Unknown

Editors :
Sc hrie r, Robe rt W .

Title : Inte rna l Me dic ine Ca s e book , The : Re a l P a tie nts , Re a l Ans w e rs ,
3rd Edition
Copy r i ght Â©2007 Li ppi ncott Wi l l i am s & Wi l k i ns
> Fr o nt o f B o o k > Ed ito r s
Editor
Robe rt W . Sc hrie r MD
Pr of essor
Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado School of Medi ci ne, Denv er ,
Col or ado
Secondary Editors
Sonya Se iga fus e
Acqui si ti ons Edi tor
Fra nny Murphy
Dev el opm ental Edi tor
Na nc y W inte r
Managi ng Edi tor
Nic ole W a lz
Pr oject Manager
Ka thy Brow n
Manuf actur i ng Manager
Kimbe rly Sc honbe rge r

Mar k eti ng Manager
Doug Smoc k
Cr eati v e Di r ector
Ca ndic e Ca rta Mye rs

Cov er Desi gner
La s e rw ords P riva te Limite d, Che nna i, India

Pr oducti on Ser v i ces
RR Donne lle y Cra w fords ville

Pr i nter
Contributing Authors
Contributing Authors
Toma s Be rl MD
Pr of essor of Medi ci ne
Di v i si on of Renal Di seases and Hy per tensi on, Depar tm ent of Medi ci ne,
U ni v er si ty of Col or ado School of Medi ci ne, Denv er and Aur or a, Col or ado
W illia m R. Brow n MD

Di v i si on of Gastr oenter ol ogy , Depar tm ent of Medi ci ne, U ni v er si ty of
Col or ado School of Medi ci ne, Denv er and Aur or a, Col or ado
Staf f Gastr oenter ol ogi st, Denv er Heal th Medi cal Center , Denv er , Col or ado
He nry N. Cla ma n MD

Di v i si on of Al l er gy and Cl i ni cal Im m unol ogy , Depar tm ent of Medi ci ne,
Ste phe n C. Dre s k in MD

Di v i si on of Al l er gy and Cl i ni cal Im m unol ogy , Depar tm ent of Medi ci ne,
Ste phe n C. Dre s k in MD

Di r ector
Al l er gy , Asthm a, and Im m unol ogy Pr acti ce, U ni v er si ty of Col or ado Hospi tal ,
Aur or a, Col or ado
Robe rt W . Ja ns on MD

Di v i si on of Rheum atol ogy , Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado
School of Medi ci ne, Denv er and Aur or a, Col or ado
Robe rt W . Ja ns on MD

Chi ef
Rheum atol ogy Secti on, Denv er Veter ans Adm i ni str ati on Medi cal Center ,
Denv er , Col or ado
JoAnn Linde nfe ld MD

Di v i si on of Car di ol ogy , Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado
Ja ne E. B. Re us c h MD
Di v i si on of Endocr i nol ogy , Di abetes, and Metabol i sm , Depar tm ent of
Medi ci ne, U ni v er si ty of Col or ado School of Medi ci ne, Denv er and Aur or a,
Col or ado
Ja ne E. B. Re us c h MD

Staf f
Denv er Veter ans Adm i ni str ati on Medi cal Center , Denv er , Col or ado
La ure nc e Robbins MD

Associ ate Pr of essor of Medi ci ne
Di v i si on of Ger i atr i cs, Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado
La ure nc e Robbins MD

Associ ate Chi ef of Staf f
Ger i atr i cs and Ex tended Car e Depar tm ent, Easter n Col or ado Heal th Car e
Sy stem , Depar tm ent of Veter ans Af f ai r s, Denv er , Col or ado
Ire ne E. Sc ha ue r MD

Instr uctor
Di v i si on of Endocr i nol ogy , Di abetes, and Metabol i sm , Depar tm ent of
Col or ado
Robe rt T. Sc hoole y MD

Head Di v i si on of Inf ecti ous Di seases, Depar tm ent of Medi ci ne, U ni v er si ty of
Cal i f or ni a School of Medi ci ne, San Di ego, Cal i f or ni a
Ma rvin I. Sc hw a rz MD

Jam es C. Cam pbel l Pr of essor of Medi ci ne
Di v i si on of Pul m onar y Di seases and Cr i ti cal Car e Medi ci ne, Depar tm ent of
Col or ado
P a ul A. Se ligma n MD

Di v i si on of Hem atol ogy , Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado
Simon Sha k a r MD
Assi stant Pr of essor of Medi ci ne
Di v i si on of Car di ol ogy , Depar tm ent of Medi ci ne, U ni v er si ty of Col or ado
Is a a c Te ite lba um MD

Di v i si on of Renal Di seases and Hy per tensi on, Depar tm ent of Medi ci ne,
Is a a c Te ite lba um MD

Di r ector
Acute and Hom e Di al y si s Pr ogr am s, U ni v er si ty of Col or ado Hospi tal , Denv er
and Aur or a, Col or ado
Rona ld Zolty MD
Assi stant Pr of essor of Medi ci ne
Montef i or e Medi cal Center , Di v i si on of Car di ol ogy , Depar tm ent of Medi ci ne,
Br onx , N ew Yor k
Editors : Sc hrie r, Robe rt W .
3rd Edition
> Fr o nt o f B o o k > P r e f a c e
Preface
The basi s f or an i nter nal m edi ci ne casebook or i gi nated sev er al y ear s ago,
bor n of m y conv i cti on that house staf f and students ar e sti m ul ated and
m oti v ated best w hen thei r l ear ni ng i s f ocused on r eal pati ents. Steps w er e
tak en, ther ef or e, to augm ent the pati entor i ented i nstr ucti on of our house
staf f and students. Thi s w as accom pl i shed i n l ar ge par t by our i nhouse
publ i cati on of a l ar ge num ber of pati ent cases cov er i ng a v ar i ety of di seases
that f or m ed the cur r i cul um f or m edi cal students and the house staf f r otati ng
thr ough the m edi cal w ar ds and tak i ng subspeci al ty el ecti v es. These pati ent
cases becam e the basi s f or the f i r st edi ti on of The Inter nal Medi ci ne
Casebook : Real Pati ents, Real Answ er s. Si nce the f i r st tw o edi ti ons hav e
been so w el l r ecei v ed, I am ev en m or e conv i nced of the need f or such a
pati entor i ented educati onal tool .
In thi s thi r d edi ti on of the Casebook , w e hav e r ev i sed and updated the
pati entor i ented cases, w hi ch cov er appr ox i m atel y 90 ar eas of i nter nal
m edi ci ne. Fi r st, the per ti nent aspects of the pati ent's hi stor y and phy si cal
ex am i nati on ar e pr esented. Questi ons ar e then posed about the appr opr i ate
di agnosti c w or k up and tr eatm ent. Thi s sets the stage f or a Socr ati c
appr oach to l ear ni ng betw een the attendi ng phy si ci an and the house of f i cer
or m edi cal student. The f or m at of the Casebook al so l ends i tsel f to sel f
i nstr ucti on w i th thi s questi onandansw er appr oach.
The Inter nal Medi ci ne Casebook : Real Pati ents, Real Answ er s has pr ov ed to
be an i nv al uabl e l ear ni ng tool to students and house of f i cer s, and al so a
teachi ng ai d to any one i nv ol v ed i n the educati on of f utur e phy si ci ans. I am
gr atef ul f or the ex per ti se and suppor t of the author s, each of w hom i s an
em i nentl y qual i f i ed educator and hi ghl y r egar ded l eader i n hi s or her f i el d. I
al so thank Jan Dar l i ng f or her edi tor i al assi stance.
R. W. S.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 1 A lle r g y a nd C linic a l I m m uno lo g y
Chapter 1
Allergy and Clinical Immunology
Ste phe n C. Dre s k in

He nry N. Cla ma n
Anaphylaxis
1. What i s the cl i ni cal pr esentati on i n a ty pi cal case of anaphy l ax i s?
2. What i s the under l y i ng pathophy si ol ogi c pr ocess?
3. What condi ti ons shoul d be consi der ed i n the di f f er enti al di agnosi s?
P. 2
Discussion
1. What i s the cl i ni cal pr esentati on i n a ty pi cal case of anaphy l ax i s?
In the m ost sev er e cases, the cl i ni cal pr esentati on consi sts of sudden
hy potensi on w i th or w i thout cutaneous si gns, br onchospasm , or
l ar y ngeal obstr ucti on. Pati ents occasi onal l y r epor t a â€œsense of
i m pendi ng doom . â€ Thi s m ay occur w i thi n m i nutes of the i ngesti on of a
speci f i c f ood, i njecti on of an anti gen (e. g. , an anti bi oti c), or an i nsect
sti ng, and m ay be f atal . A l ess r api d onset can begi n w i th ur ti car i a,
angi oedem a, shor tness of br eath, hoar seness, and m oder ate
hy potensi on. If the of f endi ng substance has been i ngested, ther e can be
abdom i nal cr am ps, v om i ti ng, and di ar r hea. The di agnosi s of
anaphy l ax i s shoul d be easi l y m ade i f the sy m ptom s descr i bed appear
ov er the cour se of m i nutes up to an hour . The bl ood pr essur e need not
dr opâ€”that i s, ther e can be anaphy l ax i s w i thout shock .
2. What i s the under l y i ng pathophy si ol ogi c pr ocess?
Mast cel l s and basophi l s ar e acti v ated w hen an anti gen (e. g. , peni ci l l i n)
com bi nes w i th the anti gencom bi ni ng si te of i m m unogl obul i n E (IgE)
anti bodi es that ar e bound to FcÎµRI, the hi gh af f i ni ty r eceptor f or IgE.
Vasoacti v e m edi ator s such as hi stam i ne, l euk otr i ene C4 (LTC4), and
pr ostagl andi n D 2 (PGD 2 ) r api dl y enter the ci r cul ati on. In som e
ci r cum stances, m ast cel l s ar e acti v ated by nonIgE m echani sm s, such
as m ay be tr i gger ed by r adi ocontr ast dy e i njecti ons or by nonster oi dal
anti i nf l am m ator y dr ugs (N SAIDs); thi s i s cal l ed an anaphy l actoi d
r eacti on, but the basi c phy si ol ogi c char acter i sti cs and tr eatm ent ar e
other w i se si m i l ar to those of IgEm edi ated anaphy l ax i s.
3. What condi ti ons shoul d be consi der ed i n the di f f er enti al di agnosi s?
The di f f er enti al di agnosi s l i st i s not l ong. Col l apse due to septi c shock ,
car di ac ar r hy thm i a, or asy stol e m ust be consi der ed. The m ost com m on
sour ce of er r or i s f ai l i ng to r ecogni ze v asov agal . In such a si tuati on,
the pati ent's pul se i s sl ow and ther e i s no ur ti car i a, edem a, or
dy spnea. The pul se i s al w ay s r api d i n the setti ng of anaphy l ax i s unl ess
the pati ent i s tak i ng a Î²adr ener gi c bl ock er or ther e i s an under l y i ng
conducti on def ect. Pati ents w i th hy per v enti l ati on do not w heeze or hav e
hy potensi on. How ev er , deter m i ni ng the cause of the anaphy l acti c
epi sode can be di f f i cul t because antecedent ev ents ar e not al w ay s cl ear
and som e epi sodes w i l l r em ai n i di opathi c.
Case
An 18y ear ol d w om an i s seen i n a l ocal Em er gency depar tm ent (ED)
com pl ai ni ng of acute shor tness of br eath, sw el l i ng, and a pr ur i ti c r ash.
Thr ee hour s bef or e her sy m ptom s began, she had a â€œsti r f r y â€ contai ni ng
tof u w hi ch she had nev er eaten bef or e. Thi r ty m i nutes bef or e her ar r i v al i n
the ED, she w as at the gy m w her e she under took her usual br i ef (1 m i nute)
w ar m up and began r unni ng. Wi thi n 10 m i nutes she f el t f l ushed, i tchy , and
shor t of br eath, and noted the sensati on of an enl ar gi ng l um p i n her thr oat.
Her boy f r i end dr ov e her to the ED w her e she w as ex am i ned i m m edi atel y .
She r epor ts that she has nev er ex per i enced si m i l ar sy m ptom s. She appear s
anx i ous and di aphor eti c; her v i tal si gns ar e r em ar k abl e f or a r espi r ator y
r ate of 32 per m i nute, a pul se r ate of 108 per m i nute, and a bl ood pr essur e
of 85/50 m m Hg. She i s noted to be di f f usel y f l ushed,
P. 3
and car ef ul ex am i nati on of her sk i n r ev eal s m ul ti pl e ur ti car i al l esi ons on
her f ace and tr unk . Her uv ul a i s sw ol l en and i s par ti al l y obstr ucti ng her
poster i or phar y nx . Inspi r ator y str i dor i s noted ov er her thr oat and r adi ates
to both l ung f i el ds. The r em ai nder of her ex am i nati on i s nor m al .
1. What m i ght be the cause or causes of her r eacti on?

2. How shoul d she be tr eated?
3. What f ol l ow up shoul d be r ecom m ended?
Case Discussion
1. What m i ght be the cause or causes of her r eacti on?
Ther e ar e a num ber of f actor s that m i ght hav e tr i gger ed thi s r eacti on.
Al though the l i st of potenti al causes of IgEm edi ated anaphy l ax i s i s
l ong and conti nues to ex pand, agents that deser v e speci al m enti on
i ncl ude v enom ous i nsect sti ngs, f oods, i njecti on of al l er gy ex tr acts
(al l er gy shots), l atex , and m edi cati ons of any ty pe but par ti cul ar l y
anti bi oti cs and heter ol ogous pr otei ns. N onâ€“IgEm edi ated anaphy l ax i s
i s m ost of ten caused by r adi ocontr ast m edi a, opi oi ds, N SAIDs, and
phy si cal sti m ul i such as ex er ci sei nduced and f oodr el ated anaphy l ax i s.
IgEm edi ated al l er gi es to v enom s or f oods ar e com m on causes of
anaphy l ax i s i n al l agegr oups. In the absence of a k now n sti ng or
i njecti on of al l er gen, f oods and m edi cati ons shoul d be i m m edi atel y
consi der ed. The f oods m ost com m onl y i m pl i cated i n chi l dr en ar e m i l k ,
eggs, and peanuts and i n adul ts ar e peanuts, tr ee nuts, shel l f i sh, and
f i n f i sh but v i r tual l y any f ood i s a potenti al cause i n a sensi ti zed
per son. Ty pi cal r eacti ons begi n w i thi n m i nutes but m ay occur af ter
sev er al hour s.
Most cases of dr ugi nduced anaphy l ax i s ar e IgEm edi ated and ar e of ten
due to peni ci l l i n anti bi oti cs, al though al m ost any dr ug can be eti ol ogi c.
In the sur gi cal setti ng, anaphy l acti c r eacti ons ar e m ost of ten due to
m uscl e r el ax ants and l atex but can al so be due to hy pnoti cs,
anti bi oti cs, opi oi ds, col l oi ds, and other agents. Aspi r i n and N SAIDs ar e
potent i nhi bi tor s of the cy cl oox y genase pathw ay of ar achi doni c aci d
m etabol i sm , r epor tedl y causi ng ser i ous r eacti ons i n up to 10% of
i ndi v i dual s w i th asthm a and i n 1% of the gener al popul ati on. In
asthm ati c pati ents, the r eacti on consi sts of sev er e br onchospasm ;
i ndi v i dual s w ho do not hav e asthm a m ay hav e ur ti car i a, angi oedem a,
and anaphy l ax i s. Reacti ons to these dr ugs ar e usual l y not m edi ated by
IgE. The m echani sm r esponsi bl e f or causi ng them i s poor l y under stood,
but i s possi bl y r el ated to the i nhi bi ti on of cy cl oox y genase and the
shi f ti ng of ar achi donate m etabol i sm to the l i pox y genase pathw ay .
Ther e ar e no i m m unol ogi c tests that can detect thi s sensi ti v i ty , and
chal l enge tests, w hi ch r equi r e the use of str i ct pr ecauti ons, r em ai n the
onl y r el i abl e m ethod to i denti f y aspi r i n and N SAIDsensi ti v e pati ents.
How ev er , as w i th any dr ug, IgEm edi ated r eacti ons can al so occur .
Ex er ci se can cause a l i m i ted ar r ay of sy stem i c r eacti ons, par ti cul ar l y a

ty pe of ur ti car i a (hi v es) cal l ed chol i ner gi c ur ti car i a, and r ar el y
ex er ci sei nduced anaphy l ax i s. An unusual sy ndr om e of ex er ci se
i nduced and f oodr el ated anaphy l ax i s i s not uncom m on w her ei n the
pati ent can eat a speci f i c f ood and ex er ci se w i thout pr obl em s. But i f
the f ood i s eaten w i thi n as m any as sev er al hour s bef or e ex er ci se,
P. 4
the pati ent w i l l ex per i ence anaphy l ax i s. Sy stem i c m astocy tosi s i s a
r ar e di sease char acter i zed by a â€œgai n of f uncti onâ€ m utati on i n the
r eceptor f or stem cel l f actor and a r esul tant ov er gr ow th of m ast cel l s.
Ty pi cal l y , these pati ents hav e f r equent m ani f estati ons of m ast cel l
degr anul ati on such as f l ushi ng and hi v es but can pr esent w i th i sol ated
anaphy l ax i s. Fi nal l y , a f ew pati ents hav e i di opathi c anaphy l ax i s, that
i s, they hav e one or m or e epi sodes of anaphy l ax i s that r em ai n
unex pl ai ned af ter a thor ough ev al uati on.
In thi s par ti cul ar case, ther e w as no hi stor y of i ngesti on of a
m edi cati on and no ex posur e to a v enom ous i nsect. How ev er , m any of
the other di agnoses m enti oned ar e possi bl e ex pl anati ons f or the
pati ent's epi sode and the tr ue eti ol ogy m ay onl y becom e appar ent ov er
ti m e. It i s i m por tant to consi der an al l er gi c r eacti on to soy because
tof u w as i ngested shor tl y bef or e the anaphy l acti c epi sode, w as a new
f ood f or her , and ther e i s adequate oppor tuni ty to becom e sensi ti zed to
soy thr ough a num ber of com m on f oods. Of cour se a â€œsti r f r y â€
contai ns m any f oods i n addi ti on to the tof u and any of these ar e
potenti al cul pr i ts. In the ev ent that the r esul ts of al l di agnosti c
ev al uati ons ar e negati v e, thi s epi sode m ay i ndeed be i di opathi c.
2. How shoul d she be tr eated?
Ther e i s a gener al l y accepted pr otocol f or tr eati ng anaphy l acti c

sy ndr om es. Epi nephr i ne i s the m ai nstay of tr eatm ent i n anaphy l ax i s; i t
acts by i nhi bi ti ng m edi ator r el ease f r om m ast cel l s and basophi l s,
r el ax i ng br onchi al sm ooth m uscl e, and bol ster i ng bl ood pr essur e.
Of ten, al l of the si gns and sy m ptom s of anaphy l ax i s r esol v e com pl etel y
w i thi n m i nutes of a si ngl e i njecti on of epi nephr i ne but the under l y i ng
pathophy si ol ogi c ev ents per si st and sy m ptom s r ecur af ter the
epi nephr i ne i s m etabol i zed. As soon as the di agnosi s of anaphy l ax i s i s
str ongl y enter tai ned, star ti ng dose of 0. 3m L of a 1:1, 000 sol uti on of
epi nephr i ne shoul d be gi v en i ntr am uscul ar l y , pr ef er abl y i n the thi gh,
f or an adul t and 0. 01 m g/k g f or a chi l d. If no untow ar d si de ef f ects
occur , the pati ent m ay r ecei v e r epeated doses ev er y 10 m i nutes unti l
the sy m ptom s i m pr ov e. Rar el y , 1 to 2 m L of a 1:10, 000 di l uti on of
epi nephr i ne i s gi v en by i ntr av enous (IV) r oute but thi s shoul d be
av oi ded i f possi bl e because i t m ay cause potenti al l y f atal car di ac
ar r hy thm i as. In a pati ent w hose pr i m ar y si te of i nv ol v em ent i s the
upper ai r w ay (such as the one descr i bed her e), i nhal ed 2% r acem i c
epi nephr i ne i s a v al uabl e adjunct to par enter al ther apy (at a dose of
0. 5 m L). In addi ti on, an H 1 antagoni st (e. g. , di phenhy dr am i ne, 50 m g)
shoul d be gi v en sl ow l y by the IV r oute. Recent ev i dence show s that the
addi ti on of an H 2 bl ock er , such as r ani ti di ne 150 m g by sl ow IV i nf usi on
l eads to m or e r api d r esol uti on of acute al l er gi c ev ents. If the pati ent
has sev er e ai r w ay obstr ucti on at pr esentati on (cy anosi s) or the
obstr ucti on w or sens despi te the pr om pt use of epi nephr i ne,
endotr acheal i ntubati on shoul d be per f or m ed pr om ptl y usi ng a sm al l
bor e tube (no. 4 or 5). If thi s i s not possi bl e because of the degr ee of
edem a, cr i cothy r otom y shoul d be per f or m ed. In the ex am pl e gi v en,
sem i el ecti v e i ntubati on w as chosen by a sk i l l ed ED phy si ci an to av oi d
the com pl i cati ons associ ated w i th em er gency i ntubati on of pati ents w i th
sw el l i ng of the ai r w ay . The pati ent w as ex tubated af ter 8 hour s w i thout
sequel ae.
Anaphy l ax i s i n pati ents w ho ar e tak i ng Î²adr ener gi c antagoni sts m ay
be par ti cul ar l y di f f i cul t to tr eat. If w heezi ng does not r espond to i ni ti al
epi nephr i ne or i nhal ed
P. 5
Î²agoni st ther apy , gl ucagon shoul d be adm i ni ster ed. Pati ents w i th
hy potensi on r ef r actor y to tr eatm ent w i th subcutaneous epi nephr i ne,
anti hi stam i nes, and par enter al f l ui ds m ay r equi r e par enter al
dopam i ne, nor epi nephr i ne, and gl ucagon ther apy .
In pati ents w ho hav e si gni f i cant sy m ptom s af f ecti ng any tar get or gan
sy stem , IV cor ti coster oi ds (Sol uMedr ol , 1 m g/k g) shoul d be gi v en
i m m edi atel y , f ol l ow ed by an or al dose 6 hour s l ater . Pati ents w ho hav e
a pr ol onged cl i ni cal cour se shoul d conti nue to r ecei v e cor ti coster oi ds
ev er y 6 hour s.
Ini ti al ther apy consi sti ng of the i nter v enti ons just descr i bed br i ngs
about com pl ete and sustai ned r el i ef of the si gns and sy m ptom s of
anaphy l ax i s i n 50% of pati ents. How ev er , one f our th of the pati ents
r em ai n par ti al l y r esi stant to ther apy f or sev er al hour s and occasi onal l y
f or sev er al day s (pr otr acted anaphy l ax i s). The r em ai ni ng 25% of the
pati ents r espond to i ni ti al ther apy , but af ter a v ar i abl e i nter v al (up to
8 hour s) w i thout si gns or sy m ptom s, they ex per i ence r ecur r ence of
l i f ethr eateni ng com pl i cati ons (bi phasi c anaphy l ax i s). Ther e i s no
r el i abl e w ay to pr edi ct w hi ch pati ents w i l l hav e such a r el apse.
Ther ef or e, al l pati ents w i th anaphy l ax i s shoul d be obser v ed by m edi cal
per sonnel f or at l east 8 hour s af ter the onset of the epi sode.
3. What f ol l ow up shoul d be r ecom m ended?
Al l pati ents w i th a hi stor y of anaphy l acti c r eacti on, no m atter w hat the
cause, shoul d be gi v en pr el oaded sy r i nges contai ni ng epi nephr i ne f or
sel f adm i ni str ati on (e. g. , Epi Pen 0. 3 m g or Epi Pen Jr 0. 15 m g Auto
i njector , Dey Inc. , N apa, Cal i f or ni a) and al so di phenhy dr am i ne (25 m g
capsul es). Bef or e they l eav e the ED, the pati ent and f am i l y m em ber s
shoul d be tr ai ned on how to adm i ni ster the epi nephr i ne and
di phenhy dr am i ne and tol d to cal l 911 or pr oceed i m m edi atel y to a
near by ED. Another i m por tant gener al m easur e to be i m pl em ented i s
the r epl acem ent of Î²bl ock i ng dr ugs w i th a sui tabl e al ter nati v e
m edi cati on i f possi bl e i n those i ndi v i dual s w ho ar e at possi bl e r i sk f or
f ur ther epi sodes of anaphy l ax i s.
Af ter acute tr eatm ent of the anaphy l acti c epi sode, the m ost l i k el y
cause of the r eacti on shoul d be deter m i ned so that r ecom m endati ons
on f utur e av oi dance can be m ade. In the pati ent descr i bed her e, f ood
sk i n tests to al l the i ngr edi ents i n the m eal pr ecedi ng her r eacti on
shoul d be per f or m ed by an al l er gi st/i m m unol ogi st. Soy i s par ti cul ar l y
suspi ci ous as a possi bl e cause of her anaphy l ax i s. If the sk i n test
r esul ts ar e posi ti v e to one or m or e f oods, car ef ul l y m oni tor ed, gr aded,
doubl ebl i nded, pl acebocontr ol l ed (DBPC) f ood chal l enges can be
per f or m ed to i denti f y the eti ol ogi c agent. In the ev ent that the f ood
chal l enge r esul ts ar e negati v e, i t i s not necessar y f or the pati ent to
av oi d soy or any of the other i m pl i cated f oods. In pr acti ce, m ost
pati ents just av oi d the suspect f ood or f oods. Thi s i s subopti m al
because ther e m ay be unnecessar y changes i n l i f esty l e and nutr i ti on
m ay be com pr om i sed. Pati ents w i th a hi stor y of f oodi nduced
anaphy l ax i s shoul d al w ay s car r y epi nephr i ne and di phenhy dr am i ne
(Benadr y l ) because of the possi bi l i ty of i nadv er tent ex posur e. Pati ents
w i th r ecur r ent epi sodes of i di opathi c anaphy l ax i s hav e been show n to
benef i t f r om dai l y adm i ni str ati on of anti hi stam i ne and or al
cor ti coster oi d ther apy . Thi s ty pe of ther apy , how ev er , i s unw ar r anted
i n pati ents w ho hav e k now n av oi dabl e causes of anaphy l ax i s.
The pati ent descr i bed her e had a posi ti v e sk i n test to cel er y and a
negati v e test to soy . The m ost l i k el y di agnosi s i n her case i s ex er ci se
i nduced and f oodr el ated
P. 6
anaphy l ax i s. So, she w as adv i sed to av oi d ex er ci si ng f or 6 hour s af ter
eati ng cel er y , to car r y her epi nephr i ne and di phenhy dr am i ne, to nev er
ex er ci se al one, and to nev er ex er ci se i n r em ote setti ngs.
Suggested Readings
Canter LM. Anaphy l actoi d r eacti ons to contr ast m edi a. Al l er gy Asthm a
Pr oc 2005;26:199.
Li eber m an P. Bi phasi c anaphy l acti c r eacti ons. Ann Al l er gy Asthm a

Im m unol 2005;95:217.
Li eber m an P. Anaphy l ax i s. Med Cl i n N or th Am 2006;90:77.
Si cher er SH, Sam pson HA. Food al l er gy . J Al l er gy Cl i n Im m unol

2006;117:S470.
Si m ons FE. Anaphy l ax i s, k i l l er al l er gy : l ongter m m anagem ent i n the

com m uni ty . J Al l er gy Cl i n Im m unol 2006;117:367.
Wi ener ES, Bajaj L. Di agnosi s and em er gent m anagem ent of anaphy l ax i s

i n chi l dr en. Adv Pedi atr 2005;52:195.
Angioedema
1. What ar e the cl i ni cal pi ctur es associ ated w i th angi oedem a?
2. What pathophy si ol ogi c pr ocesses under l i e angi oedem a?
3. How i s her edi tar y angi oedem a (HAE) di agnosed?
Discussion
1. What ar e the cl i ni cal pi ctur es associ ated w i th angi oedem a?
Angi oedem a can pr esent w i th sev er al di f f er ent cl i ni cal pi ctur es. It can
i ncl ude an ex agger ated f or m of ur ti car i a, w i th i tchi ng and sw el l i ng of
sof t ti ssues that can ar i se any w her e i n the body and appear w i thi n a
f ew m i nutes or ov er the cour se of hour s. Al ter nati v el y , i t m ay i nv ol v e
the br onchi al m ucosa or the v ocal cor ds, l eadi ng to ai r w ay obstr ucti on.
Other f or m s of angi oedem a do not i ncl ude i tchi ng or ur ti car i a. They
m ay be l ocal or m ay r esul t f r om tr aum a. In these cases, the sw ol l en
ti ssues m ay hur t, but do not i tch.
2. What pathophy si ol ogi c pr ocesses under l i e angi oedem a?
In angi oedem a that coex i sts w i th ur ti car i a, the under l y i ng m echani sm
i s the sam e as that i n anaphy l ax i sâ€” the acti v ati on of m ast cel l s w i th
the r el ease of m ast cel l m edi ator s, such as hi stam i ne. In the setti ng of
angi oedem a w i thout ur ti car i a, the m echani sm m ay i nv ol v e m ast cel l s
or m ay be the unbr i dl ed acti v ati on of the com pl em ent and k i ni n
sy stem s because of l ack of a m ajor com pl em ent contr ol pr otei n, C1
i nhi bi tor (C1 IN H).
3. How i s HAE di agnosed?
The cl i ni cal cl ue to HAE i s a hi stor y of r epeated bouts of angi oedem a
w i thout ur ti car i a ar i si ng any w her e i n the body , such as the f ace,
tongue, and ex tr em i ti es. The ai r w ay can be com pr om i sed. Som e
pati ents ex per i ence di f f use abdom i nal pai n and m ay hav e had
l apar otom i es at w hi ch onl y bow el edem a i s f ound. These l esi ons do not
i tch and m ay be pai nf ul . HAE i s tr ansm i tted as an autosom al dom i nant
tr ai t. N ev er thel ess, the f am i l y hi stor y i s negati v e
P. 7
i n 50% of the pati ents and these cases ar e ei ther due to new m utati ons
or m i stak en pater ni ty . The l abor ator y cl ues poi nt to the com pl em ent
sy stem , w i th a def i ci ency of com pl em ent contr ol pr otei ns at f aul t.
Case
A 25y ear ol d w om an pr esents to the ED w i th com pl ai nts of sev er e f aci al
sw el l i ng r esul ti ng i n di f f i cul ty sw al l ow i ng begi nni ng on the day af ter she had
under gone an endoscopi c pr ocedur e. She noted m i l d f aci al sw el l i ng on
aw ak eni ng i n the m or ni ng. Thr oughout the ensui ng day , the sw el l i ng has
w or sened to i nv ol v e her l ef t cheek , upper and l ow er l i ps, and tongue.
Appr ox i m atel y 6 hour s bef or e com i ng to the ED, she noted she w as
becom i ng hoar se. She had under gone the endoscopy as par t of an ev al uati on
f or i nter m i ttent abdom i nal pai n. Pr ev i ous i nv esti gati ons i ncl ude a bar i um
sw al l ow and enem a, and the r esul ts of both w er e negati v e. Si nce 19 y ear s
of age she has had abdom i nal pai n, w hi ch she descr i bes as cr am py and
occasi onal l y associ ated w i th nausea, v om i ti ng, or di ar r hea. These sy m ptom s
usual l y r esol v e w i thi n 3 to 4 day s w i th no speci f i c m edi cal i nter v enti on and
ar e not associ ated w i th her m enstr ual per i ods. The sy m ptom s began w hen
she star ted usi ng bi r th contr ol pi l l s. She has had one other epi sode of f aci al
sw el l i ng 3 y ear s bef or e, af ter a tooth ex tr acti on (al though i t w as m uch l ess
i ntense and not associ ated w i th di f f i cul ty sw al l ow i ng). The sw el l i ng r esol v ed
spontaneousl y af ter appr ox i m atel y 3 day s. Ther e i s no f am i l y hi stor y of
si m i l ar sy ndr om es.
1. What i s the m ost l i k el y di agnosi s i n thi s w om an?

2. What l abor ator y tests f or com pl em ent ar e usef ul i n m ak i ng a di agnosi s
of HAE?
3. How shoul d an acute attack of HAE be tr eated?
4. What pr ophy l acti c m easur es ar e av ai l abl e f or HAE?
Case Discussion
1. What i s the m ost l i k el y di agnosi s i n thi s w om an?
The m ost l i k el y di agnosi s i s HAE. Al though ex posur e to l atex gl ov es can
cause an al l er gi c r eacti on that i ncl udes angi oedem a, a di agnosi s of HAE
i s m uch m or e consi stent w i th thi s pati ent's case hi stor y . Local
anestheti cs, l i k e any m edi cati on, can cause angi oedem a but thi s i s
r ar e. HAE char acter i sti cal l y pr esents as a sw el l i ng of the subm ucosal
and subcutaneous ti ssues. Al though v i r tual l y any body par t can be
i nv ol v ed, usual l y the f ace and ex tr em i ti es ar e af f ected. Mucosal edem a
m ay occur . Thi s can cause abdom i nal pai n w hen the sm al l bow el i s
af f ected, or a change i n v oi ce or ev en str i dor w hen the l ar y nx i s
af f ected. Thi s pati ent had both of these sy m ptom s. U r ti car i a i s not a
par t of the HAE sy ndr om e.
The angi oedem a associ ated w i th HAE f r equentl y occur s af ter l ocal
tr aum a (i ncl udi ng dental pr ocedur es and endoscopy ), i l l ness, or
em oti onal str ess, but can al so ar i se i n the absence of a speci f i c
tr i gger . HAE epi sodes usual l y begi n dur i ng chi l dhood, but the onset can
occur at v i r tual l y any age. Attack s v ar y gr eatl y i n i ntensi ty and
f r equency . Most pati ents ex per i ence sel f l i m i ted f aci al or ex tr em i ty
sw el l i ng, but other s can hav e l i f ethr eateni ng l ar y ngeal edem a. Attack s
usual l y l ast f or 1 to 4 day s. They m ay i ncr ease i n the pr em enstr ual or
postpar tum per i ods. Thi s
P. 8
di sease ex hi bi ts an autosom al dom i nant her edi tar y patter n, but the
f am i l y hi stor y i s negati v e i n 50% of pati ents.
2. What l abor ator y tests f or com pl em ent ar e usef ul i n m ak i ng a di agnosi s
of HAE?
A ser um C4 l ev el r epr esents the best scr een f or thi s di sease because i t
i s l ow ev en w hen the pati ent i s asy m ptom ati c and i s v er y l ow w hen the
pati ent i s ex per i enci ng sw el l i ng. Measur em ent of ser um C1 IN H i s a
l abor ator y test that can be per f or m ed to establ i sh the di agnosi s. HAE i s
caused by a decr ease i n the l ev el and/or the f uncti on of C1 IN H, w hi ch
i s the i nhi bi tor of the acti v ated f i r st com ponent of com pl em ent (C1
w hi ch contai ns a cr i ti cal ester ase acti v i ty cal l ed C1s) and i s al so an
i nhi bi tor of k al l i k r ei n, w hi ch gener ates br ady k i ni n f r om k i ni nogen.
When the l ev el of thi s i nhi bi tor i s l ow or absent, the ear l y cl assi c
com pl em ent pathw ay i s acti v ated and v ar i ous com pl em ent com ponents
ar e then used up f aster than they can be sy nthesi zed. In addi ti on,
ex cess br ady k i ni n, a v er y potent v asoacti v e pepti de, i s gener ated i n
ex cess. In 85% of pati ents, the l ev el of the C1 IN H pr otei n i s
decr eased, w her eas i n 15% of the pati ents the pr otei n i s pr esent but
dy sf uncti onal . Ther ef or e, i n a subgr oup of these pati ents the C1 IN H
l ev el i s nor m al and the natur e of the di sease cannot be detected unl ess
the C1 IN H f uncti on i s assessed. Al though w e m ak e the di agnosi s by
m oni tor i ng the com pl em ent sy stem , the actual cause of the sy m ptom s
appear s to be edem a gener ated by the f or m ati on of br ady k i ni n.
Hi stam i ne r el ease i s not par t of thi s condi ti on.
3. How shoul d an acute attack of HAE be tr eated?
N ei ther anti hi stam i nes nor cor ti coster oi ds hav e a r ol e i n the tr eatm ent
of an acute attack of HAE, w her eas they ar e ef f ecti v e i n the tr eatm ent
of al l er gi c ur ti car i a that i ncl udes angi oedem a. Because the m edi cal
tr eatm ent of HAE i s not al w ay s ef f ecti v e, and i f upper ai r w ay
com pr om i se i s pr esent or pendi ng, stat otol ar y ngol ogy and
anesthesi ol ogy consul tati ons shoul d be obtai ned because a
tr acheostom y m ay be r equi r ed to pr ev ent ai r w ay cl osur e. The onl y
al ter nati v e to tr acheostom y i s nasotr acheal i ntubati on, w hi ch shoul d be
per f or m ed onl y i n an oper ati ng r oom w i th a sur geon pr esent i n the
ev ent an em er gent tr acheostom y i s r equi r ed. Tr eatm ent w i th f r esh
f r ozen pl asm a i s som ew hat contr ov er si al because thi s substance
pr ov i des f ur ther pr otei ns that, w hen acti v ated secondar y to a decr ease
i n C1 IN H, m i ght w or sen the angi oedem a. N ev er thel ess, m any
phy si ci ans r outi nel y adm i ni ster tw o uni ts of f r esh f r ozen pl asm a. As
m enti oned ear l i er , these di seases can pr esent as cr am py abdom i nal
pai n, som eti m es m i si nter pr eted as an acute abdom i nal condi ti on, but
thi s di sease can be di f f er enti ated f r om an acute abdom i nal condi ti on by
the l ack of abdom i nal r i gi di ty and f ev er and absence of an el ev ated
w hi te bl ood cel l count w i th a l ef tw ar d shi f t. Thi s abdom i nal pai n can be
r el i ev ed by nar coti cs such as m eper i di ne. Som e ex per i enced phy si ci ans
tr eat the abdom i nal or ex tr em i ty pai n associ ated w i th these
angi oedem a attack s (w hi ch, i n gener al , ar e sel f l i m i ted) usi ng
m eper i di ne. They r eser v e f r esh f r ozen pl asm a (w hi ch suppl i es C1 IN H)
and, of cour se, tr acheostom y f or thr eatened ai r w ay cl osur e. Pur i f i ed C1
IN H and a br ady k i ni n r eceptor antagoni st m ay soon be av ai l abl e f or
tr eatm ent of acute attack s.
4. What pr ophy l acti c m easur es ar e av ai l abl e f or HAE?
Chr oni c pr ophy l ax i s f or thi s l i f ethr eateni ng di sease i s i m por tant. We
use an attenuated andr ogen (such as danazol ). These â€œi m pededâ€
andr ogeni c ster oi ds cause
P. 9
an i ncr ease i n sy nthesi s of C1 IN H. Hi gh doses br i ng about cor r ecti on
of both the C1 IN H and C4 l ev el s. U nf or tunatel y , unacceptabl e si de
ef f ects m ay ar i se at these doses, i ncl udi ng w ei ght gai n, headaches,
m uscl e cr am pi ng, m enom etr or r hagi a, andr ogeni c ef f ects, and m i l d
i ncr eases i n the ser um aspar tate and al ani ne am i notr ansf er ase l ev el s.
HAE can usual l y be contr ol l ed w i th l ow er doses of these andr ogens,
w hi ch do not enti r el y cor r ect these l abor ator y abnor m al i ti es, but
pr oduce f ew er si de ef f ects. Ther ef or e, the andr ogen dose i s adjusted to
achi ev e sy m ptom ati c r el i ef , not to cor r ect the l abor ator y
abnor m al i ti es. Andr ogens ar e not hel pf ul i n m anagi ng acute
ex acer bati ons of thi s di sease, and nei ther cor ti coster oi ds nor
anti hi stam i nes hav e a pr ophy l acti c ef f ect.
Wom en w i th HAE f r equentl y note a w or seni ng of thei r di sease w hen
they star t tak i ng bi r th contr ol pi l l s. Thi s i s possi bl y due to the
anti andr ogeni c ef f ect of the pi l l s. Pr egnant w om en w i th HAE, how ev er ,
do w el l i n l ate pr egnancy and del i v er y .
Suggested Readings
Br acho FA. Her edi tar y angi oedem a. Cur r Opi n Hem atol 2005;12:493.
Ci car di M, Zi ngal e L, Zani cher l l i A, etal . C1 i nhi bi tor : m ol ecul ar and
cl i ni cal aspects. Spr i nger Sem i n Im m unopathol 2005;27:286.
Kapl an AP, Gr eav es MW. Angi oedem a. J Am Acad Der m atol 2005;53:373.
Chronic Urticaria
1. What i s the def i ni ti on of chr oni c ur ti car i a?
2. What i s the pathogenesi s of chr oni c ur ti car i a?
Discussion
1. What i s the def i ni ti on of chr oni c ur ti car i a?
Chr oni c ur ti car i a i s def i ned as ur ti car i a that per si sts f or 6 w eek s or
m or e.
2. What i s the pathogenesi s of chr oni c ur ti car i a?
The pathogenesi s of chr oni c ur ti car i a i ncl udes a spectr um of ev ents.

Com m onl y , ther e i s si m pl e l ocal edem a and i tchi ng caused by the
r el ease of hi stam i ne f r om m ast cel l s. Other m or e sev er e cases hav e an
i nf l am m ator y com ponent, such as v ascul i ti s that i s r ev eal ed by bi opsy
speci m ens. In these cases, the r esponsi bl e m echani sm m ay be ei ther
tum or necr osi s f actor Î± l eased f r om acti v ated m ast cel l s, or anti genâ
€“anti body com pl ex es, w hi ch i n tur n acti v ate the com pl em ent and l ead
to the pr oducti on of anaphy l atox i ns. These substances tr i gger l ocal
m ast cel l acti v ati on, w i th subsequent i tchi ng, er y them a, and w heal
f or m ati on.
Case
A 25y ear ol d w om an i s seen because of a pr ur i ti c r ash char acter i zed by
m ul ti pl e, ci r cum scr i bed, r ai sed ar eas of er y them a v ar y i ng i n si ze f r om 2
m m to 3 cm and occur r i ng
P. 10
ov er the sk i n. Each l esi on l asts 1 or 2 day s, but new ones ar i se as ol d ones
f ade. The r ash has per si sted f or 9 w eek s. She does not sm ok e or dr i nk
al cohol , nor has she tak en any m edi cati ons i n the l ast 10 w eek s, i ncl udi ng
anti bi oti cs or aspi r i n, al though she i s sex ual l y acti v e and on bi r th contr ol
pi l l s. She r etur ned f r om tr ek k i ng i n N epal 3 m onths ago but has been w el l
si nce, ex cept f or the r ash. Her f am i l y hi stor y i s negati v e f or atopi c di seases
such as al l er gi c r hi ni ti s, asthm a, or eczem a. Her phy si cal ex am i nati on
f i ndi ngs ar e nor m al ex cept f or the pr esence of er y them atous, papul ar
w heal s l ocated ov er her tr unk , back , and ar m s, w hi ch bl anch w i th pr essur e.
The l esi ons ar e 5 to 25 m m i n di am eter and of ten ov er l ap. She ex hi bi ts
der m atogr aphi sm . Her com pl ete bl ood count(CBC) i s nor m al and the
er y thr ocy te sedi m entati on r ate (ESR) i s 11 m m per hour (nor m al ).
1. What causes of ur ti car i a shoul d be consi der ed i n thi s w om an?
2. What di agnosti c appr oach shoul d be tak en i n thi s pati ent?
3. What ther apeuti c appr oach i s desi r abl e?
4. What i s the pr ognosi s i n thi s pati ent i f no speci f i c al l er gen i s
i denti f i ed?
Case Discussion
1. What causes of ur ti car i a shoul d be consi der ed i n thi s w om an?
The m ost com m on cause of acute ur ti car i a i s an al l er gi c r eacti on to a
f ood or dr ug. By contr ast, usual l y no ex ter nal cause i s f ound i n 80% to
90% of the pati ents w i th chr oni c ur ti car i a. As a gr oup, these pati ents
ar e not atopi c; that i s, the pr ev al ence of eczem a, al l er gi c r hi ni ti s, or
asthm a i s not i ncr eased. The pr esence of der m atogr aphi sm i ndi cates a
gener al i ncr ease i n the sensi ti v i ty of the m ast cel l s and bl ood v essel s
i n the sk i n, but the cause of der m atogr aphi sm i s unk now n.
N ev er thel ess, i t i s i m por tant to tak e a car ef ul hi stor y to uncov er any
under l y i ng cause, i f pr esent. Al m ost any m edi cati on can cause
ur ti car i a. Bi r th contr ol pi l l s as w el l as ov er thecounter pr epar ati ons
such as aspi r i n, v i tam i ns, and col d tabl ets shoul d be consi der ed as
possi bl e cul pr i ts. Foods som eti m es cause chr oni c ur ti car i a and shoul d
be consi der ed i f i ndi cated by the pati ent's hi stor y .
U r ti car i a can al so be associ ated w i th under l y i ng sy stem i c i l l nesses such
as sy stem i c l upus er y them atosus, SjÃ¶gr en's sy ndr om e, r heum atoi d
ar thr i ti s, and hy per thy r oi di sm or hy pothy r oi di sm . These pati ents of ten
hav e el ev ated ESRs, and sk i n bi opsy speci m ens m ay r ev eal the
pr esence of tr ue v ascul i ti s w i th pol y m or phonucl ear i nf i l tr ates and the
deposi ti on of i m m unogl obul i ns and com pl em ent. Inf ecti ons ar e al so
r ar e causes of ur ti car i a, i ncl udi ng v i r al i nf ecti ons such as pr odr om al
i nf ecti ous hepati ti s or i nf ecti ous m ononucl eosi s, as w el l as hel m i nthi c
i nf ecti ons.
Cer tai nl y , any sy m ptom s or si gns of i nf ecti on shoul d be pur sued and
tr eated; how ev er , i t i s not w or thw hi l e to do speci f i c w or k ups i n pur sui t
of cr y pti c i nf ecti ons.
2. What di agnosti c appr oach shoul d be tak en i n thi s pati ent?
In di agnosi ng the cause of the ur ti car i a i n thi s pati ent, a good m edi cal
hi stor y and com pl ete phy si cal ex am i nati on ar e i m por tant to ex cl ude
any under l y i ng sy stem i c di sease. Som e speci al tests m ay be done to
i nv esti gate any cl ues r ev eal ed by the hi stor y . These m i ght i ncl ude f ood
sk i n tests f or a suspected f ood sensi ti v i ty or an
P. 11
â€œi cecube testâ€ of the sk i n i f col d ur ti car i a i s suspected. If no
cause i s appar ent, any under l y i ng sy stem i c di sease can be r ul ed out by
a CBC, ur i nal y si s, ESR, and bl ood chem i str y pr of i l e. Anti bodi es to
FcÎµRI hav e been descr i bed i n up to 40%, def i ni ng a subgr oup w i th
autoi m m une ur ti car i a.
If the pr esence of an el ev ated ESR suggests the possi bi l i ty of

v ascul i ti s, the f ol l ow i ng tests shoul d be consi der ed: CH 5 0 (total
hem ol y ti c com pl em ent), C 3 (thi r d com ponent of com pl em ent), C 4
(f our th com ponent of com pl em ent), sk i n bi opsy w i th i m m unof l uor escent
stai ni ng, hepati ti s B sur f ace anti gen and anti body (HBsAg and HBsAb),
cr y ogl obul i ns, anti nucl ear anti body , and ci r cul ati ng i m m une com pl ex es.
In thi s pati ent, i t i s not unr easonabl e to obtai n stool sam pl e to test f or
ov a and par asi tes because of her r ecent tr i p to N epal .
If none of these appr oaches i s successf ul i n r ev eal i ng a cause, hav e
the pati ent stop tak i ng bi r th contr ol pi l l s f or a m onth and obser v e the
ur ti car i a, untr eated.
3. What ther apeuti c appr oach i s desi r abl e?
Ther e i s no k now n â€œcur eâ€ f or ur ti car i a unl ess the al l er gen i s
i denti f i ed and el i m i nated. Other w i se, tr eatm ent i s ai m ed at pr ov i di ng
sy m ptom ati c r el i ef . Ty pe H 1 anti hi stam i nes such as di phenhy dr am i ne
[Benadr y l (Par k eDav i s, Mor r i s Pl ai ns, N J)] or hy dr ox y zi ne [Atar ax
(Roer i g, N ew Yor k , N Y)] ar e com m onl y used f i r st. For l onger ter m
tr eatm ent, f our nonsedati ng anti hi stam i nes ar e av ai l abl e: f ex of enadi ne
[Al l egr a (Hoechst Mar i on Roussel , Kansas Ci ty , MO) and gener i c],
l or atadi ne [Cl ar i ti n (Scher i ngPl ough, Madi son, N J) and gener i c],
ceti r i zi ne [Zy r tec (Pf i zer , N ew Yor k , N Y)], and desl or atadi ne/l or atadi ne
[Cl ar i nex /Cl ar i ti n (Scher i ngPl ough, Madi son, N J)]. Thi s f or m of
tr eatm ent i s based on the concept that m ast cel l s r el ease hi stam i ne,
and hi stam i ne i s the pr i m ar y of f ender i n ur ti car i a.
Com bi ni ng H 1 and H 2 anti hi stam i nes has al so been hel pf ul i n som e
pati ents. Shor t cour ses of cor ti coster oi ds m ay be used i n sev er e,
poor l y contr ol l ed cases; how ev er , the l ongter m use of ster oi ds shoul d
be av oi ded, i f possi bl e, because of the sev er e si de ef f ects associ ated
w i th these agents. Fi nal l y , som e al l er gi sts m ay tr y out an el i m i nati on
di et or a f ast i n sev er el y af f ected pati ents to r ul e out a f ood or
pr eser v ati v e al l er gy , ev en w hen no speci f i c agent i s suspected.
Pati ents w i th sev er e di sease m ay be tr eated w i th i m m unom odul ator y
dr ugs such as hy dr ochl or oqui n, sul phasal azi ne, or cy cl ospor i n.
4. What i s the pr ognosi s i n thi s pati ent i f no speci f i c al l er gen i s

i denti f i ed?
Assum i ng that no cause has been f ound, and ther e i s no autoi m m une
di sease pr esent, the pr ognosi s i s qui te good. The si gns and sy m ptom s
al m ost al w ay sdi sappear w i thi n 2 y ear s, but the r eason f or thi s i s not
k now n.
Suggested Readings
Bax i S, Di nak ar C. U r ti car i a and angi oedem a. Im m unol Al l er gy Cl i n
N or th Am 2005;25:353.
Di bber n DA Jr . U r ti car i a: sel ected hi ghl i ghts and r ecent adv ances. Med
Cl i n N or th Am 2006;90:187.
Var adar ajul u S. U r ti car i a and angi oedem a. Contr ol l i ng acute epi sodes,
copi ng w i th chr oni c cases. Postgr ad Med 2005;117:25.
P. 12
Monoclonal Gammopathy
1. What i s the def i ni ti on of a m onocl onal gam m opathy ?
2. What cl i ni cal pi ctur es ar e seen i n pati ents w i th m onocl onal
gam m opathi es?
Discussion
1. What i s the def i ni ti on of a m onocl onal gam m opathy ?
A m onocl onal gam m opathy i s def i ned as the ov er pr oducti on of a
par ti cul ar i m m unogl obul i n pr otei n by a si ngl e cl one of ov er acti v e or
m al i gnant B cel l s. Thi s cl one can pr oduce a w hol e i m m unogl obul i n,
com posed of both heav y and l i ght chai ns, or i t can pr oduce just heav y
chai ns, just l i ght chai ns, or a com bi nati on of w hol e i m m unogl obul i n
pl us ex cess l i ght chai ns. The m onocl onal l i ght chai ns ar e cal l edBence
Jones pr otei n.
2. What cl i ni cal pi ctur es ar e seen i n pati ents w i th m onocl onal
gam m opathi es?
Som e m onocl onal ser um i m m unogl obul i ns ar e di scov er ed i nci dental l y .
These ar e usual l y sm al l (< 2 g/dL) and ther e ar e no associ ated si gns,
sy m ptom s, or l abor ator y abnor m al i ti es. Pati ents w i th pl asm a cel l
(m ul ti pl e) m y el om a usual l y pr esent w i th back pai n (v er tebr al f r actur e
or com pr essi on), anem i a, hy per cal cem i a, and of ten r enal di sease. The
cl i ni cal pi ctur e of Wal denstr om 's m acr ogl obul i nem i a r esem bl es that of
a l y m phom a, and consi sts of f ev er , l y m phadenopathy , and som eti m es
hepatospl enom egal y . Hy per v i scosi ty can be a com ponent of thi s
sy ndr om e. Li ght chai n di sease can pr esent as am y l oi dosi s.
Case
A 62y ear ol d m an i s seen i n the ED because of a r i ght upper quadr ant
abdom i nal pai n of 5 day s' dur ati on. The pai n r adi ates ar ound to hi s back and
i s w or se w i th m ov em ent and coughi ng. He deni es nausea, v om i ti ng, or a
change i n hi s bow el habi ts but adm i ts to hav i ng i nter m i ttent epi gastr i c pai n,
f r equent ni ght sw eats, a f eel i ng of â€œw eak ness, â€ gener al m al ai se, and a
15pound (6. 75k g) w ei ght l oss ov er the l ast y ear . Hi s past m edi cal hi stor y
i s r em ar k abl e f or a back i njur y i ncur r ed f r om a m otor v ehi cl e acci dent 10
y ear s bef or e and the pr esence of m i l d hy per tensi on. Hi s phy si cal
ex am i nati on f i ndi ngs ar e unr em ar k abl e, ex cept f or the f ol l ow i ng. Hi s bl ood
pr essur e i s 150/110 m m Hg. He has a gr ade 2/6 sy stol i c ejecti on m ur m ur
that can be hear d al ong the l ef t ster nal bor der . Rectal ex am i nati on r ev eal s
a 2+ pr ostate. Hi s stool i s hem e negati v e. A sl i ght k y phosi s i s noted and
ther e i s questi onabl e decr eased sensati on to pi npr i ck al ong the r i ght l ow er
r i b cage (T9 di str i buti on). A chest r adi ogr aphi c study , CBC, and chem i str y
panel ar e per f or m ed. The chest r adi ogr aph show s no i nf i l tr ates, but a
com pr essi on f r actur e of undeter m i ned age i s noted at T9. Hi s hem ogl obi n i s
10 g/dL; hem atocr i t, 31%; and pl atel et count, 275, 000. Hi s chem i str y panel
show s ser um cr eati ni ne, 2. 2 m g/dL; bl ood ur ea ni tr ogen, 22 m g/dL; total
pr otei n, 10. 2 m g/dL (nor m al , 6. 8 to 8. 4 m g/dL); al bum i n, 3. 1 m g/dL
(nor m al , 3. 7 to 4. 9 m g/dL); and cal ci um , 11. 0 m g/dL (nor m al , 8. 5 to 10. 0
m g/dL). You concl ude that hi s pai n i s m ost l i k el y due to the T9 com pr essi on
f r actur e. Because of concer n about hi s r enal i nsuf f i ci ency , y ou av oi d
pr escr i bi ng N SAIDs but i nstead pr escr i be
P. 13
acetam i nophen w i th codei ne. You or der som e addi ti onal l abor ator y studi es
on the ex tr a tubes of bl ood sam pl es bef or e the pati ent i s di schar ged.
1. If y ou w er e consi der i ng a di agnosi s of a m onocl onal gam m opathy

(w hi ch y ou shoul d hav e), w hat scr eeni ng test w oul d y ou or der ?
2. What f ur ther i m m unol ogi c tests shoul d be or der ed?
3. What f ur ther tests ar e i m por tant i n thi s case?
4. What i s the i m m unol ogi c capabi l i ty of thi s pati ent w ho has ex cess
gam m a gl obul i n?
5. What i s the cur r ent tr eatm ent f or such a pati ent?
Whi l e y ou ar e ev al uati ng thi s pati ent, y our col l eague l ear ns of y our
ex per ti se i n thi s f i el d and ask s y ou about a 61y ear ol d m an w i th
atopi c der m ati ti s w ho had the i nci dental f i ndi ng of a hi gh pr otei nto
al bum i n r ati o on a com pr ehensi v e chem i str y panel . A scr eeni ng (SPEP),
has show n a m onocl onal band, w hi ch has been i denti f i ed as IgM k on
i m m unof i x ati on el ectr ophor esi s (IFE). The band w as quanti f i ed at 2. 0
g/dL.
6. What cour se of acti on do y ou r ecom m end i n the 61y ear ol d pati ent?
7. What i s the di agnosi s i n the pati ent descr i bed i n questi on 6, and w hat
i s the pr ognosi s?
Case Discussion
1. If y ou w er e consi der i ng a di agnosi s of a m onocl onal gam m opathy
(w hi ch y ou shoul d hav e), w hat scr eeni ng test w oul d y ou or der ?
The scr eeni ng test that shoul d be or der ed i n thi s pati ent i s an SPEP,
w hi ch show s a m onocl onal spi k e i n m ost cases. The cl i ni cal suspi ci on
f or m y el om a shoul d be hi gh because he ex hi bi ts the cl assi c tr i ad of
anem i a, back pai n, and r enal i nsuf f i ci ency , w hi ch i s associ ated w i th
m ul ti pl e m y el om a. The m ost com m on pr esenti ng com pl ai nt i s back
pai n. Mul ti pl e m y el om a i s the m ost com m on l y m phor eti cul ar neopl asm
i n nonw hi te m en and the thi r d m ost com m on i n w hi tes. Its annual
i nci dence i s 3 i n 100, 000, and m or e than 90% of al l af f ected pati ents
ar e ol der than 40 y ear s. Other f actor s that i m pl i cate m ul ti pl e m y el om a
i n thi s case ar e the el ev ated total ser um pr otei n content and the
r el ati v el y decr eased al bum i n l ev el . These suggest that ther e i s an
i ncr ease i n the gl obul i n f r acti on.
2. What f ur ther i m m unol ogi c tests shoul d be or der ed?
Fur ther i m m unol ogi c tests that shoul d be done i ncl ude an IFE, w hi ch
can i denti f y the heav y and l i ght chai ns i n the m onocl onal pr otei n. A
ur i ne el ectr ophor esi s can i denti f y the spi l l i ng of l i ght chai ns (Bence
Jones pr otei n) or , i f the gl om er ul us i s dam aged, the pr esence of
com pl ete m onocl onal pr otei n.
3. What f ur ther tests ar e i m por tant i n thi s case?
A sk el etal sur v ey i s an i m por tant addi ti onal test to docum ent the
ex tent of bone di sease. In thi s si tuati on i t i s better than a bone scan.
The sk el etal sur v ey shoul d i ncl ude the sk ul l , com pl ete spi ne (both
anter oposter i or and l ater al v i ew s), the pel v i s, and the chest. A
com puted tom ogr aphi c scan of the abdom en w oul d be usef ul onl y i f a
sol i tar y ex tr am edul l ar y pl asm acy tom a i s suspected.
P. 14
A bone m ar r ow aspi r ati on i s essenti al to conf i r m the di agnosi s. In al l
but the r ar est cases, cl um ps and sheets of pl asm a cel l s ar e seen.
A ser um cal ci um deter m i nati on i s needed because hy per cal cem i a can
pr oduce sy m ptom s such as l ethar gy , nausea, and v om i ti ng. El ev ated
v al ues f or Î²2 m acr ogl obul i n, Cr eacti v e pr otei n, and l actate
dehy dr ogenase suggest a m or e di r e pr ognosi s.
4. What i s the i m m unol ogi c capabi l i ty of thi s pati ent w ho has ex cess
gam m a gl obul i n?
The i m m unol ogi c capabi l i ty i n thi s pati ent i s pr obabl y com pr om i sed,
such that he i s suscepti bl e to hi ghgr ade bacter i al pathogens. The
ex cess i m m unogl obul i n r epr esented by the spi k e on SPEP i s usel ess i n
f i ghti ng i nf ecti on, and i t i s l i k el y that he i s sev er el y depl eted of nor m al
pol y cl onal gam m a gl obul i ns. In f act, these pati ents ar e f uncti onal l y
hy pogam m agl obul i nem i c. They ar e pr one to i nf ecti ons w i th py ogeni c
or gani sm s, and they do not pr oduce adequate anti bodi es af ter
pr ophy l acti c i m m uni zati ons. They shoul d be car ef ul l y w atched f or ear l y
si gns of i nf ecti on. Som e phy si ci ans pr escr i be m onthl y IV gam m a
gl obul i n.
5. What i s the cur r ent tr eatm ent f or such a pati ent?
Mel phal an and pr edni sone consti tute the chem other apy m ost of ten used
to tr eat m y el om a. Bone m ar r ow tr anspl antati on i s bei ng used m or e
f r equentl y . Thal i dom i de has al so been show n to be ef f ecti v e.
6. What cour se of acti on do y ou r ecom m end i n the 61y ear ol d pati ent?
For the second pati ent, y ou r ecom m end that a detai l ed ex am i nati on be
under tak en f or l y m phadenopathy , hepatospl enom egal y , anem i a,
hy per cal cem i a, l y ti c bone l esi ons, and Bence Jones pr otei n. Ev er y thi ng
r etur ns nor m al . Si nce the m onocl onal spi k e i s IgM, a v er y l ar ge pr otei n
(850 k d) that pr edi sposes to hy per v i scosi ty , y ou r ecom m end that the
ser um v i scosi ty be deter m i ned. Thi s too pr ov es to be nor m al .
7. What i s the di agnosi s i n the pati ent descr i bed i n questi on 6, and w hat
i s the pr ognosi s?
Thi s i s the cl i ni cal pi ctur e of m onocl onal gam m opathy of undeter m i ned
si gni f i cance, w hi ch consi sts of a sm al l m onocl onal ser um spi k e
(gener al l y l ess than 2. 0 g/dL) w i thout other si gns, sy m ptom s, or
l abor ator y i ndi cati ons of m y el om a or m acr ogl obul i nem i a. The pr ognosi s
i n these pati ents i s uncl ear . Som e pati ents pr ogr ess to f r ank di sease;
other s do not. The best pl an i s to obser v e the pati ent by per f or m i ng a
phy si cal ex am i nati on and scr eeni ng SPEP ev er y 6 to 12 m onths.
Suggested Readings
Hi deshi m a T, Ber gsagel PL, Kuehl WM, etal . Adv ances i n bi ol ogy of
m ul ti pl e m y el om a: cl i ni cal appl i cati ons. Bl ood 2004;104:607â€“618.
Ky l e RA, Rajk um ar SV. Mul ti pl e m y el om a. N Engl J Med 2004;351

(18):1860; [Er r atum appear s i n N Engl J Med 2005;352(11):1163].
Ky l e RA, Rajk um ar SV. Monocl onal gam m opathi es of undeter m i ned
si gni f i cance. Bai l l i er e's Best Pr act Cl i n Haem atol 2005;18:689.
Ter pos E, Di m opoul os MA. My el om a bone di sease: pathophy si ol ogy and
m anagem ent. Ann Oncol 2005;16:1223.
P. 15
Penicillin Allergy
1. What ar e the cl i ni cal pi ctur es that can r esul t f r om an al l er gy to
peni ci l l i n?
2. What ar e the i m m unol ogi c m echani sm s r esponsi bl e f or the cl i ni cal

sy ndr om es associ ated w i th peni ci l l i n al l er gy ?
Discussion
1. What ar e the cl i ni cal pi ctur es that can r esul t f r om an al l er gy to
peni ci l l i n?
Ther e ar e tw o categor i es of cl i ni cal pi ctur es that can r esul t f r om
peni ci l l i n al l er gy : acute and subacute. Peni ci l l i n al l er gi es can be
m edi ated by IgE or IgG anti bodi es. The acute al l er gi c r eacti on can ar i se
i m m edi atel y or r api dl y , w i thi n a m atter of m i nutes to an hour or tw o.
It can i ncl ude sudden anaphy l ax i s w i th hy potensi on, or asthm a, r hi ni ti s,
and ur ti car i a (see questi on 1 under the secti on on Anaphy l ax i s).
Conti nued peni ci l l i n adm i ni str ati on can cause conti nued sy m ptom s. A
l ess dr am ati c pi ctur e m ay occur 7 to 10 day s af ter peni ci l l i n tr eatm ent
star ts, or 1 to 2 day s af ter r epeat ther apy . In thi s setti ng, the pi ctur e
i s subacute and can i ncl ude ur ti car i a, f ev er , and ar thr al gi as or
ar thr i ti s, and r ar el y nephr i ti s or neur i ti s.
2. What ar e the i m m unol ogi c m echani sm s r esponsi bl e f or the cl i ni cal

sy ndr om es associ ated w i th peni ci l l i n al l er gy ?
Acute r eacti ons r esul t f r om peni ci l l i n r eacti ng w i th pr ef or m ed IgE to
peni ci l l i n, a r esul t of pr ev i ous peni ci l l i n tr eatm ent that m ay hav e
pr oduced no v i si bl e al l er gi c r eacti on. The IgE i s bound to FcÎµRI on
m ast cel l s and basophi l s. When the peni ci l l i n hapten bi nds to the IgE,
the m ast cel l s and basophi l s degr anul ate, r el easi ng hi stam i ne and other
m edi ator s. These substances ar e r esponsi bl e f or pr oduci ng the si gns
and sy m ptom s. The subacute r eacti on i s caused by pr ef or m ed IgG to
peni ci l l i n, al so a r esul t of pr ev i ous peni ci l l i n tr eatm ent. The IgG f i x es
com pl em ent. The com bi nati on of peni ci l l i n and the IgG anti body f or m
an i m m une com pl ex . When thi s i s deposi ted i n the ti ssue, com pl em ent
i s acti v ated and the com pl em ent br eak dow n pr oducts pr oduce
i nf l am m ati on. The i nf l am m ati on i s r esponsi bl e f or the si gns and
sy m ptom s i n the or gans w her e the i m m une com pl ex es l odge, such as
the sk i n, joi nts, and k i dney s.
Case
A 26y ear ol d w om an w ho has m i tr al stenosi s r equi r es ex tensi v e dental
sur ger y . Peni ci l l i n pr ophy l ax i s agai nst str eptococci i s i ndi cated, but the
pati ent i s al l er gi c to peni ci l l i n. She states that 15 y ear s ago she had hi v es
and w heezi ng 30 m i nutes af ter she had tak en or al peni ci l l i n.
1. How w oul d y ou deter m i ne w hether the pati ent i s l i k el y to hav e an
al l er gi c r eacti on i f she i s tr eated w i th peni ci l l i n now ?
2. What do y ou do i f the sk i n test r esul t to peni ci l l i n i s posi ti v e?
3. What i s the pr ev al ence of al l er gi c cr osssensi ti v i ty betw een peni ci l l i n
and cephal ospor i ns?
4. If the pati ent's sk i n test r esul t to peni ci l l i n pr ov es to be negati v e, how
cer tai n i s i t that she i s not al l er gi c?
P. 16
5. If the sk i n test r esul t to peni ci l l i n i s posi ti v e, coul d y ou av oi d a
r eacti on by gi v i ng peni ci l l i n or al l y i nstead of by i njecti on?
6. If peni ci l l i n m ust be used because ther e i s no acceptabl e al ter nati v e,
can thi s pati ent be r api dl y desensi ti zed?
Case Discussion
1. How w oul d y ou deter m i ne w hether the pati ent i s l i k el y to hav e an
al l er gi c r eacti on i f she i s tr eated w i th peni ci l l i n now ?
Sk i n testi ng f or peni ci l l i n can be an ex tr em el y usef ul pr ocedur e f or

deter m i ni ng w hether a pati ent, w ho has a hi stor y of peni ci l l i n al l er gy
and i n w hom an IgEm edi ated i m m unol ogi c m echani sm i s suspected, i s
l i k el y to hav e an al l er gi c r eacti on to a l ater ex posur e to peni ci l l i n. If
al l of the r eagents ar e av ai l abl e, the r el i abi l i ty of these tests has been
as hi gh as 96% i n studi es of pati ents w ho had a hi stor y of al l er gy ,
w hose sk i n test r esul ts w er e negati v e, and w ho w er e subsequentl y
chal l enged w i th peni ci l l i n. The testi ng shoul d be done by a per son
f am i l i ar w i th the pr ocedur e. The r eagents used i ncl ude hi stam i ne (the
posi ti v e contr ol ), sal i ne (the negati v e contr ol ), peni ci l l oy l pol y l y si ne
(Pr ePen), the m i nor deter m i nant m i x (MDM), and the peni ci l l i n that
w i l l be used f or tr eatm ent. For the test r esul t to be posi ti v e, the
pati ent m ust show a posi ti v e r eacti on to hi stam i ne, a negati v e r eacti on
to sal i ne, and a posi ti v e r eacti on to Pr ePen, MDM, and/or the nati v e
peni ci l l i n. The posi ti v e r eacti on consi sts of a w heal and f l ar e that
appear s i n 15 m i nutes. U nf or tunatel y , because of the r ar e need f or thi s
test and ex tr em e cauti on by the U . S. Food and Dr ug Adm i ni str ati on
(FDA), nei ther Pr ePen nor the MDM i s av ai l abl e. For thi s r eason, w e
al m ost al w ay s use al ter nati v e dr ugs. If the hi stor y i s not suggesti v e of
a ty pe I i m m edi ate hy per sensi ti v i ty r eacti on and no al ter nati v e dr ugs
ar e sati sf actor y , a test dose i s gi v en under contr ol l ed condi ti ons. If the
hi stor y i s suggesti v e of a ty pe I r eacti on and no al ter nati v e dr ug i s
av ai l abl e, w e can desensi ti ze the pati ent (see questi on 6 i n f ol l ow i ng
tex t).
2. What do y ou do i f the sk i n test r esul t to peni ci l l i n i s posi ti v e?
Fi r st, y ou al w ay s l ook f or an ef f ecti v e nonpeni ci l l i n dr ug substi tute and
use i t. If one i s not f ound, consi der desensi ti zi ng the pati ent to
peni ci l l i n.
3. What i s the pr ev al ence of al l er gi c cr osssensi ti v i ty betw een peni ci l l i n

and cephal ospor i ns?
The cephal ospor i ns r esem bl e the peni ci l l i ns chem i cal l y , but the tr ue
pr ev al ence of cr ossr eacti v i ty betw een sem i sy ntheti c peni ci l l i ns and
cephal ospor i ns i s not k now n because i nv esti gator s ci te di scor dant
r esul ts. A r easonabl e esti m ate i s that 5% of peni ci l l i nal l er gi c pati ents
ar e sensi ti v e to thi r dgener ati on cephal ospor i ns.
4. If the pati ent's sk i n test r esul t to peni ci l l i n pr ov es to be negati v e, how
cer tai n i s i t that she i s not al l er gi c?
Assum i ng that the enti r e panel of sk i n tests (i ncl udi ng the contr ol s)
w er e done pr oper l y and the r esul ts i nter pr eted cor r ectl y , a negati v e
sk i n test r esul t i s a r el i abl e
P. 17
i ndi cator that an acute IgEm edi ated r eacti on w i l l not occur . How ev er ,
the sk i n test has no bear i ng on IgGm edi ated r eacti ons.
5. If the sk i n test r esul t to peni ci l l i n i s posi ti v e, coul d y ou av oi d a

r eacti on by gi v i ng peni ci l l i n or al l y i nstead of by i njecti on?
N o. Or al peni ci l l i n can al so sensi ti ze and el i ci t an acute r eacti on i n
al r eady sensi ti zed i ndi v i dual s.
6. If peni ci l l i n m ust be used because ther e i s no acceptabl e al ter nati v e,
can thi s pati ent be r api dl y desensi ti zed?
Yes. How ev er , thi s i s a potenti al l y danger ous and al w ay s ti m e

consum i ng pr ocedur e. It shoul d be done i n the i ntensi v e car e uni t by an
ex per i enced al l er gi st usi ng publ i shed pr otocol s.
Suggested Readings
Gr uchal l a RS, Pi r m oham ed M. Cl i ni cal pr acti ce. Anti bi ot al l er gy . N Engl J
Med 2006;354:601.
Pi chi cher o ME. A r ev i ew of ev i dence suppor ti ng the Am er i can Academ y

of Pedi atr i cs r ecom m endati on f or pr escr i bi ng cephal ospor i n anti bi oti cs
f or peni ci l l i nal l er gi c pati ents. Pedi atr i cs 2005;115:1048.
Title : Inte rna l Me dic ine Ca s e book , The : Re a l P a tie nts , Re a l Ans w e rs , 3rd Edition
> T a b le o f C o nte nts > C ha p te r 2 C a r d io lo g y
Chapter 2
Cardiology
Simon Sha k a r
Rona ld Zolty
Joa nn Linde nfe ld
Acute Pericarditis and Cardiac Tamponade
1. What ar e the m ost com m on causes of acute per i car di ti s?
2. What i s car di ac tam ponade?
3. Does acute per i car di ti s of ten r esul t i n car di ac tam ponade?
4. What ar e the si gns and sy m ptom s of per i car di ti s and tam ponade?
5. How i s the echocar di ogr am hel pf ul i n the di agnosi s of per i car di ti s or tam ponade?
6. What i s the tr eatm ent f or car di ac tam ponade?
P. 19
Discussion
1. What ar e the m ost com m on causes of acute per i car di ti s?
The m ost com m on causes of acute per i car di ti s ar e i di opathi c, v i r al i nf ecti on, ur em i a, m y ocar di al
i nf ar cti on MI), tr aum a, car di ac sur ger y , and neopl asm .
2. What i s car di ac tam ponade?
Car di ac tam ponade r esul ts f r om accum ul ati on of f l ui d w i thi n the per i car di um . As f l ui d accum ul ates,
i ntr aper i car di al pr essur e i ncr eases, l i m i ti ng f i l l i ng of the hear t and r educi ng str ok e v ol um e. As
i ntr aper i car di al pr essur e r i ses, car di ac f i l l i ng i s i ncr easi ngl y l i m i ted. U l ti m atel y , pr essur es equal i ze
i n the l ef t atr i um , pul m onar y v ascul atur e, r i ght atr i um , and super i or v ena cav a (SVC); v entr i cul ar
f i l l i ng i s pr ogr essi v el y i m pai r ed and ci r cul ator y col l apse ensues.
3. Does acute per i car di ti s of ten r esul t i n car di ac tam ponade?
Acute per i car di ti s r esul ts i n tam ponade onl y r ar el y . Tam ponade i s m or e com m on i n endstage r enal
di sease and neopl asti c di sease despi te the f r equent absence of an i denti f i abl e epi sode of acute
per i car di ti s i n these condi ti ons.
4. What ar e the si gns and sy m ptom s of per i car di ti s and tam ponade?
The m ost com m on sy m ptom of acute per i car di ti s i s chest pai n. The pai n i s gener al l y shar p and i s
w or se w i th cough, deep i nspi r ati on, and r ecum bency . A per i car di al f r i cti on r ub i s the m ost com m on
f i ndi ng i n acute per i car di ti s. It of ten has thr ee com ponents that occur i n sy stol e, and ear l y and l ate
di astol e w hen the hear t i s m ov i ng and the per i car di al sur f aces r ub agai nst one another . Sy m ptom s
of tam ponade depend on the degr ee of hem ody nam i c com pr om i se. The com m on sy m ptom s of
per i car di al ef f usi on w i th tam ponade i ncl ude dy spnea (80%), cough (30%), or thopnea (25%), and
chest pai n (20%). The com m on si gns of per i car di al ef f usi on w i th tam ponade ar e jugul ar v enous
di stensi on and tachy car di a (both near l y 100%), pul sus par adox us (89%), sy stol i c bl ood pr essur e â
‰¤90 m m Hg (52%), and per i car di al r ub (22%).
5. How i s the echocar di ogr am hel pf ul i n the di agnosi s of per i car di ti s or tam ponade?
The echocar di ogr am i s the m ost accur ate and easi l y av ai l abl e tool to detect and quanti f y
per i car di al f l ui d. How ev er , i t i s of ten not of di agnosti c v al ue i n acute per i car di ti s because the
absence of per i car di al f l ui d does not ex cl ude the di agnosi s of acute per i car di ti s, especi al l y i n
i di opathi c or v i r al per i car di ti s. In pati ents w i th per i car di ti s due to neopl asm , bacter i al i nf ecti on,
tr aum a, or car di ac sur ger y , the echocar di ogr am m ay pr ov i de hel pf ul i nf or m ati on about the eti ol ogy
of the ef f usi on. For ex am pl e, m etastases m ay be v i si bl e on the per i car di al sur f aces.
The echocar di ogr am i s the m ost com m onl y used techni que f or the di agnosi s of car di ac tam ponade.
Ty pi cal f i ndi ngs i n addi ti on to the pr esence of per i car di al f l ui d i ncl ude r i ght atr i al and r i ght
v entr i cul ar di astol i c col l apse, ex agger ated r espi r ator y changes i n tr i cuspi d and m i tr al v al v e f l ow ,
and pl ethor a of the i nf er i or v ena cav a. Because the l i m i tati on of car di ac f i l l i ng i s pr ogr essi v e as
the ef f usi on i ncr eases, f i ndi ngs of tam ponade m ay be detected by
P. 20
echocar di ogr am bef or e the cl assi cal l y descr i bed cl i ni cal tr i ad of hy potensi on, par adox i cal pul se,
and i ncr eased sy stem i c v enous pr essur e.
6. What i s the tr eatm ent f or car di ac tam ponade?
Car di ac tam ponade r equi r es i m m edi ate tr eatm ent to r el i ev e the i ncr eased enddi astol i c pr essur e
and i nadequate v entr i cul ar f i l l i ng. The tr eatm ent of car di ac tam ponade consi sts of w i thdr aw al of
f l ui d f r om the per i car di al space, gener al l y thr ough a needl e i nser ted per cutaneousl y â€”a pr ocedur e
cal l ed per i car di ocentesi s. Per i car di ocentesi s m ay be per f or m ed usi ng echocar di ogr aphi c gui dance to
pl ace a needl e or a catheter i n the i ntr aper i car di al space or i n the car di ac catheter i zati on
l abor ator y usi ng f l uor oscopi c gui dance. Intr av enous (IV) f l ui ds such as bl ood or sal i ne m ay be
used, but onl y as a tem por i zi ng m easur e. Vol um e adm i ni str ati on i s usef ul onl y i n hy pov ol em i c
pati ents. In nor m ov ol em i c pati ents, the adm i ni str ati on of f l ui d m ay ex acer bate the i ntr aper i car di al
pr essur e.
Case
A 78y ear ol d m an w i th a past hi stor y r em ar k abl e onl y f or gout i s seen because of the acute onset of
chest pai n. He descr i bes a 4day pr odr om e of r hi nor r hea, nonpr oducti v e cough, m y al gi as, and anor ex i a.
Appr ox i m atel y 8 hour s bef or e he i s seen i n the em er gency r oom (ER), he began to noti ce the gr adual
onset of shar p subster nal chest pai n, w or se w i th i nspi r ati on, r el i ev ed by si tti ng up, and associ ated w i th
di aphor esi s.
The pai n i s sl i ghtl y w or se w i th ex er ti on but i s not r el i ev ed by subl i ngual ni tr ogl y cer i n (N TG)
adm i ni ster ed i n the ER, al though m or phi ne sul f ate and ox y gen do seem to al l ev i ate hi s di scom f or t. Hi s
tem per atur e i s 101Â°F (38. 5Â°C), hi s hear t r ate i s 105 beats per m i nute and r egul ar , hi s r espi r ator y
r ate i s 17 per m i nute, and hi s bl ood pr essur e i s 105/65 m m Hg. The r em ai nder of the phy si cal
ex am i nati on i s nor m al . The el ectr ocar di ogr am (ECG) i s i nter pr eted by the ER staf f to show â€œsi nus
tachy car di a w i th STsegm ent el ev ati ons i nf er i or l y and nonspeci f i c ST and Tw av e changes el sew her e. â€
An ar ter i al bl ood gas deter m i nati on per f or m ed on r oom ai r show s nor m al ar ter i al ox y genati on. The
chest r adi ogr aphi c study i s nor m al .
The ER staf f star ts an IV hepar i n dr i p and a pl atel et gl y copr otei n IIbIIIa i nhi bi tor i nf usi on f or the
tr eatm ent of a pr esum ed acute cor onar y sy ndr om e (ACS). An IV N TG i nf usi on and ox y gen ther apy ar e
i nsti tuted but, despi te these m easur es, the pai n conti nues. The car di ac catheter i zati on team i s cal l ed to
consi der cor onar y angi ogr aphy . Antaci d ther apy does not r el i ev e the pai n and onl y m or phi ne sul f ate
seem s to of f er r el i ef . Bl ood tests r ev eal a nor m al tr oponi n, nor m al el ectr ol y tes, nor m al Ddi m er , and
nor m al r enal f uncti on. The hem ogl obi n i s nor m al but the w hi te bl ood cel l count i s m i l dl y el ev ated.
The pati ent i s tak en to the catheter i zati on l abor ator y and hi s cor onar y angi ogr am r ev eal s di f f use, m i l d,
nonobstr ucti v e cor onar y ar ter y di sease (CAD). The IIbIIIa i nhi bi tor i s di sconti nued. When the pati ent i s
tr ansf er r ed to the cor onar y car e uni t, the ECG show s conti nued â€œev ol uti onâ€ w i th STsegm ent
el ev ati ons of l ess than 2 m m i n l eads I, II, III, aVL, aVF, and V 2 to V 6 that do not r espond to IV N TG.
The pati ent's chest pai n per si sts.
Fur ther i ncr em ents of N TG ar e gi v en i n an IV i nf usi on and the pati ent's bl ood pr essur e begi ns to
decr ease. Af ter 2 hour s, the pati ent conti nues to w r i the i n pai n, com pl ai ns of f eel i ng di zzy and hav i ng a
sev er e headache, and v om i ts af ter the f i f th dose of IV m or phi ne
P. 21
sul f ate. You ar e ask ed to see the pati ent and y our ex am i nati on r ev eal s si nus tachy car di a, a bl ood
pr essur e of 82/50 m m Hg (no pul sus par adox us), a r espi r ator y r ate of 16 per m i nute, a tem per atur e of
101Â°F (38. 5Â°C), cl ear l ung f i el ds, and no el ev ati on i n the jugul ar v enous pr essur e, but a thr ee
com ponent per i car di al f r i cti on r ub i s hear d ov er the pr ecor di um . The hem ogl obi n l ev el i s stabl e.
1. What i s the m ost l i k el y cl i ni cal di agnosi s of thi s pati ent's chest pai n?
2. On the basi s of y our cl i ni cal i m pr essi on of thi s pati ent's pr esentati on, w hat f eatur es w oul d be
ex pected on the ECG?
3. Is a nor m al tr oponi n hel pf ul i n acute MI?
4. What i s the m ost ef f ecti v e tr eatm ent f or acute per i car di ti s?
5. What i s the m ost l i k el y cause of the hy potensi on i n thi s pati ent
Case Discussion
1. What i s the m ost l i k el y cl i ni cal di agnosi s of thi s pati ent's chest pai n?
The m ost l i k el y cl i ni cal di agnosi s of thi s pati ent's chest pai n i s acute i di opathi c or v i r al
per i car di ti s. Rel ati v el y com m on causes of acute chest pai n that m ust be consi der ed ar e MI or ACS,
per i car di ti s, aor ti c di ssecti on, pneum oni a, pul m onar y em bol us, costochondr i ti s, and pneum othor ax .
The per ti nent f eatur es of the hi stor y and phy si cal ex am i nati on that l ead to thi s di agnosi s ar e that
the pai n w as pr eceded by a v i r al pr odr om e and w as v er y cl ear l y posi ti onal and ex acer bated by
i nspi r ati on, w hi ch str ongl y suggests per i car di al pai n. Per i car di al pai n does not i m pr ov e w i th N TG,
but the l ack of r esponse to N TG does not ex cl ude an acute MI. The pati ent's v i tal si gns w er e stabl e
ex cept f or a sl i ght f ev er and tachy car di a that ar e al so v er y f r equent i n ei ther acute per i car di ti s or
MI. The absence of tachy pnea, together w i th the nor m al ex am i nati on f i ndi ngs and nor m al Ddi m er ,
m ak e acute pul m onar y em bol i zati on unl i k el y . Acute costochondr i ti s i s of ten posi ti onal but
associ ated w i th ex qui si te pai n on pal pati on of the i nv ol v ed costochondr al juncti on, and i s not
associ ated w i th ECG changes. If the ex am i nati on and chest r adi ogr aphi c f i ndi ngs ar e nor m al and
ther e i s no past hi stor y of sm ok i ng, f or cef ul coughi ng, or tr aum a, the l i k el i hood of acute
pneum othor ax i s l ow .
The r em ai ni ng tw o di agnoses, acute per i car di ti s v er sus MI, can of ten be di f f er enti ated on the basi s
of the hi stor y and phy si cal ex am i nati on f i ndi ngs, the ECG, and tr oponi n. The shar p qual i ty of the
subster nal chest pai n, w hi ch i s associ ated m or e w i th the r ecum bent posi ti on, deep br eathi ng, and
coughi ng, and w hi ch i s i m pr ov ed by si tti ng up, i s aty pi cal f or MI but a cl assi c sy m ptom of
per i car di ti s. The ECG w as i ni ti al l y m or e consi stent w i th per i car di ti s but an acute MI coul d not be
ex cl uded. The absence of si gni f i cant cor onar y obstr ucti on str ongl y ar gued agai nst an acute MI, a
f i ndi ng conf i r m ed by the nor m al tr oponi n.
2. On the basi s of y our cl i ni cal i m pr essi on of thi s pati ent's pr esentati on, w hat f eatur es w oul d be
ex pected on the ECG?
Si nus tachy car di a and STsegm ent el ev ati on ar e of ten the ear l i est ECG f i ndi ngs, al though the
absence of ECG changes does not ex cl ude the di agnosi s of per i car di ti s.
P. 22
The ty pi cal changes of acute per i car di ti s of ten ev ol v e ov er hour s or day s and ar e thought to be
caused by a m y ocar di al cur r ent of i njur y due to i nf l am m ati on. The ECG i n acute per i car di ti s ev ol v es
usual l y thr ough f our stages ov er sev er al day s. Ther e i s ear l y di f f use STsegm ent el ev ati on i n stage
1. Thi s di f f er s f r om the STsegm ent el ev ati on of acute MI, w hi ch i s usual l y l ocal i zed (anter i or ,
i nf er i or , or l ater al ), w i th the ST segm ents conv ex upw ar d. In per i car di ti s, the STsegm ent el ev ati on
i s concav e upw ar d and usual l y i nv ol v es al l the l eads ex cept aVR and V 1 . Stage 2 i s def i ned by
nor m al i zati on of the ST segm ents and stage 3 i s char acter i zed by the dev el opm ent of di f f use T
w av e i nv er si ons. In stage 4, the T w av es r etur n to thei r nor m al conf i gur ati on. PR segm ent
depr essi on i s al so com m on i n the ear l y phases of acute per i car di ti s ev en i n the absence of ST
segm ent el ev ati on and i s str ongl y suggesti v e of acute per i car di ti s. An i m por tant ex cepti on i s i n
per i car di ti s f ol l ow i ng an acute MI, i n w hi ch ty pi cal ECG changes of per i car di ti s m ay not be pr esent
or m ay be aty pi cal .
3. Is a nor m al tr oponi n hel pf ul i n ex cl udi ng an acute MI?
A nor m al tr oponi n 8 or m or e hour s af ter the onset of chest pai n gener al l y ex cl udes acute MI but
does not ex cl ude ACS. How ev er , a m i l dl y el ev ated tr oponi n m ay be pr esent w i th acute
m y oper i car di ti s. My ocar di ti s i s an i nf l am m ator y di sease of the car di ac m uscl e, w hi ch can be caused
by a v ar i ety of di f f er ent i l l nesses, m any of w hi ch ar e i nf ecti ous. Ty pi cal l y , m y ocar di ti s i s
associ ated w i th car di ac enzy m e el ev ati on that r ef l ects m y ocar di al necr osi s. When chest pai n occur s
i n the setti ng of m y ocar di ti s i t m ay be associ ated w i th concom i tant per i car di ti s and i s cal l ed
m y oper i car di ti s.
4. What i s the m ost ef f ecti v e tr eatm ent f or acute per i car di ti s?
In the tr eatm ent of i di opathi c or v i r al per i car di ti s, the goal s of ther apy ar e r el i ef of pai n and
r esol uti on of i nf l am m ati on. Fi r stchoi ce ther apy i s the adm i ni str ati on of nonster oi dal
anti i nf l am m ator y dr ugs (N SAIDs) or aspi r i n. The adm i ni str ati on of col chi ci ne al one or i n
com bi nati on w i th N SAIDs m i ght be another ther apeuti c al ter nati v e. The use of cor ti coster oi ds i s
usual l y r eser v ed f or pati ents w i th per i car di ti s secondar y to autoi m m une di sease.
5. What i s the m ost l i k el y cause of the hy potensi on i n thi s pati ent?
The hy potensi on i n thi s pati ent i s m ost l i k el y due to the cum ul ati v e ef f ects of the m edi cati ons he
has been gi v en (m or phi ne and N TG). The accum ul ati on and potenti ati on of m edi cati ons, especi al l y
i n the el der l y , i s a com m on cl i ni cal pr obl em i n the acute car e setti ng. The com bi nati on of m or phi ne
and N TG i n thi s pati ent m ay hav e i nduced suf f i ci ent v asodi l ati on to cause hy potensi on.
Bl eedi ng i s al so a possi bl e cause of the hy potensi on. The adm i ni str ati on of IV hepar i n, aspi r i n, and
pl atel et gl y copr otei n IIbIIIa i nhi bi tor agents m ay r esul t i n gastr oi ntesti nal bl eedi ng and m el anoti c
stool s. The absence of jugul ar v enous di stenti on and a par adox i cal pul se ar gues agai nst tam ponade,
but these f i ndi ngs m ay be absent w i th v asodi l ati on or v ol um e depl eti on. A m or e w or r i som e
possi bi l i ty i s hem or r hagi c per i car di ti s, especi al l y because a new f r i cti on r ub i s hear d. If the
hy potensi on does not r esol v e qui ck l y w i th di sconti nuati on of N TG and m or phi ne, an echocar di ogr am
i s i ndi cated to ex cl ude car di ac tam ponade.
P. 23
Suggested Readings
Im azi o M, Bobbi o M, Cecchi E, etal . Col chi ci ne i n addi ti on to conv enti onal ther apy f or acute
per i car di ti s: r esul ts of the COl chi ci ne f or acute PEr i car di ti s (COPE) tr i al . Ci r cul ati on
2005;112(13):2012â€“2016.
LeWi nter MM, Kabbani S. Per i car di al di seases. In: Br aunw al d E, ed. Hear t di sease: a tex tbook of
car di ov ascul ar m edi ci ne, 7th ed, Phi l adel phi a: WB Saunder s, 2005:1757.
Mer ce J, Sagr i staSaul eda J, Per m any er Mi r al da G, etal . Cor r el ati on betw een cl i ni cal and Doppl er
echocar di ogr aphi c f i ndi ngs i n pati ents w i th m oder ate and l ar ge per i car di al ef f usi on: i m pl i cati ons f or
the di agnosi s of car di ac tam ponade. Am Hear t J 1999;138:759â€“764.
Spodi ck DH. Acute car di ac tam ponade. N Engl J Med 2003;349:684â€“690.
Tr oughton RW, Asher CR, Kl ei n AL. Per i car di ti s. Lancet 2004;363:717â€“727.
Acute Pulmonary Edema
1. What ar e the tw o m ost com m on under l y i ng m echani sm s of pul m onar y edem a?
2. What ar e the m ost com m on causes of acute car di ogeni c pul m onar y edem a?
3. What i s the i m m edi ate tr eatm ent of acute car di ogeni c pul m onar y edem a?
Discussion
1. What ar e the tw o m ost com m on under l y i ng m echani sm s of pul m onar y edem a?
Acute pul m onar y edem a can hav e a c a rdioge nic or nonc a rdioge nic eti ol ogy . In c a rdioge nic
pulmona ry e de ma , a hi gh pul m onar y capi l l ar y pr essur e i s r esponsi bl e f or the tr ansudati on of
pr otei npoor f l ui d i nto the l ungs caused by an i m bal ance of Star l i ng's f or ces. Wi th acute r i ses i n
pul m onar y capi l l ar y pr essur e, the pul m onar y l y m phati cs cannot r api dl y i ncr ease the r ate of f l ui d
r em ov al ; as a r esul t, pul m onar y edem a occur s.
Nonc a rdioge nic pulmona ry e de ma i s caused by al ter ed al v eol ar capi l l ar y per m eabi l i ty due to
acute l ung i njur y . Tr ansudati on of f l ui d i nto the al v eol ar space i s not dependent on an el ev ated
pul m onar y capi l l ar y w edge pr essur e but i s ex acer bated by an el ev ated pul m onar y capi l l ar y
pr essur e. The di sor der s m ost f r equentl y r esul ti ng i n i ncr eased per m eabi l i ty pul m onar y edem a ar e
the acute r espi r ator y di str ess sy ndr om e (ARDS) and, l ess com m onl y , hi gh al ti tude and neur ogeni c
pul m onar y edem a.
2. What ar e the m ost com m on causes of acute car di ogeni c pul m onar y edem a?
The m ost com m on causes of acute car di ogeni c pul m onar y edem a ar e acute i schem i a and
accel er ated hy per tensi on, both causi ng a sudden i ncr ease i n l ef t v entr i cul ar enddi astol i c pr essur e.
Both eti ol ogi es r esul t i n a sti f f l ef t v entr i cl e and decr eased di astol i c v entr i cul ar com pl i ance,
i m pai r i ng v entr i cul ar f i l l i ng dur i ng di astol e (di astol i c dy sf uncti on). Sy stol i c dy sf uncti on m ay al so
occur . Other causes of acute car di ogeni c pul m onar y edem a i ncl ude acute m i tr al r egur gi tati on such
as m i ght r esul t f r om acute i schem i a or a r uptur ed chor dae
P. 24
tendi nea, or i nf ecti ous endocar di ti s, or di sconti nuati on of anti hy per tensi v e m edi cati ons. Acute
pul m onar y edem a m ay be pr eci pi tated by r api d atr i al f i br i l l ati on or other dy sr hy thm i as. Inf ecti on,
phy si cal or env i r onm ental str esses, changes or noncom pl i ance w i th m edi cal ther apy , di etar y
i ndi scr eti on, or i atr ogeni c v ol um e ov er l oad ar e l ess com m on, but i m por tant, causes.
3. What i s the i m m edi ate tr eatm ent of acute car di ogeni c pul m onar y edem a?
The i m m edi ate tr eatm ent of acute car di ogeni c pul m onar y edem a shoul d consi st of ox y gen ther apy
to m ai ntai n an ox y gen satur ati on w i thi n the nor m al r ange (95% to 98%), noni nv asi v e posi ti v e
pr essur e v enti l ati on i f ox y gen satur ati on r em ai ns l ow [i . e. , conti nuous posi ti v e ai r w ay pr essur e
(CPAP) or bi l ev el posi ti v e ai r w ay pr essur e (Bi PAP)], IV di ur esi s w i th f ur osem i de or other l oop
di ur eti cs, IV m or phi ne, and IV v asodi l ator s w i th N TG, ni tr opr ussi de, or angi otensi nconv er ti ng
enzy m e (ACE) i nhi bi tor s. The pati ent shoul d be si tti ng upr i ght unl ess hy potensi on i s pr esent. If the
pati ent has an ACS, ther apy shoul d be dom i nated by i nter v enti on to m i ni m i ze i schem i c i njur y . If the
acute pul m onar y edem a i s associ ated w i th shock , IV i notr opi c dr ugs such as m i l r i none or
dobutam i ne m ay be necessar y . If sev er e hy per tensi on i s pr esent, IV ni tr opr ussi de or other r api dl y
acti ng agents such as l abetal ol shoul d be gi v en to l ow er sy stem i c bl ood pr essur e. N oni nv asi v e
posi ti v epr essur e v enti l ati on w i th CPAP or Bi PAP has been show n to r educe the need f or i nv asi v e
m echani cal v enti l ati on i n pati ents w i th acute car di ogeni c pul m onar y edem a and ev en to r educe
m or tal i ty com par ed w i th standar d ther apy (ox y gen by f ace m ask , di ur eti cs, and ni tr ates); the sam e
has been show n i n a r ecent m etaanal y si s study . (see secti on on Essenti al Hy per tensi on and
Hy per tensi v e Em er genci es).
Case
A 65y ear ol d m an w i th a hi stor y of hy per tensi on, di abetes m el l i tus, and ex er ti onal chest pr essur e i s
seen i n the ER com pl ai ni ng of sudden onset of chest pai n and sev er e dy spnea at r est. He i s cur r entl y
tak i ng enal apr i l (5 m g tw i ce a day ) to contr ol hi s bl ood pr essur e. Phy si cal ex am i nati on r ev eal s a pal e
w hi te m al e i n acute r espi r ator y di str ess, w ho i s anx i ous and di aphor eti c. Hi s bl ood pr essur e i s 180/100
m m Hg, hi s api cal pul se i s 170 beats per m i nute and i r r egul ar l y i r r egul ar , and hi s r espi r ator y r ate i s 40
per m i nute. Ex am i nati on of the l ungs r ev eal s r al es ex tendi ng tw o thi r ds up f r om the base of the l ung
f i el ds bi l ater al l y . Ex am i nati on of the hear t r ev eal s a jugul ar v enous pr essur e of 12 cm of w ater , a thi r d
sound (S 3 ), and a gr ade 2/6 hol osy stol i c m ur m ur hear d at the apex . Ar ter i al bl ood gas deter m i nati ons
per f or m ed on r oom ai r show a par ti al pr essur e of ox y gen of 50 m m Hg, a par ti al pr essur e of car bon
di ox i de of 30 m m Hg, and a pH of 7. 48. A chest r adi ogr aph show s an enl ar ged hear t and pul m onar y
edem a. The ECG r ev eal s atr i al f i br i l l ati on w i th a v entr i cul ar r esponse of 170 beats per m i nute, a l oss of
R w av es, and 4 m m of ST el ev ati on anter i or l y â€” f i ndi ngs that ar e consi stent w i th an acute anter i or MI.
A di agnosi s of acute anter i or w al l MI com pl i cated by atr i al f i br i l l ati on and pul m onar y edem a i s m ade.
1. What i s causi ng the pul m onar y edem a i n thi s pati ent?
2. What m edi cal ther apy shoul d be used to tr eat thi s pati ent acutel y , and w hy ?
P. 25
Case Discussion
1. What i s causi ng the pul m onar y edem a i n thi s pati ent?
Ther e ar e sev er al causes of the pul m onar y edem a i n thi s pati ent.
1. MI i m pai r s both the sy stol i c and di astol i c f uncti on of the l ef t v entr i cl e. A l oss of the
contr acti l e f uncti on of the l ar ge anter i or w al l of the l ef t v entr i cl e (sy stol i c dy sf uncti on) and
acute sti f f eni ng of the dam aged m y ocar di um (di astol i c dy sf uncti on) l ead to el ev ated f i l l i ng
pr essur es of the l ef t v entr i cl e and the l ef t atr i um . El ev ated pul m onar y v enous and pul m onar y
capi l l ar y pr essur es pr oduce an i m bal ance i n the Star l i ng's f or ces, r esul ti ng i n the tr ansudati on
of f l ui d i nto the i nter sti ti um and then i nto the al v eol ar space.
2. Atria l fibrilla tion w i th a r api d v entr i cul ar r esponse (170 beats per m i nute) contr i butes to the
pul m onar y edem a because (a) the l oss of atr i al sy stol i c contr acti on i m pai r s l ef t v entr i cul ar
f i l l i ng, w hi ch f ur ther el ev ates the l ef t atr i al pr essur e; (b) the r api d v entr i cul ar r ate r esul ts i n
si gni f i cant shor teni ng of di astol i c f i l l i ng ti m e f ur ther i m pai r i ng f i l l i ng of the l ef t v entr i cl e; and
(c) the r api d v entr i cul ar r ate i ncr eases m y ocar di al ox y gen dem ands, w hi ch m ay i ncr ease
i schem i a, w hi ch i n tur n w or sens the pul m onar y edem a.
3. Hype rte ns ion, especi al l y w hen chr oni c and poor l y contr ol l ed, pr oduces a sti f f , hy per tr ophi ed
m y ocar di um causi ng el ev ated v entr i cul ar f i l l i ng pr essur es. In the setti ng of acute MI, an
i ncr ease i n bl ood pr essur e caused by anx i ety , pai n, a catechol am i ne sur ge, and per i pher al
v asoconstr i cti on augm ents the af ter l oad agai nst w hi ch the al r eady com pr om i sed l ef t v entr i cl e
has to w or k . Thi s l eads to a f ur ther el ev ati on i n v entr i cul ar f i l l i ng pr essur es, and w or sens any
i schem i a and m i tr al r egur gi tati on al r eady pr esent.
4. Anx ie ty secondar y to the pai n and br eathl essness i s l i k el y to i ncr ease the hear t r ate and
bl ood pr essur e, ther eby contr i buti ng to pul m onar y edem a by i ncr easi ng the af ter l oad.
5. A s ys tolic murmur i n thi s setti ng m ost l i k el y r epr esents m i tr al r egur gi tati on secondar y to
i schem i a and papi l l ar y m uscl e dy sf uncti on or , l ess com m onl y , r uptur e of papi l l ar y m uscl e, or
an acute v entr i cul ar septal def ect (VSD). Both acute m i tr al r egur gi tati on and a VSD r esul t i n a
sy stol i c m ur m ur at the l ow er l ef t ster nal bor der . When m i tr al r egur gi tati on i s acute and
sev er e, the sy stol i c m ur m ur m ay be sof t and m ay not be hol osy stol i c because the l ef t atr i al
pr essur e i ncr eases r api dl y i n sy stol e decr easi ng the m i tr al r egur gi tati on jet and m ur m ur . The
m ur m ur of VSD i s gener al l y l oud, har sh, and hol osy stol i c due to the v i br ati on of the m uscul ar
v entr i cul ar septum and a hi gh pr essur e gr adi ent betw een the l ef t and r i ght v entr i cl es
thr oughout sy stol e.
2. What m edi cal ther apy shoul d be used to tr eat thi s pati ent acutel y , and w hy ?
The m ost i m por tant i nter v enti on i n thi s pati ent i s acute r eper f usi on. An acute cor onar y angi ogr aphy
w i l l def i ne the cor onar y anatom y . Per cutaneous cor onar y i nter v enti on (PCI) w i th angi opl asty and/or
cor onar y stenti ng w i l l be i ndi cated i f ther e i s no papi l l ar y m uscl e r uptur e or VSD. Car di ac sur ger y
i s necessar y i f ei ther r epai r of a VSD or m i tr al v al v e r epl acem ent f or papi l l ar y m uscl e r uptur e i s
necessar y .
P. 26
Ther e ar e sev er al com ponents to the acute suppor ti v e tr eatm ent of thi s pati ent's pul m onar y edem a.
The adm i ni str ati on of ox yge n to ma inta in a rte ria l ox yge n s a tura tion a bove 90% i s i m por tant
because the al v eol ar edem a i nter f er es w i th adequate ox y gen di f f usi on. N oni nv asi v e posi ti v e
pr essur e suppor t v enti l ati on i s al so benef i ci al and shoul d be used i n pati ents w ho ar e sti l l hy pox i c
despi te m edi cal tr eatm ent. Morphine (1 to 3 m g at a ti m e i n an IV push) di m i ni shes anx i ety and
decr eases centr al sy m patheti c outf l ow , ther eby r educi ng both v enous and ar ter i al v asoconstr i cti on,
r esul ti ng i n decr eases i n v entr i cul ar pr el oad and af ter l oad, r especti v el y . Mor phi ne shoul d not be
gi v en to pati ents w i th di m i ni shed sensor i um or r espi r ator y dr i v e or hy per capni a because i t m ay
pr eci pi tate r espi r ator y ar r est. Furos e mide (20 to 80 m g i n a sl ow IV push) or other l oop di ur eti cs
cause i m m edi ate v enodi l ati on, f ol l ow ed by di ur esi s w i thi n appr ox i m atel y 5 to 10 m i nutes. IV
s odium nitroprus s ide m ay be used to r educe bl ood pr essur e i f hy per tensi on i s pr esent. NTG ,
adm i ni ster ed as subl i ngual tabl ets or by IV dr i p, r el i ev es the pul m onar y edem a by pr oduci ng
v enodi l ati on and tr eati ng acute i schem i a. Digox in m ay be used to sl ow the v entr i cul ar r esponse to
atr i al f i br i l l ati on. IV di l ti azem or a Î²bl ock er m ay be used to r educe the v entr i cul ar r esponse i f the
pati ent can tol er ate a negati v e i notr opi c agent.
Mul ti pl e studi es com par i ng N TG to f ur osem i de or m or phi ne sul f ate hav e dem onstr ated gr eater
ef f i cacy and saf ety and a f aster onset of acti on f or N TG. Al though ACE i nhi bi tor s ar e gener al l y
consi der ed the cor ner stone f or tr eati ng chr oni c hear t f ai l ur e (HF), sev er al v er y sm al l studi es hav e
dem onstr ated good r esul ts f or tr eatm ent of acute pul m onar y edem a w i th thi s cl ass of agent.
N ev er thel ess, ACE i nhi bi tor s shoul d be used w i th ex tr em e cauti on i n pati ents w i th hy potensi on or
si gni f i cantl y i m pai r ed r enal f uncti on.
It has been dem onstr ated that sy stem i c i nf usi on of nesi r i ti de has benef i ci al hem ody nam i c acti ons
but m ay cause si gni f i cant hy potensi on and no si gni f i cant benef i t i n cl i ni cal outcom es com par ed w i th
IV N TG. Al so, som e concer ns hav e been r ai sed that nesi r i ti de m ay be associ ated w i th an i ncr eased
r i sk of death and w or seni ng r enal f uncti on.
Suggested Readings
Annane D, Bel l i ssant E, Pussar d E, etal . Pl acebocontr ol l ed, r andom i zed, doubl ebl i nd study of
i ntr av enous enal apr i l at ef f i cacy and saf ety i n acute car di ogeni c pul m onar y edem a. Ci r cul ati on
1996;94(6):1316â€“1324.
Bel tr am e JF, Zei tz CJ, U nger SA, etal . N i tr ate ther apy i s an al ter nati v e to f ur osem i de/m or phi ne
ther apy i n the m anagem ent of acute car di ogeni c pul m onar y edem a. J Car d Fai l 1998;4:271â€“279.
Cotter G, Metzk or E, Kal usk i E, etal . Random i zed tr i al of hi ghdose i sosor bi de di ni tr ate pl us l ow dose
f ur osem i de v er sus hi ghdose f ur osem i de pl us l ow dose i sosor bi de di ni tr ate i n sev er e pul m onar y
edem a. Lancet 1998;351:389â€“393.
Pi er ar d LA, Lancel otti P. The r ol e of i schem i c m i tr al r egur gi tati on i n the pathogenesi s of acute
pul m onar y edem a. N Engl J Med 2004;35:1681â€“1684.
Sack ner Ber nstei n JD, Kow al sk i M, Fox M, etal . Shor tter m r i sk of death af ter tr eatm ent w i th
nesi r i ti de f or decom pensated HF: a pool ed anal y si s of r andom i zed contr ol l ed tr i al s. JAMA
2005;293:1900â€“1905.
P. 27
War e LB, Matthay MA. Cl i ni cal pr acti ce. Acute pul m onar y edem a. N Engl J Med 2005;353:2788â
€“2796.
Aortic Dissection
1. What i s acute aor ti c di ssecti on?
2. What i s the m ost com m on cause of aor ti c di ssecti on i n the gener al popul ati on, i n m en y ounger than
40 y ear s, and i n w om en y ounger than 40 y ear s?
3. What i s the m ost sensi ti v e i ni ti al di agnosti c test f or aor ti c di ssecti on?
4. Wher e ar e the m ost com m on poi nts of or i gi n f or aor ti c di ssecti ons?
Discussion
1. What i s acute aor ti c di ssecti on?
Acute aor ti c di ssecti on r esul ts f r om a tear i n the aor ti c i nti m a. Dr i v en by sy stem i c pr essur e,
ar ter i al bl ood enter s the di seased m edi a of the v essel . Wi thi n thi s l ay er , bl ood cr eates a separ ati on
pl ane as i t di ssects the aor ta l ongi tudi nal l y . The ar ea of di ssecti on f i l l ed w i th bl ood i s cal l ed the
f al se l um en. The shear f or ces of the di ssecti ng bl ood can cause addi ti onal i nti m al tear s. As the
f al se l um en f i l l s w i th bl ood, i t m ay com pr ess the tr ue l um en, r esul ti ng i n obstr ucti on of m ajor
ar ter i es. Inf r equentl y , di ssecti on can be i ni ti ated by hem or r hage i nto the m edi a w i thout an i nti m al
tear .
2. What i s the m ost com m on cause of aor ti c di ssecti on i n the gener al popul ati on, i n m en y ounger than
40 y ear s, and i n w om en y ounger than 40 y ear s?
In the ascendi ng aor ta, the m ost com m on cause of aor ti c di ssecti on i n the gener al popul ati on i s
m edi al degener ati on usual l y associ ated w i th agi ng and hy per tensi on. In the abdom i nal aor ta,
ather oscl er osi s pl ay s a m or e i m por tant r ol e. In m en y ounger than 40 y ear s, the m ost com m on
cause of di ssecti on i s Mar f an's sy ndr om e associ ated w i th the m or e ty pi cal cy sti c m edi al
degener ati on l esi ons. In w om en y ounger than 40 y ear s, 50% of al l di ssecti ons occur dur i ng
pr egnancy .
3. What i s the m ost sensi ti v e i ni ti al di agnosti c test f or aor ti c di ssecti on?
The sensi ti v i ti es of tr ansesophageal echocar di ogr aphy (TEE), m agneti c r esonance i m agi ng (MRI),
and com puted tom ogr aphy (CT) scan f or detecti on of di ssecti on ar e si m i l ar , w i th TEE pr obabl y
hav i ng a sl i ght adv antage. In m ost cases, the pr ef er r ed i ni ti al m odal i ty i s CT scanni ng because of
av ai l abi l i ty , saf ety , and conv eni ence. If the pati ent i s not stabl e, TEE shoul d be consi der ed f i r st as
i t can be per f or m ed i n a m oni tor ed setti ng w her e acute m edi cal ther apy can be adm i ni ster ed.
4. Wher e ar e the m ost com m on poi nts of or i gi n f or aor ti c di ssecti ons?
The m ost com m on poi nt of or i gi n f or ascendi ng aor ti c di ssecti on i s w i thi n 2 i n. of the aor ti c v al v e.
For descendi ng aor ti c di ssecti on, thi s poi nt i s at
P. 28
the l i gam entum ar ter i osum , just bey ond the tak eof f of the l ef t subcl av i an ar ter y .
Case
A 63y ear ol d m an w i th a hi stor y of CAD and pr ev i ous i nf er i or MI has the f ol l ow i ng car di ac r i sk f actor s:
30 y ear s of m oder atel y contr ol l ed hy per tensi on, 75 pack y ear s of tobacco use, ty pe 2 nonâ€“i nsul i n
dependent di abetes m el l i tus, and a f am i l y hi stor y of CAD. Hi s total chol ester ol l ev el 6 m onths bef or e
thi s adm i ssi on w as 260 m g/dL.
The pati ent has been ex per i enci ng hi s usual ex er ti onal angi na, w hi ch i s r el i ev ed w i th N TG and r est,
w i thout a change i n patter n or char acter dur i ng the m onth bef or e pr esentati on. At 11:00 a. m . on the day
of adm i ssi on, he w as l i f ti ng a 50l b bag of f er ti l i zer w hen he ex per i enced an acute sev er e (10/10),
tear i ng l ef t pr ecor di al chest pai n w i thout r adi ati on, but w i th di aphor esi s, nausea, and l i ghtheadedness.
The pai n w as si m i l ar to hi s angi na, but he obtai ned no r el i ef w i th N TG (0. 4 m g subl i ngual l y ). He com es
to the ER, w her e the phy si cal ex am i nati on r ev eal s a r i ght ar m bl ood pr essur e of 80/40 m m Hg, a pul se
r ate of 110 per m i nute, and a r espi r ator y r ate of 24 per m i nute. He i s a di aphor eti c el der l y m an w ho i s
w r i thi ng i n bed and com pl ai ni ng of l ef t chest pai n, w hi ch i s now r adi ati ng to the thr oat and i nter scapul ar
ar ea. The car di ov ascul ar ex am i nati on r ev eal s a tachy car di a. The f i r st (S 1 ) and second (S 2 ) sounds ar e
nor m al and a f our th sound (S 4 ) i s pr esent. Ther e i s a gr ade 3/4 di astol i c m ur m ur consi stent w i th aor ti c
i nsuf f i ci ency hear d at the second r i ght and l ef t i nter costal spaces. Ex am i nati on of the per i pher al pul ses
r ev eal s a di m i ni shed r i ght r adi al pul se, a nor m al l ef t r adi al pul se, and nor m al f em or al pul ses.
1. What tests w oul d y ou do f i r st to establ i sh a w or k i ng di agnosi s?
2. How ar e aor ti c di ssecti ons cl assi f i ed, w hat ar e the causes, and w hat ar e the com m on si gns and
sy m ptom s?
3. What i ni ti al ther apy i s i ndi cated to stabi l i ze thi s pati ent's condi ti on?
4. Because aor ti c di ssecti on i s thought to be pr esent, w hat i m agi ng techni ques shoul d be done to
conf i r m the di agnosi s and assi st i n pl anni ng f ur ther ther apy ?
5. What def i ni ti v e ther apy shoul d be i nsti tuted?
6. What l ongter m car e i s i ndi cated f or thi s pati ent?
Case Discussion
1. What tests w oul d y ou do f i r st to establ i sh a w or k i ng di agnosi s?
The f i r st pr ocedur e to per f or m i s a car ef ul phy si cal ex am i nati on. Your ex am i nati on i n thi s pati ent
conf i r m s the ER f i ndi ngs, but the bl ood pr essur e i n the l ef t ar m i s 190/110 m m Hg, and the r i ght
ar m bl ood pr essur e i s sti l l 80/40 m m Hg. The di scr epancy i n pul se and bl ood pr essur e betw een the
r i ght and l ef t ar m s i s str ongl y suggesti v e of aor ti c di ssecti on i nv ol v i ng the pr ox i m al aor ti c ar ch.
The f i ndi ng of aor ti c i nsuf f i ci ency i s consi stent w i th i nv ol v em ent of the pr ox i m al ascendi ng aor ta. A
chest r adi ogr aph shoul d al so be obtai ned. It i s l i k el y to show a w i dened m edi asti num w i th aor ti c
k nob i nti m al cal ci um separ ated f r om the adv enti ti al bor der by 1. 2 cm . Thi s â€œcal ci um si gnâ€ is
def i ned as a separ ati on that ex ceeds 1. 0 cm , and i t i s pathognom oni c f or aor ti c di ssecti on. An ECG
shoul d al so be obtai ned to deter m i ne
P. 29
i f ther e i s an acute MI, w hi ch m ay r esul t f r om occl usi on of the cor onar y ar ter y by the di ssecti on. In
thi s pati ent, the ECG show s di f f use, nonspeci f i c STsegm ent and Tw av e changes. On the basi s of
the hi stor y of â€œtear i ngâ€ pai n and these f i ndi ngs, the l i k el i hood of aor ti c di ssecti on i s deem ed
hi gh i n thi s pati ent.
2. How ar e aor ti c di ssecti ons cl assi f i ed, w hat ar e the causes, and w hat ar e the com m on si gns and
sy m ptom s?
Sev er al cl assi f i cati ons f or aor ti c di ssecti on hav e been pr oposed, but the m ost com m onl y used i s the
f ol l ow i ng DeBak ey cl assi f i cati on:
Ty pe I: Di ssecti on or i gi nati ng i n the ascendi ng aor ta, ex tendi ng to or bey ond the aor ti c ar ch
Ty pe II: Di ssecti on l i m i ted to the ascendi ng aor ta
Ty pe III: Di ssecti on or i gi nati ng i n the descendi ng aor ta and ex tendi ng di stal l y dow n the aor ta
or , r ar el y , ex tendi ng r etr ogr ade i nto the aor ti c ar ch and ascendi ng aor ta
Another cl assi f i cati on i s the Dai l y or Stanf or d schem e that i s si m pl er , and as f ol l ow s:
Ty pe A: Al l di ssecti ons i nv ol v i ng the ascendi ng aor ta, r egar dl ess of the si te of or i gi n
Ty pe B: Al l di ssecti ons not i nv ol v i ng the ascendi ng aor ta
DeBak ey ty pes I and II and Stanf or d A both i nv ol v e the ascendi ng aor ta and ar e ter m ed pr ox i m al
di ssecti ons, and DeBak ey III and Stanf or d B i nv ol v e the descendi ng aor ta and ar e ter m ed di stal
di ssecti ons.
The tr eatm ent of aor ti c di ssecti on depends on w hether the di ssecti on i nv ol v es the pr ox i m al or
di stal aor ta. The cl i ni cal m ani f estati ons ar e deter m i ned by i nv ol v em ent of ar ter i al br anches of the
aor ta (the r i ght br achi ocephal i c ar ter y i n thi s pati ent), the aor ti c v al v e (aor ti c i nsuf f i ci ency i n thi s
pati ent) or cor onar y ar ter i es, or both. A di ssecti on that r eaches pr ox i m al l y i nto the per i car di al
space can cause tam ponade. Appr ox i m atel y tw o thi r ds of aor ti c di ssecti ons ar e pr ox i m al , w her eas
one thi r d i s di stal .
The eti ol ogy of nontr aum ati c aor ti c di ssecti on i nv ol v es degener ati on of the col l agen and el asti n
f i ber s of the m edi a of the aor ta, w hi ch usual l y occur s i n pati ents ex per i enci ng a chr oni c ar ter i al
str ess, such as hy per tensi on. A speci f i c ty pe of m edi al degener ati on cal l ed cy sti c m edi al necr osi s
occur s i n pati ents w i th Mar f an's and Ehl er sDanl os sy ndr om es.
Other pr edi sposi ng f actor s f or di ssecti on i ncl ude congeni tal coar ctati on of the aor ta, bi cuspi d aor ti c
v al v e, ather oscl er osi s, N oonan's and Tur ner 's sy ndr om es, and gi ant cel l ar ter i ti s. Di r ect ex ter nal
tr aum a as w el l as i ntr av ascul ar tr aum a due to ar ter i al catheter i zati on and i ntr aaor ti c bal l oon
pum ps m ay r esul t i n aor ti c di ssecti on. Aor ti c tr aum a dur i ng car di ac sur ger y , especi al l y aor ti c v al v e
r epl acem ent, m ay r ar el y r esul t i n di ssecti on.
The i nci dence of aor ti c di ssecti on peak s i n the si x th and sev enth decades. Ther e i s a pr eponder ance
of m al e pati ents w i th a m al etof em al e r ati o of 2:1.
The m ost com m on sy m ptom at pr esentati on, seen i n m or e than 90% of pati ents, i s sudden onset of
sev er e chest pai n that i s i m m edi atel y m ax i m al i n i ntensi ty . The pai n i s unbear abl e, and of ten
descr i bed as a shar p, tear i ng or r i ppi ng sensati on. Thi s di f f er enti ates i t f r om that of an MI, w hi ch
i s f r equentl y cr escendo i n natur e and
P. 30
pr essur el i k e. The pai n can m i gr ate usual l y f ol l ow i ng the path of di ssecti on. Anter i or chest pai n i s
usual l y associ ated w i th a prox ima l dis s e c tion, w her eas an i nter scapul ar pai n i ndi cates a dis ta l
dis s e c tion. The di f f er enti al di agnosi s of aor ti c di ssecti on i ncl udes MI or i schem i a, a thor aci c
nondi ssecti ng aneur y sm , m uscul osk el etal pai n, m edi asti nal tum or s, and per i car di ti s.
Other si gns and sy m ptom s of acute aor ti c di ssecti on depend on i nv ol v em ent of m ajor ar ter i al
br anches or the aor ti c v al v e and ar e m or e com m on w i th pr ox i m al di ssecti on. Aor ti c i nsuf f i ci ency
occur s i n up to tw o thi r ds of al l cases of pr ox i m al di ssecti on and i s due to di l ati on of the aor ti c
r oot, hem atom a i nter f er i ng w i th l eaf l et coaptati on, tear i ng of the annul us or l eaf l et, or a
com bi nati on of these. Aor ti c i nsuf f i ci ency i s the m ost com m on cause of HF i n these pati ents.
N eur ol ogi c def i ci ts can i ncl ude str ok e, par apl egi a, or al ter ed consci ousness. Other com pl i cati ons
i ncl ude Hor ner sy ndr om e r esul ti ng f r om super i or cer v i cal gangl i on com pr essi on and l ef t r ecur r ent
l ar y ngeal ner v e par al y si s causi ng hoar seness. The i nv ol v em ent of m ajor ar ter i al br anches can l ead
to m y ocar di al , m esenter i c, or r enal i nf ar cti ons.
Ruptur e of an aor ti c di ssecti on i s m or e com m on w i th the pr ox i m al ty pe and can cause acute
hem oper i car di um w i th car di ac tam ponade or a l ef t pl eur al ef f usi on. Ruptur e i nto the ai r w ay s or
esophagus can r esul t i n hem opty si s or hem atem esi s.
3. What i ni ti al ther apy i s i ndi cated to stabi l i ze thi s pati ent's condi ti on?
Medi cal ther apy i s i ndi cated i ni ti al l y to stop the pr ogr essi on of the di ssecti on. The pati ent shoul d
be adm i tted to an i ntensi v e car e uni t w i th hem ody nam i c m oni tor i ng. Medi cal ther apy i s ai m ed at
r educi ng the m ean ar ter i al bl ood pr essur e and the v el oci ty of the l ef t v entr i cul ar ejecti on (ar ter i al
dP/dt) to m i ni m i ze ar ter i al shear str ess.
Sodi um ni tr opr ussi de i s a di r ect v asodi l ator and decr eases ar ter i al pr essur e i n a dosedependent
m anner . The ai m i s to r educe sy stol i c bl ood pr essur e to 100 to 120 m m Hg as l ong as ther e i s
adequate or gan per f usi on. N i tr opr ussi de i ncr eases dP/dt i f used al one and the adm i ni str ati on of Î²
bl ock i ng agents bl unts thi s ef f ect. If ther e ar e no contr ai ndi cati ons to Î²bl ock er s, they shoul d be
gi v en i ntr av enousl y to r each a hear t r ate of 60 to 80 beats per m i nute. Esm ol ol , a shor tacti ng IV
Î²bl ock er , m ay be par ti cul ar l y usef ul because i t can be ti tr ated m i nutetom i nute to r educe hear t
r ate. Labetal ol i s al so a good choi ce f or the tr eatm ent of acute aor ti c di ssecti on because i t i s both
an Î± and Î²bl ock i ng dr ug. In pati ents w ho hav e a contr ai ndi cati on to Î²bl ock er s, cal ci um channel
bl ock er s such as v er apam i l or di l ti azem del i v er ed by IV r oute coul d be used to decr ease hear t r ate
and bl ood pr essur e.
4. Because aor ti c di ssecti on i s thought to be pr esent, w hat i m agi ng techni ques shoul d be done to
conf i r m the di agnosi s of aor ti c di ssecti on and assi st i n pl anni ng f ur ther ther apy ?
A tra ns thora c ic e c hoc a rdiogra m i s a qui ck and noni nv asi v e m odal i ty to conf i r m aor ti c
i nsuf f i ci ency , assess segm ental l ef t v entr i cul ar sy stol i c f uncti on, and assess the pr ox i m al aor ti c
r oot f or the pr esence of di l ati on. How ev er , i t has poor sensi ti v i ty especi al l y f or di stal di ssecti ons.
In gener al , TEE, CT, and MRI ar e the i m agi ng m odal i ti es used to detect di ssecti on.
TEE i s m uch m or e sensi ti v e f or the detecti on of di ssecti on, l i k el y the m ost sensi ti v e of the i m agi ng
m odal i ti es. It i s l i m i ted, how ev er , i n i ts capabi l i ty to assess the di stal ascendi ng aor ta and the
pr ox i m al ar ch. It can assess the pr ox i m al aor ta, the degr ee
P. 31
of aor ti c i nsuf f i ci ency , l ef t v entr i cul ar f uncti on, the pr esence of per i car di al ef f usi on, and of ten
per m i ts v i sual i zati on of the pr ox i m al cor onar y ar ter i es. Ther ef or e, i t of f er s a m or e com pl ete
assessm ent of the di sease and i ts com pl i cati ons. In hem ody nam i cal l y unstabl e pati ents, thi s test
can be qui ck l y per f or m ed at the bedsi de w hi l e tr eatm ent i s bei ng pr ov i ded concom i tantl y , m ak i ng i t
the pr ocedur e of choi ce i n thi s i nstance.
MRI i s hi ghl y sensi ti v e and speci f i c i n assessi ng these pati ents and can v i sual i ze the enti r e
thor aci c aor ta i n one v i ew . U si ng gadol i ni um , the pr esence of aor ti c i nsuf f i ci ency as w el l as
i nv ol v em ent of m ajor br anch v essel s can be assessed i n a l ar ge num ber of pati ents (i . e. , the
subcl av i an or car oti d ar ter y ). Thi s techni que cannot be used i n pati ents w i th pacem ak er s and
def i br i l l ator s. MRI scanner s l i m i t access to the pati ent dur i ng the test f or up to 30 to 40 m i nutes,
w hi ch i s di sadv antageous i n unstabl e pati ents.
A contr ast CT s c a n (especi al l y hel i cal CT) i s good f or def i ni ng the ex tent of an aor ti c di ssecti on,
that i s, pr ox i m al v er sus di stal . CT angi ogr aphy can al so assess i nv ol v em ent of m ajor aor ti c
br anches. Its m ajor adv antages ar e v er y hi gh sensi ti v i ty and av ai l abi l i ty . A di sadv antage i s that i t
r ar el y def i nes the si te of the i nti m al tear .
The pr ev i ous gol d standar d f or the di agnosi s of aor ti c di ssecti on w as aor togr aphy . Thi s m odal i ty
can def i ne the si te of the i nti m al tear , the sev er i ty of aor ti c i nsuf f i ci ency , cor onar y ar ter y
i nv ol v em ent, and the ex tent of the di ssecti onâ€”pr ox i m al v er sus di stal . How ev er , aor togr aphy has
been show n to hav e a l ow er sensi ti v i ty com par ed w i th the other m odal i ti es di scussed abov e.
Ther ef or e, the cur r ent gol d standar d v ar i es dependi ng on the av ai l abi l i ty of i m agi ng m odal i ti es. A
hel i cal CT i s av ai l abl e i n m ost i nsti tuti ons and i s v er y accur ate. A TEE, especi al l y i n unstabl e
pati ents, has been r ecom m ended as the f i r st test by the Eur opean Soci ety of Car di ol ogy . MRI i s
consi der ed by m any as the f i r st test to be per f or m ed but i s not al w ay s av ai l abl e.
5. What def i ni ti v e ther apy shoul d be i nsti tuted?
U ntr eated acute aor ti c di ssecti on i s associ ated w i th 25% m or tal i ty at 24 hour s and a death r ate of
m or e than 75% at 1 m onth. In gener al , sur gi cal r epai r i s pr ef er r ed f or acute pr ox i m al di ssecti on or
i n di stal di ssecti ons w hen v i tal or gan or l i m b com pr om i se i s pr esent, f or r api d ex pansi on or
f or m ati on of a saccul ar aneur y sm , f or r uptur e, i n the pr esence of uncontr ol l ed pai n, or i n pati ents
w i th Mar f an's sy ndr om e. Medi cal ther apy (r educi ng the bl ood pr essur e and dP/dt) i s adequate f or
uncom pl i cated acute di stal di ssecti ons as ther e i s l ess r i sk of com pl i cati ons. It i s al so
r ecom m ended i n chr oni c (pr esent f or > 2 w eek s) pr ox i m al or di stal di ssecti ons as these pati ents
hav e sur v i v ed the per i od of hi ghest m or tal i ty r i sk .
6. What l ongter m car e i s i ndi cated f or thi s pati ent?
It i s essenti al to r api dl y contr ol the pati ent's hy per tensi on and decr ease the r ate of pr essur e r i se i n
the l ef t v entr i cl e, pr ef er abl y w i th Î²bl ock er s. The l ongter m pr ognosi s i n hospi tal sur v i v or s i s good,
w i th an actuar i al sur v i v al r ate onl y sl i ghtl y w or se than that f or agem atched subjects. The ty pe of
di ssecti on or ther apy used does not i nf l uence the outcom e af ter di schar ge f r om the hospi tal . The
hi ghest r i sk f or r ecur r ent di ssecti on or aneur y sm ex pansi on i s i n the f i r st 2 y ear s. Car ef ul f ol l ow
up dur i ng thi s i ni ti al per i od i s i m por tant to ensur e adequate bl ood pr essur e contr ol and m oni tor f or
r ecur r ence. Thi s w oul d i ncl ude phy si cal ex am i nati on and chest x r ay s. Ser i al i m agi ng w i th CT
scanni ng, TEE, or MRI shoul d al so be par t of thi s f ol l ow up.
P. 32
Suggested Readings
Hagan PG, N i enaber CA, Issel bacher EM, etal . The i nter nati onal r egi str y of acute aor ti c di ssecti on
(IRAD): new i nsi ghts i nto an ol d di sease. 2000;283(7):897â€“903.
N i enaber CA, Eagl e KA. Aor ti c di ssecti on: new f r onti er s i n di agnosi s and m anagem ent: par t I: f r om
eti ol ogy to di agnosti c str ategi es. Ci r cul ati on 2003;108:628â€“635.
N i enaber CA, Eagl e KA. Aor ti c di ssecti on: new f r onti er s i n di agnosi s and m anagem ent: Par t II:
ther apeuti c m anagem ent and f ol l ow up. Ci r cul ati on 2003;108:772â€“778.
Sabi k JF, Ly tl e BW, Bl ack stone EH, etal . Longter m ef f ecti v eness of oper ati ons f or ascendi ng aor ti c
di ssecti ons. J Thor ac Car di ov asc Sur g 2000;119(5):946â€“962.
Chronic Heart Failure
1. What ar e the m ost com m on under l y i ng di seases causi ng chr oni c HF i n the U . S. popul ati on?
2. Is HF al w ay s associ ated w i th a decr eased ejecti on f r acti on (EF)?
3. What i s m y ocar di al r em odel i ng and w hat ar e i ts consequences?
4. Whi ch dr ug cl asses hav e been show n to pr ol ong sur v i v al i n pati ents w i th HF?
5. What dev i ces hav e been show n to pr ol ong sur v i v al i n pati ents w i th HF?
Discussion
1. What ar e the m ost com m on under l y i ng di seases causi ng chr oni c HF i n the U . S. popul ati on?
In the U ni ted States and m ost dev el oped countr i es, hy per tensi on and i schem i c hear t di sease ar e
the m ost com m on causes of HF. Val v ul ar hear t di sease and car di om y opathy ar e l ess com m on
causes, but ar e sti l l f r equentl y encounter ed.
2. Is HF al w ay s associ ated w i th a decr eased EF?
Sy stol i c dy sf uncti on i s def i ned as a decr ease i n contr acti l e f uncti on m ost com m onl y m easur ed as a
decr ease i n EF. Many pati ents w i th HF hav e a decr eased EF. How ev er , al m ost hal f of al l pati ents
w i th HF hav e a nor m al EF. In som e of these pati ents, di astol i c dy sf uncti on i s the cause. Di astol i c
dy sf uncti on r esul ts w hen the hear t i s sti f f and v entr i cul ar f i l l i ng i s i m pai r ed, r esul ti ng i n i ncr eased
enddi astol i c pr essur es. Pati ents m ay hav e di astol i c dy sf uncti on w i th or w i thout sy stol i c
dy sf uncti on. Ty pi cal si gns and sy m ptom s of HF occur w i th ei ther nor m al or abnor m al EF. Ty pi cal l y ,
the pr ev al ence of HF w i th a nor m al EF i s m ost com m on i n el der l y w om en.
3. What i s m y ocar di al r em odel i ng and w hat ar e i ts consequences?
Af ter m y ocar di al i njur y w i th r esul ti ng sy stol i c dy sf uncti on, ther e i s of ten a pr ogr essi v e
deter i or ati on i n the str uctur e and f uncti on of the v entr i cul ar m y ocar di um â€”a pr ocess ter m ed
m y ocar di al r em odel i ng. My ocar di al r em odel i ng i s char acter i zed by pr ogr essi v e v entr i cul ar
enl ar gem ent and decr easi ng EF. Thi s pr ogr essi v e r em odel i ng i s at l east par ti al l y r esponsi bl e f or the
hi gh
P. 33
m or tal i ty r ates i n pati ents w i th HF. Al though the speci f i c m ol ecul ar and cel l ul ar ev ents that l ead to
r em odel i ng ar e not enti r el y under stood, m any f actor s that pr om ote r em odel i ng hav e been
descr i bed. These m echani sm s i ncl ude i ncr eased w al l str ess and acti v ati on of the r eni nâ
€“angi otensi n and Î²adr ener gi c sy stem s. Bl ock ade of these sy stem s w oul d be ex pected to sl ow or
pr ev ent m y ocar di al r em odel i ng and i m pr ov e sur v i v al i n pati ents w i th HF and sy stol i c dy sf uncti on.
4. Whi ch dr ug cl asses hav e been show n to pr ol ong sur v i v al i n pati ents w i th HF?
In pati ents w i th HF due to a decr eased EF, ACE i nhi bi tor s and Î²adr ener gi c r eceptor antagoni sts Î²
bl ock er s) hav e been show n to i m pr ov e sur v i v al . Angi otensi nr eceptor bl ock er s (ARBs) ar e pr obabl y
equi v al ent to ACE i nhi bi tor s and m ay be substi tuted, especi al l y i f ther e i s i ntol er ance to ACE
i nhi bi tor s due to cough. Ei ther al doster one antagoni sts or ARBs al so i m pr ov e sur v i v al w hen added
to ACE i nhi bi tor s and Î²bl ock er s, but car e m ust be tak en to m oni tor pati ents car ef ul l y to av oi d
hy per k al em i a; the use of al l f our dr ug cl asses together i s not adv i sed f or m ost pati ents because of
the r i sk of hy per k al em i a. Di gox i n m ay be hel pf ul to i m pr ov e sy m ptom s but does not i m pr ov e
sur v i v al . Loop di ur eti cs such as f ur osem i de, bum etani de, and tor sem i de cl ear l y r el i ev e congesti on
caused by sal t and w ater r etenti on but hav e not been show n to i m pr ov e sur v i v al . The com bi nati on
of hy dr al azi ne and i sosor bi de di ni tr ate i m pr ov es sur v i v al i n Af r i can Am er i cans w i th sy stol i c
dy sf uncti on and N ew Yor k Hear t Associ ati on (N YHA)'s cl ass IIIâ€”IV HF.
In pati ents w i th HF and nor m al EF onl y one m ajor tr i al has been conducted. Thi s tr i al usi ng the ARB
candesar tan di d not show a si gni f i cant benef i t on hospi tal i zati on or m or tal i ty r ate. Loop di ur eti cs
ar e v al uabl e i n r el i ev i ng congesti v e sy m ptom s i n these pati ents but no cl i ni cal tr i al s hav e been
conducted.
5. What dev i ces hav e been show n to pr ol ong sur v i v al i n pati ents w i th HF?
Pati ents w i th si gni f i cant sy stol i c dy sf uncti on (EF â‰¤35%), and N YHA cl ass IIIII hear t f ai l ur e hav e
i m pr ov ed sur v i v al w hen an i nter nal car di ac def i br i l l ator (ICD) i s i m pl anted. The ICD detects ser i ous
v entr i cul ar ar r hy thm i as and cor r ects them ei ther w i th paci ng or a shock . Car di ac r esy nchr oni zati on
ther apy (CRT) i s based on the concept that pati ents w i th l ef t v entr i cul ar sy stol i c dy sf uncti on of ten
hav e v entr i cul ar dy ssy nchr ony . Dy ssy nchr ony i s m ost of ten seen w hen the QRS dur ati on i s 120
m i l l i seconds or m or e and m ost cl i ni cal tr i al s hav e used thi s QRS dur ati on as an entr y cr i ter i a.
Dy ssy nchr ony m eans that the l ef t v entr i cul ar contr acti on i s di scoor di nated, r esul ti ng i n a l ow er
str ok e v ol um e and i ncr eased w al l str ess. By paci ng both the v entr i cul ar septum (w i th a pacer i n the
r i ght v entr i cul ar apex ) and the l ater al w al l of the l ef t v entr i cl e (thr ough a pacer adv anced thr ough
the cor onar y si nus i nto a l ater al cor onar y v ei n) the coor di nati on of v entr i cul ar contr acti on i s
i m pr ov ed, i ncr easi ng car di ac output. In pati ents w i th an EF of 35% or l ess and HF, CRT i m pr ov es
sy m ptom s, hospi tal i zati ons, and m or tal i ty .
P. 34
Case
A 42y ear ol d w hi te m an i s seen i n the ER w i th a chi ef com pl ai nt of shor tness of br eath that has l asted
f or 1 w eek . He r epor ts hav i ng had a v i r al sy ndr om e appr ox i m atel y 3 w eek s bef or e adm i ssi on.
Subsequentl y , he noted the dev el opm ent of l ow er ex tr em i ty edem a, a 15l b w ei ght gai n, dy spnea on
ex er ti on, and or thopnea. Cur r entl y he com pl ai ns of dy spnea at r est. Phy si cal ex am i nati on r ev eal s an
i r r egul ar l y i r r egul ar hear t r ate of 130 per m i nute. Hi s bl ood pr essur e i s 90/60 m m Hg, and hi s
r espi r ator y r ate i s 22 per m i nute. Ex am i nati on of the jugul ar v enous pr essur e dem onstr ates a m ean
pr essur e of 12 to 14 cm of w ater w i th a pr om i nent V w av e. Lung ex am i nati on r ev eal s bi basi l ar dul l ness
w i th r al es ex tendi ng one f our th of the w ay up f r om the basal l ung f i el ds bi l ater al l y . Car di ac ex am i nati on
f i ndi ngs ar e si gni f i cant f or a di f f use poi nt of m ax i m al i m pul se, w hi ch i s di spl aced to the anter i or
ax i l l ar y l i ne. The S 1 and S 2 ar e of v ar i abl e i ntensi ty , and a pr om i nent S 3 gal l op ov er the di spl aced
car di ac apex i s appr eci ated. Ther e i s a gr ade 2/6 hol osy stol i c m ur m ur that i s hear d best at the car di ac
apex , w i th pr om i nent r adi ati on to the ax i l l a and no change w i th r espi r ati on. On ex am i nati on of the
abdom en, an enl ar ged, tender l i v er i s f ound. The ex tr em i ti es ar e cool and ex hi bi t 2+ pi tti ng edem a. The
ECG show s atr i al f i br i l l ati on w i th nonspeci f i c STTâ€“w av e changes, a l ef t bundl e br anch bl ock (LBBB)
and occasi onal v entr i cul ar pr em atur e beats. Ar ter i al bl ood gas m easur em ents per f or m ed w i th the
pati ent on 4 L of ox y gen per m i nute by nasal cannul a r ev eal a pH of 7. 46, a PO 2 of 52 m m Hg, a PCO 2
of 32 m m Hg, and a bi car bonate (HCO 3 ) concentr ati on of 26 m m ol /L.
1. Does thi s pati ent hav e l ef t, r i ght, or bi v entr i cul ar f ai l ur e?

