ti on a s s a ys , a nd PCR a s s a y

Tubercul i n s ki n tes t
Even i f done ea rl i er, thes e tes ts ma y s ugges t a hel pful trend.
Uri na l ys i s , uri ne cul ture, a nd ches t x-ra y, us ua l l y a l rea dy done, a re repea ted onl y i f fi ndi ngs i ndi ca te tha t they s houl d be.
Any a va i l a bl e fl ui d or ma teri a l from a bnorma l a rea s i denti fi ed duri ng the eva l ua ti on i s cul tured (eg, for ba cteri a , mycoba cteri a , fungi , vi rus es , or
s peci fi c fa s ti di ous ba cteri a a s i ndi ca ted). Orga ni s m-s peci fi c tes ts , s uch a s PCR a nd s erol ogi c ti ters (a cute a nd conva l es cent), a re hel pful ma i nl y
when gui ded by cl i ni ca l s us pi ci on, not done i n a s hotgun a pproa ch.
Serol ogi c tes ts , s uch a s a nti nucl ea r a nti body (ANA) a nd rheuma toi d fa ctor, a re done to s creen for rheuma tol ogi c di s orders .
Imaging tests a re gui ded by s ymptoms a nd s i gns . Typi ca l l y, a rea s of di s comfort s houl d be i ma gedeg, i n pa ti ents wi th ba ck pa i n, MRI of the s pi ne
(to check for i nfecti on or tumor); i n pa ti ents wi th a bdomi na l pa i n, CT of the a bdomen. However, CT of the ches t, a bdomen, a nd pel vi s s houl d be
cons i dered to check for a denopa thy a nd occul t a bs ces s es even when pa ti ents do not ha ve l oca l i zi ng s ymptoms or s i gns . If bl ood cul tures a re
pos i ti ve or new hea rt murmurs or peri phera l s i gns s ugges t endoca rdi ti s , echoca rdi ogra phy i s done.
In genera l , CT i s us eful for del i nea ti ng a bnorma l i ti es l oca l i zed to the a bdomen or ches t. MRI i s more s ens i ti ve tha n CT for detecti ng mos t ca us es
of FUO i nvol vi ng the CNS a nd s houl d be done i f a CNS ca us e i s bei ng cons i dered. Venous dupl ex i ma gi ng ma y be us eful for i denti fyi ng ca s es of
deep venous thrombos i s . Ra di onucl i de s ca nni ng wi th i ndi um-111-l a bel ed gra nul ocytes ma y hel p l oca l i ze s ome i nfecti ous or i nfl a mma tory
proces s es . Thi s techni que ha s genera l l y fa l l en out of fa vor beca us e i t i s thought to contri bute very l i ttl e to di a gnos i s , but s ome reports s ugges t
tha t i t provi des a hi gher di a gnos ti c yi el d tha n CT. PET ma y a l s o be us eful i n detecti ng the focus of fever.
Biopsy ma y be requi red i f a n a bnorma l i ty i s s us pected i n ti s s ue tha t ca n be bi ops i ed (eg, l i ver, bone ma rrow, s ki n, pl eura , l ymph nodes , i ntes ti ne,
mus cl e). Bi ops y s peci mens s houl d be eva l ua ted by hi s topa thol ogi c exa mi na ti on a nd cul tured for ba cteri a , fungi , vi rus es , a nd mycoba cteri a or s ent
for mol ecul a r (PCR) di a gnos ti c tes ti ng. Mus cl e bi ops y or s ki n bi ops y of ra s hes ma y confi rm va s cul i ti s . Bi l a tera l tempora l a rtery bi ops y ma y confi rm
gi a nt cel l a rteri ti s i n el derl y pa ti ents wi th unexpl a i ned ESR el eva ti on.
Treatment
Trea tment focus es on the ca us a ti ve di s order. Anti pyreti cs s houl d be us ed judi ci ous l y, cons i deri ng the dura ti on of fever.
Ca us es of FUO i n the el derl y a re us ua l l y s i mi l a r to thos e i n the genera l popul a ti on, but connecti ve ti s s ue di s orders a re i denti fi ed more often. The
mos t common ca us es a re
Gi a nt cel l a rteri ti s
Leukemi a s
Lymphoma s
Abs ces s es
TB
Key Points
Cl a s s i c FUO i s body tempera ture 38.3 C recta l l y for 3 wk wi th no i denti fi ed ca us e a fter 3 da ys of hos pi ta l i nves ti ga ti on or 3 outpa ti ent vi s i ts .
Identi fi ed ca us es ca n be ca tegori zed a s i nfecti ous , rheuma tol ogi c, neopl a s ti c, or mi s cel l a neous .
Eva l ua ti on s houl d be ba s ed on s ynthes i s of hi s tory a nd phys i ca l exa mi na ti on, wi th pa rti cul a r cons i dera ti on of ri s k fa ctors a nd l i kel y ca us es
ba s ed on i ndi vi dua l ci rcums ta nces .
Abscesses
Abscesses are collections of pus in confined tissue spaces, usually caused by bacterial infection. Symptoms include local pain, tenderness, warmth, and swelling
(if abscesses are near the skin layer) or constitutional symptoms (if abscesses are deep). Imaging is often necessary for diagnosis of deep abscesses. Treatment is
surgical drainage and often antibiotics.
Etiology
Numerous orga ni s ms ca n ca us e a bs ces s es , but Staphylococcus aureus i s the mos t common. Orga ni s ms ma y enter the ti s s ue by
Di rect i mpl a nta ti on (eg, penetra ti ng tra uma wi th a conta mi na ted object)
Sprea d from a n es ta bl i s hed, conti guous i nfecti on
Di s s emi na ti on vi a l ympha ti c or hema togenous routes from a di s ta nt s i te
Mi gra ti on from a l oca ti on where there a re res i dent fl ora i nto a n a dja cent, norma l l y s teri l e a rea beca us e na tura l ba rri ers a re di s rupted (eg, by
perfora ti on of a n a bdomi na l vi s cus ca us i ng a n i ntra -a bdomi na l a bs ces s )
Abs ces s es ma y begi n i n a n a rea of cel l ul i ti s (s ee p. 694) or i n compromi s ed ti s s ue where l eukocytes a ccumul a te. Progres s i ve di s s ecti on by pus or
necros i s of s urroundi ng cel l s expa nds the a bs ces s . Hi ghl y va s cul a ri zed connecti ve ti s s ue ma y then s urround the necroti c ti s s ue, l eukocytes , a nd
debri s to wa l l off the a bs ces s a nd l i mi t further s prea d.
Predi s pos i ng fa ctors to a bs ces s forma ti on i ncl ude i mpa i red hos t defens e mecha ni s ms (eg, i mpa i red l eukocyte defens es ), the pres ence of forei gn
bodi es , obs tructi on to norma l dra i na ge (eg, i n the uri na ry, bi l i a ry, or res pi ra tory tra cts ), ti s s ue i s chemi a or necros i s , hema toma or exces s i ve fl ui d
a ccumul a ti on i n ti s s ue, a nd tra uma .
Symptoms and Signs
The s ymptoms a nd s i gns of cuta neous a nd s ubcuta neous a bs ces s es a re pa i n, hea t, s wel l i ng, tendernes s , a nd rednes s . If s uperfi ci a l a bs ces s es
a re rea dy to s ponta neous l y rupture, the s ki n over the center of the a bs ces s ma y thi n, s ometi mes a ppea ri ng whi te or yel l ow beca us e of the
underl yi ng pus (termed poi nti ng). Fever ma y occur, es peci a l l y wi th s urroundi ng cel l ul i ti s . For deep a bs ces s es , l oca l pa i n a nd tendernes s a nd
s ys temi c s ymptoms , es peci a l l y fever, a s wel l a s a norexi a , wei ght l os s , a nd fa ti gue a re typi ca l . The predomi na nt ma ni fes ta ti on of s ome a bs ces s es
i s a bnorma l orga n functi on (eg, hemi pl egi a due to a bra i n a bs ces s ).
Compl i ca ti ons of a bs ces s es i ncl ude ba cteremi c s prea d, rupture i nto a dja cent ti s s ue, bl eedi ng from ves s el s eroded by i nfl a mma ti on, i mpa i red
functi on of a vi ta l orga n, a nd i na ni ti on due to a norexi a a nd i ncrea s ed meta bol i c needs .
Diagnosis
Someti mes ul tra s onogra phy or CT
Di a gnos i s of cuta neous a nd s ubcuta neous a bs ces s es i s by phys i ca l exa mi na ti on. Di a gnos i s of deep a bs ces s es often requi res i ma gi ng.
Ul tra s onogra phy i s noni nva s i ve a nd detects ma ny s oft-ti s s ue a bs ces s es ; CT i s a ccura te for mos t, a l though MRI i s us ua l l y more s ens i ti ve.
Treatment
Surgi ca l dra i na ge
Superfi ci a l a bs ces s es ma y res ol ve wi th hea t a nd ora l a nti bi oti cs . However, hea l i ng us ua l l y requi res dra i na ge.
Mi nor cuta neous a bs ces s es ma y requi re onl y i nci s i on a nd dra i na ge. Al l pus , necroti c ti s s ue, a nd debri s s houl d be removed. El i mi na ti ng open
(dea d) s pa ce by pa cki ng wi th ga uze or by pl a ci ng dra i ns ma y be neces s a ry to prevent reforma ti on of the a bs ces s . Predi s pos i ng condi ti ons , s uch a s
obs tructi on of na tura l dra i na ge or the pres ence of a forei gn body, requi re correcti on.
Deep a bs ces s es ca n s ometi mes be a dequa tel y dra i ned by percuta neous needl e a s pi ra ti on (typi ca l l y gui ded by ul tra s onogra phy or CT); thi s
method often a voi ds the need for open s urgi ca l dra i na ge.
Sponta neous rupture a nd dra i na ge ma y occur, s ometi mes l ea di ng to the forma ti on of chroni c dra i ni ng s i nus es . Wi thout dra i na ge, a n a bs ces s
occa s i ona l l y res ol ves s l owl y a fter proteol yti c di ges ti on of the pus produces a thi n, s teri l e fl ui d tha t i s res orbed i nto the bl oods trea m. Incompl ete
res orpti on ma y l ea ve a cys ti c l ocul a ti on wi thi n a fi brous wa l l tha t ma y become ca l ci fi ed.
If the a bs ces s i s deep or i f there i s s urroundi ng cel l ul i ti s , s ys temi c a nti mi crobi a l drugs a re i ndi ca ted a s a djuncti ve thera py; they a re us ua l l y
i neffecti ve wi thout dra i na ge. Empi ri c a nti mi crobi a l thera py i s ba s ed on l oca ti on a nd l i kel y i nfecti ng pa thogen. Gra m s ta i n, cul ture, a nd
s us cepti bi l i ty res ul ts gui de further a nti mi crobi a l thera py.
Bacteremia
(See a l s o Neona ta l Seps i s on p. 2832 a nd Occul t Ba cteremi a on p. 2841.)
Bacteremia is the presence of bacteria in the bloodstream. It can occur spontaneously, during certain tissue infections, with use of indwelling GU or IV catheters,
or after dental, GI, GU, wound-care, or other procedures. Bacteremia may cause metastatic infections, including endocarditis, especially in patients with valvular
heart abnormalities. Transient bacteremia is often asymptomatic but may cause fever. Development of other symptoms usually suggests more serious infection,
such as sepsis or septic shock (see p. 2299).
Ba cteremi a ma y be tra ns i ent a nd ca us e no s equel a e, or i t ma y ha ve meta s ta ti c or s ys temi c cons equences . Sys temi c cons equences i ncl ude
s ys temi c i nfl a mma tory res pons e s yndrome a nd s epti c s hock.
Etiology
Ba cteremi a ha s ma ny pos s i bl e ca us es , i ncl udi ng
Ca theteri za ti on of a n i nfected l ower uri na ry tra ct
Surgi ca l trea tment of a n a bs ces s or i nfected wound
Col oni za ti on of i ndwel l i ng devi ces , es peci a l l y IV a nd i ntra ca rdi a c ca theters , urethra l ca theters , a nd os tomy devi ces a nd tubes
Gra m-nega ti ve ba cteremi a s econda ry to i nfecti on us ua l l y ori gi na tes i n the GU or GI tra ct or i n the s ki n of pa ti ents wi th decubi tus ul cers .
Chroni ca l l y i l l a nd i mmunocompromi s ed pa ti ents ha ve a n i ncrea s ed ri s k of gra m-nega ti ve ba cteremi a . They ma y a l s o devel op ba cteremi a wi th
gra m-pos i ti ve cocci , a na erobes , a nd fungi . Sta phyl ococca l ba cteremi a i s common a mong i njecti on drug us ers a nd pa ti ents wi th IV ca theters .
Bacteroides ba cteremi a ma y devel op i n pa ti ents wi th i nfecti ons of the a bdomen a nd the pel vi s , pa rti cul a rl y the fema l e geni ta l tra ct. If a n i nfecti on
i n the a bdomen ca us es ba cteremi a , the orga ni s m i s mos t l i kel y a gra m-nega ti ve ba ci l l us . If a n i nfecti on a bove the di a phra gm ca us es ba cteremi a ,
the orga ni s m i s mos t l i kel y gra m-pos i ti ve.
Pathophysiology
Tra ns i ent or s us ta i ned ba cteremi a ca n ca us e meta s ta ti c i nfecti on of the meni nges or s erous ca vi ti es , s uch a s the peri ca rdi um or l a rger joi nts .
Meta s ta ti c a bs ces s es ma y occur a l mos t a nywhere. Mul ti pl e a bs ces s forma ti on i s es peci a l l y common wi th s ta phyl ococca l ba cteremi a . Ba cteremi a
ma y ca us e endoca rdi ti s (s ee p.
2193), mos t commonl y wi th enterococca l , s treptococca l , or s ta phyl ococca l ba cteremi a a nd l es s commonl y wi th gra m-nega ti ve ba cteremi a or
fungemi a . Pa ti ents wi th s tructura l hea rt di s ea s e (eg, va l vul a r di s ea s e, certa i n congeni ta l a noma l i es ), pros theti c hea rt va l ves , or other
i ntra va s cul a r pros thes es a re predi s pos ed to endoca rdi ti s . Sta phyl ococci ca n ca us e ba cteri a l endoca rdi ti s , pa rti cul a rl y i n i njecti on drug us ers , a nd
ma y i nvol ve the tri cus pi d va l ve.
Symptoms and Signs
Some pa ti ents a re a s ymptoma ti c or ha ve onl y mi l d fever. Devel opment of s ymptoms s uch a s ta chypnea , s ha ki ng chi l l s , pers i s tent fever, a l tered
s ens ori um, hypotens i on, a nd GI s ymptoms (a bdomi na l pa i n, na us ea , vomi ti ng, di a rrhea ) s ugges ts s eps i s or s epti c s hock. Septi c s hock devel ops i n
25 to 40% of pa ti ents wi th s i gni fi ca nt ba cteremi a .
Diagnosis
If ba cteremi a , s eps i s , or s epti c s hock i s s us pected, cul tures a re obta i ned of bl ood a nd a ny other a ppropri a te s peci mens (s ee p. 1166).
Treatment
Anti bi oti cs
In pa ti ents wi th s us pected ba cteremi a , empi ri c a nti bi oti cs a re gi ven a fter a ppropri a te cul tures a re obta i ned. Ea rl y trea tment of ba cteremi a wi th
a n a ppropri a te a nti mi crobi a l regi men a ppea rs to i mprove s urvi va l . Conti nui ng thera py i nvol ves a djus ti ng a nti bi oti cs a ccordi ng to the res ul ts of
cul ture a nd s us cepti bi l i ty tes ti ng, s urgi ca l l y dra i ni ng a ny a bs ces s es , a nd us ua l l y removi ng a ny i nterna l devi ces tha t a re the s us pected s ource of
ba cteri a .
Biological Warfare and Terrorism
Bi ol ogi ca l wa rfa re i s the us e of mi crobi ol ogi ca l a gents for hos ti l e purpos es . Such us e i s contra ry to i nterna ti ona l l a w a nd ha s ra rel y ta ken pl a ce
duri ng forma l wa rfa re i n modern hi s tory, des pi te the extens i ve prepa ra ti ons a nd s tockpi l i ng of bi ol ogi ca l a gents ca rri ed out duri ng the 20th
century by mos t ma jor powers . For a va ri ety of rea s ons (i ncl udi ng uncerta i n mi l i ta ry effi ca cy a nd the threa t of ma s s i ve reta l i a ti on), experts
cons i der the us e of bi ol ogi ca l a gents i n forma l wa rfa re unl i kel y. The a rea of mos t concern i s the us e of s uch a gents by terrori s t groups . Bi ol ogi ca l
a gents a re thought by s ome peopl e to be a n i dea l wea pon for terrori s ts . Thes e a gents ma y be del i vered cl a ndes ti nel y, a nd they ha ve del a yed
effects , a l l owi ng the us er to rema i n undetected.
Potenti a l bi ol ogi ca l a gents i ncl ude a nthra x, botul i num toxi n, brucel l os i s , encepha l i ti s , vi rus es , hemorrha gi c fever vi rus es (Ebol a a nd Ma rburg),
pl a gue, tul a remi a , a nd s ma l l pox. Ea ch of thes e a gents i s potenti a l l y fa ta l a nd, except for a nthra x a nd botul i num toxi n, ca n be pa s s ed from pers on
to pers on. Anthra x i s of mos t concern; a nthra x s pores a re rel a ti vel y ea s y to prepa re a nd s prea d through the a i r, crea ti ng the potenti a l for
di s tri buti on by a i rpl a ne. Theoreti ca l l y, 1 kg of a nthra x coul d ki l l 10,000 peopl e, a l though techni ca l di ffi cul ti es wi th prepa ri ng the s pores i n a
s uffi ci entl y fi ne powder woul d proba bl y l i mi t a ctua l dea ths to a fra cti on of thi s number. Some other potenti a l a gents , i ncl udi ng Yersinia pestis,
Francisella tularensis, vi ra l hemorrha gi c fever vi rus es , s ma l l pox vi rus , a nd botul i num toxi n, ca n potenti a l l y be a eros ol i zed a s bi owea pons .
Des pi te thes e theoreti ca l concerns , the onl y s ucces s ful terrori s t us e of a nthra xmul ti pl e pi eces of conta mi na ted ma i l del i vered to a va ri ety of
l oca ti ons i n the US i n 2001res ul ted i n onl y a ha ndful of dea ths a nd s eri ous i nfecti ons (tota l of 22 ca s es ). A l a rger number of peopl e were
conta mi na ted wi th a nthra x s pores wi thout devel opi ng i l l nes s . However, there wa s extreme publ i c a nxi ety rel a ted to thes e i nci dents , whi ch ma y
ha ve been a ma jor goa l of the terror group res pons i bl e.
In a ddi ti on to the a ctua l i nfecti ons , a n even grea ter number of fa l s e threa ts of a nthra x ha ve been reported. In 1999, the FBI recei ved a n a vera ge of
1 fa l s e report/da y of a l l eged a nthra x us e. Fa l s e reports , both hoa xes a nd a l a rmed ci ti zens mi s percei vi ng ha rml es s ma teri a l for a nthra x, i ncrea s ed
even more a fter the 2001 a nthra x a tta ck i n the US.
The onl y other s ucces s ful us e of a bi ol ogi ca l a gent by a terror group i n the US occurred i n 1984. In thi s event, 751 peopl e were s tri cken wi th
di a rrhea when a s a l a d ba r i n Oregon wa s i ntenti ona l l y conta mi na ted wi th Salmonella. The ba cteri a were i ntroduced by a rel i gi ous cul t tryi ng to
i nfl uence the res ul ts of a l oca l el ecti on. No one di ed, a nd the el ecti on wa s not a ffected.
Defense against bioterrorism i nvol ves s evera l fa ctors :
Intel l i gence to di s rupt terrori s ts before they ca n us e the wea pons
Ea rl y detecti on
Ava i l a bi l i ty of protecti ve a nti bi oti cs
Prepa rednes s of publ i c hea l th i nfra s tructure to coordi na te ma na gement of a n i nfecti ous di s ea s e outbrea k
Va cci na ti on of s el ected popul a ti ons (eg, the mi l i ta ry)
Chapter 130. Laboratory Diagnosis of Infectious Disease

Introduction
La bora tory tes ts ma y i denti fy orga ni s ms di rectl y (eg, vi s ua l l y, us i ng a mi cros cope, growi ng the orga ni s m i n cul ture) or i ndi rectl y (eg, i denti fyi ng
a nti bodi es to the orga ni s m). Genera l types of tes ts i ncl ude mi cros copy, cul ture, i mmunol ogi c tes ts (a ggl uti na ti on tes ts s uch a s l a tex
a ggl uti na ti on, enzyme i mmunoa s s a ys , Wes tern bl ot, preci pi ta ti on tes ts , a nd compl ement fi xa ti on tes ts ), a nd nucl ei c a nd non-nucl ei c a ci d-ba s ed
i denti fi ca ti on methods . Cul ture i s norma l l y the gol d s ta nda rd for i denti fi ca ti on of orga ni s ms , but res ul ts ma y not be a va i l a bl e for da ys or weeks ,
a nd not a l l pa thogens ca n be cul tured, ma ki ng a l terna ti ve tes ts us eful . When a pa thogen i s cul tured a nd i denti fi ed, the l a bora tory ca n a l s o
a s s es s i ts s us cepti bi l i ty to a nti mi crobi a l drugs .
Some tes ts (eg, Gra m s ta i n, routi ne a erobi c cul ture) ca n detect a l a rge va ri ety of pa thogens a nd a re commonl y done for ma ny s us pected i nfecti ous
i l l nes s es . However, beca us e s ome pa thogens a re mi s s ed on thes e tes ts , cl i ni ci a ns mus t be a wa re of the l i mi ta ti ons of ea ch tes t for ea ch
s us pected pa thogen. In s uch ca s es , cl i ni ci a ns s houl d reques t tes ts s peci fi c for the s us pected pa thogen (eg, s peci a l s ta i ns or cul ture medi a ) or
a dvi s e the l a bora tory to s el ect more s peci fi c tes ts .
Microscopy
Mi cros copy ca n be done qui ckl y, but a ccura cy depends on the experi ence of the mi cros copi s t a nd qua l i ty of equi pment. Regul a ti ons often l i mi t
phys i ci a ns ' us e of mi cros copy for di a gnos ti c purpos es outs i de a certi fi ed l a bora tory.
Mos t s peci mens a re trea ted wi th s ta i ns tha t col or pa thogens , ca us i ng them to s ta nd out from the ba ckground, a l though wet mounts of uns ta i ned
s a mpl es ca n be us ed to detect fungi , pa ra s i tes (i ncl udi ng hel mi nth eggs a nd l a rva e), va gi na l cl ue cel l s , moti l e orga ni s ms (eg, Trichomonas), a nd
s yphi l i s (vi a da rkfi el d mi cros copy). Vi s i bi l i ty of fungi ca n be i ncrea s ed by a ppl yi ng 10% pota s s i um hydroxi de (KOH) to di s s ol ve s urroundi ng ti s s ues
a nd nonfunga l orga ni s ms .
The cl i ni ci a n orders a s ta i n ba s ed on the l i kel y pa thogens , but no s ta i n i s 100% s peci fi c. Mos t s a mpl es a re trea ted wi th Gra m s ta i n a nd, i f
mycoba cteri a a re s us pected, wi th a n a ci dfa s t s ta i n. However, s ome pa thogens a re not ea s i l y vi s i bl e us i ng thes e s ta i ns ; i f thes e pa thogens a re
s us pected, di fferent s ta i ns or other i denti fi ca ti on methods a re requi red. Beca us e mi cros copi c detecti on us ua l l y requi res a mi crobe concentra ti on
of a bout 1 105 /mL, mos t body fl ui d s peci mens (eg, CSF) a re concentra ted (eg, by centri fuga ti on) before exa mi na ti on.
Gram stain: The Gra m s ta i n cl a s s i fi es ba cteri a a ccordi ng to whether they reta i n crys ta l vi ol et s ta i n (gra m-pos i ti vebl ue) or not (gra m-nega ti ve
red) a nd hi ghl i ghts cel l morphol ogy (eg, ba ci l l i , cocci ) a nd cel l a rra ngement (eg, cl umps , cha i ns , di pl oi ds ). Such cha ra cteri s ti cs ca n di rect a nti bi oti c
thera py pendi ng defi ni ti ve i denti fi ca ti on. To do a Gra m s ta i n, techni ci a ns hea t-fi x s peci men ma teri a l to a s l i de a nd s ta i n i t by s equenti a l
expos ure to Gra m's crys ta l vi ol et, i odi ne, decol ori zer, a nd counters ta i n (typi ca l l y s a fra ni n).
Acid-fast and moderate (modified) acid-fast stains: Thes e s ta i ns a re us ed to i denti fy a ci d-fa s t orga ni s ms (Mycobacterium s p) a nd modera tel y a ci d-fa s t
orga ni s ms (pri ma ri l y Nocardia s p). Thes e s ta i ns a re a l s o us eful for s ta i ni ng Rhodococcus a nd rel a ted genera , a s wel l a s oocys ts of s ome pa ra s i tes
(eg, Cryptosporidium).
Al though detecti on of mycoba cteri a i n s putum requi res onl y a bout 5,000 to 10,000 orga ni s ms /mL, mycoba cteri a a re often pres ent i n l ower l evel s , s o
s ens i ti vi ty i s l i mi ted. Us ua l l y, s evera l mL of s putum a re deconta mi na ted wi th Na hydroxi de a nd concentra ted by centri fuga ti on for a ci d-fa s t
s ta i ni ng. Speci fi ci ty i s better, a l though s ome modera tel y a ci d-fa s t orga ni s ms a re di ffi cul t to di s ti ngui s h from mycoba cteri a .
Fluorescent stains: Thes e s ta i ns a l l ow detecti on a t l ower concentra ti ons (1 104 cel l s /mL). Exa mpl es a re a cri di ne ora nge (ba cteri a a nd fungi ),
a ura mi ne-rhoda mi ne a nd a ura mi ne O (mycoba cteri a ), a nd ca l cofl uor whi te (fungi , es peci a l l y derma tophytes ).
Coupl i ng a fl uores cent dye to a n a nti body di rected a t a pa thogen (di rect or i ndi rect i mmunofl uores cence) s houl d theoreti ca l l y i ncrea s e s ens i ti vi ty
a nd s peci fi ci ty. However, thes e tes ts a re di ffi cul t to rea d a nd i nterpret, a nd few (eg, Pneumocystis a nd Legionella di rect fl uores cent a nti body tes ts )
a re commerci a l l y a va i l a bl e a nd commonl y us ed.
India ink (colloidal carbon) stain: Thi s s ta i n i s us ed to detect ma i nl y Cryptococcus neoformans a nd other enca ps ul a ted fungi i n a cel l s us pens i on (eg,
CSF s edi ment). The ba ckground fi el d, ra ther tha n the orga ni s m i ts el f, i s s ta i ned, ma ki ng a ny ca ps ul e a round the orga ni s m vi s i bl e a s a ha l o. In CSF,
the tes t i s not a s s ens i ti ve a s cryptococca l a nti gen. Speci fi ci ty i s a l s o l i mi ted; l eukocytes ma y a ppea r enca ps ul a ted.
Wright's stain and Giemsa stain: Thes e s ta i ns a re us ed for detecti on of pa ra s i tes i n bl ood, Histoplasma capsulatum i n pha gocytes a nd ti s s ue cel l s ,
i ntra cel l ul a r i ncl us i ons formed by vi rus es a nd chl a mydi a , trophozoi tes of Pneumocystis jirovecii, a nd s ome i ntra cel l ul a r ba cteri a .
Trichrome stain (Gomori-Wheatley stain) and iron hematoxylin stain: Thes e s ta i ns a re us ed to detect i ntes ti na l protozoa .
The Gomori -Whea tl ey s ta i n i s us ed to detect mi cros pori di a . It ma y mi s s hel mi nth eggs a nd l a rva e a nd does not rel i a bl y i denti fy Cryptosporidium.
Fungi a nd huma n cel l s ta ke up the s ta i n.
The i ron hema toxyl i n s ta i n di fferenti a l l y s ta i ns cel l s , cel l i ncl us i ons , a nd nucl ei . Hel mi nth eggs ma y s ta i n too da rk to permi t i denti fi ca ti on.
Culture
Cul ture i s mi crobi a l growth on or i n a nutri ti ona l s ol i d or l i qui d medi um; i ncrea s ed numbers of orga ni s ms s i mpl i fy i denti fi ca ti on. Cul ture a l s o
fa ci l i ta tes tes ti ng of a nti mi crobi a l s us cepti bi l i ty.
Communi ca ti on wi th the l a bora tory i s es s enti a l . Al though mos t s peci mens a re pl a ced on genera l purpos e medi a (eg, bl ood or chocol a te a ga r),
s ome pa thogens requi re i ncl us i on of s peci fi c nutri ents a nd i nhi bi tors or other s peci a l condi ti ons (s ee
Ta bl e 130-1); i f one of thes e pa thogens i s s us pected or i f the pa ti ent ha s been ta ki ng a nti mi crobi a l s , the l a bora tory s houl d be a dvi s ed. The
s peci men's s ource i s reported s o tha t the l a bora tory ca n di fferenti a te pa thogens from s i te-s peci fi c norma l fl ora .
Speci men col l ecti on i s i mporta nt. The wrong type of s wa b ca n produce fa l s e-nega ti ve res ul ts . Wooden-s ha fted s wa bs a re toxi c to s ome vi rus es .
Cotton-ti pped s wa bs a re toxi c for s ome ba cteri a a nd chl a mydi a e. Bl ood cul tures requi re deconta mi na ti on a nd di s i nfecti on of the s ki n (eg,
povi done i odi ne s wa b, a l l owed to dry, removed wi th 70% a l cohol ). Mul ti pl e s a mpl es , ea ch from a di fferent s i te a re genera l l y us ed; they a re ta ken
nea rl y s i mul ta neous l y wi th fever s pi kes i f pos s i bl e. Norma l fl ora of s ki n a nd mucous membra nes tha t grows i n onl y a s i ngl e bl ood s a mpl e i s
us ua l l y i nterpreted a s conta mi na ti on. If a bl ood s peci men i s obta i ned from a centra l l i ne, a peri phera l bl ood s peci men s houl d a l s o be obta i ned
to hel p di fferenti a te s ys temi c ba cteremi a from ca theter i nfecti on. Cul tures from i nfected ca theters genera l l y turn pos i ti ve more qui ckl y a nd
conta i n more orga ni s ms tha n s i mul ta neous l y dra wn peri phera l bl ood cul tures . Some fungi , pa rti cul a rl y mol ds (eg, Aspergillus s p), us ua l l y ca nnot
be cul tured from bl ood.
[Table 130-1. Sel ecti ve Medi a for Is ol a ti on of Common Ba cteri a ]
The s peci men mus t be tra ns ported ra pi dl y, i n the correct medi um, a nd i n condi ti ons tha t l i mi t growth of a ny potenti a l l y conta mi na ti ng norma l
fl ora . For a ccura te qua nti fi ca ti on of the pa thogen, a ddi ti ona l pa thogen growth mus t be prevented; s peci mens s houl d be tra ns ported to the
l a bora tory i mmedi a tel y or, i f tra ns port i s del a yed, refri gera ted (i n mos t ca s es ).
Certa i n cul tures ha ve s peci a l cons i dera ti ons .
Anaerobic bacteria s houl d not be cul tured from s i tes where they a re norma l fl ora beca us e di fferenti a ti on of pa thogens from norma l fl ora ma y be
i mpos s i bl e. Speci mens mus t be s hi el ded from a i r, whi ch ca n be di ffi cul t. For s wa b s peci mens , a na erobi c tra ns port medi a a re a va i l a bl e.
Speci mens col l ected wi th a s yri nge (eg, a bs ces s contents ) s houl d be tra ns ported i n the s yri nge.
Mycobacteria a re di ffi cul t to cul ture. Speci mens conta i ni ng norma l fl ora (eg, s putum) mus t fi rs t be deconta mi na ted a nd concentra ted.
Mycobacterium tuberculosis a nd s ome other mycoba cteri a grow s l owl y. Growth of M. tuberculosis i s typi ca l l y fa s ter i n l i qui d tha n i n s ol i d medi a ;
routi ne us e of a utoma ted s ys tems wi th l i qui d medi a ca n res ul t i n growth wi thi n 2 wk vs 4 wk on s ol i d medi a s uch a s Lowens tei n-Jens en a ga r. In
a ddi ti on, few orga ni s ms ma y be pres ent i n a s peci men. Mul ti pl e s peci mens from the s a me s i te ma y hel p ma xi mi ze yi el d. Speci mens s houl d be
a l l owed to grow for 8 wk before bei ng di s ca rded. If a n a typi ca l mycoba cteri um i s s us pected, the l a bora tory s houl d be noti fi ed.
Viruses a re genera l l y cul tured from s wa bs a nd ti s s ue s peci mens us ua l l y tra ns ported i n medi a tha t conta i n a nti ba cteri a l a nd a nti funga l a gents .
Speci mens a re i nocul a ted onto ti s s ue cul tures tha t s upport the s us pected vi rus a nd i nhi bi t a l l other mi crobes . Vi rus es tha t a re hi ghl y l a bi l e (eg,
va ri cel l a zos ter) s houl d be i nocul a ted onto ti s s ue cul tures wi thi n 1 h of col l ecti on. Sta nda rd ti s s ue cul tures a re mos t s ens i ti ve. Ra pi d ti s s ue
cul tures (s hel l vi a l s ) ma y provi de more ra pi d res ul ts . Some common vi rus es ca nnot be detected us i ng routi ne cul ture methods a nd requi re
a l terna ti ve methods for di a gnos i s (eg, enzyme i mmunoa s s a y for Eps tei n-Ba rr vi rus , hepa ti ti s B a nd E vi rus es , HIV, a nd huma n T-l ymphotropi c vi rus ;
s erol ogi c tes ts for hepa ti ti s A a nd D vi rus es ; nucl ei c a ci d-ba s ed methods for HIV).
Fungi s peci mens obta i ned from nons teri l e s i tes mus t be i nocul a ted onto medi a conta i ni ng a nti ba cteri a l a gents . Speci mens s houl d be a l l owed to
grow for 4 wk before bei ng di s ca rded.
Susceptibility Testing
Sus cepti bi l i ty tes ts determi ne a mi crobe's vul nera bi l i ty to a nti mi crobi a l drugs by expos i ng a s ta nda rdi zed concentra ti on of orga ni s m to s peci fi c
concentra ti ons of a nti mi crobi a l drugs . Sus cepti bi l i ty tes ti ng ca n be done for ba cteri a , fungi , a nd vi rus es . For s ome orga ni s ms , res ul ts obta i ned
wi th one drug predi ct res ul ts wi th s i mi l a r drugs . Thus , not a l l potenti a l l y us eful drugs a re tes ted.
Sus cepti bi l i ty tes ti ng occurs i n vi tro a nd ma y not a ccount for ma ny i n vi vo fa ctors (eg, pha rma codyna mi cs a nd pha rma coki neti cs , s i te-s peci fi c drug
concentra ti ons , hos t i mmune s ta tus , s i te-s peci fi c hos t defens es ) tha t i nfl uence trea tment s ucces s . Thus , s us cepti bi l i ty tes t res ul ts do not a l wa ys
predi ct trea tment outcome.
Sus cepti bi l i ty tes ti ng ca n be done qua l i ta ti vel y, s emi qua nti ta ti vel y, or us i ng nucl ei c a ci d-ba s ed methods . Tes ti ng ca n a l s o determi ne the effect of
combi ni ng di fferent a nti mi crobi a l s (s ynergy tes ti ng).
Qualitative methods: Qua l i ta ti ve methods a re l es s preci s e tha n s emi qua nti ta ti ve. Res ul ts a re us ua l l y reported a s s us cepti bl e (S), i ntermedi a te (I),
or res i s ta nt (R). The commonl y us ed di s k di ffus i on method (a l s o known a s the Ki rby-Ba uer tes t) i s a ppropri a te for ra pi dl y growi ng orga ni s ms . It
pl a ces a nti bi oti c-i mpregna ted di s ks on a ga r pl a tes i nocul a ted wi th the tes t orga ni s m. After i ncuba ti on (typi ca l l y 16 to 18 h), the di a meter of the
zone of i nhi bi ti on a round ea ch di s k i s mea s ured. Ea ch orga ni s m-a nti bi oti c combi na ti on ha s di fferent di a meters s i gni fyi ng S, I, or R.
Other methods tha t requi re l es s ri gi d a dherence to tes t pa ra meters ca n be us ed to ra pi dl y s creen for res i s ta nce of a s i ngl e orga ni s m to a s i ngl e
drug or drug cl a s s or to s peci fi c a nti mi crobi a l combi na ti ons (eg, oxa ci l l i n res i s ta nce of methi ci l l i n-res i s ta nt Staphylococcus aureus, -l a cta ma s e
producti on).
Semiquantitative methods: Semi qua nti ta ti ve methods determi ne the mi ni ma l concentra ti on of a drug tha t i nhi bi ts growth of a pa rti cul a r orga ni s m i n
vi tro. Thi s mi ni mum i nhi bi tory concentra ti on (MIC) i s reported a s a numeri ca l va l ue tha t ma y then be tra ns l a ted to 1 of 3 groupi ngs : S (s ens i ti ve), I
(i ntermedi a te), or R (res i s ta nt). MIC determi na ti on i s us ed pri ma ri l y for ba cteri a , i ncl udi ng mycoba cteri a a nd a na erobes , a nd i s s ometi mes us ed
for fungi , es peci a l l y Candida s p, obta i ned from s teri l e s i tes . Mi ni ma l ki l l i ng (ba cteri ci da l ) concentra ti on (MBC) ca n a l s o be determi ned but i s
techni ca l l y di ffi cul t, a nd s ta nda rds for i nterpreta ti on ha ve not been a greed on. The va l ue of MBC tes ti ng i s tha t i t i ndi ca tes whether a drug ma y be
ba cteri os ta ti c or ba cteri ci da l .
The a nti bi oti c ca n be di l uted i n a ga r or broth, whi ch i s then i nocul a ted wi th the orga ni s m. Broth di l uti on i s the gol d s ta nda rd but i s l a bor
i ntens i ve beca us e onl y one drug concentra ti on ca n be tes ted per tube. A more effi ci ent method us es a s tri p of pol yes ter fi l m i mpregna ted wi th
a nti bi oti c i n a concentra ti on gra di ent a l ong i ts l ength. The s tri p i s l a i d on a n a ga r pl a te conta i ni ng the i nocul um, a nd the MIC determi ned by the
l oca ti on on the s tri p where i nhi bi ti on begi ns ; mul ti pl e a nti bi oti cs ca n be tes ted on one pl a te.
The MIC a l l ows correl a ti on between drug s us cepti bi l i ty of the orga ni s m a nd the a chi eva bl e ti s s ue concentra ti on of drug not bound to protei n (free
drug). If the ti s s ue concentra ti on of free drug i s hi gher tha n the MIC, s ucces s ful trea tment i s l i kel y. Si mi l a rl y, reports of S, I, a nd R a re correl a ted
wi th MIC but genera l l y a re not ti s s ue concentra ti on-s peci fi c. Tha t i s , they a re us ua l l y ba s ed on a chi eva bl e s erum or pl a s ma concentra ti on of free
drug.
Nucleic acid-based methods: Thes e tes ts i ncorpora te nucl ei c a ci d techni ques s i mi l a r to thos e us ed for orga ni s m i denti fi ca ti on (s ee p. 1170) but
modi fi ed to detect known res i s ta nce genes or muta ti ons . An exa mpl e i s mecA, a gene for oxa ci l l i n res i s ta nce i n S. aureus; i f thi s gene i s pres ent,
the orga ni s m i s cons i dered res i s ta nt to a l l -l a cta m drugs rega rdl es s of a ppa rent s us cepti bi l i ty res ul ts . However, a l though a number of s uch
genes a re known, thei r pres ence does not uni forml y confer i n vi vo res i s ta nce. Al s o, beca us e new muta ti ons or other res i s ta nce genes ma y be
pres ent, thei r a bs ence does not gua ra ntee drug s ens i ti vi ty. For thes e rea s ons a nd beca us e the tes ts a re l i mi ted i n number, expens i ve, a nd not
wi del y a va i l a bl e, nucl ei c a ci d methods ha ve not repl a ced s ta nda rd cul ture a nd routi ne s us cepti bi l i ty tes ti ng.
Immunologic Tests
Immunol ogi c tes ts us e a n a nti gen to detect a nti bodi es to a pa thogen or us e a n a nti body to detect a n a nti gen of the pa thogen i n the pa ti ent's
s peci men. Ha ndl i ng va ri es , but i f tes ti ng i s to be del a yed, the s peci men s houl d typi ca l l y be refri gera ted or frozen to prevent overgrowth of
ba cteri a l conta mi na nts .
Agglutination tests: In a ggl uti na ti on tes ts (eg, l a tex a ggl uti na ti on, coa ggrega ti on), a pa rti cl e (l a tex bea d or ba cteri um) i s coupl ed to a rea gent
a nti gen or a nti body. The res ul ti ng pa rti cl e compl ex i s mi xed wi th the s peci men (eg, CSF, s erum); i f the ta rget a nti body or a nti gen i s pres ent i n the
s peci men, i t cros s -l i nks the pa rti cl es , produci ng mea s ura bl e a ggl uti na ti on.
If res ul ts a re pos i ti ve, the body fl ui d i s s eri a l l y di l uted a nd tes ted. Aggl uti na ti on wi th more di l ute s ol uti ons i ndi ca tes hi gher concentra ti ons of
the ta rget a nti gen or a nti body. The ti ter i s correctl y reported a s the reci proca l of the mos t di l ute s ol uti on yi el di ng a ggl uti na ti on; eg, 32 i ndi ca tes
tha t a ggl uti na ti on occurred i n a s ol uti on di l uted to 1/32 of the s ta rti ng concentra ti on.
Us ua l l y, a ggl uti na ti on tes ts a re ra pi d but l es s s ens i ti ve tha n ma ny other methods . They ca n a l s o determi ne s erotypes of s ome ba cteri a .
Complement fixation: Thi s tes t mea s ures compl ement-cons umi ng (compl ement-fi xi ng) a nti body i n s erum or CSF. The tes t i s us ed for di a gnos i s of
s ome vi ra l a nd funga l i nfecti ons , pa rti cul a rl y cocci di oi domycos i s . The s peci men i s i ncuba ted wi th known qua nti ti es of compl ement a nd the
a nti gen tha t i s the ta rget of the a nti body bei ng mea s ured. The degree of compl ement fi xa ti on i ndi ca tes the rel a ti ve qua nti ty of the a nti body i n the
s peci men. The tes t ca n mea s ure IgM a nd IgG a nti body ti ters or ca n be modi fi ed to detect certa i n a nti gens . It i s a ccura te but ha s l i mi ted
a ppl i ca ti ons , i s l a bor i ntens i ve, a nd requi res numerous control s .
Enzyme immunoassays: Thes e tes ts us e a nti bodi es l i nked to enzymes to detect a nti gens a nd to detect a nd qua nti fy a nti bodi es . The enzyme
i mmunoa s s a y (EIA) a nd enzyme-l i nked i mmunos orbent a s s a y (ELISA) a re exa mpl es . Beca us e s ens i ti vi ti es of mos t enzyme i mmunoa s s a ys a re hi gh,
they a re us ua l l y us ed for s creeni ng. Ti ters ca n be determi ned by s eri a l l y di l uti ng the s peci men a s for a ggl uti na ti on tes ts .
Tes t s ens i ti vi ti es , a l though us ua l l y hi gh, ca n va ry, s ometi mes a ccordi ng to pa ti ent a ge, mi crobi a l s erotype, s peci men type, or s ta ge of cl i ni ca l
di s ea s e.
Precipitation tests: Thes e tes ts mea s ure a n a nti gen or a nti body i n body fl ui ds by the degree of vi s i bl e preci pi ta ti on of a nti gen-a nti body compl exes
wi thi n a gel (a ga ros e) or i n s ol uti on. There a re ma ny types of preci pi ta ti on tes ts (eg, Ouchterl ony doubl e di ffus i on, counter
i mmunoel ectrophores i s ), but thei r a ppl i ca ti ons a re l i mi ted. Us ua l l y, a bl ood s peci men i s mi xed wi th tes t a nti gen to detect pa ti ent a nti bodi es ,
mos t often i n s us pected funga l i nfecti on or pyogeni c meni ngi ti s . Beca us e a pos i ti ve res ul t requi res a l a rge a mount of a nti body or a nti gen,
s ens i ti vi ty i s l ow.
Western blot test: Thi s tes t detects a nti mi crobi a l a nti bodi es i n the pa ti ent's s a mpl e (eg, s erum, other body fl ui d) by thei r rea cti on wi th ta rget
a nti gens (eg, vi ra l components ) tha t ha ve been i mmobi l i zed onto a membra ne by bl otti ng.
The Wes tern bl ot typi ca l l y ha s good s ens i ti vi ty, a l though often l es s tha n tha t of s creeni ng tes ts s uch a s ELISA, but genera l l y i s hi ghl y s peci fi c.
Thus , i t i s us ua l l y us ed to confi rm a pos i ti ve res ul t obta i ned wi th a s creeni ng tes t.
Techni ca l modi fi ca ti ons of the Wes tern bl ot a re the l i ne i mmunoa s s a y (LIA); the recombi na nt i mmunobl ot a s s a y (RIBA), whi ch us es s yntheti c or
recombi na nt-produced a nti gens ; a nd i mmunochroma togra phi c a s s a ys , whi ch ca n ra pi dl y s creen s peci mens for s peci fi c mi crobi a l a nti gens or
pa ti ent a nti bodi es .
Non-Nucleic Acid-Based Identification Methods
Once a n orga ni s m ha s been i s ol a ted by cul ture, i t mus t be i denti fi ed. Non-nucl ei c a ci d-ba s ed i denti fi ca ti on methods us e phenotypi c (functi ona l
or morphol ogi c) cha ra cteri s ti cs of orga ni s ms ra ther tha n geneti c i denti fi ca ti on.
Cha ra cteri s ti cs of a n orga ni s m's growth on cul ture medi a , s uch a s col ony s i ze, col or, a nd s ha pe, provi de cl ues to s peci es i denti fi ca ti on a nd,
combi ned wi th Gra m s ta i n, di rect further tes ti ng. Numerous bi ochemi ca l tes ts a re a va i l a bl e; ea ch i s res tri cted to orga ni s ms of a certa i n type (eg,
a erobi c or a na erobi c ba cteri a ). Some a s s es s a n orga ni s m's a bi l i ty to us e di fferent s ubs tra tes for growth. Others a s s es s pres ence or a cti vi ty of key
enzymes (eg, coa gul a s e, ca ta l a s e). Tes ts a re done s equenti a l l y, wi th previ ous res ul ts determi ni ng the next tes t to be us ed. The s equences of tes ts
a re myri a d a nd di ffer s omewha t a mong l a bora tori es .
Non-nucl ei c a ci d-ba s ed i denti fi ca ti on tes ts ma y i nvol ve ma nua l methods , a utoma ted s ys tems , or chroma togra phi c methods . Some commerci a l l y
a va i l a bl e ki ts conta i n a ba ttery of i ndi vi dua l tes ts tha t ma y be done s i mul ta neous l y us i ng a s i ngl e s peci men a nd ma y be us eful for a wi der ra nge
of orga ni s ms . Mul ti pl e tes t s ys tems ca n be hi ghl y a ccura te but ma y requi re s evera l da ys to yi el d res ul ts .
Chromatographic methods: Mi crobi a l components or products a re s epa ra ted a nd i denti fi ed us i ng hi gh-performa nce l i qui d chroma togra phy (HPLC) or
ga s chroma togra phy. Us ua l l y, i denti fi ca ti on i s by compa ri s on of a n orga ni s m's fa tty a ci ds to a da ta ba s e. Chroma togra phi c methods ca n be us ed to
i denti fy a erobi c a nd a na erobi c ba cteri a , mycoba cteri a , a nd fungi . Tes t a ccura cy depends on the condi ti ons us ed to cul ture the s peci men a nd the
qua l i ty of the da ta ba s e, whi ch ma y be i na ccura te or i ncompl ete.
Nucleic Acid-Based Identification Methods

Nucl ei c a ci d-ba s ed methods detect orga ni s m-s peci fi c DNA or RNA s equences extra cted from the mi croorga ni s m. Sequences ma y or ma y not be
a mpl i fi ed i n vi tro. Nucl ei c a ci d-ba s ed methods a re genera l l y s peci fi c a nd hi ghl y s ens i ti ve a nd ca n be us ed for a l l ca tegori es of mi crobes . Res ul ts
ca n be provi ded ra pi dl y. Beca us e ea ch tes t typi ca l l y i s s peci fi c to a s i ngl e orga ni s m, the cl i ni ci a n mus t know the di a gnos ti c pos s i bi l i ti es a nd
reques t tes ts a ccordi ngl y. For exa mpl e, i f a pa ti ent ha s s ymptoms s ugges ti ng i nfl uenza but the i nfl uenza s ea s on i s over, doi ng a more genera l
vi ra l di a gnos ti c tes t (eg, vi ra l cul ture) ra ther tha n a s peci fi c fl u tes t i s better beca us e a nother vi rus (eg, pa ra i nfl uenza , a denovi rus ) ma y be the
ca us e.
Nucl ei c a ci d-ba s ed tes ts a re qua l i ta ti ve, but qua nti fi ca ti on methods exi s t for a l i mi ted but i ncrea s i ng number of i nfecti ons (eg, HIV,
cytomega l ovi rus , huma n T-cel l l ymphotropi c vi rus ); thes e methods ca n be us eful for di a gnos i s a nd for moni tori ng res pons e to trea tment.
Techni ques tha t do not i nvol ve nucl ei c a ci d a mpl i fi ca ti on a re us ed i f the orga ni s m ha s been fi rs t cul tured or i s pres ent i n hi gh concentra ti on i n
the s peci men (eg, i n pha ryngi ti s ca us ed by group A Streptococcus, i n geni ta l i nfecti ons ca us ed by Chlamydia trachomatis or Neisseria gonorrhoeae).
Amplification: Nucl ei c a ci d a mpl i fi ca ti on techni ques ta ke ti ny a mounts of DNA or RNA, repl i ca te them ma ny ti mes , a nd thus ca n detect mi nute
tra ces of a n orga ni s m i n a s peci men, a voi di ng the need for cul ture. Thes e techni ques a re pa rti cul a rl y us eful for orga ni s ms tha t a re di ffi cul t to
cul ture or i denti fy us i ng other methods (eg, vi rus es , obl i ga te i ntra cel l ul a r pa thogens , fungi , mycoba cteri a , s ome other ba cteri a ) or tha t a re pres ent
i n l ow numbers .
Thes e tes ts ma y i nvol ve ta rget a mpl i fi ca ti on (eg, PCR, revers e tra ns cri pta s e-PCR [RT-PCR], s tra nd di s pl a cement a mpl i fi ca ti on, tra ns cri pti on
a mpl i fi ca ti on), s i gna l a mpl i fi ca ti on (eg, bra nched DNA a s s a ys , hybri d ca pture), probe a mpl i fi ca ti on (eg, l i ga s e cha i n rea cti on, cl ea va s e-i nva der,
cycl i ng probes ), or pos ta mpl i fi ca ti on a na l ys i s (eg, s equenci ng of the a mpl i fi ed product, mi croa rra y a na l ys i s , a nd mel ti ng curve a na l ys i s , a s i s done
i n rea l -ti me PCR).
Appropri a te s peci men col l ecti on a nd s tora ge before a rri va l a t the mol ecul a r di a gnos ti c l a bora tory a re cri ti ca l . Beca us e a mpl i fi ca ti on methods a re
s o s ens i ti ve, fa l s e pos i ti ves from tra ce conta mi na ti on of the s peci men or equi pment ca n ea s i l y occur. Des pi te hi gh s ens i ti vi ty, fa l s e nega ti ves
s ometi mes occur even when a pa ti ent i s s ymptoma ti c (eg, i n Wes t Ni l e vi rus i nfecti on). Fa l s e-nega ti ve res ul ts ca n be mi ni mi zed by
Avoi di ng us e of s wa bs wi th wooden s ha fts or cotton ti ps
Tra ns porti ng s peci mens ra pi dl y
Freezi ng or refri gera ti ng s peci mens i f tra ns port i s l i kel y to ta ke > 2 h
Freezi ng i s the typi ca l s tora ge method for nucl ei c a ci d a mpl i fi ca ti on a s s a ys . However, s peci mens s houl d be refri gera ted ra ther tha n frozen i f
l a bi l e vi rus es (eg, va ri cel l a -zos ter vi rus , i nfl uenza vi rus , HIV-2) a re s us pected or i f vi ra l cul tures a re a l s o to be done (frozen s peci mens ma y not be
us a bl e for s ta nda rd cul tures ).
Chapter 131. Immunization