2. An S 3 i s hear d, but no S 4 . Why ?
3. What chest r adi ogr aphi c f i ndi ngs w oul d y ou ex pect to see i n thi s pati ent?
4. What neur ohor m onal m echani sm s ar e l i k el y to be acti v ated i n thi s pati ent?
5. What di agnosti c tests shoul d be per f or m ed?
6. What tr eatm ent opti ons w oul d l i k el y be benef i ci al i n thi s pati ent?
7. Is i t possi bl e that the v entr i cul ar f uncti on w i l l i m pr ov e w i th m edi cal ther apy ?
Your pati ent i m pr ov ed af ter di ur esi s and adm i ni ster i ng ACE i nhi bi tor s and Î²bl ock er s. Si x m onths
l ater hi s EF has i ncr eased f r om 20% to 29%. He i s on di gox i n w i th ther apeuti c l ev el s and an
al doster one antagoni st w i th nor m al ser um cr eati ni ne and potassi um . He has no r esti ng dy spnea or
edem a, but does hav e dy spnea w i th si m pl e task s.
8. In w hi ch N YHA cl ass and Am er i can Col l ege of Car di ol ogy /Am er i can Hear t Associ ati on (ACC/AHA)
stage w oul d y ou categor i ze thi s pati ent's sy m ptom s?
9. What i s thi s pati ent's ex pected m or tal i ty r ate i n hi s cur r ent condi ti on?
Case Discussion
1. Does thi s pati ent hav e l ef t, r i ght, or bi v entr i cul ar f ai l ur e?
Thi s pati ent has f i ndi ngs i ndi cati ng both r i ght and l ef t v entr i cul ar f ai l ur e (bi v entr i cul ar f ai l ur e). The
cool ex tr em i ti es, tachy car di a, and nar r ow pul se pr essur e suggest poor f or w ar d car di ac output and
coul d r ef l ect ei ther r i ght or l ef t v entr i cul ar f ai l ur e. A l ef t v entr i cul ar S 3 gal l op and pul m onar y r al es
ar e si gns of l ef t v entr i cul ar
P. 35
f ai l ur e. The bi basi l ar dul l ness suggests the pr esence of bi l ater al pl eur al ef f usi ons, w hi ch m ay be
seen i n the setti ng of ei ther r i ght or l ef t v entr i cul ar dy sf uncti on. The api cal m ur m ur m ost l i k el y
r epr esents m i tr al r egur gi tati on because i t i s l oudest at the apex , i t r adi ates to the ax i l l a, and i t
does not change w i th r espi r ati on. We do not k now f r om the hi stor y w hether the pati ent had a
pr eex i sti ng v al v ul ar di sor der . Secondar y m i tr al or tr i cuspi d r egur gi tati on occur s com m onl y i n
pati ents w i th v entr i cul ar enl ar gem ent and dy sf uncti on due to di stor ti on of the suppor ti ng str uctur es
of the atr i ov entr i cul ar v al v es. Tr i cuspi d r egur gi tati on causes a l ar ge V w av e i n the jugul ar v enous
pul se.
Ther e ar e m any si gns of r i ght v entr i cul ar f ai l ur e i n thi s pati ent. El ev ated centr al v enous pr essur e
i s appar ent f r om the pati ent's jugul ar v enous di stenti on. Kussm aul 's si gn i s the l ack of a f al l i n the
jugul ar v enous pr essur e w i th i nspi r ati on and i s due to the r i ght v entr i cl e's i nabi l i ty to handl e the
augm ented v enous r etur n. It m ay be encounter ed i n pati ents w i th r i ght v entr i cul ar f ai l ur e or
constr i cti v e per i car di al di sease. The pati ent's enl ar ged l i v er i s the r esul t of hepati c congesti on
stem m i ng f r om i ncr eased back pr essur e on the hepati c v ei n. The pi tti ng edem a i n the l ow er
ex tr em i ti es i s caused by el ev ated hy dr ostati c pr essur e i n the v enous sy stem , r esul ti ng i n
ex tr av asati on of f l ui d i nto the i nter sti ti al space of the ank l es, w her e the f or ces of gr av i ty ar e the
gr eatest.
2. An S 3 i s hear d, but no S 4 . Why ?
An S 3 i s a l ow f r equency sound hear d 0. 13 to 0. 16 second af ter S 2 . An S 3 occur s at the end of the
r api d phase of v entr i cul ar f i l l i ng and i s m ost l i k el y due to the v i br ati on of the chor dae tendi neae or
the l ef t v entr i cul ar w al l w i th r api d f i l l i ng, and m ay ar i se f r om the r i ght or l ef t v entr i cl e. A l ef t
v entr i cul ar S 3 i s best hear d w i th the bel l of the stethoscope at the car di ac apex . A r i ght v entr i cul ar
S 3 i s al so best hear d w i th the bel l , but i s m ost audi bl e at the l ow er l ef t ster nal bor der or ov er the
epi gastr i um . An S 3 i s a nor m al f i ndi ng i n chi l dr en or y oung adul ts, but i n m i ddl eaged or ol der
pati ents i t i s usual l y a si gn of v ol um e ov er l oad m ost of ten due to HF, as i t i s i n thi s pati ent.
An S 4 i s a pr esy stol i c atr i al sound (gal l op) that i s hear d w hen the v entr i cl e i s poor l y com pl i ant.
Gi v en the pati ent's v ol um e ov er l oad, i t i s l i k el y that both v entr i cl es ar e poor l y com pl i ant. How ev er ,
the pati ent i s i n atr i al f i br i l l ati on, and ther ef or e ther e ar e no ef f ecti v e atr i al sy stol es to gi v e r i se
to an S 4 (r ar el y , an S 4 m ay be hear d ev en i n atr i al f i br i l l ati on because of the hi gh l ef t atr i al
pr essur e and i ncr eased f l ow i n l ate di astol e).
3. What chest r adi ogr aphi c f i ndi ngs w oul d y ou ex pect to see i n thi s pati ent?
The l i k el y f i ndi ngs on a chest r adi ogr aphy stem f r om the ef f ects of v ol um e ov er l oad and el ev ated
pul m onar y v enous pr essur e. Car di om egal y , w hi ch i s def i ned as a car di actothor aci c di am eter r ati o
ex ceedi ng 0. 5, i s pr esent i n m ost cases i n w hi ch ther e i s depr essed l ef t v entr i cul ar sy stol i c
f uncti on. Cephal i zati on of the pul m onar y bl ood f l ow occur s and i s ev i denced by the enl ar ged
pul m onar y v essel s i n the super i or por ti on of the pul m onar y tr ee. The hazi ness of the centr al
v ascul atur e i s a r esul t of the i ncr eased hy dr ostati c pr essur e and subsequent tr ansudati on of f l ui d
i nto the ti ssue sur r oundi ng the v essel s. Ker l ey B l i nes ar e hor i zontal , thi n, shar p l i nes that ex tend
i nw ar d f r om the per i pher y of the l ungs. They r epr esent edem a f or m ati on
P. 36
w i thi n the l ungs and hy per tr ophy of the i nter l obul ar septa. Pl eur al ef f usi ons m ay be f ound i n the
setti ng of r i ght or l ef t v entr i cul ar f ai l ur e. When pul m onar y congesti on i s sev er e and al v eol ar edem a
i s pr esent, a â€œbutter f l y â€
or â€œbatw i ngâ€
i nf i l tr ate m ay be seen center ed ov er the m ai n
pul m onar y ar ter y .
4. What neur ohor m onal m echani sm s ar e l i k el y to be acti v ated i n thi s pati ent?
The tw o neur ohor m onal m echani sm s m ost l i k el y to be acti v ated i n thi s pati ent ar e the r eni nâ
€“angi otensi nâ€“al doster one sy stem and the adr ener gi c ner v ous sy stem . The ser um nor epi nephr i ne
l ev el has been show n to cor r el ate i nv er sel y w i th the EF and pati ent sur v i v al i n those w i th chr oni c
HF. Car di ac adr ener gi c acti v ati on occur s ev en ear l i er than sy stem i c adr ener gi c acti v ati on. Other
hor m ones that m ay be acti v ated i ncl ude v asopr essi n, endothel i n, and m ul ti pl e cy tok i nes such as
tum or necr osi s f actor Î± and i nter l euk i n 1.
5. What di agnosti c tests shoul d be per f or m ed?
Ini ti al l y a com pl ete bl ood count, and thy r oi d sti m ul ati ng hor m one (TSH), el ectr ol y te, r enal and
hepati c f uncti on tests shoul d be obtai ned to deter m i ne i f ther e ar e el ectr ol y te abnor m al i ti es that
need to be cor r ected, i f ther e i s si gni f i cant under l y i ng r enal or hepati c di sease, and to deter m i ne i f
anem i a or thy r oi d abnor m al i ti es m ay hav e ex acer bated the hear t f ai l ur e. An ECG shoul d be
per f or m ed to deter m i ne i f ther e has been an MI or i f ar r hy thm i as ar e pr esent. A chest x r ay w i l l
conf i r m the HF and detect si gni f i cant under l y i ng pul m onar y pr obl em s. An echocar di ogr am w i l l
ev al uate v entr i cul ar si ze and f uncti on, the pr esence of v al v e abnor m al i ti es, and m ay of ten suggest
the under l y i ng eti ol ogy of the v entr i cul ar dy sf uncti on. For ex am pl e, i f the anter i or w al l i s ak i neti c
and scar r ed, a pr ev i ous MI can be i nf er r ed. When the l ef t v entr i cl e i s l ar ge and has gl obal
dy sf uncti on, i t m ay be di f f i cul t to deter m i ne i f ther e i s under l y i ng CAD. When the pati ent has
stabi l i zed an ex er ci se, echocar di ogr am or nucl ear study m ay r ev eal r ev er si bl e i schem i a. Cor onar y
angi ogr aphy m ay be necessar y to ex cl ude si gni f i cant CAD i f noni nv asi v e studi es do not cl ear l y
ex cl ude i schem i a. If ther e i s no si gni f i cant cor onar y di sease and no si gni f i cant v al v e di sease, the
di agnosi s i s l i k el y i di opathi c car di om y opathy . The ty pe of car di om y opathy can gener al l y be
categor i zed by echocar di ogr am as di l ated, hy per tr ophi c, or r estr i cti v e w i th di l ated car di om y opathy
bei ng the m ost com m on. A ser i es of tests, dependi ng on the ty pe of car di om y opathy , shoul d be
car r i ed out to ex cl ude speci f i c eti ol ogi es.
6. What tr eatm ent opti ons w oul d l i k el y be benef i ci al i n thi s pati ent?
The gener al goal s f or the m edi cal tr eatm ent of HF ar e as f ol l ow s:
a. Identi f y and tr eat the under l y i ng condi ti on.
b. El i m i nate any pr eci pi tati ng f actor s.
c. Tr eat the sy m ptom s.
d. Im pr ov e sur v i v al .
The f i r st step i s to i denti f y the under l y i ng cause of HF. Thi s m ay be hy per tensi on, CAD,
car di om y opathy , v al v ul ar hear t di sease, or m any other causes. Tr eatm ent i ncl udes m edi cal
tr eatm ent f or hy per tensi on, cor onar y angi ogr aphy and cor onar y angi opl asty or cor onar y by pass
sur ger y f or cor onar y di sease, and v al v e r epl acem ent or r epai r f or v al v e di sease.
P. 37
In pati ents w i th HF, i t i s i m por tant to el i m i nate pr eci pi tati ng f actor s (e. g. , di etar y or m edi cati on
noncom pl i ance, ar r hy thm i as, anem i a). Ex cess al cohol use m ay cause a car di om y opathy , but ex cess
al cohol m ay al so ex acer bate HF of any cause.
Sy m ptom ati c i m pr ov em ent i s usual l y achi ev ed by r el i ev i ng the ex cess sal t and w ater r etenti on w i th
di ur eti cs and by i m pr ov i ng pr el oad and af ter l oad w i th v asodi l ator sâ€”par ti cul ar l y the ACE
i nhi bi tor s. Loop di ur eti cs such as f ur osem i de, tor sem i de, or bum etani de ar e m ost of ten used
because they ar e m or e ef f ecti v e than thi azi de di ur eti cs w hen r enal per f usi on i s decr eased. Car e
m ust be tak en to av oi d ov er di ur esi s and to r epl ace potassi um and m agnesi um because hy pok al em i a
and/or hy pom agnesem i a m ay pr om ote v entr i cul ar ar r hy thm i as. The com bi nati on of ACE i nhi bi tor s
and Î²adr ener gi c antagoni sts (Î²bl ock er s) i s the cor ner stone of ther apy f or pati ents w i th HF due
to sy stol i c dy sf uncti on. Many ACE i nhi bi tor s ar e now av ai l abl e (captopr i l , enal apr i l , l i si nopr i l ,
qui napr i l , r am i pr i l , benazepr i l , tr andol apr i l , f osi nopr i l , m oex i pr i l ), and ther e does not appear to be
a cl ear ther apeuti c adv antage to the use of one ov er another . How ev er , the tar get dose of an ACE
i nhi bi tor i s best deter m i ned f r om the i ndi v i dual agents that hav e been studi ed i n pati ents w i th HF.
By decr easi ng the conv er si on of angi otensi n I to angi otensi n II, these dr ugs r educe pr el oad and
af ter l oad, i m pr ov e sy m ptom s, and pr ol ong sur v i v al i n pati ents w i th sy stol i c dy sf uncti on. Cough i s
the m ost com m on si de ef f ect of ACE i nhi bi tor s, but cough i s al so a com m on sy m ptom of HF. Car e
shoul d be tak en to ex cl ude HF as a cause of the cough bef or e these dr ugs ar e di sconti nued.
Hy potensi on, r enal i nsuf f i ci ency , and hy per k al em i a ar e l ess f r equent but ser i ous si de ef f ects of the
ACE i nhi bi tor s. In gener al , these occur i n pati ents w i th sev er e HF and/or pr eex i sti ng r enal
i nsuf f i ci ency . In pati ents w i th sev er e HF or i ntr i nsi c r enal i nsuf f i ci ency , the ACE i nhi bi tor s shoul d
be star ted i n v er y l ow doses, and the bl ood pr essur e and ser um potassi um and cr eati ni ne l ev el s
m ust be m oni tor ed car ef ul l y .
Î²Adr ener gi c bl ock er s hav e al so been show n to i m pr ov e sur v i v al i n pati ents w i th sy stol i c
dy sf uncti on and HF. Al though the benef i t on sy m ptom s i s l ess cl ear than w i th ACE i nhi bi tor s, Î²
bl ock er s pr oduce a l ar ger i m pr ov em ent i n r em odel i ng, EF, and sur v i v al . Because Î²bl ock er s r educe
hear t r ate and i ni ti al l y decr ease contr acti l i ty , i ntr oducti on of tr eatm ent or upti tr ati on m ay r esul t
i n w or seni ng of sy m ptom s. These dr ugs m ust ther ef or e be star ted i n l ow doses and upti tr ated
sl ow l y , and pati ents m ust be m oni tor ed car ef ul l y . Pati ents w i th decom pensated HF usual l y shoul d
not be gi v en Î²bl ock er s. Sev er al Î²bl ock er s (car v edi l ol , m etopr ol ol , and bi sopr ol ol ) hav e been
show n to r educe m or tal i ty i n pati ents w i th HF. It i s not y et cl ear i f ther e ar e adv antages of one
ov er another .
Ther e ar e sev er al possi bl e addi ti ons to m edi cal ther apy i n pati ents w i th chr oni c HF due to sy stol i c
dy sf uncti on, w ho r em ai n sy m ptom ati c af ter m ax i m um tol er abl e doses of ACE i nhi bi tor s and Î²
bl ock er s. The addi ti on of al doster one antagoni sts r educes m or tal i ty i n pati ents w i th sev er e chr oni c
HF and i n those w ho hav e ex per i enced HF f ol l ow i ng an MI. ARBs such as l osar tan, candesar tan,
i r besar tan, and v al sar tan bl ock the angi otensi n II r eceptor di r ectl y . They appear to hav e benef i ci al
ef f ects i n r educi ng car di ov ascul ar m or tal i ty and hospi tal i zati on f or HF w hen added to ACE i nhi bi tor s
and Î²bl ock er s. Addi ng both al doster one antagoni sts and ARBs to ACE i nhi bi tor s i s pr obabl y not
r easonabl e f or m ost pati ents because of the i ncr eased r i sk
P. 38
of hy per k al em i a. The com bi nati on of hy dr al azi ne and i sosor bi de di ni tr ate r educes m or tal i ty and
hospi tal i zati ons and i m pr ov es qual i ty of l i f e i n Af r i can Am er i cans w i th sev er e chr oni c HF due to
sy stol i c dy sf uncti on. The benef i ts ar e l ess cl ear i n nonâ€“Af r i can Am er i cans. Another opti on i s the
use of di gox i n, w hi ch r esul ts i n an i m pr ov em ent i n sy m ptom s and a r educti on i n hospi tal
adm i ssi ons but no r educti on i n m or tal i ty . Sodi um r estr i cti on i s an essenti al par t of any pr ogr am
desi gned to tr eat pati ents w i th HF. Pati ents shoul d av oi d ex cess sal t and w ater , w ei gh them sel v es
dai l y , av oi d N SAIDs, and r epor t any i ncr ease i n sy m ptom s or w ei ght gai n pr om ptl y to thei r
phy si ci ans.
7. Is i t possi bl e that v entr i cul ar f uncti on w i l l i m pr ov e w i th m edi cal ther apy ?
Thi s pati ent has an EF of 20%. ACE i nhi bi tor s hel p pr ev ent f ur ther deter i or ati on i n EF. Î²Bl ock er s,
i f upti tr ated to r ecom m ended doses, ar e l i k el y to i m pr ov e thi s i ndi v i dual 's EF by 7% to 10%. The
f ul l i m pr ov em ent m ay not be seen f or up to 6 m onths. Your pati ent i m pr ov ed af ter di ur esi s and
adm i ni ster i ng ACE i nhi bi tor s and Î²bl ock er s. Si x m onths l ater hi s EF has i ncr eased f r om 20% to
29%. He i s on di gox i n w i th ther apeuti c l ev el s and an al doster one antagoni st w i th nor m al ser um
cr eati ni ne and potassi um . He has no r esti ng dy spnea or edem a, but does hav e dy spnea w i th si m pl e
task s.
8. In w hi ch N YHA cl ass and AHA/ACC stage w oul d y ou categor i ze thi s pati ent's sy m ptom s?
Thi s pati ent conti nues to hav e sy m ptom s of N YHA cl ass III HF.
The f our categor i es that m ak e up the N YHA cl assi f i cati on, and thei r def i ni ti ons, ar e:
Cl ass I: N o sy m ptom s w i th any l ev el of ex er ci se
Cl ass II: Sy m ptom s on m or e than or di nar y acti v i ty
Cl ass III: Sy m ptom s on acti v i ti es of dai l y l i v i ng
Cl ass IV: Sy m ptom s at r est
The AHA/ACC stages of HF ar e:
Stage A: Ri sk f actor s f or HF
Stage B: Str uctur al hear t di sease, but no HF
Stage C: Str uctur al hear t di sease and HF
Stage D: Str uctur al hear t di sease and r ef r actor y HF.
Your pati ent w as i ni ti al l y i n N YHA cl ass IV and AHA/ACC stage Câ€“D. He has i m pr ov ed to N YHA
cl ass III, stage C.
9. What i s thi s pati ent's ex pected m or tal i ty r ate i n hi s cur r ent condi ti on?
Hi s ex pected m or tal i ty r ate i n N YHA cl ass IV HF, i f untr eated, w as 25% to 50% i n 1 y ear . Wi th
good m edi cal ther apy and i nter nal car di ac def i br i l l ator (ICD)bi v entr i cul ar paci ng dev i ce, hi s y ear l y
m or tal i ty m ay i m pr ov e to as l ow as 8% per y ear . An ICD can pr ol ong sur v i v al i n pati ents w i th HF
and sy stol i c dy sf uncti on and shoul d be i m pl anted at thi s poi nt as m edi cal ther apy i s unl i k el y to
cause si gni f i cant addi ti onal gai ns i n l ef t v entr i cul ar f uncti on. Bi v entr i cul ar paci ng (i m pl anted i n
conjuncti on w i th the ICD) i s i ndi cated i n thi s pati ent w ho has sy stol i c dy sf uncti on, ongoi ng HF
sy m ptom s, and a QRS dur ati on gr eater than 120 m i l l i seconds. Bi v entr i cul ar paci ng i s l i k el y to
i m pr ov e v entr i cul ar f uncti on, sy m ptom s, and sur v i v al .
P. 39
Suggested Readings
Adam s KF, Li ndenf el d J, Ar nol d JMO, etal . Ex ecuti v e sum m ar y : HFSA 2006 com pr ehensi v e HF pr acti ce
gui del i nes. J Car d Fai l 2006;12:10â€“38.
Br i stow MR. Betaadr ener gi c r eceptor bl ock ade i n chr oni c HF. Ci r cul ati on 2000;101:558â€“569.
Cl el and JG, Dauber t JC, Er dm ann E, etal . The ef f ect of car di ac r esy nchr oni zati on on m or bi di ty and
m or tal i ty i n HF. N Engl J Med 2005;352:1539â€“1549.
Fr anci s GS, Tang WH. Pathol ogy of congesti v e HF. Rev Cadi ov asc Med 2003;4(Suppl 2):S14â€“S20.
Hunt SA, Abr aham WT, Chi n MH, etal . ACC/AHA 2005 gui del i ne update f or the di agnosi s and
m anagem ent of chr oni c HF i n the adul t. Ci r cul ati on 2005;112:e154â€“e235.
Jessup M, Br ozena S. Hear t f ai l ur e. N Engl J Med 2003;348:2007â€“2018.
McCl el l an MB, Loeb JM, Cl ancy CM, etal . Angi otensi nconv er ti ng enzy m e i nhi bi tor s and angi otensi n
r eceptor bl ock er s i n chr oni c HF. Ann Inter n Med 2005;142:386â€“387.
Essential Hypertension and Hypertensive Emergencies
1. What i s the esti m ated pr ev al ence of sy stem i c hy per tensi on i n the U . S. popul ati on?
2. What i s the m ost com m on cause of sy stem i c hy per tensi on?
3. How i s hy per tensi on cl assi f i ed?
4. What i s the natur al hi stor y of untr eated hy per tensi on?
5. Does m edi cal ther apy i m pr ov e outcom es i n hy per tensi on?
6. What i s a hy per tensi v e cr i si s?
Discussion
1. What i s the esti m ated pr ev al ence of sy stem i c hy per tensi on i n the U . S. popul ati on?
Hy per tensi on i n the U ni ted States af f ects appr ox i m atel y 65 m i l l i on Am er i cans. How ev er , the
pr ev al ence i ncr eases w i th age, so that m or e than 60% of the popul ati on ol der than 70 y ear s has
hy per tensi on. The Fr am i ngham Hear t Study has dem onstr ated that 55y ear ol d nor m otensi v e
i ndi v i dual s hav e a 90% l i f eti m e r i sk of dev el opi ng hy per tensi on. The i nci dence of hy per tensi on and
i ts sev er i ty i s gr eater i n bl ack s than w hi tes i n ev er y agegr oup bey ond adol escence.
2. What i s the m ost com m on cause of sy stem i c hy per tensi on?
N o cause i s f ound f or appr ox i m atel y 90% of pati ents w i th hy per tensi on. These pati ents ar e sai d to
hav e essenti al hy per tensi on. Al though the m echani sm of essenti al hy per tensi on i s unk now n, ther e
ar e appar entl y both geneti c and env i r onm ental f actor s.
3. How i s hy per tensi on cl assi f i ed?
N or m al bl ood pr essur e i s l ess than 120/80 m m Hg. Bl ood pr essur es of 130 to 139 m m Hg sy stol i c
and 80 to 89 m m Hg di astol i c ar e consi der ed
P. 40
pr ehy per tensi on. Indi v i dual s w i th pr ehy per tensi on hav e tw i ce the l i f eti m e r i sk of dev el opi ng
hy per tensi on as thei r nor m otensi v e counter par ts. Stage 1 hy per tensi on i s def i ned as a sy stol i c
bl ood pr essur e of 140 to 159 m m Hg and a di astol i c bl ood pr essur e of 90 to 99 m m Hg, w her eas
stage 2 hy per tensi on i s a sy stol i c bl ood pr essur e of 160 m m Hg and gr eater and a di astol i c bl ood
pr essur e of 100 m m Hg and gr eater (Tabl e 21).
4. What i s the natur al hi stor y of untr eated hy per tensi on?
U ncom pl i cated hy per tensi on of ten r em ai ns asy m ptom ati c f or 10 to 20 y ear s or m or e. How ev er ,
ther e i s a di r ect r el ati onshi p betw een the l ev el s of both sy stol i c and di astol i c bl ood pr essur es and
the i nci dence of str ok e, CAD, and HF. Indeed, f or ev er y 20 and 10 m m Hg i ncr em ent i n sy stol i c and
di astol i c pr essur e r especti v el y , i ndi v i dual s aged 40 to 70 y ear s hav e a doubl i ng of car di ov ascul ar
r i sk f r om bl ood pr essur es of 115/75 to 185/115 m m Hg. The ov er al l r i sk of pr em atur e
car di ov ascul ar di sease i ncr eases substanti al l y w hen addi ti onal car di ov ascul ar r i sk f actor s ar e
pr esent. In f act, the l i k el i hood of a v ascul ar ev ent ov er the nex t 10 y ear s can be esti m ated f or any
pati ent on the basi s of thei r age, sex , and other r i sk s (Am er i can Hear t Associ ati on's Cor onar y and
Str ok e Ri sk Handbook ). If pati ents w i th hy per tensi on ar e not tr eated, appr ox i m atel y 50% di e of
cor onar y di sease, 33% of str ok e, and 10% to 15% of r enal f ai l ur e.
5. Does m edi cal ther apy i m pr ov e outcom es i n hy per tensi on?
Cl i ni cal tr i al s of anti hy per tensi v e ther apy hav e dem onstr ated an av er age m ean r educti on of 40%
f or str ok e, 50% f or HF, and 20% to 25% f or MI.
6. What i s a hy per tensi v e cr i si s?
A hy per tensi v e cr i si s i s an acute l i f ethr eateni ng com pl i cati on of accel er ated hy per tensi on. In
pati ents w i th chr oni c hy per tensi on and hy per tensi v e cr i si s, the bl ood pr essur e i s gener al l y 180/120
m m Hg or gr eater , but m ay be l ow er i n pati ents w hose bl ood pr essur e w as pr ev i ousl y nor m al (e. g. ,
ecl am psi a). Mal i gnant hy per tensi on i s pr esent w hen ther e ar e r eti nal hem or r hages, ex udates or
papi l l edem a, and/or m al i gnant nephr oscl er osi s. When ther e ar e si gns of cer ebr al edem a,
hy per tensi v e encephal opathy i s sai d to be pr esent. Ex am pl es of hy per tensi v e cr i ses i ncl ude:
Accel er ated/m al i gnant hy per tensi on
Hy per tensi v e encephal opathy
Ather othr om boti c cer ebr al i nf ar cti on w i th sev er e hy per tensi on
Aor ti c di ssecti on
Acute pul m onar y edem a or l ef t v entr i cul ar f ai l ur e
Acute MI
Ecl am psi a
Dr ugi nduced hy per tensi on (cocai ne)
Case
A 45y ear ol d Af r i canAm er i can m an i s seen i n the outpati ent depar tm ent com pl ai ni ng of i nter m i ttent
thr obbi ng headaches that hav e occur r ed ev er y m or ni ng f or 2 w eek s. He has a hi stor y of untr eated,
asy m ptom ati c, sustai ned hi gh bl ood pr essur e (160 to
P. 41
P. 42
170/100 m m Hg) of 4 y ear s' dur ati on. He has no hi stor y of pal pi tati ons, sw eati ng, tr em or , or per i odi c
par al y si s. Hi s f ather w as al so hy per tensi v e and di ed of str ok e at 67 y ear s. The pati ent has sm ok ed
ci gar ettes, tw o pack s per day , f or 30 y ear s. He i s tak i ng no m edi cati ons.
Table 21 Classification and Management of Blood Pressure for Adults
Aged 18 Years or Older
Ma na ge me nt a
Initia l Drug The ra py
BP Sys tolic Dia s tolic Life s tyle W ithout W ith Compe lling

Cla s s ific a tion BP BP (mm Modific a tion Compe lling Indic a tions b
(mm Hg) a Indic a tions
Hg) a
N or m al < 120 and < 80 Encour age
Pr ehy per tensi on 120 or 80 89 Yes No Dr ug(s) f or the

139 anti hy per tensi v e com pel l i ng
dr ug i ndi cated i ndi cati ons c
Stage 1 140 or 9099 Yes Thi azi dety pe Dr ug(s) f or the

hy per tensi on 159 di ur eti cs f or com pel l i ng
m ost; m ay i ndi cati ons
consi der ACE
i nhi bi tor , ARB,
Î²bl ock er , CCB,
or com bi nati on
Other
anti hy per tensi v e
dr ugs (di ur eti cs,

ACE i nhi bi tor ,
ARB, Î²bl ock er ,
CCB) as needed
Stage 2 â‰ or â‰ Yes Tw odr ug Dr ug(s) f or the

hy per tensi on ￥160 ￥100 com bi nati on f or com pel l i ng
m ost (usual l y i ndi cati ons
thi azi dety pe
di ur eti c and ACE
i nhi bi tor or ARB
or Î²bl ock er or
CCB) d
Other
anti hy per tensi v e
dr ugs (di ur eti cs,

ACE i nhi bi tor ,
ARB, Î²bl ock er ,
CCB) as needed
a Tr eatm ent deter m i ned by hi ghest BP categor y .
b See r ef er ence bel ow .
c Tr eat pati ents w i th chr oni c k i dney di sease or di abetes to BP goal of < 130/80 m m Hg.
d Ini ti al com bi ned ther apy shoul d be used cauti ousl y i n those at r i sk f or or thostati c hy potensi on.
BP, bl ood pr essur e; ACE, angi otensi nconv er ti ng enzy m e; ARB, angi otensi nr eceptor bl ock er ; CCB,
cal ci um channel bl ock er .
Fr om Chobani an AV, Bak r i s GL, Bl ack GL, et al . JAMA 2003;289:25602572.
Hi s phy si cal ex am i nati on r ev eal s a bl ood pr essur e of 170/110 m m Hg and a hear t r ate of 90 per m i nute
and r egul ar . Hi s w ei ght i s 244 l b and he i s 5 f t 10 i n. tal l . Fundus ex am i nati on r ev eal s the pr esence of
ar ter i al v asoconstr i cti on. Car di ac ex am i nati on r ev eal s a l ater al l y di spl aced sustai ned poi nt of m ax i m al
i m pul se, S 4 , no S 3 , and no m ur m ur . Dur i ng abdom i nal ex am i nati on, no br ui t or m ass i s f ound and the
neur ol ogi c and other sy stem s ar e unr em ar k abl e.
1. How shoul d bl ood pr essur e be m easur ed?

2. What i s the m ost l i k el y cause of thi s pati ent's hy per tensi on?
3. What l abor ator y tests ar e i ndi cated?
4. Wi l l l i f esty l e changes i m pr ov e hi s bl ood pr essur e?
5. Is dr ug ther apy i ndi cated at thi s ti m e?
6. What i s the tar get bl ood pr essur e w i th tr eatm ent?
Case Discussion
1. How shoul d bl ood pr essur e be m easur ed?
The pati ent shoul d be seated i n a chai r w i th hi s f eet on the f l oor i n a qui et pl ace f or at l east 5
m i nutes. At l east tw o m easur em ents shoul d be m ade w i th a cal i br ated i nstr um ent. Sy stol i c bl ood
pr essur e i s def i ned as the bl ood pr essur e at w hi ch the f i r st sound i s hear d and di astol i c pr essur e i s
def i ned as the pr essur e at the di sappear ance of the sounds.
2. What i s the m ost l i k el y cause of thi s pati ent's hy per tensi on?
The m ost l i k el y cause of thi s pati ent's hy per tensi on i s essenti al hy per tensi on.
3. What l abor ator y tests ar e i ndi cated?
The l abor ator y i nv esti gati on shoul d i ncl ude chest r adi ogr aphy (nor m al ), ECG (si nus r hy thm w i th
i ncr eased v ol tage but no STTâ€“w av e changes), ur i nal y si s, hem atocr i t, cal ci um (al l nor m al ), and
m easur em ent of the f asti ng bl ood sugar (nor m al ), bl ood ur ea ni tr ogen, ser um cr eati ni ne,
el ectr ol y tes (nor m al ), chol ester ol [total and l ow densi ty l i popr otei n (LDL) and hi ghdensi ty
l i popr otei n (HDL)], and tr i gl y cer i de (total chol ester ol i s 240 w i th LDL of 170, HDL of 40, and nor m al
tr i gl y cer i des).
4. Wi l l l i f esty l e changes i m pr ov e hi s bl ood pr essur e?
Li f esty l e m odi f i cati ons ar e an i m por tant par t of bl ood pr essur e m anagem ent. Benef i ci al l i f esty l e
m odi f i cati ons i ncl ude w ei ght r educti on i n ov er w ei ght or obese peopl e, r egul ar ex er ci se, adopti on of
theDASH (Di etar y Appr oaches to Stop Hy per tensi on) di et w hi ch i s hi gh i n cal ci um and potassi um ,
l i m i tati on of sodi um i ntak e, and m oder ati on of al cohol consum pti on.
5. Is dr ug ther apy i ndi cated at thi s ti m e?
Medi cal ther apy i s i ndi cated i n thi s pati ent w ho has dem onstr ated stage 2 hy per tensi on (Tabl e 21
and Fi g. 21). The pl an of m anagem ent shoul d com m ence
P. 43
w i th i nstr ucti on i n l i f esty l e changes and or al anti hy per tensi v e dr ugs w i th the ai m of m ai ntai ni ng
bl ood pr essur e at l ess than 140/90 m m Hg. El i m i nati ng coex i sti ng car di ov ascul ar r i sk f actor s
(especi al l y sm ok i ng) and tr eati ng the el ev ated chol ester ol w i l l not l ow er the bl ood pr essur e but w i l l
l ow er hi s r i sk of subsequent car di ov ascul ar ev ents.
Figure 21 Al gor i thm f or tr eatm ent of hy per tensi on. BP, bl ood pr essur e; ACE, angi otensi n
conv er ti ng enzy m e; ARB, angi otensi nr eceptor bl ock er ; CCB, cal ci um channel bl ock er . (Fr om
Chobani an AV, Bak r i s GL, Bl ack GL, etal . The sev enth r epor t of the Joi nt N ati onal Com m i ttee
on pr ev enti on, detecti on, ev al uati on, and tr eatm ent of hi gh bl ood pr essur e. JAMA
2003;289:2560â€“2572. )
6. What i s the tar get bl ood pr essur e w i th tr eatm ent?
The tar get bl ood pr essur e w i th tr eatm ent i s l ess than 140/90 m m Hg. If the pati ent had di abetes or
chr oni c k i dney di sease the r ecom m ended tar get bl ood pr essur e w oul d be l ess than 130/80 m m Hg.
You i nstr uct y our pati ent i n l i f esty l e changes and star t hi m on l i si nopr i l 10 m g once dai l y . In 2
w eek s y ou i ncr ease the l i si nopr i l to 20 m g dai l y because the bl ood pr essur e i s sti l l 160/98 m m Hg.
El ectr ol y tes and cr eati ni ne l ev el s ar e unchanged. The i ncr eased l i si nopr i l does not si gni f i cantl y
al ter the pr essur e and y ou add chl or thal i done at 25 m g dai l y . In 4 w eek s hi s bl ood pr essur e i s
139/88 m m Hg
P. 44
and hi s el ectr ol y tes and cr eati ni ne l ev el s ar e nor m al . The bl ood pr essur e r em ai ns w el l contr ol l ed
f or the nex t 6 m onths, but the pati ent does not r etur n f or the nex t f ol l ow up v i si t and does not
r espond to phone cal l s. Tw o y ear s l ater , he pr esents to the ER com pl ai ni ng of bl ur r ed v i si on and
sev er e headaches. Hi s phy si cal ex am i nati on at that ti m e r ev eal s a bl ood pr essur e of 240/140 m m
Hg and hear t r ate of 100 per m i nute. He i s m i l dl y conf used and the f undus ex am i nati on r ev eal s
r eti nal hem or r hages, ex udates, and papi l l edem a. Hear t ex am i nati on show s cl ear l ungs and a
sustai ned l ef t v entr i cul ar api cal i m pul se and S 4 . The chest r adi ogr aph show s m i l d to m oder ate
car di om egal y . Hi s ser um cr eati ni ne l ev el i s 2. 4 m g/dL. The ECG show s nor m al si nus r hy thm w i th
i ncr eased v ol tage and STsegm ent depr essi on and Tw av e i nv er si on. Tr oponi n i s nor m al and he has
no chest pai n.
a. What i s the di agnosi s?
b. What i s the m ost l i k el y r eason f or the f undus f i ndi ngs and the ser um cr eati ni ne l ev el of 2. 4
m g/dL?
c. What shoul d be the pl an of tr eatm ent now ?
a. What i s the di agnosi s?
The di agnosi s i s hy per tensi v e cr i si s and accel er ated m al i gnant hy per tensi on. A hy per tensi v e
cr i si s i s consi der ed a m edi cal em er gency . Such hi gh bl ood pr essur e can cause i m m edi ate
v ascul ar dam age, as seen i n thi s pati ent. The pr esence of sev er e hy per tensi on (di astol i c bl ood
pr essur e of 115 m m Hg or gr eater ) i n conjuncti on w i th gr ade 3 (r eti nal hem or r hage and
ex udate) or gr ade 4 (papi l l edem a) f unduscopi c changes i s def i ned as accel er ated or m al i gnant
hy per tensi on.
b. What i s the m ost l i k el y r eason f or the f undus f i ndi ngs and the ser um cr eati ni ne l ev el of 2. 4
m g/dL?
Modest i ncr eases i n bl ood pr essur e r esul t i n ar ter i ol ar v asoconstr i cti on. The v asoconstr i cti on
k eeps ti ssue per f usi on constant. How ev er , w i th the m ar k ed i ncr ease i n bl ood pr essur e causi ng
a sudden i ncr ease i n ti ssue per f usi on, ther e i s dam age to the v ascul ar endothel i um causi ng
f i br i noi d necr osi s i n the v essel s of the ey e and i n the k i dney . These changes ar e ex acer bated
by acti v ati on of the r eni nâ€“angi otensi n sy stem .
c. What shoul d be the pl an of tr eatm ent now ?
The pati ent shoul d be adm i tted to a m oni tor ed uni t. An ECG, chest x r ay , el ectr ol y tes,
ur i nal y si s, hem atocr i t, and tr oponi n shoul d be obtai ned. Because the papi l l edem a i s consi stent
w i th the pr esence of sev er e hy per tensi on and r epr esents ear l y br ai n edem a, w hi ch m ay
com pr om i se the autor egul ati on of cer ebr al bl ood f l ow , the tr eatm ent appr oach shoul d be to
star t hi m on par enter al anti hy per tensi v e dr ug ther apy . The goal of tr eatm ent shoul d be to
decr ease the bl ood pr essur e by 20% to 25% m ai ntai ni ng the di astol i c bl ood pr essur e betw een
100 and 110 m m Hg or the m ean ar ter i al pr essur e at not l ess than 120 m m Hg, because an
abr upt decr ease i n the bl ood pr essur e to â€œnor m al â€ l ev el s m ay pr oduce hy poper f usi on to
the br ai n, hear t, and k i dney due to l ack of autor egul ati on.
P. 45
A l i st of par enter al agents used to tr eat hy per tensi v e em er genci es i s gi v en i n Tabl e 22.
Table 22 Parenteral Agents Used to Treat Hypertensive
Emergencies
Drug Route Ons e t Dura tion Dos e or Dos a ge
Va s odila tors
Sodi um IV Seconds 35 m i n 0. 2510 Âµ g/k g/m i n

ni tr opr ussi de i nf usi on 1 m i n
N i car di pi ne IV 510 m i n 14 hr 210 m g/hr

hy dr ochl or i de
Fenol dopam IV < 5 m i n 30 m i n 0. 10 . 3 Âµ g/k g/m i n

m esy l ate i nf usi on
N i tr ogl y cer i n IV 12 m i n 35 m i n 5100 Âµ g/m i n

i nf usi on
Di azox i de IV bol us 15 m i n 612 hr 50 m g IV ev er y 510 m i n ov er 30 s,

or or 1530 m g/m i n by IV i nf usi on
i nf usi on
Hy dr al azi ne IV 1020 38 hr 1020 m g IV

min
IM (al so 30 m i n 38 hr 1050 m g IM

or al )
Enal apr i l at IV bol us 1530 6 hr 1. 255 m g
min
Adre ne rgic

Inhibitors
Labetal ol IV 5 m i n 36 hr 0. 52 m g/m i n IV i nf usi on or 2080

m g ev er y 10 m i n to a m ax i m um
cum ul ati v e dose of 300 m g
Tr i m ethaphan IV 15 m i n 10 m i n 0. 55 m g/m i n

i nf usi on
Phentol am i ne IV bol us 12 m i n 310 Load 515 m g IV ev er y 5 m i n

min
Esm ol ol IV bol us 12 m i n 1020 250500 Âµ g/k g bol us, then 50300
then min Âµ g/k g/m i n i nf usi on
i nf usi on
IV, i ntr av enous; IM, i ntr am uscul ar .
Fr om Chobani an AV, Bak r i s GL, Bl ack GL, et al . The sev enth r epor t of the Joi nt N ati onal
Com m i ttee on pr ev enti on, detecti on, ev al uati on,
and tr eatm ent of hi gh bl ood pr essur e. Hy per tensi on 2003;42:12061252.
Ov er the subsequent 3 m onths, bl ood pr essur e shoul d be l ow er ed gr adual l y to l ess than 140/90 m m
Hg (or to 130/80 m m Hg i f ther e i s di abetes or chr oni c k i dney di sease, as i n y our pati ent) w i th or al
agents.
Suggested Readings
Appel LJ, Br ands MW, Dani el s SR, etal . Di etar y appr oaches to pr ev ent and tr eat hy per tensi on.
Hy per tensi on 2006;47:296â€“308.
Bender KR, Fi l i ppone JD, Hei tz S, etal . A sy stem ati c appr oach to hy per tensi v e ur genci es and
em er genci es. Cur r Hy per tens Rev 2005;1:275â€“281.
Bol l i P, My er s M, McKay D. Canadi an hy per tensi on educati on pr ogr am . Appl y i ng the 2005 Canadi an
hy per tensi on educati on pr ogr am r ecom m endati ons: 1. Di agnosi s of hy per tensi on. CMAJ
2005;173:480â€“483.
Chobani an AV, Bak r i s GL, Bl ack HR, etal . The sev enth r epor t of the Joi nt N ati onal Com m i ttee on
pr ev enti on, detecti on, ev al uati on, and tr eatm ent of hi gh bl ood pr essur e. JAMA 2003;289:2560â
€“2572.
P. 46
Hem m el gar n BR, Gr ov er S, Fel dm an RD. Canadi an hy per tensi on educati on pr ogr am . Appl y i ng the
2005 Canadi an hy per tensi on educati on pr ogr am r ecom m endati ons: 2. assessi ng and r educi ng gl obal
ather oscl er oti c r i sk am ong hy per tensi v e pati ents. CMAJ 2005;173:593â€“595.
Khan N A, Ham et P, Lew anczuk RZ. Canadi an hy per tensi on educati on pr ogr am . Appl y i ng the 2005
Canadi an hy per tensi on educati on pr ogr am r ecom m endati ons: 4. Managi ng uncom pl i cated
hy per tensi on. CMAJ 2005;173:865â€“867.
MacMahon S, Peto R, Cutl er J, etal . Bl ood pr essur e, str ok e, and cor onar y hear t di sease: par t 1.
pr ol onged di f f er ences i n bl ood pr essur e: pr ospecti v e obser v ati onal studi es cor r ected f or the
r egr essi on di l uti on bi as. Lancet 1990;335:827â€“838.
Padw al R, Cam pbel l N , Touy z RM. Canadi an hy per tensi on educati on pr ogr am . Appl y i ng the 2005
Canadi an hy per tensi on educati on pr ogr am r ecom m endati ons: 3. Li f esty l e m odi f i cati ons to pr ev ent
and tr eat hy per tensi on. CMAJ 2005;173:749â€“751.
Tobe S, McAl i ster FA, Lei ter L. Appl y i ng the 2005 Canadi an hy per tensi on educati on pr ogr am
r ecom m endati ons: 5. Ther apy f or pati ents w i th hy per tensi on and di abetes m el l i tus. CMAJ
2005;173:1154â€“1157.
Vasan RS, Bei ser A, Ser shadr i S, etal . Resi dual l i f eti m e r i sk f or dev el opi ng hy per tensi on i n m i ddl e
aged w om en and m en: the Fr am i ngham hear t study . JAMA 2002;287:1003â€“1010.
Wi l son PW. Establ i shed r i sk f actor s and cor onar y ar ter y di sease: The Fr am i ngham Study . Am J
Hy per tens 1994;7:7Sâ€“12S.
STElevation Myocardial Infarction
1. What ar e the m ajor k now n r i sk f actor s f or CAD?
2. What i s the l i f eti m e r i sk of i schem i c hear t di sease deaths i n m en and w om en i n the U . S.
popul ati on?
3. What i s the m ost com m on cause of acute MI?
4. In pl acebocontr ol l ed tr i al s, w hat ty pes of tr eatm ents hav e been show n to i m pr ov e outcom e i n
pati ents w i th acute MI?
Discussion
1. What ar e the m ajor k now n r i sk f actor s f or CAD?
The establ i shed m ajor r i sk f actor s f or CAD i ncl ude sm ok i ng, hy per tensi on, dy sl i pi dem i aâ
€”speci f i cal l y i ncr eased LDL chol ester ol and l ow HDL chol ester ol , di abetes m el l i tus, f am i l y hi stor y
of CAD i n a f i r stdegr ee r el ati v e, m al e gender , and age. The f i r st f our f actor s ar e m odi f i abl e w hi l e
the l ast thr ee ar e not. Ther e ar e other establ i shed r i sk f actor s that can be m odi f i ed such as
obesi ty , phy si cal i nacti v i ty , an ather ogeni c di et, m ental str ess, and depr essi on. The m etabol i c
sy ndr om e i s al so consi der ed an i m por tant r i sk f actor by the N ati onal Chol ester ol Educati on Pr ogr am
(N CEP) gui del i nes. Em er gi ng r i sk f actor s i ncl ude hi gh sensi ti v i ty Cr eacti v e pr otei n (hsCRP),
hom ocy stei ne, l i popr otei n a, sm al l dense LDL, pr othr om boti c f actor s f i br i nogen, i m bal ance betw een
ti ssue pl asm i nogen acti v ator and pl asm i nogen acti v ator i nhi bi tor 1 (PAI1), pr oi nf l am m ator y f actor s
other than hsCRP, and i ncr eased ox i dati v e str ess.
P. 47
2. What i s the l i f eti m e r i sk of i schem i c hear t di sease deaths i n m en and w om en i n the U . S.
popul ati on?
The l i f eti m e r i sk of dev el opi ng CAD af ter age 40 i s 49% i n m en and 32% i n w om en. CAD i s the
l eadi ng cause of death i n both m en and w om en, accounti ng f or appr ox i m atel y 20% of al l deaths i n
the U ni ted States. How ev er , w om en dev el op sy m ptom ati c CAD 10 to 15 y ear s l ater than m en.
3. What i s the m ost com m on cause of acute MI?
Pl aque r uptur e, i n the setti ng of cor onar y ather oscl er osi s, i s the under l y i ng cause of MI i n m ost
pati ents. At the si te of pl aque r uptur e, ther e i s, i n m ost cases, f or m ati on of an acute thr om bus.
Inf r equent causes of MI i ncl ude i nf l am m ati on (ar ter i ti s), tr aum a, or cor onar y em bol i sm .
4. In pl acebocontr ol l ed tr i al s, w hat ty pes of tr eatm ents hav e been show n to i m pr ov e outcom e i n
pati ents w i th acute MI?
Aspi r i n, cl opi dogr el , r ev ascul ar i zati on w i th thr om bol y ti c agents or PCI, Î²adr ener gi c bl ock er s, ACE
i nhi bi tor s or ARBs, and al doster one i nhi bi tor s (epl er enone) hav e al l been show n to r educe m or tal i ty
af ter MI. Ther e ar e l ess com pel l i ng data r egar di ng the uti l i ty of GIK (gl ucose, i nsul i n, and
potassi um ) sol uti on i nf usi on, and hepar i n and ni tr ate use. In the l ong ter m , l ow er i ng the LDL
chol ester ol w i th HMGCoA r eductase i nhi bi tor s (stati ns) and the use of w ar f ar i n hav e been show n to
be benef i ci al . The benef i t of epl er enone has been show n onl y i n hi ghr i sk pati ents. The use of
w ar f ar i n i s cum ber som e and not w i despr ead. The use of aspi r i n i m par ts near l y the sam e sur v i v al
benef i t as the use of thr om bol y ti cs and other m or e ex pensi v e ther api es. Fi nal l y , ear l y tr eatm ent
al so i m par ts the hi ghest benef i t (the gol den hour ).
Case 1
A 62y ear ol d m an w i th a hi stor y of hy per tensi on i s m ow i ng hi s l aw n at 9:00 a. m . on a Satur day
m or ni ng w hen he ex per i ences a heav y sensati on i n hi s chest. He stops m ow i ng the l aw n and w i thi n 10
m i nutes hi s sy m ptom s r esol v e, and he r esum es cutti ng the gr ass. Appr ox i m atel y 10 m i nutes l ater , he
ex per i ences sev er e, cr ushi ng chest pai n associ ated w i th shor tness of br eath and pai n r adi ati ng dow n hi s
l ef t ar m . As he w al k s to hi s house, he becom es di aphor eti c and nauseated, and v om i ts tw i ce. At thi s
poi nt, he cal l s an am bul ance and i s tak en to the ER. When y ou ar r i v e to ex am i ne hi m , he i s sti l l
ex per i enci ng sev er e pai n. A 12l ead ECG r ev eal s 3m m STsegm ent el ev ati on i n l eads V 2 , V 3 , V 4 , and V 5
w i th i nf er i or STsegm ent depr essi on. The pai n has been pr esent f or a total of appr ox i m atel y 45 m i nutes.
1. What i ni ti al acti ons shoul d be tak en i n thi s pati ent?
2. Is thi s pati ent's hy per tensi on a contr ai ndi cati on to thr om bol y ti c ther apy ?
3. What ar e the r i sk s associ ated w i th thr om bol y ti c ther apy and how l ong af ter the onset of acute MI i s
ther apy benef i ci al ?
4. Whi ch i s the better r eper f usi on ther apy f or acute MIâ€”thr om bol y ti c ther apy or pr i m ar y
per cutaneous tr ansl um i nal cor onar y angi opl asty (PTCA)?
5. What ther api es shoul d be adm i ni ster ed acutel y w i th thr om bol y si s or pr i m ar y PTCA?
P. 48
6. What m easur es shoul d be car r i ed out bef or e thi s pati ent i s di schar ged?
7. U nder w hat ci r cum stances shoul d the pati ents under go cor onar y angi ogr aphy i f they di d not
under go acute angi opl asty and/or stenti ng on adm i ssi on?
Case Discussion
1. What i ni ti al acti ons shoul d be tak en i n thi s pati ent?
The f i r st acti ons that shoul d be tak en i n thi s pati ent ar e to adm i ni ster subl i ngual N TG, adm i ni ster
ox y gen i f ox y gen satur ati on i s bel ow 90%, and establ i sh v enous access. IV Î²bl ock er s and aspi r i n
shoul d be gi v en. Anal gesi cs such as m or phi ne shoul d be gi v en i f the pai n does not r esol v e w i th
N TG. Im m edi ate tr ansf er to the car di ac catheter i zati on l abor ator y f or cor onar y angi opl asty and
r eper f usi on of the i nf ar ctr el ated ar ter y i s the tr eatm ent of choi ce i f i t can be accom pl i shed w i thi n
3 hour s of the onset of chest pai n. If not, thr om bol y ti c agents shoul d be adm i ni ster ed i m m edi atel y
i f ther e ar e no contr ai ndi cati ons. Pati ents shoul d be questi oned about contr ai ndi cati ons to
thr om bol y ti c agents bef or e adm i ni str ati on. Inv asi v e pr ocedur es such as ar ter i al punctur e shoul d be
m i ni m i zed i f thr om bol y ti c agents ar e to be adm i ni ster ed to av oi d bl eedi ng. If the pati ent pr esents
m or e than 3 hour s f ol l ow i ng the onset of chest pai n PCI i s cl ear l y pr ef er abl e, because of the
di f f i cul ty i n l y si ng the cl ot af ter 3 hour s. How ev er , studi es hav e show n that ei ther thr om bol y ti cs or
PCI i s benef i ci al f or at l east 12 hour s af ter the onset of pai n.
2. Is thi s pati ent's hy per tensi on a contr ai ndi cati on to thr om bol y ti c ther apy ?
Hy per tensi on al one i s not a contr ai ndi cati on to thr om bol y ti c ther apy . If the hy per tensi on i s
uncontr ol l ed and cannot be l ow er ed qui ck l y to a l ev el bel ow 180/110 m m Hg, the r i sk of
i ntr acr ani al bl eedi ng i s i ncr eased. These thr om bol y ti c agents can sti l l be consi der ed i n i ndi v i dual
pati ents. Absol ute contr ai ndi cati ons to thr om bol y ti c ther apy i ncl ude any pr i or i ntr acr ani al
hem or r hage (ICH), k now n cer ebr ov ascul ar or i ntr acr ani al neopl asti c l esi on, i schem i c str ok e w i thi n
3 m onths, acti v e bl eedi ng ex cl udi ng m enses, suspected aor ti c di ssecti on, and si gni f i cant cl osed
head or f aci al tr aum a w i thi n 3 m onths. Rel ati v e contr ai ndi cati ons i n addi ti on to uncontr ol l ed
hy per tensi on ar e an ol d hi stor y of str ok e, pr ol onged car di opul m onar y r esusci tati on (CPR) (m or e
than 10 m i nutes) or m ajor sur ger y w i thi n 3 w eek s, i nter nal bl eedi ng i n the l ast 4 w eek s, acti v e
pepti c ul cer , a k now n bl eedi ng di athesi s or use of anti coagul ants, and pr egnancy .
3. What ar e the r i sk s associ ated w i th thr om bol y ti c ther apy and how l ong af ter the onset of acute MI i s
ther apy benef i ci al ?
The m ajor r i sk of thr om bol y ti c ther apy i s bl eedi ng. Thi s r i sk i s l ow est w i th str eptok i nase, and
hi ghest w i th new er agents and w hen hepar i n i s added to ther apy . Wi th al tepl asel i k e agents, m ajor
bl eedi ng occur s i n appr ox i m atel y 5% of pati ents and ICH occur s i n 0. 9%. Factor s that i ncr ease ICH
i ncl ude age (especi al l y gr eater than 75 y ear s), w ei ght l ess than 70 k g, and hy per tensi on (160/95 or
hi gher ) at pr esentati on and the use of al tepl ase. Pati ents w i th m or e than thr ee r i sk f actor s hav e
tw o or thr ee ti m es hi gher r i sk of ICH. Pati ents w i th acute MI benef i t f r om
P. 49
thr om bol y ti cs f or up to 12 hour s af ter the onset of the i nf ar cti on w i th ear l i er tr eatm ent l eadi ng to
hi gher sur v i v al .
4. Whi ch i s the better r eper f usi on ther apy f or acute MIâ€”thr om bol y ti c ther apy or pr i m ar y PTCA?
PTCA i s gener al l y pr ef er r ed ov er thr om bol y ti c agents as a r eper f usi on ther apy . Thr om bol y ti cs can
be used i n pati ents pr esenti ng ear l y (< 3 hour s) especi al l y w hen a catheter i zati on l abor ator y i s not
r eadi l y av ai l abl e. Pr i m ar y PTCA i s pr ef er r ed i n m ost i nstances w her e ther e i s r api d access to a
sk i l l ed l abor ator y , especi al l y i n hi gher r i sk pati ents ei ther due to car di ogeni c shock or si gni f i cant
HF. It i s al so pr ef er r ed i n pati ents pr esenti ng l ater than 3 hour s f r om sy m ptom onset, w hen ther e
ar e si gni f i cant contr ai ndi cati ons to thr om bol y ti cs or w hen the di agnosi s i s i n doubt.
5. What ther api es shoul d be adm i ni ster ed acutel y w i th thr om bol y si s or pr i m ar y PTCA?
Chew abl e aspi r i n (162. 5 m g) shoul d be adm i ni ster ed i m m edi atel y once the di agnosi s i s m ade i n al l
pati ents unl ess ther e i s a contr ai ndi cati on to aspi r i n (i . e. , aspi r i n al l er gy or acti v e bl eedi ng). IV Î²
bl ock ade shoul d be i nsti tuted unl ess ther e ar e contr ai ndi cati ons to thei r use such as pul m onar y
edem a, si gni f i cant atr i ov entr i cul ar bl ock , hear t r ate l ess than 60 per m i nute, sy stol i c bl ood
pr essur e l ess than 100 m m Hg or si gni f i cant br onchospasm and hi stor y of asthm a. ACE i nhi bi tor s
(or ARBs f or al l er gi c pati ents) shoul d be begun w i thi n the f i r st 24 hour s i n the absence of
contr ai ndi cati ons such as sy stol i c bl ood pr essur e l ess than 100 m m Hg, r enal i nsuf f i ci ency (ser um
cr eati ni ne gr eater than 3. 0 m g/dL), or hy per k al em i a. Cl opi dogr el shoul d al so be used dur i ng the
hospi tal stay .
6. What m easur es shoul d be car r i ed out bef or e thi s pati ent i s di schar ged?
Ther apy w i th a stati n shoul d be star ted. LDL chol ester ol l ev el s f al l af ter the f i r st 24 hour s af ter an
acute MI, so l i pi d l ev el m easur em ents shoul d be done w i thi n 24 hour s of adm i ssi on. Ri sk
str ati f i cati on w i th subm ax i m al ex er ci se test and assessm ent of l ef t v entr i cul ar EF shoul d be
per f or m ed i n pati ents w ho w er e not str ati f i ed by angi ogr aphy . If a stent w as pl aced dur i ng PTCA,
cl opi dogr el i s added f or 3 to 6 m onths and per haps l onger i f a dr ugel uti ng stent w as pl aced.
Fi nal l y , an al doster one antagoni st shoul d be added f or pati ents w i th abnor m al car di ac f uncti on and
HF or di abetes.
Al l pati ents shoul d be counsel ed on sm ok i ng cessati on and a l ow f at di et. Each pati ent shoul d be
taught how to use N TG and shoul d be i nstr ucted w hen to cal l f or pr obl em s.
7. U nder w hat ci r cum stances shoul d pati ents under go cor onar y angi ogr aphy i f they di d not under go
acute angi opl asty and/or stenti ng on adm i ssi on?
Resi dual i schem i c m y ocar di um and l ow EF ar e m ajor r i sk f actor s f or m or tal i ty . Thi s i s w hy pati ents
w i th r ecur r ent i schem i c chest pai n, a posi ti v e subm ax i m al ex er ci se test, or an EF l ess than 40%
usual l y under go cor onar y angi ogr aphy to deter m i ne i f r esi dual l esi ons causi ng i schem i a can be
cor r ected.
Case 2
A 67y ear ol d w om an i s i n tow n v i si ti ng her chi l dr en w hen she pr esents to y our of f i ce com pl ai ni ng of
sev er e sy m ptom s of shor tness of br eath that has w or sened ov er the l ast 12 hour s. She tel l s y ou that
she has had di abetes m el l i tus f or the l ast 20 y ear s and
P. 50
hy per tensi on that has been f ai r l y w el l contr ol l ed f or 15 y ear s. Your ex am i nati on r ev eal s an S 3 gal l op
and r al es to her m i dscapul ar ar ea. She al so tel l s y ou that she has ex per i enced r ecur r ent chest
heav i ness ov er the l ast 2 day s. When the ECG i s done, ther e ar e Q w av es i n l eads V 2 , V 3 , V 4 , and V 5 . A
cal l to her r egul ar phy si ci an r ev eal s she had a nor m al ECG w hen he saw her 1 m onth ago.
1. At thi s poi nt, w hat shoul d y ou do?

2. What ther apeuti c i nter v enti ons shoul d be i nsti tuted at the ti m e of adm i ssi on?
3. Bef or e di schar ge, she has an echocar di ogr am per f or m ed. What f i ndi ngs w oul d f av or l ongter m
anti coagul ant ther apy w i th sodi um w ar f ar i n?
4. Shoul d thi s pati ent under go cor onar y angi ogr aphy or shoul d she hav e a subm ax i m al ex er ci se test?
5. Woul d y ou r ecom m end PTCA, sur ger y , or m edi cal ther apy
Case Discussion
1. At thi s poi nt, w hat shoul d y ou do?
Your pati ent has had a r ecent anter i or MI w i th l ef t v entr i cul ar f ai l ur e causi ng her sy m ptom s. She
needs to be hospi tal i zed i m m edi atel y , tr eated f or HF, m oni tor ed f or ar r hy thm i as and r ecur r ent
i schem i a, and r i sk str ati f i ed. Thr om bol y ti c ther apy or PCI i s not i ndi cated because thi s i s a
com pl eted i nf ar cti on, near l y 48 hour s ol d.
2. What ther apeuti c i nter v enti ons shoul d be i nsti tuted at the ti m e of adm i ssi on?
Ini ti al tr eatm ent consi sts of ox y gen adm i ni str ati on f or hy pox em i a and di ur esi s w hi l e av oi di ng
hy pok al em i a. The goal of di ur esi s i s to r esol v e pul m onar y congesti on. Aspi r i n shoul d be star ted.
Tel em etr y m oni tor i ng i s necessar y to detect ar r hy thm i as. ACE i nhi bi tor s (or an ARB i f al l er gi c)
shoul d be star ted i f the pati ent i s not hy potensi v e and has no contr ai ndi cati ons to thei r use.
Al doster one bl ock er s shoul d be i ntr oduced. Hepar i n shoul d be consi der ed i n thi s pati ent w i th a
l ar ge anter i or MI because of the r i sk of l ef t v entr i cul ar api cal thr om bus f or m ati on and em bol i sm . A
Î²bl ock er shoul d be consi der ed onl y af ter r esol uti on of the pati ent's sy m ptom s of HF.
3. Bef or e di schar ge, she has an echocar di ogr am per f or m ed. What f i ndi ngs w oul d f av or l ongter m
anti coagul ant ther apy w i th sodi um w ar f ar i n?
An api cal thr om bus, especi al l y i f m obi l e, i ncr eases the r i sk of em bol i sm and i s consi der ed an
acceptabl e i ndi cati on f or anti coagul ati on. The sam e i s tr ue of a dy sk i neti c or ak i neti c v entr i cul ar
segm ent. In these cases, w ar f ar i n i s conti nued f or 3 to 6 m onths or unti l a thr om bus i s no l onger
pr esent. How ev er , these r ecom m endati ons ar e not based on pr ospecti v e r andom i zed tr i al s.
Tw o cl ear i ndi cati ons f or anti coagul ati on i n thi s setti ng ar e the pr esence of atr i al f i br i l l ati on or a
hi stor y of a pr ev i ous em bol i c epi sode.
4. Shoul d thi s pati ent under go cor onar y angi ogr aphy or shoul d she hav e a subm ax i m al ex er ci se test?
Thi s w om an pr esented w i th a l ar ge MI and HF suggesti ng sev er e CAD. Her m or tal i ty r i sk i s hi gh and
ther ef or e ex er ci se testi ng f or r i sk str ati f i cati on i s not necessar y . She shoul d ther ef or e be
ev al uated di r ectl y w i th cor onar y angi ogr aphy .
P. 51
Cor onar y angi ogr aphy show s a 90% pr ox i m al r i ght cor onar y ar ter y obstr ucti on, a 90% pr ox i m al l ef t
anter i or descendi ng (LAD) obstr ucti on, and a 100% pr ox i m al ci r cum f l ex obstr ucti on. Her EF by l ef t
v entr i cul ar angi ogr aphy i s 34%, w i th m oder ate anter i or hy pok i nesi s.
5. Woul d y ou r ecom m end PTCA, sur ger y , or m edi cal ther apy ?
Wi th sev er e thr eev essel di sease and l ef t v entr i cul ar dy sf uncti on, cor onar y ar ter y by pass sur ger y
i s i ndi cated i n thi s pati ent. The pr esence of di abetes f av or s sur ger y ov er PTCA i n thi s par ti cul ar
case ev en i f the EF i s not l ow .
Suggested Readings
Antm an EM, Anbe DT, Ar m str ong PW, etal . ACC/AHA gui del i nes f or the m anagem ent of pati ents w i th
STel ev ati on m y ocar di al i nf ar cti onâ€”ex ecuti v e sum m ar y : a r epor t of the Am er i can Col l ege of
Car di ol ogy /Am er i can Hear t Associ ati on Task For ce on Pr acti ce Gui del i nes (Wr i ti ng Com m i ttee to
Rev i se the 1999 gui del i nes f or the m anagem ent of pati ents w i th acute m y ocar di al i nf ar cti on).
Ci r cul ati on 2004;110:588â€“636.
Keel ey EC, Bour a JA, Gr i nes CL. Pr i m ar y angi opl asty v er sus i ntr av enous thr om bol y ti c ther apy f or
acute m y ocar di al i nf ar cti on: a quanti tati v e r ev i ew of 23 r andom i zed tr i al s. Lancet 2003;361:13â€“20.
Li bby P. Cur r ent concepts of the pathogenesi s of the acute cor onar y sy ndr om es. Ci r cul ati on
2001;104:365â€“372.
Ver m a VK, Hol l enber g SM. U pdate on acute cor onar y sy ndr om es and STel ev ati on m y ocar di al
i nf ar cti on. Cur r Opi n Cr i t Car e 2005;11:401â€“405.
Unstable Angina and Nonâ€“STElevation Myocardial Infarction
1. What i s an ACS?
2. What i s unstabl e angi na?
3. What i s a nonâ€“STel ev ati on m y ocar di al i nf ar cti on (N STEMI)?
4. What com m on pathophy si ol ogi c pr ocesses under l i e both unstabl e angi na and N STEMI?
5. What i s the esti m ated i nci dence of si l ent i schem i c epi sodes i n the setti ng of unstabl e angi na?
6. What m easur es hav e been show n to i m pr ov e the cl i ni cal outcom e i n the setti ng of ACSs?
Discussion
1. What i s an ACS?
The ACS spectr um i ncl udes unstabl e angi na, N STEMI, and STel ev ati on m y ocar di al i nf ar cti on
(STEMI). Pati ents hav i ng ACS pr esent to the ER w i th chest pai n. The pathophy si ol ogy of the
sy ndr om e i s si m i l ar i n these pati ents.
P. 52
2. What i s unstabl e angi na?
Stabl e angi na i s a stabl e patter n of chest or ar m di scom f or t caused by si m i l ar degr ees of phy si cal
or em oti onal str ess. U nstabl e angi na i s angi na that occur s at r est or w i th m i ni m al ex er ti on, or i s of
r ecent onset (l ess than 1 m onth) or has a cr escendo qual i ty (i . e. , occur s m or e f r equentl y ), and i s
m or e sev er e or of l onger dur ati on.
3. What i s an N STEMI?
Thi s def i ni ti on ev ol v ed f r om the ol d descr i pti on of nonâ€“Qw av e MI. It appl i es to pati ents w ho
hav e a pr esentati on si m i l ar to unstabl e angi na, especi al l y w i th pr ol onged pai n at r est, and w ho
hav e ev i dence of m y ocar di al necr osi s. They ar e di sti nct f r om those w i th STEMI because they do not
hav e per si stent ST el ev ati on on pr esentati on. Instead, ei ther ST depr essi on or Tw av e changes i s
m or e com m on. Thi s cl assi f i cati on has ther apeuti c i m pl i cati ons because Q w av es do not al w ay s
i ndi cate a tr ansm ur al MI and subendocar di al necr osi s occur s onl y i n 50% of the cases of nonâ€“Q
w av e MI. Ther ef or e, the new cl assi f i cati on of STEMI and N STEMI w as i ntr oduced. N STEMI i s
f r equentl y seen i n the el der l y , those w i th a pr ev i ous MI, and com par ed w i th STEMI i s m or e
com m onl y associ ated w i th i ncom pl ete occl usi on of the cor onar y ar ter y . Thi s def i ni ti on al l ow s
pati ents w i th STEMI to go ur gentl y f or r ev ascul ar i zati on w hi l e N STEMI pati ents can of ten w ai t. Ear l y
m or tal i ty i s hi gher w i th STEMI. A Qw av e or a nonâ€“Qw av e MI can be caused by ei ther STEMI or
N STEMI. Pati ents w i th STEMI hav e hi gher i nhospi tal m or tal i ty w her eas those w i th N STEMI hav e
hi gher r ei nf ar cti on and m or tal i ty r ates i n the subsequent 6 m onths to 1 y ear .
4. What com m on pathophy si ol ogi c pr ocesses under l i e both unstabl e angi na and N STEMI?
By f ar the m ost com m on m echani sm of unstabl e angi na/N STEMI i s ather oscl er osi sr el ated cor onar y
pl aque r uptur e, usual l y w i th super i m posed thr om bus. Other possi bl e m echani sm s i ncl ude cor onar y
spasm or i nf l am m ati on as w el l as i ncr eased m y ocar di al ox y gen r equi r em ents. These v ul ner abl e
pl aques ar e l i pi d r i ch w i th a thi n f i br ous cap. Inf i l tr ati on of thi s cap w i th i nf l am m ator y cel l s l eads
to i ts di sr upti on, f ol l ow ed by ex posur e of the subendothel i al m atr i x to the bl ood str eam w i th
pl atel et acti v ati on and aggr egati on. Thi s l eads i ni ti al l y to the f or m ati on of a pl atel etr i ch (gr ay )
thr om bus. Later , how ev er , ther e i s al so acti v ati on of the coagul ati on cascade w i th f or m ati on of a
f i br i n (r ed) thr om bus. In N STEMI, thi s thr om bus i s nonoccl usi v e i n m ost cases.
5. What i s the esti m ated i nci dence of si l ent i schem i c epi sodes i n the setti ng of unstabl e angi na?
Si l ent i schem i a i s the pr esence of i schem i c ECG changes w i thout angi na. The r epor ted i nci dence
af ter unstabl e angi na/N STEMI v ar i es f r om one f our th to tw o thi r ds of the pati ents. It i s detected by
conti nuous ECG m oni tor i ng usi ng a hol ter m oni tor . Si l ent i schem i a i s f r equentl y pr eceded by
i ncr eases i n bl ood pr essur e and hear t r ate, causi ng i ncr eased m y ocar di al ox y gen consum pti on. It i s
associ ated w i th hi gher death and MI r ates and shoul d be tr eated once detected.
P. 53
6. What m easur es hav e been show n to i m pr ov e the cl i ni cal outcom e i n the setti ng of ACSs?
Dur i ng the acute phase of car e, the use of aspi r i n, thi enopy r i di ne der i v ati v es (e. g. , cl opi dogr el ),
gl y copr otei n IIb/IIIa i nhi bi tor s, unf r acti onated and l ow m ol ecul ar w ei ght hepar i ns, and di r ect
thr om bi n i nhi bi tor s (e. g. , l epi r udi n) as w el l as r ev ascul ar i zati on (especi al l y i n hi ghr i sk pati ents)
hav e been show n to r educe the r ate of MI and death. The use of Î²bl ock er s w as show n to r educe
r ecur r ent i nf ar cti ons. The use of cer tai n cal ci um channel bl ock er s i n pati ents i ntol er ant to Î²
bl ock er s has al so been show n to r educe r ecur r ent MI. In the i nter m edi ate and l ong ter m s, the use
of aspi r i n, cl opi dogr el , stati ns, ACE i nhi bi tor s, and Î²bl ock er s i s r ecom m ended to r educe m or tal i ty
and r ecur r ent MI. The concom i tant use of w ar f ar i n has been show n to i m pr ov e outcom es but i ts use
i s l i m i ted to pati ents w ho hav e another i ndi cati on f or w ar f ar i n (such as atr i al f i br i l l ati on).
Modi f i cati on of cor onar y r i sk f actor s i s al so w ar r anted.
Case 1
A 42y ear ol d r egi ster ed nur se i s seen because of pai n i n the chest. She descr i bes a â€œpai n i n m y
hear tâ€ and poi nts to a 1cm 2 ar ea abov e the l ef t br east. The pai n i s i ntensi f i ed by deep br eathi ng,
coughi ng, r ecum bency , and tw i sti ng m oti ons. It has l asted conti nuousl y f or 2 day s. Thr ee day s ago, she
noted ex tr em e f ati gue and shor tness of br eath l asti ng f or 24 hour s. Fi ndi ngs f r om a com pl ete phy si cal
ex am i nati on ar e nor m al .
1. What i s the m ost l i k el y di agnosi s i n thi s pati ent, and w hy ?

As y ou ar e about to di schar ge thi s pati ent, her husband tel l s y ou he i s concer ned about hi s w i f e
because her si ster under w ent cor onar y by pass sur ger y at 44 y ear s and her br other at 34 y ear s.
Because the pai n has som e f eatur es of per i car di ti s, y ou deci de to do an ECG. It show s nor m al si nus
r hy thm w i th Q w av es i n the i nf er i or l eads and di f f use STsegm ent el ev ati on.
2. What i s y our di agnosi s, and w hat w oul d y ou do?
Case Discussion
Chest w al l pai n or per i car di ti s w oul d be the m ost l i k el y i ni ti al di agnosi s i n thi s pati ent. Angi na
pector i s i s uncom m on i n w om en i n thi s agegr oup, and thi s pai n i s not angi nal i n char acter . Aor ti c
di ssecti on pai n i s ty pi cal l y v er y sev er e f r om the star t, â€œshar p, tear i ngâ€ and can r adi ate to the
back . Acute chol ecy sti ti s m ani f ests cl i ni cal l y w i th r i ght upper quadr ant tender ness and occasi onal l y
a pal pabl e gal l bl adder . Pneum oni a and pl eur i sy ar e di f f er enti ated because of the associ ati on w i th
f ev er and cough w i th abnor m al chest ex am i nati on. A pneum othor ax i s associ ated w i th acute
shor tness of br eath f i ndi ngs of hy per r esonance to per cussi on and di m i ni shed br eath sounds on the
af f ected si de. Pai n ar i si ng f r om the chest w al l i s the m ost com m on cause of chest pai n i n any age
gr oup, and of ten has no di scer ni bl e cause. It can be r epr oduced by pr essur e ov er the pai nf ul ar ea.
Per i car di ti s i s of ten accom pani ed
P. 54
by a f r i cti on r ub. Thi s r ub has a coar se, â€œl eather y , â€
or â€œw al k i ng on cr unchy snow â€ sound,
w i th accentuati on dur i ng sy stol e as w el l as ear l y and l ate di astol e (how ev er , som eti m es onl y one
or tw o com ponents ar e audi bl e). Inspi r ati on i ntensi f i es the r ub. Its f eatur es of ten i ncl ude a pr eci se
l ocal i zati on and tender ness on pal pati on ov er the af f ected ar ea. Deep br eathi ng, posi ti on changes,
and speci f i c body m ov em ents such as tw i sti ng of ten accentuate the pai n. Its dur ati on v ar i es f r om a
f ew seconds to day s. Ther apy i s nonspeci f i c, consi sti ng of r eassur ance and si m pl e anal gesi cs or
nonster oi dal dr ugs.
2. What i s y our di agnosi s, and w hat do y ou do?
Thi s pati ent pr obabl y had a si l ent i nf er i or MI a f ew day s ago and now pr esents w i th posti nf ar cti on
per i car di ti s. The Q w av es ar e i nf er i or l y r el ated to the MI w hi l e the di f f use STsegm ent el ev ati on i s
com pati bl e w i th per i car di ti s. Addi ti onal hi stor y i s that she has had ty pe 2 di abetes m el l i tus f or 20
y ear s and a r ecent chol ester ol scr eeni ng at a heal th f ai r . Her LDL chol ester ol w as 242 m g/dL,
consi stent w i th f am i l i al heter ozy gous hy per chol ester em i a.
The pati ent shoul d be adm i tted f or tel em etr y obser v ati on. Tr oponi n I i s l i k el y to be el ev ated and
shoul d be dr aw n. When y ou ask the pati ent to si t up, l ean f or w ar d, and ex hal e, a tw ocom ponent
per i car di al f r i cti on r ub i s noted. Aspi r i n shoul d be gi v en f or her MI and can be used at m uch hi gher
doses to tr eat the concom i tant per i car di ti s. Ibupr of en i s the N SAID of choi ce f or per i car di ti s;
how ev er , i ts use shoul d be av oi ded i n the setti ng of an acute MI as i t coul d i nter f er e w i th scar
f or m ati on. The r em ai nder of her tr eatm ent i s as di scussed f or pati ents w i th acute MI, ex cept that
thi s i nf ar cti on i s ol der and acute r eper f usi on i s not i ndi cated. Si l ent i schem i a i s m or e com m on i n
di abetes. Al though w om en y ounger than 50 y ear s do not of ten hav e sy m ptom ati c cor onar y di sease,
thi s adv antage i s neutr al i zed by the pr esence of di abetes. When ev al uati ng pati ents w i th chest
pai n, attenti on to CAD r i sk f actor s i s par am ount.
Case 2
A 57y ear ol d autom obi l e sal esm an w ho i s hy per tensi v e and a heav y ci gar ette sm ok er descr i bes a
pr essur el i k e sensati on that dev el oped f or the f i r st ti m e 3 w eek s bef or e. The di scom f or t, w hi ch begi ns
i n the r etr oster nal ar ea, r adi ates to the l ef t si de of hi s l ow er jaw , occur s w hen he w al k s r api dl y i n col d
ai r , and m or e r ecentl y occur s at r est. Car ef ul hi stor y r ev eal s that i t l asts f or 10 to 15 m i nutes, but an
especi al l y sev er e epi sode aw ak ened hi m the ni ght bef or e and l asted near l y hal f an hour bef or e r esol v i ng
spontaneousl y . Ex cept f or a bl ood pr essur e of 150/100 m m Hg, the phy si cal ex am i nati on f i ndi ngs ar e
nor m al . An ECG (obtai ned af ter the pai n has di sappear ed) r ev eal s deep and sy m m etr i c Tw av e i nv er si on
i n l eads V 1 to V 4 . The pati ent i s adm i tted and gi v en IV hepar i n and or al aspi r i n.
1. What i s y our di agnosi s?

2. What ar e som e com m on phy si cal f i ndi ngs dur i ng an i schem i c epi sode?
Appr ox i m atel y 4 hour s af ter adm i ssi on, the pati ent agai n ex per i ences tr ansi ent chest pr essur e. You
or der an ECG. The T w av es ar e now upr i ght i n l eads V 1 to V 4 .
3. What ar e these ECG changes cal l ed, and w hat do they r epr esent?
4. How shoul d the r ecur r ent chest pai n be tr eated?
5. What shoul d be done nex t?
P. 55
Case Discussion
1. What i s y our di agnosi s?
Thi s pati ent has ei ther unstabl e angi na or an N STEMI. The pai n i s both new i n onset and occur s at
r est. The Tw av e i nv er si ons conf i r m the di agnosi s of i schem i a. The r esul ts of car di ac enzy m e tests
separ ate unstabl e angi na (negati v e enzy m es) f r om N STEMI (posi ti v e enzy m es).
2. What ar e som e com m on phy si cal f i ndi ngs dur i ng an i schem i c attack ?
Incr eases i n hear t r ate and bl ood pr essur e ar e the m ost com m on f i ndi ngs dur i ng i schem i a. Phy si cal
ex am i nati on per f or m ed dur i ng an i schem i c attack m ay r ev eal an S 4 or a m ur m ur of m i tr al
r egur gi tati on. If the i schem i c ar ea i s l ar ge then an S 3 , pul m onar y r al es, a dy sk i neti c api cal
i m pul se, and hy potensi on coul d be noted. Ischem i a decr eases l ef t v entr i cul ar com pl i ance (i ncr eased
â€œsti f f nessâ€ ) w i th subsequent i ncr ease i n l ef t v entr i cul ar f i l l i ng pr essur e. The r esi stance to
f i l l i ng dur i ng atr i al contr acti on i s w hat pr oduces the S 4 sound. How ev er , an S 4 i s a nonspeci f i c
f i ndi ng and i s f r equentl y hear d i n ol der adul ts. Local i zed contr acti on abnor m al i ti es m ay pr oduce
tr ansi ent papi l l ar y m uscl e dy sf uncti on and f ai l ur e of com pl ete apposi ti on of the l eaf l ets, r esul ti ng
i n m i tr al r egur gi tati on. Si m i l ar contr acti on abnor m al i ti es can cause an outw ar d bul ge of the l ef t
v entr i cl e w i th dy sk i neti c api cal i m pul se. Thi s can be f el t by usi ng the pal m of the hand w hi l e the
pati ent i s i n the l ef t l ater al decubi tus posi ti on.
3. What ar e these ECG changes cal l ed, and w hat do they r epr esent?
When pr ev i ousl y i nv er ted T w av es becom e upr i ght i n the pr esence of chest pai n, i t i s cal l ed
pseudonor m al i zati on. Thi s i s str ongl y suggesti v e of i schem i a.
4. How shoul d the r ecur r ent chest pai n be tr eated?
The pseudonor m al i zati on of the T w av es cl ear l y i ndi cates m y ocar di al i schem i a. Thi s pai n shoul d be
tr eated w i th subl i ngual N TG and IV m or phi ne, f ol l ow ed by IV N TG and Î²bl ock ade i f ther e ar e no
contr ai ndi cati ons. The pati ent i s al r eady r ecei v i ng aspi r i n and hepar i n (l ow m ol ecul ar w ei ght
hepar i n can al so be used i n thi s case). Pl atel et gl y copr otei n IIb/IIIa i nhi bi tor s ar e of v al ue i n the
tr eatm ent of hi ghr i sk pati ents w i th unstabl e angi na/N STEMI. Stati ns hav e been show n to r educe
car di ac ev ent r ates w hen used acutel y i n thi s popul ati on. If the pati ent i s not a candi date f or
cor onar y ar ter y by pass gr af t (CABG), then cl opi dogr el shoul d be consi der ed.
5. What shoul d be done nex t?
Thi s pati ent had si gns of m y ocar di al i schem i a on adm i ssi on w i th r ecur r ent pai n on IV hepar i n. Thi s
i s suspi ci ous f or the pr esence of substanti al i schem i a, and the deepl y i nv er ted T w av es i n l eads V 1
to V 4 m ostl y l i k el y r epr esent a hi ghgr ade pr ox i m al LAD stenosi s. Thi s pati ent shoul d under go
cor onar y angi ogr aphy . PCI shoul d be per f or m ed i n gener al f or one or tw ov essel di sease and
nor m al or near nor m al l ef t v entr i cul ar f uncti on. For m ost pati ents w i th thr eev essel di sease or l ef t
v entr i cul ar dy sf uncti on, especi al l y i n the pr esence of di abetes, cor onar y ar ter y by pass sur ger y
(usi ng w henev er possi bl e an i nter nal m am m ar y ar ter y gr af t to the LAD) i s i ndi cated. The use of PCI
v er sus cor onar y by pass sur ger y m ay v ar y dependi ng on pati ent or phy si ci an pr ef er ence, l esi on
anatom y , the pr esence of pr ox i m al LAD di sease, or the pati ent's com or bi di ti es.
P. 56
Suggested Readings
Antm ann EM, Cohen M, Ber ni nk PJLM, etal . The TIMI r i sk scor e f or unstabl e angi na/nonST el ev ati on
MI. A m ethod f or pr ognosti cati on and ther apeuti c deci si on m ak i ng. JAMA 2000;284:835â€“842.
Boden WE, McKay RG. Opti m al tr eatm ent of acute cor onar y sy ndr om es an ev ol v i ng str ategy . N Engl
J Med 2001;344:1939â€“1942.
Br aunw al d E, Antm an EM, Beasl ey JW, etal . Am er i can Col l ege of Car di ol ogy /Am er i can Hear t
Associ ati on Task For ce on Pr acti ce Gui del i nes (Com m i ttee on the Managem ent of Pati ents Wi th
U nstabl e Angi na). ACC/AHA gui del i ne update f or the m anagem ent of pati ents w i th unstabl e angi na
and nonSTsegm ent el ev ati on m y ocar di al i nf ar cti onâ€”2002: sum m ar y ar ti cl e: a r epor t of the
Am er i can Col l ege of Car di ol ogy /Am er i can Hear t Associ ati on Task For ce on Pr acti ce Gui del i nes
(Com m i ttee on the Managem ent of Pati ents Wi th U nstabl e Angi na). Ci r cul ati on 2002;106:1893â
€“1900.
Cannon CP, Wei ntr aub WS, Dem opoul os LA, etal . Com par i son of ear l y i nv asi v e and conser v ati v e
str ategi es i n pati ents w i th unstabl e cor onar y sy ndr om es tr eated w i th the gl y copr otei n IIb/IIIa
i nhi bi tor ti r of i ban. For the TACTICSthr om bol y si s i n m y ocar di al i nf ar cti on 18 i nv esti gator s. N Engl J
Med 2001;344:1879â€“1887.
Cohn PF, Fox KM, Dal y C. Si l ent m y ocar di al i schem i a. Ci r cul ati on 2003;108:1263.
Fuster V, Mor eno PR, Fay ad ZA, etal . Ather othr om bosi s and the hi ghr i sk pl aque. Par t I: ev ol v i ng
concepts. J Am Col l Car di ol 2005;46:937â€“954.
Sudden Cardiac Death
1. What k i nd of hear t di sease i s seen m ost com m onl y i n adul ts w ho di e suddenl y ? In y oung athl etes?
2. Whi ch ty pes of ar r hy thm i as ar e associ ated w i th car di ac ar r est and sudden car di ac death (SCD)?
3. Whi ch pati ents ar e at hi ghest r i sk f or SCD?
4. What i s the cause of SCD i n the l ong QT sy ndr om e?

Discussion
1. What k i nd of hear t di sease i s seen m ost com m onl y i n adul ts w ho di e suddenl y ? In y oung athl etes?
Appr ox i m atel y 90% of cases of SCD ar e due to v entr i cul ar f i br i l l ati on i n the setti ng of pr eex i sti ng
str uctur al hear t di sease; 5% to 10% occur i n the absence of or gani c hear t di sease. In i ndi v i dual s
y ounger than 30 y ear s and y oung athl etes, SCD i s v er y r ar e, but w hen i t does occur i t i s usual l y
due to hy per tr ophi c car di om y opathy . Ar r hy thm ogeni c r i ght v entr i cul ar dy spl asi a and acute
m y ocar di ti s ar e other i nf r equent causes of SCD i n the y oung adul t. Af ter the age of 40, 65% to 70%
of al l SCDs ar e attr i butabl e to CAD.
P. 57
2. Whi ch ty pes of ar r hy thm i as ar e associ ated w i th car di ac ar r est and SCD?
In the f i el d, par am edi cs m ost com m onl y r ecor d v entr i cul ar f i br i l l ati on or v entr i cul ar tachy car di a
dur i ng car di ac ar r est. Less f r equentl y seen, and associ ated w i th a poor er pr ognosi s, ar e
br ady ar r hy thm i as, asy stol e, and pul sel ess el ectr i cal acti v i ty (el ectr i cal â€“m echani cal di ssoci ati on).
Car di ac ar r est due to any ar r hy thm i a r esul ts i n r api d depl eti on of ox y gen i n v i tal or gans. Af ter 6
m i nutes, br ai n dam age i s ex pected to occur , ex cept i n cases of hy pother m i a. Ther ef or e, ear l y CPR
and r api d adv anced car di ac l i f e suppor t (ACLS), w i th def i br i l l ati on, ar e essenti al i n i m pr ov i ng
sur v i v al and neur ol ogi c r ecov er y .
3. Whi ch pati ents ar e at hi ghest r i sk f or SCD?
Pati ents at hi ghest r i sk f or SCD ar e those w ho hav e pr ev i ousl y sur v i v ed an epi sode of SCD or hav e
a hi stor y of r api d, sustai ned v entr i cul ar tachy car di a especi al l y i n the setti ng of r educed l ef t
v entr i cul ar f uncti on. One of the best m easur es of r i sk of SCD i s l ef t v entr i cul ar f uncti on and the
r i sk of SCD i ncr eases as l ef t v entr i cul ar f uncti on decr eases.
The i nci dence of SCD i s gr eater i n m en than i n w om en. Thi s i ncr eased r i sk r em ai ns despi te
adjusti ng f or the pr esence of com or bi di ti es such as i schem i c hear t di sease and age. The r i sk of SCD
i ncr eases w i th age.
4. What i s the cause of SCD i n the l ong QT sy ndr om e?
The l ong QT sy ndr om e i s a cause of sy ncope and SCD i n pati ents w i th str uctur al l y nor m al hear ts,
but m ay al so r esul t i n SCD i n pati ents w i th str uctur al hear t di sease. The l ong QT sy ndr om e can be
ei ther acqui r ed or i nher i ted. Sev er al geneti c def ects i nv ol v i ng car di ac i on channel s hav e been
i denti f i ed i n f am i l i es w i th i nher i ted l ong QT sy ndr om e. In acqui r ed l ong QT sy ndr om e, sev er al
cl asses of dr ugs that af f ect car di ac i on channel s and sev er al m edi cal condi ti ons associ ated w i th
el ectr ol y te abnor m al i ti es hav e been i denti f i ed. In both i nher i ted and acqui r ed f or m s, car di ac
r epol ar i zati on i s pr ol onged, and r ef l ected i n a l ong QT i nter v al on the ECG. Sy ncope and SCD i n
l ong QT sy ndr om e ar e caused by a speci f i c, pol y m or phi c v entr i cul ar tachy car di a cal l ed tor sade de
poi ntes (â€ t w i sti ng of the poi ntsâ€ ) . Dr ugs that pr ol ong the QT i nter v al (e. g. , phenothi azi nes,
tr i cy cl i c anti depr essants, and cer tai n anti ar r hy thm i cs) ar e par ti cul ar l y l i k el y to cause SCD i n
pati ents w i th another cause of pr ol onged QT i nter v al or i n pati ents w i th str uctur al hear t di sease.
Case
A 65y ear ol d m an com pl ai ns of chest di scom f or t on the gol f cour se and w i thi n seconds col l apses and i s
unr esponsi v e. Hi s com pani ons i ni ti ate by stander CPR and an am bul ance i s cal l ed. Par am edi cs ar r i v e
w i thi n 10 m i nutes. A â€œqui ck l ook â€ at the r hy thm usi ng the def i br i l l ator paddl es r ev eal s v entr i cul ar
f i br i l l ati on. Af ter one shock at 200 J usi ng a bi phasi c f i br i l l ator , si nus r hy thm i s r estor ed and a pul se i s
f el t. The pati ent i s tr anspor ted to the hospi tal . Ini ti al ECG show s Q w av es i n the pr ecor di al l eads, and
di f f use, nonspeci f i c STsegm ent and Tw av e abnor m al i ti es, w i th a nor m al QT i nter v al . Ser um
el ectr ol y tes ar e
P. 58
nor m al . Ini ti al and subsequent car di ac enzy m e deter m i nati ons do not i ndi cate ev i dence of an acute MI.
Fam i l y m em ber s state that the pati ent w as not on car di ac m edi cati ons and had no car di ac hi stor y . The
pati ent, i ni ti al l y unr esponsi v e and r equi r i ng m echani cal v enti l ati on, r ecov er s neur ol ogi cal l y ov er the
nex t 48 hour s and i s ex tubated. Apar t f r om a m i l d shor tter m m em or y def i ci t, he seem s to be back to
hi s usual sel f and none the w or se f or the ex per i ence. Tr oponi n w as not el ev ated dur i ng the
hospi tal i zati on.
1. What tests shoul d be per f or m ed on thi s pati ent now ?
2. Wi l l cor onar y r ev ascul ar i zati on be of benef i t i n pr ev enti ng r ecur r ent SCD i n thi s pati ent?
3. Is ther e a r ol e f or el ectr ophy si ol ogi c testi ng i n thi s pati ent?
4. What i s the best tr eatm ent to pr ev ent r ecur r ent SCD i n thi s pati ent?
Case Discussion
1. What tests shoul d be per f or m ed on thi s pati ent now ?
Despi te the near m i r acul ous r ecov er y of thi s pati ent, hi s r i sk of r ecur r ent SCD i s hi gh and
m easur es shoul d be tak en to i denti f y the cause of SCD i n hi s case and pr ev ent r ecur r ence. Al though
m ost cases of SCD i n hi s agegr oup ar e r el ated to CAD, i t can be uncl ear i n a par ti cul ar pati ent
w hether the i ni ti ati ng ev ent w as a pr i m ar y ar r hy thm i a or i schem i a. Ischem i a can be due to
i ncr eased m etabol i c dem ands (e. g. , ex er ci se) i n the f ace of a f i x ed cor onar y obstr ucti on, or due to
tr ansi ent decr eased cor onar y bl ood f l ow caused by ather oscl er oti c pl aque r uptur e or cor onar y
v asospasm . It i s l i k el y that m any epi sodes of SCD ar e m ul ti f actor i al , super i m posi ng tr ansi ent
tr i gger i ng ev ents (e. g. , i schem i a, changes i n autonom i c tone, el ectr ol y te abnor m al i ti es, or
pr em atur e v entr i cul ar com pl ex es) on an ar r hy thm ogeni c substr ate such as the cel l dam age cr eated
by a pr ev i ous MI. Thi s pati ent's com pl ai nt of chest di scom f or t bef or e col l apse m ay on f i r st
consi der ati on suggest i schem i a as the i ni ti ati ng ev ent, but pati ents w i th cor onar y di sease w ho hav e
v entr i cul ar tachy car di a som eti m es com pl ai n of chest pai n because they becom e i schem i c secondar y
to the r api d hear t r ate. The ECG ev i dence of an anter i or i nf ar cti on w i thout the enzy m e changes
char acter i sti c of acute i nf ar cti on suggests that, despi te hi s negati v e car di ac hi stor y , he m ay hav e
had a pr ev i ous â€œsi l entâ€ MI. Thi s ol d v entr i cul ar scar m ay be a substr ate f or a pr i m ar y
r eentr ant v entr i cul ar tachy car di a. To def i ne hi s car di ac di sease better , i ncl udi ng hi s l ef t v entr i cul ar
f uncti on, and to deter m i ne i f he has a substr ate f or r ecur r ent i schem i a, car di ac catheter i zati on
shoul d be per f or m ed. In a Fr ench study of 84 sur v i v or s of outof hospi tal car di ac ar r est w i thout
obv i ous noncar di ac cause of the ar r est, i m m edi ate cor onar y angi ogr aphy w i th angi opl asty w as
show n to be saf e w i th potenti al l ongter m benef i t w hen per f or m ed by an ex per i enced team . Car di ac
catheter i zati on i n thi s pati ent show ed a 100% pr ox i m al LAD ar ter y occl usi on as w el l as a 90%
occl usi on of the f i r st obtuse m ar gi nal br anch of the l ef t ci r cum f l ex ar ter y . The r i ght cor onar y
ar ter y w as nor m al . The l ef t v entr i cul ar EF w as r educed at 30% (nor m al â‰￥55%). Ther e w as an
anter oapi cal l ef t v entr i cul ar aneur y sm . The l ater al w al l of the l ef t v entr i cl e (suppl i ed by the l ef t
ci r cum f l ex ar ter y ) had nor m al m oti on.
P. 59
2. Wi l l cor onar y r ev ascul ar i zati on be of benef i t i n pr ev enti ng r ecur r ent SCD i n thi s pati ent?
As di scussed pr ev i ousl y , SCD m ay be m ul ti f actor i al and i t i s di f f i cul t to deter m i ne the pr eci se
tr i gger s f or an SCD epi sode. Thi s pati ent has ev i dence on catheter i zati on of a pr ev i ous anter i or
i nf ar cti on, w i th an anter oapi cal l ef t v entr i cul ar aneur y sm . Thi s aneur y sm m ay be a substr ate f or
r eentr antsustai ned m onom or phi c v entr i cul ar tachy car di a. In addi ti on, he has a si gni f i cant stenosi s
i n an obtuse m ar gi nal ar ter y , w i th nor m al l ef t v entr i cul ar w al l m oti on i n the r egi on ser v ed by thi s
ar ter y . Thi s i s a substr ate f or i schem i a. In an attem pt to cor r ect possi bl e tr i gger i ng f actor s l i k e
i schem i a, i t w oul d be r easonabl e to di l ate the obtuse m ar gi nal stenosi s w i th bal l oon angi opl asty ,
and thi s w as per f or m ed i n thi s pati ent. U nf or tunatel y , i n pati ents w i th r educed l ef t v entr i cul ar
f uncti on w ho hav e an abor ted epi sode of SCD, ther e i s no ev i dence that anti i schem i a m easur es
al one pr ev ent r ecur r ent SCD.
3. Is ther e a r ol e f or el ectr ophy si ol ogi c testi ng i n thi s pati ent?
Most pati ents w i th si m i l ar pr esentati ons hav e i nduci bl e sustai ned m onom or phi c v entr i cul ar
tachy car di a dur i ng el ectr ophy si ol ogi c testi ng. In the past, m any such pati ents under w ent
el ectr ophy si ol ogi c testi ng and w er e then tr eated w i th anti ar r hy thm i c dr ug ther apy gui ded by ser i al
el ectr ophy si ol ogi c testi ng. Pati ents w ho f ai l ed dr ug ther apy or w ho di d not hav e i nduci bl e sustai ned
m onom or phi c v entr i cul ar tachy car di a w er e tr eated w i th em pi r i c am i odar one or an i m pl antabl e
def i br i l l ator . A num ber of r andom i zed contr ol l ed cl i ni cal tr i al s hav e been per f or m ed that com par e
the ef f i cacy of the i m pl antabl e def i br i l l ator w i th anti ar r hy thm i c dr ug ther apy . Al l these tr i al s
suggest that pr ophy l acti c ther apy w i th i m pl antabl e def i br i l l ator i s super i or to anti ar r hy thm i c dr ug
ther apy gui ded by el ectr ophy si ol ogi c testi ng or em pi r i c am i odar one i n pr ev enti ng r ecur r ent SCD. In
the AVID (Anti ar r hy thm i cs Ver sus Im pl antabl e Def i br i l l ator s) tr i al , pati ents w ho w er e enr ol l ed had
hem ody nam i cal l y si gni f i cant sustai ned v entr i cul ar tachy car di a and a l ef t v entr i cul ar EF of 40% or
l ess, or v entr i cul ar f i br i l l ati on. Ther e w as a 31% r educti on i n the total m or tal i ty r ate af ter 3 y ear s
w i th i m pl antabl e def i br i l l ator s com par ed w i th anti ar r hy thm i c dr ug ther apy . The tr i al w as stopped
ear l y w hen a sur v i v al benef i t w as noted i n pati ents r ecei v i ng the ICD com par ed w i th those tr eated
w i th am i odar one or sotal ol . The MADIT II (Mul ti center Autom ati c Def i br i l l ator Im pl antati on Tr i al )
dem onstr ated that ICDs si gni f i cantl y i m pr ov e sur v i v al i n pati ents w i th CAD and l ef t v entr i cul ar EF
of 30% or l ess. In those pati ents w ho hav e sur v i v ed SCD and/or hav e r educed LV f uncti on, an ICD
i s the tr eatm ent of choi ce. El ectr ophy si ol ogi c testi ng i s usual l y not per f or m ed i n SCD sur v i v or s,
and w as not per f or m ed i n thi s pati ent.
4. What i s the best tr eatm ent to pr ev ent r ecur r ent SCD i n thi s pati ent?
Thi s pati ent w as a good candi date f or an i m pl antabl e def i br i l l ator , and he r ecei v ed one. The
def i br i l l ator w as i m pl anted i n the l ef t pector al r egi on i n the el ectr ophy si ol ogy l abor ator y , usi ng
l ocal anesthesi a and consci ous sedati on. The pati ent w as di schar ged hom e the day af ter the
i m pl ant. In addi ti on, thi s pati ent r ecei v ed other m edi cal ther apy that has been show n to r educe the
r i sk of SCD. Î²Bl ock i ng dr ugs hav e been show n to r educe total m or tal i ty af ter MI as w el l as
i m pr ov e pum p f uncti on i n som e cases. Aspi r i n m ay hel p pr ev ent r ei nf ar cti on. ACE i nhi bi tor s hav e
P. 60
been show n to i m pr ov e sur v i v al i n pati ents w i th r educed l ef t v entr i cul ar f uncti on. Spi r onol actone, a
m i ner al ocor ti coi d r eceptor antagoni st has been si m i l ar l y show n to r educe al l cause m or tal i ty and
SCD i n pati ents w i th l ef t v entr i cul ar sy stol i c f uncti on of 35% or l ess. Li pi dl ow er i ng agents m ay
pr ev ent pr ogr essi on of ather oscl er osi s and shoul d be used i n pati ents w i th l i pi d abnor m al i ti es.
Other r i sk f actor m odi f i cati ons such as sm ok i ng cessati on w oul d be r ecom m ended. Am i odar one m ay
r educe SCD af ter MI, but i t does not cl ear l y r educe total m or tal i ty . In the SCDHeFT study ,
am i odar one w as show n to be not benef i ci al i n pr ev enti ng SCDs i n pati ents w i th a l ef t v entr i cul ar
sy stol i c f uncti on of 35% or l ess com par ed w i th the pl acebo gr oup i n both i schem i c and noni schem i c
pati ents. In thi s pati ent, ther e w oul d be no added v al ue i n usi ng am i odar one because he al r eady
has an i m pl antabl e def i br i l l ator . In f act, am i odar one, by i ts ef f ect of i ncr easi ng the el ectr i cal
def i br i l l ati on thr eshol d, m i ght actual l y i nter f er e w i th the f uncti on of the def i br i l l ator , and shoul d
ther ef or e be av oi ded. How ev er , because ICDs do not pr ev ent ar r hy thm i as, pati ents w ho hav e
f r equent dev i ce di schar ges f r om r ecur r ent ar r hy thm i as m ay benef i t f r om adjuncti v e anti ar r hy thm i c
dr ug ther apy , l i k e am i odar one. Such tr eatm ent, by r educi ng the f r equency of appr opr i ate shock s,
i m pr ov es the pati ent's qual i ty of l i f e.
Suggested Readings
The Anti ar r hy thm i cs Ver sus Im pl antabl e Def i br i l l ator s (AVID) Inv esti gator s. A com par i son of
anti ar r hy thm i c dr ug ther apy w i th i m pl antabl e def i br i l l ator s i n pati ents r esusci tated f r om near f atal
v entr i cul ar ar r hy thm i as. N Engl J Med 1997;337:1576.
Bar dy GH, Lee KL, Mar k DB, etal . Am i odar one or an i m pl antabl e car di ov er ter def i br i l l ator f or
congesti v e hear t f ai l ur e. N Engl J Med 2005;352:225.
Hui k ur i HV, Castel l anos A, My er bur g RJ. Sudden death due to car di ac ar r hy thm i as. N Engl J Med
2001;345:1473â€“1482.
Mar on BJ, Shi r ani J, Pol i ac LC, etal . Sudden death i n y oung com peti ti v e athl etes: cl i ni cal ,
dem ogr aphi c, and pathol ogi cal pr of i l es. JAMA 1996;276(3):199â€“204.
Moss AJ, Long QT. Sy ndr om e. JAMA 2003;289:2041â€“2044.
Moss AJ, Zar eba W, Hal l WJ, etal . Pr ophy l acti c i m pl antati on of a def i br i l l ator i n pati ents w i th
m y ocar di al i nf ar cti on and r educed ejecti on f r acti on. N Engl J Med 2002;346:877.
Spaul di ng CM, Jol y LM, Rosenber g A, etal . Im m edi ate cor onar y angi ogr aphy i n sur v i v or s of outof
hospi tal car di ac ar r est. N Engl J Med 1997;336:1629.
Zheng ZJ, Cr of t JB, Gi l es WH, etal . Sudden car di ac death i n the U ni ted States, 1989 to 1998.
Ci r cul ati on 2001;104:2158.
Valvular Heart Disease
1. What i s the di f f er ence betw een v al v ul ar i nsuf f i ci ency and v al v ul ar r egur gi tati on?
2. What ty pes of m y ocar di al hy per tr ophy can r esul t f r om v al v ul ar abnor m al i ti es?
3. What i s the m ost ser i ous l ongter m consequence of ei ther concentr i c or eccentr i c hy per tr ophy ?
P. 61
4. What i s the r el ati onshi p betw een the pr essur e gr adi ent acr oss a stenoti c v al v e, the bl ood f l ow
acr oss the v al v e, and the v al v e ar ea?
Discussion
1. What i s the di f f er ence betw een v al v ul ar i nsuf f i ci ency and v al v ul ar r egur gi tati on?
Regur gi tati on and i nsuf f i ci ency ar e i nter changeabl e ter m s to descr i be back w ar d f l ow of bl ood
acr oss a v al v e at a ti m e i n the car di ac cy cl e w hen ther e w oul d be no si gni f i cant f l ow acr oss a
com petent v al v e.
2. What ty pes of m y ocar di al hy per tr ophy can r esul t f r om v al v ul ar abnor m al i ti es?
When ther e i s a pr essur e l oad i m posed on the v entr i cl e (such as aor ti c stenosi s f or the l ef t
v entr i cl e or pul m oni c stenosi s f or the r i ght v entr i cl e), concentr i c hy per tr ophy dev el ops. Concentr i c
hy per tr ophy m eans that the m y ocar di al w al l thi ck ness i s i ncr eased w i th a nor m al or decr eased
i nter nal v entr i cul ar di am eter . A v ol um e l oad (such as aor ti c i nsuf f i ci ency or m i tr al r egur gi tati on f or
the l ef t v entr i cl e or tr i cuspi d r egur gi tati on f or the r i ght v entr i cl e) r esul ts i n eccentr i c hy per tr ophy ;
the w al l thi ck ness i s nor m al but the i nter nal di am eter of the v entr i cl e i s i ncr eased. Ov er al l , l ef t
v entr i cul ar m ass i s i ncr eased i n both ty pes of hy per tr ophy .
3. What i s the m ost ser i ous l ongter m consequence of ei ther concentr i c or eccentr i c hy per tr ophy ?
Wi th l ongstandi ng hy per tr ophy of ei ther ty pe, m y ocar di al dy sf uncti on m ay occur r esul ti ng i n HF.
4. What i s the r el ati onshi p betw een the pr essur e gr adi ent acr oss a stenoti c v al v e, the bl ood f l ow
acr oss the v al v e, and the v al v e ar ea?
The pr essur e gr adi ent acr oss a v al v e i s pr opor ti onal to the bl ood f l ow acr oss the v al v e di v i ded by
the v al v e ar ea. The pr essur e gr adi ent i s a r esul t of the f l ow acr oss the stenoti c v al v e and the
degr ee of stenosi s. For ex am pl e, i f f l ow r em ai ns the sam e and the v al v e becom es m or e stenoti c
ov er ti m e, the pr essur e gr adi ent i ncr eases. How ev er , an i ncr eased pr essur e gr adi ent m ay not
al w ay s m ean that stenosi s has pr ogr essed. For ex am pl e, bl ood f l ow m ay i ncr ease w i th f ev er or
anem i a, r esul ti ng i n an i ncr eased pr essur e gr adi ent w i thout any change i n v al v e ar ea. On the other
hand, a decr ease i n the pr essur e gr adi ent does not m ean an i m pr ov em ent i n v al v e stenosi s. For
ex am pl e, i f m y ocar di al f uncti on deter i or ates and bl ood f l ow (car di ac output) decr eases, the
pr essur e gr adi ent decr eases. Thi s decr ease, how ev er , does not r ef l ect a l ess stenoti c v al v e, but
i ndi cates a deter i or ati on i n m y ocar di al f uncti on because the hear t can no l onger pum p the sam e
bl ood f l ow .
Case 1
A pr ev i ousl y heal thy but i nacti v e 42y ear ol d m an i s seen i n the ER af ter a f i r st epi sode of sy ncope,
w hi ch occur r ed w hi l e he w as pl ay i ng bask etbal l . On questi oni ng, he descr i bes a 2m onth hi stor y of
ex er ti onal chest pai n. He has not seen a phy si ci an dur i ng hi s adul t l i f e. Phy si cal ex am i nati on r ev eal s the
f ol l ow i ng f i ndi ngs. Hi s supi ne bl ood pr essur e i s 116/80 m m Hg w i thout any si gni f i cant or thostati c
change. Ther e i s no jugul ar v enous
P. 62
di stenti on, but ther e ar e sl ow l y r i si ng, sm al l am pl i tude, and som ew hat sustai ned car oti d pul ses. Hi s
l ungs ar e cl ear . A sustai ned and sl i ghtl y l ater al l y di spl aced apex i m pul se i s noted, as w el l as a sof t f i r st
hear t sound and a si ngl e second hear t sound, a pr om i nent f our th hear t sound, and a gr ade 3/6 har sh,
l atepeak i ng, cr escendoâ€“decr escendo sy stol i c m ur m ur hear d best at the car di ac base and r adi ati ng to
the car oti ds w i th a hi ghf r equency com ponent at the car di ac apex . N o cl ubbi ng, cy anosi s, or edem a i s
noted.
1. What i s the m ost l i k el y v al v ul ar l esi on i n thi s pati ent?

2. What i s the m ost l i k el y cause of aor ti c stenosi s i n thi s agegr oup?
3. What i s the av er age sur v i v al of pati ents w i th uncor r ected aor ti c stenosi s af ter the onset of
sy ncope?
4. How i s the sev er i ty of aor ti c stenosi s m ost accur atel y deter m i ned?
5. What i s the best ther apy f or sy m ptom ati c aor ti c stenosi s?
Case Discussion
The hi stor y of angi na and sy ncope and the cl assi c phy si cal ex am i nati on f i ndi ngs m ak e aor ti c
stenosi s an al m ost cer tai n di agnosi s i n thi s pati ent. The char acter i sti c ar ter i al pul ses descr i bed
hav e been r ef er r ed to as pul sus par v us et tar dus. The si ngl e second hear t sound i ndi cates the
absence of the aor ti c com ponent, suggesti ng sev er e i m m obi l i ty of the aor ti c v al v e. The m ur m ur i s
al so char acter i sti c of aor ti c stenosi s w i th i ts cr escendoâ€“decr escendo qual i ty and the l ate peak i ng.
Do not be f ool ed by the hi ghf r equency com ponent at the car di ac apex . Al though the m ur m ur of
aor ti c stenosi s i s m ost of ten hear d at the upper car di ac bor der w i th r adi ati on to the car oti d
ar ter i es, the m ur m ur m ay al so r adi ate to the apex , w her e i t m ay be m i stak en f or the m ur m ur of
m i tr al r egur gi tati on.
2. What i s the m ost l i k el y cause of aor ti c stenosi s i n thi s agegr oup?
Betw een 35 and 65 y ear s of age, degener ati v e change i n a congeni tal l y bi cuspi d aor ti c v al v e i s the
pr edom i nant cause of aor ti c stenosi s. Bey ond 65 y ear s of age, aor ti c stenosi s usual l y r esul ts f r om
cal ci f i cati on of a pr ev i ousl y nor m al tr i cuspi d aor ti c v al v e (seni l e cal ci f i c aor ti c stenosi s). Al though
the ex act cause of seni l e aor ti c stenosi s i s unk now n, i t i s associ ated w i th hy per tensi on and
hy per l i pi dem i a. Isol ated aor ti c stenosi s i n the U ni ted States r ar el y r esul ts f r om r heum ati c di sease.
3. What i s the av er age sur v i v al of pati ents w i th uncor r ected aor ti c stenosi s af ter the onset of
sy ncope?
Pati ents w i th aor ti c stenosi s m ay r em ai n asy m ptom ati c f or y ear s, but once sy m ptom s dev el op the
cour se of the di sease m ay be qui te f ul m i nant. Accor di ng to studi es conducted bef or e v al v e sur ger y
w as av ai l abl e, such pati ents w i th sy ncope due to aor ti c stenosi s coul d ex pect to sur v i v e an av er age
of 3 y ear s af ter the onset of sy ncope. The av er age sur v i v al af ter the onset of angi na pector i s or HF
i s 5 and 2 y ear s, r especti v el y . Ther ef or e, the onset of angi na, sy ncope, or HF due to aor ti c
stenosi s si gnal s the need f or v al v e r epl acem ent. Pati ents shoul d al so be questi oned
P. 63
about m or e subtl e sy m ptom s such as ex er ti onal dy spnea or a decr ease i n ex er ci se capaci ty , as
these sy m ptom s m ay al so i ndi cate the need f or sur ger y .
4. How i s the sev er i ty of aor ti c stenosi s m ost accur atel y deter m i ned?
The sev er i ty of aor ti c stenosi s can be pr eci sel y deter m i ned by ei ther car di ac catheter i zati on or
Doppl er /echocar di ogr aphy . Both techni ques can pr ov i de accur ate esti m ati ons of the pr essur e
gr adi ent and the aor ti c v al v e ar ea. Doppl er echocar di ogr aphy i s gener al l y used f or ev al uati on and
f ol l ow up because i t i s noni nv asi v e and easi l y r epeated. The nor m al aor ti c v al v e ar ea i s 3 cm 2 .
Mi l d, m oder ate, and sev er e aor ti c stenosi s ar e pr esent w hen the v al v e ar ea i s > 1. 5 cm 2 , betw een
1. 5 and 1 cm 2 , and < 1 cm 2 , r especti v el y . Aor ti c stenosi s i s sai d to be cr i ti cal w hen the v al v e ar ea
i s 0. 7 cm 2 or l ess. Pr essur e gr adi ent m easur em ents al one ar e not adequate to deter m i ne the
sev er i ty of aor ti c stenosi s because, as al r eady di scussed, pr essur e gr adi ents ar e deter m i ned by
both the ar ea of the stenoti c v al v e and the bl ood f l ow acr oss the v al v e. Phy si cal ex am i nati on
f i ndi ngs such as the l atepeak i ng m ur m ur and the absent aor ti c com ponent of the second hear t
sound m ay be suggesti v e of sev er e aor ti c stenosi s but ar e poor l y sensi ti v e and speci f i c com par ed
w i th the i nf or m ati on y i el ded by the aor ti c v al v e ar ea. Echocar di ogr aphy can al so ev al uate
v entr i cul ar f uncti on and hy per tr ophy as w el l as pr ov i de i nf or m ati on about the eti ol ogy of the aor ti c
stenosi s.
5. What i s the best ther apy f or sy m ptom ati c aor ti c stenosi s?
Aor ti c v al v e r epl acem ent i s the best ther apy f or sy m ptom ati c aor ti c stenosi s. In sy m ptom ati c
pati ents w i th sev er e aor ti c stenosi s, aor ti c v al v e r epl acem ent r esul ts i n a postoper ati v e sur v i v al
that i s cl ose to that of the gener al popul ati on. Ol der pati ents al so gener al l y hav e a good sur v i v al
f ol l ow i ng aor ti c v al v e r epl acem ent f or aor ti c stenosi s.
Longter m r esul ts of bal l oon aor ti c v al v ul opl asty (a catheter based pr ocedur e) hav e been
di sappoi nti ng. Ther ef or e, i t i s used pr i m ar i l y f or pal l i ati on i n pati ents w ho ar e not candi dates f or
aor ti c v al v e r epl acem ent because of other m edi cal pr obl em s or as a br i dge to aor ti c v al v e
r epl acem ent i n pati ents deem ed too i l l f or sur ger y . How ev er , ser i ous com pl i cati ons and m or tal i ty
ar e hi gh i n these pati ents and r estenosi s gener al l y r ecur s w i thi n 6 to 12 m onths.
Case 2
A 50y ear ol d w om an w ho had an â€œi nnocentâ€ m ur m ur di agnosed i n chi l dhood pr esents w i th dy spnea
on ex er ti on, or thopnea, and par ox y sm al noctur nal dy spnea of sev er al m onths' dur ati on. On questi oni ng,
she descr i bes a 1y ear hi stor y of f ati gue and ex hausti on that has l i m i ted her dai l y acti v i ti es. She has
not seen a phy si ci an i n y ear s.
On phy si cal ex am i nati on, her bl ood pr essur e i s 110/70 m m Hg. Her jugul ar v enous pr essur e i s nor m al
and she has m i l dl y di m i ni shed ar ter i al pul se am pl i tude w i th a nor m al ar ter i al upstr ok e. Her l ungs ar e
cl ear to per cussi on and auscul tati on. Ther e i s a l ater al l y di spl aced apex i m pul se and a pal pabl e thi r d
hear t sound that i s easi l y hear d. The f i r st hear t sound i s sof t and ther e i s a w i del y spl i t second hear t
sound w i th nor m al r espi r ator y spl i tti ng. A gr ade 3/4 bl ow i ng, hi ghpi tched sy stol i c m ur m ur i s hear d at
the apex and r adi ates to the ax i l l a and l ef t i nf r ascapul ar ar ea. Ther e i s tr ace edem a but no cl ubbi ng or
cy anosi s.
P. 64
1. What i s the v al v ul ar l esi on i n thi s pati ent?

2. What i s the m ost com m on under l y i ng cause of sev er e m i tr al r egur gi tati on i n the adul t U . S.
popul ati on?
3. Does m edi cal ther apy pr ev ent pr ogr essi on of m i tr al r egur gi tati on?
4. When shoul d sur ger y be consi der ed f or pati ents w i th sev er e m i tr al r egur gi tati on?
5. What ar e the choi ces f or m i tr al v al v e sur ger y ?
Case Discussion
1. What i s the v al v ul ar l esi on i n thi s pati ent?
Chr oni c m i tr al r egur gi tati on, the m ost i nsi di ous of al l l ef tsi ded v al v ul ar l esi ons, i s the m ost l i k el y
di agnosi s i n thi s pati ent. Sev er e l ef t v entr i cul ar dy sf uncti on i s not uncom m on at pr esentati on i n
thi s di sor der . The hol osy stol i c api cal m ur m ur i s char acter i sti c of chr oni c m i tr al r egur gi tati on. The
thi r d hear t sound suggests that the m i tr al r egur gi tati on i s sev er e, and i s a r ef l ecti on of the l ar ge
v ol um e of bl ood cr ossi ng the m i tr al v al v e i n ear l y di astol e. How ev er , the thi r d hear t sound does
not necessar i l y i m pl y HF. In chr oni c m i tr al r egur gi tati on, the l ar ge r egur gi tant v ol um e enter i ng the
l ef t atr i um r esul ts i n l ef t atr i al enl ar gem ent w i th the l ef t atr i um of ten touchi ng the spi ne. The
m ur m ur i s tr ansm i tted to the spi ne thr ough the l ef t atr i um , accounti ng f or i ts r adi ati on to the
subscapul ar ar ea.
The m ur m ur descr i bed i s ty pi cal f or chr oni c m i tr al r egur gi tati on, but m ust be di sti ngui shed f r om
such m ur m ur s as tr i cuspi d r egur gi tati on, aor ti c stenosi s, and VSD. The m ur m ur char acter i sti c of
aor ti c stenosi s i s di sti ngui shed by i ts qual i ty (cr escendoâ€“decr escendo), l ocati on, and r adi ati on,
as descr i bed i n Case 1 under secti on on Val v ul ar Hear t Di sease. A tr i cuspi d i nsuf f i ci ency m ur m ur i s
usual l y w el l l ocal i zed to the l ef t ster nal bor der w i th l i ttl e r adi ati on, and has the char acter i sti c
f eatur e of an i ncr ease i n i ntensi ty w i th i nspi r ati on. The m ur m ur char acter i sti c of VSD i s ty pi cal l y
hear d best at the l ef t ster nal bor der , of ten has a har sh qual i ty , and does not change w i th
r espi r ati on. The m ur m ur of VSD i s r ar el y hear d i n adul ts because m ost congeni tal VSDs ar e
detected i n chi l dhood and r esol v e spontaneousl y or ar e sur gi cal l y cor r ected. A VSD i s a r ar e
com pl i cati on of acute MI i n adul ts.
2. What i s the m ost com m on under l y i ng cause of sev er e m i tr al r egur gi tati on i n the adul t U . S.
popul ati on?
My x om atous m i tr al v al v e di sease, usual l y as an i sol ated l esi on or som eti m es associ ated w i th other
connecti v e ti ssue di sor der s (e. g. , Mar f an's and Ehl er sDanl os sy ndr om es), consti tutes the m ost
com m on cause of sev er e m i tr al r egur gi tati on necessi tati ng m i tr al v al v e r epl acem ent or r epai r i n
the U ni ted States, especi al l y i n y ounger peopl e. A sm al l er num ber of cases ar e due to r heum ati c
hear t di sease, i nf ecti v e endocar di ti s, or spontaneousl y r uptur ed chor dae tendi neae. In ol der peopl e,
sev er e m i tr al r egur gi tati on of ten accom pani es l ef t v entr i cul ar enl ar gem ent and dy sf uncti on due to
CAD and MI. The m i tr al r egur gi tati on i s not due to an abnor m al i ty
P. 65
of the v al v e l eaf l ets but due to a com bi nati on of abnor m al i ti es of the suppor ti ng str uctur es of the
v al v e i ncl udi ng str etchi ng of the m i tr al annul us al ong w i th papi l l ar y m uscl e dy sf uncti on and w al l
m oti on abnor m al i ti es.
3. Does m edi cal ther apy pr ev ent pr ogr essi on of m i tr al r egur gi tati on?
Ther e ar e no cl i ni cal tr i al s dem onstr ati ng benef i ts of any m edi cal ther apy f or chr oni c m i tr al
r egur gi tati on that i s due to a pr i m ar y abnor m al i ty of the m i tr al v al v e. If m i tr al r egur gi tati on i s due
to l ef t v entr i cul ar enl ar gem ent w i th dy sf uncti on of the m i tr al v al v e appar atus, ACE i nhi bi tor s and
Î²bl ock er s ar e i ndi cated to i m pr ov e v entr i cul ar f uncti on. If v entr i cul ar f uncti on i m pr ov es i n
pati ents w i th m i tr al r egur gi tati on due to v entr i cul ar dy sf uncti on, the m i tr al r egur gi tati on w i l l
i m pr ov e as the v al v e appar atus becom es m or e f uncti onal .
4. When shoul d sur ger y be consi der ed f or pati ents w i th sev er e m i tr al r egur gi tati on?
Mi tr al r egur gi tati on r esul ts i n a chr oni c v ol um e ov er l oad on the l ef t v entr i cl e and ul ti m atel y r esul ts
i n l ef t v entr i cul ar contr acti l e dy sf uncti on. Mi tr al v al v e sur ger y shoul d be per f or m ed bef or e
v entr i cul ar dy sf uncti on occur s, but ther e i s no m ethod to pr eci sel y pr edi ct the onset of v entr i cul ar
dy sf uncti on. Ser i al Doppl er echocar di ogr aphy studi es shoul d be per f or m ed to ev al uate l ef t
v entr i cul ar si ze and f uncti on and assess pul m onar y pr essur es. Sur ger y i s r ecom m ended i n the
asy m ptom ati c pati ent i f the EF f al l s bel ow 60%, or w hen the l ef t v entr i cul ar enddi astol i c
di m ensi on ex ceeds 45 m m , or i f pul m onar y hy per tensi on or atr i al f i br i l l ati on dev el ops. Sur ger y i s
r ecom m ended f or pati ents w i th sy m ptom s of HF due to m i tr al r egur gi tati on unl ess they hav e sev er e
l ef t v entr i cul ar dy sf uncti on or other contr ai ndi cati ons to sur ger y .
5. What ar e the choi ces f or m i tr al v al v e sur ger y ?
Mi tr al v al v e r epl acem ent w i th m echani cal or bi opr ostheti c v al v es and, m or e r ecentl y , m i tr al v al v e
r epai r consti tute the sur gi cal tr eatm ents av ai l abl e f or sev er e m i tr al r egur gi tati on due to a pr i m ar y
v al v e abnor m al i ty . Mi tr al v al v e r epai r i s associ ated w i th a l ow er sur gi cal m or tal i ty r ate and a
better l ongter m outcom e than m i tr al v al v e r epl acem ent, and i s the pr ef er r ed pr ocedur e w hen
r epai r i s possi bl e. Mi tr al v al v e sur ger y i s gener al l y not i ndi cated i f the m i tr al r egur gi tati on i s due
to l ef t v entr i cul ar dy sf uncti on w i thout a pr i m ar y v al v e abnor m al i ty .
Case 3
A 56y ear ol d m an i s seen because of pr ogr essi v e f ati gue, dy spnea on ex er ti on, or thopnea, and
par ox y sm al noctur nal dy spnea. On phy si cal ex am i nati on hi s bl ood pr essur e i s 160/60 m m Hg. Ther e i s
no jugul ar v enous di stenti on, but sy stol i c pul sati ons of the uv ul a ar e noted, as i s qui ck col l apse of the
ar ter i al pul ses, w hi ch i s seen i n the nai l beds w i th gentl e pr essur e. The l ungs ar e cl ear to per cussi on
and auscul tati on. Ther e i s a di f f use and hy per dy nam i c apex beat that i s di spl aced l ater al l y and
i nf er i or l y , sof t f i r st and second hear t sounds, a l oud thi r d hear t sound, and a gr ade 3/6, hi ghpi tched,
near l y hol odi astol i c m ur m ur hear d best at the upper l ef t ster nal bor der al ong w i th a gr ade 3/6 sy stol i c
ejecti on ty pe m ur m ur at the upper l ef t ster nal bor der r adi ati ng to the car oti ds. A l ate di astol i c r um bl e i s
hear d at the apex as w el l as a thi r d hear t sound.
P. 66

2. What i s the l i k el y under l y i ng cause of aor ti c r egur gi tati on i n thi s pati ent?
3. What i s the appr opr i ate m edi cal ther apy f or the pati ent w i th aor ti c r egur gi tati on?
4. When shoul d aor ti c v al v e r epl acem ent be consi der ed i n a pati ent w i th chr oni c aor ti c r egur gi tati on?
5. What i s the sur gi cal ther apy f or sev er e aor ti c r egur gi tati on?
Case Discussion
Thi s pati ent has chr oni c sev er e aor ti c r egur gi tati on. Ther e ar e m any phy si cal si gns to l ook f or i n
the setti ng of aor ti c r egur gi tati on, som e of w hi ch ar e seen i n thi s pati ent. These i ncl ude de
Musset's si gn (the head bobs w i th each hear tbeat), Cor r i gan's si gn or w ater ham m er pul ses,
Tr aube's si gn (boom i ng sy stol i c and di astol i c sounds hear d ov er the f em or al ar ter i es), Mul l er 's si gn
(sy stol i c pul sati on of the uv ul a), Qui nck e's si gn (capi l l ar y pul sati ons seen i n the nai l beds), and
other s. Al l of these ar e si gns of l ar ge str ok e v ol um e and w i de pul se pr essur e char acter i sti c of
chr oni c aor ti c r egur gi tati on. The l oud 3/6 di astol i c m ur m ur hear d at the upper l ef t ster nal bor der i s
the m ur m ur of aor ti c i nsuf f i ci ency and the sy stol i c m ur m ur i s due to tur bul ent f l ow acr oss the
aor ti c v al v e because of the l ar ge am ount of bl ood cr ossi ng the aor ti c v al v e. The m i dtol ate
di astol i c r um bl e, nam el y the Austi n Fl i nt m ur m ur , i s cr eated by r api d r etr ogr ade f l ow f r om the
aor ta str i k i ng the anter i or m i tr al l eaf l et. Another ex pl anati on f or thi s m ur m ur i s that the l ar ge
v ol um e of r egur gi tant f l ow par ti al l y cl oses the m i tr al v al v e, cr eati ng a l ate di astol i c m i tr al v al v e
gr adi ent.
2. What i s the l i k el y under l y i ng cause of aor ti c r egur gi tati on i n thi s pati ent?
In thi s agegr oup, the m ost l i k el y cause of aor ti c r egur gi tati on i s a bi cuspi d aor ti c v al v e. Causes of
aor ti c r egur gi tati on can be br ok en dow n i nto tw o gener al categor i esâ€”v al v ul ar di sease and aor ti c
r oot di sease. Rheum ati c hear t di sease, i nf ecti v e endocar di ti s, tr aum a, bi cuspi d v al v e, other
congeni tal v al v ul ar def ects (e. g. , a f enestr ated v al v e), sy stem i c l upus er y them atosus, r heum atoi d
ar thr i ti s, ank y l osi ng spondy l i ti s, and Whi ppl e's di sease m ay cause pr i m ar y v al v ul ar di sease. Cy sti c
m edi al necr osi s of the aor ta (i sol ated or associ ated w i th Mar f an's sy ndr om e or Ehl er sDanl os
sy ndr om e), ather oscl er osi s, hy per tensi on, sy phi l i ti c aor ti ti s, and other s m ay cause aor ti c r oot
di l atati on and def or m i ty of the aor ti c v al v e, l eadi ng to i nabi l i ty of the v al v e to coapt. A di ssecti on
of the aor ta m ay al so cause aor ti c r egur gi tati on by di ssecti ng i nto the v al v e i tsel f .
3. What i s the appr opr i ate m edi cal ther apy f or the pati ent w i th aor ti c r egur gi tati on?
The use of v asodi l ator s to del ay the pr ogr essi on of aor ti c r egur gi tati on and l ef t v entr i cul ar
dy sf uncti on i n asy m ptom ati c pati ents i s contr ov er si al and def i ni te ev i dence of a benef i t has not
been dem onstr ated. In pati ents w i th sy m ptom s of HF due to aor ti c r egur gi tati on, v asodi l ator s m ay
pr ov i de sy m ptom ati c benef i t but shoul d not del ay r ef er r al f or aor ti c v al v e r epl acem ent.
P. 67
4. When shoul d aor ti c v al v e r epl acem ent be consi der ed i n a pati ent w i th chr oni c aor ti c r egur gi tati on?
Aor ti c v al v e sur ger y shoul d be consi der ed i f the pati ent has sy m ptom s of HF. In the asy m ptom ati c
pati ent, aor ti c v al v e r epl acem ent i s r ecom m ended i f the EF f al l s bel ow nor m al or i f the endsy stol i c
di m ensi on of the l ef t v entr i cl e i s l ar ger than 55 m m .
5. What i s the sur gi cal ther apy f or sev er e aor ti c r egur gi tati on?
Aor ti c v al v e r epl acem ent w i th a pr ostheti c v al v e i s the onl y sur gi cal opti on i n m ost pati ents.
Case 4
A 32y ear ol d w om an w ho r ecentl y m ov ed to the U ni ted States f r om Mex i co i s seen because of the
r ecent onset of pal pi tati ons associ ated w i th dy spnea on ex er ti on, or thopnea, and par ox y sm al noctur nal
dy spnea w i th hem opty si s.
On phy si cal ex am i nati on, her bl ood pr essur e i s 112/90 m m Hg and her hear t r ate i s 120 per m i nute and
i r r egul ar l y i r r egul ar . Jugul ar v enous di stenti on to 10 cm H 2 O w i th a pr om i nent V w av e i s noted, as ar e
di m i ni shed ar ter i al pul ses and bi basi l ar r al es (up to hal f of the l ung f i el ds bi l ater al l y ). Addi ti onal
f i ndi ngs i ncl ude a nondi spl aced apex beat, a r i ght v entr i cul ar heav e pal pabl e i n the l ef t par aster nal
r egi on, a pal pabl e pul m oni c cl osur e sound i n the second l ef t i nter costal space, an accentuated S 4 , a l oud
pul m oni c second sound (P 2 ) ov er the l ef t v entr i cul ar apex , a snappi ng sound ov er the l ef t v entr i cul ar
apex i m pul se just af ter the second hear t sound, and a gr ade 3/4, l ow pi tched, r um bl i ng, near l y
hol odi astol i c m ur m ur hear d best at the car di ac apex . Ther e i s 1 to 2+ pi tti ng edem a noted i n the l ow er
ex tr em i ti es and pr esacr al ar ea.

2. What i s the m ost com m on cause of m i tr al stenosi s i n adul t pati ents?
3. What i s the m or tal i ty r ate associ ated w i th m edi cal l y tr eated m i tr al stenosi s?
4. What ar e the m ajor com pl i cati ons of m i tr al stenosi s?
5. What i s the best tr eatm ent f or sy m ptom ati c pati ents w i th m i tr al stenosi s?
Case Discussion
The cl i ni cal pi ctur e ex hi bi ted by thi s pati ent i s char acter i sti c of sev er e m i tr al stenosi s w i th
secondar y pul m onar y hy per tensi on and cor pul m onal e. The sev er i ty of the m i tr al stenosi s i s
i ndi cated by the m i tr al openi ng snap, w hi ch cl osel y f ol l ow s the second hear t sound and the
hol odi astol i c r um bl e. The m i tr al openi ng snap i s a char acter i sti c si gn of m i tr al stenosi s and
appear s to be due to a sudden tensi ng of the v al v e l eaf l ets af ter the v al v e cusps hav e com pl eted
thei r openi ng ex cur si ons, and occur s shor tl y af ter (0. 08 to 0. 12 second) the aor ti c com ponent of
the second hear t sound. The m i tr al openi ng snap m ov es cl oser to the second hear t sound as the
pr essur e betw een the l ef t atr i um and l ef t v entr i cl e i ncr eases. The r um bl i ng,
P. 68
l ow pi tched di astol i c m ur m ur hear d at the apex i s char acter i sti c of m i tr al stenosi s. The dur ati on of
the m ur m ur thr oughout di astol e i ndi cates that ther e i s a pr essur e gr adi ent acr oss the m i tr al v al v e
thr oughout di astol e. Pul m onar y hy per tensi on i s i ndi cated by the l oud pul m oni c com ponent of the
second hear t sound and r i ght v entr i cul ar heav e. A P 2 that can be hear d at the l ef t v entr i cul ar apex
i ndi cates pul m onar y hy per tensi on. Cor pul m onal e i s r ef l ected by the el ev ated neck v ei ns, and
per i pher al edem a. The l ar ge V w av e i ndi cates tr i cuspi d r egur gi tati onâ€”a r esul t of the pul m onar y
hy per tensi on and cor pul m onal e. Par ox y sm al noctur nal dy spnea w i th hem opty si s i s a m ajor cl ue to
thi s di agnosi s and r ef l ects a sudden i ncr ease i n pul m onar y capi l l ar y pr essur e w i th i ntr aal v eol ar
edem a and hem or r hage such as m i ght occur w i th ex er ci se or new onset of atr i al f i br i l l ati on.
2. What i s the m ost com m on cause of m i tr al stenosi s i n adul t pati ents?
Mi tr al stenosi s i n adul ts i s al m ost ex cl usi v el y due to r heum ati c hear t di sease. Thi s pati ent
descr i bed a pr ol onged i l l ness at 12 y ear s of age consi stent w i th acute r heum ati c f ev er but hal f of
al l pati ents w i th r heum ati c m i tr al stenosi s w i l l not hav e a cl ear chi l dhood hi stor y of r heum ati c
f ev er .
3. What i s the m or tal i ty r ate associ ated w i th m edi cal l y tr eated m i tr al stenosi s?
Fr om the ti m e of the i ni ti al di agnosi s, pati ents w i th m edi cal l y tr eated m i tr al stenosi s can ex pect a
m or tal i ty r ate of 20% at 5 y ear s and 40% at 10 y ear s. Thi s pati ent f aces a m uch l ess f av or abl e
pr ognosi s because of her pul m onar y hy per tensi on and r i ght v entr i cul ar HF. How ev er , the r i sk i s
si gni f i cantl y r educed i f she under goes v al v e r epl acem ent, com m i ssur otom y , or m i tr al bal l oon
v al v otom y .
4. What ar e the m ajor com pl i cati ons of m i tr al stenosi s?
In pati ents w i th uncor r ected m i tr al stenosi s, ther e i s a 20% l i f eti m e r i sk of thr om boem bol i sm . Thi s
i s of ten a dev astati ng com pl i cati on because the em bol us m ost of ten tr av el s to the br ai n, r esul ti ng
i n a str ok e. Ei ghty per cent of pati ents w i th sy stem i c em bol i ar e i n atr i al f i br i l l ati on. Thi s r i sk i s
decr eased by the use of anti coagul ant ther apy w i th sodi um w ar f ar i n. Inf ecti v e endocar di ti s occur s
l ess f r equentl y but m ay be a di sastr ous com pl i cati on. Atr i al f i br i l l ati on i s a com m on com pl i cati on
of m i tr al stenosi s. The l ef t atr i um i s of ten v er y l ar ge due to a com bi nati on of r heum ati c
i nv ol v em ent of the atr i al m uscl e and the hi gh l ef t atr i al pr essur es, pr edi sposi ng to atr i al
f i br i l l ati on.
5. What i s the best tr eatm ent f or sy m ptom ati c pati ents w i th m i tr al stenosi s?
Opti ons f or cor r ecti on of m i tr al stenosi s i ncl ude per cutaneous tr ansv enous m i tr al v al v ul opl asty ,
sur gi cal m i tr al com m i ssur otom y , or m i tr al v al v e r epai r . In bal l oon v al v ul opl asty , the bal l oon i s
passed f r om the f em or al v ei n to the r i ght atr i um , acr oss the atr i al septum , and acr oss the m i tr al
v al v e. The bal l oon i s i nf l ated, cr ack i ng open the v al v e. Thi s i s the pr ef er r ed pr ocedur e i n
ex per i enced hands i f the v al v e anatom y i s f av or abl e and ther e ar e no contr ai ndi cati ons. Resul ts ar e
al so good w i th sur gi cal com m i ssur otom y or m i tr al v al v e r epl acem ent.
Suggested Readings
Bonow RO, Lak atos E, Mar on BJ, etal . Ser i al l ongter m assessm ent of the natur al hi stor y of
asy m ptom ati c pati ents w i th chr oni c aor ti c r egur gi tati on and nor m al l ef t v entr i cul ar sy stol i c f uncti on.
Ci r cul ati on 1991;84:1625â€“1635.
P. 69
Car abel l o BA. Concentr i c v s eccentr i c r em odel i ng. J Car d Fai l 2002;8:S258â€“S263.
Car abel l o BA. Moder n m anagem ent of m i tr al stenosi s. Ci r cul ati on 2005;112:432â€“437.
Car abel l o BA. Vasodi l ator s i n aor ti c r egur gi tati onw her e i s the ev i dence of thei r ef f ecti v eness? N
Engl J Med 2005;353:1400â€“1402.
Fr eem an RV, Otto CM. Spectr um of cal ci f i c aor ti c v al v e di sease: pathogenesi s, di sease pr ogr essi on,
and tr eatm ent str ategi es. Ci r cul ati on 2005;111:3316â€“3326.
Gol dsm i th I, Tur pi e AG, Li p GY. Val v ul ar hear t di sease and pr ostheti c hear t v al v es. Br Med J
2002;325:1228â€“1231.
Lam bo N J, Del l 'Ital i a LJ, Cr aw f or d MH, etal . Bedsi de di agnosi s of sy stol i c m ur m ur s. N Engl J Med
1988;318:1572â€“1579.
Li eber m an EG, Bashor e TM, Her m i l l er JB, etal . Bal l oon aor ti c v al v ul opl asty i n adul ts: f ai l ur e of
pr ocedur e to i m pr ov e l ongter m sur v i v al . J Am Col l Car di ol 1995;26:1522â€“1528.
Pel l i k k a PA, N i shi m ur a RA, Bai l ey KR, etal . The natur al hi stor y of adul ts w i th asy m ptom ati c,
hem ody nam i cal l y si gni f i cant aor ti c stenosi s. J Am Col l Car di ol 1990;15:1012â€“1017.
Rey es VP, Raju BS, Wy nne J, etal . Per cutaneous bal l oon v al v ul opl asty com par ed w i th open sur gi cal
com m i ssur otom y f or m i tr al stenosi s. N Engl J Med 1994;331:961â€“967.
Rozi ch JD, Car abel l o BA, U sher BW, etal . Mi tr al v al v e r epl acem ent w i th and w i thout chor dal
pr eser v ati on i n pati ents w i th chr oni c m i tr al r egur gi tati on: m echani sm s f or di f f er ences i n
postoper ati v e ejecti on per f or m ance. Ci r cul ati on 1992;86:1718â€“1726.
Vongpastanasi n W, Hi l l s LD, Lange RA. Medi cal pr ogr ess: pr ostheti c hear t v al v es. N Engl J Med
1996;335:407â€“416.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 3 End o c r ino lo g y , Me ta b o lis m , a nd D ia b e te s
Chapter 3
Endocrinology, Metabolism, and Diabetes
Ire ne E. Sc ha ue r

Ja ne E. B. Re us c h
P. 71
Adrenal Insufficiency
1. What ar e the gener al categor i es of adr enocor ti cal i nsuf f i ci ency ?
2. Can y ou ex pl ai n w hy thy r oi d f uncti on tests shoul d be ev al uated i n a

pati ent w i th pr i m ar y adr enal f ai l ur e?
3. What ar e the char acter i sti c si gns and sy m ptom s of acute and chr oni c
adr enal i nsuf f i ci ency ?
4. What cr i ter i a ar e used to m ak e the di agnosi s of adr enal i nsuf f i ci ency ?
5. What ar e the consi der ati ons i n deci di ng on l ongter m r epl acem ent ther apy
f or Addi son's di sease?
6. What other m etabol i c abnor m al i ti es m ay occur i n associ ati on w i th adr enal
i nsuf f i ci ency ?
7. What ar e the ev ents that tak e pl ace i n the r egul ati on of cor ti sol secr eti on
by the hy pothal am i câ€“pi tui tar y â€“adr enal ax i s?
8. What ar e the speci f i c causes of pr i m ar y and secondar y adr enal f ai l ur e?
Discussion
1. What ar e the gener al categor i es of adr enocor ti cal i nsuf f i ci ency ?
Adr enocor ti cal i nsuf f i ci ency r esul ts pr i m ar i l y f r om def i ci ent cor ti sol
pr oducti on and i n som e cases def i ci ent al doster one and andr ogen
pr oducti on by the adr enal gl and. Because the adr enal cor tex i s nor m al l y
sti m ul ated by pi tui tar y adr enocor ti cotr opi c hor m one (ACTH;
cor ti cotr opi n), cor ti sol def i ci ency m ay r esul t f r om adr enal di sease
(prima ry a dre na l ins uffic ie nc y or Addi son's di sease) or f r om pi tui tar y or
hy pothal am i c di sease w i th ACTH def i ci ency (s e c onda ry a dre na l
ins uffic ie nc y).
2. Can y ou ex pl ai n w hy thy r oi d f uncti on tests shoul d be ev al uated i n a
pati ent w i th pr i m ar y adr enal f ai l ur e?
The associ ati on betw een autoi m m une thy r oi di ti s and autoi m m une adr enal
di sease i s w el l r ecogni zed. In gener al , pati ents w i th Addi son's di sease ar e
af f l i cted m or e f r equentl y w i th Hashi m oto's thy r oi di ti s than w i th Gr av es'
di sease. Appr ox i m atel y 50% or m or e of af f ected pati ents hav e hi gh ti ter s
of thy r oi d anti m i cr osom al anti bodi es, al though these pati ents of ten hav e
no thy r oi dr el ated sy m ptom s. Gr av es' hy per thy r oi di sm can occur i n
associ ati on w i th pr i m ar y adr enal f ai l ur e. The associ ati on betw een thy r oi d
f ai l ur e and adr enal f ai l ur e can al so r ef l ect hy popi tui tar i sm , w i th a
consequent def i ci ency of both ACTH and thy r oi dsti m ul ati ng hor m one
(TSH). Ther ef or e, abnor m al r esul ts f r om thy r oi d f uncti on tests hav e been
seen i n the setti ngs of both pr i m ar y and secondar y hy poadr enal i sm ,
m ak i ng thy r oi d f uncti on tests an i m por tant com ponent of the ev al uati on
of a pati ent w i th pr i m ar y or secondar y adr enal f ai l ur e.
3. What ar e the char acter i sti c si gns and sy m ptom s of acute and chr oni c
adr enal i nsuf f i ci ency ?
Acute adr enal i nsuf f i ci ency i s a potenti al l y f atal m edi cal em er gency , and
the cl i ni cal f eatur es i ncl ude nausea, f ev er , and shock , pr ogr essi ng to
P. 72
di ar r hea, m uscul ar w eak ness, i ncr eased and then decr eased body
tem per atur e, hy pogl y cem i a, hy ponatr em i a, and hy per k al em i a.
The car di nal si gns of chr oni c adr enal i nsuf f i ci ency ar e w eak ness, f ati gue,
and anor ex i a, al ong w i th gastr oi ntesti nal com pl ai nts of nausea, v om i ti ng,
di ar r hea, and v ague abdom i nal pai n. Other sy m ptom s i ncl ude sal t cr av i ng
(20% of the pati ents) and m uscl e cr am ps. Phy si cal f i ndi ngs m ay com pr i se
w ei ght l oss, hy per pi gm entati on, hy potensi on, and v i ti l i go. The ear
car ti l age m ay cal ci f y i n pati ents w i th l ongstandi ng adr enal i nsuf f i ci ency .
4. What cr i ter i a ar e used to m ak e the di agnosi s of adr enal i nsuf f i ci ency ?
The di agnosi s of adr enocor ti cal i nsuf f i ci ency i s based pr i m ar i l y on the
pl asm a cor ti sol deter m i nati ons m ade dur i ng the r api d ACTH sti m ul ati on
test (Cor tr osy n test). Any scr eeni ng tests f or adr enal i nsuf f i ci ency m ust
i ncl ude deter m i nati on of a basal l ev el of cor ti sol and ACTH, together w i th
a r api d ACTH sti m ul ati on test. Thi s test i s per f or m ed by adm i ni ster i ng 25
uni ts (0. 25 m g) of sy ntheti c ACTH i ntr av enousl y /i ntr am uscul ar l y (IV or
IM) and m easur i ng the r esponse of cor ti sol and al doster one. It i s
per f or m ed to assess i ni ti al l y w hether the adr enal s can r espond to
ex ogenous ACTH. A cl ear l y nor m al r esponse ex cl udes the possi bi l i ty of
pr i m ar y and chr oni c, but not acute, secondar y adr enal f ai l ur e. For the
cor ti sol r esponse to be nor m al , the cor ti sol l ev el af ter ACTH
adm i ni str ati on shoul d be at l east 18 ng/dL and i ncr eased by at l east 9
ng/dL abov e the basal l ev el s. N or m al l y , the al doster one l ev el s par al l el
the cor ti sol l ev el s, w i th an i ncr ease of at l east 14 ng/dL abov e the basal
l ev el s. Pati ents w i th Addi son's di sease ex hi bi t v er y l ow cor ti sol l ev el s
and a cl ear l y el ev ated ACTH l ev el , w her eas the l ev el s of both tend to be
l ow i n pati ents w i th hy popi tui tar i sm . In the cl assi c si tuati on, the r esponse
of al doster one to ACTH i s absent i n pati ents w i th pr i m ar y adr enal f ai l ur e,
w her eas i t i s pr eser v ed i n pati ents w i th secondar y adr enal f ai l ur e. The
m easur em ent of al doster one i s not r outi ne but can add di agnosti c
i nf or m ati on f or pr i m ar y adr enal f ai l ur e. A l ow dose (1 Âµg cor tr osy n)
cor tr osy n sti m ul ati on test i s al so av ai l abl e and m ay be m or e sensi ti v e
w hen appr opr i ate cutof f v al ues ar e used. How ev er , addi ti onal techni cal
di f f i cul ti es i n cor tr osy n adm i ni str ati on and ti m i ng of bl ood tests hav e
pr ev ented thi s test f r om becom i ng r outi nel y accepted.
5. What ar e the consi der ati ons i n deci di ng on l ongter m r epl acem ent ther apy
f or Addi son's di sease?
Longter m r epl acem ent ther apy i n pati ents w i th Addi son's di sease
i nv ol v es the or al adm i ni str ati on of a cor ti sone pr epar ati on i n phy si ol ogi c
r epl acem ent doses. U sual l y , tw o thi r ds of the total dose i s gi v en i n the
m or ni ng and the r em ai nder i s gi v en i n the ev eni ng to m i m i c the nor m al
ci r cadi an secr eti on of cor ti sol . Cor ti sone acetate can be tak en as a dose
of 25 m g i n the m or ni ng and 12. 5 m g i n the ev eni ng. Al ter nati v el y ,
hy dr ocor ti sone can be tak en i n a dosage of 30 to 40 m g per day .
How ev er , because cor ti sone m ust be conv er ted to hy dr ocor ti sone i n the
body , hy dr ocor ti sone i s consi der ed the m or e phy si ol ogi c agent. Despi te
thi s, pr edni sone (5â€“7. 5 m g per day ) i s f r equentl y pr escr i bed f or l ong
ter m r epl acem ent because i t costs l ess than hy dr ocor ti sone. The si de
ef f ects f r om the ex cessi v e adm i ni str ati on of the abov e
P. 73
gl ucocor ti coi ds i ncl ude i ncr eased appeti te, w ei ght gai n, i nsom ni a, edem a,
and hy per tensi on.
Mi ner al ocor ti coi d r epl acem ent (f l uor ohy dr ocor ti sone ther apy ) i s
necessar y i n pati ents w i th pr i m ar y Addi son's di sease, al though the ex act
r epl acem ent dose m ust be ti tr ated to the pati ent's r esponse. Dr am ati c
f l ui d r etenti on m ay occur w i th the i ni ti al tr eatm ent, but thi s subsi des
once the dose i s adjusted.
6. What other m etabol i c abnor m al i ti es m ay occur i n associ ati on w i th adr enal
i nsuf f i ci ency ?
Hype rk a le mia occur s f r equentl y i n pati ents w i th pr i m ar y adr enal f ai l ur e

(appr ox i m atel y 64%). Thi s i s l ar gel y due to r enal tubul ar absor pti on of
potassi um at the ex pense of sodi um stem m i ng f r om the m i ner al ocor ti coi d
def i ci ency . In addi ti on, gl ucocor ti coi ds hel p i n m ai ntai ni ng the f uncti on of
the sodi um pum p and the nor m al gr adi ent betw een the i ntr acel l ul ar and
ex tr acel l ul ar concentr ati ons of sodi um and potassi um . Wi thout cor ti sol ,
thi s gr adi ent i s not m ai ntai ned, so that potassi um m ov es out of the cel l
and sodi um m ov es i nto the cel l , ther eby r esul ti ng i n hy per k al em i a. Of
note, i n pati ents w i th secondar y (pi tui tar y ) adr enal i nsuf f i ci ency , the
m i ner al ocor ti coi d ax i s i s i ntact and hy per k al em i a, ar i si ng f r om the
second m echani sm onl y , i s m i l d or absent.
Hypoglyc e mia occur s i nf r equentl y , and pr i m ar i l y i n pati ents w i th

Addi son's di sease w ho hav e f asted f or any per i od. It i s due to def ecti v e
gl uconeogenesi s.
A m i l d a c idos is m ay ev entuate i n pati ents w i th m i ner al ocor ti coi d
def i ci ency because of the decr eased secr eti on of am m oni a and hy dr ogen
i ons.
Ci r cul ati ng l ev el s of a ntidiure tic hormone (ADH) m ay i ncr ease and
contr i bute to the hy ponatr em i a. The ex cessi v e l oss of sodi um by the r enal
tubul es l eads to an i ncr eased w ater l oss. Thi s i s counter bal anced by an
i ncr ease i n the ADH l ev el s, w hi ch tends to cause w ater r etenti on. The l ow
car di ac output and hy pov ol em i a al so ser v e as sti m ul i f or ADH r el ease.
The ina bility to e x c re te a w a te r loa d w as once used as a di agnosti c test
f or Addi son's di sease. Thi s phenom enon i s pr i m ar i l y caused by
gl ucocor ti coi d def i ci ency , ev en i n the pr esence of euv ol em i a. A bol us of
cor ti sol com pl etel y r ev er ses the ef f ect and a â€œw ater di ur esi sâ€
ensues, but thi s al so i nv ol v es the i nter pl ay of other f actor s, such as an
i m pr ov em ent i n car di ac output, an i ncr ease i n the ef f ecti v e ci r cul ati ng
v ol um e, an i ncr ease i n the gl om er ul ar f i l tr ati on r ate, a r educti on i n ADH
l ev el s, and di r ect ef f ects on the r enal tubul e.
Per i pher al e os inophilia i s a com m on f i ndi ng i n the setti ng of pr i m ar y
adr enal i nsuf f i ci ency .
7. What ar e the ev ents that tak e pl ace i n the r egul ati on of cor ti sol secr eti on
by the hy pothal am i câ€“pi tui tar y â€“adr enal ax i s?
Adr enocor ti cal cel l gr ow th and ster oi d secr eti on ar e pr i m ar i l y contr ol l ed
by the pi tui tar y hor m one ACTH. The secr etor y r egul ati on of the
hy pothal am i câ€“pi tui tar y â€“adr enal ax i s i nv ol v es the r el ease of
cor ti cotr opi nr el easi ng hor m one (CRH) by the hy pothal am us i nto the
hy pophy seal por tal sy stem . Thi s hor m one causes the pi tui tar y secr eti on
of ACTH, w hi ch i s tr anspor ted by the per i pher al ci r cul ati on to the adr enal
gl ands, w her e i t i s bound by
P. 74
speci f i c r eceptor s and tr i gger s ster oi d sy nthesi s and secr eti on. Cor ti sol
i nhi bi ts both CRH and ACTH r el ease, w her eas ACTH has a negati v e
f eedback ef f ect on CRH r el ease. Hor m onal and neur al i nput f r om hi gher
br ai n center s sti m ul ates or i nhi bi ts CRH sy nthesi s and secr eti on i n a 24
hour cy cl e, w hi ch causes both ACTH and cor ti sol secr eti on to ex hi bi t a
ci r cadi an r hy thm . The ci r cadi an r hy thm can be ov er com e by str ess,
how ev er , l eadi ng to chr oni c cor ti sol sy nthesi s. Cor ti sol ci r cul ates bound
to cor ti sol bi ndi ng gl obul i n (tr anscor ti n) and the f r ee cor ti sol enter s a
cel l and i nter acts w i th a speci f i c r eceptor to ex er t i ts phy si ol ogi c ef f ects.
8. What ar e the speci f i c causes of pr i m ar y and secondar y adr enal f ai l ur e?
Pr i m ar y adr enal i nsuf f i ci ency (Addi son's di sease) i s m ost com m onl y
caused by i di opathi c adr enal atr ophy stem m i ng f r om autoi m m une
destr ucti on (68%), tuber cul osi s (17%), or som e other eti ol ogy (15%).
N i nety per cent of the gl and m ust hav e been destr oy ed bef or e Addi son's
di sease becom es appar ent. Less com m on causes of adr enal i nsuf f i ci ency
i ncl ude other gr anul om atous di seases, such as hi stopl asm osi s and
sar coi dosi s, or i nf i l tr ati v e di seases, such as am y l oi dosi s,
hem ochr om atosi s, m etastati c tum or , and adr enal l euk ody str ophy , as w el l
as chr oni c anti coagul ati on and bi l ater al adr enal hem or r hage. Gr am
negati v e septi cem i a, bi l ater al adr enal ectom y , abdom i nal i r r adi ati on,
adr enal v ei n thr om bosi s, adr enal ar ter y em bol us, and adr enol y ti c dr ugs
ar e al so r ar e causes of adr enal f ai l ur e.
Adr enal i nsuf f i ci ency i s f ound i n som e pati ents w i th acqui r ed
i m m unodef i ci ency sy ndr om e (AIDS). The m ai n pr esentati on of adr enal
i nsuf f i ci ency i n AIDS i s f ati gue; el ectr ol y te abnor m al i ti es ar e uncom m on.
Dev el opm ent of adr enal i nsuf f i ci ency i n pati ents w i th at l east one AIDS
def i ni ng di sease i s associ ated w i th poor pr ognosi s.
Secondar y adr enal i nsuf f i ci ency i s com m onl y caused by i atr ogeni c
cor ti coster oi d ther apy , w hi ch suppr esses CRH and ACTH secr eti on and
r esul ts i n adr enal atr ophy . Other , l ess com m on causes i ncl ude pi tui tar y
and hy pothal am i c tum or s, i r r adi ati on, tr aum a, pi tui tar y necr osi s, and
l y m phocy ti c hy pophy si ti s sur gi cal pr ocedur es.
Case
A 60y ear ol d m an i s hospi tal i zed because of sev er e nausea, v om i ti ng, and
di ar r hea of 4 day s' dur ati on. He adm i ts to hav i ng ex per i enced m i l d i ncr easi ng
f ati gue and m al ai se f or the l ast 6 m onths pl us poor appeti te, f r equent
abdom i nal cr am ps, and a 20l b (9k g) w ei ght l oss ov er the l ast 4 m onths. He
f eel s di zzy i n the m or ni ng and l i ghtheaded af ter standi ng f or m or e than an
hour . He notes that he tends to tak e a nap i n the l ate af ter noon. Four day s
bef or e pr esentati on, abdom i nal cr am ps, v om i ti ng, and di ar r hea dev el oped. He
deni es any sk i n changes and pr ol onged sun ex posur e. He adm i ts to a decl i ne
i n sex ual desi r e. He has no hi stor y of hy per tensi on, di abetes, asthm a, or
tuber cul osi s, and tak es no m edi cati ons.
Phy si cal ex am i nati on r ev eal s a v er y tanned m an, w ho appear s acutel y i l l and
som ew hat dehy dr ated. He w ei ghs 63 k g. Hi s supi ne bl ood pr essur e (BP) i s
106/68 m m Hg and hi s supi ne pul se i s 90 beats per m i nute; hi s standi ng BP i s
80/50 m m Hg and hi s standi ng pul se i s 104 beats per m i nute.
P. 75
Hi s sk i n show s decr eased tur gor . Hi s f ace, hands, ex tensor sur f aces, chest,
and back ar e notabl y tanned. The f i ndi ngs f r om the head, ey es, ear , nose, and
thr oat ex am i nati on ar e nor m al , ex cept f or the pr esence of har dened ear l obes.
N o hear t abnor m al i ti es ar e noted and hi s l ungs ar e cl ear . Abdom i nal
ex am i nati on r ev eal s the pr esence of di f f use tender ness, but no r ebound or
l ocal i zed tender ness. The bow el sounds ar e hy per acti v e. Ther e i s decr eased
ax i l l ar y hai r . Hi s testes ar e nor m al and centr al ner v ous sy stem f i ndi ngs ar e
unr em ar k abl e.
The f ol l ow i ng l abor ator y data ar e obtai ned: hem ogl obi n (Hgb), 10. 6 g,
nor m ochr om i c nor m ocy ti c anem i a; w hi te bl ood cel l (WBC) count, 6, 600
cel l s/m m 3 ; sodi um , 128 m Eq/L; potassi um , 5. 9 m Eq/L; cr eati ni ne, 2. 0 m g/dL;
bi car bonate (HCO 3 ), 20 m Eq/L; chl or i de, 96 m Eq/L; bl ood ur ea ni tr ogen
(BU N ), 39 m g/dL; and cal ci um , 11. 1 m g/dL.
The chest r adi ogr aphi c study f i ndi ngs ar e nor m al and the abdom i nal
r adi ogr aphi c study show s a nor m al gas patter n, but bi l ater al adr enal
cal ci f i cati on. Hi s el ectr ocar di ogr am (ECG) i s nor m al .
Sev en m onths l ater , the pati ent becom es sev er el y f ati gued and w eak and
com pl ai ns of col d i ntol er ance, dr y sk i n, som nol ence, and consti pati on.
Phy si cal ex am i nati on at that ti m e r ev eal s a pal e pati ent, w i th a supi ne BP of
110/60 m m Hg and supi ne pul se of 64 per m i nute. He w ei ghs 72 k g. Hi s sk i n i s
dr y and w ar m and ex hi bi ts decr eased tur gor . Per i or bi tal f r eck l i ng and v i ti l i go
ar e pr esent, as w el l as m i l d, di f f use thy r om egal y . N eur ol ogi c ex am i nati on
r ev eal s gener al i zed m uscl e w eak ness and decr eased deep tendon r ef l ex es
sy m m etr i cal l y .
Labor ator y data ar e as f ol l ow s: WBC, 6, 900 cel l s/m m 3 w i th nor m al
di f f er enti al ; ser um sodi um , 135 m Eq/L; potassi um , 4. 7 m Eq/L; chl or i de, 99
m Eq/L; HCO 3 , 24. 8 m Eq/L; gl ucose, 78 m g/dL; cr eati ni ne, 1. 0 m g/dL; and
BU N , 18 m g/dL. Thy r oi d f uncti on tests r ev eal the f ol l ow i ng f i ndi ngs: ser um
thy r ox i ne (T 4 ), 3. 2 Âµg/dL (nor m al , 4 to 12 Âµg/dL); tr i i odothy r oni ne (T 3 )
r esi n uptak e, 20% (nor m al , 25% to 35%); and TSH, 16 ÂµU /m L (nor m al ,
0. 55. 0 ÂµU /m L). The test r esul t f or anti m i cr osom al anti bodi es i s posi ti v e, w i th
a v al ue of 1:50, 000.
1. What i s the m ost l i k el y di agnosi s i n thi s pati ent?

2. What w oul d be the f i r st step i n the di agnosti c ev al uati on of thi s pati ent?
3. On the basi s of the f i ndi ngs f r om the i ni ti al di agnosti c ev al uati on, w hat i s
the di agnosi s i n thi s pati ent?
4. What w oul d y ou r ecom m end as an i ni ti al ther apy ?
5. How w oul d y ou tr eat thi s pati ent's hy per cal cem i a?
6. What addi ti onal abnor m al i ti es m ay be seen i n associ ati on w i th Addi son's
di sease?
7. On the basi s of the f i ndi ngs w hen the pati ent i s seen 7 m onths l ater ,
w hat k i nd of thy r oi d di sease does he hav e?
8. What i s the m ost i m por tant adv i ce to gi v e thi s pati ent?
Case Discussion
The m ost l i k el y di agnosi s i n thi s pati ent i s acute adr enal i nsuf f i ci ency
r esul ti ng f r om ei ther pr i m ar y or secondar y adr enal f ai l ur e. Thi s pati ent
i l l ustr ates the
P. 76
nonspeci f i c natur e of sy m ptom s i n the setti ng of chr oni c adr enal
i nsuf f i ci ency , ev en though he ex hi bi ts the cl assi c hi stor y and f i ndi ngs.
Thi s pati ent's hy per pi gm entati on and el ectr ol y te changes suggest pr i m ar y
adr enal f ai l ur e. The hy per k al em i a and hy ponatr em i a ar e due to
m i ner al ocor ti coi d def i ci ency , of ten seen i n the setti ng of pr i m ar y adr enal
f ai l ur e. Because ACTH i s not the pr edom i nant r egul ator of al doster one
secr eti on, el ectr ol y te abnor m al i ti es ar e l ess com m on i n pati ents w i th
secondar y adr enal f ai l ur e.
Adr enal cr i si s occur s w hen a str essf ul si tuati on br i ngs about
decom pensati on. The natur e of the str ess m ay r ange f r om m i l d (e. g. , the
f l u) to sev er e (e. g. , tr aum a or sur ger y ). Adr enal decom pensati on i s
m ar k ed by dehy dr ati on, hy pov ol em i a, pr of ound hy potensi on,
hy ponatr em i a, hy per k al em i a, hy pogl y cem i a, and hy pother m i a. Cl assi c
r enal f ai l ur e can m i m i c sev er al aspects of chr oni c adr enal f ai l ur e,
i ncl udi ng f ati gue, m al ai se, anor ex i a, hy ponatr em i a, and hy per k al em i a. In
thi s pati ent, the BU N and cr eati ni ne abnor m al i ti es ar e m or e i ndi cati v e of
pr er enal azotem i a than of acute r enal f ai l ur e.
Decr eased l i bi do, w hi ch i s com m on i n pati ents w i th hy popi tui tar i sm , can
al so be seen i n pati ents w i th Addi son's di sease and i s due to the
debi l i tati ng natur e of the i l l ness, the associ ated pr i m ar y gonadal f ai l ur e,
and possi bl y the decr eased adr enal andr ogens.
Cal ci f i cati on of the aur i cul ar and costal car ti l age i s uncom m on i n pati ents
w i th Addi son's di sease, but can occur i nci dental l y . A l ack of ax i l l ar y hai r
i s actual l y a m or e com m on f i ndi ng i n f em al e pati ents. The am ount of
pubi c hai r m ay al so be di m i ni shed.
2. What w oul d be the f i r st step i n the di agnosti c ev al uati on of thi s pati ent?
The ACTH sti m ul ati on test shoul d be per f or m ed i ni ti al l y to assess w hether
the adr enal gl ands can r espond to ex ogenous ACTH by i ncr easi ng the
l ev el s of cor ti sol and al doster one. Si m ul taneousl y , the pl asm a ACTH l ev el
shoul d be m easur ed because pati ents w i th Addi son's di sease hav e v er y
l ow cor ti sol l ev el s but el ev ated ACTH l ev el s. It i s cr i ti cal to hav e the
l abor ator y pr ocess the sam pl es cor r ectl y (check w i th y our l abor ator y to
deter m i ne the appr opr i ate pr ocess f or bl ood col l ecti on). Adr enal
autoanti body testi ng i s now av ai l abl e and has a 70% sensi ti v i ty . In
addi ti on, because of the abdom i nal r adi ogr aphi c f i ndi ng of adr enal
cal ci f i cati on, a pur i f i ed pr otei n der i v ati v e (PPD) sk i n test shoul d be
per f or m ed to assess f or tuber cul osi s.
An ACTH sti m ul ati on test r ev eal s a basal cor ti sol l ev el of 2. 8 Âµg/dL,
w hi ch i s then 2. 8 Âµg/dL at 30 m i nutes and 3. 0 Âµg/dL at 60 m i nutes. The
al doster one l ev el i s 2. 5 ng/m L at 0 m i nutes, 2. 5 ng/m L at 30 m i nutes,
and 3. 1 ng/m L at 60 m i nutes (nor m al v al uesâ€”cor ti sol , 9 to 25 Âµg/dL
a. m . f asti ng, and 2 to 16 Âµg/dL p. m . f asti ng; al doster one, nor m al sal t
upr i ght: m en, 6 to 22 ng/dL; w om en, 4 to 31 ng/dL). The pl asm a ACTH
l ev el i s f ound to be 779 pg/m L (nor m al , < 580 pg/m L at 8:00 a. m .
upr i ght; 526 pg/m L at 8:00 a. m . supi ne; and < 517 pg/m L at 4:00 p. m .
supi ne). The PPD test r esul t i s negati v e.
3. On the basi s of the f i ndi ngs f r om the i ni ti al di agnosti c ev al uati on, w hat i s
the di agnosi s i n thi s pati ent?
The r esul ts of the ACTH sti m ul ati on test i n thi s pati ent ar e cl ear l y
abnor m al , show i ng subnor m al r esponses to ACTHâ€”i ndi cati v e of adr enal
f ai l ur e. Thi s i s the
P. 77
cl assi c si tuati on i n pati ents w i th pr i m ar y adr enal f ai l ur e, that i s, the
r esponse of both cor ti sol and al doster one to ACTH i s absent; i n secondar y
adr enal f ai l ur e, the al doster one r esponse i s pr eser v ed.
The pl asm a ACTH l ev el i s m ar k edl y el ev ated i n thi s pati ent, and such
ex tr em e el ev ati ons m ay be seen i n the contex t of sev er e str ess, such as
that caused by sur ger y , anesthesi a, and hy pogl y cem i a. Cal ci f i cati on of
the adr enal gl ands can occur i n the setti ng of tuber cul osi s,
hi stopl asm osi s, and occasi onal l y i n autoi m m une adr enal di sease.
Ther ef or e, the cause of thi s pati ent's adr enal gl and f ai l ur e i s pr i m ar y
adr enal f ai l ur e, m ost l i k el y secondar y to the autoi m m une destr ucti on of
the adr enal s. The negati v e PPD r esul t suppor ts a nontuber cul ous eti ol ogy
of the pr i m ar y adr enal f ai l ur e.
4. What w oul d y ou r ecom m end as an i ni ti al ther apy ?
Because the cl i ni cal pr esentati on suggests adr enal cr i si s, ther apy shoul d
be i nsti tuted i m m edi atel y because adr enal cr i si s i s a l i f ethr eateni ng
em er gency and any del ay i n tr eatm ent coul d pr ov e f atal . Such ther apy
i ncl udes the i m m edi ate IV adm i ni str ati on of a sol ubl e cor ti coster oi d
pr epar ati on, such as hy dr ocor ti sone (100 m g), f ol l ow ed by r api d i nf usi ons
of gl ucose and nor m al sal i ne at a r ate of 2 to 4 L per day . For tr ue cr i si s,
l ar ge v ol um es (2 to 3 L) of 0. 9% sal i ne sol uti on or 5% dex tr ose i n 0. 9%
sal i ne shoul d be i nf used i ntr av enousl y as qui ck l y as possi bl e.
The gl ucocor ti coi ds and v ol um e r epl eti on cause the ser um potassi um
l ev el s to decr ease. Def i ni ti v e di agnosti c testi ng shoul d be car r i ed out
af ter the acute ther apy has been i nsti tuted. Mi ner al ocor ti coi d ther apy
shoul d be def er r ed unti l the pati ent can tak e m edi cati on or al l y .
5. How w oul d y ou tr eat thi s pati ent's hy per cal cem i a?
Because thi s pati ent's hy per cal cem i a i s m i l d, no speci al tr eatm ent other
than hy dr ati on w i th nor m al sal i ne i s r equi r ed. Both hy per cal cem i a and
hy pocal cem i a hav e been r epor ted to occur dur i ng an adr enal cr i si s. Thi s
m ay stem f r om dehy dr ati on, but m ay al so be a consequence of the
i ncr eased absor pti on of cal ci um f r om the gut, due to gl ucocor ti coi d
def i ci ency . Occasi onal l y , m i l d hy per cal cem i a and hy per par athy r oi di sm
m ay coex i st w i th adr enal f ai l ur e caused by a pi tui tar y tum or that
com pr om i ses the f uncti on of cor ti cotr ophs [m ul ti pl e endocr i ne neopl asi a
ty pe 1 (MEN 1)]. Hy pocal cem i a m ay occur i n pati ents w hose
hy poadr enal i sm i s a par t of the autoi m m une pol y gl andul ar sy ndr om e ty pe
I (pol y gl andul ar f ai l ur e).
6. What addi ti onal abnor m al i ti es m ay be seen i n associ ati on w i th Addi son's
di sease?
Other abnor m al i ti es that m ay ar i se i n pati ents w i th Addi son's di sease
i ncl ude hy pogl y cem i a, hy per k al em i a, hi gh ADH l ev el s, m etabol i c aci dosi s,
v i ti l i go, and hi gh l ev el s of anti thy r oi d anti bodi es. Al l of these can be a
f r equent com ponent of the cl i ni cal pi ctur e i n pati ents w i th adr enal
i nsuf f i ci ency .
7. On the basi s of the f i ndi ngs w hen the pati ent i s seen 7 m onths l ater , w hat
k i nd of thy r oi d di sease does he hav e?
The f i ndi ngs ar e consi stent w i th those of Hashi m oto's thy r oi di ti s. Pati ents
w i th i di opathi c Addi son's di sease ar e pr one to other autoi m m une
di sor der s, w hi ch m ay dev el op bef or e or af ter adr enal f ai l ur e i s
di agnosed. These di sor der s i ncl ude Gr av es' hy per thy r oi di sm , Hashi m oto's
thy r oi di ti s, per ni ci ous anem i a, di abetes, hy popar athy r oi di sm , pr i m ar y
hy pogonadi sm , v i ti l i go, and m oni l i asi s. Ar eas of v i ti l i go
P. 78
f or m i n 4% to 6% of the pati ents w i th Addi son's di sease, especi al l y i n
those w hose di sease has an autoi m m une cause.
In thi s m an w ho has a goi ter , l ow T 4 and hi gh TSH l ev el s, and str ongl y
posi ti v e anti thy r oi d anti body ti ter s, l ev othy r ox i ne ther apy shoul d be
star ted, but onl y w hen adequate ster oi d r epl acem ent has been achi ev ed
and af ter the pati ent has been on ster oi d r epl acem ent ther apy f or at l east
2 w eek s. An adr enal cr i si s coul d be pr eci pi tated i f l ev othy r ox i ne i s gi v en
to a pati ent w ho i s i n a hy poadr enal state because of the r esul ti ng
i ncr eased m etabol i c dem ands that l ev othy r ox i ne i m poses on the body .
8. What i s the m ost i m por tant adv i ce to gi v e thi s pati ent?
In any pati ent w i th adr enal i nsuf f i ci ency , i t i s cr i ti cal to em phasi ze the
need f or i ncr easi ng the dosage of gl ucocor ti coi ds dur i ng per i ods of str ess
or i l l ness, such as col ds, f l u, di ar r hea, i nf ecti ons, tr aum a, or sur ger y .
Fai l ur e to do so m i ght pr eci pi tate the r api d dev el opm ent of an acute
adr enal cr i si s. In addi ti on, the pati ent m ust be i nstr ucted to w ear an
i denti f i cati on br acel et or car r y a car d at al l ti m es i ndi cati ng that he has
the di sease and needs suppl em ental ster oi ds dur i ng str ess. Thi s i s a
cr uci al l i f epr eser v i ng m easur e and cannot be ov er em phasi zed.
Suggested Readings
Annane D, Sebi l l e V, Char penti er C, et al . Ef f ect of tr eatm ent w i th l ow
doses of hy dr ocor ti sone and f l udr ocor ti sone on m or tal i ty i n pati ents w i th
septi c shock . JAMA 2002;288(7):862â€“871.
Ar af ah BM. Medi cal m anagem ent of hy popi tui tar i sm i n pati ents w i th
pi tui tar y adenom as. Pi tui tar y 2002;5:109â€“117.
Knapp PE, Ar um SM, Mel by JC. Rel ati v e adr enal i nsuf f i ci ency i n cr i ti cal
i l l ness: a r ev i ew of the ev i dence. Cur r Opi n Endocr i nol Di abetes
2004;11:147â€“152.
Li ndsay JR, N i em an LK. The hy pothal am i cpi tui tar y adr enal ax i s i n
pr egnancy : chal l enges i n di sease detecti on and tr eatm ent. Endocr Rev
2005;26:775â€“799.
N i em an LK. Dy nam i c ev al uati on of adr enal hy pof uncti on. J Endocr i nol
Inv est 2003;26(7 Suppl ):74â€“82.
Schr i er RW. Cur r ent m edi cal ther apy , 2nd ed. N ew Yor k : Rav en Pr ess,
1989.
Wi l son JD, Foster DW, eds. Wi l l i am s' tex tbook of endocr i nol ogy , 8th ed.
Phi l adel phi a: WB Saunder s, 1992.
Cushing's Syndrome
1. What i s the di f f er ence betw een Cushi ng's sy ndr om e and Cushi ng's
di sease?
2. What i s the m ost com m on cause of Cushi ng's sy ndr om e?
3. What ar e the cl i ni cal f eatur es of Cushi ng's sy ndr om e?
4. What ar e the bi ol ogi c ef f ects of gl ucocor ti coi ds?
5. What ar e the scr eeni ng tests used to di agnose Cushi ng's sy ndr om e?
P. 79
Discussion
1. What i s the di f f er ence betw een Cushi ng's sy ndr om e and Cushi ng's
di sease?
Cushi ng's sy ndr om e r ef er s to the phenoty pi c and cl i ni cal sequel ae due to
hy per cor ti sol i sm r esul ti ng f r om any cause. Cushi ng's di sease r ef er s
speci f i cal l y to the hy per cor ti sol i sm due to an ACTHsecr eti ng pi tui tar y
cor ti cotr oph adenom a or pi tui tar y cor ti cotr oph hy per pl asi a.
2. What i s the m ost com m on cause of Cushi ng's sy ndr om e?
The w i despr ead use of potent cor ti coster oi ds i n the pr acti ce of cl i ni cal
m edi ci ne, par ti cul ar l y i n the tr eatm ent of autoi m m une, al l er gi c, and
pul m onar y di sor der s, has m ade i atr ogeni c hy per cor ti sol i sm the m ost
com m on cause of Cushi ng's sy ndr om e. How ev er , once the i atr ogeni c
causes ar e el i m i nated, pi tui tar y adenom a (68%) becom es the m ost
com m on cause.
3. What ar e the cl i ni cal f eatur es of Cushi ng's sy ndr om e?
Cushi ng's sy ndr om e i s associ ated w i th m any cl i ni cal f eatur es. Obe s ity,
f ound i n 94%, i s the m ost com m on m ani f estati on and w ei ght gai n i s
usual l y the ear l i est sy m ptom of Cushi ng's sy ndr om e. The obesi ty tends to
be centr al , but f at can al so be r edi str i buted to the f ace (m oon f aci es;
75%), as w el l as supr acl av i cul ar (80%) and dor socer v i cal ar eas (â
€œbuf f al o hum pâ€ ; 80%). The l atter tw o ar eas, par ti cul ar l y the
supr acl av i cul ar f at pad, ar e m or e speci f i c f i ndi ngs f or Cushi ng's
sy ndr om e.
Sk in c ha nge s occur i n 85% of the pati ents and ar i se because cor ti sol
i nduced atr ophy of the epi der m i s l eads to thi nni ng and a tr anspar ent
appear ance of the sk i n, f aci al pl ethor a, easy br ui sabi l i ty , and the
f or m ati on of str i ae. The l atter ar e pur pl i sh r ed ar eas that ar e depr essed
bel ow the sk i n sur f ace, but ar e w i der than the pi nk i sh w hi te str i ae that
appear af ter pr egnancy or w ei ght l oss. Wounds heal sl ow l y i n these
pati ents and m ay dehi sce. Hy per pi gm entati on occur s i n the setti ng of the
ectopi c ACTH sy ndr om e, but i s r ar e i n pati ents w i th Cushi ng's di sease and
shoul d not be f ound i n those w i th pr i m ar y adr enal Cushi ng's sy ndr om e.
Acne (40%) i s al so a sy m ptom and i s due to andr ogen ex cess; i t m ay be
m or e gener al i zed than w hat the pati ent ex per i enced bef or e.
Hirs utis m af f ects 80% of the pati ents and ty pi cal l y consi sts of a
dar k eni ng and coar seni ng of the hai r . Fem al e pati ents com pl ai n of
i ncr eased gr ow th of hai r ov er the f ace, upper thi ghs, abdom en, and
br easts. Vi r i l i sm occur s i n appr ox i m atel y 20% of the cases of adr enal
car ci nom a. Hype rte ns ion i s a pr obl em i n 75% of the pati ents. El ev ated
di astol i c BP i s a cl assi c f eatur e of spontaneous Cushi ng's sy ndr om e, and
i t contr i butes gr eatl y to the m or bi di ty and m or tal i ty associ ated w i th the
di sor der . The i ncr eased sodi um r etenti on al so l eads to edem a (18%).
Congesti v e hear t f ai l ur e (22%) can be aggr av ated because of the
i ncr eased BP and f l ui d l oad.
G ona da l dys func tion occur s i n 75% of the pati ents. El ev ated andr ogen
l ev el s can r esul t i n am enor r hea and i nf er ti l i ty i n 75% of af f ected
pr em enopausal w om en. In m en, the el ev ated cor ti sol l ev el m ay cause a
decr ease i n l i bi do.
P. 80
Mus c le w e a k ne s s ar i ses i n 60% of pati ents, i n par ti cul ar pr ox i m al
w eak ness that m ost of ten occur s i n the l ow er ex tr em i ti es. Thi s w eak ness
stem s f r om the catabol i c ef f ects of gl ucocor ti coi ds on m uscl e ti ssues,
ster oi di nduced m y opathy , and possi bl y el ectr ol y te i m bal ances. Weak ness
can be assessed cl i ni cal l y by ask i ng the pati ent to stand f r om the chai r
w i thout assi stance of ar m s. Radi ogr aphi cal l y detectabl e os te oporos is i s
pr esent i n m ost pati ents w i th Cushi ng's sy ndr om e (60%), and back pai n i s
the i ni ti al com pl ai nt i n 58% of the cases. Pathol ogi c f r actur es ar e f ound
i n the r i bs and v er tebr ae i n sev er e cases. It tak es som e ti m e f or the
hy per cor ti sol i sm to decal ci f y bone; ther ef or e, Cushi ng's sy ndr om e due to
adr enal car ci nom a and som e ectopi c ACTH cases i s not pr esent l ong
enough to cause osteopor osi s.
P s yc hologic a l dis turba nc e s can ar i se i n 40% of pati ents. These

com pl ai nts r ange f r om m i l d sy m ptom s, such as em oti onal l abi l i ty ,
i ncr eased i r r i tabi l i ty , anx i ety , i nsom ni a, euphor i a, poor concentr ati on,
poor m em or y , and m i l d depr essi on, to sev er e sy m ptom s, w hi ch i ncl ude
f r ank psy chosi s associ ated w i th del usi ons or hal l uci nati ons, par anoi a,
sev er e depr essi on, and ev en sui ci dal behav i or .
Re na l c a lc uli f or m i n 15% of pati ents as a r esul t of gl ucocor ti coi d

i nduced hy per cal cem i a. Renal col i c m ay be the pr esenti ng sy m ptom of
Cushi ng's sy ndr om e. Thirs t and polyuria ar e seen i n 10% of pati ents.
The thi r st i s due to gl ucocor ti coi di nduced hy per gl y cem i a [or w or seni ng
of ex i sti ng di abetes m el l i tus (DM)] that causes an osm oti c (gl ucose)
di ur esi s. Di abeti c k etoaci dosi s (DKA) and di abeti c m i cr ov ascul ar
com pl i cati ons ar e r ar e i n the di abetes seen w i th Cushi ng's sy ndr om e.
4. What ar e the bi ol ogi c ef f ects of gl ucocor ti coi ds?
Fr om a mole c ula r per specti v e, gl ucocor ti coi d hor m ones enter the cel l by
di f f usi on and acti v ate speci f i c gene tr anscr i pti on by bi ndi ng to the
nucl ear gl ucocor ti coi d r eceptor . The gl ucocor ti coi d r eceptor i s ther ef or e a
condi ti onal tr ansacti v ator that i nf l uences the r ate of RN A pol y m er ase II
tr anscr i pti on i ni ti ati on by bi ndi ng to speci f i c shor t DN A sequence
el em ents (gl ucocor ti coi d r esponse el em ents) i n the pr om oter r egul ator y
r egi on of the v ar i ous tar get genes. Al though thi s i s the bestestabl i shed
pathw ay of gl ucocor ti coi d acti on, other m echani sm s that m edi ate the
r api d ef f ects of gl ucocor ti coi ds, such as the f astf eedback i nhi bi ti on of
ACTH secr eti on and possi bl y m odul ati on of the Î³am i nobuty r i c aci d
r eceptor , m ust al so ex i st.
In ter m s of thei r ef f ects on me ta bolis m, gl ucocor ti coi ds accel er ate
hepati c gl uconeogenesi s by sti m ul ati ng phosphoenol py r uv ate
car box y k i nase and gl ucose6phosphatase acti v i ty , and i nduce a
per m i ssi v e ef f ect i n other gl uconeogeni c hor m ones (gl ucagon and
catechol am i nes). Gl ucocor ti coi ds al so enhance hepati c gl y cogen sy nthesi s
and stor age and i nhi bi t gl y cogen br eak dow n. In m uscl es, gl ucocor ti coi ds
i nhi bi t am i no aci d uptak e and pr otei n sy nthesi s and sti m ul ate pr otei n
br eak dow n as w el l as the r el ease of am i no aci ds, l actate, f r ee f atty aci ds
(FFAs), and gl y cer ol . In adi pose ti ssue, gl ucocor ti coi ds pr i m ar i l y
accel er ate l i pol y si s, w i th a r esul tant r el ease i n the f or m ati on of gl y cer ol
and FFAs. Al though gl ucocor ti coi ds ar e l i pol y ti c, an i ncr eased centr al f at
deposi ti on i s a
P. 81
cl assi c f eatur e of Cushi ng's sy ndr om e. The ster oi di nduced i ncr ease i n
appeti te and hy per i nsul i nem i a m ay account f or thi s, but the basi s f or thi s
abnor m al f at deposi ti on i n the setti ng of hy per cor ti sol i sm r em ai ns
unk now n.
5. What ar e the scr eeni ng tests used to di agnose Cushi ng's sy ndr om e?
A k ey aspect of the i ni ti al w or k up i n a pati ent w i th suspected Cushi ng's

sy ndr om e i s to di sti ngui sh tr ue hy per cor ti sol i sm f r om obesi ty ,
depr essi on, or al cohol i sm , or a com bi nati on of these, because m any
cl i ni cal and l abor ator y f eatur es of these di sor der s di spl ay si gni f i cant
ov er l ap. A k ey ai d i n establ i shi ng the cl i ni cal di agnosi s of
hy per cor ti sol i sm i s ex am i ni ng the pati ent's sequenti al photogr aphs that
span sev er al y ear s. Once Cushi ng's sy ndr om e i s suspected on cl i ni cal
gr ounds, the ov er ni ght 1m g dex am ethasone suppr essi on test (DST) and
the 24hour ur i nar y f r ee cor ti sol (U FC) deter m i nati on ar e used as
scr eeni ng tests. If the r esul ts of the ov er ni ght 1m g DST ar e nor m al (8
a. m . pl asm a cor ti sol < 2 Âµg/dL af ter the adm i ni str ati on of 1 m g of
dex am ethasone at 11 p. m . the ni ght bef or e), the di agnosi s i s v er y
unl i k el y . If the r esul ts of the U FC test ar e al so nor m al (i . e. , < 90 to 100
Âµg per day ), Cushi ng's sy ndr om e i s ef f ecti v el y ex cl uded. A thi r d,
r ecentl y av ai l abl e, but not y et w i del y accepted scr eeni ng test i s the l ate
ni ght sal i v ar y cor ti sol . Thi s test tak es adv antage of the l oss of nor m al
ci r cadi an v ar i ati on i n cor ti sol l ev el i n Cushi ng's di sease by m easur i ng
cor ti sol at a ti m e w hen i t i s nor m al l y v i r tual l y absent. Sev er al si tuati ons
can cause f al seposi ti v e r esul ts f or the scr eeni ng DST, i ncl udi ng acute
and chr oni c i l l ness, obesi ty , hi ghestr ogen states, cer tai n dr ugs
(pheny toi n and phenobar bi tal ), al cohol i sm , anor ex i a, r enal f ai l ur e, and
depr essi on. How ev er , i n the setti ng of obesi ty , hi ghestr ogen states, and
cer tai n dr ugs, the r esul ts of a 24hour U FC ar e nor m al . In the other
si tuati ons, r epeated testi ng i s necessar y to ex cl ude the di agnosi s. Rar el y
f al senegati v e r esul ts can occur , such as i n the ev ent of pr ol onged
dex am ethasone cl ear ance or epi sodi c hy per cor ti sol i sm .
Case
A 36y ear ol d w hi te w om an com es to y ou com pl ai ni ng of f ati gue, i r r i tabi l i ty ,
depr essi on, and a 30l b (13. 5k g) w ei ght gai n ov er the l ast 2 y ear s. She
r ecounts that she has noti ced a si gni f i cant change i n her ener gy l ev el f or at
l east the l ast 2 y ear s. She states that she has al w ay s been a har d w or k er but
6 m onths bef or e she had to qui t her job as a w ai tr ess because of ex tr em e
m uscl e w eak ness and f ati gue. She has al so noted i ncr eased m ood sw i ngs,
m ani f ested by i ncr eased i r r i tabi l i ty , spontaneous cr y i ng epi sodes, and
depr essi on. She r epor ts that her f ace seem s r ounder than i t w as 2 y ear s
bef or e. On f ur ther questi oni ng, she adm i ts that her m enstr ual per i ods hav e
been i r r egul ar f or the l ast 2 y ear s. She al so adm i ts to dr i nk i ng â€œa si x pack
of beer â€ at l east once a w eek , but deni es sm ok i ng. She has al so noted that
she br ui ses easi l y . She deni es any other m edi cal pr obl em s, and states that
she i s not tak i ng any m edi cati ons. She speci f i cal l y deni es any gl ucocor ti coi d
ther apy . On ask i ng about her f am i l y hi stor y , y ou f i nd out that her m other has
adul tonset DM.
Phy si cal ex am i nati on r ev eal s an obese w hi te w om an w ho i s cr y i ng w hi l e she
si ts on the ex am i ni ng tabl e, but other w i se she does not appear to be v er y i l l .
Her w ei ght i s 193 l b (87 k g); hei ght, 5 f t 7 i n. (167. 5 cm ); BP, 165/100 m m
Hg; and hear t r ate, 86 per m i nute and r egul ar .
P. 82
Her f ace i s v er y r ound and pl ethor i c com par ed w i th that i n ol d photogr aphs.
Dor socer v i cal (buf f al o hum p) and supr acl av i cul ar f at pads ar e noted. She has
m i l d f aci al hi r suti sm , som e acne i s noted ov er the f ace and chest, and w i de
pur pl e str i ae ar e pr esent on the l ow er abdom en. Her ex tr em i ti es ar e thi n and
she has pr ox i m al m uscl e w eak ness.
The f ol l ow i ng ar e the l abor ator y f i ndi ngs: f asti ng bl ood gl ucose, 180 m g/dL;
potassi um , 3 m Eq/L; HCO 3 , 34 m Eq/L; l i v er f uncti on tests, al l nor m al ; 8 a. m .
cor ti sol , 38 Âµg/dL, w hi ch decr eases to 32 Âµg/dL af ter the adm i ni str ati on of 1
m g of dex am ethasone. The 24hour U FC l ev el i s 876 Âµg.

2. What studi es w oul d y ou per f or m to establ i sh the anatom i c cause of her
hy per cor ti sol i sm ?
3. What i s the r ol e of m agneti c r esonance i m agi ng (MRI) and com puted
tom ogr aphi c (CT) scanni ng of the pi tui tar y and adr enal gl ands, as w el l as
i nf er i or petr osal si nus sam pl i ng, i n pati ents w i th Cushi ng's sy ndr om e?
4. What i s the opti m al ther apeuti c appr oach f or thi s pati ent?
5. Why i s ther e a need f or ster oi d ther apy i n the postoper ati v e per i od, and
som eti m es bey ond, i n pati ents w i th Cushi ng's di sease?
Case Discussion
Hav i ng ex cl uded ex ogenous gl ucocor ti coi d m edi cati ons i n the hi stor y , the
di f f er enti al di agnosi s l i st w oul d i ncl ude (a) pi tui tar y cor ti cotr oph
adenom a or hy per pl asi a (Cushi ng's di sease), (b) ectopi c ACTH or
cor ti cotr opi nr el easi ng f actor (CRF) sy ndr om e, (c) adr enal adenom a, (d)
adr enal cancer , (e) obesi ty , (f ) depr essi on, and (g) al cohol i sm .
The m ost f r equentl y encounter ed di l em m a i n the di f f er enti al di agnosi s of

Cushi ng's sy ndr om e i s the cl i ni cal pi ctur e consi sti ng of an obese,
depr essed pati ent w ho consum es ex cessi v e am ounts of al cohol . These
pati ents can di spl ay m any of the phenoty pi c f eatur es and l abor ator y
f i ndi ngs consi stent w i th hy per cor ti sol i sm , and y et not hav e Cushi ng's
sy ndr om e. Ther ef or e, the pati ent's hi stor y of consum i ng a si x pack of
beer per w eek i s of concer n because thi s coul d pr oduce al cohol i c pseudo
Cushi ng's sy ndr om e. In thi s di sor der , the ef f ects of chr oni c al cohol i sm
r esul t i n centr al obesi ty (asci tes), a r ound pl ethor i c f ace, easy br ui si ng,
and som e abnor m al r esul ts f r om the scr eeni ng tests f or Cushi ng's
sy ndr om e. How ev er , thi s pati ent has no abnor m al l i v er f uncti on f i ndi ngs
and she has phy si cal f i ndi ngs (a m ar k ed change i n her f aci al appear ance
com par ed w i th that i n ol d photogr aphs, hy per tensi on, dor socer v i cal and
supr acl av i cul ar f at pads, pur pl e abdom i nal str i ae, acne, and hi r suti sm )
and l abor ator y data (hy per gl y cem i a, hy pok al em i a, an el ev ated basal
cor ti sol l ev el that does not suppr ess i n r esponse to the 1m g DST, and an
el ev ated 24hour U FC) that ar e al l hi ghl y consi stent w i th the cl i ni cal
suspi ci on of hy per cor ti sol i sm .
The l ack of v i r i l i zati on and the r el ati v el y sl ow (> 2 y ear s) onset of the
cl i ni cal sy m ptom s ar gue agai nst adr enal car ci nom a. In addi ti on, the l ack
of a sm ok i ng hi stor y and any hy per pi gm entati on, together w i th the sl ow
onset, suggest that
P. 83
ectopi c ACTH ar i si ng f r om sm al l cel l l ung car ci nom a i s unl i k el y to be the
cause. Thi s l eav es pi tui tar y adenom a (or hy per pl asi a), ectopi c ACTH or
CRF (f r om a car ci noi d, pancr eati c i sl et cel l tum or , m edul l ar y thy r oi d
car ci nom a, or pheochr om ocy tom a), and adr enal adenom a i n the
di f f er enti al di agnosi s. Gi v en that pi tui tar y adenom as consti tute 68% of al l
noni atr ogeni c causes of hy per cor ti sol i sm , thi s i s the m ost l i k el y
di agnosi s. How ev er , f ur ther w or k up i s r equi r ed to docum ent the pr eci se
sour ce of the el ev ated cor ti sol l ev el s i n thi s pati ent.
2. What studi es w oul d y ou per f or m to establ i sh the anatom i c cause of her
hy per cor ti sol i sm ?
Once the di agnosi s of hy per cor ti sol i sm (Cushi ng's sy ndr om e) has been
conf i r m ed by the f i ndi ngs of the cl i ni cal ev al uati on and scr eeni ng
l abor ator y tests, the com bi ned use of the f ol l ow i ng di agnosti c techni ques
can establ i sh the di agnosi s i n al m ost al l i nstances: deter m i nati on of a
basal pl asm a ACTH l ev el , a hi ghdose (8 m g) DST, r adi ogr aphi c i m agi ng,
and i nf er i or petr osal sam pl i ng (w i th or w i thout CRF sti m ul ati on). By
si m ul taneousl y m easur i ng the pl asm a cor ti sol and ACTH l ev el s the
possi bi l i ty of an adr enal adenom a can be assessed because the
autonom ous pr oducti on of gl ucocor ti coi ds by the adr enal adenom a
suppr esses ACTH to l ev el s bel ow 20 pg/m L. To di f f er enti ate betw een a
pi tui tar y adenom a and the ectopi c tum or pr oducti on of ACTH, sev er al
tests need to be per f or m ed because m any of the l abor ator y and
r adi ogr aphi c r esul ts can ov er l ap f or these tw o di sti nct causes of Cushi ng's
sy ndr om e. For ex am pl e, the ACTH l ev el can r ange betw een 40 and 200
pg/m L i n the setti ng of Cushi ng's di sease and betw een 100 and 10, 000
pg/m L i n the setti ng of ectopi c ACTH. In the cl assi c 2day hi ghdose DST
(2 m g of dex am ethasone i s gi v en ev er y 6 hour s f or 2 day s, and 24hour
U FC sam pl es ar e col l ected the day bef or e and on the second day of
dex am ethasone adm i ni str ati on), pati ents w i th pi tui tar y tum or s (Cushi ng's
di sease) ty pi cal l y ex hi bi t a suppr essi on to l ess than 50% of basel i ne
v al ues; those w i th ectopi c ACTH or pr i m ar y adr enal hy per cor ti sol i sm
di spl ay l i ttl e or no r educti on. How ev er , som e car ci noi d tum or s that
pr oduce ACTH ectopi cal l y m ai ntai n som e degr ee of negati v e f eedback
thr ough the i nf l uence of ex ogenous ster oi ds, and the suppr essi on
obser v ed m ay be equi v al ent to that seen i n pati ents w i th pi tui tar y
tum or s.
The abbr ev i ated hi ghdose DST i nv ol v es adm i ni ster i ng 8 m g of

dex am ethasone at 11 p. m . the ni ght bef or e and m easur i ng the pl asm a
cor ti sol l ev el the nex t m or ni ng at 8 a. m . In thi s test, a suppr essi on bel ow
50% of basal pl asm a cor ti sol l ev el s i s seen i n pati ents w i th pi tui tar y
tum or , but not i n those w i th ectopi c ACTH and pr i m ar y adr enal
cor ti sol i sm . Thi s v er si on of the hi ghdose DST i s pr ef er r ed because i t
appear s to be m or e speci f i c and does not r equi r e tw o 24hour ur i ne
col l ecti ons. For a m or e pr eci se def i ni ti on of the cause of the di sor der ,
how ev er , speci f i c r adi ogr aphi c pr ocedur es m ust be per f or m ed.
3. What i s the r ol e of MRI and CT scanni ng of the pi tui tar y and adr enal
gl ands, as w el l as i nf er i or petr osal si nus sam pl i ng, i n pati ents w i th
Cushi ng's sy ndr om e?
The m ajor pr obl em w i th the CT and MRI ev al uati on of the pi tui tar y and
adr enal gl ands i s that they can detect asy m ptom ati c l esi ons i n up to 15%
and 8%, r especti v el y , of the nor m al popul ati on. Because of thi s i nci dence
of nonspeci f i c r adi ogr aphi c â€œl esi onsâ€ , the cl i ni ci an m ust be cauti ous
about basi ng the di agnosi s of pi tui tar y or adr enal Cushi ng's sy ndr om e on
the r esul ts of these i m agi ng studi es.
P. 84
P ituita ry a de noma s causi ng Cushi ng's di sease tend to be sm al l (1 to 5
m m ; r ar el y > 10 m m ), and ar e ther ef or e detectabl e by contr astenhanced
CT scanni ng i n as f ew as 30% to 35% of cases and by gadol i ni um â
€“DTPAenhanced MRI i n 55% of cases. Ther ef or e, because of i ts better
sensi ti v i ty , MRI has r epl aced CT i n the assessm ent of these tum or s.
Pati ents w hose i m agi ng studi es y i el d negati v e f i ndi ngs need to under go
i nf er i or petr osal sam pl i ng to f ur ther docum ent the pi tui tar y anatom i c
l ocati on of the tum or . In addi ti on, as al r eady di scussed, ev en i f an
abnor m al i ty i s detected by these i m agi ng m ethods, thi s does not
consti tute unequi v ocal ev i dence that the abnor m al i ty i s r esponsi bl e f or
the sy ndr om e. As the r esol uti on of CT and MRI i m pr ov es, the abi l i ty to
detect these â€œi nci dental â€ and cl i ni cal l y si l ent m i cr oadenom as w i l l
al so i ncr ease and f ur ther conf ound the di agnosti c w or k up. An ectopi c CRF
sy ndr om e coul d al so r esul t i n an enl ar ged pi tui tar y due to cor ti cotr oph
hy per pl asi a, and y et the pr i m ar y di sor der m ay actual l y be a car ci noi d of
the l ung.
CT, MRI, ul tr asonogr aphy , and i sotope scanni ng w i th i odochol ester ol can
be used to def i ne the natur e of a dre na l le s ions . These pr ocedur es ar e
not necessar y i n pati ents w i th ACTH hy per secr eti on, how ev er .
N ev er thel ess, som e phy si ci ans use these tests to ex cl ude the pr esence of
a sol i tar y adr enal adenom a or car ci nom a, and ther eby conf i r m the
pr esence of bi l ater al adr enal hy per pl asi a or nodul ar adr enal hy per pl asi a
i n the setti ng of pi tui tar y based di sease. These pr ocedur es ar e m ost
usef ul f or l ocal i zi ng adr enal tum or s because these tum or s m ust usual l y
be l ar ger than 1. 5 cm to cause si gni f i cant cor ti sol pr oducti on and r esul t
i n Cushi ng's sy ndr om e. How ev er , as noted pr ev i ousl y , because of the 1%
to 8% i nci dence of si l ent adr enal nodul es bi ochem i cal testi ng m ust be
per f or m ed w i th l ocal i zati on studi es to ensur e that the l esi on i denti f i ed i s
bi ol ogi cal l y si gni f i cant.
To di sti ngui sh betw een the v ar i ous causes of Cushi ng's sy ndr om e w hen
conf l i cti ng or ov er l appi ng data ar e obtai ned, bi l ater al si m ul taneous
infe rior pe tros a l ve nous s a mpling (w i th or w i thout CRF sti m ul ati on) can
successf ul l y di sti ngui sh Cushi ng's di sease f r om ectopi c ACTH secr eti on
and adr enal di sease w i th gr eater accur acy than any other test. Because
ACTH i s r api dl y m etabol i zed (hal f l i f e, 7 to 12 m i nutes) and i s secr eted
epi sodi cal l y , adv antage can be tak en of the concentr ati on gr adi ent
betw een the pi tui tar y v enous dr ai nage thr ough the i nf er i or petr osal si nus
(centr al ) and the per i pher al v enous v al ues of ACTH to f ur ther deter m i ne
w hether an ACTHpr oduci ng cor ti cotr oph adenom a i s pr esent i n the
pi tui tar y ; the i ncl usi on of CRF sti m ul ati on m ak es the test m or e sensi ti v e.
Bi l ater al and si m ul taneous i nf er i or petr osal si nus sam pl es ar e obtai ned to
ci r cum v ent the pr obl em of i sol ated secr etor y bur sts or ti m i ng i ssues i f
catheter s hav e to be r eposi ti oned. Ther ef or e, ACTH sam pl es ar e obtai ned
f r om the i nf er i or petr osal si nus, f r om the jugul ar bul b, and f r om other
si tes (e. g. , super i or or i nf er i or v ena cav a), and the f i ndi ngs ar e
com par ed w i th those f r om si m ul taneousl y obtai ned per i pher al v ei n
sam pl es. In pati ents w i th Cushi ng's di sease, the i nf er i or petr osal
si nus/per i pher al (IPS : P) r ati o of ACTH ex ceeds 2. In pati ents w i th
ectopi c ACTH, the r ati o i s l ess than 2 and sel ecti v e v enous sam pl i ng
(e. g. , of the pul m onar y , pancr eati c, or i ntesti nal beds) m ay l ocal i ze the
ectopi c tum or . The adm i ni str ati on of CRF dur i ng bi l ater al i nf er i or petr osal
si nus sam pl i ng can i ncr ease the di agnosti c accur acy of the test by
el i ci ti ng
P. 85
an ACTH r esponse i n the f ew pati ents w i th pi tui tar y tum or s w ho do not
ex hi bi t a di agnosti c IPS : P gr adi ent i n the basal sam pl es. Most pati ents
w i th Cushi ng's di sease hav e an IPS : P r ati o gr eater than 3 af ter CRF
sti m ul ati on, w her eas pati ents w i th ectopi c ACTH or adr enal di sease hav e
an IPS : P r ati o of ACTH l ess than 3 af ter CRF sti m ul ati on. Inf er i or
petr osal si nus sam pl i ng (w i th or w i thout CRF sti m ul ati on) has not been
ex tensi v el y studi ed i n the contex t of heal thy peopl e, how ev er , and
ther ef or e the cor r ect i nter pr etati on of the r esul ts r equi r es that the
pati ent m ust be hy per cor ti sol em i c at the ti m e of the study so that the
r esponse of nor m al cor ti cotr ophs to CRF i s suppr essed.
4. What i s the opti m al ther apeuti c appr oach f or thi s pati ent, and w hy ?
Once the tum or has been l ocal i zed to the pi tui tar y , the nex t goal i s to
sur gi cal l y r em ov e the cor ti cotr oph adenom a usi ng the techni que of
sel ecti v e tr anssphenoi dal sur ger y . Because the tum or s ar e sm al l , i t
r equi r es an ex per i enced neur osur geon to successf ul l y i denti f y and r esect
the adenom a. Meti cul ous ex pl or ati on of the i ntr asel l ar contents i s
m andator y , and any i denti f i ed adenom a i s sel ecti v el y r em ov ed, l eav i ng
the r em ai ni ng nor m al pi tui tar y i ntact. If the tum or cannot be i denti f i ed, i t
i s necessar y to per f or m l ar ger pi tui tar y r esecti ons and, i n som e cases, a
total hy pophy sectom y m ay be necessar y . Tr anssphenoi dal sur ger y i s
successf ul i n appr ox i m atel y 85% of pati ents w i th m i cr oadenom as (tum or
< 10 m m ), and sur gi cal dam age to the nor m al anter i or pi tui tar y i s r ar e.
The m ajor si de ef f ects of the pr ocedur e i ncl ude tr ansi ent di abetes
i nsi pi dus, cer ebr ospi nal f l ui d l eak , si nusi ti s, and, r ar el y , postoper ati v e
bl eedi ng. Al l pati ents w i th Cushi ng's di sease w ho ar e successf ul l y tr eated
w i th tr anssphenoi dal sur ger y becom e adr enal l y i nsuf f i ci ent f or v ar i abl e
per i ods of ti m e and m ust r ecei v e r epl acem ent doses of gl ucocor ti coi ds
(see questi on 5 w hi ch f ol l ow s).
The success r ates f or tr anssphenoi dal sur ger y dr op dr asti cal l y (15% to
25%) i n the setti ng of l ar ge (> 10 m m ) tum or s, l ocal l y i nv asi v e tum or s,
tum or s not i denti f i ed at sur ger y , and cor ti cotr oph hy per pl asi a. In these
i nstances, adjuncti v e r adi ati on ther apy i s usual l y adm i ni ster ed. How ev er ,
the m ajor pr obl em w i th r adi ati on ther apy i s the l ag ti m e (6 to 12 m onths)
f or i t to tak e ef f ect and the 10% to 20% i nci dence of hy popi tui tar i sm and
v i sual f i el d def i ci ts, ev en bl i ndness, that m ay ev entuate. A new er opti on
i s the m or e pr eci se ster eotacti c r adi osur ger y usi ng the gam m a k ni f e or
photon k ni f e. Ri sk of v i sual com pl i cati ons i s l ar gel y el i m i nated, and the
r i sk of pi tui tar y def i ci ency i s r educed.
5. Why i s ther e a need f or ster oi d ther apy i n the postoper ati v e per i od and
bey ond, i n pati ents w i th Cushi ng's di sease?
The successf ul sur gi cal r em ov al of the ACTHpr oduci ng pi tui tar y
m i cr oadenom a el i m i nates the dr i v e f or adr enal gl ucocor ti coi d pr oducti on
and r ender s the pati ent dependent on the r em ai ni ng nor m al cor ti cotr ophs.
How ev er , because these cel l s hav e been suppr essed f or y ear s by the
ex cess cor ti sol they ar e dor m ant. Ther ef or e, those pati ents w i th
Cushi ng's di sease w ho hav e been successf ul l y tr eated ex per i ence
tr ansi ent (1 to 18 m onths) adr enocor ti cal i nsuf f i ci ency and r equi r e
ex ogenous gl ucocor ti coi d suppor t; i n those pati ents not cur ed by the
sur gi cal pr ocedur e, the pr oducti on of ex cessi v e am ounts of
gl ucocor ti coi ds conti nues and they do not depend on an ex ogenous sour ce
of ster oi ds.
P. 86
Suggested Readings
Fel i g P, Bax ter JD, Br oadus AE, et al . eds. Di seases of the anter i or
pi tui tar y . In: Endocr i nol ogy and m etabol i sm , 2nd ed. N ew Yor k : McGr aw
Hi l l , 1987.
Fi ndl i ng JW, Raf f H. Scr eeni ng and di agnosi s of Cushi ng's sy ndr om e.
Endocr i nol Metab Cl i n N or th Am 2005;34:385â€“402.
Mansm ann G, Lau J, Bal k E, et al . The cl i ni cal l y i nappar ent adr enal m ass:
update i n di agnosi s and m anagem ent. Endocr Rev 2004;25(2):309â€“340.
N ew el l Pr i ce J, Tr ai ner P, Besser M, et al . The di agnosi s and di f f er enti al

di agnosi s of Cushi ng's sy ndr om e and pseudoCushi ng's states. Endocr Rev
1998;19:657.
Schuf f KG. Issues i n the di agnosi s of Cushi ng's sy ndr om e f or the pr i m ar y

car e phy si ci an. Pr i m Car e Of f i ce Pr act 2003;30:791â€“799.
Ty r r el l JB, Ron DC, For sham PH. Gl ucocor ti coi ds and adr enal andr ogens.
In: Gr eenspan FS, ed. Basi c and cl i ni cal endocr i nol ogy , 3r d ed. N or w al k ,
CT: Appl eton & Lange, 1991.
Xi ao XR, Ye LY, Shi LX, et al . Di agnosi s and tr eatm ent of adr enal tum our s:
a r ev i ew of 35 y ear s' ex per i ence. Br J U r ol 1998;82:199.
Diabetes Mellitus
1. What ar e the cl i ni cal m ani f estati ons of DM?
2. What ar e the m ajor ty pes of DM and w hat ar e thei r di sti ngui shi ng
f eatur es?
3. What ar e the m ajor acute and chr oni c com pl i cati ons of the di sease?
4. What aspects of the m edi cal hi stor y r equi r e speci al em phasi s?
5. What aspects of the phy si cal ex am i nati on r equi r e speci al attenti on?
6. What l abor ator y tests ar e essenti al i n the ev al uati on of the pati ent w i th
suspected di abetes?
7. What ar e the goal s of di abetes ther apy and w hat tr eatm ent m odal i ti es ar e
av ai l abl e? How shoul d these be i ndi v i dual i zed?
Discussion
1. What ar e the cl i ni cal m ani f estati ons of DM?
DM i s a com pl ex m etabol i c di sor der char acter i zed by abnor m al i ti es of
car bohy dr ate, l i pi d, and pr otei n m etabol i sm r esul ti ng ei ther f r om a
def i ci ency of i nsul i n or f r om tar get ti ssue r esi stance to i ts cel l ul ar
m etabol i c ef f ects. It i s the m ost com m on endocr i nem etabol i c di sor der
and af f ects an esti m ated 22 m i l l i on peopl e i n the U ni ted States, w i th the
i nci dence of new cases i ncr easi ng by m or e than 700, 000 per y ear .
Di abetes i s m ani f ested by the f i ndi ng of hy per gl y cem i a and the ti m e
dependent dev el opm ent of chr oni c com pl i cati ons (r eti nopathy ,
neur opathy , nephr opathy , and accel er ated ather oscl er osi s) r esul ti ng f r om
the m ul ti pl e m etabol i c der angem ents. Accor di ngl y , the pr esenti ng cl i ni cal
si gns and sy m ptom s can be due to hy per gl y cem i a or the com pl i cati ons of
the di sease, or both. In gener al , the m ajor cl assi c sy m ptom s of
pol y di psi a, pol y ur i a, w ei ght l oss,
P. 87
and f ati gue ar e f ound i n the setti ng of new onset di abetes i n y oung
pati ents w hose di sease i s due to i nsul i nopeni a. On the other hand, ol der
pati ents w i th di abetes m ay be r el ati v el y f r ee of sy m ptom s f or a l ong
ti m e. In such pati ents, the di abetes i s f i r st detected ei ther i nci dental l y or
because one of i ts chr oni c com pl i cati ons i s di scov er ed. It i s esti m ated
that appr ox i m atel y one thi r d of al l the adul t cases of di abetes i n the
U ni ted States r em ai n undi agnosed.
2. What ar e the m ajor ty pes of DM and w hat ar e thei r di sti ngui shi ng
f eatur es?
The cur r ent cl assi f i cati on (accor di ng to the N ati onal Di abetes Data Gr oup)
of DM and other categor i es of gl ucose i ntol er ance consi sts of thr ee
cl i ni cal cl asses: (a) DM w hi ch i ncl udes ty pe 1 di abetes m el l i tus (T1DM),
[pr ev i ousl y i nsul i ndependent di abetes m el l i tus (IDDM) or juv eni l e onset
di abetes], and ty pe 2 di abetes m el l i tus (T2DM), [pr ev i ousl y nonâ
€“i nsul i ndependent di abetes m el l i tus (N IDDM)]; (b) i m pai r ed gl ucose
tol er ance/i m pai r ed f asti ng gl ucose; and (c) gestati onal DM. Of these,
T1DM and T2DM r epr esent the l ar gest categor y and ar e di scussed her e i n
f ur ther detai l . Im pai r ed gl ucose tol er ance and i m pai r ed f asti ng gl ucose
ar e def i ned as an abnor m al i ty i n gl ucose l ev el s i nter m edi ate betw een
nor m al and ov er t di abetes, w her eas gestati onal DM i s def i ned as
car bohy dr ate i ntol er ance w i th onset or f i r st r ecogni ti on dur i ng pr egnancy .
T1DM consti tutes appr ox i m atel y 5% to 10% of al l cases of di abetes and i s
due to i nsul i n def i ci ency r esul ti ng f r om the autoi m m une destr ucti on of
i nsul i npr oduci ng pancr eati c i sl et cel l s. Ther ef or e, such pati ents ar e
pr one to k etoaci dosi s and ar e absol utel y dependent on ex ogenous i nsul i n
to sustai n l i f e (hence the ter m i nsul i ndependent di abetes). The onset i n
these pati ents i s r el ati v el y abr upt and occur s usual l y i n y outh (m ean age,
12 y ear s), al though i t m ay ar i se at any age and i s of ten m i sdi agnosed i n
adul ts.
T2DM accounts f or appr ox i m atel y 90% to 95% of al l cases of di abetes.

These pati ents hav e a dual i m pai r m ent of i nsul i n r esi stance (decr eased
tar get or gan r esponse to i nsul i n, i . e. , decr eased gl ucose tr anspor t to
m uscl e or i nef f ecti v e suppr essi on of hepati c gl ucose output) and
i nadequate i nsul i n secr eti on to com pensate f or the i nsul i n r esi stance. The
r ecent obesi ty ex pl osi on, w hi ch i s r el ated to sedentar y l i f esty l e and
i ncr eased f ood i ntak e, has ex agger ated i nsul i n r esi stance i n suscepti bl e
peopl e and contr i buted to the di abetes epi dem i c. Fi g. 31 i l l ustr ates the
natur al hi stor y of the tr ansi ti on f r om i m pai r ed gl ucose tol er ance to ov er t
di abetes. T2DM i s now af f ecti ng 3% to 6% of the popul ati on and occur r i ng
i n y ounger peopl e (ev en i ncl udi ng chi l dr en). Ther e i s usual l y a str ong
f am i l y hi stor y of DM i n pati ents dev el opi ng T2DM i n y outh.
3. What ar e the m ajor acute and chr oni c com pl i cati ons of the di sease?
DKA, hy per gl y cem i c, hy per osm ol ar , nonk etoti c com a (HHN KC), and
hy pogl y cem i a ar e the m ajor acute com pl i cati ons of DM. DKA i s m ost
com m onl y a com pl i cati on of T1DM and i s i ni ti ated by an absol ute or
r el ati v e i nsul i n def i ci ency and an i ncr ease i n counter r egul ator y hor m ones
(gl ucagon, epi nephr i ne), l eadi ng to the hepati c ov er pr oducti on of gl ucose
and k etone bodi es. HHN KC i s char acter i zed by the i nsi di ous dev el opm ent
of m ar k ed hy per gl y cem i a, hy per osm ol ar i ty , dehy dr ati on, and pr er enal
azotem i a i n the
P. 88
absence of si gni f i cant hy per k etonem i a or aci dosi s. Fi nal l y , hy pogl y cem i a
can occur as an acute com pl i cati on of the ther apy of both T1DM and
T2DM, and i s the m ost com m on acute l i f ethr eateni ng com pl i cati on of
di abetes. It i s m ost com m on w i th i ntensi v e i nsul i n ther apy , and r ecur r ent
hy pogl y cem i a can i nduce a condi ti on k now n as hy pogl y cem i a
unaw ar eness, a bl unti ng of the adr ener gi c and neur ogl y copeni c si gns and
sy m ptom s of hy pogl y cem i a. The r i sk of hy pogl y cem i a unaw ar eness can be
m i ni m i zed and ex i sti ng unaw ar eness tr eated by str i ct av oi dance of
hy pogl y cem i a.
Figure 31 N atur al hi stor y of ty pe 2 di abetes m el l i tus. Adapted f r om

Ber genstal RM, Kendal l DM, Fr anz MJ, et al . Managem ent of ty pe 2 di abetes:
a sy stem ati c appr oach to m eeti ng the standar ds of car e. II: or al agents,
i nsul i n, and m anagem ent of com pl i cati ons. In: Degr oot LJ, Jam eson JL, eds.
Endocr i nol ogy . phi l adel phi a: WB Saunder s, 2001:821â€“835. w i th per m i ssi on
f r om El sev i er .
The m ost com m on chr oni c com pl i cati on of di abetes and the l eadi ng cause
of death f or peopl e w i th di abetes i s car di ov ascul ar (CV) di sease.
Sev enty sev en per cent of al l hospi tal i zati ons and 80% of al l m or tal i ty i n
di abetes i s secondar y to CV di sease. Di abetes i s an i ndependent r i sk
f actor f or CV di sease. The i nci dence of CV ev ents i s so hi gh i n subjects
w i th di abetes that di abetes i s consi der ed a CV r i sk equi v al ent. CV di sease
i ncl udes m y ocar di al i schem i a, str ok e, and per i pher al v ascul ar di sease.
Peopl e w i th di abetes al so hav e an i ncr eased i nci dence of hear t f ai l ur e,
w hi ch w i l l not be addr essed i n thi s secti on, as the pathophy si ol ogy i s
poor l y under stood. Outcom es af ter acute m y ocar di al i nf ar cti on (MI) i n
peopl e w i th di abetes ar e w or se than contr ol s, but can be i m pr ov ed w i th
i ntensi v e gl y cem i c contr ol i n the hospi tal . Inter v enti onal studi es
dem onstr ate that l i pi d l ow er i ng si gni f i cantl y decr eases m or tal i ty and CV
ev ents i n peopl e w i th di abetes. In f act, i t appear s that peopl e w i th DM
m ay benef i t f r om stati ns r egar dl ess of i ni ti al l ow densi ty l i popr otei n
(LDL). Addi ti onal l ar ge pr ospecti v e tr i al s dem onstr ate decr eased CV
m or tal i ty w i th i ntensi v e BP contr ol . Ther e i s no com pel l i ng data that
i m pr ov em ent of gl y cem i c contr ol af f ects CV m or bi di ty or m or tal i ty ex cept
i n subjects w i th T1DM.
Mi cr ov ascul ar com pl i cati ons (r eti nopathy , nephr opathy and neur opathy )
ar e speci f i c to di abetes and ar e r el ated di r ectl y to poor gl y cem i c contr ol
w i th
P. 89
a sm al l er contr i buti on f r om hy per tensi on and dy sl i pi dem i a. Di abetes i s
the l eadi ng cause of bl i ndness i n the U ni ted States. By 10 y ear s' dur ati on
of di abetes, appr ox i m atel y 90% of i ndi v i dual s w i l l hav e som e degr ee of
r eti nopathy . Reti nopathy i s l ar gel y a pr ev entabl e com pl i cati on of
di abetes. Annual ophthal m ol ogi c ex am i nati ons per m i t i denti f i cati on of
i ndi v i dual s w i th pr ogr essi v e r eti nopathy . Tw o l ar ge m ul ti center studi es
hav e pr ov ed that ear l y i nter v enti on at thi s stage w i th panr eti nal
photocoagul ati on can pr ev ent or decr ease v i sual l oss. The Di abetes
Contr ol and Com pl i cati ons Tr i al (DCCT) establ i shed that ti ght gl y cem i c
contr ol al so pr ev ents or del ay s r eti nopathy . Macul ar edem a, cor neal
ul cer ati on, gl aucom a, and catar acts ar e addi ti onal ocul ar com pl i cati ons of
di abetes.
Di abetes i s the l eadi ng cause of r enal f ai l ur e/di al y si s and

tr anspl antati ons nati onw i de. For ty per cent to 60% of i ndi v i dual s w i th
T1DM and 10% to 30% of i ndi v i dual s w i th T2DM w i l l dev el op
m i cr oal bum i nur i a, pr otei nur i a, and endstage r enal di sease secondar y to
di abetes. Hy per tensi on and gl y cem i c contr ol ar e the pr i m ar y f actor s that
pr om ote pr ogr essi on of nephr opathy i n peopl e w i th di abetes.
N or m al i zati on of BP and gl ucose dr am ati cal l y sl ow the pr ogr essi on f r om
i nci pi ent nephr opathy (detectabl e m i cr oal bum i n) to ov er t nephr opathy . Al l
peopl e w i th DM shoul d hav e a BP l ow er than 130/80 m m Hg, pr ef er abl y
m uch l ow er . Aggr essi v e contr ol of hy per gl y cem i a (w i th i ntensi v e ther apy )
and BP [w i th angi otensi nconv er ti ng enzy m e (ACE) i nhi bi tor s or
angi otensi n r eceptor bl ock er s] has been show n to r etar d the pr ogr essi on
of nephr opathy i n pati ents w i th DM.
N eur opathy i s a com m on com pl i cati on of di abetes af f ecti ng m or e than
50% of pati ents w i th ti m e. The m ost com m on f or m of ner v e i njur y i n
di abetes i s di stal sy m m etr i c pol y neur opathy , w hi ch occur s i n a stock i ng
gl ov e di str i buti on; i t can be pai nl ess or pai nf ul . Thi s ty pe of neur opathy
i ncr eases the r i sk f or tr aum ati c f oot i njur y and am putati on. Other f or m s
of neur opathy i ncl ude: autonom i c neur opathy (associ ated w i th an
i ncr eased r i sk of CV death and hy pogl y cem i a unaw ar eness); m ononeur i ti s
m ul ti pl ex (a v ascul ar occl usi on to a si ngl e ner v e di str i buti on that w i l l
ty pi cal l y r ecov er w i th ti m e); and di abeti c am y otr ophy (a pr of ound,
uncom m on dem y el i nati ng neur om uscul ar w asti ng sy ndr om e).
Di abetes i s al so associ ated w i th i m pai r ed bl ood f l ow and sensati on to the
ex tr em i ti es. Thi s l eads to a hi gh i nci dence of m echani cal tr aum a and
i nf ecti ous com pl i cati ons, l eadi ng to am putati on and hospi tal i zati on.
Di abetes i s the m ost f r equent cause of nontr aum ati c l ow er l i m b
am putati ons. Each y ear , m or e than 56, 200 am putati ons ar e per f or m ed
am ong peopl e w i th di abetes. Thi s com pl i cati on i s l ar gel y pr ev entabl e by
appr opr i ate f ootw ear , r egul ar f oot ex am i nati on, and educati on.
4. What aspects of the m edi cal hi stor y r equi r e speci al em phasi s?
A com pr ehensi v e m edi cal hi stor y i n a pati ent w i th suspected di abetes
shoul d be di r ected not onl y tow ar d conf i r m i ng the di agnosi s but shoul d
al so be used to r ev i ew the natur e of pr ev i ous tr eatm ent pr ogr am s and
di abetes educati on, f am i l y hi stor y , the degr ee of past and r ecent
gl y cem i c contr ol , and hi stor y of acute and chr oni c com pl i cati ons. Pati ents
shoul d al so be quer i ed
P. 90
about thei r di etar y , w ei ght, and ex er ci se hi stor y . Cur r ent m edi cati ons f or
the m anagem ent of di abetes, as w el l as other m edi cati ons that m ay
af f ect gl y cem i c contr ol , shoul d be r ecor ded. In addi ti on, the pr esence,
sev er i ty , and tr eatm ent of the acute and chr oni c com pl i cati ons of
di abetes shoul d be r ev i ew ed, i ncl udi ng sex ual f uncti on and dental car e.
Al l pati ents shoul d hav e a car ef ul hi stor y f or di abeti c heal th car e
m ai ntenance docum ented at each v i si t. Thi s i ncl udes gl y cem i c contr ol ,
l i pi d m anagem ent (LDL < 100, or < 70 i n hi gh r i sk or k now n CV di sease),
BP m anagem ent (< 130/80 m m Hg), ey e ex am i nati on (annual ), f oot
ex am i nati on (each v i si t), di et, ex er ci se, and sel f m anagem ent (Fi g. 32).
Figure 32 Di abetes car e f l ow sheet. BMI, body m ass i ndex ; BP,
bl ood pr essur e; LDL, l ow densi ty l i popr otei n; CAD, cor onar y ar ter y
di sease; HDL, hi ghl ev el l i popr otei n.
P. 91
5. What aspects of the phy si cal ex am i nati on r equi r e speci al attenti on?
The v i tal si gns ar e cr i ti cal f or pati ents w i th di abetes. BP gr eater than
130/80 m m Hg i ncr eases the r i sk f or al l com pl i cati ons, r esti ng
tachy car di a suggests autonom i c ner v ous sy stem dy sf uncti on, and w ei ght
gai n or l oss pr ov i des v al uabl e i nf or m ati on on sev er i ty of i l l ness and
adher ence to ther apy . On phy si cal ex am i nati on, denti ti on i s i m por tant as
per i odontal di sease can i m pact gl y cem i c contr ol and i s a r i sk f actor f or
ather oscl er osi s (chr oni c i nf l am m ati on). Com pl ete CV ex am i nati on
[i ncl udi ng br ui ts and ank l e br achi al i ndex (ABI)] and ev al uati on f or
edem a can detect CV di sease and hear t f ai l ur e. Loss of r espi r ator y
v ar i ati on i n hear t r ate i s an ear l y w ar ni ng of autonom i c neur opathy . Foot
ex am i nati on, i ncl udi ng pul ses and m onof i l am ent testi ng, can i denti f y
hi ghr i sk f eet and pr ev ent am putati ons. The r eti nal ex am i nati on
[undi l ated by a pr i m ar y car e phy si ci an (PCP)] i s not sensi ti v e f or
detecti on of r eti nopathy and needs to be done by an
P. 92
ophthal m ol ogi st or by usi ng r eti nal photogr aphs. It m ay be conducted by
the PCP, but the needed f or m al annual ev al uati on shoul d al so be
ar r anged.
6. What l abor ator y tests ar e essenti al i n the ev al uati on of the pati ent w i th
suspected di abetes?
The Am er i can Di abetes Associ ati on (ADA) and r egul ator y agenci es hav e
establ i shed standar ds f or l abor ator y ev al uati on of di abetes. The di agnosi s
of di abetes i s f or m al l y m ade on the basi s of one of the f ol l ow i ng cr i ter i a:
(a) f asti ng gl ucose 126 m g/dL or m or e on tw o occasi ons, (b) r andom
gl ucose 200 m g/dL or m or e on tw o occasi ons, or (c) one abnor m al
r eadi ng as abov e together w i th sy m ptom s consi stent w i th di abetes
(pol y ur i a, noctur i a, pol y di psi a, w ei ght l oss, bl ur r ed v i si on). Hem ogl obi n
A I c (HbA I c ) i s not y et r ecom m ended as a di agnosti c test because of a l ack
of standar di zati on of ex i sti ng assay s, but i s i ncr easi ngl y bei ng consi der ed
by the ADA and r egul ator y agenci es as a potenti al di agnosti c tool .
7. What ar e the goal s of di abetes ther apy and w hat tr eatm ent m odal i ti es ar e
av ai l abl e? How shoul d these be i ndi v i dual i zed?
In gener al , the goal s of di abetes ther apy ar e (a) to al l ev i ate the si gns
and sy m ptom s of the di sease (e. g. , pol y di psi a, pol y ur i a, and noctur i a);
(b) to pr ev ent the acute com pl i cati ons (i . e. , hy pogl y cem i a, DKA, and
HHN KC); and (c) to pr ev ent the l ongter m com pl i cati ons of the di sease
(i . e. , r eti nopathy , nephr opathy , neur opathy , and ather oscl er oti c CV
di sease). The DCCT f i r st dem onstr ated that ti ght m etabol i c contr ol of
T1DM l eads to def i ni te benef i ci al ef f ects on the r ate of com pl i cati ons.
Thi s al so hel d tr ue f or pati ents w i th T2DM i n the r ecentl y com pl eted
U ni ted Ki ngdom Pr ospecti v e Di abetes Study (U KPDS). Ev i dence
docum enti ng the i m por tance of gl y cem i c contr ol f or the pr ev enti on of
m i cr ov ascul ar com pl i cati on i s unequi v ocal . Ther ef or e, i ntensi v e gl y cem i c
contr ol i s now r outi ne w i th HbA I c goal s of 6. 5% to 7%. The l i m i ti ng f actor
i n such attem pts i s an i ncr eased f r equency of hy pogl y cem i c epi sodes.
Recent data f r om the DCCT f ol l ow up study Epi dem i ol ogy of Di abetes
Inter v enti ons and Com pl i cati ons (EDIC) now i ndi cate that i ntensi v e
contr ol of bl ood gl ucose i n T1DM al so pr ev ents m acr ov ascul ar di sease. In
pati ents w i th T2DM, m ul ti tar geted ther apy (l i pi d, BP, and gl ucose contr ol )
i s the m ost ef f ecti v e str ategy f or CV di sease pr ev enti on.
Insul i n i s r equi r ed f or gl y cem i c contr ol i n T1DM w her eas T2DM r equi r es a
m ul ti f aceted appr oach. Di et and ex er ci se ar e the m ai nstay s of T2DM
ther apy . They shoul d be i nsti tuted f i r st and pati ent adher ence encour aged
and m ax i m i zed. Regar dl ess of the ul ti m ate r egi m en, di et and ex er ci se
r em ai n i m por tant. Or al sul f ony l ur ea agents that enhance Î²cel l i nsul i n
secr eti on, m etf or m i n that decr eases hepati c gl ucose output, or
thi azol i di nedi ones that enhance i nsul i n acti on i n the per i pher y ar e added
to thi s tr eatm ent i f di et and ex er ci se al one f ai l to contr ol hy per gl y cem i a
opti m al l y . These agents can al so be used i n com bi nati on because they
hav e di f f er ent m echani sm s and thei r acti ons ar e addi ti v e. Com bi nati on
ther apy w i th m ul ti pl e cl asses of dr ugs i s ef f ecti v e, but cost and
m oni tor i ng f or tox i ci ty can be pr ohi bi ti v e. Wi th i ncr eased dur ati on of
T2DM, Î²cel l m ass and f uncti on ar e di m i ni shed and l ead to r el ati v e
P. 93
i nsul i n i nsuf f i ci ency . At som e poi nt, i nsul i n ther apy becom es necessar y
f or opti m al gl y cem i c contr ol . In f act, i nsul i n ther apy i s the best w ay to
nor m al i ze gl ucose i n pati ents not r espondi ng w el l to or al agents and
shoul d be em pl oy ed as soon as gl ucose r i ses and not as a l ast r esor t.
N ew i njectabl e agents that r egul ate gl ucagon, gastr i c em pty i ng, sati ety
and i nsul i n secr eti on: am y l i n and gl ucagonl i k e pepti de1 (GLP1)
agoni sts ar e r ecent addi ti ons to the l i st of anti hy per gl y cem i c agents. The
m ost r ecent addi ti on(s) ar e or al i nhi bi tor s of di pepti dy l pepti dase 4
(DPP4), the enzy m e that i nacti v ates GLP1. These agents ar e cur r entl y
used by pr ov i der s speci al i zi ng i n di abetes.
Case 1
A 14y ear ol d boy w i th an 8y ear hi stor y of DM has been si ck si nce y ester day
w hen he began v om i ti ng. Hi s di abetes has been r easonabl y w el l contr ol l ed
w i th a dosage of 20 uni ts of gl ar gi ne i nsul i n tak en dai l y . He uses a
car bohy dr ate r ati o of 1:20 and cor r ecti on f actor of 1:50 f or m eal ti m e bol us
i nsul i n. He has had sev er al epi sodes of DKA i n the past, but not f or
appr ox i m atel y 4 y ear s. Yester day , w hen he began v om i ti ng, gl ucose
concentr ati on w as 400 and hi s ur i ne acetone w as negati v e, so he took hi s
usual dose of i nsul i n. He has had i ntense pol y ur i a and pol y di psi a f or the l ast
24 hour s. Thi s m or ni ng, appr ox i m atel y 6 hour s ago, hi s m other deci ded to
w i thhol d hi s i nsul i n because of conti nued nausea and v om i ti ng.
Phy si cal ex am i nati on r ev eal s a dr ow sy y oung m an w ho can r espond to
questi oni ng. Hi s BP i s 90/70 m m Hg; pul se, 124 per m i nute; r espi r ati ons, 30
per m i nute; and tem per atur e, 38. 3Â°C (100. 9Â°F). Hi s m ucous m em br anes ar e
dr y and the ocul ar gl obes ar e sof t and sunk en, but the f unduscopi c f i ndi ngs
ar e nor m al . Bow el sounds ar e absent and he has gener al i zed abdom i nal
tender ness w i thout r ebound. The deep tendon r ef l ex es ar e hy poacti v e, but
ther e ar e no l ocal i zi ng neur ol ogi c si gns. The r est of the ex am i nati on f i ndi ngs
ar e nor m al .
Labor ator y data consi st of the f ol l ow i ng: Hgb, 16. 4 g/dL; hem atocr i t (Hct),
53%; WBC, 16, 942/ m m 3 (93% pol y m or phonucl ear l euk ocy tes); BU N , 40
m g/dL; cr eati ni ne, 1. 8 m g/dL; gl ucose, 847 m g/dL; ser um k etones, str ongl y
posi ti v e at 1:4 di l uti on; sodi um , 126 m Eq/L; potassi um , 4. 3 m Eq/L; chl or i de,
100 m Eq/L; and bi car bonate, 6 m Eq/L. U r i nal y si s r ev eal s a speci f i c gr av i ty of
1. 030; gl ucose of 4+ ; acetone, str ongl y posi ti v e; and tr ace am ounts of
pr otei n. Ar ter i al bl ood gas anal y si s r ev eal s a pH of 7. 08, par ti al pr essur e of
car bon di ox i de (PCO 2 ) of 12 m m Hg, and par ti al pr essur e of ox y gen (PO 2 ) of
80 m m Hg. An ECG show s si nus tachy car di a w i th f l at T w av es. Chest
r adi ogr aphi c study i s nor m al . Abdom i nal r adi ogr aphs show gastr i c di stenti on,
but other w i se the f i ndi ngs ar e nor m al .
1. What i s the di agnosi s and pathophy si ol ogi c pr ocess of thi s pati ent's
di sease?
2. How i s the l i v er i nv ol v ed i n the genesi s of DKA?
3. What i s the status of the pati ent's f l ui d and el ectr ol y te l ev el s?
4. What ar e the m ajor goal s of ther apy ?
5. What pr eci pi tated thi s epi sode of DKA?
Case Discussion
1. What i s the di agnosi s and pathophy si ol ogi c pr ocess of thi s pati ent's
di sease?
Thi s pati ent has T1DM and i s pr esenti ng w i th an epi sode of DKA. DKA i s
i ni ti ated by an absol ute or r el ati v e i nsul i n def i ci ency and an i ncr ease i n
the l ev el
P. 94
of counter r egul ator y catabol i c hor m ones, l eadi ng to the hepati c
ov er pr oducti on of gl ucose and k etone bodi es. Consi stent w i th thi s, the
pati ent's l abor ator y data show the pr esence of m ar k ed hy per gl y cem i a,
k etonem i a, k etonur i a, and sev er e m etabol i c aci dosi s. The pati ent's
tachy pnea i s al so consi stent w i th hi s aci doti c state.
The destr ucti on of pancr eati c Î² cel l s l eadi ng to T1DM i s thought to be
m edi ated by the acti v ati on of autoi m m une pr ocesses i n geneti cal l y
pr edi sposed peopl e. The pr esence of anti i sl et and anti i nsul i n anti bodi es,
the ex i stence of i nf l am m ator y cel l s ar ound the i sl et cel l s, and the
tem por ar y am el i or ati on of new onset T1DM by i m m unosuppr essi v e
ther apy al l pr ov i de str ong ev i dence f or an autoi m m une basi s of
pancr eati c Î²cel l destr ucti on.
2. How i s the l i v er i nv ol v ed i n the genesi s of DKA?
Hepati c k etogenesi s and the dev el opm ent of DKA depend on both the r ate
of substr ate (FFA) suppl y to the l i v er and the acti v ati on of the hepati c
k etogeni c pr ocess, the l atter bei ng m odul ated by the r el ati v e i ncr ease i n
the gl ucagontoi nsul i n r ati o that pr ev ai l s dur i ng DKA. The i nsul i n
def i ci ency l eads to the acti v ati on of l i pol y si s and an i ncr eased suppl y of
ci r cul ati ng FFA. In the l i v er these m ol ecul es under go successi v e Î²
ox i dati on to acety l coenzy m e A (CoA). Dur i ng DKA the unr estr ai ned FFA
m obi l i zati on and ox i dati on tr i gger the pr oducti on of ex cess am ounts of
acety l CoA, w hi ch under go condensati on to acetoacety l CoA, a pr ecur sor
of the k etone bodi es acetoacetate, acetone, and Î²hy dr ox y buty r ate.
3. What i s the status of the pati ent's f l ui d and el ectr ol y te l ev el s?
The pati ent's phy si cal ex am i nati on r ev eal s si gns of sev er e dehy dr ati on
and i ntr av ascul ar hy pov ol em i a (note hi s hy potensi on, tachy car di a, and
the dr y m ucous m em br anes). DKA, i f not tr eated ear l y , r esul ts i n a
sev er e total body depl eti on of f l ui d (usual l y sev er al l i ter s) and
el ectr ol y tes due to the f ol l ow i ng f actor s:
1. The hy per gl y cem i a and hy per k etonem i a l ead to osm oti c di ur esi s and
the ur i nar y l oss of f l ui d and el ectr ol y tes.
2. Because of aci dosi s, potassi um i s al so shi f ted f r om the i ntr acel l ul ar
to ex tr acel l ul ar f l ui d space and then l ost dur i ng osm oti c di ur esi s.
Ther ef or e, the ser um potassi um l ev el s m ay not accur atel y r ef l ect
the total body def i ci ency .
3. Vom i ti ng, as i n thi s pati ent, causes the f ur ther l oss of f l ui d and
el ectr ol y tes.
4. Muscl e catabol i sm (pr oteol y si s), w hi ch r esul ts f r om the i nsul i n
def i ci ency , l eads to the l oss of potassi um , phosphate, m agnesi um ,
and ni tr ogen.
4. What ar e the m ajor goal s of ther apy ?
The i m m edi ate ther apeuti c goal s ar e (a) to r epl eni sh the f l ui d (star ti ng
w i th i sotoni c sal i ne) and el ectr ol y tes; and (b) to pr ov i de adequate i nsul i n
to i nhi bi t l i pol y si s and k etogenesi s and nor m al i ze car bohy dr ate
m etabol i sm , both i n the l i v er (by i nhi bi ti ng gl ucose pr oducti on) and i n the
per i pher al ti ssues (by enhanci ng di sposal of gl ucose and k etone bodi es).
Insul i n ther apy i s best adm i ni ster ed i n the f or m of a conti nuous IV
i nf usi on. Dur i ng the f l ui d, el ectr ol y te, and i nsul i n ther apy , the pati ent's
bl ood gl ucose and el ectr ol y te l ev el s (especi al l y potassi um ) shoul d be
m oni tor ed f r equentl y and appr opr i ate adjustm ents m ade. Addi ti onal
ther apeuti c objecti v es i ncl ude the i denti f i cati on and m anagem ent of
possi bl e pr eci pi tati ng f actor s (e. g. , i nf ecti on, str ess, and m edi cati on
er r or s) and the i m pl em entati on of m easur es to pr ev ent the r ecur r ence of
DKA.
P. 95
5. What pr eci pi tated thi s epi sode of DKA?
The i m m edi ate pr eci pi tati ng ev ent of thi s pati ent's DKA i s the w i thhol di ng
of i nsul i n. An under l y i ng str ess or i nf ecti on (e. g. , gastr oenter i ti s), w hi ch
m ay al so be pr esent i n thi s pati ent, shoul d be ev al uated and m anaged.
Case 2
A 63y ear ol d m an i s br ought to the em er gency r oom i n an unconsci ous state.
He w as appar entl y i n good heal th unti l 1 w eek bef or e adm i ssi on, w hen he
ex per i enced an i nsati abl e thi r st that he attem pted to sati sf y by dr i nk i ng l ar ge
quanti ti es of beer and soda dr i nk s. He had com pl ai ned of hav i ng noctur i a f or
sev er al day s, and had sev er al bouts of di ar r hea y ester day . He took to hi s bed
y ester day and w as f ound unconsci ous thi s m or ni ng. He tak es no dr ugs, has not
seen a phy si ci an f or sev er al y ear s, and w or k s r egul ar l y as a house pai nter .
Hi s heal th has been good pr ev i ousl y . Hi s m other had di abetes i n her ei ghti es
and di ed of a str ok e.
Phy si cal ex am i nati on r ev eal s a deepl y unconsci ous, acutel y i l l m an w ho has
sev er al f ocal r i ghtsi ded sei zur es dur i ng ex am i nati on. Hi s sk i n and m ucous
m em br anes ar e dr y and hi s ocul ar gl obes ar e qui te sof t. Hi s BP i s 98/60 m m
Hg, pul se i s 120 per m i nute, and r ectal tem per atur e i s 38Â°C (100. 9Â°F), and
he ex hi bi ts unl abor ed r espi r ati ons at a r ate of 13 per m i nute. Ex cept f or the
f i ndi ngs of m i ni m al hepatom egal y , absent k nee jer k s, and bi l ater al Babi nsk i 's
r ef l ex es, the ex am i nati on f i ndi ngs ar e other w i se nor m al .
Labor ator y data consi st of the f ol l ow i ng: Hgb, 16. 2 g/dL; Hct, 51%; and WBC,
21, 340/ m m 3 (92% pol y m or phonucl ear l euk ocy tes). U r i nal y si s r ev eal s a
speci f i c gr av i ty of 1. 030; pH, 6. 0; gl ucose, 4+ ; acetone, m oder ate am ounts;
and pr otei n, tr ace am ounts. Ar ter i al bl ood gas anal y si s r ev eal s a pH of 7. 41,
PCO 2 of 35 m m Hg, and PO 2 of 68 m m Hg. Both chest r adi ogr aphi c and head
CT scan f i ndi ngs ar e nor m al . Hi s ECG show s si nus tachy car di a w i th nonspeci f i c
STTâ€“w av e changes. Ser um f i ndi ngs ar e BU N , 68 m g/dL; cr eati ni ne, 2. 3
m g/dL; gl ucose, 1, 420 m g/dL; k etones, tr ace am ounts; sodi um , 153 m Eq/L;
potassi um , 4. 6 m Eq/L; chl or i de, 110 m Eq/L; and bi car bonate, 26 m Eq/L.
1. What i s the di agnosi s i n thi s pati ent and how w oul d y ou r el ate i t to the
m ajor phy si cal and l abor ator y f i ndi ngs?
2. What i s the natur e of thi s pati ent's endogenous i nsul i n secr eti on, and i s
thi s ty pe of di abetes her edi tar y ?
3. Why di d k etoaci dosi s not dev el op i n thi s pati ent?
4. How i s hi s l i v er i nv ol v ed i n the pathogenesi s of hi s hy per gl y cem i a?
5. What ar e the m ajor hor m ones that ar e counter r egul ator y to i nsul i n
acti on? Ar e they pl ay i ng any r ol e i n thi s m an's i l l ness?
6. What w oul d y ou pr edi ct about the state of hi s i ntr av ascul ar v ol um e?
7. What ar e the m ajor ther apeuti c goal s i n thi s pati ent?
Case Discussion
1. What i s the di agnosi s i n thi s pati ent and how w oul d y ou r el ate i t to the
m ajor phy si cal and l abor ator y f i ndi ngs?
Thi s el der l y pati ent pr esents i n a com atose state pr eceded by sev er al
day s of pr ogr essi v e sy m ptom s of pol y ur i a, pol y di psi a, and noctur i a. Hi s
l abor ator y data show
P. 96
the pr esence of m ar k ed hy per gl y cem i a but no aci dosi s. In thi s setti ng, hi s
m oder ate k etonem i a and k etonur i a ar e m ost l i k el y secondar y to
star v ati on. Ther ef or e, the di agnosi s i n thi s pati ent i s HHN KC. Hi s ser um
osm ol al i ty can be cal cul ated usi ng the f or m ul a: esti m ated osm ol al i ty =
2([N a] + [K]) + [gl ucose]/18 + [BU N ]/2. 8. For thi s pati ent, the esti m ated
osm ol al i ty i s cal cul ated to be 418, w hi ch i s consi stent w i th a sev er e
hy per osm ol ar state.
2. What i s the natur e of thi s pati ent's endogenous i nsul i n secr eti on, and i s
thi s ty pe of di abetes her edi tar y ?
Thi s pati ent has T2DM. When T2DM i s of shor t dur ati on, such as i n thi s
pati ent, and w hen pati ents ar e obese, the endogenous i nsul i n l ev el s ar e
ty pi cal l y nor m al or el ev ated. Such pati ents ar e sti l l abl e to m ai ntai n
suf f i ci ent endogenous i nsul i n secr eti on to pr ev ent k etoaci dosi s f r om
dev el opi ng under basal condi ti ons. Onl y sev er e str ess w i th el ev ated
catechol am i nes pl us gl ucagon and decr eased i nsul i n secr eti on w i l l
pr eci pi tate DKA i n peopl e w i th T2DM.
Her edi ty pl ay s an i m por tant r ol e i n T2DM, al though the m ode of

i nher i tance i s l ar gel y unk now n. T2DM i s al so a heter ogeneous di sor der ,
and di f f er ent f or m s of geneti c i nf l uences or def ects m ay ex i st. Ev i dence
f or a geneti c i nf l uence i n the acqui si ti on of T2DM i ncl ude (a) a str ong
f am i l y hi stor y of the di sease, (b) a v er y hi gh pr ev al ence of the di sease i n
cer tai n popul ati on gr oups (e. g. , the Pi m a Indi ans and Mi cr onesi ans of
N aur u), (c) a concor dance r ate of 90% to 100% i n m onozy goti c tw i ns, and
(d) an appar ent autosom al dom i nant m ode of tr ansm i ssi on of m atur i ty
onset di abetes of the y oung (an uncom m on m onogeni c f or m of T2DM).
3. Why di d k etoaci dosi s not dev el op i n thi s pati ent?
Thi s pati ent has suf f i ci ent endogenous i nsul i n to pr ev ent (a) l i pol y si s (FFA
l ev el s ar e l ow er i n the setti ng of HHN KC than of DKA), and (b) f ul l
acti v ati on of the hepati c k etogeni c sy stem . In the pr esence of a
r easonabl e l ev el of endogenous i nsul i n, the gl ucagontoi nsul i n r ati o i s
not hi gh enough to l ead to si gni f i cant k etogenesi s and k etoaci dosi s.
4. How i s hi s l i v er i nv ol v ed i n the pathogenesi s of hi s hy per gl y cem i a?
The hy per gl y cem i a i n thi s pati ent r esul ts f r om the i ncr eased hepati c
pr oducti on of gl ucose due to i ncr eased gl y cogenol y si s and
gl uconeogenesi s, and f r om the decr eased uptak e and uti l i zati on of
gl ucose by the l i v er , m uscl e, and adi pose ti ssue. Al l of these changes ar e
due to the under l y i ng i nsul i n r esi stance of T2DM and the r el ati v e, but not
absol ute, i nsul i n def i ci ency i n the pr esence of acute str essf ul condi ti ons.
In addi ti on, peopl e w i th T1DM and under l y i ng r enal di sease m ay pr esent
w i th HHN KC due to decr eased cl ear ance of i nsul i n.
5. What ar e the m ajor hor m ones that ar e counter r egul ator y to i nsul i n
acti on? Ar e they pl ay i ng any r ol e i n thi s m an's i l l ness?
Gl ucagon, cor ti sol , catechol am i nes, and gr ow th hor m one (GH) ar e the
chi ef i nsul i n counter r egul ator y hor m ones that ar e el ev ated i n m ajor
str essf ul condi ti ons l i k e HHN KC. Thr ough the oper ati on of sev er al speci f i c
m echani sm s, they counter act the ef f ects of i nsul i n, and thi s w or sens the
hy per gl y cem i c state.
6. What w oul d y ou pr edi ct about the state of hi s i ntr av ascul ar v ol um e?
The i ntr av ascul ar v ol um e i s sev er el y depl eted i n thi s pati ent (note the
r el ated f i ndi ngs r ev eal ed by the phy si cal ex am i nati on). The f ol l ow i ng
sequence of ev ents
P. 97
m ay tak e pl ace i n pati ents w i th T2DM i f they ar e not adequatel y tr eated:
hy per gl y cem i a â†’ osm oti c di ur esi s â†’ l oss of f l ui d and el ectr ol y tes â†’
dehy dr ati on â†’ w or seni ng hy per osm ol ar i ty and osm oti c di ur esi s â†’
el ev ated counter r egul ator y hor m ones â†’ hem oconcentr ati on and
hy pov ol em i a â†’ pr er enal azotem i a â†’ ci r cul ator y
i nsuf f i ci ency /shock /l acti c aci dosi s â†’ i r r ev er si bl e com a â†’ death.
Ther ef or e, i f thi s pati ent's condi ti on i s not r api dl y tr eated, i r r ev er si bl e
com a and death m ay ensue.
7. What ar e the m ajor ther apeuti c goal s i n thi s pati ent?
The m ajor i m m edi ate ther apeuti c goal s ar e (a) r epl acem ent of f l ui d and
el ectr ol y tes, (b) cor r ecti on of the hy per gl y cem i a (r el ati v el y sm al l doses
of i nsul i n ar e suf f i ci ent f or pati ents i n HHN KC com par ed w i th DKA), and
(c) i denti f i cati on and m anagem ent of the pr eci pi tati ng f actor s. HHN KC i s
a v er y ser i ous m edi cal em er gency w i th a hi gh r i sk of m or tal i ty unl ess an
i m m edi ate, aggr essi v e, and com pr ehensi v e m anagem ent r egi m en i s
i nsti tuted. Once the acute si tuati on i s r esol v ed, the di abetes m ay be
m anaged i n the l ong ter m ei ther w i th di et and or al agents or w i th i nsul i n.
Suggested Readings
Am er i can Col l ege of Endocr i nol ogy Task For ce on Inpati ent Di abetes and
Metabol i c Contr ol . Am er i can Col l ege of Endocr i nol ogy posi ti on statem ent on
i npati ent di abetes and m etabol i c contr ol . Endocr Pr act 2004;10(1):77â€“82.
Am er i can Di abetes Associ ati on. Standar ds of m edi cal car e i n di abetesâ
€”2006. Di abetes Car e 2006;29(Suppl 1):S4â€“S42.
Bode BW, Br ai thw ai te SS, Steed RD, et al . Intr av enous i nsul i n i nf usi on
ther apy : i ndi cati ons, m ethods, and tr ansi ti on to subcutaneous i nsul i n
ther apy . Endocr Pr act 2004;10(Suppl 2):71â€“80.
Br etzel RG, Voi gt K, Schatz H. The U ni ted Ki ngdom pr ospecti v e di abetes
study (U KPDS) i m pl i cati ons f or the phar m acother apy of ty pe 2 di abetes
m el l i tus. Ex p Cl i n Endocr i nol Di abetes 1998;106:369.
Cr y er PE. Di v er se causes of hy pogl y cem i aassoci ated autonom i c f ai l ur e i n

di abetes. N Engl J Med 2004;350(22):2272â€“2279.
Di abetes Contr ol and Com pl i cati ons Tr i al Resear ch Gr oup. The ef f ect of
i ntensi v e tr eatm ent of di abetes on the dev el opm ent and pr ogr essi on of
l ongter m com pl i cati ons i n i nsul i n dependent di abetes m el l i tus. N Engl J
Med 1993;329:977.
Eck el RH, Bar ouch WW, Er show AG. Repor t of the N ati onal Hear t, Lung, and
Bl ood Insti tuteN ati onal Insti tute of Di abetes and Di gesti v e and Ki dney
Di seases Wor k i ng Gr oup on the pathophy si ol ogy of obesi ty associ ated
car di ov ascul ar di sease. Ci r cul ati on 2002;105(24):2923â€“2928.
Eck el RH, Gr undy SM, Zi m m et PZ. The m etabol i c sy ndr om e. Lancet
2005;365:1415â€“1428.
Eck el RH, Wassef M, Chai t A, et al . Pr ev enti on conf er ence VI: di abetes and
car di ov ascul ar di sease: w r i ti ng gr oup II: pathogenesi s of ather oscl er osi s i n
di abetes. Ci r cul ati on 2002;105(18):e138â€“e143.
Ex per t Panel on Detecti on, Ev al uati on, and Tr eatm ent of Hi gh Bl ood
Chol ester ol i n Adul ts. Ex ecuti v e sum m ar y of the thi r d r epor t of the
nati onal chol ester ol educati on pr ogr am (N CEP) ex per t panel on detecti on,
ev al uati on, and tr eatm ent of hi gh bl ood chol ester ol i n adul ts (Adul t
Tr eatm ent Panel III). JAMA 2001;285(19):2486â€“2497.
P. 98
Gr undy SM, Br ew er HB, Cl eem an JI, et al . For the conf er ence par ti ci pants.
Def i ni ti on of m etabol i c sy ndr om e: r epor t of the N ati onal Hear t, Lung, and
Bl ood Insti tute/Am er i can Hear t Associ ati on Conf er ence on Sci enti f i c Issues
Rel ated to Def i ni ti on. Ci r cul ati on 2004;109:433â€“438.
Gr undy SM, Cl eem an JI, Mer z CN , et al . N ati onal Hear t, Lung, and Bl ood
Insti tute; Am er i can Col l ege of Car di ol ogy Foundati on; Am er i can Hear t
Associ ati on. Im pl i cati ons of r ecent cl i ni cal tr i al s f or the N ati onal
Chol ester ol Educati on Pr ogr am Adul t Tr eatm ent Panel III Gui del i nes.
Ci r cul ati on 2004;110(2):227â€“239.
Hi l l JO, Catenacci V, Wy att HR. Obesi ty : ov er v i ew of an epi dem i c.

Psy chi atr Cl i n N or th Am 2005;28:1â€“23.
Kushner RF, Roth JL. Assessm ent of the obese pati ent. Endocr i nol Metab
Cl i n N or th Am 2003;32:915â€“933.
Moghi ssi ES, Hi r sch IB. Hospi tal m anagem ent of di abetes. Endocr i nol Metab
Cl i n N or th Am 2005;34:99â€“116.
N ati onal Di abetes Data Gr oup. Cl assi f i cati on and di agnosi s of di abetes
m el l i tus and other categor i es of gl ucose i ntol er ance. Di abetes
1979;28:1039.
Ri ddl e MC. Gl y cem i c m anagem ent of ty pe 2 di abetes: an em er gi ng str ategy
w i th or al agents, i nsul i ns, and com bi nati ons. Endocr i nol Metab Cl i n N or th
Am 2005;34:77â€“98.
Tur ner RC. The U . K. pr ospecti v e di abetes study : a r ev i ew . Di abetes Car e

1998;21:35.
U K Pr ospecti v e Di abetes Study (U KPDS) Gr oup. Ef f ect of i ntensi v e bl ood

gl ucose contr ol w i th m etf or m i n on com pl i cati ons i n ov er w ei ght pati ents
w i th ty pe 2 di abetes (U KPDS 34): U K Pr ospecti v e Di abetes Study (U KPDS)
Gr oup. Lancet 1998;352:854.
U K Pr ospecti v e Di abetes Study (U KPDS) Gr oup. Intensi v e bl oodgl ucose

contr ol w i th sul phoy l ur eas or i nsul i n com par ed w i th conv enti onal tr eatm ent
and r i sk of com pl i cati ons i n pati ents w i th ty pe 2 di abetes (U KPDS 33): U K
Pr ospecti v e Di abetes Study (U KPDS) Gr oup. Lancet 1998;352:837.
Wy att HR, Hi l l JO. What r ol e f or w ei ghtl oss m edi cati on? Wei ghi ng the pr os
and cons f or obese pati ents. Postgr ad Med 2004;115(1):38â€“40, 43â
€“45, 58.
Disorders of the Thyroid
1. What ar e the k ey f eatur es i n a pati ent's hi stor y that ar e i m por tant i n
assessi ng f or a possi bl e f uncti onal thy r oi d di sor der ?
2. What ar e the i m por tant phy si cal ex am i nati on f i ndi ngs?
3. What l abor ator y data ar e used to conf i r m or r ef ute the ex i stence of a
f uncti onal thy r oi d abnor m al i ty ?
Discussion
1. What ar e the k ey f eatur es i n a pati ent's hi stor y that ar e i m por tant i n
assessi ng f or a possi bl e f uncti onal thy r oi d di sor der ?
When assessi ng a pati ent's hi stor y f or cl ues to a f uncti onal thy r oi d
di sease, i t i s i m por tant to k eep i n m i nd that thy r oi d hor m ones i n gener al
contr ol m etabol i sm . Ther ef or e, w hen questi oni ng pati ents about thei r
m edi cal hi stor y , i t i s i m por tant to ask speci f i cal l y about el em ents r el ated
to m etabol i sm . For ex am pl e, i n the setti ng of hy per thy r oi di sm , w ei ght
l oss, anx i ety , tr em or , pal pi tati ons, heat i ntol er ance, hy per def ecati on,
i nsom ni a, r estl essness, and changes i n the hai r or sk i n ar e i m por tant
f eatur es. In contr ast, i n pati ents w i th
P. 99
suspected hy pothy r oi di sm , l ook f or cl ues that i ndi cate decr eased
m etabol i c acti v i ty . These i ncl ude w ei ght gai n; col d i ntol er ance;
consti pati on; dr y , scal y sk i n; thi ck hai r ; depr essi on; i ncr eased sl eepi ng
and f ati gue; and gener al i zed l ethar gy .
2. What ar e the i m por tant phy si cal ex am i nati on f i ndi ngs?
Li k e the hi stor y , the phy si cal ex am i nati on shoul d be per f or m ed to l ook
f or si gns of hy per m etabol i sm or hy pom etabol i sm . In the setti ng of
hy per thy r oi di sm , a f ast pul se; tr em or ; sw eati ng; thi n, sof t, and v el v ety
hai r ; v er y br i sk r ef l ex es; and a hy per dy nam i c pr ecor di um ar e al l f eatur es
of i ncr eased m etabol i sm . In addi ti on, a v er y cr i ti cal f i ndi ng i s an
enl ar ged thy r oi d gl and. If thi s i s f ound i n conjuncti on w i th a br ui t, then
the cl i ni ci an can assum e that the thy r oi d gl and i tsel f i s ov er acti v e and
ov er pr oduci ng thy r oi d hor m one. In contr ast, the f i ndi ngs char acter i sti c of
hy pothy r oi di sm i ncl ude pal e, sal l ow sk i n; thi ck hai r ; puf f i ness i n the f ace
and ank l es; cool ex tr em i ti es; v er y del ay ed deep tendon r el ax ati on;
br ady car di a; and a v er y qui et pr ecor di um . Agai n, an enl ar ged thy r oi d i s
an i m por tant phy si cal ex am i nati on f i ndi ng. In thi s ev ent, a f i r m , w oody ,
or pebbl y tex tur e w oul d i ndi cate the pr esence of l y m phocy ti c i nf i l tr ati on
or Hashi m oto's thy r oi di ti s.
3. What l abor ator y data ar e used to conf i r m or r ef ute the ex i stence of a
f uncti onal thy r oi d abnor m al i ty ?
Ther e i s now a v er y sensi ti v e and speci f i c l abor ator y pr otocol to

deter m i ne w hether the pati ent has a f uncti onal thy r oi d di sor der . The f i r st
di agnosti c test shoul d be m easur em ent of the ser um TSH l ev el usi ng the
sensi ti v e TSH assay s. If thi s assay r esul t pr ov es to be w i thi n the nor m al
r ange, then a f uncti onal abnor m al i ty of the thy r oi d has v i r tual l y been
ex cl uded. In contr ast, an el ev ated TSH l ev el m eans the thy r oi d gl and i s
f ai l i ng and the pati ent has pr i m ar y thy r oi d gl and f ai l ur e, m ost com m onl y
due to autoi m m une thy r oi d di sease. Conv er sel y , i f the ser um TSH l ev el i s
l ow and undetectabl e, thi s i ndi cates hy per thy r oi di sm due to Gr av es'
di sease, a m ul ti nodul ar goi ter , a hot nodul e, ex cessi v e thy r oi d hor m one
i ngesti on, subacute thy r oi di ti s, postpar tum thy r oi di ti s, or si l ent
thy r oi di ti s. If the TSH v al ue i s abnor m al , then thy r oi d hor m one status
shoul d be assessed. Thi s can be done ei ther by obtai ni ng a total T 4 w i th a
T 3 r esi n uptak e (to assess T 4 bi ndi ng gl obul i n), or by si m pl y or der i ng a
f r ee T 4 . Onl y i n speci al ci r cum stances i s i t necessar y to test f or total T 3
or f r ee T 3 l ev el s. Fi nal l y , i n ev al uati ng a pati ent w i th suspected
hy per thy r oi di sm , i f both the TSH l ev el i s l ow and the f r ee T 4 l ev el i s
hi gh, the nex t step i s to per f or m a r adi oacti v e i odi ne uptak e test and
scan. Thi s test i s v er y i m por tant i n di sti ngui shi ng causes of
hy per thy r oi di sm r el ated to ov er pr oducti on (i . e. , Gr av es' di sease, a
m ul ti nodul ar goi ter , or a hot nodul e) f r om those r el ated to ex cessi v e
r el ease but not pr oducti on (i . e. , subacute thy r oi di ti s, postpar tum
thy r oi di ti s, or si l ent thy r oi di ti s), as w el l as ex cessi v e thy r oi d hor m one
i ngesti on. The scan al so i nf er s the ther apeuti c appr oach. In the setti ng of
str ong cl i ni cal ev i dence f or hy pothy r oi di sm w i th a l ow or nor m al TSH, i t
i s al so i m por tant to consi der the r el ati v el y r ar e possi bi l i ty of centr al , or
secondar y , hy pothy r oi di sm (def ecti v e TSH pr oducti on by the pi tui tar y
gl and).
P. 100
Case
A 31y ear ol d m other of tw o i s seen because of com pl ai nts of headaches and
am enor r hea, w hi ch hav e l asted f or 3 m onths. She del i v er ed her second chi l d
10 m onths ago. The headaches dev el oped af ter she w as i n a m otor v ehi cl e
acci dent 4 m onths bef or e. At that ti m e, the pati ent ex per i enced a tem por ar y
l oss of consci ousness but has si nce been nor m al ; an ex tensi v e neur ol ogi c
ex am i nati on i n the em er gency r oom y i el ded negati v e f i ndi ngs. On f ur ther
questi oni ng, the pati ent al so adm i ts to a 15l b (6. 75k g) w ei ght l oss despi te a
nor m al appeti te, as w el l as m i l d heat i ntol er ance and ex cessi v e sw eati ng
dur i ng the sum m er m onths. Recentl y , she has noted that her hands shak e and
her handw r i ti ng has becom e unev en. Of si gni f i cance i s her ex er ci se hi stor y ;
she had been r unni ng 5 to 6 m i a day , 5 day s a w eek , and has par ti ci pated i n
m ar athon r unni ng com peti ti ons. How ev er , ov er the l ast 3 m onths, her
tol er ance f or ex er ci se has decr eased, and her r unni ng ti m es hav e
deter i or ated. On questi oni ng her about her f am i l y hi stor y , i t i s f ound that her
m other tak es l ev othy r ox i ne f or hy pothy r oi di sm , a m ater nal gr andm other has
T2DM, and her f ather has hy per l i pi dem i a and cor onar y ar ter y di sease.
Phy si cal ex am i nati on r ev eal s a w el l dev el oped, w el l nour i shed, thi n w om an
w ho appear s som ew hat anx i ous. Her BP i s 130/50 m m Hg and her pul se i s 120
beats per m i nute. Her hai r i s f i ne w i th str eak s of gr ay . Her ey es ex hi bi t no
ex ophthal m os, but ther e i s a star e and l i d l ag. The ex tr aocul ar m uscl es ar e
nor m al . The thy r oi d i s di f f usel y enl ar ged at appr ox i m atel y 40 g. Ther e i s a
hi ghi ntensi ty br ui t audi bl e ov er the r i ght l obe of the thy r oi d. The car di ac
ex am i nati on r ev eal s a nor m al f i r st and second hear t sound and a gr ade 1/6
sy stol i c ejecti on m ur m ur . The l ungs ar e cl ear to auscul tati on and per cussi on.
Abdom i nal ex am i nati on f i ndi ngs ar e negati v e. Her hands ex hi bi t an
outstr etched tr em or and her sk i n i s noted to be w ar m , sm ooth, and sl i ghtl y
m oi st. Her r ef l ex es ar e sy m m etr i cal l y br i sk . Ther e i s sl i ght pr ox i m al m uscl e
w eak ness detected i n the thi ghs and shoul der gi r dl e m uscl es.
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, and shoul d i t i ncl ude a
nor m al pr egnancy ?
2. What i s the m ost ef f i ci ent appr oach to the l abor ator y ev al uati on i n thi s
pati ent?
3. To di sti ngui sh si l ent thy r oi di ti s f r om Gr av es' hy per thy r oi di sm , w hat i s the
m ost i m por tant di agnosti c tool ?
4. If the pati ent has si l ent thy r oi di ti s, w hat i s the appr opr i ate ther apy ?
5. If the pati ent has Gr av es' di sease and i s tr eated w i th r adi oacti v e i odi ne,
w hat i s l i k el y to occur ?
6. If the pati ent i s tr eated w i th anti thy r oi d dr ugs, w hat i s the l i k el y shor t
and l ongter m pr ognosi s?
Case Discussion
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, and shoul d i t i ncl ude a
nor m al pr egnancy ?
A nor m al pr egnancy can m i m i c m any of the sy m ptom s of

hy per thy r oi di sm , i ncl udi ng i ncr eased ener gy , anx i ety , heat i ntol er ance,
sw eati ng, and, i n ar eas of the w or l d w her e i odi ne def i ci ency i s com m on,
a m i l d i ncr ease i n the thy r oi d gl and si ze. In addi ti on, pr egnancy can
cer tai nl y decr ease the tol er ance f or m ax i m al ex er ci se. Featur es that ar e
not char acter i sti c of pr egnancy ar e the m oder ate (40 g) thy r oi d
P. 101
enl ar gem ent, the l i d l ag and star e, and, m ost i m por tant, the br ui t ov er
the r i ght si de of the thy r oi d gl and. A br ui t i n the thy r oi d gl and r ef l ects
the pr esence of i ncr eased bl ood f l ow due to hy per pl asi a and ex cessi v e
thy r oi d gl and f uncti on. These f eatur es ar e absent i n pr egnancy , and
ther ef or e a br ui t w oul d not be hear d. How ev er , pr ev i ousl y si l ent thy r oi d
di sease m ay becom e appar ent dur i ng pr egnancy . In addi ti on, a 15l b
(6. 75k g) w ei ght l oss, despi te a nor m al appeti te, w oul d be di sti nctl y
unusual i n the pr egnant state. Ther ef or e, a nor m al pr egnancy i s an
unl i k el y cause of thi s pati ent's sy m ptom s. The di f f er enti al di agnosi s
ther ef or e consi sts of hy per thy r oi di sm due to Gr av es' di sease, a
m ul ti nodul ar goi ter , and si l ent thy r oi di ti s. A m ul ti nodul ar goi ter i s
unusual i n a 31y ear ol d pati ent, and i s usual l y seen i n the ol der
popul ati on. Fur ther m or e, m ul ti nodul ar goi ter s ar e not associ ated w i th a
br ui t, ev en w hen pr oduci ng hy per thy r oi di sm . The di f f use enl ar gem ent of
the thy r oi d gl and at 40 g i s al so unusual i n the setti ng of a m ul ti nodul ar
goi ter because, i n thi s ev ent, m ul ti pl e nodul es shoul d be appr eci ated on
the phy si cal ex am i nati on. A star e and l i d l ag can be f ound i n pati ents
w i th hy per thy r oi di sm due to a m ul ti nodul ar goi ter because these f i ndi ngs
r ef l ect the hy per thy r oi di sm , not the autoi m m une pr ocess.
The i m por tant di f f er enti al di agnosti c ex er ci se i n thi s case shoul d f ocus on
w hether the hy per thy r oi di sm i s due to Gr av es' di sease or si l ent
thy r oi di ti s. Gr av es' di sease i s the m ost com m on cause of hy per thy r oi di sm
and i s f ound m or e f r equentl y i n w om en than i n m en, w i th a r ati o of 4:1.
In addi ti on, hy per thy r oi di sm due to Gr av es' di sease usual l y af f l i cts
y ounger peopl e betw een 20 and 50 y ear s of age. The 15l b (6. 75k g)
w ei ght l oss, heat i ntol er ance, ex cessi v e sw eati ng, tr em or , decr eased
ex er ci se tol er ance, m oder ate enl ar gem ent of the thy r oi d w i th a br ui t, and
the w ar m , sm ooth, and sl i ghtl y m oi st sk i n ar e al l char acter i sti c of
hy per thy r oi di sm due to Gr av es' di sease. In addi ti on, the pati ent has a
f am i l y hi stor y of autoi m m une di sease, i n that the m other i s bei ng tr eated
f or hy pothy r oi di sm and the gr andm other has adul tonset DM. In addi ti on,
the pati ent appear s to hav e pr em atur e gr ay hai r . The absence of
ex ophthal m os does not conf l i ct w i th thi s di agnosi s because thi s f i ndi ng
m ay be cl i ni cal l y ev i dent i n onl y 10% to 20% of pati ents w i th Gr av es'
hy per thy r oi di sm . (How ev er , w hen m or e sophi sti cated techni ques f or
ev al uati ng ey e f uncti on ar e used, as m any as 80% to 90% of the pati ents
w i th Gr av es' hy per thy r oi di sm pr ov e to hav e di scer ni bl e ey e
abnor m al i ti es. )
Hy per thy r oi di sm due to si l ent thy r oi di ti s i s becom i ng an i ncr easi ngl y
w el l r ecogni zed di agnosti c enti ty . The ex act eti ol ogy of thi s di sor der i s
obscur e, but appear s to be an autoi m m une pr ocess. Si l ent thy r oi di ti s i s
per haps i denti cal to postpar tum thy r oi di ti s, w hi ch ar i ses i n 5% to 8% of
al l pr egnanci es i n the U ni ted States. Thi s di sor der appear s usual l y
betw een 2 and 6 m onths postpar tum (10 m onths i s sl i ghtl y ex cessi v e).
The pati ent ex hi bi ts the si gns and sy m ptom s of hy per thy r oi di sm and an
enl ar ged thy r oi d gl and, but has no ev i dence of ex ophthal m os or pr eti bi al
P. 102
of the tw o di sor der s ar e qui te di f f er ent. Because am enor r hea can occur i n
al l f or m s of hy per thy r oi di sm , i t i s not a hel pf ul cl ue f or i denti f y i ng the
ul ti m ate cause of the hy per thy r oi di sm . Fi nal l y , the br ui t ov er the r i ght
l obe of the thy r oi d i s an i m por tant cl ue that poi nts tow ar d a di agnosi s of
Gr av es' di sease i n thi s pati ent. A br ui t ov er the thy r oi d gl and i s usual l y
not pr esent i n hy per thy r oi di sm due to a m ul ti nodul ar goi ter , si l ent
thy r oi di ti s, or subacute thy r oi di ti s. Ther ef or e, on the basi s of the
pati ent's hi stor y , phy si cal ex am i nati on f i ndi ngs, and stati sti cal
consi der ati ons the m ost l i k el y di agnosi s i s hy per thy r oi di sm due to
Gr av es' di sease. How ev er , f or m al l abor ator y studi es shoul d be done f i r st
to deter m i ne w hether hy per thy r oi di sm i s i ndeed pr esent and then to
i denti f y the cause of the hy per thy r oi di sm .
2. Whi ch i s the m ost ef f i ci ent appr oach to the l abor ator y ev al uati on i n thi s
pati ent?
The k ey i ssue i n deci di ng on the natur e of the l abor ator y ev al uati on i s
w hi ch test best deter m i nes i f hy per thy r oi di sm i s i ndeed pr esent. Total T 4
and T 3 r esi n uptak e w er e tr adi ti onal l y r egar ded as the best tests f or
establ i shi ng the pr esence of hy per thy r oi di sm and f or di sti ngui shi ng
hy per thy r oi di sm f r om a nor m al pr egnancy . In al l f or m s of
hy per thy r oi di sm , both total T 4 and T 3 r esi n uptak e ar e el ev ated, w her eas
i n pr egnancy , the total T 4 i s el ev ated because of an i ncr ease i n the T 4
bi ndi ng gl obul i n l ev el , and the T 3 r esi n uptak e i s r educed, agai n because
of the i ncr eased T 4 bi ndi ng gl obul i n l ev el . How ev er , these sam e
abnor m al i ti es i n thy r oi d f uncti on can occur i n the absence of pr egnancy ,
such as i n a pati ent tak i ng bi r th contr ol pi l l s or r epl acem ent estr ogen, or
i n a w om an w i th congeni tal Xl i nk ed T 4 bi ndi ng gl obul i n ex cess.
Fur ther m or e, conf usi on can ar i se w hen both hy per thy r oi di sm and
ex cessi v e estr ogens coex i st because the T 4 concentr ati on can be el ev ated
and the T 3 r esi n uptak e m ay be v ar i abl e (l ow , nor m al , or hi gh v al ues) i n
thi s setti ng. The total T 3 i s a good test f or hy per thy r oi di sm but because
T 3 i s al so bound to T 4 bi ndi ng gl obul i n i ts l ev el s ar e el ev ated i n the
contex t of a nor m al pr egnancy or ex ogenous estr ogen. The m ost ef f i ci ent
l abor ator y tests i n thi s case ar e deter m i nati ons of the f r ee T 4 and TSH
l ev el s. The f r ee T 4 l ev el i s el ev ated i n hy per thy r oi di sm but nor m al i n
pr egnancy . Li k ew i se, the TSH l ev el i s suppr essed and undetectabl e i n the
setti ng of hy per thy r oi di sm but nor m al i n pr egnancy . Ther ef or e, thi s
l abor ator y pr of i l e i s i deal f or di scr i m i nati ng betw een hy per thy r oi di sm and
pr egnancy r el ated changes i n thy r oi d l ev el s. How ev er , the f r ee T 4 and
TSH l ev el s cannot di scr i m i nate betw een hy per thy r oi di sm due to Gr av es'
di sease, a m ul ti nodul ar goi ter , or si l ent thy r oi di ti s.
3. To di sti ngui sh si l ent thy r oi di ti s f r om Gr av es' hy per thy r oi di sm , w hat i s the
m ost i m por tant di agnosti c tool ?
The m ost i m por tant di agnosti c tool f or di sti ngui shi ng si l ent thy r oi di ti s
f r om Gr av es' di sease i s a r adi oacti v e i odi ne uptak e test. Gr av es' di sease,
w hi ch i s a state of thy r oi d hor m one ov er pr oducti on, i nv ol v es an ex cessi v e
uptak e of i odi ne i nto the thy r oi d gl and and ther ef or e a hi gh r adi oacti v e
i odi ne uptak e. In contr ast, si l ent thy r oi di ti s i s not an ov er pr oducti on
state but a state i n w hi ch ther e i s an ex cessi v e r el ease of thy r oi d
hor m one i nto the ci r cul ati on that suppr esses TSH, stem m i ng f r om
autoi m m une dam age to thy r oi d f ol l i cul ar cel l s. These ev ents r ender the
thy r oi d gl and i ncapabl e of tak i ng up i odi ne. Ther ef or e, i n the setti ng of
si l ent thy r oi di ti s, the r adi oacti v e i odi ne uptak e i s v er y l ow , i n str i k i ng
contr ast to the el ev ated v al ues f ound i n pati ents w i th Gr av es'
hy per thy r oi di sm .
P. 103
4. If the pati ent has si l ent thy r oi di ti s, w hat i s the appr opr i ate ther apy ?
Di sti ngui shi ng si l ent thy r oi di ti s f r om Gr av es' di sease i s i m por tant because
the ther api es f or the tw o condi ti ons ar e dr am ati cal l y di f f er ent. Because
si l ent thy r oi di ti s i s a destr ucti v e pr ocess w i thout ov er pr oducti on, i t does
not r espond to ei ther anti thy r oi d dr ugs or r adi oacti v e i odi ne. The l ow
r adi oacti v e i odi ne uptak e i n si l ent thy r oi di ti s r ender s r adi oacti v e i odi ne
ther apy i nef f ecti v e, and the l ack of ov er pr oducti on of thy r oi d hor m ones
negates the ef f ecti v eness of anti thy r oi d dr ugs. Because si l ent thy r oi di ti s
i s a sel f l i m i ted pr ocess w i th a tr i phasi c cour se, the r ecom m ended
ther apy i s the judi ci ous use of Î²bl ock er s to contr ol sy m ptom s,
par ti cul ar l y tr em or and tachy car di a, and obser v ati on of the pati ent dur i ng
the spontaneous r esol uti on of the pr ocess. Ty pi cal l y , the hy per thy r oi d
phase l asts f or 1 to 3 m onths, af ter w hi ch the pr ocess i s dr am ati cal l y
r ev er sed; i n f act, hy pothy r oi di sm can occur tr ansi entl y f or another 1 to 3
m onths. Dur i ng the hy pothy r oi d phase, m any pati ents benef i t f r om a
shor t cour se of thy r oi d hor m one r epl acem ent. How ev er , i n m ost cases,
both the hy per thy r oi di sm and hy pothy r oi di sm r esol v e spontaneousl y and
nor m al thy r oi d f uncti on i s r estor ed. In onl y 10% to 25% of cases does
per m anent hy pothy r oi di sm ev entuate. Per haps the m ost i m por tant cl i ni cal
cl ue to the r esol uti on of si l ent thy r oi di ti s i s nor m al i zati on of the thy r oi d
gl and si ze. Because si l ent thy r oi di ti s i s a sel f l i m i ted pr ocess that
r esol v es spontaneousl y , thy r oi d sur ger y i s usual l y unnecessar y . How ev er ,
thi s opti on can be r eser v ed f or par ti cul ar l y sev er e cases that hav e
pr otr acted or r ecur r ent cour ses.
5. If the pati ent has Gr av es' di sease and i s tr eated w i th r adi oacti v e i odi ne,
w hat i s l i k el y to occur ?
The m ost com m on ther apy f or Gr av es' di sease i n the U ni ted States i s
r adi oacti v e i odi ne, w hi ch i s gi v en i n the f or m of a sm al l capsul e
contai ni ng 5 to 10 m Ci of i odi ne131 ( 1 3 1 I). The r adi oacti v e i odi ne i s
qui ck l y absor bed f r om the gastr oi ntesti nal tr act i nto the bl oodstr eam and
then i ncor por ated i nto the thy r oi d gl and, w her e i t i nduces r adi oacti v e
dam age and k i l l s thy r oi d cel l s. Radi oacti v e i odi ne that does not enter the
thy r oi d gl and i s qui ck l y ex cr eted thr ough the k i dney s i nto the ur i ne.
Because r adi oacti v e i odi ne i nduces dam age and ev entual death of thy r oi d
f ol l i cul ar cel l s, the chance of hy pothy r oi di sm dev el opi ng i s v er y hi gh. In
gener al , hy pothy r oi di sm dev el ops i n the f i r st y ear i n 50% to 60% of the
pati ents tr eated; ther eaf ter , the r ate of dev el opm ent of hy pothy r oi di sm i s
1% to 3% per y ear . Ther ef or e, hy pothy r oi di sm w i l l dev el op i n m ost
pati ents tr eated w i th r adi oacti v e i odi ne and they w i l l r equi r e l i f el ong
thy r oi d hor m one r epl acem ent ther apy .
6. If the pati ent i s tr eated w i th anti thy r oi d dr ugs, w hat i s the l i k el y shor t
and l ongter m pr ognosi s?
Anti thy r oi d dr ugs (pr opy l thi our aci l and m ethi m azol e) ar e der i v ati v es of
thi our ea and thei r m echani sm of acti on i s to i nhi bi t both thy r oi d hor m one
sy nthesi s and, i n the case of pr opy l thi our aci l , the per i pher al conv er si on
of T 4 to T 3 . These dr ugs ar e an i deal choi ce of ther apy f or pati ents w i th
hy per thy r oi di sm due to Gr av es' di sease. They ar e m ost com m onl y used i n
chi l dr en and pr egnant pati ents, and i n r el ati v el y m i l d cases of
hy per thy r oi di sm i n w hi ch the thy r oi d gl and i s onl y m oder atel y enl ar ged.
Pr opy l thi our aci l i s gi v en i n a dose of appr ox i m atel y 100 m g thr ee or f our
ti m es a day . Methi m azol e (Tapazol e; El i Li l l y , Indi anapol i s, IN ) has a
sl i ghtl y l onger hal f l i f e
P. 104
than pr opy l thi our aci l and m ay be gi v en i n a si ngl e dai l y dose of 10 to 30
m g each day . Both agents ex hi bi t a si m i l ar pr of i l e of si de ef f ects, w hi ch
occur i n 1% to 3% of the pati ents. The m ost com m on si de ef f ects ar e
sk i n r ash, ur ti car i a, ar thr al gi as, f ev er , and tr ansi ent l euk openi a. Mi nor
gastr oi ntesti nal si de ef f ects and ar thr i ti s occur occasi onal l y . The m ajor
r ar e si de ef f ect i s agr anul ocy tosi s, w hi ch occur s i n 0. 2% to 0. 5% of the
pati ents. Other r ar e si de ef f ects i ncl ude apl asti c anem i a, hepati ti s,
thr om bocy topeni a, v ascul i ti s, and chol estati c jaundi ce. The si de ef f ects
usual l y ar i se ear l y i n the cour se of ther apy , and i n the case of
m ethi m azol e the r eacti ons appear to be dose dependent.
The anti thy r oi d dr ugs ar e usual l y gi v en f or a 1 to 2y ear per i od i n the
hope of i nduci ng per m anent r em i ssi on. The f r equency w i th w hi ch
per m anent r em i ssi on tak es pl ace has been anal y zed i n m any studi es and
has been f ound to occur i n those pati ents w ho hav e m i l d di sease and
sm al l er thy r oi d gl ands. How ev er , w hen al l pati ents ar e consi der ed, the
chance f or per m anent r em i ssi on i s onl y 20% to 40%. Ther ef or e, 60% to
80% of pati ents hav e a r el apse of thei r hy per thy r oi di sm , usual l y w i thi n 2
y ear s of di sconti nui ng the anti thy r oi d dr ug. In cases of r el apse, the
anti thy r oi d dr ug can ei ther be r ei nsti tuted or a m or e def i ni ti v e abl ati v e
f or m of ther apy , such as r adi oacti v e i odi ne, can be adm i ni ster ed.
Suggested Readings
Bar tal ena L, Mar cocci C, Bogazzi F, et al . Rel ati on betw een ther apy f or
hy per thy r oi di sm and the cour se of Gr av es' ophthal m opathy . N Engl J Med
1998;338:73.
Bur guer a B, Ghar i b H. Thy r oi d i nci dental om as: pr ev al ence, di agnosi s,

si gni f i cance, and m anagem ent. Endocr i nol Metab Cl i n N or th Am
2000;29(1):187â€“203.
Castr o MR, Ghar i b H. Conti nui ng contr ov er si es i n the m anagem ent of
thy r oi d nodul es. Ann Inter n Med 2005;142:926â€“931.
Cooper DS, Doher ty GM, Haugen BR, et al . Managem ent gui del i nes f or
pati ents w i th thy r oi d nodul es and di f f er enti ated thy r oi d cancer . Thy r oi d
2006;16(2):1â€“33.
Ghar i b H, Tuttl e RM, Bask i n HJ, et al . Subcl i ni cal thy r oi d dy sf uncti on: a
joi nt statem ent on m anagem ent f r om the Am er i can Associ ati on of Cl i ni cal
Endocr i nol ogi sts, the Am er i can Thy r oi d Associ ati on, and the Endocr i ne
Soci ety . J Cl i n Endocr i nol Metab 2005;90(1):581â€“585; di scussi on586â
€“587.
Haugen BR. Ini ti al tr eatm ent of di f f er enti ated thy r oi d car ci nom a. Rev
Endocr Metab Di sor d 2000;1(3):139â€“145.
Kahal y JG, Di l l m ann HW. Thy r oi d hor m one acti on i n the hear t. Endocr Rev
2005;26:704â€“728.
Lev y EG, Ri dgw ay EC, War tof sk y L. Al gor i thm s f or di agnosi s and
m anagem ent of thy r oi d di sor der s, Â© 20032004. Av ai l abl e f r om :
http://w w w . Thy r oi dtoday . com /Ex per tOpi ni ons/Thy r oi dDi seaseAl gor i thm s. pdf .
Sar l i es N J, Gour gi oti s L. Thy r oi d em er genci es. Rev Endocr Metab Di sor d
2003;4:129â€“136.
Stathatos N , War tof sk y L. The euthy r oi d si ck sy ndr om e: i s ther e a

phy si ol ogi c r ati onal e f or thy r oi d hor m one tr eatm ent? J Endocr i nol Inv est
2003;26(12):1174â€“1179.
Sur k s MI, Or ti z E, Dani el s GH, et al . Subcl i ni cal thy r oi d di sease: sci enti f i c
r ev i ew and gui del i nes f or di agnosi s and m anagem ent. JAMA
2004;291(2):228â€“238.
P. 105
Growth HormoneSecreting Pituitary Tumors
1. What ar e the cl i ni cal sy m ptom s of GH ex cess (i . e. , acr om egal y )?
2. What ar e the phy si cal si gns of acr om egal y ?
3. What i s the best scr eeni ng test to ex cl ude the di agnosi s of acr om egal y ?
4. What l abor ator y tests can conf i r m the di agnosi s of acr om egal y and assess
other pi tui tar y hor m one f uncti ons?
5. What i m agi ng studi es ar e necessar y ?
6. What i s the tr eatm ent of choi ce and w hat ar e the al ter nati v es?
Discussion
1. What ar e the cl i ni cal sy m ptom s of GH ex cess (i . e. , acr om egal y )?
Acr om egal y i s the cl i ni cal sy ndr om e r esul ti ng f r om ex cessi v e GH

pr oducti on and i s usual l y due to a pi tui tar y tum or . The sy m ptom s and
si gns ar e gr adual i n onset, w hi ch of ten cause di agnosi s to be del ay ed f or
6 to 8 y ear s. The cl assi c sy m ptom s consi st of headache, v i sual
di stur bances (due to an enl ar gi ng tum or com pr essi ng on the opti c
ner v es), enl ar gem ent i n gl ov e and shoe si ze, ex cessi v e sw eati ng,
ar thr al gi as, l oss of l i bi do, i m potence i n m en, am enor r hea i n w om en,
m uscl e w eak ness, and pr obl em s w i th an under bi te or spaces betw een the
teeth.
2. What ar e the phy si cal si gns of acr om egal y ?
The phy si cal si gns of acr om egal y i ncl ude coar seni ng of the phy si cal
f eatur es (w hi ch can be deter m i ned by l ook i ng at ol d photogr aphs); f r ontal
bossi ng; thi ck , coar se sk i n; doughy , sw eaty pal m s; pr ognathi sm (an
enl ar ged m andi bl e); w i del y spaced teeth and under bi te; sev er e
osteoar thr i ti s; pr om i nent l i ps, tongue, and nose; acanthosi s ni gr i cans;
sk i n tags; enl ar gem ent of al l or gans; entr apm ent of per i pher al ner v es
(i . e. , car pal tunnel ); hy per tensi on w i th car di om y opathy ; obstr ucti v e sl eep
apnea v i sual f i el d abnor m al i ti es; gl ucose i ntol er ance; and di abetes.
3. What i s the best scr eeni ng test to ex cl ude the di agnosi s of acr om egal y ?
The best scr eeni ng test f or acr om egal y i s m easur em ent of the i nsul i nl i k e
gr ow th f actor I (IGFI; som atom edi n C) l ev el . Thi s i s a l i v er pr otei n
i nduced by GH and the test consti tutes an i ntegr ated assessm ent of GH
acti on. GH l ev el s ar e pul sati l e i n natur eâ€”f asti ng l ev el s ar e usual l y l ess
than 10 ng/m L i n adul ts and the GH concentr ati on i ncr eases at ni ght
dur i ng sl eep. As the l ev el s i n pati ents w i th acr om egal y can be as l ow as
5â€“10 ng/m L, the GH l ev el i s hel pf ul i f v er y hi gh, but i s nei ther
sensi ti v e nor speci f i c i f nor m al or m i l dl y el ev ated.
4. What l abor ator y tests can conf i r m the di agnosi s of acr om egal y and assess
other pi tui tar y hor m one f uncti ons?
To conf i r m the di agnosi s and assess the pi tui tar y f uncti on i n a pati ent,
the GH r esponse to an or al gl ucose l oad i s assessed. To per f or m thi s, 100
g or al gl ucose i s gi v en to the f asti ng pati ent and bl ood f or GH
deter m i nati on i s
P. 106
obtai ned at 0, 30, 60, 90, and 120 m i nutes. In a nor m al r esponse to a
gl ucose l oad, the GH l ev el s ar e suppr essed to l ess than 2 ng/m L. In
pati ents w i th acr om egal y , the GH l ev el s ar e ei ther not suppr essed or they
par adox i cal l y i ncr ease (appr ox i m atel y 30% of pati ents). Thi s test, i f done
i n conjuncti on w i th an IGF1 test, i s the best w ay of assessi ng a cur e
af ter sur ger y . In addi ti on, appr ox i m atel y 30% of the pati ents show an
i ncr ease i n thei r GH l ev el s af ter a thy r otr opi nr el easi ng hor m one (500
Âµg) IV push; heal thy i ndi v i dual s do not. Thi s test i s m or e of ten used i n a
r esear ch setti ng or f or the pur pose of assessi ng tum or r ecur r ence.
Other bl ood tests f or deter m i ni ng pi tui tar y f uncti on i ncl ude m easur em ent
of the pr ol acti n l ev el , w hi ch can be el ev ated because of the i nter r upti on
of dopam i ne tone secondar y to stal k com pr essi on or the cosecr eti on of
pr ol acti n by the tum or . The f ol l i cl esti m ul ati ng hor m one (FSH), l utei ni zi ng
hor m one (LH), and testoster one or estr ogen l ev el s ar e used to assess the
status of the r epr oducti v e ax i s. The thy r oi d status i s check ed by a f r ee
T 4 ; m easur em ent of the TSH l ev el i s not hel pf ul because, i f ther e i s
thy r oi d def i ci ency , i t i s secondar y to TSH def i ci ency . The adr enal ax i s i s
assessed w i th a m or ni ng cor ti sol deter m i nati on; i f l ess than 5 m g/dL, a
f or m al cosy ntr opi n (Cor tr osy n; Or ganon Tek ni k a, Dur ham , N C)
sti m ul ati on test of the ACTH r eser v e shoul d be per f or m ed. Bl ood i s dr aw n
at 0, 30, and 60 m i nutes af ter one am pul e (0. 25 m g) of sy ntheti c ACTH IV
push or IM. In heal thy subjects, the cor ti sol l ev el s i ncr ease to 18 or m or e
and ar e of ten doubl e the basel i ne v al ue. An Î± subuni t l ev el m ay be
hel pf ul as a tum or m ar k er because som e GH tum or s cosecr ete other
pi tui tar y hor m ones.
5. What i m agi ng studi es ar e necessar y ?
The i m agi ng pr ocedur e of choi ce i s an MRI scan of the pi tui tar y . It
pr ov i des the gr eatest detai l of the tum or 's ex tent and l andm ar k s f or the
sur geon's use dur i ng sur gi cal r em ov al . A cor onal CT scan w i th f i ne cuts
can detect m ost l ar ge tum or s, but a l ater al sk ul l f i l m i s not sensi ti v e.
For m al v i sual f i el d testi ng shoul d be done i n al l pati ents w i th
m acr oadenom as to ser v e as a basel i ne f or assessi ng postoper ati v e
i m pr ov em ent.
6. What i s the tr eatm ent of choi ce and w hat ar e the al ter nati v es?
The tr eatm ent of choi ce f or these tum or s, w hi ch ar e usual l y
m acr oadenom as (> 1 cm ), i s tr anssphenoi dal r esecti on of the tum or ,
al though sur gi cal cur e i s of ten di f f i cul t. If postoper ati v e hor m onal testi ng
r ev eal s conti nued abnor m al GH pr oducti on, r adi ati on ther apy i s of ten
necessar y . Medi cal ther apy w i th br om ocr i pti ne (i f the tum or costai ns f or
pr ol acti n) m ay al so r educe the GH l ev el s and tum or si ze, w hi l e the
r esul ts of i r r adi ati on ar e aw ai ted. Som atostati n anal ogs can i nhi bi t GH
pr oducti on. They ar e now av ai l abl e i n shor tacti ng and l ongacti ng f or m s.
Longacti ng octr eoti de nor m al i zes IGFI l ev el s i n 41% to 75% and r educes
tum or si ze i n 30% of subjects i n publ i shed tr i al s.
Mor e r ecentl y a GH r eceptor antagoni st, pegv i som ant, has pr ov ed
ef f ecti v e f or r educti on of IGFI l ev el s i n acr om egal y and has r ecei v ed
U . S. Food and Dr ug Adm i ni str ati on (FDA) appr ov al . Studi es dem onstr ate
that pegv i som ant nor m al i zes IGFI l ev el s i n m or e than 95% of pati ents
w ho hav e
P. 107
f ai l ed other ther api es. Ini ti al concer ns that pi tui tar y tum or gr ow th w oul d
pr oceed uncheck ed w i th thi s tr eatm ent hav e not been bor ne out by
ex per i ence to date.
Case
A 40y ear ol d m an i s seen because of headaches, m uscl e aches, and chr oni c
l ow back and joi nt pai n. As he enter s the of f i ce, y ou noti ce hi s coar se f aci al
f eatur es, f r ontal bossi ng, and l ar ge jaw . When y ou shak e hi s hand, y ou f i nd he
has l ar ge, doughy , sw eaty pal m s and, w hen he sm i l es, y ou note hi s teeth ar e
w i del y spaced.
He has not seen a phy si ci an i n 10 y ear s and i s tak i ng no m edi cati ons. Hi s back
and joi nt pai n hav e been w or seni ng f or 6 y ear s, but hi s headaches star ted 6
m onths ago.
Hi s phy si cal ex am i nati on f i ndi ngs ar e si gni f i cant f or a BP of 150/100 m m Hg,
pul se of 60 per m i nute, and r espi r ator y r ate of 12 per m i nute.
He r etur ns i n 2 w eek s w i th ol d photogr aphs that conf i r m a change i n hi s
phy si cal appear ance ov er ti m e, and the l abor ator y test r esul ts conf i r m y our
cl i ni cal i m pr essi on.
1. What i s y our i ni ti al di agnosi s i n thi s pati ent?

2. Besi des the back and joi nt pai n and the headaches, w hat other sy m ptom s
w oul d y ou l ook f or to conf i r m or r ef ute y our di agnosi s?
3. Besi des the phy si cal f eatur es y ou obser v e i ni ti al l y , w hat other
abnor m al i ti es w oul d y ou l ook f or on phy si cal ex am i nati on?
4. What l abor ator y tests shoul d be per f or m ed i ni ti al l y ?
5. What addi ti onal testi ng shoul d be per f or m ed once the i ni ti al l abor ator y
r esul ts ar e k now n?
6. What i s the pr ef er r ed tr eatm ent i n thi s pati ent?
Case Discussion
1. What i s y our i ni ti al di agnosi s i n thi s pati ent?
Acr om egal y shoul d be y our i ni ti al di agnosi s.
2. Besi des the back and joi nt pai n and the headaches, w hat other sy m ptom s
w oul d y ou l ook f or to conf i r m or r ef ute y our di agnosi s?
Other sy m ptom s to l ook f or i n thi s pati ent i ncl ude a change i n gl ov e,
r i ng, and shoe si zes, spaces betw een the teeth and an under bi te,
decr eased l i bi do and i m potence, sw eati ng, new snor i ng, pol y ur i a,
pol y di psi a, and a change i n v i si on.
3. Besi des the phy si cal f eatur es y ou obser v e i ni ti al l y , w hat other
abnor m al i ti es w oul d y ou l ook f or on phy si cal ex am i nati on?
Other phy si cal f eatur es to l ook f or i n thi s pati ent i ncl ude thi ck coar se
sk i n, sk i n tags, enl ar ged ex tr em i ti es and or gans, entr apm ent
neur opathi es, v i sual f i el d abnor m al i ti es, and decr eased body hai r and
testi cul ar si ze. Ol d pi ctur es w oul d conf i r m the cl i ni cal suspi ci on.
4. What l abor ator y tests shoul d be per f or m ed i ni ti al l y ?
Ini ti al l abor ator y tests i n thi s pati ent w oul d consi st of the m easur em ent
of IGF1 (som atom edi n C) and f asti ng GH l ev el s. If the l ev el s ar e
el ev ated i t w oul d suggest the di agnosi s of acr om egal y , w hi ch w oul d be
conf i r m ed i f the GH l ev el s di d not
P. 108
suppr ess to l ess than 2 ng/m L i n r esponse to a gl ucose l oad (som e
studi es suggest 1 ng/m L, w hi ch m ay r ef l ect the i ncr eased sensi ti v i ty of
the assay ).
5. What addi ti onal testi ng shoul d be per f or m ed once the i ni ti al l abor ator y
r esul ts ar e k now n?
If the i ni ti al l abor ator y r esul ts i ndi cate acr om egal y , a f asti ng bl ood sugar
test shoul d be per f or m ed to r ul e out di abetes. Pi tui tar y tests shoul d
i ncl ude m easur em ent of the pr ol acti n, FSH, LH, testoster one, and Î±
subuni t l ev el s. An MRI scan can show the ex tent of the tum or , and f or m al
v i sual f i el d testi ng shoul d be per f or m ed.
6. What i s the pr ef er r ed tr eatm ent i n thi s pati ent?
The pr ef er r ed i ni ti al tr eatm ent i s sur gi cal r em ov al of the tum or .