Introduction
Immuni ty ca n be a chi eved a cti vel y by us i ng a nti gens (eg, va cci nes , toxoi ds ) or pa s s i vel y by us i ng a nti bodi es (eg, i mmune gl obul i ns , a nti toxi ns ). A
toxoi d i s a ba cteri a l toxi n tha t ha s been modi fi ed to be nontoxi c but tha t ca n s ti l l s ti mul a te a nti body forma ti on. A va cci ne i s a s us pens i on of
whol e (l i ve or i na cti va ted) or fra cti ona ted ba cteri a or vi rus es rendered nonpa thogeni c. For va cci nes a va i l a bl e i n the US, s ee
Ta bl e 131-1. The mos t current recommenda ti ons for i mmuni za ti on a re a va i l a bl e a t the Centers for Di s ea s e Control a nd Preventi on (CDC) web s i te.
Va cci nes s houl d be gi ven exa ctl y a s recommended on the pa cka ge i ns ert; however, the i nterva l between a s eri es of dos es ma y be l engthened
wi thout l os i ng effi ca cy. Injecti on va cci nes a re us ua l l y gi ven IM i nto the mi d-l a tera l thi gh (i n i nfa nts a nd toddl ers ) or i nto the del toi d mus cl e (i n
s chool -a ged chi l dren a nd a dul ts ). Pa rents s houl d keep a wri tten hi s tory of ea ch chi l d's va cci na ti ons .
[Table 131-1. Va cci nes Ava i l a bl e i n the US]
Risks, Restrictions, and High-Risk Groups
Li ve-mi crobi a l va cci nes s houl d not be gi ven s i mul ta neous l y wi th bl ood, pl a s ma , or i mmune gl obul i n, whi ch ca n i nterfere wi th devel opment of
des i red a nti bodi es ; i dea l l y, s uch va cci nes s houl d be gi ven 2 wk before or 6 to 12 wk a fter the i mmune gl obul i ns .
Immunocompromi s ed pa ti ents s houl d not recei ve l i ve-vi rus va cci nes , whi ch coul d provoke s evere or fa ta l i nfecti ons . In pa ti ents recei vi ng s hortterm (i e, < 14 da ys ) i mmunos uppres s i ve thera py (eg, corti cos teroi ds , a nti meta bol i tes , a l kyl a ti ng compounds , ra di a ti on), l i ve-vi rus va cci nes s houl d
be wi thhel d unti l a fter trea tment. Pa ti ents recei vi ng l onger-term i mmunos uppres s i ve thera py ma y recei ve i na cti va ted va cci nes s uch a s DTa P; 3
mo a fter i mmunos uppres s i ve thera py i s s topped, they s houl d be gi ven a n a ddi ti ona l dos e of i na cti va ted va cci ne a nd ma y recei ve l i ve-vi rus
va cci nes .
As pl eni c pa ti ents a re predi s pos ed to overwhel mi ng ba cteremi c i nfecti on, us ua l l y due to Streptococcus pneumoniae, Neisseria meningitidis, or
Haemophilus influenzae type b (Hi b). They s houl d be gi ven the fol l owi ng:
Hi b conjuga te va cci ne (HbCV)
Meni ngococca l pol ys a ccha ri de va cci ne
Annua l i nfl uenza va cci ne
Pneumococca l conjuga te (i f a ge < 5 yr) or pol ys a ccha ri de (i f a ge > 5 yr) va cci ne
Before s ol i d orga n tra ns pl a nta ti on, pa ti ents s houl d recei ve a l l a ppropri a te va cci nes . Pa ti ents who ha ve ha d hema topoi eti c cel l tra ns pl a nta ti on
s houl d be cons i dered uni mmuni zed a nd s houl d recei ve repea t dos es of a l l a ppropri a te va cci nes .
Pa ti ents wi th AIDS s houl d genera l l y recei ve i na cti va ted va cci nes (eg, DTP, pol i o [IPV], HbCV) a ccordi ng to routi ne recommenda ti ons but s houl d
us ua l l y not recei ve l i ve-vi rus or ba cteri a l va cci nes (eg, mea s l es -mumps -rubel l a , OPV, BCG). However, they ca n recei ve mea s l es -mumps -rubel l a i f
i mmunos uppres s i on i s not s evere beca us e na tura l l y occurri ng mea s l es ca n ca us e s evere, often fa ta l i nfecti on i n AIDS pa ti ents , a nd mea s l es mumps -rubel l a va cci ne ra rel y ca us es s eri ous compl i ca ti ons .
Ri s ks of va cci nes s houl d be di s cus s ed wi th pa ti ents . Pa rents s houl d gi ve wri tten cons ent for va cci na ti on of thei r chi l dren. In the US, s el ected
events tha t occur a fter routi ne va cci na ti on mus t be reported to the ma nufa cturer, the US Depa rtment of Hea l th a nd Huma n Servi ces , a nd the
Centers for Di s ea s e Control a nd Preventi on's Va cci ne Advers e Event Reporti ng Sys tem (VAERS). Forms a nd i ns tructi ons ca n be obta i ned by ca l l i ng
800-822-7967 (Hea l th a nd Huma n Servi ces ) or from the VAERS web s i te (http://va ers .hhs .gov).
A tempera ture of > 39 C requi res del a yi ng va cci na ti on, but mi nor i nfecti ons , s uch a s the common col d (even wi th l ow-gra de fever), do not. Some
va cci nes produced i n cel l cul ture s ys tems conta i n tra ce a mounts of egg a nti gens . Al though egg a l l ergi es a re often cons i dered contra i ndi ca ti ons to
thes e va cci nes , the va cci nes do not a ppea r to ca us e s i gni fi ca nt a dvers e rea cti ons i n pa ti ents who ca n ea t foods tha t conta i n eggs , s uch a s brea d
or cooki es . A hi s tory of other a l l ergi c rea cti ons ma y contra i ndi ca te us e of certa i n va cci nes (s ee
Ta bl e 131-2).
Pregna ncy i s a rel a ti ve contra i ndi ca ti on to va cci na ti on wi th huma n pa pi l l oma vi rus (HPV), mea s l es -mumps -rubel l a , pneumococca l pneumoni a ,
va ri cel l a , a nd other l i ve-vi rus va cci nes .
Concern ha s been ra i s ed a bout the s a fety i n i nfa nts of thi meros a l , a n Hg-ba s ed pres erva ti ve pres ent i n s ome va cci nes , but there i s no evi dence of
ha rm. In pa rti cul a r, there i s no convi nci ng evi dence tha t va cci nes conta i ni ng thi meros a l a re rel a ted to the devel opment of a uti s m. Neverthel es s ,
mos t ma nufa cturers ha ve devel oped thi meros a l -free va cci nes for us e i n i nfa nts . Informa ti on a bout va cci nes tha t currentl y conta i n l ow l evel s of Hg
or thi meros a l i s a va i l a bl e a t the Ins ti tute for Va cci ne Sa fety web s i te.
Pa ti ents wi th a fl uctua ti ng or progres s i ve neurol ogi c di s order, s uch a s Gui l l a i n-Ba rre s yndrome, s houl d not be va cci na ted unti l thei r condi ti on ha s
been s ta bl e for a t l ea s t 1 yr beca us e cerebra l i rri ta ti on i s a ri s k. If a neurol ogi c di s order i s s ta bl e, va cci na ti ons s houl d proceed norma l l y. The ri s k
i n pa ti ents wi th mul ti pl e s cl eros i s i s unknown.
Routine Vaccinations
For the s chedul e of va cci na ti ons for i nfa nts a nd chi l dren, s ee
Ta bl e 268-10 on p. 2718 (s ee a l s o the Centers for Di s ea s e Control a nd Preventi on's [CDC's ] Na ti ona l Immuni za ti on Progra m 2010 Chi l dhood a nd
Adol es cent Immuni za ti on Schedul e a t www.cdc.gov/va cci nes /recs /s chedul es /).
For va cci na ti ons to be cons i dered for a l l a dul ts , s ee Ta bl e 131-2 (s ee a l s o the CDC's Na ti ona l Immuni za ti on Progra m Adul t Immuni za ti on
Recommenda ti ons a t www.cdc.gov/va cci nes /recs /s chedul es /a dul t-s chedul e). Us es of nonrouti ne a cti ve va cci nes (eg, for ra bi es , typhoi d, yel l ow
fever, a nd mycoba cteri a l i nfecti ons ) a nd s ome routi ne va cci na ti ons a re di s cus s ed under s peci fi c di s orders el s ewhere i n THE MANUAL.
Diphtheria-Tetanus-Pertussis
Preparations: Di phtheri a (D) va cci nes conta i n toxoi ds prepa red from Corynebacterium diphtheriae. Teta nus (T) va cci nes conta i n toxoi ds prepa red from
Clostridium tetani. Acel l ul a r (a ) pertus s i s (P) va cci nes conta i n s emi puri fi ed or puri fi ed components of Bordetella pertussis. Whol e-cel l pertus s i s
va cci ne i s no l onger a va i l a bl e i n the US beca us e of concerns a bout a dvers e effects , but i t i s s ti l l a va i l a bl e i n other pa rts of the worl d. There a re 2
prepa ra ti ons of the a cel l ul a r va cci ne:
DTa P for chi l dren < 7 yr
Tda p for a dol es cents a nd a dul ts
Tda p conta i ns l ower dos es of di phtheri a a nd pertus s i s components (i ndi ca ted by the l ower ca s e d a nd p).
Administration: The va cci ne i s gi ven a s 5 pri ma ry a nd 1 boos ter IM i njecti ons duri ng chi l dhood a s fol l ows : the fi rs t 3 dos es a t 2-mo i nterva l s ,
s ta rti ng a t a ge 2 mo; the 4th a t a ge 12 to 15 mo; a nd the l a s t before s chool entry a t a ge 4 to 6 yr. A s i ngl e boos ter of Tda p i s gi ven a t a ge 11 or 12 yr.
Adverse effects: Advers e effects a re ra re a nd a re mos tl y a ttri buta bl e to the pertus s i s component. They i ncl ude encepha l opa thy wi thi n 7 da ys ; a
s ei zure, wi th or wi thout fever, wi thi n 3 da ys ; pers i s tent, s evere, i ncons ol a bl e s crea mi ng or cryi ng for 3 h; col l a ps e or s hock wi thi n 48 h;
tempera ture of 40.5 C, unexpl a i ned by a nother ca us e, wi thi n 48 h; a nd i mmedi a te s evere or a na phyl a cti c rea cti on to the va cci ne. Thes e rea cti ons
contra i ndi ca te further us e of pertus s i s va cci ne; combi ned di phtheri a a nd teta nus va cci ne i s a va i l a bl e wi thout the pertus s i s component.
Mi l d a dvers e effects i ncl ude rednes s , s wel l i ng, a nd s orenes s a t the i njecti on s i te.
Tetanus-Diphtheria
Al though teta nus i s ra re i n the US, i t ha s a hi gh morta l i ty ra te. Beca us e one thi rd of ca s es
[Table 131-2. Common Va cci na ti ons for Adul ts ]
occur unpredi cta bl y (a fter mi nor or i na ppa rent i njuri es ), uni vers a l teta nus va cci na ti on rema i ns neces s a ry.
Preparations: The mos t wi del y us ed prepa ra ti ons combi ne teta nus toxoi d wi th di phtheri a toxoi d (Td for a dul ts , DT for chi l dren); a prepa ra ti on wi th
onl y teta nus toxoi d (TT) i s a l s o a va i l a bl e. Td conta i ns a l ower dos e of di phtheri a toxoi d tha n DTa P a nd DT, whi ch a re us ed i n chi l dren.
Administration: Td boos ters , 0.5 mL IM, a re gi ven every 10 yr a fter the Tda p boos ter tha t i s gi ven a t a ge 11 to 12 yr. Boos ters a re needed to ma i nta i n
i mmuni ty. Beca us e the i nci dence of pertus s i s i s i ncrea s i ng, a t l ea s t one boos ter before a ge 65 s houl d be Tda p. Adul ts who mi s s ed the pri ma ry
s eri es of va cci na ti ons i n chi l dhood s houl d recei ve i t a s a dul ts .
Adverse effects: Advers e effects a re very ra re. They i ncl ude a na phyl a cti c rea cti ons , Gui l l a i n-Ba rre s yndrome, a nd bra chi a l neuri ti s . Mi l d effects
i ncl ude rednes s , s wel l i ng, a nd s orenes s a t the i njecti on s i te.
Haemophilus influenzae Type b
Preparations: Thes e va cci nes a re prepa red from the puri fi ed ca ps ul e of Haemophilus influenzae type b (Hi b). Al l Hi b va cci nes us e pol yri bos yl ri bi tol
phos pha te (PRP) a s the pol ys a ccha ri de, but 4 di fferent protei n ca rri ers produce 4 di fferent Hi b conjuga te va cci nes : di phtheri a toxoi d (PRP-D),
Neisseria meningitidis outer membra ne protei n (PRP-OMP), teta nus toxoi d (PRP-T), a nd di phtheri a muta nt ca rri er protei n CRM197 (HbOC).
Administration: A pri ma ry s eri es i s gi ven i n 3 IM dos es a t a ge 2, 4, a nd 6 mo or i n 2 IM dos es a t a ge 2 a nd 4 mo, dependi ng on the formul a ti on. In
ei ther ca s e, a boos ter i s recommended a t a ge 12 to 15 mo. Some a dul ts a t i ncrea s ed ri s k (eg, beca us e of AIDS or a s pl eni a ) ma y benefi t from thi s
va cci ne.
Adverse effects: Advers e effects a re ra re. They ca n i ncl ude pa i n, rednes s , a nd s wel l i ng a t the i njecti on s i te.
Hepatitis A
Preparations: Hepa ti ti s A va cci nes a re prepa red from forma l i n-i na cti va ted, cel l cul ture-deri ved hepa ti ti s A vi rus . There a re 2 formul a ti ons ; ei ther
ca n be us ed i n chi l dren or a dul ts .
Administration: The va cci ne i s gi ven i n 2 IM dos es 6 mo a pa rt. It i s recommended for chi l dren a ged 12 to 18 mo a nd for ol der chi l dren a nd a dul ts
who a re a t i ncrea s ed of the di s ea s e (s ee Ta bl e 131-2).
Adverse effects: No s eri ous a dvers e effects ha ve been reported. Mi l d effects i ncl ude pa i n a nd occa s i ona l l y i ndura ti on a t the i njecti on s i te.
Hepatitis B
Preparations: Hepa ti ti s B va cci ne us es recombi na nt DNA technol ogy. Si ngl e-a nti gen a nd combi na ti on formul a ti ons a re a va i l a bl e.
Administration: The va cci ne i s gi ven i n 2 or 3 IM dos es , dependi ng on the formul a ti on. Uni vers a l va cci na ti on i s recommended begi nni ng a t bi rth.
Adverse effects: Seri ous a dvers e effects a re very ra re a nd i ncl ude a na phyl a xi s . Mi l d effects i ncl ude pa i n a t the i njecti on s i te a nd occa s i ona l l y a n
i ncrea s e i n tempera ture to > 38C.
Human Papillomavirus
Preparations: Recombi na nt technol ogy i s us ed to prepa re the va cci ne. The va cci ne i s ma de from HPV-l i ke pa rti cl es (VLP) from s erotypes 6, 11, 16, a nd
18, whi ch ca us e 70% of cervi ca l ca ncers a nd 90% of geni ta l wa rts .
Administration: The va cci ne i s gi ven i n 3 IM dos es : i ni ti a l l y, then a t 1 to 2 a nd 4 to 6 mo a fter the i ni ti a l dos e. It i s recommended for fema l es a ged
11 to 13 but ca n be gi ven a s ea rl y a s a ge 9 or up to a ge 26 for ca tch-up. Va cci na ti on i s not recommended a fter a ge 26.
Adverse effects: No s eri ous a dvers e effects ha ve been reported. Mi l d effects i ncl ude rednes s , s wel l i ng, a nd tendernes s a t the i njecti on s i te.
Influenza
Preparations: Infl uenza va cci nes ma y be i na cti va ted tri va l ent va cci nes (TIV) or l i ve-a ttenua ted va cci nes (LAIV). Ea ch type ta rgets 3 vi rus s tra i ns (2
from i nfl uenza A a nd 1 from i nfl uenza B). Beca us e a nti geni c dri ft i s conti nua l , 1 or 2 s tra i ns a re cha nged ea ch yea r i n a nti ci pa ti on of the expected
predomi na nt i nfl uenza s tra i ns . An i na cti va ted va cci ne a ga i ns t a vi a n i nfl uenza ha s been devel oped but i s not commerci a l l y a va i l a bl e. It i s bei ng
na ti ona l l y s tockpi l ed i n ca s e pers on-to-pers on tra ns mi s s i on of a vi a n i nfl uenza becomes pos s i bl e.
Administration: The va cci ne i s requi red a nnua l l y for a t-ri s k pa ti ents beca us e of a nti geni c dri ft. Beca us e outbrea ks us ua l l y begi n i n ea rl y wi nter or
mi dwi nter, the va cci ne i s gi ven i n the fa l l , us ua l l y October a nd November i n the Northern Hemi s phere.
TIV, gi ven a s a s i ngl e IM i njecti on, i s recommended for peopl e a t hi gh ri s k of s eri ous s equel a e, i ncl udi ng chi l dren a ged 6 mo to 8 yr a nd a nyone >
50 yr (s ee Ta bl e 131-2), a s wel l a s a nyone who reques ts va cci na ti on.
LAIV, gi ven a s a n i ntra na s a l s pra y, i s i ndi ca ted for hea l thy peopl e a ged 2 to 49 yr; i t i s contra i ndi ca ted duri ng pregna ncy.
Adverse effects: Ra rel y, TIV ha s a dvers e effects , s uch a s Gui l l a i n-Ba rre s yndrome, a na phyl a cti c rea cti ons , s orenes s a t the i njecti on s i te, a nd fever.
Advers e effects of LAIV a re unus ua l ; they i ncl ude pos s i bl e tri ggeri ng of a s thma a nd tra ns mi s s i on of the vi rus to uni mmuni zed conta cts .
Egg protei n i s us ed i n both va cci ne types ; thus , the va cci ne i s contra i ndi ca ted for peopl e who ha ve s evere a na phyl a cti c rea cti ons to egg protei n.
Measles, Mumps, and Rubella
Preparations: The va cci ne conta i ns l i ve-a ttenua ted vi rus prepa red i n chi cken embryo cel l cul tures . Mea s l es va cci ne i s a va i l a bl e a s a s i ngl e-a nti gen
(mea s l es -onl y) va cci ne or combi ned wi th rubel l a (MR), mumps a nd rubel l a (MMR), or mumps , rubel l a , a nd va ri cel l a (MMRV). There a re a l s o s i ngl ea nti gen va cci nes for mumps , rubel l a , a nd va ri cel l a .
Administration: Mos t commonl y, the combi na ti on va cci ne MMR or MMRV i s gi ven s c. The va cci ne s houl d be gi ven to a l l chi l dren i n thei r 2nd yr of l i fe,
typi ca l l y a t a ge 12 to 15 mo, wi th a 2nd dos e a t a ge 4 to 6 yr. Adul ts a t ri s k i ncl ude thos e who ha ve never recei ved the va cci ne a nd ha ve never
become na tura l l y i nfected. Genera l l y, peopl e born before 1956 a re cons i dered i mmune beca us e i nfecti on duri ng thei r chi l dhood wa s ubi qui tous .
Unl es s the va cci ne i s contra i ndi ca ted, peopl e who were born a fter 1956 a nd ha ve not ha d 2 dos es of the va cci ne or the i nfecti ons s houl d recei ve a t
l ea s t one dos e of the combi ned va cci ne; peopl e who ha ve been or a re l i kel y to be expos ed (eg, col l ege s tudents , hea l th ca re workers ,
i nterna ti ona l tra vel ers ) s houl d recei ve a 2nd dos e.
Al though the components of the va cci ne ca n be gi ven s epa ra tel y, the combi ned form i s preferred beca us e peopl e who need one va cci ne proba bl y
need a l l 3, a nd reva cci na ti on pos es no pa rti cul a r ri s k.
Adverse effects: A mi l d, noncommuni ca bl e i nfecti on occurs i n 15% of va cci ne reci pi ents . Symptoms a ppea r 7 to 11 da ys a fter i mmuni za ti on a nd
i ncl ude fever, ma l a i s e, a nd a mea s l es -l i ke exa nthem. Mumps va cci ne ha s a dvers e effects onl y ra rel y; they i ncl ude encepha l i ti s (onl y from a
Ja pa nes e mumps va cci ne s tra i n), s ei zures , nerve dea fnes s , pa roti ti s , purpura , ra s h, a nd pruri tus .
Rubel l a va cci ne ca n ca us e joi nt pa i n, us ua l l y i n the s ma l l peri phera l joi nts 2 to 8 wk a fter i mmuni za ti on, i n < 1% of i nfa nts but i n 26% of women.
Ra s h or l ympha denopa thy occa s i ona l l y occurs . The va cci ne i s not recommended for pregna nt women beca us e of the theoreti c ri s k to the fetus .
However, i na dvertent a dmi ni s tra ti on duri ng pregna ncy does not neces s a ri l y mea n a thera peuti c a borti on i s recommended beca us e the a ctua l
feta l ri s k ma y be ni l .
Wi th a l l of the va cci ne formul a ti ons , l oca l a dvers e effects a re unus ua l a nd i ncl ude s orenes s a t the i njecti on s i te.
Pneumococcal Disease
Preparations: Pneumococca l conjuga te va cci ne (PCV7) conta i ns 7 puri fi ed ca ps ul a r pol ys a ccha ri des of Streptococcus pneumoniae; ea ch i s coupl ed to a
va ri a nt of di phtheri a toxi n. Pneumococca l pol ys a ccha ri de va cci ne (PPV23) conta i ns a nti gens from the 23 mos t vi rul ent of the 83 s ubtypes of S.
pneumococcus. Unl i ke the ol der 23-va l ent va cci ne, PCV7 ca n s ti mul a te a nti body res pons es i n i nfa nts . It a l s o s eems to confer grea ter protecti on
a ga i ns t i nva s i ve pneumococca l di s orders tha n PPV23. PPV23 reduces ba cteremi a by 56 to 81% i n a dul ts overa l l but i s l es s effecti ve i n debi l i ta ted
el derl y peopl e. It reduces pneumoni a i nci dence onl y mi ni ma l l y.
Administration: PCV7 i s recommended a s a 4-dos e IM s eri es for i nfa nts a t a ge 2, 4, 6, a nd 12 to 15 mo. Chi l dren a t hi gh ri s k of pneumococca l di s ea s e
(eg, chi l dren wi th s i ckl e cel l di s ea s e, a s pl eni a , or a chroni c di s order) s houl d recei ve a dos e of PPV23 a t a ge 24 mo a nd a n a ddi ti ona l dos e 3 to 5 yr
a fter the fi rs t. PPV23 s houl d be gi ven to a ny ol der chi l d or a dul t a t hi gh ri s k of pneumococca l di s ea s e (s ee Ta bl e 131-2). One i mmuni za ti on i s
recommended for l i feti me protecti on; however, reva cci na ti on a fter 5 yr s houl d be cons i dered for pa ti ents a t pa rti cul a rl y hi gh ri s k.
Adverse effects: Advers e effects a re us ua l l y mi l d a nd i ncl ude fever, i rri ta bi l i ty, drows i nes s , a norexi a , vomi ti ng, a nd l oca l erythema .
Poliomyelitis
Preparations: Ina cti va ted pol i ovi rus va cci ne (IPV) conta i ns a mi xture of forma l i ni na cti va ted pol i ovi rus types 1, 2, a nd 3. IPV ma y conta i n tra ce
a mounts of s treptomyci n, neomyci n, a nd pol ymyxi n B. A combi na ti on va cci ne wi th IPV, DTa P, a nd hepa ti ti s B i s a l s o a va i l a bl e. The l i ve-a ttenua ted
ora l formul a ti on i s no l onger a va i l a bl e i n the US beca us e i t ca us es pol i o i n a bout 1 of every 2.4 mi l l i on peopl e who recei ve the va cci ne.
Administration: A 4-dos e IM s eri es i s gi ven a t a ge 2 mo, 4 mo, 6 to 18 mo, a nd 4 to 6 yr. Typi ca l l y, a combi na ti on va cci ne i s us ed for the fi rs t 3
va cci na ti ons a nd a s i ngl e-a nti gen va cci ne for the l a s t dos e.
Adverse effects: No a dvers e effects ha ve been a s s oci a ted wi th IPV. Beca us e i t ma y conta i n tra ce a mounts of neomyci n, s treptomyci n, a nd pol ymyxi n
B, peopl e who a re s ens i ti ve to a ny of thes e drugs ma y ha ve a n a l l ergi c rea cti on to the va cci ne.
Varicella
Preparations: The va cci ne conta i ns a n a ttenua ted wi l d s tra i n of va ri cel l a a nd tra ce a mounts of gel a ti n a nd neomyci n. It i s a va i l a bl e a s a s i ngl ea nti gen va cci ne or a s a combi na ti on va cci ne wi th MMR.
Administration: The va cci ne i s gi ven s c i n 2 dos es : a t a ge 12 to 15 mo a nd a t a ge 4 to 6 yr. The 2nd dos e i s a new recommenda ti on; thus , a ca tch-up
dos e i s s ugges ted for chi l dren, a dol es cents , a nd a dul ts who ha ve recei ved onl y one dos e. The va cci ne s houl d be gi ven to a l l chi l dren a nd to young
a dul ts not previ ous l y i nfected, es peci a l l y hea l th ca re pra cti ti oners a nd cl os e conta cts of i mmunocompromi s ed pa ti ents . If a dul ts ha ve not ha d
va ri cel l a , l evel s of protecti ve a nti bodi es s houl d be mea s ured to determi ne the need for va cci na ti on. No i mmune gl obul i ns , pa rti cul a rl y va ri cel l a zos ter i mmune gl obul i n, s houl d be gi ven wi thi n 5 mo before or 2 mo a fter va cci na ti on beca us e i mmune gl obul i ns ma y prevent devel opment of
protecti ve a nti bodi es .
Adverse effects: Advers e effects a re mi ni ma l a nd i ncl ude tra ns i ent pa i n, tendernes s , a nd rednes s a t the i njecti on s i te. Occa s i ona l l y, wi thi n 1 mo of
va cci na ti on, a mi l d ma cul opa pul a r or va ri cel l a -l i ke ra s h devel ops . Pa ti ents who devel op thi s ra s h s houl d a voi d conta ct wi th i mmunocompromi s ed
peopl e unti l i t res ol ves . Sprea d of the vi rus from va cci ne reci pi ents to s us cepti bl e peopl e ha s been documented i n < 1% of reci pi ents but onl y
from thos e who devel oped a ra s h.
Beca us e Reye's s yndrome ca n devel op, reci pi ents < 16 yr s houl d a voi d s a l i cyl a tes for 6 wk.
Herpes Zoster
Preparations: The va cci ne conta i ns a n a ttenua ted wi l d s tra i n of va ri cel l a , s i mi l a r to the va ri cel l a va cci ne but wi th a hi gher a mount of the
a ttenua ted vi rus .
Administration: The va cci ne i s recommended for a dul ts 60 yr rega rdl es s of pri or i nfecti on. It i s gi ven s c.
Adverse effects: No s eri ous a dvers e effects ha ve been reported. Sorenes s a t the s i te of the i njecti on ma y occur.
Simultaneous Administration of Different Vaccines
Si mul ta neous a dmi ni s tra ti on i s s a fe, effecti ve, a nd conveni ent; i t i s pa rti cul a rl y recommended when chi l dren ma y be una va i l a bl e for future
va cci na ti on or when a dul ts requi re mul ti pl e s i mul ta neous va cci nes (eg, before i nterna ti ona l tra vel ). Si mul ta neous a dmi ni s tra ti on ma y i nvol ve
combi na ti on va cci nes (s ee Ta bl e 131-1) or us e of 1 s i ngl e-a nti gen va cci nes . More tha n one va cci ne ma y be gi ven a t the s a me ti me us i ng di fferent
i njecti on s i tes a nd s yri nges . If l i ve-vi rus va cci nes (va ri cel l a a nd MMR) a re not gi ven a t the s a me ti me, they s houl d be gi ven a t l ea s t 4 wk a pa rt.
Immunizations for Travelers
Immuni za ti ons ma y be requi red for tra vel to a rea s where i nfecti ous di s ea s es a re endemi c. The Centers for Di s ea s e Control a nd Preventi on ca n
provi de i nforma ti on; a tel ephone s ervi ce (1-877-394-8747) a nd web s i te (wwwnc.cdc.gov/tra vel /content/va cci na ti ons .a s px) a re a va i l a bl e 24 h/da y.
Passive Immunization
Pa s s i ve i mmuni za ti on i s provi ded i n the fol l owi ng ci rcums ta nces :
When peopl e ca nnot s ynthes i ze a nti body
When peopl e ha ve been expos ed to a di s ea s e tha t they a re not i mmune to or tha t i s l i kel y to ca us e compl i ca ti ons
When peopl e ha ve a di s ea s e a nd the effects of the toxi n mus t be a mel i ora ted
For i mmune gl obul i ns a nd a nti toxi ns a va i l a bl e i n the US, s ee
Ta bl e 131-3.
Human immune globulin (IG): IG i s a concentra ted a nti body-conta i ni ng s ol uti on prepa red from pl a s ma obta i ned from norma l donors . It cons i s ts
pri ma ri l y of IgG, a l though tra ce a mounts of IgA, IgM, a nd other s erum protei ns ma y be pres ent. IG very ra rel y conta i ns tra ns mi s s i bl e vi rus es (eg,
hepa ti ti s B or C, HIV) a nd i s s ta bl e for ma ny months i f s tored a t 4C. IG i s gi ven IM. Beca us e ma xi ma l s erum a nti body l evel s ma y not occur unti l
a bout 48 h a fter IM i njecti on, IG mus t be gi ven a s s oon a fter expos ure a s pos s i bl e. Ha l f-l i fe of IG i n the ci rcul a ti on i s a bout 3 wk.
IG ma y be us ed for prophyl a xi s i n hepa ti ti s A, mea s l es , i mmunogl obul i n defi ci ency, va ri cel l a (i n i mmunocompromi s ed pa ti ents when va ri cel l a zos ter IG i s una va i l a bl e), a nd rubel l a expos ure duri ng the 1s t tri mes ter of pregna ncy.
[Table 131-3. Immune Gl obul i ns a nd Anti toxi ns * Ava i l a bl e i n the US]
IG provi des onl y tempora ry protecti on; the a nti body content a ga i ns t s peci fi c a gents va ri es by a s much a s 10-fol d a mong prepa ra ti ons .
Admi ni s tra ti on i s pa i nful , a nd a na phyl a xi s ca n occur.
IV immune globulin (IVIG) wa s devel oped to provi de l a rger a nd repea ted dos es of huma n i mmune gl obul i n. IVIG i s us ed to trea t or prevent s evere
ba cteri a l a nd vi ra l i nfecti ons , a utoi mmune di s orders , a nd i mmunodefi ci ency di s orders , pa rti cul a rl y the fol l owi ng:
Ka wa s a ki di s ea s e
HIV i nfecti on i n chi l dren
Chroni c B-cel l l ymphocyti c l eukemi a
Pri ma ry i mmunodefi ci enci es
Autoi mmune thrombocytopeni c purpura
Preventi on of gra ft-vs -hos t di s ea s e
IVIG or a s peci fi c monocl ona l a nti body a ga i ns t RSV i s a va i l a bl e for preventi on of RSV i n chi l dren who a re < 24 mo a nd ha ve bronchopul mona ry
dys pl a s i a or a hi s tory of prema ture bi rth (< 35 wk ges ta ti on).
Advers e effects a re uncommon, a l though fever, chi l l s , hea da che, fa i ntnes s , na us ea , vomi ti ng, hypers ens i ti vi ty, a na phyl a cti c rea cti ons , coughi ng,
a nd vol ume overl oa d ha ve occurred.
Subcutaneous immune globulin (SCIG) i s a l s o prepa red from pool ed huma n pl a s ma ; SCIG i s i ntended for home us e i n pa ti ents wi th a pri ma ry
i mmunodefi ci ency.
Injecti on s i te rea cti ons a re common, but s ys temi c a dvers e effects (eg, fever, chi l l s ) a re much l es s common tha n wi th IVIG.
Hyperimmune globulin: Hyperi mmune gl obul i n i s prepa red from the pl a s ma of peopl e wi th hi gh ti ters of a nti body a ga i ns t a s peci fi c orga ni s m or
a nti gen. It i s deri ved from peopl e conva l es ci ng from na tura l i nfecti ons or donors a rti fi ci a l l y i mmuni zed.
Hyperi mmune gl obul i ns a re a va i l a bl e for hepa ti ti s B, res pi ra tory s yncyti a l vi rus (RSV), ra bi es , teta nus , cytomega l ovi rus , va cci ni a , a nd va ri cel l a zos ter. Admi ni s tra ti on i s pa i nful , a nd a na phyl a xi s ma y occur.
Chapter 132. Bacteria and Antibacterial Drugs

Introduction
Ba cteri a a re mi croorga ni s ms tha t ha ve ci rcul a r doubl e-s tra nded DNA a nd (except for mycopl a s ma s ) cel l wa l l s . Mos t ba cteri a l i ve extra cel l ul a rl y.
Some ba cteri a (eg, Salmonella typhi; Neisseria gonorrhoeae; Legionella, Mycobacterium, Chlamydia, a nd Chlamydophila s pp) preferenti a l l y res i de a nd
repl i ca te i ntra cel l ul a rl y. Some ba cteri a s uch a s chl a mydi a e a nd ri cketts i a e a re obl i ga te i ntra cel l ul a r pa thogens (i e, a bl e to grow, reproduce, a nd
ca us e di s ea s e onl y wi thi n the cel l s of the hos t). Others (eg, Salmonella typhi, Brucella s p, Francisella tularensis, N. gonorrhoeae, N. meningitidis, Legionella
a nd Listeria s pp, Mycobacterium tuberculosis) a re fa cul ta ti ve i ntra cel l ul a r pa thogens .
Ma ny ba cteri a a re pres ent i n huma ns a s norma l fl ora , often i n l a rge numbers a nd i n ma ny a rea s (eg, i n the GI tra ct). Onl y a few ba cteri a l s peci es
a re huma n pa thogens .
Ba cteri a a re cl a s s i fi ed by the fol l owi ng cri teri a (s ee
Ta bl e 132-1).
Morphology: Ba cteri a ma y be cyl i ndri c (ba ci l l i ), s pheri ca l (cocci ), or s pi ra l (s pi rochetes ). A few cocca l , ma ny ba ci l l a ry, a nd mos t s pi rocheta l s peci es
a re moti l e.
Staining: The mos t common s ta i n for genera l ba cteri a l i denti fi ca ti on i s Gra m s ta i n. Gra m-pos i ti ve ba cteri a reta i n crys ta l vi ol et dye (a ppea ri ng da rk
bl ue) a fter i odi ne fi xa ti on a nd a l cohol decol ori za ti on; gra m-nega ti ve ba cteri a do not. Gra m-nega ti ve ba cteri a ha ve a n a ddi ti ona l outer membra ne
conta i ni ng l i popol ys a ccha ri de (endotoxi n), i ncrea s i ng the vi rul ence of thes e ba cteri a . (For other fa ctors tha t enha nce ba cteri a l pa thogeni ci ty, s ee
Fa ctors Fa ci l i ta ti ng Mi crobi a l Inva s i on on p. 1150.)
Zi ehl -Neel s en s ta i n (a ci d-fa s t s ta i n) i s us ed to i denti fy ma i nl y mycoba cteri a , pa rti cul a rl y M. tuberculosis. It a l s o ca n i denti fy Nocardia s p.
Ca rbol fuchs i n i s a ppl i ed wi th hea t, fol l owed by decol ori za ti on wi th hydrochl ori c a ci d a nd etha nol a nd counters ta i ni ng wi th methyl ene bl ue.
Encapsulation: Some ba cteri a a re encl os ed i n ca ps ul es ; for s ome enca ps ul a ted ba cteri a (eg, Streptococcus pneumoniae, Haemophilus influenzae), the
ca ps ul e hel ps protect them from i nges ti on by pha gocytes . Enca ps ul a ti on i ncrea s es ba cteri a l vi rul ence.
Oxygen requirements: Aerobi c ba cteri a (obl i ga te a erobes ) requi re O2 to produce energy a nd to grow i n cul ture. They produce energy us i ng a erobi c
cel l ul a r res pi ra ti on.
Ana erobi c ba cteri a (obl i ga te a na erobes ) do not requi re O2 a nd do not grow i n cul ture i f a i r i s pres ent. They produce energy us i ng fermenta ti on or
a na erobi c res pi ra ti on. Ana erobi c ba cteri a a re common i n the GI tra ct, va gi na , denta l crevi ces , a nd wounds when bl ood s uppl y i s i mpa i red.
Fa cul ta ti ve ba cteri a ca n grow wi th or wi thout O2 . They produce energy by fermenta ti on or a na erobi c res pi ra ti on when O2 i s a bs ent a nd by a erobi c
cel l ul a r res pi ra ti on when O2 i s pres ent. Mi croa erophi l i c ba cteri a prefer a reduced O2
[Table 132-1. Cl a s s i fi ca ti on of Common Pa thogeni c Ba cteri a ]
tens i on (eg, 2 to 10%). Chl a mydi a e a re obl i ga te i ntra cel l ul a r pa ra s i tes tha t a cqui re energy from the hos t cel l a nd do not produce i t thems el ves .
Antibacterial Drugs
Anti ba cteri a l drugs a re deri ved from ba cteri a or mol ds or a re s ynthes i zed de novo. Techni ca l l y, "a nti bi oti c" refers onl y to a nti mi crobi a l s deri ved
from ba cteri a or mol ds but i s often (i ncl udi ng i n THE MANUAL) us ed s ynonymous l y wi th "a nti ba cteri a l drug."
Anti bi oti cs ha ve ma ny mecha ni s ms of a cti on, i ncl udi ng i nhi bi ti ng cel l wa l l s ynthes i s , a cti va ti ng enzymes tha t des troy the cel l wa l l , i ncrea s i ng cel l
membra ne permea bi l i ty, a nd i nterferi ng wi th protei n s ynthes i s a nd nucl ei c a ci d meta bol i s m.
Anti bi oti cs s ometi mes i ntera ct wi th other drugs , ra i s i ng or l oweri ng s erum l evel s of other drugs by i ncrea s i ng or decrea s i ng thei r meta bol i s m or by
va ri ous other mecha ni s ms (s ee
Ta bl e 132-2). The mos t cl i ni ca l l y i mporta nt i ntera cti ons i nvol ve drugs wi th a l ow thera peuti c ra ti o (i e, toxi c l evel s a re cl os e to thera peuti c l evel s ).
Al s o, other drugs ca n i ncrea s e or decrea s e l evel s of a nti bi oti cs .
Ma ny a nti bi oti cs a re chemi ca l l y rel a ted a nd a re thus grouped i nto cl a s s es . Al though drugs wi thi n ea ch cl a s s s ha re s tructura l a nd functi ona l
s i mi l a ri ti es , they often ha ve di fferent pha rma col ogy a nd s pectra of a cti vi ty.
Selection and Use of Antibiotics
Anti bi oti cs s houl d be us ed onl y i f cl i ni ca l or l a bora tory evi dence s ugges ts ba cteri a l i nfecti on. Us e for vi ra l i l l nes s or undi fferenti a ted fever i s
i na ppropri a te, s ubjects pa ti ents to drug compl i ca ti ons wi thout a ny benefi t, a nd contri butes to ba cteri a l res i s ta nce. Certa i n ba cteri a l i nfecti ons
(eg, a bs ces s es , i nfecti ons wi th forei gn bodi es ) requi re s urgi ca l i nterventi on a nd do not res pond to a nti bi oti cs a l one.
Spectrum of activity: Cul tures a nd a nti bi oti c s ens i ti vi ty tes ti ng a re es s enti a l for s el ecti ng a drug for s eri ous i nfecti ons . However, trea tment mus t
often begi n before cul ture res ul ts a re a va i l a bl e, neces s i ta ti ng s el ecti on a ccordi ng to the mos t l i kel y pa thogens (empi ri c a nti bi oti c s el ecti on).
Whether chos en a ccordi ng to cul ture res ul ts or not, drugs wi th the na rrowes t s pectrum of a cti vi ty tha t ca n control the i nfecti on s houl d be us ed. For
empi ri c trea tment of s eri ous i nfecti ons tha t ma y i nvol ve a ny one of s evera l pa thogens (eg, fever i n neutropeni c pa ti ents ) or tha t ma y be due to
mul ti pl e pa thogens (eg, pol ymi crobi a l a na erobi c i nfecti on), a broa d s pectrum of a cti vi ty i s des i ra bl e. The mos t l i kel y pa thogens a nd thei r
s us cepti bi l i ty to a nti bi oti cs va ry a ccordi ng to geogra phi c l oca ti on (wi thi n ci ti es or even wi thi n a hos pi ta l ) a nd ca n cha nge from month to month.
For s eri ous i nfecti ons , combi na ti ons of a nti bi oti cs a re often neces s a ry beca us e mul ti pl e s peci es of ba cteri a ma y be pres ent or beca us e
combi na ti ons a ct s ynergi s ti ca l l y a ga i ns t a s i ngl e s peci es of ba cteri a . Synergi s m i s us ua l l y defi ned a s a more ra pi d a nd compl ete ba cteri ci da l
a cti on from a combi na ti on of a nti bi oti cs tha n occurs wi th ei ther a nti bi oti c a l one. A common exa mpl e i s a cel l wa l l -a cti ve a nti bi oti c (eg, a -
l a cta m, va ncomyci n) pl us a n a mi nogl ycos i de.

Effectiveness: In vi vo a nti bi oti c effecti venes s i nvol ves ma ny fa ctors , i ncl udi ng
Pha rma col ogy (eg, a bs orpti on, di s tri buti on, concentra ti on i n fl ui ds a nd ti s s ues , protei n bi ndi ng, ra te of meta bol i s m or excreti on)
Pha rma codyna mi cs (i e, the ti me cours e of a nti ba cteri a l effects exerted by drug l evel s i n bl ood a nd a t the s i te of i nfecti on)
Drug i ntera cti ons or i nhi bi ti ng s ubs ta nces
Hos t defens e mecha ni s ms
[Table 132-2. Common Effects of Anti bi oti cs on Other Drugs ]
In vi tro ki l l i ng power but us ua l l y onl y i f the s i te of i nfecti on (eg, i n meni ngi ti s or endoca rdi ti s ) i s res i s ta nt to trea tment or i f s ys temi c hos t
defens es a re wea k (eg, i n neutropeni c or other i mmunocompromi s ed pa ti ents )
Ba cteri ci da l drugs ki l l ba cteri a i n vi tro. Ba cteri os ta ti c drugs s l ow or s top i n vi tro ba cteri a l growth. Thes e defi ni ti ons a re not a bs ol ute;
ba cteri os ta ti c drugs ma y ki l l s ome ba cteri a , a nd ba cteri ci da l drugs ma y not ki l l a l l of the ba cteri a i n vi tro. More preci s e qua nti ta ti ve methods
i denti fy the mi ni mum i n vi tro concentra ti on a t whi ch a n a nti bi oti c ca n i nhi bi t growth (mi ni mum i nhi bi tory concentra ti on, or MIC) or ki l l (mi ni mum
ba cteri ci da l concentra ti on, or MBC).
The predomi na nt determi na nt of ba cteri ol ogi c res pons e to a nti bi oti cs i s the ti me tha t bl ood l evel s of the a nti bi oti c exceed the MIC (ti medependence) or the pea k bl ood l evel rel a ti ve to MIC (concentra ti on-dependence).
-La cta ms a nd va ncomyci n exhi bi t ti me-dependent ba cteri ci da l a cti vi ty. Increa s i ng thei r concentra ti on a bove the MIC does not i ncrea s e thei r
ba cteri ci da l a cti vi ty, a nd thei r i n vi vo ki l l i ng i s genera l l y s l ow. In a ddi ti on, beca us e there i s no or very bri ef res i dua l i nhi bi ti on of ba cteri a l growth
a fter concentra ti ons fa l l bel ow the MIC (pos ta nti bi oti c effect, or PAE), -l a cta ms a nd va ncomyci n a re mos t often effecti ve when s erum l evel s of free
drug (drug not bound to s erum protei n) exceed the MIC for 50% of the ti me. Beca us e ceftri a xone ha s a l ong s erum ha l f-l i fe, free s erum l evel s
exceed the MIC of very s us cepti bl e pa thogens for the enti re 24-h dos i ng i nterva l . However, for -l a cta ms tha t ha ve s erum ha l f-l i ves of 2 h,
frequent dos i ng or conti nuous i nfus i on i s requi red. For va ncomyci n, trough l evel s s houl d be ma i nta i ned a t l ea s t a t 10 to 15 g/mL.
Ami nogl ycos i des , fl uoroqui nol ones , a nd da ptomyci n exhi bi t concentra ti on-dependent ba cteri ci da l a cti vi ty. Increa s i ng thei r concentra ti ons from
l evel s s l i ghtl y a bove the MIC to l evel s fa r a bove the MIC i ncrea s es thei r ra te of ba cteri ci da l a cti vi ty a nd decrea s es the ba cteri a l l oa d. In a ddi ti on,
i f concentra ti ons exceed the MIC even bri efl y, a mi nogl ycos i des a nd fl uoroqui nol ones ha ve a PAE on res i dua l ba cteri a ; dura ti on of PAE i s a l s o
concentra ti on-dependent. If PAEs a re l ong, drug l evel s ca n be bel ow the MIC for extended peri ods wi thout l os s of effi ca cy, a l l owi ng l es s frequent
dos i ng. Cons equentl y, a mi nogl ycos i des a nd fl uoroqui nol ones a re us ua l l y mos t effecti ve a s i ntermi ttent bol us es tha t rea ch pea k free s erum l evel s
10 ti mes the MIC of the ba cteri a .
Route: For ma ny a nti bi oti cs , ora l a dmi ni s tra ti on res ul ts i n thera peuti c bl ood l evel s nea rl y a s ra pi dl y a s IV a dmi ni s tra ti on. However, IV
a dmi ni s tra ti on i s preferred i n the fol l owi ng ci rcums ta nces :
Ora l a nti bi oti cs ca nnot be tol era ted (eg, beca us e of vomi ti ng).
Ora l a nti bi oti cs ca nnot be a bs orbed (eg, beca us e of ma l a bs orpti on a fter i ntes ti na l s urgery).
Intes ti na l moti l i ty i s i mpa i red (eg, beca us e of opi oi d us e).
No ora l formul a ti on i s a va i l a bl e (eg, for a mi nogl ycos i des ).
Pa ti ents a re cri ti ca l l y i l l , pos s i bl y i mpa i ri ng GI tra ct perfus i on or ma ki ng even the bri ef del a y wi th ora l a dmi ni s tra ti on detri menta l .
Special populations: Dos es a nd s chedul i ng of a nti bi oti cs ma y need to be a djus ted for the fol l owi ng:
Infa nts
The el derl y
Pa ti ents wi th rena l fa i l ure (s ee
Ta bl e 132-3)
Pa ti ents wi th hepa ti c i ns uffi ci ency (mos t commonl y for cefopera zone, ceftri a xone, chl ora mpheni col , cl i nda myci n, metroni da zol e, na fci l l i n,
ri fa buti n, a nd ri fa mpi n)
Pregna ncy a nd brea s tfeedi ng a ffect choi ce of a nti bi oti c. Peni ci l l i ns , cepha l os pori ns , a nd erythromyci n a re a mong the s a fes t a nti bi oti cs duri ng
pregna ncy; tetra cycl i nes a re contra i ndi ca ted. Mos t a nti bi oti cs rea ch s uffi ci ent concentra ti ons i n brea s t mi l k to a ffect a brea s tfed ba by, s ometi mes
contra i ndi ca ti ng thei r us e i n women who a re brea s tfeedi ng.
Duration: Anti bi oti cs s houl d be conti nued unti l objecti ve evi dence of s ys temi c i nfecti on (eg, fever, s ymptoms , a bnorma l l a bora tory fi ndi ngs ) i s
a bs ent for s evera l da ys . For s ome i nfecti ons (eg, endoca rdi ti s , TB, os teomyel i ti s ), a nti bi oti cs a re conti nued for weeks or months to prevent
rel a ps e.
Complications: Compl i ca ti ons of a nti bi oti c thera py i ncl ude s uperi nfecti on by nons us cepti bl e ba cteri a or fungi a nd cuta neous , rena l , hema tol ogi c,
a nd GI a dvers e effects . Advers e effects frequentl y requi re s toppi ng the ca us a ti ve drug a nd s ubs ti tuti ng a nother a nti bi oti c to whi ch the ba cteri a
a re s us cepti bl e; s ometi mes , no a l terna ti ves exi s t.

Antibiotic Resistance
Res i s ta nce to a n a nti bi oti c ma y be i nherent i n a pa rti cul a r ba cteri a l s peci es or ma y be a cqui red through muta ti ons or a cqui s i ti on of genes for
a nti bi oti c res i s ta nce tha t a re obta i ned
[Table 132-3. Us ua l Dos es of Commonl y Pres cri bed Anti bi oti cs ]
[
Table 132-4. Common Mecha ni s ms of Anti bi oti c Res i s ta nce]
from a nother orga ni s m. Di fferent mecha ni s ms for res i s ta nce a re encoded by thes e genes (s ee Ta bl e 132-4). Res i s ta nce genes ca n be tra ns mi tted
between 2 ba cteri a l cel l s by the fol l owi ng mecha ni s ms :
Tra ns forma ti on (upta ke of na ked DNA from a nother orga ni s m)
Tra ns ducti on (i nfecti on by a ba cteri opha ge)
Conjuga ti on (excha nge of geneti c ma teri a l i n the form of ei ther pl a s mi ds , whi ch a re pi eces of i ndependentl y repl i ca ti ng extra -chromos oma l DNA,
or tra ns pos ons , whi ch a re mova bl e pi eces of chromos oma l DNA) Pl a s mi ds a nd tra ns pos ons , whi ch ca n ra pi dl y di s s emi na te res i s ta nce genes
Anti bi oti c us e preferenti a l l y el i mi na tes non-res i s ta nt ba cteri a , i ncrea s i ng the proporti on of res i s ta nt ba cteri a tha t rema i n. Anti bi oti c us e ha s thi s
effect not onl y on pa thogeni c ba cteri a but a l s o on norma l fl ora ; res i s ta nt norma l fl ora ca n become a res ervoi r for res i s ta nce genes tha t ca n s prea d
to pa thogens .
Aminoglycosides
Ami nogl ycos i des (s ee
Ta bl e 132-5) ha ve concentra ti on-dependent ba cteri ci da l a cti vi ty. They bi nd to the 30S ri bos ome, thereby i nhi bi ti ng ba cteri a l protei n s ynthes i s .
Pharmacology
Ami nogl ycos i des a re poorl y a bs orbed ora l l y but a re wel l a bs orbed from the peri toneum, pl eura l ca vi ty, a nd joi nts (a nd s houl d never be i ns ti l l ed
i n thes e body ca vi ti es ) a nd from denuded s ki n. Ami nogl ycos i des a re us ua l l y gi ven IV. Ami nogl ycos i des a re di s tri buted wel l i nto ECF except for
vi treous humor, CSF, res pi ra tory s ecreti ons , a nd bi l e (pa rti cul a rl y i n pa ti ents wi th bi l i a ry obs tructi on). Intra vi treous i njecti on i s requi red to trea t
endophtha l mi ti s . Intra ventri cul a r i njecti on i s often requi red to rea ch i ntra ventri cul a r l evel s hi gh enough to trea t meni ngi ti s .
[Table 132-5. Ami nogl ycos i des ]
Ami nogl ycos i des a re excreted by gl omerul a r fi l tra ti on a nd ha ve a s erum ha l f-l i fe of 2 to 3 h; the ha l f-l i fe i ncrea s es exponenti a l l y a s the GFR fa l l s
(eg, i n rena l i ns uffi ci ency, i n the el derl y).
Indications
Ami nogl ycos i des a re us ed for
Seri ous gra m-nega ti ve ba ci l l a ry i nfecti ons (es peci a l l y thos e due to Pseudomonas aeruginosa)
Ami nogl ycos i des a re a cti ve a ga i ns t mos t gra m-nega ti ve a erobi c a nd fa cul ta ti ve a na erobi c ba ci l l i but l a ck a cti vi ty a ga i ns t a na erobes a nd mos t
gra m-pos i ti ve ba cteri a , except for mos t s ta phyl ococci ; however, s ome gra m-nega ti ve ba ci l l i a nd methi ci l l i n-res i s ta nt s ta phyl ococci a re res i s ta nt.
Ami nogl ycos i des tha t a re a cti ve a ga i ns t P. aeruginosa i ncl ude tobra myci n (pa rti cul a rl y), genta mi ci n, a nd a mi ka ci n. Streptomyci n, neomyci n, a nd
ka na myci n a re not a cti ve a ga i ns t P. aeruginosa. Genta mi ci n a nd tobra myci n ha ve s i mi l a r a nti mi crobi a l s pectra a ga i ns t gra m-nega ti ve ba ci l l i , but
tobra myci n i s more a cti ve a ga i ns t P. aeruginosa, a nd genta mi ci n i s more a cti ve a ga i ns t Serratia marcescens. Ami ka ci n i s frequentl y a cti ve a ga i ns t
genta mi ci n- a nd tobra myci n-res i s ta nt pa thogens .
Ami nogl ycos i des a re i nfrequentl y us ed a l one, typi ca l l y for pl a gue a nd tul a remi a . They a re us ua l l y us ed wi th a broa d-s pectrum -l a cta m for s evere
i nfecti on s us pected to be due to a gra m-nega ti ve ba ci l l a ry s peci es . However, beca us e of i ncrea s i ng a mi nogl ycos i de res i s ta nce, a fl uoroqui nol one
ca n be s ubs ti tuted for the a mi nogl ycos i de i n i ni ti a l empi ri c regi mens , or i f the pa thogen i s found to be s us cepti bl e to the a ccompa nyi ng
a nti bi oti c, the a mi nogl ycos i de ca n be s topped a fter 2 to 3 da ys unl es s a n a mi nogl ycos i de-s ens i ti ve P. aeruginosa i s i denti fi ed.
Genta mi ci n or, l es s commonl y, s treptomyci n ma y be us ed wi th other a nti bi oti cs to trea t endoca rdi ti s due to s treptococci or enterococci .
Enterococca l res i s ta nce to a mi nogl ycos i des ha s become a common probl em. Beca us e trea tment of enterococca l endoca rdi ti s requi res prol onged
us e of a potenti a l l y nephrotoxi c a nd ototoxi c a mi nogl ycos i de pl us a ba cteri a l cel l wa l l -a cti ve drug (eg, peni ci l l i n, va ncomyci n) to a chi eve
ba cteri ci da l s ynergy, the choi ce of a mi nogl ycos i de mus t be ba s ed on s peci a l i n vi tro s us cepti bi l i ty tes ti ng. Sus cepti bi l i ty onl y to hi gh l evel s of
a mi nogl ycos i des i n vi tro predi cts s ynergy when l ow-dos e a mi nogl ycos i de thera py i s combi ned wi th a cel l wa l l -a cti ve drug. If the s tra i n i s
s us cepti bl e to hi gh l evel s of genta mi ci n a nd s treptomyci n, genta mi ci n i s preferred beca us e s erum l evel s ca n be rea di l y determi ned a nd toxi ci ty i s
l es s . Hi gh-l evel enterococca l res i s ta nce to genta mi ci n i n vi tro does not rul e out s us cepti bi l i ty of thes e s tra i ns to hi gh l evel s of s treptomyci n; i n
s uch ca s es , s treptomyci n s houl d be us ed. Few thera peuti c opti ons a re a va i l a bl e for endoca rdi ti s due to enterococci tha t a re res i s ta nt to hi gh
l evel s of genta mi ci n a nd s treptomyci n; no s ynergi s ti c cel l wa l l -a cti ve drug/a mi nogl ycos i de combi na ti on exi s ts for endoca rdi ti s due to s uch s tra i ns ,
but l ong cours es of a cel l wa l l -a cti ve drug a l one or combi ned wi th da ptomyci n or l i nezol i d ha ve ha d l i mi ted s ucces s .
Streptomyci n ha s l i mi ted us es beca us e of res i s ta nce a nd toxi ci ty. It i s us ed wi th other a nti bi oti cs to trea t TB.
Beca us e of toxi ci ty, neomyci n a nd ka na myci n a re l i mi ted to topi ca l us e i n s ma l l a mounts . Neomyci n i s a va i l a bl e for eye, ea r, ora l , a nd recta l us e
a nd a s a bl a dder i rri ga nt. Ora l neomyci n i s us ed topi ca l l y a ga i ns t i ntes ti na l fl ora to prepa re the bowel before s urgery a nd to trea t hepa ti c coma .
Contraindications
Ami nogl ycos i des a re contra i ndi ca ted i n pa ti ents who a re a l l ergi c to them.
Use During Pregnancy and Breastfeeding
Ami nogl ycos i des a re i n pregna ncy ca tegory D (there i s evi dence of huma n ri s k, but cl i ni ca l benefi ts ma y outwei gh ri s k). Ami nogl ycos i des enter
brea s t mi l k but a re not wel l a bs orbed ora l l y. Thus , they a re cons i dered compa ti bl e wi th us e duri ng brea s tfeedi ng.
Adverse Effects
Al l a mi nogl ycos i des ca us e
Rena l toxi ci ty (often revers i bl e)
Ves ti bul a r a nd a udi tory toxi ci ty (often i rrevers i bl e)
Prol onga ti on of effects of neuromus cul a r bl ockers
Symptoms a nd s i gns of ves ti bul a r da ma ge a re verti go, na us ea , vomi ti ng, nys ta gmus , a nd a ta xi a .
Risk factors for rena l , ves ti bul a r, a nd a udi tory toxi ci ty a re
Frequent or very hi gh dos es
Very hi gh bl ood l evel s of the drug
Long dura ti on of thera py (pa rti cul a rl y > 3 da ys )
Ol der a ge
A preexi s ti ng rena l di s order
Coa dmi ni s tra ti on of va ncomyci n, cycl os pori ne, or a mphoteri ci n B
For rena l toxi ci ty, coa dmi ni s tra ti on of contra s t a gents
For a udi tory toxi ci ty, preexi s ti ng hea ri ng probl ems a nd coa dmi ni s tra ti on of l oop di ureti cs
Pa ti ents recei vi ng a mi nogl ycos i des for > 2 wk a nd thos e a t ri s k of ves ti bul a r a nd a udi tory toxi ci ty s houl d be moni tored wi th s eri a l a udi ogra phy. At
the fi rs t s i gn of toxi ci ty, the drug s houl d be s topped (i f pos s i bl e), or dos i ng s houl d be a djus ted.
Ami nogl ycos i des ca n prol ong the effect of neuromus cul a r bl ockers (eg, s ucci nyl chol i ne, cura re-l i ke drugs ) a nd wors en wea knes s i n di s orders
a ffecti ng neuromus cul a r tra ns mi s s i on (eg, mya s theni a gra vi s ). Thes e effects a re pa rti cul a rl y l i kel y when the drug i s gi ven too ra pi dl y or s erum
l evel s a re exces s i vel y hi gh. The effects s ometi mes res ol ve more ra pi dl y i f pa ti ents a re gi ven neos ti gmi ne or IV Ca . Other neurol ogi c effects i ncl ude
pa res thes i a s a nd peri phera l neuropa thy.
Hypers ens i ti vi ty rea cti ons a re uncommon. Hi gh ora l dos es of neomyci n ca n ca us e ma l a bs orpti on.
Dosing considerations: Beca us e toxi ci ty depends more on dura ti on of thera peuti c l evel s tha n on pea k l evel s a nd beca us e effi ca cy i s concentra ti ondependent ra ther tha n ti medependent, frequent dos es a re a voi ded. Once/da y IV dos i ng i s preferred for mos t i ndi ca ti ons except enterococca l
endoca rdi ti s . IV a mi nogl ycos i des a re gi ven s l owl y (30 mi n for di vi ded da i l y dos i ng or 30 to 45 mi n for once/da y dos i ng).
In pa ti ents wi th norma l rena l functi on, once/da y dos i ng of genta mi ci n or tobra myci n i s 5 mg/kg (7 mg/kg i f pa ti ents a re cri ti ca l l y i l l ) q 24 h, a nd
once/da y dos i ng for a mi ka ci n i s 15 mg/kg q 24 h. If pa ti ents res pond to the hi gher dos e of genta mi ci n cl i ni ca l l y a nd rena l
[
Table 132-6. Dos i ng for Ami nogl ycos i des i n Adul ts ]
functi on conti nues to be norma l , the once/da y dos e ca n be reduced to the l ower dos e a fter the fi rs t few da ys of trea tment.
In cri ti ca l l y i l l pa ti ents , pea k s erum l evel s s houl d be determi ned a fter the fi rs t dos e. In a l l pa ti ents , pea k a nd trough l evel s a re mea s ured a fter
the 2nd or 3rd dos e (when the da i l y dos e i s di vi ded) or when thera py l a s ts > 3 da ys , a s wel l a s a fter the dos e i s cha nged. Serum crea ti ni ne i s
mea s ured every 2 to 3 da ys , a nd i f i t i s s ta bl e, s erum a mi nogl ycos i de l evel s need not be mea s ured a ga i n. Pea k concentra ti on i s the l evel 60 mi n
a fter a n IM i njecti on or 30 mi n a fter the end of a 30-mi n IV i nfus i on. Trough l evel s a re mea s ured duri ng the 30 mi n before the next dos e.
Pea k l evel s i n s erum of a t l ea s t 10 ti mes the MIC a re des i ra bl e. Dos i ng i s a djus ted to ens ure a thera peuti c pea k s erum l evel (to fa ci l i ta te
concentra ti on-dependent a cti vi ty) a nd nontoxi c trough l evel s (s ee Ta bl e 132-6). In cri ti ca l l y i l l pa ti ents , who a re l i kel y to ha ve expa nded vol umes
of di s tri buti on a nd who a re gi ven hi gher i ni ti a l dos es , ta rget pea k s erum l evel s a re 16 to 24 g/mL for genta mi ci n a nd tobra myci n a nd 56 to 64
g/mL for a mi ka ci n. For genta mi ci n a nd tobra myci n, trough l evel s s houl d be < 1 g/mL a t 18 to 24 h a fter the fi rs t dos e wi th once/da y dos i ng a nd
between 1 a nd 2 g/mL wi th di vi ded da i l y dos i ng.