Br om ocr i pti ne or a som atostati n (octr eoti de) anal og m ay be usef ul as
m edi cal adjuncts. Pegv i som ant m ay be consi der ed f or r esi dual tum or s
that ar e r ef r actor y to other m edi cal m anagem ent. Radi ati on ther apy m ay
be i ndi cated f or the destr ucti on of r esi dual tum or i f r eoper ati on or
sur gi cal cur e i s not f easi bl e. Postoper ati v e hor m onal testi ng i s i ndi cated
to r eassess pi tui tar y f uncti on. Echocar di ogr aphy and col onoscopy shoul d
be per f or m ed to ev al uate f or car di om egal y and col on pol y ps.
ProlactinSecreting Pituitary Tumors
1. What sy m ptom s and si gns ar e associ ated w i th an el ev ated pr ol acti n l ev el
i n w om en and i n m en?
2. What i s the under l y i ng pathophy si ol ogi c pr ocess r esponsi bl e f or the

ef f ects of el ev ated pr ol acti n l ev el s?
3. What ar e the causes of an el ev ated pr ol acti n l ev el other than a pi tui tar y
tum or ?
4. What testi ng i s necessar y to conf i r m or r ef ute a di agnosi s of a

pr ol acti nom a?
5. What ar e the tr eatm ent opti ons f or a pr ol acti nom a?
Discussion
1. What sy m ptom s and si gns ar e associ ated w i th an el ev ated pr ol acti n l ev el
i n w om en and i n m en?
In w om en, an el ev ated pr ol acti n l ev el i s associ ated w i th di stur bance of
the m enstr ual cy cl eâ€”r angi ng f r om the occur r ence of shor t cy cl es w i th
an i nadequate l uteal phase, ol i goov ul ati on, and i nf er ti l i ty , to am enor r hea.
Gal actor r hea, hi r suti sm , m ood di stur bances, and headaches ar e al so
f r equent com pl ai nts. In m en, sy m ptom s i ncl ude decr eased l i bi do,
i m potence, and i nf er ti l i ty . Gal actor r hea i s a r ar e f i ndi ng. Vi sual f i el d
def ects ar e seen i n the setti ng of l ar ge tum or s. Osteopeni a and f r actur es
can occur i n both sex es and ar e due to the secondar y hy pogonadi sm .
2. What i s the under l y i ng pathophy si ol ogi c pr ocess r esponsi bl e f or the

ef f ects of el ev ated pr ol acti n l ev el s?
Pr ol acti n i s under toni c i nhi bi tor y contr ol f r om dopam i ne i n the

hy pothal am us. Stal k com pr essi on, w hi ch causes dopam i ne tone to be
i nhi bi ted, or pr ol acti n secr eti on f r om a tum or i nhi bi ts the hy pothal am i câ
€“pi tui tar y â€“gonadal
P. 109
ax i s at al l thr ee l ev el s. The m ajor ef f ect, how ev er , i s ter m i nati on of the
gonadotr opi nr el easi ng hor m oneâ€“i nduced pul sati l e r el ease of the
pi tui tar y gonadotr opi ns, LH and FSH. Thi s di sor der ed gonadotr opi n
secr eti on then r esul ts i n i nadequate gam etogenesi s and ster oi dogenesi s,
and hence hy pogonadi sm w i th or w i thout i nf er ti l i ty . For gal actor r hea to
occur , ther e m ust be estr ogen pr i m i ng of the br east i n addi ti on to an
el ev ated pr ol acti n l ev el , w hi ch i s w hy m i l k pr oducti on does not dev el op i n
m ost m en unl ess thei r pr ol acti n l ev el i s chr oni cal l y v er y el ev ated w i th
suppr essi on of testoster one r el ease, el ev ati on of the estr adi ol l ev el , and
gy necom asti a.
3. What ar e the causes of an el ev ated pr ol acti n l ev el other than a pi tui tar y
tum or ?
El ev ated pr ol acti n l ev el s m ay be due to phy si ol ogi c causes such as
pr egnancy , str ess, sl eep, ex er ci se, or f r equent br east sti m ul ati on.
Sy stem i c di sor der s associ ated w i th el ev ated pr ol acti n l ev el s i ncl ude
hy pothy r oi di sm , hy poadr enal i sm , chr oni c r enal f ai l ur e (el ev ated
pr oducti on and decr eased cl ear ance), and l i v er f ai l ur e. Dr ugs that el ev ate
the pr ol acti n l ev el i ncl ude phenothi azi des, tr i cy cl i c anti depr essants,
opi ates, m etocl opr am i de, ci m eti di ne, m ethy l dopa, r eser pi ne, and
am phetam i nes, al l of w hi ch i nter f er e w i th dopam i ne i nhi bi tor y tone.
4. What testi ng i s necessar y to conf i r m or r ef ute a di agnosi s of a

pr ol acti nom a?
A pr ol acti n l ev el of m or e than 100 ng/m L suggests the pr esence of a

tum or , al though tum or s or other causes can be associ ated w i th l ow er
el ev ati ons. N o sti m ul ati on or suppr essi on test i s needed. An MRI of the
pi tui tar y i s necessar y to detect a m i cr oadenom a and ex cl ude a l ar ge
pi tui tar y or hy pothal am i c m ass that i s causi ng stal k com pr essi on.
5. What ar e the tr eatm ent opti ons f or a pr ol acti nom a?
The tr eatm ent of choi ce f or pr ol acti nom as i s the dopam i ne agoni st,
br om ocr i pti ne. It ef f ecti v el y l ow er s pr ol acti n l ev el s and r educes tum or
si ze. Other dopam i ne agoni sts com m onl y used i ncl ude caber gol i ne and
per gol i de. Sur gi cal r em ov al i s r eser v ed f or noncom pl i ant or
br om ocr i pti nei ntol er ant pati ents because of the hi gh r ecur r ence r ate of
20% to 50% at 5 y ear s. Major si de ef f ects of br om ocr i pti ne ther apy
i ncl ude or thostati c di zzi ness, dr y m outh, nausea, and v om i ti ng, al though
these m ay be m i ni m i zed by sl ow ti tr ati on of the dr ug al ong w i th f ood
i ntak e at ni ght. Li f el ong ther apy i s pr obabl y necessar y . Lack of tr eatm ent
l eads to pr ol onged gonadal ster oi d def i ci ency and the r i sk of osteopeni a
and f r actur e. The pr em atur e CV r i sk has not been assessed.
Case
A 28y ear ol d w om an i s seen because of i r r egul ar per i ods and i nf er ti l i ty . Her
m enar che occur r ed at 12 y ear s of age and she had r egul ar per i ods w i th
m ol i m i nal sy m ptom s (br east tender ness, bl oati ng, and cr am pi ng) unti l
appr ox i m atel y 2 y ear s ago. Af ter that, her per i ods hav e becom e l i ghter and
i r r egul ar w i thout m ol i m i nal sy m ptom s. She has decr eased l i bi do, occasi onal
headaches, and i s m oody and i r r i tabl e. She has noted a m i l k y di schar ge f r om
both ni ppl es. She took bi r th contr ol pi l l s f or 2 y ear s, 5 y ear s ago.
Her ex am i nati on i s si gni f i cant f or the f ol l ow i ng f i ndi ngs: nor m al v i sual f i el ds,
gal actor r hea, and a decr eased estr ogen ef f ect on the v agi nal m ucosa.
P. 110

2. What other hi stor i cal f acts ar e i m por tant to el i ci t i n an ef f or t to
deter m i ne the cause of her sy m ptom s?
3. What l abor ator y tests or studi es w oul d y ou hav e done?
4. What i s the tr eatm ent of choi ce i n thi s pati ent?
Case Discussion
The m ost l i k el y di agnosi s i n thi s pati ent i s hy per pr ol acti nem i a.
2. What other hi stor i cal f acts ar e i m por tant to el i ci t i n an ef f or t to

deter m i ne the cause of her sy m ptom s?
It i s i m por tant to f i nd out w hether she m i ght be pr egnant and w hether
she tak es dr ugs that w oul d i nhi bi t dopam i ne tone. In addi ti on, a hi stor y
of hy pothy r oi di sm , hy poadr enal i sm , ex cessi v e br east sti m ul ati on, and
r enal or l i v er di sease shoul d be sought.
3. What l abor ator y tests or studi es w oul d y ou hav e done?
A ser um pr ol acti n l ev el shoul d be m easur ed to deter m i ne the ex tent of
the el ev ati on. In addi ti on, l i v er f uncti on studi es and deter m i nati on of the
BU N and cr eati ni ne l ev el s shoul d be done to r ul e out l i v er or k i dney
di sease. The hum an chor i oni c gonadotr opi n l ev el shoul d be m easur ed to
r ul e out pr egnancy , as w el l as the TSH and cor ti sol l ev el s, i f ther e ar e
sy m ptom s or si gns of hy pothy r oi di sm or hy poadr enal i sm . An MRI scan
shoul d be obtai ned to di sti ngui sh betw een a m i cr oadenom a and a
m acr oadenom a.
4. What i s the tr eatm ent of choi ce i n thi s pati ent?
The tr eatm ent of choi ce i s the dopam i ne agoni st br om ocr i pti ne.
Tr eatm ent i s begun at ni ght w i th the i ntak e of f ood to decr ease the si de
ef f ects of postur al hy potensi on, nausea, and dr y m outh. The goal i s to
nor m al i ze the pr ol acti n l ev el s. Other l ongacti ng dopam i ne agoni sts such
as caber gol i ne, per gol i de, and di hy dr oer gotox i ne ar e av ai l abl e i f pati ents
f ai l to tol er ate br om ocr i pti ne.
Suggested Readings
Ar af ah BM. Medi cal m anagem ent of hy popi tui tar i sm i n pati ents w i th
pi tui tar y adenom as. Pi tui tar y 2002;5:109â€“117.
Ar on DC, How l ett TA. Pi tui tar y i nci dental om as. Endocr i nol Metab Cl i n N or th
Am 2000;29(1):205â€“221.
Mel m ed S, Casanuev a FF, Cav agni ni F, et al . Gui del i nes f or acr om egal y
m anagem ent. J Cl i n Endocr i nol Metab 2002;87(9):4054â€“4058.
Mol i tch ME. Medi cal m anagem ent of pr ol acti nsecr eti ng pi tui tar y adenom as.
Pi tui tar y 2002;5:55â€“65.
Pi ck ett CA. Di agnosi s and m anagem ent of pi tui tar y tum or s: r ecent
adv ances. Pr i m Car e Of f i ce Pr act 2003;30:765â€“789.
Shi m on I, Mel m ed S. Managem ent of pi tui tar y tum or s. Ann Inter n Med
1998;129:472.
P. 111
Sw ear i ngen B, Bar k er FG II, Katznel son L, et al . Longter m m or tal i ty af ter
tr anssphenoi dal sur ger y and adjuncti v e ther apy f or acr om egal y . J Cl i n
Endocr i nol Metab 1998;83:3419.
Hypercalcemia
1. What condi ti ons can cause hy per cal cem i a?
2. What tw o m edi cal condi ti ons account f or m ost cases of hy per cal cem i a?
3. In the hy per cal cem i c pati ent, w hat ar e the l abor ator y f i ndi ngs seen i n the
setti ng of hy per par athy r oi di sm ?
4. What i s the tr eatm ent f or hy per cal cem i a?
5. What ar e the i ndi cati ons f or par athy r oi dectom y ?
Discussion
1. What condi ti ons can cause hy per cal cem i a?
The causes of hy per cal cem i a that need to be consi der ed i n any pati ent
w ho ex hi bi ts a bona f i de el ev ati on i n the ser um cal ci um l ev el as
docum ented i n at l east thr ee r epeat deter m i nati ons ar e l i sted i n Tabl e 3
1.
2. What tw o m edi cal condi ti ons account f or m ost cases of hy per cal cem i a?
Of the m any causes of hy per cal cem i a l i sted i n Tabl e 31, the m ost
com m on ar e m al i gnancy (45%) and hy per par athy r oi di sm (45%). The
l engthy di f f er enti al di agnosi s (see Tabl e 31) i ncl udes the other 10% of
the causes. Hence, f r om a pr acti cal standpoi nt, hy per cal cem i c di sor der s
can be br ok en dow n i nto tw o categor i es: par athy r oi d hor m one (PTH)
m edi ated hy per cal cem i a and nonâ€“PTHm edi ated hy per cal cem i a.
3. In the hy per cal cem i c pati ent, w hat ar e the l abor ator y f i ndi ngs seen i n the
setti ng of hy per par athy r oi di sm ?
For the sak e of si m pl i ci ty , the m any causes of hy per cal cem i a can be
separ ated i nto tw o categor i es accor di ng to the PTH l ev el and l abor ator y
f i ndi ngs r esul t f r om the pr esence or absence of the acti on of PTH. (Tabl es
32 and 33).
4. What i s the tr eatm ent of hy per cal cem i a?
A hy per cal cem i c em er gency i s di agnosed w hen the cal ci um l ev el ex ceeds

14 m g/dL or the pati ent ex hi bi ts sy m ptom s of hy per cal cem i a, consi sti ng
of pr of ound w eak ness, i m pai r ed m ental f uncti on, nausea and v om i ti ng,
and centr al ner v ous sy stem depr essi on l eadi ng to stupor , l ethar gy , or
com a. U r gent tr eatm ent of the hy per cal cem i a i s m andator y i n these
si tuati ons (Tabl e 34).
5. What ar e the i ndi cati ons f or par athy r oi dectom y ?
The f ol l ow i ng i ndi cati ons f or par athy r oi dectom y i n hy per par athy r oi d
pati ents hav e been pr oposed by a N ati onal Insti tutes of Heal th (N IH)
consensus conf er ence:
1. Pati ent y ounger than 50 y ear s
2. El ev ated ser um cal ci um to a concentr ati on of 1. 0 to 1. 6 m g/dL abov e
nor m al l abor ator y v al ues
P. 112
3. Hi stor y of a l i f ethr eateni ng hy per cal cem i c epi sode
4. Reduced cr eati ni ne cl ear ance
5. Pr esence of k i dney stones
6. U r i ne cal ci um ex cr eti on of gr eater than 400 m g per 24 hour s
7. Bone m ass r educed by m or e than 2 standar d dev i ati ons bel ow

nor m al
Table 31 Causes of Hypercalcemia
Pr i m ar y hy per par athy r oi di sm

Spor adi c (90%95% of al l cases of hy per par athy r oi di sm )
Fam i l i al sy ndr om es (MEN 1 and MEN 2)
MEN 1 (tum or s of pi tui tar y , pancr eas, and par athy r oi d)
MEN 2A (m edul l ar y thy r oi d car ci nom a,
hy per par athy r oi di sm , pheochr om ocy tom a)
MEN 2B (m edul l ar y thy r oi d car ci nom a,
pheochr om ocy tom a, m ucosal neur om as, m ar f anoi d
habi tus, and par athy r oi d hy per pl asi a)
N eopl asti c di seases
Local osteol y si s (br east and l ung car ci nom a m etastati c to
bone, and m y el om a)
Hum or al hy per cal cem i a of m al i gnancy
Endocr i ne di sor der s
Hy per thy r oi di sm
Adr enal i nsuf f i ci ency
Beni gn f am i l i al hy pocal ci ur i c hy per cal cem i a
Medi cati ons
Thi azi de di ur eti cs
Vi tam i n D and r ar el y v i tam i n A i ntox i cati on
Mi l k al k al i sy ndr om e
Li thi um
Gr anul om atous di seases
Sar coi dosi s
Ber y l l i osi s, tuber cul osi s, cocci di oi dom y cosi s, hi stopl asm osi s
Mi scel l aneous
Im m obi l i zati on (associ ated w i th hi gh bonetur nov er states
such as i n chi l dr en or i n pati ents w i th Paget's di seases)
Recov er y phase of acute and r enal f ai l ur e (r ar e)
Idi opathi c hy per cal cem i a of i nf ancy (r ar e)
Dehy dr ati on (due to hem oconcentr ati on)
MEN , m ul ti pl e endocr i ne neopl asi a.
Case
A 47y ear ol d w hi te m al e com puter consul tant i s seen i n the w al k i n cl i ni c
com pl ai ni ng of sev er e r i ght hi p pai n and di f f i cul ty i n w al k i ng. He has been
tak i ng i bupr of en f or pai n r el i ef . The pai n i n hi s r i ght hi p and r i ght pr ox i m al
l ow er ex tr em i ty has been pr esent f or appr ox i m atel y 4 m onths, and has
pr ogr essed to becom e a shar p, l ocal i zed r i ght hi p joi nt pai n dur i ng the past
m onth. The pati ent has noted a 10l b (4. 5k g) w ei ght l oss ov er the pr ecedi ng
2 m onths, but ascr i bes thi s to a sel f enf or ced di et. He has noctur i a w i th tw o
to
P. 113
f i v e m i ctur i ti ons per ni ght, and com pl ai ns of ex cessi v e thi r st. In addi ti on, he
i s aw ar e of a decr ease i n hi s abi l i ty to concentr ate ov er the pr ecedi ng sev er al
m onths.
Table 32 Parathyroid Hormone Action on Kidney
Ac tion Ma nife s ta tion
Incr eases tubul ar r esor pti on of cal ci um Hy per cal cem i a, m i l d
hy per cal ci ur i a
Inhi bi ts pr ox i m al tubul e bi car bonate Ty pe II r enal tubul ar

r esor pti on aci dosi s,
hy per chl or em i c
m etabol i c aci dosi s
Incr eases phosphate cl ear ance (decr eases Phosphatur i a,
tubul ar r esor pti on of PO 4 ) decr eased [PO 4 ]
(i ncr eased Cl /PO 4
> 33)
Sti m ul ates r enal cAMP Incr eased

nephr ogenous cAMP
Incr eases 1Î± hy dr ox y l ase acti v i ty f or 1, 25 Incr eased l ev el s of

di hy dr ox y v i tam i n D sy nthesi s 1, 25
di hy dr ox y v i tam i n D
Am i noaci dur i a Am i noaci dur i a
Acti v ates r enal tubul ar enzy m es (al k al i ne Incr eased r enal
phosphatase, gl ucose6phosphate dehy dr o gl ucose pr oducti on
genase), pr om otes r enal gl uconeogenesi s
PO 4 , phosphate r adi cal ; [PO 4 ], PO 4 concentr ati on; cAMP, cy cl i c

adenosi ne m onophosphate.
Hi s past m edi cal hi stor y i s si gni f i cant f or nephr ol i thi asi s r equi r i ng
hospi tal i zati on 10 y ear s ear l i er , and an upper gastr oi ntesti nal hem or r hage 5
y ear s ago, secondar y to pepti c ul cer di sease. Hi s f am i l y hi stor y i s
noncontr i butor y .
Radi ogr aphi c studi es of the pati ent's pel v i s and r i ght hi p show a l y ti c l esi on i n
the r i ght sacr um and f em or al acetabul um . The pati ent i s adm i tted f or f ur ther
ev al uati on.
Phy si cal ex am i nati on r ev eal s a pl easant, m i ddl eaged m an w ho i s ex per i enci ng
consi der abl e pai n i n hi s r i ght hi p. Hi s BP i s 160/98 m m Hg; pul se, 96 beats
per m i nute; r espi r ator y r ate, 20 per m i nute; and tem per atur e, 97. 8Â°F (36. 8Â
°C). N o si gni f i cant sk i n
P. 114
P. 115
l esi ons ar e f ound. On ex am i nati on of the or al phar y nx , a w hi te m ass on the
har d pal ate i s noted. The pati ent has no cer v i cal , ax i l l ar y , or i ngui nal
adenopathy . Thy r oi d ex am i nati on r ev eal s a f ul l ness i n the l ef t l ow er l obe.
Rangeof m oti on ex er ci ses of the r i ght l ow er ex tr em i ty el i ci t sev er e r i ght hi p
tender ness. A neur ol ogi c ex am i nati on r ev eal s di m i ni shed str ength i n the r i ght
hi p f l ex or s and ex tender s w i th nor m al deep tendon r ef l ex es thr oughout. The
pati ent's m ental status i s appr opr i ate.
Table 33 Causes of Hypercalcemia
Va ria ble s P THMe dia te d NonP THMe dia te d
Phosphate Low (< 2. 2 m g/dL) Low , nor m al , or hi gh
Chl or i de Hi gh (> 104 U sual l y < 100

m Eq/dL) m Eq/dL
Metabol i c aci dosi s Mi l d N ot pr esent
Cl /PO 4 > 33 < 33
PTH Hi gh Low
Hy per par athy r oi di sm a N eopl asi a w i th or w i thout hum or al

hy per cal cem i a of m al i gnancy
Other nonâ€“PTHm edi ated causes (see

Tabl e 31)
a Rem em ber to ex cl ude beni gn f am i l i al hy pocal ci ur i c hy per cal cem i a.
PTH, par athy r oi d hor m one; PO 4 , phosphate r adi cal .
Table 34 Therapy for Hypercalcemia
U r gent ther apy
1. Sal i ne
a. U sual l y saf e w i th 200â€“300 m L/hr but m ay need > 10 L/d
w i th car ef ul m oni tor i ng. U se N S: D 5 W al ter nate i n 4 : 1
r ati o w i th 20 m Eq KCl /bottl e (can f ol l ow ur i nar y K + , N a + ,

and v ol um e to docum ent l osses)
b. May need 15 m g m agnesi um /hr
2. Sal i ne pl us f ur osem i de
a. Wi th aggr essi v e m anagem ent, 80100 m g f ur osem i de IV
q1â€“2 h and r epl ace ur i nar y el ectr ol y tes (Suk i WN , Yi um
JJ, Von Mi nden M, et al . Acute tr eatm ent of hy per cal cem i a
w i th f ur osem i de. N Engl J Med 1970;283:836).
b. Less ur gent m anagem entâ€”40 m g f ur osem i de q46 h
c. Bef or e usi ng f ur osem i de, be sur e pati ent i s adequatel y
hy dr ated
3. Cal ci toni n: 48 IU /k g subcutaneousl y q612 h
4. Cal ci toni n pl us gl ucocor ti coi ds
a. 48 MRC uni ts/k g q612 h
b. Pr edni sone: 4060 m g/d
5. IV bi sphosphonates
a. IV eti dr onate (Di dr onel ): 7. 5 m g/k g, w i th 3 L of sal i ne
gi v en ov er 24 hr and r epeat dai l y f or 3 d
b. IV pam i dr onate (Ar edi a): 6090 m g as si ngl e 24hr i nf usi on
w i th adequate sal i ne hy dr ati on; al l ow a m i ni m um of 7 d to
el apse bef or e r etr eatm ent
c. IV zol edr onate (Zom eta): 4 m g IV ov er 15 m i nutes.
d. IV i bandr onate (Boni v a): 24 m g IV
6. Gal l i um ni tr ate (av oi d use i f cr eati ni ne > 2. 5 m g/dL): 100200
m g/m 2 of body sur f ace ar ea i n 1, 000 m L N S ov er 24 hr dai l y f or
5 d
7. IV phosphate
a. Gi v en as 1, 000 m g of el em ental phosphate (0. 16 m g/k g)
ov er 812 hr dur i ng each 24hr per i od (cauti on: can cause
hy potensi on)
b. Av oi d use i f ser um phosphate el ev ated
8. Di al y si s
9. IV EDTA
a. Av oi d use because of f or m ati on of i nsol ubl e cal ci um
com pounds that dam age k i dney
Longter m ther apy (adjunct ther apy i n addi ti on to tr eatm ent of
pr i m ar y cause)
1. Mobi l i zati on
2. Or al phosphates
a. 1, 0002, 000 m g of el em ental phosphate (KPhos; thr ee
tabl ets thr i ce dai l y )
b. Av oi d use i f el ev ated ser um phosphate
3. Mi thr am y ci n (m ay al so be used i n sem i acute si tuati ons): 25
Âµg/k g i n 50 m L D5W gi v en as i nf usi on ov er 3 hr
4. Gl ucocor ti coi dsâ€”pr edni sone: 5060 m g/d
5. Di phosphonatesâ€”or al eti dr onate: 520 m g/k g/d
N S, nor m al sal i ne; D5W, 5% dex tr ose i n w ater ; MRC, Medi cal
Resear ch Counci l ; IV, i ntr av enous; EDTA, ethy l enedi am i netetr a
acetate.
Ini ti al l abor ator y data r ev eal the f ol l ow i ng: WBC, 5, 800; Hgb, 13. 3 g/dL; Hct,
39. 7%; and pl atel et count, 274 Ã— 10 3 m m 3 . The f ol l ow i ng el ectr ol y te and
ser um chem i str y v al ues ar e r epor ted: sodi um , 138 m Eq/L; potassi um , 3. 9
m Eq/L; chl or i de, 108 m Eq/L; CO 2 , 21. 5 m Eq/L; BU N , 18 m g/dL; cr eati ni ne, 1. 0
m g/dL; and f asti ng gl ucose, 94 m g/dL. Other si gni f i cant l abor ator y v al ues
i ncl ude the f ol l ow i ng: cal ci um , 11. 5 m g/dL; phosphate, 2. 0 m g/dL; total
pr otei n, 6. 8 g/dL; al bum i n, 2. 8 g/dL; and m agnesi um , 1. 7 m Eq/L. U r i nal y si s
f i ndi ngs ar e nor m al . The er y thr ocy te sedi m entati on r ate i s 9 m m per hour and
the al k al i ne phosphatase l ev el i s 396 IU /L.
Chest f i l m f i ndi ngs ar e nor m al . In a r ev i ew of the pel v i s and hi p r adi ogr aphi c
studi es, l y ti c changes w i th bony destr ucti on ar e f ound i n both hem i pel v es, but
these ar e gr eater on the r i ght. Ri ght f em or al head i nv ol v em ent i s al so noted.
A pel v i c CT scan show s the ex i stence of m ul ti pl e destr ucti v e sof t ti ssue
l esi ons i n the bone of the pel v i s; the l ar gest of the l esi ons m easur es 8 cm . A
r adi onucl i de bone scan r ev eal s i ncr eased uptak e i n the pel v i c l esi ons and i n
sev er al r i bs, as w el l . A l ar gebor e needl e bi opsy speci m en f r om the
gi ngi v opal atal m ass and the r i ght i l i um show s the appear ance of a gi ant cel l
tum or m i x ed w i th f i br obl asts.
Speci al endocr i ne studi es r ev eal an i oni zed cal ci um l ev el of 2. 7 m m ol /L
(nor m al , 1. 15 to 1. 35 m m ol /L). The 24hour ur i ne cal ci um and phosphate
ex cr eti ons ar e 290 and 856 m g, r especti v el y .
1. Gi v en the pati ent's hy poal bum i nem i a of 2. 8 g/dL, w hat i s the cor r ected
cal ci um l ev el ?
2. What i s the ex pl anati on f or the pati ent's pol y ur i a and pol y di psi a?
3. Based sol el y on the pati ent's adm i ssi on el ectr ol y te l ev el s, w hat i s the
l i k el y di agnosi s?
4. What i s the m ost l i k el y ex pl anati on f or the m ul ti pl e bone l esi ons i n thi s
pati ent?
5. What i s the speci al l abor ator y test that needs to be per f or m ed i n thi s
pati ent?
6. What i s the best l ocal i zi ng pr ocedur e i n pati ents such as thi s one?
Case Discussion
1. Gi v en the pati ent's hy poal bum i nem i a of 2. 8 g/dL, w hat i s the cor r ected
cal ci um l ev el ?
As a r ul e, appr ox i m atel y 45% of the m easur ed ser um cal ci um i s pr otei n
bound; 55% i s di f f usi bl e. The pr otei nbound f r acti on i s gr eater f or
al bum i n than f or gl obul i n. For a ser um cal ci um l ev el of 10 m g/dL,
appr ox i m atel y 0. 8 m g/dL i s bound to gl obul i n and 3. 7 m g/dL i s bound to
al bum i n. In the setti ng of a l ow al bum i n state, appr ox i m atel y 1 g of
al bum i n bi nds 0. 8 m g of cal ci um . For ex am pl e, thi s pati ent has
P. 116
a ser um cal ci um l ev el of 11. 5 m g/dL and a ser um al bum i n l ev el of 2. 8
g/dL. The cor r ected cal ci um l ev el i s cal cul ated as f ol l ow s:
2. What i s the ex pl anati on f or the pati ent's pol y ur i a and pol y di psi a?
Hy per cal cem i a causes a v asopr essi nr esi stant nephr ogeni c di abetes
i nsi pi dus. Thi s can pr om ote dehy dr ati on i n hy per cal cem i c pati ents,
ther eby aggr av ati ng the sy m ptom s and w or seni ng the hy per cal cem i a.
3. Based sol el y on the pati ent's adm i ssi on el ectr ol y te l ev el s, w hat i s the
l i k el y di agnosi s?
The el ectr ol y te l ev el s i n thi s pati ent str ongl y suppor t a di agnosi s of
pr i m ar y hy per par athy r oi di sm . Hy pophosphatem i a i s seen i n near l y 40% to
60% of pati ents w i th hy per par athy r oi di sm , and i ts pr esence depends on
the di etar y phosphate i ntak e. In addi ti on, the chl or i de concentr ati on
gr eater than 104 m m ol /L and the ser um bi car bonate v al ue i n the m i l dl y
aci doti c r ange suggest hy per par athy r oi di sm . A chl or i detophosphate r ati o
of gr eater than 33 i s seen i n the setti ng of hy per par athy r oi di sm . In thi s
pati ent, thi s r ati o i s 54, w hi ch i ndi cates PTHm edi ated hy per cal cem i a. An
el ev ated 1, 25di hy dr ox y v i tam i n D l ev el m ay be seen i n pati ents w i th
pr i m ar y hy per par athy r oi di sm , but, i f ther e i s m agnesi um def i ci ency ,
these l ev el s m ay be nor m al or l ow .
4. What i s the m ost l i k el y ex pl anati on f or the m ul ti pl e bone l esi ons i n thi s
pati ent?
The tur nov er state of bone f or m ati on and r esor pti on i s hi gh i n pati ents
w i th hy per par athy r oi di sm . The cl assi c hi stol ogi c pi ctur e f ound i n bone
bi opsy speci m ens i s an i ncr eased num ber of osteocl asts, together w i th
i ncr eased tetr acy cl i ne l abel i ng and i ncr eased r ates of bone f or m ati on.
The m ar r ow i n these pati ents m ay show f ocal ar eas of f i br osi s. In
ex tr em el y adv anced cases of hy per par athy r oi di sm , osteocl astom as or
gi ant cel l tum or s of bone m ay be seen. Thi s pati ent had m ul ti pl e such
tum or s.
5. What i s the speci al l abor ator y test that needs to be per f or m ed i n thi s
pati ent?
The speci al l abor ator y test that needs to be done i n thi s pati ent i s
m easur em ent of hi s PTH l ev el , w hi ch pr ov es to be m ar k edl y el ev ated to a
v al ue of 811 pg/m L (nor m al , 10 to 65 pg/m L).
6. What i s the best l ocal i zi ng pr ocedur e i n pati ents such as thi s one?
Appr ox i m atel y 80% to 90% of pati ents w i th pr i m ar y hy per par athy r oi di sm
hav e a si ngl e par athy r oi d adenom a, 10% to 15% hav e par athy r oi d
hy per pl asi a, and l ess than 1% hav e par athy r oi d car ci nom a. The
pr eoper ati v e l ocal i zi ng pr ocedur es such as a Sestam i bi scan add to the
m anagem ent of thi s di sease as they per m i t a di r ected m i ni m al l y i nv asi v e
appr oach. How ev er , the m ost r el i abl e appr oach to l ocal i zati on i s an
ex per i enced sur geon w ho can, i n al m ost al l cases, r em ov e the adenom a
or i denti f y the par athy r oi d hy per pl asi a and r em ov e thr ee and onehal f
gl ands. Thi s pati ent pr ov ed to hav e a l ar ge, 16g par athy r oi d adenom a,
w hi ch w as i denti f i ed easi l y and r em ov ed.
P. 117
Suggested Readings
Bi l ezi k i an JB. Managem ent of acute hy per cal cem i a. N Engl J Med
1992;326:1196.
Bi l ezi k i an JP, Br andi ML, Rubi n M, et al . Pr i m ar y hy per par athy r oi di sm : new
concepts i n cl i ni cal , densi tom etr i c and bi ochem i cal f eatur es. J Inter n Med
2005;257(1):6â€“17.
Br oadus AE, Mangi n M, Ik eda K, et al . Hum or al hy per cal cem i a of cancer :
i denti f i cati on of a nov el par athy r oi d hor m onel i k e pepti de. N Engl J Med
1988;319:556.
Col ao A, Di Sar no A, Landi ML, et al . Longter m and l ow dose tr eatm ent
w i th caber gol i ne i nduces m acr opr ol acti n shr i nk age. J Cl i n Endocr i nol Metab
1997;82:3574.
Consensus Dev el opm ent Conf er ence. Di agnosi s and m anagem ent of
asy m ptom ati c pr i m ar y hy per par athy r oi di sm . Ann Inter n Med 1991;114:593.
Dav i es PH, Stew ar t SE, Lancr anjan L, et al . Longter m ther apy w i th l ong
acti ng octr eoti de (Sandostati nLAR) f or the m anagem ent of acr om egal y .
Cl i n Endocr i nol 1998;48:311.
De Luca F, Bar on J. Mol ecul ar bi ol ogy and cl i ni cal i m por tance of the
Ca(2+ )sensi ng r eceptor . Cur r Opi n Pedi atr 1998;10:435.
Hender son JE, Shusti k C, Kr em er R, et al . Ci r cul ati ng concentr ati ons of
par athy r oi d hor m onel i k e pepti de i n m al i gnancy and i n
hy per par athy r oi di sm . J Bone Mi ner Res 1990;5:105.
Inzucchi SE. Managem ent of hy per cal cem i a. Di agnosti c w or k up, ther apeuti c
opti ons f or hy per par athy r oi di sm and other com m on causes. Postgr ad Med
2004;115(5):27â€“36.
Inzucchi SE. U nder standi ng hy per cal cem i a: i ts m etabol i c basi s, si gns and
sy m ptom s. Postgr ad Med 2004;115(4):69â€“76.
Luf k i n EG, Kao PC, Heath H. Par athy r oi d hor m one r adi oi m m unoassay s i n
the di f f er enti al di agnosi s of hy per cal cem i a due to pr i m ar y
hy per par athy r oi di sm or m al i gnancy . Ann Inter n Med 1987;160:559.
Mur ator i M, Ar osi o M, Gam bi no G, et al . U se of caber gol i ne i n the l ong
ter m tr eatm ent of hy per pr ol acti nem i c and acr om egal i c pati ents. J
Endocr i nol Inv est 1997;20:537.
Ral ston SH, Gal l acher SJ, Patel U , et al . Cancer associ ated hy per cal cem i a:
m or bi di ty and m or tal i ty . Ann Inter n Med 1990;112:499.
Yeh PJ, Chen JW. Pi tui tar y tum or s: sur gi cal and m edi cal m anagem ent. Sur g
Oncol 1997;6:67.
Hypoglycemia
1. What consti tutes m edi cal l y si gni f i cant hy pogl y cem i a?
2. What ar e the com m on sy m ptom s of hy pogl y cem i a?
3. What i s the best f i r st step i n cl assi f y i ng hy pogl y cem i a?
4. What ar e the causes of m edi cal l y si gni f i cant hy pogl y cem i a?
5. In peopl e w i th di abetes, w hat f actor s ar e associ ated w i th an i ncr eased
r i sk of hy pogl y cem i a?
6. What i s r eacti v e hy pogl y cem i a and how shoul d i t be ev al uated?
Discussion
1. What consti tutes m edi cal l y si gni f i cant hy pogl y cem i a?
Medi cal l y si gni f i cant hy pogl y cem i a i s di agnosed on the basi s of onl y thr ee
f i ndi ngs (Whi ppl e's tr i ad): (a) bl ood gl ucose l ev el of l ess than 50 m g/dL;
(b) the
P. 118
pr esence of sy m ptom s consi stent w i th hy pogl y cem i a; and (c) the
r esol uti on of sy m ptom s af ter the i ngesti on of car bohy dr ates. The l ow er
l i m i t of nor m al f or gl ucose i s 70 m g/dL, but thi s i s the l ow er l i m i t f or â
€œheal thy â€ peopl e af ter a 12hour f ast. Dur i ng a 72hour f ast, up to
40% of â€œheal thy â€ w om en m ay hav e bl ood gl ucose v al ues bel ow 45
m g/dL and som e as l ow as betw een 20 and 30 m g/dL. These l ow v al ues
m ay al so be seen i n appar entl y heal thy w om en 3 to 4 hour s af ter the
adm i ni str ati on of 75 g of gl ucose or al l y (the or al gl ucose tol er ance test),
but al m ost none hav e sy m ptom s of hy pogl y cem i a and, ther ef or e,
m edi cal l y si gni f i cant hy pogl y cem i a. Conv er sel y , m any peopl e w ho ex hi bi t
sy m ptom s consi stent w i th hy pogl y cem i a 3 to 4 hour s af ter eati ng, w hi ch
r espond to the i ngesti on of car bohy dr ate, al so do not hav e tr ue
hy pogl y cem i a. The bl ood gl ucose l ev el s i n these i ndi v i dual s ar e r ar el y
l ess than 50 m g/dL at the ti m e they ex per i ence sy m ptom s. These peopl e
hav e a condi ti on that has been cal l ed postpr andi al sy ndr om e or f uncti onal
hy pogl y cem i a.
2. What ar e the com m on sy m ptom s of hy pogl y cem i a?
The sy m ptom s of hy pogl y cem i a can be di v i ded i nto tw o categor i es:
adr ener gi c and neur ogl y copeni c (Tabl e 35). A substanti al r educti on i n the
bl ood gl ucose l ev el sti m ul ates the r el ease of cor ti sol , GH, gl ucagon, and
catechol am i nes. The attendant r i se i n sy m patheti c ner v ous sy stem
acti v i ty i s ex per i enced as ner v ousness, sw eati ng, and pal pi tati ons.
Because the br ai n i s
P. 119
cr i ti cal l y dependent on gl ucose f or nor m al neur onal f uncti oni ng,
i nadequate del i v er y of gl ucose to the br ai n r api dl y r esul ts i n al ter ati ons
i n m entati on, w hi ch can tak e m any f or m s. The si gns and sy m ptom s of
neur ogl y copeni a can ev en m i m i c those associ ated w i th str uctur al br ai n
l esi ons or psy chi atr i c condi ti ons.
Table 35 Symptoms of Hypoglycemia
Adr ener gi c N eur ogl y copeni c
Anx i ety Headache
N er v ousness Bl ur r ed v i si on
Tr em ul ousness Par esthesi as
Sw eati ng Weak ness

Hunger Ti r edness
Pal pi tati ons Conf usi on
Ir r i tabi l i ty Di zzi ness
Pal l or Am nesi a
N ausea Incoor di nati on
Fl ushi ng Abnor m al m entati on
Angi na Behav i or al change
Feel i ng col d
Di f f i cul ty w ak i ng i n the m or ni ng
Seni l e dem enti a
Or gani c per sonal i ty sy ndr om e
Tr ansi ent hem i pl egi a
Tr ansi ent aphasi a
Sei zur es
Com a
3. What i s the best f i r st step i n cl assi f y i ng hy pogl y cem i a?
Ther e ar e a v ar i ety of m ethods f or categor i zi ng the condi ti ons that cause
hy pogl y cem i a, but none of these schem es i s com pl etel y sati sf actor y . One
appr oach i s to di v i de the causes i nto those i nv ol v i ng i ncr eased i nsul i n
l ev el s, those i nv ol v i ng i ncr eased gl ucose consum pti on, or those i nv ol v i ng
decr eased gl ucose pr oducti on. In r eal i ty , how ev er , m ost of the causes of
hy pogl y cem i a em br ace a com bi nati on of these m echani sm s. An
al ter nati v e and m or e usef ul schem e i s based on the hi stor y and phy si cal
ex am i nati on f i ndi ngs. The k ey f eatur es of thi s appr oach ar e to assess
w hether the hy pogl y cem i a occur s w i th f asti ng or postpr andi al l y , and
w hether the af f ected per son appear s heal thy . In gener al , the
hy pogl y cem i a that occur s w i th f asti ng or that i s f ound i n peopl e w ho
appear gener al l y i l l i s a m or e om i nous f or m of the di sor der .
4. What ar e the causes of m edi cal l y si gni f i cant hy pogl y cem i a?
The speci f i c causes of hy pogl y cem i a ar e num er ous (Tabl e 36). The
hi stor y , phy si cal ex am i nati on, and i ni ti al l abor ator y tests ar e per f or m ed
i n an ef f or t to r ul e out the com m on causes.
The m ost com m on cause of hy pogl y cem i a ov er al l i s the adm i ni str ati on of
a hy pogl y cem i c agent, ei ther i nsul i n or an or al hy pogl y cem i c agent.
These m edi cati ons m ay hav e been pr escr i bed f or the contr ol of di abetes
or m ay be i ngested i n er r or . If thi s cause i s not obv i ous f r om the
pati ent's hi stor y , the di agnosi s can be m ade by per f or m i ng an or al
hy pogl y cem i c scr een on a sam pl e of pl asm a, or by m easur i ng the i nsul i n
and C pepti de l ev el at the ti m e of hy pogl y cem i a. C pepti de i s a by
pr oduct of endogenous i nsul i n pr oducti on. If the i nsul i n pr oduci ng
hy pogl y cem i a i s ex ogenous, the i nsul i n l ev el i s hi gh and the C pepti de
l ev el i s suppr essed.
In one ser i es consi sti ng of hospi tal i zed pati ents w i th hy pogl y cem i a, the
second m ost com m on cause of hy pogl y cem i a w as r enal f ai l ur e. Renal
f ai l ur e causes hy pogl y cem i a f or sev er al r easons. Fi r st, because the
k i dney s pl ay an i m por tant r ol e i n i nsul i n cl ear ance, i nsul i n cl ear ance m ay
be decr eased and i nsul i n l ev el s i nappr opr i atel y hi gh i n the pr esence of
r enal f ai l ur e. Second, dur i ng pr ol onged f asti ng, the k i dney s m ay be
r esponsi bl e f or as m uch as 30% of the net gl uconeogenesi s that tak es
pl ace, and thi s w oul d be com pr om i sed i n the setti ng of r enal f ai l ur e.
Fi nal l y , i t appear s that ur em i c tox i ns m ay suppr ess hepati c gl ucose
output. As w i th other f or m s of hy pogl y cem i a, i nadequate cal or i c i ntak e
dur i ng a m edi cal i l l ness of ten contr i butes to the dev el opm ent of
hy pogl y cem i a.
Hy pogl y cem i a m ay occur i n associ ati on w i th a num ber of tum or s i ncl udi ng
i sl et cel l tum or s and nonâ€“i sl et cel l tum or s (Tabl e 37). The l atter ar e
usual l y l ar ge tum or s l ocated i n the m edi asti num or r etr oper i toneum . The
m echani sm by w hi ch these tum or s cause hy pogl y cem i a r em ai ns som ew hat
obscur e. One
P. 120
ex pl anati on m ay be hi gh l ev el s of gl ucose ex tr acti on and uti l i zati on by
the tum or m ass. A second contr i buti ng f eatur e i s poor nutr i ti on i n these
pati ents. An i ncr eased acti v i ty of IGFII has been show n i n som e pati ents
w i th nonâ€“i sl et cel l tum or s. IGFII can i nter act w i th the i nsul i n r eceptor ,
al though w i th l ess af f i ni ty than i nsul i n i tsel f . N or m al l y , IGFII cl eav es to
a sm al l er pr otei n w i th m i ni m al i nsul i nl i k e acti v i ty . It has been show n
that al though the IGFII l ev el s ar e not i ncr eased i n these pati ents w i th
hy pogl y cem i a associ ated w i th cancer , ther e ar e i ncr eased l ev el s of â
€œbi g IGFII. â€ Thi s i s the uncl eav ed f or m of the hor m one that has m or e
i nsul i nl i k e acti v i ty .
Table 36 Etiologic Classification of
Hypoglycemia
Hy pogl y cem i a associ ated pr edom i nantl y w i th f asti ng

Hy per secr eti on of i nsul i n due to i sl et cel l adenom a,
car ci nom a, hy per pl asi a, or nesi di obl astosi s
Hepati c di sease
Gener al i zed hy pof uncti on
Ethanol hy pogl y cem i a associ ated w i th pr i or poor
nutr i ti on and decr eased gl y cogen stor es
Sepsi s
Endocr i ne def i ci enci es
Anter i or pi tui tar y i nsuf f i ci ency â€”gr ow th
hor m one, adr enocor ti cotr opi c hor m one
Adr enocor ti cal i nsuf f i ci ency
Hy pothy r oi di sm
Lar ge noni sl et cel l tum or s
Renal di sease
Def i ci ent car bohy dr ate stor es or i ntak e
Sev er e i nani ti on
Sev er e ex er ci se
Autoi m m une w i th i nsul i n anti bodi es or anti bodi es to
the i nsul i n r eceptor
Dr ug i nduced
Reacti v e or sti m ul ati v e hy pogl y cem i a
Idi opathi c f uncti onal hy pogl y cem i a
Al i m entar y hy per i nsul i ni sm
Pr edi abeti c f uncti onal hy pogl y cem i a
Endocr i ne def i ci enci es
Facti ti ous and ar ti f actual hy pogl y cem i a
Sur r epti ti ous i nsul i n adm i ni str ati on
Sur r epti ti ous sul f ony l ur ea i ngesti on
El ev ated l euk ocy te countâ€”l euk em i a or pol y cy them i a
Hy pogl y cem i a of i nf ancy
Abnor m al i ti es i n hor m one secr eti on
Abnor m al i ti es of pr oducti on and uti l i zati on of
m etabol i c f uel s
Abnor m al i ti es i n substr ate av ai l abi l i ty
Another com m on cause of hy pogl y cem i a i s the i ngesti on of a dr ug that
sti m ul ates per i pher al gl ucose uti l i zati on, i nhi bi ts hepati c gl ucose
pr oducti on,
P. 121
or sti m ul ates i nsul i n r el ease, and ther e ar e a l ar ge num ber of such dr ugs.
The dr ugs m ost of ten i m pl i cated ar e i n par t a f uncti on of the age of the
pati ent (Tabl e 38). Al cohol m ay actual l y be the m ost com m on dr ug
associ ated w i th hy pogl y cem i a because i t causes an i ncr ease i n the r ati o
of ni coti nam i de adeni ne di nucl eoti de hy dr ogenase (N ADH) to N AD + , w hi ch
decr eases the gl uconeogeni c capaci ty of the l i v er . The anti par asi ti c dr ug
pentam i di ne i s now w i del y used i n the tr eatm ent of Pneum ocy sti s car i ni i
pneum oni a i n pati ents w i th AIDS. It can pr oduce hy pogl y cem i a by i njur i ng
the pancr eati c i sl et cel l s, ther eby causi ng i nsul i n r el ease and
i nappr opr i ate hy per i nsul i nem i a. As w i th al l f or m s of hy pogl y cem i a,
i nadequate cal or i c i ntak e of ten contr i butes to the dev el opm ent of
sy m ptom ati c hy pogl y cem i a.
Table 37 Nonâ€“Islet Cell Tumors Associated
with Hypoglycemia
Mesenchy m al
Mesothel i om a
Fi br osar com a
Rhabdom y osar com a
Lei om y osar com a
Li posar com a
Hem angi oper i cy tom a
Car ci nom as
Hepati c: hepatom a, bi l i ar y car ci nom a
Adr enocor ti cal car ci nom a
Geni tour i nar y : hy per nephr om a, Wi l m s' tum or , pr ostate
car ci nom a
Repr oducti v e: cer v i cal car ci nom a, br east car ci nom a
N eur ol ogi c and neur oendocr i ne
Pheochr om ocy tom a
Car ci noi d tum or
N eur of i br om a
Hem atol ogi c
Leuk em i as
Ly m phom a
My el om a
Leuk em i a and pol y cy them i a v er a can cause pseudohy pogl y cem i a because
of the hi gh WBC or Hct v al ue i n these setti ngs, w hi ch can r esul t i n
conti nued gl ucose consum pti on i n the test tube af ter the bl ood sam pl e has
been obtai ned. In thi s si tuati on, the bl ood gl ucose l ev el i s ex tr em el y l ow
but the pati ent i s w i thout sy m ptom s. To deter m i ne the actual bl ood
gl ucose l ev el i n such pati ents, bl ood shoul d be dr aw n i nto a tube that
contai ns a substance that poi sons the bl ood el em ents and pr ev ents
gl y col y si s f r om occur r i ng af ter col l ecti on.
Postpr andi al (r eacti v e) hy pogl y cem i a can occur i n as m any as 20% of
pati ents af ter gastr i c sur gi cal pr ocedur es. Thi s condi ti on i s al so cal l ed
P. 122
al i m entar y hy pogl y cem i a and can occur af ter a v ar i ety of pr ocedur es,
i ncl udi ng gastr i c by pass, gastr ectom y , gastr oenter ostom y , py l or opl asty ,
and v agotom y . Al though bi ochem i cal hy pogl y cem i a i s not r ar e i n these
pati ents dur i ng a l ong or al gl ucose tol er ance test, sy m ptom ati c
hy pogl y cem i a i s uncom m on.
Table 38 Drugs Associated with
Hypoglycemia in a Variety of Agegroups
Age No. of Drugs Mos t Fre que ntly U s e d (No. of
Ra nge P a tie nts Ca s e s )
(yr)
N ew bor n 47 Sul f ony l ur ea (m other ) (14); pr opr anol ol

(19); r i todr i ne, etc. (14)
02 26 Sal i cy l ate (17); pr opr anol ol (9)
210 48 Al cohol (28); qui ni ne (15); pr opr anol ol

(3); sul f ony l ur ea (2)
1130 79 Sul f ony l ur ea (34); i nsul i n (f acti ti ous)

(20); qui ni ne (10); al cohol
(8); i nsul i n + dr ug a (3); i nsul i n +
al cohol (2); pr opr anol ol (2)
3140 78 Al cohol (50); sul f ony l ur ea (14); qui ni ne

(4); i nsul i n + al cohol
(3) or dr ug (3); i nsul i n (f acti ti ous) (2);
pr opr anol ol (2)
4150 71 Al cohol (33); sul f ony l ur ea (19); i nsul i n

+ al cohol (5); pr o pr anol ol
(3); al cohol + dr ug (2); qui ni ne (2);
di sopy r am i de (1)
5160 177 Sul f ony l ur ea (86); al cohol (72);
pr opr anol ol (4);
sul f ony l ur ea + i nsul i n (3) or al cohol
(3) or dr ug (3);
di sopy r am i de (3); qui ni ne (1)
6170 242 Sul f ony l ur ea (173); al cohol (35);

sul f ony l ur ea + dr ug (10) or
pheny l butazone (8) or i nsul i n (4);
di sopy r am i de (5); pr o
pr anol ol (3)
Ol der 273 Sul f ony l ur ea (219); al cohol (23);

than 71 sul f ony l ur ea + dr ug (12) or
phenf or m i n (6); di sopy r am i de (5);
pr opr anol ol (3)
Total 1, 041

(69%) b
a An agent w i thout i ntr i nsi c hy pogl y cem i c acti v i ty .
b Per centage of 1, 418 pati ents f or w hom data w er e av ai l abl e.
Other causes of hy pogl y cem i a ar e m uch l ess com m on. Fasti ng by i tsel f i s
a r ar e cause. How ev er , ex tr em el y l ong per i ods of i nadequate nutr i ti on
ar e r equi r ed f or hy pogl y cem i a to occur i n the absence of other m etabol i c
def ects. Thi s i s seen i n the setti ng of anor ex i a ner v osa and star v ati on.
Li k ew i se, l i v er di sease pr oduces hy pogl y cem i a onl y i n i ts m ost sev er e
f or m s or i n conjuncti on w i th i nadequate cal or i c i ntak e. Hy pogl y cem i a i s
occasi onal l y pr oduced by the pr esence of autoanti bodi es ei ther to i nsul i n
i tsel f or to the i nsul i n r eceptor , but these condi ti ons usual l y occur i n the
pr esence of a k now n autoi m m une sy ndr om e. Fi nal l y , age pl ay s an
i m por tant r ol e i n the suscepti bi l i ty to hy pogl y cem i a. El der l y peopl e l ose
counter r egul ator y hor m one r esponses to hy pogl y cem i a, ar e f r equentl y on
m ul ti pl e m edi cati ons, and m ay hav e m i l d or gan dy sf uncti on (r enal f ai l ur e,
l i v er dy sf uncti on, or congesti v e hear t f ai l ur e), al l of w hi ch can i ncr ease
the l i k el i hood of m ul ti f actor i al hy pogl y cem i a. In addi ti on, el der l y pati ents
m ay hav e dem enti a that can i nter f er e w i th i nsi ght and nor m al f ood
seek i ng behav i or .
P. 123
5. In peopl e w i th di abetes, w hat f actor s ar e associ ated w i th an i ncr eased
r i sk of hy pogl y cem i a?
Hy pogl y cem i a occur s al l too f r equentl y i n tr eated di abeti c pati ents, and i s
ei ther di r ectl y or i ndi r ectl y the cause of death i n 3% to 5% of al l pati ents
w i th T1DM. It r esul ts f r om ex cessi v e i nsul i n adm i ni str ati on, i nadequate
cal or i c i ntak e, or ex cessi v e ex er ci se. In nondi abeti c peopl e, i f
hy pogl y cem i a dev el ops, a num ber of hor m ones r espond to i ncr eased
gl ucose pr oducti on and m ai ntai n a nor m al bl ood sugar l ev el . In addi ti on,
the per son noti ces sy m ptom s of hy pogl y cem i a and i ngests car bohy dr ate
to counter act these. In peopl e w i th l ongstandi ng di abetes, how ev er ,
ther e m ay be hy pogl y cem i c unaw ar eness and autonom i c neur opathy , both
of w hi ch bl unt the nor m al r esponse to hy pogl y cem i a. Another f actor that
pl ay s a r ol e i n the hy pogl y cem i a that occur s i n di abeti c pati ents has to do
w i th the i ntr oducti on of r ecom bi nant hum an i nsul i n, such that v er y f ew
pati ents now r em ai n on pur i f i ed por k i nsul i n.
Dur i ng the dev el opm ent of T1DM, ther e m ay be a per i od w hen i sl et cel l s
ar e dam aged but sti l l r etai n thei r capaci ty to sy nthesi ze and stor e
i nsul i n. Dur i ng thi s per i od, i nsul i n m ay be r el eased i n a dy sf uncti onal
m anner i n r esponse to nonphy si ol ogi c sti m ul i , or i n i nappr opr i ate
quanti ti es. Thi s m ay r esul t i n epi sodes of sy m ptom ati c hy pogl y cem i a,
but, l ater , as the i sl et cel l s ar e com pl etel y destr oy ed, i nsul i nopeni a and
hy per gl y cem i a pr edom i nate.
Hi stor i cal l y , ther e has been a str ong desi r e to nor m al i ze the bl ood
gl ucose l ev el s i n pati ents w i th di abetes i n an ef f or t to pr ev ent l ongter m
com pl i cati ons. Wi th the adv ent of hom e gl ucose m oni tor i ng, m ul ti pl e dai l y
i njecti ons of shor t and l ongacti ng i nsul i ns, i nsul i n pum ps, and
gl y cosy l ated Hgb deter m i nati ons, ti ght contr ol i s attai nabl e. What has
been l ear ned, how ev er , i s that ther e i s a tr adeof f , i n that ti ght contr ol
can be achi ev ed onl y by accepti ng a substanti al i ncr ease i n the r i sk of
sy m ptom ati c and l i f ethr eateni ng hy pogl y cem i a. The DCCT has
dem onstr ated that ti ght contr ol of bl ood gl ucose i n pati ents w i th T1DM
pr ev ents or del ay s the dev el opm ent of di abeti c com pl i cati ons. It i s
pr udent to str i v e tow ar d ti ght contr ol w hi l e av oi di ng f r equent
hy pogl y cem i c epi sodes.
6. What i s r eacti v e hy pogl y cem i a and how shoul d i t be ev al uated?
The ter m hy pogl y cem i a i s r ecogni zed by m uch of the l ay publ i c as a
com m on pr obl em that occur s at 10:30 a. m . i n w om en w hose br eak f ast
consi sted of a cup of cof f ee and a str aw ber r y Dani sh. Som e phy si ci ans
hav e ev al uated these r eacti v e hy pogl y cem i c sy m ptom s w i th or al gl ucose
tol er ance tests. How ev er , thi s appr oach i s pr obl em ati c because m ost of
the w om en w i th these sy m ptom s do not hav e bl ood gl ucose l ev el s that
ar e l ess than 50 m g/dL at the ti m e of thei r sy m ptom s and, i n f act, m ost
of these sy m ptom s r esol v e spontaneousl y w i thout the i ngesti on of
car bohy dr ate. In addi ti on, som e â€œheal thy â€ w om en can hav e bl ood
gl ucose v al ues that ar e l ess than 50 m g/dL 3 to 4 hour s af ter a 100g or al
gl ucose l oad, and y et not hav e sy m ptom s. In gener al , these peopl e do not
hav e a ser i ous i l l ness and v i r tual l y nev er hav e an i nsul i nom a i n the
absence of m or e ty pi cal epi sodes that occur w i th f asti ng. Instead, they
need r eassur ance and a pr acti cal appr oach to thei r sy m ptom s. Di ets that
ar e l ow i n car bohy dr ate, hi gh
P. 124
i n pr otei n, and hi gh i n f i ber hav e not been concl usi v el y show n to be of
benef i t, and ex tr em e di ets shoul d be av oi ded. The r egul ar i ngesti on of a
bal anced di et i n per haps f our to f i v e m eal s ov er the cour se of the day
i nstead of the tr adi ti onal thr ee m ay be of benef i t i n these peopl e. In
som e cases, r eacti v e hy pogl y cem i a m ay be a r esul t of i nsul i n r esi stance,
hy per i nsul i nem i a i n r esponse to a hi gh car bohy dr ate m eal , and m i sm atch
of i nsul i n and gl ucose cl ear ance af ter the m eal . In these cases,
hy pogl y cem i a m ay r espond to i nsul i n sensi ti zer s as w el l as the abov e
m easur es.
Case
A 52y ear ol d w hi te w om an has an 18m onth hi stor y of epi sodi c conf usi on and
poor w or k per f or m ance but neur ol ogi c ev al uati on, i ncl udi ng CT scan of the
head and an el ectr oencephal ogr am , i s unr ev eal i ng. Di l anti n and then
phenobar bi tal ar e pr escr i bed but do not al ter the f r equency of the attack s, and
ar e ev entual l y di sconti nued. On the day of adm i ssi on, she has a gener al i zed
sei zur e at w or k . The par am edi cs ar e cal l ed, f i nd her unconsci ous, and
adm i ni ster nal ox one hy dr ochl or i de [N ar can (Du Pont Mer ck Phar m aceuti cal ,
Wi l m i ngton, DE)] and 1 am pul e of 50% dex tr ose IV. She then r egai ns
consci ousness. Her bl ood gl ucose l ev el bef or e r ecei v i ng the 50% dex tr ose i s
28 m g/dL. She deni es consum i ng al cohol or tak i ng any pr escr i pti on
m edi cati ons. Her f am i l y hi stor y i s unr em ar k abl e and she has no hi stor y of
gastr i c sur ger y . On phy si cal ex am i nati on, she i s f ound to be a thi n w om an w ho
appear s to be i n good heal th. Her ex am i nati on f i ndi ngs ar e nor m al , as ar e her
i ni ti al l abor ator y r esul ts.
1. What i s the l i k el y di agnosi s i n thi s pati ent?

2. If she had a f am i l y hi stor y of thi s pr obl em , w hat other endocr i ne tum or s
w oul d y ou l ook f or ?
3. What di agnosti c test, or tests, ar e usef ul i n m ak i ng thi s di agnosi s?
4. If the r esul ts of the bi ochem i cal studi es i ndi cate she has an i nsul i nom a,
w hat shoul d the nex t test be?
5. What i s the pr oper ther apy f or an i nsul i nom a?
Case Discussion
1. What i s the l i k el y di agnosi s i n thi s pati ent?
The pati ent's hi stor y suggests the pr esence of an i nsul i nom a because the
hy pogl y cem i a i s sev er e, r ecur r ent, pr ogr essi v e, sy m ptom ati c, and
r ev er sed by the adm i ni str ati on of IV gl ucose. The sy m ptom ati c epi sodes
of hy pogl y cem i a associ ated w i th an i nsul i nom a m ay occur i n the
postpr andi al state, but al m ost nev er ex cl usi v el y i n thi s state (Tabl e 39).
Most peopl e w i th adr enal i nsuf f i ci ency , tum or associ ated hy pogl y cem i a,
or al i m entar y hy pogl y cem i a hav e other si gns or sy m ptom s, appear i l l , or
hav e a k now n sur gi cal hi stor y .
2. If she had a f am i l y hi stor y of thi s pr obl em , w hat other endocr i ne tum or s
w oul d y ou l ook f or ?
Ther e ar e thr ee gener al l y r ecogni zed sy ndr om es of MEN [or m ul ti pl e
endocr i ne adenom atosi s (MEA)]. Peopl e w i th MEN 1 can hav e tum or s of
the pi tui tar y (e. g. ,
P. 125
pr ol acti nom as or Cushi ng's di sease), the pancr eas (i nsul i nom a and
gastr i nom a m ost com m onl y ), or the par athy r oi d gl ands. U sual l y ,
hy per cal cem i a due to hy per par athy r oi di sm dev el ops f i r st. Those af f ected
w i th MEN 2A ar e at r i sk f or m edul l ar y car ci nom a of the thy r oi d,
pheochr om ocy tom a, and, l ess com m onl y , hy per par athy r oi di sm . Al l these
f eatur es can be f ound i n peopl e w i th MEN 2B, together w i th m ucosal
neur om as. These sy ndr om es can occur ei ther i n f am i l i es or spor adi cal l y .
In al l pati ents w i th i nsul i nom as, the ser um cal ci um and pr ol acti n l ev el s
shoul d be check ed and a com pl ete hi stor y and phy si cal ex am i nati on
per f or m ed to l ook f or ev i dence of the other potenti al l y associ ated
condi ti ons. Am ong the cases of spor adi c nonf am i l i al i nsul i nom as, 80% ar e
sol i tar y and beni gn, 11% ar e m ul ti pl e and beni gn, and 6% ar e si ngl e and
m al i gnant. The r em ai ni ng 3% of the pati ents hav e m ul ti pl e m al i gnant
tum or s or i sl et hy per pl asi a. Ten per cent of the i nsul i nom as occur i n
associ ati on w i th MEN 1, and ar e m ul ti f ocal 80% of the ti m e.
Table 39 Association of Hypoglycemia
Symptoms with Eating in People with
Insulinoma
Timing of Symptoms No. of P e rc e nta ge of

P a tie nts Tota l
1. Sy m ptom s dur i ng or af ter 20 26

ov er ni ght f ast
onl y (bef or e br eak f ast)
2. Fasti ng and day ti m e 21 27

postpr andi al (bef or e
l unch or di nner ) sy m ptom s
3. Sy m ptom s af ter m i ssed m eal 6 8

onl y
4. Postpr andi al (bef or e l unch 23 29

and di nner )
sy m ptom s onl y
5. U ncer tai n about ti m i ng of 7 9

sy m ptom s
6. N o sy m ptom s ex per i enced 1/78 1/100
Sy m ptom s ex acer bated by 24 31

ex er ci se
3. What di agnosti c test, or tests, ar e usef ul i n m ak i ng thi s di agnosi s?
The tr adi ti onal di agnosti c appr oach i n pati ents w i th a suspected
i nsul i nom a i s a super v i sed 72hour f ast. If sy m ptom ati c hy pogl y cem i a
dev el ops and the bl ood gl ucose l ev el i s l ess than 50 m g/dL, then i nsul i n
and C pepti de l ev el s shoul d be deter m i ned. In one ser i es of pati ents w i th
i nsul i nom as, hy pogl y cem i a occur r ed i n the f i r st 12 hour s of f asti ng i n
29%, w i thi n 24 hour s i n 71%, w i thi n 48 hour s i n 92%, w i thi n 60 hour s i n
92%, and w i thi n 72 hour s i n 98%. In thi s ser i es, the bl ood gl ucose l ev el
at the ti m e sy m ptom s appear ed w as l ess than 46 m g/dL i n 100%, l ess
than 39 m g/dL i n 70%, l ess than 35 m g/dL i n 50%, and l ess than 28
m g/dL i n 25%. Because the i nsul i n secr eti on f r om an i nsul i nom a i s of ten
spor adi c, not al l i nsul i nom as can be di agnosed on the basi s of a si ngl e
f ast. It i s i m por tant to deter m i ne the C pepti de l ev el to dem onstr ate that
the i nsul i n i s pr oduced endogenousl y . A pr oi nsul i n l ev el can al so be
hel pf ul i n di agnosi ng i nsul i nom as. Pr oi nsul i n i s the pr ohor m one f r om
w hi ch i nsul i n and C pepti de ar e cl eav ed, and accounts f or onl y 15% to
20% of the ci r cul ati ng i m m unor eacti v e i nsul i n i n heal thy peopl e. In those
P. 126
w i th an i nsul i nom a, how ev er , i t consti tutes 30% to 90% of the i nsul i n
m ass. Ther e ar e other speci al i zed tests f or ev al uati ng a pati ent w i th a
suspected i nsul i nom a but, al though adv ocated by som e, they ar e usual l y
not necessar y . A ser um dr ug scr een to r ul e out a dr ugi nduced
hy pogl y cem i a and an ACTH sti m ul ati on test to r ul e out adr enal
i nsuf f i ci ency ar e usef ul i n the ev al uati on of hy pogl y cem i a of unk now n
cause, but ar e not hel pf ul i n establ i shi ng the di agnosi s of
hy per i nsul i ni sm .
4. If the r esul ts of the bi ochem i cal studi es i ndi cate she has an i nsul i nom a,
w hat shoul d the nex t test be?
Once the bi ochem i cal di agnosi s of i nsul i nom a has been establ i shed, an
anatom i c study i s usual l y done. Al though no si ngl e study i s com pl etel y
sati sf actor y , abdom i nal CT scanni ng and ul tr asonogr aphy possess a
r el ati v el y hi gh sensi ti v i ty , pose no r i sk to the pati ent, and ar e r el ati v el y
i nex pensi v e, m ak i ng them a good f i r st step. Abdom i nal ul tr asonogr aphy i s
adv ocated by som e as the super i or study , but i ts uti l i ty v ar i es f r om
i nsti tuti on to i nsti tuti on. Angi ogr aphy i s m or e sensi ti v e but car r i es som e
r i sk and i s qui te ex pensi v e. Som e gr oups hav e adv ocated tr anshepati c
v enous sam pl i ng. In thi s m ethod, by m easur i ng i nsul i n l ev el s i n the
v enous bl ood dr ai ni ng a par ti cul ar r egi on of the pancr eas, the tum or can
be l ocal i zed, al though not v i sual i zed. The new est pr eoper ati v e l ocal i zi ng
techni que i s endoscopi c ul tr asonogr aphy . In thi s techni que, the ul tr asound
tr ansducer i s endoscopi cal l y pl aced i n the duodenum . Fr om thi s si te, the
head of the pancr eas can be w el l v i sual i zed, y i el di ng a better sensi ti v i ty
than that of tr adi ti onal abdom i nal ul tr asonogr aphy . How ev er , thi s
technol ogy i s not y et w i del y av ai l abl e. The m ai n pr obl em w i th al l these
appr oaches i s that m ost i nsul i nom as ar e sm al l (av er age, 1. 5 cm , 2 g),
and the di agnosi s hi nges on the cl i ni cal pr esentati on and the r esul ts of
bi ochem i cal studi es. If the anatom i c studi es ar e unr ev eal i ng and the
bi ochem i cal r esul ts ar e conv i nci ng, the pati ent shoul d under go
ex pl or ator y sur ger y per f or m ed by an ex per i enced pancr eati c sur geon. For
thi s r eason, ex tensi v e pr eoper ati v e anatom i c studi es ar e not adv ocated.
5. What i s the pr oper ther apy f or an i nsul i nom a?
Sur gi cal r em ov al per f or m ed by an ex per i enced sur geon i s the pr i m ar y
f or m of ther apy f or i nsul i nom as. Intr aoper ati v e di r ect ul tr asonogr aphi c
ex am i nati on of the pancr eas com bi ned w i th m anual pal pati on by an
ex per i enced sur geon successf ul l y l ocal i zes the tum or 80% to 90% of the
ti m e. Once the tum or s ar e r esected, m ost pati ents ar e cur ed. For those
w ho ar e not cur ed by sur gi cal m eans, l ongacti ng som atostati n anal ogs
can be used to decr ease the f r equency and sev er i ty of the hy pogl y cem i c
epi sodes. Di azox i de, v er apam i l , pheny toi n, and pr opr anol ol hav e been
used successf ul l y i n a f ew cases. In these pati ents, f r equent schedul ed
m eal s ar e an i m por tant com ponent of ther apy .
Suggested Readings
Adr ogue HJ. Gl ucose hom eostasi s and the k i dney . Ki dney Int 1992;42:1266.
Fi el d JB. Hy pogl y cem i a: def i ni ti on, cl i ni cal pr esentati ons, cl assi f i cati on,
and l abor ator y tests. Endocr i nol Metab Cl i n N or th Am 1989;18:27.
Fi scher KF, Lees JA, N ew m an JH. Hy pogl y cem i a i n hospi tal i zed pati ents:
causes and outcom es. N Engl J Med 1986;315:1245.
P. 127
Kur l an R. Postpr andi al (r eacti v e) hy pogl y cem i a and r estl ess l eg sy ndr om e:
r el ated neur ol ogi c di sor der s? Mov Di sor d 1998;13:619.
Leonetti F, Foni ci el l o M, Iozzo P, et al . Incr eased nonox i dati v e gl ucose

m etabol i sm i n i di opathi c r eacti v e hy pogl y cem i a. Metabol i sm 1996;45:606.
Pi edr ol a G, Cassado JL, Lopez E, et al . Cl i ni cal f eatur es of adr enal
i nsuf f i ci ency i n pati ents w i th acqui r ed i m m unodef i ci ency sy ndr om e. Cl i n
Endocr i nol 1996;45:97.
Ross RJ, Tr ai ner PJ. Endocr i ne i nv esti gati on: Cushi ng's sy ndr om e. Cl i n
Sel tzer HS. Dr ugi nduced hy pogl y cem i a: a r ev i ew of 1418 cases.
Endocr i nol Metab Cl i n N or th Am 1989;18:163.
Ser v i ce FJ. Hy pogl y cem i as. West J Med 1991;154:442.
Ser v i ce FJ. Hy pogl y cem i a. Endocr i nol Metab Cl i n N or th Am 1997;26:937.
Soder ber gh A, Wi nqv i st O, N or hei m I, et al . Adr enal autoanti bodi es and
or ganspeci f i c autoi m m uni ty i n pati ents w i th Addi son's di sease. Cl i n
Metabolic Bone Disease
1. Whi ch di seases of bone ar e consi der ed to be m etabol i c i n or i gi n?
2. What i s osteopeni a?
3. What condi ti ons m ay cause osteopeni a?
4. What ar e the r i sk f actor s f or osteopor osi s?
5. What si m pl e l abor ator y tests can hel p assess the pati ent w i th osteopeni a?
6. When ar e bone densi ty m easur em ents i ndi cated?
Discussion
1. Whi ch di seases of bone ar e consi der ed to be m etabol i c i n or i gi n?
Metabol i c bone di seases ar e those condi ti ons i n w hi ch al l the m etabol i c

bone uni ts thr oughout the sk el eton ar e equal l y af f ected by the di sease
pr ocess. These di seases i ncl ude osteopor osi s, osteom al aci a, ostei ti s
f i br osa cy sti ca, and osteogenesi s i m per f ecta. Di seases that af f ect ei ther
a si ngl e ar ea or m ul ti pl e ar eas i n bone ar e consi der ed l ocal i zed bone
di seases, and i ncl ude Paget's di sease, f i br ous dy spl asi a, bone cy sts,
heal i ng f r actur es, Sudeck 's atr ophy , and i njur y di suse osteopor osi s.
2. What i s osteopeni a?
Osteopeni a consti tutes a di agnosi s based on r adi ogr aphi c f i ndi ngs, i n that
the m i ner al content of the bones i s seen to be r educed on r adi ogr aphy .
U sual l y , bef or e these studi es can show bone l oss, how ev er ,
appr ox i m atel y 30% to 40% of the sk el eton m ust hav e dem i ner al i zed. In
addi ti on, osteopeni a i s now def i ned as a bone densi ty that i s 1 to 2. 5
standar d dev i ati ons bel ow the m ean f or y oung w om en, on dual ener gy x
r ay absor pti om etr y (DEXA) i m agi ng. Any of the m etabol i c bone condi ti ons
l i sted can cause osteopeni a.
3. What condi ti ons m ay cause osteopeni a?
Ther e ar e m any di sease pr ocesses to be consi der ed i n the osteopeni c
pati ent. The condi ti on m ost of ten encounter ed i n such pati ents i s age
r el ated,
P. 128
i di opathi c osteopor osi s. Ty pe I osteopor osi s i s postm enopausal
osteopor osi s and i s usual l y m ani f ested cl i ni cal l y by v er tebr al f r actur es;
ty pe II osteopor osi s has been ter m ed seni l e osteopor osi s and i s
char acter i zed by hi p f r actur e.
Ther e ar e m any secondar y causes of osteopeni a seen i n the setti ng of

nutr i ti onal def i ci ency ; r enal , l i v er , gastr oi ntesti nal , and endocr i ne and
m etabol i c di sease; dr ug usage; and cer tai n l i f esty l es (Tabl e 310). In
m any of these condi ti ons, al ter ati ons i n the cal ci um l ev el or v i tam i n D
m etabol i sm , secondar y hy per par athy r oi di sm , osteom al aci a, aci dosi s, or a
com bi nati on of these condi ti ons i s the under l y i ng m echani sm r esponsi bl e
f or the osteopeni a.
4. What ar e the r i sk f actor s f or osteopor osi s?
Sm ok i ng, poor cal ci um i ntak e, i m m obi l i zati on, m al nutr i ti on, a

hy pogonadal state, and a f am i l y hi stor y ar e al l r i sk f actor s f or
osteopor osi s. Sm ok i ng i s a r i sk f actor because i t i nduces hepati c enzy m es
to i nacti v ate ci r cul ati ng sex hor m ones, such as estr ogen. A hy pogonadal
state can occur i n ei ther m en or w om en, but i n w om en i t m ay r esul t f r om
a total hy ster ectom y and oophor ectom y or f r om the spontaneous
m enopausal state, both of w hi ch l ead to l ow er ed estr ogen l ev el s. Other
f actor s i ncl ude the i ngesti on of sof t dr i nk s, m ost of w hi ch contai n
phosphor i c aci d. Thi s substance i ncr eases the i ngested phosphate l oad,
w hi ch i n tur n depr esses the ser um cal ci um l ev el and sti m ul ates PTH
r el ease. Cof f ee i s a cal ci ur eti c substance, and, as such, ex cessi v e
consum pti on contr i butes to osteopor osi s. The f at cel l can act as an
endocr i ne or gan; ther ef or e, i n l ean peopl e w hose f at cel l m ass i s
decr eased, the conv er si on of adr enal andr ogens to estr ogens i s
decr eased, and thi s can l ead to osteopor osi s. Som e of the l i f esty l e r i sk
f actor s can be m odi f i ed to pr ev ent osteopor osi s.
5. What si m pl e l abor ator y tests can hel p assess the pati ent w i th osteopeni a?
A com pl ete bl ood count w i th er y thr ocy te sedi m entati on r ate and a
standar d ser um chem i str y pr of i l e that i ncl udes el ectr ol y te, cal ci um ,
phosphate, al k al i ne phosphatase, cr eati ni ne, BU N , cal ci um , and phosphate
m easur em ents pl us l i v er f uncti on tests ar e the si m pl e bl ood tests needed.
A 24hour ur i ne speci m en i s obtai ned f or deter m i nati on of the cal ci um ,
phosphate, and cr eati ni ne content. Bone densi tom etr y establ i shes the
sev er i ty of bone l oss. Al l these l abor ator y tests can be used to qui ck l y
assess the pati ent w i th osteopeni a. If the pati ent has anem i a and an
el ev ated sedi m entati on r ate, the cl i ni ci an shoul d consi der the possi bi l i ty
of a m ul ti pl e m y el om a and hav e ei ther a ser um pr otei n or ur i ne pr otei n
el ectr ophor esi s, or both, per f or m ed. Abnor m al i ti es i n cal ci um bal ance can
be assessed by i denti f y i ng hy pocal cem i c or hy per cal cem i c di sor der s.
Abnor m al i ti es of l i v er and k i dney f uncti on r epr esent secondar y causes of
osteopor osi s. The el ectr ol y te l ev el s hel p suggest the pr esence of r enal
tubul ar aci dosi s sy ndr om es. Al k al i ne phosphatase i s a m ar k er of bone
osteobl ast f uncti on and i ts m easur em ent hel ps i denti f y those pati ents
w i th hi ghtur nov er osteopor osi s or osteom al aci a. A 24hour ur i ne cal ci um
deter m i nati on can i denti f y pati ents w ho hav e i di opathi c hy per cal ci ur i a or
l ow ur i ne cal ci um l osses, suggesti ng a cal ci um def i ci ent state. An
ex tr em el y l ow ur i ne phosphate v al ue m ay r ef l ect the consum pti on of a
v egetar i an di et. A 25hy dr ox y v i tam i n
P. 129
P. 130
D l ev el assesses f or v i tam i n D def i ci ency , a condi ti on now r ecogni zed to
be m or e com m on than pr ev i ousl y appr eci ated. Di agnosi s i s i m por tant, as
r epl eti on i s essenti al bef or e bi sphosphonate ther apy . Other l abor ator y
tests, i ncl udi ng m easur em ent of the PTH l ev el , ser um osteocal ci n l ev el ,
and ur i ne hy dr ox y pr ol i ne or hy dr ox y py r i di ni um , ar e r eser v ed f or those
pati ents i n w hom these ar e speci f i cal l y i ndi cated. A bone densi ty
m easur em ent establ i shes the pr esence or absence of si gni f i cant
osteopor osi s.
Table 310 Causes of Osteopenia
Idi opathi c ager el ated

Juv eni l e
Young adul ts
Postm enopausal (ty pe I)
Seni l e (ty pe II)
Secondar y to di sease states
Metabol i c condi ti ons
Cal ci um def i ci ency
Vi tam i n D def i ci ency states
Mal nutr i ti on
Idi opathi c hy per cal ci ur i a
Renal tubul ar aci dosi s and other sy stem i c
aci dosi s
Di abetes m el l i tus
Scur v y
Endocr i ne condi ti ons
Thy r otox i cosi s
Cushi ng's sy ndr om e
Mal e and f em al e hy pogonadal state
Hy poam enor r hei c f em al e r unner s
Pr ol acti nom a
Hy per par athy r oi di sm
Renal di sease
Gastr oi ntesti nal l i v er di sease
Inher i Tabl e connecti v e ti ssue di sease
Osteogenesi s i m per f ecta
Hom ocy sti nur i a
Ehl er sDanl os sy ndr om e
Mar f an's sy ndr om e
Bone m ar r ow i nf i l tr ati on
Mul ti pl e m y el om a
Ly m phom a
Leuk em i a
Dr ugs
Di l anti n
Phenobar bi tal
Thy r oi d hor m one
Cor ti coster oi ds
Pr ol onged hepar i n ther apy
Li f esty l e
N utr i ti on
Al cohol
Sm ok i ng
Inacti v i ty
Im m obi l i zati on
Ex cessi v e cof f ee and sof t dr i nk s
Mi scel l aneous
Rheum atoi d ar thr i ti s
Sy stem i c m astocy tosi s
6. When ar e bone densi ty m easur em ents i ndi cated?
The N ati onal Osteopor osi s Foundati on has r ecom m ended that bone
m i ner al densi ty be m easur ed i n al l postm enopausal w om en y ounger than
65 y ear s w i th one or m or e r i sk f actor s f or osteopor osi s other than
m enopause, and i n al l w om en ol der than 65. For m al r ecom m endati ons f or
scr eeni ng i n m en do not ex i st at thi s ti m e, but scr eeni ng shoul d be
consi der ed i n m en w i th r i sk f actor s (especi al l y hy pogonadi sm , ster oi d
use, or untr eated hy per par athy r oi di sm ) or af ter a f r actur e.
Case
A thi n, 55y ear ol d, w hi te, postm enopausal w om an i s seen i n her pr i m ar y car e
cl i ni c because of m uscl e aches and w eak ness. She has been seen by num er ous
phy si ci ans f or ev al uati on of thi s condi ti on, and has been r ef er r ed to the
psy chi atr y depar tm ent f or tr eatm ent of a â€œstr ess r eacti on. â€ The pati ent's
past m edi cal hi stor y i s si gni f i cant f or a gastr ectom y appr ox i m atel y 15 y ear s
ear l i er f or the tr eatm ent of pepti c ul cer di sease. She has noti ced l oose stool s
si nce that ti m e. The pati ent adm i ts to a poor cal ci um i ntak e, but other w i se
consum es a nonv egetar i an di et. She suf f er s hot f l ashes and i nsom ni a, but has
nev er been ev al uated f or estr ogen ther apy . Dur i ng her ev al uati on, osteopeni c
changes ar e noted on the chest f i l m . The pati ent's l abor ator y ev al uati on
r ev eal s the f ol l ow i ng f i ndi ngs: cal ci um , 8. 4 m g/dL (nor m al , 8. 7 to 10. 3
m g/dL); phosphate, 2. 0 m g/dL (nor m al , 2. 7 to 4. 5 m g/dL); chl or i de, 108
m Eq/L; sodi um , 145 m Eq/L; potassi um , 4. 5 m Eq/L; CO 2 , 23 m Eq/L; and
al bum i n, 4. 1 g/dL. Her k i dney and l i v er f uncti on test r esul ts ar e nor m al . The
al k al i ne phosphatase l ev el i s el ev ated to 380 IU /L (nor m al , 39 to 117 IU /L).
Her 24hour ur i ne ex cr eti on of cal ci um i s 40 m g (nor m al , 100 to 300 m g);
cr eati ni ne, 1. 1 g; total hy dr ox y pr ol i ne, 86 m g (nor m al , 25 to 77 m g); and
phosphate, 780 m g (nor m al , 400 to 800 m g). The osteocal ci n l ev el i s 7. 1
ng/m L (nor m al , 1. 8 to 6. 6 ng/m L).
1. What ar e the r i sk f actor s f or osteopor osi s i n thi s pati ent?

2. On the basi s of the pati ent's hi stor y and l abor ator y f i ndi ngs, w hat i s the
di f f er enti al di agnosi s?
3. What addi ti onal l abor ator y tests shoul d be obtai ned i n thi s pati ent?
4. On the basi s of the l abor ator y f i ndi ngs, w hat w oul d y ou anti ci pate the
bone bi opsy speci m en to show ?
5. What shoul d the tr eatm ent be i n thi s pati ent?
6. What w oul d y ou adv i se thi s pati ent r egar di ng the adv antages and
di sadv antages of estr ogen r epl acem ent ther apy ?
P. 131
Case Discussion
1. What ar e the r i sk f actor s f or osteopor osi s i n thi s pati ent?
Thi s thi n, w hi te, postm enopausal w om an w i th poor cal ci um i ntak e i s at
r i sk f or osteopor osi s.
2. On the basi s of the pati ent's hi stor y and l abor ator y f i ndi ngs, w hat i s the
di f f er enti al di agnosi s?
Thi s pati ent's hi stor y suggests that, at her age of 55 y ear s, she i s
enter i ng a postm enopausal state, as i ndi cated by the hot f l ashes and
i nsom ni a. In addi ti on, poor cal ci um bal ance m ay be l i k el y because of her
l i f el ong hi stor y of poor cal ci um i ntak e and the gastr ectom y f or pepti c
ul cer di sease, w hi ch coul d l ead to poor v i tam i n D absor pti on. Conf i r m i ng
a state of negati v e cal ci um bal ance i s the pati ent's hy pocal cem i a, l ow
ur i ne cal ci um ex cr eti on, and el ectr ol y te l ev el s, al l of w hi ch suggest the
pr esence of secondar y hy per par athy r oi di sm w i th hy per chl or em i a and l ow
ser um phosphate l ev el s.
3. What addi ti onal l abor ator y tests shoul d be obtai ned i n thi s pati ent?
The pati ent m ay be def i ci ent i n v i tam i n D. Measur i ng the 25
hy dr ox y v i tam i n D l ev el , w hi ch i s the m ajor ci r cul ati ng f or m of v i tam i n D,
can establ i sh the di agnosi s of si m pl e v i tam i n D def i ci ency . Som e pati ents
m ay al so hav e a def i ci ency of 1, 25di hy dr ox y v i tam i n D, par ti cul ar l y ol der
pati ents and those w i th r enal di sease. A PTH v al ue can establ i sh the
di agnosi s of secondar y hy per par athy r oi di sm due to a cal ci um def i ci ent
state stem m i ng f r om the v i tam i n D def i ci ency . Once tr eatm ent i s
i ni ti ated, a PTH v al ue that r etur ns to nor m al conf i r m s a state of nor m al
cal ci um bal ance.
In thi s pati ent, the 25v i tam i n D l ev el i s 10 ng/m L (nor m al , 16 to 74
ng/m L) and the PTH v al ue i s 120 pg/m L (nor m al , 10 to 65 pg/m L).
4. On the basi s of the l abor ator y f i ndi ngs, w hat w oul d y ou anti ci pate the
bone bi opsy speci m en to show ?
A tetr acy cl i nel abel ed bone bi opsy i s per f or m ed by hav i ng the pati ent
i ngest 250 m g of tetr acy cl i ne f our ti m es a day f or 3 day s, then w i thhol d
the tetr acy cl i ne f or 10 day s, and then tak e tetr acy cl i ne f or another 3
day s. These tw o tetr acy cl i ne l abel s deter m i ne the r ate of bone f or m ati on.
Osteocl ast counts can be deter m i ned f r om bone hi stom or phol ogi c
anal y si s, and the am ount of tetr acy cl i ne that has sur f aced can be
m easur ed as an i ndi cati on of acti v e bone f or m ati on. Thi s pati ent pr ov ed
to hav e a hi ghtur nov er osteopor osi s w i th an i ncr eased tetr acy cl i ne
sur f ace and an i ncr eased osteocl ast count, as bor ne out by the hi gh PTH
l ev el . In addi ti on, the hi gh osteocal ci n, al k al i ne phosphatase, and ur i nar y
hy dr ox y pr ol i ne or py r i di ni um l ev el s i ndi cate a state of hi gh bone
tur nov er . Ear l y i n v i tam i n D def i ci ency (hy pov i tam i nosi sD I), secondar y
hy per par athy r oi di sm pr edom i nates, l eadi ng to a hi ghtur nov er
osteopor osi s. In the setti ng of sev er e v i tam i n D def i ci ency , especi al l y
chi l dhood r i ck ets (hy pov i tam i nosi sD II and III), a l ow â€“bonetur nov er
state ex i sts i n w hi ch ther e i s l i ttl e tetr acy cl i ne uptak e.
5. What shoul d the tr eatm ent be i n thi s pati ent?
Thi s pati ent has a com bi ned di sor der of both estr ogen and v i tam i n D
def i ci ency contr i buti ng to her pr esum ed osteopeni a. Ther e i s no doubt
that she w i l l benef i t
P. 132
f r om v i tam i n D r epl eti on and thi s shoul d be i ni ti ated i m m edi atel y . She
w i l l m ost l i k el y not r espond to sm al l doses of v i tam i n D, but m ay r equi r e
50, 000 uni ts of v i tam i n D (er gocal ci f er ol ), gi v en once or tw i ce w eek l y , or
cal ci f edi ol (Cal der ol ), 20 to 50 Âµg dai l y , because of the poor
gastr oi ntesti nal absor pti on of v i tam i n D stem m i ng f r om her gastr ectom y .
Bef or e the r el ease of the r esul ts of the Wom en's Heal th Ini ti ati v e (WHI),
thi s pati ent w oul d al so hav e been tr eated w i th hor m one r epl acem ent
ther apy of dai l y estr ogen w i th ei ther dai l y or cy cl i c pr ogester one. Si nce
the WHI, thi s has becom e a deci si on that r equi r es car ef ul consi der ati on of
the r i sk s and benef i ts of hor m one ther apy descr i bed f ur ther bel ow .
Another ef f ecti v e m eans of tr eati ng osteopor osi s i s w i th bi sphosphonates.
The i ni ti al ex per i ence w i th i ncr eased bone densi ty usi ng bi sphosphonates
w as w i th eti dr onate (Di dr onel ). How ev er , eti dr onate w as nev er f or m al l y
appr ov ed f or osteopor osi s and has been super ceded by the new er or al
bi sphosphonates, al endr onate (Fosam ax ), r i sedr onate (Actonel ), and
r ecentl y i bandr onate (Boni v a). Al l thr ee ar e av ai l abl e as or al
f or m ul ati ons and hav e been show n to i ncr ease bone m i ner al densi ty and
decr ease v er tebr al f r actur e r i sk . Al endr onate and r i sedr onate can be
adm i ni ster ed dai l y or w eek l y , i bandr onate dai l y or m onthl y . Other
bi sphosphonates (pam i dr onate, eti dr onate, and zol edr onate) ar e appr ov ed
f or bone pr eser v ati on and ser um cal ci um r educti on i n m al i gnancy , but not
f or osteopor osi s. Bi sphosphonates shoul d not be adm i ni ster ed to pati ents
w i th v i tam i n D or cal ci um def i ci ency bef or e at l east par ti al r epl eti on.
6. What w oul d y ou adv i se thi s pati ent r egar di ng the adv antages and
di sadv antages of estr ogen r epl acem ent ther apy ?
Estr ogens ar e ef f ecti v e agents f or tr eati ng osteopor osi s by stabi l i zi ng

bone densi ty and pr ev enti ng f r actur es. How ev er , estr ogen ther apy al one
i n a pati ent w i th an i ntact uter us i s associ ated i n a dosedependent
m anner w i th an i ncr eased i nci dence of endom etr i al cancer ; that can be
abol i shed by the addi ti on of 10 to 14 day s of a pr ogesti n at l east thr ee to
f our ti m es annual l y . On the basi s of obser v ati onal studi es, hor m one
r epl acem ent ther apy w as pr ev i ousl y thought to hav e addi ti onal
car di opr otecti v e benef i ts. How ev er , such benef i ts w er e not f ound i n the
l ar ge r andom i zed por ti on of the WHI. Thi s study , i n f act, dem onstr ated
that hor m one r epl acem ent ther apy i s not w i thout r i sk and m ay i ncr ease
the r i sk f or CV di sease and str ok e, as w el l as f or br east cancer . A cav eat
to thi s concl usi on i s that a l ar ge por ti on of the w om en i n the study w er e
m any y ear s postm enopausal and m ay hav e r esponded v er y di f f er entl y to
hor m one ther apy than w om en w ho w er e r ecentl y estr ogen suf f i ci ent.
How ev er , as the onl y l ar ge r andom i zed contr ol l ed study to date, the WHI
m ust be car ef ul l y consi der ed w hen the deci si on to star t estr ogen f or
osteopor osi s i s m ade.
As a r esul t of the WHI, estr ogen ther apy shoul d now be consi der ed as
tr eatm ent f or osteopor osi s onl y i n w om en w ho ar e sy m ptom ati cal l y
postm enopausal . Ev en i n these w om en i t i s contr ai ndi cated i n pati ents
w ho hav e: (a) a per sonal hi stor y of estr ogenr el ated neopl asi a of the
br east, (b) a per sonal or str ong f am i l y hi stor y of br east car ci nom a, (c) a
per sonal hi stor y of thr om boem bol i c di sease or k now n v ascul ar di sease, or
(d) si gni f i cant CV r i sk f actor s, especi al l y tobacco use, obesi ty , or
hy per tensi on. Estr ogen ther apy i s r el ati v el y contr ai ndi cated i n pati ents
P. 133
w i th estr ogenr el ated headaches. The use of estr ogen ther apy m ay al so
be associ ated w i th an i ncr eased i nci dence of gal l stones. A m ar k ed
tr i gl y cer i de el ev ati on m ay dev el op i n som e pati ents w hen estr ogen
ther apy i s i ni ti ated; hence, l i pi d l ev el s need to be check ed w i thi n 4 to 8
w eek s of star ti ng ther apy . Pati ents w ho dev el op adv er se l i pi d
abnor m al i ti es to or al estr ogens m ay do better w i th tr ansder m al estr adi ol
ther apy .
Suggested Readings
Ar m anentoVi l l er eal R, Vi l l er eal DT, Av i ol i LV, et al . Estr ogen status and
her edi ty ar e m ajor deter m i nants of pr em enopausal bone m ass. J Cl i n
Inv est 1992;90:2464.
Ber enson JR, Li pton A. Phar m acol ogy and cl i ni cal ef f i cacy of
bi sphosphonates. Cur r Opi n Oncol 1998;10:566.
Ful f ar o F, Casucci o A, Ti cozzi C, et al . The r ol e of bi sphosphonates i n the

tr eatm ent of pai nf ul m etastati c bone di sease: a r ev i ew of phase III tr i al s.
Pai n 1998;78:157.
Hodsm an BA, Bauer DC, Dem pster DW, et al . Par athy r oi d hor m one and
ter i par ati de f or the tr eatm ent of osteopor osi s: a r ev i ew of the ev i dence
and suggested gui del i nes f or i ts use. Endocr Rev 2005;26:688â€“703.
Hof el dt FD. Pr ox i m al f em or al f r actur es. Cl i n Or thop 1987;218:12.
Hol i ck MF. Vi tam i n D: the under appr eci ated Dl i ghtf ul hor m one that i s
i m por tant f or sk el etal and cel l ul ar heal th. Cur r Opi n Endocr i nol Di abetes
2002;9:87â€“98.
Jack son RD, Wactaw sk i Wende J, Lacr oi x AZ, et al . For the Wom en's Heal th
Ini ti ati v e Inv esti gator s. Ef f ects of conjugated equi ne estr ogen on r i sk of
f r actur es and BMD i n postm enopausal w om en w i th hy ster ectom y : r esul ts
f r om the w om en's heal th i ni ti ati v e r andom i zed tr i al . J Bone Mi ner Res
2006;21(6):817â€“828.
McCl ung M, Cl em m esen B, Dai f oti s A, et al . Al endr onate pr ev ents

postm enopausal bone l oss i n w om en w i thout osteopor osi s: a doubl ebl i nd,
r andom i zed, contr ol l ed tr i al : Al endr onate Osteopor osi s Pr ev enti on Study
Gr oup. Ann Inter n Med 1998;128:253.
Ol szy nsk i WP, Shaw n DK, Adachi JD, et al . Osteopor osi s i n m en:
epi dem i ol ogy , di agnosi s, pr ev enti on, and tr eatm ent. Cl i n Ther
2004;26(1):15â€“28.
Par f i tt AM, Rao DS, Stanci u AR, et al . Ir r ev er si bl e bone l oss i n
osteom al aci a: com par i son of r adi al photon absor pti om etr y w i th i l i ac bone
hi stom or phom etr y dur i ng tr eatm ent. J Cl i n Inv est 1985;76:2403.
Ri ggs BL, Mel ton U . The pr ev enti on and tr eatm ent of osteopor osi s. N Engl J
Med 1992;327:620.
Rosen CJ. Postm enopausal osteopor osi s. N Engl J Med 2005;353(6):595â

€“603.
Rubi n MR, Bi l ezi k i an JP. N ew anabol i c ther api es i n osteopor osi s. Endocr i nol
Metab Cl i n N Am 2003;32(1):285â€“307.
Sr i v astav a AK, Vl i et EL, Lew i eck i EM, et al . Cl i ni cal use of ser um and ur i ne
bone m ar k er s i n the m anagem ent of osteopor osi s. Cur r Med Res Opi n
2005;21(7):1015â€“1026.
Stei n E, Shane E. Secondar y osteopor osi s. Endocr i nol Metab Cl i n N Am

2003;32:115â€“134.
U del l JA, Fi scher MA, Br ook har t MA, et al . Ef f ect of the w om en's heal th
i ni ti ati v e on osteopor osi s ther apy and ex pendi tur e i n m edi cai d. J Bone
Mi ner Res 2006;21(5):765â€“771.
Wi m al aw ansa SJ. A f our y ear r andom i zed contr ol l ed tr i al of hor m one
r epl acem ent and bi sphosphonate, al one or i n com bi nati on, i n w om en w i th
postm enopausal osteopor osi s. Am J Med 1998;104:219.
P. 134
Erectile Dysfunction
Case 1
A 65y ear ol d m an pr esented w i th er ecti l e dy sf uncti onâ€”he had noted gr adual
onset of di f f i cul ty i n achi ev i ng and m ai ntai ni ng an er ecti on dur i ng the l ast 4
y ear s. He had had hy per tensi on f or 10 y ear s and has r ecentl y been tol d that
hi s bl ood chol ester ol l ev el w as hi gh. Hi s f am i l y hi stor y w as posi ti v e f or
cor onar y ar ter y di sease, hy per tensi on, and hy per chol ester ol em i a.
The pati ent's m edi cati ons i ncl uded atenol ol , 50 m g tw i ce a day ;
hy dr ochl or othi azi de, 50 m g per day ; and aspi r i n, 325 m g per day . He had
sm ok ed a pack of ci gar ettes a day f or 30 y ear s, but qui t 2 y ear s ear l i er . He
dr ank thr ee beer s each ni ght.
Phy si cal ex am i nati on show ed a BP of 160/90 m m Hg, the pr esence of ar cus
cor neae, and an S 4 hear t sound. The l i v er and testi cul ar ex am i nati ons w er e
nor m al , as w er e r ef l ex es. The pedal pul ses w er e di m i ni shed.
Labor ator y test r esul ts w er e testoster one, 450 ng/dL (nor m al , 300 to 1, 000
ng/dL); l i v er enzy m es, nor m al ; total chol ester ol , 350 m g/dL; tr i gl y cer i des,
300 m g/dL; and hi ghdensi ty l i popr otei n (HDL), 25 m g/dL.
Case Discussion
Fr om the hi stor y al one, i t w oul d be ex pected that thi s pati ent's er ecti l e
dy sf uncti on had a v ascul ar cause and per haps i atr ogeni c ex acer bati on.
Cor onar y ar ter y di sease i s a r i sk f actor f or er ecti l e dy sf uncti on, and r ecent
studi es hav e suggested that m er el y hav i ng a hi stor y of hy per chol ester ol em i a
poi nts to an under l y i ng v ascul ar eti ol ogy . Hi s l ongstandi ng hy per tensi on al so
suggests v ascul ar di sease.
Thi s pati ent i s tak i ng tw o m edi cati ons that hav e been associ ated w i th er ecti l e
dy sf uncti on. Am ong the cl asses of cur r entl y used anti hy per tensi v e agents, Î²
bl ock er s and di ur eti cs ar e m ost of ten at f aul t. Of the di ur eti cs,
hy dr ochl or othi azi de i s m or e of a pr obl em than f ur osem i de.
Sm ok i ng, of cour se, i ncr eases the r i sk of v ascul ar di sease. Ex cessi v e al cohol
i ntak e i s di r ectl y tox i c to the testi cl es and can r esul t i n decr eased
testoster one pr oducti on. Al cohol i s al so di r ectl y tox i c to the l i v er , and the
r esul ti ng l i v er dy sf uncti on can cause i m bal ance i n testoster one and estr adi ol
m etabol i sm , w hi ch i s of ten associ ated w i th gy necom asti a.
The pati ent's BP r eadi ng i ndi cates that hi s hy per tensi on i s i nadequatel y
contr ol l ed, and the S 4 hear t sound i ndi cates that the hy per tensi on i s l ong
standi ng and has af f ected hi s hear t. The pr esence of ar cus cor neae si gni f i es
pr ol onged hy per chol ester ol em i a. Di m i ni shed pedal pul ses of f er f ur ther
ev i dence f or v ascul ar di sease.
Hy pogonadi sm cannot be r el i abl y detected by cl i ni cal assessm ent al one;

hence, m easur em ent of the testoster one l ev el w as i ndi cated. Li v er f uncti on
testi ng w as per f or m ed i n l i ght of the hi stor y of si gni f i cant al cohol i ntak e. The
l i pi d panel conf i r m ed hy per chol ester ol em i a.
Ther e hav e been m any studi es on how to di sti ngui sh betw een psy chogeni c and
v ascul ar er ecti l e dy sf uncti onâ€”f or ex am pl e, by m oni tor i ng f or noctur nal
er ecti ons. N o contr ol l ed study has show n that the m ethods change the
m anagem ent str ategy ; how ev er ,
P. 135
the w or k up can be l i m i ted to the hi stor y , phy si cal ex am i nati on, and som e
l abor ator y testi ng to ex cl ude other tr eatabl e causes of er ecti l e dy sf uncti on.
In thi s pati ent, atenol ol and hy dr ochl or othi azi de w er e r epl aced w i th enal apr i l .
The pati ent w as counsel ed on di etar y changes that w oul d hel p l ow er hi s
chol ester ol l ev el . A v acuum pum p dev i ce w as pr escr i bed f or the er ecti l e
dy sf uncti on.
Tw o m onths l ater , the pati ent's BP w as nor m al . He r epor ted successf ul
r esum pti on of sex ual i nter cour se usi ng the v acuum pum p.
Ev al uati on of thi s pati ent's er ecti l e dy sf uncti on pr ov i ded the oppor tuni ty to
addr ess the under l y i ng hy per tensi on and hy per chol ester ol em i a. Other w i se, he
m i ght not hav e pr esented unti l a str ok e or hear t attack occur r ed.
Changi ng anti hy per tensi v e m edi cati on i s especi al l y i m por tant i f the i ni ti ati on
of tr eatm ent and onset of er ecti l e dy sf uncti on coi nci de. In thi s case, a
m edi cati on change w as f ur ther justi f i ed because of i nadequate BP contr ol . ACE
i nhi bi tor s do not appear to cause er ecti l e dy sf uncti on and cal ci um channel
bl ock er s r ar el y do, so these ar e the dr ugs that m ay be pr escr i bed i f
m edi cati on i s i nter f er i ng w i th sex ual f uncti oni ng. U nf or tunatel y , a change i n
anti hy per tensi v e m edi cati on al one i s unl i k el y to r estor e er ecti l e f uncti on.
Cor r ecti on of thi s pati ent's bl ood l i pi ds i s l ong ov er due. If di etar y changes do
not suf f i ci entl y i m pr ov e hi s l i pi d pr of i l e w i thi n a f ew m onths, he w i l l be a
candi date f or ther apy w i th an HMGCoA r eductase i nhi bi tor .
The v acuum pum p dev i ce can tr eat er ecti l e dy sf uncti on i n a case l i k e thi s. The
v acuum pum p dev i ce consi sts of a Luci te tube and pum p; the sucti on pul l s
bl ood i nto the peni s. Once an er ecti on has been pr oduced, a r ubber r i ng i s
pl aced at the base of the peni s to m ai ntai n the er ecti on. The v acuum pum p has
no m ajor si de ef f ects, i t can be used as of ten as the pati ent w i shes, i t can be
used i n al l ty pes of er ecti l e dy sf uncti on, and i t has the hi ghest success r ateâ
€”i t i s ef f ecti v e i n 90% to 95% of cases. Obv i ousl y , i t i s not m eant f or a m an
w ho i s not i n a stabl e r el ati onshi p, l ar gel y because of poor pati ent acceptance.
Ther e has been som e specul ati on that v acuum pum p dev i ces m i ght be
contr ai ndi cated i n pati ents tak i ng w ar f ar i n because of the potenti al f or
ecchy m osi s f r om the r i ng, but studi es hav e el i m i nated that concer n.
Case 2
A 52y ear ol d m an w i th di abetes pr esented w i th er ecti l e dy sf uncti on. Hi s
puber tal dev el opm ent had been nor m al . The di abetes had been di agnosed 15
y ear s ear l i er . At the ti m e of di agnosi s, he had had pr obl em s w i th i m potence
that r esol v ed as the hy per gl y cem i a w as br ought under contr ol . Er ecti l e
dy sf uncti on had r etur ned gr adual l y dur i ng the l ast 2 y ear s. He r ar el y had
m or ni ng er ecti ons. The er ecti l e dy sf uncti on has cr eated str ess i n hi s
r el ati onshi p w i th hi s w i f e.
The pati ent had tak en an or al hy pogl y cem i c agent f or 5 y ear s af ter di agnosi s
of di abetes and had been on i nsul i n f or the l ast 10 y ear s. He had di abeti c
com pl i cati ons, i ncl udi ng m i l d r eti nopathy , pr otei nur i a, and m i l d per i pher al
neur opathy . Sy m ptom s of gastr opar esi s had dev el oped dur i ng the l ast 6
m onths.
Hi s cur r ent i nsul i n r egi m en consi sted of 30 uni ts of N PH (neutr al pr otam i ne
Hagedor n) and 15 uni ts of r egul ar i nsul i n i n the m or ni ng, and 10 uni ts of N PH
and 8 uni ts of r egul ar i nsul i n i n the ev eni ng.
Other m edi cati ons i ncl uded l i si nopr i l (15 m g per day ) and si m v astati n (10 m g
per day ). He di d not sm ok e or dr i nk ex cessi v e am ounts of al cohol .
P. 136
N otew or thy f i ndi ngs on the phy si cal ex am i nati on i ncl uded a BP r eadi ng of
120/80 m m Hg w i thout si gni f i cant or thostasi s, r eti nopathy , absence of an S 4
hear t sound, and sl i ghtl y sof t testes. Sensati on to pi npr i ck on the cal f w as
decr eased.
Labor ator y test r esul ts w er e ser um testoster one, 200 ng/dL; total chol ester ol ,
150 m g/dL; tr i gl y cer i des, 250 m g/dL; and HDL, 35 m g/dL. Gl y cosy l ated Hgb
w as 10% (nor m al , < 6. 5%).
Case Discussion
Di abetes i s one of the m ost com m on causes of er ecti l e dy sf uncti on. A
com bi nati on of v ascul ar and neur ol ogi c di sease i s usual l y at f aul t, al though
hor m one def i ci ency , m edi cati ons, and psy chogeni c aspects al so m ay be
i nv ol v ed. Al l f i v e com ponents m ay be pr esent i n a si ngl e pati ent.
Men w i th T2DM of ten hav e acute er ecti l e dy sf uncti on at the onset of the
di sease, si m pl y as a r esul t of sev er e hy per gl y cem i a. The m echani sm of
er ecti l e dy sf uncti on m ay i ncl ude hy pogonadotr opi c hy pogonadi sm as w el l as
m etabol i c and neur ol ogi c dy sf uncti on (caused by gl ucose tox i ci ty ) i n the
testes. Vascul ar f actor s m ay al so be i nv ol v ed because the hy per gl y cem i a i s
usual l y associ ated w i th sev er e hy per l i pi dem i a. The er ecti l e dy sf uncti on
associ ated w i th new onset di abetes m ay i m pr ov e w hen hy per gl y cem i a i s
br ought under contr ol .
In a pati ent w i th l ongstandi ng di abetes, the pr esence of other endor gan
com pl i cati ons m ak es i t m or e l i k el y that er ecti l e dy sf uncti on i s due to di abetes.
In thi s pati ent, cl i ni cal assessm ent suggests a str ong neur ogeni c com ponent;
the di m i ni shed sensati on denotes per i pher al neur opathy and the gastr opar esi s
i ndi cates autonom i c neur opathy (al though the l ack of or thostasi s suggests that
the neur opathy i s not sev er e). The pr otei nur i a suggests a v ascul ar com ponent
and, ev en though the absence of an S 4 ar gues agai nst that, i t shoul d be
r em em ber ed that an S 4 i s not al w ay s pr esent i n di abeti c pati ents w i th
cor onar y ar ter y di sease.
Dr ugi nduced er ecti l e dy sf uncti on does not appear to be an i ssue i n thi s
pati ent because nei ther the ACE i nhi bi tor nor the HMGCoA r eductase i nhi bi tor
causes er ecti l e dy sf uncti on.
The testi cul ar sof tness suggests a m i nor hor m onal com ponent, and i ndeed the
testoster one l ev el i s sl i ghtl y decr eased. A l ow nor m al or sl i ghtl y l ow
testoster one l ev el i s a ty pi cal f i ndi ng i n di abeti c pati ents w i th er ecti l e
dy sf uncti on. Al though the r eadi ng conf i r m s that hor m one def i ci ency i s one of
hi s pr obl em s, a testoster one l ev el of 200 ng/dL w oul d not by i tsel f cause
si gni f i cant hy pogonadi sm and sy m ptom s.
In addi ti on, thi s pati ent's BP needs to be m oni tor ed; i f i t i ncr eases, he w i l l
need an addi ti onal anti hy per tensi v e m edi cati on because he i s al r eady tak i ng a
m ax i m al dose of l i si nopr i l . Incr easi ng data suggest that ti ght contr ol of BP
w i th ACE i nhi bi tor s hel ps pr ev ent both the r enal and the v ascul ar com pl i cati ons
of di abetes. Consequentl y , aggr essi v e anti hy per tensi v e ther apy to l ow er BP to
l ess than 130/85 m m Hg i s i ndi cated.
The pati ent's LDL l ev el i s l ow , but the tr i gl y cer i de l ev el i s not opti m al . If
changes i n hi s di et do not r educe the tr i gl y cer i de l ev el , he w i l l be a candi date
f or tr eatm ent w i th gem f i br ozi l or a stati n.
P. 137
The pati ent w as m anaged w i th i ntr acav er nosal i njecti on of al pr ostadi l and
andr ogen r epl acem ent w i th a l ow dose testoster one patch. He r epor ted
i m pr ov ed er ecti l e f uncti on, i ncr eased ener gy , and a sense of w el l bei ng. In
addi ti on, the pati ent r ecei v ed di etar y counsel i ng and the i nsul i n r egi m en w as
adjusted. The gl y cosy l ated Hgb decr eased to 8%.
In di abeti c pati ents w i th er ecti l e dy sf uncti on, i njecti on of al pr ostadi l i nto the
cor por a cav er nosa of the peni s can be ef f ecti v e. The tr eatm ent i s par ti cul ar l y
sui ted to di abeti c pati ents because they of ten hav e neur ol ogi c com pl i cati ons,
m ak i ng the i njecti ons l ess pai nf ul than i n other pati ents. In addi ti on, those
w ho ar e tak i ng i nsul i n ar e al r eady f am i l i ar w i th needl es and sy r i nges and ar e
l ess l i k el y to be squeam i sh about i njecti ng the peni s. Intr acav er nosal i njecti on
i s ef f ecti v e i n appr ox i m atel y 65% of cases. The v acuum pum p i s hel d i n
r eser v e as secondl i ne tr eatm ent.
Im pl antabl e peni l e pr ostheses w er e com m onl y used to tr eat er ecti l e

dy sf uncti on i n the 1970s and 1980s. They ar e used m uch l ess f r equentl y today
because they ar e ex pensi v e and m ay hav e m any com pl i cati ons. Inf ecti on and
poor w ound heal i ng ar e par ti cul ar pr obl em s i n di abeti c pati ents, of ten
necessi tati ng r em ov al of the i m pl antâ€”at w hi ch poi nt the opti on f or i njecti on
ther apy has been el i m i nated. How ev er , som e of the new er i m pl ants m ay be
appr opr i ate f or y oung m en w i th sev er e er ecti l e dy sf uncti on that does not
r espond to other ther apy .
Intr aur ethr al pl acem ent of v asoacti v e m edi cati on w as i ntr oduced as an
al ter nati v e to i ntr acav er nosal i njecti ons. How ev er , sev er al studi es hav e show n
i t to be l ess ef f ecti v e, w i th a success r ate as l ow as 30% i n di abeti c pati ents.
Si de ef f ects of i ntr acav er nosal i njecti on i ncl ude pr i api sm and peni l e f i br osi s.
Pati ents w i th neur ogeni c or psy chogeni c er ecti l e dy sf uncti on shoul d use a l ow
dose of al pr ostadi l . If the dose i s too hi gh, the r i sk of pr i api sm i s si gni f i cant.
When pr i api sm occur s, the pati ent has to go to an em er gency r oom , w her e he
i s tr eated w i th IV epi nephr i ne or an 18gauge needl e that i s i nser ted i nto the
cor por a cav er nosa to w i thdr aw bl ood. Ther e hav e been onl y r ar e r epor ts of
m or e sev er e consequences, such as l oss of the peni s due to i nf ar cti on.
The r ate of pr i api sm as a com pl i cati on v ar i es accor di ng to the agent used.
Al pr ostadi l has a m uch l ow er r i sk of pr i api sm and f i br osi s than do papav er i ne
and phentol am i ne. How ev er , al pr ostadi l i s m or e l i k el y to cause a bur ni ng
sensati on. For that r eason, i t used to be m i x ed w i th papav er i ne, but
papav er i ne has been w i thdr aw n as a tr eatm ent f or outpati ents. Because of
neur opathy , di abeti c pati ents m ay not ex per i ence a bur ni ng sensati on w i th
al pr ostadi l .
It i s not cl ear w hether better contr ol of thi s pati ent's di abetes dur i ng the
pr ev i ous 10 y ear s w oul d hav e pr ev ented er ecti l e dy sf uncti on. It seem s l ogi cal
that ti ght contr ol of bl ood gl ucose l ev el s w i l l f or estal l er ecti l e dy sf uncti on, just
as i t can pr ev ent r eti nopathy , r enal f ai l ur e, and m acr ov ascul ar di sease.
N ev er thel ess, ther e ar e no pr ospecti v e, doubl ebl i nded, pl acebocontr ol l ed
studi es to conf i r m that l ongter m ti ght bl ood gl ucose contr ol r educes the
i nci dence of er ecti l e dy sf uncti on.
Case 3
A 48y ear ol d m an had ex per i enced acute onset of er ecti l e dy sf uncti on 6
m onths ear l i er . He had no other m edi cal pr obl em s. Puber tal dev el opm ent had
been nor m al . He w as the f ather of thr ee chi l dr en.
P. 138
On f ur ther questi oni ng, the pati ent sai d that he had l ost hi s job 4 m onths ago.
He w as hav i ng pr obl em s i n hi s r el ati onshi p w i th hi s w i f e, and had i ncr eased
hi s al cohol consum pti on f r om tw o beer s a w eek to f our beer s a day .
The phy si cal ex am i nati on w as nor m al . The ser um testoster one l ev el w as 450
ng/dL.
The pati ent w as adv i sed that hi s dr i nk i ng w as pr obabl y contr i buti ng to hi s
er ecti l e dy sf uncti on and that he shoul d r educe hi s i ntak e. Ref er r al f or
psy chol ogi cal counsel i ng w as of f er ed, but he r ef used because of the cost.
Instead, the phy si ci an di scussed the pati ent's ci r cum stances w i th hi m . A 6
w eek tr i al of y ohi m bi ne, 5. 4 m g thr i ce a day , w as pr escr i bed.
The pati ent r etur ned 8 w eek s l ater and r epor ted som e i m pr ov em ent i n er ecti l e
f uncti on.
He f el t that y ohi m bi ne had been hel pf ul ; how ev er , he had al so f ound a job,
w as ex per i enci ng l ess psy chol ogi cal str ess, and had r educed hi s al cohol
consum pti on.
1. What w as the m ajor f actor i n thi s pati ent's er ecti l e dy sf uncti on?
2. How do y ou appr oach psy chol ogi cal er ecti l e dy sf uncti on?
3. What ar e the phar m acol ogi c opti ons f or tr eatm ent?
Case Discussion
1. What w as the m ajor f actor i n thi s pati ent's er ecti l e dy sf uncti on?
Al though the hi stor y i n thi s case i ndi cated that psy chol ogi cal str ess w as
the m ajor tr i gger f or the er ecti l e dy sf uncti on, i t w as i m por tant to
consi der the possi bi l i ty of other com ponents. As noted, er ecti l e
dy sf uncti on r ar el y r esul ts f r om an i sol ated cause. In thi s case, f ur ther
questi oni ng w as needed to r ev eal that al cohol w as al m ost cer tai nl y a
m ajor contr i butor .
Obtai ni ng an accur ate hi stor y of al cohol i ntak e i s notor i ousl y di f f i cul t.
Instead of ask i ng the pati ent, â€œDo y ou dr i nk ?â€ ask , â€œWhen y ou
dr i nk , do y ou dr i nk beer , w hi sk ey , or w i ne?â€ Af ter i denti f y i ng the dr i nk
of choi ce, pi ck a l ar ge am ount and l et pati ents com e dow n f r om ther e;
w i th beer , f or ex am pl e, ask i f they dr i nk a si x pack at a ti m e.
Deter m i ni ng the tr ue am ount of al cohol i ntak e of ten r equi r es sev er al
di scussi ons.
Al so ask pati ents w hen they dr i nk , because they m ay not under stand that
i nter m i ttent dr i nk i ng can hav e per si stent ef f ects. Som e pati ents w ho
dr ank heav i l y on the w eek end and nothi ng at al l dur i ng the w eek m ay
pr esent w i th er ecti l e dy sf uncti on and pai nf ul r i ghtsi ded gy necom asti a
(w hi ch w as w or se on Monday s). Thei r l i v er enzy m es w er e not sev er el y
el ev ated, but the dr i nk i ng had nev er thel ess caused a sy m ptom ati c
i m bal ance of testoster one and estr adi ol .
In pati ents w i th a hi stor y of chr oni c al cohol abuse, l i v er f uncti on tests
shoul d be or der ed. Thei r er ecti l e f uncti on m ay not r etur n ev en i f they
r educe thei r al cohol i ntak e. Because thi s pati ent's i ncr ease i n al cohol
i ntak e w as f ai r l y acute, hi s er ecti l e f uncti on i m pr ov ed as soon as he
began to dr i nk l ess.
2. How do y ou appr oach psy chol ogi cal er ecti l e dy sf uncti on?
Despi te the ubi qui ty of the psy chol ogi cal com ponent i n er ecti l e
dy sf uncti on, ther e hav e been no contr ol l ed studi es to show w hether
psy chother apy or counsel i ng actual l y hel ps. Ev en assum i ng that such
i nter v enti on w oul d be hel pf ul , ther e ar e no
P. 139
data on the best appr oach. Shoul d pati ents r ecei v e behav i or al ther apy ?
Counsel i ng? Is si m pl y tal k i ng w i th the pr i m ar y car e phy si ci an suf f i ci ent?â
€”consi der ati ons such as these can hel p i n appr oachi ng psy chol ogi cal
er ecti l e dy sf uncti on, but ther e ar e no cl ear answ er s.
The pr i m ar y car e phy si ci an shoul d at l east ack now l edge psy chol ogi cal
str ess as a com ponent of er ecti l e dy sf uncti on. Som eti m es ack now l edgi ng
the pr obl em i s enough; the pati ent just needs to tal k about i t. Som eti m es
f ur ther i nter v enti on i s r equi r ed. Whether thi s i s pr ov i ded by the pr i m ar y
car e phy si ci an depends on hi s or her l ev el of com f or t w i th that aspect of
tr eatm ent. Insur ance cov er age i s of ten an i m por tant f actor as w el l .
3. What ar e the phar m acol ogi c opti ons f or tr eatm ent?
The opti ons f or tr eatm ent of er ecti l e dy sf uncti on hav e r adi cal l y changed
w i th the i ntr oducti on of si l denaf i l (Vi agr a), the f i r st tr ul y ef f ecti v e or al
m edi cati on f or thi s condi ti on, and m or e r ecentl y appr ov ed r el ated
m edi cati ons, v ar denaf i l (Lev i tr a) and tadal af i l (Ci al i s).
Adv ances i n our k now l edge of the phy si ol ogy of er ecti on hav e f aci l i tated
under standi ng of the phar m acody nam i cs of si l denaf i l . Er ecti on i s i ni ti ated
by di l ati on of the ar ter i al bed, w hi ch i ncr eases bl ood f l ow and pr essur e;
i t i s m ai ntai ned by r estr i cti on of v enous outf l ow . Pr ev i ousl y i t w as
bel i ev ed that the par asy m patheti c sy stem w as cr i ti cal i n m ai ntai ni ng
er ecti on. N ow , w e k now that the m ajor pl ay er i s the nonadr ener gi c,
nonchol i ner gi c (N AN C) sy stem , w hi ch w as i denti f i ed 50 y ear s ago but
nev er studi ed i n detai l unti l r el ati v el y r ecentl y . The N AN C sy stem uses
ni tr i c ox i de as a neur otr ansm i tter . Thr ough i ts second m essenger , cy cl i c
guani ne m onophosphate (cGMP), ni tr i c ox i de tr i gger s r el ax ati on of peni l e
endothel i um and sm ooth m uscl e, al l ow i ng ex pansi on of the l acunar spaces
w i thi n the cor por a and the tr appi ng of bl ood by com pr essi on of per i pher al
dr ai ni ng v enul es.
Si l denaf i l , a ty pe 5 phosphodi ester ase i nhi bi tor , pr ev ents the br eak dow n
of cGMP, ther eby pr ol ongi ng er ecti on. It has no ef f ect on l i bi do and does
not cause er ecti on w i thout sti m ul ati on, but i t m ai ntai ns an er ecti on once
i t has been achi ev ed. Al though the N AN C sy stem i s par ti cul ar l y
pr om i nent i n the peni s, i t i s al so f ound i n the hear t, the br ai n, and other
or gans. Its pr esence i n the ey e ex pl ai ns the bl ue v i sual hue that som e
pati ents ex per i ence af ter tak i ng si l denaf i l .
The m ost com m on si de ef f ects of si l denaf i l ar e headache, f l ushi ng, and
dy spepsi a. It can al so decr ease BP. Because the decr ease i n BP m ay be
sy ner gi sti c w i th the hy potensi v e acti on of ni tr ates, si l denaf i l i s
contr ai ndi cated i n pati ents tak i ng a m edi cati on that contai ns ni tr ates,
such as ni tr ogl y cer i n.
In addi ti on, si l denaf i l al ter s the hal f l i f e of m any other m edi cati ons, and
m any m edi cati ons change the hal f l i f e of si l denaf i l . The l i st of agents
that can i nter act w i th si l denaf i l i ncl udes such com m on m edi cati ons as
nonsel ecti v e Î²bl ock er s, er y thr om y ci n, i tr aconazol e, potassi um spar i ng
di ur eti cs, and ci m eti di ne. It i s not k now n w hether those i nter acti ons
af f ect the si de ef f ects of si l denaf i l , par ti cul ar l y the i nci dence or sev er i ty
of hy potensi on. In i ni ti al cl i ni cal tr i al s, hy potensi on w as r epor ted i n
appr ox i m atel y 3% of pati ents, but those tr i al s i ncl uded a l ar ge
per centage of y oung m en w i th psy chogeni c i m potence. Obv i ousl y , pati ents
w i th v ascul ar di sease or di abetes hav e m or e pr obl em s w i th BP r egul ati on
and theor eti cal l y w i th or thostati c
P. 140
hy potensi on. Deaths hav e been r epor ted am ong pati ents tak i ng si l denaf i l
si nce i t becam e av ai l abl e. The FDA i s i nv esti gati ng those deaths.
The f i r st study of data on di f f er ent pati ent popul ati ons tak i ng si l denaf i l
w as publ i shed sev er al m onths af ter the dr ug becam e av ai l abl e f or cl i ni cal
use. Al though the pack age i nser t i ndi cated an ov er al l ef f i cacy of 82% (v s.
24% f or pl acebo), anal y si s si nce has f ound m or e m odest ef f i cacy of 68%
i n pati ents w i th hy per tensi on, 57% i n di abetes, and 61% af ter
tr ansur ethr al pr ostatectom y . Mor eov er , publ i shed r esul ts ar e f r equentl y
obtai ned i n a sel ected pati ent popul ati on, not f r om gener al cl i ni cal use.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 4 G a s tr o e nte r o lo g y
Chapter 4
Gastroenterology
W illia m R. Brow n
Chronic Inflammatory Bowel Disease
1. What i s the pathogenesi s r esponsi bl e f or chr oni c ul cer ati v e col i ti s
(CU C) and Cr ohn's di sease?
2. Com par e and contr ast the pr i nci pal cl i ni cal f eatur es of CU C and Cr ohn's
di sease.
3. What ar e the r especti v e r i sk s of i ntesti nal m al i gnancy i n CU C and

Cr ohn's di sease?
4. What ar e the pr i nci pal m edi cal ther apeuti c m easur es used f or pati ents
w i th CU C and Cr ohn's di sease?
P. 142
Discussion
1. What i s the pathogenesi s r esponsi bl e f or CU C and Cr ohn's di sease?
The cause and pathogenesi s of both these chr oni c i nf l am m ator y bow el
di seases (CIBDs) ar e unk now n. Both ar e char acter i zed by a chr oni c
i nf l am m ator y cel l i nf i l tr ate of the bow el . How ev er , w her eas CU C i s
r estr i cted to the col on, Cr ohn's di sease can i nv ol v e the enti r e
al i m entar y tr act f r om the m outh to the anus, al though the di stal i l eum
and col on ar e the por ti ons m ost f r equentl y af f ected. Another
di sti ngui shi ng f eatur e of Cr ohn's di sease i s the i nv ol v em ent of al l
l ay er s of the bow el , w her eas the i nf l am m ati on seen i n CU C i s m ostl y
l i m i ted to the m ucosa. In addi ti on, f ocal gr anul om as ar e com m on i n
Cr ohn's di sease but r ar e i n CU C. How ev er , nei ther di sease has
pathognom oni c f eatur es, and Cr ohn's di sease of the col on cannot be
hi stol ogi cal l y di sti ngui shed f r om CU C i n 15% to 25% of cases of
chr oni c col i ti s.
2. Com par e and contr ast the pr i nci pal cl i ni cal f eatur es of CU C and Cr ohn's
di sease.
The sev er i ty , cl i ni cal cour se, and pr ognosi s of CU C and Cr ohn's di sease
ar e w i del y v ar i abl e. Onset i n both di seases occur s m ost of ten i n ear l y
adul thood. The sy m ptom s of CU C m ay r ange f r om sl i ght r ectal bl eedi ng
to f ul m i nant di ar r hea w i th col oni c hem or r hage and hy potensi on. Most
pati ents hav e i nter m i ttent attack s, al though som e can hav e conti nuous
sy m ptom s w i thout r em i ssi on. The cl i ni cal f eatur es of Cr ohn's di sease
depend on the sev er i ty and l ocati on of the bow el i nv ol v em ent; the
pr i nci pal f eatur es ar e di ar r hea, abdom i nal pai n, hem atochezi a,
i ntesti nal obstr ucti on, f i ssur es, and f i stul as.
Ex tr ai ntesti nal m ani f estati ons ar e com m on i n both Cr ohn's di sease and
CU C, but m or e com m on i n CU C. The m ani f estati ons i ncl ude ar thr i ti s,
ar thr al gi a, i r i ti s, uv ei ti s, l i v er di sease, and sk i n l esi ons. The ar thr i ti s
m ay pr esent as a m i gr ator y ar thr i ti s, i nv ol v i ng l ar ge joi nts, sacr oi l i i ti s,
or ank y l osi ng spondy l i ti s. Pr i m ar y scl er osi ng chol angi ti s, w hi ch i s
associ ated w i th an i ncr eased f r equency of chol angi ocar ci nom a, and
chr oni c hepati ti s ar e com m on hepatobi l i ar y abnor m al i ti es.
The pr i nci pal f eatur es that di f f er enti ate Cr ohn's di sease f r om CU C ar e
l i sted i n Tabl e 4. 1.
3. What ar e the r especti v e r i sk s of i ntesti nal m al i gnancy i n CU C and

Cr ohn's di sease?
The f r equency of i ntesti nal cancer i s i ncr eased i n Cr ohn's di sease, but
not to the ex tent i n CU C. Accor di ng to som e r epor ts, the f r equency of
col on cancer i n adul ts w ho hav e CU C i nv ol v i ng the enti r e col on i s
appr ox i m atel y 25 ti m es gr eater than that i n the gener al popul ati on. The
r i sk of col on cancer dev el opi ng i n pati ents w i th CU C i s posi ti v el y
cor r el ated w i th the ex tent and dur ati on of the di sease.
4. What ar e the pr i nci pal m edi cal ther apeuti c m easur es used f or pati ents
w i th CU C and Cr ohn's di sease?
The ge ne ra l me a s ure s to contr ol the sy m ptom s of both di seases

i ncl ude cor r ecti on of f l ui dâ€“el ectr ol y te i m bal ances; i r on, f ol ate, or
v i tam i n B 1 2 suppl em entati on as needed f or the tr eatm ent of anem i a;
and di etar y adjustm ents ai m ed at m ai ntai ni ng adequate nutr i ti on. Tota l
pa re nte ra l nutrition m ay be
P. 143
r equi r ed f or the shor tter m tr eatm ent of sev er e acute di sease, but â
€œbow el r estâ€ and hy per al i m entati on ar e of dubi ous v al ue i n the l ong
ter m . Antidia rrhe a l a ge nts such as l oper am i de ar e usual l y
contr ai ndi cated i n pati ents w i th CU C because they m ay contr i bute to
the dev el opm ent of tox i c m egacol on, but they m ay hel p al l ev i ate the
di ar r hea and abdom i nal cr am ps i n the setti ng of stabl e Cr ohn's di sease.
Table 41 Features that Distinguish between
Crohn's Disease and Ulcerative Colitis
Crohn's Disease and Ulcerative Colitis
Fa c tors Crohn's Dis e a s e U lc e ra tive Colitis
Pathol ogi c Tr ansm ur al Mucosal

f eatur es i nf l am m ati on i nf l am m ati on
Deep ul cer s Super f i ci al ul cer s
Gr anul om as Gr anul om as absent

com m on
Di str i buti on Mouth to anus Col on

(i l eum and
pr ox i m al col on
m ost com m on)
Cl i ni cal

f eatur es
Rectal bl eedi ng 20%â€“40% 98%
Ful m i nati ng U ncom m on Com m on

epi sodes
Obstr ucti on Com m on Rar e
Fi stul as Com m on Rar e
Per i anal Com m on Less com m on

di sease
Si gm oi doscopi c

and
r adi ogr aphi c

f i ndi ngs
Rectal 50% 95%â€“100%
i nv ol v em ent
Ex tent Patchy Conti nuous
U l cer s Longi tudi nal , deep Shal l ow , col l ar

button
Pseudopol y ps U ncom m on Com m on
Str i ctur es Com m on U ncom m on
Il eal N ar r ow ed l um en Di l ated l um en w i th

i nv ol v em ent w i th thi ck ened di m i ni shed f ol ds but
w al l hi stol ogi cal l y nor m al
Fr om Schaef er J, Mal l or y A. Gastr oi ntesti nal di sease. In:

Schr i er RW, ed. Medi ci ne: di agnosi s and tr eatm ent. Boston:
Li ttl e, Br ow n and Com pany , 1988.
In CU C, c ortic os te roids ar e usef ul f or i nduci ng r em i ssi ons or

i m pr ov em ent i n an acute attack , and they m ay be r equi r ed f or l ong
ter m m anagem ent. How ev er , the possi bl e benef i ts of cor ti coster oi ds i n
the l ong ter m ar e of f set by thei r m any adv er se si de ef f ects. The r ectal
adm i ni str ati on of ster oi ds or m esal am i ne can be benef i ci al , especi al l y
w hen r ectal i nv ol v em ent (pr octi ti s) i s sev er e. How ev er , si gni f i cant
absor pti on of r ectal ster oi ds can occur , so sy stem i c ef f ects of the
agents (both benef i ci al and undesi r abl e) m ay ar i se w hen they ar e gi v en
by thi s r oute. Sulfa s a la zine i s m etabol i zed by col oni c bacter i a,
r el easi ng sul f apy r i di ne and 5am i nosal i cy l ate (5ASA); the l atter i s
bel i ev ed to be the
P. 144
acti v e com pound. Sul f apy r i di ne i s absor bed sy stem i cal l y , w hi ch
accounts f or the si de ef f ects of sul f asal azi ne (e. g. , headache,
occasi onal m egal obl asti c anem i a, sk i n r ash). The gr eatest uti l i ty of
sul f asal azi ne i n pati ents w i th CU C i s i n l ongter m m anagem ent, w her e
i t has been pr ov ed to r educe the f r equency of r el apses. 5ASA, gi v en
r ectal l y by enem a or supposi tor y , i s w el l tol er ated and ef f ecti v e. Gi v en
or al l y , 5ASA i s r api dl y denatur ed by gastr i c aci d, so al ter nati v es to
pl ai n 5ASA, such as m i cr oencapsul ated (Pentasa; Hoechst Mar i on
Roussel , Kansas Ci ty , MO) or acr y l i cbased r esi ncoated (Asacol ;
Pr octer & Gam bl e Phar m aceuti cal , N or w i ch, N Y) f or m s of 5ASA, m ay
be used. Because the r el ati v e r i sk f or dev el opm ent of CU C i s gr eater i n
nonsm ok er s than i n sm ok er s (the opposi te i s tr ue i n Cr ohn's di sease),
ni coti ne i s bei ng tr i ed i n the tr eatm ent of CU C; som e benef i t has been
r epor ted, but addi ti onal r esear ch i s needed.
Ther e i s no uni f or m l y ef f ecti v e tr eatm ent av ai l abl e f or Cr ohn's di sease.

How ev er , cor ti coster oi ds hav e docum ented ef f i cacy i n di m i ni shi ng the
acti v i ty of the di sease pr ocess. Longter m use of cor ti coster oi ds i s not
r ecom m ended because of thei r m any si de ef f ects, such as osteopor osi s,
di abetes, and catar acts. Sul f asal azi ne has som e ef f ecti v eness,
especi al l y i n col oni c Cr ohn's di sease, but i s l ess ef f ecti v e than
cor ti coster oi ds. Pentasa, i n doses of m or e than 3 m g per day m ay be
ef f i caci ous i n m i l d to m oder ate Cr ohn's di sease, par ti cul ar l y i n i l eal
di sease. Metr oni dazol e m ay be at l east as ef f ecti v e as sul f asal azi ne.
When Cr ohn's di sease cannot be contr ol l ed by these m edi cati ons, the
i m m unosuppr essi v e agent azathi opr i ne and i ts m etabol i te 6
m er captopur i ne ar e of ten used. These dr ugs ar e ef f ecti v e i n both
i nduci ng and m ai ntai ni ng r em i ssi on i n i nf l am m ator y ty pe and
f i stul i zi ngty pe Cr ohn's di sease. Thei r use can r esul t i n a r educti on i n
the cor ti coster oi d dose needed, but thi s adv antage m ay be of f set by
thei r tox i c ef f ects (e. g. , pancr eati ti s, al l er gi c r eacti ons, and
l eucopeni a). Mor e r ecentl y , i nf l i x i m ab, a chi m er i c m onocl onal
anti tum or necr osi s f actor anti body , has been show n to be ef f ecti v e i n
Cr ohn's di sease, both i n the i nf l am m ator y and the f i stul i zi ng ty pes. The
r ol e of i m m unodul ator dr ugs i n CU C i s l ess cl ear than i n Cr ohn's
di sease.
Case
A 37y ear ol d m an w i th docum ented CU C w as f i r st seen at 19 y ear s because
of sev er e bl oody di ar r hea and l ef t l ow er quadr ant abdom i nal pai n that
necessi tated hospi tal i zati on. Af ter 10 day s of tr eatm ent w i th hi ghdose
pr edni sone and sul f asal azi ne hi s sy m ptom s w er e contr ol l ed, and he has
si nce been m anaged w i th these m edi ci nes, w i th the dosages adjusted
dependi ng on hi s di sease acti v i ty . He has not r equi r ed cor ti coster oi ds
ex cept f or f l ar eups of di sease. Subsequent to hi s i ni ti al pr esentati on, af ter
hi s di sease acti v i ty had subsi ded, he under w ent col onoscopy f or hi stol ogi c
conf i r m ati on of the di sease and to deter m i ne the ex tent of i ntesti nal
i nv ol v em ent; thi s ex am i nati on r ev eal ed di f f use m ucosal i nf l am m ati on
i nv ol v i ng the enti r e col on (pancol i ti s). The ter m i nal i l eum appear ed nor m al .
Col oni c bi opsy speci m ens r ev eal ed a di f f use m ucosal i nf l am m ator y i nf i l tr ate
w i th l i ttl e i nv ol v em ent of the subm ucosa, acute and chr oni c i nf l am m ator y
cel l s, and f r equent cr y pt abscesses but no gr anul om as.
P. 145
The pati ent w ent on to gr aduate f r om col l ege and w as then hi r ed as a sal es
r epr esentati v e f or a phar m aceuti cal com pany . Because hi s di sease has been
qui escent and hi s schedul e v er y busy he has not tak en hi s m edi cati ons
r egul ar l y and has r ar el y seen hi s phy si ci an.
Appr ox i m atel y 2 m onths ago, he began to f eel ti r ed, and i nter m i ttent r ectal
bl eedi ng dev el oped. Hi s phy si cal ex am i nati on f i ndi ngs ar e unr em ar k abl e,
but the f ecal occul t bl ood test r esul t i s posi ti v e. The hem ogl obi n i s 11 g/dL;
hem atocr i t, 33%; and l euk ocy te count, 7, 700 cel l s/m m 3 , w i th a nor m al
di f f er enti al count.
1. What i s y our di f f er enti al di agnosi s of hi s r ecent sy m ptom s?

2. What tests ar e necessar y to m ak e the cor r ect di agnosi s?
3. How shoul d thi s pati ent's CU C hav e been m anaged ov er the pr ev i ous 18
y ear s?
Case Discussion
1. What i s y our di f f er enti al di agnosi s of hi s r ecent sy m ptom s?
The di f f er enti al di agnosi s i n thi s pati ent i ncl udes thr ee possi bi l i ti es.
Fi r st, thi s epi sode coul d be an acute f l ar eup or ex acer bati on of hi s
ul cer ati v e col i ti s. Second, he coul d hav e an acute, sel f l i m i ted col i ti s
super i m posed on hi s ul cer ati v e col i ti s; i nf ecti on w i th Cam py l obacter ,
Sal m onel l a, or Shi gel l a speci es, or w i th par asi tes can cause such a
col i ti s. Thi r d, the r ectal bl eedi ng and anem i a coul d be the r esul t of
adenocar ci nom a.
2. What tests ar e necessar y to m ak e the cor r ect di agnosi s?
Stool cul tur es and the ex am i nati on of stool f or ov a and par asi tes w oul d
be an i m por tant i ni ti al l abor ator y test i n thi s pati ent. These pr ov ed to
be negati v e.
Fl ex i bl e si gm oi doscopy or col onoscopy w i th the acqui si ti on of bi opsy

speci m ens i s al so an i m por tant di agnosti c pr ocedur e. In contr ast to
CIBD, the hi stol ogi c f eatur es of acute sel f l i m i ted col i ti s consi st of
nor m al cr y pt ar chi tectur e and an acute but not chr oni c i nf l am m ator y
i nf i l tr ate i n the l am i na pr opr i a. Inf l am m ati on i s m or e l i k el y to be f ound
i n the upper m ucosa i n acute col i ti s, and i n the cr y pt bases i n CIBD.
When an acute sel f l i m i ted col i ti s, such as i nf ecti on w i th
Cam py l obacter jejuni , Sal m onel l a, or Shi gel l a, r esol v es, the m ucosa i s
nor m al , w her eas cr y pt di stor ti on and atr ophy ar e of ten seen i n the
setti ng of heal ed CIBD. In other acute col i ti des, the hi stol ogi c f eatur es
f ound i n m ucosal bi opsy speci m ens m ay suggest a speci f i c i nf ecti on;
these i ncl ude v i r al i ncl usi ons, par asi tes, or pseudom em br anes.
In thi s pati ent, f l ex i bl e si gm oi doscopy w as per f or m ed to a depth of 30
cm and r ev eal ed m i l d gr anul ar i ty of the m ucosa w i thout bl eedi ng,
al though som e bl ood w as seen com i ng f r om abov e 30 cm . Acti v e CU C
al m ost al w ay s i nv ol v es the r ectum , so the f i ndi ng of onl y m i l d changes
i n thi s pati ent's r ectum suggests that the si gni f i cant pathol ogi c pr ocess
w as hi gher i n the col on. A col onoscopi c ex am i nati on show ed a sessi l e,
f ungati ng m ass i n the descendi ng col on, w hi ch pr ov ed to be an
adenocar ci nom a.
3. How shoul d thi s pati ent's CU C hav e been m anaged ov er the pr ev i ous 18
y ear s?
Ther e i s not y et agr eem ent on the m ost costef f ecti v e appr oach f or the
sur v ei l l ance f or col oni c cancer i n pati ents w i th CU C. How ev er , af ter a
pati ent has
P. 146
had ex tensi v e di sease f or 8 to 10 y ear s, i t i s pr obabl y w i se to per f or m
com pl ete col onoscopy ev er y 1 to 2 y ear s, w i th m ul ti pl e bi opsy
speci m ens obtai ned ev er y 10 to 12 cm f r om nor m al appear i ng m ucosa
and tar geted speci m ens obtai ned f r om v i l l ous ar eas of m ucosa, ar eas
of ul cer ati on w i th a r ai sed edge, and str i ctur es. Col ectom y i s
r ecom m ended i f m ul ti f ocal or hi ghgr ade dy spl asi a i s seen i n the
bi opsy speci m ens and conf i r m ed by an ex per i enced pathol ogi st. If a
m ass l esi on associ ated w i th any degr ee of dy spl asi a i s i denti f i ed, thi s
i s al so a gener al l y accepted i ndi cati on f or col ectom y . The m anagem ent
of per si stent l ow gr ade dy spl asi a w i thout a m ass i s m or e contr ov er si al ,
but, i ncr easi ngl y , col ectom y i s bei ng r ecom m ended f or l ow gr ade
dy spl asi a (Fi g. 4. 1).
Figure 41 A pr oposed sy stem of sur v ei l l ance f or cancer i n

ul cer ati v e col i ti s usi ng col onoscopy and bi opsy . (Fr om Stenson WF
and Kor zeni k J. Inf l am m ator y bow el di sease. In: Yam ada T,
Al per s, DH, Kapl ow i tz N , etal . eds. Tex tbook of gastr oenter ol ogy ,
4th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:1748, f i g
8329. )
Cancer pr ev enti on i s an i m por tant topi c to consi der w hen adv i si ng
y oung pati ents w i th ex tensi v e col i ti s about the possi bl e need f or
sur gi cal tr eatm ent. The deci si on to r ecom m end pr ophy l acti c
pr octocol ectom y af ter m any y ear s of col i ti s m ust be based on sev er al
consi der ati ons i n the i ndi v i dual pati ent. These i ncl ude the i ntr actabi l i ty
of sy m ptom s, age, psy chol ogi cal m ak eup, m edi cal com pl i ance, and the
av ai l abi l i ty of new er sur gi cal pr ocedur es. A pr ophy l acti c col ectom y
shoul d be r ecom m ended to a noncom pl i ant pati ent w ho acqui r es
ex tensi v e ul cer ati v e col i ti s at a y oung age. Pati ents w ho hav e CU C
shoul d be f ul l y i nf or m ed of thei r r i sk f or dev el opm ent of cancer , as
w el l as the l i m i tati ons of endoscopi c sur v ei l l ance and the av ai l abi l i ty of
sur gi cal al ter nati v es. If a pati ent i s unw i l l i ng to assent to the sur gi cal
pr ocedur e, then he or she m ust be com m i tted to under goi ng r egul ar
sur v ei l l ance.
P. 147
Suggested Readings
Jew el l DP. U l cer ati v e col i ti s. In: Fel dm an M, Fr i edm an LS, Sl ei senger
MH, eds. Sl ei senger and For dtr an's gastr oi ntesti nal and l i v er di sease.
Pathophy si ol ogy , di agnosi s, m anagem ent, 7th ed. Phi l adel phi a: WB
Saunder s, 2002: 2039â€“2067.
Sands BE. Cr ohn's di sease. In: Fel dm an M, Fr i edm an LS, Sl ei senger MH,
eds. Sl ei senger and For dtr an's gastr oi ntesti nal and l i v er di sease.
Saunder s, 2002: 2005â€“2038.
Stenson WF, Kor zeni k J. Inf l am m ator y bow el di sease. In: Yam ada T,
Al per s DH, Kapl ow i tz N , etal . eds. Tex tbook of gastr oenter ol ogy , 4th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003: 1699.
Chronic Liver Disease
1. What ar e som e speci f i c causes of chr oni c l i v er di sease?
2. What ar e the pr i nci pal l abor ator y abnor m al i ti es i n the setti ng of
chr oni c l i v er di sease?
3. What ar e the tw o m ajor hi stol ogi c categor i es of chr oni c hepati ti s due to
v i r al i nf ecti on?
Discussion
1. What ar e som e speci f i c causes of chr oni c l i v er di sease?
Chr oni c l i v er di sease m ay be the sequel a of sev er al k i nds of tox i c,

m etabol i c, i nf ecti ous, i m m unol ogi c, or her edi tar y condi ti ons. Tabl e 42
contai ns a par ti al l i st.
2. What ar e the pr i nci pal l abor ator y abnor m al i ti es i n the setti ng of
chr oni c l i v er di sease?
The cl i ni cal l y av ai l abl e l i v er f uncti on tests i ncl ude those that assess, at
l east i n par t, l i v er sy ntheti c f uncti on (ser um al bum i n and bi l i r ubi n
concentr ati ons, and pr othr om bi n ti m e) and those that m ostl y ev al uate
the hepatocel l ul ar r el ease of enzy m es (am i notr ansf er ases and al k al i ne
phosphatase). Of ten, the l ev el s of am i notr ansf er ase [al ani ne
am i notr ansf er ase (ALT), aspar tate am i notr ansf er ase (AST), and
al k al i ne phosphatase] ar e not m ar k edl y el ev ated i n pati ents w i th
chr oni c l i v er di sease, and consequentl y do not accur atel y pr edi ct
pr ognosi s. The ser um al bum i n and bi l i r ubi n concentr ati ons and the
pr othr om bi n ti m e ar e m or e l i k el y to be di sti nctl y abnor m al , and m or e
accur atel y r ef l ect the tr ue status of the l i v er 's f uncti onal capaci ty .
3. What ar e the tw o m ajor hi stol ogi c categor i es of chr oni c hepati ti s due to
v i r al i nf ecti on?
Categor i es of these di seases, constr ucted by i nter nati onal com m i ttees,
consi st of thr ee com ponents: the eti ol ogy of the di seases, gr adi ng of
di sease acti v i ty (i . e. , the sev er i ty of the necr oi nf l am m ator y pr ocess),
and stagi ng of the di sease (i . e. , the degr ee of f i br osi s subsequent to
necr oi nf l am m ator y i nsul ts). The gr adi ng and stagi ng ar e usual l y gi v en
a sem i quanti tati v e scor e (0 to 4) or a descr i pti v e char acter i zati on
(e. g. , m i ni m al to sev er e i nf l am m ati on, or no f i br osi s to ci r r hosi s).
P. 148
Table 42 Specific Causes of Chronic Liver
Disease
Dr ugs and chem i cal s

Acetam i nophen
Al cohol a
Am i odar one
Ar seni c and i nor gani c sal ts
Isoni azi d
N i tr of ur antoi n
Pr opy l thi our aci l
Vi ny l chl or i de
Vi r al hepati ti s
Hepati ti s B and C a
Cy tom egal ov i r us hepati ti s
Gr anul om atous i nf ecti ons
Bacter i al (tuber cul osi s), spi r ochetal (secondar y sy phi l i s),
m y coti c a
Dr ugs and f or ei gn substances
Other sour ces
Sar coi dosi s
Pr i m ar y bi l i ar y ci r r hosi s
Im m uni ty di sor der s
Com pl i cati ons of ul cer ati v e col i ti s and Cr ohn's di sease
[pr i m ar y bi l i ar y ci r r hosi s and
sm al l duct pr i m ar y scl er osi ng chol angi ti s
(per i choangi ti s)] a
Pr i m ar y bi l i ar y ci r r hosi s a
Autoi m m une chr oni c hepati ti s a
Inher i ted di seases
Wi l son's di sease a
Hem ochr om atosi s a
Inbor n er r or s of m etabol i sm (gl y cogen stor age di sease
and Gaucher 's di sease)
Î± 1Anti tr y psi n def i ci ency
a Most f r equentl y encounter ed.
Case
A 60y ear ol d m an i s br ought to the hospi tal by hi s w i f e because he has not
been acti ng hi s usual sel f . For the l ast 3 day s, he has not been sl eepi ng at
ni ght and has been nappi ng dur i ng the day . Ther e i s no hi stor y of r ecent
tr aum a, tak i ng new m edi cati ons, or sui ci dal i deati on. He has been tak i ng
di azepam , 5 m g ni ghtl y , f or i nsom ni a. Ri sk f actor s f or chr oni c l i v er di sease,
accor di ng to hi s w i f e, i ncl ude the consum pti on of tw o beer s ni ghtl y f or 35
y ear s and a bl ood tr ansf usi on f or the tr eatm ent of a bl eedi ng pepti c ul cer
25 y ear s ago, at w hi ch ti m e he under w ent an â€œul cer sur ger y . â€
On phy si cal ex am i nati on, he appear s sl eepy but ar ousabl e. The v i tal si gns
ar e nor m al . Sev er al l ar ge spi der angi om as ar e pr esent on the tor so. Ther e
i s no scl er al i cter us. The par oti d gl ands ar e enl ar ged bi l ater al l y , and
w asti ng of the tem por al m uscl es i s noted. The hear t and l ung ex am i nati on
f i ndi ngs ar e nor m al . Hi s abdom en i s sl i ghtl y di stended, and
P. 149
shi f ti ng dul l ness and a m i dl i ne scar ar e pr esent. The l i v er i s not pal pabl e
bel ow the r i ght costal m ar gi n but i s pal pabl e 10 cm bel ow the x i phoi d
pr ocess; i t i s f i r m and per cussed to a span of 8 cm i n the r i ght
m i dcl av i cul ar l i ne. The spl een i s pal pabl e. The abdom en i s not tender to
pal pati on or per cussi on. The testes ar e sm al l . The r ectum i s f ound to
contai n har d, br ow n stool , w hi ch i s posi ti v e f or occul t bl ood. Ther e i s m i l d
edem a of the l egs and m oder ate m uscl e w asti ng. Aster i x i s i s pr esent. The
cr ani al ner v es and deep tendon r ef l ex es ar e i ntact. The pati ent i s som ew hat
uncooper ati v e but hi s m uscul ar str ength i s not f ocal l y di m i ni shed; hi s
pl antar r ef l ex es (Babi nsk i 's si gn) ar e nor m al .
Labor ator y data ar e as f ol l ow s: per i pher al bl ood w hi te cel l count, 2, 500
cel l s/m m 3 ; hem ogl obi n, 10 g/dL; hem atocr i t, 33%; pl atel et count, 125, 000/
m m 3 ; ser um AST, 100 IU /L (nor m al , < 30 IU /L); ALT, 80 IU /L (nor m al , < 45
IU /L); total bi l i r ubi n, 1. 2 m g/dL; al k al i ne phosphatase, 150 IU /L (nor m al ,
< 130 IU /L); total pr otei n, 8. 0 g/dL; al bum i n, 3. 1 g/dL; and pr othr om bi n
ti m e, 13 seconds (contr ol , 11 seconds).
1. What f eatur es hel p y ou to di agnose chr oni c v er sus acute l i v er di sease
i n thi s pati ent?
2. Does any par ti cul ar f actor hel p y ou deter m i ne the cause of thi s m an's
l i v er di sease?
3. What r ev er si bl e f actor s coul d be contr i buti ng to thi s m an's pr esum ed
por tosy stem i c encephal opathy (PSE)?
4. When, i f ev er , shoul d thi s m an's asci tes be sam pl ed? If i t shoul d, how
and w her e shoul d i t be sam pl ed?
5. What ar e thr ee possi bl e ex pl anati ons f or the occul t bl ood i n hi s stool ?
6. What i s the ser um â€“asci tes al bum i n gr adi ent, and of w hat v al ue i s i t?
7. Woul d y ou star t di ur eti c ther apy now ? Why or w hy not?
8. Why ar e hi s testes sm al l ?
9. Why ar e hi s par oti d gl ands enl ar ged?
10. Is thi s m an at i ncr eased r i sk f or hepatocel l ul ar car ci nom a?
11. How w oul d y ou ex cl ude hepatocel l ul ar car ci nom a?
12. What i s i ncl uded i n y our di f f er enti al di agnosi s of thi s m an's chr oni c
l i v er di sease?
13. Why i s hepati ti s A not i n y our di f f er enti al di agnosi s?
The r esul ts of addi ti onal tests ar e av ai l abl e w i thi n 4 hour s of
adm i ssi on. The asci tes i s sam pl ed f r om a l ef t l ow er quadr ant
par acentesi s, y i el di ng a cl ear y el l ow f l ui d w i th a w hi te bl ood cel l count
of 380 cel l s/m m 3 , 2% pol y m or phonucl ear l euk ocy tes, an al bum i n
concentr ati on of 0. 5 g/dL, and a total pr otei n l ev el of 1 g/dL. N o
or gani sm s ar e seen on Gr am 'sstai ned speci m ens.
14. Do the f i ndi ngs f r om the addi ti onal tests on the asci ti c f l ui d suppor t
the di agnosi s of por tal hy per tensi onassoci ated asci tes? Why or w hy
not?
15. Wi th these data i n m i nd, w hat tr eatm ent w oul d y ou of f er thi s pati ent
now , and w hy ?
16. What ar eas of the pati ent's hi stor y shoul d y ou ex am i ne at gr eater
l ength, and w hy ?
17. Woul d y ou of f er thi s pati ent a l i v er bi opsy and, i f so, w hen?
Case Discussion
1. What f eatur es hel p y ou to di agnose chr oni c v er sus acute l i v er di sease
i n thi s pati ent?
In thi s pati ent, ther e ar e no pathognom oni c f eatur es of chr oni c l i v er
di sease, but sev er al that suggest thi s condi ti on. La rge s pide r
a ngioma s ar e com m on i n
P. 150
the setti ng of chr oni c l i v er di sease, but not acute l i v er di sease,
al though sm al l , nonpal pabl e spi der angi om as m ay be pr esent. Mus c le
w a s ting i s com m on i n m oder atel y adv anced chr oni c l i v er di sease, but
i s not due to poor eati ng habi ts. Muscl e w asti ng i s not a f eatur e of
acute l i v er di sease unl ess i t i s the r esul t of a concom i tant, unr el ated
pr obl em . A pa lpa ble , firm le ft lobe of the live r (that por ti on pal pabl e
caudad to the x i phoi d pr ocess) i s usual l y a m ani f estati on of chr oni c
l i v er di sease. It i s al w ay s i m por tant to pal pate and per cuss f or the
l i v er i n the m i dl i ne, as w el l as i n the m i dcl av i cul ar l i ne. As c ite s , due
to por tal hy per tensi on, i s m uch m or e a f eatur e of chr oni c l i v er di sease
than of any other di sor der . Asci tes m ay occur i n the setti ng of sev er e
acute l i v er di sease, but i t i s usual l y not of si gni f i cant quanti ty to
w ar r ant tr eatm ent. One notabl e ex cepti on i s the BuddChi ar i sy ndr om e,
i n w hi ch ther e m ay be asci tes, al though the abdom i nal di stenti on i n
thi s sy ndr om e i s par ti al l y due to a congested and enl ar ged l i v er
stem m i ng f r om the hepati c v ei n occl usi on. Shifting dullne s s i s
i ndi cati v e of a l ar ge am ount (> 1. 0 to 1. 5 L) of asci tes.
P a nc ytope nia i s r el ated to the spl eni c sequestr ati on of bl ood cel l s and
i s not a pr om i nent f eatur e of l i v er di sease unl ess the spl een i s
af f ected; w hen i t i s, i t i s usual l y enl ar ged. The degr ee of pancy topeni a
(or of i ndi v i dual cy topeni as) m ay not cor r el ate w i th spl een si ze.
Hepati ti s C m ay be associ ated w i th the dev el opm ent of apl asti c
anem i a, but thi s i s r ar e. Tr ansi ent cy topeni as m ay be seen i n hepati ti s,
as i n other v i r al i nf ecti ons. A low s e rum a lbumin l ev el m ay be seen i n
any f or m of l i v er di sease that has l asted f or m or e than sev er al w eek s.
A high s e rum globulin (total pr otei nal bum i n) l ev el i s a f eatur e of
chr oni c l i v er di sease r egar dl ess of the cause. Ex tr em el y hi gh ser um
gl obul i n l ev el s (i . e. , â‰￥10 g/dL) shoul d suggest the possi bi l i ty of
autoi m m une or â€œl upoi dâ€ hepati ti s; thi s di sor der i s usual l y seen i n
w om en and i s f r equentl y accom pani ed by other autoi m m une f eatur es,
such as thy r oi di ti s. Autoi m m une hepati ti s i s i m por tant to r ecogni ze
because i t can usual l y be tr eated w i th cor ti coster oi ds.
2. Does any par ti cul ar f actor hel p y ou deter m i ne the cause of thi s m an's
l i v er di sease?
Ther e ar e no par ti cul ar f actor s that poi nt to the cause of thi s pati ent's
l i v er di sease. The m ajor di f f er enti al di agnoses her e ar e al cohol i c l i v er
di sease and chr oni c acti v e hepati ti s (hepati ti s C f r om hi s bl ood
tr ansf usi on), pr obabl y i n the ci r r hoti c stage. N o f eatur e of hi s hi stor y ,
phy si cal ex am i nati on, or r outi ne l abor ator y tests hel ps di sti ngui sh
betw een these tw o causes.
3. What r ev er si bl e f actor s coul d be contr i buti ng to thi s m an's pr esum ed
PSE?
Be nzodia ze pine s , other sedati v e or hy pnoti c dr ugs, and opi ates m ay

pr eci pi tate PSE i n a pati ent w i th sev er el y i m pai r ed hepati c f uncti on.
Cons tipa tion m ay al so pr eci pi tate PSE i n suscepti bl e pati ents because
of the col oni c absor pti on of ni tr ogenous pr oducts. Both these r ev er si bl e
r i sk f actor s ar e pr esent i n thi s pati ent. Other r ev er si bl e f actor s
contr i buti ng to an epi sode of PSE i ncl ude e le c trolyte dis turba nc e s ,
notabl y hy pok al em i a and m etabol i c al k al osi s; inc re a s e d inte s tina l
a bs orption of nitroge nous produc ts , r esul ti ng f r om r el ati v el y
ex cessi v e di etar y pr otei n i ntak e or an upper gastr oi ntesti nal (GI)
hem or r hage; and a s e rious infe c tion of any natur e. In pati ents w i th
chr oni c l i v er di sease w ho hav e acute PSE, cul tur e of the body f l ui dsâ
€”asci ti c f l ui d, bl ood, ur i ne, and sputum â€”shoul d be done. Thi s
pati ent's PSE i ndi cates that he has sev er e l i v er di sease.
P. 151
4. When, i f ev er , shoul d thi s m an's asci tes be sam pl ed? If i t shoul d, how
and w her e shoul d i t be sam pl ed?
Di agnosti c par acentesi s shoul d be per f or m ed as soon as possi bl e to
deter m i ne w hether the pati ent has subacute bacter i al per i toni ti s. Thi s
f or m of i nf ecti ous per i toni ti s i s a f r equent cause of cl i ni cal
deter i or ati on i n pati ents w i th chr oni c l i v er di sease, and m ay be f atal i f
not r ecogni zed and tr eated ear l y .
The thr ee saf est l ocati ons f or par acentesi s ar e the l ef t l ow er quadr ant,
r i ght l ow er quadr ant, and the i nf r aum bi l i cal m i dl i ne ar ea. A
supr aum bi l i cal appr oach shoul d nev er be used because the um bi l i cal or
par aum bi l i cal v essel s, w hi ch cour se just under the par i etal per i toneum ,
ar e f r equentl y r ecanal i zed i n pati ents w i th por tal hy per tensi on w hose
por tal v ei n i s patent. It i s al so i m por tant to al w ay s stay cl ear of
(m edi al or l ater al to) the r ectus m uscl es because the super f i ci al
epi gastr i c v essel s cour se under them and m ay be punctur ed. Sk i n
punctur e thr ough or near an abdom i nal scar i n a pati ent w i th suspected
or k now n por tal hy per tensi on shoul d al w ay s be av oi ded.
5. What ar e thr ee possi bl e ex pl anati ons f or the occul t bl ood i n hi s stool ?
Thr ee possi bl e ex pl anati ons ar e (a) por tal hy per tensi v e gastr opathy or
enter opathy , (b) r ectal v ar i ces, and (c) esophageal v ar i ceal
hem or r hage due to por tal hy per tensi on. Var i ceal bl eedi ng i s usual l y a
sudden ev ent of l ar ge v ol um e, al though uncom m onl y v ar i ces â€œooze. â
€
6. What i s the ser um â€“asci tes al bum i n gr adi ent, and of w hat v al ue i s i t?
The ser um â€“asci tes al bum i n gr adi ent i s the num er i c di f f er ence (not
r ati o) betw een the ser um al bum i n concentr ati on and the asci tes
al bum i n concentr ati on. When the gr adi ent i s 1. 1 or gr eater , por tal
hy per tensi on i s contr i buti ng to or enti r el y causi ng the asci tes. When
the gr adi ent i s l ess than 1. 1, per i toneal car ci nom atosi s or
i nf l am m ator y di seases ar e l i k el y causes of the asci tes. On the basi s of
thi s m an's hi stor y , the tw o m ai n causes to be consi der ed ar e por tal
hy per tensi on and per i toneal m al i gnancy . Deter m i nati on of the ser um â
€“asci tes al bum i n di f f er ence i s a si m pl e, m i ni m al l y i nv asi v e, and f ai r l y
accur ate w ay to di agnose por tal hy per tensi on.
7. Woul d y ou star t di ur eti c ther apy now ? Why or w hy not?
N o. Di ur eti cs ar e not essenti al now , and they m ay onl y w or sen the PSE
and i ncr ease the r i sk of hepator enal sy ndr om e.
8. Why ar e hi s testes sm al l ?
In the setti ng of hepati c di sease, the pr oducti on of estr one f r om
ci r cul ati ng andr ostenedi one m ay be i ncr eased. The ex act cause of thi s
conv er si on i s unk now n but m ay be r el ated to the decr eased cl ear ance
of andr ostenedi one by the l i v er . The consum pti on of ex cessi v e am ounts
of ethanol m ay al so hav e contr i buted to the testi cul ar atr ophy i n thi s
pati ent.
9. Why ar e hi s par oti d gl ands enl ar ged?
Par oti d enl ar gem ent i s seen i n peopl e w ho i ngest ex cessi v e am ounts of
ethanol , and i s associ ated w i th f atty i nf i l tr ati on of the gl ands. A si m i l ar
si tuati on m ay be seen i n di abeti c pati ents.
10. Is thi s m an at i ncr eased r i sk f or hepatocel l ul ar car ci nom a?
Yes. Ther e i s a r i sk f or the dev el opm ent of hepatocel l ul ar car ci nom a i n

the setti ng of any f or m of ci r r hoti c l i v er , w hi ch thi s m an m ost l i k el y
has. Cer tai n condi ti ons
P. 152
ar e associ ated w i th hi gher r i sk s than other s. Those associ ated w i th
hi ghest r i sk ar e geneti c hem ochr om atosi s, chr oni c hepati ti s B, chr oni c
hepati ti s C, and al cohol i c l i v er di sease.
11. How w oul d y ou ex cl ude hepatocel l ul ar car ci nom a?
U sef ul tests f or i denti f y i ng hepatocel l ul ar car ci nom a ar e an i m agi ng

test [ul tr asonogr aphy or com puted tom ogr aphy (CT) or m agneti c
r esonance i m agi ng] and a ser um Î± f etopr otei n l ev el . The pr ef er r ed
i m agi ng test (to ex cl ude a f ocal l esi on) depends on the ex per ti se of the
i nsti tuti on. Ar ter i al phase CT i s r egar ded as m ost r el i abl e.
Hepatocel l ul ar car ci nom as ar e especi al l y di f f i cul t to detect i n ci r r hoti c
l i v er s; ther ef or e i t i s i m por tant that ar ter i al phase CT be used i n thi s
setti ng. The ser um Î± f etopr otei n l ev el i s v er y hi gh i n 60% of pati ents
w i th al cohol i c l i v er di sease w ho hav e a super i m posed hepatocel l ul ar
car ci nom a and i n appr ox i m atel y 80% to 90% of pati ents w i th chr oni c
hepati ti s B w ho hav e thi s com pl i cati on.
12. What i s i ncl uded i n y our di f f er enti al di agnosi s of thi s m an's chr oni c
l i v er di sease?
The di f f er enti al di agnosi s i n thi s pati ent i ncl udes al cohol i c l i v er di sease
and chr oni c acti v e hepati ti s w i th ci r r hosi s, due to ei ther hepati ti s B or
C, al though hepati ti s shoul d be r egar ded as the m or e l i k el y di agnosi s.
The hepati ti s v i r uses m ay hav e been tr ansm i tted to hi m by the bl ood
he r ecei v ed m any y ear s ago, or they m ay hav e been â€œspor adi cal l y â€
acqui r ed.
13. Why i s hepati ti s A not i n y our di f f er enti al di agnosi s?
Hepati ti s A has nev er been r epor ted to cause chr oni c l i v er di sease.
14. Do the f i ndi ngs f r om the addi ti onal tests on the asci ti c f l ui d suppor t the
di agnosi s of por tal hy per tensi onassoci ated asci tes? Why or w hy not?
Yes, the f i ndi ngs f r om the tests on the asci ti c f l ui d do suppor t the
di agnosi s of por tal hy per tensi onassoci ated asci tes because the ser um â
€“asci tes al bum i n gr adi ent (2. 6) ex ceeds 1. 1. Ther e ar e tw o cav eats to
r em em ber w hen usi ng the ser um â€“asci tes al bum i n gr adi ent i n the
di agnosi s of asci tes. Fi r st, i f m assi v e hepati c m etastases cause enough
l i v er di sease to r esul t i n por tal hy per tensi on and asci tes, the gr adi ent
r esem bl es that seen i n por tal hy per tensi on. Second, i n asci tes of m i x ed
eti ol ogy (e. g. , por tal hy per tensi on pl us tuber cul ous per i toni ti s), the
gr adi ent usual l y r esem bl es that seen i n the setti ng of por tal
hy per tensi on.
15. Wi th these data i n m i nd, w hat tr eatm ent w oul d y ou of f er thi s pati ent
now , and w hy ?
Hospi tal adm i ssi on i s r equi r ed. Str i ct bed r est (f or f ear of sel f har m )
seem s pr udent. N o benzodi azepi nes shoul d be adm i ni ster ed, al though
the pati ent shoul d be m oni tor ed f or the si gns of ethanol w i thdr aw al â
€”agi tati on, tachy car di a, f ev er , and hal l uci nosi s. The pati ent shoul d
r ecei v e an enem a i f he i s consti pated. Lactul ose shoul d al so be
adm i ni ster ed (by m outh or nasogastr i c tube) i f the pati ent becom es too
di sor i ented and uncooper ati v e. The or al or nasogastr i c l actul ose dose i s
v ar i abl e; the goal of ther apy i s to pr oduce tw o to thr ee sof t stool s per
day . Al ter nati v el y , a nonabsor babl e anti bi oti c coul d be used, such as
neom y ci n at a dosage of 500 to 1, 000 m g gi v en or al l y or by nasogastr i c
tube ev er y 6 hour s, or r i f ax i m i n. Ther e i s no ev i dence that gi v i ng
l actul ose and an anti bi oti c together i s m or e ef f ecti v e than
adm i ni ster i ng ei ther al one. Lactul ose i s pr obabl y benef i ci al i n the
tr eatm ent of PSE by v i r tue of i ts abi l i ty to decr ease the am ount of
ni tr ogen av ai l abl e f or absor pti on (as ur ea) f r om the col on. Lactul ose
m ay accom pl i sh thi s
P. 153
by al ter i ng the col oni c f l or a to m or e ur easenegati v e f or m s and by
i nduci ng an osm oti c di ar r hea.
16. What ar eas of the pati ent's hi stor y shoul d y ou ex am i ne at gr eater
l ength, and w hy ?
One ar ea of the pati ent's hi stor y that shoul d be ex am i ned at gr eater
l ength i s hi s e tha nol c ons umption his tory. Thi s i nv ol v es m or e
i nter v i ew i ng of hi s f am i l y and f r i ends. The al l eged am ount of ethanol
i ngested (per the pati ent's w i f e) i s too l ow to cause l i v er di sease i n
m en because the al cohol content of tw o cans of beer i s appr ox i m atel y
12 g. How ev er , the par oti d gl and enl ar gem ent and testi cul ar atr ophy
ar e f i ndi ngs that suggest hi s ethanol i ngesti on has been m or e than he
has adm i tted. The am ount and dur ati on of al cohol i ngesti on necessar y
to cause chr oni c l i v er di sease i s hi ghl y v ar i abl e am ong i ndi v i dual s,
al though the i nci dence of bi opsy pr ov ed ci r r hosi s, al cohol i c hepati ti s,
or both, i ncr eases as consum pti on i s i ncr eased. It i s usual l y bel i ev ed
that the thr eshol d am ount of al cohol consum pti on that l eads to these
ser i ous f or m s of chr oni c l i v er di sease i s i n the or der of 100 to 150 g
per day f or sev er al y ear s i n m en, but l ess i n w om en. How ev er , a l ar ge
pr opor ti on of heav y dr i nk er s do not contr act ser i ous l i v er di seases. It
i s adv i sabl e to r ecor d al cohol consum pti on i n ter m s of gr am s per day
ti m es the num ber of y ear s of consum pti on. A quar t of 80 pr oof w hi sk ey
contai ns appr ox i m atel y 300 g of ethanol , a si x pack of 4% beer
appr ox i m atel y 75 g, and 750 m L of w i ne appr ox i m atel y 90 g (150 g f or
â€œf or ti f i edâ€ w i ne).
A second ar ea of i nqui r y shoul d be the pati ent's fa mily his tory. In thi s
pati ent, y ou shoul d al so ask w hether any one i n the f am i l y has had l i v er
di sease, i ncl udi ng geneti c hem ochr om atosi s. You m i ght phr ase the
questi on i n thi s w ay : â€œDo y ou hav e any f am i l y m em ber s w ho hav e
condi ti ons that r equi r e bl ood to be r em ov ed as tr eatm ent?â€ The
m ani f estati ons of hem ochr om atosi s m ay di f f er i n v ar i ous f am i l y
m em ber s, and m ay consi st of car di om y opathy , di abetes, ar thr i ti s, or
pi tui tar y i nsuf f i ci ency . In thi s pati ent, the sm al l l i v er i s i nconsi stent
w i th a di agnosi s of hem ochr om atosi s, al though al l el se i s. Mor eov er , he
i s an ol der m anâ€”the ty pi cal age and sex of pati ents w ho hav e sev er e
chr oni c l i v er di sease caused by hem ochr om atosi s.
17. Woul d y ou of f er thi s pati ent a l i v er bi opsy and, i f so, w hen?
A l i v er bi opsy w oul d be of no hel p i n the i ni ti al m anagem ent of hi s

decom pensated l i v er di sease. How ev er , w hen concl usi v e docum entati on
of the di agnosi s w oul d hel p deter m i ne m anagem ent, l i v er bi opsy m i ght
be i m por tant. Thi s m i ght be the case i n a pati ent w i th suspected Budd
Chi ar i sy ndr om e because i t i s of ten tr eatabl e by hepati c decom pr essi on
(as, e. g. , w i th a si detosi de por tacav al anastom osi s), or i t m i ght be
the case i n a pati ent w i th hem ochr om atosi s. Once the pati ent's
condi ti on has stabi l i zed, a l i v er bi opsy m i ght be of f er ed, f or thr ee
r easons. Fi r st, he m ay be a candi date f or speci f i c ther apy . How ev er , i t
i s unl i k el y that ther e i s any ther apy f or thi s pati ent. If , as seem s
l i k el y , he has al cohol i c ci r r hosi s ther e i s no ef f ecti v e tr eatm ent other
than absti nence; i f he has hepati ti s Câ€“r el ated ci r r hosi s, i nter f er on
tr eatm ent m ay be danger ous because of the hepatocy tol y si s br ought
about by ther apy . Second, som e author i ti es bel i ev e that l i v er bi opsy i s
i ndi cated i n pati ents w i th suspected al cohol i c l i v er di sease because
conf i r m ati on of that di agnosi s m i ght hel p per suade the pati ent to
abstai n f r om f ur ther ethanol i ngesti on. Thi r d, i f the pati ent becom es a
candi date f or hepati c tr anspl antati on, m ost center s r equi r e a def i ni ti v e
pr eoper ati v e di agnosi s bef or e goi ng ahead w i th the pr ocedur e.
P. 154
Suggested Readings
Batts KP, Ludw i g J. Chr oni c hepati ti s: an update on ter m i nol ogy and
r epor ti ng. Am J Pathol 1995;19: 1409.
Dasar athy S, McCul l ough AJ. Al cohol i c l i v er di sease. In: Schi f f ER,
Sor r el l MF, Maddr ey WC, eds. Schi f f 's di seases of the l i v er , 9th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003: 1019â€“1057.
Dav i s GL. Hepati ti s C. In: Schi f f ER, Sor r el l MF, Maddr ey WC, eds.
Schi f f 's di seases of the l i v er , 9th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2003: 807â€“861.
Diarrhea
1. What i s the di agnosti c i m por tance of noctur nal di ar r hea i n a pati ent
w i th chr oni c di ar r hea?
2. What i s the di f f er ence betw een a secr etor y and an osm oti c di ar r hea?
3. What happens to di ar r heal stool v ol um e af ter f asti ng i n the f ol l ow i ng

setti ngs: A v asoacti v e i ntesti nal pepti de (VIP) tum or , the abr upt onset
of w ater y di ar r hea af ter tr av el i ng outsi de of the U ni ted States, or
di ar r hea onl y w hen dr i nk i ng l ar ge am ounts of car bonated bev er ages?
4. What i s the m ost l i k el y cause of di ar r hea i n a pati ent w ho has r ecentl y
tak en am pi ci l l i n and then has l ow gr ade f ev er and w ater y di ar r hea?
What i s the m ost costef f ecti v e w ay to di agnose thi s di sease, and how
w oul d y ou tr eat thi s pati ent?
5. Why do pati ents w i th gi ar di asi s of ten com pl ai n of i ncr eased stool
v ol um e and abdom i nal cr am pi ng w hen they consum e m i l k pr oducts?
6. Whi ch or gani sm s ar e m ost com m onl y associ ated w i th di ar r hea of l ess
than 2 to 3 w eek s' dur ati on, and w hat ar e thei r cl i ni cal char acter i sti cs?
How ar e such cases ev al uated, and w hat ar e the v ar i ous appr oaches to
tr eatm ent?
7. What i s the uti l i ty of stai ni ng stool speci m ens f or l euk ocy tes?
8. What w oul d the cl i ni ci an l ook f or i f sur r epti ti ous l ax ati v e abuse i s
suspected as a cause of chr oni c di ar r hea?
9. A 24y ear ol d w om an w ho has had a r ecur r i ng r ectov agi nal f i stul a f or 2
y ear s com pl ai ns of f r equent sm al l v ol um e stool s, w hi ch occasi onal l y
contai n bl ood and m ucus. Stool cul tur es y i el d negati v e f i ndi ngs. What
i s the l i k el y di sease i n thi s w om an w ho has a r ectov agi nal f i stul a, and
w hat w oul d be the nex t step i n ev al uati ng her ?
Discussion
1. What i s the di agnosti c i m por tance of noctur nal di ar r hea i n a pati ent
w i th chr oni c di ar r hea?
N octur nal di ar r hea suggests an or gani c cause of the di ar r hea. Pati ents
w i th i r r i tabl e bow el sy ndr om e or other â€œf uncti onal â€
di ar r heas
r ar el y hav e di ar r hea that aw ak ens them f r om sl eep.
P. 155
2. What i s the di f f er ence betw een a secr etor y and an osm oti c di ar r hea?
Se c re tory dia rrhe a i s due to the acti v e secr eti on of w ater and
el ectr ol y tes i nto the i ntesti nal l um en. The m echani sm of acti on
r esponsi bl e f or the r el ease of the secr etagogues i s v ar i abl e. For
i nstance, the di ar r hea of chol er a, the cl assi c ex am pl e of a secr etor y
di ar r hea, i s caused by the sti m ul ati on of adeny l ate cy cl ase acti v i ty by
chol er a tox i n; thi s, i n tur n, causes an i ncr ease i n the i ntr acel l ul ar
concentr ati on of cy cl i c adenosi ne m onophosphate, w hi ch sti m ul ates
el ectr ogeni c chl or i de secr eti on and i nhi bi ts el ectr oneutr al sodi um
chl or i de absor pti on. Incr eases i n i ntr acel l ul ar concentr ati ons of Ca 2 + as
w el l as cy cl i c guanosi ne m onophosphate hav e been pr oposed as the
abnor m al i ti es at w or k i n v ar i ous other f or m s of secr etor y di ar r hea.
In os motic dia rrhe a , an unabsor babl e sol ute (of ten a car bohy dr ate or
di v al ent m i ner al ) i ncr eases the osm ol al i ty of the i ntesti nal contents.
Thi s i ncr eased osm ol al i ty passi v el y â€œdr agsâ€ w ater i nto the
i ntesti nal l um en. Pati ents w i th osm oti c di ar r hea usual l y hav e a stool
osm ol al i ty m easur e that i s m uch gr eater than that y i el ded by the
f or m ul a: 2 Ã— ser um N a + + ser um K + ; thi s condi ti on consti tutes an
osm oti c gap. A com m on osm oti c di ar r hea i s that w hi ch occur s af ter the
i ngesti on of m i l k or m i l k pr oducts i n peopl e w ho ar e def i ci ent i n the
i ntesti nal enzy m e l actase, or those w ho i ngest m agnesi um contai ni ng
antaci ds or l ax ati v es.
3. What happens to di ar r heal stool v ol um e af ter f asti ng i n the f ol l ow i ng

setti ngs: a VIP tum or , the abr upt onset of w ater y di ar r hea af ter
tr av el i ng outsi de of the U ni ted States, or di ar r hea onl y w hen dr i nk i ng
l ar ge am ounts of car bonated bev er ages?
VIP i s pr oduced by the i ntesti nal m ucosa i n i ncr eased am ounts i n the
WDHA (w ater y di ar r hea, hy pok al em i a, and achl or hy dr i a) sy ndr om e. VIP
causes di ar r hea by sti m ul ati ng m ucosal adeny l ate cy cl ase acti v i ty , and
ther ef or e w oul d be ex pected to cause a secr etor y di ar r hea. In such a
condi ti on, f asti ng w oul d not decr ease the stool v ol um e unti l the pati ent
becom es sev er el y dehy dr ated.
Ty pi cal l y , tr av el er sâ€™ di ar r hea i s w ater y and occur s w i thi n 3 to 6

day s of ar r i v i ng i n another countr y , or on r etur n. Sy m ptom s usual l y
l ast f or 2 to 3 day s and r esol v e spontaneousl y . The m ost com m on
pathogens r esponsi bl e ar e the enter otox i geni c str ai ns of Escher i chi a
col i , w hi ch can el abor ate heatl abi l e and heatstabl e enter otox i ns. The
heatl abi l e tox i n acts si m i l ar l y to chol er a tox i n, w her eas the heat
stabl e tox i n sti m ul ates m ucosal guany l ate cy cl ase acti v i ty . Other ty pes
of di ar r heapr oduci ng E. col i and thei r associ ated sy m ptom s ar e the
enter opathogeni c ty pe, w hi ch causes w ater y di ar r hea, pr edom i nantl y i n
chi l dr en and new bor ns; the enter oi nv asi v e ty pe, w hi ch causes bl oody
di ar r hea (dy senter y ) i n chi l dr en and adul ts, usual l y af ter the i ngesti on
of contam i nated f ood and w ater ; and the enter ohem or r hagi c ty pe,
w hi ch causes bl oody di ar r hea i n peopl e of al l ages and i s tr ansm i tted
thr ough contam i nated f ood (of ten poor l y cook ed ham bur ger ). Ser oty pe
0157:H7 of the enter ohem or r hagi c ty pe has been i denti f i ed i n sev er al
outbr eak s of i nf ecti on char acter i zed by par ti cul ar l y sev er e di sease
(hem ol y ti c ur em i c sy ndr om e).
P. 156
Other pathogens associ ated w i th tr av el er sâ€™ di ar r hea i ncl ude Shi gel l a
and Sal m onel l a speci es, C. jejuni , and Vi br i o par ahaem ol y ti cus.
Because of the num er ous causes of tr av el er 's di ar r hea, the ef f ect of
f asti ng i s usual l y unpr edi ctabl e.
The osm oti c di ar r hea that occur s onl y af ter dr i nk i ng l ar ge am ounts of
car bonated bev er ages i s due to the i ngesti on of l ar ge am ounts of
f r uctose, w hi ch i s the sugar used to sw eeten these bev er ages (al though
not di et dr i nk s) and com es i n the f or m of cor n sy r up. Fr uctose i s poor l y
absor bed by the pr ox i m al sm al l i ntesti nal m ucosa. Cessati on of
f r uctose i ntak e shoul d stop the di ar r hea.
4. What i s the m ost l i k el y cause of di ar r hea i n a pati ent w ho has r ecentl y
tak en am pi ci l l i n and then has l ow gr ade f ev er and w ater y di ar r hea?
What i s the m ost costef f ecti v e w ay to di agnose thi s di sease, and how
w oul d y ou tr eat thi s pati ent?
Pseudom em br anous col i ti s (PMC) caused by Cl ostr i di um di f f i ci l e i s a

l i k el y di agnosi s i n thi s i nstance, gi v en the pati ent's r ecent anti bi oti c
use. The di sease i s usual l y sel f l i m i ted, w i th the di ar r hea di ssi pati ng 5
to 10 day s af ter di sconti nuati on of the of f endi ng anti bi oti c. Cl i ndam y ci n
w as the f i r st dr ug pr ov ed to cause PMC; l ater , am pi ci l l i n, because of
i ts w i despr ead use, w as the dr ug m ost com m onl y i m pl i cated, but
v i r tual l y any anti bi oti c can be r esponsi bl e. In heal thy adul ts, C.
di f f i ci l e col oni zati on r ates of 2% to 3% hav e been r epor ted, w her eas
the r ates i n adul ts r ecei v i ng anti m i cr obi al s but w i thout di ar r heal
sy m ptom s ar e as hi gh as 10% to 15%.
The m ost com m onl y used m ethod f or di agnosi ng PMC i s the cy totox i ci ty
assay , w hi ch i nv ol v es obser v ati on of the cy topathi c ef f ect pr oduced by
the tox i n on a cel l cul tur e; the assay has a sensi ti v i ty of 95% to 97%.
Al though the l atex aggl uti nati on test f or the pr esence of tox i n i s both
cheaper and f aster to per f or m , i t has a sensi ti v i ty of onl y
appr ox i m atel y 85%. Gr oss col oni c abnor m al i ti es i n pati ents w i th PMC,
w hi ch can be seen endoscopi cal l y , ty pi cal l y occur i n the descendi ng and
si gm oi d col on, m ak i ng f l ex i bl e si gm oi doscopy an adequate ex am i nati on
i n m ost cases; how ev er , cases w i th onl y r i ghtsi ded i nv ol v em ent hav e
been r epor ted. The endoscopi c f i ndi ngs i n pati ents w i th PMC i ncl ude
er y them atous, f r i abl e m ucosa w i th char acter i sti c pseudom em br anes.
Car e m ust be tak en to r ul e out bacter i al or par asi ti c i nf ecti ons
(especi al l y C. jejuni and Entam oeba hi stol y ti ca) and i nf l am m ator y
bow el di sease.
The r ecom m ended tr eatm ent f or l ess sev er e cases of PMC consi sts of
ei ther or al m etr oni dazol e (250 m g f our ti m es a day ) or v ancom y ci n
(125 to 500 m g f our ti m es a day ). Par enter al doses of m etr oni dazol e
[500 m g i ntr av enousl y (IV) ev er y 6 hour s] shoul d be gi v en onl y w hen
or al m edi cati on cannot be tol er ated. The IV adm i ni str ati on of
v ancom y ci n i s not ef f ecti v e. The r ates of r el apse ar e si m i l ar f or both
m etr oni dazol e and v ancom y ci n and r ange f r om 10% to 15%.
Chol esty r am i ne has been r epor ted to be ef f ecti v e i n the tr eatm ent of
m i l d PMC or as an adjuncti v e m easur e, pr esum abl y by bi ndi ng the tox i n
i ntr al um i nal l y . Chol esty r am i ne m ay be used i n conjuncti on w i th
m etr oni dazol e but not w i th v ancom y ci n, because i t can bi nd and
i nacti v ate v ancom y ci n. Recentl y , the or al adm i ni str ati on of the
nonabsor bed anti bi oti c r i f ax i m i n and pr obi oti cs (pr epar ati ons of v i abl e
bacter i a w i th ther apeuti c phy si ol ogi c ef f ects) has been r epor ted
ef f ecti v e i n the tr eatm ent of r ecur r ent PMC.
P. 157
5. Why do pati ents w i th gi ar di asi s of ten com pl ai n of i ncr eased stool
v ol um e and abdom i nal cr am pi ng w hen they consum e m i l k pr oducts?
Gi ar di a l am bl i a i nf ecti on causes a def i ci ency i n the i ntesti nal

di sacchar i dases, i ncl udi ng l actase. The di sacchar i dase def i ci ency can
cause cr am pi ng and f l atul ence af ter the i ngesti on of car bohy dr ates,
especi al l y m i l k pr oducts.
6. Whi ch or gani sm s ar e m ost com m onl y associ ated w i th di ar r hea of l ess
than 2 to 3 w eek s' dur ati on, and w hat ar e thei r cl i ni cal char acter i sti cs?
How ar e such cases ev al uated, and w hat ar e the v ar i ous appr oaches to
tr eatm ent?
The ev al uati on of a case of acute di ar r hea i nv ol v es r outi ne cul tur e of
the stool s, ex am i nati on of the stool s f or the pr esence of ov a and
par asi tes, and, i n som e i nstances, f l ex i bl e si gm oi doscopy .
One of the vira l c a us e s of acute di ar r hea i s the N or w al k agent that i s

seen i n f am i l y and com m uni ty epi dem i cs, usual l y i n ol der chi l dr en and
adul ts. It has an i ncubati on per i od of 1 to 2 day s. Vom i ti ng and l ow
gr ade f ev er ar e com m on. Rotav i r us i nf ecti on i s seen i n i nf ants and
y oung chi l dr en, pr i m ar i l y i n w i nter ; the i ncubati on per i od i s 1 to 3
day s. Vom i ti ng (occur r i ng i n 80%), upper r espi r ator y sy m ptom s, and
f ev er (f ound i n 30%) ar e com m on. Enter i c adenov i r us i s a spor adi c
di sease of i nf ants and y oung chi l dr en, and i s of ten associ ated w i th
f ev er and upper r espi r ator y sy m ptom s.
Ther e ar e m any ba c te ria l c a us e s of acute di ar r hea. In Shi gel l a

i nf ecti on, the m ajor si te of m ucosal i nv asi on i s the col on. Penetr ati on
of the m ucosa and i nv asi on of the bl oodstr eam ar e r ar e. Cr am py
abdom i nal pai n and tenesm us ar e hal l m ar k s of the di sease. The
or gani sm pr oduces an enter otox i n (Shi ga tox i n) that acti v ates
adeny l ate cy cl ase and causes a w ater y di ar r hea i n the ear l y stages of
the di sease. Bl oody di ar r hea soon f ol l ow s. The m ai nstay of ther apy i s
suppor ti v e, w i th r ehy dr ati on m ost i m por tant. N ar coti cs and
anti chol i ner gi c m edi cati ons shoul d be av oi ded. Anti bi oti c tr eatm ent i s
r eser v ed f or those cases that do not r esol v e spontaneousl y i n sev er al
day s; am pi ci l l i n (500 m g f our ti m es a day , or al l y , f or 5 day s) i s
usual l y ef f ecti v e, but tr i m ethopr i m /sul f am ethox azol e (one doubl e
str ength tabl et tw i ce dai l y ) can be used f or r esi stant str ai ns. Chr oni c
car r i er s, al though uncom m on, ar e pr one to i nter m i ttent attack s of the
di sease.
The m ajor si te of Sal m onel l a i nv asi on i s the i l eal and, som eti m es, the
col oni c m ucosa. Bacter em i a, w i th or w i thout associ ated GI sy m ptom s,
occur s i n appr ox i m atel y 10% of the cases. Car r i er s ar e usual l y
asy m ptom ati c, w i th the or gani sm har bor ed i n the gal l bl adder .
Per i um bi l i cal pai n and bl oody di ar r hea l ast appr ox i m atel y 5 day s.
Because anti m i cr obi al tr eatm ent si gni f i cantl y i ncr eases the car r i er
r ate, i t i s r eser v ed f or those cases that do not r esol v e spontaneousl y
or f or those pati ents w ho hav e an under l y i ng pr edi sposi ng condi ti on.
C. jejuni i s a com m on bacter i al pathogen i sol ated f r om pati ents w i th

acute baci l l ar y di ar r hea. Inv asi on of the m ucosa occur s pr edom i nantl y
i n the col on. Tw o f eatur es that m ay di sti ngui sh C. jejuni i nf ecti on f r om
other causes of bacter i al di ar r hea ar e (a) a pr odr om e of consti tuti onal
sy m ptom s, and (b) a bi phasi c cour se, w i th i ni ti al i m pr ov em ent f ol l ow ed
by w or seni ng. N o anti bi oti c r egi m en has been show n to l essen the
sy m ptom s or the ti m e cour se of the di sease.
P. 158
Yer si ni a enter ocol i ti ca can cause enter ocol i ti s, w i th a cl i ni cal pi ctur e
consi sti ng of f ev er , abdom i nal cr am pi ng, and bl oody di ar r hea l asti ng 1
to 3 w eek s. Water y di ar r hea i s seen, possi bl y due to enter otox i n
pr oducti on. Inv asi v e i l ei ti s i s al so a f eatur e of these i nf ecti ons.
Other di ar r heapr oduci ng enter i c pathogens i ncl ude E. hi stol y ti ca, G.
l am bl i a, and Str ongy l oi des ster cor al i s.
7. What i s the uti l i ty of stai ni ng stool speci m ens f or l euk ocy tes?
The pr esence of num er ous l euk ocy tes i n stool speci m ens i m pl i es the
ex i stence of acti v e i nf l am m ati on of the i ntesti nal m ucosa. In cases of
acute di ar r hea, the pr esence of pus i m pl i es i nv asi on (Shi gel l a,
Sal m onel l a, C. jejuni , and E. hi stol y ti ca). Al though Shi gel l a, E.
hi stol y ti ca, and C. jejuni i nf ecti ons ar e usual l y associ ated w i th m ost
pus, pati ents w i th PMC al so of ten hav e l ar ge num ber s of f ecal
l euk ocy tes. In cases of chr oni c di ar r hea, the pr esence of pus m ost
of ten i m pl i es tuber cul osi s, am ebi c col i ti s, i schem i c col i ti s, or
i nf l am m ator y bow el di sease (ul cer ati v e col i ti s m or e so than Cr ohn's
di sease, unl ess the l atter i nv ol v es the col on).
8. What w oul d the cl i ni ci an l ook f or i f sur r epti ti ous l ax ati v e abuse i s
suspected as a cause of chr oni c di ar r hea?
Ther e ar e sev er al tel l tal e cl ues to sur r epti ti ous l ax ati v e abuse.
Mel anosi s col i , a dar k pi gm entati on of the col or ectal m ucosa, m ay ex i st
i f the di ar r hea i s due to l ongstandi ng use of anthr acene l ax ati v es
(al oe and cascar a). The pi gm entati on usual l y di sappear s w i thi n 12
m onths of di sconti nuati on of the l ax ati v e. If the i ngesti on of
phenol phthal ei ncontai ni ng l ax ati v es i s the cause of the di ar r hea,
al k al i zati on of a stool speci m en by addi ng sodi um hy dr ox i de tur ns i t
pi nk . (How ev er , r ai si ng the pH too hi gh r esul ts i n l oss of the col or and
hence a f al senegati v e r esul t. ) An osm oti c gap of the stool m ay be
pr esent i f the i ngesti on of m agnesi um sul f ate i s the cause of the
di ar r hea. Sodi um sul f ate and phosphate, how ev er , w hi ch cause an
osm oti c di ar r hea due to the f or m ati on of the ani ons sul f ate and
phosphate, do not cause an osm oti c gap, and shoul d be suspected i n
those thought to abuse l ax ati v es but hav e an appar ent secr etor y
di ar r hea.
9. What i s the l i k el y di sease i n thi s w om an w ho has a r ectov agi nal f i stul a,
and w hat w oul d be the nex t step i n ev al uati ng her ?
Cr ohn's di sease i s the m ost com m on cause of r ectov agi nal f i stul as i n
y oung w om en and m ust be consi der ed i n the ev al uati on of such
f i stul as. Sm al l v ol um e, bl oody di ar r hea i s suggesti v e of anor ectal
i nv ol v em ent. Af ter r outi ne stool cul tur e and ex am i nati on f or ov a and
par asi tes, f l ex i bl e si gm oi doscopy or col onoscopy shoul d be per f or m ed.
In cases of Cr ohn's di sease i n w hi ch sm al l bow el i nv ol v em ent i s
consi der ed l i k el y , a sm al l bow el r adi ogr aphi c study m i ght be nex t i n
or der . In any ev ent, cul tur es and ti ssue f or hi stol ogi c anal y si s shoul d
be obtai ned bef or e em pi r i c tr eatm ent w i th cor ti coster oi ds i s i nsti tuted,
to ensur e that i nf ecti ous col i ti s i s not the cause.
Case
A 32y ear ol d w om an w i th a hi stor y of Cr ohn's di sease si nce chi l dhood
com pl ai ns of hav i ng 10 to 12 l oose, f r othy , bur ni ng bow el m ov em ents. Bl ood
i s occasi onal l y i nter m i x ed
P. 159
i n the stool . The i ncr eased stool f r equency has been a pr obl em ev er si nce
her m ost r ecent hospi tal i zati on f or the tr eatm ent of sm al l bow el
obstr ucti on, 5 w eek s ear l i er . At that ti m e, the r em ai ni ng 120 cm of her
i l eum and 100 cm of her jejunum w er e r esected because of f i stul i zati on and
the f or m ati on of adhesi ons. She deni es hav i ng f ev er , chi l l s, and ni ght
sw eats. Her appeti te has been good, and she deni es hav i ng abdom i nal pai n
associ ated w i th f ood i ngesti on; how ev er , she has l ost 15 l b (6. 75 k g) si nce
her l ast sur ger y . Her m edi cati ons hav e not been changed si nce her
di schar ge f r om the hospi tal , and consi st of m etr oni dazol e (250 m g f our
ti m es dai l y ), pr edni sone (20 m g dai l y ), cal ci um , and m onthl y v i tam i n B 1 2
i njecti ons. She has had a l ongstandi ng hi stor y of w ater y di ar r hea, w hi ch
w as contr ol l ed w i th the use of chol esty r am i ne bef or e the m ost r ecent
sur ger y . Her w ei ght had been stabl e f or m any y ear s.
The pati ent i s pal e but i n no acute di str ess and w i thout f ev er . N o or thostati c
changes i n her v i tal si gns ar e noted. Her abdom en i s sof t w i th acti v e bow el
sounds. A heal i ng m i dl i ne i nci si on and m ul ti pl e scar s f r om pr ev i ous
sur ger i es ar e pr esent. The l i v er span i s 7 cm i n the m i dcl av i cul ar l i ne. N o
abdom i nal or r ectal m asses ar e f ound. Her l egs ar e sl i ghtl y edem atous. Her
stool i s dar k br ow n and posi ti v e f or occul t bl ood.
The f ol l ow i ng l abor ator y r esul ts ar e obtai ned: hem atocr i t, 32%; m ean
cor puscul ar v ol um e, 98 Âµ m 3 ; ser um sodi um , 136 m Eq/L; potassi um , 3. 0
m Eq/L; chl or i de, 91 m Eq/L; bi car bonate, 19 m Eq/L; and cr eati ni ne, 0. 6
m g/dL. The w hi te bl ood cel l count, pl atel et count, pr othr om bi n ti m e, and
l i v er test r esul ts ar e al l nor m al .
1. What i s the f i r st set of tests y ou w oul d or der i n thi s pati ent to hel p
ex pl ai n the di ar r hea?
2. Is thi s l i k el y to be a f l ar eup of the pati ent's Cr ohn's di sease?
3. If the chol esty r am i ne tr eatm ent i s r esum ed, how w i l l thi s af f ect the
v ol um e of her di ar r hea, and w hy ?
4. What other tr eatm ent m i ght be pr escr i bed i n an attem pt to contr ol her
di ar r hea and ai d her nutr i ti on?
Case Discussion
1. What i s the f i r st set of tests y ou w oul d or der i n thi s pati ent to hel p
ex pl ai n the di ar r hea?
The f i r st step i n ev al uati ng the pati ent w i th postoper ati v e di ar r hea,
w hose condi ti on i s stabl e, i s to r ul e out enter i c i nf ecti on, w i th cul tur es
and ex am i nati on of the stool s f or ov a and par asi tes. Because thi s
pati ent i s tak i ng m etr oni dazol e, the possi bi l i ty of PMC shoul d al so be
consi der ed, and a stool cy totox i ci ty assay car r i ed out. (Al though
m etr oni dazol e i s com m onl y used to tr eat PMC, the dr ug has al so been
i m pl i cated i n sev er al cases as the causati v e anti bi oti c. ) Fl ex i bl e
si gm oi doscopy coul d pr obabl y be saf el y per f or m ed soon af ter the
r esecti on, but as l ong as the pati ent's condi ti on i s stabl e, the pr ocedur e
can be postponed pendi ng the cul tur e r esul ts.
2. Is thi s l i k el y to be a f l ar eup of the pati ent's Cr ohn's di sease?
N o, because consti tuti onal sy m ptom s hav e not appear ed or changed,
and al so because the char acter of the stool i s m or e suggesti v e of a
m al absor pti v e di sor der than of an acti v e f l ar eup of Cr ohn's di sease.
P. 160
3. If the chol esty r am i ne tr eatm ent i s r esum ed, how w i l l thi s af f ect the
v ol um e of her di ar r hea, and w hy ?
Most l i k el y the pati ent's di ar r hea w i l l w or sen i f she tak es

chol esty r am i ne, w her eas i t w as ef f ecti v e bef or e her r ecent sur ger y .
The ex pl anati on f or thi s di f f er ence i n ef f ect i s as f ol l ow s: Because bi l e
aci ds ar e nor m al l y absor bed acti v el y i n the di stal i l eum and r esecr eted
by the l i v er i nto bi l e, w hen the di stal i l eum i s ei ther sev er el y di seased
or r esected, unabsor bed bi l e aci ds enter the col on and sti m ul ate w ater
and el ectr ol y te secr eti on, r esul ti ng i n di ar r hea. If the am ount of i l eum
i nv ol v ed or r esected i s l ess than appr ox i m atel y 100 cm , the l i v er can
com pensate f or the l oss of bi l e aci ds by i ncr easi ng bi l e aci d sy nthesi s,
and f at m al absor pti on and w ei ght l oss ar e ther eby l ar gel y pr ev ented.
Chol esty r am i ne i s ef f ecti v e i n contr ol l i ng di ar r hea i n thi s si tuati on by
bi ndi ng bi l e aci ds i n the sm al l bow el and pr ev enti ng thei r secr etor y
ef f ects i n the col on. Such a set of ci r cum stances appar entl y ex i sted i n
thi s pati ent bef or e her r ecent sur ger y . How ev er , her l ast sur ger y
r esul ted i n the l oss of her r em ai ni ng i l eum and par t of the jejunum .
Such a l ar ge l oss of bow el w oul d m ost l i k el y r esul t i n depl eti on of her
bi l e aci d pool bey ond the l i v er 's abi l i ty to com pensate f or i t by
i ncr easi ng bi l e aci d sy nthesi s, w i th consequent m al absor pti on of f at.
The adm i ni str ati on of chol esty r am i ne w oul d f ur ther depl ete the bi l e
aci d pool and aggr av ate the f at m al absor pti on, w hi ch i n tur n w oul d
w or sen the di ar r hea. The m echani sm r esponsi bl e f or thi s l atter ev ent i s
the sti m ul ator y ef f ect of unabsor bed f atty aci ds or thei r hy dr ox y
der i v ati v es on col oni c w ater and el ectr ol y te secr eti on.
4. What other tr eatm ent m i ght be pr escr i bed i n an attem pt to contr ol her
di ar r hea and ai d her nutr i ti on?
Medi um chai n tr i gl y cer i des gi v en or al l y shoul d be tr i ed to contr ol her
di ar r hea and enhance nutr i ti on. They do not r equi r e sol ubi l i zati on by
bi l e aci ds f or ef f i ci ent absor pti on. At the sam e ti m e, the pati ent shoul d
obser v e a l ow f at di et.
Suggested Readings
Bar tl ett JG. Anti bi oti cassoci ated di ar r hea. In: Bl aser MJ, Sm i th PD,
Rav di n JI, etal . eds. Inf ecti ons of the gastr oi ntesti nal tr act. N ew Yor k :
Rav en Pr ess, 1995:893.
DuPont HL. Tr av el er 's di ar r hea. In: Bl aser MJ, Sm i th PD, Rav di n JI, etal .
eds. Inf ecti ons of the gastr oi ntesti nal tr act. N ew Yor k : Rav en Pr ess,
1995:299.
Pow el l DW. Appr oach to the pati ent w i th di ar r hea. In: Yam ada T, Al per s
DH, Kapl ow i tz N , etal . eds. Tex tbook of gastr oenter ol ogy , 4th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:844.
Schi l l er LR, Sel l i n JH. Di ar r hea. In: Fel dm an M, Fr i edm an LS, Sl ei senger
MH, eds. Sl ei senger and For dtr an's gastr oi ntesti nal and l i v er di sease.
Saunder s, 2002:131.
Malabsorption
1. What ar e the m ajor steps i n the di gesti on and absor pti on of di etar y
l i pi ds, car bohy dr ates, and pr otei ns?
P. 161
2. What ar e the pr i nci pal si tes of i ntesti nal absor pti on of v ar i ous
nutr i ents?
3. Of w hat does the enter ohepati c ci r cul ati on of bi l e aci ds consi st?
4. What ar e som e of the m ajor di sor der s of m al di gesti on or

m al absor pti on?
Discussion
1. What ar e the m ajor steps i n the di gesti on and absor pti on of di etar y
l i pi ds, car bohy dr ates, and pr otei ns?
The pr ocess of di gesti on can be di v i ded i nto thr ee m ajor steps: (a)
i ntr al um i nal di gesti on, i ncl udi ng the acti on of bi l e aci ds and pancr eati c
enzy m es; (b) di gesti on by the i ntesti nal epi thel i um ; and (c) the
tr anspor t of nutr i ents acr oss the epi thel i um to the ci r cul ati on.
The m ajor ev ents i n the dige s tion a nd a bs orption of die ta ry lipid

i ncl ude (a) the l i pol y si s of di etar y tr i gl y cer i des by pancr eati c l i pase;
(b) m i cel l ar sol ubi l i zati on of the r esul ti ng l ongchai n f atty aci ds and Î²
m onogl y cer i des by bi l e aci ds; (c) the absor pti on of f atty aci ds and Î²
m onogl y cer i des i nto enter ocy tes; (d) the r eester i f i cati on and
i ncor por ati on (al ong w i th chol ester ol , chol ester ol ester s, phosphol i pi d,
and Î²l i popr otei ns) i nto chy l om i cr ons and v er y l ow â€“densi ty
l i popr otei ns; and (e) the tr anspor t of chy l om i cr ons f r om the m ucosal
cel l i nto the i ntesti nal l y m phati cs.
In the dige s tion a nd a bs orption of die ta ry c a rbohydra te s , star ch,
w hi ch accounts f or m ost of the car bohy dr ate i ntak e, i s i ni ti al l y
hy dr ol y zed m ostl y by pancr eati c am y l ase, y i el di ng sm al l er sugar s
(m al tose, m al totr i ose, and dex tr i ns). These pr oducts, as w el l as
i ngested di sacchar i des such as l actose (m i l k sugar ) and sucr ose, ar e
hy dr ol y zed f ur ther i nto thei r com ponent m onosacchar i des by
gl ucosi dases (m al tase, sucr ase Î± dex tr i nase, and l actase), w hi ch ar e
pr esent i n the br ush bor der of epi thel i al cel l s i n the pr ox i m al i ntesti ne.
The m onosacchar i des ar e then absor bed by the epi thel i al cel l s and
enter the por tal ci r cul ati on.
For the dige s tion a nd a bs orption of die ta ry prote in to tak e pl ace,
pr otei ns ar e f i r st hy dr ol y zed by pancr eati c enzy m es i n the i ntesti nal
l um en. These enzy m es i ncl ude endopepti dases (tr y psi n, chy m otr y psi n,
and el astase) and ex opepti dases (car box y pepti dases A and B).
Ol i gopepti des pr oduced by the pancr eati c enzy m es ar e f ur ther
hy dr ol y zed by am i nopepti dases l ocated on the br ush bor der as w el l as
i n the cy topl asm of i ntesti nal epi thel i al cel l s. The r esul tant am i no
aci ds, and cer tai n di pepti des and tr i pepti des, then enter the por tal
ci r cul ati on.
2. What ar e the pr i nci pal si tes of i ntesti nal absor pti on of v ar i ous
nutr i ents?
Al l di etar y nutr i ents, w i th the ex cepti on of v i tam i n B 1 2 (cobal am i n),
ar e absor bed pr ef er enti al l y i n the pr ox i m al sm al l i ntesti ne; m ost
absor pti on of the com ponents of a m eal occur s w i thi n the f i r st 150 cm ,
al though absor pti on (especi al l y of sugar s and am i no aci ds) can occur
m or e di stal l y (as i n the ev ent of di sease or sur gi cal by pass of the
pr ox i m al i ntesti ne). Vi tam i n B 1 2 i s absor bed by the di stal i l eum , w her e
ther e i s a speci f i c r eceptor f or the cobal am i n â€“ i ntr i nsi c f actor
com pl ex .
P. 162
3. Of w hat does the enter ohepati c ci r cul ati on of bi l e aci ds consi st?
Bi l e aci ds ar e sy nthesi zed f r om chol ester ol by the l i v er and ar e

conjugated to ei ther taur i ne or gl y ci ne bef or e secr eti on i nto bi l e.
Dur i ng f asti ng, the bi l e aci ds ar e stor ed i n the gal l bl adder . Af ter a
m eal , they ar e secr eted i nto the duodenum . The bi l e aci ds ar e v er y
ef f i ci entl y absor bed f r om the di stal i l eum , car r i ed back to the l i v er by
the por tal v ei n, ef f i ci entl y ex tr acted and r econjugated by the l i v er , and
then secr eted agai n i nto bi l e. Dur i ng each cy cl e, m or e than 95% of the
bi l e aci ds ar e absor bed, but onl y sm al l am ounts ar e absor bed i n the
pr ox i m al sm al l i ntesti ne.
4. What ar e som e of the m ajor di sor der s of m al di gesti on or

m al absor pti on?
Tabl e 4. 3 l i sts the r epr esentati v e di sor der s.
Case
A 27y ear ol d w om an com pl ai ns of 11 m onths of di ar r hea, gas, and
abdom i nal cr am ps. She has f i v e or si x l oose bow el m ov em ents a day , and
di ar r hea of ten aw ak ens her f r om sl eep. She al so com pl ai ns of abdom i nal
cr am ps that ar e m ost sev er e just bef or e a bow el m ov em ent, and ar e then
tem por ar i l y r el i ev ed w i th the bow el m ov em ent. In addi ti on,
P. 163
she f eel s ti r ed and has l ost appr ox i m atel y 8 l b (3. 6 k g) w i thout di eti ng. She
has noted a tendency to br ui se easi l y . She dr i nk s f our gl asses of m i l k a
day .
Table 43 Major Disorders of Maldigestion or
Malabsorption
Intr al um i nal di sor der s

Pancr eati c ex ocr i ne (enzy m e) i nsuf f i ci ency
Chr oni c pancr eati ti s
Pancr eati c r esecti on
Cy sti c f i br osi s
Bi l e aci d def i ci ency
Pancr eati c or bi l e duct car ci nom a
Ex tensi v e di stal i l eal r esecti on or di sease
Bacter i al ov er gr ow th i n the pr ox i m al i ntesti ne
Sur gi cal di sr upti on of the conti nui ty of the upper bow el
(a Bi l l r oth II gastr ojejunostom y )
Di sor der s of enter ocy tes
Pr i m ar y def ects (epi thel i um hi stol ogi cal l y nor m al )
Pr i m ar y l actase def i ci ency
Sucr aseâ€“i som al tase def i ci ency
Secondar y def ects (epi thel i um hi stol ogi cal l y abnor m al )
N ontr opi cal spr ue (cel i ac di sease and gl uten
sensi ti v e enter opathy )
Tr opi cal spr ue
Acqui r ed i m m unodef i ci ency sy ndr om e enter opathy
Whi ppl e's di sease
Di stur bed tr ansf er of m etabol i tes f r om enter ocy tes i nto l y m ph
or por tal bl ood Inf i l tr ati v e pr ocesses of the m ucosa
(am y l oi dosi s and l y m phom a) Intesti nal l y m phangi ectasi a
Her past m edi cal hi stor y i s posi ti v e onl y f or f ati gue, f or w hi ch she saw
another phy si ci an 11 m onths ago, bef or e the di ar r hea dev el oped. The
phy si ci an tol d her that she had an i r ondef i ci ency anem i a. Si nce then, she
has tak en f er r ous sul f ate (300 m g f our ti m es dai l y ), but sti l l f eel s f ati gued.
She tak es no other m edi cati on.
Phy si cal ex am i nati on r ev eal s a y oung w om an w ho appear s m i l dl y
under w ei ght but i s other w i se nor m al .
Labor ator y test r esul ts ar e as f ol l ow s: w hi te bl ood cel l count, nor m al ;
hem atocr i t, 34%; m ean cor puscul ar v ol um e, 74 Âµm 3 ; ser um i r on, 50
m g/dL; total i r onbi ndi ng capaci ty , 435 m g/dL; stool l euk ocy te test,
negati v e; stool ex am i nati on f or ov a and par asi tes, negati v e; ser um al bum i n,
3. 2 m g/dL; ser um el ectr ol y tes, nor m al ; and pr othr om bi n ti m e, 2 seconds
gr eater than contr ol .
Whi l e aw ai ti ng these l abor ator y r esul ts, y ou adv i se the pati ent to stop
i ngesti ng al l m i l k pr oducts. The pati ent r epor ts that thi s r educes but does
not el i m i nate the di ar r hea or gas.
1. What addi ti onal hi stor y shoul d y ou obtai n f r om the pati ent?
2. What m i ght l ead y ou to suspect that m al absor pti on i s the cause of thi s
pati ent's di ar r hea, and w hy ? What test shoul d be per f or m ed to conf i r m
thi s, and w hy ?
Thi s pati ent's f ecal f at ex cr eti on i s m easur ed and f ound el ev ated,
w hi ch pr ov es she has m al di gesti on or m al absor pti on.
3. Consi der i ng that the pati ent has ei ther m al di gesti on or m al absor pti on,
w hat ar e the tw o di sor der s that m ay decr ease the bi l e aci d pool , tw o
di sor der s that decr ease pancr eati c l i pase acti v i ty , and tw o di sor der s
that m ay decr ease absor pti on by sm al l bow el enter ocy tes?
4. How does the Dx y l ose test di f f er enti ate pr obl em s w i th di gesti on (e. g. ,
bi l e sal t depl eti on and pancr eati c l i pase def i ci ency ) f r om pr obl em s w i th
absor pti on? N am e one di sor der that m ay pr oduce a f al seposi ti v e
r esul t.
The Dx y l ose test i n thi s pati ent r ev eal s poor absor pti on of thi s sugar ,
w hi ch i ndi cates that the sm al l bow el absor pti on pr obabl y i s abnor m al .
5. On the basi s of the r esul ts of the Dx y l ose test, w hat test shoul d be
per f or m ed now ?
A sm al l bow el bi opsy speci m en i n thi s pati ent r ev eal s m ucosal v i l l ous
atr ophy and cr y pt hy per pl asi a, accom pani ed by an i ncr eased num ber of
pl asm a cel l s and l y m phocy tes i n the l am i na pr opr i a and an i ncr eased
num ber of l y m phocy tes i n the epi thel i um .
6. Al though the bi opsy f i ndi ngs i ndi cate cel i ac spr ue, w hat other di sor der s
coul d pr oduce such a â€œf l atâ€ m ucosa?
7. How can the di agnosi s of cel i ac spr ue be conf i r m ed?
8. If the Dx y l ose test r esul t w as abnor m al , but the sm al l bow el bi opsy
f i ndi ngs w er e nor m al , a bacter i al ov er gr ow th i n the pr ox i m al sm al l
i ntesti ne m i ght be suspected. How shoul d thi s possi bi l i ty be ev al uated?
9. If thi s pati ent's Dx y l ose absor pti on test r esul t had been nor m al , w hat
di sor der m i ght y ou suspect and how shoul d y ou ev al uate thi s
possi bi l i ty ?
10. Why di d the sy m ptom s i n thi s pati ent, w ho had cel i ac spr ue, abate
w hen she stopped dr i nk i ng m i l k ?
P. 164
Case Discussion
1. What addi ti onal hi stor y shoul d y ou obtai n f r om the pati ent?
Thi s pati ent has chr oni c di ar r hea, w hi ch i s ar bi tr ar i l y def i ned as
di ar r hea that l asts l onger than 3 w eek s. Chr oni c di ar r hea i s a f ai r l y
com m on com pl ai nt, w i th a l engthy di f f er enti al di agnosi s. The cl i ni cal
hi stor y r em ai ns the m ai nstay of the i ni ti al appr oach to di agnosi s, and
the hi stor y tak i ng m ust i ncl ude questi ons concer ni ng the f ol l ow i ng
f actor s:
Food: Mi l k consum pti on, sor bi tol (added to di et f oods and f r ui t),
f r uctose (f ound i n nondi et sof t dr i nk s, candy , and f r ui t), and
unpasteur i zed m i l k (Yer si ni a i nf ecti on).
Tr av el : To ar eas w her e gi ar di asi s, am ebi asi s, or schi stosom i asi s

m i ght be contr acted.
Iatr ogeni c f actor s: Sur ger i es i n the GI tr act. A par ti al gastr ectom y
can r esul t i n dum pi ng (r api d em pty i ng of the gastr i c contents i nto
the sm al l i ntesti ne) and, i f a stagnant ar ea of bow el i s cr eated,
bacter i al ov er gr ow th can r esul t (the bl i nd l oop sy ndr om e).
Medi cati ons ar e al so a com m on cause of di ar r hea. The
adm i ni str ati on of anti bi oti cs can r esul t i n C. di f f i ci l e col i ti s, and
antaci d use can pr oduce an osm oti c di ar r hea. Î²Adr ener gi c
antagoni sts, col chi ci ne, l ax ati v es, and i nnum er abl e other dr ugs
can al so cause di ar r hea.
Ri sk f actor s f or acqui r ed i m m unodef i ci ency sy ndr om e (AIDS).
Rev i ew of sy stem s: Thi s m ay r ev eal ar thr i ti s, w hi ch can

accom pany i nf l am m ator y bow el di sease or Whi ppl e's di sease;
pepti c ul cer di sease, w hi ch can be associ ated w i th the Zol l i nger
El l i son sy ndr om e; sy m ptom s or a hi stor y of di abetes; or
hy per thy r oi di sm .
Past m edi cal pr obl em s, w i th an em phasi s on chi l dhood di ar r hea or
m al nutr i ti on and sur ger i es.
Fur ther char acter i zati on of the di ar r hea: Does i t aw ak en the
pati ent at ni ght? Is i t constant or does i t al ter nate w i th
consti pati on? The m ost com m on cause of chr oni c di ar r hea i n the
U . S. popul ati on i s the i r r i tabl e bow el sy ndr om e, w hi ch i s a poor l y
under stood m oti l i ty di sor der . It r ar el y r esul ts i n di ar r hea that
aw ak ens the pati ent at ni ght, r ar el y pr oduces w ei ght l oss, and
m ay hav e di ar r hea al ter nati ng w i th consti pati on.
2. What m i ght l ead y ou to suspect that m al absor pti on i s the cause of thi s
pati ent's di ar r hea, and w hy ? What test shoul d be per f or m ed to conf i r m
thi s, and w hy ?
Mal absor pti on i s suspected as the cause of the di ar r hea because of the
i r on def i ci ency that does not r espond to or al i r on tr eatm ent and
because the pr othr om bi n ti m e i s el ev ated w i thout si gns of l i v er
di sease. A 2 or 3day stool col l ecti on f or quanti tati v e f at anal y si s i s
the si ngl e m ost usef ul test to docum ent m al absor pti on. Because f at
absor pti on i s a com pl ex pr ocess (r equi r i ng the di gesti on of
tr i gl y cer i des by pancr eati c l i pase, sol ubi l i zati on of these pr oducts by
bi l e sal ts, and absor pti on of the subsequent pr oducts by enter ocy tes of
the sm al l i ntesti ne), abnor m al i ti es i n any of these steps r esul t i n f at
m al absor pti on and an i ncr ease i n f ecal f at ex cr eti on. Ther ef or e,
m easur em ent of the f ecal f at content i s a test f or m any steps i n the
P. 165
di gesti on and absor pti on pathw ay s. One of the f ew k i nds of
m al absor pti on that does not cause i ncr eased f ecal f at l oss i s that due
to the l ack of an i ntesti nal enzy m e needed i n the di gesti on of a
par ti cul ar car bohy dr ate, despi te a hi stol ogi cal l y nor m al i ntesti ne. The
m ost com m on ex am pl e of thi s i s pr i m ar y l actase def i ci ency , i n w hi ch
l actose i s not absor bed nor m al l y but f at i s.
3. Consi der i ng that the pati ent has ei ther m al di gesti on or m al absor pti on,
w hat ar e the tw o di sor der s that m ay decr ease the bi l e aci d pool , tw o
di sor der s that decr ease pancr eati c l i pase acti v i ty , and tw o di sor der s
that m ay decr ease absor pti on by sm al l bow el enter ocy tes?
Resecti on or di sease of the di stal sm al l bow el can cause a decr eased
r eabsor pti on of bi l e aci ds, r esul ti ng i n i nsuf f i ci ent bi l e sal t
concentr ati ons i n the pr ox i m al i ntesti ne to al l ow the nor m al
sol ubi l i zati on and absor pti on of f at. Com pl ete bl ock age of the com m on
bi l e duct, as by pancr eati c cancer or cancer of the duct, pr ev ents bi l e
aci ds f r om enter i ng the duodenum .
Chr oni c pancr eati ti s or pancr eati c cancer can bl ock the pancr eati c duct,
r esul ti ng i n decr eased secr eti on of l i pase. Incr eased aci d content i n the
duodenum , such as occur s i n the Zol l i nger El l i son sy ndr om e, can
i nacti v ate pancr eati c l i pase i n the i ntesti nal l um en.
Decr eased absor pti on by sm al l bow el enter ocy tes m ay be caused by
cel i ac spr ue, tr opi cal spr ue, Whi ppl e's di sease, sm al l i ntesti nal
l y m phom a, AIDS enter opathy , and sev er al other di seases.
4. How does the Dx y l ose test di f f er enti ate pr obl em s w i th di gesti on (e. g. ,
bi l e sal t depl eti on and pancr eati c l i pase def i ci ency ) f r om pr obl em s w i th
absor pti on? N am e one di sor der that m ay pr oduce a f al seposi ti v e
r esul t.
Dx y l ose i s a f i v ecar bon sugar that can be absor bed w i thout the ai d of
bi l e sal ts, pancr eati c enzy m es, or i ntesti nal enzy m es. It shoul d be
absor bed nor m al l y i f the sm al l bow el i s i ntact. Ther ef or e, the test i s
usef ul i n di sti ngui shi ng pancr eati c enzy m e i nsuf f i ci ency f r om
enter ocy te abnor m al i ti es. How ev er , bacter i al ov er gr ow th i n the
pr ox i m al i ntesti ne i s a condi ti on that can cause m al absor pti on of D
x y l ose w i thout af f ecti ng the enter ocy te (the bacter i a w i l l consum e the
Dx y l ose bef or e i t can be absor bed), ther eby pr oduci ng a f al seposi ti v e
r esul t.
5. On the basi s of the r esul ts of the Dx y l ose test, w hat test shoul d be
per f or m ed now ?
The sm al l bow el shoul d be ex am i ned, and ther e ar e tw o appr opr i ate
w ay s to do thi s: sm al l bow el bi opsy and a sm al l bow el bar i um
r adi ogr aph. A bi opsy speci m en gi v es m or e i nf or m ati on about the
m ucosa, w her eas the r adi ogr aph m ay per m i t better ev al uati on of
di v er ti cul a, r egi onal i l ei ti s, or bl i nd l oops.
6. Al though the bi opsy f i ndi ngs i ndi cate cel i ac spr ue, w hat other di sor der s
coul d pr oduce such a â€œf l atâ€ m ucosa?
Tr opi cal spr ue, soy and m i l k pr otei n al l er gy (pr i m ar i l y i n chi l dr en),
di f f use i ntesti nal l y m phom a, hy pogam m agl obul i nem i a, and the
Zol l i nger El l i son sy ndr om e can pr oduce a f l at m ucosal l esi on that
r esem bl es that of cel i ac spr ue.
7. How can the di agnosi s of cel i ac spr ue be conf i r m ed?
The di agnosi s of cel i ac spr ue can be conf i r m ed by obser v i ng the
pati ent's r esponse to a gl utenf r ee di et. Adher ence to a gl utenf r ee di et
shoul d br i ng about a
P. 166
cessati on or m ar k ed r educti on i n the di ar r hea and other i ntesti nal
sy m ptom s, w ei ght gai n, and hi stol ogi c i m pr ov em ent i n the i ntesti nal
m ucosa. Gl uten i s f ound i n w heat, r y e, bar l ey , and oats, but not i n r i ce
and cor n.
8. If the Dx y l ose test r esul t w as abnor m al , but the sm al l bow el bi opsy
f i ndi ngs w er e nor m al , a bacter i al ov er gr ow th i n the pr ox i m al sm al l
i ntesti ne m i ght be suspected. How shoul d thi s possi bi l i ty be ev al uated?
Thi s w oul d be m or e l i k el y to occur i n pati ents w ho hav e had a sur ger y
that r esul ted i n a bl i nd l oop of sm al l i ntesti ne, or i n el der l y pati ents
w ho ar e m or e l i k el y to hav e m ul ti pl e sm al l bow el di v er ti cul a. A sm al l
bow el bar i um r adi ogr aphi c ex am i nati on shoul d r ev eal these
abnor m al i ti es. The bi l e aci d br eath test coul d be used to docum ent
bacter i al deconjugati on of bi l e aci ds. In thi s test, a r adi ol abel ed
conjugated bi l e aci d, such as [ 1 4 C]gl y cochol i c aci d, i s gi v en or al l y ,
and the am ount and the ti m e cour se of the [ 1 4 C]O 2 ex hal ed i s
m easur ed. N or m al l y , m ost of the l abel ed bi l e aci d i s absor bed i ntact i n
the di stal i l eum ; a m i nor am ount r eaches the col on, w her e anaer obi c
bacter i a cl eav e the gl y ci ne m oi ety f r om the chol i c aci d m oi ety . The
[ 1 4 C]O 2 r el eased i n the col on i s absor bed and ex hal ed. If the upper
i ntesti ne i s popul ated by ex cessi v e num ber s of anaer obi c bacter i a, the
deconjugati on of [ 1 4 C]gl y cochol i c aci d occur s ear l i er and to a gr eater
degr ee than nor m al , r esul ti ng i n an ear l y and hi gh r i se i n the ex hal ed
[ 1 4 C]O 2 l ev el .
9. If thi s pati ent's Dx y l ose absor pti on test r esul t had been nor m al , w hat
di sor der m i ght y ou suspect and how shoul d y ou ev al uate thi s
possi bi l i ty ?
Pancr eati c i nsuf f i ci ency shoul d be suspected i n pati ents w ho hav e a
hi stor y of chr oni c pancr eati ti s or , l ess com m onl y , i n m i ddl eaged or
el der l y peopl e w ho m ay pr esent w i th a pancr eati c cancer obstr ucti ng
the pancr eati c duct. A pati ent w ho has m al absor pti on and a hi stor y of
pancr eati ti s shoul d under go a tr i al of pancr eati c enzy m e tr eatm ent. If
thi s al l ev i ates the di ar r hea, the tr i al can be both di agnosti c and
ther apeuti c. The secr eti n test can be used to ev al uate pancr eati c
f uncti on, but i t i s ex pensi v e and di f f i cul t to per f or m , so i t i s r ar el y
used. If a pancr eati c cancer i s suspected, an i m agi ng study such as CT
scanni ng or endoscopi c r etr ogr ade chol angi opancr eatogr aphy (ERCP)
shoul d be per f or m ed.
10. Why di d the sy m ptom s i n thi s pati ent, w ho had cel i ac spr ue, abate
w hen she stopped dr i nk i ng m i l k ?
Cel i ac spr ue dam ages the i ntesti nal epi thel i um , ther eby decr easi ng the
am ounts of di gesti v e enzy m es, such as l actase, that ar e nor m al l y
pr esent i n the v i l l us cel l s.
Suggested Readings
Far r el RJ, Kel l y CP. Cel i ac spr ue and r ef r actor y spr ue. In: Fel dm an M,
Fr i edm an LS, Sl ei senger MH, eds. Sl ei senger and For dtr an's
gastr oi ntesti nal and l i v er di sease: pathophy si ol ogy , di agnosi s,
m anagem ent, 7th ed. Phi l adel phi a: WB Saunder s, 2002:1817.
Hogenauer C, Ham m er HF. Mal di gesti on and m al absor pti on. In: Fel dm an
M, Fr i edm an LS, Sl ei senger MH, eds. Sl ei senger and For dtr an's
gastr oi ntesti nal and l i v er di sease: pathophy si ol ogy , di agnosi s,
m anagem ent, 7th ed. Phi l adel phi a: WB Saunder s, 2002:1751.
P. 167
Pancreatitis
1. What ar e the com m on and uncom m on causes of acute pancr eati ti s?
2. What pathogeneti c m echani sm i s hy pothesi zed to be com m on to these
causes of acute pancr eati ti s, and how does i t ex pl ai n the cl i ni cal
f eatur es of the di sease?
3. What sy m ptom s and si gns ty pi f y acute pancr eati ti s?
4. What di f f i cul ti es m ay be encounter ed i n conf i r m i ng the di agnosi s of
acute pancr eati ti s thr ough the m easur em ent of am y l ase l ev el s, and
how m i ght the di agnosti c accur acy be i m pr ov ed?
5. What cl i ni cal and l abor ator y i ndi ces can be used to assess the
pr ognosi s i n a case of acute pancr eati ti s?
6. What ev ents si gnal the dev el opm ent of l ocal com pl i cati ons of acute
pancr eati ti s, and how ar e they best ev al uated?
7. What ar e the m ai nstay s of tr eatm ent of acute pancr eati ti s, and w hat i s
the r ati onal e f or thei r use?
8. What car di nal f eatur e di sti ngui shes chr oni c pancr eati ti s f r om acute
pancr eati ti s?
9. How does the eti ol ogy of chr oni c pancr eati ti s di f f er f r om that of acute
pancr eati ti s?
10. What ar e the m ai nstay s of tr eatm ent of chr oni c pancr eati ti s?
Discussion
1. What ar e the com m on and uncom m on causes of acute pancr eati ti s?
The com m on causes of acute pancr eati ti s ar e al cohol (60%), gal l stones
(25% to 30%), and i di opathi c causes. Tabl e 4. 4 l i sts uncom m on causes.
2. What pathogeneti c m echani sm i s hy pothesi zed to be com m on to these
causes of acute pancr eati ti s, and how does i t ex pl ai n the cl i ni cal
f eatur es of the di sease?
Autodi gesti on i s the pathogeneti c m echani sm com m on to al l the causes
of acute pancr eati ti s. Eti ol ogi c f actor s ar e bel i ev ed to l ead to the
pr em atur e acti v ati on of pancr eati c pr oenzy m es w i thi n the gl and.
Destr ucti on of the pancr eas by the acti v ated enzy m es l eads to l ocal
i njur y (edem a, necr osi s, and hem or r hage). In addi ti on, the acti v ati on
and r el ease of pr oi nf l am m ator y cy tok i nes, v asoacti v e pepti des, and
enzy m es l eads to the sy stem i c ef f ects that of ten accom pany pancr eati c
i njur y (shock , di ssem i nated i ntr av ascul ar coagul ati on, adul t r espi r ator y
di str ess sy ndr om e, r enal f ai l ur e, hy per gl y cem i a, and hy pocal cem i a).
3. What sy m ptom s and si gns ty pi f y acute pancr eati ti s?
Pai n i s a char acter i sti c sy m ptom of acute pancr eati ti s and i s l ocated i n
the m i depi gastr i c and per i um bi l i cal r egi ons. Com m onl y , i t r adi ates to
the back and i s m or e constant and sustai ned than the pai n associ ated
w i th other abdom i nal pr ocesses. It i s of ten m or e i ntense i n the supi ne
posi ti on and am el i or ated by si tti ng f or w ar d. Pati ents m ay ex hi bi t
m ar k ed abdom i nal tender ness and guar di ng.
N ausea and v om i ti ng ar e other sy m ptom s. In thi s setti ng, the abdom en
m ay be di stended f r om the accum ul ati on of i ntr aabdom i nal and
P. 168
f l ui d, par al y ti c i l eus, and chem i cal per i toni ti s. The bow el sounds m ay
be di m i ni shed.
Table 44 Common and Uncommon Causes
of Acute Pancreatitis
Postoper ati v e causes

Af ter endoscopi c r etr ogr ade chol angi opancr eatogr aphy
Tr aum a
Metabol i c causes (hy per tr i gl y cer i dem i a,
hy per par athy r oi di sm , r enal f ai l ur e, and acute f atty l i v er
of pr egnancy )
Her edi tar y causes
Inf ecti ons (m um ps, My copl asm a, cox sack i e v i r us, and
echov i r us)
Vascul i ti des (sy stem i c l upus er y them atosus, thr om boti c
thr om bocy topeni c pur pur a, HenochSchonl ei n pur pur a,
necr oti zi ng angi i ti s)
Am pul l a of Vater obstr ucti on (Cr ohn'sease, duodenal
di v er ti cul a, penetr ati ng duodenal ul cer , pancr eas
di v i sum , and scor pi on v enom )
Dr ugs
Azathi opr i ne/6m er captopur i ne
Thi azi de di ur eti cs
Estr ogens
Fur osem i de
Sul f onam i des (sul f asal azi ne, tr i m ethopr i m â
€“sul f am ethox azol e)
Tetr acy cl i ne
Methy l dopa
Sul i ndac
Val pr oate
Pentam i di ne
Di danosi ne
Or al 5am i nosal i cy l ate (ol sal zi ne and m esal am i ne)
Octr eoti de
Hy potensi on m ay be pr esent i n as m any as hal f of the pati ents; i t
r esul ts f r om v asodi l ati on, m y ocar di al depr essant f actor , and the l oss of
pl asm a and bl ood i nto the r etr oper i toneum .
Less com m on, but i m por tant, f i ndi ngs i ncl ude per i um bi l i cal (Cul l en's
si gn) or f l ank ecchy m oses (Gr ey Tur ner 's si gn).
4. What di f f i cul ti es m ay be encounter ed i n conf i r m i ng the di agnosi s of
acute pancr eati ti s thr ough the m easur em ent of am y l ase l ev el s, and
how m i ght the di agnosti c accur acy be i m pr ov ed?
Al though the ser um am y l ase l ev el usual l y r i ses w i thi n 12 hour s of the
onset of pai n and r em ai ns el ev ated f or 3 to 5 day s, a nor m al ser um
am y l ase v al ue does not ex cl ude pancr eati ti s. Spur i ousl y nor m al ser um
am y l ase l ev el s m ay r esul t f r om the r api d cl ear ance of am y l ase i nto the
ur i ne, and m ay be seen w i th hy per tr i gl y cer i dem i a and i n l atestage (â
€œbur ned outâ€ ) chr oni c pancr eati ti s. The m agni tude of the am y l ase
el ev ati on i n ser um or ur i ne does not cor r el ate
P. 169
w i th the sev er i ty of pancr eati ti s. In addi ti on, hy per am y l asem i a i s not a
speci f i c f i ndi ng f or pancr eati ti s because i t m ay occur i n a v ar i ety of
pancr eati c and nonpancr eati c di seases. Ther e ar e sal i v ar y as w el l as
pancr eati cty pe i soam y l ases, and sal i v ar y am y l ase accounts f or 60% to
65% of the total am y l ase content. Sal i v ar y hy per am y l asem i a can occur
i n the setti ngs of di abeti c k etoaci dosi s, al cohol i sm , and m al i gnancy
(especi al l y w i th hepati c m etastasi s). Macr oam y l asem i a occur s w i thout
any r el ati onshi p to pancr eati ti s and r esul ts i n el ev ated ser um (but not
ur i ne) am y l ase l ev el s.
Attem pts at i m pr ov i ng the sensi ti v i ty , and especi al l y the speci f i ci ty , of
the l abor ator y based di agnosi s of pancr eati ti s hav e i ncl uded
m easur em ent of the r enal am y l ase cl ear ance and the r ati o of r enal
am y l ase cl ear ance to cr eati ni ne cl ear ance (C am /C cr ). How ev er , the
speci f i ci ty of the C am /C cr i s questi onabl e because i t m ay be el ev ated i n
the setti ngs of di abeti c k etoaci dosi s, bur ns, r enal f ai l ur e, chr oni c
hem odi al y si s, pancr eati c neopl asm s, and al cohol i c l i v er di sease.
Measur em ent of the pancr eati c i soam y l ase l ev el s has al so been tr i ed.
Thi s m ay pr ov i de i nf or m ati on that changes the cl i ni cal di agnosi s i n 20%
to 40% of pati ents w i th hy per am y l asem i a. Measur em ent of the ser um
l i pase l ev el i s sl i ghtl y l ess sensi ti v e f or the di agnosi s of pancr eati ti s
than that of the ser um am y l ase l ev el , but the l i pase concentr ati on
r em ai ns el ev ated l onger and i s m or e speci f i c than the am y l ase v al ue.
5. What cl i ni cal and l abor ator y i ndi ces can be used to assess the
pr ognosi s i n a case of acute pancr eati ti s?
A set of the ear l y r i sk f actor s, k now n as Ranson's cr i ter i a, has been
used to pr edi ct the potenti al com pl i cati ons and m or tal i ty i n a pati ent
w i th acute pancr eati ti s (see Tabl es 4. 4â€“4. 5).
The m or tal i ty r ate associ ated w i th these si gns has been deter m i ned as
f ol l ow s: tw o or f ew er si gns, 1%; thr ee or f our si gns, 16%; f i v e or si x
si gns, 40%; and m or e than si x si gns, 100%.
Table 45 Ranson's
At adm i ssi on

Age, ol der than 55 y
Whi te bl ood cel l count, > 16, 000/ m m 3
Bl ood gl ucose, > 200 m g/dL
Ser um l actate dehy dr ogenase, < 350 IU /L
Aspar tate am i notr ansf er ase, > 250 IU /L
Dur i ng i ni ti al 48 hr
Hem atocr i t decr ease, > 10%
Bl ood ur ea ni tr ogen r i se, > 5 m g/dL
Ser um cal ci um , < 8 m g/dL
Ar ter i al par ti al pr essur e of ox y gen (Po2), < 60 m m
Hg
Base def i ci t, > 4 m Eq/L
Esti m ated f l ui d sequestr ati on, > 6 L
P. 170
Measur em ent of tryps inoge n a c tiva tion pe ptide i n ur i ne m ay
di sti ngui sh m i l d f r om sev er e pancr eati ti s, but the test i s not gener al l y
av ai l abl e.
6. What ev ents si gnal the dev el opm ent of l ocal com pl i cati ons of acute
pancr eati ti s, and how ar e they best ev al uated?
Loc a l a nd infe c tious c omplic a tions of acute pancr eati ti s account f or
80% of the m or tal i ty associ ated w i th the di sease; ther ef or e, detecti on
of these com pl i cati ons i s cr uci al i n m i ni m i zi ng the l i k el i hood of a f atal
outcom e. A pa nc re a tic ps e udoc ys t shoul d be suspected i n the setti ng
of per si stent pai n and hy per am y l asem i a, and m ay be m ani f ested as a
pal pabl e m ass i n the upper abdom en. P a nc re a tic ne c ros is or
phl egm on, and pa nc re a tic a bs c e s s ar e of ten di f f i cul t to di sti ngui sh
because they both com m onl y cause pr ol onged abdom i nal pai n and
tender ness, f ev er , l euk ocy tosi s, and a pal pabl e m ass.
A CT scan w i th or al and IV contr ast enhancem ent i s the best m ethod f or
i m agi ng these com pl i cati ons. Ex tr al um i nal gas m ay be seen on the
studi es and can be used to di sti ngui sh pancr eati c necr osi s f r om
pancr eati c abscess. How ev er , i t i s CTgui ded per cutaneous needl e
aspi r ati on that usual l y al l ow s f or the ear l y di agnosi s of pancr eati c
i nf ecti on and abscess, w hi ch r equi r e ei ther per cutaneous or sur gi cal
dr ai nage.
7. What ar e the m ai nstay s of tr eatm ent of acute pancr eati ti s, and w hat i s
the r ati onal e f or thei r use?
By el i m i nati ng or al i ntak e (N PO), the neur al and hor m onal sti m ul i to
pancr eati c ex ocr i ne secr eti on m ay be m i ni m i zed, ther eby l i m i ti ng the
cy cl e of pancr eati c autodi gesti on and i nf l am m ati on. El i m i nati ng f ood
i ntak e r educes the v agal sti m ul ati on of pancr eati c secr eti on and
r educes the del i v er y of aci d, f atty aci ds, and am i no aci ds to the
duodenum , w hi ch w oul d el i ci t r el ease of secr eti n and chol ecy stok i ni n.
Par enter al nutr i ti on i s of ten adm i ni ster ed, but enter al nutr i ti on thr ough
a tube pl aced i n the jejunum i s pr ef er r ed because of i ts l ow er cost and
f ew er com pl i cati ons. N asogastr i c sucti on i s usual l y not adv ocated, but
i t m ay be usef ul i n those pati ents ex per i enci ng nausea and v om i ti ng
r esul ti ng f r om par al y ti c i l eus. Adequate r epl acem ent of f l ui d and
el ectr ol y te l osses (especi al l y cal ci um ) stem m i ng f r om the
r etr oper i toneal i nf l am m ati on and ex udati on i s essenti al . Hy pocal cem i a
i s bel i ev ed to r esul t f r om a com bi nati on of f actor s: hy poal bum i nem i a,
the sequestr ati on of cal ci um i n ar eas of f at necr osi s, and an i nadequate
par athor m one r esponse. Anal gesi c adm i ni str ati on i s usual l y r equi r ed to
contr ol the pai n, w hi ch i s of ten i ntense and pr ol onged.
8. What car di nal f eatur e di sti ngui shes chr oni c pancr eati ti s f r om acute
pancr eati ti s?
The per m anent destr ucti on of the pancr eati c gl and i s a car di nal f eatur e
of chr oni c pancr eati ti s. Pathol ogi cal l y , ther e i s atr ophy of the aci ni , a
l oss of i sl et cel l s, f i br osi s, and pl uggi ng of i r r egul ar pancr eati c ducts
by pr otei n. The pr otei n pl ugs m ay be cal ci f i ed and, on r adi ogr aphi c
studi es, 30% of pati ents ex hi bi t pancr eati c cal ci f i cati on. The cl i ni cal
sequel ae of gl andul ar destr ucti on i ncl ude ex ocr i ne and endocr i ne
i nsuf f i ci ency , m ani f ested by steator r hea and di abetes m el l i tus,
r especti v el y (the f or m er occur r i ng onl y w hen ther e i s a m or e than 90%
r educti on i n ex ocr i ne f uncti on). Abdom i nal pai n i s not
P. 171
uni f or m l y seen and m ay be i nter m i ttent, constant, or absent. Because
of the aci nar destr ucti on, the ser um am y l ase l ev el s m ay be onl y m i l dl y
el ev ated or nor m al .
9. How does the eti ol ogy of chr oni c pancr eati ti s di f f er f r om that of acute
pancr eati ti s?
In w ester n countr i es, m ost (appr ox i m atel y 90%) cases of chr oni c
pancr eati ti s ar e attr i butabl e to al cohol i sm . Other possi bl e causes
i ncl ude m etabol i c di sor der s such as hy per cal cem i a of any cause
(per haps hy per par athy r oi di sm ), hy per l i pi dem i a, and congeni tal or
her edi tar y condi ti ons (pancr eas di v i sum , cy sti c f i br osi s, and her edi tar y
pancr eati ti s).
10. What ar e the m ai nstay s of tr eatm ent of chr oni c pancr eati ti s?
Acute r el apses of chr oni c pancr eati ti s m ay r equi r e m anagem ent

i denti cal to that f or acute pancr eati ti s, and m ay be accom pani ed by
pseudocy st f or m ati on and pancr eati c asci tes. Ex ocr i ne i nsuf f i ci ency
r esul ti ng i n steator r hea and w ei ght l oss i s tr eated w i th or al pancr eati c
enzy m e r epl acem ent, w her eas endocr i ne i nsuf f i ci ency (di abetes
m el l i tus) r equi r es i nsul i n ther apy . Managem ent of the chr oni c pai n has
been pr obl em ati c, and pati ents f r equentl y becom e addi cted to nar coti c
anal gesi cs. The or al adm i ni str ati on of hi gh doses of pancr eati c
enzy m es m ay r educe the pai n. Sur gi cal i nter v enti on (gangl i onectom y ,
par ti al and total pancr eatectom y , and pancr eati c duct dr ai nage
oper ati ons) conf er s i nconsi stent benef i ts and i s f r aught w i th l ongter m
m or bi di ty .
Case 1
A 66y ear ol d m an i s adm i tted w i th com pl ai nts of pr ogr essi v el y sev er e,
constant upper abdom i nal pai n, nausea, and v om i ti ng of 48 hour sâ€™
dur ati on. Recentl y , he has consum ed l ar ge quanti ti es of v odk a, but has no
hi stor y of bi l i ar y tr act di sease and i s tak i ng no m edi cati ons.
He i s a thi n m an, w i nci ng and cl utchi ng hi s abdom en. Hi s tem per atur e i s
38Â°C (100. 4Â°F); bl ood pr essur e, 100/60 m m Hg; pul se, 90 beats per
m i nute; and r espi r ati ons, 18 per m i nute. Hi s abdom en i s f l at and the bow el
sounds ar e hy poacti v e. Ther e i s m ar k ed di r ect tender ness w i th guar di ng i n
the m i depi gastr i um , but no per i toneal si gns.
The f ol l ow i ng l abor ator y data ar e gather ed: w hi te bl ood cel l count, 10, 000
cel l s/m m 3 ; hem atocr i t, 50%; ser um cr eati ni ne, 1. 3 m g/dL; total ser um
bi l i r ubi n, 3. 4 m g/dL; al k al i ne phosphatase, 246 IU /L; AST, 209 IU /L; and
ser um am y l ase, 741 U /L.
Pl ai n abdom i nal r adi ogr aphs r ev eal the pr esence of scatter ed ai r f l ui d
l ev el s, pr edom i nantl y i n the sm al l bow el , but no cal ci f i cati on or
subdi aphr agm ati c f r ee ai r . An abdom i nal ul tr asound ex am i nati on r ev eal s a
di l ated, f l ui df i l l ed gal l bl adder , a di l ated com m on bi l e duct w i thout def i ni te
cal cul i , and a poor l y v i sual i zed pancr eas because of ov er l y i ng bow el gas.
A nasogastr i c tube i s i nser ted and pl aced at l ow sucti on, and the pati ent
r em ai ns N PO, r ecei v i ng onl y IV f l ui ds. Ov er the ensui ng 48 hour s, he
r equi r es r egul ar doses of m eper i di ne f or the contr ol of per si stent, sev er e
pai n and i s noted to hav e a r i se i n hi s bi l i r ubi n (8. 0 m g/dL), al k al i ne
phosphatase (450 IU /L), and AST (375 IU /L) l ev el s. ERCP, per f or m ed on the
thi r d hospi tal day , dem onstr ates a di l ated com m on bi l e duct that taper s
sm oothl y i n i ts i ntr apancr eati c por ti on and contai ns no stones. The
gal l bl adder i s di l ated and al so contai ns no stones. N o pancr eatogr am i s
obtai ned.
P. 172
The af or em enti oned m anagem ent i s conti nued, and total par enter al nutr i ti on
i s star ted. The pati ent's pai n, abdom i nal tender ness, and l i v er test
abnor m al i ti es gr adual l y abate ov er the subsequent 10 day s.
1. Why w as an ERCP obtai ned?

2. What w as the cause of the pati ent's bi l i ar y obstr ucti on?
Case Discussion
1. Why w as an ERCP obtai ned?
The pati ent's l abor ator y data i ncl uded abnor m al l i v er test r esul ts
consi stent w i th chol estasi s, and com m on bi l e duct di l ati on w as seen on
the ul tr asound ex am i nati on. These f i ndi ngs and the f ai l ur e of hi s
sy m ptom s to subsi de dur i ng the ear l y hospi tal cour se r ai sed concer n
about a gal l stone at the am pul l a of Vater and â€œgal l stone
pancr eati ti s. â€ Per f or m i ng an em er gency ERCP, w i th papi l l otom y w hen
am pul l ar y or com m on bi l e duct stones ar e f ound, has been adv ocated
w i thi n 24 hour s i n pati ents w ho hav e acute bi l i ar y pancr eati ti s.
2. What w as the cause of the pati ent's bi l i ar y obstr ucti on?
Com pr essi on of the i ntr apancr eati c com m on bi l e duct by an i nf l am ed
pancr eas i s the cause of the bi l i ar y obstr ucti on i n thi s pati ent. Thi s i s
show n by the absence of gal l stones on the ERCP study and the pati ent's
gr adual i m pr ov em ent w i th conser v ati v e m anagem ent of acute
pancr eati ti s.
Case 2
A 40y ear ol d, al cohol i c m an com pl ai ns of chr oni c abdom i nal pai n and
w ei ght l oss. He had consum ed tw o pi nts of bour bon dai l y f or the l ast 10
y ear s, unti l 4 y ear s ago, w hen he had hi s f i r st epi sode of abdom i nal pai n,
w hi ch w as char acter i zed as a shar p, conti nuous epi gastr i c pai n r adi ati ng to
the back , and associ ated w i th nausea and v om i ti ng. He w as adm i tted to the
hospi tal , w her e hi s sy m ptom s gr adual l y abated w i th tr eatm ent, consi sti ng of
bow el r est and IV f l ui ds f or 1 w eek . Hi s abdom i nal r adi ogr aphs at that ti m e
r ev eal ed cal ci f i cati on i n the ar ea of the pancr eas. He subsequentl y r educed
hi s al cohol i ntak e, but r equi r ed r eadm i ssi on to the hospi tal on sev er al
occasi ons af ter the consum pti on of r el ati v el y sm al l quanti ti es of al cohol .
In r ecent m onths, the pati ent has l ost 25 l b (11. 25 k g), coi nci dent w i th the
passi ng of per si stentl y l oose and occasi onal l y gr easy stool s. Hi s abdom i nal
pai n has becom e constant, and a m acr ocy ti c anem i a has dev el oped.
The pati ent i s cachecti c, w ei ghi ng 125 l b (56. 25 k g). He has a scaphoi d
abdom en w i th nor m al bow el sounds and m i l d di r ect tender ness i n the
m i depi gastr i um i n r esponse to pal pati on. Ther e i s m oder ate pedal edem a.
Rel ev ant l abor ator y data ar e: w hi te bl ood cel l count, 4, 900 cel l s/m m 3 , w i th
65% segm ented cel l s, 20% l y m phocy tes, and 10% m onocy tes; hem atocr i t,
37%; m ean cor puscul ar v ol um e, 106 Âµm 3 ; pr othr om bi n ti m e, 14 seconds
(contr ol , 12 seconds); ser um al bum i n, 2. 7 g/dL; ser um gl ucose, nor m al ;
ser um and el ectr ol y tes and l i v er f uncti on tests ar e other w i se nor m al ; ser um
v i tam i n B 1 2 , 96 pg/m L (nor m al , > 200 pg/m L); ser um f ol ate, nor m al ; and
72hour f ecal f at ex cr eti on, 42 g (nor m al , < 15 g).
P. 173
The pati ent i s star ted on a r egi m en of m onthl y v i tam i n B 1 2 i njecti ons and
or al pancr eati c enzy m es, thr ee capsul es w i th each m eal and one capsul e
w i th snack s. At f i r st, he f ai l s to gai n w ei ght and obser v es no r educti on i n
the f r equency of hi s bow el m ov em ents; hi s abdom i nal pai n per si sts at a
m oder ate sev er i ty . The dose of enzy m es i s i ncr eased to si x capsul es w i th
each m eal , and he al so begi ns tak i ng ci m eti di ne (300 m g or al l y f our ti m es a
day ). Ov er a per i od of 1 m onth, hi s pai n subsi des consi der abl y and he gai ns
15 l b (6. 75 k g).
1. Is i t unusual that the pati ent had hi s f i r st attack of pancr eati ti s pai n
af ter 10 y ear s of heav y al cohol consum pti on, and at that ti m e he
al r eady had si gns of chr oni c pancr eati ti s (pancr eati c cal ci f i cati on)?
2. What i s the pathophy si ol ogi c basi s f or v i tam i n B 1 2 def i ci ency i n the
setti ng of chr oni c pancr eati ti s?
3. Why di d the pati ent begi n to gai n w ei ght onl y af ter hi s pancr eati c
enzy m e dose w as i ncr eased and ci m eti di ne added?
4. Why m i ght the pati ent's pai n hav e subsi ded tow ar d the end of the
descr i bed cour se?
Case Discussion
1. Is i t unusual that the pati ent had hi s f i r st attack of pancr eati ti s pai n
af ter 10 y ear s of heav y al cohol consum pti on, and at that ti m e he
al r eady had si gns of chr oni c pancr eati ti s (pancr eati c cal ci f i cati on)?
N o. It i s bel i ev ed that m ost peopl e m ust consum e at l east 50 g of
al cohol dai l y on a pr ol onged basi s bef or e chr oni c pancr eati ti s dev el ops,
and m ost hav e been dr i nk i ng ex cessi v el y f or 5 to 20 y ear s bef or e thei r
f i r st attack . Al cohol i nduced pancr eati ti s i s pr obabl y chr oni c, ev en at
the ti m e of the f i r st attack . Pancr eati c cal ci f i cati ons ar e seen i n 25% to
50% of the pati ents and ar e par ti cul ar l y com m on i n al cohol i cs w ho
hav e chr oni c pancr eati ti s.
2. What i s the pathophy si ol ogi c basi s f or v i tam i n B 1 2 def i ci ency i n the

setti ng of chr oni c pancr eati ti s?
The v i tam i n B 1 2 def i ci ency stem s f r om the ex ocr i ne i nsuf f i ci ency .
Pancr eati c pr oteases ar e necessar y to cl eav e R pr otei n f r om v i tam i n
B 1 2 i n the pr ox i m al i ntesti ne, so that the l atter m ay be absor bed as a
com pl ex w i th i ntr i nsi c f actor (i n the ter m i nal i l eum ). Appr ox i m atel y
50% of pati ents w i th adv anced pancr eati ti s hav e v i tam i n B 1 2 def i ci ency
due to ex ocr i ne i nsuf f i ci ency .
3. Why di d the pati ent begi n to gai n w ei ght onl y af ter hi s pancr eati c
enzy m e dose w as i ncr eased and ci m eti di ne added?
Pancr eati c enzy m es can be i nacti v ated by gastr i c aci d, and thi s
i nacti v ati on can be r educed by the adm i ni str ati on of antaci ds or
hi stam i ne 2 (H 2 ) r eceptor antagoni sts. In addi ti on, ev i dence suggests
that cer tai n enzy m e capsul es ar e m or e ef f ecti v e at del i v er i ng acti v e
enzy m e to the sm al l i ntesti ne than other s.
4. Why m i ght the pati ent's pai n hav e subsi ded tow ar d the end of the
descr i bed cour se?
Sustai ned pai n r el i ef i n pati ents w i th chr oni c pancr eati ti s of ten occur s
af ter sev er al y ear s and onl y w i th m ar k ed pr ogr essi on of the pancr eati c
ex ocr i ne i nsuf f i ci ency , r ather than bei ng a r esul t of ther apeuti c
i nter v enti on. How ev er , thi s
P. 174
pati ent's pai n seem ed to subsi de r ather qui ck l y w i th the i nsti tuti on of
hi gh doses of pancr eati c enzy m e ther apy . The suppr essi on of
pancr eati c ex ocr i ne secr eti on has been accom pl i shed i n pati ents w ho
r ecei v ed i ntr aduodenal per f usi ons of pancr eati c ex tr act, and the pai n of
chr oni c pancr eati ti s has been show n to r espond to tr eatm ent w i th or al l y
adm i ni ster ed pancr eati c enzy m es i n som e pati ents.
Suggested Readings
Ow y ang C. Chr oni c pancr eati ti s. In: Yam ada T, Al per s DH, Kapl ow i tz N ,
etal . eds. Tex tbook of gastr oenter ol ogy , 4th ed. Phi l adel phi a: Li ppi ncott
Wi l l i am s & Wi l k i ns, 2003: 2061.
Topazi an M, Gor el i ck FS. Acute pancr eati ti s. In: Yam ada T, Al per s DH,
Kapl ow i tz N , etal . eds. Tex tbook of gastr oenter ol ogy , 4th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:2026.
Acute Lower Gastrointestinal Hemorrhage
1. What i s one of the m ost i m por tant di agnosi s to r ul e out i n a pati ent
w i th l ar gev ol um e hem atochezi a?
2. Whi ch m ethod of i m agi ng the GI tr act has no r ol e i n the ev al uati on of a
pati ent w i th acute l ow er GI bl eedi ng?
3. What ar e the tw o m ost com m on causes of acute m ajor l ow er GI

bl eedi ng?
Discussion
1. What i s one of the m ost i m por tant di agnosi s to r ul e out i n a pati ent
w i th l ar gev ol um e hem atochezi a?
An upper GI bl eedi ng sour ce m ust be r ul ed out i n ev er y pati ent w i th
l ar gev ol um e hem atochezi a. Low er GI bl eedi ng i s def i ned as bl eedi ng
f r om a sour ce di stal to the l i gam ent of Tr ei tz, the str uctur e that
di v i des the duodenum f r om the jejunum . Appr ox i m atel y 10% of pati ents
w i th upper GI bl eedi ng hav e hem atochezi a because of a r api d r ate of
bl ood l oss and the subsequent r api d tr ansi t of bl ood thr ough the GI
tr act. Because the str ategy f or tr eatm ent of an upper GI hem or r hage
m ay di f f er dr asti cal l y f r om that f or a l ow er GI hem or r hage, f i r st r ul i ng
out an upper GI bl eedi ng sour ce i s m andator y i n pati ents pr esenti ng
w i th hem atochezi a.
The easi est w ay to ex cl ude a si gni f i cant upper GI hem or r hage w i th
substanti al r el i abi l i ty i s thr ough nasogastr i c l av age and aspi r ati on. The
aspi r ati on of bi l i ous contents f r om a nasogastr i c tube m ak es i t v er y
l i k el y that the bl eedi ng or i gi nates f r om a l ow er sour ce, but thi s i s not
an i nf al l i bl e f i ndi ng. If the sour ce of bl eedi ng r em ai ns i n doubt af ter
nasogastr i c l av age, upper GI endoscopy shoul d be per f or m ed.
P. 175
2. Whi ch m ethod of i m agi ng the GI tr act has no r ol e i n the ev al uati on of a
pati ent w i th acute l ow er GI bl eedi ng?
A bar i um enem a ex am i nati on shoul d not be per f or m ed i n the setti ng of
acute l ow er GI bl eedi ng because i t has no ther apeuti c potenti al , and
the bar i um i nter f er es w i th the per f or m ance of m or e appr opr i ate tests,
nam el y techneti um Tc 99m ( 9 9 m Tc)l abel ed er y thr ocy te scanni ng,
angi ogr aphy , and col onoscopy .
At m ost hospi tal s, the 9 9 m Tcl abel ed er y thr ocy te scan i s the pr ef er r ed
nucl ear m edi ci ne test f or l ocal i zi ng the sour ce of acute l ow er GI
bl eedi ng. To per f or m thi s, the pati ent's r ed bl ood cel l s ar e l abel ed w i th
r adi oacti v e techneti um . A sci nti l l ati on cam er a then tr ack s w her e the
l abel ed r ed bl ood cel l s col l ect i n the pati ent. The 9 9 m Tcl abel ed
er y thr ocy te scan m ay hel p l ocal i ze a bl eedi ng sour ce to the gener al
r egi on of the sm al l bow el , r i ght col on, or l ef t col on, ther eby di r ecti ng
the cour se of ther apy . U nder the cor r ect ci r cum stances, thi s scan m ay
l ocal i ze a sour ce of bl eedi ng at r ates as l ow as 0. 5 m L per m i nute.
If ar ter i al bl eedi ng i s occur r i ng at a r ate of appr ox i m atel y 1 m L per
m i nute, angi ogr aphy i s usef ul f or both di agnosi s and ther apy . Once
catheter i zed, the bl eedi ng ar ter y m ay then be sel ecti v el y i nf used w i th
v asopr essi n, or em bol i zed w i th m etal coi l s. Angi ogr aphy i s usual l y not
usef ul i f the bl eedi ng has stopped.
Col onoscopy , because i t m ay y i el d a di agnosi s and pr ov i de a m eans f or

del i v er i ng ther apy , r egar dl ess of w hether the pati ent i s acti v el y
bl eedi ng, shoul d be per f or m ed bef or e nucl ear m edi ci ne scans or
angi ogr aphy i n m ost pati ents w i th acute l ow er GI bl eedi ng. If possi bl e,
the l ow er bow el shoul d be r api dl y f l ushed w i th a pol y ethy l ene gl y col
el ectr ol y te sol uti on bef or e col onoscopy i s per f or m ed. Wi th m oder n
techni ques, the di agnosti c accur acy of col onoscopy i s at l east as good
as that of angi ogr aphy , unl ess the r ate of bl eedi ng i s so br i sk as to
obscur e col onoscopi c v i sual i zati on com pl etel y .
3. What ar e the tw o m ost com m on causes of acute m ajor l ow er GI

bl eedi ng?
The m ost com m on cause of m ajor l ow er GI bl eedi ng i s di v er ti cul osi s,
accounti ng f or appr ox i m atel y 40% of al l cases. Di v er ti cul a ar e
her ni ati ons i n the col on w al l that ar e bel i ev ed to be acqui r ed w i th age.
Causal associ ati ons betw een l ow di etar y f i ber i ntak e and di v er ti cul osi s
hav e not been uni v er sal l y accepted, and the tr ue eti ol ogy i s pr obabl y
m ul ti f actor i al . In di v er ti cul osi s, as the col on w al l her ni ates, the
i ntr am ur al ar ter i es (v asa r ecta) m ay r uptur e, ther eby pr oduci ng a br i sk
but pai nl ess hem or r hage. Al though the hem or r hage stops spontaneousl y
i n appr ox i m atel y 80% of pati ents, di v er ti cul ar bl eedi ng m ay l ead to
l i f ethr eateni ng bl ood l oss, par ti cul ar l y i n the el der l y . Di v er ti cul a ar e
m or e com m on i n the l ef t col on, y et di v er ti cul ar bl eedi ng m ost of ten
or i gi nates f r om the r i ght col on. The di agnosi s i s usual l y m ade on the
basi s of f i ndi ngs r ev eal ed by ur gent col onoscopy or by angi ogr aphy .
Ther apy w i th sel ecti v e angi ogr aphi c catheter i zati on i s successf ul i n
m any cases.
Ar ter i ov enous m al f or m ati ons (AVMs) or angi ody spl asi as i n the col on
ar e the second m ost com m on cause of m ajor l ow er GI bl eedi ng,
accounti ng f or appr ox i m atel y 20% of al l cases. These v ascul ar ectasi as
ar e l ocated just beneath the col um nar epi thel i um , and m ost ar e due to
the degener ati v e changes of agi ng. A
P. 176
causal associ ati on betw een aor ti c stenosi s and col oni c AVMs has been
pr oposed but not def i ni tel y establ i shed. AVMs ar e usual l y l ocated i n the
r i ght col on and m ay pr esent as ei ther an acute l ow er GI hem or r hage or
as chr oni c l ow v ol um e bl eedi ng m ani f ested by i r ondef i ci ency anem i a.
If the bl eedi ng i s br i sk and per si stent, angi ogr aphy i s usual l y the
pr ef er r ed m ethod f or m ak i ng the di agnosi s and car r y i ng out ther apy . If
the bl eedi ng has sl ow ed or stopped, ur gent col onoscopi c ther apy w i th
ther m al cauter i zati on or i njecti on i s of ten usef ul .
Less com m on causes of acute l ow er GI bl eedi ng ar e col oni c neopl asm s,
i nf l am m ator y bow el di sease, i nf ecti ous col i ti s, and i schem i c col i ti s.
Ischem i c col i ti s usual l y pr esents w i th acute, cr am py l ow er abdom i nal
pai n, the ur ge to def ecate, and passage of bl oody di ar r hea. â
€œWater shedâ€ ar eas of the col on, such as the spl eni c f l ex ur e and
si gm oi d col on, ar e m ost com m onl y i nv ol v ed because of thei r poor bl ood
f l ow .
Case
A 70y ear ol d w om an i s seen i n the em er gency r oom com pl ai ni ng of r ectal
bl eedi ng. Her f i r st epi sode occur r ed appr ox i m atel y 6 hour s ago, w hen she
passed r ed bl ood and cl ots. At f i r st she attr i buted the bl eedi ng to her
hem or r hoi ds, but she has had f i v e m or e epi sodes si nce, the l ast of w hi ch
w as accom pani ed by a sensati on of di zzi ness. She does not sm ok e or dr i nk
al cohol i c bev er ages. She tak es sev er al aspi r i n a day f or the tr eatm ent of
ar thr i ti s. Phy si cal ex am i nati on r ev eal s a w om an w ho i s pal e and anx i ous.
Her bl ood pr essur e and pul se i n the supi ne posi ti on ar e 110/70 m m Hg and
100 beats per m i nute, r especti v el y . When she stands, her bl ood pr essur e
and pul se ar e 85/50 m m Hg and 130 beats per m i nute, r especti v el y . The
abdom i nal ex am i nati on r ev eal s no abnor m al f i ndi ngs. Rectal ex am i nati on
r ev eal s r ed bl ood i n the v aul t and no m asses.
1. What ar e the thr ee m ost l i k el y causes of thi s w om an's hem atochezi a?
2. What di agnosti c and ther apeuti c m aneuv er s m ust y ou do w i thi n the
f i r st hour ?
3. What di agnosti c and ther apeuti c tests shoul d y ou consi der doi ng ov er
the nex t 24 to 48 hour s?
Case Discussion
1. What ar e the thr ee m ost l i k el y causes of thi s w om an's hem atochezi a?
Di v er ti cul osi s, col oni c AVMs, and upper GI bl eedi ng ar e the m ost l i k el y
causes of thi s w om an's bl eedi ng, w hi ch i s associ ated w i th hem ody nam i c
i nstabi l i ty . Hem or r hoi ds, i nf l am m ator y bow el di sease, and col oni c
neopl asm s r ar el y cause bl eedi ng of thi s degr ee.
2. What di agnosti c and ther apeuti c m aneuv er s m ust y ou do w i thi n the f i r st
hour ?
Thi s w om an ex hi bi ts si gni f i cant hem ody nam i c i nstabi l i ty , as

dem onstr ated by the or thostati c changes i n her bl ood pr essur e and
pul se. You m ust pl ace at l east tw o l ar gebor e (18gauge) IV catheter s
and star t IV v ol um e ex pansi on usi ng cr y stal l oi d f l ui d (usual l y , 0. 9%
sodi um chl or i de or an equi v al ent of l actated Ri nger 's sol uti on). At the
sam e ti m e, y ou shoul d dr aw bl ood f or ty pi ng and cr ossm atch studi es,
hem ogr am , coagul ati on studi es, and ser um chem i str y pr of i l e. N ex t, y ou
shoul d pl ace a nasogastr i c tube to obtai n gastr i c contents and
deter m i ne w hether
P. 177
ther e i s an upper GI bl eedi ng sour ce. The aspi r ati on of bl ood shoul d
pr om pt str ong consi der ati on f or per f or m i ng em er gency upper GI
endoscopy .
3. What di agnosti c and ther apeuti c tests shoul d y ou consi der doi ng ov er
the nex t 24 to 48 hour s?
If the bl eedi ng sl ow s or stops, r api d GI l av age w i th pol y ethy l ene gl y col
el ectr ol y te sol uti on f ol l ow ed by col onoscopy i s usual l y the best test f or
di agnosi s, w i th a y i el d of 40% to 50% i n thi s setti ng. Col onoscopy can
sti l l be usef ul i f the bl eedi ng i s per si stentl y br i sk ; how ev er , i n thi s
si tuati on, angi ogr aphy i s the pr ef er r ed test i n m any hospi tal s. If
col onoscopy and angi ogr aphy f ai l to i denti f y the sour ce of the bl eedi ng,
a 9 9 m Tcl abel ed er y thr ocy te scan m ay hel p l ocal i ze the sour ce.
Suggested Readings
El ta GH. Appr oach to the pati ent w i th gr oss gastr oi ntesti nal bl eedi ng. In:
Yam ada T, Al per s DH, Kapl ow i tz N , etal . eds. Tex tbook of
gastr oenter ol ogy , 4th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns,
2003:698.
Zuccar o G Jr . Am er i can Col l ege of Gastr oenter ol ogy . Pr acti ce

Par am eter s Com m i ttee. Managem ent of the adul t pati ent w i th acute
l ow er gastr oi ntesti nal bl eedi ng. Am J Gastr oenter ol 1998;93:1202.
Acute Upper Gastrointestinal Hemorrhage
1. Is m easur em ent of the hem ogl obi n concentr ati on and hem atocr i t the
best w ay to deter m i ne the sev er i ty of GI bl eedi ng? Why or w hy not?
2. Is esophagi ti s a com m on cause of sev er e upper GI bl eedi ng?
3. Is Î²adr enor eceptor bl ock ade a tr eatm ent opti on f or acute v ar i ceal
bl eedi ng? If so, w hy ? If not, w hat ar e som e tr eatm ent opti ons?
Discussion
1. Is m easur em ent of the hem ogl obi n concentr ati on and hem atocr i t the
best w ay to deter m i ne the sev er i ty of GI bl eedi ng? Why or w hy not?
N o. The best w ay to deter m i ne the sev er i ty of GI bl eedi ng i s to
m easur e the v i tal si gns w i th the pati ent i n the supi ne and standi ng
posi ti ons. If or thostati c changes i n the v i tal si gns (postur al
hy potensi on) occur i n the setti ng of GI bl eedi ng, they usual l y i ndi cate
at l east a 20% l oss i n the total bl ood v ol um e. Thi s f i ndi ng m andates
i m m edi ate IV v ol um e ex pansi on and pr epar ati on f or bl ood tr ansf usi on.
Other phy si cal f i ndi ngs associ ated w i th sev er e bl ood l oss ar e r esti ng
tachy car di a and hy potensi on, pal l or , and agi tati on.
The i ni ti al bl ood count (hem ogr am ) obtai ned f r om an acutel y bl eedi ng
pati ent i s a v er y poor r ef l ecti on of the am ount of bl ood l ost. To be
accur ate, the bl ood count m ust be obtai ned w hen the pati ent's
i ntr av ascul ar v ol um e i s nor m al . Af ter an acute l oss of bl ood,
r eequi l i br ati on m ay tak e up to 72 hour s. The IV adm i ni str ati on of
cr y stal l oi d hastens thi s pr ocess (of ten k now n as hem odi l uti on).
P. 178
Pl acem ent of a nasogastr i c tube i s v er y hel pf ul i n the i ni ti al
assessm ent of a pati ent w i th GI bl eedi ng, but the f i ndi ngs y i el ded can
be m i sl eadi ng. The absence of bl oody aspi r ate m ay suggest that
bl eedi ng has stopped f or the m om ent, y et the am ount of bl ood al r eady
l ost m ay be l i f e thr eateni ng. Conv er sel y , up to 15% of pati ents w i th an
acti v el y bl eedi ng upper GI sour ce m ay hav e a nonbl oody gastr i c
aspi r ate. The pr esence of bi l e i n the gastr i c aspi r ate of f er s som e
r eassur ance that an upper GI bl eed has stopped; how ev er , up to 50%
of phy si ci ans m i sjudge the pr esence or absence of a bi l i ous aspi r ate.
The per si stence of bl oody gastr i c aspi r ate i ndi cates si gni f i cant ongoi ng
bl eedi ng.
Mel ena i s pr oduced w hen hem ogl obi n i s degr aded by bacter i a i n the GI
tr act, and m ay or i gi nate f r om ei ther an upper or l ow er GI sour ce. The
i ngesti on of appr ox i m atel y 100 to 200 m L of bl ood i s enough to cause
m el ena; hence, the pr esence of m el ena al one does not necessar i l y
m ean the pati ent has had a substanti al l oss of bl ood. On the other
hand, f r equent epi sodes of m el ena i ndi cate si gni f i cant bl eedi ng.
Hem atochezi a r esul ti ng f r om an upper GI bl eedi ng sour ce i ndi cates
m assi v e bl eedi ng.
2. Is esophagi ti s a com m on cause of sev er e upper GI bl eedi ng?
N o. Esophagi ti s accounts onl y f or appr ox i m atel y 8% of al l cases of

upper GI bl eedi ng. It i s usual l y caused by gastr oesophageal r ef l ux of
aci d, but m ay al so be caused by i nf ecti ous agents such as Candi da
al bi cans, her pes si m pl ex v i r us, and cy tom egal ov i r us. Sev er e bl eedi ng
r esul ti ng f r om esophagi ti s i s r ar e and usual l y occur s i n the setti ng of
an al r eady hospi tal i zed and cr i ti cal l y i l l pati ent, especi al l y dur i ng
m echani cal r espi r ati on.
P e ptic ulc e r dis e a s e , w hi ch accounts f or 40% to 50% of al l the cases
of upper GI bl eedi ng, i s di scussed i n the nex t secti on.
Va ric e a l ble e ding accounts f or 10% to 30% of al l cases of upper GI

bl eedi ng. Var i ces ar e a com pl i cati on of por tal hy per tensi on, the cause
of w hi ch m ay be cl assi f i ed as pr ehepati c (por tal v ei n obstr ucti on),
hepati c (ci r r hosi s), or posthepati c (thr om bosi s of the hepati c v ei ns or
i nf er i or v ena cav a). The m ost com m on cause of por tal hy per tensi on i n
the U . S. popul ati on i s ethanol i nduced ci r r hosi s, al though hepati ti s Câ
€“associ ated ci r r hosi s i s an i ncr easi ngl y com m on cause. The 6w eek
m or tal i ty r ate associ ated w i th bl eedi ng v ar i ces i s appr ox i m atel y 40%,
and pati ents w i th v ar i ceal bl eedi ng shoul d be m anaged i n an i ntensi v e
car e uni t. These pati ents of ten hav e concur r ent m edi cal pr obl em s, such
as a coagul opathy and hepati c encephal opathy .
Ma lloryW e is s te a rs ar e par ti al thi ck ness m ucosal l acer ati ons near
the gastr oesophageal juncti on, usual l y caused by f or cef ul r etchi ng,
of ten i n the setti ng of ethanol i ngesti on. These tear s account f or
appr ox i m atel y 10% of upper GI hem or r hages. Most Mal l or y Wei ss tear s
stop bl eedi ng spontaneousl y . Per si stent bl eedi ng can be tr eated w i th
ei ther endoscopi c hem ostasi s or angi ogr aphi c em bol i zati on.
Si gni f i cant acute and chr oni c bl ood l oss, som eti m es l eadi ng to i r on
def i ci ency anem i a, can occur f r om gastr i c er osi ons or ul cer s associ ated
w i th l ar ge sl i di ng hi atal her ni as. These l esi ons, som eti m es cal l ed
Cam er on l esi ons, w hi ch ar e usual l y l ocated on the cr ests of m ucosal
f ol ds at or near the l ev el of
P. 179
the di aphr agm , seem to r esul t f r om the r i di ng m oti on of the her ni ated
stom ach i n and out of the chest dur i ng r espi r ati on.
3. Is Î²adr enor eceptor bl ock ade a tr eatm ent opti on f or acute v ar i ceal
bl eedi ng? If so, w hy ? If not, w hat ar e som e tr eatm ent opti ons?
N o. Î²Adr enor eceptor bl ock er s, such as pr opr anol ol , pr oduce a

negati v e chr onotr opi c and i notr opi c ef f ect. The use of such dr ugs i n an
acutel y bl eedi ng pati ent, w ho i s dependi ng on an adr ener gi c r esponse
to m ai ntai n an adequate bl ood pr essur e, i s ther ef or e contr ai ndi cated.
Som e ev i dence suppor ts the use of Î²adr enor eceptor bl ock er s i n
sel ected pati ents to r educe the r i sk of r ecur r ent v ar i ceal bl eedi ng af ter
the acute hem or r hage has been w el l contr ol l ed. Al though the com pl ete
m echani sm of acti on of these dr ugs i s y et to be del i neated, they ar e
thought to ex er t thei r benef i ci al ef f ect i n par t by l ow er i ng the por tal
pr essur e.
Other phar m acol ogi c appr oaches to the contr ol of acute v ar i ceal
bl eedi ng ar e the use of par enter al v asopr essi n or som atostati n.
Al though v asopr essi n has been com m onl y used, i ts ef f i cacy has not
been f i r m l y establ i shed and i t has associ ated car di ov ascul ar si de
ef f ects. The dr ug's m echani sm of acti on i s thought to be spl anchni c
ar ter i ol ar v asoconstr i cti on, r esul ti ng i n decr eased por tal pr essur e.
Incr easi ngl y , som atostati n or i ts l onger acti ng anal og, octr eoti de, has
becom e popul ar f or the contr ol of v ar i ceal bl eedi ng, and al so because
of i ts pur por ted l ow er i ng of por tal pr essur e. Som atostati n has been
show n to be as ef f ecti v e as, or m or e ef f ecti v e than, v asopr essi n i n
contr ol l i ng acute v ar i ceal hem or r hage.
Endoscopi c hem ostasi s can be achi ev ed by e ndos c opic inje c tion
s c le rothe ra py or e ndos c opic va ric e a l liga tion. The l atter i s now the
m or e popul ar techni que because i t i s as ef f ecti v e as scl er other apy and
consi der abl y saf er .
If endoscopi c techni ques ar e unav ai l abl e or unsuccessf ul , acute

hem ostasi s m ay be achi ev ed w i th bal l oon tam ponade dev i ces. Al though
the tam ponade accom pl i shed w i th dev i ces such as the Sengstak en
Bl ak em or e tube or the Mi nnesota tube i s ef f ecti v e i n appr ox i m atel y
40% to 90% of pati ents, the r ebl eedi ng r ate associ ated w i th thei r use
i s appr ox i m atel y 50%. Ther e i s al so an appr ox i m atel y 30% r ate of
ser i ous com pl i cati ons, such as aspi r ati on pneum oni a or esophageal
r uptur e, r esul ti ng f r om the use of these tubes; ther ef or e, thei r use i s
consi der ed a tem por ar y m easur e onl y .
Inter v enti onal r adi ol ogi c techni ques, such as the angi ogr aphi c
em bol i zati on of v ar i ces or the pl acem ent of a tr ansjugul ar i ntr ahepati c
por tosy stem i c stent shunt (TIPS), m ay al so be usef ul i f endoscopi c
hem ostasi s f ai l s or i s unav ai l abl e. The sur gi cal cr eati on of a
por tosy stem i c shunt i n an acutel y bl eedi ng pati ent i s associ ated w i th
m or tal i ty r ates of 50% to 80%, and has f al l en out of f av or .
Fur ther m or e, such shunts m ak e l i v er tr anspl antati on techni cal l y m or e
di f f i cul t.
Case
A 42y ear ol d m an i s br ought to the em er gency r oom by am bul ance af ter an
epi sode of hem atem esi s and sy ncope at a l ocal bar . He has not had pr ev i ous
GI bl eedi ng. He r egul ar l y tak es aspi r i n f or the r el i ef of chr oni c back pai n.
Dur i ng y our i nter v i ew , he passes sev er al l i qui d, m ar oon stool s. Phy si cal
ex am i nati on r ev eal s a supi ne bl ood pr essur e and pul se of 120/75 m m Hg
and 110 beats per m i nute, r especti v el y . When y ou m ak e hi m
P. 180
si t upr i ght he com pl ai ns of f eel i ng f ai nt and hi s sy stol i c pr essur e dr ops to
90 m m Hg by pal pati on. Hi s abdom en i s nontender and di stended. Shi f ti ng
dul l ness i s el i ci ted and the spl een ti p i s pal pabl e. The i ni ti al hem ogl obi n i s
15 g/dL and the hem atocr i t i s 45%.
1. How do y ou k now thi s m an has l ost a si gni f i cant am ount of bl ood?
2. What ar e the m ost l i k el y causes of thi s m an's upper GI bl eedi ng, and
w hat shoul d the nex t di agnosti c step be?
Case Discussion
1. How do y ou k now thi s m an has l ost a si gni f i cant am ount of bl ood?
He has si gni f i cant or thostati c changes i n hi s v i tal si gns, i ndi cati ng at
l east a 20% l oss of total bl ood v ol um e. The hem ogl obi n concentr ati on
or the hem atocr i t m ay be f al sel y r eassur i ng i n the setti ng of acute GI
bl eedi ng.
2. What ar e the m ost l i k el y causes of thi s m an's upper GI bl eedi ng, and
w hat shoul d the nex t di agnosti c step be?
The m ost l i k el y causes of such sev er e upper GI bl eedi ng ar e pepti c
ul cer di sease and esophageal or gastr i c v ar i ces, the l atter r esul ti ng
f r om por tal hy per tensi on. Thi s m an has r i sk f actor s f or both condi ti ons.
Ther e i s no w ay to di sti ngui sh one f r om the other based on the hi stor y
and ex am i nati on f i ndi ngs. Af ter hem ody nam i c stabi l i zati on, em er gency
esophagogastr oduodenoscopy (EGD) shoul d be per f or m ed f or di agnosi s
and, i f i ndi cated, to car r y out acute hem ostasi s.
Suggested Readings
Bar k un A, Bar dou M, Mar shal l JK. N onv ar i ceal U pper GI Bl eedi ng
Consensus Conf er ence Gr oup. Consensus r ecom m endati ons f or m anagi ng
pati ents w i th nonv ar i ceal upper gastr oi ntesti nal bl eedi ng. Ann Inter n Med
2003;139:843.
El ta GH. Appr oach to the pati ent w i th gr oss gastr oi ntesti nal bl eedi ng. In:
Yam ada T, Al per s DH, Kapl ow i tz N , etal . eds. Tex tbook of
gastr oenter ol ogy , 4th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns,
2003:698.
Peptic Ulcer Disease
1. What ar e the m ajor r i sk f actor s f or the dev el opm ent of pepti c ul cer s?
2. Is di etar y adher ence to bl and m eal s and m i l k an accepted tr eatm ent of
pepti c ul cer di sease? If not, w hat shoul d the tr eatm ent be?
Discussion
1. What ar e the m ajor r i sk f actor s f or the dev el opm ent of pepti c ul cer s?
The m ajor r i sk f actor s f or the dev el opm ent of pepti c ul cer di sease ar e
ci gar ette sm ok i ng, the i ngesti on of nonster oi dal anti i nf l am m ator y dr ugs
(N SAIDs), and a f am i l y hi stor y of pepti c ul cer . Pepti c ul cer s ar e
thought to f or m
P. 181
w hen the ef f ects of gastr i c aci d and pepsi n ov er w hel m the pr otecti v e
m ucosal bar r i er . Di seases such as the Zol l i nger El l i son sy ndr om e
i ncr ease the secr eti on of gastr i c aci d. Other f actor s pr om ote the
br eak dow n of the m ucosal bar r i er .
U l cer s ar e tw i ce as l i k el y to dev el op i n ci gar ette sm ok er s than i n

nonsm ok er s. In addi ti on, ul cer s heal m or e sl ow l y and ar e m or e l i k el y
to r ecur i n sm ok er s. The m echani sm r esponsi bl e f or ci gar ette sm ok e's
ul cer ogeni c ef f ect i s not com pl etel y under stood. N SAIDs di sr upt the
m ucusâ€“bi car bonate bar r i er , al l ow i ng aci d to dam age the under l y i ng
m ucosa. The GI com pl i cati ons of N SAIDs ar e a m ajor cause of upper GI
bl eedi ng and per f or ati on, par ti cul ar l y i n el der l y w om en, and ar e
r esponsi bl e f or a tw o to thr eef ol d i ncr eased m or tal i ty r i sk i n l ong
ter m user s of N SAIDs. The com bi ned use of N SAIDs and cor ti coster oi ds
appear s to i ncr ease the r i sk ev en f ur ther .
Peopl e w ho hav e f i r stdegr ee r el ati v es w i th pepti c ul cer s hav e thr ee
ti m es the r i sk of acqui r i ng ul cer s com par ed w i th the gener al
popul ati on. The r i sk i s ev en hi gher f or the i denti cal tw i n of a pati ent
w i th ul cer di sease.
Inf ecti on of the gastr i c m ucosa by Hel i cobacter py l or i i s str ongl y
associ ated w i th l ow er r ates of duodenal ul cer heal i ng and w i th hi gher
r ates of ul cer r ecur r ence. The ex act m anner i n w hi ch H. py l or i i nf ecti on
pr om otes ul cer s i s not k now n.
N o concl usi v e ev i dence l i nk s di etar y substances, i ncl udi ng ethanol ,

caf f ei ne, and spi cy f oods, w i th the dev el opm ent of pepti c ul cer s.
Si m i l ar l y , al though a cr i ti cal l y i l l hospi tal i zed pati ent m ay hav e str ess
ul cer s, env i r onm ental str essor s at hom e or at w or k hav e not been
concl usi v el y l i nk ed w i th the dev el opm ent of pepti c ul cer s.
2. Is di etar y adher ence to bl and m eal s and m i l k an accepted tr eatm ent of
pepti c ul cer di sease? If not, w hat shoul d the tr eatm ent be?
N o. Bef or e the adv ent of m oder n phar m acol ogi c ther apy , the tr eatm ent
of ul cer di sease w i th f r equent bl and m eal s and m i l k w as w i del y
accepted. U nf or tunatel y , such tr eatm ent actual l y i ncr eases the
pr oducti on of gastr i c aci d and does not accel er ate ul cer heal i ng.
H 2 r eceptor antagoni sts, of w hi ch ci m eti di ne w as the f i r st agent
r el eased f or use, ar e w i del y accepted as saf e and ef f ecti v e f or the
tr eatm ent of pepti c ul cer s. These agents di r ectl y i nhi bi t hi stam i ne
sti m ul ated gastr i c aci d secr eti on and i ndi r ectl y i nhi bi t the hi stam i ne
potenti ated, gastr i nsti m ul ated aci d secr eti on. When gi v en i n suf f i ci ent
doses, the v ar i ous H 2 r eceptor antagoni sts act equal l y w el l , w i th
duodenal ul cer heal i ng r ates of 75% af ter 4 w eek s, and 85% to 95%
af ter 8 w eek s of ther apy . The sel ecti on of a par ti cul ar agent shoul d be
deter m i ned by the pati ent's abi l i ty to com pl y w i th the dosi ng r egi m en,
as w el l as the cost per dose.
Pr oton pum p i nhi bi tor s, such as om epr azol e, and esom epr azol e, ar e
concentr ated i n the hi ghl y aci di c env i r onm ent of the par i etal cel l
secr etor y canal i cul i . When acti v ated by pr otonati on, these agents
cov al entl y bi nd to H + /K + ATPase, ther eby causi ng i r r ev er si bl e
i nhi bi ti on of the enzy m e and a 90% to 99% suppr essi on of gastr i c aci d
pr oducti on w i thi n 24 hour s. At doses of 20 to 40 m g per day ,
om epr azol e achi ev es m or e r api d pai n r el i ef
P. 182
and f aster heal i ng of pepti c ul cer s than do standar d doses of H 2
r eceptor antagoni sts. Pr oton pum p i nhi bi tor s ar e the tr eatm ent of
choi ce f or pati ents w i th nonsur gi cal l y cor r ectabl e Zol l i nger El l i son
sy ndr om e. These agents hav e di spl ay ed an ex cel l ent shor tter m saf ety
pr of i l e, and, w i th i ncr easi ng use, thei r l ongter m r i sk seem s l ess than
i ni ti al l y f ear ed.
Sucr al f ate i s an al um i num sal t of sul f ated sucr ose. When pl aced i n an
aci di c env i r onm ent, i t bi nds tenaci ousl y to ul cer s and pr om otes
heal i ng. It has no ef f ect on aci d secr eti on and has m i ni m al aci d
neutr al i zi ng ef f ects. The enti r e m echani sm of sucr al f ate's benef i ci al
acti ons has not been deter m i ned. Sucr al f ate appear s to be as ef f ecti v e
as H 2 r eceptor antagoni sts i n pr om oti ng the heal i ng of acute pepti c
ul cer s. Its sy stem i c absor pti on i s m i ni m al , al though i ts l ongter m
ef f ects on al um i num deposi ti on ar e unk now n. Its pr i m ar y si de ef f ect i s
doser el ated consti pati on.
Antaci ds ar e al so ef f ecti v e i n pr om oti ng the heal i ng of gastr i c and
duodenal ul cer s. Fr equent dosi ng i s usual l y r equi r ed to achi ev e
ef f ecti v eness equal to that of H 2 r eceptor antagoni sts. Such a dosi ng
schedul e of ten r esul ts i n poor pati ent com pl i ance, not to m enti on the
si de ef f ect of di ar r hea associ ated w i th the use of m agnesi um
contai ni ng antaci ds.
Ther e i s no ev i dence to suppor t the use of these agents i n v ar i ous
com bi nati ons f or the pr i m ar y tr eatm ent of pepti c ul cer s. Com bi nati on
ther apy w i th anti bi oti cs, aci dsuppr essi v e m edi cati ons, and bi sm uth
com pounds i s ef f ecti v e i n heal i ng duodenal ul cer s associ ated w i th H.
py l or i i nf ecti on, and i n pr ev enti ng the r ecur r ence of such ul cer s.
Case
A 50y ear ol d m an has had r ecur r ent and at ti m es sev er e epi gastr i c
abdom i nal pai n f or the l ast sev er al y ear s. Antaci ds hav e gi v en hi m
sy m ptom ati c r el i ef . The m ost r ecent epi sode began 1 w eek ago and has not
r esponded com pl etel y to antaci ds. The pai n now w ak es hi m up at ni ght. He
sm ok es one pack of ci gar ettes per day , and he tak es aspi r i n sev er al ti m es a
w eek . Hi s f am i l y hi stor y i s unr em ar k abl e. Phy si cal ex am i nati on r ev eal s
m oder ate epi gastr i c tender ness w i thout ev i dence of a m ass. The stool i s
br ow n and posi ti v e f or occul t bl ood.
1. What ar e thi s m an's r i sk f actor s f or pepti c ul cer di sease?

2. What di agnosti c tests shoul d y ou consi der ?
3. When w oul d y ou consi der tr eatm ent f or H. py l or i ?
Case Discussion
1. What ar e thi s m an's r i sk f actor s f or pepti c ul cer di sease?
Hi s sm ok i ng and N SAID i ngesti on ar e both r i sk f actor s f or pepti c ul cer

di sease.
2. What di agnosti c tests shoul d y ou consi der ?
If the pati ent w er e y ounger than 40 y ear s, had onl y m i l d and
i nter m i ttent sy m ptom s, and had no ev i dence of sy stem i c di sease or
r i sk f actor s f or m al i gnancy , a tr i al of em pi r i c anti ul cer ther apy
w i thout pr i or di agnosti c tests w oul d be acceptabl e. Other w i se, ei ther
EGD or a doubl econtr ast upper GI r adi ogr aphi c ser i es i s r ecom m ended.
When ther e i s a possi bi l i ty of m al i gnancy and i f bi opsy speci m ens
P. 183
ar e needed, EGD i s consi der ed super i or to r adi ogr aphy f or the pur pose
of di agnosi s. Because the m an descr i bed i s ol der than 40 y ear s,
sm ok es ci gar ettes, has occul t bl ood i n the stool , and i s hav i ng
i ncr easi ngl y sev er e pai n, a di agnosti c w or k up (pr ef er abl y EGD) r ather
than em pi r i c ther apy i s r ecom m ended.
3. When w oul d y ou consi der tr eatm ent f or H. py l or i ?
Er adi cati on of H. py l or i i s usual l y adv ocated w hen associ ated w i th

duodenal ul cer , and r esul ts i n a dr am ati c r educti on i n ul cer r ecur r ence.
Inf ecti on can be dem onstr ated by endoscopi c bi opsy , ser ol ogy , or
r adi oi sotope br eath test f i ndi ngs. A m ul ti pl edr ug r egi m en i s r equi r ed
f or r el i abl e er adi cati on of the or gani sm s. A com m onl y used
com bi nati on has been that of a bi sm uthcontai ni ng com pound,
tetr acy cl i ne, m etr oni dazol e, and ei ther a pr oton pum p i nhi bi tor or H 2
r eceptor antagoni st. Better pati ent com pl i ance and equal ef f i cacy hav e
been r epor ted w i th com bi nati ons of cl ar i thr om y ci n, am ox i ci l l i n,
bi sm uth, and a pr oton pum p i nhi bi tor or H 2 r eceptor antagoni st.
Suggested Readings
Del Val l e J, Chey WD, Schei m an JM. Aci d pepti c di sor der s. In: Yam ada T,
Al per s DH, Kapl ow i tz N , etal . eds. Tex tbook of gastr oenter ol ogy , 4th ed.
Spechl er SJ. Pepti c ul cer and i ts com pl i cati ons. In: Fel dm an M, Fr i edm an
LS, Sl ei senger MH, eds. Sl ei senger and For dtr an's gastr oi ntesti nal and
l i v er di sease: pathophy si ol ogy , di agnosi s, m anagem ent, 7th ed.
Phi l adel phi a: WB Saunder s, 2002:747.
Gallstone Disease
1. Whi ch gr oup of peopl e has the hi ghest k now n pr ev al ence of gal l stones?
2. What ar e the di f f er ent ty pes of gal l stones, and how do they f or m ?
3. Shoul d al l pati ents w i th gal l stones under go chol ecy stectom y ?
4. What ar e the com m on sy m ptom s of gal l stone di sease, and w hat
per centage of pati ents w i th asy m ptom ati c gal l stones ev entual l y
ex hi bi ts sy m ptom s?
5. What i s the best i m agi ng techni que to dem onstr ate chol el i thi asi s?
6. What tr eatm ent of sy m ptom ati c chol el i thi asi s i s the standar d agai nst
w hi ch other tr eatm ents ar e com par ed?
Discussion
1. Whi ch gr oup of peopl e has the hi ghest k now n pr ev al ence of gal l stones?
Ex am i nati on of autopsy f i ndi ngs hav e r ev eal ed that the hi ghest k now n
pr ev al ence of gal l stones i s i n the N or th Am er i can Pi m a Indi ans:
appr ox i m atel y 60% f or w om en and 25% f or m en. The popul ati on of
Thai l and has one of the l ow est k now n pr ev al ences: appr ox i m atel y 5%
f or w om en and 3% f or m en. The pr ev al ence r ate f or w hi tes i n the
U ni ted States and i n nor thcentr al Eur ope i s appr ox i m atel y 30% f or
w om en and 15% f or m en.
P. 184
The com posi ti on of gal l stones v ar i es w i del y f r om popul ati on to
popul ati on. The w hi te popul ati on of the U ni ted States tends to hav e
gal l stones consi sti ng l ar gel y of chol ester ol , w her eas the Asi an
popul ati on tends to hav e br ow n, cal ci um bi l i r ubi nate stones.
The w i despr ead v ar i ati on i n gal l stone pr ev al ence r ates, the v ar i ati on i n
gal l stone com posi ti on am ong ethni c popul ati ons, and the gener al
f em al etom al e r ati o of appr ox i m atel y 2:1 al l str ongl y i m pl i cate both
her edi tar y and env i r onm ental f actor s i n the eti ol ogy of gal l stone
di sease.
2. What ar e the di f f er ent ty pes of gal l stones, and how do they f or m ?
Ther e ar e thr ee ty pes of gal l stones: chol ester ol , br ow n pi gm ent, and
bl ack pi gm ent. Chol ester ol gal l stones ar e com posed pr i m ar i l y of
chol ester ol m onohy dr ate cr y stal s m i x ed w i th m uci n gl y copr otei n. Br ow n
pi gm ent gal l stones, w hi ch ar e associ ated w i th bacter i al i nf ecti on of the
bi l i ar y tr ee and usual l y f or m i n the bi l e ducts, ar e com posed pr i m ar i l y
of cal ci um bi l i r ubi nate. Bl ack pi gm ent gal l stones f or m i n the gal l
bl adder and ar e associ ated w i th chr oni c hem ol y si s, adv anci ng age,
l ongter m par enter al nutr i ti on and ci r r hosi s; these stones ar e
com posed pr i m ar i l y of an i nsol ubl e bi l i r ubi n pi gm ent pol y m er .
The f or m ati on of gal l stones depends on the i nter pl ay of thr ee f actor s:
the pr oducti on of l i thogeni c bi l e, gal l bl adder m oti l i ty , and the
nucl eati on of gal l stones. Condi ti ons that f oster i ncr eased bi l i ar y
chol ester ol secr eti on, such as obesi ty , r educed bi l e aci d secr eti on (as
i n ter m i nal i l eal Cr ohn's di sease), and i ncr eased bi l i r ubi n pr oducti on
(as i n si ck l e cel l hem ogl obi nopathy ), m ay al l cause the pr oducti on of
l i thogeni c bi l e. Bi l i ar y stasi s, such as that associ ated w i th pr ol onged
total par enter al nutr i ti on, al so pr om otes gal l stone f or m ati on.
Decr eased bi l i ar y i m m unogl obul i n A (IgA) secr eti on, such as that f ound
i n m any Asi ans, m ay al l ow the gr ow th of bacter i a that pr oduce Î²
gl ucur oni dase; the r esul ti ng hy dr ol y si s of conjugated bi l i r ubi n pr om otes
the pr eci pi tati on of cal ci um bi l i r ubi nate. These cal ci um sal ts m ay then
f or m the nucl ei f or gal l stones.
3. Shoul d al l pati ents w i th gal l stones under go chol ecy stectom y ?
N o. Most pati ents w i th gal l stones r em ai n asy m ptom ati c, and those w ho
do becom e sy m ptom ati c ar e not at i ncr eased r i sk of death f r om ei ther
the di sease or the sur ger y . Thi s i s al so tr ue f or pati ents w i th
concur r ent di abetes m el l i tus. Ther ef or e, pr ophy l acti c chol ecy stectom y
i s not r ecom m ended f or m ost asy m ptom ati c pati ents, i ncl udi ng those
w i th di abetes m el l i tus. How ev er , pr ophy l acti c chol ecy stectom y f or
asy m ptom ati c gal l stones i s r ecom m ended f or cer tai n gr oups w ho f ace a
hi gh r i sk of m or bi di ty . The r i sk of gal l bl adder cancer i s hi gh i n N ati v e
Am er i cans w i th chol el i thi asi s. Sy m ptom s dev el op i n near l y al l chi l dr en
w ho hav e chol el i thi asi s. The l i k el i hood of com pl i cati ons af ter
em er gency chol ecy stectom y i s i ncr eased i n pati ents w i th si ck l e cel l
hem ogl obi nopathy .
Pati ents w i th asy m ptom ati c stones i n the com m on bi l e duct
(chol edochol i thi asi s) ex per i ence a m or e m or bi d cour se; i n 50% of
pati ents w i th chol edochol i thi asi s f ound postm or tem , these ductal stones
contr i buted to thei r death. Ther ef or e, such stones shoul d be r em ov ed
ei ther sur gi cal l y or by ERCP.
P. 185
4. What ar e the com m on sy m ptom s of gal l stone di sease, and w hat
per centage of pati ents w i th asy m ptom ati c gal l stones ev entual l y ex hi bi t
sy m ptom s?
Onl y 10% to 20% of the peopl e w i th asy m ptom ati c gal l stones
ev entual l y ex hi bi t sy m ptom s. The onset of sy m ptom s m ost com m onl y
consi sts of r ecur r ent bi l i ar y pai n due to a stone i n the cy sti c duct. Thi s
pai n star ts usual l y i n the r i ght upper quadr ant or epi gastr i um and m ay
r adi ate to the back or r i ght shoul der . Bi l i ar y pai n ty pi cal l y i s gr adual i n
onset and l asts sev er al hour s. Contr ar y to com m on bel i ef , ther e i s no
par ti cul ar tem por al r el ati onshi p to f ood i ntak e or di et.
Per si stent bl ock age of the cy sti c duct r esul ts i n acute i nf l am m ati on of
the gal l bl adder , or acute chol ecy sti ti s. Pati ents w i th acute chol ecy sti ti s
usual l y ex per i ence nausea, v om i ti ng, and f ev er , and they com pl ai n of
sev er e r i ght upper quadr ant pai n. El i ci tati on of r i ght upper quadr ant
abdom i nal tender ness i n com bi nati on w i th l euk ocy tosi s i s al so hi ghl y
suggesti v e of acute chol ecy sti ti s. The def i ni ti v e tr eatm ent i s
chol ecy stectom y .
Obstr ucti on of the com m on bi l e duct by a gal l stone m ay r esul t i n
chol angi ti s. Char cot's tr i ad of sy m ptom s (f ev er , chi l l s, and jaundi ce) i s
ex hi bi ted by onl y 50% to 75% of pati ents w i th acute chol angi ti s. Most
pati ents r espond r api dl y to appr opr i ate anti bi oti c ther apy ; how ev er ,
def i ni ti v e tr eatm ent consi sts of decom pr essi on of the bi l e duct by
ERCP, per cutaneous dr ai nage, or bi l i ar y sur ger y .
Acute bi l i ar y pancr eati ti s m ay r esul t f r om a com m on bi l e duct stone

that i s tr ansi entl y bl ock i ng the pancr eati c duct w i thi n the am pul l a of
Vater . U r gent ERCP w i th endoscopi c sphi ncter otom y shoul d be
consi der ed f or these pati ents.
5. What i s the best i m agi ng techni que to dem onstr ate chol el i thi asi s?
U l tr asonogr aphy i s the best i ni ti al m ethod f or dem onstr ati ng

chol el i thi asi s because i t has 90% to 95% sensi ti v i ty and 95%
speci f i ci ty . Al so, i t i s noni nv asi v e and unencum ber ed by m any techni cal
l i m i tati ons. Its m ai n uti l i ty i s i n the dem onstr ati on of gal l stones,
al though i t i s capabl e of detecti ng som e addi ti onal f i ndi ngs, such as
per i chol ecy sti c f l ui d, thi ck eni ng of the gal l bl adder w al l , and di stenti on
of the gal l bl adder , w hi ch ar e ev i dence of acti v e i nf l am m ati on.
U l tr asonogr aphy can of ten r ev eal ductal di l atati on or com m on bi l e duct
stones, but f ai l ur e to do so does not r ul e out chol edochol i thi asi s.
Bef or e ul tr asonogr aphy becam e av ai l abl e, or al chol ecy stogr aphy w as

the test of choi ce f or i denti f y i ng gal l stones. How ev er , thi s pr ocedur e
tak es sev er al hour s to per f or m , i s not ef f ecti v e w hen the bi l i r ubi n l ev el
ex ceeds 2. 0 m g/dL, and can be m ade unr el i abl e by v om i ti ng and
di ar r hea. Thi s techni que m ay be usef ul i f ther e i s a str ong cl i ni cal
suspi ci on of chol el i thi asi s but the ul tr asonogr aphi c f i ndi ngs ar e
equi v ocal .
Hepatobi l i ar y sci nti gr aphy i s pr i m ar i l y used to assi st i n establ i shi ng the
di agnosi s of acute chol ecy sti ti s. If the r adi oacti v e tr acer does not
i m age the gal l bl adder , obstr ucti on of the cy sti c duct i s hi ghl y l i k el y ;
how ev er , thi s techni que cannot i denti f y stones w i thi n the gal l bl adder .
P. 186
ERCP i s the best techni que f or di agnosi ng com m on bi l e duct stones, but
i t i s f ar l ess sensi ti v e i n detecti ng stones i n the gal l bl adder than
ul tr asonogr aphy or or al chol ecy stogr aphy . Magneti c r esonance
chol angi opancr eatogr aphy (MRCP) i s i ncr easi ngl y r ecogni zed as an
accur ate, noni nv asi v e m eans of v i sual i zi ng the bi l e ducts and
pancr eati c ducts.
In gener al , CT scanni ng v i sual i zes gal l stones poor l y and adds l i ttl e
i nf or m ati on i n the ov er al l ef f or t to di agnose gal l stone di sease.
6. What tr eatm ent f or sy m ptom ati c chol el i thi asi s i s the standar d agai nst
w hi ch other tr eatm ents ar e com par ed?
Open chol ecy stectom y has been the standar d tr eatm ent of sy m ptom ati c
gal l stone di sease. In a pati ent y ounger than 50 y ear s w ho i s f r ee of
com pl i cati ng f actor s, the m or tal i ty r ate associ ated w i th el ecti v e open
chol ecy stectom y i s l ess than 1%. The pati ent i s usual l y hospi tal i zed f or
appr ox i m atel y 5 day s and r em ai ns on m edi cal di sabi l i ty l eav e f or an
addi ti onal 4 to 6 w eek s.
Incr easi ngl y , l apar oscopi c chol ecy stectom y has becom e the pr ef er r ed
tr eatm ent of sy m ptom ati c gal l stone di sease i n m ost pati ents. Al though
thi s m ethod has a sl i ghtl y hi gher r ate of com m on bi l e duct i njur y ,
pati ents w ho under go thi s usual l y r equi r e a shor ter hospi tal stay and
l ess ti m e of f f r om w or k than those w ho under go open chol ecy stectom y .
The di ssol uti on of gal l stones thr ough the or al adm i ni str ati on of bi l e
aci ds, such as ur sodeox y chol i c aci d (ur sodi ol ), i s r eser v ed f or those
pati ents w ho ar e ei ther unabl e or unw i l l i ng to under go sur ger y . Thi s
ther apy i s m ost ef f ecti v e f or those 15% of pati ents w i th chol el i thi asi s
w ho hav e sm al l chol ester ol gal l stones f l oati ng i n a f uncti onal
gal l bl adder . Af ter the 6 to 12 m onths of ther apy i s com pl eted, the
r ecur r ence r ate of gal l stones i s appr ox i m atel y 50% at 5 y ear s.
Case
A 54y ear ol d Hi spani c w om an pr esents to the em er gency r oom com pl ai ni ng
of constant, sev er e r i ght upper quadr ant pai n r adi ati ng to her r i ght scapul a
that has l asted f or appr ox i m atel y 6 hour s. She has v om i ted tw i ce w i thout
r el i ef of the pai n. She ex per i enced tw o si m i l ar , but l ess sev er e, epi sodes of
such pai n sev er al w eek s ago, f or w hi ch she di d not seek m edi cal car e. She
does not hav e any chr oni c i l l ness. Ex am i nati on r ev eal s a m oder atel y obese
w om an w i th a tem per atur e of 38Â°C (100. 4Â°F). Her scl er ae ar e sl i ghtl y
i cter i c. She ex hi bi ts abdom i nal guar di ng, w i th m oder ate r i ght upper
quadr ant tender ness on pal pati on, hal ti ng of i nspi r ati on dur i ng pal pati on,
and nor m al bow el sounds. The w hi te bl ood cel l count i s 14, 000 cel l s/m m 3 ,
and the al k al i ne phosphatase l ev el i s el ev ated at 200 IU /L. The total
bi l i r ubi n l ev el i s 4 m g/dL. The ser um am i notr ansf er ase v al ues ar e nor m al .

2. What i m agi ng study shoul d be per f or m ed?
3. How shoul d y ou m anage thi s pati ent's condi ti on?
P. 187
Case Discussion
The m ost l i k el y di agnosi s i s acute chol ecy sti ti s associ ated w i th

chol edochol i thi asi s and obstr ucti on of the com m on bi l e duct by a
gal l stone. Thi s w om an's pr ev i ous sy m ptom s, w hi ch ar e consi stent w i th
r ecur r ent bi l i ar y pai n, suggest gal l stone di sease. The m or e sev er e
sy m ptom s she now has, w hi ch ar e associ ated w i th a l euk ocy tosi s, r i ght
upper quadr ant abdom i nal tender ness and i nspi r ator y ar r est w i th
pal pati on i n the r i ght upper quadr ant (Mur phy 's si gn), suggest acute
chol ecy sti ti s. The el ev ated al k al i ne phosphatase and total bi l i r ubi n
l ev el s ar e ev i dence that the com m on bi l e duct i s obstr ucted. (The total
bi l i r ubi n l ev el r ar el y r i ses abov e 3 m g/dL i n chol ecy sti ti s al one. )
2. What i m agi ng study shoul d be per f or m ed?
Abdom i nal ul tr asonogr aphy shoul d be per f or m ed r outi nel y i n pati ents
suspected of hav i ng gal l stone di sease. In thi s pati ent, the ty pi cal
pr esentati on, w hi ch poi nts tow ar d acute chol ecy sti ti s and chol el i thi asi s,
m ak es addi ti onal i m agi ng studi es unnecessar y . If the ul tr asonogr am
f ai l s to dem onstr ate stones, a hepatobi l i ar y sci nti gr am coul d assi st i n
m ak i ng the di agnosi s.
3. How shoul d y ou m anage thi s pati ent's condi ti on?
Ini ti al m anagem ent shoul d consi st of the IV adm i ni str ati on of f l ui ds and
anti bi oti c cov er age f or gr am negati v e or gani sm s, together w i th
nasogastr i c sucti on. Chol ecy stectom y shoul d be per f or m ed soon af ter
the pati ent's condi ti on has stabi l i zed; a del ay i n sur ger y i s associ ated
w i th hi gher m or bi di ty r ates. If open chol ecy stectom y i s per f or m ed, an
ex pl or ati on of the com m on bi l e duct shoul d be str ongl y consi der ed. If
the l apar oscopi c m ethod i s chosen, pr eoper ati v e ERCP shoul d be
per f or m ed to r em ov e the stone i n the com m on bi l e duct. If the
pati ent's condi ti on does not i m pr ov e r api dl y and she sti l l has
obstr ucti v e jaundi ce, an ur gent ERCP shoul d be per f or m ed to
decom pr ess the bi l i ar y sy stem .
Suggested Readings
Lee SP, Ko CW. Gal l stones. In: Yam ada T, Al per s DH, Kapl ow i tz N , etal .
eds. Tex tbook of gastr oenter ol ogy , 4th ed. Phi l adel phi a: Li ppi ncott
Pom posel l i J, Jenk i ns RL. Sur gi cal appr oaches to di seases of the bi l i ar y
sy stem . In: Schi f f ER, Sor r el l MF, Maddr ey WC, eds. Schi f f 's di seases of
the l i v er , 9th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:713.
Acute Hepatocellular Disease
1. What ar e the m ajor si gns and sy m ptom s of acute hepatocel l ul ar i njur y ,
and w hi ch ar e speci f i c to a par ti cul ar pr ocess?
P. 188
2. At w hat ser um bi l i r ubi n l ev el i s jaundi ce detectabl e, and w hat ar e the
m ai n deter m i nants of the ser um bi l i r ubi n concentr ati on?
3. What ar e the f our gener al causes of acute l i v er i njur y ?
4. What ar e the f eatur es of v i r al hepati ti s A, B, C, D, and E?
5. Match the f ol l ow i ng ser ol ogi c r esul ts w i th the m ost l i k el y cl i ni cal state.
a . HBsAg, anti HBs+ , anti 1. Acute hepati ti s B

HBc+
b. HBsAg, anti HBs+ , anti HBc 2. Acute hepati ti s A
c . HBsAg+ , IgM anti HBc+ 3. Pr i or HBV i nf ecti on, now

i m m une
d. HBsAg+ , IgM anti HBc 4. Pr i or HAV i nf ecti on, now

i m m une
e . Anti HAV(total )+ , IgM anti 5. Hepati ti s B chr oni c car r i er

HAV
f. Anti HAV(total )+ , IgM anti 6. Recei v ed hepati ti s B v acci ne

HAV+
HBsAg, hepati ti s B sur f ace anti gen; anti HBs, anti body to hepati ti s B
sur f ace anti gen; anti HBc, anti body to hepati ti s B cor e anti gen; anti
HAV, anti bodi es to hepati ti s A anti gens [total and i m m unogl obul i n M
(IgM) cl ass];, negati v e; + , posi ti v e; HBV, hepati ti s B v i r us; HAV,
hepati ti s A v i r us.
6. Whi ch hepati c enzy m e patter n suggests the pr esence of al cohol i c l i v er
di sease?
7. What ar e the cl i ni cal and l abor ator y f i ndi ngs char acter i sti c of i schem i c
l i v er i njur y ?
8. What i s f ul m i nant hepati c f ai l ur e?
Discussion
1. What ar e the m ajor si gns and sy m ptom s of acute hepatocel l ul ar i njur y ,
and w hi ch ar e speci f i c to a par ti cul ar pr ocess?
The ty pi cal sy m ptom s of acute hepati ti s i ncl ude m al ai se, f ati gue,
anor ex i a, nausea, dar k ur i ne, abdom i nal pai n, headache, f ev er ,
m y al gi a, and ar thr al gi a. Si gns i ncl ude jaundi ce, scl er al i cter us,
hepatom egal y , tender l i v er , spl enom egal y , and r ash. In gener al , these
f eatur es ar e nonspeci f i c and do not hel p i n i denti f y i ng the cause of
l i v er i njur y .
2. At w hat ser um bi l i r ubi n l ev el i s jaundi ce detectabl e, and w hat ar e the
m ai n deter m i nants of the ser um bi l i r ubi n concentr ati on?
A ser um bi l i r ubi n l ev el i n the r ange of 2. 5 to 3. 0 m g/dL usual l y

pr oduces detectabl e scl er al i cter us. The ser um bi l i r ubi n concentr ati on
i s deter m i ned by the r ates of bi l i r ubi n pr oducti on (r esul ti ng f r om the
catabol i sm of hem ogl obi n and other hem econtai ni ng enzy m es) and
el i m i nati on (i ncl udi ng ex cr eti on i nto bi l e and the r enal ex cr eti on of
conjugated bi l i r ubi n). As a r esul t, hem ol y si s and changes i n r enal
f uncti on can consi der abl y al ter the ser um bi l i r ubi n concentr ati on.
3. What ar e the f our gener al causes of acute l i v er i njur y ?
Ex pos ure to tox ins i s a com m on cause of acute l i v er i njur y . Such
tox i ns i ncl ude ethanol , acetam i nophen, hal ogenated hy dr ocar bons, and
the tox i n f r om
P. 189
the m ushr oom Am ani ta phal l oi des. Infe c tions can al so cause acute
l i v er i njur y . The m ost com m on i nf ecti ons ar e those caused by hepati ti s
v i r uses A, B, C, D, and E, but par asi tes, bacter i a, and f ungi al so can
cause i nf ecti ous hepati ti s. Hepati c i njur y can al so stem f r om is c he mia ;
thi s i s usual l y a r esul t of sev er e sy stem i c hy potensi on or congesti v e
hear t f ai l ur e. Other sour ces of acute l i v er i njur y ar e the v ar i ous
me ta bolic dis orde rs such as Wi l son's di sease and Rey e's sy ndr om e.
4. What ar e the f eatur es of v i r al hepati ti s A, B, C, D, and E?
He pa titis A i s caused by an RN A enter ov i r us that i s usual l y tr ansm i tted
by f ecal â€“or al contam i nati on. The hepati ti s A v i r us i s pr esent i n the
stool f or appr ox i m atel y 2 w eek s af ter i nf ecti on, but sy m ptom s do not
appear unti l appr ox i m atel y 4 w eek s af ter i nf ecti on. Thi s per i od of
asy m ptom ati c i nf ecti v i ty i s par ti al l y r esponsi bl e f or the occasi onal
outbr eak s of hepati ti s A spr ead by an unsuspecti ng f ood handl er at a
r estaur ant, or by chi l dr en at a day car e center . Sy m ptom s usual l y
consi st of nausea, v om i ti ng, jaundi ce, and m al ai se, al though the enti r e
cour se of the di sease m ay be subcl i ni cal , especi al l y i n chi l dr en.
Pr ogr essi on to f ul m i nant hepati c f ai l ur e i s v er y r ar e, and f ul l r ecov er y
i s ex pected af ter 3 w eek s of sy m ptom s. The best ser ol ogi c test f or
conf i r m i ng acute v i r al hepati ti s A i s the IgM anti HAV deter m i nati on,
w hi ch shoul d be posi ti v e at the onset of sy m ptom s. The pr esence of
IgG anti HAV i m pl i es that the per son had hepati ti s A i n the past and i s
i m m une. Suscepti bl e peopl e shoul d be passi v el y i m m uni zed w i th hum an
i m m une ser um gl obul i n w i thi n 2 w eek s of ex posur e to the hepati ti s A
v i r us. Acti v e pr ophy l ax i s agai nst hepati ti s A f or cer tai n hi ghr i sk
popul ati ons and pati ents w i th chr oni c l i v er di sease i s av ai l abl e i n the
f or m of hepati ti s A v acci ne.
He pa titis B i s caused by a DN A v i r us that i s tr ansm i tted by par enter al

ex posur e to i nf ected bl ood, usual l y thr ough sk i n punctur es by
contam i nated needl es. Because thi s v i r us can al so be tr ansm i tted
thr ough m i nute br eak s i n m ucous m em br anes, r i sk f actor s f or hepati ti s
B i nf ecti on i ncl ude sex ual contact and the shar i ng of r azor s and
toothbr ushes w i th an i nf ected per son; tr ansm i ssi on at bi r th f r om
m other to chi l d i s al so com m on. The hepati ti s B v i r us i s pr esent i n the
bl ood appr ox i m atel y 2 m onths af ter i nf ecti on, w i th sy m ptom s appear i ng
at appr ox i m atel y 3 m onths. IgM anti HBc appear s ear l y i n the di sease
and i ts m easur em ent i s the best si ngl e ser ol ogi c test to conf i r m acute
v i r al hepati ti s B. The cl i ni cal cour se m ay pr ogr ess to f ul m i nant hepati c
f ai l ur e and death i n up to 2% of the pati ents, or the i nf ecti on m ay
sm ol der i n a chr oni c car r i er state i n up to 10% of the pati ents. Chr oni c
car r i er s ar e at hi gh r i sk f or ear l y death f r om ci r r hosi s or
hepatocel l ul ar car ci nom a and shoul d be consi der ed candi dates f or
tr eatm ent w i th agents ai m ed at suppr essi ng hepati ti s B r epl i cati on, f or
ex am pl e, Î± i nter f er on, l am i v udi ne, or adef ov i r . Im m uni zati on w i th
v acci ne m ade f r om r ecom bi nant HBsAg i s hi ghl y ef f ecti v e and conf er s
l ongl asti ng pr otecti on agai nst i nf ecti on.
He pa titis C i s caused by an RN A v i r us that, l i k e the hepati ti s B v i r us,

i s bel i ev ed to be tr ansm i tted pr i m ar i l y by par enter al ex posur e to
i nf ected bl ood, al though a substanti al per centage of pati ents hav e no
i denti f i abl e r i sk f actor s. Sy m ptom s of acute i nf ecti on ar e of ten m i l d.
Mor e than 50% of i nf ected peopl e
P. 190
becom e chr oni c car r i er s. Such per sons ar e at hi gh r i sk f or chr oni c
hepati ti s, ci r r hosi s, and hepatocel l ul ar car ci nom a. Pati ents w i th chr oni c
hepati ti s C shoul d be consi der ed candi dates f or tr eatm ent w i th Î±
i nter f er on or the com bi nati on of i nter f er on and r i bav i r i n. Ser ol ogi c
tests f or hepati ti s C conti nue to be i m pr ov ed as our k now l edge of the
v i r us i ncr eases. Ther e i s no k now n pr otecti v e anti body and no k now n
v acci ne.
He pa titis D i s caused by a def ecti v e RN A v i r us that r equi r es the
pr esence of HBsAg f or ex pr essi on. Hence, i nf ecti on w i th the hepati ti s D
v i r us occur s onl y as a coi nf ecti on w i th hepati ti s B v i r us, or as a
super i nf ecti on i n those w ho ar e chr oni c hepati ti s B v i r us car r i er s. The
sy m ptom s of hepati ti s D ar e usual l y m or e sev er e than those seen w i th
acute hepati ti s B, w i th pr ogr essi on to f ul m i nant hepati c f ai l ur e and
death i n up to 20% of the pati ents. The speci f i c ser ol ogi c test f or
hepati ti s D, anti HD, shoul d be car r i ed out onl y i f the HBsAg ser ol ogy
i s posi ti v e. Ther e i s no v acci ne speci f i c to the hepati ti s D v i r us,
al though i m m uni zati on agai nst hepati ti s B conf er s pr otecti on agai nst
hepati ti s D.
He pa titis E i s caused by an RN A v i r us that, l i k e the hepati ti s A v i r us,

i s tr ansm i tted pr i m ar i l y by f ecal â€“or al contam i nati on. Outbr eak s of
the di sease can r each epi dem i c pr opor ti ons i n ar eas of the w or l d w her e
f l oodi ng and poor sani tati on ar e pr ev al ent. Al though sy m ptom s ar e m i l d
i n m ost pati ents, hepati ti s E has a 20% m or tal i ty r ate i f i t i s acqui r ed
dur i ng pr egnancy . Speci f i c ser ol ogi c tests ar e under dev el opm ent.
Ther e i s no k now n v acci ne f or i t.
5. Match the f ol l ow i ng ser ol ogi c r esul ts w i th the m ost l i k el y cl i ni cal state.
The cor r ect pai r i ngs of the ser ol ogi c r esul ts w i th the m ost l i k el y
cl i ni cal state ar e: a w i th 3, b w i th 6, c w i th 1, d w i th 5, e w i th 4, and f
w i th 2. HBsAg i s pr esent i n the setti ngs of acute i nf ecti on, chr oni c
i nf ecti on, and the car r i er state. Anti HBs and anti HBc appear and the
HBsAg l ev el decl i nes as the acute i nf ecti on r esol v es. IgM anti HBc or
IgM anti HAV i s usual l y pr esent onl y dur i ng acute i nf ecti on, w her eas
the IgG cl asses of anti HBc and anti HAV per si st, i ndi cati ng a state of
i m m uni ty af ter r esol uti on of the acute i nf ecti on. Anti HBs appear s
al one, w i thout anti HBc, i n r esponse to hepati ti s B v acci ne.
6. Whi ch hepati c enzy m e patter n suggests the pr esence of al cohol i c l i v er

di sease?
In the setti ng of al cohol i c hepati ti s, the ser um AST l ev el i s usual l y
hi gher than the ser um ALT l ev el . In addi ti on, the ser um l ev el of Î³
gl utam y l tr anspepti dase i s of ten el ev ated because of i nducti on of thi s
enzy m e by chr oni c ethanol i ngesti on.
7. What ar e the cl i ni cal and l abor ator y f i ndi ngs char acter i sti c of i schem i c
l i v er i njur y ?
Ischem i c l i v er i njur y , or â€œshock l i v er , â€ usual l y occur s i n the setti ng

of a r ecogni zed ci r cul ator y di stur bance, such as hy potensi on or acute
m y ocar di al i nf ar cti on. A r api d and dr am ati c r i se i n the AST and ALT
l ev el s i s seen, w i th an equal l y r api d decl i ne. The am i notr ansf er ase
l ev el s can r i se i nto the thousands, appr oachi ng l ev el s seen w i th acute
v i r al hepati ti s. A sl ow , steady i ncr ease i n the ser um bi l i r ubi n
concentr ati on subsequentl y occur s and peak s sev er al day s
P. 191
l ater . A l i v er bi opsy i s not needed f or di agnosi s, but, w hen speci m ens
ar e obtai ned, they show centr i l obul ar necr osi s.
8. What i s f ul m i nant hepati c f ai l ur e?
Ful m i nant hepati c f ai l ur e i s def i ned as pr ogr essi on to si gns of l i v er
f ai l ur e, i ncl udi ng hepati c encephal opathy , w i thi n 8 w eek s of the onset
of sy m ptom s. Such a pi ctur e occur r i ng 8 to 24 w eek s f r om the onset of
sy m ptom s i s consi der ed subf ul m i nant hepati c f ai l ur e. Ful m i nant hepati c
f ai l ur e m ay be caused by v i r al , tox i c, i schem i c, or other causes of
hepatocel l ul ar i njur y . The m or tal i ty r ate f or these enti ti es i s ex tr em el y
hi gh. Intensi v e suppor t i s i ndi cated i n af f ected pati ents, and l i v er
tr anspl antati on shoul d be consi der ed i f spontaneous r ecov er y does not
occur .
Case
A 37y ear ol d housew i f e r epor ts 3 w eek s of gener al f ati gue, sev er al day s of
dar k ur i ne, and 1 day of scl er al i cter us. She deni es v om i ti ng, but com pl ai ns
of m i l d, conti nuous pai n i n the r i ght upper quadr ant, and i nter m i ttent
nausea.
Phy si cal ex am i nati on r ev eal s the pati ent to be jaundi ced but com f or tabl e.
She show s no si gns of m al nutr i ti on and has no spi der angi om as or pal m ar
er y them a. The l i v er i s tender and m easur es 15 cm by per cussi on i n the
m i dcl av i cul ar l i ne; i t i s pal pabl e 4 cm bel ow the costal m ar gi n on
i nspi r ati on. The spl een i s not pal pabl e, and the ex am i nati on f i ndi ngs ar e
other w i se unr em ar k abl e.
1. What i s y our f i r st di agnosti c i m pr essi on, and w hy ? Match the

l abor ator y f i ndi ngs w i th the v ar i ous di agnosti c possi bi l i ti es.
Tota l Alk a line