For pa ti ents wi th rena l i ns uffi ci ency, the l oa di ng dos e i s the s a me a s tha t for pa ti ents wi th norma l rena l functi on; us ua l l y, the dos i ng i nterva l i s
i ncrea s ed ra ther tha n the dos e decrea s ed. Gui del i nes for ma i ntena nce dos es ba s ed on s erum crea ti ni ne or crea ti ni ne cl ea ra nce va l ues a re
a va i l a bl e (s ee Ta bl e 132-6), but they a re not preci s e, a nd mea s urement of bl ood l evel s i s preferred.
If pa ti ents a re ta ki ng a hi gh dos e of a -l a cta m (eg, pi pera ci l l i n, ti ca rci l l i n) a nd a n a mi nogl ycos i de, the hi gh s erum l evel s of the -l a cta m ca n
i na cti va te the a mi nogl ycos i de i n vi tro i n s erum s peci mens obta i ned to determi ne drug l evel s unl es s the s peci men i s a s s a yed i mmedi a tel y or
frozen. If pa ti ents wi th rena l fa i l ure a re concurrentl y ta ki ng a n a mi nogl ycos i de a nd a hi gh-dos e -l a cta m, the s erum a mi nogl ycos i de l evel ma y be
l ower beca us e i ntera cti on i n vi vo i s prol onged.
Spectinomycin
Specti nomyci n i s a ba cteri os ta ti c a nti bi oti c chemi ca l l y rel a ted to the a mi nogl ycos i des . Specti nomyci n bi nds to the 30S s ubuni t of the ri bos ome,
thus i nhi bi ti ng ba cteri a l protei n s ynthes i s . Its a cti vi ty i s res tri cted to gonococci . Specti nomyci n i s excreted by gl omerul a r fi l tra ti on.
Indications i ncl ude
Gonococca l urethri ti s
Cervi ci ti s
Procti ti s
Specti nomyci n i s not effecti ve for gonococca l pha ryngi ti s . It i s res erved for pa ti ents who ca nnot be trea ted wi th ceftri a xone, cefpodoxi me, cefi xi me,
or a fl uoroqui nol one.
Advers e effects , i ncl udi ng hypers ens i ti vi ty rea cti ons a nd fever, a re ra re.
-Lactams
-La cta ms a re a nti bi oti cs tha t ha ve a -l a cta m ri ng nucl eus . Subcl a s s es i ncl ude
Cepha l os pori ns a nd cepha myci ns (cephems )
Ca rba cephems (l ora ca rbef)
Peni ci l l i ns
Cl a va ms
Ca rba penems
Monoba cta ms
Al l -l a cta ms bi nd to a nd i na cti va te enzymes requi red for ba cteri a l cel l wa l l s ynthes i s .
Cephalosporins
Cepha l os pori ns a re ba cteri ci da l (s ee
Ta bl e 132-7). They i nhi bi t enzymes i n the cel l wa l l of s us cepti bl e ba cteri a , di s rupti ng cel l s ynthes i s .
Pharmacology
Cepha l os pori ns penetra te wel l i nto mos t body fl ui ds a nd the ECF of mos t ti s s ues , es peci a l l y when i nfl a mma ti on (whi ch enha nces di ffus i on) i s
pres ent. However, the onl y cepha l os pori ns tha t rea ch CSF l evel s hi gh enough to trea t meni ngi ti s a re
Ceftri a xone
Cefota xi me
Cefta zi di me
Cefepi me
Al l cepha l os pori ns penetra te poorl y i nto ICF a nd the vi treous humor.
Mos t cepha l os pori ns a re excreted pri ma ri l y i n uri ne, s o thei r dos es mus t be a djus ted i n pa ti ents wi th rena l i ns uffi ci ency. Cefopera zone a nd
ceftri a xone, whi ch ha ve s i gni fi ca nt bi l i a ry excreti on, do not requi re s uch dos e a djus tment.
Indications
Cepha l os pori ns a re ba cteri ci da l for mos t of the fol l owi ng:
Gra m-pos i ti ve ba cteri a

Gra m-nega ti ve ba cteri a
Cepha l os pori ns a re cl a s s i fi ed i n genera ti ons (s ee Ta bl e 132-7). The 1s t-genera ti on
[Table 132-7. Cepha l os pori ns *]
drugs a re effecti ve ma i nl y a ga i ns t gra m-pos i ti ve orga ni s ms . Hi gher genera ti ons genera l l y ha ve expa nded s pectra a ga i ns t a erobi c gra m-nega ti ve
ba ci l l i . The 5th-genera ti on cepha l os pori n ceftobi prol e, whi ch i s not yet a va i l a bl e i n the US, i s a cti ve a ga i ns t methi ci l l i n-res i s ta nt Staphylococcus
aureus. Cepha l os pori ns ha ve the fol l owi ng l i mi ta ti ons :
La ck of a cti vi ty a ga i ns t enterococci
La ck of a cti vi ty a ga i ns t methi ci l l i n-res i s ta nt s ta phyl ococci (except for ceftobi prol e)
La ck of a cti vi ty a ga i ns t a na erobi c gra m-nega ti ve ba ci l l i (except for cefoteta n a nd cefoxi ti n)
First-generation cephalosporins: Thes e drugs ha ve excel l ent a cti vi ty a ga i ns t
Gra m-pos i ti ve cocci
Ora l 1s t-genera ti on cepha l os pori ns a re commonl y us ed for uncompl i ca ted s ki n a nd s oft-ti s s ue i nfecti ons , whi ch a re us ua l l y due to s ta phyl ococci
a nd s treptococci . Pa rentera l cefa zol i n i s frequentl y us ed for endoca rdi ti s due to methi ci l l i n-s ens i ti ve S. aureus a nd for prophyl a xi s before
ca rdi othora ci c, orthopedi c, a bdomi na l , a nd pel vi c s urgery.
Second-generation cephalosporins and cephamycins: Second-genera ti on cepha l os pori ns a re a cti ve a ga i ns t
Gra m-pos i ti ve cocci
Certa i n gra m-nega ti ve ba ci l l i
Cepha myci ns a re a cti ve a ga i ns t
Bacteroides s p, i ncl udi ng B. fragilis
Thes e drugs ma y be s l i ghtl y l es s a cti ve a ga i ns t gra m-pos i ti ve cocci tha n 1s t-genera ti on cepha l os pori ns . Second-genera ti on cepha l os pori ns a nd
cepha myci ns a re often us ed for pol ymi crobi a l i nfecti ons tha t i ncl ude gra m-nega ti ve ba ci l l i a nd gra m-pos i ti ve cocci . Beca us e cepha myci ns a re
a cti ve a ga i ns t Bacteroides s p, they ca n be us ed when a na erobes a re s us pected (eg, i n i ntra -a bdomi na l s eps i s , decubi tus ul cers , a nd di a beti c foot
i nfecti ons ). However, i n s ome medi ca l centers , thes e ba ci l l i a re no l onger rel i a bl y s us cepti bl e to cepha myci ns .
Third-generation cephalosporins: Thes e drugs a re a cti ve a ga i ns t
Haemophilus influenzae a nd s ome Entero-ba cteri a cea e (eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis) tha t do not produce a mpC l a cta ma s e or extended-s pectrum -l a cta ma s e (ESBL)
Cefta zi di me a nd cefopera zone a re a l s o a cti ve a ga i ns t
Pseudomonas aeruginosa
Some 3rd-genera ti on cepha l os pori ns ha ve rel a ti vel y poor a cti vi ty a ga i ns t gra m-pos i ti ve cocci . Ora l cefi xi me a nd cefti buten ha ve l i ttl e a cti vi ty
a ga i ns t S. aureus a nd, i f us ed for s ki n a nd s oft-ti s s ue i nfecti ons , s houl d be res tri cted to uncompl i ca ted i nfecti ons due to s treptococci . Thes e
cepha l os pori ns ha ve ma ny cl i ni ca l us es , a s does the 4th-genera ti on cepha l os pori n (s ee
Ta bl e 132-8).
Fourth-generation cephalosporin: The 4th-genera ti on cepha l os pori n cefepi me ha s a cti vi ty a ga i ns t
Gra m-pos i ti ve cocci (s i mi l a r to cefota xi me)
Gra m-nega ti ve ba ci l l i (enha nced a cti vi ty), i ncl udi ng P. aeruginosa (s i mi l a r to cefta zi di me), ESBL-produci ng K. pneumoniae a nd E. coli, a nd a mpC l a cta ma s e-produci ng Enteroba cteri a cea e, s uch a s Enterobacter s p
Fifth-generation cephalosporin: The 5th-genera ti on cepha l os pori n ceftobi prol e i s a cti ve a ga i ns t
Methi ci l l i n-res i s ta nt S. aureus
[Table 132-8. Some Cl i ni ca l Us es of 3rd- a nd 4th-Genera ti on Cepha l os pori ns ]
Contraindications
Cepha l os pori ns a re contra i ndi ca ted i n pa ti ents who a re a l l ergi c to them or who ha ve ha d a n a na phyl a cti c rea cti on to peni ci l l i ns .
Cepha l os pori ns a re i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but
huma n s tudi es do not).
Cepha l os pori ns enter brea s t mi l k a nd ma y a l ter bowel fl ora of the i nfa nt. Thus , us e duri ng brea s tfeedi ng i s often di s coura ged.
Adverse Effects
Si gni fi ca nt a dvers e effects i ncl ude
Hypers ens i ti vi ty rea cti ons (mos t common)
Clostridium difficile-i nduced di a rrhea (ps eudomembra nous col i ti s )
Leukopeni a
Thrombocytopeni a
Pos i ti ve Coombs ' tes t (a l though hemol yti c a nemi a i s very uncommon)
Hypers ens i ti vi ty rea cti ons a re the mos t common s ys temi c a dvers e effects ; ra s h i s common, but i mmedi a te IgE-medi a ted urti ca ri a a nd a na phyl a xi s
a re ra re.
Cros s -s ens i ti vi ty between cepha l os pori ns a nd peni ci l l i ns i s uncommon; cepha l os pori ns ca n be gi ven ca uti ous l y to pa ti ents wi th a hi s tory of
del a yed hypers ens i ti vi ty to peni ci l l i n i f neces s a ry. However, cepha l os pori ns s houl d not be us ed i n pa ti ents who ha ve ha d a n a na phyl a cti c
rea cti on to peni ci l l i n. Pa i n a t the IM i njecti on s i te a nd thrombophl ebi ti s a fter IV us e ma y occur.
Cefa ma ndol e (no l onger a va i l a bl e i n the US), cefopera zone, a nd cefoteta n ma y ha ve a di s ul fi ra m-l i ke effect when etha nol i s i nges ted, ca us i ng
na us ea a nd vomi ti ng. Cefa ma ndol e, cefopera zone, a nd cefoteta n ma y el eva te the PT/INR a nd PTT, a n effect tha t i s revers i bl e wi th vi ta mi n K.
Contraindications
Ceftri a xone i s contra i ndi ca ted a s fol l ows :
Ceftri a xone IV mus t not be coa dmi ni s tered wi th Ca -conta i ni ng IV s ol uti ons (i ncl udi ng conti nuous Ca -conta i ni ng i nfus i ons s uch a s pa rentera l
nutri ti on) i n neona tes 28 da ys beca us e preci pi ta ti on of ceftri a xone-Ca s a l t i s a ri s k. Fa ta l rea cti ons wi th ceftri a xone-Ca preci pi ta tes i n the
l ungs a nd ki dneys of neona tes ha ve been reported. In s ome ca s es , di fferent i nfus i on l i nes were us ed, a nd ceftri a xone a nd Ca -conta i ni ng
s ol uti ons were gi ven a t di fferent ti mes . To da te, no i ntra va s cul a r or pul mona ry preci pi ta tes ha ve been reported i n pa ti ents other tha n
neona tes who a re trea ted wi th ceftri a xone a nd Ca -conta i ni ng IV s ol uti ons . However, beca us e a n i ntera cti on between ceftri a xone a nd IV Ca conta i ni ng s ol uti ons i s theoreti ca l l y pos s i bl e i n pa ti ents other tha n neona tes , ceftri a xone a nd Ca -conta i ni ng s ol uti ons s houl d not be mi xed or
gi ven wi thi n 48 h of ea ch other (ba s ed on 5 ha l f-l i ves of ceftri a xone)even vi a di fferent i nfus i on l i nes a t di fferent s i tes to a ny pa ti ent
rega rdl es s of a ge. No da ta on potenti a l i ntera cti on between ceftri a xone a nd ora l Ca -conta i ni ng products or on i ntera cti on between IM
ceftri a xone a nd Ca -conta i ni ng products (IV or ora l ) a re a va i l a bl e.
Ceftri a xone s houl d not be gi ven to hyperbi l i rubi nemi c a nd preterm neona tes beca us e i n vi tro, ceftri a xone ca n di s pl a ce bi l i rubi n from s erum
a l bumi n, potenti a l l y tri ggeri ng kerni cterus .
Penicillins
Peni ci l l i ns (s ee
Ta bl e 132-9) a re ba cteri ci da l by unknown mecha ni s ms but perha ps by a cti va ti ng a utol yti c enzymes tha t des troy the cel l wa l l i n s ome ba cteri a .
Some ba cteri a produce -l a cta ma s e, whi ch i na cti va tes the drug; thi s effect ca n be bl ocked by a ddi ng a -l a cta ma s e i nhi bi tor (cl a vul a na te,
s ul ba cta m, or ta zoba cta m). However, a va i l a bl e -l a cta ma s e i nhi bi tors do not i nhi bi t a mpC -l a cta ma s es , commonl y produced by Enterobacter,
Serratia, Citrobacter, Providencia, a nd Morganella s pp or by P. aeruginosa, a nd thes e drugs ma y onl y pa rti a l l y i nhi bi t ESBL produced by s ome K.
pneumoniae, E. coli, a nd other Enteroba cteri a cea e.
[Table 132-9. Peni ci l l i ns ]
Pharmacology
Food does not i nterfere wi th a bs orpti on of a moxi ci l l i n, but peni ci l l i n G s houl d be gi ven 1 h before or 2 h a fter a mea l . Amoxi ci l l i n ha s genera l l y
repl a ced a mpi ci l l i n for ora l us e beca us e a moxi ci l l i n i s a bs orbed better, ha s fewer GI effects , a nd ca n be gi ven l es s frequentl y.
Peni ci l l i ns a re di s tri buted ra pi dl y i n the ECF of mos t ti s s ues , pa rti cul a rl y when i nfl a mma ti on i s pres ent.
Al l peni ci l l i ns except na fci l l i n a re excreted i n uri ne a nd rea ch hi gh l evel s i n uri ne. Pa rentera l peni ci l l i n G i s ra pi dl y excreted (s erum ha l f-l i fe 0.5
h), except for repos i tory forms (the benza thi ne or proca i ne s a l t of peni ci l l i n G); thes e forms a re i ntended for deep IM i njecti on onl y a nd provi de a
ti s s ue depot from whi ch a bs orpti on ta kes pl a ce over s evera l hours to s evera l da ys . Benza thi ne peni ci l l i n rea ches i ts pea k l evel more s l owl y a nd
i s genera l l y l ongera cti ng tha n proca i ne peni ci l l i n.
Indications
Peni ci l l i n G-l i ke drugs (i ncl udi ng peni ci l l i n V) a re pri ma ri l y us ed a ga i ns t
Gra m-pos i ti ve ba cteri a
Some gra m-nega ti ve cocci (eg, meni ngococci )

A mi nori ty of gra m-nega ti ve ba ci l l i a re a l s o s us cepti bl e to l a rge pa rentera l dos es of peni ci l l i n G. Mos t s ta phyl ococci , mos t Neisseria gonorrhoeae,
ma ny a na erobi c gra m-nega ti ve ba ci l l i , a nd a bout 30% of H. influenzae a re res i s ta nt. Peni ci l l i n G i s the drug of choi ce for s yphi l i s a nd, wi th
genta mi ci n, for endoca rdi ti s due to s us cepti bl e enterococci .
Benza thi ne peni ci l l i n G i s a va i l a bl e a s pure benza thi ne peni ci l l i n, a mi xture of equa l a mounts of benza thi ne a nd proca i ne peni ci l l i n G, a nd a
mi xture of 0.9 mi l l i on uni ts benza thi ne a nd 0.3 mi l l i on uni ts proca i ne peni ci l l i n G. Of the 3 products , onl y pure benza thi ne peni ci l l i n i s
recommended for trea ti ng s yphi l i s a nd preventi ng rheuma ti c fever. Whether the mi xture of equa l a mounts i s effecti ve i n trea ti ng s yphi l i s i s
unknown. Pure benza thi ne peni ci l l i n a nd the mi xture of equa l a mounts a re i ndi ca ted for trea ti ng URIs a nd s ki n a nd s oft-ti s s ue i nfecti ons ca us ed
by s us cepti bl e s treptococci .
Amoxicillin and ampicillin: Thes e drugs a re more a cti ve a ga i ns t
Enterococci
Certa i n gra m-nega ti ve ba ci l l i , s uch a s non--l a cta ma s e-produci ng H. influenzae, E. coli, a nd P. mirabilis; Salmonella s p; a nd Shigella s p
The a ddi ti on of a -l a cta ma s e i nhi bi tor a l l ows us e a ga i ns t methi ci l l i n-s ens i ti ve s ta phyl ococci , H. influenzae, N. gonorrhoeae, Moraxella catarrhalis,
Bacteroides s p, E. coli, a nd K. pneumoniae. Ampi ci l l i n i s i ndi ca ted pri ma ri l y for i nfecti ons typi ca l l y ca us ed by s us cepti bl e gra m-nega ti ve ba cteri a :
UTIs
Meni ngococca l meni ngi ti s
Bi l i a ry s eps i s
Res pi ra tory i nfecti ons
Listeria meni ngi ti s
Enterococca l i nfecti ons
Some typhoi d fever a nd typhoi d ca rri ers
Penicillinase-resistant penicillins: Thes e drugs a re us ed pri ma ri l y for
Peni ci l l i na s e-produci ng methi ci l l i n-s ens i ti ve S. aureus
Thes e drugs a re a l s o us ed to trea t s ome S. pneumoniae, group A s treptococca l , a nd methi ci l l i n-s ens i ti ve coa gul a s e-nega ti ve s ta phyl ococca l
i nfecti ons .
Broad-spectrum (antipseudomonal) penicillin: Thes e drugs ha ve a cti vi ty a ga i ns t
Ba cteri a s us cepti bl e to a mpi ci l l i n
Some s tra i ns of Enterobacter a nd Serratia s pp
Ma ny s tra i ns of P. aeruginosa
Ti ca rci l l i n i s l es s a cti ve a ga i ns t enterococci tha n pi pera ci l l i n. The a ddi ti on of a -l a cta ma s e i nhi bi tor enha nces a cti vi ty a ga i ns t -l a cta ma s eproduci ng methi ci l l i n-s ens i ti ve S. aureus, E. coli, K. pneumoniae, H. influenzae, a nd gra m-nega ti ve a na erobi c ba ci l l i , but not a ga i ns t gra m-nega ti ve
ba ci l l i tha t produce a mpC -l a cta ma s e, a nd ma y onl y pa rti a l l y i nhi bi t ESBL produced by s ome K. pneumoniae, E. coli, a nd other Enteroba cteri a cea e.
Broa d-s pectrum peni ci l l i ns exhi bi t s ynergy wi th a mi nogl ycos i des a nd a re us ua l l y us ed wi th thi s cl a s s to trea t P. aeruginosa i nfecti ons .
Contraindications
Peni ci l l i ns a re contra i ndi ca ted i n pa ti ents who ha ve ha d s eri ous a l l ergi c rea cti ons to them.
Peni ci l l i ns a re i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n
s tudi es do not).
Peni ci l l i ns enter brea s t mi l k i n s ma l l a mounts . Thei r us e i s us ua l l y cons i dered compa ti bl e wi th brea s tfeedi ng.
Adverse Effects
Advers e effects i ncl ude
Hypers ens i ti vi ty rea cti ons , i ncl udi ng ra s hes (mos t common)
Other a dvers e effects occur l es s commonl y.
Hypersensitivity: Mos t a dvers e effects a re hypers ens i ti vi ty rea cti ons :

Immedi a te rea cti ons : Ana phyl a xi s (whi ch ca n ca us e dea th wi thi n mi nutes ), urti ca ri a a nd a ngi oneuroti c edema (i n 1 to 5/10,000 i njecti ons ), a nd
dea th (i n a bout 0.3/10,000 i njecti ons )
Del a yed rea cti ons (i n up to 8% of pa ti ents ): Serum s i cknes s , ra s hes (eg, ma cul a r, pa pul a r, morbi l l i form), a nd exfol i a ti ve derma ti ti s (whi ch
us ua l l y a ppea rs a fter 7 to 10 da ys of thera py)
Mos t pa ti ents who report a n a l l ergi c rea cti on to peni ci l l i n do not rea ct to s ubs equent expos ure to peni ci l l i n. Al though s ma l l , ri s k of a n a l l ergi c
rea cti on i s a bout 10 ti mes hi gher for pa ti ents who ha ve ha d a previ ous a l l ergi c rea cti on. Ma ny pa ti ents report a dvers e rea cti ons to peni ci l l i n tha t
a re not trul y a l l ergi c (eg, GI a dvers e effects , nons peci fi c s ymptoms ). If pa ti ents ha ve a va gue or i ncons i s tent hi s tory of peni ci l l i n a l l ergy a nd ta ki ng
a l terna ti ve a nti bi oti cs i s not effecti ve or conveni ent, s ki n tes ti ng ma y be done (s ee p. 1123). Des ens i ti za ti on ma y be a ttempted i n pa ti ents wi th a
pos i ti ve s ki n tes t i f there i s no a l terna ti ve to a peni ci l l i n-type drug. However, pa ti ents wi th a hi s tory of a na phyl a xi s to peni ci l l i n s houl d not be
gi ven a ny -l a cta m a ga i n (i ncl udi ng for s ki n tes ti ng), except i n very ra re ci rcums ta nces when no s ubs ti tute ca n be found. In s uch ca s es , s peci a l
preca uti ons a nd des ens i ti za ti on regi mens a re requi red (s ee p. 1124).
Rashes: Ra s hes occur more often wi th a mpi ci l l i n a nd a moxi ci l l i n tha n wi th other peni ci l l i ns . Pa ti ents wi th i nfecti ous mononucl eos i s often devel op
a nona l l ergi c ra s h, typi ca l l y ma cul opa pul a r, us ua l l y begi nni ng between da ys 4 a nd 7 of trea tment.
Other adverse effects: Peni ci l l i ns ca n a l s o ca us e
CNS toxi ci ty (eg, s ei zures ) i f dos es a re hi gh, es peci a l l y i n pa ti ents wi th rena l i ns uffi ci ency
Nephri ti s
C. difficile-i nduced di a rrhea (ps eudomembra nous col i ti s )
Coombs '-pos i ti ve hemol yti c a nemi a
Leukopeni a
Thrombocytopeni a
Leukopeni a s eems to occur mos t often wi th na fci l l i n. Any peni ci l l i n us ed i n very hi gh IV dos es ca n i nterfere wi th pl a tel et functi on a nd ca us e
bl eedi ng, but ti ca rci l l i n i s the mos t common ca us e, es peci a l l y i n pa ti ents wi th rena l i ns uffi ci ency.
Other a dvers e effects i ncl ude pa i n a t the IM i njecti on s i te, thrombophl ebi ti s when the s a me s i te i s us ed repea tedl y for IV i njecti on, a nd, wi th ora l
formul a ti ons , GI di s turba nces . Ra rel y, bl a ck tongue, due to i rri ta ti on of the gl os s a l s urfa ce a nd kera ti ni za ti on of the s uperfi ci a l l a yers , occurs ,
us ua l l y when ora l formul a ti ons a re us ed. Ti ca rci l l i n i n hi gh dos es ma y ca us e Na overl oa d beca us e ti ca rci l l i n i s a di s odi um s a l t. Ti ca rci l l i n ca n
a l s o ca us e hypoka l emi c meta bol i c a l ka l os i s beca us e the l a rge a mount of nona bs orba bl e a ni on pres ented to the di s ta l tubul es a l ters H + i on
excreti on a nd s econda ri l y res ul ts i n K+ l os s .
Dosing Considerations
Beca us e peni ci l l i ns , except na fci l l i n, rea ch hi gh l evel s i n uri ne, dos es mus t be reduced i n pa ti ents wi th s evere rena l i ns uffi ci ency. Probeneci d
i nhi bi ts rena l tubul a r s ecreti on of ma ny peni ci l l i ns , i ncrea s i ng bl ood l evel s . It i s s ometi mes gi ven to ma i nta i n hi gh bl ood l evel s .
Other -Lactams
Carbapenems (i mi penem, meropenem, dori penem, a nd erta penem) a re pa rentera l ba cteri ci da l a nti bi oti cs tha t ha ve a n extremel y broa d s pectrum.
They a re a cti ve a ga i ns t
H. influenzae
Ana erobes
Mos t Enteroba cteri a cea e (i ncl udi ng thos e tha t produce a mpC -l a cta ma s e a nd ESBL, a l though P. mirabilis tends to ha ve hi gher i mi penem MICs )
Methi ci l l i n-s ens i ti ve s ta phyl ococci a nd s treptococci , i ncl udi ng S. pneumoniae (except pos s i bl y s tra i ns wi th reduced peni ci l l i n s ens i ti vi ty)
Mos t Enterococcus faecalis a nd ma ny P. aeruginosa s tra i ns , i ncl udi ng thos e res i s ta nt to broa d-s pectrum peni ci l l i ns a nd cepha l os pori ns , a re
s us cepti bl e to i mi penem, meropenem, a nd dori penem but a re res i s ta nt to erta penem. Ca rba penems a re a cti ve s ynergi s ti ca l l y wi th
a mi nogl ycos i des a ga i ns t P. aeruginosa. E. faecium a nd methi ci l l i n-res i s ta nt s ta phyl ococci a re res i s ta nt.
Ma ny mul ti drug-res i s ta nt hos pi ta l -a cqui red ba cteri a a re s ens i ti ve onl y to ca rba penems . However, expa nded us e of ca rba penems ha s res ul ted i n
s ome ca rba penem res i s ta nce.
Imi penem a nd meropenem penetra te i nto CSF when meni nges a re i nfl a med. Meropenem i s us ed for gra m-nega ti ve ba ci l l a ry meni ngi ti s ;
i mi penem i s not us ed i n meni ngi ti s beca us e i t ma y ca us e s ei zures . Mos t s ei zures occur i n pa ti ents who ha ve CNS a bnorma l i ti es or rena l
i ns uffi ci ency a nd who a re gi ven i na ppropri a tel y hi gh dos es .
Aztreonam i s a pa rentera l ba cteri ci da l a nti bi oti c; i t i s a s a cti ve a s cefta zi di me a ga i ns t
Enteroba cteri a cea e tha t do not produce a mpC -l a cta ma s e or ESBL

P. aeruginosa
Aztreona m i s not a cti ve a ga i ns t a na erobes . Gra m-pos i ti ve ba cteri a a re res i s ta nt to a ztreona m (i n contra s t to cepha l os pori ns ). Aztreona m a cts
s ynergi s ti ca l l y wi th a mi nogl ycos i des . Beca us e the meta bol i c products of a ztreona m di ffer from thos e of other -l a cta ms , cros s -hypers ens i ti vi ty i s
unl i kel y. Thus , a ztreona m i s us ed ma i nl y for
Severe a erobi c gra m-nega ti ve ba ci l l a ry i nfecti ons , i ncl udi ng meni ngi ti s , i n pa ti ents who ha ve a s eri ous -l a cta m a l l ergy but who neverthel es s
requi re -l a cta m thera py
Other a nti bi oti cs a re a dded to cover a ny s us pected gra m-pos i ti ve cocci a nd a na erobes . The dos e i s reduced i n rena l fa i l ure.
Chloramphenicol
Chl ora mpheni col i s pri ma ri l y ba cteri os ta ti c. It bi nds to the 50S s ubuni t of the ri bos ome, thereby i nhi bi ti ng ba cteri a l protei n s ynthes i s .
Pharmacology
Chl ora mpheni col i s wel l a bs orbed ora l l y. Pa rentera l thera py s houl d be IV.
Chl ora mpheni col i s di s tri buted wi del y i n body fl ui ds , i ncl udi ng CSF, a nd i s excreted i n uri ne. Beca us e of hepa ti c meta bol i s m, a cti ve
chl ora mpheni col does not a ccumul a te when rena l i ns uffi ci ency i s pres ent.
Indications
Chl ora mpheni col ha s a wi de s pectrum of a cti vi ty a ga i ns t
Gra m-pos i ti ve a nd gra m-nega ti ve cocci a nd ba ci l l i (i ncl udi ng a na erobes )
Rickettsia, Mycoplasma, Chlamydia, a nd Chlamydophila s pp
Beca us e of bone ma rrow toxi ci ty, the a va i l a bi l i ty of a l terna ti ve a nti bi oti cs , a nd the emergence of res i s ta nce, chl ora mpheni col i s no l onger a drug
of choi ce for a ny i nfecti on, except for
Seri ous i nfecti ons due to a few mul ti drug-res i s ta nt ba cteri a tha t rema i n s us cepti bl e to thi s a nti bi oti c
However, when chl ora mpheni col ha s been us ed to trea t meni ngi ti s ca us ed by rel a ti vel y peni ci l l i n-res i s ta nt pneumococci , outcomes ha ve been
di s coura gi ng, proba bl y beca us e chl ora mpheni col ha s poor ba cteri ci da l a cti vi ty a ga i ns t thes e s tra i ns .
Contraindications
Chl ora mpheni col i s contra i ndi ca ted i f a nother drug ca n be us ed i ns tea d.
Us e of chl ora mpheni col duri ng pregna ncy res ul ts i n feta l drug l evel s a l mos t a s hi gh a s ma terna l l evel s . Gra y ba by s yndrome i s a theoreti ca l
concern, pa rti cul a rl y nea r term, but there i s no cl ea r evi dence of feta l ri s k.
Chl ora mpheni col enters brea s t mi l k. Sa fety duri ng brea s tfeedi ng ha s not been determi ned.
Adverse Effects
Bone ma rrow depres s i on (mos t s eri ous )
Na us ea , vomi ti ng, a nd di a rrhea
Gra y ba by s yndrome (i n neona tes )
There a re 2 types of bone ma rrow depres s i on:
Revers i bl e dos e-rel a ted i nterference wi th i ron meta bol i s m: Thi s effect i s mos t l i kel y wi th hi gh dos es or prol onged trea tment or i n pa ti ents wi th
a s evere l i ver di s order.
Irrevers i bl e i di os yncra ti c a pl a s ti c a nemi a : Thi s a nemi a occurs i n < 1/25,000 trea ted pa ti ents . It ma y not devel op unti l a fter thera py i s s topped.
Chl ora mpheni col s houl d not be us ed topi ca l l y beca us e s ma l l a mounts ma y be a bs orbed a nd, ra rel y, ca us e a pl a s ti c a nemi a .
Hypers ens i ti vi ty rea cti ons a re uncommon. Opti c a nd peri phera l neuri ti s ma y occur wi th prol onged us e.
The neona ta l gra y ba by s yndrome, whi ch i nvol ves hypothermi a , cya nos i s , fl a cci di ty, a nd ci rcul a tory col l a ps e, i s often fa ta l . The ca us e i s hi gh bl ood
l evel s , whi ch occur beca us e the i mma ture l i ver ca nnot meta bol i ze a nd excrete chl ora mpheni col . To a voi d the s yndrome, cl i ni ci a ns s houl d not gi ve
i nfa nts 1 mo > 25 mg/kg/da y i ni ti a l l y, a nd dos es s houl d be a djus ted ba s ed on bl ood l evel s of the drug.
Daptomycin
Da ptomyci n i s a cycl i c l i popepti de a nti bi oti c tha t ha s a uni que mecha ni s m of a cti on. It bi nds to the ba cteri a l cel l membra nes , ca us i ng ra pi d
depol a ri za ti on of the membra ne due to K effl ux a nd a s s oci a ted di s rupti on of DNA, RNA, a nd protei n s ynthes i s ; the res ul t i s ra pi d concentra ti ondependent ba cteri a l dea th.
Indications
Da ptomyci n ha s a cti vi ty a ga i ns t the fol l owi ng:
Gra m-pos i ti ve ba cteri a (broa d-s pectrum a cti vi ty)
Mul ti drug-res i s ta nt gra m-pos i ti ve ba cteri a (beca us e cros s -res i s ta nce wi th other cl a s s es of a nti bi oti cs does not occur)
Da ptomyci n i s us ed ma i nl y for i nfecti ons ca us ed by
Va ncomyci n- a nd methi ci l l i n-res i s ta nt Staphylococcus aureus
Va ncomyci n-res i s ta nt enterococci
Pneumococci wi th reduced peni ci l l i n s ens i ti vi ty
However, methi ci l l i n-res i s ta nt S. aureus a nd va ncomyci n-res i s ta nt enterococci ma y become res i s ta nt duri ng da ptomyci n thera py, res ul ti ng i n
rel a ps i ng or pers i s tent i nfecti on.
Da ptomyci n i s i nferi or to ceftri a xone for pneumoni a , pres uma bl y beca us e da ptomyci n ca n bi nd to pul mona ry s urfa cta nt, reduci ng da ptomyci n's
a cti vi ty i n the a l veol a r epi thel i a l l i ni ng fl ui d.
Contraindications
Da ptomyci n i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to i t.
Da ptomyci n i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete).
Whether da ptomyci n enters brea s t mi l k a nd i s s a fe to us e duri ng brea s tfeedi ng i s unknown.
Adverse Effects
Eos i nophi l i c pneumoni a
Myopa thy
Chroni c us e ma y ca us e revers i bl e orga ni zi ng pneumoni a wi th eos i nophi l i c pul mona ry i nfi l tra tes , pres uma bl y beca us e da ptomyci n bi nds to
pul mona ry s urfa cta nt a nd thus a ccumul a tes i n the a l veol a r s pa ces .
Skel eta l myopa thy due to da ptomyci n i s revers i bl e but s el dom occurs wi th once/da y dos i ng.
Da ptomyci n i s gi ven pa rentera l l y once/da y. Over 90% i s bound to s erum protei n. Dos i ng i s a djus ted for rena l fa i l ure. Beca us e da ptomyci n ca n
ca us e revers i bl e s kel eta l myopa thy, pa ti ents s houl d be moni tored for mus cl e pa i n or wea knes s , a nd s erum crea ti ne ki na s e l evel s s houl d be
checked weekl y.
Fluoroquinolones
Fl uoroqui nol ones (s ee
Ta bl e 132-10) exhi bi t concentra ti on-dependent ba cteri ci da l a cti vi ty by i nhi bi ti ng the a cti vi ty of DNA gyra s e a nd topoi s omera s e, enzymes es s enti a l
for ba cteri a l DNA repl i ca ti on. Fl uoroqui nol ones a re di vi ded i nto 2 groups , ba s ed on a nti mi crobi a l s pectrum a nd pha rma col ogy:
Ol der group: Ci profl oxa ci n, norfl oxa ci n, a nd ofl oxa ci n
Newer group: Gemi fl oxa ci n, l evofl oxa ci n, a nd moxi fl oxa ci n
[Table 132-10. Fl uoroqui nol ones ]
Some newer fl uoroqui nol ones ha ve been wi thdra wn beca us e of toxi ci ty; they i ncl ude trova fl oxa ci n (beca us e of s evere hepa ti c toxi ci ty) a nd
ga ti fl oxa ci n (beca us e of hypogl ycemi a a nd hypergl ycemi a ).
Pharmacology
Ora l a bs orpti on i s di mi ni s hed by coa dmi ni s tra ti on of ca ti ons (a l umi num, Mg, Ca , zi nc, a nd i ron prepa ra ti ons ). After ora l a nd pa rentera l
a dmi ni s tra ti on, fl uoroqui nol ones a re wi del y di s tri buted i n mos t extra cel l ul a r a nd i ntra cel l ul a r fl ui ds a nd a re concentra ted i n the pros ta te, l ungs ,
a nd bi l e.
Mos t fl uoroqui nol ones a re meta bol i zed i n the l i ver a nd excreted i n uri ne, rea chi ng hi gh l evel s i n uri ne. Moxi fl oxa ci n i s el i mi na ted pri ma ri l y i n
bi l e.
Indications
Fl uoroqui nol ones a re a cti ve a ga i ns t the fol l owi ng:
Neisseria s p
Haemophilus influenzae
Moraxella catarrhalis
Mycoplasma s p
Chlamydia s p
Chlamydophila s p
Legionella s p
Enteroba cteri a cea e
Pseudomonas aeruginosa (pa rti cul a rl y ci profl oxa ci n)
Mycobacterium tuberculosis
Some a typi ca l mycoba cteri a
Methi ci l l i n-s ens i ti ve s ta phyl ococci
Nos ocomi a l methi ci l l i n-res i s ta nt s ta phyl ococci a re us ua l l y res i s ta nt. Ol der fl uoroqui nol ones ha ve poor a cti vi ty a ga i ns t s treptococci a nd
a na erobes . Newer fl uoroqui nol ones ha ve rel i a bl e a cti vi ty a ga i ns t s treptococci (i ncl udi ng Streptococcus pneumoniae wi th reduced peni ci l l i n
s ens i ti vi ty) a nd s ome a na erobes . As us e ha s i ncrea s ed, res i s ta nce, pa rti cul a rl y to ol der fl uoroqui nol ones , i s devel opi ng a mong
Enteroba cteri a cea e, P. aeruginosa, S. pneumoniae, a nd Neisseria s p. Nonethel es s , fl uoroqui nol ones ha ve ma ny cl i ni ca l us es (s ee
Ta bl e 132-11).
Fl uoroqui nol ones a re no l onger recommended for trea tment of gonorrhea i n the US beca us e of i ncrea s i ng res i s ta nce.
Contraindications
Contra i ndi ca ti ons i ncl ude
Previ ous a l l ergi c rea cti on to the drugs
Certa i n di s orders tha t predi s pos e to a rrhythmi a s (eg, QT-i nterva l prol onga ti on, uncorrected hypoka l emi a or hypoma gnes emi a , s i gni fi ca nt
bra dyca rdi a )
Us e of drugs known to prol ong the QT i nterva l or to ca us e bra dyca rdi a (eg, metocl opra mi de, ci s a pri de, erythromyci n, cl a ri thromyci n, cl a s s es Ia
a nd III a nti a rrhythmi cs , tri cycl i c a nti depres s a nts )
Fl uoroqui nol ones ha ve tra di ti ona l l y been cons i dered to be contra i ndi ca ted i n chi l dren beca us e they ma y ca us e ca rti l a ge l es i ons i f growth pl a tes
a re open. However, s ome experts , who cha l l enge thi s vi ew beca us e evi dence i s wea k, ha ve recommended pres cri bi ng fl uoroqui nol ones a s a 2ndl i ne a nti bi oti c a nd res tri cti ng us e to a few s peci fi c s i tua ti ons , i ncl udi ng P. aeruginosa i nfecti ons i n pa ti ents wi th cys ti c fi bros i s , prophyl a xi s a nd
trea tment of ba cteri a l i nfecti ons i n i mmunocompromi s ed pa ti ents , l i fe-threa teni ng mul ti res i s ta nt ba cteri a l i nfecti ons i n neona tes a nd i nfa nts ,
a nd Salmonella or Shigella GI tra ct i nfecti ons .
Fl uoroqui nol ones a re i n pregna ncy ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n a nd a ni ma l s tudi es i s i na dequa te, but cl i ni ca l
benefi t s ometi mes exceeds ri s k).
[Table 132-11. Some Cl i ni ca l Us es of Fl uoroqui nol ones ]
Fl uoroqui nol ones enter brea s t mi l k. Us e duri ng brea s tfeedi ng i s not recommended.
Adverse Effects
Seri ous a dvers e effects a re uncommon; ma i n concerns i ncl ude the fol l owi ng:
Upper GI a dvers e effects occur i n a bout 5% of pa ti ents beca us e of di rect GI i rri ta ti on a nd CNS effects .
CNS a dvers e effects (eg, mi l d hea da che, drows i nes s , i ns omni a , di zzi nes s , mood a l tera ti on) occur i n < 5%. NSAIDs ma y enha nce the CNS
s ti mul a tory effects of fl uoroqui nol ones . Sei zures a re ra re, but fl uoroqui nol ones s houl d not be us ed i n pa ti ents wi th CNS di s orders .
Tendi nopa thy, i ncl udi ng rupture of the Achi l l es tendon, ma y occur even a fter s hort-term us e of fl uoroqui nol ones .
QT-i nterva l prol onga ti on ca n occur, potenti a l l y l ea di ng to ventri cul a r a rrhythmi a s a nd s udden ca rdi a c dea th.
Fl uoroqui nol one us e ha s been s trongl y a s s oci a ted wi th Clostridium difficile-a s s oci a ted di a rrhea (ps eudomembra nous col i ti s ), es peci a l l y tha t due
to the hypervi rul ent C. difficile ri botype 027.
Di a rrhea , l eukopeni a , a nemi a , a nd photos ens i ti vi ty a re uncommon. Ra s h i s uncommon unl es s gemi fl oxa ci n i s us ed for > 1 wk a nd i s more l i kel y
to devel op i n women < 40. Nephrotoxi ci ty i s ra re.
Dos e reducti on, except for moxi fl oxa ci n, i s requi red for pa ti ents wi th rena l i ns uffi ci ency. Ol der fl uoroqui nol ones a re norma l l y gi ven twi ce/da y;
newer ones a nd a n extended-rel ea s e form of ci profl oxa ci n a re gi ven once/da y.
Ci profl oxa ci n ra i s es theophyl l i ne l evel s , s ometi mes res ul ti ng i n theophyl l i ne-rel a ted a dvers e effects .
Lincosamides, Oxazolidinones, and Streptogramins
Li ncos a mi des (cl i nda myci n), oxa zol i di nones (l i nezol i d), s treptogra mi ns (da l fopri s ti n [s treptogra mi n A] a nd qui nupri s ti n [s treptogra mi n B]) a re
grouped together beca us e they ha ve a s i mi l a r mode of a nti ba cteri a l a cti on a nd s i mi l a r a nti ba cteri a l s pectra . Ma crol i des (s ee p. 1212) a nd the
ketol i de tel i thromyci n (s ee p. 1214) ma y be i ncl uded wi th thi s group for s i mi l a r rea s ons . Al l i nhi bi t protei n s ynthes i s by bi ndi ng to the 50S
ri bos oma l s ubuni t. Cros s -res i s ta nce occurs a mong the fol l owi ng a nti bi oti cs beca us e they bi nd to the s a me ta rget:
Ma crol i des
Cl i nda myci n
Qui nupri s ti n
Tel i thromyci n (to s ome extent)
However, cros s -res i s ta nce does not occur between thes e a nti bi oti cs a nd da l fopri s ti n a nd l i nezol i d, whi ch bi nd to di fferent ta rgets on the 50S
ri bos oma l s ubuni t.
Lincosamides
Cl i nda myci n i s pri ma ri l y ba cteri os ta ti c. It bi nds to the 50S s ubuni t of the ri bos ome, thus i nhi bi ti ng ba cteri a l protei n s ynthes i s .
Pharmacology
Cl i nda myci n i s a bs orbed wel l ora l l y a nd ca n be gi ven pa rentera l l y. Cl i nda myci n di ffus es wel l i nto body fl ui ds except CSF; i t i s concentra ted i n
pha gocytes . Mos t of the drug i s meta bol i zed; meta bol i tes a re excreted i n bi l e a nd uri ne.
Indications
The s pectrum of a cti vi ty for cl i nda myci n i s s i mi l a r to tha t of the ma crol i de erythromyci n (s ee
Ta bl e 132-13 on p. 1213) except tha t cl i nda myci n i s
Effecti ve for i nfecti ons due to a na erobes (pa rti cul a rl y Bacteroides s p, i ncl udi ng B. fragilis), communi ty-a cqui red methi ci l l i n-res i s ta nt Staphylococcus
aureus, a nd ma crol i de-res i s ta nt, cl i nda myci n-s us cepti bl e Streptococcus pneumoniae
Not rel i a bl y a cti ve a ga i ns t mycopl a s ma s , chl a mydi a e, Chlamydophila s p, a nd l egi onel l a e
Aerobi c gra m-nega ti ve ba ci l l i a nd enterococci a re res i s ta nt.
Cl i nda myci n i s us ua l l y us ed for a na erobi c i nfecti ons ; however, cl i nda myci n res i s ta nce ha s emerged a mong thes e orga ni s ms i n s ome regi ons .
Beca us e thes e i nfecti ons often a l s o i nvol ve a erobi c gra m-nega ti ve ba ci l l i , a ddi ti ona l a nti bi oti cs a re a l s o us ed. Cl i nda myci n i s pa rt of
combi na ti on thera py for the fol l owi ng:
Infecti ons ca us ed by toxi geni c s treptococci (beca us e cl i nda myci n decrea s es the ba cteri a 's toxi n producti on)
Cerebra l toxopl a s mos i s
Ba bes i os i s
Fa l ci pa rum ma l a ri a
Pneumocystis jirovecii pneumoni a

Cl i nda myci n ca n be us ed for i nfecti ons (eg, s ki n a nd s oft-ti s s ue i nfecti ons ) i n communi ti es where communi ty-a s s oci a ted methi ci l l i n-res i s ta nt
Staphylococcus aureus (CA-MRSA) i s common; whether cl i nda myci n i s us eful depends on l oca l res i s ta nce pa tterns .
Cl i nda myci n ca n be us ed for i nfecti ons due to cl i nda myci n- a nd erythromyci n-s us cepti bl e s tra i ns . However, s ome CA-MRSA s tra i ns a re cl i nda myci ns us cepti bl e a nd erythromyci n-res i s ta nt; erythromyci n res i s ta nce i n thes e s tra i ns ma y be due to a n a cti ve effl ux mecha ni s m or to erythromyci ni nduci bl e modi fi ca ti on of the ri bos oma l ta rget. If the i nfecti ng s tra i n of cl i nda myci n-s us cepti bl e CA-MRSA i s res i s ta nt to erythromyci n beca us e of
the effl ux mecha ni s m, pa ti ents ca n be expected to res pond to cl i nda myci n. However, i f the s tra i n i s erythromyci n-res i s ta nt beca us e of
erythromyci n-i nduci bl e ri bos oma l ta rget modi fi ca ti on, pa ti ents ma y not res pond cl i ni ca l l y to cl i nda myci n beca us e certa i n muta nts ca n emerge
duri ng cl i nda myci n thera py; thes e muta nts a re res i s ta nt to cl i nda myci n a nd erythromyci n beca us e of cons ti tuti ve modi fi ca ti on of the ri bos oma l
ta rget. (Cons ti tuti ve mea ns tha t res i s ta nce i s a l wa ys pres ent rega rdl es s of whether a n i nducer, s uch a s erythromyci n, i s pres ent.)
Erythromyci n res i s ta nce due to effl ux ca n be di fferenti a ted from tha t due to i nduci bl e ri bos oma l ta rget modi fi ca ti on wi th a commonl y us ed doubl e
di s k di ffus i on a s s a y (D tes t). A cl i nda myci n di s k i s pl a ced a t a s ta nda rd di s ta nce from a n erythromyci n di s k on a n a ga r pl a te s trea ked wi th a
s ta nda rd i nocul um of the CA-MRSA s tra i n i n ques ti on. Zone of growth i nhi bi ti on (s ha ped l i ke the l etter "D") a round the cl i nda myci n di s k, wi th a
fl a ttened zone nea res t the erythromyci n di s k i ndi ca tes i nduci bl e ri bos oma l res i s ta nce. Pa ti ents who ha ve modera te to s evere i nfecti on wi th a n
i nduci bl e ri bos oma l -res i s ta nt CA-MRSA s tra i n a nd a pos i ti ve D tes t s houl d not be trea ted wi th cl i nda myci n.
Cl i nda myci n ca nnot be us ed for CNS i nfecti ons (other tha n cerebra l toxopl a s mos i s ) beca us e penetra ti on i nto the bra i n a nd CSF i s poor.
Topi ca l cl i nda myci n i s us ed for a cne.
Contraindications
Cl i nda myci n i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to i t or ha ve a hi s tory of regi ona l enteri ti s , ul cera ti ve col i ti s , or
a nti bi oti c-a s s oci a ted col i ti s .
Cl i nda myci n i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k but huma n evi dence i s i na dequa te, or a ni ma l s tudi es s how ri s k a nd huma n
s tudi es do not).
Cl i nda myci n enters brea s t mi l k. Us e duri ng brea s tfeedi ng i s not recommended.
Adverse Effects
The ma i n a dvers e effect i s
Clostridium difficile-a s s oci a ted di a rrhea (ps eudomembra nous col i ti s )
Cl i nda myci n, peni ci l l i ns , cepha l os pori ns , a nd, mos t recentl y, fl uoroqui nol ones ha ve been a s s oci a ted wi th C. difficile-a s s oci a ted di a rrhea .
Cl i nda myci n ha s been a s s oci a ted wi th C. difficile-a s s oci a ted di a rrhea i n up to 10% of pa ti ents rega rdl es s of route, i ncl udi ng topi ca l .
Hypers ens i ti vi ty rea cti ons ma y occur. If not s wa l l owed wi th wa ter, cl i nda myci n ma y ca us e es opha gi ti s .
Dos e a djus tments a re not requi red for rena l fa i l ure. Cl i nda myci n i s gi ven q 6 to 8 h.
Oxazolidinones
Li nezol i d ha s a cti vi ty a ga i ns t the fol l owi ng:
Streptococci
Enterococci (Enterococcus faecalis a nd E. faecium)
Sta phyl ococci , i ncl udi ng s tra i ns res i s ta nt to other cl a s s es of a nti bi oti cs
Mycoba cteri a
Ana erobes , s uch a s Fusobacterium, Prevotella, Porphyromonas, a nd Bacteroides s pp a nd peptos treptococci
Contraindications
Li nezol i d i s contra i ndi ca ted i n pa ti ents wi th a pri or a l l ergi c rea cti on to i t.
Li nezol i d i s a revers i bl e, nons el ecti ve mona mi ne oxi da s e i nhi bi tor (MAOI). Thus , l i nezol i d, when us ed wi th drugs tha t ha ve s erotonergi c a cti vi ty
(eg, SSRIs , MAOIs , tri cycl i c a nti depres s a nts , L-tryptopha n, a mpheta mi nes , l i thi um), ha s the potenti a l for ca us i ng s erotoni n s yndrome, a
hypers erotonergi c s ta te cha ra cteri zed by menta l s ta tus cha nges , neurol ogi c a bnorma l i ti es , a nd a utonomi c i ns ta bi l i ty.
Li nezol i d i s contra i ndi ca ted i n the fol l owi ng pa ti ents unl es s they a re ca reful l y obs erved for s ymptoms a nd s i gns of s erotoni n s yndrome:
Thos e who ha ve ta ken MAO i nhi bi tors (eg, phenel zi ne, i s oca rboxa zi d), s erotoni n reup-ta ke i nhi bi tors , tri cycl i c a nti depres s a nts , s erotoni n 1B,1D
receptor a goni s ts (tri pta ns ), meperi di ne, or bus pi rone wi thi n 2 wk
Thos e wi th ca rci noi d s yndrome
Li nezol i d s houl d not be gi ven to the fol l owi ng pa ti ents unl es s they a re moni tored for potenti a l i ncrea s es i n BP:
Thos e ta ki ng a ny of the fol l owi ng: s ympa thomi meti c drugs (eg, ps eudoephedri ne), va s opres s ors (eg, epi nephri ne, norepi nephri ne),
dopa mi nergi c drugs (eg, dopa mi ne, dobuta mi ne)
Thos e wi th uncontrol l ed hypertens i on
Thos e wi th thyrotoxi cos i s
Thos e wi th a pheochromocytoma
Li nezol i d i s i n pregna ncy ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n s tudi es i s i na dequa te, but cl i ni ca l benefi t s ometi mes
exceeds ri s k).
Whether l i nezol i d i s excreted i n brea s t mi l k or i s s a fe to us e duri ng brea s tfeedi ng i s unknown.
Adverse Effects
Revers i bl e myel os uppres s i on
Irrevers i bl e peri phera l neuropa thy
Revers i bl e opti c neuropa thy
Serotoni n s yndrome
Advers e effects a re mi ni ma l , a l though revers i bl e myel os uppres s i on, i ncl udi ng thrombocytopeni a , l eukopeni a , a nd a nemi a , occurs i n a bout 3% of
pa ti ents , us ua l l y when thera py i s us ed > 2 wk. Cons equentl y, CBC i s moni tored weekl y, es peci a l l y when thera py l a s ts > 2 wk. Peri phera l a nd opti c
neuropa thy ma y occur wi th prol onged us e, a nd pa ti ents ta ki ng l ong-term l i nezol i d thera py s houl d be cl os el y moni tored for thes e di s orders .
Streptogramins
Qui nupri s ti n a nd da l fopri s ti n a re s emi s yntheti c deri va ti ves of pri s ti na myci n, a na tura l l y occurri ng s treptogra mi n. Qui nupri s ti n/da l fopri s ti n (Q/D)
i s gi ven together i n a fi xed 30/70 combi na ti on; thi s combi na ti on ha s s ynergi s ti c ba cteri ci da l a cti vi ty a ga i ns t the fol l owi ng:
Streptococci a nd s ta phyl ococci , i ncl udi ng s tra i ns res i s ta nt to other a nti bi oti c cl a s s es
Some gra m-nega ti ve a na erobi c ba ci l l i
Clostridium perfringens
Peptostreptococcus s p
Atypi ca l res pi ra tory pa thogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila)
Q/D i nhi bi ts E. faecium, i ncl udi ng va ncomyci n-res i s ta nt s tra i ns . E. faecalis i s res i s ta nt.
Q/D i s gi ven vi a a centra l IV ca theter beca us e phl ebi ti s frequentl y occurs when Q/D i s gi ven vi a a peri phera l vei n. Up to 30% of pa ti ents devel op
s i gni fi ca nt mya l gi a s .
Dos a ge reducti on i s requi red for s evere hepa ti c i ns uffi ci ency but not for rena l i ns uffi ci ency.
Q/D ma y i nhi bi t drugs tha t a re meta bol i zed by the cytochrome P-450 (CYP450) 3A4 i s oenzyme s ys tem.
Macrolides
Ma crol i des (s ee
Ta bl e 132-12) a re pri ma ri l y ba cteri os ta ti c; by bi ndi ng to the 50S s ubuni t of the ri bos ome, they i nhi bi t ba cteri a l protei n s ynthes i s .
Pharmacology
Di ri thromyci n i s a prodrug tha t i s converted to i ts a cti ve form duri ng i ntes ti na l a bs orpti on. Except for tel i thromyci n, ma crol i des a re rel a ti vel y poorl y
a bs orbed ora l l y. Food ha s the fol l owi ng effects on a bs orpti on:
For di ri thromyci n a nd extended-rel ea s e cl a ri thromyci n, i ncrea s ed a bs orpti on
For i mmedi a te-rel ea s e cl a ri thromyci n ta bl et or s us pens i on, no effect