AST ALT
Bilirubin P hos pha ta s e Dia gnos is
(IU /L) (IU /L)
(mg/dL) (IU /L)
a . 235 90 5. 5 190 1. Acute v i r al

hepati ti s
b. 1, 320 5. 5 190 2. Chr oni c

1, 100 v i r al
hepati ti s
c . 235 325 5. 5 190 3. Al cohol i c

hepati ti s
d. 235 325 10. 5 990 4. Bi l e duct

obstr ucti on
AST, aspar tate am i notr ansf er ase; ALT, al ani ne am i notr ansf er ase.
2. What other hi stor i cal i nf or m ati on i s needed per tai ni ng to r i sk f actor s?
3. What tests w oul d y ou or der i f y ou suspected acute v i r al hepati ti s?
4. If the pati ent has acute hepati ti s A or hepati ti s B, w hat shoul d y ou tel l
her about the r i sk to her f am i l y , and w hat i s the appr opr i ate f ol l ow up
af ter she r ecov er s?
5. What i f al l i ni ti al v i r al hepati ti s ser ol ogy r esul ts ar e nonr eacti v e?
6. If the pati ent has a str ong f am i l y hi stor y of l i v er di sease, w hat tests
ar e av ai l abl e to scr een f or i nher i ted di sor der s?
7. Is a l i v er bi opsy i ndi cated i n thi s pati ent?
8. Shoul d thi s pati ent be adm i tted to the hospi tal ?
P. 192
Case Discussion
1. What i s y our f i r st di agnosti c i m pr essi on, and w hy ? Match the l abor ator y
f i ndi ngs w i th the v ar i ous di agnosti c possi bi l i ti es.
The sy m ptom s and ex am i nati on f i ndi ngs ar e nonspeci f i c, and the
l abor ator y f i ndi ngs and the v ar i ous di agnosti c possi bi l i ti es ar e pai r ed,
as f ol l ow s: a w i th 3, b w i th 1, c w i th 2, and d w i th 4. Ver y hi gh
am i notr ansf er ase l ev el s (> 1, 000 IU /L) usual l y i ndi cate an acute
hepatocel l ul ar i njur y . Moder atel y hi gh l ev el s (tw o to f i v e ti m es nor m al )
can be seen i n m any si tuati ons, such as ear l y or l ate i n the cour se of
an acute i njur y , or i n chr oni c di seases such as chr oni c v i r al hepati ti s or
al cohol i c l i v er di sease. An AST/ALT r ati o that ex ceeds 1 suggests the
pr esence of al cohol i c l i v er di sease. Al k al i ne phosphatase and bi l i r ubi n
l ev el s that ar e el ev ated out of pr opor ti on to the am i notr ansf er ase
concentr ati ons suggest a bi l i ar y obstr ucti v e pr ocess, but these ar e not
speci f i c w i th r egar d to the l ev el of obstr ucti on (ex tr ahepati c
obstr ucti on v er sus i ntr ahepati c chol estasi s).
2. What other hi stor i cal i nf or m ati on i s needed per tai ni ng to r i sk f actor s?
A pati ent pr esenti ng w i th l i v er di sease shoul d be ask ed about tr av el
and hepati ti s ex posur e (hepati ti s A); par enter al r i sk f actor s, i ncl udi ng
tr ansf usi ons, IV dr ug use, sex ual contacts, and pr of essi onal ex posur e
(heal th car e w or k er sâ€”hepati ti s B and C); m edi cati ons; env i r onm ental
ex posur e; al cohol i ntak e; chi l dhood l i v er di sease; and f am i l y hi stor y .
Al though pr ol onged ex cessi v e al cohol i ntak e i s of ten easi l y r ecogni zed,
som eti m es i t i s cov er t.
3. What tests w oul d y ou or der i f y ou suspected acute v i r al hepati ti s?
The sel ecti on of tests shoul d be gui ded by the natur e of the cl i ni cal
hi stor y . The f ol l ow i ng tests shoul d be done i n a per son suspected of
hav i ng acute v i r al hepati ti s: (a) IgM anti HAV to check f or acute
hepati ti s A; (b) IgM anti HBc to check f or acute hepati ti s B; and (c)
anti bodi es to hepati ti s C anti gens (anti HCV) to check f or acute
hepati ti s C.
4. If the pati ent has acute hepati ti s A or hepati ti s B, w hat shoul d y ou tel l
her about the r i sk to her f am i l y , and w hat i s the appr opr i ate f ol l ow up
af ter she r ecov er s?
The househol d and sex ual contacts of peopl e w i th acute hepati ti s A
shoul d be passi v el y i m m uni zed w i th i m m une gl obul i n, and they shoul d
ex er ci se car ef ul standar d pr ecauti ons to av oi d f ecal â€“ or al
tr ansm i ssi on. The househol d contacts of peopl e w i th acute hepati ti s B
shoul d av oi d par enter al contact (the shar i ng of r azor s, toothbr ushes,
and the l i k e). Sex ual contact shoul d be m i ni m i zed dur i ng the acute
stage of the i l l ness. Af ter cl i ni cal r ecov er y , i t i s i m por tant to
deter m i ne w hether the HBsAg has di sappear ed and anti HBs has
appear ed. Fai l ur e to cl ear HBsAg suggests dev el opm ent of a chr oni c
hepati ti s B car r i er state. Sex ual or househol d contacts of hepati ti s B
car r i er s shoul d be i m m uni zed w i th hepati ti s B v acci ne.
5. What i f al l i ni ti al v i r al hepati ti s ser ol ogy r esul ts ar e nonr eacti v e?
Repeat testi ng f or anti HCV i n 6 m onths i s appr opr i ate because thi s
test m ay not be posi ti v e i n the acute setti ng.
P. 193
6. If the pati ent has a str ong f am i l y hi stor y of l i v er di sease, w hat tests
ar e av ai l abl e to scr een f or i nher i ted di sor der s?
A l ow ser um cer ul opl asm i n l ev el and a hi gh ur i nar y copper ex cr eti on

ar e hi ghl y suggesti v e of Wi l son's di sease. A hi gh ser um f er r i ti n l ev el
and hi gh tr ansf er r i n satur ati on ar e hi ghl y suggesti v e of
hem ochr om atosi s. The def i ni ti v e test f or both of these di sor der s i s a
l i v er bi opsy . Geneti c testi ng f or f am i l i al hem ochr om atosi s i s now
av ai l abl e.
7. Is a l i v er bi opsy i ndi cated i n thi s pati ent?
Li v er bi opsy i s not usual l y needed f or di agnosi s or pr ognosi s i n pati ents

w i th acute l i v er di seases. Ex cepti ons m i ght i ncl ude establ i shi ng the
di agnosi s of dr ugi nduced or tox i c hepati ti s, i schem i c l i v er i njur y ,
gr anul om atous di sease, and, r ar el y , al cohol i c hepati ti s.
8. Shoul d thi s pati ent be adm i tted to the hospi tal ?
Most pati ents w i th acute hepati ti s do not r equi r e hospi tal adm i ssi on.
How ev er , those w ho ex hi bi t ev i dence of sev er e l i v er i njur y , such as
hepati c encephal opathy , a bi l i r ubi n l ev el abov e 15 m g/dL, or an
i ncr easi ng pr othr om bi n ti m e, and those w i th sev er e anor ex i a or
nausea, shoul d be hospi tal i zed.
Suggested Readings
Ber enguer M, Wr i ght TL. Vi r al hepati ti s. In: Fel dm an M, Fr i edm an LS,
Sl ei senger MH, eds. Sl ei senger and For dtr an's gastr oi ntesti nal and l i v er
di sease: pathophy si ol ogy , di agnosi s, m anagem ent, 7th ed. Phi l adel phi a:
WB Saunder s, 2002:1278.
Schi f f ER. Vi r al hepati ti s. In: Schi f f ER, Sor r el l MF, Maddr ey WC, eds.
Schi f f 's di seases of the l i v er , 9th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2003:741.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 5 G e r ia tr ic s
Chapter 5
Geriatrics
La ure nc e Robbins
Dementia
1. What i s the m ost com m on cause of pr i m ar y dem enti a i n the U . S.
popul ati on?
2. What ar e the pathognom oni c postm or tem f i ndi ngs of Al zhei m er 's
di sease (AD)?
3. Can the chi l dr en of pati ents w i th AD be geneti cal l y tested and tol d w i th
assur ance w hether they w i l l i nher i t the di sease?
4. How can cogni ti v e f uncti on be tested qui ck l y and r el i abl y ?
5. Can the i ntel l ectual decl i ne seen i n pati ents w i th AD be hal ted or
r ev er sed w i th m edi cati ons?
Discussion
1. What i s the m ost com m on cause of pr i m ar y dem enti a i n the U . S.
popul ati on?
AD i s the m ost com m on cause of dem enti a i n the U . S. popul ati on.
Dem enti a cur r entl y af f ects appr ox i m atel y 4. 5 m i l l i on peopl e i n the
U ni ted States and thi s num ber w i l l gr ow to an esti m ated 10 m i l l i on by
2050. As the m ost com m on eti ol ogy of dem enti a, i t accounts f or 70%
or m or e of al l
P. 195
dem enti a di agnoses. Adv anci ng age r em ai ns the si ngl e gr eatest r i sk
f actor f or AD. Cur r entl y , i t af f l i cts appr ox i m atel y 2% of the popul ati on
betw een 65 and 70 y ear s of age, and appr ox i m atel y 30% of the
popul ati on ol der than 80 y ear s. The i nci dence of new di sease i s
appr ox i m atel y 3% per y ear i n com m uni ty dw el l i ng el der l y w i th an
av er age age of 75. Acqui r ed i m pai r m ent of shor tter m m em or y i s i ts
hal l m ar k w i th at l east one of the f ol l ow i ng f our sy m ptom s as w el l :
aphasi a, apr ax i a, agnosi a, and ex ecuti v e dy sf uncti on. Aphasi a m ay be
f l uent or nonf l uent. Pati ents m ay hav e di f f i cul ty com i ng up w i th the
cor r ect w or d w hen tr y i ng to nam e objects, of ten substi tuti ng w or ds that
descr i be an object (e. g. , w hen ask ed to nam e a w atch, the pati ent w i th
AD m i ght say â€œi t's a thi ng y ou use to tel l ti m eâ€ ) . Apr ax i a i s the
i nabi l i ty to car r y out m otor task s i n the absence of m otor w eak ness
(e. g. , a pati ent i s no l onger abl e to k ni t al though ther e i s no w eak ness
of hands or ar m s because they cannot r epr oduce the necessar y m oti on
to cr eate a sti tch). Agnosi a i s the i nabi l i ty to r ecogni ze sensor y
i nf or m ati on (v i sual , audi tor y , etc. ); i t m ay i ncl ude getti ng l ost i n
f am i l i ar sur r oundi ngs or f ai l i ng to r ecogni ze f am i l i ar peopl e. Ex ecuti v e
dy sf uncti on i s the i nabi l i ty to com pl ete a sequence of task s i n pr oper
or der . An ex am pl e of ex ecuti v e dy sf uncti on m i ght i ncl ude l osi ng the
abi l i ty to bal ance a check book . On a m or e basi c l ev el , i t m i ght af f ect
the abi l i ty to get dr essed (i . e. , i nabi l i ty to put cl othes on i n the pr oper
sequence).
Other causes of dem enti a ar e l ess com m on. The absence of cl i ni cal
di agnosti c cr i ter i a that unequi v ocal l y separ ate one cause of dem enti a
f r om another obf uscates ef f or ts to pi npoi nt the pr ev al ence of any
speci f i c cause of dem enti a. Vascul ar dem enti a (VD) i s ar guabl y the
second m ost com m on cause of dem enti a. Tw o f eatur es hel p di sti ngui sh
VD f r om AD, cl i ni cal l y . Al though AD pr i m ar i l y af f ects the gr ay m atter
of the tem por al l obes, VD tends to i ncl ude m ul ti pl e sm al l i nf ar cts i n the
deep w hi te m atter of the br ai n. In VD, thi s di str i buti on of i schem i a
l eads to m ar k ed sl ow i ng i n pati ent r esponse ti m e to questi ons and i s
m or e l i k el y to pr oduce f ocal neur ol ogi c m otor and sensor y f i ndi ngs,
i ncl udi ng gai t di sor der s. Spar i ng of the m otor cor tex m ak es m otor
f i ndi ngs, i ncl udi ng gai t di sor der s, m uch l ess com m on i n ear l y AD than
i n VD.
Si nce f i r st descr i bed i n 1961, di f f use Lew y body dem enti a (DLBD) has
r ecei v ed i ncr easi ng attenti on as a m or e com m on cause of degener ati v e
dem enti a than pr ev i ousl y r ecogni zed. Al though Lew y bodi es ar e the
hal l m ar k of Par k i nson's di sease w hen f ound i n the basal gangl i a,
par ti cul ar l y the substanti a ni gr a, they m ay appear i n cor ti cal and
subcor ti cal ar eas as w el l . The astute cl i ni ci an w i l l suspect a di agnosi s
of DLBD w hen pati ents pr esent w i th a tr i ad of pr ogr essi v e but
f l uctuati ng cogni ti v e decl i ne, par k i nsoni sm , and v i sual hal l uci nati ons
(hal l uci nati ons ar e not ty pi cal ear l y i n the cour se of AD). Si m i l ar l y ,
pati ents w i th a di agnosi s of Par k i nson's di sease m ay i ni ti al l y appear
cogni ti v el y i ntact but ov er ti m e, usual l y w el l af ter the m otor si gns of
Par k i nson's di sease hav e pr ogr essed, they dev el op pr ogr essi v e
dem enti a. These l atter pati ents hav e som ew hat ar bi tr ar i l y been
di agnosed as hav i ng the â€œdem enti a of
P. 196
Par k i nson's di seaseâ€
to di sti ngui sh them f r om pati ents w i th DLBD w ho
hav e the si m ul taneous onset of m otor and cogni ti v e dy sf uncti on.
Fr ontotem por al dem enti as ar e a heter ogeneous gr oup of di sor der s that
pr i m ar i l y af f ect the f r ontal and tem por al ar eas of the br ai n. Most hav e
nonspeci f i c degener ati v e changes and not the Pi ck bodi es that
char acter i ze Pi ck 's di sease, the f i r st of these di sor der s to be
speci f i cal l y r ecogni zed. These pati ents m ost of ten com e to m edi cal
attenti on f or behav i or al and speech pr obl em s (both f l uent and
nonf l uent) r ather than pr i m ar i l y f or m em or y l oss.
Besi des VD, the nonAD causes of dem enti a ar e r el ati v el y uncom m on,
each accounti ng f or l ess than 5% of al l dem enti a. Other eti ol ogi es ar e
ev en m or e r ar e, such as Cr eutzf el dtJak ob di sease, a pr i onr el ated
di sease that m ay af f ect as f ew as one i n a m i l l i on peopl e i n the U ni ted
States. Other r ar e pr i m ar y degener ati v e neur ol ogi c di seases causi ng
dem enti a w oul d i ncl ude Hunti ngton's chor ea or pr ogr essi v e
supr anucl ear pal sy , each w i th i ts ow n r el ati v el y di sti nct set of cl i ni cal
f eatur es.
2. What ar e the pathognom oni c postm or tem f i ndi ngs of AD?
N eur of i br i l l ar y tangl es and neur i ti c pl aques ar e postm or tem f i ndi ngs
pathognom oni c f or AD, and the di agnosi s i s cer tai n onl y i f the
pathol ogi st i denti f i es a si gni f i cant num ber of these l esi ons i n the
ty pi cal di str i buti on (i . e. , heav y concentr ati ons i n the hi ppocam pus and
sur r oundi ng ar eas of the tem por al l obes). N i nety per cent or m or e of
pati ents w i th cl i ni cal l y di agnosed dem enti a of the Al zhei m er 's ty pe
hav e the di agnosi s conf i r m ed at postm or tem ex am i nati on. Pl aques and
neur of i br i l l ar y tangl es ar e al so f ound i n the br ai ns of heal thy el der l y
subjects, but i n m uch sm al l er num ber s than i n the el der l y pati ents w i th
AD. Depl eti on of chol i ner gi c neur ons i s another pathol ogi c hal l m ar k ,
and m ai ntenance or suppl em entati on of chol i ner gi c f uncti on has been
the f ocus of sev er al tr eatm ents of AD.
Other condi ti ons that m ay be cl i ni cal l y conf used w i th AD ar e associ ated
w i th di f f er ent pathol ogi c f i ndi ngs. A m ul ti f ocal l oss of br ai n ti ssue
secondar y to i schem i a i s seen i n the setti ng of m ul ti i nf ar ct dem enti a.
Degener ati on of the dopam i ner gi c cel l s i n the substanti a ni gr a and
Lew y bodi es ar e f ound i n pati ents w i th Par k i nson's di sease. Som eti m es
pathol ogi sts f i nd cor ti cal and subcor ti cal neur onal l oss associ ated w i th
Lew y bodi es outsi de the tr adi ti onal di str i buti on of these l esi ons i n
Par k i nson's di sease. Thi s enti ty i s now i denti f i ed as DLBD and m ay
r epr esent the second m ost com m on cause of neur odegener ati v e
dem enti a af ter AD.
3. Can the chi l dr en of pati ents w i th AD be geneti cal l y tested and tol d w i th
assur ance w hether they w i l l i nher i t the di sease?
The ev i dence f or a her edi tar y pr edi sposi ti on of AD has l ed to geneti c
r esear ch that has i denti f i ed sev er al chr om osom al abnor m al i ti es that
i ncr ease the r i sk f or dev el opi ng AD. Resear cher s hav e i denti f i ed
def ecti v e genes i n chr om osom es 1, 14, and 21 that ar e l i nk ed to
autosom al dom i nant i nher i tance patter ns of AD i n a sm al l num ber of
f am i l i es. Af f l i cted pati ents i n these f am i l i es of ten hav e ear l i er onset of
dem enti a, betw een 35 and 65 y ear s of age, w hi ch i s consi der abl y
ear l i er than the usual onset i n pati ents w i th l atel i f e AD ty pi cal l y
P. 197
begi nni ng i n the ei ghth decade or l ater . Latel i f e onset of AD occur s
m or e of ten i n pati ents w ho hav e the Apol i popr otei n (Apo) E4 al l el e on
chr om osom e 19. Thr ee ApoE al l el es hav e been descr i bed, nam el y
ApoE2, ApoE3, and ApoE4. Al though ApoE4 appear s to i ncr ease the r i sk
f or dev el opm ent of l ateonset AD, ApoE3 i s the m ost com m onl y
i nher i ted al l el e and appear s to conf er nei ther a gr eater nor l esser r i sk
of dev el opi ng AD. ApoE2 i s v er y r ar e (appr ox i m atel y 1% of the
popul ati on) and m ay conf er a sl i ghtl y l ow er r i sk of AD. N ot al l
i ndi v i dual s w i th an ApoE4 al l el e w i l l dev el op AD and, conv er sel y , AD
occur s am ong m any peopl e w ho ar e hom ozy gous f or ApoE3. Ther ef or e,
geneti c testi ng, w i th the ex cepti on of an autosom al dom i nant patter n
i nher i tance of the di sease, does not r el i abl y pr edi ct an i ndi v i dual 's r i sk
of dev el opi ng AD. Adv anci ng age r em ai ns the si ngl e gr eatest r i sk f or
dev el opi ng AD. The absence of consi stent cor r el ati on betw een the
pr esence or absence of cur r entl y k now n geneti c m ar k er s and the r i sk
of AD, and the absence of i nter v enti ons that cl ear l y del ay or pr ev ent
the dev el opm ent of AD (see f ol l ow i ng tex t) suggest that geneti c testi ng
cur r entl y has l i ttl e cl i ni cal uti l i ty .
4. How can cogni ti v e f uncti on be tested qui ck l y and r el i abl y ?
N um er ous studi es hav e show n that phy si ci ans ov er l ook m or e than 50%
of pati ents w ho hav e cogni ti v e i m pai r m ent. Thi s i s m ost of ten due to
the cl i ni ci an's f ai l ur e to do f or m al m ental status testi ng that w oul d
objecti v el y i denti f y these def i ci ts. The Fol stei n Mi ni â€“Mental Status
Ex am i nati on (MMSE) and si m i l ar br i ef m ental status tests (e. g. , the
Pf ei f f er and the Bl essed Dem enti a Scal es) ar e qui ck , r el i abl e scr eeni ng
tool s to assess cogni ti v e f uncti on and m ay esti m ate the sev er i ty of
m ental status i m pai r m ent. The MMSE m easur es or i entati on, m em or y ,
and attenti on as w el l as the status of w r i tten and spok en l anguage and
v i suospati al sk i l l s. Wi th a sensi ti v i ty of 87% and speci f i ci ty of 82%,
the MMSE r esul ts ar e r epr oduci bl e w hen the test i s adm i ni ster ed ei ther
by a heal th car e pr of essi onal or by som eone tr ai ned to adm i ni ster the
test. One of the best si ngl ei tem scr eeni ng tests i s cl ock dr aw i ng. The
i nabi l i ty to dr aw f am i l i ar , r el ati v el y si m pl e objects m ay r ef l ect
apr ax i a, of ten an ear l y si gn of dem enti a. The ex am i ner ask s the
pati ent to dr aw a cl ock f ace, f i l l i n the num ber s, and then dr aw the
hour and m i nute hands i ndi cati ng a ti m e, such as â€œ10 m i nutes past
2. â€ Studi es suggest that thi s si m pl e test has a sensi ti v i ty and
speci f i ci ty si m i l ar to m or e el abor ate scr eeni ng tool s l i k e the MMSE.
5. Can the i ntel l ectual decl i ne seen i n pati ents w i th AD be hal ted or
r ev er sed w i th m edi cati ons?
Ef f or ts to hal t or at l east del ay the pr ogr essi on of cogni ti v e decl i ne i n
pati ents suspected of hav i ng AD i s ex tr em el y chal l engi ng. Fi r st, the
cl i ni ci an m ust r ul e out potenti al r ev er si bl e f actor s that m ay hasten a
pati ent's deter i or ati on. Depr essi on i s a com m on com pl i cati on of AD.
Lef t unr ecogni zed, depr essi on m ay l ead to a l oss of i nter est, and
decr ease i n abi l i ty to concentr ate and f uncti on i n pati ents w i th AD.
Tr eatm ent of depr essi on can â€œr ev er seâ€ som e of the addi ti onal
decl i ne i n i ntel l ectual f uncti on that occur s w hen depr essi on i s l ef t
untr eated. Second, m edi cati on si de ef f ects can gi v e the appear ance of
pr ogr essi on of AD. A l ar ge num ber of m edi cati ons, i ncl udi ng
anti conv ul sants, m uscl e
P. 198
r el ax er s, anal gesi cs, and other s, m ay be i m pl i cated. Psy choacti v e
m edi cati ons, par ti cul ar l y those w i th anti chol i ner gi c si de ef f ects such as
tr i cy cl i c anti depr essants, ar e notor i ous f or causi ng r ev er si bl e i ncr eased
conf usi on and cogni ti v e decl i ne i n pati ents w i th under l y i ng dem enti a.
The ex per i enced phy si ci an w i l l w or k m ethodi cal l y to r educe or
el i m i nate m edi cati ons that m ay ex acer bate cogni ti v e l osses of pati ents
w i th AD, r ecogni zi ng that m edi cati ons ar e the si ngl e m ost com m on
cause of r ev er si bl e cogni ti v e i m pai r m ent. In addi ti on to r educi ng
m edi cati ons that m ay ex acer bate cogni ti v e decl i ne, cl i ni ci ans shoul d
r ul e out abnor m al i ti es such as B 1 2 def i ci ency , hy pothy r oi di sm , hy po or
hy per gl y cem i a, hy ponatr em i a, or other m etabol i c pr obl em s that m ay
al so hasten cogni ti v e i m pai r m ent. Fi nal l y , str uctur al abnor m al i ti es such
as subdur al hem atom as, nor m al pr essur e hy dr ocephal us, or br ai n
tum or s occasi onal l y l ead to r ev er si bl e deter i or ati on i n m em or y and
r el ated i ntel l ectual f uncti on. The pr esence of f ocal neur ol ogi c si gns
and/or the pr esence of a gai t di sor der ar e not consi stent w i th a
di agnosi s of AD and m ay tr i gger a r equest f or a br ai n i m agi ng study to
r ul e out one of the thr ee str uctur al centr al ner v ous sy stem pr obl em s
noted i n the pr ecedi ng tex t that m ay pr esent oppor tuni ti es f or
i nter v enti on to r ev er se cogni ti v e l osses.
When pati ents w i th AD hav e no ev i dence of r ev er si bl e contr i butor s to
thei r cogni ti v e decl i ne, ther api es ai m ed at hal ti ng or r ev er si ng di sease
pr ogr essi on hav e been onl y m odestl y successf ul to date. Recogni zi ng
that chol i ner gi c neur onal l oss i s a pr edom i nant pathol ogi c f i ndi ng i n
AD, i nv esti gator s hav e f ocused on f i ndi ng w ay s to enhance cer ebr al
chol i ner gi c acti v i ty . Thi s ef f or t l ed to the dev el opm ent of
chol i nester ase i nhi bi tor s that bl ock the br eak dow n of acety l chol i ne i n
the br ai ns of pati ents w i th AD. The U . S. Food and Dr ug Adm i ni str ati on
(FDA) has appr ov ed a total of f i v e m edi cati ons f or the tr eatm ent of AD,
f our of w hi ch ar e chol i nester ase i nhi bi tor s. The f i r st of the
chol i nester ase i nhi bi tor s, nam el y tacr i ne (Cognex ), i s no l onger used
because i t m ust be tak en on an em pty stom ach f our ti m es a day and
has been associ ated w i th gastr oi ntesti nal and hepati c tox i ci ty .
Donepezi l (Ar i cept) w as the second agent appr ov ed and can be tak en
once a day , usual l y at bedti m e and has m i ni m al gastr oi ntesti nal
tox i ci ty and no r epor ted hepatotox i ci ty . The FDA al so appr ov ed
gal antam i ne (Razady ne) and r i v asti gm i ne (Ex el on) w hi ch ar e pr escr i bed
tw i ce a day and m ay cause sl i ghtl y m or e gastr oi ntesti nal upset but al so
hav e no appar ent hepatotox i ci ty . Mor e than 9, 000 pati ents hav e now
par ti ci pated i n r andom i zed contr ol l ed tr i al s of chol i nester ase i nhi bi tor s
l asti ng up to 1 y ear . Al l w er e phar m aceuti cal com pany sponsor ed and
had str i ct cr i ter i a f or par ti ci pati on that som e ex per ts suggest w oul d
hav e ex cl uded 90% of pati ents w i th dem enti a. Al l of these studi es
show ed m odest sl ow i ng of pr ogr essi on on scal es that m easur ed
cogni ti v e f uncti on, behav i or , and gl obal f uncti on. Thi s ef f ect i s
equi v al ent to pr ev enti ng pr ogr essi on of AD f or a f ew m onths. In a
m odestl y successf ul attem pt to study l onger ter m ef f ects of
chol i nester ase i nhi bi tor s i n a m or e i ncl usi v e gr oup of dem ented
pati ents ov er sev er al y ear s, a gr oup of Br i ti sh i nv esti gator s r epor ted
thei r r esul ts i n 2004 f or a study enti tl ed â€œAD 2000. â€ At the end of
thi s 3y ear study , they f ound no di f f er ences i n cl i ni cal l y si gni f i cant
outcom es such as
P. 199
car egi v er r epor t of the pati ents' f uncti on, car egi v er bur nout, nur si ng
hom e pl acem ent, or hospi tal i zati on. The study di d dem onstr ate a
per si stent sl ow i ng of decl i ne i n cogni ti v e tests that w as equi v al ent to
del ay i ng di sease pr ogr essi on f or 3 m onths. The absence of a cl i ni cal l y
si gni f i cant benef i t w as di sappoi nti ng. Mem anti ne (N am enda) i s the onl y
other m edi cati on cur r entl y FDA appr ov ed f or tr eatm ent of AD. Thi s dr ug
i s a par ti al antagoni st of the N m ethy l Daspar tate (N MDA) r eceptor i n
the br ai n, an i m por tant m edi ator of gl utam ate acti v i ty . Ex per i m ental
ev i dence suggested that ex cessi v e acti v i ty of the N MDA r eceptor m ay
be associ ated w i th pr ogr essi on of AD and suppr essi on of N MDA acti v i ty
m i ght sl ow the pr ogr essi on of the di sease. In studi es of appr ox i m atel y
1, 000 pati ents, m em anti ne has a si m i l ar ef f ect as the chol i nester ase
i nhi bi tor s i n sl ow i ng the deter i or ati on of pati ent per f or m ance on
sev er al scal es i n studi es l asti ng up to 1 y ear . Li k e the chol i nester ase
i nhi bi tor s, m em anti ne has m i ni m al tox i ci ty but has not been subjected
to l ongter m r andom i zed tr i al s to deter m i ne i ts ef f ecti v eness i n sl ow i ng
the cl i ni cal deter i or ati on of AD.
Epi dem i ol ogi c and sm al l i nter v enti on studi es hav e suggested that
m edi cati ons i ncl udi ng estr ogen, nonster oi dal anti i nf l am m ator y agents
such as i bupr of en, v i tam i n E, sel egi l i ne (a m onoam i ne ox i dase
i nhi bi tor ), gi nk go bi l oba, and other s m ay sl ow the pr ogr essi on of AD.
U nf or tunatel y , none of these agents hav e pr ov ed ef f ecti v e to date i n
l ongter m , r andom i zed studi es. Ther ef or e, none of these m edi cati ons
has r ecei v ed FDA appr ov al i n the pr ev enti on or tr eatm ent of AD.
In sum m ar y , no cur r entl y av ai l abl e m edi cati ons f or the tr eatm ent of AD
hav e si gni f i cant cl i ni cal i m pact on the pr ev enti on or pr ogr essi on of thi s
di sease. Im pr ov em ent i n cogni ti on and f uncti on i s m ost l i k el y to occur
w hen the cl i ni ci an r educes or di sconti nues m edi cati on that can i nter f er e
w i th cogni ti v e f uncti on, r ecogni zes and tr eats depr essi on, and cor r ects
ov er l ook ed m edi cal condi ti ons (e. g. , congesti v e hear t f ai l ur e,
em phy sem a) or m etabol i c abnor m al i ti es (e. g. , hy ponatr em i a,
hy pogl y cem i a).
Case
An 80y ear ol d w hi te m an i s br ought to y ou by hi s 77y ear ol d w i f e because
she i s concer ned about hi s m em or y . The pati ent's onl y m edi cal pr obl em i s
m i l d hy per tensi on, tr eated w i th hy dr ochl or othi azi de (12. 5 m g dai l y ). Dur i ng
the i ni ti al outpati ent i nter v i ew , hi s w i f e conf i des that appr ox i m atel y 2 y ear s
ago she began to noti ce he w as becom i ng m or e f or getf ul and i r r i tabl e. A
r eti r ed school teacher , he had al w ay s been a l i ttl e stubbor n but i ncr easi ng
stubbor nness i s tax i ng hi s w i f e's pati ence. One y ear ago, the w i f e took ov er
r esponsi bi l i ti es f or w r i ti ng check s and pay i ng bi l l s w hen her husband f el l
behi nd i n thi s r esponsi bi l i ty and they began to r ecei v e ov er due noti ces.
Gr adual l y , hi s i nter ests and i nv ol v em ent i n acti v i ti es that he pr ev i ousl y
enjoy ed hav e decl i ned. He has begun to nap dur i ng the day and then stay up
at ni ght. Som eti m es she has f ound hi m i n the k i tchen â€œpr epar i ng di nner â
€ at 3:00 a. m . She has becom e af r ai d to l eav e hi m al one at hom e. Si x
m onths ago, he w as i nv ol v ed i n a m i nor m otor v ehi cl e acci dent and w as
char ged w i th f ai l ur e to y i el d the r i ghtof w ay , but has r ef used to stop
dr i v i ng despi te sev er al near col l i si ons si nce then.
P. 200
You f i nd the pati ent to be a tal l , w el l dr essed m an w i th a f r i endl y m anner
but l i ttl e spontanei ty . Hi s bl ood pr essur e i s 165/80 m m Hg; pul se, 75 beats
per m i nute and r egul ar ; and r espi r ati ons, 18 per m i nute. Hi s tem per atur e i s
37Â°C (98. 6Â°F). Fi ndi ngs dur i ng the phy si cal ex am i nati on, i ncl udi ng a
thor ough neur ol ogi c ex am i nati on, ar e nor m al ex cept f or bi l ater al gr asp
r ef l ex es (i nv ol untar y gr aspi ng of the ex am i ner 's hand w hen the pati ent's
pal m s ar e str ok ed by the ex am i ner 's f i nger s). He ex hi bi ts di f f i cul ty
f ol l ow i ng si m pl e com m ands. Hi s Fol stei n MMSE scor e i s 20/30 (nor m al , > 23)
and he i s unaw ar e of hi s er r or s. He scor es 3/30 on the Ger i atr i c Depr essi on
Scal e (nor m al < 15/30), suggesti ng that he i s not depr essed. When ask ed
how thi ngs ar e at hom e, he hesi tates and say s, â€œf i ne. â€ On f ur ther
questi oni ng about hi s r el ati onshi p w i th hi s w i f e, al l he say s i s that hi s w i f e
i s a â€œgood w om an. â€ Hi s sel f assessm ent i s that he i s doi ng w el l â€œf or
an ol d m an. â€ When ask ed about hi s m em or y , he say s that â€œi t's goodâ€
and he has no pr obl em s r em em ber i ng â€œi m por tant thi ngs. â€ Labor ator y
ev al uati on r ev eal s nor m al hem atocr i t and ser um cr eati ni ne v al ues. Li v er
f uncti on test r esul ts ar e nor m al . Hi s v i tam i n B 1 2 l ev el i s 480 pg/m L
(nor m al , 225 to 800 pg/m L); f ol ate, at 10 ng/m L, and thy r oi dsti m ul ati ng
hor m one, at 3 IU /m L, w er e al so nor m al . A r api d pl asm a r eagi n test (f or
sy phi l i s) i s nonr eacti v e. A head com puted tom ogr aphy (CT) scan obtai ned at
the ti m e of hi s autom obi l e acci dent 6 m onths ago r epor tedl y show ed â
€œcer ebr al atr ophy , consi stent w i th age. â€
1. Whi ch aspect of thi s pati ent's pr esentati on i s m ost v al uabl e i n
f or m ul ati ng a di f f er enti al di agnosi s?
2. On a CT scan or m agneti c r esonance i m agi ng (MRI), w hat f i ndi ngs ar e
m ost char acter i sti c of AD or other causes of dem enti a?
3. For w hat potenti al l y tr eatabl e cause of m em or y l oss shoul d thi s pati ent
be scr eened?
4. Can any thi ng be done to hel p hi s w i f e m anage the behav i or of her
husband?
Case Discussion
1. Whi ch aspect of thi s pati ent's pr esentati on i s m ost v al uabl e i n
f or m ul ati ng a di f f er enti al di agnosi s?
An i m m edi ate cl ue to the pati ent's di agnosi s i s hi s pr esentati on. Hi s
w i f e m ade the appoi ntm ent because she i s concer ned about hi s
m em or y , al though the pati ent seem s l ess aw ar e of hi s def i ci ts. Thi s
patter n i s char acter i sti c of dem enti a. If the pati ent had m ade the
appoi ntm ent hi m sel f and had com e al one com pl ai ni ng about hi s
m em or y or di f f i cul ty i n concentr ati on, thi s patter n w oul d be m or e
consi stent w i th depr essi on. When dem enti a i s adv anced, i ts di agnosi s i s
obv i ous. Ear l y on, how ev er , the pati ent m ay hi de or r ati onal i ze hi s
def i ci ts and hi s cogni ti v e changes m ay be so subtl e that they ar e m or e
appar ent at hom e than i n the cl i ni ci an's of f i ce. Thi s i s w her e the
f am i l y 's obser v ati ons becom e ex tr em el y hel pf ul . In thi s case, the
pati ent's w i f e suppl i ed m any cl ues to her husband's dem enti a.
A nor m al phy si cal ex am i nati on i s com m on i n a pati ent w i th ear l y AD.
The f i r st pathol ogi c changes i n AD occur m ostl y i n the tem por al and
par i etal l obes of the br ai n and spar e the m otor str i p. Ther ef or e, the
f i r st si gns of di sease ar e f r equentl y l i m i ted to m em or y i m pai r m ent,
subtl e per sonal i ty changes (e. g. , i ncr eased i r r i tabi l i ty or f l atteni ng of
af f ect), aphasi a, and apr ax i a. Gai t di sor der and m otor f i ndi ngs ar e
unusual .
P. 201
The onl y si gni f i cant f i ndi ng dur i ng thi s pati ent's neur ol ogi c
ex am i nati on, besi des hi s abnor m al m ental status ex am i nati on, w as
bi l ater al gr asp r ef l ex es. Thi s r esponse, the i nv ol untar y gr aspi ng of the
ex am i ner 's f i nger s w hen the ex am i ner str ok es the pati ent's pal m , i s a
pr i m i ti v e r ef l ex that m ay appear w i th bi l ater al f r ontal l obe di sease,
w hi ch m ay occur i n AD as w el l as other dem enti as.
2. On a CT scan or MRI, w hat f i ndi ngs ar e m ost char acter i sti c of AD or
other causes of dem enti a?
CT scanni ng or MRI m ay show ev i dence of tem por al l obe atr ophy i n
ear l y AD. How ev er , neur oi m agi ng ev i dence of cer ebr al atr ophy
cor r el ates m or e w i th adv anci ng age than i t does w i th m ental status
decl i ne. CT scan or MRI f i ndi ngs of w hi te m atter di sease consi stent
w i th m ul ti i nf ar ct dem enti a hav e been r epor ted i n pati ents w i th nor m al
cogni ti on. Conv er sel y , MRI and CT scan f ai l to show abnor m al i ti es i n
20% of pati ents w ho hav e cl i ni cal l y di agnosed AD. Ther ef or e, i t i s not
sur pr i si ng that the pati ent's CT scan f i ndi ngs w er e nor m al f or hi s age.
If the dem enti a has gr adual l y pr ogr essed f or 2 or m or e y ear s, i f the
m ental status ex am i nati on show s sev er e i m pai r m ent, and i f the pati ent
has no f ocal neur ol ogi c f i ndi ngs or gai t di sor der , neur oi m agi ng i s
ex tr em el y unl i k el y to r ev eal f i ndi ngs that w i l l al ter m anagem ent.
3. For w hat potenti al l y tr eatabl e cause of m em or y l oss shoul d thi s pati ent
be scr eened?
The goal of the ev al uati on i s to i denti f y di seases that can be di agnosed
conf i dentl y , or f or w hi ch ther e i s tr eatm ent that m i ght r ev er se the
cogni ti v e def i ci ts. Ther ef or e, the phy si ci an shoul d r outi nel y tak e a
car ef ul hi stor y , com pl ete a car ef ul phy si cal ex am i nati on, and or der a
basi c l abor ator y ev al uati on i ncl udi ng a com pl ete bl ood count, ser um
el ectr ol y tes, cal ci um , cr eati ni ne, thy r oi dsti m ul ati ng hor m one, and
v i tam i n B 1 2 l ev el . The phy si ci an shoul d or der other tests, such as CT
scan or MRI, based on the r esul ts of the hi stor y and phy si cal
ex am i nati on. For ex am pl e, i f the pati ent has had a hi stor y of r ecent or
sudden onset of cogni ti v e i m pai r m ent af ter head tr aum a, the possi bi l i ty
of a subdur al hem atom a w oul d i ndi cate the need f or br ai n i m agi ng.
Thi s i s par ti cul ar l y tr ue i f the phy si cal ex am i nati on r ev eal s a gai t
di sor der or f ocal neur ol ogi c si gns. The tr i ad of dem enti a of r ecent
onset, gai t di sor der , and ur i nar y i nconti nence m ay suggest the
di agnosi s of nor m al pr essur e hy dr ocephal us, another potenti al l y
r ev er si bl e cause of cogni ti v e decl i ne. Thi s di sor der i s ex tr em el y r ar e,
and, al though som e pati ents m ay ex per i ence i m pr ov em ent w i th
v entr i cul ar shunti ng, postoper ati v e com pl i cati ons (e. g. , subdur al
hem atom a, i nf ecti on, and shunt obstr ucti on) ar e v er y com m on. For the
pati ent descr i bed i n the pr ecedi ng tex t, these di agnosti c possi bi l i ti es
w oul d not be l i k el y .
Hy pothy r oi di sm and v i tam i n B 1 2 def i ci ency suf f i ci ent to af f ect neur onal
f uncti on usual l y cause di stur bances i n attenti on and consci ousness, and
ar e di agnosed and tr eated l ong bef or e dem enti a appear s. Occasi onal l y ,
how ev er , a pati ent del ay s getti ng m edi cal car e unti l dem enti a i s
pr esent, so al l pati ents shoul d be ev al uated f or these condi ti ons.
N eur osy phi l i s i s no l onger a com m on cause of cogni ti v e i m pai r m ent.
These pati ents usual l y hav e other neur ol ogi c f i ndi ngs, such as dor sal
col um n di sease m ani f est by l oss of posi ti on and v i br ator y sensati on, i n
addi ti on to m ental status decl i ne.
A sev er el y depr essed pati ent m ay seem di sor i ented and per f or m poor l y
on tests of cogni ti v e f uncti on. These def i ci ts m ay be due to r ev er si bl e
changes that m i m i c
P. 202
the i r r ev er si bl e changes of dem enti a. Because the di agnosi s of
depr essi on can be di f f i cul t and i t i s based on subtl e f i ndi ngs i n an
el der l y pati ent, m any tool s, such as the Ger i atr i c Depr essi on Scal e,
hav e been dev el oped to ai d i n i ts di agnosi s.
U nf or tunatel y , the pati ent descr i bed her e di d not ex hi bi t any of these
potenti al l y tr eatabl e abnor m al i ti es.
4. Can any thi ng be done to hel p hi s w i f e m anage the behav i or of her
husband?
Yes. Ther e ar e w ay s to hel p the pati ent's w i f e m anage her husband's
behav i or . Car i ng f or a dem ented pati ent i s a phy si cal l y and em oti onal l y
ex hausti ng job. As r ecom m endati ons ar e m ade, the phy si ci an m ust
consi der not onl y the pati ent but al so the car egi v er . Al l ow i ng
car egi v er s to v ent em oti ons, ack now l edgi ng the di f f i cul ty of thei r task ,
tel l i ng them w hat to ex pect as the di sease pr ogr esses, of f er i ng r espi te
car e, and r ef er r i ng them to suppor t gr oups ar e sm al l thi ngs that m ay
hel p them cope better w i th the pati ent and hi s or her needs.
The tr eatm ent of behav i or al pr obl em s i s di f f i cul t, but can be ef f ecti v e.
Regul ar ex er ci se and l i m i ti ng the num ber and dur ati on of l ate af ter noon
or ev eni ng naps m ay hel p r educe the noctur nal i nsom ni a that of ten
com pl i cates the m anagem ent of dem ented el der l y pati ents. Most
sedati v es and hy pnoti cs, par ti cul ar l y the l ongacti ng ones, shoul d not
be used because they m ay cause ov er sedati on or a par adox i cal
i ncr ease i n agi tati on, and m ay onl y w or sen cogni ti v e and behav i or al
def i ci ts.
Del usi ons ar e com m on i n dem enti a sy ndr om es. In f act, appr ox i m atel y
50% of the pati ents w i th AD or m ul ti i nf ar ct dem enti a ex per i ence
del usi ons. Agi tati on and com bati v e behav i or s can accom pany these
sy m ptom s. The cauti ous use of l ow doses of hal oper i dol , or other
anti psy choti cs, m ay be hel pf ul i n am el i or ati ng these behav i or s.
Suggested Readings
AD 2000 Col l abor ati v e Gr oup. Longter m donepezi l tr eatm ent i n 565
pati ents w i th Al zhei m er 's di sease (AD2000): r andom i zed doubl ebl i nd
tr i al . Lancet 2004;363:2105.
Boustani M, Peter son B, Hanson L, etal . Scr eeni ng f or dem enti a i n
pr i m ar y car e: a sum m ar y of the ev i dence f or the U . S. Pr ev enti v e
Ser v i ces Task For ce. Ann Inter n Med 2003;138:927.
Inouy e SK. Del i r i um i n ol der per sons. N Engl J Med 2006;354:11.
Kaw as C. Ear l y Al zhei m er 's di sease. N Eng J Med 2003;349:1056.
Falls in the Elderly
1. How com m onl y do f al l s occur i n the el der l y ?
2. How of ten does i njur y or death r esul t f r om a f al l ?
3. What f actor s m ak e the el der l y m or e l i k el y to f al l ?
4. What shoul d the hi stor y and phy si cal ex am i nati on f ocus on i n a pati ent
w ho i s hav i ng pr obl em s w i th f al l i ng?
P. 203
Discussion
1. How com m onl y do f al l s occur i n the el der l y ?
Thi r ty per cent of the el der l y ol der than 65 y ear s w ho l i v e out i n the
com m uni ty ex per i ence f al l s annual l y . Most pati ents ar e r el uctant to tel l
thei r phy si ci an or f am i l y m em ber s of these f al l s, so thi s f i gur e i s
pr obabl y an under esti m ate. N ear l y 8% of i ndi v i dual s ol der than 70
y ear s w i l l v i si t an em er gency r oom annual l y and one thi r d of these w i l l
be hospi tal i zed f or an av er age of m or e than 1 w eek . Because a hi stor y
of f al l s i ncr eases the r i sk of f utur e f al l s (i . e. , 60% chance w i th the
f i r st y ear af ter an i ndex f al l ) and ser i ous i njur y , phy si ci ans shoul d
r outi nel y ask el der l y pati ents i f they hav e f al l en and then i nter v ene to
r educe the r i sk of f utur e f al l s.
2. How of ten does i njur y or death r esul t f r om a f al l ?
Acci dental i njur y i s the si x th l eadi ng cause of death i n peopl e ol der
than 65 y ear s, and tw o thi r ds of these deaths ar e r el ated to f al l s.
Fr actur es occur i n appr ox i m atel y 5% of f al l s, and the m ost com m on
f r actur e si tes ar e the spi ne, hi p, hum er us, w r i st, and pel v i s. Another
5% of f al l s cause sof t ti ssue i njur i es, such as spr ai ns, joi nt
di sl ocati ons, and hem atom as. Ev en i n those cases i n w hi ch no i njur y i s
ev i dent, ther e ar e sti l l consequences; a per son w ho has f al l en m ay
becom e em oti onal l y par al y zed by a â€œf ear of f al l i ngâ€ and begi n to
l i m i t acti v i ti es. Soon they becom e soci al l y i sol ated and becom e ev en
w eak er as they ar e l ess acti v e. Ther ef or e, ev en w hen a f al l does not
cause si gni f i cant str uctur al dam age, i t m ay hav e a negati v e i m pact on
a per son's qual i ty of l i f e and i ndependence. In nur si ng hom es, 50% or
m or e of the am bul ator y r esi dents f al l each y ear , despi te the pr esence
of tr ai ned staf f and car ef ul obser v ati on of saf ety m easur es.
Appr ox i m atel y 4% of al l pati ents i n nur si ng hom es hav e tr aum ati c bone
f r actur es annual l y , i ncl udi ng a 1% r i sk of hi p f r actur e each y ear .
3. What f actor s m ak e the el der l y m or e l i k el y to f al l ?
Fr equentl y , m ul ti pl e f actor s, r ather than a si ngl e pr obl em , contr i bute to

an el der l y pati ent's r i sk of f al l i ng. It i s of ten best to di v i de these
f actor s i nto tw o categor i es: i ntr i nsi c and ex tr i nsi c. Intrins ic fa c tors
ar e those r el ated to agi ng and di sease pr ocesses. These i ncl ude
changes i n bal ance and gai t, pai n and sti f f ness due to ar thr i ti s,
decr eased m uscl e str ength, di zzi ness, postur al hy potensi on, sensor y
l osses (hear i ng, v i si on, and pr opr i ocepti on), cogni ti v e i m pai r m ent, and
sy ncope. Other i ntr i nsi c causes to consi der ar e v er tebr obasi l ar
i nsuf f i ci ency , depr essi on, hy pothy r oi di sm , m echani cal f oot pr obl em s,
or car di ac ar r hy thm i as.
Pati ents tend to attr i bute thei r f al l s to e x trins ic fa c tors , such as
tr i ppi ng ov er obstacl es, but, w i th adv anci ng age, i t becom es l ess l i k el y
that ex tr i nsi c f actor s al one ar e at f aul t. Indeed, m ost f al l s i n f r ai l
el der l y occur dur i ng r outi ne acti v i ti es of dai l y l i v i ng. For ex am pl e, a
one out of f our f al l s occur s w hen the pati ent i s cl i m bi ng or descendi ng
stai r s. How ev er , cer tai n ex tr i nsi c f actor s such as m edi cati on si de
ef f ects (e. g. , or thostasi s, di zzi ness, i m bal ance) ar e com m on. Si m i l ar l y ,
f al l i ng m ay be the f i r st cl ue to suggest a di agnosi s of occul t
al cohol i sm , l eadi ng to poor bal ance and subsequent f al l s. Other
ex tr i nsi c f actor s that m ay contr i bute to f al l s i ncl ude i nadequate
l i ghti ng, sl i pper y f l oor s, l oose
P. 204
thr ow r ugs, ex posed el ectr i cal cor ds, i tem s out of r each (so that
pati ents stand on unstabl e chai r s or other suppor ts and l ose thei r
bal ance m or e easi l y ), l ack of assi sti v e dev i ces such as bathr oom r ai l s
to steady them sel v es w hen they ar e usi ng the tub or show er , too hi gh a
bed (so that f al l s f r om the bed m or e l i k el y r esul t i n si gni f i cant i njur y ),
unsaf e stai r s, and poor l y f i tti ng shoes. Identi f y i ng and el i m i nati ng or
r educi ng ex tr i nsi c f actor s r equi r e a com pr ehensi v e r ev i ew of the
pati ent's l i v i ng si tuati on, as w el l as f i ndi ngs on phy si cal ex am i nati on.
An occupati onal ther api st or other m em ber s of a hom e car e team m ay
com pl ete a hom e saf ety ev al uati on, i denti f y hazar ds, and cor r ect them
and ther eby r educe the r i sk of subsequent f al l s.
4. What shoul d the hi stor y and phy si cal ex am i nati on f ocus on i n a pati ent
w ho i s hav i ng pr obl em s w i th f al l i ng?
A car ef ul hi stor y of the f al l i ng epi sodes shoul d be obtai ned. Thi s
i ncl udes the f r equency of f al l s, the pati ent's acti v i ty at the ti m e of the
f al l , w her e they occur , and associ ated sy m ptom s such as l oss of
consci ousness. It i s i m por tant to get i nf or m ati on f r om any one w ho m ay
hav e w i tnessed the f al l and can pr ov i de a m or e detai l ed descr i pti on of
the ci r cum stances. For ex am pl e, i f the f al l s ar e associ ated w i th
di zzi ness and consi stentl y occur 30 to 60 m i nutes af ter a m eal ,
postpr andi al or thostati c hy potensi on m ay be suspected. Ask car ef ul l y
about dr ug usage, i ncl udi ng ov er thecounter m edi cati ons as ev en
dr ugs such as di phenhy dr am i ne (Benadr y l ), a com m on i ngr edi ent i n
ov er thecounter sl eep ai ds, hav e anti chol i ner gi c pr oper ti es that m ay
contr i bute to poor bal ance and subsequent f al l s. Phy si cal ex am i nati on
m ust i ncl ude com pr ehensi v e v i tal si gns, i ncl udi ng pul se and bl ood
pr essur e, tak en l y i ng and standi ng, to i denti f y or thostati c hy potensi on
that of ten contr i butes to f al l r i sk . On neur ol ogi c ex am i nati on, v i sual
acui ty and per i pher al v i si on, str ength, and cer ebel l ar , sensor y , and
m ental status m ust be assessed, l ook i ng f or i m pai r ed v i si on, w eak ness,
atax i a, neur opathy , or dem enti a. A usef ul scr eeni ng test f or bal ance,
str ength, m obi l i ty , and endur ance i s the â€œgetupandgoâ€ test. The
ex am i ner ask s the pati ent to get up f r om a chai r (w i thout usi ng hi s or
her hands to push up f r om the chai r ), w al k appr ox i m atel y 15 to 20
f eet, tur n ar ound, w al k back to the chai r , and si t dow n, agai n w i thout
usi ng thei r ar m s to l ow er them sel v es i nto the chai r . The â€œgetup
andgoâ€ test tak es v er y l i ttl e ti m e and r ev eal s m uch about the
pati ent's gai t and saf ety . Bey ond scr eeni ng l abor ator y tests such as a
com pl ete bl ood count or chem i str y panel , v i tam i n B 1 2 and thy r oi d
sti m ul ati ng hor m one l ev el s shoul d be m easur ed i f ther e i s ev i dence of
a per i pher al neur opathy or of di f f use m uscul ar w eak ness. Other tests
such as v i sual acui ty , assessm ent of v esti bul ar f uncti on (e. g. ,
el ectr ony stagm ogr aphy ), am bul ator y car di ac m oni tor i ng, or CT
scanni ng shoul d be done onl y i f ther e ar e cl i ni cal cl ues to speci f i c
di sor der s that m ay cause f al l s (i . e. , v er ti go, sy ncope, or f ocal
neur ol ogi c f i ndi ngs).
Case
An 86y ear ol d m an i s seen because of a hi stor y of f r equent f al l s, r epor ted
by hi s w i f e. She r epor ts that he f al l s at l east thr ee ti m es per w eek , usual l y
w i thout i njur y . How ev er , he has r equi r ed tw o tr i ps to the em er gency r oom
i n the l ast 3 m onths w her e he r equi r ed
P. 205
sutur i ng of l acer ati ons r ecei v ed i n the f al l s. These f al l s ar e not
accom pani ed by l oss of consci ousness, pal pi tati ons, or sei zur e acti v i ty . Hi s
m edi cal hi stor y i s r em ar k abl e f or m i l d dem enti a, sev er e degener ati v e joi nt
di sease w i th chr oni c l ow back pai n, decr eased hear i ng and v i si on, beni gn
f am i l i al tr em or , and ur i nar y i nconti nence (r el ated to hi s dem enti a). Hi s
cur r ent m edi cati ons i ncl ude cal ci um suppl em entati on, pr opr anol ol (40 m g
thr ee ti m es a day ), an ov er thecounter sl eep m edi cati on that contai ns 50
m g of di phenhy dr am i ne w hi ch he tak es ni ghtl y f or chr oni c i nsom ni a, and
acetam i nophen as needed. Hi s w i f e r epor ts that he has a cane and a w al k er
but r ar el y uses them .
Phy si cal ex am i nati on r ev eal s a pl easant, thi n, dem ented m an. Hi s
tem per atur e i s 37Â°C (98. 6Â°F); r espi r ati ons 20 per m i nute; pul se, 55 beats
per m i nute; and supi ne bl ood pr essur e 105/70 m m Hg. On standi ng, hi s
pul se r ate r em ai ns at 55 beats per m i nute but hi s bl ood pr essur e dr ops to
85/65 m m Hg and, w hen ask ed, he say s he f eel s â€œw oozy . â€ Car di ac
ex am i nati on f i ndi ngs ar e unr em ar k abl e; the r hy thm i s r egul ar and ther e ar e
no m ur m ur s or gal l ops. Hi s gai t i s som ew hat atax i c. Hi s cr ani al ner v es ar e
i ntact and ther e i s no ny stagm us. He has a f i ne tr em or i n both hands w hen
they ar e hel d i n ex tensi on, but he has nor m al tone and str ength i n al l
ex tr em i ti es. Sensor y ex am i nati on i s i ntact. Fi nger tonose and heel toshi n
testi ng dem onstr ates no dy sm etr i a. Hi s postur e i s stooped and hi s w i de
based gai t i s unsteady . He w al k s by hol di ng on to the of f i ce f ur ni tur e.
Labor ator y tests consi sti ng of com pl ete bl ood count and el ectr ol y te and
cr eati ni ne m easur em ents y i el d unr em ar k abl e f i ndi ngs.
1. What pr obl em s ar e contr i buti ng to thi s pati ent's f al l s?

2. What di agnosti c tests m ay be the m ost hel pf ul i n thi s pati ent?
3. What i nter v enti on, or i nter v enti ons, w oul d y ou i nsti tute to decr ease
thi s pati ent's r i sk of f al l i ng?
Case Discussion
1. What pr obl em s ar e contr i buti ng to thi s pati ent's f al l s?
The hi stor y and phy si cal ex am i nati on f i ndi ngs suggest a num ber of
f actor s contr i buti ng to thi s pati ent's f al l s. Degener ati v e joi nt di sease
i ncr eases the r i sk of f al l s i n a num ber of w ay s. Fi r st, sti f f ness and
change i n postur e af f ect bal ance and, second, joi nt pai n ex per i enced
w hi l e w al k i ng m ay di scour age acti v i ty and ex er ci se, w hi ch, i n tur n,
contr i butes to decr eased m uscl e tone and bal ance and an i ncr eased r i sk
of f al l i ng. Thi s v i ci ous cy cl e m ay f oster a f ear of f al l i ng and the
ev entual cessati on of w al k i ng. Dem enti a m ay be associ ated w i th poor
judgm ent, w hi ch al so adds to the r i sk of f al l i ng. For ex am pl e, w i thout
super v i si on, a dem ented pati ent m ay tr y to m ai ntai n hi s bal ance by
gr aspi ng an unstabl e chai r or other object that cannot suppor t hi s or
her w ei ght. Ev en i f a dem ented pati ent has a cane or a w al k er , he or
she m ay not r em em ber to use i t. The pati ent's car egi v er needs to be
educated about the need f or the f r equent v er bal â€œcuei ngâ€ of
dem ented pati ents (e. g. , r em i ndi ng them to use assi sti v e dev i ces or
not to gr asp unstabl e objects f or bal ance). The phy si ci an m ust al w ay s
r ev i ew the natur e of the pati ent's m edi cati on to deter m i ne i f si de
ef f ects m ay be contr i buti ng to f al l r i sk . In thi s case, the pati ent i s
tak i ng a Î²adr ener gi c bl ock er (pr opr anol ol ) f or the tr eatm ent of
tr em or , w hi ch m ay be
P. 206
causi ng br ady car di a, and thi s, i n tur n, m ay contr i bute to the pati ent's
w eak ness and r i sk of f al l i ng. Or thostati c hy potensi on caused by v ar i ous
m edi cati ons i s a f r equent sour ce of f al l r i sk . Anti hy per tensi v e
m edi cati ons and anti chol i ner gi c m edi cati ons (e. g. , hi s di phenhy dr am i ne
or tr i cy cl i c anti depr essants, such as am i tr i pty l i ne) ar e tw o cl asses of
m edi cati ons that f r equentl y cause or thostati c hy potensi on. Sedati v e
m edi cati ons not onl y al ter the l ev el of consci ousness but m ay al so
bl unt postur al r ef l ex es. Car di ac dy sr hy thm i as ar e r esponsi bl e f or 25%
to 35% of al l sy ncopal epi sodes, and they account f or 2% to 10% of
f al l s. How ev er , i n thi s pati ent, w ho has no hi stor y of car di ac di sease or
l oss of consci ousness, a dy sr hy thm i a i s an unl i k el y contr i butor to hi s
f al l s.
2. What di agnosti c tests m ay be the m ost hel pf ul i n thi s pati ent?
Because sensor y def i ci ts and untr eated m edi cal pr obl em s m ay
contr i bute to the r i sk of f al l s and m ay hav e cor r ectabl e eti ol ogi es,
ev al uati on shoul d i ncl ude a com pr ehensi v e assessm ent f or these
pr obl em s. Ophthal m ol ogi c ev al uati on of hi s poor v i si on m ay i denti f y a
r ev er si bl e pr obl em such as catar acts. Wi th better v i si on, the pati ent
m ay be abl e to nav i gate m or e saf el y and ther eby r educe hi s f al l r i sk .
Cor r ecti on of hear i ng l oss, al though not di r ectl y r el ated to v esti bul ar
f uncti on, m ay hel p i n i m pr ov i ng gai t stabi l i ty and r educi ng f al l s.
Im pai r m ent of sensati on i n the di stal ex tr em i ti es, par ti cul ar l y l oss of
posi ti on sensati on, suggesti ng dor sal spi nal tr ack di sease shoul d
tr i gger a sear ch f or tr eatabl e causes of per i pher al neur opathy such as
di abetes or B 1 2 def i ci ency .
Thi s pati ent's ur i nar y ur gency m ay contr i bute to hi s f al l s w hen he tr i es
to r ace to the bathr oom . Check i ng f or a ur i nar y tr act i nf ecti on or
tr eati ng sy m ptom ati c pr ostati c hy per tr ophy m ay r educe ur ge sy m ptom s
and r educe the r i sk of f al l i ng.
Mor e sophi sti cated and ex pensi v e tests, such as

el ectr oencephal ogr aphy , Hol ter m oni tor i ng, and CT scanni ng of the
head, m ay be per f or m ed i n pati ents w ho hav e f al l s but shoul d be done
sel ecti v el y , based on the pati ent's hi stor y and phy si cal ex am i nati on
f i ndi ngs. Because thi s pati ent has no ev i dence of sei zur e acti v i ty , an
el ectr oencephal ogr am i s unl i k el y to be r ev eal i ng. Li k ew i se, the
di agnosti c y i el d of 24hour am bul ator y car di ac m oni tor i ng w oul d
pr obabl y be v er y l ow , gi v en the l ack of car di ac sy m ptom s, and i s
unnecessar y f or thi s pati ent. If he had any f ocal neur ol ogi c def i ci ts, a
gai t di sor der , or changes i n cogni ti on, an i m agi ng study of the br ai n
(i . e. , CT scan or MRI) m i ght be hel pf ul i n r ul i ng out a subdur al
hem atom a, a str ok e, a br ai n tum or , or nor m al pr essur e hy dr ocephal us
(char acter i zed by a tr i ad of cogni ti v e i m pai r m ent, gai t di sor der , and
ur i nar y i nconti nence). If the pati ent has ev i dence of upper m otor
neur on di sease (e. g. , hy per r ef l ex i a, pl antar f l ex or or Babi nsk i 's
r esponse, i ncr eased m uscl e tone) and no ev i dence of cr ani al ner v e or
cor ti cal si gns (e. g. , m em or y i m pai r m ent, aphasi a, etc. ), then cer v i cal
m y el opathy m ay be the eti ol ogy of the pati ent's poor bal ance and
i m agi ng of the neck shoul d be consi der ed, par ti cul ar l y i f the pati ent i s
consi der ed to be a candi date f or sur gi cal cor r ecti on of spi nal cor d
i m pi ngem ent. Because thi s pati ent i s atax i c and has m i l d dem enti a and
ur i nar y i nconti nence, an i m agi ng study of hi s br ai n w oul d hel p r ul e out
a potenti al l y tr eatabl e cause of hi s gai t di sor der and f al l s, such as
nor m al pr essur e hy dr ocephal us.
P. 207
3. What i nter v enti on, or i nter v enti ons, w oul d y ou i nsti tute to decr ease
thi s pati ent's r i sk of f al l i ng?
Car ef ul scr uti ny of thi s pati ent's m edi cati on l i st m ay r ev eal
oppor tuni ti es to r educe or el i m i nate m edi cati ons that contr i bute to hi s
r i sk of f al l i ng. Pr opr anol ol m ay r educe hi s tr em or m odestl y but the
l ow er i ng of hi s bl ood pr essur e and pul se m ay be contr i buti ng to hi s f al l
r i sk . If the di phenhy dr am i ne i s causi ng hi m to be m or e cogni ti v el y
i m pai r ed, then he i s al so m or e l i k el y to hav e an i ncr eased r i sk of f al l s
as w el l . Er i c Lar son etal . noted that pati ents w hose cogni ti v e
i m pai r m ent w as i n par t due to m edi cati on si de ef f ects w er e al so thr ee
ti m es m or e l i k el y to f al l than those w hose cogni ti v e i m pai r m ent w as
due to other causes. A tr i al per i od of r educi ng or stoppi ng the
pr opr anol ol and di phenhy dr am i ne shoul d be consi der ed to see i f the
pati ent's conf usi on, di zzi ness, and or thostasi s r esol v e and hi s bal ance
i m pr ov es.
Ev en w hen a phy si ci an f ai l s to i denti f y speci f i c, r ev er si bl e eti ol ogi es of
a pati ent's r i sk f or f al l i ng, sev er al i nter v enti ons m ay hel p i n r educi ng
the r i sk of subsequent f al l s and i njur y . A pati ent w ho i s el der l y and has
m any m edi cal pr obl em s i s of ten ex pected to be f r ai l and w eak .
How ev er , ev en the f r ai l el der l y m ay i m pr ov e thei r str ength and bal ance
by par ti ci pati ng i n a r egul ar ex er ci se pr ogr am . Ev i dence has em er ged
that m odest r esi stance tr ai ni ng, i n addi ti on to aer obi c condi ti oni ng,
m ay f ur ther hel p i n i ncr easi ng m uscl e m ass and bal ance, and r educe
the r i sk of f al l s. Ref er r al to a phy si cal ther api st m ay l ead to a bal ance
and str engtheni ng pr ogr am that m ay r educe the r i sk of f al l s. How ev er ,
i f a phy si cal ther api st i s not av ai l abl e, studi es hav e show n that
enr ol l m ent i n a gr oup f i tness pr ogr am m ay hav e the sam e benef i ts as
i ndi v i dual ther apy . In one study , el der l y pati ents r andom i zed to
par ti ci pate i n the anci ent m ar ti al ar t of Tai Chi had i m pr essi v e
r educti on i n f al l r i sk com par ed w i th those w ho di d not par ti ci pate.
Ther ef or e, r egul ar ex er ci se thr ough a v ar i ety of opti ons m ay hel p i n
r educi ng the r i sk of f al l i ng.
Most f al l s am ong the el der l y occur i n the hom e setti ng. Appr ox i m atel y
one thi r d of f al l s ar e r el ated to acci dents or env i r onm ental f actor s. A
hom e saf ety assessm ent, usual l y com pl eted by a phy si cal or
occupati onal ther api st, m ay i denti f y pr ev entabl e ex tr i nsi c causes of
f al l s such as thr ow r ugs that sl i p w hen stepped on, poor l i ghti ng,
w ear i ng of unsuppor ti v e or sl i pper y f ootw ear , stor age of com m onl y
used i tem s i n out of r each pl aces, etc. Because a si ngl e v i si t m ay
i denti f y and el i m i nate m any of these r i sk s, a hom e saf ety assessm ent
i s l i k el y to be a costef f ecti v e i nter v enti on to r educe the r i sk of f al l i ng.
Recent data al so suggests that i ncr easi ng the i ntak e of v i tam i n D m ay
not onl y i ncr ease bone densi ty (and ther eby r educe r i sk of f r actur e)
but al so r educe the l i k el i hood that f al l s w i l l occur . The m echani sm i s
not w el l def i ned, but m ay , i n par t, be r el ated to the posi ti v e ef f ects of
v i tam i n D on m uscl e str ength. The opti m al dose of suppl em ental
v i tam i n D that shoul d be pr escr i bed i s not cl ear , but 800 IU dai l y
appear s to be saf e and adequate.
Fi nal l y , pati ents, thei r f am i l i es, and thei r phy si ci ans m ay be f aced w i th
the conti nued occur r ence of f al l s despi te com pr ehensi v e, m ul ti f actor i al
i nter v enti ons to pr ev ent them . The choi ces ar e not easy ones. Al l ow i ng
the pati ent to conti nue to
P. 208
am bul ate w i l l i ncur a r i sk of f utur e f al l s. Restr i cti ng a pati ent's
m obi l i ty m ay r educe the r i sk of f al l s but at the cost of i ncr easi ng
w eak ness, di suse atr ophy , l oss of i ndependence, and a sense of
despai r . Al though any i njur y that occur s dur i ng a f al l i s si gni f i cant, hi p
f r actur es cl ear l y car r y the gr eatest m or bi di ty and m or tal i ty . Studi es of
speci al l y desi gned hi p pads suggest that i f el der l y i ndi v i dual s can be
per suaded to w ear them , the r i sk of hi p f r actur e, i f they do f al l , i s
r educed.
Suggested Readings
Bi schof f Fer r ar i HA, Daw sonHughes B, Wi l l ett C, etal . Ef f ect of Vi tam i n
D on f al l s: a m etanal y si s. JAMA 2004;291:1999.
Kannus P, Par k k ar i J, N i em i S, etal . Pr ev enti on of hi p f r actur e i n el der l y

peopl e w i th use of a hi p pr otector . N Eng J Med 2000;343:1506.
Ki ng MD, Ti netti ME. Fal l s i n com m uni ty dw el l i ng ol der per sons. J Am
Ger i atr Soc 1995;43:1146.
Ti netti ME. Pr ev enti ng f al l s i n el der l y per sons. N Eng J Med 2003;348:42.
Ti netti ME, Wi l l i am s CS. Fal l s, i njur i es due to f al l s, and the r i sk of
adm i ssi on to a nur si ng hom e. N Eng J Med 1997;337:1279.
Urinary Incontinence
1. How com m on i s ur i nar y i nconti nence i n the el der l y ?
2. What ar e the nor m al changes i n bl adder phy si ol ogy that occur w i th

agi ng?
3. How i s i nconti nence cl assi f i ed, and w hat ar e the char acter i sti cs of the
di f f er ent ty pes?
4. Of w hat does the di f f er enti al di agnosi s of tr ansi ent ur i nar y i nconti nence
consi st?
Discussion
1. How com m on i s ur i nar y i nconti nence i n the el der l y ?
U r i nar y i nconti nence, the i nv ol untar y l oss of ur i ne, af f ects 10 m i l l i on

Am er i cans. Of peopl e ol der than 65 y ear s, 5% of m en and 25% of
w om en hav e pr obl em s w i th i nconti nence. In 1987 al one, the di r ect cost
of the pr obl em w as m or e than $10 bi l l i on. Inconti nence adds $3 to $12
per day to the cost of nur si ng hom e car e, and 50% to 90% of al l
nur si ng hom e r esi dents ex per i ence som e i nconti nence.
Besi des the si gni f i cant ex pense caused, i nconti nence i s a sour ce of
m any m edi cal com pl i cati ons, such as r ashes, pr essur e ul cer s,
catheter i zati on, ur i nar y tr act i nf ecti ons, f al l s, and f r actur es. Ther e ar e
al so soci al consequences, such as em bar r assm ent, i sol ati on, and
depr essi on. It al so adds to car egi v er str ess.
2. What ar e the nor m al changes i n bl adder phy si ol ogy that occur w i th

agi ng?
Bl adder capaci ty and com pl i ance decl i ne w i th agi ng, as does the abi l i ty
to postpone v oi di ng. Ther e ar e al so m or e f r equent uni nhi bi ted bl adder
P. 209
contr acti ons and an i ncr ease i n the r esi dual v ol um e of ur i ne. Because
of an ager el ated decr ease i n the gl om er ul ar f i l tr ati on r ate and a del ay
i n the ex cr eti on of a w ater l oad, appr ox i m atel y tw o thi r ds of f l ui d i s
ex cr eted i n the ev eni ng r ather than dur i ng the day . Thi s l eads to
noctur nal ur i nar y f r equency and the r i sk of noctur nal ur i nar y
i nconti nence.
Ther e ar e al so sex speci f i c changes. Estr ogen def i ci ency i n w om en

l eads to w eak ened sphi ncter tone and changes i n the posi ti on of the
bl adder neck . The ur ethr al l ength shor tens and the m ax i m al ur ethr al
cl osur e pr essur es decl i ne. In m en, pr ostati c enl ar gem ent can
potenti al l y bl ock ur i ne outf l ow . Al l of these changes pr edi spose el der l y
pati ents to i nconti nence. The encour agi ng new s i s that 50% of the
cases ar e tr ansi ent and tw o thi r ds of the r em ai ni ng cases can be ei ther
cur ed or m ar k edl y al l ev i ated w i th ther apy .
3. How i s i nconti nence cl assi f i ed, and w hat ar e the char acter i sti cs of the
di f f er ent ty pes?
U rge inc ontine nc e i s the m ost com m on ty pe of i nconti nence i n the
el der l y , accounti ng f or appr ox i m atel y 80% of cases. Af f l i cted pati ents
of ten descr i be a sudden uncontr ol l abl e ur ge to v oi d that m ay not al l ow
them ti m e to r each the bathr oom . The ur ge i s caused by contr acti on of
the bl adder 's detr usor m uscl e, w hi ch f or ces m oder ate to l ar ge v ol um es
of ur i ne out thr ough the ur ethr a. Centr al ner v ous sy stem di seases
(e. g. , str ok e, AD, Par k i nson's di sease, a pr i m ar y br ai n tum or , or
m etastati c di sease) and pr i m ar y di sease of the bl adder (e. g. ,
car ci nom a, the ef f ects of r adi ati on tr eatm ent, or bl adder outl et
obstr ucti on) m ay be associ ated w i th ur ge i nconti nence.
Stre s s inc ontine nc e i s par ti cul ar l y com m on i n el der l y w om en. In pur e
str ess i nconti nence, l eak age occur s w i th i ncr eases i n pr essur e caused
by coughi ng, sneezi ng, l aughi ng, or l i f ti ng; onl y a sm al l am ount of
ur i ne l eak s out af ter a del ay of 5 to 15 seconds. The sour ce of the
pr obl em i n w om en i s usual l y ur ethr al hy per m obi l i ty due to l ax i ty of the
pel v i c f l oor m uscul atur e caused by chi l dbear i ng. In m en, str ess
i nconti nence i s l ess com m on but m ay occur i f the ur ethr al sphi ncter i s
dam aged dur i ng tr ansur ethr al or r adi cal pr ostatectom y .
Ove rflow inc ontine nc e i s caused ei ther by outl et obstr ucti on or by an
atoni c bl adder (i . e. , i nef f ecti v e detr usor contr acti on due to m y ogeni c
or neur ol ogi c causes). Leak age of sm al l am ounts of ur i ne m ay occur
thr oughout the day and ni ght. Pati ents m ay al so descr i be ur i nar y
hesi tancy and a f eel i ng of i ncom pl ete em pty i ng. On abdom i nal
ex am i nati on, a di stended bl adder m ay be pal pated ev en af ter the
pati ent has attem pted to v oi d.
Re fle x inc ontine nc e i s usual l y due to a supr asacr al spi nal cor d l esi on.
As the bl adder di stends, contr acti on occur s. Leak age i s not associ ated
w i th str ess and ther e i s no w ar ni ng bef or e the onset of ur i nati on.
Inconti nence epi sodes ar e of m oder ate v ol um e and occur f r equentl y .
Func tiona l inc ontine nc e i s due to a pr obl em unr el ated to the ur i nar y
tr act. Ex am pl es ar e i m pai r ed m obi l i ty or m etabol i c pr obl em s such as
hy per gl y cem i a or m i l d r enal i nsuf f i ci ency . Thi s di agnosi s can be m ade
onl y by tak i ng a v er y car ef ul hi stor y and af ter ex cl udi ng the pr ev i ousl y
l i sted causes. Functi onal i nconti nence m ay r esul t f r om the use of
i atr ogeni c dr ugs that i m pai r cogni ti on or f r om i m posed l i m i tati ons on
m obi l i ty , such as r estr ai nts.
P. 210
Because ur i nar y i nconti nence i n the el der l y i s of ten m ul ti f actor i al , al l
potenti al l y contr i buti ng r i sk f actor s shoul d be car ef ul l y r ev i ew ed to
deter m i ne i ts cause.
4. Of w hat does the di f f er enti al di agnosi s of tr ansi ent ur i nar y i nconti nence
consi st?
An acute change i n a pati ent's m ental status (del i r i um ) or a m ood

di sor der (depr essi on) m ay contr i bute to f uncti onal i nconti nence, such
as the pati ent w ho i s too conf used to f i nd a bathr oom or too
despondent to car e about per sonal hy gi ene. Endstage dem enti a m ay
r ender a pati ent i ncapabl e of r ecogni zi ng the ur ge to v oi d.
U r i nar y tr act i nf ecti on m ay l ead to i r r i tati on of the detr usor m uscl e and
ther ef or e cause ur i nar y f r equency and ur gency . Si m i l ar l y , i nf l am m ati on
caused by atr ophi c ur ethr i ti s or v agi ni ti s m ay contr i bute to i ncr eased
ur ge.
Medi cati ons m ay f oster ur i nar y i nconti nence i n a v ar i ety of w ay s.

Sedati v es depr ess the l ev el of consci ousness, l eadi ng to a f uncti onal
i nconti nence. Di ur eti cs i ncr ease the ur i ne v ol um e, w hi ch then i ncr eases
ur i nar y f r equency . A l ar ger ur i ne v ol um e m ay then tr i gger m or e
f r equent epi sodes of bl adder spasm and augm ent the r i sk of ur ge
i nconti nence. Anti chol i ner gi c m edi cati ons, such as anti hi stam i nes,
tr i cy cl i c anti depr essants, and anti psy choti cs, i nhi bi t detr usor
contr acti ons and l ead to ov er f l ow i nconti nence. Cal ci um channel
bl ock er s (e. g. , ni f edi pi ne, v er apam i l , and di l ti azem ) m ay si m i l ar l y
decr ease detr usor contr acti l i ty and w or sen ov er f l ow i nconti nence.
Endocr i ne condi ti ons such as hy per gl y cem i a and hy per cal cem i a cause
ur i nar y f r equency and, l i k e di ur eti cs, i ncr ease ur i ne v ol um es, and
hence the r i sk of i nconti nence. Restr i cted m obi l i ty due to sev er e
ar thr i ti s, str ok e, car di ac di sease, or any other debi l i tati ng condi ti on
m ay si m pl y pr ev ent a pati ent f r om r eachi ng the bathr oom i n ti m e (i . e. ,
f uncti onal i nconti nence). Fi nal l y , stool i m pacti on m ay contr i bute to
pel v i c ner v e com pr essi on, l eadi ng to an atoni c bl adder and ov er f l ow
i nconti nence.
Case
A 73y ear ol d m other of si x i s br ought to y our of f i ce by her daughter to
establ i sh her m other 's pr i m ar y car e i n tow n. The pati ent has com e to l i v e
w i th her daughter af ter her husband di ed 6 m onths ago. The pati ent's
chi l dr en ar e concer ned that she i s depr essed and r epor t she i s not getti ng
out of her house ex cept w hen she has a doctor 's appoi ntm ent. Her past
m edi cal hi stor y i s r em ar k abl e f or hy per tensi on (f or w hi ch she tak es
hy dr ochl or othi azi de dai l y ) and som e ar thr i ti s i n her k nees. She has
under gone no sur gi cal pr ocedur es. She deni es any other pr obl em s, but,
w hen speci f i cal l y ask ed, she adm i ts to hav i ng ur i nar y i nconti nence f or
sev er al y ear s, w hi ch has been w or se dur i ng the past f ew w eek s. She
descr i bes getti ng the ur ge to v oi d al m ost ev er y hour and, i f she does not
get to the bathr oom i n a m atter of m i nutes, she has star ted to l ose enough
ur i ne such that she now needs to w ear adul t pads. When ask ed i f she l oses
ur i ne w hen she coughs or l aughs, she conf i r m s that thi s has occur r ed f or
m any y ear s. She say s that she has not r epor ted thi s em bar r assi ng pr obl em
to her pr ev i ous phy si ci ans because they nev er ask ed, and has attr i buted i t
to â€œjust getti ng ol d. â€ She and her husband had stopped hav i ng sex
because she w as af r ai d that i t w oul d m ak e her i nconti nence w or se.
P. 211
Phy si cal ex am i nati on r ev eal s a heal thy appear i ng el der l y w om an w hose v i tal
si gns ar e nor m al , i ncl udi ng her bl ood pr essur e, w hi ch i s 130/76 m m Hg. Her
ex am i nati on f i ndi ngs ar e unr em ar k abl e ex cept f or her pel v i s, w hi ch ex hi bi ts
atr ophi c m ucosa and a gr ade III cy stocel e (bl adder and ur ethr a pr otr udi ng).
She i s ask ed to cough and a sm al l am ount of ur i ne l eak s f r om the ur ethr a.
The r ectal f i ndi ngs ar e nor m al and ther e i s good r ectal tone. N eur ol ogi c
f i ndi ngs ar e nor m al , i ncl udi ng a nor m al anal w i nk (suggesti ng i ntact
sphi ncter ), and ther e ar e no l um bosacr al neur ol ogi c f i ndi ngs. Labor ator y
ev al uati on r ev eal s nor m al el ectr ol y te and cr eati ni ne v al ues and a r andom
bl ood gl ucose l ev el of 240 m g/dL. U r i nal y si s, w i th ur i ne obtai ned by
catheter i zati on, r ev eal s 5 to 10 w hi te bl ood cel l s per hi ghpow er f i el d, no
epi thel i al cel l s, 2+ bacter i a, and 3+ gl ucose.
1. Of w hat does the di f f er enti al di agnosi s of thi s pati ent's i nconti nence
consi st?
2. What conser v ati v e tr eatm ents coul d y ou tr y i n thi s pati ent?
3. If these m easur es hel p but do not el i m i nate her i nconti nence
com pl etel y , w hat w oul d be the nex t step i n tr eatm ent?
4. How w oul d the em phasi s of y our ev al uati on di f f er f or a m al e pati ent?
Case Discussion
1. Of w hat does the di f f er enti al di agnosi s of thi s pati ent's i nconti nence
consi st?
Thi s pati ent descr i bes sy m ptom s of the m ost com m on ty pe of
i nconti nence i n the el der l y , nam el y , ur ge i nconti nence. She has a
hi stor y of si x v agi nal del i v er i es and al so has cor r espondi ng sy m ptom s
of str ess i nconti nence, w i th suggesti v e f i ndi ngs di scov er ed on
ex am i nati on (i . e. , ur i ne l eak s w hen she l aughs). The ur i nal y si s f i ndi ngs
ar e abnor m al , i ndi cati ng a possi bl e ur i nar y tr act i nf ecti on that coul d be
ex acer bati ng her sy m ptom s of ur gency and f r equency . It m ay ex pl ai n
the w or seni ng of sy m ptom s i n the past f ew w eek s. An el ev ated bl ood
gl ucose l ev el m ay f oster an osm oti c di ur esi s that i ncr eases ur i ne
v ol um es and ther eby adds to the r i sk of i nconti nence.
Fear of l eav i ng her hom e and the consequent soci al i sol ati on m ay hav e
been pr eci pi tated by her i nconti nence because pati ents pr one to ur ge
i nconti nence of ten l i m i t thei r acti v i ti es to av oi d em bar r assi ng
acci dents. On v i sual i nspecti on, she w as f ound to hav e an atr ophi c
m ucosa, w hi ch m ay suggest estr ogen def i ci ency . Si m i l ar atr ophy m ay
occur i n the ur ethr al m ucosa, w hi ch i n tur n r educes ur ethr al sphi ncter
com petence.
She i s on a di ur eti c, w hi ch m ay al so ex acer bate her i nconti nence. Her
bl ood pr essur e m ay r espond ei ther to another agent or to di et al one,
w i th w ei ght r educti on and sodi um r estr i cti on. She al so has ar thr i ti s i n
her k nees, w hi ch l i m i ts her abi l i ty to get to the bathr oom i n ti m e. It
m ay be that the bathr oom i s f ar ther f r om the bedr oom i n her
daughter 's hom e, and thi s coul d contr i bute to the r ecent w or seni ng of
sy m ptom s. A si m pl e r ear r angem ent of her bedr oom f ur ni tur e m ay put
her bed cl oser to the toi l et and r educe the r i sk of noctur nal
i nconti nence by shor teni ng the di stance she needs to tr av el to the
bathr oom .
2. What conser v ati v e tr eatm ents coul d y ou tr y i n thi s pati ent?
Fi r st, the easi l y r ev er si bl e causes need to be el i m i nated. A car ef ul

ev al uati on, i ncl udi ng a pel v i c ex am i nati on, m ust pr ecede any
tr eatm ent. It w oul d be r easonabl e
P. 212
to hav e her ur i ne cul tur ed and to tr eat her f or a ur i nar y tr act i nf ecti on,
to see i f the ur gency di ssi pates. If she has no contr ai ndi cati ons to
estr ogen r epl acem ent, such tr eatm ent coul d be gi v en or al l y or topi cal l y
to al l ev i ate the atr ophi c ur ethr i ti s. Her di ur eti c m edi cati on coul d be
di sconti nued and r epl aced w i th a di f f er ent agent, i f w ei ght l oss and
sodi um r educti on f ai l to contr ol her bl ood pr essur e. If the di stance
f r om the bedr oom to the bathr oom i s a sour ce of noctur nal
i nconti nence, getti ng the pati ent a bedsi de com m ode can al l ev i ate the
pr obl em . Tr eatm ent of her di abetes, ei ther w i th di et, or al agents, or
i nsul i n, w i l l hel p decr ease the ur i ne v ol um e. In gener al , i t i s
r easonabl e to counsel al l pati ents com pl ai ni ng of i nconti nence to
r ef r ai n f r om dr i nk i ng too m uch f l ui d bef or e goi ng out or near bedti m e.
3. If these m easur es hel p but do not el i m i nate her i nconti nence
com pl etel y , w hat w oul d be the nex t step i n tr eatm ent?
The pati ent has sy m ptom s of both ur ge and str ess i nconti nence.
How ev er , the possi bi l i ty of ov er f l ow i nconti nence shoul d al so be
assessed. Thi s i s done by catheter i zi ng the pati ent af ter she has v oi ded
to see i f ther e i s ur i nar y r etenti on (> 100 m L), w hi ch w oul d i ndi cate
possi bl e ov er f l ow i nconti nence. N ei ther str ess nor ur ge i nconti nence
al one shoul d cause a hi gh postv oi d r esi dual v ol um e. Behav i or al
techni ques ar e v er y ef f ecti v e i n al l ev i ati ng both ur ge and str ess
i nconti nence. Because the uni nhi bi ted bl adder spasm s associ ated w i th
ur ge i nconti nence ar e br i ef , the pati ent shoul d be i nstr ucted to si t
cal m l y and al l ow the ur ge to pass. Jum pi ng up to go to the bathr oom
onl y accentuates abdom i nal pr essur e dur i ng the contr acti on and m ak es
the l eak age of ur i ne m or e l i k el y . Behav i or m odi f i cati on al one can
consi der abl y ease the pati ent's ur ge i nconti nence. Wom en w i th str ess
i nconti nence m ay r educe l oss of ur i ne by per f or m i ng ex er ci ses that
str engthen the pel v i c f l oor m uscl es. To teach pati ents these ex er ci ses
(Kegel ex er ci ses), ask the pati ent to f eel the m uscl es she uses to stop
her str eam of ur i ne or a bow el m ov em ent. She m ust contr act these
m uscl es w i thout al so contr acti ng the abdom i nal m uscl es 10 to 15 ti m es,
thr ee ti m es a day . Thi s pr acti ce m ust be conti nued to r em ai n ef f ecti v e.
If the i nconti nence per si sts ev en af ter di l i gent ex er ci si ng f or sev er al
w eek s or m onths, the pati ent shoul d be r ef er r ed to a gy necol ogi st f or
consi der ati on of sur gi cal cor r ecti on of pel v i c f l oor l ax i ty .
4. How w oul d the em phasi s of y our ev al uati on di f f er f or a m al e pati ent?
Ov er f l ow i nconti nence associ ated w i th bl adder outl et obstr ucti on
r esul ti ng f r om beni gn pr ostati c hy per tr ophy i s an i m por tant cause of
i nconti nence, uni que to m en. Ther ef or e, m en shoul d be ask ed car ef ul l y
about ur i nar y f r equency and hesi tancy , a decr ease i n the f or ce of the
ur i ne str eam , and i f they ex per i ence a sensati on of i ncom pl ete
em pty i ng. It i s m or e i m por tant to ev al uate the postv oi d r esi dual
v ol um e ear l y i n the w or k up of a m an. A l ow r esi dual v ol um e does not
absol utel y r ul e out obstr ucti on because of the i nter m i ttent natur e of
such an obstr ucti on. How ev er , i f the v ol um e i s gr eater than
appr ox i m atel y 250 m L, the di agnosi s of bl adder outl et obstr ucti on i s
v er y l i k el y . Most ur ol ogi sts per f or m cy stoscopy bef or e pr ostati c
sur ger y to conf i r m the di agnosi s and r ul e out detr usor f l acci di ty i n m en
w i th l ar ge postv oi d r esi dual ur i ne v ol um es. If the pati ent has a f l acci d
bl adder , the ur ol ogi st m ay be r el uctant to per f or m pr ostate sur ger y
because such pati ents ar e l i k el y to conti nue to r equi r e ei ther
per m anent or i nter m i ttent postoper ati v e catheter i zati on.
P. 213
U r ge i nconti nence i s al so an i m por tant di agnosi s i n m al e pati ents. It
of ten coex i sts w i th obstr ucti on because a di stended bl adder i s m or e
pr one to contr acti ons. Ther ef or e, m en tr eated f or sy m ptom s of outl et
obstr ucti on m ust al so be ask ed about sy m ptom s of ur gency that m ay
r equi r e addi ti onal tr eatm ent to pr ev ent conti nued ur i nar y i nconti nence
af ter sur gi cal cor r ecti on of ur i nar y tr act obstr ucti on.
Suggested Readings
Consensus Conf er ence. U r i nar y i nconti nence i n adul ts. JAMA
1989;261:2685.
Fantl JA, N ew m an DK, Col l i ng J, etal . U r i nar y i nconti nence i n adul ts:
acute and chr oni c m anagem ent. U . S. Depar tm ent of Heal th and Hum an
Ser v i ces, Agency f or Heal th Car e Pol i cy and Resear ch. Rock v i l l e, MD,
U . S. Gov er nm ent Pr i nti ng Of f i ce, 1996.
McDow el l BJ, Bur gi o KL, Dom br ow sk i M, etal . An i nter di sci pl i nar y
appr oach to the assessm ent and behav i or al tr eatm ent of ur i nar y
i nconti nence i n ger i atr i c outpati ents. J Am Ger i atr Soc 1991;40:370.
Medication Use in the Elderly
1. What i s pol y phar m acy , and i s i t a si gni f i cant pr obl em i n the el der l y ? If
so, w hy ?
2. Why do el der l y pati ents ex per i ence an i ncr eased i nci dence of adv er se
dr ug r eacti ons (ADRs)?
3. N am e sev er al w ay s i n w hi ch ADRs m i ght be associ ated w i th each of the
f ol l ow i ng i n el der l y pati ents: new m edi cati ons, the l ongter m use of
dr ugs, and the sudden cessati on of m edi cati ons.
Discussion
1. What i s pol y phar m acy , and i s i t a si gni f i cant pr obl em i n the el der l y ? If
so, w hy ?
Pol y phar m acy i s the concur r ent use of m any m edi cati ons. Al though thi s
ter m i s m ost of ten used to r ef er to the use of â€œtoo m any
m edi cati ons, â€ som e pati ents w i th m ul ti pl e m edi cal pr obl em s m ay be
appr opr i atel y r ecei v i ng sev er al pr escr i pti on m edi cati ons. Because
m edi cati ons ar e a com m on cause of r ev er si bl e pr obl em s i n the el der l y
(e. g. , dr ugi nduced conf usi on and or thostati c hy potensi on), each
m edi cati on pr escr i bed f or an el der l y per son m ust be car ef ul l y
scr uti ni zed to deter m i ne w hether the benef i ts outw ei gh the adv er se
ef f ects of the dr ug. Because the adv er se ef f ects f r equentl y outw ei gh
the benef i ts, i t has been sai d of good ger i atr i ci ans that they â€œstop
m or e m edi cati ons than they star t. â€
Pol y phar m acy i s a ser i ous pr obl em i n the el der l y . An av er age el der l y
per son tak es tw o to f i v e pr escr i pti on m edi cati ons as w el l as thr ee to
f our ov er thecounter dr ugs. Al though el der l y Am er i cans (ol der than 65
y ear s) consti tute 12% of the U . S. popul ati on, they consum e
appr ox i m atel y 25% of
P. 214
al l pr escr i pti on m edi cati ons. They ar e ther ef or e not onl y ex posed to
m or e dr ugs but al so to m or e potenti al adv er se dr ug ef f ects. Indeed,
ol der peopl e hav e thr ee to sev en ti m es m or e ADRs than y ounger
pati ents, and the f r equency of ADRs cor r el ates w i th the num ber of
m edi cati ons used.
2. Why do el der l y pati ents ex per i ence an i ncr eased i nci dence of ADRs?
The m anagem ent of dr ug ther apy i n the el der l y di f f er s f r om that i n

y ounger pati ents, and the r esul ti ng hi gher i nci dence of pol y phar m acy i n
the el der l y popul ati on i ncr eases the r i sk of dr ugâ€“dr ug i nter acti ons.
These i nter acti ons m ay r esul t f r om the al ter ed absor pti on, ex cr eti on,
or pr otei n bi ndi ng of the dr ugs i nv ol v ed. In addi ti on, unanti ci pated dr ug
ef f ects m ay occur i f one dr ug enhances or i nter f er es w i th the hepati c
m etabol i sm of another . Such i nter acti ons m ay r esul t i n ei ther tox i c or
subther apeuti c dr ug l ev el s.
Com or bi di ty adds to the i nci dence of ADRs because the si gns and
sy m ptom s of a pr eex i sti ng di sease m ay be w or sened by the ef f ects of
m edi cati ons gi v en to tr eat another di sor der . Thi s can r esul t ei ther f r om
the w or seni ng of an under l y i ng di sease pr ocess by the of f endi ng dr ug
(e. g. , the use of Î² 2 bl ock er s i n pati ents w i th chr oni c obstr ucti v e
pul m onar y di sease or congesti v e hear t f ai l ur e) or because the si gns
and sy m ptom s of the dr ug's si de ef f ects m i r r or and, ther ef or e,
i ntensi f y those of the under l y i ng di sease pr ocess. An ex am pl e of thi s i s
the ur i nar y r etenti on caused by anti chol i ner gi c m edi cati ons (e. g. ,
tr i cy cl i c anti depr essants and di phenhy dr am i ne) i n a pati ent w i th an
enl ar ged pr ostate. The r etenti on occur s because the enl ar ged pr ostate
obstr ucts the ur i ne f l ow and the anti chol i ner gi c m edi cati on w eak ens
detr usor contr acti on.
El der l y pati ents of ten hav e l ess phy si ol ogi c r eser v e and ther ef or e
handl e phy si ol ogi c str ess l ess successf ul l y than y ounger pati ents. The
am ount of phy si ol ogi c r eser v e v ar i es am ong el der l y pati ents and ev en
am ong di f f er ent or gan sy stem s i n the sam e i ndi v i dual . Som eti m es
phy si ci ans obtai n basel i ne m easur em ents to assess a pati ent's r eser v e.
For ex am pl e, the cr eati ni ne cl ear ance m ay suggest how m uch k i dney
r eser v e i s l ef t. Ther ef or e, the r i sk of ADRs m ay be m i ni m i zed by the
car ef ul ev al uati on of an i ndi v i dual el der l y pati ent's r enal f uncti on
bef or e pr escr i bi ng potenti al l y tox i c m edi cati ons. Som eti m es, si m pl y
r educi ng the dosage m ay conf er an adequate ther apeuti c ef f ect w i thout
pr oduci ng tox i ci ty . Those el der l y pati ents w i th better r eser v e w ho ar e
capabl e of m or e nor m al m etabol i sm of m edi cati ons m ay need the sam e
dosage as y ounger pati ents to obtai n a ther apeuti c ef f ect. In sum m ar y ,
ther apy m ust be i ndi v i dual i zed to obtai n the opti m um ef f ect f r om
m edi cati on w hi l e av oi di ng tox i ci ty .
Ager el ated phy si ol ogi c changes i n the el der l y i ncl ude a decl i ne i n l ean
m uscl e m ass and total body w ater content, w i th an i ncr eased
pr opor ti on of total body f at. These changes af f ect dr ug di sposi ti on i n
the f ol l ow i ng m anner : l ess total body w ater tr ansl ates i nto a sm al l er
v ol um e of di str i buti on f or w ater sol ubl e m edi cati ons, r esul ti ng i n
hi gher thananti ci pated ser um concentr ati ons. Because adi pose ti ssue
i s of ten pr opor ti onatel y gr eater i n ol der pati ents, the v ol um e of
di str i buti on f or f atsol ubl e m edi cati ons i ncr eases,
P. 215
pr ol ongi ng the el i m i nati on per i od. Another phy si ol ogi c change of gr eat
i m por tance i s a decl i ne i n r enal f uncti on w i th age, occur r i ng i n
appr ox i m atel y 65% of el der l y peopl e. For the el der l y , the ser um
cr eati ni ne concentr ati on al one i s an unr el i abl e i ndi cator of k i dney
f uncti on because i t depends on the am ount of m uscl e m ass, w hi ch
decr eases w i th adv anci ng age. Instead, cr eati ni ne cl ear ance i s a m or e
accur ate esti m ate of r enal f uncti on i n the el der l y . Ager el ated
phy si ol ogi c changes i n hepati c m etabol i sm and pr otei n bi ndi ng usual l y
hav e l ess i m pact on dr ug m etabol i sm than the decl i ne i n r enal f uncti on.
3. N am e sev er al w ay s i n w hi ch ADRs m i ght be associ ated w i th each of the
f ol l ow i ng i n el der l y pati ents: new m edi cati ons, the l ongter m use of
dr ugs, and the sudden cessati on of m edi cati ons.
Ne w me dic a tions m ay el i ci t ADRs by pr oduci ng pr edi ctabl e si de

ef f ects, especi al l y i f the si de ef f ects ex acer bate pr eex i sti ng di sease
r el ated sy m ptom s. For ex am pl e, pr eex i sti ng postur al hy potensi on can
be w or sened by tr i cy cl i c anti depr essants. N ew m edi cati ons can al so
cause adv er se ef f ects i f the dosages pr escr i bed ar e not appr opr i ate f or
the el der l y , l eadi ng to dr ug i ntox i cati on. For ex am pl e, di gox i n tox i ci ty
m ay occur i f the phy si ci an f ai l s to adjust the dosage to accom m odate
r enal i m pai r m ent. When new m edi cati ons ar e added to an al r eady
com pl i cated m edi cal r egi m en, thi s m ay al so f oster noncom pl i ance,
ei ther because of pati ent f r ustr ati on about hav i ng to tak e so m any pi l l s
or because of conf usi on ov er com pl i cated dosi ng schedul es. N ew
m edi cati ons can pr eci pi tate ADRs w hen they becom e i nv ol v ed i n dr ugâ
€“dr ug i nter acti ons, as pr ev i ousl y di scussed. Fi nal l y , pati ents m ay not
tol er ate new m edi cati ons f or i di osy ncr ati c r easons, ther eby
em phasi zi ng the need f or phy si ci ans to m ai ntai n v i gi l ance i n detecti ng
an ADR. Contr i buti ng to thi s i s the f act that dr ug si de ef f ects m ay not
be r ecogni zed as such by pati ents because they ascr i be thei r sy m ptom s
to ol d age.
The longte rm us e of me dic a tions m ay be associ ated w i th an ADR
w hen a pati ent's r enal , hepati c, or nutr i ti onal status changes w i thout a
concom i tant dose adjustm ent. For i nstance, a dr ug dose tol er ated f or
m any y ear s m ay becom e tox i c as r enal cl ear ance decl i nes. In addi ti on,
ADRs r esul t w hen new m edi cati ons adv er sel y af f ect the
phar m acok i neti cs of m edi cati ons that el der l y pati ents hav e other w i se
tol er ated f or y ear s. An ex am pl e of such i nter acti ons i s the di gox i n
tox i ci ty that occur s secondar y to decr eased cl ear ance af ter the addi ti on
of v er apam i l to a m edi cal r egi m en.
Changes i n com pl i ance can r esul t i n ADRs. N oncom pl i ance i s a com m on

ger i atr i c pr obl em , w i th esti m ates r angi ng f r om 26% to 59% f or the
ger i atr i c popul ati on, and pol y phar m acy i ncr eases the i nci dence of
noncom pl i ance. Com pl i ance can be i m pr ov ed w hen phy si ci ans r egul ar l y
ask thei r pati ents i n a nonjudgm ental m anner about thei r m edi cati on
use, si m pl i f y the m edi cal r egi m en, and r em i nd el der l y pati ents about
the need f or each m edi cati on. Other f actor s that i nf l uence com pl i ance
i ncl ude cogni ti v e, f i nanci al , and f uncti onal changes.
P. 216
ADRs can al so occur w hen a pati ent i s hospi tal i zed and star ted on a
m edi cal r egi m en that the phy si ci an i ncor r ectl y assum ed w as bei ng
f ol l ow ed at hom e. If the pati ent has been tak i ng f ew er pi l l s than
actual l y pr escr i bed, thi s â€œenf or cedâ€ com pl i ance m ay pr eci pi tate
tox i ci ty al though the dosi ng schedul e m ay seem cor r ect.
Fi nal l y , m any dr ugs com m onl y used i n the el der l y ar e associ ated w i th
w ithdra w a l s yndrome s . Of par ti cul ar i m por tance ar e the psy chotr opi c
dr ugs, such as the benzodi azepi nes, anti psy choti cs, and
anti depr essants. Dr ug w i thdr aw al sy ndr om es m ay occur i f these
m edi cati ons ar e di sconti nued abr uptl y or taper ed too qui ck l y , and
shoul d be consi der ed as a potenti al sour ce of a m ar k ed change i n an
el der l y pati ent's behav i or . Dr ug w i thdr aw al m ay occur ev en w hen
ther apeuti c and not necessar i l y hi gh doses ar e abr uptl y di sconti nued.
U nf or tunatel y , dr ug w i thdr aw al f r equentl y goes unr ecogni zed, l eadi ng
to potenti al l y pr ev entabl e adv er se com pl i cati ons. Agi tati on and
del i r i um ar e am ong the m or e com m on sy m ptom s associ ated w i th
w i thdr aw al f r om som e psy chotr opi c dr ugs. For thi s r eason, i t i s
i m por tant to consi der dr ug w i thdr aw al as a possi bl e cause of any
unex pl ai ned del i r i um .
Case
An 81y ear ol d m an w ho w as adm i tted to the hospi tal 2 day s ago f or the
ev al uati on of epi gastr i c bur ni ng i n conjuncti on w i th hem occul tposi ti v e
stool s and anem i a suddenl y ex hi bi ts conf usi on. He has under gone endoscopy
and w as f ound to hav e gastr i ti s. Hi s hem atocr i t r eadi ng has r em ai ned stabl e
and di schar ge pl anni ng i s i n pr ogr ess. Hi s abdom i nal sy m ptom s hav e been
al l ev i ated w i th the addi ti on of the H 2 bl ock er , ci m eti di ne.
Hi s past m edi cal hi stor y i s l i m i ted, and he i s v ague w hen answ er i ng
questi ons about i t. Hi s daughter has r epor ted that he has dem enti a. N o
other m edi cal pr obl em s hav e been i denti f i ed. The pati ent deni ed al cohol or
tobacco use on adm i ssi on. The m edi cati ons he w as tak i ng bef or e adm i ssi on
ar e unk now n, but he i s cur r entl y bei ng gi v en ci m eti di ne (400 m g or al l y
tw i ce dai l y ) and di phenhy dr am i ne (25 m g or al l y at ni ght, as needed) f or
i nsom ni a. He has no k now n dr ug al l er gi es.
The pati ent i s a w i dow ed, r eti r ed pl um ber w ho l i v es al one. Hi s f am i l y
hi stor y i s noncontr i butor y and a r ev i ew of sy stem s i s si gni f i cant f or
i nsom ni a.
The nur ses r el ate that the pati ent w as w el l dur i ng the day , but becam e
pr ogr essi v el y conf used dur i ng the ev eni ng. He i s f ound to be di sor i ented
and i r r i tabl e, w i th hi s m ental status f l uctuati ng betw een agi tati on, w i th
per ceptual di stor ti ons and v i sual hal l uci nati ons, and hy per som nol ence.
Phy si cal ex am i nati on r ev eal s the f ol l ow i ng f i ndi ngs: bl ood pr essur e, 140/80
m m Hg; tem per atur e, 98. 6Â°F (37. 0Â°C); pul se, 80 beats per m i nute; and
r espi r ati ons, 16 per m i nute. Ther e ar e no or thostati c changes.
The pati ent i s unabl e to cooper ate f ul l y w i th m ental status testi ng but i s
noted to be di sor i ented to ti m e and pl ace and appear s anx i ous. He i s
f l ushed. Head, ey e, ear , nose, and thr oat f i ndi ngs, as w el l as the car di ac,
pul m onar y , and abdom i nal f i ndi ngs ar e unr em ar k abl e. N eur ol ogi c
ex am i nati on r ev eal s nonf ocal f i ndi ngs. Hi s cr ani al ner v es ar e i ntact and
ther e
P. 217
i s no aster i x i s. Hi s r ef l ex es ar e 2+ and sy m m etr i c. Hi s m otor abi l i ty i s
scor ed as 5/5 and sy m m etr i c. Hi s sensati on i s i ntact to l i ght touch, al though
other sensor y m odal i ti es cannot be tested. Hi s toes ar e dow ngoi ng
bi l ater al l y and he has no cer ebel l ar abnor m al i ti es.
You cor r ectl y ascer tai n that the pati ent's cur r ent behav i or cannot si m pl y be
due to w or seni ng of hi s under l y i ng dem enti a but i s consi stent w i th del i r i um .
To ex cl ude m etabol i c, i nf ecti ous, tr aum ati c, or neur ol ogi c causes, the
f ol l ow i ng data ar e obtai ned: w hi te bl ood cel l count, 6, 000 cel l s/m m 3 w i th a
nor m al di f f er enti al ; hem atocr i t, 35% and stabl e com par ed w i th adm i ssi on;
pl atel ets, 350 Ã— 10 3 /m m 3 ; sodi um , 140 m Eq/L; chl or i de, 105 m Eq/L;
cr eati ni ne, 0. 9 m g/dL; potassi um , 4. 0 m Eq/L; CO 2 , 27 m Eq/L; bl ood ur ea
ni tr ogen, 12 m g/dL; gl ucose, 125 m g/dL; cal ci um , 9. 0 m g/dL; ar ter i al bl ood
gases, nor m al ; aspar tate am i notr ansf er ase, 20 U /L (nor m al r ange, 14 to 30
IU /L); al k al i ne phosphatase, 175 IU /L (nor m al r ange, 30 to 110 IU /L); total
bi l i r ubi n, 0. 4 m g/dL; thy r oi dsti m ul ati ng hor m one, 4 U /m L (nor m al r ange,
0. 5 to 5 Âµ U /m L); v i tam i n B 1 2 , 600 pg/m L (nor m al r ange, 225 to 800
pg/m L); and r api d pl asm a r eagi n, nonr eacti v e.
N o py ur i a i s f ound on ur i nal y si s and bl ood speci m ens ar e sent f or cul tur e. A
chest r adi ogr aph and el ectr ocar di ogr am ar e nor m al , as i s a CT scan of the
head, w hi ch show s no ev i dence of hem or r hage.
The di phenhy dr am i ne i s di sconti nued and the pati ent's daughter i s cal l ed
and tol d of her f ather 's condi ti on. She r epor ts that on enter i ng her f ather 's
apar tm ent that ev eni ng, she di scov er ed a hal f em pty bottl e of l or azepam (a
benzodi azepi ne) that she had not k now n he w as tak i ng.
1. Whi ch of the pati ent's sy m ptom s ar e consi stent w i th del i r i um ?
2. Is the pr esentati on of benzodi azepi ne w i thdr aw al i n el der l y pati ents
di f f er ent f r om that i n y ounger pati ents?
3. How coul d thi s w i thdr aw al sy ndr om e hav e been pr ev ented?
4. Ar e ther e other dr ugs ci ted i n the case that can cause conf usi on? If so,
how ?
Case Discussion
1. Whi ch of the pati ent's sy m ptom s ar e consi stent w i th del i r i um ?
The sy m ptom s that ar e consi stent w i th del i r i um i n thi s pati ent, w hi ch
m ay r ef l ect benzodi azepi ne w i thdr aw al , i ncl ude f l uctuati ons i n
consci ousness, anx i ety , conf usi on, i r r i tabi l i ty , per ceptual di stur bances,
and hal l uci nati ons. Because dr ug w i thdr aw al i s f r equentl y
unr ecogni zed, phy si ci ans shoul d consi der the possi bi l i ty of w i thdr aw al
i n any ger i atr i c pati ent w ho ex hi bi ts an abr upt al ter ati on i n behav i or
and cogni ti on, par ti cul ar l y w hen other sy stem i c causes hav e been
ex cl uded. Phy si ci ans m ust al so m ai ntai n a hi gh i ndex of suspi ci on f or
al cohol w i thdr aw al i n both el der l y m en and w om en. Fi nal l y , as
ex em pl i f i ed i n thi s pati ent, com m uni cati on w i th f am i l y , f r i ends, and
car egi v er s m ay pr ov i de v al uabl e i nf or m ati on about other w i se
unr epor ted psy choacti v e dr ug use or abuse.
Lor azepam i s an i nter m edi ateacti ng benzodi azepi ne, w i th an onset of
w i thdr aw al sy m ptom s ty pi cal l y occur r i ng i n the f i r st 24 to 72 hour s
af ter di sconti nuati on,
P. 218
w hi ch i s consi stent w i th thi s pati ent's cl i ni cal pi ctur e. Rar el y ,
w i thdr aw al sy m ptom s m ay be del ay ed f or up to 2 w eek s i n pati ents
tak i ng l onger acti ng benzodi azepi nes, such as di azepam and
f l ur azepam . The ager el ated i ncr ease i n the pr opor ti on of total body f at
of ger i atr i c pati ents m ay pr ov i de a l ar ger v ol um e of di str i buti on f or
f atsol ubl e benzodi azepi nes, ther eby l engtheni ng the el i m i nati on per i od
and postponi ng the onset of w i thdr aw al sy m ptom s.
2. Is the pr esentati on of benzodi azepi ne w i thdr aw al i n el der l y pati ents
di f f er ent f r om that i n y ounger pati ents?
The cl i ni cal m ani f estati ons of benzodi azepi ne w i thdr aw al i n the el der l y
f r equentl y di f f er f r om those seen i n y ounger pati ents. The di f f er ence i n
the cl i ni cal m ani f estati ons of w i thdr aw al i n el der l y pati ents i s i n
gener al due to com or bi di ty stem m i ng f r om other di seases and i m pai r ed
hom eostati c r eser v e. In som e cases, these f actor s r esul t i n m or e
sev er e and ev en l i f ethr eateni ng w i thdr aw al sy m ptom s. Benzodi azepi ne
w i thdr aw al i s associ ated w i th i ncr eased autonom i c ner v ous sy stem
acti v i ty . In y ounger pati ents, thi s m ani f ests as tachy car di a, m i l d
hy per tensi on, and di aphor esi s. In el der l y pati ents w i th l i m i ted
phy si ol ogi c r eser v e, the i ncr eased autonom i c ner v ous sy stem acti v i ty
m ay pr eci pi tate sev er e car di ov ascul ar com pl i cati ons. In other
si tuati ons, com or bi di ty or i m pai r ed hom eostati c r eser v e, or both, m ay
r esul t i n m or e subtl e w i thdr aw al sy m ptom s i n el der l y pati ents. Heal th
car e pr of essi onal s m ay m i stak enl y attr i bute changes i n m ental status
to w or seni ng dem enti a. In ger i atr i c pati ents, abr upt and i sol ated
conf usi on i s som eti m es the onl y cl ue to benzodi azepi ne w i thdr aw al .
3. How coul d thi s w i thdr aw al sy ndr om e hav e been pr ev ented?
Thi s pati ent's benzodi azepi ne w i thdr aw al m i ght hav e been pr ev ented,
f i r st, by f i ndi ng out w hether he i s tak i ng a m edi cati on associ ated w i th
a w i thdr aw al sy ndr om e. When adm i tti ng el der l y pati ents w i th cogni ti v e
i m pai r m ent, i t i s i m por tant to com m uni cate w i th the pr i m ar y car egi v er
because thi s f r equentl y pr ov i des v i tal l y i m por tant i nf or m ati on. Second,
i f benzodi azepi nes ar e to be di sconti nued, the dose shoul d be gr adual l y
taper ed by 10% to 20% per w eek .
4. Ar e ther e other dr ugs ci ted i n the case that can cause conf usi on? If so,
how ?
The pati ent w as star ted on tw o new m edi cati ons dur i ng hi s
hospi tal i zati onâ€”ci m eti di ne and di phenhy dr am i ne. Both of these dr ugs
can cause conf usi on i n el der l y pati ents, and dr ugi nduced del i r i um i s
m or e com m on i n pati ents w i th pr eex i sti ng dem enti a (an ex am pl e of a
dr ugâ€“di sease i nter acti on).
Ci m eti di ne, an H 2 bl ock er , can pr oduce a host of sy stem i c ef f ects and
m ay par ti ci pate i n dr ugâ€“dr ug i nter acti ons because of i ts abi l i ty to
decr ease the m etabol i sm of m edi cati ons that ar e el i m i nated by the
l i v er . Ci m eti di ne al so r ar el y causes centr al ner v ous sy stem sy m ptom s
such as conf usi on and hal l uci nati ons. The m echani sm r esponsi bl e f or
ci m eti di nem edi ated m ental status changes i s unk now n.
Di phenhy dr am i ne i s f r equentl y used to pr om ote sl eep, but i s actual l y a

poor choi ce f or f r ai l , el der l y pati ents. Of par ti cul ar concer n ar e i ts
potenti al anti chol i ner gi c si de ef f ects, w hi ch i ncl ude dr y m outh, ur i nar y
r etenti on, consti pati on, bl ur r ed v i si on, and conf usi on. Ger i atr i c pati ents
m ay be m or e sensi ti v e to anti chol i ner gi c si de ef f ects than y ounger
peopl e because of ager el ated changes i n acety l chol i ne
neur otr ansm i ssi on.
P. 219
Suggested Readings
Ahr onhei m JC. Handbook of pr escr i bi ng m edi cati ons f or ger i atr i c
pati ents. Boston: Li ttl e, Br ow n and Com pany , 1992:1â€“12, 96â
€“100, 347â€“348.
Beer s MH. Pol y phar m acy and appr opr i ate pr escr i bi ng. In: Beck JC, ed.
Ger i atr i c r ev i ew sy l l abus, 1991â€“1992 ed. N ew Yor k : Am er i can
Ger i atr i c Soci ety , 1991:218.
Ger ber JG, Br ass EP. Dr ug use i n the el der l y . In: Jahni gen DW, Schr i er
RW, eds. Ger i atr i c m edi ci ne, 2nd ed. Cam br i dge, MA: Bl ack w el l Sci ence,
1996.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 6 I nf e c tio us D is e a s e s
Chapter 6
Infectious Diseases
Robe rt T. Sc hoole y
Urinary Tract Infection
1. What host f actor s l ead to the dev el opm ent of ur i nar y tr act i nf ecti ons
(U TIs), and how ar e these f actor s di f f er ent f or m en and w om en?
2. What or gani sm s com m onl y cause l ow er U TIs?
3. What ar e the si gns and sy m ptom s of l ow er U TI, and how do these di f f er
f r om those of py el onephr i ti s?
Discussion
1. What host f actor s l ead to the dev el opm ent of U TIs, and how ar e these
f actor s di f f er ent f or m en and w om en?
Im pr oper hy gi ene, sex ual acti v i ty , i nconti nence, ur i nar y tr act

i nstr um entati on, contr acepti v e di aphr agm s w i th or w i thout sper m i ci des,
di abetes m el l i tus, a geneti c pr edi sposi ti on, and dehy dr ati on ar e al l
f actor s that can i ncr ease the
P. 221
l i k el i hood of a U TI. Most U TIs ar e caused by endogenous f l or a or i gi nati ng
f r om the gastr oi ntesti nal tr act. These or gani sm s hav e been show n to
col oni ze the v agi nal i ntr oi tus and per i ur ethr al ar ea bef or e U TI occur s.
Wom en w ho w i pe thei r per i neal ar ea f r om the poster i or to anter i or
di r ecti on af ter def ecati on, r ather than v i ce v er sa, or those w ho ar e
i nconti nent of stool , m ay be subject to m or e f r equent col oni zati on of the
shor t f em al e ur ethr a w i th Enter obacter i aceae. The l onger ur ethr a i n m en
m ak es access to the bl adder m or e di f f i cul t f or enter i c f l or a; how ev er ,
thi s f l or a m ay be i ntr oduced to the nor m al l y ster i l e bl adder ar ea as the
r esul t of Fol ey catheter i zati on or cy stoscopy . One of the natur al def enses
agai nst cy sti ti s af ter ur ethr al col oni zati on i s the m echani cal f l ushi ng of
the ur i nar y bl adder , w hi ch tak es pl ace dur i ng ur i nati on. Obv i ousl y ,
any one w ho i s dehy dr ated cannot benef i t f r equentl y f r om thi s natur al
def ense m echani sm . Sex ual acti v i ty can pr edi spose w om en to acqui r i ng
U TI. In addi ti on, as the r esul t of a poor l y under stood m echani sm , w om en
w ho use a di aphr agm f or contr acepti on, especi al l y w i th sper m i ci des,
seem to be m or e suscepti bl e to ur ethr al col oni zati on and U TI. It has been
pr oposed that thi s pr edi sposi ti on m i ght be due, at l east i n par t, to a shi f t
i n v agi nal m i cr obi al f l or a caused by the acti v i ty of sper m i ci des. Di abetes
m el l i tus m ay pr edi spose to U TI thr ough a v ar i ety of m echani sm s,
i ncl udi ng the def ecti v e chem otax i s of l euk ocy tes, phagocy ti c def ects, and
enhanced gr ow th condi ti ons f or bacter i a. Geneti cal l y deter m i ned f actor s,
such as the ty pe and num ber of r eceptor s on ur oepi thel i al cel l s to w hi ch
bacter i a m ay attach, al so appear to hei ghten suscepti bi l i ty to U TIs.
2. What or gani sm s com m onl y cause l ow er U TIs?
Escher i chi a col i causes m ost (up to 80%) of the com m uni ty acqui r ed
uncom pl i cated U TIs, w i th Kl ebsi el l a, Enter obacter , and Pr oteus or gani sm s
m or e l i k el y to cause com pl i cated or hospi tal acqui r ed U TIs. These ar e al l
gr am negati v e or gani sm s that usual l y or i gi nate f r om the pati ent's ow n
gastr oi ntesti nal f l or a. Ther e ar e, how ev er , sev er al gr am posi ti v e
or gani sm s that occur as ur i nar y pathogens. Staphy l ococcus sapr ophy ti cus,
a coagul asenegati v e Staphy l ococcus or gani sm , causes 20% or m or e of
the U TIs i n w om en 16 to 35 y ear s of age. Str eptococcus f aecal i s causes
2% to 3% of the U TIs i n other w i se heal thy y oung w om en. When
Staphy l ococcus aur eus i s f ound i n the ur i ne, a bacter em i c i nf ecti on of the
k i dney shoul d be suspected.
Chl am y di a, U r eapl asm a, My copl asm a, and N ei sser i a gonor r hoeae ar e

sex ual l y tr ansm i tted pathogens that usual l y cause v agi nal or cer v i cal
i nf ecti ons; how ev er , they m ay be i m pl i cated i n cases of acute ur ethr al
sy ndr om e i n w hi ch Gr am 'sstai ned ur i ne sam pl es ex hi bi t py ur i a w i thout
bacter i ur i a.
Pseudom onas and Ser r ati a ar e m or e com m onl y nosocom i al gr am negati v e

pathogens that ar e not usual l y seen i n com m uni ty acqui r ed,
uncom pl i cated U TIs.
3. What ar e the si gns and sy m ptom s of l ow er U TI, and how do these di f f er
f r om those of py el onephr i ti s?
The ter m l ow er U TI actual l y encom passes cy sti ti s and ur ethr i ti s, as w el l
as pr ostati ti s. Sy m ptom s cl assi cal l y i ncl ude ur i nar y f r equency , ur gency ,
dy sur i a,
P. 222
and supr apubi c di scom f or t. Si gns m ay i ncl ude f ev er , cl oudy or f oul
sm el l i ng ur i ne, and hem atur i a. Because upper U TIs (i . e. , py el onephr i ti s,
acute l obar nephr i ti s, and a per i nephr i c abscess) of ten star t as cy sti ti s,
the sam e si gns and sy m ptom s m ay ex i st; how ev er , the f ev er i s usual l y
m or e sev er e, and m ay be accom pani ed by shak i ng chi l l s. An upper U TI i s
of ten accom pani ed by costov er tebr al angl e tender ness on the i nv ol v ed
si de. El der l y peopl e and those w i th di abetes m ay ex hi bi t f ew er si gns and
sy m ptom s than other w i se nor m al hosts.
Case
A 19y ear ol d, sex ual l y acti v e w om an pr esents to the em er gency r oom
com pl ai ni ng of a 2day hi stor y of ur i nar y f r equency , bur ni ng, and ur gency .
She deni es v agi nal di schar ge or i tchi ng, f ev er , chi l l s, nausea, v om i ti ng, back
pai n, abdom i nal pai n, or hem atur i a. She has no hi stor y of U TI or a sex ual l y
tr ansm i tted di sease. She r ecentl y began usi ng a di aphr agm f or bi r th contr ol ,
and r epor ts that her l ast m enstr ual per i od occur r ed 3 w eek s ago. She has onl y
one sex ual par tner , w ho deni es peni l e di schar ge or bur ni ng on ur i nati on. On
phy si cal ex am i nati on, she i s noted to be af ebr i l e w i th a nor m al bl ood pr essur e
and pul se. Ther e i s no costov er tebr al angl e tender ness. Her abdom en i s sof t
and ther e i s m i l d supr apubi c tender ness i n r esponse to pal pati on. A ur i nal y si s
r ev eal s 1+ pr otei n, 2+ l euk ocy tes, and 1+ bl ood. The ur i ne pH i s 5. 6. Gr am 's
stai ni ng of an unspun ur i ne speci m en r ev eal s abundant pol y m or phonucl ear
l euk ocy tes and m oder ate gr am negati v e r ods. A cl eancatch ur i ne speci m en i s
sent to the m i cr obi ol ogy l abor ator y f or cul tur e.
The em er gency r oom phy si ci an di agnoses an uncom pl i cated U TI and pr escr i bes
tr i m ethopr i m sul f am ethox azol e (TMPSMX), one doubl estr ength tabl et tw i ce a
day f or 3 day s.
1. What other ther apeuti c opti ons w oul d hav e been appr opr i ate i n thi s
pati ent?
2. What can thi s w om an do to hel p pr ev ent r ecur r ent U TIs?
3. Shoul d thi s w om an's sex ual par tner be ev al uated f or U TI?
4. Was the Gr am 's stai ni ng an i m por tant di agnosti c test, and i n w hat w ay
di d the f i ndi ngs al ter the m anagem ent of thi s case?
5. What i s the v al ue of k now i ng the ur i ne pH i n thi s setti ng?
6. What other di agnosti c or l abor ator y tests shoul d hav e been per f or m ed?
7. What w oul d be an appr opr i ate anal gesi c f or a pati ent w i th U TI w ho i s
ex per i enci ng sev er e ur ethr al di scom f or t?
8. What si de ef f ects of ther apy shoul d thi s w om an k now about?
9. What possi bl e consequences coul d ar i se i f thi s w om an does not com pl y
w i th ther apy ?
Case Discussion
1. What other ther apeuti c opti ons w oul d hav e been appr opr i ate i n thi s
pati ent?
TMPSMX r em ai ns the dr ug of choi ce f or the em pi r i cal l y based tr eatm ent
of uncom pl i cated U TIs. For sul f aal l er gi c pati ents, am pi ci l l i n, am ox i ci l l i n,
a f i r stgener ati on cephal ospor i n, or a qui nol one i s the appr opr i ate
al ter nati v e. Ther apy m ay then be m odi f i ed on the basi s of the ur i ne
cul tur e r esul ts and the sensi ti v i ti es of the i nf ecti ng or gani sm . Enter ococci
ar e not suscepti bl e to ei ther TMPSMX or
P. 223
cephal ospor i ns, w hi ch poi nts out the uti l i ty of per f or m i ng ur i ne Gr am 's
stai ni ng w hen deci di ng on anti bi oti c ther apy . The pr ev al ence of
am pi ci l l i nr esi stant E. col i m ay be as hi gh as 30% i n som e com m uni ti es,
and thi s needs to be consi der ed w hen sel ecti ng an appr opr i ate anti bi oti c.
S. sapr ophy ti cus r esponds to am pi ci l l i n, TMPSMX, and the qui nol ones. In
the past, tr eatm ent of l ow er U TIs f or 5 to 7 day s w as r ecom m ended.
Shor t cour se ther apy w i th agents that achi ev e hi gh and sustai ned ur i nar y
concentr ati ons (si ngl e dose w i th one or tw o doubl estr ength TMP/SMX or
3 g of am ox i ci l l i n) w i l l usual l y suf f i ce f or uncom pl i cated i nf ecti ons.
Fai l ur es of shor t cour se ther apy ar e i ndi cati ons that com pl i cati ng f actor s
r equi r i ng m or e ex tensi v e ev al uati on m i ght be pr esent. In gener al , si ngl e
dose ther apy i s contr ai ndi cated i n pati ents w i th k now n anatom i c or
f uncti onal abnor m al i ti es, or w i th i m m unocom pr om i si ng di seases such as
di abetes m el l i tus. Af ter si ngl edose ther apy ur i ne cul tur es shoul d be
per f or m ed 1 to 2 w eek s l ater , to docum ent the cur e. In the ev ent of
tr eatm ent f ai l ur e, a l onger cour se of the appr opr i ate anti bi oti c shoul d be
adm i ni ster ed and an ev al uati on of potenti al l y com pl i cati ng f actor s shoul d
be under tak en.
Regar dl ess of the pathogen and the choi ce of anti bi oti cs, aggr essi v e or al
hy dr ati on i s a r easonabl e r ecom m endati on i n the m anagem ent of an
uncom pl i cated U TI. Al though ther e i s no ev i dence that hy dr ati on i m pr ov es
the r esul ts of appr opr i ate anti m i cr obi al ther apy , i t does di l ute the
bacter i a and r em ov es i nf ected ur i ne by f r equent bl adder em pty i ng.
2. What can thi s w om an do to hel p pr ev ent r ecur r ent U TIs?
Som e w om en f i nd that sw i tchi ng to another m ethod of bi r th contr ol
consi der abl y r educes the f r equency of r ecur r ent bacter i al U TIs. Thor ough
cl eansi ng of the per i neal ar ea bef or e sex ual r el ati ons m ay decr ease the
i nci dence of postcoi tal U TI i n those pr one to U TI; how ev er , m ost pati ents
f i nd thi s to be an i m pr acti cal and not com pl etel y ef f ecti v e pr ev enti v e
m easur e.
Choosi ng another m ethod of bi r th contr ol m ay not be necessar y f or m ost
w om en i f they r em em ber to dr i nk a l ar ge gl ass of w ater bef or e
i nter cour se and v oi d af ter i nter cour se; how ev er , studi es hav e show n that
di aphr agm usage i s an i ndependent r i sk f actor f or U TI. Regul ar anti bi oti c
pr ophy l ax i s shoul d be r eser v ed f or those pati ents w i th a hi stor y of
m ul ti pl e r ecur r ent U TIs, or com pl i cated U TI or upper tr act i nf ecti ons, or
f or i m m unocom pr om i sed hosts. The di sadv antages of ongoi ng pr ophy l ax i s
i ncl ude the dev el opm ent of dr ugr el ated si de ef f ects and col oni zati on w i th
m ul ti dr ugr esi stant or gani sm s.
3. Shoul d thi s w om an's sex ual par tner be ev al uated f or U TI?
N o. Al though l ow er U TIs i n w om en ar e associ ated w i th sex ual acti v i ty ,

thi s i s not a sex ual l y tr ansm i tted di sease. The i nf ecti ng or gani sm s ar e
usual l y endogenous f l or a. Heal thy m en w i thout pr edi sposi ng f actor s such
as ur i nar y tr act i nstr um entati on or di abetes m el l i tus r ar el y get l ow er
U TIs. Bacter i al pr ostati ti s does not put hi s sex ual par tner at r i sk f or
cy sti ti s.
4. Was the Gr am 's stai ni ng an i m por tant di agnosti c test, and i n w hat w ay
di d the f i ndi ngs al ter the m anagem ent of thi s case?
When bacter i ur i a i s f ound i n Gr am 'sstai ned, uncentr i f uged ur i ne, thi s i s a

v er y speci f i c f i ndi ng f or the di agnosi s of U TI. The f i ndi ng of m i cr oscopi c
bacter i ur i a cor r esponds to ur i ne cul tur e col ony counts of 10 5 /m L i n m or e
than 90% of such
P. 224
speci m ens. Di sti ngui shi ng betw een gr am posi ti v e and gr am negati v e
i nf ecti ons can be qui te usef ul i n m ak i ng ther apeuti c deci si ons.
5. What i s the v al ue of k now i ng the ur i ne pH i n thi s setti ng?
Al k al i ne ur i ne m ay be caused by i nf ecti on w i th Pr oteus speci es, w hi ch
pr oduce ur ease. The pr esence of nonal k al i ne ur i ne i n thi s pati ent m ak es
i nf ecti on w i th a ur easpl i tti ng or gani sm unl i k el y .
6. What other di agnosti c or l abor ator y tests shoul d hav e been per f or m ed?
The phy si cal ex am i nati on and di agnosti c studi es per f or m ed i n an
em er gency r oom setti ng shoul d be di r ected tow ar d el uci dati ng the natur e
of the pati ent's chi ef com pl ai nt and hi stor y . A pel v i c ex am i nati on w oul d
be appr opr i ate i f the pati ent had r epor ted sy m ptom s of i ncr eased v agi nal
di schar ge, dy spar euni a, or ex posur e to a k now n sex ual l y tr ansm i tted
di sease i n the par tner . The i ndi cati ons f or per f or m i ng cul tur es f or
sex ual l y tr ansm i tted pathogens ar e si m i l ar to those f or a pel v i c
ex am i nati on. Chl am y di a, U r eapl asm a, N . gonor r hoeae, or My copl asm a
i nf ecti on shoul d hav e been consi der ed i n thi s pati ent i f no or gani sm s
w er e seen on the Gr am 'sstai ned ur i ne speci m ens, or i f subsequent
r outi ne bacter i al cul tur es gr ew no or gani sm s.
Intr av enous py el ogr aphy and a r enal ul tr asound ex am i nati on shoul d be
r eser v ed f or w hen a com pl i cated U TI or upper U TI such as py el onephr i ti s
i s suspected. A pr egnancy test shoul d be per f or m ed i n any w om an of
chi l dbear i ng age bef or e pr escr i bi ng an anti bi oti c that m ay be
contr ai ndi cated i n pr egnancy .
7. What w oul d be an appr opr i ate anal gesi c f or a pati ent w i th U TI w ho i s
ex per i enci ng sev er e ur ethr al di scom f or t?
Phenazopy r i di ne hy dr ochl or i de i s a ur i nar y tr act anal gesi c agent that
ex er ts a topi cal anal gesi c ef f ect on the m ucosa of the ur i nar y tr act
thr ough an unk now n m echani sm of acti on. The si de ef f ects ar e m i ni m al ,
and i ncl ude the ur i ne acqui r i ng a r ed or or ange col or that m ay stai n
f abr i c. It i s usual l y not necessar y to pr escr i be m or e than a 2day suppl y
to pati ents w i th uncom pl i cated U TIs w ho ar e r ecei v i ng appr opr i ate
anti bi oti c ther apy . Opi oi d anal gesi cs ar e r el ati v el y contr ai ndi cated i n U TI
because they m ay cause acute ur i nar y r etenti on.
8. What si de ef f ects of ther apy shoul d thi s w om an k now about?
Vagi nal candi di asi s com m onl y dev el ops af ter anti m i cr obi al ther apy
because anti bi oti cs el i m i nate m uch of the nor m al v agi nal f l or a and cr eate
an i deal env i r onm ent f or the ov er gr ow th of Candi da al bi cans.
Hy per sensi ti v i ty r eacti ons m ay occur w i th any anti bi oti c; how ev er , TMP
SMX m ay r ar el y al so be associ ated w i th i nter sti ti al nephr i ti s, asepti c
m eni ngi ti s, Stev ensJohnson sy ndr om e, or er y them a m ul ti f or m e. A
car ef ul hi stor y to r ul e out k now n dr ug al l er gy i s i m por tant.
9. What possi bl e consequences coul d ar i se i f thi s w om an does not com pl y
w i th ther apy ?
The consequences of noncom pl i ance w i th ther apy i ncl ude conti nui ng
sy m ptom s, the i nducti on of anti bi oti cr esi stant str ai ns of m i cr oor gani sm s,
and, m ost i m por tant, ascendi ng i nf ecti on l eadi ng to acute py el onephr i ti s
or ev en a per i nephr i c abscess.
Suggested Readings
Bent S, Sai nt S. The opti m al use of di agnosti c testi ng i n w om en w i th acute
uncom pl i cated cy sti ti s. Am J Med 2002;113(Suppl 1A):20S.
P. 225
Dunagan WC, Ri dner ML. Manual of m edi cal ther apeuti cs, 26th ed. Boston:
Li ttl e, Br ow n and Com pany , 1995:257.
Fi hn SD, Latham RH, Rober ts P, et al . Associ ati on betw een di aphr agm use
and ur i nar y tr act i nf ecti on. JAMA 1985;254:240.
Hooten TM, Schol es D, Hughes JP, et al . A pr ospecti v e study of r i sk f actor s
f or sy m ptom ati c ur i nar y tr act i nf ecti ons i n y oung w om en. N Engl J Med
1996;335:468.
Latham RH, Runni ng K, Stam m WE. U r i nar y tr act i nf ecti on i n y oung adul t
w om en caused by Staphy l ococcus sapr ophy ti cus. JAMA 1983;250:3063.
Lei bov i ci L, Al per t G, Laor L, et al . U r i nar y tr act i nf ecti ons and sex ual
acti v i ty i n y oung w om en. Ar ch Inter n Med 1987;147:345.
N or r by SR. Shor t ter m tr eatm ent of uncom pl i cated l ow er ur i nar y tr act

i nf ecti ons i n w om en. Rev Inf ect Di s 1990;12:458.
Rubi n RH, Fang LST, Jones SR, et al . Si ngl edose am ox i ci l l i n ther apy f or
ur i nar y tr act i nf ecti on. JAMA 1980;244:561.
Sobel JD, Kay e D. U r i nar y tr act i nf ecti ons. In: Mandel l GL, Bennett JE,
Dol i n R, eds. Pr i nci pl es and pr acti ce of i nf ecti ous di seases, 6th ed. N ew
Yor k : El sev i er Sci ence, 2005:875.
Stam ey TA. Pathogenesi s and tr eatm ent of ur i nar y tr act i nf ecti ons.
Bal ti m or e: Wi l l i am s & Wi l k i ns, 1980.
The Acquired Immunodeficiency Syndrome
1. What ar e the pr i nci pl es of anti r etr ov i r al chem other apy ?
2. When shoul d anti r etr ov i r al chem other apy be star ted?
3. What ar e the m ost i m por tant hum an i m m unodef i ci ency v i r us HIV1â
€“associ ated oppor tuni sti c i nf ecti ons, and the tr eatm ents used i n the HIV
1â€“i nf ected i ndi v i dual s w ho l i v e i n dev el oped countr i es?
Discussion
1. What ar e the pr i nci pl es of anti r etr ov i r al chem other apy ?
HIV1â€“associ ated m or bi di ty and m or tal i ty i s the di r ect r esul t of

i m m unosuppr essi on m edi ated by v i r al r epl i cati on. The goal of
anti r etr ov i r al chem other apy i s to dr i v e pl asm a HIV1 l ev el s to bel ow the
l i m i ts of detecti on w i th the m ost sensi ti v e av ai l abl e assay . Thi s appr oach
af f or ds tw o m ajor benef i ts: (a) Successf ul suppr essi on of v i r al r epl i cati on
ar r ests destr ucti on of the i m m une r esponse and al l ow s f or i m m une
r econsti tuti on. Thi s, i n tur n, r esul ts i n a dr am ati c decl i ne i n HIV1â
€“associ ated m or bi di ty and m or tal i ty . (b) The em er gence of dr ug
r esi stance can be el i m i nated or gr eatl y r educed by dr i v i ng v i r al
r epl i cati on r ates to ex tr em el y l ow l ev el s.
Suppr essi on of pl asm a HIV1 RN A to l ev el s of 20 copi es/m L i s cur r entl y
best achi ev ed thr ough the use of a com bi nati on r egi m en contai ni ng at
l east thr ee agents. The i ncl usi on of m ul ti pl e agents i s r equi r ed both f or
potency and f or i nter posi ng a si gni f i cant geneti c bar r i er to the v i r us w i th
r espect to the em er gence of r esi stance. HIV1 r epl i cati on occur s at the
r ate of appr ox i m atel y 10 bi l l i on v i r al par ti cl es per day i n each i nf ected
per son. Wi th the
P. 226
r epl i cati v e i nf i del i ty of HIV1's r ev er se tr anscr i pti on m echani sm , thi s
hi gh l ev el of r epl i cati on r api dl y r esul ts i n the cr eati on of a di v er se
quasi speci es of v i r us. Ther ef or e, i t i s l i k el y that at the i nsti tuti on of
ther apy , v i r al v ar i ants ex i st that ar e r esi stant to each cur r entl y av ai l abl e
agent. The use of m ul ti pl e agents w i th nonov er l appi ng r esi stance
m echani sm s r equi r es the v i r us to m ak e m ul ti pl e geneti c changes i n each
v i r i on i n or der to per si st i n the pr esence of al l agents i n the r egi m en.
At pr esent, r educti on of HIV1 RN A to 20 copi es/m L i s best achi ev ed w i th
the sel ecti on of tw o nucl eosi de anal ogs usual l y adm i ni ster ed as f i x ed
dose com bi nati ons (and an â€œanchor â€ dr ugâ€”ef av i r enz or a r i tonav i r
boosted pr otease i nhi bi tor ). Al though ther e i s no si ngl e r egi m en that i s
appr opr i ate f or al l pati ents, the nucl eosi de com bi nati on of tenof ov i r and
em tr i ci tabi ne w i th ef av i r enz has becom e the m ost f r equent i ni ti al
com bi nati on r egi m en. The r ecent i ntr oducti on of a si ngl e tabl et contai ni ng
these tw o nucl eosi des and ef av i r enz has pr ov i ded the f i r st oncedai l y
si ngl e pi l l anti r etr ov i r al r egi m en. Other f i x eddose nucl eosi de
com bi nati ons, i ncl udi ng ei ther zi dov udi ne and l am i v udi ne or abacav i r and
l am i v udi ne, m ay al so be used i n com bi nati on w i th ef av i r enz.
Al though ef av i r enz i s potent and w el l tol er ated i n m ost pati ents, i t cannot
be used i n 15% to 20% of pati ents. Ef av i r enz i s associ ated w i th centr al
ner v ous sy stem (CN S) si de ef f ects that r equi r e up to 10% of pati ents to
seek another dr ug. Ef av i r enz i s al so ter atogeni c and shoul d not be used i n
sex ual l y acti v e w om en of chi l dbear i ng age w ho ar e not usi ng ef f ecti v e
bi r th contr ol m ethods. Because tr ansm i ssi on of dr ugr esi stant v i r uses i s
i ncr easi ngl y f r equent, i t i s best to check dr ug suscepti bi l i ty bef or e
i ni ti ati ng anti r etr ov i r al dr ugs. Tr ansm i tted dr ug r esi stance to ef av i r enz i s
f ound i n appr ox i m atel y 10% of pati ents i ni ti ati ng ther apy f or the f i r st
ti m e i n cer tai n l ocati ons i n the U ni ted States and Eur ope. In pati ents f or
w hom ef av i r enz i s not an opti m al choi ce, a r i tonav i r boosted pr otease
i nhi bi tor (usual l y r /l opi nav i r or r /atazanav i r ) i s gener al l y the best i ni ti al
choi ce. Appr opr i ate m anagem ent of anti r etr ov i r al chem other apy i s both
an ar t and a sci ence that i s best accom pl i shed by phy si ci ans w i th
substanti al ex per i ence i n m anagem ent of pati ents w i th HIV1 i nf ecti on.
2. When shoul d anti r etr ov i r al chem other apy be star ted?
Ther e i s no si ngl e answ er that i s appr opr i ate f or ev er y pati ent. Ongoi ng
v i r al r epl i cati on i s al w ay s dam agi ng to the i m m une r esponse of the host.
On the other hand, cur r ent anti r etr ov i r al r egi m ens m ay be associ ated
w i th si de ef f ects, and r equi r e si gni f i cant di sci pl i ne to achi ev e the l ev el of
v i r al suppr essi on associ ated w i th dur abl e success. As CD4 cel l counts
decl i ne, pati ents ar e at gr eater r i sk f or HIV1â€“associ ated oppor tuni sti c
i nf ecti ons. Ri si ng pl asm a HIV1 RN A l ev el s ar e associ ated w i th m or e
r api d i m m unol ogi c and cl i ni cal di sease pr ogr essi on. Adequate suppr essi on
of HIV1 i s best achi ev ed i n pati ents w i th hi gh CD4 cel l counts and l ow
pl asm a HIV1 RN A l ev el s. Ther ef or e, al l thi ngs bei ng equal , i t coul d be
ar gued that ear l y i nsti tuti on of ther apy i s associ ated w i th the best chance
of l ongter m success. The desi r e to star t ther apy ear l y m ust be bal anced
by a consi der ati on of l ongter m tox i ci ti es and the com m i tm ent of the
pati ent to str i ct adher ence of the r egi m en chosen. In gener al , the ur gency
to
P. 227
star t ther apy i ncr eases as CD4 cel l counts f al l and the pl asm a HIV1 RN A
l ev el s r i se. Most ex per ts r ecom m end tr eatm ent f or any pati ent w i th HIV
1â€“r el ated sy m ptom s and that the ther apy be star ted f or asy m ptom ati c
HIV1 i nf ected per sons as thei r CD4 cel l count passes i nto the 250 to 350
cel l /m L r ange.
3. What ar e the m ost i m por tant HIV1â€“associ ated oppor tuni sti c i nf ecti ons,
and the tr eatm ents used i n the HIV1â€“i nf ected i ndi v i dual s w ho l i v e i n
dev el oped countr i es?
In gener al , the r i sk of v ar i ous HIV1â€“r el ated i nf ecti ons i ncr eases w i th
di sease pr ogr essi on and decl i ni ng CD4 cel l counts. Tw o notabl e
ex cepti ons to thi s r ul e, how ev er , ar e pneum ococcal pneum oni a and
tuber cul osi s. Al l HIV1â€“i nf ected pati ents ar e at i ncr eased r i sk f or
acqui r i ng pneum ococcal pneum oni a and sepsi s. Whether the
adm i ni str ati on of pneum ococcal v acci ne can pr ev ent or l essen the
sev er i ty of pneum ococcal di sease i n these pati ents has not been pr ov ed,
but the cur r ent pr acti ce i s to adm i ni ster pneum ococcal v acci ne to al l HIV
1â€“i nf ected pati ents w hose CD4 l y m phocy te counts ex ceed 500/m m 3 . The
r esponse to v acci nati on i n pati ents w i th counts of l ess than 500/m m 3 i s
l i k el y to be enhanced i f they ar e on ef f ecti v e anti r etr ov i r al ther apy at the
ti m e of v acci nati on.
Tuber cul osi s i s one of the f ew HIV1â€“r el ated i nf ecti ons that i s
tr ansm i ssi bl e to i m m unocom petent per sons. HIVi nf ected per sons ar e at
i ncr eased r i sk f or acqui r i ng tuber cul osi s r egar dl ess of the stage of thei r
HIV1 i nf ecti on. Because pati ents w i th HIV1 i nf ecti on hav e r educed
cel l ul ar i m m uni ty , a thr eshol d of 5 cm i s consi der ed to be a posi ti v e
tuber cul i n sk i n test. As the CD4 cel l counts f al l , pati ents m ay becom e
aner gi c and the tuber cul i n sk i n test f ur ther l oses i t sensi ti v i ty .
Or al candi di asi s (thr ush) m ost f r equentl y occur s w hen the CD4
l y m phocy te count f al l s bel ow 300/m m 3 . Thr ush can usual l y be tr eated
w i th topi cal anti f ungal agents (ny stati n sw i sh and sw al l ow , or
cl otr i m azol e tr oches), but m or e sev er e cases, especi al l y w hen esophageal
l esi ons ar e pr esent, m ay r equi r e sy stem i c anti f ungal agents such as
f l uconazol e.
Ear l y i n the acqui r ed i m m unodef i ci ency sy ndr om e (AIDS) epi dem i c,
Pneum ocy sti c ji r ov eci (f or m er l y car i ni i ) pneum oni a w as the m ost com m on
AIDSdef i ni ng i l l ness. Wi th the adv ent of ef f ecti v e pr ophy l acti c r egi m ens,
thi s i l l ness has becom e m uch l ess f r equent. Pneum ocy sti s pneum oni a i s
usual l y tr eated w i th TMPSMX. Al ter nati v el y , i ntr av enous pentam i di ne,
or al tr i m ethopr i m / dapsone, or or al atov aquone can be used i n sul f a
al l er gi c pati ents.
HIV1â€“i nf ected per sons w i th l ess than 200 CD4 l y m phocy tes/m m 3 ar e at
r i sk f or sev er al ty pes of CN S i nf ecti ons. One of the m ost com m on causes
of i ntr acr ani al m asses i n HIV1â€“i nf ected pati ents, Tox opl asm a gondi i , i s
tr eated w i th py r i m etham i ne and sul f adi azi ne. Cr y ptococcus neof or m ans,
Hi stopl asm a capsul atum , and Cocci di oi des i m m i ti s can cause CN S di sease
or di ssem i nated di sease i n HIV1â€“i nf ected pati ents; i nf ecti on w i th these
pathogens i s usual l y tr eated w i th am photer i ci n B.
Pati ents w i th l ess than 50 CD4 l y m phocy tes/m m 3 ar e at r i sk f or suf f er i ng
di ssem i nated i nf ecti on w i th My cobacter i um av i um [m y cobacter i um av i um
com pl ex (MAC)] or ocul ar or sy stem i c cy tom egal ov i r us i nf ecti ons.
Di ssem i nated
P. 228
MAC i s com m onl y m ani f ested cl i ni cal l y by the appear ance of sy stem i c
sy m ptom s (f ev er , w ei ght l oss, ni ght sw eats, and anem i a). Tr eatm ent w i th
a com bi nati on of tw o or thr ee acti v e agents i s r equi r ed f or MAC i nf ecti on.
Cy tom egal ov i r us r eti ni ti s pr esents w i th pai nl ess l oss of v i si on and m ay be
accom pani ed by sy stem i c ev i dence of i nf ecti on, m ani f est by f ev er , w ei ght
l oss, or gastr oi ntesti nal sy m ptom s. Tr eatm ent w i th ganci cl ov i r (or
v al ganci cl ov i r ), f oscar net, or ci dof ov i r i s usual l y ef f ecti v e.
Case
A 32y ear ol d w om an i s f ound to be HIV1 ser oposi ti v e at the ti m e of a l i f e
i nsur ance phy si cal ex am i nati on. The pati ent has had no pr i or ser i ous m edi cal
i l l nesses al though she has ex per i enced i ncr eased v agi nal i tchi ng dur i ng the
l ast y ear . Her phy si cal ex am i nati on i s nor m al ex cept f or v agi nal thr ush. Her
soci al hi stor y r ev eal s that she has been m ar r i ed to the sam e m an f or the l ast
3 y ear s. He i s al so heal thy . U pon detai l ed questi oni ng, he adm i tted to hav i ng
ex per i m ented w i th sex w i th m en on sev er al occasi ons w hi l e tr av el i ng to San
Fr anci sco 8 y ear s ear l i er . He i s subsequentl y f ound to be HIV1 ser oposi ti v e
w i th a CD4 cel l count of 860 cel l s/m m 3 and a pl asm a HIV1 RN A l ev el of
13, 000 copi es/m L.
The l abor ator y ev al uati on r ev eal s that she has a posi ti v e enzy m el i nk ed
i m m unosor bent assay (ELISA) f or anti bodi es to HIV1. HIV1 ser oposi ti v i ty
w as conf i r m ed by a Wester n bl ot assay . Her pur i f i ed pr otei n der i v ati v e (PPD)
i s negati v e, as i s her ser ol ogy f or T. gondi i . Her r api d pl asm a r eagi n (RPR) i s
negati v e. Her hem atocr i t i s 43. Her w hi te bl ood cel l count i s 5, 200/m m 3 . Her
CD4 cel l count i s 340 cel l s/m m 3 . Her pl asm a HIV1 RN A l ev el i s 143, 000
copi es/m L.
1. What w oul d y ou r ecom m end to her w i th r espect to anti r etr ov i r al
chem other apy ?
2. How w oul d y ou al ter y our r ecom m endati ons i f y ou l ear ned she i s
pr egnant at the ti m e of pr esentati on? If she w er e pr egnant, i s i t l i k el y
that her chi l d w oul d be i nf ected?
3. What w oul d y ou r ecom m end to her husband w i th r espect to anti r etr ov i r al
chem other apy ?
Case Discussion
1. What w oul d y ou r ecom m end to her w i th r espect to anti r etr ov i r al
chem other apy ?
You shoul d r ecom m end to her that she i ni ti ate anti r etr ov i r al ther apy .
Al though her CD4 cel l count i s i n a r ange that w oul d pr om pt som e
pr acti ti oner s to r ecom m end def er r i ng ther apy , the pr esence of v agi nal
thr ush i s a cl i ni cal i ndi cator of HIV1 di sease and pl aces her at gr eater
r i sk f or an oppor tuni sti c i nf ecti on than a w om an w i th the sam e CD4 cel l
count and no sy m ptom s. Ther apy shoul d not be i ni ti ated unti l a v i r al
suscepti bi l i ty test r esul t has been obtai ned. In her case, i t r ev eal s that
her v i r us i s r esi stant to ef av i r enz, l i k el y r ef l ecti ng the acqui si ti on of the
dr ugr esi stant v i r us f r om her husband. Because of thi s, y ou shoul d
r ecom m end a r egi m en that uses a boosted pr otease i nhi bi tor as the
anchor dr ug such as tenof ov i r , em tr i ci tabi ne, and r /l opi nav i r .
2. How w oul d y ou al ter y our r ecom m endati ons i f y ou l ear ned she i s
pr egnant at the ti m e of pr esentati on? If she w er e pr egnant, i s i t l i k el y
that her chi l d w oul d be i nf ected?
The gener al appr oach to anti r etr ov i r al chem other apy i n pr egnancy shoul d
be the sam e as i t i s i n a nonpr egnant w om an. Ef f ecti v e m anagem ent of
an i nf ected
P. 229
w om an r equi r es cl ose col l abor ati on am ong an i nter ni st or i nf ecti ous
di sease speci al i st w i th ex per i ence usi ng anti r etr ov i r al ther apy , an
obstetr i ci an w i th ex per i ence deal i ng w i th HIV1â€“i nf ected m other s, and a
pedi atr i ci an w i th HIV1 ex per ti se. The dual goal s of ther apy i n thi s
setti ng ar e to suppr ess v i r al r epl i cati on to benef i t the m other and to
decr ease the r i sk of tr ansm i ssi on of HIV1 to her baby . Wi th her CD4 cel l
count and pl asm a HIV1 RN A l ev el , she i s at r i sk f or di sease pr ogr essi on
ov er the nex t sev er al y ear s and, as m enti oned i n the pr ecedi ng tex t,
m ost ex per ts w oul d r ecom m end anti r etr ov i r al chem other apy to her once
she i s thr ough her f i r st tr i m ester of pr egnancy . Al though ther e i s no
ev i dence that tenof ov i r pl aces f etuses at r i sk , ther e i s m or e ex per i ence
w i th zi dov udi ne and l am i v udi ne i n pr egnancy ; so i t w oul d be pr ef er abl e to
use these agents i nstead of tenof ov i r and em tr i ci tabi ne. Because her
v i r us i s not suscepti bl e to ef av i r enz, i t w oul d not be used. N onethel ess,
ev en i f her v i r us w er e suscepti bl e to the dr ug, i t shoul d not be used i n
pr egnancy because of concer ns about ter atogeni ci ty . Al though d4T and ddI
ar e used l ess f r equentl y these day s, they shoul d be av oi ded w henev er
possi bl e i n pr egnant w om en because of l acti c aci dosi s, hepati c steatosi s,
and pancr eati ti s. N ev i r api ne has been associ ated w i th sev er e hepati ti s,
especi al l y i n w om en w i th CD4 cel l count m or e than 250/m m 3 and shoul d
be av oi ded i n thi s pati ent f or that r eason. Ther ef or e, she w oul d best be
tr eated w i th a pr otease i nhi bi tor as the anchor dr ug i n her r egi m en.
Al though nel f i nav i r i s of ten used i n pr egnancy , concer ns about i ts potency
dam pen the enthusi asm f or i tâ€”ev en i n thi s setti ng. R/l opi nav i r i s a v er y
r easonabl e choi ce, al though ther e ar e data that suggest i ncr eased
m etabol i sm of l opi nav i r dur i ng pr egnancy . Ther ef or e, dr ug l ev el s shoul d
be f ol l ow edup.
Bef or e the adv ent of anti r etr ov i r al chem other apy , the l i k el i hood of
tr ansm i tti ng HIV1 f r om m other to chi l d w as i n the r ange of 25%.
Zi dov udi ne m onother apy adm i ni ster ed dur i ng the thi r d tr i m ester of
pr egnancy , coupl ed w i th i ntr av enous zi dov udi ne dur i ng del i v er y and 6
w eek s of zi dov udi ne f or the i nf ant, r educed the r i sk of per i natal
tr ansm i ssi on to 8%. Mor e potent contem por ar y anti r etr ov i r al
chem other apeuti c r egi m ens hav e r educed thi s r i sk to bel ow 1%. The goal
of ther apy i n the m other shoul d be to r educe pl asm a HIV1 RN A l ev el s to
l ess than 20 copi es/m L by del i v er y . The baby shoul d al so r ecei v e
anti r etr ov i r al chem other apy as par t of the per i natal tr ansm i ssi on
pr ev enti on str ategy . The neonate shoul d not be br eastf ed, r egar dl ess of
the m other 's pl asm a HIV1 l ev el , i n v i ew of the r i sk of tr ansm i ssi on of
HIV1 by thi s r oute.
3. What w oul d y ou r ecom m end to her husband w i th r espect to anti r etr ov i r al
chem other apy ?
Her husband has been i nf ected f or m or e than 5 y ear s and has m ai ntai ned
a l ow pl asm a HIV1 RN A l ev el and a near nor m al CD4 cel l count. Al though
he i s techni cal l y not a l ongter m nonpr ogr essor because he has not been
docum ented to be i nf ected f or m or e than 10 y ear s, hi s pl asm a HIV1 RN A
l ev el and CD4 cel l count pr edi ct that hi s di sease pr ogr essi on r i sk i s v er y
l ow . Most ex per ts w oul d not r ecom m end anti r etr ov i r al chem other apy to
hi m at thi s poi nt. Al though anti r etr ov i r al chem other apy i s not i ndi cated,
he shoul d under go a f ul l i ni ti al ev al uati on f or HIV1 i ncl udi ng a PPD, an
RPR, and T. gondi i and cy tom egal ov i r us ser ol ogy and shoul d be f ol l ow ed
up at 3 to 6m onth i nter v al s f or ev i dence of a r i si ng pl asm a HIV1
P. 230
RN A l ev el and/or a f al l i ng CD4 cel l count. He shoul d al so be v acci nated
agai nst pneum ococcal di sease. It w oul d al so be pr udent to test hi s v i r us
f or r esi stance to anti r etr ov i r al dr ugs to gui de sel ecti on of hi s r egi m en
w hen he r equi r es ther apy . Ev en i f hi s v i r us i s f ound to be suscepti bl e to
ef av i r enz, i t shoul d not be r el i ed upon i n hi s case because i t i s pr esum ed
that hi s w i f e acqui r ed her r esi stant v i r us f r om hi m and i t i s k now n that
dr ugr esi stant v i r us m ay be ov er gr ow n by w i l d ty pe v i r us i n the pl asm a.
In these si tuati ons, the l i f el ong per si stence of dr ugr esi stant m i nor
speci es v ar i ants l eads to tr eatm ent f ai l ur e i f these agents ar e used.
Suggested Readings
Bar nes PF, Bl och AP, Dav i dson PT, et al . Tuber cul osi s i n pati ents w i th
hum an i m m unodef i ci ency v i r us i nf ecti on. N Engl J Med 1991;324:1644.
Car penter CJ, Fi schl MA, Ham m er SM, et al . Anti r etr ov i r al ther apy f or HIV
Inf ecti on i n 1998. JAMA 1998;280:78â€“86.
Connor EM, Sper l i ng RS, Gel ber R, et al . Pedi atr i c ACTG Pr otocol 076 Study
Gr oup. Reducti on of m ater nal i nf ant tr ansm i ssi on of hum an
i m m unodef i ci ency v i r us ty pe 1 w i th zi dov udi ne tr eatm ent. N Engl J Med
1994;331:1173â€“1180.
Gal l ant JE, Staszew sk i S, Pozni ak AL, et al . Ef f i cacy and saf ety of
tenof ov i r DF v s stav udi ne i n com bi nati on ther apy i n anti r etr ov i r al naÃ¯v e
pati ents: a 3y ear r andom i zed tr i al . JAMA 2004;292:191.
Depar tm ent of Heal th and Hum an Ser v i ces (DHHS) Panel on Anti r etr ov i r al
Gui del i nes f or Adul ts and Adol escents. Gui del i nes f or the use of
anti r etr ov i r al agents i n HIV1 i nf ected adul ts and adol escents. AIDS
Tr eatm ent Gui del i nes Panel of the Depar tm ent of Heal th and Hum an
Ser v i ces, Web si te (http://AIDSinfo. nih. gov), 2006.
Ham m er SM, Saag MS, Schechter M, et al . Tr eatm ent f or adul t HIV
i nf ecti on: 2006 r ecom m endati ons of the Inter nati onal AIDS Soci ety â€“U SA
Panel . JAMA, 2006;296:827â€“843.
Ho DD, N eum ann AU , Per el son AS. Rapi d tur nov er of pl asm a v i r i ons and
CD4 l y m phocy tes i n HIV1 i nf ecti on. N atur e 1995;373:123â€“126.
Ki tahata MM, Koepsel l TD, Dey o RA, et al . Phy si ci ans' ex per i ence w i th the
acqui r ed i m m unodef i ci ency sy ndr om e as a f actor i n pati ents' sur v i v al . N
Engl J Med 1996;334(11):701â€“706.
Masur H, Ogni bene FP, Yar choan R, et al . CD4 counts as pr edi ctor s of
oppor tuni sti c pneum oni as i n hum an i m m unodef i ci ency v i r us (HIV) i nf ecti on.
Ann Inter n Med 1989;111:223.
Pal el l a FJ, Del aney KM, Moor m an AC, et al . Decl i ni ng m or bi di ty and
m or tal i ty am ong pati ents w i th adv anced hum an i m m unodef i ci ency v i r us
i nf ecti on. HIV outpati ent study i nv esti gator s. N Engl J Med 1998;338:853â
€“860.
Cellulitis
1. What f actor s pr edi spose to the dev el opm ent of cel l ul i ti s?
2. What ar e the si gns and sy m ptom s of cel l ul i ti s?
3. What or gani sm s m ost f r equentl y cause cel l ul i ti s?
P. 231
Discussion
1. What f actor s pr edi spose to the dev el opm ent of cel l ul i ti s?
Al though any per son can acqui r e cel l ul i ti s, ther e ar e sev er al f actor s that
hei ghten the r i sk of thi s i nf ecti on. Any com pr om i se of sk i n i ntegr i ty can
i ntr oduce or gani sm s i nto the sk i n and subcutaneous ti ssues. Ther ef or e,
sur gi cal pr ocedur es, tr aum a, the pl acem ent of i ntr av enous catheter s,
bur ns, and bi te w ounds ar e al l f actor s that pr edi spose to the dev el opm ent
of cel l ul i ti s. The r i sk f or dev el opm ent of cel l ul i ti s i s al so i ncr eased i n
hosts w hose sensati on i s i m pai r ed, such as di abeti c pati ents w i th
per i pher al neur opathy w hose abi l i ty to per cei v e and r eact appr opr i atel y
to tr aum a i s di m i ni shed.
Im pai r ed ar ter i al ci r cul ati on al so pr edi sposes to the dev el opm ent of
cel l ul i ti s. Host i m m une m echani sm s, such as pol y m or phonucl ear
l euk ocy tes and com pl em ent, ar e del i v er ed thr ough the ci r cul ati on.
Ther ef or e, i f the host ci r cul ati on i s i m pai r ed, nor m al i m m une
m echani sm s, w hi ch m i ght easi l y er adi cate an or gani sm , cannot be
m ounted. Thi s i s w hy cel l ul i ti s i s m or e f r equent i n pati ents w i th i m pai r ed
ar ter i al ci r cul ati on, such as those w i th di abetes and sm ok er s w i th
per i pher al v ascul ar di sease.
Pati ents w hose v enous and l y m phati c dr ai nage i s com pr om i sed ar e al so

l ess abl e to cl ear bacter i a f r om thei r bodi es, and ar e consequentl y
pr edi sposed to cel l ul i ti s. Pati ents w i th chr oni c edem a of the l ow er
ex tr em i ti es ar e par ti cul ar l y v ul ner abl e to cel l ul i ti s, w hi ch m ay spr ead
v er y r api dl y . A di sti ncti v e f or m of cel l ul i ti s has been f ound i n pati ents
w hose saphenous v ei ns hav e been r em ov ed f or cor onar y ar ter y by pass
gr af ti ng. These pati ents, w ho m ost l i k el y hav e both v enous i nsuf f i ci ency
and i m pai r ed l y m phati c dr ai nage, hav e been f ound to acqui r e cel l ul i ti s at
the si te of the saphenous v enectom y . Fr equentl y , the por tal of entr y f or
the i nf ecti on i s associ ated w i th ti nea pedi s. Besi des the tr eatm ent of
cel l ul i ti s, the ti nea pedi s shoul d be tr eated w i th a topi cal anti f ungal
agent.
Im m unocom pr om i sed pati ents, such as those under goi ng chem other apy or
tr anspl antati on pr ocedur es, ar e al so v ul ner abl e to cel l ul i ti s. The i nf ecti on
i n these pati ents m ay be m or e di f f i cul t to di agnose because the
char acter i sti c sy m ptom s and si gns m ay be m or e subtl e ow i ng to the
anti i nf l am m ator y pr oper ti es of the i m m unosuppr essi on.
2. What ar e the si gns and sy m ptom s of cel l ul i ti s?
The cl assi c appear ance ex hi bi ted by cel l ul i ti s i s a hot, sw ol l en, r ed, and
tender sk i n l esi on. The pati ent m ay be f ebr i l e, and r egi onal
l y m phadenopathy i s com m on. Acute l y m phangi ti s, i ndi cated by r ed
str eak s cour si ng up the pati ent's l i m b f r om the si te of the cel l ul i ti s,
si gni f i es the spr ead of i nf ecti on al ong subcutaneous l y m phati c channel s.
N ot al l cases of cel l ul i ti s ar e associ ated w i th l y m phangi ti s, but i t m ay be
the har bi nger of ser i ous sy stem i c i l l ness w i th bacter em i a.
3. What or gani sm s m ost f r equentl y cause cel l ul i ti s?
The m ost com m on causes of cel l ul i ti s i n gener al ar e gr oup A str eptococci
and S. aur eus. These gr am posi ti v e cocci ar e nor m al consti tuents of the
P. 232
hum an sk i n f l or a and ar e easi l y i ntr oduced i nto w ounds by tr aum a. Other
str eptococci m ay al so occasi onal l y cause cel l ul i ti s. Al though one coul d
r el y on Î²l actam ase r esi stant peni ci l l i ns or cephal ospor i ns i n the past to
tr eat m ost cases of com m uni ty acqui r ed S. aur eus i nf ecti on, ther e has
been a dr am ati c i ncr ease i n m ethi ci l l i nr esi stant S. aur eus i nf ecti on
am ong pati ents w i th com m uni ty acqui r ed i nf ecti on i n m any par ts of the
U ni ted States. In these ar eas, pr esum pti v e ther apy w i th v ancom y ci n or
l i nezol i d, pendi ng i denti f i cati on and suscepti bi l i ty testi ng, i s r equi r ed.
Pr acti ti oner s m ust be aw ar e of l ocal condi ti ons i n m ak i ng em pi r i c
anti m i cr obi al choi ces.
Less com m on pathogens m ay al so be i ntr oduced i nto a w ound by tr aum a.
For ex am pl e, soi l contam i nated w ounds m ay becom e i nf ected w i th f ungi
or Cl ostr i di um speci es. Ani m al bi te w ounds m ay becom e i nf ected w i th
bacter i a f r om the ani m al 's m outh. Er y si pel oi d, caused by Er y si pel othr i x
r husi opathi ae, i s a cel l ul i ti s that af f ects peopl e w ho handl e sal tw ater
f i sh, shel l f i sh, poul tr y , m eat, or ani m al hi des. Var i ous Vi br i o speci es m ay
cause cel l ul i ti s i n peopl e w i th w ounds ex posed to sal t w ater or r aw
seaf ood.
Less f r equentl y , cel l ul i ti s m ay be acqui r ed thr ough bacter em i a. Rar e
cases of pneum ococcal cel l ul i ti s hav e been r epor ted.
Im m unocom pr om i sed pati ents m ay al so acqui r e cel l ul i ti s by m eans of a
bacter em i a caused by or gani sm s, such as C. neof or m ans or E. col i , that
ar e not usual causes of cel l ul i ti s i n heal thy hosts.
Case
A 27y ear ol d m an pr esents to the em er gency r oom com pl ai ni ng of pai n i n hi s
r i ght hand. He w as w el l unti l the pr ev i ous day , w hen he sustai ned a deep
scr atch at the base of hi s r i ght thum b w hi l e pl ay i ng w i th hi s cat. He w ashed
the w ound and bandaged i t ti ghtl y to stop the bl eedi ng. Ov er ni ght, how ev er ,
hi s pal m began to sw el l , tur ned r ed, and becam e i ncr easi ngl y pai nf ul .
Hi s bl ood pr essur e i s 120/70 m m Hg, hear t r ate i s 90 beats per m i nute,
r espi r ator y r ate i s 12 per m i nute, and tem per atur e i s 38. 5Â°C (101. 3Â°F).
Phy si cal ex am i nati on f i ndi ngs ar e notabl e f or a l acer ati on on the r i ght thenar
em i nence that i s 2 cm l ong and 0. 5 cm deep. The w ound i s par ti al l y cr usted
ov er w i th bl ood, w i th a sm al l am ount of ser osangui neous di schar ge. The
sur r oundi ng ti ssue i s er y them atous, hot, and ex qui si tel y tender . Ther e ar e tw o
r ed str eak s ascendi ng the l ow er hal f of hi s anter i or f or ear m . He has a tender ,
m obi l e, 1cm l y m ph node i n the r i ght ax i l l a. Ther e i s f ul l r ange of m oti on
w i thout di scom f or t i n any of the di gi ts or the w r i st of hi s r i ght upper
ex tr em i ty . N eur ol ogi c ex am i nati on of the hand r ev eal s nor m al f i ndi ngs, and
Al l en's test r esul t i s nor m al .
The f ol l ow i ng l abor ator y data ar e f ound: w hi te bl ood cel l count, 15, 000/m m 3 ,
w i th a di f f er enti al count of 75% pol y m or phonucl ear l euk ocy tes, 5% band
f or m s, 17% l y m phocy tes, 2% m onocy tes, and 1% eosi nophi l s. Hi s ser um
chem i str y v al ues ar e nor m al . A r adi ogr aphi c study of the hand r ev eal s no
ev i dence of a f or ei gn body or subcutaneous em phy sem a. Gr am 's stai ni ng of
the ser osangui neous di schar ge f r om the w ound r ev eal s l ar ge num ber s of sm al l
gr am negati v e r ods and a f ew gr am posi ti v e cocci i n chai ns. Sam pl es of the
di schar ge and bl ood ar e sent f or cul tur e.
The pati ent w as bor n and r ai sed i n the U ni ted States. He has been i n good
heal th bef or e thi s i l l ness and has no hi stor y of hospi tal i zati ons. He r ecal l s
hav i ng had a tetanus
P. 233
booster shot 7 y ear s ago. He has no hi stor y of al l er gi c r eacti ons to
m edi cati ons. Hi s 7y ear ol d cat w as al so bor n and r ai sed i n the U ni ted States,
has r ecei v ed al l appr opr i ate v acci nati ons, and i s appar entl y heal thy .
1. What i nf ecti ous agents shoul d be consi der ed as possi bl e causes of thi s
pati ent's cel l ul i ti s?
2. What w oul d be the m ost appr opr i ate anti bi oti c tr eatm ent f or thi s pati ent?
3. In addi ti on to anti bi oti cs, w hat other m easur es shoul d be tak en to tr eat
thi s cel l ul i ti s?
Case Discussion
1. What i nf ecti ous agents shoul d be consi der ed as possi bl e causes of thi s
pati ent's cel l ul i ti s?
Gr oup A str eptococci and S. aur eus m ust al w ay s be consi der ed as
potenti al causes of cel l ul i ti s because they ar e the m ost com m on eti ol ogi c
agents. In the ev ent of ani m al bi tes or scr atches, the or al f l or a of the
ani m al m ay be an i m por tant sour ce of i nf ecti on as w el l . Pasteur el l a
m ul toci da i s f ound i n the or ophar y nx of 50% to 70% of heal thy cats and
12% to 60% of heal thy dogs. Thi s gr am negati v e r od i s f r equentl y
i m pl i cated i n i nf ecti ons r esul ti ng f r om cat bi tes or scr atches, and i s f ound
l ess of ten i n w ounds i nf l i cted by dogs. Other i m por tant ani m al or al f l or a
to consi der i n pati ents w i th bi tes and scr atch w ounds i ncl ude aer obi c and
anaer obi c str eptococcal or gani sm s, as w el l as gr am negati v e anaer obes
such as Bacter oi des speci es and Fusobacter i um . Or gani sm s f ound i n soi l ,
such as Cl ostr i di a speci es, m ay al so be tr ansm i tted by scr atches or bi tes.
The r api d tem po of thi s pati ent's i l l ness, w i th the dev el opm ent of an
ex qui si tel y pai nf ul cel l ul i ti s w i thi n 24 hour s of a cat scr atch, i s
char acter i sti c of P. m ul toci da i nf ecti on, al though such a r api d cour se m ay
al so be seen i n the setti ng of str eptococcal i nf ecti ons. It w oul d be
unusual , how ev er , f or a staphy l ococcal i nf ecti on to pr ogr ess thi s r api dl y .
Mor eov er , the di schar ge f r om a staphy l ococcal i nf ecti on w oul d m or e
l i k el y be pur ul ent than ser osangui neous. The f i ndi ng of m any gr am
negati v e r ods on the Gr am 'sstai ned speci m en of the w ound di schar ge
al so suggests a P. m ul toci da i nf ecti on, or a gr am negati v e anaer obi c
i nf ecti on. How ev er , a f ew gr am posi ti v e cocci i n chai ns w er e al so f ound,
m ak i ng str eptococcal i nf ecti on a par t of the di f f er enti al di agnosi s.
2. What w oul d be the m ost appr opr i ate anti bi oti c tr eatm ent f or thi s pati ent?
Thi s pati ent has a ser i ous hand i nf ecti on, al ong w i th an i m pendi ng
sy stem i c i l l ness. Any one w i th such a ser i ous hand i nf ecti on shoul d be
hospi tal i zed and r ecei v e i ntr av enous anti bi oti cs to pr ev ent adv anci ng
i nf ecti on, as w el l as to av er t the potenti al l y dev astati ng consequences of
subopti m al ther apy . Peni ci l l i n i s the dr ug of choi ce f or P. m ul toci da
i nf ecti ons, and w oul d al so be ef f ecti v e f or the m anagem ent of both
str eptococcal and anaer obi c i nf ecti ons. Ther ef or e, i ntr av enous peni ci l l i n
w oul d be the best anti bi oti c i n thi s case. For pati ents w ho ar e al l er gi c to
peni ci l l i n, tetr acy cl i ne i s the best al ter nati v e dr ug f or the tr eatm ent of P.
m ul toci da i nf ecti ons. The pati ent shoul d al so be seen i n consul tati on w i th
a hand sur geon to be cer tai n that sur gi cal i nter v enti on f or dr ai nage or
decom pr essi on i s not r equi r ed.
P. 234
3. In addi ti on to anti bi oti cs, w hat other m easur es shoul d be tak en to tr eat
thi s cel l ul i ti s?
Ov er esti m ati ng the ef f i cacy of anti bi oti cs, and under esti m ati ng the
cr i ti cal r ol es pl ay ed by debr i dem ent, dr ai nage, w ound el ev ati on, and
i m m obi l i zati on, ar e pr obabl y the m ost f r equent m i stak es m ade i n the
tr eatm ent of cel l ul i ti s. Dr ai nage of a cl osedspace i nf ecti on and r em ov al
of necr oti c ti ssue ar e essenti al f or cur i ng any i nf ecti on. Ev en w hen the
appr opr i ate anti bi oti cs ar e adm i ni ster ed, an i nf ecti on can w or sen i f
abscesses or necr oti c ti ssue ar e not dr ai ned or r em ov ed. The r eason f or
thi s i s that abscesses and necr oti c ti ssue ar e not w el l v ascul ar i zed,
m ak i ng them i naccessi bl e to both the anti bi oti cs and the host i m m une
m echani sm s, such as pol y m or phonucl ear l euk ocy tes and com pl em ent,
w hi ch ar e nor m al l y conv ey ed thr ough the bl oodstr eam . Ther ef or e, i n
these i naccessi bl e r egi ons bacter i a can f r eel y m ul ti pl y and, i n som e
i nstances, such i nf ecti on can r esul t i n sepsi s and death despi te an
appr opr i ate anti bi oti c r egi m en.
Abscesses tend to dev el op i n the setti ng of P. m ul toci da i nf ecti on. In
addi ti on, the hand contai ns sev er al phy si ol ogi c spaces, such as the thenar
em i nence, that can ser v e as pock ets of i nf ecti on. Ther ef or e, a P.
m ul toci da cel l ul i ti s of the hand m ay r equi r e sur gi cal debr i dem ent and
dr ai nage. Inci si on of a hand w ound shoul d not be per f or m ed by a nov i ce,
because ther e i s a gr eat potenti al f or dam agi ng i nter nal str uctur es or
cr eati ng w ounds that w oul d r esul t i n ser i ous contr actur es. A hand sur geon
shoul d be consul ted f or thi s pur pose.
The objecti v e of el ev ati on and i m m obi l i zati on i n the tr eatm ent of
cel l ul i ti s i s to di m i ni sh the edem a, w hi ch i m pedes the bl ood f l ow to an
i nf ected r egi on. El ev ati on of the af f ected l i m b abov e the l ev el of the
hear t i s necessar y to achi ev e opti m al r esul ts. In the ev ent of a l ow er
ex tr em i ty cel l ul i ti s, m er el y pl aci ng the af f ected l i m b on a chai r w hi l e
seated i s not adequate because the abdom i nal contents sti l l ex er t
pr essur e on the l y m phati c v essel s i n thi s posi ti on, ther eby per petuati ng
the edem a. In addi ti on to the m easur es just descr i bed, thi s pati ent shoul d
r ecei v e a tetanus booster shot. Any pati ent w i th a bi te or deep scr atch
w ound w ho has not had a tetanus booster shot w i thi n the pr ecedi ng 5
y ear s shoul d r ecei v e one.
Suggested Readings
Center s f or Di sease Contr ol . Di phther i a, tetanus, and per tussi s: gui del i nes
f or v acci ne pr ophy l ax i s and other pr ev enti v e m easur es. Ann Inter n Med
1985;103:896.
El l i ot DL, Tol l e SW, Gol dber g L, et al . Petassoci ated i l l ness. N Engl J Med
1985;313:985.
Fr anci s DP, Hol m es MA, Br andon G. Pasteur el l a m ul toci da: i nf ecti ons af ter
dom esti c ani m al bi tes and scr atches. JAMA 1975;233:42.
Fr i dk i n SK, Hagem an JC, Mor r i son M, et al . Methi ci l l i nr esi stant
Staphy l ococcus aur eus di sease i n thr ee com m uni ti es. N Engl J Med
2005;352:1436â€“1444.
Gol dstei n EJC. Bi tes. In: Mandel l GL, Bennett JE, Dol i n R, eds. Pr i nci pl es
and pr acti ce of i nf ecti ous di seases, 6th ed. N ew Yor k : El sev i er Sci ence,
2005:3552.
Mi l l er LG, Per dr eauRem i ngton F, Rei g G, et al . Four teen pati ents w i th
necr oti zi ng f asci i ti s caused by com m uni ty associ ated m ethi ci l l i nr esi stant
Staphy l ococcus aur eus i n Los Angel es. N Engl J Med 2005;352:1445.
Stev ens DL, Her r D, Lam per i s H, et al . Li nezol i d v er sus v ancom y ci n f or the
tr eatm ent of m ethi ci l l i nr esi stant Staphy l ococcus aur eus i nf ecti ons. Cl i n
Inf ect Di s 2002;34:1481.
P. 235
Sw ar tz MN , Paster nak MS. Cel l ul i ti s and subcutaneous ti ssue i nf ecti ons. In:
Mandel l GL, Bennett JE, Dol i n R, eds. Pr i nci pl es and pr acti ces of i nf ecti ous
di seases, 6th ed. N ew Yor k : El sev i er Sci ence, 2005:1172.
A Late Complication of Tuberculosis
1. What ar e the goal s of the m oder n dr ug tr eatm ent of acti v e pul m onar y
tuber cul osi s?
2. What f actor s ar e l i k el y to pr om ote r el apse?
3. What f actor s ar e l i k el y to f oster the acqui si ti on of dr ugr esi stant di sease?
Discussion
1. What ar e the goal s of the m oder n dr ug tr eatm ent of acti v e pul m onar y
tuber cul osi s?
Fundam ental to the m oder n dr ug tr eatm ent of tuber cul osi s i s the use of
m ul ti pl edr ug r egi m ens. Ther e ar e tw o goal s to thi s appr oach.
The f i r st object of m ul ti pl edr ug tr eatm ent i s to pr ev ent the em er gence of
r esi stant or gani sm s. The f i ndi ngs f r om ear l y studi es on the use of
str eptom y ci n dr am ati cal l y dem onstr ated the f uti l i ty of m onother apy , i n
that pati ents w i th sev er e di sease show ed an i ni ti al gr ati f y i ng r esponse to
tr eatm ent, but af ter som e w eek s thei r condi ti on began to deter i or ate.
Thei r sputum sm ear s becam e posi ti v e f or or gani sm s once agai n, and
dr ugr esi stant di sease dev el oped. It i s bel i ev ed that m onother apy sel ects
f or , r ather than i nduces the m utati on of , r esi stant or gani sm s. Ther ef or e,
the l ar ger the popul ati on of or gani sm s, the hi gher the l i k el i hood that
r esi stant or gani sm s ar e pr esent. Ther ef or e, i n the setti ng of an
asy m ptom ati c pr i m ar y i nf ecti on that i nv ol v es f ew or gani sm s,
m onother apy (usual l y consi sti ng of i soni azi d) can be used saf el y as
pr ophy l ax i s. In pati ents w i th acti v e di sease (especi al l y cav i tati ng
pul m onar y di sease i n w hi ch the bur den of i nf ecti on i s i m m ense), the
pr obabi l i ty of r esi stant or gani sm s i s hi gh. Mutati ons l eadi ng to dr ug
r esi stance ar e unl i nk ed, how ev er , so the use of tw o dr ugs (e. g. , i soni azi d
pl us r i f am pi n) ef f ecti v el y pr ev ents the em er gence of secondar y dr ug
r esi stance (i . e. , dr ug r esi stance acqui r ed dur i ng tr eatm ent).
The second goal of ther apy i s to shor ten the dur ati on of tr eatm ent. To
achi ev e a l asti ng cur e i n a hi gh pr opor ti on of cases, r egi m ens that
com pr i se onl y r i f am pi n pl us i soni azi d m ust be conti nued f or 9 m onths.
How ev er , thi s can be r educed to 6 m onths by the addi ti on of
py r azi nam i de f or the f i r st 2 m onths. Py r azi nam i de i s a pow er f ul
ster i l i zi ng dr ug that m ay ex er t i ts ef f ect by acti ng on speci al
subpopul ati ons of or gani sm s, such as those i n a m or e aci d env i r onm ent.
It has been show n that ther e i s no addi ti onal benef i t i n conti nui ng thi s
ex pensi v e dr ug bey ond the f i r st 2 m onths.
A f actor to be consi der ed w hen pl anni ng m ul ti dr ug tr eatm ent i s that
i ni ti al dr ug r esi stance ex i sts w hen the di sease i s caused by or gani sm s
that ar e r esi stant to at l east one dr ug bef or e any tr eatm ent i s gi v en.
When thi s i s suspected on epi dem i ol ogi c gr ounds, an addi ti onal dr ug
(usual l y str eptom y ci n
P. 236
or etham butol ) i s added to the r egi m en dur i ng the f i r st 2 m onths, w hi l e
the r esul ts of dr ug suscepti bi l i ty studi es ar e aw ai ted. Thi s appr oach
r educes the r i sk of onl y one ef f ecti v e dr ug bei ng gi v en.
2. What f actor s ar e l i k el y to pr om ote r el apse?
Rel apse (i . e. , the endogenous r eacti v ati on of pr ev i ousl y tr eated

tuber cul osi s) i s m ost l i k el y to occur dur i ng the f i r st y ear af ter the end of
tr eatm ent and i n those pati ents w ho i ni ti al l y had m or e ex tensi v e di sease.
Pati ents w ho di sconti nue thei r tr eatm ent ear l y ar e m ost l i k el y to hav e a
r el apse. Ther ef or e, ensur i ng com pl i ance w i th tr eatm ent i s centr al to
pr ev enti ng r el apse.
3. What f actor s ar e l i k el y to f oster the acqui si ti on of dr ugr esi stant di sease?
For the r easons al r eady outl i ned, dr ugr esi stant or gani sm s em er ge w hen
a pati ent ef f ecti v el y r ecei v es onl y m onother apy . Thi s m ay occur f or a
v ar i ety of r easons, and the f ol l ow i ng i l l ustr ates how i t can happen. A
pati ent on r i f am pi n pl us i soni azi d m ay sel l hi s pow er f ul r ed r i f am pi n
capsul es to hi s f r i ends (or the w i tch doctor ) f or use i n the tr eatm ent of
gonor r hea and then tak e onl y the i soni azi d hi m sel f , r esul ti ng i n i soni azi d
m onother apy ! Thi s m an acqui r es i soni azi d r esi stance, cough r ecur s, and
etham butol i s added by a k i ndl y phy si ci an, w hi ch ef f ecti v el y now
consti tutes etham butol m onother apy . Soon, r esi stance to etham butol
em er ges and the m an's heal th conti nues to decl i ne. Per haps he w i l l star t
tak i ng hi s r i f am pi n, w hi ch m eans he i s r ecei v i ng r i f am pi n m onother apy .
Such pati ents f i r st need to k now that they m ust ei ther tak e both
m edi cati ons and get better , or tak e nei ther and get w or se, but at l east, i n
thi s l atter i nstance, the di sease r em ai ns dr ug suscepti bl e. It i s al w ay s a
m i stak e to add one dr ug at a ti m e to a f ai l i ng r egi m en. Instead, at l east
tw o new dr ugs shoul d be added to pr otect agai nst the em er gence of
r esi stance to each other . Ful l y super v i sed ther apy pr ev ents scenar i os
such as these f r om happeni ng, but, unf or tunatel y , at pr esent i t i s not
f easi bl e on a gl obal scal e.
Case
A 73y ear ol d m an i s adm i tted because of a 3m onth hi stor y of i nter m i ttent
hem opty si s. Appr ox i m atel y once a w eek he has been coughi ng up sm al l
am ounts of bl oodstr eak ed sputum , but, on the day bef or e adm i ssi on, he
star ted to cough f r equentl y and pr oduced appr ox i m atel y hal f a cupf ul of r ed
and cl otted bl ood ov er a 24hour per i od. The pati ent had em i gr ated to Am er i ca
i n the 1940s af ter hav i ng been i nter ned i n a l abor cam p i n Eur ope dur i ng
Wor l d War II. A m edi cal ex am i nati on at the ti m e of hi s l i ber ati on r ev eal ed he
had tuber cul osi s. He w as then adm i tted to a sanator i um , w her e he stay ed f or
18 m onths, w i th tr eatm ent consi sti ng of ar ti f i ci al pneum othor ax . In the 1950s,
he had a r el apse and w as tr eated f or 18 m onths w i th i soni azi d,
par aam i nosal i cy l i c aci d, and str eptom y ci n. He conti nued to sm ok e a pack of
ci gar ettes per day unti l an attack of pneum oni a 5 y ear s bef or e, w hi ch caused
hi m to stop sm ok i ng. For the past y ear , he has been i ncr easi ngl y di sabl ed by
ex er ti onal dy spnea, such that he i s now unabl e to cl i m b a f l i ght of stai r s
w i thout stoppi ng. He has al so had r ecur r ent ex acer bati ons of br eathl essness
w i th pr oducti v e cough, but no pr ev i ous hem opty si s. He has r ecentl y noted
i ncr easi ng ank l e edem a. He has no hi stor y of w ei ght l oss or f ev er .
P. 237
On ex am i nati on, he i s f ound to be thi n and anx i ous, af ebr i l e, and
nor m otensi v e, w i th a r egul ar pul se of 110 beats per m i nute. He i s sl i ghtl y
tachy pnei c and has both centr al and per i pher al cy anosi s. The jugul ar v enous
pul se i s v i si bl e appr ox i m atel y 3 cm abov e the cl av i cl e w hen he i s at an angl e
of 45 degr ees. He has a di scr ete, f i r m , nontender l y m ph node that i s enl ar ged
to appr ox i m atel y 2 cm i n the r i ght supr acl av i cul ar f ossa. The tr achea i s
dev i ated to the r i ght, and the r i ght upper chest i s noted to be i ndr aw n bel ow
the cl av i cl e; i t i s dul l to per cussi on and br onchi al br eath sounds ar e hear d.
The apex of the hear t i s not pal pabl e and auscul tati on of the hear t r ev eal s a
l oud pul m onar y second sound. He has bi l ater al ank l e edem a.
The chest r adi ogr aphi c study on adm i ssi on depi cts bi l ater al , sev er e f i br oti c
l ung di sease, w hi ch i s m ost m ar k ed i n the upper l obes, w i th el ev ati on of the
hi l a; the abnor m al i ti es ar e m or e pr onounced on the r i ght. The hor i zontal
f i ssur e i s el ev ated on the r i ght and pr ojects upw ar d. Dev i ati on of the tr achea
to the r i ght i s conf i r m ed. Ther e ar e thi nw al l ed cav i ti es bi l ater al l y , and a
cav i ty on the r i ght i s f ound to contai n an opaci ty that i s outl i ned by a
cr escentshaped r i m of ai r . A r ev i ew of hi s l abor ator y r ecor ds r ev eal s that
ser um pr eci pi ti ns f or asper gi l l us w er e f ound i n hi s bl ood on a test sent f r om
the outpati ent depar tm ent ear l i er i n the m onth.

2. If m assi v e hem opty si s super v enes, how shoul d thi s be m anaged?
3. What i s the m ost usef ul i nv esti gati on to conf i r m the di agnosi s?
4. Shoul d the pati ent r ecei v e i ntr av enous am photer i ci n B?
5. What addi ti onal l ate com pl i cati on of tuber cul osi s does thi s pati ent
ex hi bi t, and how can thi s be r el i ev ed?
Case Discussion
Di agnoses that shoul d be consi der ed i n thi s pati ent i ncl ude asper gi l l om a,
r eacti v ati on of the tuber cul osi s, car ci nom a of the br onchus, and
br onchi ectasi s. How ev er , thi s pati ent ex hi bi ts the cl assi c cl i ni cal pi ctur e
of asper gi l l om a. Asper gi l l us col oni zes and gr ow s sapr ophy ti cal l y i n
cav i ti es cr eated by pr eex i sti ng l ung di sease (ty pi cal l y those caused by
tuber cul osi s, al though occasi onal l y other di seases such as sar coi dosi s,
br onchi ectasi s, or pul m onar y f i br osi s can cause the f or m ati on of cav i ti es
hospi tabl e to such i nf ecti on). A f ungus bal l dev el ops i n the pr eex i sti ng
cav i ty , w hi ch i s l i ned w i th br onchi al epi thel i um or gr anul ati on ti ssue.
Chest r adi ogr aphi c studi es, tom ogr am s, or com puted tom ogr aphi c (CT)
scans can show the r ounded opaci ty w i thi n the cav i ty , together w i th a
cr escentshaped r i m of ai r betw een the cav i ty and i ts w al l . The bal l m ay
l i e f r ee w i thi n the cav i ty (i n w hi ch case i t can be seen to change posi ti on
on decubi tus chest r adi ogr aphs) or i t m ay be attached by gr anul ati on
ti ssue. Of ten the pati ent i s asy m ptom ati c, but hem opty si s i s the m ost
i m por tant com pl i cati on of asper gi l l om a. Ser um pr eci pi ti ns to asper gi l l us
ar e f ur ther suppor ti v e ev i dence f or thi s di agnosi s because these ar e
f ound i n 90% to 95% of cases of asper gi l l om a.
In thi s pati ent, r eacti v ati on of the tuber cul osi s i s l ess l i k el y than
asper gi l l om a because, despi te a 3m onth hi stor y , the pati ent has not l ost
w ei ght or had a f ev er . In
P. 238
addi ti on, the cav i ti es seen on the chest r adi ogr aphs hav e thi n w al l s,
suggesti ng the pr esence of i nacti v e di sease. How ev er , r adi ol ogi cal l y , i t i s
i m possi bl e to di sti ngui sh w i th cer tai nty betw een acti v e and i nacti v e
tuber cul osi s.
Car ci nom a of the br onchus m i ght al so be ex pected to cause w ei ght l oss,
and i t i s an i m por tant consi der ati on i n pati ents w i th a hi stor y of
tuber cul osi s because they ar e at hi gher r i sk than the gener al popul ati on
because of the car ci nom a (usual l y adenocar ci nom a or al v eol ar cel l
car ci nom a) that can f or m i n scar r ed ti ssue, as an af ter m ath of i nf ecti on.
Thi s pati ent i s al so at r i sk f or br onchi al car ci nom a because of hi s l ong
hi stor y of sm ok i ng.
Tuber cul osi s com m onl y l eads to br onchi ectasi s, w hi ch w oul d undoubtedl y
coex i st i n a pati ent l i k e thi s w ho has sev er e destr ucti v e l ung di sease.
How ev er , thi s pati ent's epi sode i s dom i nated by hem opty si s, r ather than
by the ex pector ati on of copi ous, pur ul ent sputum , w hi ch w oul d be m or e
suggesti v e of an ex acer bati on of br onchi ectasi s.
2. If m assi v e hem opty si s super v enes, how shoul d thi s be m anaged?
The m ajor r i sk f r om asper gi l l om a i s l i f ethr eateni ng hem opty si s. The

pr ognosi s f or pul m onar y asper gi l l om a i s negati v el y i nf l uenced by a
num ber of f actor s i ncl udi ng the docum entati on of i ncr easi ng si ze or
num ber s of the asper gi l l om as on chest r adi ogr aphs, sev er e under l y i ng
l ung di sease, i ncr easi ng Asper gi l l usspeci f i c i m m unogl obul i n G (IgG)
anti bodi es, i m m unosuppr essi on such as cor ti coster oi ds or HIV i nf ecti on,
and the pr esence of sar coi dosi s. Sur gi cal r em ov al i s the pr ef er r ed
tr eatm ent i n the setti ng of l i f ethr eateni ng hem opty si s due to
asper gi l l om a, al though i n thi s pati ent (as i n m any w i th asper gi l l om a),
sev er e under l y i ng l ung di sease i ndi cates the l i k el i hood of a poor outcom e
af ter pul m onar y sur ger y . Em bol i zati on of the br onchi al ar ter y has been
used successf ul l y to contr ol sev er e hem opty si s due to tuber cul osi s,
am ong other causes, but has not been successf ul i n the m anagem ent of
sev er e hem opty si s caused by asper gi l l om a, pr obabl y because of the l ar ge
col l ater al ci r cul ati on i nv ol v ed.
Whi l e ar r angem ents ar e m ade f or def i ni ti v e m anagem ent, a pati ent w i th

sev er e hem opty si s shoul d be posi ti oned on the si de of the suspected
sour ce (i n thi s case, the r i ght si de) to m i ni m i ze f l oodi ng of the
unaf f ected l ung w i th bl ood. Sedati on of the pati ent i s l i k el y to be
r equi r ed. An i ntr av enous l i ne shoul d be establ i shed and bl ood
cr ossm atched and adm i ni ster ed w hen needed.
3. What i s the m ost usef ul i nv esti gati on to conf i r m the di agnosi s?
N o i nv esti gati on (other than pathol ogi c anal y si s of the sur gi cal speci m en)
i s speci f i c i n conf i r m i ng the di agnosi s of asper gi l l om a, but Asper gi l l us
pr eci pi ti ns ar e pr esent i n a hi gh pr opor ti on of cases of asper gi l l om a and
can ser v e to conf i r m the di agnosi s i n a pati ent w i th the char acter i sti c
cl i ni cal and r adi ol ogi c pr esentati on, such as that descr i bed her e. Sputum
cul tur e f or Asper gi l l us or gani sm s i s l ess hel pf ul because i t m ay y i el d no
or gani sm s i f the cav i ty does not com m uni cate w i th the br onchus. Sk i n
tests w i th Asper gi l l us anti gens ar e al so l ess r el i abl e.
Mi cr oscopi c ex am i nati on of the sputum f or aci dal cohol â€“f ast baci l l i
shoul d be done i n a case such as thi s to ex cl ude coex i sti ng acti v e
tuber cul osi s, al though, both cl i ni cal l y and r adi ol ogi cal l y , thi s i s a l ess
l i k el y di agnosi s. A r easonabl e pr ecauti on
P. 239
w oul d be to pl ace the pati ent i n r espi r ator y i sol ati on unti l negati v e sm ear
r esul ts hav e been obtai ned.
4. Shoul d the pati ent r ecei v e i ntr av enous am photer i ci n B?
Ther e hav e been no pr ospecti v e studi es com par i ng the outcom e i n
pati ents w i th asper gi l l om a tr eated w i th i ntr av enous am photer i ci n B
v er sus the outcom e i n untr eated pati ents. The f i ndi ngs f r om r etr ospecti v e
studi es suggest, how ev er , that thi s tr eatm ent conf er s no benef i ci al ef f ect,
and thi s i s not sur pr i si ng, gi v en that the f ungal bal l i s i sol ated f r om the
bl oodstr eam . Asy m ptom ati c pati ents m ay si m pl y be m oni tor ed and
r esol uti on m ay occur spontaneousl y . Pr ophy l acti c sur gi cal r em ov al m ay
be consi der ed i n pati ents w ho ar e f i t f or the pr ocedur e because of the
potenti al of asper gi l l om a to cause f atal hem opty si s, and because sur ger y
m ay ef f ect a l asti ng cur e. How ev er , the poor ex er ci se tol er ance and the
cl i ni cal f i ndi ngs i ndi cati ng r espi r ator y f ai l ur e i n thi s case suggest that the
pati ent w oul d be unl i k el y to tol er ate the pr ocedur e. Thi s coul d be
conf i r m ed by f or m al pul m onar y f uncti on tests. Poor pr ognosti c i ndi cator s
w oul d be an ar ter i al bl ood gas anal y si s show i ng an el ev ated par ti al
pr essur e of car bon di ox i de (PCO 2 ) and a f or ced ex pi r ator y v ol um e of l ess
than 1 L per second.
5. What addi ti onal l ate com pl i cati on of tuber cul osi s does thi s pati ent
ex hi bi t, and how can thi s be r el i ev ed?
The pati ent has centr al cy anosi s, i ndi cati ng that he has hy pox i a at r est.
Thi s i s an addi ti onal l ate com pl i cati on of pul m onar y tuber cul osi s,
pr obabl y ex acer bated i n hi s case by chr oni c obstr ucti v e pul m onar y
di sease due to sm ok i ng. The hy pox i a has r esul ted i n pul m onar y
v asoconstr i cti on and, hence, i n pul m onar y hy per tensi on (i ndi cated by the
l oud pul m onar y second sound hear d on auscul tati on of the hear t). Thi s, i n
tur n, has r esul ted i n r i ght v entr i cul ar f ai l ur e (i ndi cated by the r ai sed
jugul ar v enous pr essur e and edem a), or cor pul m onal e. Conti nuous
adm i ni str ati on of ox y gen i s i ndi cated f or r el i ef of thi s sy ndr om e.
Suggested Readings
Ak bar i JG, Var m a PK, N eem a PK, et al . Cl i ni cal pr of i l e and sur gi cal
outcom e f or pul m onar y asper gi l l om a: a si ngl e center ex per i ence. Ann
Thor aci c Sur g 2005;80:1067.
Gl i m p RA, Bay er AS. Pul m onar y asper gi l l om a: di agnosti c and ther apeuti c
consi der ati ons. Ar ch Inter n Med 1983;143:303.
Gr eene R. The r adi ol ogi cal spectr um of pul m onar y asper gi l l osi s. Med My col
2005;43(Suppl 1):S147.
Kauf f m an C. Quandar y about tr eatm ent of asper gi l l om as per si sts. Lancet
1996;347:1640.
Ki m YT, Kang MC, Sung SW, et al . Good l ongter m outcom es af ter sur gi cal
tr eatm ent of si m pl e and com pl ex pul m onar y asper gi l l om a. Ann Thor ac Sur g
2005;79:294.
Mi tchi son DA. Basi c m echani sm s of chem other apy . Chest 1979;76(6
Suppl ):771.
Shapi r o MJ, Al bel da SM, May ock RL, et al . Sev er e hem opty si s associ ated
w i th pul m onar y asper gi l l om a: per cutaneous i ntr acav i tar y tr eatm ent. Chest
1988;94:1225.
Stev ens DA, Vi r gi ni a L, Kan VL, et al . Pr acti ce gui del i nes f or di seases
caused by asper gi l l us. Cl i n Inf ect Di s 2000;30:696.
P. 240
Sepsis
1. Is ther e a cl i ni cal di sti ncti on betw een bacter em i a and sepsi s?
2. What i s the di sti ncti on betw een chi l l s and r i gor s?
3. What f actor s ar e associ ated w i th a poor pr ognosi s i n the setti ng of gr am
negati v e sepsi s?
Discussion
1. Is ther e a cl i ni cal di sti ncti on betw een bacter em i a and sepsi s?
It i s i m por tant to di f f er enti ate am ong bacter em i a, sepsi s, and septi c
shock . Bacter em i a i s def i ned as the pr esence of v i abl e bacter i a i n the
bl ood, as dem onstr ated by a posi ti v e bl ood cul tur e. Bacter em i as m ay be
f ur ther cl assi f i ed as tr ansi ent, sustai ned, or i nter m i ttent, dependi ng on
the l ength of ti m e bl ood cul tur es ar e posi ti v e. Tr ansi ent bacter em i as ar e
com m on and l ast f or onl y sev er al m i nutes. When m ul ti pl e bl ood cul tur es
ar e posi ti v e ov er the cour se of sev er al hour s to sev er al day s, thi s
i ndi cates a sustai ned bacter em i a. Inter m i ttent bacter em i as ar e those i n
w hi ch the bl ood cul tur es ar e i nter m i ttentl y posi ti v e. Sepsi s i s a cl i ni cal
ter m that r ef er s to a phy si ol ogi c state that i s associ ated w i th sev er e
i nf ecti on. In septi c shock , ther e i s hy potensi on (sy stol i c bl ood pr essur e
< 90 m m Hg or a onethi r d r educti on f r om the pr i or sy stol i c bl ood
pr essur e) and ev i dence of endor gan dam age secondar y to r educed bl ood
f l ow .
2. What i s the di sti ncti on betw een chi l l s and r i gor s?
It i s v er y i m por tant to k now the di f f er ence betw een chi l l s and r i gor s.
Ri gor (a tr ue shak i ng chi l l ) i s v er y of ten associ ated w i th bacter em i a. The
pati ent m ay ex per i ence teeth chatter i ng and body tr em or s that usual l y
l ast f or 15 to 30 m i nutes. A chi l l i s m or e appr opr i atel y descr i bed as a
chi l l y sensati on, not a cl i ni cal pr esentati on. Ri gor s m ay be seen i n the
setti ng of v i r al i nf ecti ons as w el l as bacter em i as.
3. What f actor s ar e associ ated w i th a poor pr ognosi s i n the setti ng of gr am
negati v e sepsi s?
Despi te adv ances i n suppor ti v e ther apy , the m or tal i ty r ate associ ated
w i th gr am negati v e septi c shock appr oaches 40%. Factor s that contr i bute
to thi s poor pr ognosi s ar e i ncr eased age, poor nutr i ti onal status, ster oi d
use, ci r r hosi s, di abetes, congesti v e hear t f ai l ur e, and gr anul ocy topeni a.
Outcom e i s al so adv er sel y af f ected by v ol um e depl eti on, i nappr opr i ate
anti bi oti c use, and del ay i n ther apy .
Case
A 74y ear ol d w hi te m an w i th Al zhei m er 's di sease i s br ought to the em er gency
r oom by am bul ance af ter a 1day hi stor y of f ev er and m ental status changes.
On ar r i v al i n the em er gency r oom , hi s bl ood pr essur e i s f ound to be 100/60
m m Hg, hear t r ate i s 100 beats per m i nute, tem per atur e i s 38. 5Â°C (101. 3Â
°F), and r espi r ator y r ate i s 24 per m i nute. The pati ent i s unabl e to gi v e any
hi stor y ; how ev er , hi s w i f e states that he had been i n hi s usual heal th unti l the
ev eni ng bef or e adm i ssi on, w hen he began to com pl ai n of gener al i zed
abdom i nal pai n and had becom e m or e conf used than usual .
P. 241
Phy si cal ex am i nati on r ev eal s an agi tated el der l y m an w ho i s i n no acute
di str ess. Hi s or al m ucosa i s dr y and the l ung ex am i nati on r ev eal s decr eased
br eath sounds at the bases bi l ater al l y . Car di ac ex am i nati on r ev eal s si nus
tachy car di a. Abdom i nal ex am i nati on r ev eal s nor m al bow el sounds and a
pal pabl e m ass i n the l ow er abdom en ex tendi ng f r om 2 cm bel ow the um bi l i cus
dow n to the pel v i s. Rectal ex am i nati on r ev eal s an enl ar ged, f i r m pr ostate, and
the stool i s hem e negati v e. Hi s ex tr em i ti es ar e cool and cl am m y and ther e i s
decr eased sk i n tur gor .
Adm i ssi on l abor ator y r esul ts ar e as f ol l ow s: w hi te bl ood cel l count,
16, 000/m m 3 w i th a di f f er enti al count of 85% pol y m or phonucl ear l euk ocy tes,
10% band f or m s, and 5% l y m phocy tes; hem atocr i t, 47%; cr eati ni ne, 2. 3
m g/dL; bl ood ur ea ni tr ogen, 40 m g/dL; sodi um , 141 m Eq/L; potassi um , 4. 5
m Eq/L; chl or i de, 107 m Eq/L; and car bon di ox i de, 17 m Eq/L. Ar ter i al bl ood gas
m easur em ent per f or m ed on r oom ai r r ev eal s a pH of 7. 29, a PO 2 of 68 m m
Hg, and a PCO 2 of 30 m m Hg. Hi s chest r adi ogr aphi c f i ndi ngs ar e
unr em ar k abl e. The pati ent i s ask ed f or a ur i ne speci m en but i s abl e to v oi d
onl y 5 m L of cl oudy , dar k y el l ow ur i ne, w hi ch i s sent to the l abor ator y f or
ur i nal y si s and cul tur e.
A Fol ey catheter w as subsequentl y pl aced and 500 m L of f oul sm el l i ng ur i ne
w as obtai ned. A Gr am 's stai n r ev eal ed num er ous pol y m or phonucl ear cel l s and
gr am negati v e r ods. On r epeat ex am i nati on, hi s abdom en w as f ound to be sof t
and the m ass had di sappear ed.
1. What sy stem i s the l i k el y sour ce of i nf ecti on i n thi s pati ent, and how
coul d i nf ecti on at thi s si te ex pl ai n hi s other si gns and sy m ptom s?
2. What gr oup of or gani sm s i s m ost l i k el y associ ated w i th the sepsi s
sy ndr om e i n thi s pati ent, and how does thi s gr oup di f f er f r om the other
m ajor gr oups of bacter i a and f ungi ?
3. How does endotox i n af f ect m acr ophages, and w hat chem i cal si gnal s ar e
pr oduced by m acr ophages to contr i bute to the sepsi s sy ndr om e?
4. Of w hat shoul d the i ni ti al m anagem ent of a pati ent w i th the sepsi s
sy ndr om e consi st?
Case Discussion
1. What sy stem i s the l i k el y sour ce of i nf ecti on i n thi s pati ent, and how
coul d i nf ecti on at thi s si te ex pl ai n hi s other si gns and sy m ptom s?
The m ost l i k el y di agnosi s that f i ts w i th thi s pati ent's constel l ati on of
sy m ptom s i s ur osepsi s. As br ought to l i ght by the phy si cal ex am i nati on,
the pati ent has the si gns of septi c shock â€”i m pai r ed ti ssue per f usi on,
hy potensi on, and l acti c aci dosi s i n associ ati on w i th posi ti v e bl ood
cul tur es. Tachy car di a, tachy pnea, and ol i gur i a ar e al so usual l y seen i n
the setti ng of geni tour i nar y , gastr oi ntesti nal , bi l i ar y , and gy necol ogi c
i nf ecti ons, and ther ef or e ar e not speci f i c to ur osepsi s. Abnor m al i ti es i n
m ental status m ay al so be a f eatur e of the i ni ti al pr esentati on, ev en
w i thout i nf ecti on i n the CN S. In el der l y pati ents, the sy m ptom s of m ental
obtundati on m ay be subtl e and consi st onl y of w i thdr aw al or agi tati on,
and they m ay consti tute the sol e i ndi cati on of sev er e i nf ecti on. The chest
r adi ogr aphi c study i n thi s pati ent w as negati v e w i th no ev i dence of an
i nf i l tr ate, m ak i ng pneum oni a unl i k el y . How ev er , the cl i ni ci an m ust al w ay s
k eep i n m i nd that w i th hy dr ati on an i nf i l tr ate m ay bl ossom , so the
pati ent's
P. 242
r espi r ator y status shoul d be m oni tor ed cl osel y . Because the m ental status
changes m ay be the onl y ear l y m ani f estati on of sepsi s i n the el der l y ,
m or e of ten than not a l um bar punctur e y i el ds nor m al f l ui d. Thi s pati ent's
phy si cal ex am i nati on f i ndi ngs w er e al so r em ar k abl e f or an abdom i nal
m ass, and i ndeed he had com pl ai ned of di f f use abdom i nal pai n f or at
l east 1 day bef or e adm i ssi on. Cer tai nl y , el der l y pati ents m ay hav e
appendi ci ti s, di v er ti cul i ti s w i th an abscess, or a col on car ci nom a w i th
subsequent bacter em i a, and al l these condi ti ons m ust be i ncl uded i n the
di f f er enti al di agnosi s. He w as noted to hav e an enl ar ged pr ostate and
al so had di f f i cul ty v oi di ng.
2. What gr oup of or gani sm s i s m ost l i k el y associ ated w i th the sepsi s

sy ndr om e i n thi s pati ent, and how does thi s gr oup di f f er f r om the other
m ajor gr oups of bacter i a and f ungi ?
The or gani sm s m ost f r equentl y i sol ated i n the bl ood of pati ents w i th the
sepsi s sy ndr om e ar e gr am negati v e baci l l i . Shock occur s l ess f r equentl y
i n the setti ng of bacter em i a due to gr am posi ti v e or gani sm s. Thi s
di f f er ence m ay stem f r om v ar i ati ons i n the host r esponse to di f f er ent
bacter i al cel l w al l consti tuents. The l i popol y sacchar i de por ti on of the cel l
w al l of gr am negati v e baci l l i (cal l ed endotox i n) el i ci ts a v i gor ous
i nf l am m ator y r esponse w hen i njected i ntr av enousl y i nto ani m al s. The
i nf l am m ator y r esponse to l i potei choi c aci d, a cel l w al l consti tuent of
gr am posi ti v e or gani sm s, i s m uch l ess pr onounced. Thi s pati ent had not
been hospi tal i zed, nor had he under gone any k i nd of i nstr um entati on.
Ther ef or e, the m ost l i k el y or gani sm to cause a U TI w i th subsequent
bacter em i a and sepsi s sy ndr om e i n thi s pati ent i s E. col i . Other potenti al
gr am negati v e or gani sm s that m ay pr eci pi tate septi c shock i ncl ude
Kl ebsi el l a pneum oni ae, Pseudom onas aer ugi nosa, Enter obacter aer ogenes,
and Ser r ati a m ar cescens. The pr i m ar y por tal of entr y i s the geni tour i nar y
tr act, but the gastr oi ntesti nal tr act, r espi r ator y tr act, and sk i n ar e al so
i m por tant sour ces of bacter em i a. Enter ococcus m ust al so be consi der ed
as a potenti al cause of thi s pati ent's i l l ness because i t can f r equentl y
cause pr ostati ti s. Other gr am posi ti v e or gani sm s, such as coagul ase
posi ti v e and coagul asenegati v e Staphy l ococcus speci es, can cer tai nl y
cause bacter em i a and sepsi s sy ndr om e; how ev er , thi s occur s m ost
com m onl y i n hospi tal i zed pati ents w ho hav e had som e ty pe of
i ntr av ascul ar dev i ce i nstal l ed. Gr am 's stai ns ar e par ti cul ar l y usef ul i n
establ i shi ng pr esum pti v e di agnoses i n U TIs, as i t w as i n thi s case.
3. How does endotox i n af f ect m acr ophages, and w hat chem i cal si gnal s ar e
pr oduced by m acr ophages to contr i bute to the sepsi s sy ndr om e?
Sev er al bacter i al f actor s ar e pow er f ul m edi ator s of sepsi s, and one of the
m ost potent i s endotox i n. As stated, endotox i n i s the l i popol y sacchar i de
com ponent of the cel l w al l i n gr am negati v e bacter i a. It appear s that
w hen cel l i njur y occur s w i th the acti v ati on of i m m une def enses or the
i ni ti ati on of anti m i cr obi al ther apy , bacter i al cel l l y si s tak es pl ace and the
ti ter of detectabl e endotox i n i n the pati ent's bl ood r i ses dr am ati cal l y .
Endotox i n bi nds to the CD14 m ol ecul e on the sur f ace of m acr ophages that
acti v ate one of the m em ber s of the Tol l l i k e r eceptor f am i l y (TLR4).
TLR4 tr i gger i ng acti v ates a cascade of i nf l am m ator y cy tok i nes i ncl udi ng
tum or necr osi s f actor Î± (TN FÎ± ) and a num ber of addi ti onal dow nstr eam
m edi ator s i ncl udi ng i nter l euk i n (IL)1, IL2, IL6, and pl atel etacti v ati ng
f actor . Af ter the r el ease of TN FÎ± , IL1, and pl atel etacti v ati ng f actor ,
ar achi doni c aci d i s m etabol i zed to f or m l euk otr i enes,
P. 243
thr om box ane A 2 , and pr ostagl andi n E 2 . IL1 and IL6 acti v ate T cel l s to
pr oduce i nter f er onÎ³, IL2, IL4, and gr anul ocy teâ€“m acr ophage col ony
sti m ul ati ng f actor . The coagul ati on cascade and com pl em ent sy stem ar e
al so acti v ated (Fi g. 61). Cl i ni cal l y , thi s phenom enon r esul ts i n a l ow
centr al v enous or pul m onar y capi l l ar y w edge pr essur e, as w el l as a
m ar k ed decr ease i n total sy stem i c v ascul ar r esi stance. In addi ti on, ther e
i s a com pensator y i ncr ease i n car di ac output i n an attem pt to m ai ntai n
ar ter i al per f usi on. The end r esul t of thi s pr ocess i s an i ncr ease i n car di ac
output, a m ar k ed f al l i n per i pher al v ascul ar r esi stance, and hy potensi on.
If uncontr ol l ed, pr ogr essi v e l acti c aci dosi s ensues, ul ti m atel y l eadi ng to
death.
Figure 61 Pathogenesi s of the m i cr ov ascul ar i njur y and death due to
endotox i n shock . (Fr om Kar chm er AW, Bar za M, Dr ew WL, et al . Inf ecti ous
di sease m edi ci ne (MKSAP IX). Phi l adel phi a: Am er i can Col l ege of Phy si ci ans,
1991. )
4. Of w hat shoul d the i ni ti al m anagem ent of a pati ent w i th the sepsi s
sy ndr om e consi st?
Al though anti bi oti c ther apy i s the m ai nstay of tr eatm ent of sepsi s caused
by gr am negati v e or gani sm s, the am el i or ati on of under l y i ng condi ti ons,
el i m i nati on of pr edi sposi ng f actor s, dr ai nage of abscesses, r em ov al of
i nf ected f or ei gn bodi es, and adequate suppor ti v e car e ar e al so of
par am ount i m por tance f or cur i ng the i nf ecti on. It i s cr i ti cal to r em em ber
that the i m m edi ate ther apeuti c i nter v enti on shoul d be di r ected at
i ncr easi ng car di ac output and ox y gen del i v er y to pr ev ent or m i ni m i ze
hy poper f usi on and r educe ti ssue hy pox i a. An opti m al i ntr av ascul ar
v ol um e m ust be r estor ed and m ai ntai ned. Fl ui d r equi r em ents ar e v er y
unpr edi ctabl e because of capi l l ar y l eak , and, at the v er y l east, centr al
v enous pr essur es shoul d be m oni tor ed so that these r equi r em ents can be
appr opr i atel y m et. Respi r ator y status and aci dâ€“base di stur bances can
be obser v ed w i th ser i al ar ter i al bl ood gas m easur em ents, w hi ch ar e al so
hel pf ul i n deter m i ni ng a pati ent's pr ognosi s. The chance f or sur v i v al i s
r educed i n pati ents w ho ar e aci dem i c. The nex t step i s to obtai n
appr opr i ate cul tur es and adm i ni ster appr opr i ate bacter i ci dal agents. The
anti bi oti c r egi m en shoul d be chosen on the basi s of the pr esum ed sour ce
of the bacter i a and the suscepti bi l i ty patter n of or gani sm s f r om that
sour ce. Anti m i cr obi al ther apy shoul d be adjusted on the basi s of
m i cr obi ol ogi c data as they becom e av ai l abl e. Addi ti onal ther api es that
ar e under i nv esti gati on ar e based on the em er gi ng k now l edge of the
pathophy si ol ogi c sequence of bacter em i c shock . The conduct and
i nter pr etati on of m any of these studi es hav e been com pl i cated by a l ack
of pr eci si on of entr y cr i ter i a that m ak e the ex tr apol ati on of study r esul ts
to cl i ni cal pr acti ce, di f f i cul t.
Suggested Readings
Abr aham E, Later r e PF, Gar g R, et al . Dr otr ecogi n al f a (acti v ated) f or
adul ts w i th sev er e sepsi s and a l ow r i sk of death. N Engl J Med
2005;353:1332.
Abr aham E, Rei nhar t K, Opal S, et al . Ef f i cacy and saf ety of ti f acogi n
(r ecom bi nant ti ssue f actor pathw ay i nhi bi tor ) i n sev er e sepsi s: a
r andom i zed contr ol l ed tr i al . JAMA 2003;290:238.
Cr oss AS, Opal SM. A new par adi gm f or the tr eatm ent of sepsi s: i s i t ti m e
to consi der com bi nati on ther apy ? Ann Inter n Med 2003;138:502.
Munf or d RE. Sepsi s, sev er e sepsi s and septi c shock . In: Mandel l GL,
Bennett JE, Dol i n R, eds. Pr i nci pl es and pr acti ces of i nf ecti ous di seases,
6th ed. N ew Yor k : El sev i er Sci ence, 2005:906.
Ri edem ann N C, Guo RF, War d PA. N ov el str ategi es f or the tr eatm ent of
sepsi s. N at Med 2003;9:517.
P. 244
P. 245
Sands KE, Bates DW, Lank en PN , et al . Epi dem i ol ogy of sepsi s sy ndr om e i n
8 academ i c m edi cal center s. JAMA 1997;278:234.
Tak eda K, Kai sho T, Ak i r a S. Tol l l i k e r eceptor . Annu Rev Im m unol

2003;21:335.
Endocarditis
1. What ty pes of or gani sm s can cause i nf ecti v e endocar di ti s?
2. What ar e som e i m por tant f actor s that i ncr ease the r i sk f or the
dev el opm ent of endocar di ti s?
3. What ar e the tw o cl i ni cal ty pes of bacter i al endocar di ti s and thei r cl i ni cal

char acter i sti cs?
4. What condi ti ons cal l f or sur gi cal i nter v enti on?
5. Ar e ther e any di f f er ences i n the char acter i sti cs of endocar di ti s betw een
the i ntr av enous dr ug abuse popul ati on and nonâ€“dr ug abuser s?
Discussion
1. What ty pes of or gani sm s can cause i nf ecti v e endocar di ti s?
Ther e ar e m any or gani sm s that can i nf ect the hear t and cause
endocar di ti s. The m ost com m on ones ar e â€œtr adi ti onal â€ bacter i a, but
other or gani sm s i ncl udi ng f ungi , Ri ck ettsi a, and Chl am y di a m ay i nv ade
m y ocar di al ti ssues and pr oduce di sease.
2. What ar e som e i m por tant f actor s that i ncr ease the r i sk f or the
dev el opm ent of endocar di ti s?
The tw o m ajor cl asses of r i sk f actor s contr i buti ng to the dev el opm ent of
endocar di ti s i ncl ude str uctur al dam age to car di ac ti ssue i n contact w i th
bl ood and condi ti ons associ ated w i th bacter em i a. U nder l y i ng hear t
di seases such as r heum ati c v al v ul ar dam age, a bi cuspi d aor ti c v al v e,
patent ductus ar ter i osus, and sm al l v entr i cul ar septal def ects cause
dam aged ti ssue or abnor m al bl ood f l ow , condi ti ons under w hi ch bacter i a
can adher e to the sur f ace and cause i nf ecti on. Al so i m pl i cated f or the
sam e r easons ar e pr ostheti c v al v es. Intr av enous dr ug abuser s ar e at r i sk
f or endocar di ti s because thei r v al v es ar e bei ng constantl y bom bar ded
w i th i m pur i ti es such as tal c, w hi ch causes scar r i ng of the v al v es, and
al so because they m i x thei r dr ug of choi ce w i th contam i nated w ater .
N osocom i al i nf ecti ons m ay r esul t f r om the pl acem ent of i ntr av enous
catheter s or pacem ak er w i r es, or f r om w ound i nf ecti ons or geni tour i nar y
m ani pul ati on. El der l y pati ents ar e al so at i ncr eased r i sk f or endocar di ti s.
3. What ar e the tw o cl i ni cal ty pes of bacter i al endocar di ti s and thei r cl i ni cal

char acter i sti cs?
Al though ther e i s ov er l ap, the tw o cl i ni cal ty pes of bacter i al endocar di ti s

ar e acute and subacute. Acute bacter i al endocar di ti s i s m ost com m onl y
associ ated w i th i ntr av enous dr ug abuse, i ntr av enous catheter i nf ecti on,
and pr ostheti c v al v e i nf ecti ons. These i nf ecti ons m ay be r api dl y f atal i f
l ef t untr eated, and sur gi cal r epai r or r epl acem ent of the dam aged v al v e
m ay be necessar y . Subacute
P. 246
endocar di ti s dev el ops m ost of ten i n the setti ng of str uctur al hear t di sease
(e. g. , m i tr al v al v e pr ol apse), a hi stor y of r heum ati c hear t di sease, or
pr ostheti c v al v es. It al so af f ects el der l y pati ents, or i t m ay occur i n the
setti ng of no k now n v al v ul ar di sease. Its onset tends to be m or e i ndol ent.
Sy m ptom s such as w eak ness, f ati gue, ni ght sw eats, and w ei ght l oss m ay
hav e ex i sted f or w eek s to m onths bef or e di agnosi s. Its onset m ay be
r el ated to antecedent ev ents such as dental w or k , al though no def i ni te
pr edi sposi ng ev ent i s appar ent i n m ost cases. Because som e pati ents m ay
hav e m ul ti pl e r i sk f actor s and ex hi bi t a v ar i abl e cl i ni cal pi ctur e, thei r
di sease cannot be easi l y cl assi f i ed. It i s al w ay s i m por tant to k eep i n m i nd
the m ax i m that â€œi f y ou don't thi nk about endocar di ti s, y ou w on't
di agnose i t!â€
4. What condi ti ons cal l f or sur gi cal i nter v enti on?
Sur gi cal i nter v enti on shoul d be consi der ed i f (a) ther e i s m or e than one
em bol i c ev ent; (b) bacter em i a per si sts despi te 2 to 3 w eek s of adequate
anti bi oti c ther apy ; (c) ther e i s pr ogr essi v e or r ef r actor y congesti v e hear t
f ai l ur e; (d) ther e i s si gni f i cant v al v ul ar dy sf uncti on r esul ti ng i n m oder ate
to sev er e congesti v e hear t f ai l ur e as dem onstr ated by echocar di ogr aphy
or other l abor ator y techni ques; (e) l ocal suppur ati v e com pl i cati ons ar i se,
as r ef l ected by the appear ance of new , per si stent el ectr ocar di ogr aphi c
conducti on di stur bances, echocar di ogr aphi c ev i dence of a par av al v ul ar
abscess or f i stul a, pur ul ent per i car di ti s, or per si stent unex pl ai ned f ev er
despi te appr opr i ate anti bi oti c ther apy ; (f ) ther e i s f ungal endocar di ti s; or
(g) ther e i s appr opr i atel y tr eated pr ostheti c v al v e endocar di ti s due to
dr ugr esi stant or gani sm s that r ecur despi te appr opr i ate anti m i cr obi al
ther apy .
5. Ar e ther e any di f f er ences i n the char acter i sti cs of endocar di ti s betw een
the i ntr av enous dr ug abuse popul ati on and nonaddi ct popul ati on?
Ther e ar e sev er al char acter i sti cs of endocar di ti s r el ati v el y uni que to
i ntr av enous dr ug abuser s, al though these ar e onl y gener al i zati ons. A
hi stor y of docum ented pr i or hear t di sease i s unusual , and the i nci dence of
tr i cuspi d v al v e i nv ol v em ent i s appr ox i m atel y 50% i n thi s popul ati on,
w hi ch i s m uch hi gher than that i n the nonaddi ct popul ati on. In addi ti on, a
m ur m ur i s f r equentl y undetectabl e and ther e i s i sol ated tr i cuspi d v al v e
i nv ol v em ent, unl i k e the m ur m ur s of aor ti c or m i tr al v al v e i nsuf f i ci ency
seen m ost com m onl y i n the nonaddi ct popul ati on.
Case
A 27y ear ol d w hi te m an pr esents to the em er gency r oom w i th a chi ef
com pl ai nt of f ev er s, shak i ng chi l l s, cough, and headache of 2 day s' dur ati on.
He deni es nausea, v om i ti ng, di ar r hea, or dy sur i a. Hi stor y r ev eal s that the
pati ent sm ok es one pack of ci gar ettes per day , dr i nk s a si x pack of beer per
day , and has r ecentl y star ted â€œsk i npoppi ngâ€ cocai ne. He has had no
pr ev i ous hospi tal i zati ons nor has he under gone any sur gi cal pr ocedur es.
Phy si cal ex am i nati on r ev eal s a tem per atur e of 39. 0Â°C (102. 2Â°F), bl ood
pr essur e of 120/80 m m Hg, pul se of 114 beats per m i nute, and r espi r ator y
r ate of 18 per m i nute. Hi s conjuncti v ae ar e nor m al . Hi s or al m ucosa i s m oi st
and hi s denti ti on i s good. Lung ex am i nati on r ev eal s som e coar se r honchi
bi l ater al l y . Car di ac ex am i nati on r ev eal s a gr ade 2/6
P. 247
sy stol i c m ur m ur that i s hear d best at the l ef t ster nal bor der but does not
r adi ate. Abdom i nal and ex tr em i ty f i ndi ngs ar e unr em ar k abl e. N eur ol ogi c
ex am i nati on r ev eal s nonf ocal f i ndi ngs, al though the pati ent does com pl ai n of a
gl obal headache. Ther e i s no m eni ngi sm us.
Labor ator y v al ues ar e as f ol l ow s: w hi te bl ood cel l count, 18, 000/m m 3 (85%
pol y m or phonucl ear cel l s, 10% bands, and 5% l y m phocy tes); hem atocr i t, 38%;
and pl atel ets, 170, 000/m m 3 . A chest r adi ogr aphi c study r ev eal s bi l ater al
nodul ar i nf i l tr ates. The pati ent i s adm i tted to the m edi cal ser v i ce f or f ur ther
ev al uati on and tr eatm ent.
1. What ty pe of endocar di ti s does thi s pati ent l i k el y hav e?

2. What i s the l i k el y cause of hi s pul m onar y i nf i l tr ates?
3. What ar e the m ost com m on of f endi ng pathogens i n thi s setti ng?
4. What w oul d y ou pr escr i be as an i ni ti al anti bi oti c r egi m en?
Case Discussion
1. What ty pe of endocar di ti s does thi s pati ent l i k el y hav e?
Thi s pati ent's cl i ni cal pr esentati on i l l ustr ates a case of acute
endocar di ti s. Tr i cuspi d v al v e (r i ghtsi ded) endocar di ti s i s m ost l i k el y
because i t i s com m onl y associ ated w i th i ntr av enous dr ug abuse, al though
the m i tr al and aor ti c v al v es coul d al so be i nv ol v ed.
2. What i s the l i k el y cause of hi s pul m onar y i nf i l tr ates?
The cause of thi s pati ent's pul m onar y i nf i l tr ates i s septi c em bol i that
hav e tr av el ed to the l ung. In both acute and subacute bacter i al
endocar di ti s, si gns and sy m ptom s of em bol i c phenom ena m ay appear .
These epi sodes of v ascul ar occl usi on cause pai n i n the chest (pul m onar y
or cor onar y ), abdom en (m esenter i c or spl eni c), or the ex tr em i ti es. Bone
pai n (par ti cul ar l y v er tebr al and sacr oi l i ac) i s al so com m on because of the
hem atogenous spr ead of i nf ecti on to these si tes. Other em bol i c
phenom ena that m ay occur i ncl ude hem atur i a (em bol i to the k i dney s),
bl i ndness r esul ti ng f r om r eti nal ar ter y occl usi on, and acute neur ol ogi c
sy m ptom s (str ok e, m eni ngi ti s, sei zur es, and headache). Cer tai nl y ,
car di ac i nv ol v em ent such as congesti v e hear t f ai l ur e m ay occur i n thi s
setti ng as the r esul t of pr ogr essi v e v al v ul ar i nsuf f i ci ency or m y ocar di ti s;
how ev er , thi s w oul d be ev i denced by the f i ndi ng of Ker l ey 's B l i nes or
f l uf f y pul m onar y i nf i l tr ates on chest r adi ogr aphi c studi es.
3. What ar e the m ost com m on of f endi ng pathogens i n thi s setti ng?
The or gani sm that w oul d m ost l i k el y be the sour ce of thi s pati ent's
i nf ecti on i s S. aur eus. Thi s or gani sm accounts f or appr ox i m atel y 20% of
the cases of endocar di ti s i n the gener al popul ati on, and f or 55% of the
cases associ ated w i th i ntr av enous dr ug abuse. It shoul d ther ef or e be
suspected as the eti ol ogi c agent i n i nf ecti ons associ ated w i th a hi stor y of
i ntr av enous dr ug abuse, as w el l as i n the contex t of acute em bol i c
phenom ena and acute bacter i al endocar di ti s. Coagul asenegati v e
staphy l ococci ar e com m on i n the setti ng of pr ostheti c v al v e endocar di ti s,
but not i n the setti ng of nonpr ostheti c v al v eâ€“associ ated i nf ecti on.
Str eptococci account f or appr ox i m atel y 70% of al l cases of nati v e
v al v ul ar bacter i al endocar di ti s i n the nonaddi ct popul ati on, and i nf ecti on
due to the v ar i ous speci es i s br ok en dow n as f ol l ow s: 40% due to
v i r i dans str eptococci ; 10% due to enter ococci (gr oup E
P. 248
str eptococci ); and 20% due to other nonhem ol y ti c, m i cr oaer ophi l i c,
anaer obi c, or nonenter ococcal gr oup D str eptococci . Appr ox i m atel y 10%
of the cases ar e caused by other f asti di ous or gani sm s, such as f ungi and
gr am negati v e baci l l i .
4. What w oul d y ou pr escr i be as an i ni ti al anti bi oti c r egi m en?
The i ni ti al tr eatm ent of suspected acute bacter i al endocar di ti s shoul d be

di r ected tow ar d S. aur eus because i t i s the m ost com m on or gani sm i n
pati ents w i th acute bacter i al endocar di ti s. The cl i ni ci an shoul d al w ay s
dr aw thr ee to f our bl ood speci m ens f or cul tur e bef or e i ni ti ati ng anti bi oti c
ther apy . Af ter thi s i s done, v ancom y ci n (1 g i ntr av enousl y ev er y 12
hour s) pl us gentam i ci n (1 m g/k g i ntr av enousl y ev er y 8 hour s) ar e
appr opr i ate as an i ni ti al com bi nati on unti l the cul tur e r esul ts ar e k now n.
Thi s com bi nati on cov er s both S. aur eus (m ethi ci l l i n sensi ti v e and
r esi stant) and enter ococci i nf ecti ons, and, w i th f ew ex cepti ons, any other
l i k el y bacter i a. In the past, i ni ti al ther apy m i ght hav e consi sted of
naf ci l l i n and gentam i ci n but the i ncr easi ng i nci dence of m ethi ci l l i n
r esi stant Staphy l ococcus aur eus (MRSA) i nf ecti ons m ak es v ancom y ci n a
m or e pr udent em pi r i c choi ce, especi al l y i n com m uni ti es i n w hi ch MRSA i s
f r equent. The anti m i cr obi al r egi m en shoul d be adjusted on the basi s of
r esul ts f r om the cl i ni cal m i cr obi ol ogy l abor ator y , i ncl udi ng bl ood cul tur es
and suscepti bi l i ty tests. Al though ther e ar e a v ar i ety of r ecom m endati ons
i n the l i ter atur e, i t i s gener al l y agr eed that a pr ol onged adm i ni str ati on of
r el ati v el y hi gh doses of bacter i ci dal agents i s i ndi cated. Wi th the
ex cepti on of i nf ecti on caused by hi ghl y r esi stant or gani sm s, i t i s usual l y
f ai r l y easy to obtai n a good sy m ptom ati c r esponse (e. g. , decl i ne i n f ev er
and decr eased m y al gi as) and ster i l i zati on of bl ood cul tur es w i thi n a f ew
day s of the star t of ther apy . A bacter i ol ogi c cur e w i th ster i l i zati on of the
l esi ons i s m uch m or e di f f i cul t, how ev er , because al though v al v ul ar
l esi ons ar e bathed i n bl ood, the v al v es them sel v es ar e r el ati v el y
av ascul ar . Bacter i a i n v egetati ons ar e sur r ounded by f i br i n. Thi s, i n
com bi nati on w i th the hi gh f l ow r ates i n the car di ac cham ber s, m ak es i t
di f f i cul t f or phagocy ti c cel l s to adher e to the si te of i nf ecti on. Ther ef or e,
pr ol onged tr eatm ent w i th hi gh doses of bacter i ci dal anti bi oti cs i s
essenti al f or cur e. Ther e i s i nv i tr o and i nv i v o ev i dence that l ow dose
gentam i ci n i n com bi nati on w i th sem i sy ntheti c peni ci l l i n ef f ects m or e r api d
k i l l i ng of staphy l ococci and ster i l i zati on of v al v es than does peni ci l l i n
al one. Thi s suggests that the addi ti on of gentam i ci n (1 m g/k g ev er y 8
hour s f or 3 to 5 day s) i s a r easonabl e r egi m en (i f the pati ent has no
contr ai ndi cati ons to am i nogl y cosi de use, such as r enal f ai l ur e) i n an
attem pt to cl ear the bacter em i a r api dl y and m i ni m i ze dam age to the
hear t v al v es. Ther e ar e, how ev er , no data f r om r andom i zed, bl i nded
studi es show i ng that thi s appr oach has an i m pact on the ul ti m ate cl i ni cal
outcom e. The use of com bi nati on ther apy has al so per m i tted shor ter
cour se ther apy of r i ghtsi ded S. aur eus i nf ecti v e endocar di ti s i n
i ntr av enous dr ug user s.
Suggested Readings
Br andr i ss MW, Lam ber t JS. Car di ac i nf ecti ons. In: Reese RE, Betts RF, eds.
A pr acti cal appr oach to i nf ecti ous di seases, 3r d ed. Boston: Li ttl e, Br ow n
and Com pany , 1991:278.
Cham ber s HF, Kor zeni ow sk i OM, Sande MA, et al . Staphy l ococcus aur eus
endocar di ti s: cl i ni cal m ani f estati ons i n addi cts and nonaddi cts. Medi ci ne
(Bal ti m or e) 1983;62:170.
P. 249
Cham ber s HF, Mi l l er RT, N ew m an MD. Ri ghtsi ded Staphy l ococcus aur eus
endocar di ti s i n i ntr av enous dr ug abuser s: tw ow eek com bi nati on ther apy .
Ann Inter n Med 1988;109:619.
Di N ubl e M. Abbr ev i ated ther apy f or r i ght si ded Staphy l ococcus aur eus
endocar di ti s i n i njecti ng dr ug user s. Ann Inter n Med 1994;121:873.
Di Sal v o G, Habi b G, Per gol a V, et al . Echocar di ogr aphy pr edi cts em bol i c
ev ents i n i nf ecti v e endocar di ti s. J Am Col l Car di ol 1991;37:1069.
Fr i dk i n SK, Hagem an JC, Mor r i son M, et al . Methi ci l l i nr esi stant
Staphy l ococcus aur eus di sease i n thr ee com m uni ti es. N Engl J Med
2005;352:1436â€“1444.
Mi l l er LG, Per dr eauRem i ngton F, Rei g G, et al . Four teen pati ents w i th
necr oti zi ng f asci i ti s caused by com m uni ty associ ated m ethi ci l l i nr esi stant
Staphy l ococcus aur eus i n Los Angel es. N Engl J Med 2005;352:1445.
Moon MR, Sti nson EB, Mi l l er DC. Sur gi cal tr eatm ent of i nf ecti v e
endocar di ti s. Pr og Car di ov asc Di s 1997;40:239.
Sul l am PM, Dr ak e TA, Sande MA. Pathogenesi s of endocar di ti s. Am J Med

1985;78:110.
Fever and Abdominal Pain
1. What i s the si ngl e best test to ev al uate the f ebr i l e pati ent w i th abdom i nal
pai n?
2. What ar e the m ost i m por tant pathogens i n the bow el f l or a?
3. Besi des obstr ucti on, i schem i a, and i njur y i nv ol v i ng the gut (and i ts
outpouchi ngs), w hat ar e the other causes of per i toni ti s?
4. What ar e sev er al ex am pl es of ex tr aper i toneal di seases that can pr esent

w i th abdom i nal pai n as a pr om i nent sy m ptom ?
Discussion
1. What i s the si ngl e best test to ev al uate the f ebr i l e pati ent w i th abdom i nal
pai n?
The f ebr i l e pati ent w i th abdom i nal pai n can be a daunti ng pr ospect. The
di f f er enti al di agnosi s i n thi s setti ng r anges f r om beni gn, sel f l i m i ted
i nf ecti ons such as v i r al enter i ti s to sev er e, l i f ethr eateni ng i nf ecti ons
such as per i toni ti s r esul ti ng f r om an i schem i c bow el . How ev er , despi te
the av ai l abi l i ty of a tr em endous v ar i ety of i m agi ng pr ocedur es and tests
of bodi l y f l ui ds, the si ngl e best appr oach to di agnosi s i n a pati ent w i th
f ev er and abdom i nal pai n r em ai ns a car ef ul hi stor y and phy si cal
ex am i nati on. Som eti m es the i nf or m ati on y i el ded i s suf f i ci ent to m ak e a
di agnosi s. Mor e of ten tests ar e necessar y , but a car ef ul cl i ni cal
ev al uati on nar r ow s the l i st of questi ons that need to be answ er ed by
tests. Fi shi ng w i th a l ong ser i es of tests w i thout w el l consi der ed cl i ni cal
questi ons occasi onal l y hook s the tr ue cul pr i t, but m or e of ten nets a catch
of r ed her r i ngs.
2. What ar e the m ost i m por tant pathogens i n the bow el f l or a?
A com m on concer n i n the f ebr i l e pati ent w i th abdom i nal pai n i s the
possi bl e contam i nati on of the per i toneal space w i th pathogens f r om the
bow el . Al though a gr eat v ar i ety of or gani sm s l i v e i n the gut, the num ber
of i m por tant pathogens i s, f or tunatel y , sm al l . The Enter obacter i aceae ar e
per haps the best
P. 250
k now n such pathogens. Anaer obes ar e the dom i nant or gani sm s i n the
col on and, of thi s cl ass Bacter oi des speci es ar e the i m por tant pathogens.
Fi nal l y , str eptococci , especi al l y enter ococci , can be pr om i nent pathogens
(they ar e al so i m por tant because of thei r r esi stance to a num ber of
com m onl y used anti bi oti cs, such as cephal ospor i ns).
3. Besi des obstr ucti on, i schem i a, and i njur y i nv ol v i ng the gut (and i ts
outpouchi ngs), w hat ar e the other causes of per i toni ti s?
Pr eex i sti ng asci ti c f l ui d, especi al l y that due to hepati c ci r r hosi s, can
becom e i nf ected and cause per i toni ti s. Sal pi ngi ti s and endom etr i ti s can
l ead to per i toni ti s thr ough di r ect ex tensi on of the i nf ecti on out of the
open abdom i nal osti um of the tube. Pr i m ar y per i toni ti s i s an unusual f or m
of bacter i al per i toni ti s that has no cl ear pr edi sposi ng f actor s; i t m ost
of ten af f ects chi l dr en. Fi nal l y , ther e ar e noni nf ecti ous causes of
per i toni ti s, i ncl udi ng bl eedi ng i nto the per i toneum , w hi ch can cause pai n
and l ow gr ade f ev er s, pl us the r ar e f am i l i al Medi ter r anean f ev er .
4. What ar e sev er al ex am pl es of ex tr aper i toneal di seases that can pr esent

w i th abdom i nal pai n as a pr om i nent sy m ptom ?
Low er l obe pneum oni a can be a sour ce of consi der abl e abdom i nal pai n
and tender ness. N eur i ti c pai n r esul ti ng f r om a v ar i ety of causes
(i nf ecti ous causes i ncl ude her pes zoster , Ly m e di sease, and tabes
dor sal i s) can pr oduce sev er e abdom i nal pai n, w hi ch i s conv i nci ng enough
at ti m es to pr om pt per f or m ance of an ex pl or ator y l apar otom y .
Case
A 24y ear ol d w om an com es to the em er gency r oom because of a 4day
hi stor y of abdom i nal pai n, w hi ch she descr i bes as a shar p, pr ogr essi v el y
sev er e pai n i n the r i ght l ow er chest and upper abdom en that i s ex acer bated by
tak i ng a deep br eath, w al k i ng, or si tti ng er ect. She f eel s nauseated, but has
not v om i ted. At hom e she has had f ev er s as hi gh as 38Â°C (100. 4Â°F), but no
r i gor s. She has had no pr ev i ous si m i l ar epi sodes and has nev er under gone
abdom i nal sur ger y . She deni es cough or dy spnea, f atty f ood i ntol er ance,
jaundi ce or dar k ur i ne, dy sur i a, or ur i nar y f r equency . She has nev er been
pr egnant; her l ast m enstr ual per i od began 1 w eek ago and i s now endi ng. Her
past m edi cal hi stor y i s unr em ar k abl e; her onl y m edi cati on i s an or al
contr acepti v e. She dr i nk s soci al l y on w eek ends, but does not use tobacco. Her
f am i l y hi stor y i s notabl e i n that her m other had a chol ecy stectom y at 34
y ear s.
On phy si cal ex am i nati on, she i s f ound to be a m i l dl y obese y oung w om an w ho
i s i n m oder ate di str ess and l y i ng cur l ed up on her r i ght si de. Her tem per atur e
i s 37. 8Â°C (100. 04Â°F), bl ood pr essur e i s 96/60 m m Hg, and pul se i s 110
beats per m i nute. Ex am i nati on of her head and neck y i el d unr em ar k abl e
f i ndi ngs; speci f i cal l y , ther e i s no scl er al i cter us or cer v i cal adenopathy . Her
chest i s cl ear to auscul tati on and per cussi on, al though she i s unabl e to tak e a
deep br eath because of the pai n i n her r i ght l ow er chest. She has hy poacti v e
bow el sounds and ex hi bi ts substanti al tender ness i n the r i ght upper quadr ant
associ ated w i th a posi ti v e Mur phy 's si gn (an i nabi l i ty to tak e a deep br eath
dur i ng deep pal pati on of the r i ght upper quadr ant). The edge of her l i v er i s
not pal pabl e
P. 251
and the span, by per cussi on, i s nor m al . N o m asses or tender ness ar e f ound
el sew her e i n the abdom en, and the spl een i s not pal pabl e. Rectal ex am i nati on
r ev eal s no tender ness and the stool i s guai ac negati v e. Her sk i n and
ex tr em i ti es appear nor m al .
She has a w hi te bl ood cel l count of 10, 500/m m 3 w i th 85% segm ented
neutr ophi l s and 7% band f or m s, a hem atocr i t of 39%, and a pl atel et count of
216, 000/m m 3 . Ser um el ectr ol y te and cr eati ni ne v al ues ar e nor m al . The
aspar tate am i notr ansf er ase (AST) l ev el i s el ev ated at 56 U /m L (nor m al , < 30
IU /m L), but her ser um bi l i r ubi n, al k al i ne phosphatase, and am y l ase l ev el s ar e
nor m al . U r i nal y si s i s notabl e f or 20 to 50 w hi te bl ood cel l s, 20 to 50 r ed bl ood
cel l s, m any bacter i a, and m any epi thel i al cel l s per hi ghpow er f i el d. She i s
thought to hav e acute chol ecy sti ti s, but an ul tr asound scan of the l i v er , bi l i ar y
ducts, and pancr eas i s negati v e.
1. What ar e the v ar i ous w ay s f or y ou to pr oceed at thi s poi nt?
2. What i s the m ost l i k el y di agnosi s based on the f i ndi ngs f r om y our f ur ther
i nv esti gati ons?
3. What pathogens can cause sal pi ngi ti s w i th per i hepati ti s?
4. What noni nv asi v e tests ar e hel pf ul f or conf i r m i ng a speci f i c cause of
sal pi ngi ti s w i th per i hepati ti s?
Case Discussion
1. What ar e the v ar i ous w ay s f or y ou to pr oceed at thi s poi nt?
To el uci date the natur e of thi s pati ent's di sor der , y ou deci de to pr oceed
w i th the f ol l ow i ng: r adi onucl i de bi l i ar y (l i dof eni n) scanni ng, a chest
r adi ogr aphi c study , r epeat ur i nal y si s and cul tur e, ser ol ogi c tests f or
hepati ti s A, B, and C, ser um Î²hum an chor i oni c gonadotr opi n (hCG)
m easur em ent, and sex ual hi stor y and pel v i c ex am i nati on.
Addi ti onal case detai l s: Because i t i s 6:00 p. m . , the nucl ear m edi ci ne
f aci l i ti es ar e not av ai l abl e, and ther ef or e i t i s not possi bl e to hav e a
r adi onucl i de bi l i ar y scan per f or m ed. The chest r adi ogr aphi c study i s
nor m al . Repeat ur i nal y si s on a catheter i zed speci m en y i el ds nor m al
f i ndi ngs, but the cul tur e r esul ts ar e pendi ng, as ar e the r esul ts of
ser ol ogi c tests f or hepati ti s A, B, and C. The ser um Î²hCG l ev el show s
that she i s not pr egnant. Sex ual hi stor y and pel v i c ex am i nati on r ev eal
she i s sex ual l y acti v e w i th a new par tner i n the l ast m onth. Because she
uses an or al contr acepti v e, her par tner does not use condom s. She has
had geni tal w ar ts and y east i nf ecti ons i n the past, but has no k now n
hi stor y of other sex ual l y tr ansm i tted di seases. She does not use
i ntr av enous dr ugs, has nev er r ecei v ed a bl ood tr ansf usi on, and has had
no occupati onal ex posur e to bl ood. On pel v i c ex am i nati on, her ex ter nal
geni tal i a ar e f ound to be nor m al . Ther e i s a sm al l am ount of dar k bl ood
f r om the cer v i cal os, and m i l d tender ness w i th cer v i cal m oti on and
pal pati on of the r i ght adnex a. The si ze of the uter us i s nor m al and ther e
ar e no adnex al m asses.
2. What i s the m ost l i k el y di agnosi s based on the f i ndi ngs f r om y our f ur ther
i nv esti gati ons?
Al l these tests i nv esti gate i m por tant causes of acute abdom i nal pai n and
f ev er . Inter pr etati on of the r esul ts al l ow s a f ai r l y conf i dent di agnosi s to
be m ade. The
P. 252
i ni ti al concer n w as acute chol ecy sti ti s, but the nor m al ul tr asound f i ndi ngs
m ak e thi s di agnosi s unl i k el y , al though they do not com pl etel y r ul e i t out
because a si ngl e stone m ay be l odged i n the di stal com m on duct and be
m i ssed on ul tr asound scanni ng. Ar gui ng agai nst chol ecy sti ti s ar e her age
and l ack of pr ev i ous pr egnanci es. Another possi bi l i ty i s r i ght l ow er l obe
pneum oni a. In m ost cases of pneum oni a, r espi r ator y sy m ptom s ar e the
chi ef com pl ai nt, but l ow er l obe pneum oni a, by i r r i tati ng the par i etal
pl eur a ov er l y i ng the di aphr agm , can assum e the char acter i sti cs of an
abdom i nal pr esentati on. In thi s case, the nor m al chest r adi ogr aphi c
f i ndi ngs and l ack of pul m onar y sy m ptom s m ak e thi s di agnosi s v er y
unl i k el y .
Pati ents w i th py el onephr i ti s can ex per i ence pai n anter i or l y (i n the upper
and m i dabdom en) as w el l as the cl assi c costov er tebr al angl e tender ness
i n the back . How ev er , the l ack of l ow er ur i nar y tr act sy m ptom s (dy sur i a,
ur i nar y f r equency , and supr apubi c pai n) i n thi s pati ent i s not concl usi v e
ev i dence agai nst thi s di agnosi s because these sy m ptom s ar e f r equentl y
m i l d or ev en absent i n pati ents w i th upper U TIs. The i ni ti al ur i nal y si s
r ev eal ed m any w hi te bl ood cel l s, a f i ndi ng that at f i r st bl ush seem s to
conf i r m the di agnosi s of py el onephr i ti s. How ev er , ther e ar e m any
epi thel i al cel l s as w el l , w hi ch m ak es i t i m possi bl e to tel l w hether the
w hi te bl ood cel l s cam e f r om the ur i nar y or the r epr oducti v e tr act. A
catheter i zed ur i ne speci m en answ er s thi s questi on, and the subsequent
nor m al ur i nal y si s f i ndi ngs al m ost r ul e out the possi bi l i ty of
py el onephr i ti s. Rar el y , i f ther e i s i nf ecti on causi ng an obstr ucti on of the
ur eter , the ur i nal y si s r esul ts can be nor m al . Such pati ents ar e usual l y
sev er el y i l l , how ev er , r ender i ng thi s di agnosi s v er y unl i k el y i n thi s case.
Al though acute v i r al hepati ti s can cause pr onounced r i ght upper quadr ant
pai n and tender ness, i t i s a v er y unl i k el y di agnosi s i n thi s pati ent. At the
onset of sy m ptom s, the tr ansam i nase l ev el s i n the setti ng of v i r al
hepati ti s ar e m ar k edl y el ev atedâ€”usual l y ex ceedi ng 10 ti m es nor m al .
The m i nor el ev ati on i n the AST l ev el i n thi s pati ent w oul d be v er y
aty pi cal of acute v i r al hepati ti s.
The possi bi l i ty of a r uptur ed ectopi c pr egnancy shoul d al w ay s be

consi der ed i n a y oung w om an w i th abdom i nal pai n and v agi nal bl eedi ng,
but the ser um Î²hCG m easur em ent r ul es out thi s possi bi l i ty .
Acute sal pi ngi ti s (i nf ecti on of the f al l opi an tubes or pel v i c i nf l am m ator y
di sease) can be m ani f ested by r i ght upper quadr ant pai n. Thi s sy m ptom i s
thought to ar i se as a r esul t of secr eti ons f r om the i nf ected tube l eak i ng
i nto the per i toneum and tr av el i ng up the r i ght per i col i c gutter to the r i ght
upper quadr ant. Thi s can pr oduce i nf ecti on of the hepati c capsul e, ter m ed
per i hepati ti s (or Fi tzHughâ€“Cur ti s sy ndr om e). Sur pr i si ngl y , the
sy m ptom s of per i hepati ti s ar e f r equentl y m uch m or e pr om i nent than
those stem m i ng f r om the or i gi nal f ocus of i nf ecti on i n the tube.
Ther ef or e, these pati ents ar e adm i tted f r equentl y and som eti m es tak en to
sur ger y f or tr eatm ent of a pr esum ed chol ecy sti ti s. Ther e ar e no
pathognom oni c l abor ator y or i m agi ng f i ndi ngs that can conf i r m thi s
di agnosi s; thi s r equi r es l apar oscopy . How ev er , acute sal pi ngi ti s shoul d be
ser i ousl y consi der ed i n thi s pati entâ€”a sex ual l y acti v e w om an w i th r i ght
upper quadr ant pai n, f ev er s, and no si gns of chol ecy sti ti s. Wi th the
addi ti onal f actor that she has a new sex ual par tner coupl ed w i th the
f i ndi ng of r i ght adnex al tender ness, sal pi ngi ti s w i th per i hepati ti s becom es
the m ost l i k el y di agnosi s.
P. 253
3. What pathogens can cause sal pi ngi ti s w i th per i hepati ti s?
N ei sser i a gonor r hea i s the cl assi c cause of thi s sy ndr om e. In Fi tzHugh's
or i gi nal descr i pti on, Gr am 's stai ni ng of the f l ui d f r om the hepati c capsul e
show ed gr am negati v e di pl ococci . Si nce then, as i n the case of acute
ur ethr i ti s, i t has becom e cl ear that Chl am y di a tr achom ati s i s a com m on
cause of acute sal pi ngi ti s w i th per i hepati ti s.
4. What noni nv asi v e tests ar e hel pf ul f or conf i r m i ng a speci f i c cause of

sal pi ngi ti s w i th per i hepati ti s?
Gr am 's stai ni ng of a cer v i cal sm ear , al though r el ati v el y i nsensi ti v e (50%)
f or detecti ng gonococci , i s speci f i c enough (95%) to be used as the basi s
f or pr esum pti v e ther apy i f r esul ts ar e posi ti v e. A cer v i cal cul tur e f or
gonor r hea al l ow s the detecti on of sm ear negati v e cases. It i s possi bl e to
cul tur e Chl am y di a, but thi s i s a r el ati v el y ex pensi v e pr ocedur e and the
m eans of doi ng so ar e not av ai l abl e i n m any cl i ni cs and sm al l hospi tal s.
How ev er , a num ber of anti gen detecti on sy stem s (usi ng, f or ex am pl e, an
ELISA) hav e been dev el oped and m ar k eted. These hav e an acceptabl e
sensi ti v i ty and speci f i ci ty , w i th r esul ts av ai l abl e i n 24 hour s or l ess.
Suggested Readings
Fi tzHugh T. Acute gonococci c per i toni ti s of the r i ght upper quadr ant i n
w om en. JAMA 1934;102:2094.
Katzm an DK, Fr i edm an IM, McDonal d CA, et al . Chl am y di a tr achom ati s Fi tz
Hughâ€“Cur ti s sy ndr om e w i thout sal pi ngi ti s i n f em al e adol escents. Am J
Di s Chi l d 1988;142:996.
Mul l er Schoop JW, Wang SP, Munzi nger J, et al . Chl am y di a tr achom ati s as
possi bl e cause of per i toni ti s and per i hepati ti s i n y oung w om en. BMJ
1978;1:1022.
Shol es D, Ster gachi s A, Hei dr i ch FE, et al . Pr ev enti on of pel v i c
i nf l am m ator y di sease by scr eeni ng f or cer v i cal chl am y di al i nf ecti on. N Engl
J Med 1996;334:1362.
Soper DE, Br ock w el l N J, Dal ton HP, et al . Obser v ati ons concer ni ng the
m i cr obi al eti ol ogy of acute sal pi ngi ti s. Am J Obstet Gy necol
1994;170:1008.
Wood JJ, Bol ton JP, Cannon SR, et al . Bi l i ar y ty pe pai n as a m ani f estati on
of geni tal tr act i nf ecti on: the Cur ti sâ€“Fi tzHugh sy ndr om e. Br J Sur g
1982;69:251.
Central Nervous System Infection
1. What pr i nci pl es ar e i m por tant i n sel ecti ng an anti m i cr obi al r egi m en to
tr eat a CN S i nf ecti on?
2. How do cer ebr ospi nal f l ui d (CSF) f i ndi ngs such as the pr otei n and gl ucose
l ev el s, the w hi te bl ood cel l count, and di f f er enti al hel p deter m i ne the
di f f er enti al di agnosi s of a CN S i nf ecti on?
3. What ar e the m ost com m on pathogens causi ng bacter i al m eni ngi ti s, and
how does the pr ev al ence of the bacter i al pathogens that cause m eni ngi ti s
v ar y , dependi ng on the age of the host?
P. 254
Discussion
1. What pr i nci pl es ar e i m por tant i n sel ecti ng an anti m i cr obi al r egi m en to
tr eat a CN S i nf ecti on?
The bl oodâ€“br ai n bar r i er f uncti ons to hel p pr ev ent the entr y of
ci r cul ati ng pathogens i nto the CN S. U nf or tunatel y , how ev er , i t al so has
the ef f ect of decr easi ng anti bi oti c penetr ati on i nto the CSF.
Cephal ospor i ns, peni ci l l i ns, chl or am pheni col , and TMPSMX ar e the
com m onl y used anti bi oti cs that dem onstr ate good CSF penetr ati on. In
contr ast, the am i nogl y cosi des hav e ex tr em el y poor CSF penetr ati on, and
an i nf ecti on r equi r i ng am i nogl y cosi de ther apy m ust usual l y be m anaged
w i th the i ntr athecal adm i ni str ati on of these anti bi oti cs. Other dr ugs, such
as v ancom y ci n, ex hi bi t i nter m edi ate CSF penetr ati on, and thei r ef f i cacy
depends on the pr esence of i nf l am ed m eni nges to per m i t a ther apeuti c
l ev el of anti bi oti c to be r eached.
Another i m por tant pr i nci pl e i s to choose an em pi r i c anti bi oti c r egi m en
that cov er s the m ost l i k el y pathogens. Thi s choi ce ther ef or e depends on
the epi dem i ol ogi c back gr ound of the pati ent and on hi s or her r ecent
ex posur e hi stor y . Af ter the pathogen has been i denti f i ed and the dr ug
suscepti bi l i ty deter m i ned, ther apy can be m or e speci f i cal l y tai l or ed.
Fi nal l y , as w i th any new dr ug r egi m en, the pati ent's hi stor y of dr ug
al l er gy shoul d be car ef ul l y r ev i ew ed.
2. How do CSF f i ndi ngs such as the pr otei n and gl ucose l ev el s, the w hi te
bl ood cel l count, and di f f er enti al hel p deter m i ne the di f f er enti al di agnosi s
of a CN S i nf ecti on?
In adul ts, the nor m al r ange of the CSF gl ucose l ev el i s 45 to 80 m g/dL. A
gl ucose l ev el of l ess than 30 m g/dL suggests bacter i al , f ungal , or
tuber cul ous m eni ngi ti s. An el ev ated l ev el m ay be seen i n the setti ng of
di abetes m el l i tus. A CSF pr otei n l ev el gr eater than 150 m g/dL suggests
bacter i al m eni ngi ti s, and an ex tr em el y hi gh pr otei n l ev el (> 350 m g/dL)
suggests a com pl ete bl ock of the spi nal canal , as seen i n cer tai n cases of
epi dur al abscesses or tum or s. The nor m al r ange f or the l um bar CSF
pr otei n l ev el i n adul ts i s 9 to 58 m g/dL. A w hi te bl ood cel l count gr eater
than 1, 200/m m 3 suggests bacter i al m eni ngi ti s. How ev er , a l esser count
does not necessar i l y i m pl y v i r al i nf ecti on because bacter i al m eni ngi ti s i s
al so f r equentl y associ ated w i th thi s f i ndi ng. N eutr ophi l pr edom i nance
(> 50%) al so suggests bacter i al m eni ngi ti s, al though ther e i s consi der abl e
ov er l ap w i th other ty pes of m eni ngi ti s i n thi s r egar d. Ly m phocy te
pr edom i nance m ay be seen i n the contex t of tuber cul ous, v i r al , f ungal ,
par ti al l y tr eated bacter i al , or asepti c m eni ngi ti s.
3. What ar e the m ost com m on pathogens causi ng bacter i al m eni ngi ti s, and
how does the pr ev al ence of the bacter i al pathogens that cause m eni ngi ti s
v ar y , dependi ng on the age of the host?
The f our m ost com m on pathogens causi ng m eni ngi ti s f or al l agegr oups
ar e Str eptococcus pneum oni ae, Haem ophi l us i nf l uenzae, N ei sser i a
m eni ngi ti di s, and E. col i . How ev er , ther e i s consi der abl e v ar i ati on i n the
pr ev al ence of these v ar i ous pathogens am ong the di f f er ent agegr oups.
The hi ghest attack r ate of bacter i al m eni ngi ti s occur s i n the v er y y oung
and v er y ol d. Low er attack r ates ar e seen i n y oung to m i ddl eaged adul ts.
In the U ni ted States, i nf ants up to
P. 255
1 m onth of age m ost com m onl y acqui r e gr oup B str eptococcus, E. col i ,
and Li ster i a m eni ngi ti s; chi l dr en 1 m onth to 5 y ear s of age pr edom i nantl y
acqui r e H. i nf l uenzae m eni ngi ti s (up to 70% of the cases). For ty per cent
of the pati ents 5 to 29 y ear s of age acqui r e N . m eni ngi ti di s i nf ecti on, and
S. pneum oni ae i s the m ost com m on m eni ngi ti s pathogen i n pati ents 29
y ear s of age and ol der . El der l y pati ents ar e m or e v ul ner abl e to Li ster i a
m onocy togenes, gr am negati v e baci l l i , and pneum ococcus.
Case
A 79y ear ol d m an w ho i s a r esi dent of a nur si ng hom e i s br ought to the
em er gency r oom by the nur si ng hom e staf f . He had been i n hi s usual state of
heal th unti l that m or ni ng, w hen headache, f ev er , and chi l l s dev el oped. He
sl ept thr ough br eak f ast, af ter w hi ch hi s car etak er s f ound hi m to be l ethar gi c,
and thi s pr om pted them to br i ng hi m to the hospi tal . On i ni ti al ex am i nati on he
i s f ound to be stupor ous. Hi s tem per atur e i s 102. 6Â°F (39Â°C), and he has
pr om i nent nuchal r i gi di ty . Funduscopi c ex am i nati on r ev eal s no ev i dence of
papi l l edem a. A gr ade 2/6 sy stol i c ejecti on m ur m ur i s f ound on car di ac
ex am i nati on. Pul m onar y auscul tati on r ev eal s the pr esence of bi basi l ar f i ne
cr ack l es. An i ndw el l i ng Fol ey catheter i s i n pl ace, w hi ch the nur si ng hom e
staf f ex pl ai ns he has r equi r ed f or the past 18 m onths because of ur i nar y
i nconti nence. A past m edi cal hi stor y i s notabl e f or tw o epi sodes of U TIs, both
occur r i ng af ter the i nser ti on of the Fol ey catheter , and m i l d chr oni c i nter sti ti al
l ung di sease.
A CT scan of the head r ev eal s no ev i dence of i ncr eased i ntr acr ani al pr essur e,
no shi f t or m ass ef f ect, and no i ntr acr ani al bl eedi ng, but atr ophi c changes
consi stent w i th age. A l um bar punctur e i s per f or m ed, bl ood and ur i ne cul tur es
ar e obtai ned, and appr opr i ate ther apy i s begun.
1. What i s the m ost l i k el y pathogenesi s of thi s m an's m eni ngi ti s?

2. What aspects of the em er gency r oom m anagem ent shoul d hav e been
di f f er ent i n thi s case?
3. What em pi r i c i ntr av enous anti bi oti c ther apy w oul d be m ost appr opr i ate to
tr eat the bacter i al m eni ngi ti s i n a pati ent of thi s age, and how l ong
shoul d he be tr eated?
4. What phy si cal f i ndi ngs coul d poi nt to an anatom i c sour ce of bacter i al
m eni ngi ti s?
5. What CSF f i ndi ngs w oul d be ex pected i f thi s pati ent has bacter i al
m eni ngi ti s?
6. If the Gr am 's stai ni ng of the CSF and the cul tur es had y i el ded no
or gani sm s i n thi s pati ent, w hat shoul d y ou suspect?
7. If thi s pati ent had ex per i enced the gr adual onset of f ev er s, headache,
and nuchal r i gi di ty , w hat other possi bl e di agnoses m i ght y ou hav e
enter tai ned?
8. Shoul d the pati ent be tr eated w i th dex am ethasone?
Case Discussion
1. What i s the m ost l i k el y pathogenesi s of thi s m an's m eni ngi ti s?
Sev er al possi bl e scenar i os coul d ex pl ai n the pr esence of bacter i a i n

nor m al l y ster i l e CSF, despi te an i ntact bl oodâ€“br ai n bar r i er . These
i ncl ude any of a num ber of
P. 256
pr ocesses l eadi ng to the dev el opm ent of bacter em i a and m eni ngeal
seedi ng. One of the m or e com m on sour ces of i nf ecti on i s nasophar y ngeal
col oni zati on by bacter i a, w hi ch i s then f ol l ow ed by si nusi ti s, l ocal
i nv asi on, bacter em i a, and m eni ngeal seedi ng. Another pathogeni c
m echani sm i s tr aum a (such as an occul t sk ul l f r actur e), l eadi ng to a
br each i n the bl oodâ€“br ai n bar r i er and the entr y of sk i n f l or a.
The m ost l i k el y scenar i o i n thi s pati ent i s that a pl ugged Fol ey catheter
l ed to the r ef l ux of bl adder contents i nto the ur eter s up to the k i dney s,
w i th consequent seedi ng of the bl oodstr eam by ur i nar y pathogens.
Bacter em i a can then l ead to m eni ngi ti s, especi al l y i n the
i m m unocom pr om i sed or el der l y host. Al though the m echani sm of bacter i al
tr anspor t acr oss a pr esum abl y i ntact bl oodâ€“br ai n bar r i er i s l ar gel y
unk now n, the f i ndi ngs f r om som e studi es hav e suggested that a hi gh
concentr ati on of bacter i a i n the bl oodstr eam , and the pr esence of
bacter i al v i r ul ence f actor s such as anti phagocy ti c pol y sacchar i de
capsul es, the Sf i m br i ae of E. col i , or other com ponents of bacter i al cel l
w al l s, m ay f aci l i tate thi s pr ocess.
2. What aspects of the em er gency r oom m anagem ent shoul d hav e been
di f f er ent i n thi s case?
The head CT scan w as unnecessar y because the f unduscopi c and nonf ocal
neur ol ogi c f i ndi ngs w er e suf f i ci ent to r ul e out a si gni f i cant i ntr acr ani al
m ass ef f ect. Other w i se, the m anagem ent of thi s pati ent w as cor r ect, and
i t i l l ustr ated a num ber of i m por tant concepts. It i s i m por tant to attem pt
to i denti f y the pathogen i n a pati ent w i th m eni ngi ti s bef or e the i ni ti ati on
of anti bi oti c ther apy . Lum bar punctur e shoul d be del ay ed or def er r ed onl y
i n the f ol l ow i ng tw o i nstances. Fi r st, l um bar punctur e shoul d not be
per f or m ed i f a m i nor del ay i n ther apy coul d be hazar dous, as i n pati ents
i n bacter i al shock or those w ho f ace a hi gh r i sk of bacter i al shock
because of the r api d onset of pur pur a or because of l ow bl ood pr essur e.
It al so shoul d not be per f or m ed w hen ther e i s a possi bl e danger of uncal
her ni ati on, as i n the ev ent of r api dl y dev el opi ng com a, f ocal neur ol ogi c
si gns, conv ul si ons, or papi l l edem a. Other w i se, appr opr i ate m anagem ent
consi sts of qui ck l y ex cl udi ng papi l l edem a, f ocal neur ol ogi c si gns, shock ,
and pur pur a, f ol l ow ed by pr om pt l um bar punctur e and the subsequent
adm i ni str ati on of appr opr i ate anti bi oti cs.
The r espi r ator y i sol ati on of pati ents w i th suspected m eni ngi ti s i s
appr opr i ate onl y w hen ther e i s a str ong suspi ci on of N . m eni ngi ti di s,
My cobacter i um tuber cul osi s, or H. i nf l uenzae ty pe b (i n pedi atr i c
pati ents). The cl ose contacts of pati ents w i th N . m eni ngi ti di s (such as the
per son per f or m i ng an i ntubati on) shoul d r ecei v e pr ophy l acti c r i f am pi n
tr eatm ent (10 m g/k g or al l y tw i ce a day f or 2 day s, to a m ax i m um of 600
m g tw i ce a day ).
3. What em pi r i c i ntr av enous anti bi oti c ther apy w oul d be m ost appr opr i ate to
tr eat the bacter i al m eni ngi ti s i n a pati ent of thi s age, and how l ong
shoul d he be tr eated?
The appr oaches to agespeci f i c em pi r i c anti bi oti c ther apy f or bacter i al
m eni ngi ti s ar e based on k now l edge of the m ost com m on pathogens that
af f ect each gr oup, as al r eady outl i ned. For i nf ants y ounger than 1 m onth,
a com bi nati on of am pi ci l l i n and gentam i ci n or am pi ci l l i n and cef otax i m e
i s a r easonabl e em pi r i c anti bi oti c choi ce. The com bi nati on of v ancom y ci n
pl us a thi r dgener ati on cephal ospor i n i s appr opr i ate f or i nf ants 1 to 24
m onths of age. For chi l dr en aged 2 y ear s or ol der and adul ts y ounger
than 50, v ancom y ci n and a thi r dgener ati on cephal ospor i n ar e
P. 257
appr opr i ate. Am pi ci l l i n shoul d be added to thi s r egi m en f or those ol der
than 50 y ear s to ensur e cov er age f or L. m onocy togenes. Once the
pathogen and i ts suscepti bi l i ty patter n ar e k now n, ther apy can be
i ndi v i dual i zed. The dur ati on of anti bi oti c ther apy f or bacter i al m eni ngi ti s
i s sti l l l ar gel y based on tr adi ti on: 10 to 14 day s f or acute bacter i al
m eni ngi ti s caused by any of the thr ee m ajor m eni ngeal pathogens, and
appr ox i m atel y 3 w eek s f or gr am negati v e baci l l ar y m eni ngi ti s. The
dosages of the anti bi oti cs f or the tr eatm ent of m eni ngi ti s ar e usual l y
hi gher than those used f or other i nf ecti ons to ensur e adequate
bacter i ci dal acti v i ty i n the CSF. For ex am pl e, i ntr av enous peni ci l l i n G
shoul d be gi v en ev er y 4 hour s to a total dai l y dose of 20 to 24 m i l l i on
uni ts, and 2 g of cef tr i ax one shoul d be gi v en ev er y 12 hour s. The
am i nogl y cosi des, w hi ch do not adequatel y tr av er se the bl oodâ€“br ai n
bar r i er , m ust be adm i ni ster ed i ntr athecal l y as w el l as i ntr av enousl y w hen
i ndi cated, as i n the ev ent of m eni ngi ti s due to a hi ghl y r esi stant gr am
negati v e or gani sm .
4. What phy si cal f i ndi ngs coul d poi nt to an anatom i c sour ce of bacter i al
m eni ngi ti s?
Im por tant phy si cal f i ndi ngs that ar e cl ues to an anatom i c sour ce of
bacter i al m eni ngi ti s i ncl ude oti ti s m edi a, si nusi ti s, sk ul l f r actur e, or
other ev i dence of cr ani al tr aum a such as CSF l eak i ng f r om the ex ter nal
audi tor y m eatus, neur osur gi cal scar s, or the pr esence of a
v entr i cul ostom y shunt.
Most cases of m eni ngi ti s r esul t f r om the attachm ent of bacter i a to

epi thel i al cel l s of the nasophar y ngeal and or ophar y ngeal m ucosa,
f ol l ow ed by tr ansgr essi on of the m ucosal bar r i er . These ev ents ar e al so
associ ated w i th the dev el opm ent of oti ti s m edi a and si nusi ti s. Any
anatom i c br each of the bl oodâ€“br ai n bar r i er , ei ther thr ough tr aum a or
neur osur ger y , can i ntr oduce bacter i a i nto the CN S. Meni ngi ti s dev el ops i n
up to 30% of pati ents w ho hav e a v entr i cul oatr i al or v entr i cul oper i toneal
shunt. Other per ti nent phy si cal f i ndi ngs i n a pati ent w i th m eni ngi ti s
i ncl ude a der m al si nus or m astoi di ti s.
5. What CSF f i ndi ngs w oul d be ex pected i f thi s pati ent has bacter i al
m eni ngi ti s?
The cl i ni ci an w oul d ex pect to see the f ol l ow i ng constel l ati on of f i ndi ngs: a
l ow gl ucose l ev el , a hi gh pr otei n content, and an el ev ated w hi te bl ood
cel l count, w i th a neutr ophi l pr edom i nance (see ear l i er di scussi on).
6. If the Gr am 's stai ni ng of the CSF and the cul tur es had y i el ded no
or gani sm s i n thi s pati ent, w hat shoul d y ou suspect?
The l ack of or gani sm s on Gr am 'sstai ned CSF speci m ens does not r ul e out
bacter i al m eni ngi ti s; how ev er , thi s test shoul d be per f or m ed on a
centr i f uged sedi m ent of CSF. N egati v e f i ndi ngs ar e encounter ed i n 10% to
20% of pati ents w i th bacter i al m eni ngi ti s w hose CSF cul tur es ar e posi ti v e
f or or gani sm s. In cases of par ti al l y tr eated bacter i al m eni ngi ti s, Gr am 's
stai ni ng of the CSF m or e of ten y i el ds negati v e f i ndi ngs. An aci df ast
sm ear of spun CSF i s onl y r ar el y posi ti v e i n cases of tuber cul ous
m eni ngi ti s.
7. If thi s pati ent had ex per i enced the gr adual onset of f ev er s, headache, and
nuchal r i gi di ty , w hat other possi bl e di agnoses m i ght y ou hav e
enter tai ned?
Fungal m eni ngi ti s, a br ai n abscess, tuber cul ous m eni ngi ti s, and
car ci nom atous m eni ngi ti s al l tend to be r ather i nsi di ous i n onset and
assum e a m or e chr oni c cour se than that seen w i th acute bacter i al
m eni ngi ti s. The onset of tuber cul ous m eni ngi ti s m ay be occasi onal l y r api d
i n an i m m unocom pr om i sed host, but thi s w oul d usual l y
P. 258
occur onl y i n the cour se of m i l i ar y tuber cul osi s or w i th the r uptur e of a
subependy m al tuber cl e. Mor e com m onl y , how ev er , pati ents w i th
tuber cul ous m eni ngi ti s hav e sy m ptom s f or m or e than 2 w eek s. One of the
hal l m ar k s of tuber cul ous m eni ngi ti s i s the dev el opm ent of ocul ar pal si es,
seen i n 30% to 70% of the cases.
An epi dem i ol ogi c hi stor y i s usef ul i n di agnosi ng chr oni c m eni ngi ti s. Pr i or
ex posur e to tuber cul osi s, a hi stor y of sk i n test posi ti v i ty , or r ecent tr av el
to or r esi dence i n ar eas endem i c to Hi stopl asm a or Cocci di oi des i s
i m por tant i nf or m ati on to el i ci t. Car ci nom atous m eni ngi ti s occur s usual l y
i n the setti ng of a k now n under l y i ng m al i gnancy .
8. Shoul d the pati ent be tr eated w i th dex am ethasone?
The adjuncti v e use of dex am ethasone i n the tr eatm ent of bacter i al

m eni ngi ti s has been the subject of cl i ni cal i nv esti gati on f or m any y ear s.
As i n the case of anti bi oti c sel ecti on, cur r ent r ecom m endati ons about the
use of dex am ethasone ar e age dependent. Cl i ni cal tr i al s best suppor t the
use of dex am ethasone i n chi l dr en w i th H. i nf l uenzae ty pe b m eni ngi ti s
and i n adul ts w i th k now n or suspected pneum ococcal m eni ngi ti s. The use
of dex am ethasone i n i nf ants and chi l dr en w i th pneum ococcal m eni ngi ti s
r em ai ns contr ov er si al . Concer ns hav e been r ai sed that the use of
dex am ethasone i n chi l dr en and adul ts w i th pneum ococcal m eni ngi ti s due
to r esi stant or gani sm s m i ght be detr i m ental because a r educti on i n
m eni ngeal i nf l am m ati on caused by the dex am ethasone ther apy m i ght
com pr om i se penetr ati on of v ancom y ci n acr oss the m eni nges. Al though
these concer ns hav e been r ai sed, cl i ni cal data ar e i nsuf f i ci ent i n ei ther
di r ecti on to m ak e a cl i ni cal l y v al i dated r ecom m endati on.
Suggested Readings
de Gans J, v an de Beek D. Dex am ethasone i n adul ts w i th bacter i al
m eni ngi ti s. N Engl J Med 2002;347:1549â€“1556.
Quagl i ar el l o V, Schel d WM. Bacter i al m eni ngi ti s: pathogenesi s,

pathophy si ol ogy and pr ogr ess. N Engl J Med 1992;327:864.
Schel d WM, Whi tl ey RJ, Dur ak DT. Cer ebr ospi nal f l ui d i n centr al ner v ous
sy stem i nf ecti ons. In: Gi l l i n BG, Wei ngar ten K, Gam ache PW, et al . eds.
Inf ecti ons of the centr al ner v ous sy stem . N ew Yor k : Rav en Pr ess,
1991:861.
Schoenbaum SC, Gar dner P, Shi l l i to J. Inf ecti ons of cer ebr ospi nal f l ui d
shunts: epi dem i ol ogy , cl i ni cal m ani f estati ons and ther apy . J Inf ect Di s
1975;131:543.
Tunk el AR. Bacter i al m eni ngi ti s. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2001.
Tunk el AR, Har tm an BJ, Kapl an SL, et al . Pr acti ce gui del i nes f or the
m anagem ent of bacter i al m eni ngi ti s. Cl i n Inf ect Di s 2004;39:1267.
Tunk el AR, Wi spel w ay B, Schei d WM. Bacter i al m eni ngi ti s: r ecent adv ances
i n pathophy si ol ogy and tr eatm ent. Ann Inter n Med 1990;112:610.
Fever of Unknown Origin
1. What ar e the def i ni ti ons of f ev er and f ev er of unk now n or i gi n?
2. What i s the pathogenesi s of f ev er ?
P. 259
3. What ar e the gener al categor i es of di sease that can cause f ev er , and
w hi ch gener al categor i es ar e the m ost com m onl y encounter ed?
4. Whi ch l abor ator y tests shoul d be r outi nel y per f or m ed i n a pati ent w i th
f ev er of unk now n or i gi n?
5. In m ost l ar ge ser i es, w hat per centage of pati ents w i th f ev er of unk now n
or i gi n hav e been f ound to ev ade di agnosi s?
Discussion
Discussion
1. What ar e the def i ni ti ons of f ev er and f ev er of unk now n or i gi n?
Fev er i s def i ned as an el ev ati on of the body tem per atur e. The nor m al
tem per atur e m ay v ar y f r om per son to per son, and r anges f r om 97. 0Â°F to
99. 2Â°F (36. 1Â°C to 37. 5Â°C) i n heal thy peopl e. The tem per atur e can
al so dem onstr ate a di ur nal v ar i ati on, i n that i t tends to be som ew hat
l ow er ear l y i n the m or ni ng. It i s i m por tant to docum ent a f ev er ov er the
cour se of an enti r e day , and, to do thi s, pati ents shoul d be i nstr ucted to
k eep a l og of thei r tem per atur e at hom e.
An el ev ated tem per atur e can be the hal l m ar k of i nf ecti on; how ev er , a
pati ent w i th a ser i ous i nf ecti on can be hy pother m i c or ev en hav e a
nor m al tem per atur e, especi al l y i f he or she i s el der l y or
i m m unosuppr essed. N ot al l f ev er s ar e caused by i nf ecti ons.
Peter sdor f and Beeson or i gi nal l y def i ned f ev er of unk now n or i gi n as f ev er
that ex ceeds 38. 3Â°C (100. 94Â°F) on sev er al occasi ons, l asts at l east 3
w eek s, and def i es di agnosi s af ter at l east 1 w eek of r outi ne study i n the
hospi tal . The 1w eek r outi ne study i s thought to el i m i nate m ost shor t
l i v ed f ev er s (e. g. , v i r al i l l ness, postoper ati v e f ev er , and f acti ti ous
f ev er ). It has been suggested that thi s l ast cr i ter i on (hospi tal adm i ssi on)
shoul d be m odi f i ed to â€œ1 w eek of i ntel l i gent and i ntensi v e
i nv esti gati on, â€ w hi ch f or m ost pati ents coul d be done on an outpati ent
basi s. Thi s def i ni ti on does not appl y to i m m unocom pr om i sed pati ents,
how ev er .
2. What i s the pathogenesi s of f ev er ?
The body tem per atur e i s cl osel y r egul ated w i thi n a cer tai n nor m al r ange,
and f ev er occur s w hen the cor e body tem per atur e ex ceeds thi s r ange.
Ther e ex i sts a bal ance betw een net heat pr oducti on and heat l oss. Heat i s
pr oduced thr ough body m etabol i sm and m uscl e acti v i ty ; heat i s l ost by
m eans of di ssi pati on thr ough the sk i n and the l ungs.
A centr al r egul ator of body tem per atur e i s the pr eopti c nucl eus of the
anter i or hy pothal am us. The hy pothal am us contr ol s body tem per atur e by
sti m ul ati ng the autonom i c ner v ous sy stem to pr oduce per i pher al
v asodi l ati on and sw eati ng. The hy pothal am us can al so cause heat to be
conser v ed by br i ngi ng about cutaneous v asoconstr i cti on. Shi v er i ng can
al so i ncr ease heat pr oducti on.
In the setti ng of i nf ecti on or other i nf l am m ator y states, m ononucl ear
phagocy tes pr oduce cy tok i nes such as IL1 and TN F that ar e capabl e of
r ai si ng the set poi nt of the hy pothal am us. Thi s i ni ti ates the com pl ex
m echani sm s that pr oduce py r ex i a. IL1 appear s to sti m ul ate the
hy pothal am us thr ough a pr ostagl andi n m echani sm , w hi ch ex pl ai ns w hy
pr ostagl andi n i nhi bi tor s such as aspi r i n ar e ef f ecti v e anti py r eti c agents.
P. 260
3. What ar e the gener al categor i es of di sease that can cause f ev er , and
w hi ch gener al categor i es ar e the m ost com m onl y encounter ed?
Fev er s that def y al l attem pts at di agnosi s pose a chal l enge to the
cl i ni ci an. Because m any causes of f ev er of unk now n eti ol ogy ar e obscur e
on the i ni ti al ev al uati on of a pati ent, i t i s hel pf ul to categor i ze the
di agnosti c possi bi l i ti es i nto gr oups accor di ng to the l i k el i hood of causi ng
the f ev er .
Ther e ar e num er ous di sease states associ ated w i th f ev er , but i nf ecti ons
w ar r ant speci al attenti on. Most i nf ecti ous causes ar e obv i ous to the
ev al uati ng cl i ni ci an once a car ef ul hi stor y and phy si cal ex am i nati on
coupl ed w i th r outi ne di agnosti c tests ar e com pl eted. Cer tai n sy stem i c
i nf ecti ous di seases that ar e par ti cul ar l y associ ated w i th f ev er of unk now n
or i gi n i ncl ude tuber cul osi s (par ti cul ar l y the ex tr apul m onar y f or m ) and
bacter i al endocar di ti s. A com pl ete l i st of i nf ecti ous causes of f ev er of
unk now n or i gi n i s bey ond the scope of thi s tex t; how ev er , py ogeni c
bacter i al , f ungal , m y cobacter i al , v i r al , r i ck ettsi al , par asi ti c, and
spi r ochetal i nf ecti ons hav e al l been associ ated w i th pr ol onged f ev er .
Local i zed causes of f ev er of unk now n eti ol ogy i ncl ude i ntr aabdom i nal ,
per i nephr i c, pr ostati c, and tooth abscesses, hepatobi l i ar y i nf ecti ons, and
pel v i c i nf ecti ons. These sour ces of i nf ecti on can be occul t and need to be
consi der ed i n a pati ent w i th a per pl ex i ng f ev er .
Other gener al categor i es of f ev er i ncl ude m al i gnancy and col l agen
v ascul ar di sor der s. Less com m on m i scel l aneous di sor der s i ncl ude
sar coi dosi s, i nf l am m ator y bow el di sor der s, pul m onar y em bol l i ,
thy r oi di ti s, a r etr oper i toneal hem atom a, gr anul om atous hepati ti s, al l er gi c
r eacti ons (dr ug f ev er s), and i nher i ted di seases (f am i l i al Medi ter r anean
f ev er ). Facti ti ous and f abr i cated f ev er s hav e al so been descr i bed, but
these consti tute a di agnosi s of ex cl usi on. Fi nal l y , a si gni f i cant m i nor i ty of
f ev er s w i th an undeter m i ned cause ar e i di opathi c.
4. Whi ch l abor ator y tests shoul d be r outi nel y per f or m ed i n a pati ent w i th
f ev er of unk now n or i gi n?
Al m ost now her e i n the pr acti ce of m edi ci ne ar e an i ndepth hi stor y and
com pl ete phy si cal ex am i nati on as essenti al as i n the ev al uati on of a
pati ent w i th f ev er of unk now n or i gi n, and, as Peter sdor f obser v ed i n
1969, i t i s i m por tant to r em em ber that â€œat the end of the needl e, the
x r ay tube, and ev en the scal pel , i s a si ck pati ent w ho deser v es the m ost
thoughtf ul di agnosti c appr oach of w hi ch w e ar e capabl e. â€
The appr opr i ate ev al uati on of each pati ent w i th f ev er of unk now n or i gi n
needs to be i ndi v i dual i zed. Attenti on shoul d be pai d to the pati ent's
ex posur e hi stor y , tr av el hi stor y , occupati on, ani m al ex posur e, hobbi es,
and m edi cati ons. The ex am i nati on shoul d be thor ough and par ti cul ar
attenti on shoul d f ocus on the l y m phoi d or gans, sk i n, hear t, ey e gr ounds,
and conjuncti v ae i n a sear ch f or ev i dence of occul t di sease, such as
bacter i al endocar di ti s, m al i gnancy , and v ascul i ti s.
Bl ood cul tur es shoul d be done r outi nel y , as w el l as a com pl ete bl ood
count w i th a di f f er enti al . Chest r adi ogr aphi c studi es shoul d al so be
obtai ned to r ul e out i nf ecti on or m al i gnancy . Var i ous other di agnosti c
studi es, i ncl udi ng r adi ol ogi c ex am i nati ons and bl ood tests, shoul d al so be
per f or m ed as di ctated
P. 261
by the natur e of the cl i ni cal pr esentati on. Cer tai n ser ol ogi c tests (such as
a Ly m e anti body test) m ay be i ndi cated i n the appr opr i ate epi dem i ol ogi c
setti ng. Cl ear l y , a r andom sear ch f or answ er s i s not appr opr i ate.
5. In m ost l ar ge ser i es, w hat per centage of pati ents w i th f ev er of unk now n
or i gi n hav e been f ound to ev ade di agnosi s?
In the f ew l ar ge tr i al s that hav e ex am i ned thi s questi on, 5% to 25% of
pati ents w i th f ev er of unk now n or i gi n hav e been f ound to el ude a speci f i c
di agnosi s. Tabl e 61 sum m ar i zes the obser v ati ons f r om thr ee of the
m ajor ser i es of pati ents w i th f ev er of unk now n or i gi n.
Case
A 61y ear ol d w hi te m an i s seen because of a f ev er . He w as w el l unti l 2
m onths bef or e, w hen he noted the onset of f ati gue, f ev er , chi l l s, and w ei ght
l oss. Tem per atur es as hi gh as 40Â°C (104Â°F) hav e occur r ed i n a cy cl i c
m anner (ev er y 2 to 3 day s), but r esol v e w i th acetam i nophen. He deni es
headaches, ar thr al gi as, v i sual di stur bances, abdom i nal pai n, and di ar r hea. Hi s
m edi cal hi stor y i s r em ar k abl e f or asthm a, env i r onm ental al l er gi es f or w hi ch
he i s under goi ng i m m unother apy , and a hi atal her ni a. Hi s f am i l y hi stor y i s
unr em ar k abl e. The pati ent does not consum e al cohol or sm ok e ci gar ettes. He
i s a r eti r ed f i r em an and has not tr av el ed or had ex posur e to i l l contacts. He
has no pets or other ani m al ex posur es. Ther e ar e none of the usual l y
r ecogni zed r i sk f actor s f or HIV i nf ecti on. He i s tak i ng no m edi cati ons.
On phy si cal ex am i nati on, the pati ent i s f ound to be a ti r edappear i ng, el der l y
m an. Hi s bl ood pr essur e i s 146/85 m m Hg; pul se, 106 beats per m i nute;
r espi r ati ons, 20 per m i nute; and tem per atur e, 38. 3Â°C (100. 94Â°F). The head,
ey es, ear s, nose, and thr oat ex am i nati on i s r em ar k abl e f or the f i ndi ng of dr y
m ucous m em br anes; hi s or ophar y nx i s cl ear and the ty m pani c m em br anes ar e
nor m al . Ther e i s no l y m phadenopathy ex cept f or a sm al l , 1. 5 Ã— 2cm ,
nontender l y m ph node i n the r i ght i ngui nal ar ea. The hear t sounds ar e
unr em ar k abl e ex cept f or a r egul ar tachy car di a. The l ungs ar e cl ear to
auscul tati on and per cussi on. Abdom i nal ex am i nati on r ev eal s nor m al bow el
sounds, and no hepatospl enom egal y or m asses ar e pal pated. Pr ostate and
r ectal f i ndi ngs ar e nor m al and a test f or occul t bl ood i s negati v e. Hi s sk i n
appear s jaundi ced. The neur ol ogi c f i ndi ngs ar e nor m al .
Table 61 Summary of Study Findings in Patients
with Fever of Unknown Origin a
Ca us e Ja c oby a nd La rs on e t a l. , Knoc k a e rt e t

Sw a rtz, 1973 (n 1982 (n = a l. , 1992 (n =
= 128) 105) 199)
Inf ecti on 40 30 23
N eopl asm s 20 31 7
Col l agen 15 9 19
v ascul ar
di sease
Mi scel l aneous b 1720 17 25
U ndi agnosed 58 12 26
a N um ber s ar e per centages.
b Incl udes al l di agnoses not f i tti ng i nto other categor i es (e. g. ,
sar coi d).
P. 262
A chest r adi ogr aph i s nor m al . A CT scan of the abdom en r ev eal s enl ar ged
por tacav al l y m ph nodes. The ser um el ectr ol y te v al ues ar e nor m al , and the
f ol l ow i ng l abor ator y data ar e r epor ted: w hi te bl ood cel l count, 4, 000/Âµ L;
hem ogl obi n, 11. 4 g/dL; and pl atel et count, 134, 000/m m 3 . The di f f er enti al
count r ev eal s 33% segm ented neutr ophi l s, 6% band f or m s, 18% l y m phocy tes,
4% r eacti v e l y m phocy tes, 20% m ononucl ear cel l s, and 15% eosi nophi l s. The
al bum i n content i s 3. 1 m g/dL; total bi l i r ubi n, 2. 8 m g/dL; al ani ne
am i notr ansf er ase, 31 IU /L; AST, 35 IU /L; al k al i ne phosphatase, 242 IU /L; and
l actate dehy dr ogenase, 567 IU /L. Al l bl ood cul tur es ar e negati v e. The
er y thr ocy te sedi m entati on r ate i s 50 m m per hour . A PPD of My cobacter i um
tuber cul osi s sk i n test i s negati v e, as i s the ser um anti nucl ear anti body test.
A bone m ar r ow bi opsy speci m en show s m i l d chr oni c i nf l am m ati on and
ex tensi v e gr anul om atosi s. The gr anul om atous f oci ar e com posed of
eosi nophi l s, sm al l l y m phocy tes w i th i r r egul ar nucl ei , and hi sti ocy tes. Routi ne
bacter i al , aci df ast baci l l i , and f ungal cul tur es and stai ns ar e negati v e. A test
f or ur i nar y Hi stopl asm a anti gen i s negati v e. A needl e bi opsy speci m en of the
l i v er r ev eal s si nusoi dal di l atati on, tr i adi ti s, bi l e stasi s, and f ocal per i por tal
f i br osi s w i th gr anul om as and di l atati on of the por tal v enous channel s.
The pati ent i s begun em pi r i cal l y on a r egi m en of i soni azi d, etham butol , and
r i f am pi n f or a pr esum pti v e di agnosi s of ex tr apul m onar y tuber cul osi s, but
ther e i s l i ttl e attendant i m pr ov em ent i n hi s cl i ni cal status.

2. What di agnosti c test shoul d be per f or m ed nex t?
3. What di sor der s coul d be causi ng the gr anul om as and f ev er i n thi s
pati ent?
Case Discussion
The m ost l i k el y cause of thi s pati ent's i l l ness i s l y m phom a. M.

tuber cul osi s i s one of the m ost com m on or gani sm s to be cul tur ed f r om
pati ents w i th f ev er of unk now n or i gi n and, ther ef or e, i t i s i m por tant to
r ul e i t out, especi al l y consi der i ng that the num ber of cases of M.
tuber cul osi s i nf ecti on hav e been i ncr easi ng i n the U ni ted States si nce the
m i d1980s. How ev er , the di agnosi s m ay be del ay ed because i t can tak e
cul tur es 4 to 6 w eek s to becom e posi ti v e, al though sm ear s of sputum or
other appr opr i ate cl i ni cal speci m ens m ay be posi ti v e w hen stai ned w i th
aci df ast stai n. Occasi onal l y , the PPD sk i n test i s negati v e, especi al l y i n
pati ents w i th di ssem i nated di sease. Thi s em phasi zes the i m por tance of
usi ng contr ol sk i n tests i n addi ti on to the PPD test. Thi s pati ent r epor ted
no ex posur e to tuber cul osi s, and hi s condi ti on di d not i m pr ov e on
anti tuber cul ous m edi cati ons, m ak i ng thi s di sease l ess l i k el y .
Cer tai n bacter i al i nf ecti ons ar e pr one to di ssem i nate and i nf ect the
r eti cul oendothel i al sy stem , i ncl udi ng Br ucel l a and Li ster i a speci es.
Al though Br ucel l a i nf ecti ons can be associ ated w i th l y m phadenopathy and
f ev er , thi s pati ent had had no contact w i th l ar ge ani m al s or occupati onal
ex posur es that w oul d pl ace hi m at r i sk f or br ucel l osi s. In addi ti on,
assum i ng the l abor ator y i s al er ted to thi s possi bi l i ty , bone m ar r ow
cul tur es can be posi ti v e i n a l ar ge per centage of pati ents w i th Br ucel l a.
P. 263
Col l agenv ascul ar di sor der s and v ascul i ti s ar e other causes of f ev er of
unk now n or i gi n. Am ong them ar e di seases such as pol y m y al gi a
r heum ati ca, sy stem i c l upus er y them atosus, m i x ed connecti v e ti ssue
di sor der s, and juv eni l e r heum atoi d ar thr i ti s. The l ack of appr opr i ate
sy m ptom s i n thi s pati ent, and a negati v e anti nucl ear anti body test, m ak e
thi s categor y of di sease l ess l i k el y .
Gi ant cel l ar ter i ti s deser v es speci al m enti on because 15% of pati ents w i th
thi s di sease can pr esent w i th f ev er . Of ten, the sedi m entati on r ate i n
these pati ents ex ceeds 100 m m per hour . The l ack of v i sual di stur bances,
tem por al ar ter y tender ness, or jaw cl audi cati on does not com pl etel y r ul e
out thi s di agnosi s, and occasi onal l y a tem por al ar ter y bi opsy i s i ndi cated
to el uci date the si tuati on. In one l ar ge ser i es, gi ant cel l ar ter i ti s w as
f ound to be the m ost com m on cause of f ev er of unk now n or i gi n i n
pati ents ol der than 50 y ear s.
N um er ous m al i gnanci es hav e been associ ated w i th f ev er . N eopl asm s of
the r eti cul oendothel i al sy stem ar e the m ost com m on cl ass of tum or s
causi ng f ev er . Fev er i n a pati ent of thi s age w ho ex hi bi ts both w ei ght l oss
and adenopathy suggests a m al i gnancy . A cy cl i c patter n of f ev er s, such
as that dem onstr ated by thi s pati ent, suggestsâ€”but does not cl i nchâ€”a
di agnosi s of Hodgk i n's di sease.
Pati ents w i th l y m phom a can pr esent w i th r ecur r ent f ev er that r em ai ns
obscur e. Other m al i gnanci es associ ated w i th f ev er i ncl ude nonâ
€“Hodgk i n's l y m phom a, r enal cel l car ci nom a, and atr i al m y x om as.
2. What di agnosti c test shoul d be per f or m ed nex t?
The phy si ci an shoul d al w ay s pr oceed i n a l ogi cal and stepw i se m anner i n
the ev al uati on of a pati ent such as thi s one. The w or k up shoul d star t w i th
a detai l ed hi stor y and phy si cal ex am i nati on, f ol l ow ed by di r ected
l abor ator y ev al uati ons and not a r andom sear chi ng f or an answ er . Thi s
pati ent under w ent a v er y ex tensi v e w or k up, i ncl udi ng r outi ne bl ood tests,
r adi ol ogi c ev al uati ons, and cul tur es that di d not y i el d a di agnosi s. The
nex t m ost l ogi cal step w oul d be to per f or m an ex ci si onal l y m ph node
bi opsy . It i s i m por tant to tr y to obtai n the enti r e l y m ph node, f or the
pur poses of both hi stol ogi c ex am i nati on and the per f or m ance of speci al
stai ns and cul tur es. Occasi onal l y , f i neneedl e aspi r ati on of a l y m ph node
can be a r api d and r el i abl e m ethod f or di agnosi s, but the am ount of
m ater i al obtai ned m ay not be adequate f or com pl ete hi stol ogi c
conf i r m ati on of l y m phom a. If no per i pher al l y m ph nodes ar e am enabl e to
bi opsy , a l apar otom y w i th sam pl i ng of i ntr aabdom i nal nodes m ay be
needed but thi s shoul d not be under tak en unti l noni nv asi v e r adi ogr aphi c
studi es hav e been uti l i zed to ev al uate the i ntr athor aci c and
i ntr aabdom i nal cav i ti es f or abnor m al i ti es that coul d f ocus the sur gi cal
di agnosti c i nter v enti on.
How ev er , i f a CT scan or ul tr asound study detects an i ntr aabdom i nal
abnor m al i ty that cannot be cul tur ed or sam pl ed f or bi opsy
per cutaneousl y , l apar otom y m ay be essenti al to obtai n adequate m ater i al
f or hi stol ogi c studi es and cul tur e.
In ter m s of i nf ecti ous di seases, cer tai n ser ol ogi c tests can be i nv al uabl e
i n the ev al uati on of a pati ent w i th a f ev er of undeter m i ned eti ol ogy .
Ri si ng anti body ti ter s can be di agnosti c f or cer tai n i nf ecti ous di seases,
but of ten acute and conv al escent ti ter s need to be deter m i ned as a pai r
to conf i r m the ex i stence of an acute i nf ecti on. Ther e ar e speci f i c
ser ol ogi c tests f or m any i nf ecti ous di seases, i ncl udi ng those caused
P. 264
by Br ucel l a, Fr anci sel l a tul ar ensi s, and Cox i el l a bur neti i , but r esul ts
w oul d unl i k el y be posi ti v e i n thi s setti ng unl ess ther e i s an ex posur e
hi stor y f or these or gani sm s.
Inf ecti on w i th HIV m ust be sought, especi al l y i f the accepted
epi dem i ol ogi c r i sk f actor s ex i st (e. g. , hom osex ual ex posur es, i ntr av enous
dr ug abuse, and bl ood pr oduct tr ansf usi on bef or e the w i despr ead
scr eeni ng f or HIV).
3. What di sor der s coul d be causi ng the gr anul om as and f ev er i n thi s pati ent?
Gr anul om as i n the l i v er and bone m ar r ow ar e nonspeci f i c f i ndi ngs.

Because these or gans ar e r i ch i n r eti cul oendothel i al cel l s, they can
r espond to anti gens and f or m gr anul om as. Gr anul om as ar e k now n to be
associ ated w i th a num ber of f ebr i l e di seases such as i nf ecti ons. Am ong
the i nf ecti ous causes of gr anul om a ar e tuber cul osi s, f ungal i nf ecti ons
(e. g. , hi stopl asm osi s), br ucel l osi s, Q f ev er , tul ar em i a, schi stosom i asi s,
sy phi l i s, and Whi ppl e's di sease.
Am ong the noni nf ecti ous causes of gr anul om a, sar coi dosi s i s the m ost
com m on. Hepati c gr anul om as can al so be f ound i n the setti ng of
connecti v e ti ssue di seases, hy per sensi ti v i ty r eacti ons, pr i m ar y l i v er
di seases, and m al i gnancy . Of the m al i gnanci es, hepati c gr anul om as can
be seen w i th l y m phom as. Fi nal l y , i n near l y a thi r d of the pati ents w i th
hepati c gr anul om as, the cause cannot be ascer tai ned, and these cases ar e
deem ed i di opathi c.
Suggested Readings
Ar now JP, Fl aher ty JP. Fev er of unk now n or i gi n. Lancet 1997;350:575.
Cor ey L, Boeck h M. Per si stent f ev er i n pati ents w i th neutr openi a. N Engl J
Med 2002;346:222.
Jacoby GA, Sw ar tz MN . Fev er of undeter m i ned or i gi n. N Engl J Med

1973;289:1407.
Lar son EB, Feather sone HJ, Peter sdor f RG. Fev er of undeter m i ned or i gi n:
di agnosi s and f ol l ow up of 105 cases, 1970â€“1980. Medi ci ne (Bal ti m or e)
1982;61:269.
Peter sdor f RG. Fev er of unex pl ai ned or i gi n: r epor t on 100 cases. Medi ci ne
(Bal ti m or e) 1961;40:1.
Peter sdor f RG. Fev er of unk now n or i gi n: an ol d f r i end r ev i si ted. Ar ch
Inter n Med 1992;152:21.
Pneumonia
1. What sy m ptom s and phy si cal , l abor ator y , and r adi ogr aphi c f i ndi ngs ar e
com m onl y obser v ed i n pati ents w i th com m uni ty acqui r ed pneum oni a?
2. What ar e the com m on causes of com m uni ty acqui r ed pneum oni a?
3. What i s the r ol e of the spl een i n com bati ng bacter i al i nf ecti ons?
Discussion
1. What sy m ptom s and phy si cal , l abor ator y , and r adi ogr aphi c f i ndi ngs ar e
com m onl y obser v ed i n pati ents w i th com m uni ty acqui r ed pneum oni a?
The cl i ni cal f i ndi ngs i n pati ents w i th com m uni ty acqui r ed pneum oni a ar e
di v er se, but can of ten be hel pf ul i n f or m ul ati ng a di f f er enti al di agnosi s.
In
P. 265
the setti ng of bacter i al pneum oni a, the sy m ptom s ar e of ten acute at
onset. Fr equentl y , ther e ar e shak i ng r i gor s, hi gh f ev er , and cough
pr oducti v e of pur ul ent sputum . On phy si cal ex am i nati on, the pati ent m ay
appear i l l , and si gns of l obar consol i dati on ar e of ten f ound on chest
ex am i nati on. A com pl ete bl ood count m ay r ev eal a br i sk l euk ocy tosi s w i th
a l ef t shi f t, and a chest r adi ogr aphi c study m ay show segm ental or l obar
i nf i l tr ates.
Aty pi cal pneum oni a (e. g. , due to v i r uses, or Ri ck ettsi a, Chl am y di a, or
My copl asm a or gani sm s) m ay al so be acute at onset, but the cough i s
usual l y dr y and nonpr oducti v e and r i gor s ar e absent. Chest ex am i nati on
m ay r ev eal f i ne di f f use r al es, or f i ndi ngs m ay be nor m al . Sk i n
ex am i nati on m ay r ev eal a r ash. A com pl ete bl ood count m ay show a m i l d
l euk ocy tosi s, or r esul ts m ay be nor m al . A chest r adi ogr aphi c study
ty pi cal l y show s the pr esence of di f f use i nf i l tr ates thr oughout both l ungs.
Pneum oni a due to anaer obi c or gani sm s (e. g. , aspi r ati on pneum oni a) i s
usual l y i nsi di ous at onset and the f ev er m ay be l ow gr ade. The cough
m ay be pr oducti v e of f oul sm el l i ng sputum . The pati ent's denti ti on m ay
be poor and he or she m ay hav e f oul sm el l i ng br eath. Chest ex am i nati on
m ay r ev eal consol i dati on i n the l ow er l ung f i el ds. A m i l d l euk ocy tosi s and
l ow er l obe i nf i l tr ates (par ti cul ar l y i n the r i ght l ow er l obe) m ay be seen
on chest r adi ogr aphi c f i l m s.
Pul m onar y tuber cul osi s i s al so i nsi di ous at onset. The f ev er m ay be
accom pani ed by dr enchi ng ni ght sw eats, and cough i s usual l y pr oducti v e.
Chest auscul tati on m ay r ev eal si gns of upper l obe or api cal consol i dati on.
The com pl ete bl ood count i s of ten nor m al and chest r adi ogr aphi c studi es
m ay show upper l obe i nf i l tr ates, of ten w i th cav i tati on. Cal ci f i ed hi l ar
l y m ph nodes, w hi ch ar e a r esi dual ef f ect f r om the pr i m ar y tuber cul ous
i nf ecti on, ar e of ten obser v ed.
2. What ar e the com m on causes of com m uni ty acqui r ed pneum oni a?
The di f f er enti al di agnosi s of com m uni ty acqui r ed pneum oni a i s br oad, but
can be nar r ow ed consi der abl y by the f i ndi ngs obtai ned f r om a car ef ul
hi stor y and phy si cal ex am i nati on, sputum Gr am 's stai ni ng, and chest
r adi ogr aphi c ev al uati on. Bacter i al pneum oni a can be caused by S.
pneum oni ae, H. i nf l uenzae, S. aur eus, Br anham el l a catar r hal i s, and
Legi onel l a pneum ophi l a. U ncom m on causes of bacter i al pneum oni a i ncl ude
Yer si ni a pesti s (pl ague), F. tul ar ensi s (tul ar em i a), and Baci l l us anthr aci s
(anthr ax ). Aty pi cal pneum oni as ar e com m onl y due to My copl asm a speci es
or r espi r ator y v i r uses. Less com m on causes of aty pi cal pneum oni a
i ncl ude Chl am y di a speci es (psi ttacosi s), C. bur neti i (Q f ev er ), H.
capsul atum , C. i m m i ti s, and M. tuber cul osi s. Anaer obi c or cav i tar y
pneum oni a i s m ost com m onl y caused by or al anaer obes or by M.
tuber cul osi s. Less com m on causes i ncl ude My cobacter i um k ansasi i , H.
capsul atum , C. i m m i ti s, and Bl astom y ces der m ati ti di s.
The i ni ti al assessm ent of pati ents w i th pneum oni a shoul d i ncl ude a
car ef ul occupati onal and soci al hi stor y to deter m i ne w hether ther e has
been ex posur e to w ater cool i ng f aci l i ti es (L. pneum ophi l a), w i l d ani m al s
(tul ar em i a or pl ague), bi r ds (psi ttacosi s), or f ar m ani m al s (anthr ax or Q
f ev er ), and w hether ther e has been a r ecent l oss of consci ousness
(aspi r ati on pneum oni a) or ex posur e to peopl e w i th tuber cul osi s. Li k ew i se,
the tr av el hi stor y i s al so i m por tant
P. 266
i n nar r ow i ng the di f f er enti al di agnosi s. Recent tr av el to the southw ester n
deser ts of the U ni ted States w oul d suggest cocci di oi dom y cosi s; ex posur e
to bi r d dr oppi ngs or bat guano i n the Mi dw est w oul d suggest
hi stopl asm osi s.
3. What i s the r ol e of the spl een i n com bati ng bacter i al i nf ecti ons?
The spl een i s par t of the r eti cul oendothel i al sy stem and i s i m por tant i n
cl ear i ng cer tai n bacter i al pathogens f r om the bl oodstr eam . Aspl eni c
peopl e ar e suscepti bl e to sepsi s stem m i ng f r om encapsul ated bacter i a
(pneum ococci , H. i nf l uenzae, and N . m eni ngi ti di s). They shoul d ther ef or e
be v acci nated agai nst these i nf ecti ons, pr ef er abl y bef or e spl enectom y i f
done el ecti v el y , because the spl een i s al so i m por tant i n the dev el opm ent
of an anti body r esponse to these v acci nes.
Case
A 64y ear ol d w om an f r om Topek a, Kansas, pr esents w i th an 8hour hi stor y of
f ev er , r i gor s, and a cough pr oducti v e of bl oodti nged sputum . She has been i n
good heal th al l of her l i f e ex cept f or abdom i nal tr aum a that necessi tated a
spl enectom y 30 y ear s ago. As y ou ar e ex am i ni ng her , she ex per i ences shak i ng
r i gor s and her f ev er i s f ound to be 39Â°C (102. 6Â°F); she al so com pl ai ns of a
pl eur i ti c pai n ov er the r i ght poster i or chest. Phy si cal ex am i nati on r ev eal s an
i l l appear i ng w om an w i th a per si stent cough pr oducti v e of pur ul ent sputum .
Ther e i s dul l ness to per cussi on, egophony , and m oi st r al es i n the r i ght
poster i or chest. Her w hi te bl ood cel l count i s 15, 000/m m 3 and a chest
r adi ogr aphi c study show s a dense consol i dati on i n the r i ght l ow er l obe w i th ai r
br onchogr am s. Gr am 's stai ni ng of a sputum sam pl e r ev eal s num er ous
neutr ophi l s and abundant i ntr acel l ul ar gr am posi ti v e di pl ococci .