For a zi thromyci n ca ps ul es a nd erythromyci n (i ncl udi ng ba s e a nd s tea ra te formul a ti ons ), decrea s ed a bs orpti on
Al l ma crol i des di ffus e wel l i nto body fl ui ds , except CSF, a nd a re concentra ted i n pha gocytes . Excreti on i s ma i nl y i n bi l e.
Indications
Ma crol i des a re a cti ve a ga i ns t
Aerobi c a nd a na erobi c gra m-pos i ti ve cocci , except for mos t enterococci , ma ny Staphylococcus aureus s tra i ns (es peci a l l y methi ci l l i n-res i s ta nt
s tra i ns ), a nd s ome Streptococcus pneumoniae a nd S. pyogenes s tra i ns
Mycoplasma pneumoniae
Chlamydia trachomatis
Chlamydophila pneumoniae
Legionella s p
[Table 132-12. Ma crol i des ]
Corynebacterium diphtheriae
Campylobacter s p
Treponema pallidum
Propionibacterium acnes
Borrelia burgdorferi
Bacteroides fragilis i s res i s ta nt. Cl a ri thromyci n a nd a zi thromyci n ha ve enha nced a cti vi ty a ga i ns t Haemophilus influenzae a nd a cti vi ty a ga i ns t
Mycobacterium avium compl ex.
Ma crol i des ha ve been cons i dered the drug of choi ce for group A s treptococca l a nd pneumococca l i nfecti ons when peni ci l l i n ca nnot be us ed.
However, pneumococci wi th reduced peni ci l l i n s ens i ti vi ty a re often res i s ta nt to ma crol i des , a nd i n s ome communi ti es , up to 20% of S. pyogenes a re
ma crol i de-res i s ta nt. Beca us e they a re a cti ve a ga i ns t a typi ca l res pi ra tory pa thogens , they a re often us ed empi ri ca l l y for l ower res pi ra tory tra ct
i nfecti ons , but a nother drug i s often neces s a ry to cover ma crol i de-res i s ta nt pneumococci . Ma crol i des ha ve other cl i ni ca l us es (s ee Ta bl e 132-13).
Ma crol i des a re not us ed to trea t meni ngi ti s .
Contraindications
Ma crol i des a re contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to them.
Concomi ta nt a dmi ni s tra ti on of ma crol i des wi th a s temi zol e, ci s a pri de, pi mozi de, or terfena di ne i s contra i ndi ca ted. Pos tma rketi ng s urvei l l a nce ha s
reported ca rdi a c a rrhythmi a s (QT prol onga ti on, ventri cul a r ta chyca rdi a , ventri cul a r fi bri l l a ti on, tors a des de poi ntes ) when cl a ri thromyci n or
erythromyci n wa s coa dmi ni s tered wi th a s temi zol e, ci s a pri de, pi mozi de, or terfena di ne; thi s effect wa s mos t l i kel y due to i nhi bi ti on of
meta bol i s m of thes e drugs by erythromyci n a nd cl a ri thromyci n. Dea ths ha ve been reported.
Erythromyci n a nd a zi thromyci n a re i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es
s how ri s k but huma n s tudi es do not). Erythromyci n i s cons i dered s a fer beca us e cl i ni ca l us e ha s been much more extens i ve.
Cl a ri thromyci n i s i n ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n s tudi es i s i na dequa te, but cl i ni ca l benefi t s ometi mes
outwei ghs ri s k).
Erythromyci n i s cons i dered compa ti bl e wi th brea s tfeedi ng. Sa fety of other ma crol i des duri ng brea s tfeedi ng i s unknown.
Adverse Effects
Ma i n concerns i ncl ude
GI di s turba nces (ma i nl y wi th erythromyci n)
QT-i nterva l prol onga ti on by erythromyci n
Inhi bi ti on of hepa ti c meta bol i s m, l ea di ng to numerous drug i ntera cti ons
Erythromyci n commonl y ca us es dos e-rel a ted GI di s turba nces , i ncl udi ng na us ea , vomi ti ng, a bdomi na l cra mps , a nd di a rrhea ; di s turba nces a re l es s
common wi th cl a ri thromyci n a nd a zi thromyci n. Ta ki ng the drug wi th food ma y hel p
[Table 132-13. Some Cl i ni ca l Us es of Ma crol i des ]

decrea s e GI di s turba nces . Erythromyci n ma y ca us e dos e-rel a ted ti nni tus , di zzi nes s , a nd revers i bl e hea ri ng l os s . Chol es ta ti c ja undi ce occurs mos t
commonl y wi th erythromyci n es tol a te. Ja undi ce us ua l l y a ppea rs a fter 10 da ys of us e, pri ma ri l y i n a dul ts but ca n occur ea rl i er i f the drug ha s been
gi ven previ ous l y. Erythromyci n i s not gi ven IM beca us e i t ca us es s evere pa i n; when gi ven IV, i t ma y ca us e phl ebi ti s or pa i n. Hypers ens i ti vi ty
rea cti ons a re ra re.
Erythromyci n ca us es QT-i nterva l prol onga ti on a nd predi s pos es to ventri cul a r ta chya rrhythmi a , es peci a l l y i n women, i n pa ti ents who ha ve QTi nterva l prol onga ti on or el ectrol yte a bnorma l i ti es , a nd i n pa ti ents ta ki ng a nother drug tha t ma y prol ong the QT i nterva l .
For a zi thromyci n a nd di ri thromyci n, no dos a ge a djus tment i s requi red for rena l i ns uffi ci ency.
Erythromyci n a nd, to s ome extent, cl a ri thromyci n i ntera ct wi th numerous drugs beca us e they i nhi bi t hepa ti c meta bol i s m vi a the cytochrome P-450
(CYP450) s ys tem. Azi thromyci n i s the l ea s t l i kel y to i ntera ct wi th other drugs . Intera cti ons ma y occur when erythromyci n or cl a ri thromyci n a re ta ken
wi th the fol l owi ng:
Wa rfa ri n: Further el eva ti on of the PT/INR
Lova s ta ti n a nd s i mva s ta ti n: Rha bdomyol ys i s
Mi da zol a m a nd tri a zol a m: Somnol ence
Theophyl l i ne: Na us ea , vomi ti ng, a nd s ei zures
Ta crol i mus , cycl os pori ne, a nd ergot a l ka l oi ds : El eva ted s erum l evel s of thes e drugs
Telithromycin
Tel i thromyci n i s a ketol i de a nti bi oti c. Ketol i des a re chemi ca l l y rel a ted to ma crol i des a nd i nhi bi t ba cteri a l ri bos oma l protei n s ynthes i s wi thout
i nduci ng res i s ta nce to ma crol i des , cl i nda myci n, or s treptogra mi ns .
Tel i thromyci n i s ra pi dl y a bs orbed ora l l y wi th or wi thout food a nd i s meta bol i zed pri ma ri l y i n the l i ver.
Indications
Tel i thromyci n i s a cti ve a ga i ns t erythromyci n-s us cepti bl e s ta phyl ococci a nd s treptococci a nd mul ti drug-res i s ta nt S. pneumoniae. Tel i thromyci n i s
a l s o a cti ve a ga i ns t erythromyci n-s us cepti bl e enterococci , Bordetella pertussis, H. influenzae, Helicobacter pylori, Moraxella catarrhalis, M. pneumoniae, C.
pneumoniae, a nd Legionella, Prevotella, a nd Peptostreptococcus s pp.
Beca us e of s a fety concerns , tel i thromyci n i s recommended onl y for the trea tment of a dul ts 18 yr wi th communi ty a cqui red mi l d to modera te
pneumoni a due to the fol l owi ng:
S. pneumoniae (i ncl udi ng mul ti drug-res i s ta nt s tra i ns , i e, peni ci l l i n-res i s ta nt S. pneumoniae; i s ol a tes res i s ta nt to 2 of the fol l owi ng: peni ci l l i n,
2nd-genera ti on cepha l os pori ns [eg, cefuroxi me], ma crol i des , tetra cycl i nes , tri methopri m/s ul fa methoxa zol e)
H. influenzae
M. catarrhalis
C. pneumoniae
M. pneumoniae
Contraindications
Contra i ndi ca ti ons i ncl ude
Previ ous a l l ergi c rea cti on to tel i thromyci n or a ny ma crol i de
Previ ous hepa ti ti s or ja undi ce a fter ta ki ng tel i thromyci n or a ma crol i de
Concurrent us e of pi mozi de or ci s a pri de beca us e of ca rdi a c a rrhythmi a s (QT prol onga ti on, ventri cul a r ta chyca rdi a , ventri cul a r fi bri l l a ti on,
tors a des de poi ntes )
Mya s theni a gra vi s beca us e tel i thromyci n ma y exa cerba te s ymptoms a nd fa ta l res pi ra tory fa i l ure ha s occurred i n pa ti ents wi th thi s di s order
Tel i thromyci n i s i n pregna ncy ca tegory C beca us e a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n s tudi es i s i na dequa te, but cl i ni ca l benefi t
s ometi mes outwei ghs ri s k.
Sa fety of tel i thromyci n duri ng brea s tfeedi ng i s unknown.

Adverse Effects
GI di s turba nces
QT-i nterva l prol onga ti on
Severe hepa ti ti s
Di a rrhea , na us ea , vomi ti ng, a nd di zzi nes s a re the mos t common a dvers e effects . Prol onga ti on of the QT i nterva l , hyperbi l i rubi nemi a , el eva ti on of
l i ver enzymes , tra ns i ent l os s of cons ci ous nes s (s ometi mes a s s oci a ted wi th va ga l s yndrome), a nd vi s ua l di s turba nces (pa rti cul a rl y a s l owed a bi l i ty
to a ccommoda te a nd to rel ea s e a ccommoda ti on) a re l es s common. Severe hepa totoxi ci ty, whi ch ma y requi re l i ver tra ns pl a nta ti on a nd whi ch ma y
be fa ta l , ma y occur.
Cros s -s ens i ti vi ty wi th ma crol i des ca n occur.
Tel i thromyci n i nhi bi ts cytochrome P-450 (CYP450) 3A4, i ncrea s i ng l evel s of the fol l owi ng drugs :
Di goxi n: Di goxi n a dvers e effects or s erum l evel s s houl d be moni tored.
Ergot a l ka l oi ds : Concomi ta nt us e s houl d be a voi ded.
Benzodi a zepi nes : Concomi ta nt us e requi res ca uti on.
Metoprol ol : Concomi ta nt us e i n pa ti ents wi th hea rt fa i l ure requi res ca uti on.
Sta ti ns : Concomi ta nt us e of s i mva s ta ti n, l ova s ta ti n, or a torva s ta ti n (but not pra va s ta ti n or fl uva s ta ti n) s houl d be a voi ded.
Ci s a pri de: Concomi ta nt us e i s contra i ndi ca ted.
Pi mozi de: Concomi ta nt us e i s contra i ndi ca ted.
Si rol i mus
Ta crol i mus
CYP3A4 i nducers s uch a s ri fa mpi n, phenytoi n, ca rba ma zepi ne, a nd phenoba rbi ta l decrea s e l evel s of tel i thromyci n; the CYP3A4 i nhi bi tors
i tra cona zol e a nd ketocona zol e i ncrea s e l evel s of tel i thromyci n. Tel i thromyci n decrea s es a bs orpti on of s ota l ol .
Metronidazole
Metroni da zol e i s ba cteri ci da l . It enters ba cteri a l cel l wa l l s a nd i nterrupts DNA.
Pharmacology
Ora l metroni da zol e i s a bs orbed wel l . It i s us ua l l y gi ven IV onl y i f pa ti ents ca nnot be trea ted ora l l y. It i s di s tri buted wi del y i n body fl ui ds a nd
penetra tes i nto CSF, res ul ti ng i n hi gh concentra ti ons . Metroni da zol e i s meta bol i zed pres uma bl y i n the l i ver a nd excreted ma i nl y i n uri ne, but
el i mi na ti on i s not decrea s ed i n pa ti ents wi th rena l i ns uffi ci ency.
Indications
Metroni da zol e i s a cti ve a ga i ns t
Al l obl i ga te a na erobi c ba cteri a (i t i s i na cti ve a ga i ns t fa cul ta ti ve a na erobi c a nd a erobi c ba cteri a )
Certa i n protozoa n pa ra s i tes (eg, Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis [lamblia])
Metroni da zol e i s us ed pri ma ri l y for i nfecti ons ca us ed by obl i ga te a na erobes , often wi th other a nti mi crobi a l s . Metroni da zol e i s the drug of choi ce
for ba cteri a l va gi nos i s . The drug ha s other cl i ni ca l us es (s ee
Ta bl e 132-14).
Contraindications
Metroni da zol e i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to i t.
Metroni da zol e i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n
s tudi es do not). Nonethel es s , metroni da zol e s houl d be a voi ded duri ng the 1s t tri mes ter beca us e muta geni ci ty i s a concern.
[Table 132-14. Some Cl i ni ca l Us es of Metroni da zol e]

Metroni da zol e enters brea s t mi l k; us e duri ng brea s tfeedi ng i s not recommended.
Adverse Effects
GI di s turba nces
CNS effects a nd peri phera l neuropa thy
Di s ul fi ra m-l i ke rea cti on
Na us ea , vomi ti ng, hea da che, s ei zures , s yncope, other CNS effects , a nd peri phera l neuropa thy ca n occur; ra s h, fever, a nd revers i bl e neutropeni a
ha ve been reported. Metroni da zol e ca n ca us e a meta l l i c ta s te a nd da rk uri ne. A di s ul fi ra m-l i ke rea cti on ma y occur i f a l cohol i s i nges ted wi thi n 7
da ys of us e.
Metroni da zol e dos es a re not decrea s ed i n pa ti ents wi th rena l fa i l ure but a re us ua l l y decrea s ed 50% i n pa ti ents wi th s i gni fi ca nt l i ver di s ea s e.
Metroni da zol e i nhi bi ts meta bol i s m of wa rfa ri n a nd ma y i ncrea s e i ts a nti coa gul a nt effect.
Mupirocin
Mupi roci n i nhi bi ts ba cteri a l RNA a nd protei n s ynthes i s . It i s a va i l a bl e onl y a s a 2% topi ca l prepa ra ti on, whi ch i s ba cteri ci da l a ga i ns t s ta phyl ococci
a nd -hemol yti c s treptococci . Sys temi c a bs orpti on of topi ca l mupi roci n i s negl i gi bl e.
Mupi roci n i s us ed for i mpeti go a nd for mi nor s uperfi ci a l s econda ri l y i nfected s ki n l es i ons . Mupi roci n ca n a l s o era di ca te Staphylococcus aureus
na s a l ca rri a ge, a l though rel a ps e ra tes ma y be hi gh. Chroni c thera py l ea ds to mupi roci n-res i s ta nt s ta phyl ococci .
Mupi roci n i s nontoxi c but, when a ppl i ed to denuded s ki n or mucous membra nes , ma y ca us e i tchi ng a nd burni ng.
Nitrofurantoin
Ni trofura ntoi n i s ba cteri ci da l ; the exa ct mecha ni s m i s unknown.
Ni trofura ntoi n i s a va i l a bl e onl y for ora l us e.
Pharmacology
After a s i ngl e dos e, s erum drug l evel s a re very l ow, but uri ne drug l evel s a re thera peuti c.
Indications
Ni trofura ntoi n i s a cti ve a ga i ns t common uropa thogens , s uch a s
Escherichia coli
Staphylococcus saprophyticus
Enterococcus faecalis
E. faecium, i ncl udi ng va ncomyci n-res i s ta nt s tra i ns , a nd Klebsiella a nd Enterobacter s p a re l es s s us cepti bl e. Mos t s tra i ns of Proteus, Providencia,
Morganella, Serratia, Acinetobacter, a nd Pseudomonas s pp a re res i s ta nt. There i s no cros s -res i s ta nce wi th other a nti bi oti c cl a s s es .
Ni trofura ntoi n i s us ed onl y for
Trea tment or prophyl a xi s of uncompl i ca ted UTI
In women wi th recurrent UTIs , i t ma y decrea s e the number of epi s odes .
Contraindications
Contra i ndi ca ti ons to ni trofura ntoi n us e i ncl ude
Previ ous a l l ergi c rea cti on to i t
Rena l i ns uffi ci ency (crea ti ni ne cl ea ra nce < 60 L/mi n)
Age < 1 mo

Ni trofura ntoi n i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n
s tudi es do not). Nonethel es s , ni trofura ntoi n i s contra i ndi ca ted a t term a nd duri ng l a bor or del i very beca us e i t i nterferes wi th i mma ture enzyme
s ys tems i n RBCs of neona tes , da ma gi ng the cel l s a nd res ul ti ng i n hemol yti c a nemi a .
Ni trofura ntoi n enters brea s t mi l k a nd i s contra i ndi ca ted duri ng the fi rs t month of brea s t-feedi ng.
Adverse Effects
GI di s turba nces
Pul mona ry toxi ci ty
Peri phera l neuropa thy
Hemol yti c a nemi a
Hepa ti c toxi ci ty
Common a dvers e effects a re na us ea a nd vomi ti ng, whi ch a re l es s l i kel y wi th the ma crocrys ta l l i ne form. Fever, ra s h, a cute hypers ens i ti vi ty
pneumoni ti s (a ccompa ni ed by fever a nd eos i nophi l i a ), a nd chroni c progres s i ve pul mona ry i nters ti ti a l fi bros i s ma y occur. Pa res thes i a s ma y res ul t
a nd ma y be fol l owed by a s evere a s cendi ng motor a nd s ens ory pol yneuropa thy i f the drug i s conti nued, es peci a l l y i n pa ti ents wi th rena l fa i l ure.
Leukopeni a a nd hepa ti c toxi ci ty (a cute chol es ta ti c or chroni c a cti ve hepa ti ti s ) ha ve been reported, a nd hemol yti c a nemi a ca n occur i n pa ti ents
wi th G6PD defi ci ency a nd i n i nfa nts < 1 mo. Chroni c pul mona ry a nd hepa ti c rea cti ons occur when the drug i s us ed for > 6 mo.
Polypeptides
Pol ypepti de a nti bi oti cs di s rupt ba cteri a l cel l wa l l s (s ee
Ta bl e 132-15).
Ba ci tra ci n i s a pol ypepti de a nti bi oti c tha t i nhi bi ts cel l wa l l s ynthes i s a nd i s a cti ve a ga i ns t gra m-pos i ti ve ba cteri a .
Col i s ti n (pol ymyxi n E) a nd pol ymyxi n B a re ca ti oni c pol ypepti de a nti bi oti cs tha t di s rupt the outer ba cteri a l cel l membra ne by bi ndi ng to the
a ni oni c outer membra ne, whi ch conta i ns l i popol ys a ccha ri de (endotoxi n), a nd thereby neutra l i zi ng the ba cteri a 's toxi ci ty.
Col i s ti n metha ne s ul fona te (col i s ti metha te s odi um [CMS]) i s a pa rentera l prepa ra ti on of a prodrug tha t i s tra ns formed i n bl ood a nd uri ne to
col i s ti n. CMS i s l es s toxi c tha n col i s ti n.
Pol ypepti des a re us ua l l y us ed topi ca l l y; s ys temi c a bs orpti on i s negl i gi bl e.
Indications
Pol ymyxi n B a nd col i s ti n ha ve ra pi d concentra ti on-dependent ba cteri ci da l a cti vi ty a ga i ns t
Mos t fa cul ta ti ve a nd a erobi c gra m-nega ti ve ba ci l l i , i ncl udi ng Pseudomonas aeruginosa a nd Acinetobacter s p
Thes e drugs a re not a cti ve a ga i ns t Proteus, Providencia, Burkholderia, and Serratia s pp a nd s ome obl i ga te a na erobes , i ncl udi ng Bacteroides fragilis a nd
gra m-pos i ti ve ba cteri a . Devel opment of res i s ta nce i s uncommon.
Pol ypepti des a re us ed for s evera l types of i nfecti ons (s ee
Ta bl e 132-16).
Contraindications
Al l pol ypepti des a re contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to them. CMS a nd pol ymyxi n B s houl d not be gi ven
s i mul ta neous l y wi th drugs tha t bl ock neuromus cul a r tra ns mi s s i on or a re nephrotoxi c (eg, a mi nogl ycos i des , cura re-l i ke drugs ).
Ba ci tra ci n ma y pos e mi ni ma l ri s k duri ng pregna ncy a nd brea s tfeedi ng beca us e s ys temi c a bs orpti on i s mi ni ma l ; however, s a fety ha s not been
es ta bl i s hed.
Pol ymyxi n B i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n
s tudi es do not).
[Table 132-15. Pol ypepti des ]
Col i s ti n i s i n pregna ncy ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n s tudi es i s i na dequa te, but cl i ni ca l benefi t s ometi mes
outwei ghs ri s k); thi s drug cros s es the pl a centa . Whether us e duri ng brea s tfeedi ng i s s a fe i s unknown.
Adverse Effects

Nephrotoxi ci ty
Centra l a nd peri phera l neurotoxi ci ty
Pol ymyxi ns a re nephrotoxi c. CMS a nd pol ymyxi n B ma y ca us e ci rcumora l a nd extremi ty pa res thes i a s , verti go, s l urred s peech, a nd mus cl e wea knes s
a nd res pi ra tory di ffi cul ty due to neuromus cul a r bl ocka de, es peci a l l y i n pa ti ents wi th rena l i ns uffi ci ency.
Rifamycins
The ri fa myci ns a re ba cteri ci da l a nd i nhi bi t ba cteri a l DNA-dependent RNA pol ymera s e, s uppres s i ng RNA s ynthes i s (s ee
Ta bl e 132-17).
Rifampin and Rifabutin
Ri fa mpi n a nd ri fa buti n ha ve s i mi l a r pha rma col ogy, a nti mi crobi a l s pectra , a nd a dvers e effects .
Pharmacology
Ora l a bs orpti on i s good, produci ng wi de di s tri buti on i n body ti s s ues a nd fl ui ds , i ncl udi ng CSF. Ri fa mpi n i s concentra ted i n pol ymorpho-nucl ea r
gra nul ocytes a nd ma cropha ges , fa ci l i ta ti ng cl ea ra nce of ba cteri a from a bs ces s es . It i s meta bol i zed i n the l i ver a nd el i mi na ted i n bi l e a nd, to a
much l es s er extent, i n uri ne.
Indications
Rifampin i s a cti ve a ga i ns t
Mos t gra m-pos i ti ve a nd s ome gra m-nega ti ve ba cteri a
Mycobacterium s p
Res i s ta nce devel ops ra pi dl y, s o ri fa mpi n i s ra rel y us ed a l one. Ri fa mpi n i s us ed wi th other a nti bi oti cs for
TB (s ee p.
1307)
Atypi ca l mycoba cteri a l i nfecti on (ri fa mpi n i s a cti ve a ga i ns t ma ny nontubercul ous mycoba cteri a , but ra pi dl y growi ng mycoba cteri a , s uch a s M.
fortuitum or M. chelonae, a re na tura l l y res i s ta nt)
Lepros y (wi th da ps one wi th or wi thout cl ofa zi mi ne)
Sta phyl ococca l i nfecti ons , i ncl udi ng os teomyel i ti s , pros theti c va l ve endoca rdi ti s , a nd
[Table 132-16. Some Cl i ni ca l Us es of Pol ypepti des ]
i nfecti ons i nvol vi ng forei gn bodi es s uch a s a pros theti c joi nt (wi th other a nti s ta phyl ococca l a nti bi oti cs )
Legionella i nfecti ons (ol der da ta s ugges t better outcomes for ri fa mpi n when us ed wi th erythromyci n; us e of ri fa mpi n wi th a zi thromyci n or a
fl uoroqui nol one offers no a dva nta ge)
Pneumococca l meni ngi ti s when orga ni s ms a re s us cepti bl e to ri fa mpi n (wi th va ncomyci n
[Table 132-17. Ri fa myci ns ]
wi th or wi thout ceftri a xone or cefota xi me for ceftri a xone- or cefota xi me-res i s ta nt orga ni s ms [MIC > 4 g/mL]) or when expected cl i ni ca l or
mi crobi ol ogi c res pons e i s del a yed
Ri fa mpi n ca n be us ed a l one for prophyl a xi s of cl os e conta cts of pa ti ents wi th meni ngococca l or Haemophilus influenzae type b meni ngi ti s .
Ri fa buti n a nd ri fa mpi n a re equa l l y effi ca ci ous i n regi mens for TB i n HIV-pos i ti ve a nd HIV-nega ti ve pa ti ents .
Rifabutin i s more a cti ve tha n ri fa mpi n a ga i ns t M. avium compl ex a nd i s us ed preferenti a l l y i n mul ti drug regi mens for thes e i nfecti ons , but
otherwi s e, ri fa mpi n i s preferred.
Contraindications
Ri fa mpi n a nd ri fa buti n a re contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to them.
Ri fa buti n i s i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n
s tudi es do not). Sa fety duri ng brea s t-feedi ng i s unknown.
Ri fa mpi n i s i n pregna ncy ca tegory C (a ni ma l s tudi es s how s ome ri s k [i n thi s ca s e, tera togeni ci ty], evi dence i n huma n s tudi es i s i na dequa te, but
cl i ni ca l benefi t s ometi mes outwei ghs ri s k). The drug cros s es the pl a centa . Sti l l , i f ri s k of ma terna l TB i s modera te or hi gh, trea tment i s thought to
be l es s ha rmful for the fetus tha n untrea ted ma terna l TB a nd i s thus recommended. Beca us e of potenti a l tumori geni ci ty s hown i n a ni ma l s tudi es ,
a deci s i on to s top brea s tfeedi ng or to s top the drug s houl d be ma de, dependi ng on the i mporta nce of the drug to the mother.
Adverse Effects
Hepa ti ti s (mos t s eri ous )
GI di s turba nces
CNS effects
Myel os uppres s i on
Hepa ti ti s occurs much more often when i s oni a zi d or pyra zi na mi de i s us ed concurrentl y wi th ri fa mpi n. Duri ng the fi rs t week of thera py, ri fa mpi n
ma y ca us e a tra ns i ent ri s e i n unconjuga ted s erum bi l i rubi n, whi ch res ul ts from competi ti on between ri fa mpi n a nd bi l i rubi n for excreti on a nd
whi ch i s not i n i ts el f a n i ndi ca ti on for i nterrupti ng trea tment.
CNS effects ma y i ncl ude hea da che, drows i nes s , a ta xi a , a nd confus i on. Ra s h, fever, l eukopeni a , hemol yti c a nemi a , thrombocytopeni a , i nters ti ti a l
nephri ti s , a cute tubul a r necros i s , rena l i ns uffi ci ency, a nd i nters ti ti a l nephri ti s a re genera l l y cons i dered to be hypers ens i ti vi ty rea cti ons a nd occur
when thera py i s i ntermi ttent or when trea tment i s res umed a fter i nterrupti on of a da i l y dos a ge regi men; they a re revers ed when ri fa mpi n i s
s topped.
Les s s eri ous a dvers e effects a re common; they i ncl ude hea rtburn, na us ea , vomi ti ng, a nd di a rrhea . Ri fa mpi n col ors uri ne, s a l i va , s wea t, s putum,
a nd tea rs red-ora nge.
If pa ti ents ha ve a l i ver di s order, l i ver functi on tes ts s houl d be done before ri fa mpi n thera py i s s ta rted a nd every 2 to 4 wk duri ng thera py, or a n
a l terna te drug s houl d be us ed. Dos e a djus tments a re unneces s a ry for rena l i ns uffi ci ency.
Ri fa mpi n i ntera cts wi th ma ny drugs beca us e i t i s a potent i nducer of hepa ti c cytochrome P-450 (CYP450) mi cros oma l enzymes . Ri fa mpi n a ccel era tes
el i mi na ti on a nd thereby ma y decrea s e the effecti venes s of the fol l owi ng drugs : ACE i nhi bi tors , a tova quone, ba rbi tura tes , -bl ockers , Ca cha nnel
bl ockers , chl ora mpheni col , cl a ri thromyci n, ora l a nd s ys temi c hormone contra cepti ves , corti cos teroi ds , cycl os pori ne, da ps one, di goxi n, doxycycl i ne,
fl ucona zol e, ha l operi dol , i tra cona zol e, ketocona zol e, the nonnucl eos i de revers e tra ns cri pta s e i nhi bi tors del a vi rdi ne a nd nevi ra pi ne, opi oi d
a na l ges i cs , phenytoi n, protea s e i nhi bi tors , qui ni di ne, s ul fonyl urea s , ta crol i mus , theophyl l i ne, thyroxi ne, toca i ni de, tri cycl i c a nti -depres s a nts ,
vori cona zol e, wa rfa ri n, a nd zi dovudi ne. To ma i nta i n opti mum thera peuti c effect of thes e drugs , cl i ni ci a ns ma y ha ve to a djus t the dos a ge when
ri fa mpi n i s s ta rted or s topped. Convers el y, protea s e i nhi bi tors , a s wel l a s other drugs (eg, a zol es , the ma crol i de cl a ri thromyci n, nonnucl eos i de
revers e tra ns cri pta s e i nhi bi tors ) i nhi bi t CYP450 enzymes a nd i ncrea s e l evel s of ri fa myci ns a nd thus potenti a l l y i ncrea s e the frequency of toxi c
rea cti ons . For exa mpl e, uvei ti s occurs more commonl y when ri fa buti n i s us ed wi th cl a ri thromyci n or a zol es .
Rifaximin
Ri fa xi mi n i s a deri va ti ve of ri fa myci n tha t i s poorl y a bs orbed a fter ora l a dmi ni s tra ti on; 97% i s recovered pri ma ri l y uncha nged i n feces . Ri fa xi mi n
ca n be us ed for empi ri c trea tment of tra vel er's di a rrhea , whi ch i s ca us ed pri ma ri l y by enterotoxi geni c a nd enteroa ggrega ti ve Escherichia coli.
Ri fa xi mi n i s not known to be effecti ve for di a rrhea due to enteri c pa thogens other tha n E. coli. Beca us e ri fa xi mi n i s not s ys temi ca l l y a bs orbed, i t
s houl d not be us ed to trea t i nfecti ous di a rrhea ca us ed by i nva s i ve enteri c ba cteri a l pa thogens (eg, s a l monel l a e, Campylobacter s p).
The dos e i s 200 mg q 8 h for 3 da ys i n a dul ts a nd chi l dren > 12 yr.
Advers e effects i ncl ude na us ea , vomi ti ng, a bdomi na l pa i n, a nd fl a tul ence.
Sulfonamides
Sul fona mi des (s ee
Ta bl e 132-18) a re s yntheti c ba cteri os ta ti c a nti bi oti cs tha t competi ti vel y i nhi bi t convers i on of p-a mi nobenzoi c a ci d to di hydropteroa te, whi ch
ba cteri a need for fol a te s ynthes i s a nd ul ti ma tel y puri ne a nd DNA s ynthes i s . Huma ns do not s ynthes i ze fol a te but a cqui re i t i n thei r di et, s o thei r
DNA s ynthes i s i s l es s a ffected.
Two s ul fona mi des , s ul fi s oxa zol e a nd s ul fa methi zol e, a re a va i l a bl e a s s i ngl e drugs for ora l us e. Sul fa methoxa zol e ma y be combi ned wi th
tri methopri m (TMP/SMXs ee p. 1221). Sul fa doxi ne pl us pyri metha mi ne i s a va i l a bl e (but not i n the US) a s a n ora l , fi xed combi na ti on for ma l a ri a
due to chl oroqui ne-res i s ta nt Plasmodium falciparum.
Sul fona mi des a va i l a bl e for topi ca l us e i ncl ude s i l ver s ul fa di a zi ne, va gi na l crea m a nd s uppos i tori es conta i ni ng s ul fa ni l a mi de, a nd ophtha l mi c
s ul fa ceta mi de.
Pharmacology
Mos t s ul fona mi des a re rea di l y a bs orbed ora l l y a nd, when a ppl i ed to burns , topi ca l l y. Sul fona mi des a re di s tri buted throughout the body. They a re
meta bol i zed ma i nl y by the l i ver a nd excreted by the ki dneys . Sul fona mi des compete for bi l i rubi n-bi ndi ng s i tes on a l bumi n.
[Table 132-18. Sul fona mi des ]

Indications
Sul fona mi des a re a cti ve a ga i ns t
A broa d s pectrum of gra m-pos i ti ve a nd ma ny gra m-nega ti ve ba cteri a
Plasmodium a nd Toxoplasma s pp
However, res i s ta nce i s wi des prea d, a nd res i s ta nce to one s ul fona mi de i ndi ca tes res i s ta nce to a l l .
Sul fa s a l a zi ne ca n be us ed ora l l y for i nfl a mma tory bowel di s ea s e. Sul fona mi des a re mos t commonl y us ed wi th other drugs (eg, for noca rdi os i s ,
UTI, a nd chl oroqui ne-res i s ta nt fa l ci pa rum ma l a ri a ).
Topi ca l s ul fona mi des ca n be us ed to trea t the fol l owi ng:
Burns : Si l ver s ul fa di a zi ne a nd ma feni de a ceta te
Va gi ni ti s : Va gi na l crea m a nd s uppos i tori es wi th s ul fa ni l a mi de
Superfi ci a l ocul a r i nfecti ons : Ophtha l mi c s ul fa ceta mi de
Contraindications
Sul fona mi des a re contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to them or who ha ve porphyri a . Sul fona mi des do not era di ca te
group A s treptococci i n pa ti ents wi th pha ryngi ti s a nd s houl d not be us ed to trea t group A s treptococca l pha ryngi ti s .
Mos t s ul fona mi des a re i n pregna ncy ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but
huma n s tudi es do not). However, us e nea r term a nd i n brea s tfeedi ng mothers i s contra i ndi ca ted, a s i s us e i n pa ti ents < 2 mo (except a s a djuncti ve
thera py wi th pyri metha mi ne to trea t congeni ta l toxopl a s mos i s ). If us ed duri ng pregna ncy or i n neona tes , thes e drugs i ncrea s e bl ood l evel s of
unconjuga ted bi l i rubi n a nd i ncrea s e ri s k of kerni cterus i n the fetus or neona te.
Sul fona mi des enter brea s t mi l k.
Adverse Effects
Advers e effects ca n res ul t from ora l a nd s ometi mes topi ca l s ul fona mi des ; effects i ncl ude
Hypers ens i ti vi ty rea cti ons , s uch a s ra s hes , Stevens -Johns on s yndrome (s ee p. 689), va s cul i ti s , s erum s i cknes s , drug fever, a na phyl a xi s , a nd
a ngi oedema
Crys ta l l uri a , ol i guri a , a nd a nuri a
Hema tol ogi c rea cti ons , s uch a s a gra nul ocytos i s , thrombocytopeni a , a nd, i n pa ti ents wi th G6PD defi ci ency, hemol yti c a nemi a
Kerni cterus i n neona tes
Photos ens i ti vi ty
Neurol ogi c effects , s uch a s i ns omni a , a nd hea da che
Hypothyroi di s m, hepa ti ti s , a nd a cti va ti on of qui es cent SLE ma y occur i n pa ti ents ta ki ng s ul fona mi des . Thes e drugs ca n exa cerba te porphyri a s .
Inci dence of a dvers e effects i s di fferent for the va ri ous s ul fona mi des , but cros s -s ens i ti vi ty i s common.
Sul fa s a l a zi ne ca n reduce i ntes ti na l a bs orpti on of fol a te (fol i c a ci d). Thus , us e of thi s drug ma y tri gger fol a te defi ci ency i n pa ti ents wi th
i nfl a mma tory bowel di s ea s e, whi ch a l s o reduces a bs orpti on, es peci a l l y i f di eta ry i nta ke i s a l s o i na dequa te.
Ma feni de ma y ca us e meta bol i c a ci dos i s by i nhi bi ti ng ca rboni c a nhydra s e.
To a voi d crys ta l l uri a , cl i ni ci a ns s houl d hydra te pa ti ents wel l (eg, to produce a uri na ry output of 1200 to 1500 mL/da y). Sul fona mi des ca n be us ed i n
pa ti ents wi th rena l i ns uffi ci ency, but pea k pl a s ma l evel s s houl d be mea s ured a nd s ul fa methoxa zol e l evel s s houl d not exceed 120 g/mL.
Sul fona mi des ca n potenti a te s ul fonyl urea s (wi th cons equent hypogl ycemi a ), phenytoi n (wi th i ncrea s ed a dvers e effects ), a nd couma ri n
a nti coa gul a nts .
Trimethoprim and Sulfamethoxazole
Tri methopri m i s a va i l a bl e a s a s i ngl e drug or i n combi na ti on wi th s ul fa methoxa zol e. The drugs a ct s ynergi s ti ca l l y to bl ock s equenti a l s teps i n
ba cteri a l fol a te meta bol i s m. Tri methopri m prevents reducti on of di hydrofol a te to tetra hydrofol a te, a nd s ul fa methoxa zol e i nhi bi ts convers i on of pa mi nobenzoi c a ci d to di hydropteroa te. Thi s s ynergy res ul ts i n ma xi ma l a nti ba cteri a l a cti vi ty, whi ch i s often ba cteri ci da l .
Tri methopri m/s ul fa methoxa zol e (TMP/SMX) i s a va i l a bl e a s a fi xed combi na ti on cons i s ti ng of a 1:5 ra ti o (80 mg TMP pl us 400 mg SMX or a doubl es trength ta bl et of 160 mg TMP pl us 800 mg SMX).
Pharmacology
Both drugs a re wel l a bs orbed ora l l y a nd a re excreted i n the uri ne. They ha ve a s erum ha l f-l i fe of a bout 11 h i n pl a s ma a nd penetra te wel l i nto
ti s s ues a nd body fl ui ds , i ncl udi ng CSF. TMP i s concentra ted i n pros ta ti c ti s s ue.
Indications
TMP a nd TMP/SMX a re a cti ve a ga i ns t (s ee
Ta bl e 132-19)
A broa d s pectrum of gra m-pos i ti ve ba cteri a (i ncl udi ng s ome methi ci l l i n-res i s ta nt Staphylococcus aureus)
A broa d s pectrum of gra m-nega ti ve ba cteri a
The combi na ti on i s i na cti ve a ga i ns t a na erobes , Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma s p, a nd Pseudomonas aeruginosa.
Enterococci , ma ny Enteroba cteri a cea e, a nd Streptococcus pneumoniae s tra i ns a re res i s ta nt. TMP/SMX i s not cl i ni ca l l y effecti ve for group A
s treptococca l pha ryngi ti s .
[Table 132-19. Some Indi ca ti ons for TMP/SMX]
TMP a l one i s es peci a l l y us eful for chroni c ba cteri a l pros ta ti ti s a nd for prophyl a xi s a nd trea tment of UTI i n pa ti ents a l l ergi c to s ul fona mi des .
Contraindications
TMP/SMX i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to ei ther drug. Rel a ti ve contra i ndi ca ti ons i ncl ude fol a te defi ci ency, l i ver
dys functi on, a nd rena l i ns uffi ci ency.
TMP/SMX i s i n pregna ncy ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n s tudi es i s i na dequa te, but cl i ni ca l benefi t s ometi mes
outwei ghs ri s k). However, us e nea r term i s contra i ndi ca ted; i f us ed duri ng pregna ncy or i n neona tes , TMP/SMX i ncrea s es bl ood l evel s of
unconjuga ted bi l i rubi n a nd i ncrea s es ri s k of kerni cterus i n the fetus or neona te.
Sul fona mi des enter brea s t mi l k a nd us e duri ng brea s tfeedi ng i s us ua l l y di s coura ged.
Adverse Effects
Thos e a s s oci a ted wi th s ul fona mi de
Fol a te defi ci ency
Hyperka l emi a (TMP ca n decrea s e rena l tubul a r K excreti on, l ea di ng to hyperka l emi a )
Rena l fa i l ure i n pa ti ents wi th underl yi ng rena l i ns uffi ci ency i s proba bl y s econda ry to i nters ti ti a l nephri ti s or tubul a r necros i s . Al s o, TMP
competi ti vel y i nhi bi ts rena l tubul a r crea ti ni ne s ecreti on a nd ma y ca us e a n a rti fi ci a l i ncrea s e i n s erum crea ti ni ne, a l though GFR rema i ns
uncha nged. Increa s es i n s erum crea ti ni ne a re more l i kel y i n pa ti ents wi th preexi s ti ng rena l i ns uffi ci ency a nd es peci a l l y i n thos e wi th di a betes
mel l i tus .
Mos t a dvers e effects a re the s a me a s for s ul fona mi des . TMP ha s a dvers e effects i denti ca l to thos e of SMX, but they a re l es s common. Na us ea ,
vomi ti ng, a nd ra s h occur mos t often. AIDS pa ti ents ha ve a hi gh i nci dence of a dvers e effects , es peci a l l y fever, ra s h, a nd neutropeni a .
Fol a te defi ci ency (res ul ti ng i n ma crocyti c a nemi a ) ca n a l s o occur. Us e of fol i ni c a ci d ca n prevent or trea t ma crocyti c a nemi a , l eukopeni a , a nd
thrombocytopeni a , whi ch s ometi mes occur wi th prol onged TMP/SMX us e.
Ra rel y, s evere hepa ti c necros i s occurs . The drug ma y a l s o ca us e a s yndrome res embl i ng a s epti c meni ngi ti s .
TMP/SMX ma y i ncrea s e wa rfa ri n a cti vi ty a nd l evel s of phenytoi n, methotrexa te, a nd ri fa mpi n. SMX ca n i ncrea s e the hypogl ycemi c effects of
s ul fonyl urea s .
Tetracyclines
Tetra cycl i nes (s ee
Ta bl e 132-20) a re ba cteri os ta ti c a nti bi oti cs tha t bi nd to the 30S s ubuni t of the ri bos ome, thus i nhi bi ti ng ba cteri a l protei n s ynthes i s .
Pharmacology
About 60 to 80% of tetra cycl i ne a nd 90% of doxycycl i ne a nd mi nocycl i ne a re a bs orbed a fter ora l us e. However, a bs orpti on i s decrea s ed by meta l l i c
ca ti ons (eg, a l umi num, Ca , Mg, i ron); thus , tetra cycl i nes ca nnot be ta ken wi th prepa ra ti ons conta i ni ng thes e s ubs ta nces (eg, a nta ci ds , ma ny
vi ta mi n a nd mi nera l s uppl ements ). Food decrea s es a bs orpti on of tetra cycl i ne but not of doxycycl i ne or mi nocycl i ne.
Tetra cycl i nes penetra te i nto mos t body ti s s ues a nd fl ui ds . Al l a re concentra ted i n unobs tructed bi l e. However, CSF l evel s a re not rel i a bl y
thera peuti c. Mi nocycl i ne i s the onl y tetra cycl i ne tha t rea ches hi gh concentra ti ons i n tea rs a nd s a l i va . Tetra cycl i ne a nd mi nocycl i ne a re excreted
pri ma ri l y i n uri ne. Doxycycl i ne i s excreted pri ma ri l y i n the i ntes ti na l tra ct.
Indications
Tetra cycl i nes a re effecti ve a ga i ns t i nfecti ons ca us ed by the fol l owi ng:
Ri cketts i a e
Spi rochetes (eg, Treponema pallidum, Borrelia burgdorferi)
Helicobacter pylori
Vibrio s p
Yersinia pestis
Francisella tularensis
Brucella s p
Bacillus anthracis
Plasmodium vivax
Plasmodium falciparum
Mycoplasma s p
Chlamydia a nd Chlamydophila s p
Some methi ci l l i n-res i s ta nt Staphylococcus aureus
About 5 to 10% of pneumococca l s tra i ns a nd ma ny group A -hemol yti c s treptococci , ma ny gra m-nega ti ve ba ci l l a ry uropa thogens , a nd
peni ci l l i na s e-produci ng gonococci a re res i s ta nt.
[Table 132-20. Tetra cycl i nes ]
Tetra cycl i nes a re i ntercha ngea bl e for mos t i ndi ca ti ons , a l though mi nocycl i ne ha s been mos t s tudi ed for methi ci l l i n-res i s ta nt S. aureus i nfecti ons .
Doxycycl i ne i s us ua l l y preferred for a l l of the fol l owi ng beca us e i t i s better tol era ted a nd ca n be gi ven twi ce/da y:
Infecti ons ca us ed by ri cketts i a e a nd Chlamydia, Chlamydophila, Mycoplasma, a nd Vibrio s pp
Acute exa cerba ti ons of chroni c bronchi ti s
Lyme di s ea s e
Brucel l os i s
Anthra x
Pl a gue
Tul a remi a
Gra nul oma i ngui na l e
Syphi l i s
Prophyl a xi s of ma l a ri a ca us ed by chl oroqui ne-res i s ta nt P. falciparum
Beca us e of i ts hi gh concentra ti on i n tea rs a nd s a l i va , mi nocycl i ne i s the onl y tetra cycl i ne tha t ca n era di ca te meni ngococci i n ca rri ers a nd i s a n
a l terna te to ri fa mpi n for thi s i ndi ca ti on.
Contraindications
Tetra cycl i nes a re contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to them, pa ti ents wi th rena l i ns uffi ci ency (except for doxycycl i ne,
whi ch ha s no dos a ge a djus tment for rena l i ns uffi ci ency), a nd chi l dren 8 yr (except s ometi mes for i nha l a ti ona l a nthra x).
Tetra cycl i nes a re i n pregna ncy ca tegory D (there i s evi dence of huma n ri s k, but cl i ni ca l benefi ts ma y outwei gh ri s k). Tetra cycl i nes cros s the
pl a centa , enter feta l ci rcul a ti on, a ccumul a te i n feta l bones , a nd, i f us ed duri ng the 2nd or 3rd tri mes ter, ma y ca us e perma nent di s col ora ti on of
teeth. Hepa totoxi ci ty ma y occur i n pregna nt women, pa rti cul a rl y a fter IV a dmi ni s tra ti on a nd i n thos e wi th a zotemi a or pyel onephri ti s . Ta ki ng hi gh
dos es duri ng pregna ncy ca n l ea d to fa tty degenera ti on of the l i ver, whi ch ma y be fa ta l .
Tetra cycl i nes enter brea s t mi l k, but us ua l l y i n s ma l l a mounts (pa rti cul a rl y tetra cycl i ne). Us e duri ng brea s tfeedi ng i s us ua l l y di s coura ged.
Adverse Effects
GI di s turba nces
Clostridium difficile-i nduced di a rrhea (ps eudomembra nous col i ti s )
Ca ndi di a s i s
Bone a nd denta l effects i n chi l dren
Fa tty l i ver
Ves ti bul a r dys functi on (wi th mi nocycl i ne)
Al l ora l tetra cycl i nes ca us e na us ea , vomi ti ng, a nd di a rrhea a nd ca n ca us e C. difficile-i nduced di a rrhea (ps eudomembra nous col i ti s ) a nd ca ndi da l
s uperi nfecti ons . If not s wa l l owed wi th wa ter, tetra cycl i nes ca n ca us e es opha gea l eros i ons . Photos ens i ti vi ty due to tetra cycl i nes ma y ma ni fes t a s
a n exa ggera ted s unburn rea cti on. Bone a nd denta l effects i ncl ude s ta i ni ng of teeth, hypopl a s i a of denta l ena mel , a nd a bnorma l bone growth i n
chi l dren 8 yr a nd i n fetus es . In i nfa nts , tetra cycl i nes ma y ca us e i di opa thi c i ntra cra ni a l hypertens i on a nd bul gi ng fonta nel l es .
Exces s i ve bl ood l evel s due to us e of hi gh dos es or rena l i ns uffi ci ency ma y l ea d to fa ta l a cute fa tty degenera ti on of the l i ver, es peci a l l y duri ng
pregna ncy.
Mi nocycl i ne commonl y ca us es ves ti bul a r dys functi on, pa rti cul a rl y i n women, l i mi ti ng i ts us e. Us e of mi nocycl i ne ha s been a s s oci a ted wi th
devel opment of a utoi mmune di s orders s uch a s SLE a nd pol ya rteri ti s nodos a , whi ch ma y be revers i bl e.
Tetra cycl i ne ca n exa cerba te a zotemi a i n pa ti ents wi th rena l i ns uffi ci ency. Expi red tetra cycl i ne pi l l s ca n degenera te a nd, i f i nges ted, ca us e Fa nconi
s yndrome. Pa ti ents s houl d be i ns tructed to di s ca rd the drugs when they expi re.
Doxycycl i ne, excreted pri ma ri l y i n the i ntes ti na l tra ct, requi res no dos e reducti on i n rena l i ns uffi ci ency.
Tetra cycl i nes ma y decrea s e the effecti venes s of ora l contra cepti ves a nd potenti a te the effects of ora l a nti coa gul a nts .
Tigecycline
Ti gecycl i ne, a deri va ti ve of the tetra cycl i ne mi nocycl i ne, i s the fi rs t a va i l a bl e gl ycyl cycl i ne. Ti gecycl i ne i nhi bi ts protei n s ynthes i s by bi ndi ng to the
30S ri bos oma l s ubuni t. It i s ba cteri os ta ti c.
Ti gecycl i ne i s gi ven IV. Ti gecycl i ne ha s a l a rge vol ume of di s tri buti on (> 12 L/kg), penetra ti ng wel l i nto bone, l ung, l i ver, a nd ki dney ti s s ues . A ha l fl i fe of 36 h s houl d provi de for once/da y dos i ng. Mos t of the drug i s excreted i n bi l e a nd feces .
Indications
Ti gecycl i ne i s effecti ve a ga i ns t ma ny res i s ta nt ba cteri a , i ncl udi ng thos e wi th res i s ta nce to tetra cycl i nes . Ti gecycl i ne i s a cti ve a ga i ns t
Ma ny gra m-pos i ti ve ba cteri a , i ncl udi ng methi ci l l i n-s us cepti bl e a nd methi ci l l i n-res i s ta nt Staphylococcus aureus, Streptococcus pneumoniae wi th
reduced peni ci l l i n s ens i ti vi ty, va ncomyci n-s ens i ti ve Enterococcus faecalis, va ncomyci n-res i s ta nt E. faecium, a nd Listeria s p
Ma ny gra m-nega ti ve ba cteri a , s uch a s mul ti drug-res i s ta nt Acinetobacter baumannii, Stenotrophomonas maltophilia, Haemophilus influenzae, a nd mos t
Enteroba cteri a cea e (i ncl udi ng s ome s tra i ns tha t produce extended-s pectrum -l a cta ma s es [ESBLs ] a nd other s tra i ns tha t were ca rba penemres i s ta nt ba s ed on producti on of a ca rba penema s e or meta l l o--l a cta ma s e)
Ma ny a typi ca l res pi ra tory pa thogens (chl a mydi a e, Mycoplasma s p), Mycobacterium abscessus, M. fortuitum, a nd a na erobes , i ncl udi ng Bacteroides
fragilis, Clostridium perfringens, a nd C. difficile
It i s not effecti ve a ga i ns t Pseudomonas aeruginosa, Providencia s p, Morganella morganii, or Proteus s p.
Ti gecycl i ne i s i ndi ca ted for compl i ca ted s ki n a nd s oft-ti s s ue i nfecti ons a nd compl i ca ted i ntra -a bdomi na l i nfecti ons , but the drug s hows promi s e
for other i nfecti ons a s wel l . Cl i ni ca l l y, ti gecycl i ne i s us ed ma i nl y for the fol l owi ng:
Compl i ca ted i ntra -a bdomi na l i nfecti ons , i ncl udi ng a bs ces s es , a ppendi ci ti s , chol ecys ti ti s , di verti cul i ti s , perfora ti ons , a nd peri toni ti s
Compl i ca ted s ki n a nd s oft-ti s s ue i nfecti ons , i ncl udi ng a bs ces s es a nd i nfected burns or ul cers
Communi ty-a cqui red ba cteri a l pneumoni a ca us ed by S. pneumoniae (peni ci l l i n-s us cepti bl e i s ol a tes ), i ncl udi ng ca s es wi th concurrent ba cteremi a ,
H. influenzae (-l a cta ma s e nega ti ve i s ol a tes ), a nd Legionella pneumophila
Venti l a tor-a s s oci a ted hos pi ta l -a cqui red pneumoni a due to mul ti drug res i s ta nt pa thogens
Contraindications
Ti gecycl i ne i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to i t a nd i n chi l dren 8 yr.
Ti gecycl i ne i s i n pregna ncy ca tegory D (there i s evi dence of huma n ri s k, but cl i ni ca l benefi ts ma y outwei gh ri s k); i t, l i ke tetra cycl i nes , ca n a ffect
feta l bones a nd teeth.
Whether ti gecycl i ne enters brea s t mi l k a nd i s s a fe to us e duri ng brea s tfeedi ng i s unknown.
Adverse Effects
Na us ea , vomi ti ng, a nd di a rrhea
Hepa totoxi ci ty
Na us ea a nd vomi ti ng a re common. Increa s es i n s erum a myl a s e, tota l bi l i rubi n concentra ti on, PT, a nd tra ns a mi na s es ca n occur i n pa ti ents trea ted
wi th ti gecycl i ne. Is ol a ted ca s es of s i gni fi ca nt hepa ti c dys functi on a nd hepa ti c fa i l ure ha ve been reported i n pa ti ents bei ng trea ted wi th
ti gecycl i ne. Ma ny of ti gecycl i ne's a dvers e effects a re s i mi l a r to thos e of tetra cycl i nes (eg, photos ens i ti vi ty).
Dos e i s a djus ted i n pa ti ents wi th hepa ti c dys functi on but not i n thos e wi th rena l dys functi on. Serum l evel s of wa rfa ri n ma y i ncrea s e, but INR does
not a ppea r to i ncrea s e.
Vancomycin
Va ncomyci n i s a ti me-dependent ba cteri ci da l a nti bi oti c tha t i nhi bi ts cel l wa l l s ynthes i s .
Pharmacology
Va ncomyci n i s not a ppreci a bl y a bs orbed from a norma l GI tra ct a fter ora l a dmi ni s tra ti on. Gi ven pa rentera l l y, i t penetra tes i nto bi l e a nd pl eura l ,
peri ca rdi a l , s ynovi a l , a nd a s ci ti c fl ui ds . However, penetra ti on i nto even i nfl a med CSF i s l ow a nd erra ti c. Va ncomyci n i s excreted uncha nged by
gl omerul a r fi l tra ti on.
Indications
Va ncomyci n i s a cti ve a ga i ns t
Mos t gra m-pos i ti ve cocci a nd ba ci l l i , i ncl udi ng a l mos t a l l Staphylococcus aureus a nd coa gul a s e-nega ti ve s ta phyl ococca l s tra i ns tha t a re res i s ta nt
to peni ci l l i ns a nd cepha l os pori ns
Ma ny s tra i ns of enterococci (vi a a ba cteri os ta ti c mecha ni s m)
However, ma ny s tra i ns of enterococci a nd s ome s tra i ns of S. aureus a re res i s ta nt.
Va ncomyci n i s the drug of choi ce for s eri ous i nfecti on a nd endoca rdi ti s ca us ed by the fol l owi ng:
Methi ci l l i n-res i s ta nt S. aureus
Methi ci l l i n-res i s ta nt coa gul a s e-nega ti ve s ta phyl ococci
Streptococcus pneumoniae
-Hemol yti c s treptococci (when -l a cta ms ca nnot be us ed beca us e of drug a l l ergy or res i s ta nce)
Corynebacterium group JK
Vi ri da ns s treptococci (when -l a cta ms ca nnot be us ed beca us e of drug a l l ergy or res i s ta nce)
Enterococci , (when -l a cta ms ca nnot be us ed beca us e of drug a l l ergy or res i s ta nce)
However, va ncomyci n i s l es s effecti ve tha n a nti s ta phyl ococca l -l a cta ms for S. aureus endoca rdi ti s . Va ncomyci n i s us ed wi th other a nti bi oti cs when
trea ti ng methi ci l l i n-res i s ta nt coa gul a s e-nega ti ve s ta phyl ococca l pros theti c va l ve endoca rdi ti s or enterococca l endoca rdi ti s . Va ncomyci n ha s a l s o
been us ed a s a n a l terna ti ve drug for pneumococca l meni ngi ti s ca us ed by s tra i ns wi th reduced peni ci l l i n s ens i ti vi ty; however, the erra ti c
penetra ti on of va ncomyci n i nto CSF (es peci a l l y duri ng concomi ta nt us e of dexa metha s one) a nd reports of cl i ni ca l fa i l ures ma ke i t l es s tha n
opti ma l when us ed a l one to trea t pneumococca l meni ngi ti s . Before denta l procedures l i kel y to res ul t i n ba cteremi a a re done, va ncomyci n i s us ed
to prevent endoca rdi ti s i n peni ci l l i n-a l l ergi c hi gh-ri s k pa ti ents who ca nnot tol era te ora l a nti bi oti cs .
Ora l va ncomyci n i s us ed to trea t Clostridium difficile-i nduced di a rrhea (ps eudomembra nous col i ti s ) onl y i f pa ti ents do not res pond to
metroni da zol e.
Contraindications
Va ncomyci n i s contra i ndi ca ted i n pa ti ents who ha ve ha d a n a l l ergi c rea cti on to i t.
Va ncomyci n ha s not ha d a dvers e effects i n a ni ma l s , a nd evi dence i n huma n s tudi es i s i na dequa te. Ora l va ncomyci n ta bl ets a re i n pregna ncy
ca tegory B (a ni ma l s tudi es s how no ri s k a nd huma n evi dence i s i ncompl ete, or a ni ma l s tudi es s how ri s k but huma n s tudi es do not). Ora l -s ol uti on
va ncomyci n a nd IV va ncomyci n a re i n ca tegory C (a ni ma l s tudi es s how s ome ri s k, evi dence i n huma n a nd a ni ma l s tudi es i s i na dequa te, but
cl i ni ca l benefi t s ometi mes exceeds ri s k).
Va ncomyci n enters brea s t mi l k, a nd s o i ts us e duri ng brea s tfeedi ng i s di s coura ged; however, beca us e ora l a bs orpti on i s poor from a norma l GI
tra ct, a dvers e effects i n i nfa nts a re us ua l l y cons i dered unl i kel y.
Adverse Effects
The ma i n concern i s
Hypers ens i ti vi ty
Hypers ens i ti vi ty rea cti ons (eg, ra s h, fever, revers i bl e neutropeni a a nd thrombocytopeni a ) ma y occur, es peci a l l y when thera py l a s ts for > 2 wk.
Nephrotoxi ci ty i s ra re unl es s hi gh dos es a re us ed or a n a mi nogl ycos i de i s gi ven concomi ta ntl y. Phl ebi ti s occurs uncommonl y duri ng IV i nfus i on.
Infus i on s houl d be gi ven over a t l ea s t 60 mi n to a voi d the red-pers on s yndrome, a hi s ta mi ne-medi a ted rea cti on tha t ca n ca us e pruri tus a nd
fl us hi ng on the fa ce, neck, a nd s houl ders .
Dos e-rel a ted ototoxi ci ty i s unus ua l wi th current formul a ti ons .
Dos es us ed for meni ngi ti s mus t be hi gher tha n us ua l . Dos e reducti on i s requi red i n rena l i ns uffi ci ency. In cri ti ca l l y i l l pa ti ents , s erum l evel s
s houl d be mea s ured a fter the 2nd or 3rd dos e a nd kept between 10 a nd 15 g/mL (trough l evel s ).
Va ncomyci n MIC ha s been i ncrea s i ng i n the pa s t deca de. S. aureus wi th va ncomyci n MIC of 2 g/mL a re cons i dered s ens i ti ve; thos e wi th
va ncomyci n MIC of 4 to 8 g/mL a re cons i dered i ntermedi a te, a nd thos e wi th va ncomyci n MIC of > 8 g/mL a re cons i dered res i s ta nt. However,
i nfecti ons due to S. aureus wi th va ncomyci n MIC of 2 to 8 g/mL ma y res pond s ubopti ma l l y to s ta nda rd dos i ng a nd requi re hi gher dos es wi th trough
l evel s between 15 to 20 g/mL, but thi s a pproa ch ma y be compl i ca ted by i ncrea s ed ra tes of nephrotoxi ci ty.
Chapter 133. Gram-Positive Cocci

Introduction
Ma ny gra m-pos i ti ve cocci a re commens a l orga ni s ms tha t ca us e i nfecti on onl y when they fi nd thei r wa y i nto norma l l y s teri l e a rea s . They a re the
mos t common ca us e of s ki n i nfecti ons a nd a frequent ca us e of pneumoni a a nd s epti cemi a . Al though they a re genera l l y s us cepti bl e to a broa d
ra nge of a nti bi oti cs , certa i n s tra i ns ha ve devel oped res i s ta nce to ma ny a va i l a bl e a nti mi crobi a l drugs .
Pneumococcal Infections
Streptococcus pneumoniae (pneumococci) are gram-positive, -hemolytic, aerobic, encapsulated diplococci. In the US, pneumococcal infection annually causes
about 7 million cases of otitis media, 500,000 cases of pneumonia, 50,000 cases of sepsis, 3,000 cases of meningitis, and 40,000 deaths. Diagnosis is by Gram
stain and culture. Treatment depends on the resistance profile and includes a -lactam, a macrolide, a respiratory fluoroquinolone, and sometimes vancomycin.
Pneumococci a re fa s ti di ous mi croorga ni s ms tha t requi re ca ta l a s e to grow on a ga r pl a tes . In the l a bora tory, pneumococci a re i denti fi ed by hemol ys i s on bl ood a ga r, s ens i ti vi ty to optochi n, a nd l ys i s by bi l e s a l ts .
Pneumococci commonl y col oni ze the huma n res pi ra tory tra ct, pa rti cul a rl y i n wi nter a nd ea rl y s pri ng. Sprea d i s vi a a i rborne dropl ets . True
epi demi cs of pneumococca l i nfecti ons a re ra re.
Serotypes: The pneumococcus ca ps ul e cons i s ts of a compl ex pol ys a ccha ri de tha t determi nes s erol ogi c type a nd contri butes to vi rul ence a nd
pa thogeni ci ty. Vi rul ence va ri es s omewha t wi thi n s erol ogi c types beca us e of di fferences i n DNA compos i ti on.
Currentl y, > 90 di fferent s erotypes ha ve been i denti fi ed, but mos t s eri ous i nfecti ons a re ca us ed by s erotypes 4, 6, 9, 14, 18, 19, a nd 23. Thes e
s erotypes ca us e a bout 90% of i nva s i ve i nfecti ons i n chi l dren a nd 60% i n a dul ts . However, thes e pa tterns a re s l owl y cha ngi ng, i n pa rt beca us e of
the wi des prea d us e of pol yva l ent va cci ne. Serotype 19A, a nonva cci ne s erotype tha t i s hi ghl y vi rul ent a nd mul ti -drug-res i s ta nt, ha s emerged a s a n
i mporta nt ca us e of res pi ra tory tra ct i nfecti on a nd i nva s i ve di s ea s e.
Risk factors: Pa ti ents mos t s us cepti bl e to s eri ous a nd i nva s i ve pneumococca l i nfecti ons a re thos e wi th chroni c i l l nes s (eg, chroni c
ca rdi ores pi ra tory di s ea s e, di a betes , l i ver di s ea s e, a l cohol i s m), i mmunos uppres s i on (eg, HIV), functi ona l or a na tomi c a s pl eni a , or s i ckl e cel l
di s ea s e, a s wel l a s res i dents of l ong-term ca re fa ci l i ti es , s mokers , a bori gi nes , Al a s ka n na ti ves , a nd certa i n Ameri ca n Indi a n popul a ti ons . The
el derl y, even thos e wi thout other di s ea s e, tend to ha ve a poor prognos i s wi th pneumococca l i nfecti ons . Da ma ge to the res pi ra tory epi thel i um by
chroni c bronchi ti s or common res pi ra tory vi ra l i nfecti ons , nota bl y i nfl uenza , ma y predi s pos e to pneumococca l i nva s i on.
Diseases Caused by Pneumococci
Pneumococca l di s ea s es i ncl ude
Oti ti s medi a
Pneumoni a
Si nus i ti s
Meni ngi ti s
Endoca rdi ti s
Septi c a rthri ti s
Peri toni ti s (ra re)
Pri ma ry i nfecti on us ua l l y i nvol ves the mi ddl e ea r or l ungs . The di s ea s es l i s ted bel ow a re further di s cus s ed el s ewhere i n THE MANUAL.
Pneumococcal bacteremia ca n occur i n i mmunocompetent a nd i mmunos uppres s ed pa ti ents ; pa ti ents who ha ve ha d s pl enectomy a re a t pa rti cul a r
ri s k. Ba cteremi a ma y be the pri ma ry i nfecti on, or i t ma y a ccompa ny the a cute pha s e of a ny foca l pneumococca l i nfecti on. When ba cteremi a i s
pres ent, s econda ry s eedi ng of di s ta nt s i tes ma y ca us e i nfecti ons s uch a s s epti c a rthri ti s , meni ngi ti s , a nd endoca rdi ti s . Des pi te trea tment, the
overa l l morta l i ty ra te for ba cteremi a i s 15 to 20% i n chi l dren a nd a dul ts a nd 30 to 40% i n the el derl y; ri s k of dea th i s hi ghes t duri ng the fi rs t 72 h.
Pneumonia (s ee p. 1923) i s the mos t frequent s eri ous i nfecti on ca us ed by pneumococci ; i t ma y ma ni fes t a s l oba r pneumoni a or, l es s commonl y, a s
bronchopneumoni a . About 4 mi l l i on ca s es of communi ty-a cqui red pneumoni a occur ea ch yea r i n the US; when communi ty-a cqui red pneumoni a
requi res hos pi ta l i za ti on, pneumococci a re the mos t common eti ol ogi c a gent i n pa ti ents of a l l a ges . Pl eura l effus i on occurs i n up to 40% of
pa ti ents , but mos t effus i ons res ol ve duri ng drug trea tment; onl y a bout 2% of pa ti ents devel op empyema , whi ch ma y become l ocul a ted, thi ck, a nd
fi bri nopurul ent. Lung a bs ces s forma ti on i s ra re.
Acute otitis media i n i nfa nts (a fter the neona ta l peri od) a nd chi l dren i s ca us ed by pneumococci i n a bout 30 to 40% of ca s es (s ee p. 448). More tha n
one thi rd of chi l dren i n mos t popul a ti ons devel op a cute pneumococca l oti ti s medi a duri ng the fi rs t 2 yr of l i fe, a nd pneumococca l oti ti s commonl y
recurs . Rel a ti vel y few s erotypes of S. pneumoniae a re res pons i bl e for mos t ca s es . After uni vers a l i mmuni za ti on of i nfa nts i n the US begi nni ng i n
2000, nonva cci ne s erotypes of S. pneumoniae (pa rti cul a rl y s erotype 19A) ha ve become the mos t common pneumococca l ca us e of a cute oti ti s medi a .
Compl i ca ti ons i ncl ude mi l d conducti ve hea ri ng l os s , ves ti bul a r ba l a nce dys functi on, tympa ni c membra ne perfora ti on, ma s toi di ti s , petros i ti s , a nd
l a byri nthi ti s . Intra cra ni a l compl i ca ti ons a re ra re i n devel oped countri es but ma y i ncl ude meni ngi ti s , epi dura l a bs ces s , bra i n a bs ces s , l a tera l
venous s i nus thrombos i s , ca vernous s i nus thrombos i s , s ubdura l empyema , a nd ca roti d a rtery thrombos i s .
Paranasal sinusitis (s ee p. 479) ma y be ca us ed by pneumococci a nd ma y become chroni c a nd pol ymi crobi c. Mos t commonl y, the ma xi l l a ry a nd
ethmoi d s i nus es a re a ffected. Infecti on of the s i nus es ma y extend i nto the cra ni um, ca us i ng ca vernous s i nus thrombos i s ; bra i n, epi dura l , or
s ubdura l a bs ces s es ; s epti c corti ca l thrombophl ebi ti s ; or meni ngi ti s .

Acute purulent meningitis (s ee p. 1735) i s frequentl y ca us ed by pneumococci a nd ma y be s econda ry to ba cteremi a from other foci (nota bl y
pneumoni a ); di rect extens i on from i nfecti on of the ea r, ma s toi d proces s , or pa ra na s a l s i nus es ; or ba s i l a r fra cture of the s kul l i nvol vi ng one of
thes e s i tes or the cri bri form pl a te. Compl i ca ti ons a fter pneumococca l meni ngi ti s i ncl ude hea ri ng l os s (i n up to 50% of pa ti ents ), s ei zures , l ea rni ng
di s a bi l i ti es , menta l dys functi on, a nd pa l s i es .
Endocarditis (s ee p.
2193) ma y res ul t from pneumococca l ba cteremi a , even i n pa ti ents wi thout va l vul a r hea rt di s ea s e, but i s ra re. Pneumococca l endoca rdi ti s ma y
produce a corros i ve va l vul a r l es i on, wi th s udden rupture or fenes tra ti on, l ea di ng to ra pi dl y progres s i ve hea rt fa i l ure.
Septic arthritis, s i mi l a r to s epti c a rthri ti s ca us ed by other gra m-pos i ti ve cocci , i s us ua l l y a compl i ca ti on of pneumococca l ba cteremi a from a nother
s i te (s ee Acute Infecti ous Arthri ti s on p. 365).
Spontaneous pneumococcal peritonitis occurs mos t often i n pa ti ents wi th ci rrhos i s a nd a s ci tes , wi th no fea tures to di s ti ngui s h i t from s ponta neous
ba cteri a l peri toni ti s of other ca us es (s ee p. 106).
Diagnosis
Gra m s ta i n a nd cul ture
Pneumococci a re rea di l y i denti fi ed by thei r typi ca l a ppea ra nce on Gra m s ta i n a s l a ncet-s ha ped di pl ococci . The cha ra cteri s ti c ca ps ul e ca n be bes t
detected us i ng the Quel l ung tes t. In thi s tes t, a ppl i ca ti on of a nti s erum fol l owed by s ta i ni ng wi th Indi a i nk ca us es the ca ps ul e to a ppea r l i ke a
ha l o a round the orga ni s m. The ca ps ul e i s a l s o vi s i bl e i n s mea rs s ta i ned wi th methyl ene bl ue. Cul ture confi rms i denti fi ca ti on; a nti mi crobi a l
s us cepti bi l i ty tes ti ng s houl d be done. Serotypi ng a nd genotypi ng of i s ol a tes ca n be hel pful for epi demi ol ogi c rea s ons (eg, to fol l ow the s prea d of
s peci fi c cl ones a nd a nti mi crobi a l res i s ta nce pa tterns ).
Treatment
A -l a cta m or ma crol i de
If pneumococca l i nfecti on i s s us pected, i ni ti a l thera py pendi ng s us cepti bi l i ty s tudi es s houl d be determi ned by l oca l res i s ta nce pa tterns . Al though
preferred trea tment for pneumococca l i nfecti ons i s a -l a cta m or ma crol i de a nti bi oti c, trea tment ha s become more cha l l engi ng beca us e res i s ta nt
s tra i ns ha ve emerged. Stra i ns hi ghl y res i s ta nt to peni ci l l i n, a mpi ci l l i n, a nd other -l a cta ms a re common worl dwi de. The mos t common
predi s pos i ng fa ctor to -l a cta m res i s ta nce i s us e of thes e drugs wi thi n the pa s t s evera l months .
Intermedi a tel y res i s ta nt orga ni s ms ma y be trea ted wi th us ua l or hi gh dos es of peni ci l l i n G or a nother -l a cta m.
Seri ous l y i l l pa ti ents wi th nonmeni ngea l i nfecti ons ca us ed by orga ni s ms tha t a re hi ghl y res i s ta nt to peni ci l l i n ca n often be trea ted wi th
ceftri a xone or cefota xi me. Very hi gh dos es of pa rentera l peni ci l l i n G (20 to 40 mi l l i on uni ts /da y IV for a dul ts ) a l s o work, unl es s the mi ni mum
i nhi bi tory concentra ti on of the i s ol a te i s very hi gh. Fl uoroqui nol ones (eg, ga ti fl oxa ci n, gemi fl oxa ci n, l evofl oxa ci n, moxi fl oxa ci n) a re effecti ve for
res pi ra tory i nfecti ons wi th hi ghl y peni ci l l i n-res i s ta nt pneumococci i n a dul ts .
Al l peni ci l l i n-res i s ta nt i s ol a tes ha ve been s us cepti bl e to va ncomyci n s o fa r, but pa rentera l va ncomyci n does not a l wa ys produce concentra ti ons i n
CSF a dequa te for trea tment of meni ngi ti s (es peci a l l y i f corti cos teroi ds a re a l s o bei ng us ed). Therefore, i n pa ti ents wi th meni ngi ti s , ceftri a xone or
cefota xi me, ri fa mpi n, or both a re commonl y us ed wi th va ncomyci n.
Prevention
Infecti on produces type-s peci fi c i mmuni ty tha t does not genera l i ze to other s erotypes . Otherwi s e, preventi on i nvol ves
Va cci na ti on
Prophyl a cti c a nti bi oti cs
Vaccines: Two pneumococca l va cci nes a re a va i l a bl e: a conjuga ted va cci ne a ga i ns t 7 s erotypes (PCV7) a nd a pol yva l ent pol ys a ccha ri de va cci ne
di rected a ga i ns t the 23 s erotypes (PPV23) tha t a ccount for 80 to 95% of s eri ous pneumococca l i nfecti ons .
Conjugated vaccine i s recommended for a l l chi l dren a ged 6 wk through 59 mo. The s chedul e va ri es dependi ng on a ge a nd underl yi ng medi ca l
condi ti ons (s ee
Ta bl e 268-10 on p. 2718). If va cci na ti on i s begun a t a ge 6 mo, chi l dren s houl d recei ve a 3-dos e pri ma ry s eri es a t a bout 2-mo i nterva l s , fol l owed by
a 4th dos e a t a ge 12 to 15 mo. The cus toma ry a ge for the fi rs t dos e i s 2 mo. If va cci na ti on i s begun a t a ge 7 to 11 mo, a 2-dos e pri ma ry s eri es a nd a
boos ter a re gi ven. From a ge 12 to 23 mo, 2 dos es a nd no boos ter a re gi ven. From a ge 24 mo to 9 yr, chi l dren recei ve 1 dos e.
Polysaccharide vaccine i s i neffecti ve i n chi l dren < 2 yr but reduces pneumococca l ba cteremi a by 50% i n a dul ts . There i s no documented reducti on i n
pneumoni a . Protecti on genera l l y l a s ts ma ny yea rs , but reva cci na ti on a fter 5 yr ma y be des i ra bl e i n hi ghl y s us cepti bl e peopl e. The pol ys a ccha ri de
va cci ne i s i ndi ca ted for a dul ts 65 yr a nd peopl e 2 to 64 yr wi th i ncrea s ed s us cepti bi l i ty (s ee p. 1226) a nd before s pl enectomy. It i s not
recommended for chi l dren < 2 yr or a nyone hypers ens i ti ve to the va cci ne's components .
Prophylactic antibiotics: For functi ona l or a na tomi c a s pl eni c chi l dren < 5 yr, peni ci l l i n V 125 mg po bi d i s recommended. The dura ti on for
chemoprophyl a xi s i s empi ri c, but s ome experts conti nue prophyl a xi s throughout chi l dhood a nd i nto a dul thood for hi gh-ri s k pa ti ents wi th
a s pl eni a . Peni ci l l i n 250 mg po bi d i s recommended for ol der chi l dren or a dol es cents for a t l ea s t 1 yr a fter s pl enectomy.
Staphylococcal Infections
Staphylococci are gram-positive, aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia,
endocarditis, and osteomyelitis. It commonly leads to abscess formation. Some strains elaborate toxins that cause gastroenteritis, scalded skin syndrome, and
toxic shock syndrome. Diagnosis is by Gram stain and culture. Treatment is usually with penicillinase-resistant b-lactams, but because antibiotic resistance is
common, vancomycin or other newer antibiotics may be required. Some strains are partially or totally resistant to all but the newest antibiotics, which include
linezolid, quinupristin/dalfopristin, daptomycin, telavancin, dalbavancin, and tigecycline.
The a bi l i ty to cl ot bl ood by produci ng coa gul a s e determi nes the vi rul ence of the s evera l s peci es of s ta phyl ococci . Coa gul a s e-pos i ti ve
Staphylococcus aureus i s a mong the mos t ubi qui tous a nd da ngerous huma n pa thogens , for both i ts vi rul ence a nd i ts a bi l i ty to devel op a nti bi oti c
res i s ta nce. Coa gul a s e-nega ti ve s peci es s uch a s S. epidermidis a re i ncrea s i ngl y a s s oci a ted wi th hos pi ta l -a cqui red i nfecti ons ; S. saprophyticus ca us es
uri na ry i nfecti ons . S. lugdunensis, a coa gul a s e-nega ti ve s peci es , ha s recentl y been found to ca us e i nva s i ve di s ea s e wi th vi rul ence s i mi l a r to tha t of
S. aureus. Unl i ke mos t coa gul a s e-nega ti ve s ta phyl ococca l s peci es , S. lugdunensis, often rema i ns s ens i ti ve to peni ci l l i na s e-res i s ta nt -l a cta m
a nti bi oti cs .
Pa thogeni c s ta phyl ococci a re ubi qui tous . They a re ca rri ed, us ua l l y tra ns i entl y, i n the a nteri or na res of a bout 30% of hea l thy a dul ts a nd on the s ki n
of a bout 20%. Ra tes a re hi gher i n hos pi ta l pa ti ents a nd pers onnel .
Risk factors: Neona tes a nd brea s tfeedi ng mothers a re predi s pos ed to s ta phyl ococca l i nfecti ons , a s a re pa ti ents wi th i nfl uenza , chroni c
bronchopul mona ry di s orders (eg, cys ti c fi bros i s , emphys ema ), l eukemi a , tumors , tra ns pl a nts , i mpl a nted pros thes es or other forei gn bodi es , burns ,
chroni c s ki n di s orders , s urgi ca l i nci s i ons , di a betes mel l i tus , or i ndwel l i ng i ntra va s cul a r pl a s ti c ca theters . Pa ti ents recei vi ng a drena l s teroi ds ,
i rra di a ti on, i mmunos uppres s a nts , or a nti tumor chemothera py a re a l s o a t i ncrea s ed ri s k. Predi s pos ed pa ti ents ma y a cqui re a nti bi oti c-res i s ta nt
s ta phyl ococci from other pa ti ents , hea l th ca re pers onnel , or i na ni ma te objects i n hea l th ca re s etti ngs . Tra ns mi s s i on vi a the ha nds of pers onnel i s
the mos t common mea ns of s prea d, but a i rborne s prea d ca n a l s o occur.
Diseases Caused by Staphylococci
Sta phyl ococci ca us e di s ea s e by
Di rect ti s s ue i nva s i on
Someti mes exotoxi n producti on
S. aureus bacteremia, whi ch frequentl y ca us es meta s ta ti c foci of i nfecti on, ma y occur wi th a ny l oca l i zed s ta phyl ococca l i nfecti on but i s pa rti cul a rl y
common wi th i nfecti on rel a ted to i ntra va s cul a r ca theters or other forei gn bodi es . It ma y a l s o occur wi thout a ny obvi ous pri ma ry s i te. S. epidermidis
a nd other coa gul a s e-nega ti ve s ta phyl ococci i ncrea s i ngl y ca us e hos pi ta l -a cqui red ba cteremi a a s s oci a ted wi th i ntra va s cul a r ca theters a nd other
forei gn bodi es beca us e they ca n form bi ofi l ms on thes e ma teri a l s . They a re i mporta nt ca us es of morbi di ty (es peci a l l y prol onga ti on of
hos pi ta l i za ti on) a nd morta l i ty i n debi l i ta ted pa ti ents . The di s ea s es l i s ted bel ow a re further di s cus s ed el s ewhere i n THE MANUAL.
Direct invasion: Mos t s ta phyl ococca l di s ea s e res ul ts from di rect ti s s ue i nva s i on. Exa mpl es a re
Ski n i nfecti ons
Pneumoni a
Endoca rdi ti s
Os teomyel i ti s
Septi c a rthri ti s
Skin infections a re the mos t common form of s ta phyl ococca l di s ea s e (s ee p. 694). Superfi ci a l i nfecti ons ma y be di ffus e, wi th ves i cul a r pus tul es a nd
crus ti ng (i mpeti go) or s ometi mes cel l ul i ti s or wi th foca l a nd nodul a r a bs ces s es (furuncl es a nd ca rbuncl es ). Deeper cuta neous a bs ces s es a re
common. Severe necroti zi ng s ki n i nfecti ons ma y occur. Sta phyl ococci a re commonl y i mpl i ca ted i n wound a nd burn i nfecti ons , pos topera ti ve
i nci s i on i nfecti ons , a nd ma s ti ti s or brea s t a bs ces s i n brea s tfeedi ng mothers .
Neonatal infections us ua l l y a ppea r wi thi n 6 wk a fter bi rth a nd i ncl ude s ki n l es i ons wi th or wi thout exfol i a ti on, ba cteremi a , meni ngi ti s , a nd
pneumoni a .
Pneumonia tha t occurs i n a communi ty s etti ng i s not common but ma y devel op i n pa ti ents who ha ve i nfl uenza , who a re recei vi ng corti cos teroi ds or
i mmunos uppres s a nts , or who ha ve chroni c bronchopul mona ry or other hi gh-ri s k di s ea s es . However, S. aureus i s a common ca us e of hos pi ta l a cqui red pneumoni a . Sta phyl ococca l pneumoni a i s occa s i ona l l y cha ra cteri zed by forma ti on of l ung a bs ces s es fol l owed by ra pi d devel opment of
pneuma tocel es a nd empyema . Communi ty-a s s oci a ted methi ci l l i n-res i s ta nt S. aureus (CA-MRSA) often ca us es s evere necroti zi ng pneumoni a .
Endocarditis ca n devel op, pa rti cul a rl y i n IV drug a bus ers a nd pa ti ents wi th pros theti c hea rt va l ves . Beca us e i ntra va s cul a r ca theter us e a nd
i mpl a nta ti on of ca rdi a c devi ces ha ve i ncrea s ed, S. aureus ha s become a l ea di ng ca us e of ba cteri a l endoca rdi ti s . S. aureus endoca rdi ti s i s a n a cute
febri l e i l l nes s often a ccompa ni ed by vi s cera l a bs ces s es , embol i c phenomena , peri ca rdi ti s , s ubungua l petechi a e, s ubconjuncti va l hemorrha ge,
purpuri c l es i ons , hea rt murmurs , a nd hea rt fa i l ure s econda ry to ca rdi a c va l ve da ma ge.
Osteomyelitis occurs more commonl y i n chi l dren, ca us i ng chi l l s , fever, a nd pa i n over the i nvol ved bone. Rednes s a nd s wel l i ng s ubs equentl y
a ppea r. Arti cul a r i nfecti on ma y occur; i t frequentl y res ul ts i n effus i on, s ugges ti ng s epti c a rthri ti s ra ther tha n os teomyel i ti s .
Toxin-mediated disease: Sta phyl ococci ma y produce mul ti pl e toxi ns . Some ha ve l oca l effects ; others tri gger cytoki ne rel ea s e from certa i n T cel l s ,
ca us i ng s eri ous s ys temi c effects (eg, s ki n l es i ons , s hock, orga n fa i l ure, dea th). Pa nton-Va l enti ne l eukoci di n (PVL) i s a toxi n produced by s tra i ns
i nfected wi th a certa i n ba cteri opha ge. PVL i s typi ca l l y pres ent i n s tra i ns of CA-MRSA a nd ha s been thought to medi a te the a bi l i ty to necroti ze;
however, thi s effect ha s not been veri fi ed.

Toxi n-medi a ted s ta phyl ococca l di s ea s es i ncl ude the fol l owi ng:
Toxi c s hock s yndrome
Sta phyl ococca l s ca l ded s ki n s yndrome
Sta phyl ococca l food poi s oni ng
Toxic shock syndrome (s ee p. 1235) ma y res ul t from us e of va gi na l ta mpons or occur a s a compl i ca ti on of a s eemi ngl y mi nor pos topera ti ve i nfecti on.
Al though mos t ca s es ha ve been due to methi ci l l i n-s us cepti bl e S. aureus (MSSA), ca s es due to MRSA a re becomi ng more frequent.
Staphylococcal scalded skin syndrome (s ee p. 701 a nd Pl a te 45), whi ch i s ca us ed by s evera l toxi ns termed exfol i a ti ns , i s a n exfol i a ti ve derma ti ti s of
chi l dhood cha ra cteri zed by l a rge bul l a e a nd peel i ng of the upper l a yer of s ki n. Eventua l l y, exfol i a ti on occurs .
Staphylococcal food poisoning i s ca us ed by i nges ti ng a preformed hea t-s ta bl e s ta phyl ococca l enterotoxi n. Food ca n be conta mi na ted by
s ta phyl ococca l ca rri ers or peopl e wi th a cti ve s ki n i nfecti ons . In food tha t i s i ncompl etel y cooked or l eft a t room tempera ture, s ta phyl ococci
reproduce a nd el a bora te enterotoxi n. Ma ny foods ca n s erve a s growth medi a , a nd des pi te conta mi na ti on, they ha ve a norma l ta s te a nd odor.
Severe na us ea a nd vomi ti ng begi n 2 to 8 h a fter i nges ti on, typi ca l l y fol l owed by a bdomi na l cra mps a nd di a rrhea . The a tta ck i s bri ef, often l a s ti ng <
12 h.
Diagnosis
Di a gnos i s i s by Gra m s ta i n a nd cul ture of i nfected ma teri a l . Sus cepti bi l i ty tes ts s houl d be done beca us e methi ci l l i n-res i s ta nt orga ni s ms a re now
common a nd requi re a l terna ti ve thera py.
When s ta phyl ococca l s ca l ded s ki n s yndrome i s s us pected, cul tures s houl d be obta i ned from bl ood, uri ne, the na s opha rynx, the umbi l i cus ,
a bnorma l s ki n, or a ny s us pected focus of i nfecti on; the i nta ct bul l a e a re s teri l e. Al though the di a gnos i s i s us ua l l y cl i ni ca l , a bi ops y of the a ffected
s ki n ma y hel p confi rm the di a gnos i s .
Sta phyl ococca l food poi s oni ng i s us ua l l y s us pected beca us e of ca s e cl us teri ng (eg, wi thi n a fa mi l y, a ttendees of a s oci a l ga theri ng, or cus tomers
of a res ta ura nt). Confi rma ti on (typi ca l l y by the hea l th depa rtment) enta i l s i s ol a ti ng s ta phyl ococci from s us pect food a nd s ometi mes tes ti ng for
enterotoxi ns .
X-ra y cha nges of os teomyel i ti s ma y not be a ppa rent for 10 to 14 da ys , a nd bone ra refa cti on a nd peri os tea l rea cti on ma y not be detected for even
l onger. Abnorma l i ti es i n MRI, CT, or ra di onucl i de bone s ca ns a re often a ppa rent ea rl i er. Bone bi ops y (open or percuta neous ) s houl d be done for
pa thogen i denti fi ca ti on a nd s us cepti bi l i ty tes ti ng.
Screening: Some i ns ti tuti ons tha t ha ve a hi gh i nci dence of MRSA nos ocomi a l i nfecti ons routi nel y s creen a dmi tted pa ti ents for MRSA (a cti ve
s urvei l l a nce) by us i ng ra pi d l a bora tory techni ques to eva l ua te na s a l s wa b s peci mens . Some i ns ti tuti ons s creen onl y hi gh-ri s k pa ti ents (eg, thos e
who a re a dmi tted to the ICU, who ha ve ha d previ ous MRSA i nfecti on, or who a re a bout to undergo va s cul a r, orthopedi c, or ca rdi a c s urgeri es ). Qui ck
i denti fi ca ti on of MRSA a l l ows ca rri ers to be pl a ced i n conta ct i s ol a ti on. Thi s pra cti ce decrea s es the s prea d of MRSA a nd ma y decrea s e the
i nci dence of nos ocomi a l i nfecti ons wi th MRSA.
Treatment
Loca l mea s ures (eg, debri dement, remova l of ca theters )
Anti bi oti cs s el ected ba s ed on s everi ty of i nfecti on a nd l oca l res i s ta nce pa tterns
Ma na gement i ncl udes a bs ces s dra i na ge, debri dement of necroti c ti s s ue, remova l of forei gn bodi es (i ncl udi ng i ntra va s cul a r ca theters ), a nd us e of
a nti bi oti cs . Ini ti a l choi ce a nd dos a ge of a nti bi oti cs depend on i nfecti on s i te, i l l nes s s everi ty, a nd proba bi l i ty tha t res i s ta nt s tra i ns a re i nvol ved.
Thus , i t i s es s enti a l to know l oca l res i s ta nce pa tterns for i ni ti a l thera py (a nd ul ti ma tel y, to know a ctua l drug s us cepti bi l i ty).
Trea tment of toxi n-medi ca ted s ta phyl ococca l di s ea s e (the mos t s eri ous of whi ch i s toxi c s hock s yndrome) i nvol ves deconta mi na ti on of the toxi nproduci ng a rea (expl ora ti on of s urgi ca l wounds , i rri ga ti on, debri dement), i ntens i ve s upport (i ncl udi ng va s opres s ors a nd res pi ra tory a s s i s ta nce),
el ectrol yte ba l a nci ng, a nd a nti mi crobi a l s . In vi tro evi dence s upports a preference for protei n s ynthes i s i nhi bi tors (eg, cl i nda myci n 900 mg IV q 8 h)
over other cl a s s es of a nti bi oti cs . IV i mmune gl obul i n ha s been benefi ci a l i n s evere ca s es .
Antibiotic resistance: Ma ny s ta phyl ococca l s tra i ns produce peni ci l l i na s e, a n enzyme tha t i na cti va tes s evera l -l a cta m a nti bi oti cs ; thes e s tra i ns a re
res i s ta nt to peni ci l l i n G, a mpi ci l l i n, a nd a nti ps eudomona l peni ci l l i ns . Mos t communi ty-a cqui red s tra i ns a re s us cepti bl e to peni ci l l i na s eres i s ta nt peni ci l l i ns (eg, methi ci l l i n, oxa ci l l i n, na fci l l i n, cl oxa ci l l i n, di cl oxa ci l l i n), cepha l os pori ns , ca rba penems (eg, i mi penem, meropenem,
erta penem, dori penem), ma crol i des , fl uoroqui nol ones , tri methopri m/s ul fa methoxa zol e (TMP/SMX), genta mi ci n, va ncomyci n, a nd tei copl a ni n.
MRSA i s ol a tes ha ve become common, es peci a l l y i n hos pi ta l s . In a ddi ti on, CA-MRSA ha s emerged over the pa s t s evera l yea rs i n ma ny geogra phi c
regi ons . CA-MRSA tends to be l es s res i s ta nt to mul ti pl e drugs tha n hos pi ta l -a cqui red MRSA. Thes e s tra i ns , a l though res i s ta nt to mos t -l a cta ms ,
a re us ua l l y s us cepti bl e to TMP/SMX, doxycycl i ne, or mi nocycl i ne a nd a re often s us cepti bl e to cl i nda myci n, but there i s the potenti a l for emergence
of cl i nda myci n res i s ta nce by s tra i ns i nduci bl y res i s ta nt to erythromyci n (l a bora tori es ma y report thes e s tra i ns a s D-tes t pos i ti ve). Va ncomyci n i s
effecti ve a ga i ns t mos t MRSA, s ometi mes wi th the a ddi ti on of ri fa mpi n a nd a n a mi no-gl ycos i de for s eri ous i nfecti ons .
Vancomycin-resistant S. aureus (VRSA) a nd va ncomyci n-i ntermedi a te-s us cepti bl e S. aureus (VISA) s tra i ns ha ve a ppea red i n the US. Thes e orga ni s ms
ma y requi re l i nezol i d, qui nupri s ti n/da l fopri s ti n, or da ptomyci n.

Beca us e i nci dence of MRSA ha s i ncrea s ed, i ni ti a l empi ri c trea tment for s eri ous s ta phyl ococca l i nfecti ons (pa rti cul a rl y thos e tha t occur i n a hea l th
ca re s etti ng) s houl d i ncl ude a drug wi th rel i a bl e a cti vi ty a ga i ns t MRSA. Thus , for proven or s us pected bl oods trea m i nfecti ons , va ncomyci n or
da ptomyci n woul d be a ppropri a te. For pneumoni a , va ncomyci n or l i nezol i d s houl d be us ed beca us e da ptomyci n i s not rel i a bl y a cti ve i n the l ungs .
Ta bl e 133-1 s umma ri zes trea tment opti ons .
Prevention
As epti c preca uti ons (eg, thoroughl y wa s hi ng ha nds between pa ti ent exa mi na ti ons , s teri l i zi ng s ha red equi pment) hel p decrea s e s prea d i n
i ns ti tuti ons . Stri ct i s ol a ti on procedures s houl d be us ed for pa ti ents ha rbori ng res i s ta nt mi crobes unti l thei r i nfecti ons ha ve been cured. An
a s ymptoma ti c na s a l ca rri er need not be i s ol a ted unl es s the s tra i n i s MRSA or i s the s us pected s ource of a n outbrea k. Cl oxa ci l l i n, di cl oxa ci l l i n,
TMP/SMX, ci profl oxa ci n (ea ch of thes e drugs i s often combi ned wi th ri fa mpi n), a nd topi ca l mupi roci n ha ve been us eful i n trea ti ng MRSA i n ca rri ers ,
but the orga ni s m recurs i n up to 50% a nd frequentl y becomes res i s ta nt.
Sta phyl ococca l food poi s oni ng ca n be prevented by a ppropri a te food prepa ra ti on. Pa ti ents wi th s ta phyl ococca l s ki n i nfecti ons s houl d not ha ndl e
food, a nd food s houl d be cons umed i mmedi a tel y or refri gera ted a nd not kept a t room tempera ture.
Streptococcal and Enterococcal Infections
(See a l s o Pneumococca l Infecti ons on p. 1225, Rheuma ti c Fever on p. 2861, a nd Tons i l l opha ryngi ti s on p. 473.)
Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and
endocarditis. Symptoms vary with the organ infected. Sequelae include
[Table 133-1. Anti bi oti c Trea tment of Sta phyl ococca l Infecti ons i n Adul ts ]
rheumatic fever and glomerulonephritis. Clinical diagnoses are confirmed by Gram stain and culture. Most strains are sensitive to penicillin, with the exception of
enterococci, which can be resistant to multiple drugs. Recently, macrolide-resistant strains have emerged.
Classification: Three di fferent types of s treptococci a re i ni ti a l l y di fferenti a ted by thei r a ppea ra nce when they a re grown on s heep bl ood a ga r. Hemol yti c s treptococci produce zones of cl ea r hemol ys i s a round ea ch col ony, -hemol yti c s treptococci (i ncl udi ng vi ri da ns group s treptococci ) a re
s urrounded by green di s col ora ti on res ul ti ng from i ncompl ete hemol ys i s , a nd -hemol yti c s treptococci a re nonhemol yti c.
Subs equent cl a s s i fi ca ti on, ba s ed on ca rbohydra tes i n the cel l wa l l , di vi des s treptococci i nto La ncefi el d groups A through H a nd K through T (s ee
Ta bl e 133-2). Vi ri da ns s treptococci form a s epa ra te group tha t i s di ffi cul t to cl a s s i fy. In the La ncefi el d cl a s s i fi ca ti on, enterococci were i ni ti a l l y
i ncl uded a mong the group D s treptococci . More recentl y, enterococci ha ve been cl a s s i fi ed a s a s epa ra te genus .
Virulence factors: Ma ny s treptococci el a bora te vi rul ence fa ctors , i ncl udi ng s treptol ys i ns , DNAa s es , a nd hya l uroni da s e, whi ch contri bute to ti s s ue
des tructi on a nd s prea d of i nfecti on. A few s tra i ns rel ea s e exotoxi ns tha t a cti va te certa i n T cel l s , tri ggeri ng rel ea s e of cytoki nes , i ncl udi ng tumor
necros i s fa ctor-, i nterl euki ns , a nd other i mmunomodul a tors . Thes e cytoki nes a cti va te the compl ement, coa gul a ti on, a nd fi bri nol yti c s ys tems ,
l ea di ng to s hock, orga n fa i l ure, a nd dea th.
Diseases Caused by Streptococci
The mos t s i gni fi ca nt s treptococca l pa thogen i s S. pyogenes, whi ch i s -hemol yti c a nd i n La ncefi el d group A a nd i s thus denoted a s group A hemol yti c s treptococci (GABHS). The 2 mos t common a cute di s ea s es due to GABHS a re pha ryngi ti s a nd s ki n i nfecti ons ; i n a ddi ti on, del a yed,
nons uppura ti ve compl i ca ti ons (rheuma ti c fever, a cute gl omerul onephri ti s ) s ometi mes occur 2 wk a fter i nfecti on.
Di s ea s e ca us ed by other s treptococca l s peci es i s l es s preva l ent a nd us ua l l y i nvol ves s oft-ti s s ue i nfecti on or endoca rdi ti s (s ee Ta bl e 133-2). Some
non-GABHS i nfecti ons occur predomi na ntl y i n certa i n popul a ti ons (eg, group B s treptococci i n neona tes a nd pos tpa rtum women, enterococci i n
hos pi ta l i zed pa ti ents ).
Infecti ons ca n s prea d through the a ffected ti s s ues a nd a l ong l ympha ti c cha nnel s to regi ona l l ymph nodes . They ca n a l s o ca us e l oca l s uppura ti ve
compl i ca ti ons , s uch a s peri tons i l l a r a bs ces s , oti ti s medi a , s i nus i ti s , a nd
[Table 133-2. Cl a s s i fi ca ti on of Streptococci ]
ba cteremi a . Suppura ti on depends on the s everi ty of i nfecti on a nd the s us cepti bi l i ty of ti s s ue.
Streptococcal pharyngitis i s us ua l l y ca us ed by GABHS. About 20% of pa ti ents pres ent wi th s ore throa t, fever, a beefy red pha rynx, a nd a purul ent
tons i l l a r exuda te. The rema i nder ha ve l es s promi nent s ymptoms , a nd the exa mi na ti on res embl es tha t of vi ra l pha ryngi ti s . The cervi ca l a nd
s ubma xi l l a ry nodes ma y enl a rge a nd become tender. Streptococca l pha ryngi ti s ca n l ea d to peri tons i l l a r a bs ces s (s ee p. 474). Cough, l a ryngi ti s , a nd
s tuffy nos e a re not cha ra cteri s ti c of s treptococca l pha ryngea l i nfecti on; thei r pres ence s ugges ts a nother ca us e (us ua l l y vi ra l or a l l ergi c). An
a s ymptoma ti c ca rri er s ta te ma y exi s t i n a s ma ny a s 20%.
Scarlet fever i s uncommon toda y. Sca rl et fever i s ca us ed by group A (a nd occa s i ona l l y by group B or C) s treptococca l s tra i ns tha t produce a n
erythrogeni c toxi n, l ea di ng to a di ffus e pi nk-red cuta neous fl us h tha t bl a nches wi th pres s ure. The ra s h i s s een bes t on the a bdomen or l a tera l
ches t a s da rk red l i nes i n s ki nfol ds (Pa s ti a 's l i nes ) or a s ci rcumora l pa l l or. A s tra wberry tongue (i nfl a med pa pi l l a e protrudi ng through a bri ght red
coa ti ng) a l s o occurs a nd mus t be di fferenti a ted from tha t s een i n toxi c s hock s yndrome (s ee p. 1235) a nd Ka wa s a ki di s ea s e (s ee p. 2935).
Cha ra cteri s ti c numerous s ma l l (1- to 2-mm) pa pul a r el eva ti ons , gi vi ng a s a ndpa per qua l i ty to the s ki n, ma y be pres ent. The upper l a yer of the
previ ous l y reddened s ki n often des qua ma tes a fter fever s ubs i des . Other s ymptoms a re s i mi l a r to thos e i n s treptococca l pha ryngi ti s , a nd the
cours e a nd ma na gement of s ca rl et fever a re the s a me a s thos e of other group A i nfecti ons .
Skin infections i ncl ude i mpeti go (s ee p. 699) a nd cel l ul i ti s (s ee p. 694). Cel l ul i ti s ma y s prea d ra pi dl y beca us e of the numerous l yti c enzymes a nd
toxi ns produced ma i nl y by group A s treptococci . Erys i pel a s (s ee p. 696) i s a pa rti cul a r form of s treptococca l cel l ul i ti s .
Necrotizing fasciitis due to S. pyogenes i s a s evere derma l (or ra rel y mus cul a r) i nfecti on tha t s prea ds a l ong fa s ci a l pl a nes (s ee p. 700). Inocul a ti on
ori gi na tes through the s ki n or bowel , a nd the defect ma y be s urgi ca l , tri vi a l , di s ta nt from the di s ea s e s i te, or occul t, a s wi th col oni c di verti cul a or
a n a ppendi cea l a bs ces s . Necroti zi ng fa s ci i ti s i s preva l ent a mong IV drug a bus ers . Formerl y known a s s treptococca l ga ngrene a nd popul a ri zed a s
the fl es h-ea ti ng ba cteri a , the s a me s yndrome ma y a l s o be pol ymi crobi a l , i nvol vi ng a hos t of a erobi c a nd a na erobi c fl ora , i ncl udi ng Clostridium
perfringens. When necroti zi ng fa s ci i ti s occurs i n the peri neum, i t i s ca l l ed Fourni er's ga ngrene (s ee Pl a te 61). Comorbi d condi ti ons , s uch a s
i mpa i red i mmuni ty, di a betes , a nd a l cohol i s m, a re common. Symptoms begi n wi th fever a nd exqui s i te l oca l i zed pa i n; pa i n i ncrea s es ra pi dl y over
ti me a nd i s often the fi rs t (a nd s ometi mes onl y) ma ni fes ta ti on. Di ffus e or l oca l erythema ma y be pres ent. Thrombos i s of the mi crova s cul a ture
ca us es i s chemi c necros i s , l ea di ng to ra pi d s prea d a nd di s proporti ona l l y s evere toxi ci ty. In 20 to 40% of pa ti ents , a dja cent mus cl es a re i nva ded.
Shock a nd rena l dys functi on a re common. Morta l i ty i s hi gh, even wi th trea tment.
Other s eri ous s treptococca l i nfecti ons i ncl ude s epti cemi a , puerpera l s eps i s , endoca rdi ti s , a nd pneumoni a .
Streptococcal toxic shock syndrome (s ee p. 1235), s i mi l a r to tha t ca us ed by S. aureus, ma y res ul t from toxi n-produci ng s tra i ns of GABHS. Pa ti ents a re
us ua l l y otherwi s e hea l thy chi l dren or a dul ts wi th s ki n a nd s oft-ti s s ue i nfecti ons .
Delayed complications: The mecha ni s m by whi ch certa i n s tra i ns of GABHS ca us e del a yed compl i ca ti ons i s uncl ea r but ma y i nvol ve cros s -rea cti vi ty of
s treptococca l a nti bodi es a ga i ns t hos t ti s s ue.
Rheumatic fever (s ee p. 2861), a n i nfl a mma tory di s order, occurs i n < 3% of pa ti ents i n the weeks a fter untrea ted GABHS upper res pi ra tory tra ct
i nfecti on. It i s much l es s common toda y tha n i n the prea nti bi oti c era . Di a gnos i s i s ba s ed on a combi na ti on of a rthri ti s , ca rdi ti s , chorea , s peci fi c
cuta neous ma ni fes ta ti ons , a nd l a bora tory tes t res ul ts (Jones cri teri a ). One of the mos t i mporta nt rea s ons for trea ti ng s trep throa t i s to prevent
rheuma ti c fever.
Poststreptococcal acute glomerulonephritis (s ee p. 2392) i s a n a cute nephri ti c s yndrome fol l owi ng pha ryngi ti s or s ki n i nfecti on due to a certa i n l i mi ted
number of nephri togeni c s tra i ns of GABHS (eg, types 12 a nd 49). After a throa t or s ki n i nfecti on wi th one of thes e s tra i ns , a bout 10 to 15% of
pa ti ents devel op a cute gl omerul onephri ti s . It i s mos t common a mong chi l dren, occurri ng 1 to 3 wk a fter i nfecti on. Nea rl y a l l chi l dren, but
s omewha t fewer a dul ts , recover wi thout perma nent rena l da ma ge. Anti bi oti c trea tment of GABHS i nfecti on ha s l i ttl e effect on devel opment of
gl omerul onephri ti s .
PANDAS syndrome (pedi a tri c a utoi mmune neurops ychi a tri c di s order a s s oci a ted wi th group A s treptococci ) refers to a s ubs et of obs es s i ve di s orders
or ti c di s orders i n chi l dren thought to be exa cerba ted by GABHS i nfecti on.
Certa i n forms of psoriasis (eg, gutta te) ma y a l s o be rel a ted to -hemol yti c s treptococca l i nfecti ons .
Diagnosis
Cul ture
Someti mes ra pi d a nti gen tes ts or a nti body ti ters
Streptococci a re rea di l y i denti fi ed by cul ture on a s heep bl ood a ga r pl a te.
Rapid antigen-detection tests tha t ca n detect GABHS di rectl y from throa t s wa bs a re a va i l a bl e. Ma ny tes ts us e enzyme i mmunoa s s a y, but more
recentl y, tes ts us i ng opti ca l i mmunoa s s a y ha ve become a va i l a bl e. Thes e ra pi d tes ts ha ve hi gh s peci fi ci ty (> 95%) but va ry cons i dera bl y i n
s ens i ti vi ty (55% to 80 to 90% for the newer opti ca l i mmunoa s s a y tes t). Nega ti ve res ul ts s houl d be confi rmed by cul ture (pa rti cul a rl y i f us e of a
ma crol i de i s bei ng cons i dered beca us e of potenti a l res i s ta nce).
Duri ng conva l es cence, evi dence of i nfecti on ca n be obta i ned i ndi rectl y by demons tra ti ng a nti s treptococca l a nti bodi es i n s erum. Anti bodi es a re
mos t us eful i n di a gnos i s of pos ts treptococca l di s ea s es , s uch a s rheuma ti c fever a nd gl omerul onephri ti s . Confi rma ti on requi res tha t s equenti a l
s peci mens s how a ri s e i n ti ter beca us e a s i ngl e va l ue ma y be hi gh beca us e of a l ong a ntecedent i nfecti on. Serum s peci mens need not be ta ken
more often tha n every 2 wk a nd ma y be ta ken every 2 mo. To be cons i dered s i gni fi ca nt, a ri s e (or fa l l ) i n ti ter s houl d s pa n a t l ea s t 2 s eri a l
di l uti ons . The a nti s treptol ys i n O (ASO) ti ter ri s es i n onl y 75 to 80% of i nfecti ons . For compl etenes s i n di ffi cul t ca s es , a ny one of the other tes ts
(a nti hya l uroni da s e, a nti deoxyri bonucl ea s e B, a nti ni coti na mi de a deni ne di nucl eoti da s e, a nti s treptoki na s e) ca n a l s o be us ed. Peni ci l l i n gi ven
wi thi n the fi rs t 5 da ys for s ymptoma ti c s treptococca l pha ryngi ti s ma y del a y the a ppea ra nce a nd decrea s e the ma gni tude of the ASO res pons e.
Pa ti ents wi th s treptococca l pyoderma us ua l l y do not ha ve a s i gni fi ca nt ASO res pons e but ma y ha ve a res pons e to other a nti gens (i e, a nti -DNAa s e,
a nti hya l uroni da s e).
Treatment
Us ua l l y peni ci l l i n
Pharyngitis: Ordi na ri l y, pha ryngea l GABHS i nfecti ons , i ncl udi ng s ca rl et fever, a re s el f-l i mi ted. Anti bi oti cs s horten the cours e i n young chi l dren,
es peci a l l y thos e wi th s ca rl et fever, but ha ve onl y modes t effect on s ymptoms i n a dol es cents a nd a dul ts . However, a nti bi oti cs hel p prevent l oca l
s uppura ti ve compl i ca ti ons (eg, peri tons i l l a r a bs ces s ), oti ti s medi a , a nd rheuma ti c fever.
Peni ci l l i n i s the drug of choi ce. No i s ol a te of GABHS ha s demons tra ted peni ci l l i n res i s ta nce cl i ni ca l l y, proba bl y beca us e i t l a cks a l tered peni ci l l i nbi ndi ng protei ns , ha s a n i neffi ci ent gene tra ns fer mecha ni s m for res i s ta nce, or both. However, s ome s treptococca l s tra i ns a ppea r to ha ve i n vi tro
tol era nce to peni ci l l i n; the cl i ni ca l s i gni fi ca nce of s uch s tra i ns i s uncl ea r.
A s i ngl e i njecti on of benza thi ne peni ci l l i n G, 600,000 uni ts IM for s ma l l chi l dren (< 27.3 kg) or 1.2 mi l l i on uni ts IM for a dol es cents a nd a dul ts
us ua l l y s uffi ces . Ora l peni ci l l i n V ma y be us ed i f the pa ti ent ca n be trus ted to ma i nta i n the regi men for the requi red 10 da ys ; peni ci l l i n V 500 mg
(250 mg for chi l dren < 27 kg) po bi d or ti d i s gi ven. Ora l cepha l os pori ns a re a l s o effecti ve. Cefdi ni r, cefpodoxi me, a nd a zi thromyci n ca n be us ed for
a 5-da y cours e of thera py. Del a yi ng trea tment 1 to 2 da ys unti l l a bora tory confi rma ti on i ncrea s es nei ther the dura ti on of di s ea s e nor the i nci dence
of compl i ca ti ons .
When peni ci l l i n or a -l a cta m i s contra i ndi ca ted, erythromyci n 250 mg po qi d or cl i nda myci n 300 mg po ti d ma y be gi ven for 10 da ys , a l though
res i s ta nce of GABHS to ma crol i des ha s been detected. Some a uthori ti es recommend i n vi tro confi rma ti on of s us cepti bi l i ty i f a ma crol i de i s to be
us ed a nd there i s ma crol i de res i s ta nce i n the communi ty. Cl i nda myci n 5 mg/kg po qi d i s preferred i n chi l dren who ha ve rel a ps es of chroni c
tons i l l i ti s , pos s i bl y beca us e i t ha s good a cti vi ty a ga i ns t peni ci l l i na s e-produci ng s ta phyl ococci or a na erobes coi nfecti ng the tons i l l a r crypts a nd
i na cti va ti ng peni ci l l i n G a nd beca us e i t a ppea rs to ha l t exotoxi n producti on more ra pi dl y tha n other drugs . Amoxi ci l l i n/cl a vul a na te i s a l s o
effecti ve. TMP/SMX, s ome of the fl uoroqui nol ones , a nd tetra cycl i nes a re unrel i a bl e for trea ti ng GABHS.
Sore throa t, hea da che, a nd fever ca n be trea ted wi th a na l ges i cs or a nti pyreti cs . Bed res t a nd i s ol a ti on a re unneces s a ry. Cl os e conta cts who a re
s ymptoma ti c or ha ve a hi s tory of pos ts treptococca l compl i ca ti ons s houl d be exa mi ned for s treptococci .
Skin infection: Cel l ul i ti s i s often trea ted wi thout doi ng a cul ture beca us e i s ol a ti ng orga ni s ms ca n be di ffi cul t. Thus , regi mens effecti ve a ga i ns t both
s treptococci a nd s ta phyl ococci a re us ed (s ee p. 695).
Necroti zi ng fa s ci i ti s s houl d be trea ted i n a n ICU. Extens i ve (s ometi mes repea ted) s urgi ca l debri dement i s requi red. A recommended i ni ti a l
a nti bi oti c regi men i s a -l a cta m (often a broa d-s pectrum drug unti l eti ol ogy i s confi rmed by cul ture) pl us cl i nda myci n. Al though s treptococci
rema i n s us cepti bl e to -l a cta m a nti bi oti cs , a ni ma l s tudi es s how tha t peni ci l l i n i s not a l wa ys effecti ve a ga i ns t a l a rge ba cteri a l i nocul um beca us e
the s treptococci a re not ra pi dl y growi ng.
Other streptococcal infections: Drugs of choi ce for trea ti ng group B, C, a nd G i nfecti ons a re peni ci l l i n, a mpi ci l l i n, or va ncomyci n. Cepha l os pori ns or
ma crol i des a re us ua l l y effecti ve, but s us cepti bi l i ty tes ts mus t gui de thera py, es peci a l l y i n very i l l , i mmunocompromi s ed, or debi l i ta ted peopl e
a nd i n peopl e wi th forei gn bodi es a t the i nfecti on s i te. Surgi ca l wound dra i na ge a nd debri dement a s a djuncts to a nti mi crobi a l thera py ma y be
l i fes a vi ng.
S. bovis i s rel a ti vel y s us cepti bl e to a nti bi oti cs . Al though va ncomyci n-res i s ta nt S. bovis i s ol a tes ha ve been reported, the orga ni s m rema i ns
s us cepti bl e to peni ci l l i n a nd a mi nogl ycos i des .
Mos t vi ri da ns s treptococci a re often s us cepti bl e to peni ci l l i n G a nd other -l a cta ms . Res i s ta nce i s growi ng, a nd thera py for s uch s tra i ns s houl d be
di cta ted by res ul ts of i n vi tro s us cepti bi l i ty tes ts .
Enterococcal Infections
Enterococcus faecalis and E. faecium cause endocarditis, UTI, intra-abdominal infection, cellulitis, and wound infection as well as concurrent bacteremia.
Enterococci a s s oci a ted wi th endoca rdi ti s a re di ffi cul t to era di ca te unl es s a combi na ti on of a cel l wa l l -a cti ve drug (eg, peni ci l l i n, a mpi ci l l i n,
va ncomyci n) pl us a n a mi nogl ycos i de (eg, genta mi ci n, s treptomyci n) i s us ed.
For compl i ca ted s ki n i nfecti ons due to va ncomyci n-s us cepti bl e enterococci , da ptomyci n a nd ti gecycl i ne a re effecti ve trea tment opti ons . Ti gecycl i ne
i s recommended for compl i ca ted i ntra -a bdomi na l i nfecti ons .
Resistance: Va ncomyci n-res i s ta nt enterococci (VRE) ma y exi s t; they ma y be res i s ta nt to other gl ycopepti des (eg, tei copl a ni n), a mi nogl ycos i des , a nd
cel l wa l l -a cti ve -l a cta ms (eg, peni ci l l i n G, a mpi ci l l i n). When i denti fi ed, i nfected pa ti ents a re s tri ctl y i s ol a ted. Recommended trea tment i ncl udes
s treptogra mi ns (qui nupri s ti n/da l fopri s ti n for Enterococcus faecium onl y) a nd oxa zol i di nones (l i nezol i d). Da ptomyci n a nd ti gecycl i ne ha ve i n vi tro
a cti vi ty a ga i ns t VRE a nd ma y be off-l a bel trea tment opti ons .
-La cta ma s e-produci ng enterococci a re occa s i ona l l y encountered. Combi na ti on -l a cta m/-l a cta ma s e i nhi bi tor a nti bi oti cs (eg,
pi pera ci l l i n/ta zoba cta m, a mpi ci l l i n/s ul ba cta m) or va ncomyci n ca n be us ed.
Toxic Shock Syndrome
Toxic shock syndrome (TSS) is caused by staphylococcal or streptococcal exotoxins. Symptoms include high fever, hypotension, diffuse erythematous rash, and
multiple organ dysfunction, which may rapidly progress to severe and intractable shock. Diagnosis is made clinically and by isolating the organism. Treatment
includes antibiotics, intensive support, and immune globulin.
TSS i s ca us ed by exotoxi n-produci ng cocci . Stra i ns of pha ge-group 1 Staphylococcus aureus el a bora te the TSS toxi n-1 (TSST-1) or rel a ted exotoxi ns ;
certa i n s tra i ns of Streptococcus pyogenes produce a t l ea s t 2 exotoxi ns .
Staphylococcal toxic shock: Women who ha ve preexi s ti ng s ta phyl ococca l col oni za ti on of the va gi na a nd who us e ta mpons a re a t hi ghes t ri s k.
Mecha ni ca l or chemi ca l fa ctors rel a ted to ta mpon us e proba bl y enha nce producti on of the exotoxi n or fa ci l i ta te i ts entry i nto the bl oods trea m
through a mucos a l brea k or vi a the uterus . Es ti ma tes ma de from s ma l l s eri es s ugges t a bout 3 ca s es /100,000 mens trua ti ng women s ti l l occur, a nd
ca s es a re s ti l l reported i n women who do not us e ta mpons , i n women who ha ve ha d s urgery, a nd i n pos tpa rtum women. About 15% of ca s es occur
pos tpa rtum or a s a compl i ca ti on of pos topera ti ve s ta phyl ococca l wound i nfecti ons , whi ch frequentl y a ppea r i ns i gni fi ca nt. Ca s es ha ve a l s o been
reported i n pa ti ents wi th i nfl uenza , os teomyel i ti s , or cel l ul i ti s .
Morta l i ty from s ta phyl ococca l TSS i s < 3%. Recurrences a re common a mong women who conti nue to us e ta mpons duri ng the fi rs t 4 mo a fter a n
epi s ode.
Streptococcal toxic shock: The s yndrome i s s i mi l a r to tha t ca us ed by S. aureus, but morta l i ty i s hi gher (20 to 60%). In a ddi ti on, a bout 50% of pa ti ents
ha ve S. pyogenes ba cteremi a , a nd 50% ha ve necroti zi ng fa s ci i ti s (nei ther i s common wi th s ta phyl ococca l TSS). Pa ti ents a re us ua l l y otherwi s e
hea l thy chi l dren or a dul ts . Pri ma ry i nfecti ons i n s ki n a nd s oft ti s s ue a re more common tha n i n other s i tes . In contra s t to s ta phyl ococca l TSS,
s treptococca l TSS i s more l i kel y to ca us e a cute res pi ra tory di s tres s s yndrome (ARDS) a nd l es s l i kel y to ca us e a typi ca l cuta neous rea cti on.
S. pyogenes TSS i s defi ned a s a ny group A -hemol yti c s treptococci (GABHS) i nfecti on a s s oci a ted wi th s hock a nd orga n fa i l ure. Ri s k fa ctors for GABHS
TSS i ncl ude mi nor tra uma , s urgi ca l procedures , vi ra l i nfecti ons (eg, va ri cel l a ), a nd us e of NSAIDs .
Symptoms and Signs
Ons et i s s udden, wi th fever (39 to 40.5C, whi ch rema i ns el eva ted), hypotens i on, a di ffus e ma cul a r erythroderma , a nd i nvol vement of a t l ea s t 2
other orga n s ys tems .
Sta phyl ococca l TSS i s l i kel y to ca us e vomi ti ng, di a rrhea , mya l gi a , el eva ted CK, mucos i ti s , hepa ti c da ma ge, thrombocytopeni a , a nd confus i on. The
s ta phyl ococca l TSS ra s h i s more l i kel y to des qua ma te, pa rti cul a rl y on the pa l ms a nd s ol es , between 3 a nd 7 da ys a fter ons et.
Streptococca l TSS commonl y ca us es res pi ra tory di s tres s s yndrome, coa gul opa thy, a nd hepa ti c da ma ge a nd i s more l i kel y to ca us e fever, ma l a i s e,
a nd s evere pa i n a t the s i te of a s oft-ti s s ue i nfecti on.
Rena l i mpa i rment i s frequent a nd common to both. The s yndrome ma y progres s wi thi n 48 h to s yncope, s hock, a nd dea th. Les s s evere ca s es of
s ta phyl ococca l TSS a re fa i rl y common.
Diagnosis
Cul tures
Di a gnos i s i s ma de cl i ni ca l l y a nd by i s ol a ti ng the orga ni s m from bl ood cul tures (for Streptococcus) or from the l oca l s i te. TSS res embl es Ka wa s a ki
di s ea s e, but Ka wa s a ki di s ea s e us ua l l y occurs i n chi l dren < 5 yr of a ge a nd does not ca us e s hock, a zotemi a , or thrombocytopeni a ; the s ki n ra s h i s
ma cul opa pul a r. Other di s orders to be cons i dered a re s ca rl et fever, Reye's s yndrome, s ta phyl ococca l s ca l ded s ki n s yndrome, meni ngococcemi a ,
Rocky Mounta i n s potted fever, l eptos pi ros i s , a nd vi ra l exa nthema tous di s ea s es . Thes e di s orders a re rul ed out by s peci fi c cl i ni ca l di fferences ,
cul tures , a nd s erol ogi c tes ts .
Speci mens for cul ture s houl d be ta ken from a ny l es i ons , the nos e (for s ta phyl ococci ), throa t (for s treptococci ), va gi na (for both), a nd bl ood. MRI or
CT of s oft ti s s ue i s hel pful i n l oca l i zi ng s i tes of i nfecti on. Conti nuous moni tori ng of rena l , hepa ti c, bone ma rrow, a nd ca rdi opul mona ry functi on i s
neces s a ry.
Treatment
Loca l mea s ures (eg, deconta mi na ti on, debri dement)
Fl ui d res us ci ta ti on a nd ci rcul a tory s upport
A -l a cta m (eg, peni ci l l i n) pl us cl i nda myci n
Pa ti ents s us pected of ha vi ng TSS s houl d be hos pi ta l i zed i mmedi a tel y a nd trea ted i ntens i vel y. Ta mpons , di a phra gms , a nd other forei gn bodi es
s houl d be removed a t once. Sus pected pri ma ry s i tes s houl d be deconta mi na ted thoroughl y. Deconta mi na ti on i ncl udes rei ns pecti on a nd i rri ga ti on
of s urgi ca l wounds , even i f they a ppea r hea l thy; repea ted debri dement of devi ta l i zed ti s s ues ; a nd i rri ga ti on of potenti a l na tura l l y col oni zed s i tes
(s i nus es , va gi na ). Fl ui ds a nd el ectrol ytes a re repl a ced to prevent or trea t hypovol emi a , hypotens i on, a nd s hock. Beca us e fl ui d l os s i nto ti s s ues
ca n occur throughout the body (beca us e of s ys temi c ca pi l l a ry l ea k s yndrome a nd hypoa l bumi nemi a ), s hock ma y be profound a nd res i s ta nt.
Aggres s i ve fl ui d res us ci ta ti on a nd ci rcul a tory s upport a re s ometi mes requi red.
Obvi ous i nfecti ons s houl d be trea ted. If S. pyogenes i s i s ol a ted, a -l a cta m (eg, peni ci l l i n) pl us cl i nda myci n (900 mg IV q 8 h) conti nued for 14 da ys
i s the mos t effecti ve a nti bi oti c trea tment. If methi ci l l i n-res i s ta nt S. aureus (MRSAs ee p. 1230) i s s us pected or confi rmed, va ncomyci n, da ptomyci n,
l i nezol i d, or ti gecycl i ne i s i ndi ca ted. Anti bi oti cs gi ven duri ng the a cute i l l nes s ma y era di ca te pa thogen foci a nd prevent recurrences . Pa s s i ve
i mmuni za ti on to TSS toxi ns wi th IV i mmune gl obul i n (400 mg/kg) ha s been hel pful i n s evere ca s es of both types of TSS a nd l a s ts for weeks , but the
di s ea s e ma y not i nduce a cti ve i mmuni ty, s o recurrences a re pos s i bl e.
If a tes t for s eroconvers i on of the s erum a nti body res pons es to TSST-1 i n a cute- a nd conva l es cent-pha s e pa i red s era i s nega ti ve, women who ha ve
ha d s ta phyl ococca l TSS s houl d proba bl y refra i n from us i ng ta mpons a nd cervi ca l ca ps , pl ugs , a nd di a phra gms . Advi s i ng a l l women, rega rdl es s of
TSST-1 a nti body s ta tus , to cha nge ta mpons frequentl y or us e na pki ns i ns tea d a nd to a voi d hypera bs orbent ta mpons s eems prudent.
Chapter 134. Gram-Positive Bacilli

Introduction
Gra m-pos i ti ve ba ci l l i ca us e a nthra x, di phtheri a , erys i pel othri cos i s , l i s teri os i s , a nd noca rdi os i s . Seri ous s ymptoms ca us ed by a nthra x a nd
di phtheri a a re due to powerful toxi ns produced by the orga ni s ms .
Anthrax
Anthrax is caused by Bacillus anthracis, toxin-producing, encapsulated, aerobic or facultative anaerobic organisms. Anthrax, an often fatal disease of animals, is
transmitted to humans by contact with infected animals or their products. In humans, infection typically occurs through the skin. Inhalation infection is less
common; oropharyngeal, meningeal, and GI infections are rare. For inhalation and GI infections, nonspecific local symptoms are typically followed in several days
by severe systemic illness, shock, and often death. Empiric treatment is with ciprofloxacin or doxycycline. A vaccine is available.
Etiology
Anthra x i s a n i mporta nt domes ti c a ni ma l di s ea s e, occurri ng i n goa ts , ca ttl e, s heep, a nd hors es . Anthra x a l s o occurs i n wi l dl i fe, s uch a s hi ppos ,
el epha nts , a nd Ca pe buffa l o. It i s ra re i n huma ns a nd occurs ma i nl y i n countri es tha t do not prevent i ndus tri a l or a gri cul tura l expos ure to i nfected
a ni ma l s or thei r products (eg, hi des ). The i nci dence of na tura l i nfecti on ha s decrea s ed, pa rti cul a rl y i n the devel oped worl d.
However, the potenti a l us e of a nthra x a s a bi ol ogi ca l wea pon ha s i ncrea s ed fea r of thi s pa thogen. Spores ha ve been prepa red i n very fi nel y
powdered form (wea poni zed) to be us ed a s a gents of wa rfa re a nd bi oterrori s m (s ee p. 1164); i n a nthra x bi oa tta cks of 2001, s pores were s prea d vi a
the Uni ted Sta tes Pos ta l Servi ce.
Pathophysiology
Bacillus anthracis rea di l y form s pores when they drya n envi ronmenta l condi ti on unfa vora bl e for growth. Spores res i s t des tructi on a nd ca n rema i n
vi a bl e i n s oi l , wool , a nd a ni ma l ha i r for deca des . Spores germi na te a nd begi n mul ti pl yi ng ra pi dl y when they enter a n envi ronment ri ch i n a mi no
a ci ds a nd gl ucos e (eg, ti s s ue, bl ood).
Huma n i nfecti on ca n be a cqui red by
Cuta neous conta ct (mos t common)
Inges ti on
Inha l a ti on
Cutaneous infection i s us ua l l y a cqui red by conta ct wi th i nfected a ni ma l s or s poreconta mi na ted a ni ma l products . Open wounds or a bra s i ons
i ncrea s e s us cepti bi l i ty, but i nfecti on ma y occur when s ki n i s i nta ct. Ski n i nfecti on ma y be tra ns mi tted from pers on to pers on by di rect conta ct or
fomi tes .
GI (including oropharyngeal) infection ma y occur a fter i nges ti on of i na dequa tel y cooked mea t conta i ni ng the vegeta ti ve forms of the orga ni s m, us ua l l y
when a brea k i n the pha ryngea l or i ntes ti na l mucos a fa ci l i ta tes i nva s i on. Inges ted a nthra x s pores ca n ca us e l es i ons from the ora l ca vi ty to the
cecum. Rel ea s ed toxi n ca us es hemorrha gi c necroti c ul cers a nd mes enteri c l ympha deni ti s , whi ch ma y l ea d to i ntes ti na l hemorrha ge, obs tructi on,
or perfora ti on.
Pulmonary infection (i nha l a ti on a nthra x), ca us ed by i nha l i ng s pores , i s a l mos t a l wa ys due to occupa ti ona l expos ure to conta mi na ted a ni ma l
products (eg, hi des ) a nd i s often fa ta l .
GI a nd i nha l a ti on a nthra x a re not tra ns mi tted from pers on to pers on.
After enteri ng the body, s pores germi na te i ns i de ma cropha ges , whi ch mi gra te to regi ona l l ymph nodes where the ba cteri a mul ti pl y. In i nha l a ti on
a nthra x, s pores a re depos i ted i n a l veol a r s pa ces , where they a re i nges ted by ma cropha ges , whi ch mi gra te to medi a s ti na l l ymph nodes , us ua l l y
ca us i ng a hemorrha gi c medi a s ti ni ti s . Ba cteremi a ma y occur i n a ny form of a nthra x a nd occurs i n nea rl y a l l fa ta l ca s es ; meni ngea l i nvol vement i s
common.
Virulence factors: The vi rul ence of B. anthracis i s due to i ts a nti pha gocyti c ca ps ul e, i ts toxi ns (fa ctors ), a nd i ts ra pi d repl i ca ti on ca pa bi l i ty.
The predomi na nt toxi ns a re edema toxi n a nd l etha l toxi n. Protecti ve a nti gen bi nds to ta rget cel l s a nd fa ci l i ta tes cel l ul a r entry of edema toxi n a nd
l etha l toxi n. Edema toxi n ca us es ma s s i ve l oca l edema . Letha l toxi n tri ggers a ma s s i ve rel ea s e of cytoki nes from ma cropha ges , whi ch i s
res pons i bl e for the s udden dea th common i n a nthra x i nfecti ons .
Symptoms and Signs
Mos t pa ti ents pres ent wi thi n 1 to 6 da ys of expos ure, but for i nha l a ti on a nthra x, the i ncuba ti on peri od ca n be > 6 wk.
Cutaneous anthrax begi ns a s a pa i nl es s , pruri ti c, red-brown pa pul e 1 to 10 da ys a fter expos ure to i nfecti ve s pores . The pa pul e enl a rges wi th a
s urroundi ng zone of bra wny erythema a nd ma rked edema (s ee Pl a te 58). Ves i cul a ti on a nd i ndura ti on a re pres ent. Centra l ul cera ti on fol l ows , wi th
s eros a ngui neous exuda ti on a nd forma ti on of a bl a ck es cha r (the ma l i gna nt pus tul e). Loca l l ympha denopa thy i s common, occa s i ona l l y wi th
ma l a i s e, mya l gi a , hea da che, fever, na us ea , a nd vomi ti ng. It ma y ta ke s evera l weeks for the wound to hea l a nd the edema to res ol ve.
GI anthrax ra nges from a s ymptoma ti c to fa ta l . Fever, na us ea , vomi ti ng, a bdomi na l pa i n, a nd bl oody di a rrhea a re common. As ci tes ma y be pres ent.
Intes ti na l necros i s a nd s epti cemi a wi th potenti a l l y l etha l toxi ci ty ens ue.
Oropharyngeal anthrax ma ni fes ts a s edema tous l es i ons wi th centra l necroti c ul cers on the tons i l s , pos teri or pha ryngea l wa l l , or ha rd pa l a te. Softti s s ue s wel l i ng i n the neck i s ma rked, a nd cervi ca l l ymph nodes a re enl a rged. Symptoms i ncl ude hoa rs enes s , s ore throa t, fever, a nd dys pha gi a .
Ai rwa y obs tructi on ma y occur.
Inhalation anthrax begi ns i ns i di ous l y a s a fl u-l i ke i l l nes s . Wi thi n a few da ys , fever wors ens , a nd ches t pa i n a nd s evere res pi ra tory di s tres s devel op,
fol l owed by cya nos i s , s hock, a nd coma . Severe hemorrha gi c necroti zi ng l ympha deni ti s devel ops a nd s prea ds to a dja cent medi a s ti na l s tructures .
Seros a ngui neous tra ns uda ti on, pul mona ry edema , a nd bl oody pl eura l effus i on occur. Typi ca l bronchopneumoni a does not occur. Hemorrha gi c
meni ngoencepha l i ti s or GI a nthra x ma y devel op.
Diagnosis
Occupa ti ona l a nd expos ure hi s tory i s i mporta nt. Cul tures a nd Gra m s ta i n of s a mpl es from cl i ni ca l l y i denti fi ed s i tes , i ncl udi ng cuta neous or
mucos a l l es i ons , pl eura l fl ui d, CSF, a s ci tes , or s tool , s houl d be done. Sputum exa mi na ti on a nd Gra m s ta i n a re unl i kel y to i denti fy i nha l a ti on
a nthra x beca us e a i rs pa ce di s ea s e i s frequentl y a bs ent. A PCR tes t a nd i mmunohi s tochemi ca l methods ca n hel p. Na s a l s wa b tes ti ng for s pores i n
peopl e potenti a l l y expos ed to i nha l a ti on a nthra x i s not recommended beca us e the predi cti ve va l ue i s unknown.
Ches t x-ra y (or CT) s houl d be done i f pul mona ry s ymptoms a re pres ent. It typi ca l l y s hows wi deni ng of the medi a s ti num (beca us e of enl a rged
hemorrha gi c l ymph nodes ) a nd pl eura l effus i on. Pneumoni c i nfi l tra tes a re uncommon. Lumba r puncture s houl d be done i f pa ti ents ha ve
meni ngea l s i gns or a cha nge i n menta l s ta tus . An enzyme-l i nked i mmunos orbent a s s a y (ELISA) i s a va i l a bl e, but confi rma ti on requi res a 4-fol d
cha nge i n a nti body ti ter from a cute to conva l es cent s peci mens .
Prognosis
Morta l i ty i n untrea ted a nthra x va ri es dependi ng on i nfecti on type:
Inha l a ti on a nd meni ngea l a nthra x: 100%
Cuta neous a nthra x: 10 to 20%
GI a nthra x: About 50%
Oropha ryngea l a nthra x: 12.4 to 50%
Treatment
Ci profl oxa ci n or doxycycl i ne
Cuta neous a nthra x wi thout s i gni fi ca nt edema or s ys temi c s ymptoms i s trea ted wi th ci profl oxa ci n 500 mg (10 to 15 mg/kg for chi l dren) po q 12 h or
doxycycl i ne 100 mg (2.5 mg/kg for chi l dren) po q 12 h for 7 to 10 da ys . Trea tment i s extended to 60 da ys i f concomi ta nt i nha l a ti on expos ure wa s
pos s i bl e. Chi l dren a nd pregna nt or brea s tfeedi ng women, who typi ca l l y s houl d not be gi ven ci profl oxa ci n or doxycycl i ne, s houl d nonethel es s be
gi ven one of thes e drugs ; however, i f prol onged trea tment i s needed, they ma y be s wi tched to a moxi ci l l i n 500 mg (15 to 30 mg/kg for chi l dren) ti d
a fter 14 to 21 da ys i f the orga ni s m i s s hown to be s us cepti bl e to peni ci l l i n. Morta l i ty i s ra re wi th trea tment, but the l es i on wi l l progres s through
the es cha r pha s e.
Inha l a ti on a nd other forms of a nthra x, i ncl udi ng cuta neous a nthra x wi th s i gni fi ca nt edema or s ys temi c s ymptoms , requi re thera py wi th 2 or 3
drugs : ci profl oxa ci n 400 mg (10 to 15 mg/kg for chi l dren) IV q 12 h or doxycycl i ne 100 mg (2.5 mg/kg for chi l dren) IV q 12 h, pl us peni ci l l i n, a mpi ci l l i n,
i mi penem/ci l a s ta ti n, meropenem, ri fa mpi n, va ncomyci n, cl i nda myci n, or cl a ri thromyci n. Corti cos teroi ds ma y be us eful for meni ngi ti s a nd s evere
medi a s ti na l edema but ha ve not been eva l ua ted a dequa tel y. Ca cha nnel bl ockers , ACE i nhi bi tors , a nd s peci fi c hyperi mmune gl obul i n for B.
anthracis ma y be cons i dered. Wi th ea rl y di a gnos i s a nd i ntens i ve s upport, i ncl udi ng mecha ni ca l venti l a ti on, fl ui ds , a nd va s opres s ors , morta l i ty ma y
be reduced to 50%. If trea tment i s del a yed (us ua l l y beca us e the di a gnos i s i s mi s s ed), dea th i s l i kel y.
Drug resistance i s a theoreti ca l concern. Al though norma l l y s ens i ti ve to peni ci l l i n, B. anthracis ma ni fes ts i nduci bl e -l a cta ma s es , s o s i ngl e-drug
thera py wi th a peni ci l l i n or a cepha l os pori n i s not recommended. Bi ol ogi ca l wa rfa re res ea rchers ma y ha ve crea ted s tra i ns of a nthra x tha t a re
res i s ta nt to mul ti pl e a nti bi oti cs , but thes e s tra i ns ha ve not yet been encountered i n a cl i ni ca l s i tua ti on.
Prevention
An a nthra x va cci ne, compos ed of a cel l free cul ture fi l tra te, i s a va i l a bl e for peopl e a t hi gh ri s k (eg, mi l i ta ry pers onnel , veteri na ri a ns , l a bora tory
techni ci a ns , empl oyees of texti l e mi l l s proces s i ng i mported goa t ha i r). A s epa ra te veteri na ry va cci ne i s a l s o a va i l a bl e. Repea ted va cci na ti on i s
requi red to ens ure protecti on. Loca l rea cti ons from va cci ne ca n occur.
Li mi ted da ta s ugges t tha t cuta neous a nthra x does not res ul t i n a cqui red i mmuni ty, pa rti cul a rl y i f ea rl y effecti ve a nti mi crobi a l thera py wa s us ed.
Inha l a ti on a nthra x ma y provi de s ome i mmuni ty i n pa ti ents who s urvi ve, but da ta a re very l i mi ted.
Postexposure prophylaxis: Pos texpos ure mea s ures i ncl ude
Anti bi oti cs
Va cci na ti on
As ymptoma ti c peopl e (i ncl udi ng pregna nt women a nd chi l dren) expos ed to i nha l ed a nthra x requi re prophyl a xi s wi th ora l ci profl oxa ci n 500 mg (10
to 15 mg/kg for chi l dren) q 12 h or doxycycl i ne 100 mg (2.5 mg/kg for chi l dren) q 12 h for 60 da ys . If the orga ni s m ha s been s hown to be s us cepti bl e
to peni ci l l i n, a moxi ci l l i n 500 mg (25 to 30 mg/kg for chi l dren) ti d i s a n opti on when ci profl oxa ci n a nd doxycycl i ne a re contra i ndi ca ted.
The Centers for Di s ea s e Control a nd Preventi on (CDC) recommends tha t the a nthra x va cci ne be a dmi ni s tered wi th a nti bi oti c prophyl a xi s to pa ti ents
expos ed to a nthra x s pores . Pos texpos ure a nti bi oti c trea tment i s extended to 100 da ys i n pa ti ents who a re va cci na ted.
Diphtheria
Diphtheria is an acute pharyngeal or cutaneous infection by Corynebacterium diphtheriae; some strains produce an exotoxin. Symptoms are either nonspecific
skin infections or pseudomembranous pharyngitis followed by myocardial and neural tissue damage secondary to the exotoxin. Diagnosis is clinical and
confirmed by culture. Treatment is with antitoxin and penicillin or erythromycin. Childhood vaccination should be routine.
Corynebacterium diphtheriae us ua l l y i nfect the na s opha rynx (res pi ra tory di phtheri a ) or s ki n.
Diphtheria toxin: Di phtheri a s tra i ns i nfected by a -pha ge, whi ch ca rri es a toxi n-encodi ng gene, produce a potent toxi n. Thi s toxi n fi rs t ca us es
i nfl a mma ti on a nd necros i s of l oca l ti s s ues a nd then ca n da ma ge the hea rt, nerves , a nd s ometi mes the ki dneys . Nontoxi geni c s tra i ns of C.
diphtheriae ca n a l s o ca us e na s opha ryngea l i nfecti on a nd s ometi mes s ys temi c di s ea s e (eg, endoca rdi ti s , s epti c a rthri ti s ).
Epidemiology and transmission: Huma ns a re the onl y known res ervoi r for C. diphtheriae. The orga ni s m i s s prea d by
Res pi ra tory dropl ets
Conta ct wi th na s opha ryngea l s ecreti ons
Conta ct wi th i nfected s ki n l es i ons
Fomi tes (ra re)
A ca rri er s ta te i s common i n endemi c regi ons but not i n devel oped countri es ; mos t pa ti ents who a re a dequa tel y trea ted do not become ca rri ers .
Pa ti ents wi th cl i ni ca l i l l nes s or a s ymptoma ti c ca rri ers ma y tra ns mi t the i nfecti on.
Poor pers ona l a nd communi ty hygi ene contri butes to the s prea d of cuta neous di phtheri a . In the US, i ndi gent a dul ts l i vi ng i n endemi c a rea s a re
pa rti cul a rl y a t ri s k.
Di phtheri a i s endemi c i n ma ny counti es i n Afri ca , South Ameri ca , South a nd Southea s t As i a , the Mi ddl e Ea s t, Ha i ti , a nd the Domi ni ca n Republ i c
(tra vel i nforma ti on a bout di phtheri a i s a va i l a bl e a t the Centers for Di s ea s e Control a nd Preventi on [CDC] web s i te). Di phtheri a i s now ra re i n
devel oped countri es beca us e chi l dhood i mmuni za ti on i s wi des prea d. However, a fter the brea kup of the former Sovi et Uni on, va cci na ti on ra tes i n
i ts cons ti tuent countri es fel l , fol l owed by a ma rked ri s e i n di phtheri a ca s es .
Symptoms and Signs
Symptoms va ry dependi ng on where the i nfecti on i s a nd on whether the s tra i n produces toxi n. Mos t res pi ra tory i nfecti ons a re ca us ed by toxi geni c
s tra i ns . Cuta neous i nfecti ons a re ca us ed by toxi geni c a nd nontoxi geni c s tra i ns . Toxi n i s poorl y a bs orbed from the s ki n; thus , toxi n compl i ca ti ons
a re ra re i n cuta neous di phtheri a .
Pharyngeal infection: After a n i ncuba ti on peri od, whi ch a vera ges 5 da ys , a nd a prodroma l peri od of between 12 a nd 24 h, pa ti ents devel op mi l d s ore
throa t, dys pha gi a , l ow-gra de fever, a nd ta chyca rdi a . Na us ea , emes i s , chi l l s , hea da che, a nd fever a re more common a mong chi l dren.
If a toxi geni c s tra i n i s i nvol ved, the cha ra cteri s ti c membra ne a ppea rs i n the tons i l l a r a rea . It ma y i ni ti a l l y a ppea r a s a whi te, gl os s y exuda te but
typi ca l l y becomes di rty gra y, tough, fi bri nous , a nd a dherent s o tha t remova l ca us es bl eedi ng. Loca l edema ma y ca us e a vi s i bl y s wol l en neck (bul l
neck), hoa rs enes s , s tri dor, a nd dys pnea . The membra ne ma y extend to the l a rynx, tra chea , a nd bronchi a nd ma y pa rti a l l y obs truct the a i rwa y or
s uddenl y deta ch, ca us i ng compl ete obs tructi on.
Mi l d di s ea s e wi th a s eros a ngui neous or purul ent di s cha rge a nd i rri ta ti on of the externa l na res a nd upper l i p occurs i n pa ti ents who ha ve onl y
na s a l di phtheri a .
Skin infection: Ski n l es i ons us ua l l y occur on the extremi ti es a nd a re va ri ed i n a ppea ra nce, often i ndi s ti ngui s ha bl e from chroni c s ki n condi ti ons (eg,
eczema , ps ori a s i s , i mpeti go). A few pa ti ents ha ve nonhea l i ng, punched-out ul cers , occa s i ona l l y wi th a gra yi s h membra ne. Pa i n, tendernes s ,
erythema , a nd exuda te a re typi ca l . If exotoxi n i s produced, l es i ons ma y be numb. Concomi ta nt na s opha ryngea l i nfecti on occurs i n 20 to 40% by
di rect or i ndi rect i nocul a ti on wi th the orga ni s m, often from preexi s ti ng chroni c s ki n l es i ons .
Complications: The ma i n compl i ca ti ons a re ca rdi a c a nd neurol ogi c.
Myocarditis i s us ua l l y evi dent by the 10th to 14th da y but ca n a ppea r a ny ti me duri ng the 1s t to 6th wk, even whi l e l oca l res pi ra tory s ymptoms a re
s ubs i di ng; ri s k of ca rdi a c toxi ci ty i s rel a ted to degree of l oca l i nfecti on. Ins i gni fi ca nt ECG cha nges occur i n 20 to 30% of pa ti ents , but
a tri oventri cul a r di s s oci a ti on, compl ete hea rt bl ock, a nd ventri cul a r a rrhythmi a s ma y occur a nd a re a s s oci a ted wi th a hi gh morta l i ty ra te. Hea rt
fa i l ure ma y devel op.
Nervous system toxicity i s uncommon (a bout 5%) a nd l i mi ted to pa ti ents wi th s evere res pi ra tory di phtheri a . The toxi n ca us es a demyel i na ti ng
pol yneuropa thy tha t a ffects cra ni a l a nd peri phera l nerves . The toxi c effects us ua l l y begi n duri ng the 1s t wk of i l l nes s wi th l os s of ocul a r
a ccommoda ti on a nd bul ba r pa l s y, ca us i ng dys pha gi a a nd na s a l regurgi ta ti on. Peri phera l neuropa thy a ppea rs duri ng the 3rd to 6th wk. It i s both
motor a nd s ens ory, a l though motor s ymptoms predomi na te. Res ol uti on occurs over ma ny weeks .
Diagnosis

Di phtheri a needs to be cons i dered i n pa ti ents wi th nons peci fi c fi ndi ngs of pha ryngi ti s , cervi ca l a denopa thy, a nd l ow-gra de fever i f they a l s o ha ve
s ys temi c toxi ci ty pl us hoa rs enes s , pa l a ta l pa ra l ys i s , or s tri dor. The a ppea ra nce of the cha ra cteri s ti c membra ne s ugges ts the di a gnos i s .
Gra m s ta i n of the membra ne ma y revea l gra m-pos i ti ve ba ci l l i wi th meta chroma ti c (bea ded) s ta i ni ng i n typi ca l Chi nes e-cha ra cter confi gura ti on.
Ma teri a l for cul ture s houl d be obta i ned from bel ow the membra ne, or a porti on of membra ne i ts el f s houl d be s ubmi tted. The l a bora tory s houl d
be noti fi ed tha t C. diphtheriae i s s us pected, s o tha t s peci a l cul ture medi a (Loeffl er's or Ti nda l e's ) ca n be us ed. In vi tro tes ti ng for toxi n producti on
(modi fi ed El ek tes t) i s done to di fferenti a te toxi geni c from nontoxi geni c s tra i ns .
Cuta neous di phtheri a s houl d be cons i dered when a pa ti ent devel ops s ki n l es i ons duri ng a n outbrea k of res pi ra tory di phtheri a . Swa b or bi ops y
s peci mens s houl d be cul tured. Pa ti ents wi th cuta neous di phtheri a ma y be co-i nfected wi th group A s treptococci or Staphylococcus aureus.
Treatment
Di phtheri a a nti toxi n
Peni ci l l i n or erythromyci n
Symptoma ti c pa ti ents wi th res pi ra tory di phtheri a s houl d be hos pi ta l i zed i n a n ICU to moni tor for res pi ra tory a nd ca rdi a c compl i ca ti ons . Is ol a ti on
wi th res pi ra tory-dropl et a nd conta ct preca uti ons i s requi red a nd mus t conti nue unti l 2 cul tures , ta ken 24 a nd 48 h a fter a nti bi oti cs a re s topped,
a re nega ti ve.
Diphtheria antitoxin mus t be gi ven wi thout wa i ti ng for cul ture confi rma ti on beca us e the a nti toxi n neutra l i zes onl y toxi n not yet bound to cel l s . The
us e of a nti toxi n for cuta neous di s ea s e, wi thout evi dence of res pi ra tory di s ea s e, i s of ques ti ona bl e va l ue beca us e toxi c s equel a e ha ve ra rel y been
reported i n cuta neous di phtheri a ; however, s ome experts recommend i t. In the US, a nti toxi n mus t be obta i ned from the CDC a t 770-488-7100 (s ee
a l s o the CDC's noti ce rega rdi ng a va i l a bi l i ty of di phtheri a a nti toxi n). CAUTION: Di phtheri a a nti toxi n i s deri ved from hors es ; therefore, a s ki n (or
conjuncti va l ) tes t to rul e out s ens i ti vi ty s houl d a l wa ys precede a dmi ni s tra ti on (s ee p. 1115). The dos e, ra ngi ng from 20,000 to 100,000 uni ts IM or IV,
i s determi ned by the s i te a nd s everi ty of s ymptoms , dura ti on of the di s ea s e, a nd compl i ca ti ons . If a n a l l ergi c rea cti on occurs , 0.3 to 1 mL
epi nephri ne 1:1000 (0.01 mL/kg) s houl d i mmedi a tel y be i njected s c, IM, or s l owl y IV. In hi ghl y s ens i ti ve pa ti ents , IV a dmi ni s tra ti on of a nti toxi n i s
contra i ndi ca ted.
Antibiotics a re requi red to era di ca te the orga ni s m a nd prevent s prea d; they a re not s ubs ti tutes for a nti toxi n. Adul ts ma y be gi ven ei ther proca i ne
peni ci l l i n G 600,000 uni ts IM q 12 h or erythromyci n 250 to 500 mg IV or po q 6 h for 14 da ys . Chi l dren s houl d be gi ven proca i ne peni ci l l i n G 12,500 to
25,000 uni ts /kg IM q 12 h or erythromyci n 10 to 15 mg/kg (ma xi mum, 2 g/da y) po or IV q 6 h. Orga ni s m el i mi na ti on s houl d be documented by 2
cons ecuti ve nega ti ve throa t a nd/or na s opha ryngea l cul tures a fter compl eti on of a nti bi oti cs .
Vaccination i s requi red a fter recovery for pa ti ents who ha d di phtheri a beca us e i nfecti on does not gua ra ntee i mmuni ty.
Recovery from s evere di phtheri a i s s l ow, a nd pa ti ents mus t be a dvi s ed a ga i ns t res umi ng a cti vi ti es too s oon. Even norma l phys i ca l exerti on ma y
ha rm pa ti ents recoveri ng from myoca rdi ti s . Overa l l morta l i ty i s 3%; i t i s hi gher i n thos e wi th del a yed pres enta ti on or myoca rdi ti s a nd i n chi l dren <
15 yr.
For cuta neous di phtheri a , thorough cl ea ns i ng of the l es i on wi th s oa p a nd wa ter a nd a dmi ni s tra ti on of s ys temi c a nti bi oti cs for 10 da ys a re
recommended.
Prevention
Preventi on cons i s ts of i nfecti on control mea s ures pl us
Va cci na ti on (pri ma ry a nd pos texpos ure)
Anti bi oti cs
Vaccination: The va cci ne for di phtheri a conta i ns di phtheri a toxoi d; i t i s a va i l a bl e onl y i n combi na ti on wi th other va cci nes .
Everyone s houl d be va cci na ted a t pres cri bed i nterva l s us i ng di phtheri a -teta nus -a cel l ul a r pertus s i s (DTa P) va cci ne for chi l dren a nd teta nus di phtheri a (Td) or teta nus toxoi d, reduced di phtheri a toxoi d, a nd a cel l ul a r pertus s i s (Tda p) for a dol es cents a nd a dul ts (s ee p. 1173). (See a l s o the
CDC's Na ti ona l Immuni za ti on Progra m 2009 Chi l dhood a nd Adol es cent Immuni za ti on Schedul e a nd thei r Adul t Immuni za ti on Recommenda ti ons .)
After expos ure, di phtheri a i mmuni za ti on s houl d be upda ted i n a l l conta cts (i ncl udi ng hos pi ta l pers onnel ) who ha ve not compl eted a pri ma ry
s eri es or who ha ve gone > 5 yr s i nce thei r l a s t boos ter dos e. The va cci ne s houl d a l s o be gi ven i f i mmuni za ti on s ta tus i s unknown. An a gea ppropri a te di phtheri a toxoi d-conta i ni ng va cci ne i s us ed.
Postexposure antibiotics: Al l cl os e conta cts s houl d be exa mi ned; s urvei l l a nce for evi dence of di s ea s e i s ma i nta i ned for 7 da ys . Na s opha ryngea l a nd
throa t cul tures for C. diphtheriae s houl d be done rega rdl es s of i mmuni za ti on s ta tus .
As ymptoma ti c conta cts s houl d be trea ted wi th erythromyci n 250 to 500 mg (10 to 15 mg/kg for chi l dren) po q 6 h for 7 da ys or, i f a dherence i s
uncerta i n, a s i ngl e dos e of peni ci l l i n G benza thi ne (600,000 uni ts IM for pa ti ents < 30 kg a nd 1.2 mi l l i on uni ts IM for thos e > 30 kg).
If cul tures a re pos i ti ve, a n a ddi ti ona l 10-da y cours e of erythromyci n s houl d be gi ven; ca rri ers s houl d not be gi ven a nti toxi n. After 3 da ys of
trea tment, ca rri ers ca n s a fel y res ume work whi l e conti nui ng to ta ke a nti bi oti cs . Cul tures s houl d be repea ted; 24 h a fter the compl eti on of
a nti mi crobi a l thera py, 2 cons ecuti ve cul ture s ets of the nos e a nd throa t s houl d be col l ected 24 h a pa rt. If res ul ts a re pos i ti ve, a nother cours e of
a nti bi oti cs i s gi ven a nd cul tures a re done a ga i n.
Erysipelothricosis
Erysipelothricosis is infection caused by Erysipelothrix rhusiopathiae. The most common symptom is erysipeloid, an acute but slowly evolving localized cellulitis.
Diagnosis is by culture of a biopsy specimen or occasionally PCR testing. Treatment is with antibiotics.
Erysipelothrix rhusiopathiae (formerl y E. insidiosa) a re ca ps ul a ted, nons porul a ti ng, nonmoti l e, mi croa erophi l i c ba ci l l i wi th worl dwi de di s tri buti on;
they a re pri ma ri l y s a prophytes . They ma y i nfect a va ri ety of a ni ma l s , i ncl udi ng i ns ects , s hel l fi s h, fi s h, bi rds , a nd ma mma l s (es peci a l l y s wi ne). In
huma ns , i nfecti on i s chi efl y occupa ti ona l a nd typi ca l l y fol l ows a penetra ti ng wound i n peopl e who ha ndl e edi bl e or nonedi bl e a ni ma l ma tter (eg,
i nfected ca rca s s es , rendered products [grea s e, ferti l i zer], bones , s hel l s ). Mos t commonl y, pa ti ents ha ndl e fi s h or work i n s l a ughterhous es .
Infecti on ca n a l s o res ul t from ca t or dog bi tes . Nonderma l i nfecti on i s ra re, us ua l l y occurri ng a s a rthri ti s or endoca rdi ti s .
Symptoms and Signs
Wi thi n 1 wk of i njury, a cha ra cteri s ti c ra i s ed, purpl i s h red, nonves i cul a ted, i ndura ted, ma cul opa pul a r ra s h a ppea rs , a ccompa ni ed by i tchi ng a nd
burni ng. Loca l s wel l i ng, a l though s ha rpl y dema rca ted, ma y i nhi bi t us e of the ha nd, the us ua l s i te of i nfecti on. The l es i on's border ma y s l owl y
extend outwa rd, ca us i ng di s comfort a nd di s a bi l i ty tha t ma y pers i s t for 3 wk. The di s ea s e i s us ua l l y s el f-l i mi ted. Regi ona l l ympha denopa thy occurs
i n a bout one thi rd of ca s es . It ra rel y becomes genera l i zed cuta neous di s ea s e, whi ch i s cha ra cteri zed by purpl e s ki n l es i ons tha t expa nd a s the
l es i on's center cl ea rs , pl us bul l ous l es i ons a t the pri ma ry or di s ta nt s i tes .
Ba cteremi a i s ra re a nd i s more often a pri ma ry i nfecti on tha n di s s emi na ti on from cuta neous l es i ons . It ma y res ul t i n s epti c a rthri ti s or i nfecti ve
endoca rdi ti s , even i n peopl e wi thout known va l vul a r hea rt di s ea s e. Endoca rdi ti s tends to i nvol ve the a orti c va l ve, a nd the morta l i ty ra te a nd
percenta ge of pa ti ents needi ng ca rdi a c va l ve repl a cement a re unus ua l l y hi gh.
Diagnosis
Cul ture
Cul ture of a ful l -thi cknes s bi ops y s peci men i s s uperi or to needl e a s pi ra ti on of the a dva nci ng edge of a l es i on beca us e orga ni s ms a re l oca ted onl y
i n deeper pa rts of the s ki n. Cul ture of exuda te obta i ned by a bra di ng a fl ori d pa pul e ma y be di a gnos ti c. Is ol a ti on from s ynovi a l fl ui d or bl ood i s
neces s a ry for di a gnos i s of erys i pel othri ca l a rthri ti s or endoca rdi ti s . E. rhusiopathiae ma y be mi s i denti fi ed a s l a ctoba ci l l i or enterococci . PCR
a mpl i fi ca ti on ma y a i d ra pi d di a gnos i s .
Treatment
Peni ci l l i n, ci profl oxa ci n, or erythromyci n
For localized cutaneous disease, us ua l trea tment i s peni ci l l i n V, a mpi ci l l i n, ci profl oxa ci n, or erythromyci n (ma crol i des ma y not be cons i s tentl y a cti ve)
500 mg po qi d for 7 da ys . Tetra cycl i nes a nd cepha l os pori ns a re a l s o effecti ve. E. rhusiopathiae a re res i s ta nt to s ul fona mi des a nd va ncomyci n.
Severe diffuse cutaneous or systemic infection i s bes t trea ted wi th IV peni ci l l i n G (12 to 20 mi l l i on uni ts /da y), ceftri a xone (2 g IV once/da y), or a
fl uoroqui nol one (eg, ci profl oxa ci n 400 mg IV q 12 h).
Endocarditis i s trea ted wi th peni ci l l i n G 25,000 to 30,000 uni ts /kg IV q 4 h for 4 wk. Cepha l os pori ns a nd fl uoroqui nol ones a re a l terna ti ves .
The s a me drugs a nd dos es a re a ppropri a te for a rthri ti s (gi ven for a t l ea s t 1 wk a fter deferves cence or ces s a ti on of effus i on), but repea ted needl e
a s pi ra ti on dra i na ge of the i nfected joi nt i s a l s o neces s a ry.
Listeriosis
(See a l s o Neona ta l Li s teri os i s on p. 2829.)
Listeriosis is bacteremia, meningitis, cerebritis, dermatitis, an oculoglandular syndrome, intrauterine and neonatal infections, or rarely endocarditis caused by
Listeria sp. Symptoms vary with the organ system affected and include intrauterine death in perinatal infection. Diagnosis is by laboratory isolation. Treatment
includes penicillin, ampicillin (often with aminoglycosides), and trimethoprim/sulfamethoxazole.
Listeria a re s ma l l , non-a ci d-fa s t, nonca ps ul a ted, nons porul a ti ng, -hemol yti c, a erobi c, a nd fa cul ta ti ve a na erobi c gra m-pos i ti ve ba ci l l i tha t ha ve
cha ra cteri s ti c tumbl i ng moti l i ty. They a re pres ent worl dwi de i n the envi ronment a nd i n the gut of huma ns , nonhuma n ma mma l s , bi rds , a ra chni ds ,
a nd crus ta cea ns . There a re s evera l s peci es of Listeria, but L. monocytogenes i s the onl y pa thogen i n huma ns . Inci dence i n the US i s 7
ca s es /1,000,000 peopl e/yr, pea ki ng i n the s ummer; a tta ck ra tes a re hi ghes t i n neona tes a nd i n a dul ts 60 yr.
Beca us e L. monocytogenes i s ubi qui tous i n the envi ronment, opportuni ti es for conta mi na ti on a re numerous duri ng the food producti on proces s .
Infecti on us ua l l y occurs vi a i nges ti on of conta mi na ted da i ry products , ra w vegeta bl es , or mea ts a nd i s fa vored by the a bi l i ty of L. monocytogenes to
s urvi ve a nd grow a t refri gera tor tempera tures . Infecti on ma y a l s o occur by di rect conta ct a nd duri ng s l a ughter of i nfected a ni ma l s .
Risk factors: Gl ucocorti coi d thera py i s the mos t i mporta nt predi s pos i ng fa ctor i n nonpregna nt a dul ts . Beca us e L. monocytogenes mul ti pl i es
i ntra cel l ul a rl y, control of l i s teri os i s requi res cel l -medi a ted i mmuni ty; thus , i mmunocompromi s ed pa ti ents a re a t hi gh ri s k. Pregna nt women a re
a l s o a t i ncrea s ed ri s k of devel opi ng l i s teri a l i nfecti on, whi ch ca n s prea d a ntepa rtum a nd i ntra pa rtum from mother to chi l d a nd ca n ca us e a borti on
or ea rl y i nfa nt dea th.
Symptoms and Signs
Pri ma ry l i s teri a l ba cteremi a i s ra re a nd ca us es hi gh fever wi thout l oca l i zi ng s ymptoms a nd s i gns . Endoca rdi ti s , peri toni ti s , os teomyel i ti s ,
chol ecys ti ti s , a nd pl europneumoni a ma y occur. Li s teri a l ba cteremi a duri ng pregna ncy ca n ca us e i ntra uteri ne i nfecti on, chori oa mni oni ti s ,
prema ture l a bor, feta l dea th, or neona ta l i nfecti ons .

Meni ngi ti s i s due to Listeria i n a bout 20% of ca s es i n neona tes a nd i n pa ti ents > 60 yr. Twenty percent of ca s es progres s to cerebri ti s , ei ther di ffus e
encepha l i ti s or, ra rel y, rhombencepha l i ti s a nd a bs ces s es ; rhombencepha l i ti s ma ni fes ts a s a l tered cons ci ous nes s , cra ni a l nerve pa l s i es ,
cerebel l a r s i gns , a nd motor or s ens ory l os s .
Ocul ogl a ndul a r l i s teri os i s ca n ca us e ophtha l mi ti s a nd regi ona l l ymph node enl a rgement. It ma y fol l ow conjuncti va l i nocul a ti on a nd, i f untrea ted,
ma y progres s to ba cteremi a a nd meni ngi ti s .
Diagnosis
Cul ture
Li s teri a l i nfecti ons a re di a gnos ed by cul ture of bl ood or CSF. The l a bora tory mus t be i nformed when L. monocytogenes i s s us pected beca us e the
orga ni s m i s ea s i l y confus ed wi th di phtheroi ds . In a l l l i s teri a l i nfecti ons , IgG a ggl uti ni n ti ters pea k 2 to 4 wk a fter ons et.
Treatment
Ampi ci l l i n, us ua l l y wi th a n a mi nogl ycos i de
Li s teri a l meni ngi ti s i s bes t trea ted wi th a mpi ci l l i n 2 g IV q 4 h. Mos t a uthori ti es recommend a ddi ng a n a mi nogl ycos i de ba s ed on s ynergy i n vi tro.
Chi l dren recei ve a mpi ci l l i n 50 to 100 mg/kg IV q 6 h. Cepha l os pori ns a re not effecti ve.
Endoca rdi ti s a nd pri ma ry l i s teri a l ba cteremi a a re trea ted wi th a mpi ci l l i n 2 g IV q 4 h pl us genta mi ci n (for s ynergy) gi ven for 6 wk (for endoca rdi ti s )
or 2 wk (for ba cteremi a ) beyond deferves cence. Ocul ogl a ndul a r l i s teri os i s a nd l i s teri a l derma ti ti s s houl d res pond to erythromyci n 10 mg/kg po q 6
h, conti nued unti l 1 wk a fter deferves cence. Cepha l os pori ns ha ve no i n vi tro a cti vi ty a nd s houl d not be us ed. Tri methopri m/s ul fa methoxa zol e 5/25
mg/kg IV q 8 h i s a n a l terna ti ve.
Nocardiosis
Nocardiosis is an acute or chronic, often disseminated, suppurative or granulomatous infection caused by various aerobic soil saprophytes of the genus Nocardia.
Pneumonia is typical, but skin and CNS infections are common. Diagnosis is by culture and special stains. Treatment is usually with sulfonamides.
Nocardia a re obl i ga te a erobi c, pa rti a l l y a ci dfa s t, bea ded, bra nchi ng, gra m-pos i ti ve ba ci l l i . Severa l Nocardia s p, i n the fa mi l y Acti nomyceta cea e,
ca us e huma n di s ea s e.
N. asteroides i s the mos t common huma n pa thogen; i t us ua l l y ca us es pul mona ry a nd di s s emi na ted i nfecti on.
N. brasiliensis mos t commonl y ca us es s ki n i nfecti on, pa rti cul a rl y i n tropi ca l cl i ma tes . Infecti on i s vi a i nha l a ti on or by di rect i nocul a ti on of the s ki n.
Other Nocardia s p s ometi mes ca us e l oca l i zed or, occa s i ona l l y, s ys temi c i nfecti ons .
Noca rdi os i s occurs worl dwi de i n a l l a ge groups , but i nci dence i s hi gher i n ol der a dul ts , es peci a l l y men. Pers on-to-pers on s prea d i s ra re.
Risk factors: Lymphoreti cul a r ca ncers , orga n tra ns pl a nta ti on, hi gh-dos e corti cos teroi d or other i mmunos uppres s i ve thera py, a nd underl yi ng
pul mona ry di s ea s e a re predi s pos i ng fa ctors , but a bout one ha l f of pa ti ents ha ve no preexi s ti ng di s ea s e. Noca rdi os i s i s a l s o a n opportuni s ti c
i nfecti on i n pa ti ents wi th a dva nced HIV i nfecti on.
Symptoms and Signs
Noca rdi os i s us ua l l y begi ns a s a s uba cute pul mona ry i nfecti on tha t res embl es a cti nomycos i s , but Nocardia a re more l i kel y to di s s emi na te l oca l l y
or hema togenous l y. Di s s emi na ti on wi th a bs ces s forma ti on ma y i nvol ve a ny orga n but mos t commonl y a ffects the bra i n, s ki n, ki dneys , bone, or
mus cl e.
The mos t common s ymptoms of pul mona ry i nvol vementcough, fever, chi l l s , ches t pa i n, wea knes s , a norexi a , a nd wei ght l os s a re nons peci fi c
a nd ma y res embl e thos e of TB or s uppura ti ve pneumoni a . Pl eura l effus i on ma y a l s o occur. Meta s ta ti c bra i n a bs ces s es , occurri ng i n 30 to 50% of
ca s es , us ua l l y ca us e s evere hea da ches a nd foca l neurol ogi c a bnorma l i ti es . Infecti on ma y be a cute, s uba cute, or chroni c.
Ski n or s ubcuta neous a bs ces s es occur frequentl y, s ometi mes a s a pri ma ry l oca l i nocul a ti on. They ma y a ppea r a s fi rm cel l ul i ti s , a
l ymphocuta neous s yndrome, or a n a cti nomycetoma . The l ymphocuta neous s yndrome cons i s ts of a pri ma ry pyoderma l es i on a nd l ympha ti c nodul es
res embl i ng s porotri chos i s . An a cti nomycetoma begi ns a s a nodul e, s uppura tes , s prea ds a l ong fa s ci a l pl a nes , a nd dra i ns through chroni c fi s tul a s .
Diagnosis
Mi cros copi c exa mi na ti on or cul ture
Di a gnos i s i s by i denti fi ca ti on of Nocardia s p i n ti s s ue or i n cul ture of s a mpl es from l oca l i zed l es i ons i denti fi ed by phys i ca l exa mi na ti on, x-ra y, or
other i ma gi ng s tudi es . Cl umps of bea ded, bra nchi ng fi l a ments of gra m-pos i ti ve ba cteri a (whi ch ma y be wea kl y a ci d-fa s t) a re often s een. Nocardia
do not ha ve a cl ubbed a ppea ra nce, a s do Actinomyces israelii.
Prognosis
Wi thout trea tment, pul mona ry a nd di s s emi na ted noca rdi os i s a re us ua l l y fa ta l . Among pa ti ents who a re trea ted wi th a ppropri a te a nti bi oti cs , the
morta l i ty ra te i s hi ghes t (> 50%) i n i mmunocompromi s ed pa ti ents wi th di s s emi na ted i nfecti ons a nd l owes t (a bout 10%) i n i mmunocompetent
pa ti ents wi th l es i ons res tri cted to the l ungs . Cure ra tes for pa ti ents wi th s ki n i nfecti on a re us ua l l y > 95%.
Treatment
Tri methopri m/s ul fa methoxa zol e
Tri methopri m/s ul fa methoxa zol e or hi gh dos es of a s ul fona mi de a l one (s ul fa methoxa zol e or s ul fi s oxa zol e) a re us ed. Beca us e mos t ca s es res pond
s l owl y, a dos e tha t ma i nta i ns a s ul fona mi de bl ood concentra ti on of 12 to 15 mg/dL (eg, wi th s ul fa di a zi ne 4 to 6 g/da y po) mus t be conti nued for
s evera l months .
When s ul fona mi de hypers ens i ti vi ty or refra ctory i nfecti on i s pres ent, a mi ka ci n, a tetra cycl i ne (pa rti cul a rl y mi nocycl i ne), i mi penem/ci l a s ta ti n,
ceftri a xone, cefota xi me, extended-s pectrum fl uoroqui nol ones (eg, moxi fl oxa ci n), or cycl os eri ne ca n be us ed. In vi tro s us cepti bi l i ty da ta s houl d
gui de the choi ce of a l terna ti ve drugs .
Chapter 135. Gram-Negative Bacilli

Introduction
Gra m-nega ti ve ba ci l l i a re res pons i bl e for numerous di s ea s es . Some a re commens a l orga ni s ms pres ent a mong norma l i ntes ti na l fl ora . Thes e
commens a l orga ni s ms pl us others from a ni ma l or envi ronmenta l res ervoi rs ma y ca us e di s ea s e. UTIs , di a rrhea , peri toni ti s , a nd bl oods trea m
i nfecti ons a re commonl y ca us ed by gra m-nega ti ve ba ci l l i . Pl a gue, chol era , a nd typhoi d fever a re ra re but s eri ous gra m-nega ti ve i nfecti ons .
Bartonella Infections
Bartonella s p a re gra m-nega ti ve ba cteri a previ ous l y cl a s s i fi ed a s Ri cketts i a e. They ca us e s evera l uncommon di s ea s es : ca t-s cra tch di s ea s e, a n
a cute febri l e a nemi a , a chroni c cuta neous erupti on, a nd di s s emi na ted di s ea s e i n i mmunocompromi s ed hos ts (s ee
Ta bl e 135-1).
Cat-Scratch Disease
(Ca t-Scra tch Fever)
Cat-scratch disease is infection caused by Bartonella henselae. Symptoms are a local papule and regional lymphadenitis. Diagnosis is clinical and confirmed by
biopsy. Treatment is with local heat application and analgesics.
The domes ti c ca t i s a ma jor res ervoi r for B. henselae. The preva l ence of B. henselae a nti bodi es i n US ca ts i s 14 to 50%. About 99% of pa ti ents report
conta ct wi th ca ts , mos t of whi ch a re hea l thy. The ca t fl ea ma y be a n a ddi ti ona l vector. Chi l dren a re mos t often a ffected.
Symptoms and Signs
Wi thi n 3 to 10 da ys a fter a s cra tch, mos t pa ti ents devel op a n erythema tous , crus ted pa pul e (ra rel y, a pus tul e) a t the s cra tch s i te. Regi ona l
l ympha denopa thy devel ops wi thi n 2 wk. The nodes a re i ni ti a l l y fi rm a nd tender, l a ter becomi ng fl uctua nt, a nd ma y dra i n wi th fi s tul a forma ti on.
Fever, ma l a i s e, hea da che, a nd a norexi a ma y a ccompa ny l ympha denopa thy.
Unus ua l ma ni fes ta ti ons occur i n 5 to 14% of pa ti ents : Pa ri na ud's ocul ogl a ndul a r s yndrome (conjuncti vi ti s a s s oci a ted wi th pa l pa bl e prea uri cul a r
nodes ) i n 6%, neurol ogi c ma ni fes ta ti ons (encepha l opa thy, s ei zures , neuroreti ni ti s , myel i ti s , pa ra pl egi a , cerebra l a rteri ti s ) i n 2%, a nd
hepa tos pl eni c gra nul oma tous di s ea s e i n
[Table 135-1. Some Bartonella Infecti ons ]
< 1%. Severe di s s emi na ted i l l nes s ma y occur i n pa ti ents wi th AIDS.
Lympha denopa thy s ubs i des s ponta neous l y wi thi n 2 to 5 mo. Compl ete recovery i s us ua l , except i n s evere neurol ogi c or hepa tos pl eni c di s ea s e,
whi ch ma y be fa ta l or ha ve res i dua l effects .
Diagnosis
Di a gnos i s i s confi rmed by pos i ti ve s erum Ab ti ters or PCR tes ti ng of s a mpl es from l ymph node a s pi ra tes . Immunocompromi s ed pa ti ents a nd
pa ti ents wi th s ys temi c s ymptoms s houl d a l s o ha ve bl ood cul tures . Lymph node a s pi ra tes a re ra rel y cul ture-pos i ti ve.
Treatment
Loca l hea t a nd a na l ges i cs
Someti mes a nti bi oti cs for i mmunocompromi s ed pa ti ents
Trea tment i n i mmunocompetent pa ti ents i s l oca l hea t a ppl i ca ti on a nd a na l ges i cs . If a l ymph node i s fl uctua nt, needl e a s pi ra ti on us ua l l y rel i eves
the pa i n.
Anti bi oti c trea tment i s not cl ea rl y benefi ci a l a nd genera l l y s houl d not be gi ven for l oca l i zed i nfecti on. Ci profl oxa ci n, genta mi ci n, or doxycycl i ne
ma y be us ed for ba cteremi a i n AIDS pa ti ents . Prol onged thera py i s us ua l l y neces s a ry (eg, weeks to months ) for ba cteremi a to cl ea r. In vi tro
a nti bi oti c s us cepti bi l i ti es often do not correl a te wi th cl i ni ca l res ul ts ; tes ti ng often s hows s ens i ti vi ty to tri methopri m/s ul fa methoxa zol e (TMP/SMX)
a nd cepha l os pori ns , but thes e drugs a re cl i ni ca l l y i neffecti ve.
Oroya Fever and Verruga Peruana
Oroya fever and verruga peruana are infections caused by Bartonella bacilliformis. Oroya fever occurs after initial exposure; verruga peruana occurs after
recovery from the primary infection.
Endemi c onl y to the Andes Mounta i ns i n Col ombi a , Ecua dor, a nd Peru, both di s ea s es a re pa s s ed from huma n to huma n by the Phlebotomus s a ndfl y.
Oroya fever: Symptoms i ncl ude fever a nd profound a nemi a , whi ch ma y be s udden or i ndol ent i n ons et. The a nemi a i s pri ma ri l y hemol yti c, but
myel os uppres s i on a l s o occurs . Mus cl e a nd joi nt pa i n, s evere hea da che, a nd often del i ri um a nd coma ma y occur. Superi mpos ed ba cteremi a
ca us ed by Salmonella or other col i form orga ni s ms ma y occur. Morta l i ty ra tes ma y exceed 50% i n untrea ted pa ti ents .
Di a gnos i s i s confi rmed by bl ood cul tures . Beca us e Oroya fever i s often compl i ca ted by Salmonella ba cteremi a , chl ora mpheni col 500 to 1000 mg po q
6 h for 7 da ys i s the trea tment of choi ce; s ome cl i ni ci a ns a dd a nother a nti bi oti c, typi ca l l y a -l a cta m, but TMP/SMX, ma crol i des , a nd
fl uoroqui nol ones ha ve a l s o been us ed s ucces s ful l y.
Verruga peruana: Thi s di s order ma ni fes ts a s mul ti pl e s ki n l es i ons tha t s trongl y res embl e ba ci l l a ry a ngi oma tos i s , us ua l l y occurri ng on the l i mbs
a nd fa ce. The l es i ons ma y pers i s t for months to yea rs a nd ma y be a ccompa ni ed by pa i n a nd fever.
Verruga perua na i s di a gnos ed by i ts a ppea ra nce a nd s ometi mes by bi ops y s howi ng derma l a ngi ogenes i s . Trea tment wi th mos t a nti bi oti cs
produces remi s s i on, but rel a ps e i s common a nd requi res prol onged thera py. Typi ca l trea tment i s s treptomyci n 15 to 20 mg/kg IM once/da y for 10
da ys or ri fa mpi n 10 mg/kg po once/da y for 10 to 14 da ys . Ci profl oxa ci n 500 mg po bi d for 7 to 10 da ys ha s been us ed s ucces s ful l y, a s ha s
a zi thromyci n.
Bacillary Angiomatosis
(Epi thel i oi d Angi oma tos i s )
Bacillary angiomatosis is skin infection caused by Bartonella henselae or B. quintana.
Ba ci l l a ry a ngi oma tos i s a l mos t a l wa ys occurs i n i mmunocompromi s ed peopl e a nd i s cha ra cteri zed by protubera nt, reddi s h, berry-l i ke l es i ons on
the s ki n, often s urrounded by a col l a r of s ca l e. Les i ons bl eed profus el y i f tra uma ti zed. They ma y res embl e Ka pos i 's s a rcoma or pyogeni c
gra nul oma s . Infecti on i s s prea d by l i ce a nd ti cks a nd proba bl y by fl ea s from hous ehol d ca ts . Di s ea s e ma y s prea d throughout the
reti cul oendothel i a l s ys tem, pa rti cul a rl y i n AIDS pa ti ents .
Di a gnos i s rel i es on hi s topa thol ogy of the s ki n l es i ons , cul tures , a nd PCR a na l ys i s . The l a bora tory s houl d be noti fi ed tha t Bartonella i s s us pected
beca us e s peci a l s ta i ns a nd prol onged cul ture growth a re neces s a ry.
Trea tment i s wi th erythromyci n 500 mg po q 6 h or doxycycl i ne 100 mg po q 12 h, conti nued for a t l ea s t 3 mo.
Trench Fever
(Wol hyni a , Shi n Bone, or Qui nta n Fever)
Trench fever is a louse- or tick-borne disease caused by Bartonella quintana or B. henselae and observed originally in military populations during World Wars I
and II. Symptoms are an acute, recurring febrile illness, occasionally with a rash. Diagnosis is by blood culture. Treatment is with a macrolide or doxycycline.
Huma ns a re the onl y res ervoi r. B. quintana i s tra ns mi tted to huma ns when feces from i nfected l i ce a re rubbed i nto a bra ded s ki n or the conjuncti va .
B. henselae i s tra ns mi tted by ti ck bi tes . Trench fever i s endemi c i n Mexi co, Tuni s i a , Eri trea , Pol a nd, a nd the former Sovi et Uni on a nd i s rea ppea ri ng
i n the homel es s popul a ti on i n the US.
After a 14- to 30-da y i ncuba ti on peri od, ons et i s s udden, wi th fever, wea knes s , di zzi nes s , hea da che, a nd s evere ba ck a nd l eg pa i ns . Fever ma y
rea ch 40.5 C a nd pers i s t for 5 to 6 da ys . In a bout ha l f the ca s es , fever recurs 1 to 8 ti mes a t 5- to 6-da y i nterva l s . A tra ns i ent ma cul a r or pa pul a r
ra s h a nd, occa s i ona l l y, hepa tomega l y a nd s pl enomega l y occur. Rel a ps es a re common a nd ha ve occurred up to 10 yr a fter the i ni ti a l a tta ck.
Diagnosis
Trench fever s houl d be s us pected i n peopl e l i vi ng where l ous e i nfes ta ti on i s hea vy. Leptos pi ros i s , typhus , rel a ps i ng fever, a nd ma l a ri a mus t be
cons i dered.
The orga ni s m i s i denti fi ed by bl ood cul ture, a l though growth ma y ta ke 1 to 4 wk. The di s ea s e i s ma rked by pers i s tent ba cteremi a duri ng the i ni ti a l
a tta ck, duri ng rel a ps es , a nd throughout the a s ymptoma ti c peri ods between rel a ps es .
Treatment
Al though recovery i s us ua l l y compl ete i n 1 to 2 mo a nd morta l i ty i s negl i gi bl e, ba cteremi a ma y pers i s t for months a fter cl i ni ca l recovery, a nd
prol onged (> 1 mo) ma crol i de or doxycycl i ne trea tment ma y be needed. Body l i ce mus t be control l ed (s ee p. 711). Pa ti ents wi th chroni c ba cteremi a
s houl d be moni tored for s i gns of endoca rdi ti s .
Brucellosis
(Undul a nt, Ma l ta , Medi terra nea n, or Gi bra l ta r Fever)
Brucellosis is caused by Brucella sp. Symptoms begin as an acute febrile illness with few or no localized signs and progress to a chronic stage with relapses of
fever, weakness, sweats, and vague aches and pains. Diagnosis is by culture, usually from the blood. Optimal treatment usually requires 2 antibiotics
doxycycline or trimethoprim/sulfamethoxazole plus streptomycin or rifampin.
The ca us a ti ve orga ni s ms of huma n brucel l os i s a re B. abortus (from ca ttl e), B. melitensis (from s heep a nd goa ts ), a nd B. suis (from hogs ). B. canis
(from dogs ) ha s ca us ed s pora di c i nfecti ons . The mos t common s ources of i nfecti on a re fa rm a ni ma l s a nd ra w da i ry products . Deer, bi s on, hors es ,
moos e, ca ri bou, ha res , chi ckens , a nd des ert ra ts ma y a l s o be i nfected; huma ns ca n a cqui re the i nfecti on from thes e a ni ma l s a s wel l .
Brucel l os i s i s a cqui red by di rect conta ct wi th s ecreti ons a nd excreti ons of i nfected a ni ma l s a nd by i nges ti ng undercooked mea t, ra w mi l k, or mi l k
products conta i ni ng vi a bl e orga ni s ms . Brucel l os i s i s ra rel y tra ns mi tted from pers on to pers on. Mos t preva l ent i n rura l a rea s , brucel l os i s i s a n
occupa ti ona l di s ea s e of mea tpa ckers , veteri na ri a ns , hunters , fa rmers , a nd l i ves tock producers . Brucel l os i s i s ra re i n the US, Europe, a nd Ca na da ,
but ca s es occur i n the Mi ddl e Ea s t, Medi terra nea n regi ons , Mexi co, a nd Centra l Ameri ca .
Pa ti ents wi th a cute, uncompl i ca ted brucel l os i s us ua l l y recover i n 2 to 3 wk, even wi thout trea tment. Some go on to s uba cute, i ntermi ttent, or
chroni c di s ea s e.
Complications: Compl i ca ti ons a re ra re but i ncl ude s uba cute ba cteri a l endoca rdi ti s , meni ngi ti s , encepha l i ti s , neuri ti s , orchi ti s , chol ecys ti ti s , hepa ti c
s uppura ti on, a nd os teomyel i ti s (pa rti cul a rl y s a croi l i a c or vertebra l ).

Symptoms and Signs
The i ncuba ti on peri od va ri es from 5 da ys to s evera l months a nd a vera ges 2 wk. Ons et ma y be s udden, wi th chi l l s a nd fever, s evere hea da che, joi nt
a nd l ow ba ck pa i n, ma l a i s e, a nd occa s i ona l l y di a rrhea . Or ons et ma y be i ns i di ous , wi th mi l d prodroma l ma l a i s e, mus cul a r pa i n, hea da che, a nd
pa i n i n the ba ck of the neck, fol l owed by a ri s e i n eveni ng tempera ture. As the di s ea s e progres s es , tempera ture i ncrea s es to 40 to 41 C, then
s ubs i des gra dua l l y to norma l or nea r-norma l wi th profus e s wea ti ng i n the morni ng.
Typi ca l l y, i ntermi ttent fever pers i s ts for 1 to 5 wk, fol l owed by a 2- to 14-da y remi s s i on when s ymptoms a re grea tl y di mi ni s hed or a bs ent. In s ome
pa ti ents , fever ma y be tra ns i ent. In others , the febri l e pha s e recurs once or repea tedl y i n wa ves (undul a ti ons ) a nd remi s s i ons over months or
yea rs a nd ma y ma ni fes t a s FUO.
After the i ni ti a l febri l e pha s e, a norexi a , wei ght l os s , a bdomi na l a nd joi nt pa i n, hea da che, ba cka che, wea knes s , i rri ta bi l i ty, i ns omni a , depres s i on,
a nd emoti ona l i ns ta bi l i ty ma y occur. Cons ti pa ti on i s us ua l l y pronounced. Spl enomega l y a ppea rs , a nd l ymph nodes ma y be s l i ghtl y or modera tel y
enl a rged. Up to 50% of pa ti ents ha ve hepa tomega l y.
Diagnosis
Bl ood cul tures
Acute a nd conva l es cent s erol ogi c tes ti ng
Bl ood cul tures s houl d be obta i ned; growth ma y ta ke > 7 da ys , s o the l a bora tory s houl d be noti fi ed of the s us pi ci on of brucel l os i s .
Acute a nd conva l es cent s era s houl d be obta i ned 3 wk a pa rt. A 4-fol d i ncrea s e or a n a cute ti ter of 1:160 or hi gher i s cons i dered di a gnos ti c,
pa rti cul a rl y i f a hi s tory of expos ure a nd cha ra cteri s ti c cl i ni ca l fi ndi ngs a re pres ent. The WBC count i s norma l or reduced wi th rel a ti ve or a bs ol ute
l ymphocytos i s duri ng the a cute pha s e.
Treatment
Doxycycl i ne pl us s treptomyci n
Acti vi ty s houl d be res tri cted i n a cute ca s es , wi th bed res t recommended duri ng febri l e epi s odes .
If a nti bi oti cs a re gi ven, combi na ti on thera py i s preferred. Doxycycl i ne 100 mg po bi d for 3 to 6 wk pl us s treptomyci n 1 g IM q 12 to 24 h for 14 da ys
l owers the ra te of rel a ps es . In chi l dren < 8 yr, tri methopri m/s ul fa methoxa zol e (TMP/SMX) a nd ei ther IM s treptomyci n or ora l ri fa mpi n for 4 to 6 wk
ha ve been us ed. Severe mus cul os kel eta l pa i ns , es peci a l l y over the s pi ne, ma y requi re a na l ges i a .
Pa s teuri za ti on of mi l k hel ps prevent brucel l os i s . Chees e tha t i s ma de from unpa s teuri zed mi l k a nd i s a ged < 3 mo ma y be conta mi na ted. Peopl e
ha ndl i ng a ni ma l s or ca rca s s es l i kel y to be i nfected s houl d wea r goggl es a nd rubber gl oves a nd protect s ki n brea ks from expos ure. Progra ms to
detect i nfecti on i n a ni ma l s , el i mi na te i nfected a ni ma l s , a nd va cci na te young s eronega ti ve ca ttl e a nd s wi ne a re requi red i n the US a nd i n s evera l
other countri es . Immuni ty a fter huma n i nfecti on i s s hort-l i ved, l a s ti ng a bout 2 yr.
Campylobacter and Related Infections
Campylobacter infections commonly cause diarrhea and occasionally bacteremia, with consequent endocarditis, osteomyelitis, or septic arthritis.
Campylobacter s p a re moti l e, curved, mi croa erophi l i c, gra m-nega ti ve ba ci l l i tha t norma l l y i nha bi t the GI tra ct of ma ny domes ti c a ni ma l s a nd fowl .
Severa l s peci es a re huma n pa thogens . The ma jor pa thogens a re C. jejuni a nd C. fetus. C. jejuni ca us es di a rrhea i n a l l a ge groups , a l though pea k
i nci dence a ppea rs to be from a ge 1 to 5 yr. C. jejuni a ccounts for more ca s es of di a rrhea i n the US tha n Salmonella a nd Shigella combi ned. C. fetus a nd
s evera l others typi ca l l y ca us e ba cteremi a i n a dul ts , more often when underl yi ng predi s pos i ng di s ea s es , s uch a s di a betes , ci rrhos i s , or ca ncer, a re
pres ent. In pa ti ents wi th i mmunogl obul i n defi ci enci es , thes e orga ni s ms ma y ca us e di ffi cul t-to-trea t, rel a ps i ng i nfecti ons . C. jejuni ca n ca us e
meni ngi ti s i n i nfa nts .
Conta ct wi th i nfected a ni ma l s a nd i nges ti on of conta mi na ted food (es peci a l l y under-cooked poul try) or wa ter ha ve been i mpl i ca ted i n outbrea ks .
However, i n s pora di c ca s es , the s ource of the i nfecti ng orga ni s m i s frequentl y obs cure.
Complications: C. jejuni di a rrhea l i l l nes s i s a s s oci a ted wi th s ubs equent devel opment (up to 30% of ca s es ) of Gui l l a i n-Ba rre s yndrome beca us e of
cros s -rea cti on between C. jejuni a nti bodi es a nd s urfa ce components of peri phera l nerves .
Pos ti nfecti ous (rea cti ve) a rthri ti s ma y occur i n HLA-B27-pos i ti ve pa ti ents a few da ys to s evera l weeks a fter a n epi s ode of C. jejuni di a rrhea .
Foca l extra i ntes ti na l i nfecti ons (eg, endoca rdi ti s , meni ngi ti s , s epti c a rthri ti s ) occur ra rel y.
Symptoms and Signs
The mos t common ma ni fes ta ti on i s wa tery a nd s ometi mes bl oody di a rrhea . Fever (38 to 40 C), whi ch fol l ows a rel a ps i ng or i ntermi ttent cours e, i s
the onl y cons ta nt fea ture of s ys temi c Campylobacter i nfecti on, a l though a bdomi na l pa i n a nd hepa tos pl enomega l y a re frequent.
Pa ti ents ca n a l s o pres ent wi th s uba cute ba cteri a l endoca rdi ti s , rea cti ve a rthri ti s , meni ngi ti s , or a n i ndol ent FUO ra ther tha n wi th di a rrhea l
i l l nes s . Joi nt i nvol vement wi th rea cti ve a rthri ti s i s us ua l l y monoa rti cul a r, a ffecti ng the knees ; s ymptoms res ol ve s ponta neous l y over 1 wk to
s evera l months .
Diagnosis
Stool cul ture
Someti mes bl ood cul tures
Di a gnos i s , pa rti cul a rl y to di fferenti a te Campylobacter i nfecti on from ul cera ti ve col i ti s (s ee p. 172), requi res mi crobi ol ogi c eva l ua ti on. Stool cul ture
s houl d be obta i ned pl us bl ood cul tures for pa ti ents wi th s i gns of foca l i nfecti on or s eri ous s ys temi c i l l nes s . WBCs a re pres ent i n s ta i ned s mea rs
of s tool .
Treatment
Someti mes erythromyci n
Mos t enteri c i nfecti ons res ol ve s ponta neous l y; i f they do not, erythromyci n 500 mg po q 6 h for 5 da ys ma y be hel pful . For pa ti ents wi th
extra i ntes ti na l i nfecti ons , a nti bi oti cs (eg, i mi penem, genta mi ci n, a mpi ci l l i n, erythromyci n) s houl d be gi ven for 2 to 4 wk to prevent rel a ps es .
Cholera
Cholera is an acute infection of the small bowel by Vibrio cholerae, which secretes a toxin that causes copious watery diarrhea, leading to dehydration, oliguria,
and circulatory collapse. Infection is typically through contaminated water or seafood. Diagnosis is by culture or serology. Treatment is vigorous rehydration and
electrolyte replacement plus doxycycline.
The ca us a ti ve orga ni s m, V. cholerae, s erogroups 01 a nd 0139, i s a s hort, curved, moti l e, a erobi c ba ci l l us tha t produces enterotoxi n, a protei n tha t
i nduces hypers ecreti on of a n i s otoni c el ectrol yte s ol uti on by the s ma l l -bowel mucos a . Both the El Tor a nd cl a s s i c bi otypes of V. cholerae ca n ca us e
s evere di s ea s e. However, mi l d or a s ymptoma ti c i nfecti on i s much more common wi th the El Tor bi otype.
Chol era i s s prea d by i nges ti on of wa ter, s ea food, or other foods conta mi na ted by the excrement of peopl e wi th s ymptoma ti c or a s ymptoma ti c
i nfecti on. Chol era i s endemi c i n porti ons of As i a , the Mi ddl e Ea s t, Afri ca , South a nd Centra l Ameri ca , a nd the Gul f Coa s t of the US. Ca s es
tra ns ported i nto Europe, Ja pa n, a nd Aus tra l i a ha ve ca us ed l oca l i zed outbrea ks . In endemi c a rea s , outbrea ks us ua l l y occur duri ng wa rm months .
The i nci dence i s hi ghes t i n chi l dren. In newl y a ffected a rea s , epi demi cs ma y occur duri ng a ny s ea s on, a nd a l l a ges a re equa l l y s us cepti bl e. A
mi l der form of ga s troenteri ti s i s ca us ed by nonchol era vi bri os (s ee p. 1249).
Sus cepti bi l i ty to i nfecti on va ri es a nd i s grea ter for peopl e wi th bl ood type O. Beca us e vi bri os a re s ens i ti ve to ga s tri c a ci d, hypochl orhydri a a nd
a chl orhydri a a re predi s pos i ng fa ctors . Peopl e l i vi ng i n endemi c a rea s gra dua l l y a cqui re a na tura l i mmuni ty.
Symptoms and Signs
The i ncuba ti on peri od i s 1 to 3 da ys . Chol era ca n be s ubcl i ni ca l , a mi l d a nd uncompl i ca ted epi s ode of di a rrhea , or a ful mi na nt, potenti a l l y l etha l
di s ea s e. Abrupt, pa i nl es s , wa tery di a rrhea a nd vomi ti ng a re us ua l l y the i ni ti a l s ymptoms . Si gni fi ca nt na us ea i s typi ca l l y a bs ent. Stool l os s i n
a dul ts ma y exceed 1 L/h but i s us ua l l y much l es s . The res ul ta nt s evere wa ter a nd el ectrol yte depl eti on l ea ds to i ntens e thi rs t, ol i guri a , mus cl e
cra mps , wea knes s , a nd ma rked l os s of ti s s ue turgor, wi th s unken eyes a nd wri nkl i ng of s ki n on the fi ngers . Hypovol emi a , hemoconcentra ti on,
ol i guri a a nd a nuri a , a nd s evere meta bol i c a ci dos i s wi th K+ depl eti on (but norma l s erum Na + concentra ti on) occur. If chol era i s untrea ted,
ci rcul a tory col l a ps e wi th cya nos i s a nd s tupor ma y fol l ow. Prol onged hypovol emi a ca n ca us e rena l tubul a r necros i s .
Mos t pa ti ents a re free of V. cholerae wi thi n 2 wk a fter ces s a ti on of di a rrhea ; chroni c bi l i a ry tra ct ca rri ers a re ra re.
Diagnosis
Stool cul ture a nd s erotypi ng
Di a gnos i s i s confi rmed by s tool cul ture a nd s ubs equent s erotypi ng. Chol era ca n be di s ti ngui s hed from cl i ni ca l l y s i mi l a r di s ea s e ca us ed by
enterotoxi n-produci ng s tra i ns of Escherichia coli a nd occa s i ona l l y by Salmonella a nd Shigella. Serum el ectrol ytes , BUN, a nd crea ti ni ne s houl d be
mea s ured.
Treatment
Fl ui d repl a cement
Doxycycl i ne, fura zol i done, or tri methopri m/s ul fa methoxa zol e (TMP/SMX), dependi ng on res ul ts of s us cepti bi l i ty tes ti ng
Repl a cement of fl ui d l os s i s es s enti a l . Mi l d ca s es ca n be trea ted wi th s ta nda rd ora l repl a cement formul a s (s ee p.
2809). Ra pi d correcti on of s evere hypovol emi a i s l i fes a vi ng. Preventi on or correcti on of meta bol i c a ci dos i s a nd hypoka l emi a i s i mporta nt. For
hypovol emi c a nd s everel y dehydra ted pa ti ents , IV repl a cement wi th i s otoni c fl ui ds s houl d be us ed (for deta i l s on fl ui d res us ci ta ti on, s ee pp. 2297
a nd 2807). Wa ter s houl d a l s o be gi ven freel y by mouth. To repl a ce K+ l os s es , KCl 10 to 15 mEq/L ca n be a dded to the IV s ol uti on, or KHCO3 1 mL/kg
po of a 100-g/L s ol uti on ca n be gi ven qi d. K+ repl a cement i s es peci a l l y i mporta nt for chi l dren, who tol era te hypoka l emi a poorl y.
Once i ntra va s cul a r vol ume i s res tored, a mounts for repl a cement of conti nui ng l os s es s houl d equa l mea s ured s tool vol ume. Adequa cy of hydra ti on
i s confi rmed by frequent cl i ni ca l eva l ua ti on (pul s e ra te a nd s trength, s ki n turgor, uri ne output). Pl a s ma , pl a s ma vol ume expa nders , a nd
va s opres s ors s houl d not be us ed i n pl a ce of wa ter a nd el ectrol ytes .
Ora l gl ucos e-el ectrol yte s ol uti on i s effecti ve i n repl a ci ng s tool l os s es a nd ma y be us ed a fter i ni ti a l IV rehydra ti on, a nd i t ma y be the onl y mea ns
of rehydra ti on i n epi demi c a rea s where s uppl i es of pa rentera l fl ui ds a re l i mi ted. Pa ti ents who ha ve mi l d or modera te dehydra ti on a nd who ca n
dri nk ma y be rehydra ted excl us i vel y wi th the ora l s ol uti on (a bout 75 mL/kg i n 4 h). Thos e wi th more s evere dehydra ti on need more a nd ma y need
to recei ve the fl ui d by na s oga s tri c tube. The ora l s ol uti on recommended by the WHO conta i ns 20 g gl ucos e, 3.5 g Na Cl , 2.9 g tri s odi um ci tra te a nd
di hydra te (or 2.5 g Na HCO3 ), a nd 1.5 g KCl per l i ter of dri nki ng wa ter. Thi s s ol uti on s houl d be conti nued a d l i bi tum a fter rehydra ti on i n a mounts a t
l ea s t equa l to conti nui ng s tool a nd vomi tus l os s es . Sol i d food s houl d be gi ven onl y a fter vomi ti ng s tops a nd a ppeti te returns .
Ea rl y trea tment wi th a n effecti ve ora l a nti mi crobi a l era di ca tes vi bri os , reduces s tool vol ume by 50%, a nd s tops di a rrhea wi thi n 48 h. The choi ce of
a nti mi crobi a l s houl d be ba s ed on the s us cepti bi l i ty of V. cholerae i s ol a ted from the communi ty.
Drugs effecti ve for s us cepti bl e s tra i ns i ncl ude
Doxycycl i ne: For a dul ts , a s i ngl e dos e of 300 mg po
Fura zol i done: For a dul ts , 100 mg po qi d for 72 h; for chi l dren, 1.5 mg/kg qi d for 72 h
TMP/SMX: For a dul ts , one doubl e-s trength ta bl et bi d; for chi l dren, 5 mg/kg (of the TMP component) bi d for 72 h
Prevention
For control of chol era , huma n excrement mus t be correctl y di s pos ed of, a nd wa ter s uppl i es puri fi ed. In endemi c regi ons , dri nki ng wa ter s houl d be
boi l ed or chl ori na ted, a nd vegeta bl es a nd fi s h cooked thoroughl y.
A ki l l ed ora l whol e cel l -B s ubuni t va cci ne (not a va i l a bl e i n the US) provi des 85% protecti on a ga i ns t the 01 s erogroup for 4 to 6 mo. Protecti on l a s ts
up to 3 yr i n a dul ts but wa nes ra pi dl y i n chi l dren a nd i s grea ter for the cl a s s i c tha n for the El Tor bi otype. There i s no cros s -protecti on between 01
a nd 0139 s erogroups . Va cci nes proven effecti ve a ga i ns t both s ero-groups a re a future goa l . The pa rentera l chol era va cci ne i s not recommended
beca us e of i ts l ow effi ca cy, s hort dura ti on (43% for 3 mo), a nd frequent s evere a dvers e effects .
Prompt prophyl a xi s wi th doxycycl i ne 100 mg po q 12 h i n a dul ts (TMP/SMX ca n be us ed for prophyl a xi s i n chi l dren < 9 yr) ca n decrea s e s econda ry
ca s es a mong hous ehol d conta cts of chol era pa ti ents , but ma s s prophyl a xi s i s i na ppropri a te a nd s ome s tra i ns a re not s ens i ti ve.
Noncholera Vibrio Infections
Nonchol era vi bri os i ncl ude Vibrio parahaemolyticus, V. mimicus, V. alginolyticus, V. hollisae, a nd V. vulnificus; thes e vi bri os a re s ometi mes ca l l ed
nona ggl uti na bl e vi bri os (i e, they do not a ggl uti na te wi th s erum from chol era pa ti ents ). They typi ca l l y i nha bi t wa rm s a l t wa ter or mi xed s a l t a nd
fres h wa ter (eg, i n es tua ri es ).
V. parahaemolyticus, V. mimicus, a nd V. hollisae us ua l l y ca us e food-borne outbrea ks of di a rrhea , typi ca l l y i nvol vi ng i na dequa tel y cooked s ea food
(us ua l l y s hel l fi s h). V. parahaemolyticus i nfecti ons typi ca l l y occur i n Ja pa n a nd i n coa s ta l a rea s of the US. The orga ni s ms da ma ge i ntes ti na l mucos a
but do not produce enterotoxi n or i nva de the bl oods trea m. Al s o, wound i nfecti on ma y devel op when conta mi na ted wa rm s ea wa ter enters a mi nor
wound.
V. alginolyticus a nd V. vulnificus ca n ca us e s eri ous wound i nfecti on; nei ther ca us es enteri ti s . V. vulnificus, when i nges ted by a compromi s ed hos t
(often s omeone wi th chroni c l i ver di s ea s e or i mmunodefi ci ency), ca n cros s the i ntes ti na l mucos a wi thout ca us i ng enteri ti s a nd ca us e s epti cemi a
wi th a hi gh morta l i ty ra te; occa s i ona l l y, otherwi s e hea l thy peopl e devel op s uch i nfecti ons .
Symptoms and Signs
After a 15- to 24-h i ncuba ti on peri od, enteri c i l l nes s begi ns s uddenl y wi th cra mpi ng a bdomi na l pa i n, l a rge a mounts of wa tery di a rrhea (s tool s ma y
be bl oody a nd conta i n PMNs ), tenes mus , wea knes s , a nd s ometi mes na us ea , vomi ti ng, a nd l ow-gra de fever. Symptoms s ubs i de s ponta neous l y i n
24 to 48 h.
Cel l ul i ti s ca n ra pi dl y devel op i n conta mi na ted wounds i n s ome ca s es (typi ca l l y thos e i nvol vi ng V. vulnificus) a nd progres s to necroti zi ng fa s ci i ti s
wi th typi ca l hemorrha gi c, bul l ous l es i ons .
V. vulnificus s epti cemi a ca us es s hock, bul l ous s ki n l es i ons , a nd often ma ni fes ta ti ons of di s s emi na ted i ntra va s cul a r coa gul a ti on (eg,
thrombocytopeni a , hemorrha ge); morta l i ty ra te i s hi gh.
Diagnosis
Cul tures
Wound a nd bl oods trea m i nfecti ons a re rea di l y di a gnos ed wi th routi ne cul tures . When enteri c i nfecti on i s s us pected, Vibrio orga ni s ms ca n be
cul tured from s tool on thi os ul fa te ci tra te bi l e s a l ts s ucros e medi um. Conta mi na ted s ea food a l s o yi el ds pos i ti ve cul tures .
Treatment
Ci profl oxa ci n or doxycycl i ne for enteri c i nfecti on
Anti bi oti cs a nd often debri dement for wound i nfecti on
Nonchol era Vibrio enteri c i nfecti ons ca n be trea ted wi th a s i ngl e dos e of ci profl oxa ci n 1 g po or doxycycl i ne 300 mg po. For di a rrhea , cl os e a ttenti on
to vol ume repl eti on a nd repl a cement of l os t el ectrol ytes a re needed.
For wound i nfecti ons , a nti bi oti cs a re us edtypi ca l l y, doxycycl i ne 100 mg po q 12 h, wi th or wi thout a 3rd-genera ti on cepha l os pori n for s evere
wound i nfecti on or s epti cemi a . Pa ti ents wi th necroti zi ng fa s ci i ti s requi re s urgi ca l debri dement.
Escherichia Coli Infections

Escherichia coli are the most numerous aerobic commensal inhabitants of the large intestine. Certain strains cause diarrhea, and all can cause infection when they
invade sterile sites (eg, the urinary tract). Diagnosis is by standard culture techniques. Toxin assays may help identify the cause of diarrhea. Treatment with
antibiotics is guided by susceptibility testing.
Diseases caused by E. coli: Mos t commonl y, E. coli ca us e UTIs , whi ch us ua l l y repres ent a s cendi ng i nfecti on (i e, from the peri neum vi a the urethra ).
E. coli norma l l y i nha bi t the GI tra ct; however, s ome s tra i ns ha ve a cqui red genes tha t ena bl e them to ca us e i ntes ti na l i nfecti on. When i nges ted, the
fol l owi ng s tra i ns ca n ca us e di a rrhea :
Enterohemorrha gi c: Thes e s tra i ns (eg, type O157:H7s ee bel ow) produce s evera l cytotoxi ns , neurotoxi ns , a nd enterotoxi ns , i ncl udi ng Shi ga toxi n,
a nd ca us e bl oody di a rrhea ; hemol yti c-uremi c s yndrome devel ops i n 2 to 7% of ca s es (s ee p. 961). Such s tra i ns ha ve mos t often been a cqui red
from undercooked ground beef but ma y a l s o be a cqui red from i nfected peopl e by the feca l ora l route when hygi ene i s i na dequa te.
Enterotoxi geni c: Thes e s tra i ns ca n ca us e wa tery di a rrhea , pa rti cul a rl y i n i nfa nts a nd tra vel ers (s ee p.
150).
Enteroi nva s i ve: Thes e s tra i ns ca n ca us e i nfl a mma tory di a rrhea .
Enteropa thogeni c: Thes e s tra i ns ca n ca us e wa tery di a rrhea , pa rti cul a rl y i n i nfa nts .
Enteroa ggrega ti ve: Some s tra i ns a re emergi ng a s potenti a l l y i mporta nt ca us es of pers i s tent di a rrhea i n pa ti ents wi th AIDS a nd i n chi l dren i n
tropi ca l a rea s .
Other s tra i ns a re ca pa bl e of ca us i ng extra -i ntes ti na l i nfecti on i f norma l i ntes ti na l a na tomi c ba rri ers a re di s rupted (eg, by i s chemi a , i nfl a mma tory
bowel di s ea s e, or tra uma ), i n whi ch ca s e the orga ni s m ma y s prea d to a dja cent s tructures or i nva de the bl oods trea m. Hepa tobi l i a ry, peri tonea l ,
cuta neous , a nd pul mona ry i nfecti ons a l s o occur. E. coli ba cteremi a ma y a l s o occur wi thout a n evi dent porta l of entry.
In neona tes , pa rti cul a rl y preterm i nfa nts , E. coli ba cteremi a a nd meni ngi ti s (ca us ed by s tra i ns wi th the K1 ca ps ul e, a ma rker for
neuroi nva s i venes s ) a re common (s ee Neona ta l Ba cteri a l Meni ngi ti s on p. 2830 a nd Neona ta l Seps i s on p. 2832).
Diagnosis
Cul ture
Sa mpl es of bl ood, s tool , or other cl i ni ca l ma teri a l a re s ent for cul ture. If a n enterohemorrha gi c s tra i n i s s us pected, the l a bora tory mus t be
noti fi ed beca us e s peci a l cul ture medi a a re requi red.
Treatment
Va ri ous a nti bi oti cs dependi ng on s i te of i nfecti on a nd s us cepti bi l i ty tes ti ng
Trea tment mus t be s ta rted empi ri ca l l y ba s ed on the s i te a nd s everi ty of i nfecti on (eg, mi l d bl a dder i nfecti on, uros eps i s ) a nd then modi fi ed ba s ed
on a nti bi oti c s us cepti bi l i ty tes ti ng. Ma ny s tra i ns a re res i s ta nt to a mpi ci l l i n a nd tetra cycl i nes , s o other drugs s houl d be us ed; they i ncl ude
ti ca rci l l i n, pi pera ci l l i n, cepha l os pori ns , a mi nogl ycos i des , tri methopri m/s ul fa methoxa zol e (TMP/SMX), a nd fl uoroqui nol ones .
Surgery ma y be requi red to dra i n pus , debri de necroti c l es i ons , or remove forei gn bodi es .
E. coli O157:H7 Infection
E. coli O157:H7 typically causes acute bloody diarrhea, which may lead to hemolytic-uremic syndrome. Symptoms are abdominal cramps and diarrhea that may
be grossly bloody. Fever is not prominent. Diagnosis is by stool culture and toxin assay. Treatment is supportive; antibiotic use is controversial.
Epidemiology
Al though > 100 s erotypes of E. coli produce Shi ga a nd Shi ga -l i ke toxi ns , E. coli O157:H7 i s the mos t common i n North Ameri ca . In s ome pa rts of the US
a nd Ca na da , E. coli O157:H7 i nfecti on ma y be a more common ca us e of bl oody di a rrhea tha n s hi gel l os i s or s a l monel l os i s . E. coli O157:H7 i nfecti on
ca n occur i n peopl e of a l l a ges , a l though s evere i nfecti on i s mos t common a mong chi l dren a nd the el derl y.
E. coli O157:H7 ha s a bovi ne res ervoi r, s o outbrea ks a nd s pora di c ca s es occur a fter i nges ti on of undercooked beef (es peci a l l y ground beef) or
unpa s teuri zed mi l k. Food or wa ter conta mi na ted wi th cow ma nure or ra w ground beef ca n a l s o tra ns mi t i nfecti on. The orga ni s m ca n a l s o be
tra ns mi tted by the feca l -ora l route, es peci a l l y a mong i nfa nts i n di a pers (eg, vi a i na dequa tel y chl ori na ted chi l dren's wa di ng pool s ).
After i nges ti on, E. coli O157:H7 a nd s i mi l a r s tra i ns of E. coli (termed enterohemorrha gi c E. coli) produce hi gh l evel s of va ri ous toxi ns i n the l a rge
i ntes ti ne; thes e toxi ns a re cl os el y rel a ted to the potent cytotoxi ns produced by Shigella dysenteriae type 1. Thes e toxi ns a ppea r to di rectl y da ma ge
mucos a l cel l s a nd va s cul a r endothel i a l cel l s i n the gut wa l l . If a bs orbed, they exert toxi c effects on other va s cul a r endothel i a (eg, rena l ).
Symptoms and Signs
E. coli O157:H7 i nfecti on typi ca l l y begi ns a cutel y wi th s evere a bdomi na l cra mps a nd wa tery di a rrhea tha t ma y become gros s l y bl oody wi thi n 24 h.
Some pa ti ents report di a rrhea a s bei ng "a l l bl ood a nd no s tool ," whi ch ha s gi ven ri s e to the term hemorrha gi c col i ti s . Fever, us ua l l y a bs ent or l ow
gra de, occa s i ona l l y rea ches 39 C. Di a rrhea ma y l a s t 1 to 8 da ys i n uncompl i ca ted i nfecti ons .
About 5% of ca s es (mos tl y chi l dren < 5 yr a nd a dul ts > 60 yr) a re compl i ca ted by hemol yti c-uremi c s yndrome (s ee p. 961), whi ch typi ca l l y devel ops i n
the 2nd wk of i l l nes s . Dea th ma y occur, es peci a l l y i n the el derl y, wi th or wi thout thi s compl i ca ti on.
Diagnosis
Stool cul tures
Someti mes ra pi d s tool a s s a y for Shi ga toxi n
E. coli O157:H7 i nfecti on s houl d be di s ti ngui s hed from other i nfecti ous di a rrhea s by i s ol a ti ng the orga ni s m from s tool cul tures . Often, the cl i ni ci a n
mus t s peci fi ca l l y a s k the l a bora tory to tes t for the orga ni s m. Beca us e bl oody di a rrhea a nd s evere a bdomi na l pa i n wi thout fever s ugges t va ri ous
noni nfecti ous eti ol ogi es , E. coli O157:H7 i nfecti on s houl d be cons i dered i n s us pected ca s es of i s chemi c col i ti s , i ntus s us cepti on, a nd i nfl a mma tory
bowel di s ea s e. A ra pi d s tool a s s a y for Shi ga toxi n ma y hel p. Pa ti ents a t ri s k of noni nfecti ous di a rrhea s ma y need s i gmoi dos copy. If done,
s i gmoi dos copy ma y revea l erythema a nd edema ; ba ri um enema typi ca l l y s hows evi dence of edema wi th thumbpri nti ng.
Treatment
Supporti ve ca re
The ma i ns ta y of trea tment i s s upporti ve. Al though E. coli i s s ens i ti ve to mos t commonl y us ed a nti bi oti cs , a nti bi oti cs ha ve not been s hown to
a l l evi a te s ymptoms , reduce ca rri a ge of the orga ni s m, or prevent hemol yti c-uremi c s yndrome. Fl uoroqui nol ones a re s us pected of i ncrea s i ng
rel ea s e of enterotoxi ns .
In the week a fter i nfecti on, pa ti ents a t hi gh ri s k of devel opi ng hemol yti c-uremi c s yndrome (eg, chi l dren < 5 yr, the el derl y) s houl d be obs erved for
ea rl y s i gns , s uch a s protei nuri a , hema turi a , red cel l ca s ts , a nd ri s i ng s erum crea ti ni ne. Edema a nd hypertens i on devel op l a ter. Pa ti ents who
devel op compl i ca ti ons a re l i kel y to requi re i ntens i ve ca re, i ncl udi ng di a l ys i s a nd other s peci fi c thera pi es , a t a terti a ry medi ca l center.
Prevention
Correct di s pos a l of the s tool of i nfected peopl e, good hygi ene, a nd ca reful ha nd wa s hi ng wi th s oa p l i mi t s prea d of i nfecti on. Preventi ve mea s ures
tha t ma y be effecti ve i n the da y ca re s etti ng i ncl ude groupi ng chi l dren known to be i nfected wi th E. coli O157:H7 or requi ri ng 2 nega ti ve s tool
cul tures before a l l owi ng i nfected chi l dren to a ttend. Pa s teuri za ti on of mi l k a nd thorough cooki ng of beef prevent food-borne tra ns mi s s i on.
Reporti ng outbrea ks of bl oody di a rrhea to publ i c hea l th a uthori ti es i s i mporta nt beca us e i nterventi on ca n prevent a ddi ti ona l i nfecti ons .
Haemophilus Infections
Haemophilus sp cause numerous mild and serious infections, including bacteremia, meningitis, pneumonia, otitis media, cellulitis, and epiglottitis. Diagnosis is by
culture and serotyping. Treatment is with antibiotics.
Ma ny Haemophilus s p a re norma l fl ora i n the upper res pi ra tory tra ct a nd ra rel y ca us e i l l nes s . Pa thogeni c s tra i ns enter the upper res pi ra tory tra ct
through dropl et i nha l a ti on or di rect conta ct. Sprea d i s ra pi d i n noni mmune popul a ti ons . Chi l dren, pa rti cul a rl y ma l es , bl a cks , a nd Na ti ve
Ameri ca ns , a re a t hi ghes t ri s k of s eri ous i nfecti on. Overcrowded l i vi ng condi ti ons a nd da y ca re center a ttenda nce predi s pos e to i nfecti on, a s do
i mmunodefi ci ency s ta tes , a s pl eni a , a nd s i ckl e cel l di s ea s e.
There a re s evera l pa thogeni c s peci es of Haemophilus; the mos t common i s H. influenzae, whi ch ha s 6 di s ti nct enca ps ul a ted s erotypes (a through f)
a nd numerous nonenca ps ul a ted, nontypea bl e s tra i ns . Before the us e of H. influenzae type b (Hi b) conjuga te va cci ne, mos t ca s es of s eri ous ,
i nva s i ve di s ea s e were ca us ed by type b.
Diseases caused by Haemophilus sp: H. influenzae ca us es ma ny chi l dhood i nfecti ons , i ncl udi ng meni ngi ti s , ba cteremi a , s epti c a rthri ti s , pneumoni a ,
tra cheobronchi ti s , oti ti s medi a , conjuncti vi ti s , s i nus i ti s , a nd a cute epi gl otti ti s . Thes e i nfecti ons , a s wel l a s endoca rdi ti s a nd UTIs , ma y occur i n
a dul ts , a l though fa r l es s commonl y. Thes e i l l nes s es a re di s cus s ed el s ewhere i n THE MANUAL.
Nontypea bl e H. influenzae s tra i ns ca us e ma i nl y mucos a l i nfecti ons (eg, oti ti s medi a , s i nus i ti s , conjuncti vi ti s , bronchi ti s ). Occa s i ona l l y,
nonenca ps ul a ted s tra i ns ca us e i nva s i ve i nfecti ons i n chi l dren, but they ma y ca us e up to ha l f of s eri ous H. influenzae i nfecti ons i n a dul ts .
H. influenzae bi ogroup a egypti us (formerl y ca l l ed H. aegyptius) ma y ca us e mucopurul ent conjuncti vi ti s a nd ba cteremi c Bra zi l i a n purpuri c fever. H.
ducreyi ca us es cha ncroi d (s ee p. 1468). H. parainfluenzae a nd H. aphrophilus a re ra re ca us es of ba cteremi a , endoca rdi ti s , a nd bra i n a bs ces s .
Diagnosis
Cul tures
Someti mes s erotypi ng
Di a gnos i s i s by cul ture of bl ood a nd body fl ui ds . Stra i ns i nvol ved i n i nva s i ve i l l nes s s houl d be s erotyped.
Treatment
Va ri ous a nti bi oti cs dependi ng on s i te a nd s everi ty of i nfecti on
Trea tment depends on na ture a nd l oca ti on of the i nfecti on, but doxycycl i ne, fl uoroqui nol ones , 2nd- a nd 3rd-genera ti on cepha l os pori ns , a nd
ca rba penems a re us ed for i nva s i ve di s ea s e. The Hi b va cci ne ha s ma rkedl y reduced the ra te of ba cteremi a . Chi l dren wi th s eri ous i l l nes s a re
hos pi ta l i zed wi th conta ct a nd res pi ra tory i s ol a ti on for 24 h a fter s ta rti ng a nti bi oti cs .
Anti bi oti c choi ces depend s trongl y on the s i te of i nfecti on a nd requi re s us cepti bi l i ty tes ti ng; ma ny i s ol a tes i n the US produce -l a cta ma s e. For
i nva s i ve i l l nes s , i ncl udi ng meni ngi ti s , cefota xi me or ceftri a xone i s recommended. For l es s s eri ous i nfecti ons , ora l cepha l os pori ns , ma crol i des ,
a nd a moxi ci l l i n/cl a vul a na te a re genera l l y effecti ve. (See i ndi vi dua l di s ea s e entri es for s peci fi c recommenda ti ons .)
Prevention
Hi b conjuga te va cci nes a re a va i l a bl e for chi l dren 2 mo of a ge a nd ha ve reduced i nva s i ve i nfecti ons (eg, meni ngi ti s , epi gl otti ti s , ba cteremi a ) by
99%. A pri ma ry s eri es i s gi ven a t a ge 2, 4, a nd 6 mo or a t a ge 2 a nd 4 mo, dependi ng on the va cci ne product. A boos ter a t a ge 12 to 15 mo i s
i ndi ca ted.
Conta cts wi thi n the hous ehol d ma y ha ve a s ymptoma ti c H. influenzae ca rri a ge. Uni mmuni zed or i ncompl etel y i mmuni zed hous ehol d conta cts < 4 yr
a re a t ri s k of i l l nes s a nd s houl d recei ve a dos e of va cci ne. In a ddi ti on, a l l hous ehol d members (except pregna nt women) s houl d recei ve
prophyl a xi s wi th ri fa mpi n 600 mg (20 mg/kg for chi l dren) po once/da y for 4 da ys . Nurs ery or da y ca re conta cts s houl d recei ve prophyl a xi s i f 2 ca s es
of i nva s i ve di s ea s e occurred i n 60 da ys . The benefi t of prophyl a xi s i f onl y one ca s e occurred ha s not been es ta bl i s hed.
HACEK Infections
The HACEK group includes weakly virulent, gram-negative organisms that primarily cause endocarditis.
The HACEK group of nonmoti l e, gra m-nega ti ve ba ci l l i or coccoba ci l l i conta i ns a number of mi ni ma l l y pa thogeni c, s l ow-growi ng, fa s ti di ous genera .
Thei r pri ma ry pa thol ogy i s endoca rdi ti s i n s us cepti bl e peopl e; a bout 1% of endoca rdi ti s ca s es a re due to thi s group. The group cons i s ts of
Haemophilus s p, whi ch ma y ca us e res pi ra tory i nfecti ons or, l es s commonl y, endoca rdi ti s
Actinobacillus actinomycetemcomitans, whi ch us ua l l y occurs wi th A. israelii i n a cti nomycos i s (s ee Acti nomycos i s on p. 1289)
Cardiobacterium hominis
Eikenella corrodens, whi ch us ua l l y occurs i n huma n bi te wounds , endoca rdi ti s , bra i n a nd vi s cera l a bs ces s es , os teomyel i ti s , res pi ra tory i nfecti ons ,
uteri ne i nfecti ons rel a ted to i ntra uteri ne devi ces , a nd mi xed s oft-ti s s ue i nfecti ons
Kingella kingae
Anti bi oti c s ens i ti vi ti es di ffer a mong s peci es , s o trea tment s houl d be di rected by s us cepti bi l i ty tes ti ng.
Klebsiella, Enterobacter, and Serratia Infections
Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts.
Infecti ons wi th Klebsiella, Enterobacter, a nd Serratia a re us ua l l y hos pi ta l -a cqui red a nd occur ma i nl y i n pa ti ents wi th di mi ni s hed res i s ta nce. Us ua l l y,
Klebsiella, Enterobacter, a nd Serratia ca us e a wi de va ri ety of i nfecti ons , i ncl udi ng ba cteremi a , s urgi ca l s i te i nfecti ons , i ntra va s cul a r ca theter
i nfecti ons , a nd res pi ra tory or uri na ry tra ct i nfecti ons tha t ma ni fes t a s pneumoni a , cys ti ti s , or pyel i ti s a nd tha t ma y progres s to l ung a bs ces s ,
empyema , a nd s epti cemi a . Klebsiella pneumoni a , a ra re a nd s evere di s ea s e wi th da rk brown or red curra nt-jel l y s putum, l ung a bs ces s forma ti on,
a nd empyema , i s mos t common a mong di a beti cs a nd a l cohol i cs . Serratia, pa rti cul a rl y S. marcescens, ha s grea ter a ffi ni ty for the uri na ry tra ct.
Enterobacter ca n ca us e oti ti s medi a , cel l ul i ti s , a nd neona ta l s eps i s .
Trea tment i s wi th 3rd-genera ti on cepha l os pori ns , cefepi me, ca rba penems , fl uoroqui nol ones , pi pera ci l l i n/ta zoba cta m, or a mi nogl ycos i des .
However, beca us e s ome i s ol a tes a re res i s ta nt to mul ti pl e a nti bi oti cs , s us cepti bi l i ty tes ti ng i s es s enti a l . Klebsiella s tra i ns tha t produce extendeds pectrum -l a cta ma s e (ESBL) ma y devel op res i s ta nce to cepha l os pori ns duri ng trea tment, pa rti cul a rl y wi th cefta zi di me. Enterobacter s tra i ns ma y be
res i s ta nt to mos t -l a cta m a nti bi oti cs , i ncl udi ng 3rd-genera ti on cepha l os pori ns ; the -l a cta ma s e enzyme they produce i s not i nhi bi ted by the
us ua l -l a cta ma s e i nhi bi tors (cl a vul a na te, ta zoba cta m, s ul ba cta m). However, thes e Enterobacter s tra i ns ma y be s us cepti bl e to ca rba penems (eg,
i mi penem, meropenem, erta penem).
Legionella Infections
Legionella pneumophila most often causes pneumonia with extrapulmonary features. Diagnosis requires specific growth media, serologic testing, or PCR analysis.
Treatment is with doxycycline, macrolides, or fluoroquinolones.
The fi rs t a ppea ra nce of thi s orga ni s m wa s i n 1976 a t a conventi on of the Ameri ca n Legi onthus , the na me Legi onna i res ' di s ea s e. Thi s di s ea s e i s
the pneumoni c form of a n i nfecti on us ua l l y ca us ed by Legionella pneumophila s erogroups 1 through 6. Nonpneumoni c i nfecti on i s ca l l ed Ponti a c
fever.
The orga ni s ms a re often pres ent i n s oi l a nd fres hwa ter. A bui l di ng's wa ter s uppl y i s often the s ource of a Legionella outbrea k. Legionella orga ni s ms
a re embedded i n a bi ofi l m tha t forms on the i ns i de of wa ter pi pes a nd conta i ners . The i nfecti on i s us ua l l y a cqui red by i nha l i ng a eros ol s of
conta mi na ted wa ter (eg, a s genera ted by s hower hea ds , mi s ters , whi rl pool ba ths , or wa ter cool i ng towers for a i r-condi ti oni ng).
Diseases caused by Legionella sp: The l ungs a re the mos t common s i te of i nfecti on; communi ty- a nd hos pi ta l -a cqui red pneumoni a ma y occur.
Extra pul mona ry foci of i nfecti on occur mos t frequentl y i n hos pi ta l i zed pa ti ents a nd mos t commonl y i nvol ve the hea rt. Other s i tes i ncl ude the CNS,
l i ver, a nd i ntes ti nes . Immunocompromi s ed pa ti ents , pa ti ents wi th di a betes mel l i tus , ci ga rette s mokers , the el derl y, a nd pa ti ents wi th chroni c
l ung di s ea s e a re pri nci pa l l y a ffected.
Symptoms and Signs
Legi onna i res ' di s ea s e i s a fl u-l i ke s yndrome wi th a cute fever, chi l l s , ma l a i s e, mya l gi a s , hea da che, or confus i on. Na us ea , l oos e s tool s or wa tery
di a rrhea , a bdomi na l pa i n, cough, a nd a rthra l gi a s a l s o frequentl y occur. Pneumoni c ma ni fes ta ti ons ma y i ncl ude dys pnea , pl euri ti c pa i n, a nd
hemoptys i s .
Morta l i ty i s l ow i n otherwi s e hea l thy peopl e but ca n rea ch 50% i n hos pi ta l -a cqui red outbrea ks .
Diagnosis
Di rect fl uores cent a nti body s ta i ni ng
Sputum cul ture
Ra pi d uri na ry a nti gen tes t (for s erogroup 1 onl y)
Di rect fl uores cent a nti body s ta i ni ng of s putum or l a va ge fl ui d i s frequentl y us ed. In a ddi ti on, PCR wi th DNA probi ng i s a va i l a bl e. A uri na ry a nti gen
tes t i s 70% s ens i ti ve a nd 100% s peci fi c 3 da ys a fter s ymptom ons et but detects onl y L. pneumophila (s erogroups 1 through 6) a nd not
non-pneumophila Legionella. Pa i red a cute a nd conva l es cent a nti body a s s a ys ma y yi el d a del a yed di a gnos i s . A 4-fol d i ncrea s e or a n a cute ti ter of
1:128 i s cons i dered di a gnos ti c.
Di a gnos i s i s by cul ture of s putum or bronchoa l veol a r l a va ge fl ui d; bl ood cul tures a re unrel i a bl e. Sl ow growth on l a bora tory medi a ma y del a y
i denti fi ca ti on for 3 to 5 da ys .
Ches t x-ra y s houl d be done; i t us ua l l y s hows pa tchy a nd ra pi dl y a s ymmetri ca l l y progres s i ve i nfi l tra tes (even when effecti ve a nti bi oti c thera py i s
us ed), wi th or wi thout s ma l l pl eura l effus i ons .
Treatment
Fl uoroqui nol ones
Doxycycl i ne
A fl uoroqui nol one gi ven IV or po for 2 to 3 wk i s the preferred regi men. Doxycycl i ne i s a l s o hi ghl y effecti ve. Azi thromyci n i s effecti ve, but
erythromyci n ma y be i neffecti ve. Ri fa mpi n ma y be a dded for s evere i nfecti ons .
Melioidosis
Melioidosis is an infection caused by Burkholderia (formerly Pseudomonas) pseudomallei. Manifestations include pneumonia, septicemia, and localized infection
in various organs. Diagnosis is by staining or culture. Treatment with antibiotics, such as ceftazidime, is prolonged.
The orga ni s m ca n be i s ol a ted from s oi l a nd wa ter a nd i s endemi c i n Southea s t As i a ; Aus tra l i a ; Centra l , Wes t, a nd Ea s t Afri ca ; Indi a ; a nd Chi na .
Huma ns ma y contra ct mel i oi dos i s by conta mi na ti on of s ki n a bra s i ons or burns , i nges ti on, or i nha l a ti on but not di rectl y from i nfected a ni ma l s or
other huma ns . In endemi c a rea s , mel i oi dos i s i s l i kel y to occur i n pa ti ents wi th AIDS.
Symptoms and Signs
Infecti on ma y be a s ymptoma ti c or rema i n l a tent for yea rs . Morta l i ty i s < 10%, except i n a cute s epti cemi c mel i oi dos i s , whi ch i s frequentl y fa ta l .
Acute pulmonary infection i s the mos t common form. It va ri es from mi l d to overwhel mi ng necroti zi ng pneumoni a . Ons et ma y be a brupt or gra dua l ,
wi th hea da che, a norexi a , pl euri ti c or dul l a chi ng ches t pa i n, a nd genera l i zed mya l gi a . Fever i s us ua l l y > 39 C. Cough, ta chypnea , a nd ra l es a re
cha ra cteri s ti c. Sputum ma y be bl ood-ti nged. Ches t x-ra ys us ua l l y s how upper l obe cons ol i da ti on, frequentl y ca vi ta ti ng a nd res embl i ng TB. Nodul a r
l es i ons , thi n-wa l l ed cys ts , a nd pl eura l effus i on ma y a l s o occur. The WBC count ra nges from norma l to 20,000/L.
Disseminated septicemic infection begi ns a bruptl y, wi th s epti c s hock a nd mul ti pl e orga n i nvol vement ma ni fes ted by di s ori enta ti on, extreme
dys pnea , s evere hea da che, pha ryngi ti s , upper a bdomi na l col i c, di a rrhea , a nd pus tul a r s ki n l es i ons . Hi gh fever, hypotens i on, ta chypnea , a bri ght
erythema tous fl us h, a nd cya nos i s a re pres ent. Mus cl e tendernes s ma y be s tri ki ng. Si gns of a rthri ti s or meni ngi ti s s ometi mes occur. Pul mona ry
s i gns ma y be a bs ent or ma y i ncl ude ra l es , rhonchi , a nd pl eura l rubs .
Nondisseminated septicemic infection occurs when ba cteremi a i nvol ves onl y a s i ngl e orga n. It does not us ua l l y l ea d to s hock.
Localized (chronic suppurative) infection ca us es s econda ry a bs ces s es , mos t often i n the s ki n, l ymph nodes , or bone. Pa ti ents ma y be a febri l e. An a cute
s uppura ti ve form i s uncommon.
Diagnosis
Sta i ni ng a nd cul ture
B. pseudomallei ca n be i denti fi ed i n exuda tes by methyl ene bl ue or Gra m s ta i n a nd by cul ture. Ches t x-ra ys us ua l l y s how i rregul a r, nodul a r (4 to 10
mm) dens i ti es . The l i ver a nd s pl een ma y be pa l pa bl e. Li ver functi on tes ts , AST, a nd bi l i rubi n a re often a bnorma l . The WBC count i s norma l or
s l i ghtl y i ncrea s ed.
Treatment
Someti mes tri methopri m/s ul fa methoxa zol e (TMP/SMX) or cefta zi di me
As ymptoma ti c i nfecti on needs no trea tment. Mi l dl y i l l pa ti ents a re gi ven TMP/SMX, one doubl e-s trength ta bl et po bi d for a mi ni mum of 30 da ys .
Modera tel y or s eri ous l y i l l pa ti ents a re gi ven cefta zi di me 30 mg/kg IV q 6 h for 2 to 4 wk (i mi penem, meropenem, a nd pi pera ci l l i n a re a ccepta bl e
s ubs ti tutes ), then ora l TMP/SMX or a moxi ci l l i n/cl a vul a na te for 30 to 120 da ys .
Pertussis
(Whoopi ng Cough)
Pertussis is a highly communicable disease occurring mostly in children and adolescents and caused by Bordetella pertussis. Symptoms are initially those of
nonspecific URI followed by paroxysmal or spasmodic coughing that usually ends in a prolonged, high-pitched, crowing inspiration (the whoop). Diagnosis is by
nasopharyngeal culture, PCR, and serologic assays. Treatment is with macrolide antibiotics.
Pertus s i s i s endemi c throughout the worl d. Its i nci dence i n the US cycl es every 3 to 4 yr. In a gi ven uni mmuni zed l oca l i ty, i t becomes epi demi c every
2 to 4 yr. It occurs a t a l l a ges , but 71% of ca s es occur i n chi l dren < 5 yr, a nd 38% of ca s es , i ncl udi ng nea rl y a l l dea ths , occur i n i nfa nts < 6 mo.
Morta l i ty i s a bout 1 to 2% i n chi l dren < 1 yr a nd i s hi ghes t duri ng the fi rs t month of l i fe. Mos t dea ths a re ca us ed by bronchopneumoni a a nd
cerebra l compl i ca ti ons . It i s a l s o s eri ous i n the el derl y. One a tta ck does not confer l i fe-l ong na tura l i mmuni ty, but s econda ry a tta cks a re us ua l l y
mi l d a nd often unrecogni zed.
Tra ns mi s s i on vi a a eros ol s of B. pertussis (a s ma l l , nonmoti l e, gra m-nega ti ve coccoba ci l l us ) from i nfected pa ti ents , pa rti cul a rl y i n the ca ta rrha l a nd
ea rl y pa roxys ma l s ta ges , ca us es di s ea s e i n 90 to 100% of cl os e conta cts . Tra ns mi s s i on by conta ct wi th conta mi na ted a rti cl es i s ra re. Pa ti ents a re
us ua l l y not i nfecti ous a fter the 3rd wk of the pa roxys ma l pha s e.
Diseases caused by pertussis: Res pi ra tory compl i ca ti ons , i ncl udi ng a s phyxi a i n i nfa nts , a re mos t common. Oti ti s medi a occurs frequentl y.
Bronchopneumoni a (common a mong the el derl y) ma y be fa ta l a t a ny a ge. Sei zures a re common a mong i nfa nts but ra re i n ol der chi l dren.
Hemorrha ge i nto the bra i n, eyes , s ki n, a nd mucous membra nes ca n res ul t from s evere pa roxys ms a nd cons equent a noxi a . Cerebra l hemorrha ge,
cerebra l edema , a nd toxi c encepha l i ti s ma y res ul t i n s pa s ti c pa ra l ys i s , i ntel l ectua l di s a bi l i ty (menta l reta rda ti on), or other neurol ogi c di s orders .
Umbi l i ca l herni a ti on a nd recta l prol a ps e occa s i ona l l y occur.
Parapertussis: Thi s di s ea s e, ca us ed by B. parapertussis, ma y be cl i ni ca l l y i ndi s ti ngui s ha bl e from pertus s i s but i s us ua l l y mi l der a nd l es s often fa ta l .
Symptoms and Signs
The i ncuba ti on peri od a vera ges 7 to 14 da ys (ma xi mum 3 wk). B. pertussis i nva des res pi ra tory mucos a , i ncrea s i ng the s ecreti on of mucus , whi ch i s
i ni ti a l l y thi n a nd l a ter vi s ci d a nd tena ci ous . Uncompl i ca ted di s ea s e l a s ts a bout 6 to 10 wk a nd cons i s ts of 3 s ta ges :
Ca ta rrha l
Pa roxys ma l
Conva l es cent
The ca ta rrha l s ta ge begi ns i ns i di ous l y, genera l l y wi th s neezi ng, l a cri ma ti on, or other s i gns of coryza ; a norexi a ; l i s tl es s nes s ; a nd a troubl es ome,
ha cki ng nocturna l cough tha t gra dua l l y becomes di urna l . Hoa rs enes s ma y occur. Fever i s ra re.
After 10 to 14 da ys , the pa roxys ma l s ta ge begi ns wi th a n i ncrea s e i n the s everi ty a nd frequency of the cough. Repea ted bouts of 5 ra pi dl y
cons ecuti ve forceful coughs occur duri ng a s i ngl e expi ra ti on a nd a re fol l owed by the whoopa hurri ed, deep i ns pi ra ti on. Copi ous vi s ci d mucus
ma y be expel l ed or bubbl e from the na res duri ng or a fter the pa roxys ms . Vomi ti ng i s cha ra cteri s ti c. In i nfa nts , choki ng s pel l s (wi th or wi thout
cya nos i s ) ma y be more common tha n whoops .
Symptoms di mi ni s h a s the conva l es cent s ta ge begi ns , us ua l l y wi thi n 4 wk of ons et. Avera ge dura ti on of i l l nes s i s a bout 7 wk (ra nge 3 wk to 3 mo).
Pa roxys ma l coughi ng ma y recur for months , us ua l l y i nduced i n the s ti l l s ens i ti ve res pi ra tory tra ct by i rri ta ti on from a URI.
Diagnosis
Na s opha ryngea l cul tures
The ca ta rrha l s ta ge i s often di ffi cul t to di s ti ngui s h from bronchi ti s or i nfl uenza . Adenovi rus i nfecti ons a nd TB s houl d a l s o be cons i dered.
Cul tures of na s opha ryngea l s peci mens a re pos i ti ve for B. pertussis i n 80 to 90% of ca s es i n the ca ta rrha l a nd ea rl y pa roxys ma l s ta ges . Beca us e
s peci a l medi a a nd prol onged i ncuba ti on a re requi red, the l a bora tory s houl d be noti fi ed tha t pertus s i s i s s us pected. Speci fi c fl uores cent a nti body
tes ti ng of na s opha ryngea l s mea rs a ccura tel y di a gnos es pertus s i s but i s not a s s ens i ti ve a s cul ture. PCR ca n a l s o be us ed. The WBC count i s
us ua l l y between 15,000 a nd 20,000/L but ma y be norma l or a s hi gh a s 60,000/L, us ua l l y wi th 60 to 80% s ma l l l ymphocytes .
Pa ra pertus s i s i s di fferenti a ted by cul ture or the fl uores cent a nti body techni que.
Treatment
Supporti ve ca re
Erythromyci n or a zi thromyci n
Hos pi ta l i za ti on wi th res pi ra tory i s ol a ti on i s recommended for s eri ous l y i l l i nfa nts . Is ol a ti on i s conti nued unti l a nti bi oti cs ha ve been gi ven for 5
da ys .
In i nfa nts , s ucti on to remove exces s mucus from the throa t ma y be l i fes a vi ng. O2 a nd tra cheos tomy or na s otra chea l i ntuba ti on i s occa s i ona l l y
needed. Expectora nts , cough s uppres s a nts , a nd mi l d s eda ti on a re of l i ttl e va l ue. Beca us e a ny di s turba nce ca n preci pi ta te s eri ous pa roxys ma l
coughi ng wi th a noxi a , s eri ous l y i l l i nfa nts s houl d be kept i n a da rkened, qui et room a nd di s turbed a s l i ttl e a s pos s i bl e. Pa ti ents trea ted a t home
s houl d be qua ra nti ned, pa rti cul a rl y from s us cepti bl e i nfa nts , for a t l ea s t 4 wk from di s ea s e ons et a nd unti l s ymptoms ha ve s ubs i ded.
Anti bi oti cs gi ven duri ng the ca ta rrha l s ta ge ma y a mel i ora te the di s ea s e. After pa roxys ms a re es ta bl i s hed, a nti bi oti cs us ua l l y ha ve no cl i ni ca l
effect but a re recommended to l i mi t s prea d. Preferred drugs a re erythromyci n 10 to 12.5 mg/kg po q 6 h (ma xi mum 2 g/da y) for 14 da ys or
a zi thromyci n 10 to 12 mg/kg po once/da y for 5 da ys . Anti bi oti cs s houl d a l s o be us ed for ba cteri a l compl i ca ti ons (eg, bronchopneumoni a , oti ti s
medi a ).
Prevention
Acti ve i mmuni za ti on i s pa rt of s ta nda rd chi l dhood va cci na ti on. Fi ve dos es of va cci ne a re gi ven (us ua l l y combi ned wi th di phtheri a a nd teta nus [DTP
or DTa P]) a t a ge 2, 4, a nd 6 mo; boos ters a re gi ven a t 15 to 18 mo a nd 4 to 6 yr. Si gni fi ca nt a dvers e effects from the pertus s i s component of the
va cci ne i ncl ude encepha l opa thy wi thi n 7 da ys ; s ei zure, wi th or wi thout fever, wi thi n 3 da ys ; pers i s tent, s evere, i ncons ol a bl e s crea mi ng or cryi ng for
3 h; col l a ps e or s hock wi thi n 48 h; fever 40.5 C wi thi n 48 h; a nd i mmedi a te s evere or a na phyl a cti c rea cti on. Thes e rea cti ons contra i ndi ca te
further us e of pertus s i s va cci ne; combi ned di phtheri a a nd teta nus va cci ne i s a va i l a bl e wi thout the pertus s i s component. The a cel l ul a r va cci ne
(DTa P) i s better tol era ted.
Immuni ty a fter na tura l i nfecti on l a s ts a bout 20 yr. Pa s s i ve i mmuni za ti on i s unrel i a bl e a nd i s not recommended.
Cl os e conta cts < 7 yr who ha ve ha d < 4 dos es of va cci ne s houl d be va cci na ted. Conta cts of a l l a ges , whether va cci na ted or not, s houl d recei ve a 10da y cours e of erythromyci n 500 mg po qi d or 10 to 12.5 mg/kg po qi d.
Plague and Other Yersinia Infections
(Buboni c Pl a gue; Pes ti s ; Bl a ck Dea th)
Plague is caused by Yersinia pestis. Symptoms are either severe pneumonia or massive lymphadenopathy with high fever, often progressing to septicemia.
Diagnosis is epidemiologic and clinical, confirmed by culture and serologic testing. Treatment is with streptomycin or doxycycline.
Yersinia (formerl y Pasteurella) pestis i s a s hort ba ci l l us tha t often s hows bi pol a r s ta i ni ng (es peci a l l y wi th Gi ems a s ta i n) a nd ma y res embl e a s a fety
pi n.
Pl a gue occurs pri ma ri l y i n wi l d rodents (eg, ra ts , mi ce, s qui rrel s , pra i ri e dogs ) a nd i s tra ns mi tted from rodent to huma n by the bi te of a n i nfected
ra t fl ea vector. Huma n-to-huma n tra ns mi s s i on occurs by i nha l i ng dropl et nucl ei from pa ti ents wi th pul mona ry i nfecti on (pri ma ry pneumoni c
pl a gue), whi ch i s hi ghl y conta gi ous . In endemi c a rea s i n the US, s evera l ca s es ma y ha ve been ca us ed by hous ehol d pets , es peci a l l y ca ts .
Tra ns mi s s i on from ca ts ca n be by bi te or, i f the ca t ha s pneumoni c pl a gue, by i nha l a ti on of i nfected dropl ets .
Ma s s i ve huma n epi demi cs (eg, the Bl a ck Dea th of the Mi ddl e Ages ) ha ve occurred. More recentl y, pl a gue ha s occurred s pora di ca l l y or i n l i mi ted
outbrea ks . In the US, > 90% of huma n pl a gue occurs i n the Southwes t, es peci a l l y New Mexi co, Ari zona , Ca l i forni a , a nd Col ora do. Yersinia i s
cons i dered a pos s i bl e a gent of bi oterrori s m.
Symptoms and Signs
In bubonic plague, the mos t common form, the i ncuba ti on peri od i s us ua l l y 2 to 5 da ys but va ri es from a few hours to 12 da ys . Ons et of fever of 39.5
to 41 C i s a brupt, often wi th chi l l s . The pul s e ma y be ra pi d a nd threa dy; hypotens i on ma y occur. Enl a rged l ymph nodes (buboes ) a ppea r wi th or
s hortl y a fter the fever. The femora l or i ngui na l l ymph nodes a re mos t commonl y i nvol ved, fol l owed by a xi l l a ry, cervi ca l , or mul ti pl e nodes .
Typi ca l l y, the nodes a re extremel y tender a nd fi rm, s urrounded by cons i dera bl e edema . They ma y s uppura te i n the 2nd wk. The overl yi ng s ki n i s
s mooth a nd reddened but often not wa rm. A pri ma ry cuta neous l es i on, va ryi ng from a s ma l l ves i cl e wi th s l i ght l oca l l ympha ngi ti s to a n es cha r,
occa s i ona l l y a ppea rs a t the bi te. The pa ti ent ma y be res tl es s , del i ri ous , confus ed, a nd uncoordi na ted. The l i ver a nd s pl een ma y be enl a rged.
Buboni c pl a gue ma y be compl i ca ted by pneumoni c pl a gue.
Primary pneumonic plague ha s a 2- to 3-da y i ncuba ti on peri od, fol l owed by a brupt ons et of hi gh fever, chi l l s , ta chyca rdi a , ches t pa i n, a nd hea da che,
often s evere. Cough, not promi nent i ni ti a l l y, devel ops wi thi n 24 h. Sputum i s mucoi d a t fi rs t, ra pi dl y devel ops bl ood s pecks , a nd then becomes
uni forml y pi nk or bri ght red (res embl i ng ra s pberry s yrup) a nd foa my. Ta chypnea a nd dys pnea a re pres ent, but pl euri ti c ches t pa i n i s not. Si gns of
cons ol i da ti on a re ra re, a nd ra l es ma y be a bs ent.
Septicemic plague ma y occur wi th the buboni c form or wi thout the buboni c form (ca l l ed pri ma ry s epti cemi c pl a gue) a s a n a cute, ful mi na nt i l l nes s .
Abdomi na l pa i n, pres uma bl y due to mes enteri c l ympha denopa thy, occurs i n 40% of pa ti ents . Di s s emi na ted i ntra va s cul a r coa gul opa thy, ga ngrene
of the extremi ti es (hence, the na me Bl a ck Dea th), a nd mul ti orga n fa i l ure eventua l l y devel op. Pha ryngea l pl a gue a nd pl a gue meni ngi ti s a re l es s
common forms .
Pestis minor, a more beni gn form of buboni c pl a gue, us ua l l y occurs onl y i n endemi c a rea s . Lympha deni ti s , fever, hea da che, a nd pros tra ti on s ubs i de
wi thi n a week.
The morta l i ty ra te for untrea ted pa ti ents wi th buboni c pl a gue i s a bout 60%; mos t dea ths res ul t from s epti cemi a i n 3 to 5 da ys . Mos t untrea ted
pa ti ents wi th pneumoni c pl a gue di e wi thi n 48 h of s ymptom ons et. Septi cemi c pl a gue ma y be fa ta l before buboni c or pul mona ry ma ni fes ta ti ons
predomi na te.
Diagnosis
Sta i ni ng, cul tures , a nd s erol ogi c tes ti ng
Di a gnos i s i s ma de by s ta i n a nd cul ture of the orga ni s m, typi ca l l y by needl e a s pi ra ti on of a bubo (s urgi ca l dra i na ge ma y di s s emi na te the
orga ni s m); bl ood a nd s putum cul tures s houl d a l s o be obta i ned. Other tes ts i ncl ude i mmunofl uores cent s ta i ni ng a nd s erol ogy; a ti ter of > 1:16 or a
4-fol d ri s e between a cute a nd conva l es cent ti ters i s pos i ti ve. PCR tes ti ng, i f a va i l a bl e, i s di a gnos ti c. Pri or va cci na ti on does not excl ude pl a gue;
cl i ni ca l i l l nes s ma y occur i n va cci na ted peopl e.
Pa ti ents wi th pul mona ry s ymptoms or s i gns s houl d ha ve a ches t x-ra y, whi ch s hows a ra pi dl y progres s i ng pneumoni a i n pneumoni c pl a gue. The
WBC count i s us ua l l y 10,000 to 20,000/L wi th numerous i mma ture neutrophi l s .
Treatment
Streptomyci n
Al terna ti vel y, doxycycl i ne, genta mi ci n, or chl ora mpheni col
Immedi a te trea tment reduces morta l i ty to < 5%. In s epti cemi c or pneumoni c pl a gue, trea tment mus t begi n wi thi n 24 h wi th s treptomyci n 15 mg/kg
(up to 1 g) IM bi d for 10 da ys or unti l 3 da ys a fter tempera ture ha s returned to norma l . Doxycycl i ne 100 mg IV or po q 12 h i s a n a l terna ti ve.
Genta mi ci n a nd chl ora mpheni col a re a l s o effecti ve.
Chl ora mpheni col i s preferred for pa ti ents wi th i nfecti on of ti s s ue s pa ces i nto whi ch other drugs pa s s poorl y (eg, pl a gue meni ngi ti s ,
endophtha l mi ti s ). Chl ora mpheni col s houl d be gi ven i n a l oa di ng dos e of 25 mg/kg IV, fol l owed by 12.5 mg/kg IV or po q 6 h.
Routi ne i s ol a ti on preca uti ons a re a dequa te for pa ti ents wi th buboni c pl a gue. Thos e wi th pri ma ry or s econda ry pneumoni c pl a gue requi re s tri ct
res pi ra tory i s ol a ti on.
Prevention
Al l pneumoni c pl a gue conta cts s houl d be under medi ca l s urvei l l a nce. Tempera ture s houl d be ta ken q 4 h for 6 da ys . They a nd others i n cl os e
conta ct wi th pl a gue pa ti ents or wi th conta mi na ted fl ui ds or ti s s ue s houl d recei ve prophyl a xi s wi th doxycycl i ne 100 mg po q 12 h (for chi l dren < 8 yr,
tri methopri m/s ul fa methoxa zol e [TMP/SMX] 20 mg/kg [of the SMX component] q 12 h). Tra vel ers s houl d be gi ven prophyl a xi s wi th doxycycl i ne 100 mg
po q 12 h duri ng expos ure peri ods . Pl a gue va cci ne i s a va i l a bl e but i s recommended ma i nl y for l a bora tory workers a nd res ea rchers beca us e
i mmuni ty requi res a bout 1 mo to devel op.
Rodents s houl d be control l ed a nd repel l ents us ed to mi ni mi ze fl ea bi tes .
Other Yersinia Infections
Yersinia enterocolitica a nd Y. pseudotuberculosis a re zoonos es a cqui red by i nges ti on of conta mi na ted food or wa ter; they occur worl dwi de.
Y. enterocolitica i s a common ca us e of di a rrhea l di s ea s e a nd mes enteri c a deni ti s tha t cl i ni ca l l y mi mi cs a ppendi ci ti s . Y. pseudotuberculosis mos t
commonl y ca us es mes enteri c a deni ti s a nd ha s been s us pected i n ca s es of i nters ti ti a l nephri ti s , hemol yti c-uremi c s yndrome, a nd a s ca rl et feverl i ke i l l nes s . Both s peci es ca n ca us e pha ryngi ti s , s epti cemi a , foca l i nfecti ons i n mul ti pl e orga ns , pos ti nfecti ous erythema nodos um, a nd rea cti ve
a rthri ti s . In pa ti ents wi th chroni c l i ver di s ea s e or i ron overl oa d, morta l i ty from s epti cemi a ma y be a s hi gh a s 50%, even wi th trea tment.
The orga ni s ms ca n be i denti fi ed i n s ta nda rd cul tures from norma l l y s teri l e s i tes . Sel ecti ve cul ture methods a re requi red for nons teri l e s peci mens .
Serol ogi c a s s a ys a re a va i l a bl e but di ffi cul t a nd not s ta nda rdi zed. Di a gnos i s , pa rti cul a rl y of rea cti ve a rthri ti s , requi res a hi gh i ndex of s us pi ci on
a nd cl os e communi ca ti on wi th the cl i ni ca l l a bora tory.
Trea tment of di a rrhea i s s upporti ve beca us e the di s ea s e i s s el f-l i mi ted. Septi c compl i ca ti ons requi re -l a cta ma s e-res i s ta nt a nti bi oti cs gui ded by
s us cepti bi l i ty tes ti ng.
Preventi on focus es on food ha ndl i ng a nd prepa ra ti on, hous ehol d pets , a nd epi demi ol ogy of s us pected outbrea ks .
Proteeae Infections
The Proteeae are normal fecal flora that often cause infection in patients whose normal flora have been disturbed by antibiotic therapy.
The Proteea e cons ti tute a t l ea s t 3 genera of gra m-nega ti ve orga ni s ms :
Proteus: P. mirabilis, P. vulgaris, a nd P. myxofaciens
Morganella: M. morganii
Providencia: P. rettgeri, P. alcalifaciens, a nd P. stuartii
However, P. mirabilis ca us es mos t huma n i nfecti ons . Thes e orga ni s ms a re norma l feca l fl ora a nd a re pres ent i n s oi l a nd wa ter. They a re often
pres ent i n s uperfi ci a l wounds , dra i ni ng ea rs , a nd s putum, pa rti cul a rl y i n pa ti ents whos e norma l fl ora ha s been era di ca ted by a nti bi oti c thera py.
They ma y ca us e ba cteremi a a nd deep-s ea ted i nfecti ons , pa rti cul a rl y i n the ea rs a nd ma s toi d s i nus es , peri tonea l ca vi ty, a nd uri na ry tra ct of
pa ti ents wi th chroni c UTIs or wi th rena l or bl a dder s tones .
P. mirabilis i s often s ens i ti ve to a mpi ci l l i n, ca rbeni ci l l i n, ti ca rci l l i n, pi pera ci l l i n, cepha l os pori ns , a nd a mi nogl ycos i des a nd res i s ta nt to
tetra cycl i nes . Mul ti drug-res i s ta nt P. mirabilis i s a n emergi ng probl em. Indol e-pos i ti ve s peci es (P. vulgaris, M. morganii, P. rettgeri) tend to be more
res i s ta nt but genera l l y a re s ens i ti ve to fl uoroqui nol ones , ca rba penems , pi pera ci l l i n/ta zoba cta m, 3rd-genera ti on cepha l os pori ns , a nd cefi xi me.
Pseudomonas and Related Infections

Pseudomonas aeruginosa and other members of this group of gram-negative bacilli are opportunistic pathogens that frequently cause hospital-acquired
infections, particularly in ventilator patients, burn patients, and patients with chronic debility. Many sites can be infected, and infection is usually severe.
Diagnosis is by culture. Antibiotic choice varies with the pathogen and must be guided by susceptibility testing because resistance is common.
Epidemiology
Pseudomonas i s ubi qui tous a nd fa vors moi s t envi ronments . In huma ns , P. aeruginosa i s the mos t common pa thogen, but i nfecti on ma y res ul t from P.
paucimobilis, P. putida, P. fluorescens, or P. acidovorans. Other i mporta nt hos pi ta l -a cqui red pa thogens formerl y cl a s s i fi ed a s Pseudomonas i ncl ude
Burkholderia cepacia a nd Stenotrophomonas maltophilia. B. pseudomallei ca us es a di s ti nct di s ea s e known a s mel i oi dos i s tha t i s l i mi ted mos tl y to the
As i a n tropi cs (s ee p. 1254).
P. aeruginosa i s pres ent occa s i ona l l y i n the a xi l l a a nd a nogeni ta l a rea s of norma l s ki n but ra rel y i n s tool unl es s a nti bi oti cs a re bei ng gi ven. In
hos pi ta l s , the orga ni s m i s frequentl y pres ent i n s i nks , a nti s epti c s ol uti ons , a nd uri ne recepta cl es . Tra ns mi s s i on to pa ti ents by hea l th ca re
pra cti ti oners ma y occur, es peci a l l y i n burn a nd neona ta l ICUs , unl es s i nfecti on control pra cti ces a re meti cul ous l y fol l owed.
Diseases Caused by Pseudomonas
Mos t P. aeruginosa i nfecti ons occur i n hos pi ta l i zed pa ti ents , pa rti cul a rl y thos e who a re debi l i ta ted or i mmunocompromi s ed. P. aeruginosa i s a
common ca us e of i nfecti ons i n ICUs . HIV-i nfected pa ti ents , pa rti cul a rl y thos e i n a dva nced s ta ges , a re a t ri s k of communi ty-a cqui red P. aeruginosa
i nfecti ons .
Pseudomonas i nfecti ons ca n devel op i n ma ny a na tomi c s i tes , i ncl udi ng s ki n, s ubcuta neous ti s s ue, bone, ea rs , eyes , uri na ry tra ct, a nd hea rt va l ves .
The s i te va ri es wi th the porta l of entry a nd the pa ti ent's vul nera bi l i ty. In hos pi ta l i zed pa ti ents , the fi rs t s i gn ma y be overwhel mi ng gra m-nega ti ve
s eps i s .
Skin and soft-tissue infections: In burns , the regi on bel ow the es cha r ca n become hea vi l y i nfi l tra ted wi th orga ni s ms , s ervi ng a s a focus for
s ubs equent ba cteremi a a n often l etha l compl i ca ti on.
Deep puncture wounds of the foot a re often i nfected by P. aeruginosa. Dra i ni ng s i nus es , cel l ul i ti s , a nd os teomyel i ti s ma y res ul t. Dra i na ge from
puncture wounds often ha s a s weet, frui ty s mel l .
Fol l i cul i ti s a cqui red i n hot tubs i s often ca us ed by P. aeruginosa.
Externa l oti ti s , common i n tropi ca l cl i ma tes , i s the mos t common form of Pseudomonas i nfecti on i nvol vi ng the ea r. A more s evere form, referred to
a s ma l i gna nt externa l oti ti s (s ee p. 455), ca n devel op i n di a beti c pa ti ents . It i s ma ni fes ted by s evere ea r pa i n, often wi th uni l a tera l cra ni a l nerve
pa l s i es , a nd requi res pa rentera l thera py.
Ecthyma ga ngrenos um i s a s ki n l es i on tha t occurs i n neutropeni c pa ti ents a nd i s us ua l l y ca us ed by P. aeruginosa. It i s cha ra cteri zed by
erythema tous , centra l l y ul cera ted, purpl ebl a ck a rea s a bout 1 cm i n di a meter occurri ng mos t often i n the a xi l l a ry, i ngui na l , or a nogeni ta l a rea s .
Respiratory tract infections: P. aeruginosa i s a frequent ca us e of venti l a tor-a s s oci a ted pneumoni a . In HIV-i nfected pa ti ents , Pseudomonas mos t
commonl y ca us es pneumoni a or s i nus i ti s . Pseudomonas bronchi ti s i s common l a te i n the cours e of cys ti c fi bros i s . Is ol a tes from pa ti ents wi th cys ti c
fi bros i s ha ve a cha ra cteri s ti c mucoi d col oni a l morphol ogy.
Other infections: Pseudomonas i s a common ca us e of nos ocomi a l UTI, es peci a l l y i n pa ti ents who ha ve ha d urol ogi c ma ni pul a ti on or obs tructi ve
uropa thy. Pseudomonas commonl y col oni zes the uri na ry tra ct i n ca theteri zed pa ti ents , es peci a l l y thos e who ha ve recei ved broa d-s pectrum
a nti bi oti cs .
Ocul a r i nvol vement genera l l y ma ni fes ts a s cornea l ul cera ti on, mos t often a fter tra uma , but conta mi na ti on of conta ct l ens es or l ens fl ui d ha s been
i mpl i ca ted i n s ome ca s es .
Ra rel y, Pseudomonas ca us es a cute ba cteri a l endoca rdi ti s , us ua l l y on pros theti c va l ves i n pa ti ents who ha ve ha d open-hea rt s urgery or on na tura l
va l ves i n IV drug a bus ers .
Bacteremia: Ma ny Pseudomonas i nfecti ons ca n ca us e ba cteremi a . In noni ntuba ted pa ti ents wi thout a detecta bl e uri na ry focus , es peci a l l y i f
i nfecti on i s due to a s peci es other tha n P. aeruginosa, ba cteremi a s ugges ts conta mi na ted IV fl ui ds , drugs , or a nti s epti cs us ed i n pl a ci ng the IV
ca theter.
Diagnosis
Cul ture
Di a gnos i s depends on cul turi ng the orga ni s m from the s i te of i nfecti on: bl ood, s ki n l es i ons , dra i na ge fl ui d, uri ne, CSF, or eye. Loca l i zed i nfecti on
ma y produce a frui ty s mel l , a nd pus ma y be greeni s h.
Treatment
Va ri ous a nti bi oti cs dependi ng on s i te a nd s everi ty of i nfecti on a nd s us cepti bi l i ty tes ti ng
Localized infection: Hot-tub fol l i cul i ti s res ol ves s ponta neous l y a nd does not requi re a nti bi oti c thera py.
Externa l oti ti s i s trea ted wi th 1% a ceti c a ci d i rri ga ti ons or topi ca l drugs s uch a s pol ymyxi n B or col i s ti n. More s evere i nfecti on i s trea ted wi th
fl uoroqui nol ones .

Foca l s oft-ti s s ue i nfecti on ma y requi re ea rl y s urgi ca l debri dement of necroti c ti s s ue a nd dra i na ge of a bs ces s es i n a ddi ti on to a nti bi oti cs .
Sma l l cornea l ul cers a re trea ted wi th ci profl oxa ci n 0.3% or l evofl oxa ci n 0.5%. Forti fi ed (hi gher tha n s tock concentra ti on) a nti bi oti c drops , s uch a s
tobra myci n 15 mg/mL, a re us ed for more s i gni fi ca nt ul cers . Frequent dos i ng (eg, q 1 h a round the cl ock) i s neces s a ry i ni ti a l l y. Eye pa tchi ng i s
contra i ndi ca ted beca us e i t produces a da rk wa rm envi ronment tha t fa vors ba cteri a l growth a nd prevents a dmi ni s tra ti on of topi ca l drugs .
As ymptoma ti c ba cteri uri a i s not trea ted wi th a nti bi oti cs , except duri ng pregna ncy a nd before urol ogi c ma ni pul a ti on. Pa ti ents wi th s ymptoma ti c
UTIs ca n often be trea ted wi th l evofl oxa ci n 500 mg po once/da y or ci profl oxa ci n 400 mg po bi d.
Systemic infection: Pa rentera l thera py i s requi red, typi ca l l y wi th a n a mi nogl ycos i de pl us a n a nti ps eudomona l -l a cta m, a n a nti -ps eudomona l
cepha l os pori n (eg, cefepi me, cefopera zone), or the ca rba penems meropenem or i mi penem.
Ri ght-s i ded endoca rdi ti s ca n be trea ted wi th a nti bi oti cs , but us ua l l y the i nfected va l ve mus t be removed to cure a n i nfecti on i nvol vi ng the mi tra l ,
a orti c, or pros theti c va l ve.
In neutropeni c pa ti ents wi th ma rgi na l rena l functi on, nona mi nogl ycos i de combi na ti ons , s uch a s doubl e -l a cta ms or a -l a cta m pl us a
fl uoroqui nol one, a re a l s o s a ti s fa ctory.
P. aeruginosa res i s ta nce ma y occur a mong pa ti ents trea ted wi th cefta zi di me, ci profl oxa ci n, genta mi ci n, meropenem, or i mi penem.
Salmonella Infections
The 2200 known s erotypes of Salmonella ma y be grouped i nto
Thos e hi ghl y a da pted to huma n hos ts : Thi s group i ncl udes S. typhi a nd S. paratyphi types A, B (a l s o ca l l ed S. schottmulleri), a nd C (a l s o ca l l ed S.
hirschfeldii), whi ch a re pa thogeni c onl y i n huma ns a nd commonl y ca us e enteri c (typhoi d) fever.
Thos e a da pted to nonhuma n hos ts or ca us i ng di s ea s e a l mos t excl us i vel y i n a ni ma l s . Two s tra i ns wi thi n thi s group, S. dublin a nd S. choleraesuis,
a l s o ca us e di s ea s e i n huma ns .
Thos e una da pted to s peci fi c hos ts : Thi s group, des i gna ted S. enteritidis, i ncl udes > 2000 s erotypes tha t ca us e ga s troenteri ti s a nd a ccounts for 85%
of a l l Salmonella i nfecti ons i n the US.
Typhoid Fever
Typhoid fever is a systemic disease caused by Salmonella typhi. Symptoms are high fever, prostration, abdominal pain, and a rose-colored rash. Diagnosis is
clinical and confirmed by culture. Treatment is with ceftriaxone or ciprofloxacin.
Epidemiology
About 400 to 500 ca s es of typhoi d fever a re reported a nnua l l y i n the US, ma i nl y a mong US tra vel ers returni ng from endemi c regi ons . Typhoi d ba ci l l i
a re s hed i n s tool of a s ymptoma ti c ca rri ers or i n s tool or uri ne of peopl e wi th a cti ve di s ea s e. Ina dequa te hygi ene a fter defeca ti on ma y s prea d S.
typhi to communi ty food or wa ter s uppl i es . In endemi c a rea s where s a ni ta ry mea s ures a re genera l l y i na dequa te, S. typhi i s tra ns mi tted more
frequentl y by wa ter tha n by food. In devel oped countri es , tra ns mi s s i on i s chi efl y by food tha t ha s been conta mi na ted duri ng prepa ra ti on by
hea l thy ca rri ers . Fl i es ma y s prea d the orga ni s m from feces to food. Occa s i ona l tra ns mi s s i on by di rect conta ct (feca l -ora l route) ma y occur i n
chi l dren duri ng pl a y a nd i n a dul ts duri ng s exua l pra cti ces . Ra rel y, hos pi ta l pers onnel who ha ve not ta ken a dequa te enteri c preca uti ons ha ve
a cqui red the di s ea s e when cha ngi ng s oi l ed bedcl othes .
The orga ni s m enters the body vi a the GI tra ct a nd ga i ns a cces s to the bl oods trea m vi a the l ympha ti c cha nnel s . Intes ti na l ul cera ti on, hemorrha ge,
a nd perfora ti on ma y occur i n s evere ca s es .
Carrier state: About 3% of untrea ted pa ti ents , referred to a s chroni c enteri c ca rri ers , ha rbor orga ni s ms i n thei r ga l l bl a dder a nd s hed them i n s tool
for > 1 yr. Some ca rri ers ha ve no hi s tory of cl i ni ca l i l l nes s . Mos t of the es ti ma ted 2000 ca rri ers i n the US a re el derl y women wi th chroni c bi l i a ry
di s ea s e. Obs tructi ve uropa thy rel a ted to s chi s tos omi a s i s ma y predi s pos e certa i n typhoi d pa ti ents to uri na ry ca rri a ge. Epi demi ol ogi c da ta i ndi ca te
tha t typhoi d ca rri ers a re more l i kel y tha n the genera l popul a ti on to devel op hepa tobi l i a ry ca ncer.
Symptoms and Signs
The i ncuba ti on peri od (us ua l l y 8 to 14 da ys ) i s i nvers el y rel a ted to the number of orga ni s ms i nges ted. Ons et i s us ua l l y gra dua l , wi th fever,
hea da che, a rthra l gi a , pha ryngi ti s , cons ti pa ti on, a norexi a , a nd a bdomi na l pa i n a nd tendernes s . Les s common s ymptoms i ncl ude dys uri a ,
nonproducti ve cough, a nd epi s ta xi s .
Wi thout trea tment, the tempera ture ri s es i n s teps over 2 to 3 da ys , rema i ns el eva ted (us ua l l y 39.4 to 40C) for a nother 10 to 14 da ys , begi ns to fa l l
gra dua l l y a t the end of the 3rd wk, a nd rea ches norma l l evel s duri ng the 4th wk. Prol onged fever i s often a ccompa ni ed by rel a ti ve bra dyca rdi a a nd
pros tra ti on. CNS s ymptoms s uch a s del i ri um, s tupor, or coma occur i n s evere ca s es . In a bout 10% of pa ti ents , di s crete pi nk, bl a nchi ng l es i ons (ros e
s pots ) a ppea r i n crops on the ches t a nd a bdomen duri ng the 2nd wk a nd res ol ve i n 2 to 5 da ys . Spl enomega l y, l eukopeni a , a nemi a , l i ver functi on
a bnorma l i ti es , protei nuri a , a nd a mi l d cons umpti on coa gul opa thy a re common. Acute chol ecys ti ti s a nd hepa ti ti s ma y occur.
La te i n the di s ea s e, when i ntes ti na l l es i ons a re mos t promi nent, fl ori d di a rrhea ma y occur, a nd the s tool ma y conta i n bl ood (occul t i n 20% of
pa ti ents , gros s i n 10%). In a bout 2% of pa ti ents , s evere bl eedi ng occurs duri ng the 3rd wk, wi th a morta l i ty ra te of a bout 25%. An a cute a bdomen
a nd l eukocytos i s duri ng the 3rd wk ma y s ugges t i ntes ti na l perfora ti on, whi ch us ua l l y i nvol ves the di s ta l i l eum a nd occurs i n 1 to 2% of pa ti ents .
Pneumoni a ma y devel op duri ng the 2nd or 3rd wk a nd ma y be due to s econda ry pneumococca l i nfecti on, a l though S. typhi ca n a l s o ca us e
pul mona ry i nfi l tra tes . Ba cteremi a occa s i ona l l y l ea ds to foca l i nfecti ons s uch a s os teomyel i ti s , endoca rdi ti s , meni ngi ti s , s oft-ti s s ue a bs ces s es ,
gl omerul i ti s , or GU tra ct i nvol vement. Atypi ca l pres enta ti ons , s uch a s pneumoni ti s , fever onl y, or, very ra rel y, s ymptoms cons i s tent wi th UTI, ma y
del a y di a gnos i s . Conva l es cence ma y l a s t s evera l months .
In 8 to 10% of untrea ted pa ti ents , s ymptoms a nd s i gns s i mi l a r to the i ni ti a l cl i ni ca l s yndrome recur a bout 2 wk a fter deferves cence. For uncl ea r
rea s ons , a nti bi oti c thera py duri ng the i ni ti a l i l l nes s i ncrea s es the i nci dence of febri l e rel a ps e to 15 to 20%. If a nti bi oti cs a re res ta rted a t the ti me
of rel a ps e, the fever a ba tes ra pi dl y, unl i ke the s l ow deferves cence tha t occurs duri ng the pri ma ry i l l nes s . Occa s i ona l l y, a 2nd rel a ps e occurs .
Diagnosis
Cul tures
Other i nfecti ons ca us i ng a s i mi l a r pres enta ti on i ncl ude other Salmonella i nfecti ons , the ma jor ri cketts i os es , l eptos pi ros i s , di s s emi na ted TB,
ma l a ri a , brucel l os i s , tul a remi a , i nfecti ous hepa ti ti s , ps i tta cos i s , Yersinia enterocolitica i nfecti on, a nd l ymphoma . Ea rl y i n i ts cl i ni ca l cours e, typhoi d
fever ma y res embl e ma l a ri a .
Cul tures of bl ood, s tool , a nd uri ne s houl d be obta i ned. Bl ood cul tures a re us ua l l y pos i ti ve onl y duri ng the fi rs t 2 wk of i l l nes s , but s tool cul tures
a re us ua l l y pos i ti ve duri ng the 3rd to 5th wk. If thes e cul tures a re nega ti ve a nd typhoi d fever i s s trongl y s us pected, cul ture from a bone ma rrow
bi ops y s peci men ma y revea l the orga ni s m.
Typhoi d ba ci l l i conta i n a nti gens (O a nd H) tha t s ti mul a te the hos t to form corres pondi ng a nti bodi es . A 4-fol d ri s e i n O a nd H a nti body ti ters i n
pa i red s peci mens obta i ned 2 wk a pa rt s ugges ts S. typhi i nfecti on. However, thi s tes t i s onl y modera tel y (70%) s ens i ti ve a nd l a cks s peci fi ci ty; ma ny
nontyphoi da l Salmonella s tra i ns cros s -rea ct, a nd l i ver ci rrhos i s ca us es fa l s e-pos i ti ves .
Prognosis
Wi thout a nti bi oti cs , the morta l i ty ra te i s a bout 12%. Wi th prompt thera py, the morta l i ty ra te i s 1%. Mos t dea ths occur i n ma l nouri s hed peopl e,
i nfa nts , a nd the el derl y. Stupor, coma , or s hock refl ects s evere di s ea s e a nd a poor prognos i s . Compl i ca ti ons occur ma i nl y i n pa ti ents who a re
untrea ted or i n whom trea tment i s del a yed.
Treatment
Ceftri a xone
Someti mes a fl uoroqui nol one
Preferred a nti bi oti cs i ncl ude ceftri a xone 1 g IM or IV q 12 h (25 to 37.5 mg/kg i n chi l dren) for 14 da ys a nd va ri ous fl uoroqui nol ones (eg, ci profl oxa ci n
500 mg po bi d for 10 to 14 da ys , l evofl oxa ci n 500 mg po or IV once/da y for 14 da ys , moxi fl oxa ci n 400 mg po or IV once/da y for 14 da ys ).
Chl ora mpheni col 500 mg po or IV q 6 h i s s ti l l wi del y us ed, but res i s ta nce i s i ncrea s i ng. Fl uoroqui nol ones ma y be us ed i n chi l dren. Al terna ti ve
thera pi es , dependi ng on i n vi tro s ens i ti vi ty, i ncl ude a moxi ci l l i n 25 mg/kg po qi d, tri methopri m/s ul fa methoxa zol e (TMP/SMX) 320/1600 bi d or 10
mg/kg (of the TMP component) bi d, a nd a zi thromyci n 1 g po on da y 1, then 500 mg once/da y for 6 da ys .
Corti cos teroi ds ma y be a dded to a nti bi oti cs to trea t s evere toxi ci ty. Deferves cence a nd cl i ni ca l i mprovement us ua l l y fol l ow. Predni s one 20 to 40 mg
once/da y po (or equi va l ent) for the fi rs t 3 da ys of trea tment us ua l l y s uffi ces . Hi gher dos es of corti cos teroi ds (dexa metha s one 3 mg/kg IV i ni ti a l l y,
fol l owed by 1 mg/kg q 6 h for 48 h tota l ), a re us ed i n pa ti ents wi th ma rked del i ri um, coma , or s hock.
Nutri ti on s houl d be ma i nta i ned wi th frequent feedi ngs . Whi l e febri l e, pa ti ents a re us ua l l y kept on bed res t. Sa l i cyl a tes (whi ch ma y ca us e
hypothermi a a nd hypotens i on), a s wel l a s l a xa ti ves a nd enema s , s houl d be a voi ded. Di a rrhea ma y be mi ni mi zed wi th a cl ea r l i qui d di et;
pa rentera l nutri ti on ma y be needed tempora ri l y. Fl ui d a nd el ectrol yte thera py a nd bl ood repl a cement ma y be needed.
Intes ti na l perfora ti on a nd a s s oci a ted peri toni ti s ca l l for s urgi ca l i nterventi on a nd broa der gra m-nega ti ve a nd a nti -Bacteroides fragilis covera ge.
Rel a ps es a re trea ted the s a me a s the i ni ti a l i l l nes s , a l though dura ti on of a nti bi oti c thera py s el dom needs to be > 5 da ys .
Pa ti ents mus t be reported to the l oca l hea l th depa rtment a nd prohi bi ted from ha ndl i ng food unti l proven free of the orga ni s m. Typhoi d ba ci l l i
ma y be i s ol a ted for a s l ong a s 3 to 6 mo a fter the a cute i l l nes s i n peopl e who do not become ca rri ers . Therea fter, 3 s tool cul tures a t weekl y
i nterva l s mus t be nega ti ve to excl ude a ca rri er s ta te.
Carriers: Ca rri ers wi th norma l bi l i a ry tra cts s houl d be gi ven a nti bi oti cs . The cure ra te i s a bout 60% wi th a moxi ci l l i n 2 g po ti d for 4 wk.
In s ome ca rri ers wi th ga l l bl a dder di s ea s e, era di ca ti on ha s been a chi eved wi th TMP/SMX a nd ri fa mpi n. In other ca s es , chol ecys tectomy wi th 1 to 2
da ys of preopera ti ve a nti bi oti cs a nd 2 to 3 da ys of pos topera ti ve a nti bi oti cs i s effecti ve.
Prevention
Dri nki ng wa ter s houl d be puri fi ed, s ewa ge s houl d be di s pos ed of effecti vel y, mi l k s houl d be pa s teuri zed, chroni c ca rri ers s houl d a voi d ha ndl i ng
food, a nd a dequa te pa ti ent i s ol a ti on preca uti ons s houl d be i mpl emented. Speci a l a ttenti on to enteri c preca uti ons i s i mporta nt. Tra vel ers i n
endemi c a rea s s houl d a voi d i nges ti ng ra w l ea fy vegeta bl es , other foods s tored or s erved a t room tempera ture, a nd untrea ted wa ter. Unl es s wa ter
i s known to be s a fe, i t s houl d be boi l ed or chl ori na ted before dri nki ng.
A l i ve-a ttenua ted ora l typhoi d va cci ne i s a va i l a bl e (Ty21a s tra i n) a nd i s a bout 70% effecti ve. It i s gi ven every other da y for a tota l of 4 dos es .
Beca us e the va cci ne conta i ns l i vi ng S. typhi orga ni s ms , i t i s contra i ndi ca ted i n pa ti ents who a re i mmunos uppres s ed. In the US, the Ty21a va cci ne i s
not us ed i n chi l dren < 6 yr. An a l terna ti ve i s the s i ngl e-dos e, IM Vi pol ys a ccha ri de va cci ne, whi ch i s 64 to 72% effecti ve a nd

Diagnosis and Therapy

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THE MERCK MANUAL OF DIAGNOSIS AND THERAPY - 19th Ed.

Planet Friendly Publishing

Ma de i n the Uni ted Sta tes

Li bra ry of Congres s Ca ta l og Ca rd Number 1-31760

THE MERCK MANUAL OF GERIATRICS

Norma l La bora tory Va l ues 3491

compl ete bl ood count

chroni c obs tructi ve pul mona ry di s ea s e

over-the-counter (pha rma ceuti ca l s )

a rteri a l ca rbon di oxi de pa rti a l pres s ure

a l veol a r oxygen pa rti a l pres s ure

a rteri a l oxygen pa rti a l pres s ure

ca rbon di oxi de pa rti a l pres s ure (or tens i on)

pol ymera s e cha i n rea cti on

puri fi ed protei n deri va ti ve (tubercul l i n)

a l veol a r ca rbon di oxi de pa rti a l pres s ure

oxygen pa rti a l pres s ure (or tens i on)

a rteri a l oxygen s a tura ti on

Profes s or of Surgery a nd Chi ef of Tra uma /

Profes s or a nd Vi ce Cha i rma n, Depa rtment

DAVID H. BARAD, MD, MS

Principles of Drug Treatment in Children

Children; Perinatal Physiology; Caring for

Physical Growth and Development

Di rector, Adul t Leukemi a Res ea rch Progra ms ,

Anders on Ca ncer Center

Profes s or Emeri tus of Pedi a tri cs a nd Medi ca l

Bi ophys i cs , Ca s e Wes tern Res erve Uni vers i ty;

Uni vers i ty of Texa s Southwes tern Medi ca l

JAMES L. LEWIS, III, MD

Mus cul os kel eta l Reha bi l i ta ti on Uni t a nd

MARY LYNN R. NIERODZIK, MD

of Medi ci ne, Di vi s i on of Rheuma tol ogy,

Uni vers i ty School of Medi ci ne

School of Medi ci ne; Di rector (Emeri tus ),

Profes s or (Emeri tus ) of Orthopa edi c Surgery,

Profes s or of Medi ci ne, Di vi s i on of Geri a tri c

School of Denta l Medi ci ne; Pri va te Pra cti ce,

Pi tts burgh; Vi ce Dea n, Drexel Uni vers i ty

Trea tment of depres s i on a nd other underl yi ng di s orders

Chapter 3. Nutritional Support

Chapter 4. Vitamin Deficiency, Dependency, and Toxicity

provi de onl y a s evera l -month s uppl y.

whether vi ta mi n A defi ci ency i s the ca us e.

possible. Rarely, hereditary disorders cause impaired metabolism of vitamin D (dependency).

Chapter 5. Mineral Deficiency and Toxicity

A s i bl i ng, pa rent, or cous i n wi th Wi l s on's di s ea s e

Chapter 6. Obesity and the Metabolic Syndrome

Sidebar 6-1 Pathways Regulating Food Intake

Corti cotropi c hormone (CRH) a nd urocorti n decrea s e i t.

Eating disorders: At l ea s t 2 pa thol ogi c ea ti ng pa tterns ma y be a s s oci a ted wi th obes i ty:

Obes i ty i s a pa rti cul a r concern i n chi l dren a nd the el derl y.

a dol es cents ca n devel op

Al cohol cons umpti on

undernutri ti on, wei ght l os s , a nd meta bol i c a bnorma l i ti es .

Chapter 8. Approach to the Patient With Lower GI Complaints

thems el ves to ha ve di a rrhea .

prol onged s ymptoms (i e, > 1 wk) or red fl a g fi ndi ngs .

Sidebar 8-1 Essay on Flatulence

Chapter 9. Diagnostic and Therapeutic GI Procedures

Chapter 10. GI Bleeding

Symptoms and Signs

embolization or surgical resection may be needed.