2. What does the di f f er enti al di agnosi s of pneum oni a consi st of i n thi s
pati ent?
3. On the basi s of the sputum f i ndi ngs, w hat i s the m ost l i k el y cause of thi s
pati ent's condi ti on?
4. What w oul d be the m ost appr opr i ate tr eatm ent f or thi s pati ent?
Case Discussion
The r api d onset of sy m ptom s and pur ul ent sputum ar e f i ndi ngs m ost
suggesti v e of acute bacter i al pneum oni a. Thi s di agnosi s i s f ur ther
i ndi cated by the l obar consol i dati on depi cted on the chest r adi ogr aphi c
study . Al though a pul m onar y em bol i sm can cause the sudden onset of
pl eur i ti c chest pai n, hem opty si s, and f ev er , i t w oul d be unusual f or r i gor s
and pur ul ent sputum to occur i n thi s setti ng. Tuber cul osi s w oul d usual l y
assum e a m or e subacute pr esentati on. Br onchogeni c car ci nom a can
pr esent w i th br onchi al obstr ucti on and a postobstr ucti v e pneum oni a,
al though a hi l ar or per i hi l ar m ass w oul d l i k el y be f ound on chest
r adi ogr aphi c studi es. Thi s pati ent's pr esentati on w oul d be unusual f or
aty pi cal pneum oni as, such as those caused by v i r uses or My copl asm a or
Chl am y di a speci es. The pr esence of l ancet
P. 267
shaped di pl ococci i n the sputum Gr am 's stai n and the posi ti v e ur i nar y test
r esul t f or pneum ococcal anti gen f ur ther suppor t the di agnosi s.
2. What does the di f f er enti al di agnosi s of pneum oni a consi st of i n thi s
pati ent?
Thi s pati ent's si gns and sy m ptom s ar e m ost consi stent w i th those of acute
com m uni ty acqui r ed bacter i al pneum oni a. The m ost com m on cause of
com m uni ty acqui r ed bacter i al pneum oni a i s S. pneum oni ae
(pneum ococcus). Other potenti al causes i ncl ude H. i nf l uenzae, anaer obes
(aspi r ati on pneum oni a), and L. pneum ophi l a (usual l y spr ead by
contam i nated aer osol s gener ated by ai r condi ti oni ng sy stem s,
hum i di f i er s, and bath show er s). The di agnosi s of bacter i al pneum oni a can
usual l y be easi l y and r api dl y m ade thr ough the ex am i nati on of a Gr am 's
stai ned speci m en of ex pector ated sputum . Thi s si m pl e and i nex pensi v e
test w oul d al so be a k ey to deter m i ni ng the m ost appr opr i ate ther apy f or
thi s pati ent. The l ack of dom i nant bacter i a on the Gr am 'sstai ned sputum
sam pl e suggests the possi bi l i ty of l ess com m on causes of acute l obar
pneum oni a such as L. pneum ophi l a, tuber cul osi s, or f ungi
(cocci di oi dom y cosi s or hi stopl asm osi s). The di agnosi s of pneum oni a due
to L. pneum ophi l a i s m ade usual l y on the basi s of sputum cul tur e f i ndi ngs
or on those y i el ded by a di r ect f l uor escent anti body stai n of the sputum .
Li k ew i se, i f pul m onar y tuber cul osi s i s suspected, sputum aci df ast
stai ni ng shoul d be per f or m ed. A tuber cul i n sk i n test can scr een f or
pr ev i ous ex posur e to tuber cul osi s, but i s of l i ttl e v al ue i n the ev al uati on
of acti v e pul m onar y i nf ecti on. Fungal pneum oni as shoul d be consi der ed i f
the pati ent has been ex posed to bi r d or bat f eces, has been i nv ol v ed i n
spel unk i ng (hi stopl asm osi s), or has tr av el ed to Sonor an deser t ar eas i n
the southw ester n U ni ted States (cocci di oi dom y cosi s).
3. On the basi s of the sputum f i ndi ngs, w hat i s the m ost l i k el y cause of thi s
pati ent's condi ti on?
The pr esentati on and Gr am 's stai n f i ndi ngs ar e i ndi cati v e of pneum oni a
due to S. pneum oni ae (pneum ococcus), the m ost com m on cause of
bacter i al pneum oni a i n adul ts. The el der l y , debi l i tated, and
i m m unosuppr essed ar e especi al l y pr one to pneum ococcal pneum oni a. The
spl enectom y i n thi s pati ent al so pr edi sposes her to sepsi s caused by
encapsul ated bacter i a such as S. pneum oni ae, H. i nf l uenzae, and N .
m eni ngi ti di s.
4. What w oul d be the m ost appr opr i ate tr eatm ent f or thi s pati ent?
Ther e ar e tw o aspects to deci si on m ak i ng i n thi s pati ent: w hether she can
be tr eated as an outpati ent and w hat anti bi oti cs she shoul d r ecei v e. A
v er y w el l v al i dated tool ter m ed the Pneum oni a Sev er i ty Index (PSI) has
been dev el oped that pr ov i des ex cel l ent gui dance about w hether pati ents
shoul d best be tr eated i n an i npati ent or an outpati ent setti ng. The PSI
com bi nes dem ogr aphi c f eatur es of the pati ent such as age and sex ,
cl i ni cal f eatur es of the pati ent, and under l y i ng condi ti ons to pr ov i de a
scor e that pr ov i des ex cel l ent gui dance about w hether a pati ent can saf el y
be m anaged as an outpati ent (Fi g. 62). Once the m ost appr opr i ate
setti ng f or i ni ti al tr eatm ent has been deter m i ned, a deci si on about i ni ti al
anti bi oti cs m ust be m ade. In the past, f or a pati ent such as thi s one, i t
w oul d hav e been acceptabl e to i ni ti ate ther apy w i th peni ci l l i n. Ov er the
l ast sev er al y ear s, the pr ev al ence of str ai ns of S. pneum oni ae that ar e
r esi stant to peni ci l l i n has r i sen shar pl y i n the U ni ted States.
P. 268
Al though ther e i s contr ov er sy about w hether m ost pati ents w i th
pneum ococcal pneum oni a w i th m oder atel y r esi stant or gani sm s can be
tr eated w i th peni ci l l i n or am ox i ci l l i n, thi s pati ent i s acutel y i l l and i s
f ur ther com pr om i sed by hav i ng had a spl enectom y . Ther ef or e, i t w oul d be
i m pr udent to em pi r i cal l y use peni ci l l i n or am ox i ci l l i n i n the absence of
suscepti bi l i ty testi ng data. Thi s pati ent w oul d best be tr eated w i th a
com bi nati on of azi thr om y ci n or cl ar i thr om y ci n pl us a Î²l actam
(cef otax i m e, cef tr i ax one, am pi ci l l i nsul bactam , or er tapenem ).
Figure 62 Pneum oni a Sev er i ty Index . (Fr om Hal m EA, Tei r stei n AS.
Managem ent of com m uni ty acqui r ed pneum oni a. N Engl J Med
2002;347:2039. )
Cor ti coster oi ds hav e no r ol e i n the tr eatm ent of uncom pl i cated
pneum ococcal pneum oni a. A pneum ococcal v acci ne i s adm i ni ster ed to
pr ev ent pneum ococcal i nf ecti on i n hi ghr i sk pati ents (e. g. , aspl eni c
peopl e or those w i th a chr oni c pul m onar y
P. 269
di sease or under l y i ng i m m unodef i ci ency ), but has no r ol e i n the
m anagem ent of acute pneum ococcal pneum oni a. Pneum ococcal
v acci nati on i s al so r ecom m ended f or al l peopl e ol der than 65 y ear s, and
som e phy si ci ans adv ocate v acci nati on f or al l peopl e ol der than 55 y ear s.
Because of the spl enectom y , thi s pati ent shoul d r ecei v e pneum ococcal
v acci nati on as soon as she has r ecov er ed f r om the acute i l l ness.
Suggested Readings
Bi sno AL, Fr eem an JC. The sy ndr om e of aspl eni a, pneum ococcal sepsi s,
and di ssem i nated i ntr av ascul ar coagul ati on. Ann Inter n Med 1970;72:389.
Br oom e CV, Br ei m an RF. Pneum ococcal v acci ne: past, pr esent and f utur e.
N Engl J Med 1991;325:1506.
Fi ne MJ, Aubl e TE, Yeal y DM, et al . A pr edi cti on r ul e to i denti f y l ow r i sk
pati ents w i th com m uni ty acqui r ed pneum oni a. N Engl J Med 1997;336:243.
Guti er r ez F, Rodr i guez JC, Ay el o A, et al . Ev al uati on of the

i m m unochr om atogr aphi c Bi nax N OW assay f or detecti on of Str eptococcus
pneum oni ae ur i nar y anti gen i n a pr ospecti v e study of com m uni ty acqui r ed
pneum oni a i n Spai n. Cl i n Inf ect Di s 2003;36:286.
Hal m EA, Tei r stei n AS. Managem ent of com m uni ty acqui r ed pneum oni a. N
Engl J Med 2002;347:2039.
Jacoby GA, Ar cher GL. N ew m echani sm s of bacter i al r esi stance to

anti m i cr obi al agents. N Engl J Med 1991;324:601.
Kar l ow sk i JA, Thor nsber r y C, Jones ME, et al . Factor s associ ated w i th
r el ati v e r ates of anti m i cr obi al r esi stance am ong Str eptococcus pneum oni ae
i n the U ni ted States: r esul ts of the TRU ST sur v ei l l ance pr ogr am (1998â
€“2002). Cl i n Inf ect Di s 2003;36:963.
Mandel l LA. Rel ati onshi p of peni ci l l i n r esi stance to m or tal i ty i n
pneum ococcal pneum oni a. Cur r Inf ect Di s Rep 2001;3:9.
Mandel l LA, Bar tl ett JG, Dow el l SF, et al . U pdate of pr acti ce gui del i nes f or
the m anagem ent of com m uni ty acqui r ed pneum oni a i n i m m unocom petent
adul ts. Cl i n Inf ect Di s 2003;37:1405.
War d J. Anti bi oti cr esi stant Str eptococcus pneum oni ae: cl i ni cal and
epi dem i ol ogi c aspects. Rev Inf ect Di s 1981;3:254.
Title : Inte rna l Me dic ine Ca s e book , The : Re a l P a tie nts , Re a l Ans w e rs , 3rd
Edition
> T a b le o f C o nte nts > C ha p te r 7 He m a to lo g y a nd O nc o lo g y
Chapter 7
Hematology and Oncology
P a ul A. Se ligma n
Acute Leukemia
1. What i s the pathol ogy of acute l euk em i a?
2. What ar e the pr i m ar y cl assi f i cati ons of acute l euk em i a, and w hy i s thi s

di f f er enti ati on i m por tant?
P. 271
3. What i s the Fr ench, Am er i can, and Br i ti sh (FAB) cl assi f i cati on of acute
l euk em i a?
4. Ar e ther e any pr edi sposi ng f actor s associ ated w i th acute l euk em i a?
5. What w or k up and other pr epar ati ons shoul d be done bef or e i ni ti ati ng
anti l euk em i c ther apy ?
6. What ar e i nducti on, consol i dati on, m ai ntenance chem other apy , and m eni ngeal
pr ophy l acti c ther apy , and how do they di f f er i n the tr eatm ent of acute
l y m phocy ti c l euk em i a (ALL) and acute nonl y m phocy ti c l euk em i a (AN LL)?
7. What ar e the r i sk s associ ated w i th anti l euk em i c ther apy , and w hat r esul ts can
be ex pected?
Discussion
1. What i s the pathol ogy of acute l euk em i a?
Acute l euk em i a i s the abnor m al cl onal ex pansi on of bl ood cel l pr ecur sor s. The
abnor m al i ty m ay occur at di f f er ent stages of m atur ati on of the cel l , and thi s
ex pl ai ns the di f f er ent ty pes of l euk em i a. Acute l euk em i a i s usual l y a r api dl y
pr ogr essi v e di sease, al though ther e ar e occasi onal pati ents w hose di sease
r em ai ns stabl e f or w eek s or ev en m onths. In gener al , how ev er , i t i s not the
l euk em i c cel l s per se that cause the m or bi di ty and m or tal i ty i n thi s di sor der ,
but a l ack of nor m al bl ood cel l s, r esul ti ng i n anem i a, thr om bocy topeni a, and
l euk openi a. Thi s i s br ought about by the l euk em i c cel l s â€œcr ow di ng outâ€ the
nor m al cel l s i n the bone m ar r ow . Other data suggest that especi al l y m y el oi d
l euk em i a cel l s hav e an i nhi bi tor y ef f ect on nor m al m ar r ow cel l s. Thi s l ack of
nor m al cel l s m ay ther ef or e l ead to l i f ethr eateni ng hem or r hage and i nf ecti on.
2. What ar e the pr i m ar y cl assi f i cati ons of acute l euk em i a, and w hy i s thi s

di f f er enti ati on i m por tant?
The pr i m ar y cl assi f i cati ons of acute l euk em i a ar e ALL and acute

nonl y m phocy ti c l euk em i a (AN LL, m y el oi d l euk em i a). The di sti ncti on i s
i m por tant because the ther apy di f f er s f or each ty pe (see answ er to questi on
6). The ov er al l r ati o of ALL to AN LL i s 1 : 6. ALL occur s m ost com m onl y i n
chi l dr en, w her eas AN LL m or e com m onl y af f ects adul ts.
3. What i s the FAB cl assi f i cati on of acute l euk em i a?
The FAB cl assi f i cati on (Tabl e 71) i s based l ar gel y on the m or phol ogi c and
hi stochem i cal char acter i sti cs di spl ay ed by the l euk em i c cel l s, as w el l as on the
natur e of the cel l sur f ace anti gens and cy togeneti c f eatur es. Thi s i nf or m ati on
m ay l ead to changes i n pati ent m anagem ent, ei ther by di r ecti ng the cour se of
ther apy or by def i ni ng the pr ognosi s better . Tabl e 71 al so i ncl udes m ol ecul ar
changes that m ay af f ect ther apy , but m or e of ten af f ect r esponse to ther apy .
4. Ar e ther e any pr edi sposi ng f actor s associ ated w i th acute l euk em i a?
Cer tai n geneti c and env i r onm ental f actor s m ay pr edi spose a per son to acute
l euk em i a. Many chr om osom al al ter ati ons ex i st i n the setti ng of the l euk em i as.
The i nci dence of l euk em i a i s i ncr eased i n pati ents w i th congeni tal di sor der s
associ ated w i th aneupl oi dy , such as Dow n sy ndr om e, congeni tal
P. 272
P. 273
agr anul ocy tosi s, cel i ac di sease, Fanconi sy ndr om e, and v on Reck l i nghausen's
neur of i br om atosi s.
Table 71 The French, American and British
(FAB) Classification of Acute Leukemia
As s oc ia te d
FAB Chromos ome
c la s s ific a tion De s c ription Comme nt Abnorma litie s
ALL
L1 Sm al l bl asts w i th Most com m on 12 : 21

l i ttl e cy topl asm , m or phol ogy i n
l i ttl e cel l tocel l chi l dhood ALL
v ar i ati on
L2 Lar ger cel l s w i th Most com m on â€”

gr eater am ount m or phol ogy i n
of cy topl asm , adul t ALL
gr eater cel l to
cel l v ar i ati on;
i r r egul ar nucl ei
w i th m ul ti pl e
nucl eol i
L3 Lar ge cel l s, Com m on i n 8 : 14 (i . e. ,

str ongl y l euk em i a Bur k i tt's
basophi l i c associ ated w i th l y m phom a)
cy topl asm ; of ten Bur k i tt's
w i th v acuol es; l y m phom a
nucl eol i of ten
m ul ti pl e
ANLL
M1 Acute m y el ocy ti c â€” â€”

l euk em i a: cel l s
v er y
undi f f er enti ated
w i th onl y
occasi onal
gr anul es
M2 b Acute m y el ocy ti c â€” 8:21 a

l euk em i a: cel l s
m or e
di f f er enti ated
w i th gr anul es,
and of ten w i th
Auer r ods
M3 Acute Of ten 15:17 a

pr om y el ocy ti c associ ated w i th
l euk em i a: di ssem i nated
hy per gr anul ar i ntr av ascul ar
pr om y el ocy tes coagul ati on,
r esponds to
di f f er enti ati on
agents
M4 b Acute Of ten occur s Inv er si on a 16

m y el om onocy ti c w i th
l euk em i a: both ex tr am edul l ar y
m onocy tes and i nf i l tr ati on
m y el ocy tes (gi ngi v al
pr edom i nate hy per tr ophy ,
l euk em i a cuti s,
and m eni ngeal
l euk em i a)
M5 b Acute m onocy ti c U sual l y af f ects â€”
l euk em i a: chi l dr en or
m onobl asts w i th y oung adul ts
r el ati v el y
agr anul ar
cy topl asm
M6 Er y thr ol euk em i a: Al so cal l ed Di â€”

r ed bl ood cel l Gugl i el m o's
pr ecur sor s sy ndr om e
pr edom i nate, but
m y el oi d bl asts
m ay al so be
seen
M7 Megak ar y ocy ti c Rar e f or m of â€”

l euk em i a: l euk em i a; v er y
ex tr em el y poor pr ognosi s
v ar i abl e
m or phol ogy ;
m ay be
di agnosed w i th
m onocl onal
anti bodi es to
pl atel ets
a These k ar y oty pes ar e gener al l y consi der ed to be m or e l i k el y to
r espond to chem other apy .
b When M2, M4, and M5 l euk em i a occur af ter l ongter m m y el ody spl asi a
11q 2; 3, m onosom y 7 and other abnor m al
k ar y oty pes suggest decr eased r esponse to chem other apy .
ALL, acute l y m phocy ti c l euk em i a; AN LL, acute nonl y m phocy ti c

l euk em i a.
Env i r onm ental f actor s i m pl i cated i n the dev el opm ent of acute l euk em i a,
par ti cul ar l y AN LL, i ncl ude ex posur e to i oni zi ng r adi ati on and chem i cal s.
Occupati ons and ther apy that i nv ol v e r adi ati on ex posur e ar e k now n to i ncr ease
the r i sk f or acqui r i ng acute l euk em i a. Chem i cal s, par ti cul ar l y the i ndustr i al use
of benzene, and sev er al ther apeuti c dr ugs (chl or am pheni col , pheny l butazone,
m el phal an, chl or am buci l , and other s) ar e causal f actor s i n acute l euk em i a. The
f i ndi ngs f r om ani m al studi es l i nk cer tai n v i r uses w i th acute l euk em i a;
how ev er , i t i s uncer tai n w hi ch v i r uses ar e actual l y an eti ol ogi c f actor i n hum an
f or m s of l euk em i a, ex cept f or l y m phom as caused by v i r uses that dev el op i nto
a f or m of ALL.
5. What w or k up and other pr epar ati ons shoul d be done bef or e i ni ti ati ng
anti l euk em i c ther apy ?
The pr etr eatm ent ev al uati on shoul d i ncl ude the pati ent's m edi cal and w or k
hi stor y , especi al l y the natur e of any r adi ati on or chem i cal ex posur e. A phy si cal
ex am i nati on shoul d i ncl ude the pati ent's tem per atur e, pl us ex am i nati on of the
opti c f undi , l y m ph node ar eas, or ophar y nx and gi ngi v ae, per i anal ar ea, and
cr ani al ner v es. Labor ator y studi es shoul d consi st of a com pl ete bl ood count
w i th di f f er enti al (the phy si ci an shoul d ex am i ne the sm ear ), as w el l as a bl ood
chem i str y pr of i l e that i ncl udes the m easur em ents of ur i c aci d and l actate
dehy dr ogenase (LDH). Bone m ar r ow aspi r ates and bi opsy speci m ens shoul d be
obtai ned, and i nv esti gati ons shoul d i ncl ude cy togeneti c studi es. A tr ansf usi on
w or k up shoul d i ncl ude hum an l y m phocy te anti gen (HLA) ty pi ng. Lum bar
punctur e shoul d be per f or m ed i n al l pati ents suspected of hav i ng ALL or AN LL
M4, and the cer ebr ospi nal f l ui d speci m en shoul d be subjected to the usual
studi es, pl us cy tol ogi c anal y si s. A dental ex am i nati on shoul d be per f or m ed.
In addi ti on, the pati ent's condi ti on shoul d be stabi l i zed bef or e anti l euk em i c
ther apy i s i ni ti ated. Hem or r hage and i nf ecti on shoul d be br ought under contr ol .
Gr eatl y el ev ated m y el obl ast counts (e. g. , > 50, 000/m m 3 ) that occur i n the
setti ng of AN LL can l ead to pul m onar y com pl i cati ons as w el l as f atal
i ntr acer ebr al l euk ostasi s and hem or r hage. Cr ani al i r r adi ati on, hy dr ox y ur ea,
and l euk apher esi s hav e al l been used to decr ease the num ber s of ci r cul ati ng
l euk em i c cel l s r api dl y , and hence r educe the r i sk of com pl i cati ons. (Because of
the phy si cal pr oper ti es of the l y m phocy ti c l euk em i c cel l , thi s i s r ar el y a
pr obl em i n pati ents w i th ALL. )
Renal dam age stem m i ng f r om ur ate nephr opathy m ay ex i st at the ti m e of
pr esentati on or m ay occur w i th ther apy , ther ef or e ur i ne al k al i ni zati on m ay
pr ev ent the need f or di al y si s. Pati ents shoul d r ecei v e al l opur i nol (300 to 600
m g) f or at l east 24 hour s bef or e ther apy to r educe the ur i c aci d l oad, and thi s
tr eatm ent shoul d be conti nued unti l l euk openi a and bone m ar r ow
hy pocel l ul ar i ty hav e been achi ev ed.
P. 274
6. What ar e i nducti on, consol i dati on, m ai ntenance chem other apy , and m eni ngeal
pr ophy l acti c ther apy , and how do they di f f er i n the tr eatm ent of ALL and AN LL?
These ar e the phases of ther apy used f or acute l euk em i a. Inducti on ther apy i s
usual l y the i ni ti al ther apy and i s i ntended to accom pl i sh com pl ete r em i ssi on
(that i s, no si gns or sy m ptom s of di sease, nor m al bl ood counts, and no
ev i dence of l euk em i a, i . e. , < 5% bl asts i n the bone m ar r ow ). Thi s ther apy i s
usual l y adm i ni ster ed on an i npati ent basi s, and i s v er y tox i c. Consol i dati on
ther apy i s gi v en af ter com pl ete r em i ssi on i s achi ev ed. It i s si m i l ar l y tox i c, and
consi sts of ei ther the sam e dr ugs as those used i n i nducti on ther apy or
di f f er ent ones. Its object i s to r educe the now cl i ni cal l y undetectabl e l euk em i c
cel l m ass as m uch as possi bl e. Mai ntenance ther apy i s usual l y gi v en on an
outpati ent basi s and i s l ess tox i c, al though com pl i cati ons of ther apy can and do
ar i se. Thi s phase usual l y l asts f or 2 to 3 y ear s. Meni ngeal pr ophy l acti c ther apy
i s gi v en by m eans of l um bar punctur e or thr ough a r eser v oi r pl aced under the
scal p that cannul ates the thi r d v entr i cl e. Its goal i s to r educe the r ecur r ence
r ate of l euk em i a i n the centr al ner v ous sy stem (CN S), w hi ch i s consi der ed a
sanctuar y si te.
Al l f our ther apy phases ar e used i n ALL. In the tr eatm ent of AN LL, ther e i s
contr ov er sy ov er the use of m ai ntenance ther apy , al though a second
consol i dati on phase m ay be used. Meni ngeal pr ophy l ax i s i s not used i n the
tr eatm ent of adul t AN LL. How ev er , CN S l euk em i a i s m or e com m on i n chi l dhood
AN LL, and pr ophy l ax i s i s som eti m es used i n thi s setti ng. In gener al , the
r esponse to tr eatm ent and the pr ognosi s ar e better i n pati ents w i th ALL than i n
those w i th AN LL.
7. What ar e the r i sk s associ ated w i th anti l euk em i c ther apy , and w hat r esul ts can
be ex pected?
As al r eady noted, acute l euk em i a i s usual l y a r api dl y pr ogr essi v e di sease that
i s f atal w i thout ther apy . Because the ther apy i tsel f i s tox i c, the m or tal i ty r ate
dur i ng i nducti on ther apy f or AN LL m ay r each as hi gh as 20%. Som e tox i ci ti es
ar e speci f i c to the dr ug used, and these ar e not di scussed her e. N ear l y al l
ther api es pr ov ok e nausea and v om i ti ng, w hi ch can be contr ol l ed w i th
m edi cati ons. Mor e si gni f i cantl y , anti l euk em i c ther apy i s i ntended to depl ete
the bone m ar r ow , w i th subsequent r epopul ati on by nor m al cel l s. Dur i ng thi s
per i od of depl eti on, the pati ent becom es sev er el y thr om bocy topeni c and m ust
be suppor ted by pl atel et tr ansf usi ons (gi v en pr ophy l acti cal l y at v ar i ous
i nter v al s to k eep the pl atel et count abov e 10, 000) and, usual l y , al so by r ed
bl ood cel l tr ansf usi ons.
Pati ents al so becom e sev er el y l euk openi c, and thi s m ak es them v er y
suscepti bl e to i nf ecti on. The ty pi cal si gns and sy m ptom s of i nf ecti on (pus and
pur ul ent sputum ) ar e of ten due to the acti ons of gr anul ocy tes, so i nf ecti on i s
of ten subtl e. The or al m ucosa and per i r ectal ar eas ar e com m onl y ov er l ook ed
si tes of i nf ecti on. Fev er i n a neutr openi c pati ent m ust be consi der ed i nf ecti ous
by or i gi n, unti l pr ov ed other w i se. When thi s happens, ex am i nati on and cul tur es
shoul d be car r i ed out and br oadspectr um anti bi oti c ther apy star ted qui ck l y .
Anti f ungal agents ar e usual l y added i f no i m pr ov em ent i s seen af ter 4 to 7
day s of f ev er . The pati ent m ust be m oni tor ed car ef ul l y and tr eated f or her pes
v i r us i nf ecti on because di ssem i nated i nf ecti on can be r api dl y f atal .
P. 275
If the l euk em i c cel l bur den i s gr eat, anti l euk em i c ther apy m ay pr eci pi tate the
tum or l y si s sy ndr om e, caused by the r api d r el ease of cel l degr adati on
pr oducts. It i s char acter i zed by hy per ur i cem i a (causi ng ur ate nephr opathy ),
hy per k al em i a, hy per phosphatem i a, and hy pocal cem i a. Adv ance r ecogni ti on of
pati ents at r i sk and subsequent tr eatm ent w i th v i gor ous hy dr ati on, al l opur i nol ,
and ur i ne al k al i ni zati on 24 to 48 hour s bef or e the star t of chem other apy can
usual l y pr ev ent the sy ndr om e. These pati ents m ust hav e thei r el ectr ol y te, ur i c
aci d, phosphor us, cal ci um , and cr eati ni ne status r epeatedl y check ed. Any
m etabol i c abnor m al i ti es shoul d be cor r ected and, i f necessar y , r enal di al y si s
i nsti tuted ear l y . Once the l euk em i c cel l bur den i s decr eased and degr adati on
pr oducts cl ear ed, the sy ndr om e r esol v es.
Most chi l dr en w i th ALL r espond to ther apy and achi ev e l ongter m sur v i v al .
Al though 90% of adul ts w i th ALL ex per i ence com pl ete r em i ssi on w i th i ni ti al
ther apy , the m edi an r em i ssi on dur ati on r anges f r om 48 to 60 m onths,
dependi ng on the study . Medi an sur v i v al i s 3 to 5 y ear s. How ev er ,
appr ox i m atel y one thi r d of al l pati ents achi ev e l ongter m di seasef r ee
sur v i v al . Late r ecur r ences ar e r ar e.
Pati ents w i th AN LL f ace a w or se pr ognosi s. Appr ox i m atel y 75% ex per i ence
com pl ete r em i ssi on, but m ost cases r ecur w i thi n 36 m onths. Of those w ho
achi ev e com pl ete r em i ssi on, 20% to 25% show l ongter m di seasef r ee
sur v i v al . Bone m ar r ow or stem cel l tr anspl antati on w i th hi ghdose
chem other apy i s of ten used, but i s sti l l under i nv esti gati on as a ther apy af ter
the i ni ti al chem other apy i n ALL. The ti m i ng of tr anspl antati on (f i r st r em i ssi on,
f i r st r el apse, or second r em i ssi on), especi al l y i n ALL, i s contr ov er si al . In AN LL,
bone m ar r ow tr anspl antati on (bone m ar r ow r escue) w i th hi ghdose
chem other apy af ter a f i r st r em i ssi on has been associ ated w i th hi gher l ong
ter m sur v i v al r ates. Ol der age (> 40 y ear s), use of unr el ated donor s, and
ev i dence f or r esi dual di sease at the ti m e of tr anspl antati on r educe the ef f i cacy
of thi s tr eatm ent appr oach.
Case
A 63y ear ol d w hi te m an i s seen i n the em er gency r oom w i th com pl ai nts of f ev er ,
f ati gue, and m al ai se. He r epor ts hav i ng i nter m i ttent epi stax i s dur i ng the l ast w eek ,
m outh sor es f or the l ast 3 day s, and a nonpr ur i ti c r ash ov er hi s l ow er ex tr em i ti es,
w hi ch w as noted 24 hour s bef or e. He has ex per i enced m i dchest pai n f or the l ast
day , onl y on sw al l ow i ng. He deni es chem i cal , dr ug, or r adi ati on ex posur e.
Phy si cal ex am i nati on r ev eal s a tem per atur e of 38. 6Â°C (101. 48Â°F). He has m i l d
tachy car di a, at 108 beats per m i nute. Head, ey es, ear s, nose, and thr oat f i ndi ngs
consi st of a f ew petechi ae ov er the sof t pal ate. Mul ti pl e w hi te pl aques ar e seen on
the or al m ucosa, and ther e i s hy per tr ophy of the gi ngi v ae. Dur i ng ex am i nati on of
the sk i n, petechi ae ar e f ound ov er the di stal l ow er ex tr em i ti es. Other ex am i nati on
f i ndi ngs ar e nor m al . Speci f i cal l y , no l y m phadenopathy or hepatospl enom egal y ar e
f ound. Other si tes of possi bl e i nf ecti on, i ncl udi ng the chest and per i r ectal ar ea, ar e
cl ear . The chest r adi ogr aphi c study i s l i k ew i se nor m al .
Labor ator y f i ndi ngs ar e as f ol l ow s: w hi te bl ood cel l count, 17, 200/m m 3 w i th 2%
pol y m or phonucl ear l euk ocy tes, 1% band f or m s, 16% l y m phocy tes, 4% m onocy tes,
5%
P. 276
m etam y el ocy tes, 4% basophi l s, and 68% bl astocy tes; hem ogl obi n, 11. 1 g/dL;
hem atocr i t, 32. 6%; and pl atel ets, 14, 000/m m 3 . Hi s el ectr ol y te, bl ood ur ea ni tr ogen
(BU N ), cr eati ni ne, and am i notr ansf er ase l ev el s ar e nor m al . Hi s ur i c aci d l ev el i s
m i l dl y i ncr eased at 9. 2 m g/dL (nor m al , 3. 5 to 8. 0 m g/dL), as ar e hi s LDH l ev el at
373 IU /L (nor m al , 30 to 220 IU /L). Ex am i nati on of a per i pher al bl ood sm ear r ev eal s
occasi onal nucl eated r ed bl ood cel l s, f ew pl atel ets, and m any l ar ge cel l s contai ni ng
f i nel y r eti cul ated nucl ei , sev er al nucl eol i , cy topl asm i c gr anul es, and occasi onal
Auer r ods. Lar ge cel l s w i th f ol ded nucl ei and l ar ge, pr om i nent nucl eol i ar e al so
seen.

2. How i s the absol ute neutr ophi l count (AN C) cal cul ated, and w hat i s i t i n thi s
pati ent?
3. Of w hat i m por tance i s the AN C?
4. Do the ev al uati on f i ndi ngs poi nt to any speci f i c i nf ecti ons?
5. What w oul d y ou ex pect thi s pati ent's bone m ar r ow to show ?
6. Shoul d a l um bar punctur e be per f or m ed i n thi s pati ent?
Case Discussion
Consi der i ng the r esul ts of thi s pati ent's com pl ete bl ood count and per i pher al
bl ood sm ear , he has AN LL. The gr anul ar m y el ocy tes and m onocy tes i n the
sm ear and the cl i ni cal ev i dence of ex tr am edul l ar y l euk em i c i nf i l tr ati on
(gi ngi v al hy per tr ophy ) poi nt to a di agnosi s of M4, or acute m y el om onocy ti c
l euk em i a. Ex am i nati on of bone m ar r ow speci m ens usi ng speci al stai ns and
chr om osom al anal y si s can hel p conf i r m thi s di agnosi s.
2. How i s the AN C cal cul ated, and w hat i s i t i n thi s pati ent?
To cal cul ate the AN C, m ul ti pl y the total w hi te bl ood cel l count by the
per centage of pol y m or phonucl ear l euk ocy tes pl us the per centage of band
f or m s. In thi s case, the pati ent has 17, 200 w hi te bl ood cel l s, w i th 2%
pol y m or phonucl ear l euk ocy tes and 1% band f or m s, or : 17, 200 (0. 02 + 0. 01) =
516 absol ute neutr ophi l s.
3. Of w hat i m por tance i s the AN C?
The AN C f ur ni shes a r ough esti m ate of the pati ent's abi l i ty to f i ght i nf ecti on. A
pati ent w i th an AN C of l ess than 500 i s consi der ed neutr openi c and v er y
suscepti bl e to ov er w hel m i ng i nf ecti on. Thi s pati ent, w i th an AN C of
appr ox i m atel y 500, f ev er , and a pr esum ed di agnosi s of acute l euk em i a, f al l s
i nto thi s categor y . Car ef ul ex am i nati on, together w i th cul tur es of bl ood,
sputum , or al l esi ons, and other possi bl e si tes of i nf ecti on, shoul d be done
qui ck l y , and the pati ent star ted on br oadspectr um anti bi oti cs i m m edi atel y .
Any del ay i n the w or k up or i nsti tuti on of anti bi oti cs m ay r esul t i n
ov er w hel m i ng and possi bl y f atal i nf ecti on. Cul tur es ar e of ten negati v e i n
neutr openi c pati ents, al though cl i ni cal l y they appear to be septi c and r espond
to anti bi oti cs.
4. Do the ev al uati on f i ndi ngs poi nt to any speci f i c i nf ecti ons?
Thi s pati ent com pl ai ns of m i dchest pai n on sw al l ow i ng and phy si cal
ex am i nati on r ev eal s w hi te or al pl aques. A pr esum pti v e di agnosi s of Candi da
esophagi ti s can be
P. 277
m ade on the basi s of these f i ndi ngs, and the pati ent shoul d be star ted on
anti f ungal agents as w el l as br oadspectr um anti bacter i al anti bi oti cs.
N eutr openi c pati ents ar e suscepti bl e to oppor tuni sti c i nf ecti ons, and
candi di asi s i s v er y com m on i n them .
5. What w oul d y ou ex pect thi s pati ent's bone m ar r ow to show ?
The bone m ar r ow i n thi s pati ent w i th AN LL w oul d l i k el y ex hi bi t

hy per cel l ul ar i ty , w i th cel l ul ar el em ents of ten consti tuti ng 90% or m or e of the
m ar r ow . The num ber s of r ed bl ood cel l pr ecur sor s and m egak ar y ocy tes w i l l be
decr eased. The m or phol ogy m ay be nor m al , or ther e m ay be dy ser y thr opoi esi s
(asy nchr onous m atur i ng of the nucl ear and cy topl asm i c el em ents). The m ar r ow
w i l l pr i m ar i l y show a m onotonous patter n of cel l s si m i l ar to those seen i n the
per i pher al sm ear . Fl ow cy tom etr y shoul d show cel l sur f ace m ar k er s i ndi cati v e
of i m m atur e m y el oi d cel l s w i th m onocy toi d char acter i sti cs. The chr om osom e
anal y si s m ay show an abnor m al i ty such as m onosom y 7 (especi al l y i f the
pati ent had m y el ody spl asi a), but w i l l not show the abnor m al i ti es associ ated
w i th, f or ex am pl e, M3 l euk em i a (Tabl e 71). Recent studi es suggest com pl ex
k ar y oty pes i n pati ents ol der than 60 y ear s, that i s, thr ee or m or e aber r ati ons
hav e decr eased r esponse to ther apy and based on com or bi d f actor s these
pati ents shoul d be consi der ed f or i nv esti gati onal ther apy or suppor ti v e car e.
6. Shoul d a l um bar punctur e be per f or m ed i n thi s pati ent?
Thi s pati ent has a pr esum pti v e di agnosi s of acute m y el om onocy ti c l euk em i a.
Lum bar punctur es ar e r outi nel y done i n cases of ALL and AN LLM4 because
these l euk em i as ar e associ ated w i th m eni ngi ti s. N ev er thel ess, any pati ent w i th
acute l euk em i a and sy m ptom s of m eni ngi ti s or cr ani al ner v e pal si es shoul d
under go a di agnosti c l um bar punctur e, r egar dl ess of the l euk em i c ty pe.
How ev er , the pl atel et count i n thi s pati ent i s onl y 14, 000/m m 3 , and l um bar
punctur es shoul d not be per f or m ed w hen the pl atel et count i s l ess than
50, 000/m m 3 because of the r i sk of hem or r hage. Ther ef or e, pl atel et
tr ansf usi ons m ust be gi v en bef or e attem pti ng l um bar punctur e to br i ng the
count to 50, 000/m m 3 or m or e.
Suggested Readings
Baccar ani M, Car bel l i G, Am ador i S, et al . Adol escent and adul t acute
l y m phobl asti c l euk em i a: pr ognosti c f eatur es and outcom e of ther apy â€” a study
of 293 pati ents. Bl ood 1982;60:677.
Bennett JM, Young ML, Ander son JW, et al . Longter m sur v i v al i n acute m y el oi d
l euk em i a. Cancer 1997;8:2205.
Bur nett A, Gol dstone AH, Stev ens RMF, et al . Random i zed com par i son of
addi ti on of autol ogous bonem ar r ow tr anspl antati on to i ntensi v e r em i ssi on:
r esul ts of MRC AML 10 tr i al . Lancet 1998;351:700.
Far ag SS, Ar cher KJ, Mr ozek K, et al . Pr etr eatm ent cy togeneti cs add to other
pr ognosti c f actor s pr edi cti ng com pl ete r em i ssi on and l ongter m outcom e i n
pati ents 60 y ear s of age or ol der w i th acute m y el oi d l euk em i a: r esul ts f r om
Cancer and Leuk em i a Gr oup B 8461. Bl ood 2006;108:63.
Gal e RP, Hoel zer D. Acute l y m phobl asti c l euk em i a. N ew Yor k : Wi l ey Li ss, 1990.
Koef f l er HP. Sy ndr om es of acute nonl y m phocy ti c l euk em i a. Ann Inter n Med
1987;107:748.
P. 278
Anemia
1. What i s the def i ni ti on of anem i a, and w hat i s the di f f er enti al di agnosi s based
on the m ean cor puscul ar v ol um e (MCV)?
2. Why i s i t i m por tant to ex am i ne the per i pher al bl ood sm ear , and w hat ar e the
m any di agnosti c er y thr ocy te abnor m al i ti es and cor r espondi ng cl i ni cal
condi ti ons?
3. What i s a r eti cul ocy te, and how i s the r eti cul ocy te count used to char acter i ze
an anem i a? What i s the r eti cul ocy te i ndex , how i s i t cal cul ated, and how i s i t
used i n the di f f er enti al di agnosi s of anem i a?
4. What i s the di f f er ence betw een Î± and Î²thal assem i a, how ar e they
di sti ngui shed cl i ni cal l y , and how i s el ectr ophor esi s usef ul ?
5. What i s si ck l e cel l anem i a, and how i s i t m ani f ested cl i ni cal l y ? What i s the
si ck l e cel l tr ai t, and how i s i t m ani f ested cl i ni cal l y ?
Discussion
1. What i s the def i ni ti on of anem i a, and w hat i s the di f f er enti al di agnosi s based
on the MCV?
Anem i a i s usual l y def i ned as an abnor m al l y l ow hem atocr i t or hem ogl obi n
concentr ati on, and occur s w hen the r ate of er y thr ocy te l oss ex ceeds the r ate
of er y thr ocy te pr oducti on. The di f f er enti al di agnosi s of anem i a depends on
w hether the MCV i s l ow , hi gh, or nor m al . Tabl e 72 l i sts the v ar i ous possi bl e
di agnoses f or each of these categor i es. Som eti m es w i th m i l d anem i a, a
di agnosi s m ay be enter tai ned i f the MCV i s i n the hi gh or l ow r ange of nor m al .
2. Why i s i t i m por tant to ex am i ne the per i pher al bl ood sm ear , and w hat ar e the
m any di agnosti c er y thr ocy te abnor m al i ti es and cor r espondi ng cl i ni cal
condi ti ons?
Per i pher al bl ood sm ear ex am i nati on can r ev eal er y thr ocy te abnor m al i ti es that
poi nt to the cor r ect di agnosi s of the anem i a. Echi nocy tes, or bur r cel l s, f or
ex am pl e ar e seen i n ur em i a and py r uv ate k i nase def i ci ency . El l i ptocy tes ar e
the abnor m al er y thr ocy tes seen i n pati ents w i th her edi tar y el l i ptocy tosi s.
P. 279
N ucl eated r ed cel l s ar e f ound i n the setti ng of str ess or hem atol ogi c di sease
w i th bone m ar r ow i nv ol v em ent. Schi stocy tes or f r agm ents occur i n pati ents
w i th m i cr oangi opathi c hem ol y ti c anem i a. Si ck l e cel l s ar e f ound i n the setti ng
of si ck l e cel l anem i a. Spher ocy tes occur i n i m m unem edi ated hem ol y ti c
anem i a and her edi tar y spher ocy tosi s. Tar get cel l s f or m i n the pr esence of l i v er
di sease and i r on def i ci ency ; they al so occur af ter spl enectom y .
Table 72 Differential Diagnosis of Anemia Based
on Mean Corpuscular Volume (MCV)
Low MCV Norma l MCV High MCV
Î± Thal assem i a Acute bl ood l oss Al cohol abuse
Î²Thal assem i a Apl asti c anem i a Apl asti c anem i a

Ir on def i ci ency Chr oni c di sease Cobal am i n def i ci ency
Lead poi soni ng Com bi nati on of Fol ate def i ci ency
m acr ocy ti c and
Si der obl asti c m i cr ocy ti c causes Hem ol y si s

anem i a
Hem ogl obi nopathy Hy pothy r oi di sm
Hem ol y si s Li v er di sease
Ir on def i ci ency My el ody spl asti c

sy ndr om es
3. What i s a r eti cul ocy te, and how i s the r eti cul ocy te count used to char acter i ze
an anem i a? What i s the r eti cul ocy te i ndex , how i s i t cal cul ated, and how i s i t
used i n the di f f er enti al di agnosi s of anem i a?
A r eti cul ocy te i s a y oung ci r cul ati ng r ed bl ood cel l that ex hi bi ts basophi l i a
under v i tal stai ni ng. The r eti cul ocy te count i s used to char acter i ze the bone
m ar r ow 's attem pt to com pensate, i f at al l , f or the anem i a pr esent. The
r eti cul ocy te i ndex (Tabl e 73) i s a m or e usef ul m eans of char acter i zi ng anem i a
because i t i s deter m i ned by cor r ecti ng the r eti cul ocy te count f or the
hem atocr i t, assum i ng a nor m al hem atocr i t i s 45%. Thi s cor r ecti on i s necessar y
because r eti cul ocy tes ar e counted per 1, 000 r ed bl ood cel l s.
An i ndex of l ess than 2 i s f ound i n the setti ng of the hypoprolife ra tive
a ne mia s . These consi st of di sor der s of hem e or gl obi n sy nthesi s, such as i r on
def i ci ency , anem i a stem m i ng f r om chr oni c di sease, l ead poi soni ng,
si der obl asti c anem i as, and Î± , Î², and other thal assem i as; m egal obl asti c
anem i as r esul ti ng f r om cobal am i n or f ol ate def i ci ency ; m y el ody spl asti c
sy ndr om es; apl asti c anem i as; and other m etabol i c causes, such as r enal
i nsuf f i ci ency and hy pothy r oi di sm .
Hype rprolife ra tive a ne mia s ar e associ ated w i th a r eti cul ocy te i ndex gr eater
than 2. These anem i as ar i se as the r esul t of acute bl ood l oss; nutr i ent
r epl acem ent, such as cobal am i n, f ol ate, or i r on r epl acem ent, but bef or e the
r esol uti on of anem i a; both her edi tar y and acqui r ed hem ol y si s; and pr i m ar y or
secondar y pol y cy them i a.
Autom ated r eti cul ocy te counts i ntr oduced f or gener al cl i ni cal pr acti ce ar e m or e
accur ate than â€œhand countsâ€ and autom ati cal l y cal cul ate the r eti cul ocy te
i ndex . These autom ated v al ues al so i ncl ude the total num ber of r eti cul ocy tes,
a m easur em ent that m i ght be hel pf ul w hen obtai ni ng ser i al v al ues.
Table 73 The Reticulocyte Index
He ma toc rit (% ) Corre c tion Fa c tor
45 1. 0
35 1. 5
25 2. 0
Cor r ecti on of the r eti cul ocy te i ndex f or shi f t cel l s: shi f t cel l snew l y
r el eased er y thr ocy tes.
N ew er autom ated sy stem s that w i l l becom e av ai l abl e w i l l gi v e
cor r ected r eti cul ocy te count and a r eti cul ocy te m atur ati on i ndex to
account f or â€œshi f t cel l s. â€
P. 280
4. What i s the di f f er ence betw een Î± and Î²thal assem i a, how ar e they
di sti ngui shed cl i ni cal l y , and how i s el ectr ophor esi s usef ul ?
The Î± tha la s s e mia s consti tute abnor m al i ti es of the gene, or genes,
r esponsi bl e f or the sy nthesi s of the Î± chai n of hem ogl obi n. Hum ans contai n
f our genes f or thi s pur pose and each i s r esponsi bl e f or appr ox i m atel y a f our th
of the Î± chai ns sy nthesi zed. Any com bi nati on of f r om one to f our of these Î±
genes m ay be m i ssi ng. Thal assem i a i s unappar ent cl i ni cal l y w hen onl y one
gene i s m i ssi ng, and thi s i s cal l ed Î± 1 thal assem i a. Thi s def ect ex i sts i n up to
30% of the Am er i can bl ack popul ati on. If tw o of the Î± genes ar e m i ssi ng, the
enti ty i s r ef er r ed to as Î± 2 thal assem i a. These pati ents ar e usual l y
asy m ptom ati c, al though thei r hem atocr i t and MCV m ay be sl i ghtl y l ow . Thi s
def ect af f ects appr ox i m atel y 2% of Af r i can Am er i cans. When thr ee of the Î±
genes ar e l ack i ng, the pati ent ex hi bi ts the phenoty pe of Î± thal assem i a
(Hem ogl obi n H di sease) w i th a l ow hem atocr i t and MCV, and Î²chai n tetr am er s
or hem ogl obi n H i s f ound i n the r ed bl ood cel l s. When al l f our Î± genes ar e
m i ssi ng, the r esul t i s usual l y a sti l l bor n i nf ant w i th hy dr ops f etal i s.
Î± Thal assem i a i s the m ost com m on f or m of thal assem i a i n the Southeast
Asi an popul ati on.
The Î²tha la s s e mia s consi st of abnor m al i ti es of the gene, or genes,
r esponsi bl e f or the Î² chai n of hem ogl obi n, and they cause i nsuf f i ci ent Î²chai n
sy nthesi s. Thi s l eads to the f or m ati on of Î± chai n tetr am er s and i ncl usi ons of
thi s hem ogl obi n attached to the pl asm a m em br anes of er y thr ocy tes, r esul ti ng
i n hem ol y si s. Pati ents w i th heter ozy gous Î²thal assem i a ex hi bi t a m odest
decr ease i n thei r hem atocr i t v al ues and a m ar k ed decr ease i n thei r MCVs.
Pati ents w i th hom ozy gous Î²thal assem i a hav e sev er e anem i a and l ow MCVs.
They r equi r e tr ansf usi on, and com pl i cati ons m ay ar i se stem m i ng f r om the
ex cess accum ul ati on of i r on.
El ectr ophor esi s m ay be used to suggest the di agnosi s of Î± thal assem i a i n
pati ents m i ssi ng thr ee genes, and ther eby hav i ng suf f i ci ent f astm i gr ati ng
hem ogl obi n H (Î± l and Î± 2 thal assem i a tr ai ts m ay not be detected). The
pr eci se num ber of m i ssi ng Î± genes can be deter m i ned i n hy br i di zati on studi es
thr ough the use of a com pl em entar y DN A pr obe.
The f i ndi ngs y i el ded by hem ogl obi n el ectr ophor esi s ar e usual l y di agnosti c i n
the setti ng of Î²thal assem i a. Because Î± chai n sy nthesi s i s nor m al i n these
pati ents, the other hem ogl obi ns seen i n adul ts, i ncl udi ng hem ogl obi n A 2 and F,
ar e i ncr eased i n a com pensator y m anner . Ther ef or e, pati ents w i th
heter ozy gous Î²thal assem i a w oul d hav e el ev ated hem ogl obi n A 2 and F l ev el s
w i th hem ogl obi n A pr esent. Pati ents w i th hom ozy gous Î²thal assem i a w oul d
hav e no hem ogl obi n A and m ar k edl y el ev ated hem ogl obi n F and A 2 l ev el s.
5. What i s si ck l e cel l anem i a, and how i s i t m ani f ested cl i ni cal l y ? What i s the
si ck l e cel l tr ai t, and how i s i t m ani f ested cl i ni cal l y ?
Si ck l e cel l di sease i s the m ost com m onl y r ecogni zed cl i ni cal l y si gni f i cant
hem ogl obi nopathy . It stem s f r om a substi tuti on of v al i ne f or gl utam i c aci d i n
the Î² chai n of hem ogl obi n and can be di agnosed by el ectr ophor esi s. Si ck l e cel l
anem i a r esul ts w hen both Î² chai ns ar e abnor m al . Si ck l ed cel l s shoul d be
ev i dent on
P. 281
a per i pher al bl ood sm ear . Hem ogl obi n S i s l ess sol ubl e than nor m al
hem ogl obi n at a l ow ox y gen tensi on, causi ng the hem ogl obi n m ol ecul es to
cr y stal l i ze, w hi ch def or m s the r ed bl ood cel l s. These m i sshapen cel l s gr eatl y
i ncr ease the bl ood v i scosi ty , w hi ch l eads to sm al l v essel occl usi on and hence
pai n and or gan i nf ar cti ons, speci f i cal l y str ok e as w el l as pul m onar y , r enal , and
bone i nf ar cti on.
Si ck l e cel l di sease m ay be m ani f ested by a v ar i ety of cr i ses: P a in i s the m ost
com m on sy m ptom , and i s thought to be secondar y to r ed bl ood cel l sl udgi ng
and i nf ar cti on. Sple nic s e que s tra tion a nd da c tylitis ar e com m on i n chi l dr en,
but r ar e i n adul ts. Apla s tic a ne mia i s uncom m on, but i s ty pi cal l y associ ated
w i th i nf ecti ons, and i s anti ci pated w hen r eti cul ocy te counts decr ease i n the
f ace of w or seni ng of anem i a. Me ga lobla s tic a ne mia i s usual l y secondar y to
f ol ate def i ci ency , and ar i ses because abnor m al cel l s hav e a shor tened l i f e
span. Thi s i ncr eases the tur nov er of r ed bl ood cel l s and pl aces an i ncr eased
dem and on f ol ate stor es. Si ck l e cel l pati ents w ho enter w i th pai n cr i si s or â
€œchest sy ndr om eâ€ ar e at r i sk f or m ul ti or gan f ai l ur e. When i t becom es
appar ent that l i v er , k i dney , and/or pul m onar y f uncti on ar e decl i ni ng, these
pati ents shoul d be consi der ed f or ex change tr ansf usi on.
The si ck l e cel l tr ai t i s al m ost al w ay s asy m ptom ati c because onl y one of the
tw o Î² chai ns i s abnor m al . It can al so be di agnosed by el ectr ophor esi s, and
thi s i s m ost i m por tant f or the pur poses of geneti c counsel i ng.
Case 1
A 42y ear ol d m an i s seen by hi s pr i m ar y car e phy si ci an because of a r ectal
ur gency . On si gm oi doscopy , a m ass i s l ocated at 8 cm . He under goes r esecti on to
r em ov e the m ass and af ter sur ger y he r ecei v es adjuv ant chem other apy and
under goes pel v i c r adi ati on ther apy . Af ter he com pl etes ther apy , he r etur ns to hi s
pr i m ar y car e phy si ci an 6 m onths l ater w i th com pl ai nts of f ati gue and dy spnea on
ex er ti on. As par t of the ev al uati on, a com pl ete bl ood count i s obtai ned and r ev eal s
the f ol l ow i ng f i ndi ngs: w hi te bl ood cel l count, 3. 9 Ã— 10 9 /L; hem ogl obi n, 8. 2 g/dL;
hem atocr i t, 24. 4%; MCV, 86 f L; r eti cul ocy tes, 1%; and pl atel ets, 450, 000/m m 3 . The
pati ent has a ser um i r on content of 23 Âµg/dL, a total i r onbi ndi ng capaci ty of 256
Âµg/dL, and a f er r i ti n l ev el of 10 ng/m L.
1. What i s the l i k el y cause of thi s pati ent's anem i a, and how w oul d y ou ev al uate
hi m f ur ther ?
2. If the pati ent i s i r on def i ci ent, w hy i s hi s MCV 86 f L?
3. On the basi s of the pati ent's i r on status, w hat tr eatm ent shoul d be pr escr i bed,
and how shoul d ther apy be m oni tor ed?
Case Discussion
1. What i s the l i k el y cause of thi s pati ent's anem i a, and how w oul d y ou ev al uate
hi m f ur ther ?
The cause of thi s pati ent's anem i a i s l i k el y m ul ti f actor i al . How ev er , the f er r i ti n

l ev el bel ow 12 ng/m L and the per centage tr ansf er r i n satur ati on (total i r on
bi ndi ng Fe/capaci ty ) bel ow 10% ar e both di agnosti c f or i r on def i ci ency . He
shoul d r ecei v e or al i r on suppl em entati on, but he shoul d be ev al uated f or a
gastr oi ntesti nal sour ce of
P. 282
bl ood l oss (e. g. , r ecur r ent tum or , second pr i m ar y cancer , or som e other
nonm al i gnant sour ce).
The pati ent m ay al so be anem i c and l euk openi c due to the ex tensi v e ex posur e
of the bone m ar r ow to r adi ati on dur i ng pel v i c r adi ati on ther apy . Thi s bone
m ar r ow dam age m ay be com pounded by the concom i tant chem other apy
tr eatm ent.
Fi nal l y , the possi bi l i ty of other contr i butor y f actor s, such as f ol ate and
cobal am i n def i ci ency , shoul d al so be i nv esti gated.
2. If the pati ent i s i r on def i ci ent, w hy i s hi s MCV 86 f L?
The MCV m ay be nor m al i n the setti ngs of ear l y i r on def i ci ency , al though the
r ed bl ood cel l di str i buti on w i dth i s hi gh under these ci r cum stances. The MCV
m ay al so be nor m al i n i r ondef i ci ency anem i a com pl i cated by another
nutr i ti onal def i ci ency , such as f ol ate or cobal am i n def i ci ency . In thi s pati ent,
the MCV i s l i k el y hi gher than ex pected as a r esul t of hi s r ecent chem other apy
tr eatm ent that i s associ ated w i th i nhi bi ti on of DN A sy nthesi s.
3. On the basi s of the pati ent's i r on status, w hat tr eatm ent shoul d be pr escr i bed,
and how shoul d ther apy be m oni tor ed?
The pati ent has i r on def i ci ency . Fer r ous sul f ate (300 m g thr ee ti m es a day )
pr ov i des 180 m g of el em ental i r on per day , w hi ch shoul d nor m al i ze the
hem atocr i t ov er the cour se of sev er al m onths. The hem atocr i t shoul d i ncr ease
by 1% to 3% each w eek and hi s r eti cul ocy te count shoul d al so i ncr ease
si gni f i cantl y w i th thi s tr eatm ent.
The status of the absor pti on of or al i r on can be easi l y dem onstr ated by
deter m i ni ng the f asti ng ser um i r on l ev el bef or e and 3 to 4 hour s af ter the
i ngesti on of a si ngl e 300m g tabl et of f er r ous sul f ate. If nor m al , the l ev el
shoul d r i se by a m i ni m um of tw o ti m es the basel i ne (f asti ng) v al ue. If the
pati ent has decr eased i r on absor pti on, that i s, due to â€œi nf l am m ati on bl ock â€
that decr eases absor pti on, he shoul d be tr eated w i th i ntr av enous i r on.
Case 2
A 67y ear ol d w om an i s seen f or com pl ai nts of m i l d m em or y l oss and f ati gue. On
ev al uati on, she i s f ound to hav e an anem i a, w hi ch i s char acter i zed by the f ol l ow i ng
l abor ator y v al ues: w hi te bl ood cel l count, 5, 200/m m 3 ; hem ogl obi n, 9. 1 g/dL;
hem atocr i t, 26. 9%; MCV, 101 f L; r eti cul ocy tes, l ess than 1%; and pl atel ets,
154/m m 3 . Her ser um cobal am i n l ev el i s 260 pg/m L and her f ol ate, thy r oi d
sti m ul ati ng hor m one, and l i v er f uncti on tests ar e nor m al . The pati ent does not
abuse al cohol , and her per i pher al bl ood sm ear i s unr ev eal i ng.
1. How w oul d y ou f ur ther ev al uate thi s pati ent's anem i a?

2. On the basi s of the l abor ator y r esul ts so f ar , w hat test, or tests, m i ght be
hel pf ul i n di agnosi ng the cause of thi s pati ent's anem i a?
3. Why m i ght such a pati ent be def i ci ent i n cobal am i n?
Case Discussion
1. How w oul d y ou f ur ther ev al uate thi s pati ent's anem i a?
Ser um cobal am i n and f ol ate l ev el s shoul d be deter m i ned. In addi ti on, a sear ch
f or both ethanol abuse and l i v er di sease shoul d be under tak en and
hy pothy r oi di sm
P. 283
r ul ed out. If none of these i s f ound to be a l i k el y cause, other r easons f or the
anem i a (r ef r actor y or apl asti c anem i a) shoul d be ex pl or ed. A per i pher al bl ood
sm ear shoul d be ex am i ned f or possi bl e cl ues such as hy per segm ented
pol y m or phonucl ear l euk ocy tes (seen i n cobal am i n def i ci ency ) or tar get cel l s
(seen i n l i v er di sease).
2. On the basi s of the l abor ator y r esul ts so f ar , w hat test, or tests, m i ght be
hel pf ul i n di agnosi ng the cause of thi s pati ent's anem i a?
Thi s pati ent l i k el y has cobal am i n def i ci ency , al though her ser um cobal am i n
l ev el of 260 pg/m L i s w i thi n the nor m al r ange. Because studi es hav e show n
that such def i ci ency r esul ts i n m ethy l m al oni c aci dur i a and hom ocy sti nem i a,
these m etabol i c substr ates shoul d be m easur ed i n thi s pati ent. Other testi ng
that m i ght be consi der ed i ncl udes a Schi l l i ng test or m easur em ent of anti â
€“i ntr i nsi c f actor bl ock i ng anti bodi es.
3. Why m i ght such a pati ent be def i ci ent i n cobal am i n?
Ther e ar e v ar i ous causes of cobal am i n def i ci ency . It can stem f r om the
i ngesti on of i nsuf f i ci ent ani m al pr otei n, as seen i n tr ue v egetar i ans. Fai l ur e to
r el ease cobal am i n f r om f ood bi nder s or f ai l ur e to secr ete i ntr i nsi c f actor
r esul ts i n per ni ci ous anem i a. Fai l ur e to absor b the i ntr i nsi c f actor â€“cobal am i n
com pl ex i n the di stal i l eum , as occur s i n pati ents w ho hav e under gone an i l eal
r esecti on or w ho hav e r egi onal enter i ti s, can al so l ead to cobal am i n def i ci ency .
Rar e causes ar e abnor m al or absent enzy m es or tr anspor t pr otei ns, and ni tr ous
ox i de abuse.
Suggested Readings
Ak ar su S, Task i n E, Yi l m az E, et al . Tr eatm ent of i r on def i ci ency anem i a w i th
i ntr av enous i r on pr epar ati ons. Acta Haem atol 2006;116:51.
Beutl er E, Li chtm an MA, Col ter BS, et al . , eds. Hem atol ogy , 6th ed. N ew Yor k :
McGr aw Hi l l , 2000.
Wi ntr obe MM, ed. Cl i ni cal hem atol ogy , 10th ed. Phi l adel phi a: Lea & Febi ger ,
1998.
Bleeding Disorders
1. What ar e the m ajor di v i si ons of the coagul ati on sy stem ?
2. What ar e the gener al scr eeni ng tests f or ev al uati ng each of the m ajor di v i si ons
of the coagul ati on sy stem ?
3. What com m on di sor der s ar e associ ated w i th each of the m ajor di v i si ons of the
coagul ati on sy stem ?
4. What ar e the cl i ni cal m ani f estati ons of v ar i ous bl eedi ng di sor der s?
5. What w or k up i s i ndi cated f or a bl eedi ng pati ent?
6. What ther api es ar e av ai l abl e f or the m anagem ent of bl eedi ng di sor der s?
Discussion
1. What ar e the m ajor di v i si ons of the coagul ati on sy stem ?
The coagul ati on sy stem i s qui te com pl ex , but can be v i ew ed as consi sti ng of at
l east thr ee m ajor com ponents: the v ascul ar endothel i um , the bl ood
P. 284
coagul ati on pr otei ns (both those that pr om ote cl otti ng and those that l y se cl ots
by m eans of the f i br i nol y ti c sy stem ), and the pl atel ets. The coagul ati on
cascade r epr esents a ser i es of pr otei ns that, w hen i ni ti ated, f or m s a f i br i n
cl ot. A si m pl e outl i ne of the cascade i s show n i n Tabl e 74. Com pl ex i ssues
such as the ex act m echani sm s by w hi ch anti coagul ants, such as pr otei n C and
pr otei n S, f uncti on and how f actor VII m ay acti v ate f actor IX ar e not
com pl etel y under stood.
Table 74 The Intrinsic and Extrinsic Pathways of
the Coagulation System
2. What ar e the gener al scr eeni ng tests f or ev al uati ng each of the m ajor di v i si ons
of the coagul ati on sy stem ?
Vascul ar endothel i al i ntegr i ty can be assessed usi ng the bl eedi ng ti m e. In thi s
test, a ni ck i s m ade i n the sk i n under standar di zed condi ti ons, and the ti m e to
cessati on of bl eedi ng i s m easur ed.
The bl ood coagul ati on pr otei ns ar e usual l y ev al uated by i n v i tr o studi es usi ng
the pati ent's ci tr ateanti coagul ated pl asm a. Thi s i s done by addi ng back
v ar i ous com ponents of the coagul ati on cascade to the pati ent's pl asm a to
i nduce cl ot, and the pr ocedur e i s standar di zed agai nst pl asm a f r om an
i ndi v i dual w i th nor m al pl asm a coagul ati on com ponents. The tw o m ost com m on
tests f or doi ng
P. 285
thi s ar e the pr othr om bi n ti m e (PT) and the par ti al ti ssue thr om bopl asti n ti m e
(PTT). The PT m easur es the ex tr i nsi c pathw ay of the coagul ati on cascade, and
thi s i s done by addi ng ti ssue thr om bopl asti n to the pati ent's pl asm a. If ther e i s
a def i ci t i n any of the com m on pathw ay com ponents or f actor VII, the cl otti ng
ti m e i s pr ol onged abnor m al l y . The PTT m easur es the i ntr i nsi c and com m on
pathw ay s; a def i ci t i n the com m on or i ntr i nsi c pathw ay pr otei ns r esul ts i n a
pr ol onged PTT. A thi r d, l ess com m onl y used, scr eeni ng test i s the thr om bi n
ti m e, w hi ch m easur es onl y the l ast step i n the cascadeâ€” the conv er si on of
f i br i nogen to f i br i nâ€” and i s done by addi ng thr om bi n to the pati ent's pl asm a.
Ther ef or e, i f the pati ent has too l i ttl e f i br i nogen or a dy sf uncti onal f i br i nogen
pr otei n, the ti m e i s pr ol onged. Fi nal l y , each of the com ponents of the cascade,
i ncl udi ng f actor s I to XIII, can be assay ed di r ectl y to ev al uate f or def i ci ts.
Pl atel ets can be ev al uated both quanti tati v el y (by the pl atel et count) and
f uncti onal l y . Pl atel et f uncti on can be assessed by the bl eedi ng ti m e;
qual i tati v el y def ecti v e pl atel ets do not f or m an adequate pl atel et pl ug and the
bl eedi ng ti m e i s pr ol onged. In addi ti on, pl atel ets can be anal y zed i n v i tr o f or
thei r aggr egabi l i ty usi ng pl atel et sti m ul ants (e. g. , r i stoceti n).
3. What com m on di sor der s ar e associ ated w i th each of the m ajor di v i si ons of the
coagul ati on sy stem ?
The v ascul ar endothel i um m ay be f r agi l e i n the setti ng of sev er al acqui r ed
condi ti ons, i ncl udi ng v ascul i ti s and l ongter m ster oi d use. Thi s i s i m por tant to
r eal i ze because i t m ay cause the bl eedi ng ti m e to be pr ol onged despi te nor m al
pl atel et num ber and f uncti on.
Def i ci ts i n the bl ood coagul ati on pr otei ns m ay be congeni tal or acqui r ed. The
m ost com m on congeni tal di sor der s consi st of def i ci enci es i n f actor VIII
(hem ophi l i a A) or f actor IX (hem ophi l i a B, or Chr i stm as di sease), w hi ch ar e
i nher i ted i n an Xl i nk ed m anner . Another com m on congeni tal di sor der i s v on
Wi l l ebr and's di sease, i n w hi ch ther e i s a def i ci t i n v on Wi l l ebr and's f actor . Thi s
f actor i s bound to f actor VIII and i s necessar y f or both pl atel et f uncti on and f or
cl otti ng to tak e pl ace by the i ntr i nsi c pathw ay .
Def i ci enci es i n v ar i ous f actor s can be acqui r ed w hen thei r pr oducti on i s
antagoni zed, as occur s w i th sodi um w ar f ar i n (Coum adi n; DuPont Phar m a,
Wi l m i ngton, DE) ther apy , a substance that i nhi bi ts the pr oducti on of acti v ated
v i tam i n Kâ€“dependent f actor s (f actor s II, VII, IX, X, and pr otei n C and S).
Another com m on si tuati on that causes def i ci enci es i n v ar i ous f actor s i s l i v er
di sease; because the l i v er i s the si te f or the sy nthesi s of near l y al l the
coagul ati on f actor s, sev er e l i v er di sease r esul ts i n def i ci ent pr oducti on of
f actor s. Mal nutr i ti on, m al absor pti on, and l i v er di sease can al l l ead to a def i ci t
i n v i tam i n K, w i th a subsequent def i ci t i n the v i tam i n Kâ€“dependent f actor s.
Fi nal l y , the ov er w hel m i ng consum pti on of al l f actor s can r esul t i n a
coagul opathy , as occur s i n di ssem i nated i ntr av ascul ar coagul ati on (DIC).
The pl atel et popul ati on can be depr essed because of ei ther under pr oducti on or
ex cessi v e destr ucti on. U nder pr oducti on occur s as a consequence of bone
m ar r ow suppr essi on (br ought about by chem other apy , i nf ecti ons, dr ugs, or
i nf i l tr ati on w i th other cel l s, such as occur s i n the setti ng of l euk em i a or
P. 286
cancer ). Ex cessi v e destr ucti on can occur i n the setti ng of an enl ar ged spl een
(sequestr ati on), bl eedi ng (consum pti on) or consum pti v e di sor der s (DIC or
thr om boti c thr om bocy topeni c pur pur a/hem ol y ti c ur em i c sy ndr om e), and on an
autoi m m une basi s [i di opathi c thr om bocy topeni c pur pur a (ITP)].
Qual i tati v e def ects can be congeni tal , but ar e m or e of ten acqui r ed and due to
dr ug ex posur e (aspi r i n, nonster oi dal anti i nf l am m ator y dr ugs, and som e
anti bi oti cs) or ur em i a.
4. What ar e the cl i ni cal m ani f estati ons of v ar i ous bl eedi ng di sor der s?
Al though any of the bl eedi ng di sor der s m ay r esul t i n ex cessi v e hem or r hage
associ ated w i th such ev ents as sur gi cal pr ocedur es, tr aum a, or gastr oi ntesti nal
bl eedi ng, each di spl ay s som e char acter i sti c f eatur es. Vascul ar f r agi l i ty i s
ty pi cal l y associ ated w i th subcutaneous ecchy m oses. Pl asm a coagul ati on pr otei n
def i ci enci es i n pati ents w i th hem ophi l i a ar e associ ated w i th spontaneous sof t
ti ssue and joi nt bl eeds. Other pl asm a f actor def i ci enci es, as w el l as pl atel et
def i ci ts, ar e associ ated w i th di f f use ecchy m oses (cutaneous and sof t ti ssue).
Pl atel et def i ci ts ar e al so m ani f ested by petechi ae (sm al l capi l l ar y hem or r hages
i n m ucosal sur f aces and ar eas of i ncr eased hy dr ostati c pr essur e, such as the
ank l es and f eet) and pur pur a (l ar ger ar eas of hem or r hage). Von Wi l l ebr and's
di sease i s uni que i n that i t m ay pr esent w i th both sof t ti ssue bl eedi ng (f actor
VII def i ci ency ) and m ucosal bl eedi ng (pl atel et dy sf uncti on).
5. What w or k up i s i ndi cated f or a bl eedi ng pati ent?
Ev al uati on of the bl eedi ng pati ent begi ns w i th a good hi stor y tak i ng. It needs
to be deter m i ned i f the condi ti on i s of l ong standi ng or i s new . Questi ons about
pr ev i ous bl eedi ng epi sodes (nosebl eeds, br ui si ng, m enstr ual f l ow , bl eedi ng
w i th tr aum a, sur ger y , and del i v er y ) as w el l as f am i l y hi stor y ar e v i tal f or
deter m i ni ng the natur e of the di sor der . A car ef ul dr ug hi stor y , i ncl udi ng ov er
thecounter dr ug use, m ust be tak en. The pati ent's m edi cal hi stor y and a
r ev i ew of sy m ptom s m ay r ev eal ev i dence of autoi m m une di sor der s or
i nter cur r ent i l l ness.
Phy si cal ex am i nati on i s i m por tant i n ev al uati ng the si tes of bl eedi ng
(cutaneous, m ucosal , sof t ti ssue, or joi nt bl eedi ng si tes, as w el l as petechi ae).
An enl ar ged spl een and ev i dence of l i v er di sease (e. g. , spi der s or
hem angi om ata) or m al nutr i ti on shoul d be sought, and the pati ent's ov er al l
m edi cal condi ti on shoul d be assessed.
A scr eeni ng f or bl eedi ng di sor der s shoul d i ncl ude a pl atel et count, PT, and PTT;
i f any of these r esul ts ar e abnor m al or i f ther e i s ev i dence of m ucosal
bl eedi ng, deter m i nati on of a bl eedi ng ti m e m ay al so be i ndi cated.
If the PT or PTT i s pr ol onged, the nex t step i n the ev al uati on shoul d be a 1:1
m i x i n w hi ch the pati ent's pl asm a i s m i x ed w i th nor m al pl asm a and the PT and
PTT ar e deter m i ned agai n. If the pati ent i s def i ci ent i n som e f actor , the nor m al
pl asm a par ti al l y cor r ects thi s def i ci ency and the PT or PTT ar e cor r ected to a
nor m al v al ue. If an i nhi bi tor to a par ti cul ar f actor i s pr esent, thi s i nhi bi tor al so
bl ock s the acti on of the nor m al pl asm a, and the PT or PTT ar e not cor r ected.
The m ost com m on i nhi bi tor i s the l upus anti coagul ant, w hi ch i s seen i n the
pr esence and absence of autoi m m une di sease; i t i s usual l y
P. 287
associ ated w i th an el ev ated PTT that i s not cor r ected w i th a 1:1 m i x . It i s
associ ated w i th an i ncr eased r i sk of cl otti ng, not bl eedi ng.
If the pl atel et count i s v er y l ow (20, 000/m m 3 ) and the PT and PTT ar e nor m al ,
a bone m ar r ow bi opsy m ay be i ndi cated to deter m i ne w hether ther e ar e
adequate pl atel et pr ecur sor s i n the bone m ar r ow . If pl atel et pr ecur sor s ar e
absent, an under pr oducti on state ex i sts; i f pr ecur sor s ar e pr esent, thi s i m pl i es
that the l ow pl atel et count stem s f r om per i pher al destr ucti on. U si ng the
detecti on of anti pl atel et anti bodi es as ev i dence f or the autoi m m une destr ucti on
of pl atel ets i s not r el i abl e because som e nor m al peopl e hav e anti pl atel et
anti bodi es w i thout per i pher al destr ucti on, w her eas the ti ter s i n peopl e w i th ITP
m ay be l ow .
6. What ther api es ar e av ai l abl e f or the m anagem ent of bl eedi ng di sor der s?
Bl ood com ponents can be used to cor r ect def i ci enci es i n the di v i si ons of the
coagul ati on sy stem . Fr esh f r ozen pl asm a contai ns v ar i ous per centages of each
of the coagul ati on pr otei ns and can be used w hen m or e than one f actor i s
def i ci ent (e. g. , v i tam i n Kâ€“dependent f actor s). Cr y opr eci pi tate contai ns v on
Wi l l ebr and's f actor , f i br i nogen, and f actor VIII, but i s m ost com m onl y used i n
peopl e w i th an acqui r ed f i br i nogen def i ci ency (e. g. , DIC and l i v er di sease).
Because of the r i sk of v i r al i nf ecti on (i t i s pool ed f r om m ul ti pl e donor s),
cr y opr eci pi tate i s no l onger used as f r equentl y f or pati ents w i th m i l d
hem ophi l i a and v on Wi l l ebr and's di sease. Instead, desm opr essi n (DDAVP) i s
now used i n the tr eatm ent of these di seases, as w el l as i n the pl atel et
dy sf uncti on associ ated w i th ur em i a and other qual i tati v e def ects. Thi s dr ug
w or k s by sti m ul ati ng the r el ease of v on Wi l l ebr and's f actor (f actor VIII) f r om
the endothel i um . Ther e ar e al so speci f i c heattr eated f actor concentr ates f or
f actor s VIII and IX, w hi ch can be used i n the m anagem ent of hem ophi l i a.
Quanti tati v e pl atel et pr obl em s caused by under pr oducti on, as w el l as som e
consum pti v e states such as uncontr ol l ed bl eedi ng, can be tr eated w i th pl atel et
tr ansf usi ons. Thi s i s of ten f uti l e i n the setti ng of autoi m m une destr ucti on unti l
the autoi m m une pr ocess i s ar r ested; i n f act, pl atel et tr ansf usi on m ay
accel er ate destr ucti on by sti m ul ati ng the i m m une sy stem . The usual i ni ti al
tr eatm ent f or ITP i s w i th hi ghdose pr edni sone, f ol l ow ed by spl enectom y i f the
pr edni sone f ai l s to bl ock the i m m une destr ucti on. Tr ansf usi ng pl atel ets i nto a
pati ent w ho has ur em i a or w ho i s tak i ng a dr ug that r ender s hi s or her ow n
pl atel ets dy sf uncti onal i s al so f uti l e because the tr ansf used pl atel ets qui ck l y
becom e af f ected as w el l .
Case 1
A 47y ear ol d w hi te m an com es to the em er gency r oom com pl ai ni ng of
hem atem esi s and a 4day hi stor y of abdom i nal pai n and passi ng bl ack , tar r y stool s.
He gi v es a hi stor y of pepti c ul cer di sease that i s l i nk ed to heav y al cohol use, and
thi s w as associ ated w i th one pr ev i ous epi sode of bl eedi ng. He deni es the use of any
m edi cati ons, i ncl udi ng ov er thecounter m edi ci nes, and deni es a f am i l y hi stor y of
bl eedi ng. On r ev i ew of the sy stem s, he descr i bes som e i ncr eased br ui si ng dur i ng
the l ast 2 to 3 m onths. On phy si cal ex am i nati on he i s f ound to be jaundi ced and i n
m oder ate di str ess; al cohol i s sm el l ed on hi s br eath. Hi s sk i n i s r em ar k abl e f or
scatter ed ecchy m oses and spi der angi om as. Hi s l i v er
P. 288
span i s 15 cm and ther e i s som e tender ness pl us a pal pabl e spl een ti p. The pati ent
i s conti nui ng to pass m el ena and v om i t br i ght r ed bl ood.
The f ol l ow i ng i ni ti al l abor ator y v al ues ar e f ound: w hi te bl ood cel l count, 4, 500/m m 3
w i th a nor m al di f f er enti al ; hem ogl obi n, 6. 0 g/dL; hem atocr i t, 18%; pl atel ets,
87, 000/m m 3 ; aspar tate am i notr ansf er ase (AST), 95 m U /m L (nor m al , 0 to 35
m U /m L); al ani ne am i notr ansf er ase (ALT), 40 m U /m L (nor m al , 0 to 38 m U /m L); total
bi l i r ubi n, 3. 5 m g/dL (nor m al , < 1. 0 m g/dL); and al k al i ne phosphatase, 450 m U /m L
(nor m al , 0 to 125 m U /m L).
1. How w oul d y ou pr oceed w i th the ev al uati on of thi s pati ent's bl eedi ng pr obl em ?
2. What bl ood pr oducts, i f any , w oul d y ou gi v e thi s pati ent?
3. What other m edi ci nes, i f any , w oul d y ou gi v e thi s pati ent to m anage hi s
bl eedi ng?
4. What f actor s m ay be contr i buti ng to thi s pati ent's l ow pl atel et count?
Case Discussion
1. How w oul d y ou pr oceed w i th the ev al uati on of thi s pati ent's bl eedi ng pr obl em ?
Whi l e em er gency m edi cal m anagem ent of hi s bl eedi ng i s bei ng pr ov i ded
thr ough the pl acem ent of a nasogastr i c tube, together w i th the i ntr av enous
adm i ni str ati on of f l ui ds f or bl ood pr essur e suppor t as needed and ty pi ng and
cr ossm atchi ng i n pr epar ati on f or the adm i ni str ati on of pack ed r ed bl ood cel l s,
thi s pati ent w i th appar ent chr oni c l i v er di sease needs to hav e hi s coagul ati on
status ev al uated. Both the PT and PTT shoul d be deter m i ned pr om ptl y and
m easur em ent of the f i br i nogen l ev el shoul d be consi der ed because i t can be
decr eased i n the setti ng of chr oni c l i v er f ai l ur e. In thi s case, i f the PT and PTT
pr ov e to be el ev ated, as ex pected, ther e i s pr obabl y l i ttl e r eason f or a 1:1 m i x
i n thi s acutel y i l l pati ent because a def i ci ency state i s v er y l i k el y .
2. What bl ood pr oducts w oul d y ou gi v e thi s pati ent, i f any ?
If hi s PT or PTT pr ov es to be el ev ated, the best bl ood pr oduct f or r epl aci ng the
def i ci ent f actor s i s f r esh f r ozen pl asm a. In addi ti on, i f hi s f i br i nogen l ev el i s
m easur ed and f ound to be l ess than 100 m g/dL, cr y opr eci pi tate m ay al so be
i ndi cated. Fi nal l y , i t m ay becom e necessar y to adm i ni ster pl atel ets i f hi s count
f al l s bel ow 20, 000/m m 3 i n the f ace of acti v e bl eedi ng.
3. What other m edi ci nes, i f any , w oul d y ou gi v e thi s pati ent to m anage hi s
bl eedi ng?
If hi stor y and phy si cal ex am i nati on f i ndi ngs ar e consi stent w i th al cohol i sm and
l i v er di sease, v i tam i n K shoul d al so be gi v en.
4. What f actor s m ay be contr i buti ng to thi s pati ent's l ow pl atel et count?
Hi s l ow pl atel et count m ay stem f r om m ul ti pl e causes. Fi r st, the pl atel et count
can f al l i n the f ace of m assi v e bl eedi ng (consum pti on). Second, he m ay be
chr oni cal l y under pr oduci ng pl atel ets ow i ng to ei ther chr oni c al cohol
suppr essi on of the bone m ar r ow or f ol i c aci d def i ci ency . Fi nal l y , he has an
enl ar ged spl een, w hi ch m ay be sequester i ng hi s pl atel ets.
Case 2
A 35y ear ol d Hi spani c w om an pr esents to the em er gency r oom com pl ai ni ng of a
nosebl eed that has per si sted f or sev er al hour s. She deni es a hi stor y of pr ev i ous
bl eedi ng,
P. 289
al though she has noti ced som e i ncr eased br ui si ng dur i ng the l ast w eek and the
appear ance of a sm al l , pur pl i sh r ash on her f eet and ank l es. She deni es any
ex cessi v e bl eedi ng w i th the del i v er y of her thr ee chi l dr en and has not under gone
any sur gi cal pr ocedur es. She deni es tak i ng aspi r i n, al though she has tak en
acetam i nophen f or r el i ef of a m i l d back ache, and i s on no other m edi cati ons. On
r ev i ew of her sy m ptom s, she deni es ar thr al gi as, ar thr i ti s, f ev er s, col d sy m ptom s,
or other i nf ecti ous sy m ptom s; she has been i n good heal th unti l now . On
ex am i nati on, she i s f ound to be w el l dev el oped and i n no di str ess. Ther e i s som e
f r esh as w el l as dr i ed bl ood obscur i ng the nasal m ucosa; she has no conjuncti v al
hem or r hages but does hav e pal atal petechi ae. Her spl een i s not pal pabl e but ther e
i s a petechi al r ash ar ound both ank l es. Her nosebl eed r equi r es nasal pack i ng f or
contr ol .
The f ol l ow i ng i ni ti al l abor ator y v al ues ar e f ound: w hi te bl ood cel l count, 6, 700/m m 3
w i th a nor m al di f f er enti al ; hem ogl obi n, 14. 2 g/dL; hem atocr i t, 42. 2%; MCV, 85 Âµ 3 ;
pl atel ets, 5, 000/m m 3 ; PT, 11. 5 seconds (contr ol , 12 seconds); and PTT, 28 seconds
(contr ol , 28. 5 seconds).
1. What w oul d y ou do nex t to ev al uate thi s pati ent's bl eedi ng?
2. What r esul ts w oul d y ou ex pect f r om the f ur ther ev al uati on of thi s pati ent's
bl eedi ng?
3. What ther apy w oul d y ou i nsti tute i n thi s pati ent?
Case Discussion
1. What w oul d y ou do nex t to ev al uate thi s pati ent's bl eedi ng?
Wi th the nor m al coagul ati on f i ndi ngs and com pl ete bl ood count, ex cept f or the
pl atel et count, and the absence of other phy si cal f i ndi ngs such as an enl ar ged
spl een, a bone m ar r ow bi opsy i s not essenti al to ev al uate f or m egak ar y ocy tes.
Som e cl i ni ci ans m ay choose to tr eat f or pr esum pti v e ITP and ev al uate the
pati ent i n 24 hour s.
2. What r esul ts w oul d y ou ex pect f r om the f ur ther ev al uati on of thi s pati ent's
bl eedi ng?
Her cl i ni cal pi ctur e i s consi stent w i th that of ITP, and, i n thi s setti ng, an
adequate bone m ar r ow speci m en w oul d show an i ncr eased or nor m al num ber of
m egak ar y ocy tes. If the phy si ci an chooses to tr eat the pati ent em pi r i cal l y f or
ITP (see the f ol l ow i ng tex t), the pati ent shoul d hav e si gni f i cant i m pr ov em ent
(i . e. , pl atel et count â‰￥20, 000 w i th l ess i nci dence of bl eedi ng) i n 24 hour s.
3. What ther apy w oul d y ou i nsti tute i n thi s pati ent?
Pl atel et tr ansf usi ons w oul d not be hel pf ul i n thi s pati ent and m i ght ev en
accel er ate the destr ucti v e pr ocess. Pr edni sone tr eatm ent (60 to 100 m g per
day ) shoul d be i ni ti ated once bone m ar r ow f i ndi ngs conf i r m the di agnosi s or i f
the pati ent i s tr eated em pi r i cal l y .
Case 3
You ar e ask ed to consul t on the case of a 65y ear ol d w hi te m an w i th a hi stor y of
sev er e r heum atoi d ar thr i ti s, w ho has cer v i cal spi ne i nstabi l i ty that now r equi r es
or thopaedi c stabi l i zati on. The pr eoper ati v e l abor ator y r esul ts ar e as f ol l ow s: w hi te
bl ood cel l count, 10, 000/m m 3 w i th a nor m al di f f er enti al ; hem ogl obi n, 12 g/dL;
hem atocr i t, 36%; MCV,
P. 290
86 f L; pl atel ets, 190, 000/m m 3 ; PT, 12 seconds (contr ol , 11. 5 seconds); PTT, 52. 2
seconds (contr ol , 32. 5 seconds); and bl eedi ng ti m e, 10. 5 m i nutes (nor m al , 0 to 9. 5
m i nutes).
The pati ent deni es any bl eedi ng hi stor y , and had under gone a r i ght k nee
r epl acem ent i n the past w i thout di f f i cul ty . He has tak en l ar ge doses of aspi r i n i n
the past, but i s cur r entl y on a nonster oi dal agent and tak es no other m edi ci nes.
Ther e i s no f am i l y hi stor y of bl eedi ng di sor der s. On ex am i nati on, he ex hi bi ts the
sequel ae of sev er e chr oni c r heum atoi d ar thr i ti s, w i th def or m ed joi nts of the hands.
He has no si gni f i cant sk i n l esi ons. Hi s spl een i s not pal pabl e and hi s l i v er i s not
enl ar ged.
1. What f ur ther pr eoper ati v e ev al uati on w oul d y ou do to r eassur e the sur geon
that i ntr aoper ati v e hem ostasi s i s adequate?
2. What bl ood pr oducts, i f any , w oul d y ou use i n thi s pati ent?
3. What changes, i f any , w oul d y ou m ak e i n thi s pati ent's m edi cati ons?
Case Discussion
1. What f ur ther pr eoper ati v e ev al uati on w oul d y ou do to r eassur e the sur geon
that i ntr aoper ati v e hem ostasi s i s adequate?
The pati ent's m ai n coagul ati on abnor m al i ti es i ncl ude a sl i ghtl y pr ol onged
bl eedi ng ti m e and an el ev ated PTT. Hi s m edi cati ons i ncl ude a nonster oi dal
anti i nf l am m ator y agent, w hi ch can r ev er si bl y af f ect pl atel et f uncti on; thi s i s
the m ost l i k el y sour ce of hi s m i l dl y i ncr eased bl eedi ng ti m e. In the absence of
a bl eedi ng hi stor y and i f no em er gency ci r cum stances pr ev ai l , a 1:1 m i x of hi s
el ev ated PTT i s i ndi cated. Hi s hi stor y of a chr oni c i nf l am m ator y condi ti on i s a
str ong i ndi cator to hav e hi s l upus anti coagul ant l ev el deter m i ned.
2. What bl ood pr oducts, i f any , w oul d y ou use i n thi s pati ent?
If a 1:1 m i x does not cor r ect i n r esponse to nor m al pl asm a, thi s i ndi cates the
pr esence of an i nhi bi tor . Hi s cl i ni cal pi ctur e i s consi stent w i th a l upus
anti coagul ant, w hi ch i s actual l y associ ated w i th a r i sk of cl otti ng, not bl eedi ng,
so no bl ood pr oducts ar e i ndi cated. If hi s 1:1 m i x does cor r ect, i m pl y i ng a
def i ci ency state, then speci f i c assay s of f actor l ev el s, i ncl udi ng f actor s VIII
and IX, m ay be necessar y to i denti f y the speci f i c def i ci ency . Thi s i s hi ghl y
unl i k el y i n the absence of cl i ni cal bl eedi ng.
Thi s pati ent's sl i ghtl y pr ol onged bl eedi ng ti m e does not r equi r e any
i nter v enti on.
3. What changes, i f any , w oul d y ou m ak e i n thi s pati ent's m edi cati ons?
Hi s nonster oi dal m edi cati on shoul d be stopped f or at l east 5 to 7 day s bef or e
the spi ne stabi l i zati on pr ocedur e to al l ow nor m al pl atel et f uncti on to r etur n.
Im m edi atel y bef or e sur ger y , hi s bl eedi ng ti m e shoul d be check ed agai n to
conf i r m thi s r etur n to nor m al .
Suggested Readings
Beutl er E, Li chtm an MA, Col ter BS, et al . , eds. Hem atol ogy , 5th ed. N ew Yor k :
McGr aw Hi l l , 1995.
Wi ntr obe MW. Cl i ni cal hem atol ogy , 9th ed. Phi l adel phi a: Lea & Febi ger , 1993.
P. 291
Breast Cancer
1. What i s the i nci dence of br east cancer ?
2. What i s the natur al hi stor y of br east cancer ?
3. What ar e the r i sk f actor s f or br east cancer ?
4. Of w hat does the scr eeni ng f or br east cancer consi st?
5. What i s the TN M cl assi f i cati on, and w hat ar e the stages of br east cancer ?
6. What ar e the pr ognosti c i ndi cator s associ ated w i th br east cancer ?
7. What i s the di f f er ence betw een m odi f i ed r adi cal m astectom y and l um pectom y
pl us r adi ati on ther apy i n the tr eatm ent of stage I and II br east cancer , and
w hat ar e the i ndi cati ons f or each?
8. What i s the r ol e f or adjuv ant chem other apy i n the tr eatm ent of br east cancer ?
9. Of w hat does the tr eatm ent of nodenegati v e br east cancer consi st?
10. What i s the pur pose and the under l y i ng pr i nci pl es of endocr i ne m ani pul ati on i n
the tr eatm ent of m etastati c br east cancer ?
11. What i s the r ol e of sy stem i c chem other apy i n the tr eatm ent of m etastati c
br east cancer ?
Discussion
1. What i s the i nci dence of br east cancer ?
Br east cancer i s the m ost com m on neopl asm i n w om en, w i th an i nci dence that
conti nues to r i se and cur r entl y stands at 1 i n 10 w om en. The i nci dence r i ses
dr am ati cal l y w i th age.
2. What i s the natur al hi stor y of br east cancer ?
Br east cancer i s consi der ed to be a sy stem i c di sease f r om the ti m e of
di agnosi s, r egar dl ess of the stage. The av er age doubl i ng ti m e v ar i es f r om 23
to 500 day s. Ther ef or e, a 1cm tum or m ay hav e ex i sted f or 2 to 17 y ear s
bef or e di agnosi s.
Despi te l ocal contr ol , af f ected pati ents conti nue to di e at a r ate f aster than
that seen i n agem atched contr ol subjects f or the f i r st 30 y ear s af ter
tr eatm ent. In addi ti on, pati ents dy i ng f r om any cause ar e f ound to hav e
ev i dence of tum or at autopsy . The m ost com m on si tes of di stant m etastases
ar e the bone, l i v er , and l ung.
Par aneopl asti c condi ti ons that m ay be associ ated w i th br east cancer i ncl ude
hy per cal cem i a, neur om uscul ar di sor der s, der m atom y osi ti s, acanthosi s
ni gr i cans, and hem ostati c abnor m al i ti es.
Com m on secondar y m al i gnanci es i n pati ents w i th br east cancer consi st of
cancer i n the opposi te br east, ov ar i an cancer , and col or ectal car ci nom a.
3. What ar e the r i sk f actor s f or br east cancer ?
Highris k fa c tors (thr eef ol d or gr eater i ncr ease) f or the dev el opm ent of
br east cancer ar e:
Age gr eater than 50 y ear s
Pr ev i ous cancer i n one br east, especi al l y that occur r i ng pr em enopausal l y
P. 292
Br east cancer i n the f am i l y , al though the r i sk v ar i es dependi ng on
w hether the di sease w as i n a f i r stdegr ee f am i l y m em ber , w as uni l ater al
or bi l ater al , and occur r ed pr em enopausal l y or postm enopausal l y : bi l ater al
and pr em enopausal di sease car r i es an 8. 8 ti m es gr eater r i sk ; bi l ater al
and postm enopausal di sease car r i es a 5. 4 ti m es gr eater r i sk ; uni l ater al
and pr em enopausal di sease car r i es a 3 ti m es gr eater r i sk ; and uni l ater al
and postm enopausal di sease car r i es a 1. 5 ti m es gr eater r i sk
Par i ty . Wom en w ho ar e nul l i par ous or w ho w er e f i r st pr egnant af ter 31
y ear s of age hav e a thr ee to f our ti m es i ncr eased r i sk
Ductal car ci nom a i n si tu car r i es a 30% r i sk of becom i ng i nv asi v e
Cer tai n f or m s of beni gn br east di sease ar e associ ated w i th an i ncr eased
r i sk of cancer Gr oss cy sti c di sease w i th l esi ons ex ceedi ng 3 m m , m ul ti pl e
i ntr aductal papi l l om as, and aty pi cal ductal hy per pl asi a ar e consi der ed
pr em al i gnant
Inte rme dia te ris k fa c tors (1. 2 to 1. 5f ol d i ncr ease) f or the dev el opm ent of
br east cancer consi st of m enstr uati on (ei ther ear l y m enar che or l ate
m enopause); or al estr ogen w i th pr ogester one ther apy ; al cohol consum pti on;
di abetes m el l i tus; hi stor y of cancer of the uter us, ov ar y , or col on; and
obesi ty .
4. Of w hat does the scr eeni ng f or br east cancer consi st?
Wom en ol der than 20 y ear s shoul d per f or m br east sel f ex am i nati on ev er y
m onth. Pr em enopausal w om en shoul d ex am i ne thei r br easts 5 to 7 day s af ter
the end of thei r m enstr ual cy cl e, and postm enopausal w om en shoul d do thi s on
the sam e day of ev er y m onth.
Wom en shoul d hav e thei r br easts ex am i ned by a phy si ci an ev er y 2 to 3 y ear s
betw een the ages of 20 and 40 y ear s and annual l y ther eaf ter . The Am er i can
Cancer Soci ety and other agenci es hav e r ecom m ended that a basel i ne
m am m ogr am shoul d be obtai ned betw een the ages of 35 and 39 y ear s, w i th
m am m ogr am s obtai ned ev er y 1 to 2 y ear s i n w om en aged 40 to 49 y ear s and
then y ear l y af ter the age of 50 y ear s.
5. What i s the TN M cl assi f i cati on, and w hat ar e the stages of br east cancer ?
The TN M (pr i m ar y tum or , r egi onal nodes, m etastases) cl assi f i cati on and the
v ar i ous stages of br east cancer ar e outl i ned i n Tabl e 75.
6. What ar e the pr ognosti c i ndi cator s associ ated w i th br east cancer ?
Tabl e 76 sum m ar i zes the 5 and 10y ear sur v i v al stati sti cs associ ated w i th
the v ar i ous TN M stages. These stati sti cs do not tak e i nto account r esul ts of
adjuv ant chem other apy , but ar e usef ul i n desi gni ng tr i al s usi ng adjuv ant
chem other apy .
The pati ent's hor m onal status al so has a bear i ng on her pr ognosi s, i n that
estr ogen and pr ogester one r eceptor posi ti v e tum or s possess a 70% to 85%
chance of r espondi ng to hor m onal ther apy ; those w om en w i th onl y one
r eceptor posi ti v i ty hav e ex hi bi ted a sl i ghtl y l ow er r esponse r ate to hor m one
m ani pul ati on. Wom en w i th r eceptor negati v e tum or s do not r espond to
hor m one m ani pul ati on.
P. 293
Table 75 The TNM Classification of Breast Cancer
Dis e a s e Ex te nt
Sta ge P rima ry Lymph Node s Dis ta nt TNM

G rouping a Tumor (T) (N) b Me ta s ta s e s Cla s s ific a tion
(M)
0 N oni nv asi v e Hom ol ater al N one Ti s N 0 M1

car ci nom a ax i l l ar y nodes
i n si tu; negati v e (N 0)
Paget's
di sease of
the ni ppl e
(Ti s)
I Gr eatest Hom ol ater al N one T1 N 0 M0

di m ensi on â ax i l l ar y nodes
‰¤2 negati v e (N 0)
cm (T1) c
II Gr eatest Hom ol ater al T1 N 1 M0

di m ensi on ax i l l ar y nodes T2 N 0 or
> 2 cm and â posi ti v e but N 1 M0
‰¤5 cm not . x ed (N 1)
(T2) c
IIIA Gr eatest Hom ol ater al N one T1 N 2 M0

di m ensi on ax i l l ar y nodes T2 N 2 M0
> 5 cm (T3) c posi ti v e and T3 N 0â€“2
. x ed to one M0
another , sk i n,
or chest w al l
(N 2)
IIIB Any si ze Supr acl av i cul ar N one T4 any N M0

w i th (T4) c or Any T N 3 M0
satel l i te i nf r acl av i cul ar
sk i n nodal
nodul es, i nv ol v em ent;
sk i n edem a of the
ul cer ati on, ar m w i th or
f i x ati on to w i thout
sk i n or pal pabl e
chest w al l , ax i l l ar y l y m ph
or edem a nodes (N 3)
of br east,
i ncl udi ng
peau
d'or ange d
IV Any si ze Any status Pr esent Any T any N

M1
a The Am er i can Joi nt Com m i ttee r ecogni zes tw o stage gr oupi ngs:
postoper ati v epathol ogi c (pr esented i n thi s tabl e) and cl i ni cal di agnosti c.
b The cl i ni cal di agnosti c stage gr oupi ng subdi v i des m ov abl e hom ol ater al
ax i l l ar y l y m ph nodes i nto N 1aâ€”nodes not consi der ed to contai n tum or
(appr ox i m atel y 33% ar e hi stol ogi cal l y posi ti v e); and N 1bâ€”nodes
consi der ed to contai n tum or (appr ox i m atel y 25% ar e hi stol ogi cal l y
negati v e).
c T0 i ndi cates no tum or dem onstr abl e i n br easts; T1, T2, and T3 i ncl ude
tum or f i x ati on to under l y i ng pector al f asci a or m uscl e, w hi ch does not
change the cl assi f i cati on of l esi ons. (In f l am m ator y br east cancer i s
cl assi f i ed as a separ ate enti ty and i s not i ncl uded i n T4. )
d Sk i n di m pl i ng and ni ppl e r etr acti on do not af f ect stagi ng cl assi f i cati on.
Adapted f r om the Am er i can Joi nt Com m i ttee f or Cancer Stagi ng and End
Resul ts Repor ti ng, 1983
7. What i s the di f f er ence betw een m odi f i ed r adi cal m astectom y and l um pectom y
pl us r adi ati on ther apy i n the tr eatm ent of stage I and II br east cancer , and
w hat ar e the i ndi cati ons f or each?
Al though m astectom y contr ol s l ocal di sease, i t m ay hav e a dev astati ng

psy chol ogi cal i m pact on both the pati ents and thei r f am i l i es; ther ef or e,
sur gi cal techni ques desi gned to pr eser v e the br east ar e w ar r anted. In 1976,
the N ati onal
P. 294
Sur gi cal Adjuv ant Br east Pr oject (N SABP) began a r andom i zed tr i al com par i ng
total m astectom y , segm ental m astectom y , and segm ental m astectom y pl us
r adi ati on. Al l 1, 843 pati ents under w ent ax i l l ar y node di ssecti on. The 16y ear
f ol l ow up r ev eal ed that l um pectom y i n pati ents w i th tum or s l ess than 4 cm i n
di am eter and w i th f r ee sur gi cal m ar gi ns i s an appr opr i ate f or m of ther apy i n
stage I and II br east cancer . In addi ti on, i r r adi ati on pl us l um pectom y m ar k edl y
decr eases the l i k el i hood of l ocal r ecur r ence. Local r ecur r ence, ev en 10 y ear s
postl um pectom y , does not af f ect ov er al l sur v i v al .
Table 76 Prognostic Indicators for Breast
Cancer
P rognos tic Indic a tors 5 y (% ) 10 y (% )
Cl i ni cal stage
0 > 90 90
I 80 65
II 60 45
IIIA 50 40
IIIB 35 20
IV and i nf l am m ator y br east cancer 10 5
Tum or si ze (cm )
<1 â€” 80
3â€“4 â€” 55
5â€“7. 5 â€” 15
Ax i l l ar y nodes
N one posi ti v e 80 65
1â€“3 posi ti v e 65 40
> 3 posi ti v e 30 15
8. What i s the r ol e f or adjuv ant chem other apy i n the tr eatm ent of br east cancer ?
The l y m ph node status i s the m ost i m por tant pr ognosti c i ndi cator i n thi s
di sease. Pati ents w i th posi ti v e nodes ar e at a hi gh r i sk f or l ocal r ecur r ences as
w el l as m etastati c di sease.
A pr ospecti v e, r andom i zed tr i al show ed that the addi ti on of AC [dox or ubi ci n
(Adr i am y ci n) and cy cl ophospham i de (Cy tox an)] to the tr eatm ent pr otocol
i m pr ov es the 10y ear ov er al l sur v i v al i n both pr em enopausal and
postm enopausal w om en. The addi ti on of a tax ane to thi s r egi m en pr ov i des a
sm al l but stati sti cal l y si gni f i cant i m pr ov em ent i n di seasef r ee sur v i v al . If the
tum or i s hor m one r eceptor posi ti v e, addi ng anti estr ogen tr eatm ent to the
chem other apeuti c r egi m en has been show n i n m ul ti pl e tr i al s to i ncr ease
di seasef r ee sur v i v al , and ov er al l sur v i v al benef i t has been show n.
9. Of w hat does the tr eatm ent of nodenegati v e br east cancer consi st?
Som e pati ents thought to be node negati v e i n the past hav e been f ound to be
node posi ti v e by car ef ul anal y si s usi ng techni ques such as senti nel node
bi opsy . The tr eatm ent of nodenegati v e br east cancer i s sti l l contr ov er si al .
Or i gi nal l y ,
P. 295
w om en w i th negati v e nodes w er e thought to hav e a v er y good pr ognosi s, but
30% w er e sti l l f ound to be dy i ng of the di sease. Gi v i ng ther apy to al l such
pati ents i s not w i thout hazar d; ther ef or e, i t w oul d be of gr eat v al ue to hav e
i ndi cator s that coul d pr edi ct w ho w oul d be good candi dates f or tr eatm ent.
Tests can pr edi ct aggr essi v e tum or s such as i ncr eased cel l s i n the S phase of
the cel l cy cl e and the pr esence of gr ow th f actor m ar k er s such as Her 2 neu.
Other f actor s, such as the si ze of the pr i m ar y tum or , the hi stol ogi c gr ade, and
hor m one r eceptor status, m ay al so be i nf l uenti al . Most studi es now suggest
that pati ents w i th tum or s l ar ger than 1 cm shoul d be of f er ed adjuv ant
chem other apy . Pati ents w i th a l ow gr ade 1. 3 cm tum or that i s estr ogen
r eceptor (ER) and pr ogester one r eceptor (PR) posi ti v e and Her 2 neu negati v e
w oul d show f ar l ess benef i t f r om chem other apy than the sam e si ze tum or that
i s hi gh gr ade and both ER and PR negati v e. Her 2 neuposi ti v e tum or s benef i t
m ost f r om chem other apy and the addi ti on of m onocl onal anti body agai nst the
pr otei n (tr azati nm i b), par ti cul ar l y i f the tum or s ar e l ar ger than 1 cm or show
ev i dence f or aggr essi v e di sease. Tam ox i f en i n pr em enopausal pati ents and
ar om atase i nhi bi tor s i n postm enopausal pati ents hav e been show n to pr otect
pati ents f r om the dev el opm ent of br east cancer and ar e ef f ecti v e i n pr ev enti ng
r ecur r ence i n pati ents w i th sm al l tum or s that ar e node negati v e but posi ti v e
f or estr ogen and/or pr ogester one r eceptor s.
10. What i s the pur pose and the under l y i ng pr i nci pl es of endocr i ne m ani pul ati on i n
the tr eatm ent of m etastati c br east cancer ?
It has been k now n f or m any y ear s that ther e i s an i nter r el ati onshi p betw een
the ov ar i es and the br easts. Pati ents w i th l ocal l y r ecur r ent br east cancer hav e
ex hi bi ted a dr am ati c r esponse to bi l ater al oophor ectom y . Mor e r ecentl y , w i th
the abi l i ty to i denti f y estr ogen r eceptor s i n br east ti ssue, i t w as natur al f or
anti estr ogen ther apy to be used f or the tr eatm ent of br east cancer . The f i r st
tr i al s of hor m onal agents w er e conducted i n pati ents w i th m etastati c di sease,
and they pr ov ed that these agents w er e not onl y ef f i caci ous but al so w el l
tol er ated, w i th w ei ght gai n bei ng the onl y m ajor si de ef f ect. Tam ox i f en can
i ncr ease r i sk of uter i ne cancer and bl ood cl ots; these si de ef f ects ar e not
i ncr eased w i th ar om atase i nhi bi tor s.
Because of thei r success i n the m anagem ent of adv anced di sease, hor m onal
agents hav e been i nsti tuted as adjuv ant ther apy and chem opr ev enti on agents.
Al though the f i ndi ng of estr ogen r eceptor posi ti v i ty consti tutes the gr eatest
adv antage, m any w om en ar e negati v e f or r eceptor s, or thei r status i s
unk now n.
11. What i s the r ol e of sy stem i c chem other apy i n the tr eatm ent of m etastati c
br east cancer ?
Pati ents ar e candi dates f or chem other apy i f thei r di ssem i nated di sease i s
hi ghl y aggr essi v e, they ar e hor m one r eceptor negati v e, or they f ai l to r espond
to endocr i ne m ani pul ati on. Ther e ar e sev er al v ar i ati ons of com bi nati on
chem other apy r egi m ens contai ni ng cy cl ophospham i de, m ethotr ex ate, 5
f l uor our aci l , dox or ubi ci n, pacl i tax el , car bopl ati n, and other agents. The use of
si ngl eagent chem other apy w i th a new dr ug added af ter one f ai l s i s just as
ef f i caci ous as the use of com bi nati on chem other apy , unl ess the ex tent of
di sease r equi r es a m or e r api d r esponse f or qual i ty of l i f e i ssues.
P. 296
Case 1
A 35y ear ol d w hi te w om an w i th a f am i l y hi stor y of br east cancer di scov er s a l um p
i n her r i ght br east. The l um p i s conf i r m ed on phy si cal ex am i nati on and a
m am m ogr am i s then obtai ned. A 1. 7cm l esi on i s i denti f i ed and sam pl ed f or bi opsy .
Pathol ogi c anal y si s of the bi opsy ti ssue r ev eal s an i nf i l tr ati ng ductal car ci nom a. The
pati ent el ects to under go l um pectom y w i th senti nel l y m ph node sam pl i ng f ol l ow ed
by ax i l l ar y node di ssecti on. Tw o of ni ne l y m ph nodes ar e posi ti v e, and estr ogen and
pr ogester one r eceptor studi es ar e negati v e. The hi stol ogi c gr ade of the tum or i s
3/3, and the per centage S phase m easur ed Ki 67 m onocl onal anti body , i s 18. 5%.
The pati ent r ecei v es f our cy cl es of AC, tax ol , then l ocal i r r adi ati on. She has no
ev i dence of di sease and i s seen ev er y 3 m onths f or f ol l ow up.
1. What i s thi s pati ent's TN M cl assi f i cati on and stage?

2. Was l um pectom y an appr opr i ate tr eatm ent?
3. Does thi s pati ent hav e poor pr ognosti c i ndi cator s?
Case Discussion
1. What i s thi s pati ent's TN M cl assi f i cati on and stage?
Thi s pati ent has a T1 l esi on because her pr i m ar y tum or w as l ess than 2 cm .
Her nodal status i s N 1 because tw o of the nodes show ed tum or i nf i l tr ati on but
w er e not pal pabl e at pr esentati on, and her m etastasi s status i s gr aded as M0
because no m etastases w er e f ound. Ther ef or e, she has stage II di sease.
2. Was l um pectom y an appr opr i ate tr eatm ent?
Ev i dence suggests that l um pectom y i s an al ter nati v e to m astectom y i n the
m anagem ent of stage II di sease. Because of her tw o posi ti v e nodes, r adi ati on
ther apy to the ax i l l a i s al so r ecom m ended to l essen her i ncr eased potenti al f or
l ocal r ecur r ence. The f i ndi ng of tw o posi ti v e nodes al so m ak es her a candi date
f or m or e aggr essi v e sy stem i c chem other apy to l i m i t the chance f or
dev el opm ent of di stant m etastases.
3. Does thi s pati ent hav e poor pr ognosti c i ndi cator s?
Thi s pati ent has sev er al poor pr ognosti c f eatur es: her age of 35 y ear s; a hi gh
gr ade tum or m or phol ogy together w i th a hi ghper centage S phase; negati v i ty
f or both r eceptor s; and the posi ti v e nodes. Her chance of sur v i v i ng 10 y ear s
w i th no sy stem ati c tr eatm ent i s appr ox i m atel y 35%, w i th sy stem ati c tr eatm ent
she has a gr eater than 50% 10y ear sur v i v al . N ew studi es suggest that i f she
w er e Her 2 neu posi ti v e her sur v i v al w i thout sy stem ati c tr eatm ent i s l ess than
30%, but the addi ti on of tr astum abi b to her chem other apy m ay actual l y
i m pr ov e sur v i v al com par ed w i th Her 2 neu negati v e pati ents.
Case 2
A 62y ear ol d w om an w as f i r st seen 12 y ear s ago because of a 4cm l ef t br east
m ass. Bi opsy r esul ts r ev eal ed adenocar ci nom a, and the pati ent under w ent a
m odi f i ed r adi cal m astectom y and ax i l l ar y node di ssecti on. Tw o of 22 nodes w er e
posi ti v e, and the tum or w as posi ti v e f or estr ogen and pr ogester one r eceptor s. The
pati ent w as pl aced on chem other apy f ol l ow ed by tam ox i f en ther apy .
P. 297
She di d w el l unti l 6 y ear s ago, w hen r i ght hi p pai n dev el oped. A bone scan r ev eal ed
the pr esence of m etastati c di sease i n her spi ne, r i bs, and r i ght hi p. She w as gi v en
anastr ozol e (Ar i m i dex ; Zeneca Phar m aceuti cal s, Wi l m i ngton, DE), an ar om atase
i nhi bi tor used i n postm enopausal pati ents as hor m onal agent. Four teen m onths
l ater , pai n occur r ed i n her l ef t shoul der and she becam e i ncr easi ngl y l ethar gi c. A
r estagi ng ev al uati on show ed pr ogr essi v e bone scan f i ndi ngs and hy per cal cem i a. She
w as star ted on chem other apy and bi sphosphonates w er e i nsti tuted to tr eat her
hy per cal cem i a acutel y . The pati ent r ecei v ed si x cy cl es of chem other apy , w i th
subsequent stabi l i zati on of her di sease; how ev er , 22 m onths l ater , her di sease
pr ogr essed r api dl y . She w as tr eated w i th tw o other chem other apeuti c r egi m ens, but
af ter i ni ti al stabi l i zati on of her di sease w i th each tr eatm ent, she di ed 36 m onths
l ater .
1. What w as thi s pati ent's or i gi nal TN M cl assi f i cati on and stage?
2. Is her cl i ni cal cour se ty pi cal of br east cancer ?
3. Was a second hor m onal agent w ar r anted?
4. What w as the cause of her hy per cal cem i a, and how shoul d i t be tr eated?
Case Discussion
1. What w as thi s pati ent's or i gi nal TN M cl assi f i cati on and stage?
The pati ent or i gi nal l y had a T2 l esi on because her tum or w as 4 cm , her nodal
status w as N 1 because ax i l l ar y di ssecti on r ev eal ed sev en posi ti v e nodes, and
her m etastasi s status w as M0 because no obv i ous m etastati c l esi ons w er e
di scov er ed. Tak en together , she or i gi nal l y had stage III di sease.
2. Is her cl i ni cal cour se ty pi cal of br east cancer ?
Br east cancer i s consi der ed a chr oni c di sease based on the hy pothesi s that
m i cr om etastases ex i st at the ti m e of di agnosi s. Thi s theor y i s suppor ted by the
obser v ati on that w om en w i th ear l y stage br east cancer sti l l ex hi bi t an
i ncr eased r i sk of dy i ng of thei r di sease despi te cur ati v e i ntent, f or 20 y ear s.
3. Was a second hor m onal agent w ar r anted?
The best pr edi ctor of hor m onal r esponse i s a r esponse to a pr ev i ous hor m onal
agent. In thi s case, the pati ent theor eti cal l y r esponded to tam ox i f en (based on
del ay i n r ecur r ence); ther ef or e, another hor m onal agent w as appr opr i ate, and
thi s pr oduced 14 m onths of f ur ther r esponse.
4. What w as the cause of her hy per cal cem i a, and how shoul d i t be tr eated?
Tw o gener al m echani sm s can br i ng about hy per cal cem i a i n a pati ent w i th
cancer : (a) tum or cel l s i n di r ect contact w i th bone can i nduce an osteol y ti c
m echani sm ; and (b) tum or cel l s can secr ete hum or al substances that acti v ate
osteocl asts.
The f i r st m echani sm pr i m ar i l y oper ates i n br east cancer . Acute i nter v enti on
r equi r es bi sphosphonates w i th f l ui d di ur esi s. How ev er , the pati ent m ust f i r st
be hy dr ated adequatel y bef or e di ur esi s i s star ted, because dehy dr ati on onl y
w or sens the hy per cal cem i a. Tr eatm ent of the under l y i ng cause shoul d then be
i nsti tuted, as w as done i n thi s pati ent w i th chem other apy . Bi sphosphonates not
onl y hel p tr eat hy per cal cem i a but, w i th conti nual use, al so i m pr ov e sy m ptom s
caused by br east m etastases to bone and m ay i m pr ov e sur v i v al .
P. 298
Suggested Readings
Cl ar k GM, Dr essl er LG, Ow ens MA, et al . Pr edi cti on of r el apse or sur v i v al i n
pati ents w i th nodenegati v e br east cancer by DN A f l ow cy tom etr y . N Engl J Med
1989;320:627.
Ear l y Br east Cancer Tr i al i sts' Col l abor ati v e Gr oup. Pol y chem other apy f or ear l y
br east cancer : an ov er v i ew of the r andom i zed tr i al s. Lancet 1998;352:930.
Fi sher B, Costanti no JP, Wi ck er ham DL, et al . Tam ox i f en f or pr ev enti on of
br east cancer : r epor t of the N ati onal Sur gi cal Adjuv ant Br east and Bow el Pr oject
P{}1 Study . J N atl Cancer Inst 1998;90:1371.
Fi sher B, Redm ond C, Poi sson R, et al . Ei ghty ear r esul ts of r andom i zed cl i ni cal
tr i al com par i ng total m astectom y and l um pectom y w i th or w i thout i r r adi ati on i n
the tr eatm ent of br east cancer . N Engl J Med 1989;320:822.
McGui r e WL. Adjuv ant ther apy f or nodenegati v e br east cancer . N Engl J Med
1989;320:525.
Ol i v otto IA, Bajdi k CD, Rav di n PM, et al . Popul ati onbased v al i dati on of the
pr ognosti c m odel ADJU VAN T! f or ear l y br east cancer . J Cl i n Oncol 2005;23:2716.
Chronic Myelogenous Leukemia
1. What i s the def i ni ti on of chr oni c m y el ogenous l euk em i a (CML)?
2. What i s the eti ol ogy of CML?
3. What i s the pathogeni c m echani sm r esponsi bl e f or CML?
4. What i s the epi dem i ol ogy of CML?
5. What ar e the cl i ni cal char acter i sti cs of CML?
6. What ar e the l abor ator y f i ndi ngs encounter ed i n the setti ng of CML?
7. What ar e the cy togeneti c and bi ochem i cal abnor m al i ti es f ound ty pi cal l y i n
pati ents w i th CML?
8. What i s the tr eatm ent f or CML?
9. What i s the pr ognosi s i n pati ents w i th CML?
Discussion
1. What i s the def i ni ti on of CML?
CML i s a hem atopoi eti c stem cel l di sease char acter i zed by anem i a, ex tr em e
bl ood gr anul ocy tosi s, gr anul ocy ti c i m m atur i ty , basophi l i a, of ten
thr om bocy tosi s, and spl enom egal y .
2. What i s the eti ol ogy of CML?
The eti ol ogy of CML i s unk now n, but ex posur e to i oni zi ng r adi ati on has been
f ound to i ncr ease the r i sk of CML abov e the ex pected f r equency i n cer tai n
popul ati ons. Som e of these m ajor popul ati ons ar e (a) the Japanese ex posed to
r adi ati on f r om the N agasak i and Hi r oshi m a atom i c bom b ex pl osi ons; (b) the
Br i ti sh w i th ank y l osi ng spondy l i ti s tr eated w i th spi nal i r r adi ati on; and (c)
w om en w i th uter i ne cer v i cal car ci nom a w ho r equi r e r adi ati on ther apy . The
f r equency of CML (as w el l as acute l euk em i a) i n these popul ati ons i s
si gni f i cantl y gr eater than that ex pected f or com par abl e unex posed gr oups.
Chem i cal l euk em ogens hav e not been i denti f i ed as causati v e agents of CML.
P. 299
3. What i s the pathogeni c m echani sm r esponsi bl e f or CML?
CML r esul ts f r om the acqui r ed (som ati c m utati on) m al i gnant tr ansf or m ati on of
a si ngl e stem cel l w hose potency dom i nates hem atopoi esi s i n the af f ected
per son, w i th the i nv ol v em ent of er y thr opoi esi s, neutr ophi l opoi esi s,
eosi nophi l opoi esi s, basophi l opoi esi s, m onocy topoi esi s, and thr om bopoi esi s.
Sev er al obser v ati ons suggest that som e l y m phocy tes m ay be der i v ed f r om the
pr i m or di al m al i gnant cel l as w el l , ther eby pl aci ng the cul pr i t l esi on cl oser , i f
not i n the pl ur i potenti al stem cel l . The ex act m echani sm that causes the
tr ansf or m ati on to tak e pl ace has not been f ul l y el uci dated, but the Ph 1
(Phi l adel phi a) chr om osom e has been i m pl i cated. The hem atopoi eti c cel l s
contai n a r eci pr ocal tr ansl ocati on betw een chr om osom es 9 and 22 i n m or e than
90% of pati ents. Thi s l eads to an ov er tl y f or eshor tened l ong ar m of one of the
chr om osom e 22 pai r s. Chr om osom e 9 contai ns the cabl gene at band 34;
chr om osom e 22 has the br eak poi nt cl uster r egi on (bcr ) and csi s genes at
band 11. The cabl gene f r om chr om osom e 9 i s tr anspor ted to the chr om osom e
22 bcr , w hi ch i s the Ph 1 chr om osom e. As a consequence of these ev ents, a new
gene i s f or m ed, the bcr abl gene, w hi ch codes f or a new pr otei n thr ough the
f or m ati on of a new m essenger RN A. In som e uses the chr om osom al
abnor m al i ty i s not ev i dent but the bcr abl gene i s i denti f i ed by i n si tu by
hy br i di zati on. Thi s new pr otei n i s a phosphopr otei n w i th a m ol ecul ar w ei ght of
210, 000 (DaP210 bcr abl ) and possessi ng ty r osi ne k i nase acti v i ty . Its abnor m al
acti v i ty pr esum abl y al ter s the r esponse of the hem atopoi eti c stem cel l so that
i t conti nues to pr ol i f er ate r ather than bei ng under the contr ol of hem atopoi eti c
gr ow th f actor s.
4. What i s the epi dem i ol ogy of CML?
CML accounts f or appr ox i m atel y 2% of al l cases of l euk em i a and the associ ated
m or tal i ty r ate i s appr ox i m atel y 1. 5 per 100, 000 popul ati on per y ear . The
di sease occur s sl i ghtl y m or e of ten i n m en, but i ts m ani f estati ons and cour se
ar e si m i l ar f or both sex es. Appr ox i m atel y 10% of the cases occur i n peopl e
betw een 5 and 20 y ear s of age, and CML accounts f or appr ox i m atel y 3% of al l
the chi l dhood l euk em i as.
5. What ar e the cl i ni cal char acter i sti cs of CML?
The di sease i s char acter i zed by thr ee phases: (a) a chr oni c phase, (b) an
accel er ated phase, and (c) a bl ast cr i si s.
The m ost f r equent com pl ai nts seen dur i ng the c hronic pha s e i ncl ude easy
f ati gabi l i ty , l oss of a sense of w el l bei ng, decr eased tol er ance to ex er ti on,
anor ex i a, abdom i nal di scom f or t, ear l y sati ety , w ei ght l oss, and ex cessi v e
sw eati ng. The sy m ptom s ar e v ague, nonspeci f i c, and gr adual i n onset. Phy si cal
ex am i nati on m ay detect pal l or and spl enom egal y .
U ncom m on pr esenti ng si gns and sy m ptom s of CML i ncl ude hy per m etabol i sm
that si m ul ates thy r otox i cosi s, acute gouty ar thr i ti s, pr i api sm , ti nni tus, stupor ,
l ef t upper quadr ant and l ef t shoul der pai n as a consequence of spl eni c
i nf ar cti on and per i spl eni ti s, di abetes i nsi pi dus, and acute ur ti car i a, w hi ch i s
associ ated w i th hy per hi stam i nem i a.
In som e pati ents i n thi s phase, the di sease i s di scov er ed w hen bl ood cel l
counts ar e deter m i ned dur i ng a r outi ne m edi cal ex am i nati on. The sy m ptom s
P. 300
and si gns of the di sease and the l abor ator y f i ndi ngs ty pi cal l y r em ai n stabl e,
and the dur ati on of thi s phase i s v ar i abl e. U sual l y i t l asts appr ox i m atel y 4
y ear s, but i t can l ast f r om w eek s to m any y ear s bef or e tr ansf or m i ng to the
accel er ated phase.
In m ost cases of CML, the pati ent's di sease ev entual l y changes to a m or e
aggr essi v e, sy m ptom ati c, and tr oubl esom e f or m (the a c c e le ra te d pha s e ) that
r esponds poor l y to ther apy that f or m er l y contr ol l ed the chr oni c phase. Thi s
m etam or phosi s i s of ten gr adual and m ani f ested by r ef r actor y spl enom egal y ;
ex tr am edul l ar y tum or m asses; changes i n the bl ood, bone m ar r ow , and
di f f er enti al cel l counts; and new cy togeneti c abnor m al i ti es. The onset of f ev er
w i thout i nf ecti on, w eak ness, ni ght sw eats, w ei ght l oss, ar thr al gi as, and bone
or l ef t upper quadr ant pai n m ay occur bef or e ther e i s l abor ator y ev i dence of
the accel er ated phase. These l abor ator y abnor m al i ti es i ncl ude a decr ease i n
the hem ogl obi n content w i th i ncr easi ng r ed bl ood cel l abnor m al i ti es, an abr upt
i ncr ease or f al l i n the w hi te bl ood cel l count w i thout tr eatm ent, and an
i ncr ease i n the num ber of bl ast or i m m atur e cel l s. Thr om bocy tosi s or
thr om bocy topeni a and an i ncr ease i n the num ber of basophi l s or eosi nophi l s
ar e al so seen.
The bla s tic pha s e can be m ani f ested by an ex tr am edul l ar y bl ast i nf i l tr ati on or
by a bone m ar r ow bl ast cr i si s.
An ex tr am edul l ar y bl ast cr i si s i s the f i r st m ani f estati on of the accel er ated
phase i n appr ox i m atel y 10% of pati ents, and thi s pr i nci pal l y i nv ol v es the
l y m ph nodes, ser osal sur f aces, sk i n and sof t ti ssue, br easts, and the CN S.
Bone i nv ol v em ent m ay l ead to sev er e pai n, tender ness, and r adi ogr aphi c
changes. The CN S i nv ol v em ent i s usual l y m eni ngeal and m ay be pr eceded by
headache, v om i ti ng, stupor , cr ani al ner v e pal si es, and papi l l edem a; i t i s
associ ated w i th an i ncr ease i n the num ber of cel l s and the pr otei n l ev el , as
w el l as the pr esence of bl ast cel l s i n the spi nal f l ui d.
Acute l euk em i a, the bl ast phase, dev el ops i n m ost pati ents w i th CML, and thi s
can tak e f r om day s to y ear s to occur af ter the di agnosi s of CML dependi ng on
the ef f ecti v eness of i ni ti al tr eatm ent. The si gns and sy m ptom s ar e f ev er ,
hem or r hage, bone pai n, and l y m phadenopathy , as w el l as the other
m ani f estati ons al r eady ci ted. The bl asti c tr ansf or m ati on i s usual l y m y el obl asti c
or m y el om onocy ti c, but can be er y thr ocy ti c or l y m phoi d i n natur e. Speci al
stai ni ng techni ques, bi ochem i cal assay s, or m onocl onal anti body
deter m i nati ons ar e needed to i denti f y the ty pe of tr ansf or m ati on once the
pati ent i s i n the bl asti c phase. Pati ents usual l y di e w i thi n w eek s to m onths.
The m edi an sur v i v al i n pati ents i n the m y el oi d bl ast cr i si s i s appr ox i m atel y 6
to 12 m onths, and that i n pati ents i n the l y m phoi d bl ast cr i si s i s 12 m onths,
w i th sur v i v al bey ond 2 y ear s unusual . Sev er e i nf ecti ons, hem or r hage, and
or gan dy sf uncti on, especi al l y of the l i v er and k i dney , ar e am ong the l eadi ng
causes of death.
6. What ar e the l abor ator y f i ndi ngs encounter ed i n the setti ng of CML?
The di agnosi s of CML can be m ade on the basi s of the he ma tologic findings ,
speci f i cal l y those y i el ded by the bl ood count and the bl ood sm ear . Com m on
f i ndi ngs ar e a decr ease i n the hem atocr i t; the pr esence of nucl eated r ed bl ood
cel l s i n the ci r cul ati on; a l euk ocy te count that i s al w ay s el ev ated,
P. 301
of ten ex ceedi ng 1, 000 Ã— 10 9 /L; the pr esence of al l stages of gr anul ocy te
dev el opm ent i n the bl ood w i th a gener al l y nor m al appear ance; and a bl ast cel l
pr ev al ence r angi ng f r om 0. 5% to 5%. My el ocy tes, m etam y el ocy tes, and band
f or m s account f or appr ox i m atel y 40%. The num ber of basophi l s i s i ncr eased,
as i s the total absol ute l y m phocy te count (m ean, appr ox i m atel y 15 Ã— 10 9 /L).
In addi ti on, the pl atel et count i s el ev ated i n appr ox i m atel y 50% of pati ents at
the ti m e of di agnosi s; pl atel et counts m or e than 1, 000 Ã— 10 9 /L ar e not
unusual ; and neutr ophi l al k al i ne phosphatase acti v i ty i s l ow or absent i n m or e
than 90% of pati ents. The def ects i n w hi te cel l adhesi on, em i gr ati on, and
phagocy tosi s ar e m i l d and com pensated f or by hi gh neutr ophi l concentr ati ons,
and ther ef or e do not pr edi spose pati ents i n the chr oni c phase to i nf ecti ons.
Pl atel et dy sf uncti on can occur but i s not associ ated w i th spontaneous or
ex agger ated bl eedi ng, as w i th other m y el opr ol i f er ati v e di sor der s.
In ter m s of the morphologic findings , the bone m ar r ow i s m ar k edl y

hy per cel l ul ar and hem atopoi eti c ti ssue tak es up 75% to 90% of the m ar r ow
v ol um e. Gr anul opoi esi s i s dom i nant, w i th a gr anul ocy ti câ€“er y thr oi d r ati o of
betw een 10 and 30:1 (nor m al , 2 to 4:1). Er y thr opoi esi s i s usual l y decr eased,
the m egak ar y ocy tes ar e nor m al or i ncr eased i n num ber , and the popul ati on of
eosi nophi l s and basophi l s m ay be i ncr eased.
7. What ar e the cy togeneti c and bi ochem i cal abnor m al i ti es ty pi cal l y f ound i n
pati ents w i th CML?
The Ph 1 chr om osom e, desi gnated t(9;22)(q34;q11), i s pr esent i n m or e than

90% of pati ents w i th CML. Dur i ng the bl ast phase, m ost pati ents ex hi bi t
addi ti onal chr om osom e abnor m al i ti es, usual l y a + 8, the gai n of a second Ph 1
chr om osom e, or r ar el y a chr om osom e l oss (7).
Var i ant Ph 1 chr om osom e tr ansl ocati ons occur i n appr ox i m atel y 5% of pati ents
and usual l y consi st of com pl ex r ear r angem ents. Ev er y chr om osom e i s i nv ol v ed
ex cept the Y chr om osom e. Ther e i s a sm al l gr oup of pati ents w i th CML w ho do
not hav e the Ph 1 chr om osom e, but v i r tual l y al l pati ents hav e an abnor m al
chr om osom e 22 w i th bcr r ear r angem ents. The char acter i sti c bi ochem i cal
abnor m al i ti es consi st of an i ncr ease i n the ur i c aci d l ev el , an i ncr ease i n the
ser um l ev el of cobal am i nbi ndi ng capaci ty , a r ai sed cobal am i n concentr ati on,
an i ncr ease i n the LDH l ev el , pseudohy per k al em i a (an i n v i tr o hy per k al em i a
secondar y to K + r el ease f r om pl atel ets), pseudohy pogl y cem i a (secondar y to
l euk ocy te uti l i zati on i n v i tr o), hy per cal cem i a, hy per gam m agl obul i nem i a, and
l ow l euk ocy te al k al i ne phosphatase acti v i ty .
8. What i s the tr eatm ent f or CML?
Al l the bi ochem i cal al ter ati ons m ust be cor r ected. The hy per ur i cem i a m ust be
tr eated w i th adequate hy dr ati on and al l opur i nol . How ev er , the speci f i c
tr eatm ent f or the di sease depends on the stage and goal of ther apy .
For c he mothe ra py, hy dr ox y ur ea i s used m ost of ten because i t has f ew er si de

ef f ects than al k y l ati ng agents, w hi ch can i nduce apl asti c anem i a and acute
l euk em i a i n pati ents w i th CML. Hy dr ox y ur ea tr eatm ent has a m i ni m al ef f ect on
sur v i v al , contr ol s the hem atol ogi c al ter ati ons (w i thout suppr essi ng the Ph 1
chr om osom e), and i m pr ov es the pati ent's qual i ty of l i f e.
P. 302
Both Î± and Î³inte rfe rons hav e show n anti l euk em i c acti v i ty i n the setti ng of
CML; Î± i nter f er on pr oduces a nor m al i zati on of bl ood counts i n appr ox i m atel y
75% of pati ents and suppr esses the Ph 1 chr om osom e i n appr ox i m atel y 15% of
tr eated pati ents. The Ph 1 negati v e cel l al so l ack s the bcr r ear r angem ents.
Dr aw back s to i nter f er on tr eatm ent ar e that m ai ntenance ther apy i s r equi r ed
and i t i s not f r ee of si de ef f ects. Som e studi es suggest that the pr ol onged use
of i nter f er on (i . e. , > 1 y ear ) i n r esponder s m ay m ak e pati ents l ess r esponsi v e
to bone m ar r ow tr anspl antati on.
Most r ecentl y , ty r osi ne k i nase i nhi bi tor s, especi al l y i m ati ni b can l ead to a
bi ol ogi c r esponse (nor m al m ol ecul ar f i ndi ngs) i n m or e than 50% of pati ents.
These pati ents m ay r em ai n i n r em i ssi on f or 5 y ear s or m or e al though som e
pati ents ar e star ti ng to show r ecur r ence. Spl eni c irra dia tion m ay be usef ul to
contr ol spl enom egal y and to pal l i ate the sy m ptom s r esul ti ng f r om i t.
Sple ne c tomy m ay be usef ul i n car ef ul l y sel ected pati ents w i th sy m ptom ati c
thr om bocy topeni a, w ho do not r espond to chem other apy and hav e a gr eatl y
enl ar ged spl een; how ev er , i t i s onl y a pal l i ati v e m easur e.
Al l ogenei c bone m ar r ow tr anspl antati ons can be usef ul i n the tr eatm ent of
som e pati ents w i th CML. Thi s tr eatm ent can er adi cate the Ph 1 car r y i ng cl one
and has l ed to an appar ent cur e of som e pati ents w i th CML. How ev er , success
w i th agents such as i m ati ni b and the hi gh tox i ci ty r esul ti ng f r om the
pr ocedur e, par ti cul ar l y i n those w ho l ack sui tabl e donor s or ar e of adv anced
age, l i m i t i ts use.
Le uk a phe re s is can be usef ul i n tw o ty pes of pati ents: pr egnant w om en w i th a
v er y hi gh w hi te bl ood cel l count and hy per l euk ocy ti c pati ents w ho need r api d
cy tor educti on to al l ev i ate the si gns and sy m ptom s of l euk ostasi s.
9. What i s the pr ognosi s i n pati ents w i th CML?
In pati ents w i th CML w ho do not attai n a cy togeneti c r esponse, the m edi an
sur v i v al r anges f r om 45 to 60 m onths. Wi th i m pr ov ed i ni ti al ther apy
appr ox i m atel y 60% to 80% of pati ents sur v i v e 5 y ear s, and 40% sur v i v e 8
y ear s.
Case
A 37y ear ol d w hi te m an i s seen because of l ack of ener gy , ni ght sw eats, and poor
appeti te w i th a sensati on of f ul l ness af ter eati ng ev en v er y sm al l am ounts of f ood.
Phy si cal ex am i nati on r ev eal s si gns of anem i a, spl enom egal y , and the ex i stence of
petechi ae. A com pl ete bl ood count i s per f or m ed and y i el ds the f ol l ow i ng f i ndi ngs:
hem atocr i t, 25%; pl atel ets, 300, 000/m m 3 , and w hi te bl ood cel l s, 72, 000/m m 3 . A
bone m ar r ow bi opsy i s per f or m ed and the speci m en i s f ound to ex hi bi t a
gr anul ocy ti câ€“er y thr oi d r ati o of 10:1 w i th 100% cel l ul ar i ty and 1% bl astocy tes.
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, based on the phy si cal
ex am i nati on f i ndi ngs?
2. On the basi s of the hem atol ogi c f i ndi ngs, w hat hem atopoi eti c abnor m al i ti es
w oul d y ou ex pect i n thi s pati ent w i th suspected CML?
3. What do the bone m ar r ow f i ndi ngs i ndi cate i n thi s pati ent?
P. 303
4. What w oul d be the m ost speci f i c test f or establ i shi ng the di agnosi s of CML i n
thi s pati ent?
5. If the pati ent i s star ted on si ngl eagent chem other apy , w hat w oul d be the
l i k el y ef f ect?
Case Discussion
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, based on the phy si cal
ex am i nati on f i ndi ngs?
When the di agnosi s of CML i s consi der ed, other possi bi l i ti es, such as a sol i d
cancer , l y m phom as, and chr oni c i nf ecti ons m ust be ex cl uded. These other
di seases m ay cause a l euk em oi d r eacti on by i ncr eased sti m ul ati on of nor m al
m y el opoi esi s. U sual l y a l euk em oi d r eacti on r esul ts i n a w hi te bl ood cel l count
of l ess than 100, 000/m m 3 , and l ess than 10% of cel l s ar e m y el ocy tes or m or e
i m m atur e f or m s.
Because nor m al hem atopoi esi s i s suppr essed, the pati ent coul d ex hi bi t the
si gns and sy m ptom s of anem i a, such as headache, pal pi tati ons, pal l or , and
car di ac f ai l ur e. Ver y r ar el y , l y m ph node enl ar gem ent i s f ound i n pati ents w i th
CML. Spl enom egal y i s al m ost the r ul e i n pati ents w i th CML, and i t i s the sour ce
of poor appeti te and upper abdom i nal pai n, such as that seen i n thi s pati ent.
Fi nal l y , petechi ae, al though possi bl e, ar e not v er y f r equent f i ndi ngs i n pati ents
w i th CML.
2. On the basi s of the hem atol ogi c f i ndi ngs, w hat hem atopoi eti c abnor m al i ti es
w oul d y ou ex pect i n thi s pati ent w i th suspected CML?
N or m al hem atopoi esi s i s suppr essed by the l euk em i c acti v i ty i n the bone
m ar r ow , l eadi ng to a decr eased num ber of r ed bl ood cel l s, as w el l as
decr eased hem ogl obi n l ev el and hem atocr i t. Ty pi cal l y , the anem i a of CML i s
nor m ochr om i c nor m ocy ti c. Hy pochr om i c m i cr ocy ti c anem i a i s ty pi cal of i r on
def i ci ency .
Al though i m m atur e, m ost of the w hi te bl ood cel l s l ook m or phol ogi cal l y nor m al ,
and m atur e neutr ophi l s, band f or m s, m etam y el ocy tes, and m y el ocy tes
consti tute m ost of the w hi te bl ood cel l s i n thi s pati ent. Another char acter i sti c
f i ndi ng i s an i ncr eased num ber of basophi l s. If m ost of the cel l s ar e bl asts,
thi s i ndi cates acute l euk em i a i n m ost cases, al though i t can al so i ndi cate that
the pati ent i s i n the bl asti c phase of CML.
3. What do the bone m ar r ow f i ndi ngs i ndi cate i n thi s pati ent?
The bone m ar r ow f i ndi ngs ar e consi stent w i th a di agnosi s of CML, and bone
m ar r ow bi opsy consti tutes an i m por tant par t of the di agnosti c ev al uati on i n
pati ents w i th any k i nd of l euk em i a (acute and chr oni c). N or m al l y , the
gr anul ocy ti câ€“er y thr oi d r ati o r anges f r om 2 to 4:1, but, i n the setti ng of CML,
cel l s of w hi te l i neage pr edom i nate and i ncr em ents of any f or m of w hi te bl ood
cel l s, f r om m y el obl asts to m atur e neutr ophi l s, can be f ound. An i ncr em ent i n
l y m phocy tes and r ed bl ood cel l pr ecur sor s i s not char acter i sti c of CML. The
nor m al bone m ar r ow cel l ul ar i ty i s 50% f at and 50% or l ess cel l s, but, i n the
l euk em i as, the accel er ated pr oducti on of abnor m al cel l s causes the f at to be
r epl aced, and the cel l ul ar i ty i ncr eases to 100%. Fi nal l y , ev en i n nor m al bone
m ar r ow , a v er y sm al l num ber of bl ast cel l s can be f ound; i n CML, a sm al l
per centage of bl ast cel l s can be f ound, but thi s does not
P. 304
necessar i l y si gni f y acute l euk em i a. In bl ast cr i si s or acute l euk em i a, at l east
20% of the cel l s i n the bone m ar r ow ar e bl ast cel l s.
4. What w oul d be the m ost speci f i c test f or establ i shi ng the di agnosi s of CML i n
thi s pati ent?
The m ost speci f i c test f or establ i shi ng the di agnosi s of CML i s a cy togeneti c
i nv esti gati on f or the Ph 1 chr om osom e, or t(9;22), w hi ch i s f ound i n 90% of
cases of CML. Of the r em ai ni ng 10% at l east hal f w i l l hav e bcr r ear r angem ents
m easur ed by i n si tu by hy br i di zati on.
5. If the pati ent i s star ted on si ngl eagent chem other apy , w hat w oul d be the
l i k el y ef f ect?
The chem other apeuti c agent m ost com m onl y used i n the tr eatm ent of CML i s
hy dr ox y ur ea. Thi s ther apy can i m pr ov e the pati ent's qual i ty of l i f e by r api dl y
decr easi ng the num ber of w hi te bl ood cel l s and pl atel ets. It does not pr ol ong
sur v i v al v er y m uch, i f at al l , i n pati ents w i th CML. The i nter f er ons can i nduce
com pl ete hem atol ogi c and cy togeneti c r em i ssi ons, w i th suppr essi on of the Ph 1
chr om osom e i n pati ents w i th CML. Most i m por tantl y ty r osi ne k i nase i nhi bi tor s
hav e hi gh i nci dence of bi ol ogi c r esponses and l ess tox i ci ty .
Al l ogenei c bone m ar r ow tr anspl antati on has been the onl y cur ati v e tr eatm ent
f or CML but has a hi gh r ate of com pl i cati ons. Adv anced age and the l ack of
sui tabl e donor s pr ecl ude i ts use i n m any pati ents, but i t m ay be the ther apy of
choi ce i n thi s 37y ear ol d m an i f he does not attai n a bi ol ogi c r em i ssi on or
r el apses af ter thi s r em i ssi on i s attai ned.
Suggested Readings
Canel l os G. Cl i ni cal char acter i sti cs of the bl ast phase of chr oni c m y el ogenous
l euk em i a. Hem atol Oncol Cl i n N or th Am 1990;4:359.
Kur zr ock R, Gutter m an JU , Tal paz M. The m ol ecul ar geneti cs of Phi l adel phi a
chr om osom e posi ti v e l euk em i as. N Engl J Med 1988;319:990.
Qui ntasCar dam a A, Cor tes JE. Chr oni c m y el oi d l euk em i a: di agnosi s and
tr eatm ent. May o Cl i n Pr oc 2006;81:973.
Rei ter E, Gr ei ni x HT, Br ugger S, et al . Long ter m f ol l ow up af ter al l ogenei c stem
cel l tr anspl antati on f or chr oni c m y el ogenous l euk em i a. Bone Mar r ow Tr anspl ant
1998;4:S86.
Rodr i guez J, Cor tes J, Sm i th T, et al . Deter m i nati ons of pr ognosi s i n l ate
chr oni cphase chr oni c m y el ogenous l euk em i a. J Cl i n Oncol 1998;16:3782.
Colon Cancer
1. What i s the i nci dence of col on cancer ?
2. What ar e som e of the k now n r i sk f actor s f or col on cancer ?
3. Shoul d pati ents be scr eened f or col on cancer ?
4. What i s the cur r ent tr eatm ent f or pr i m ar y col on cancer ?
5. What stagi ng pr ocedur es need to be done to adequatel y stage a pati ent w i th
col on cancer ?
6. What i s the stagi ng sy stem f or col on cancer ?
P. 305
7. What i s the pr ognosi s f or pati ents w i th col on cancer , based on thei r stage?
8. What shoul d the f ol l ow up consi st of i n pati ents w i th col on cancer af ter they
hav e under gone pr i m ar y sur gi cal r esecti on f or cur ati v e i ntent?
9. Ar e ther e any ef f ecti v e adjuv ant tr eatm ents to decr ease the r i sk of r ecur r ence
i n pati ents w i th col on cancer w ho hav e under gone r esecti on?
10. Is ther e any ef f ecti v e chem other apy f or pati ents w i th m etastati c di sease?
Discussion
1. What i s the i nci dence of col on cancer ?
Ther e ar e m or e than 140, 000 new cases of col on cancer each y ear i n the
U ni ted States. It af f ects appr ox i m atel y 1 of ev er y 20 peopl e i n Wester n
cul tur es and accounts f or 15% of al l cancer s. In the U ni ted States, the actual
i nci dence r ate i s appr ox i m atel y 35 cases per 100, 000 popul ati on per y ear .
2. What ar e som e of the k now n r i sk f actor s f or col on cancer ?
Ther e ar e sev er al i nher i ted col oni c pol y posi s sy ndr om es associ ated w i th an
i ncr eased r i sk of cancer of the l ar ge bow el . The m ost i m por tant one i s the
f am i l i al adenom atosi s sy ndr om e, w hi ch i s i nher i ted as an autosom al dom i nant
tr ai t. In af f ected peopl e, pol y ps dev el op ov er the enti r e l ength of the col on by
30 y ear s of age. If a total col ectom y i s not per f or m ed, the cancer r ate
escal ates to as hi gh as 80% to 90% by 45 y ear s of age. Ther e ar e al so other ,
l essf r equent pol y posi s sy ndr om es pr edi sposi ng to col on cancer .
Ther e appear s to be a cer tai n geneti c tendency tow ar d col on car ci nom a that i s
i ndependent of the i nher i ted pol y posi s sy ndr om es. Fi r stdegr ee r el ati v es of
peopl e w i th col on cancer di agnosed bef or e the age of 60 hav e a tw o to
thr eef ol d gr eater chance of acqui r i ng col on cancer than the gener al popul ati on.
Pati ents w i th i nf l am m ator y bow el di sease ar e al so at i ncr eased r i sk f or col on
cancer . Those w i th ul cer ati v e col i ti s hav e appr ox i m atel y a 50% to 60% chance
f or dev el opm ent of l ar ge bow el car ci nom a i f a col ectom y i s not per f or m ed.
Cr ohn's di sease i s al so associ ated w i th an i ncr eased r i sk of col on cancer , but
to a m uch l esser degr ee than ul cer ati v e col i ti s.
The f i ndi ngs f r om sev er al popul ati on studi es hav e suggested that di et pl ay s a
l ar ge r ol e i n the dev el opm ent of col on cancer . Cul tur es i n w hi ch the popul ace
consum es a hi ghf at, l ow f i ber di et ex hi bi t an i ncr eased i nci dence of col on
cancer , com par ed w i th cul tur es i n w hi ch a l ow f at, hi ghf i ber di et i s consum ed.
Dai l y aspi r i n m ay hel p pr ev ent col on cancer .
3. Shoul d pati ents be scr eened f or col on cancer ?
The pr ognosi s f or col on cancer i s dr am ati cal l y i m pr ov ed the ear l i er i t i s
detected and tr eated. Scr eeni ng pr ogr am s ar e ai m ed at detecti ng col on cancer s
at an ear l y stage and hav e l ed to an i m pr ov em ent i n sur v i v al and i n the r i sk of
r el apse. Most scr eeni ng pr ogr am s ar e usual l y di r ected at popul ati ons w i th a
hi gh r i sk f or col on cancer , i ncl udi ng the gr oups al r eady m enti oned.
Scr eeni ng techni ques f or col on cancer com pr i se di gi tal r ectal ex am i nati on, the
testi ng of stool f or occul t bl ood, si gm oi doscopy w i th an ai r contr ast bar i um
enem a, and col onoscopy . Recom m endati ons ar e that peopl e shoul d be check ed
P. 306
f or occul t bl ood at 50 y ear s of age and y ear l y ther eaf ter , w i th col onoscopy
al so per f or m ed at 50 y ear s and ev er y 5 to 10 y ear s, i f negati v e ther eaf ter .
4. What i s the cur r ent tr eatm ent f or pr i m ar y col on cancer ?
The pr i m ar y tr eatm ent f or col on cancer i s sur gi cal . Once the cancer has been
di agnosed and pr eoper ati v e stagi ng per f or m ed, the pati ent shoul d be r ef er r ed
to an oncol ogi c sur geon f or def i ni ti v e tr eatm ent. The ex act sur gi cal appr oach
used i s di ctated by the tum or 's l ocati on i n the col on. For tr ue col on cancer s
(i . e. , cancer s abov e the per i toneal r ef l ecti on), a hem i col ectom y i s usual l y
per f or m ed. For r ectal car ci nom as (i . e. , tum or s bel ow the per i toneal
r ef l ecti on), a l ow anter i or r esecti on or an abdom i noper i neal r esecti on i s
per f or m ed. Regar dl ess of the sur gi cal pr ocedur e, a thor ough ex pl or ati on of the
enti r e abdom en, i ncl udi ng the l i v er , shoul d be car r i ed out and any suspect
l esi ons sam pl ed f or bi opsy .
5. What stagi ng pr ocedur es need to be done to adequatel y stage a pati ent w i th
col on cancer ?
The pr eoper ati v e stagi ng ev al uati on of pati ents w i th col on cancer i ncl udes
hi stor y tak i ng, phy si cal ex am i nati on, com pl ete bl ood count, l i v er f uncti on
tests, the car ci noem br y oni c anti gen (CEA) l ev el , and a chest r adi ogr aph.
Bef or e sur ger y f ur ther i nv esti gati on by com puted tom ogr aphi c (CT) scanni ng or
posi tr onem i ssi on tom ogr aphy (PET) shoul d be per f or m ed. Sur gi cal and
pathol ogi c stagi ng shoul d then be done to deter m i ne the ex act stage of the
di sease. If the pr eoper ati v e CEA l ev el i s el ev ated, r epeat m easur em ent shoul d
be per f or m ed appr ox i m atel y 1 m onth af ter sur ger y to see i f i t r etur ns to
nor m al .
6. What i s the stagi ng sy stem f or col on cancer ?
Ther e ar e m any stagi ng sy stem s f or col on cancer . The m ost w i del y used i s the
Aster Col l er m odi f i cati on of the Duk es' stagi ng sy stem (Tabl e 77). It i s based
on the depth of tum or i nv asi on, r egi onal l y m ph node i nv ol v em ent, and di stant
m etastasi s.
Table 77 The TNM Staging Modi.cation of the
Dukes' Staging System
Sta ge De pth of Inva s ion Lymph Me ta s ta s e s

Node Dis ta nt
Sta tus
Stage Inv ades subm ucosa N egati v e Absent

I
Stage Inv ades m uscul ar i s pr opr i a N egati v e Absent

I
Stage Inv ades ser osa N egati v e Absent

II
Stage Inv ades thr ough bow el w al l i nto N egati v e Absent

IIB adjacent or gans
Stage Inv ades posi ti v e m uscul ar i s Posi ti v e Absent

IIIA pr opr i a
Stage Inv ades posi ti v e ser osa Posi ti v e Absent

IIIB
Stage Inv ades thr ough bow el w al l i nto Posi ti v e Absent

IIIC adjacent or gans
Stage Any depth of i nv asi on â€” Pr esent

IV
P. 307
Table 78 FiveYear Survival Rates for Aster
Coller Stages
Sta ge a 5y Surviva l (% )
Stage I 90â€“95
Stage IIA 78
Stage IIB 63
Stage IIIA 74
Stage IIIB 48
Stage IIIC 38
Stage IV <5
a See Tabl e 77 f or def i ni ti on of stages.
7. What i s the pr ognosi s f or pati ents w i th col on cancer , based on thei r stage?
Tabl e 78 l i sts the 5y ear sur v i v al r ates f or the v ar i ous stages of the TN M
stagi ng IV and Aster Col l er m odi f i cati on of the Duk es' stagi ng sy stem ; thi s
tak es i nto account i m pr ov em ent i n sur v i v al w i th adjuv ant chem other apeuti c
r egi m ens.
8. What shoul d the f ol l ow up consi st of i n pati ents w i th col on cancer af ter they
hav e under gone pr i m ar y sur gi cal r esecti on f or cur ati v e i ntent?
Routi ne schedul ed f ol l ow up i s v er y i m por tant f or the ear l y detecti on of l ocal
and di stant r ecur r ences, as w el l as new pr i m ar y col on cancer . Pati ents shoul d
be seen ev er y 3 to 4 m onths f or the f i r st 3 y ear s. Fol l ow up ev al uati on shoul d
i ncl ude hi stor y , phy si cal ex am i nati on, l i v er f uncti on tests, m easur em ent of the
CEA l ev el , and com pl ete bl ood counts. Col onoscopy and a chest r adi ogr aph
shoul d be obtai ned y ear l y . CT scanni ng shoul d be per f or m ed f or f ur ther
ev al uati on of r i si ng l i v er f uncti on tests or CEA l ev el s. Af ter 3 y ear s, the
i nter v al betw een these ev al uati ons can be i ncr eased.
9. Ar e ther e any ef f ecti v e adjuv ant tr eatm ents to decr ease the r i sk of r ecur r ence
i n pati ents w i th col on cancer w ho hav e under gone r esecti on?
Sev er al studi es hav e show n that 6 m onths of postoper ati v e tr eatm ent w i th 5
f l uor our aci l , l eucov or i n, and ox al i pl ati n can decr ease by 50% the l i k el i hood of
stage III col on cancer r ecur r ence. The death r ate i n thi s setti ng w as r educed
by 33%. Mor e r ecentl y , sel ected studi es of 5f l uor our aci l , l eucov or i n, and
ox al i pl ati n ther apy hav e show n a decr ease i n both r ecur r ence and death r ates
f or pati ents w i th l ate stage IIB col on cancer .
10. Is ther e any ef f ecti v e chem other apy f or pati ents w i th m etastati c di sease?
5Fl uor our aci l , l eucov or i n, and ox al i pl ati n ther apy (w hi ch m odul ates ox al i pl ati n
and bev aci zum ab angi ogenesi s) has l ed to an i ncr ease i n the r esponse r ates i n
m etastati c di sease f r om 60% to 80%. The use of bi ol ogi c agents such as
anti angi ogenesi s f actor s al one and ar bi tux (anti EGFR) i ncr eased sur v i v al i n
stage IV pati ents.
Case
A 72y ear ol d w hi te m an i s seen i n the em er gency r oom because of sev er e f ati gue
and v ague abdom i nal di scom f or t. He has no si gni f i cant past m edi cal hi stor y other
than sl i ght
P. 308
anem i a, w hi ch w as noted dur i ng a phy si cal ex am i nati on 3 y ear s ago. Hi s hem atocr i t
at that ti m e w as 37%, and w hi te bl ood cel l and pl atel et counts w er e nor m al .
Phy si cal ex am i nati on w as r em ar k abl e onl y f or cachex i a and a pal e appear ance. Hi s
i ni ti al l abor ator y v al ues at the cur r ent ti m e ar e as f ol l ow s: w hi te bl ood cel l count,
7, 800/m m 3 ; hem ogl obi n, 7 g/dL; hem atocr i t, 21%; pl atel ets, 600, 000/m m 3 ; MCV,
62 f L; AST, 89 m U /m L (nor m al , 0 to 35 m U /m L); ALT, 129 m U /m L (nor m al , 0 to 38
m U /m L); al k al i ne phosphatase, 360 m U /m L (nor m al , 0 to 125 m U /m L); and total
bi l i r ubi n, 0. 7 m g/dL (nor m al , < 1. 0 m g/dL).
The pati ent i s adm i tted to the hospi tal f or bl ood tr ansf usi on and ev al uati on of hi s
anem i a. The adm i ssi on chest r adi ogr aph show s num er ous pul m onar y nodul es, and a
bar i um enem a ex am i nati on r ev eal s a near obstr ucti ng l esi on at the hepati c f l ex ur e.
A CT scan of the l i v er depi cts num er ous l ow densi ty l esi ons i n both l obes of the
l i v er . Col onoscopy i s per f or m ed, and thi s r ev eal s a m ucosal l esi on at the hepati c
f l ex ur e. Bi opsy of thi s l esi on r ev eal s adenocar ci nom a.
1. What i s the cause of thi s pati ent's anem i a?

2. Woul d ear l i er di agnosi s of the cause of thi s pati ent's anem i a hav e m ade any
di f f er ence?
3. What ty pe of tr eatm ent w oul d y ou now adv i se f or the l esi on i n the hepati c
f l ex ur e of the col on?
4. Woul d y ou r ecom m end any other tr eatm ents f or the l esi ons i n the l ung or
l i v er ?
5. What stage i s thi s pati ent's cancer ?
6. What i s the pr ognosi s i n thi s pati ent?
Case Discussion
1. What i s the cause of thi s pati ent's anem i a?
The pati ent al m ost cer tai nl y has i r ondef i ci ency anem i a secondar y to the
chr oni c bl ood l oss i n the stool stem m i ng f r om a bl eedi ng col on cancer .
2. Woul d ear l i er di agnosi s of the cause of thi s pati ent's anem i a hav e m ade any
di f f er ence?
It i s di f f i cul t to say w hether an ear l i er di agnosi s w oul d hav e def i ni tel y m ade a
di f f er ence. It shoul d cer tai nl y hav e been possi bl e to di agnose the col on cancer ,
and at an ear l i er stage the pr ognosi s w oul d l i k el y hav e been better .
Recom m ended scr eeni ng pr ocedur es, par ti cul ar l y col onoscopy , w oul d pr obabl y
hav e i m pr ov ed thi s pati ent's outcom e.
3. What ty pe of tr eatm ent w oul d y ou now adv i se f or the l esi on i n the hepati c
f l ex ur e of the col on?
The pati ent needs to under go a hem i col ectom y to pr ev ent obstr ucti on. Thi s i s
onl y f or pal l i ati on and w i l l not af f ect the ov er al l pr ognosi s.
4. Woul d y ou r ecom m end any other tr eatm ents f or the l esi ons i n the l ung or
l i v er ?
Thi s pati ent has m etastati c di sease and shoul d be of f er ed sy stem i c
chem other apy consi sti ng of 5f l uor our aci l , ox al i pl ati n, and l eucov or i n w i th an
anti angi ogenesi s f actor : the standar d appr oach f or m etastati c col on cancer .
The best doses and schedul es of adm i ni str ati on ar e y et to be deter m i ned. If
the pati ent does not r espond to thi s standar d ther apy he shoul d be enr ol l ed i n
a cl i ni cal tr i al .
P. 309
Thi s pati ent cl ear l y has m etastati c di sease, and ther ef or e i s i n stage D
accor di ng to the Aster Col l er m odi f i cati on of the Duk es' stagi ng sy stem .
6. What i s the pr ognosi s i n thi s pati ent?
Thi s pati ent has i ncur abl e cancer . He has appr ox i m atel y a 30% to 45% chance
of r espondi ng to standar d ther apy . If he r esponds, he w i l l l i k el y l i v e l onger . He
has appr ox i m atel y a 35% to 40% chance of 5y ear sur v i v al .
Suggested Readings
Mi dgl ey R, Ker r D. Col or ectal cancer . Lancet 1999;353:391.
Sm i th RE, Col angel o L, Wi eand HS, et al . Random i zed tr i al of adjuv ant ther apy
i n col on car ci nom a: 10y ear r esul ts of N SABP pr otocol C01. J N atl Cancer Inst
2004;96:1128.
Steel e G Jr . Com bi nedm odal i ty ther apy f or r ectal car ci nom a: the ti m e has
com e. N Engl J Med 1991;324:764.
Steel e G Jr , Bl eday R, May er RJ, et al . A pr ospecti v e ev al uati on of hepati c

r esecti on f or col or ectal car ci nom a m etastases to the l i v er : Gastr oi ntesti nal
Tum or Study Gr oup Pr otocol 6584. J Cl i n Oncol 1991;9:1105.
Steel e G Jr , Bur t R, Wi naw er SJ, eds. Basi c and cl i ni cal per specti v es of
col or ectal pol y ps and cancer . N ew Yor k : Al an R. Li ss, 1988.
Erythrocytosis
1. What i s er y thr ocy tosi s?
2. What ar e the tw o m ajor ty pes of er y thr ocy tosi s?
3. What ar e som e causes of secondar y er y thr ocy tosi s due to appr opr i ate
er y thr opoi eti n secr eti on?
4. What ar e som e causes of secondar y er y thr ocy tosi s due to i nappr opr i ate
5. What i s pol y cy them i a v er a?
6. What ar e the sy m ptom s of pol y cy them i a v er a?
7. How i s pol y cy them i a v er a di agnosed?
8. What i s the l i k el y l ength of sur v i v al i n a pati ent w i th pol y cy them i a v er a?
9. What i s the r ar e hepati c com pl i cati on that can ar i se i n pati ents w i th
pol y cy them i a v er a?
Discussion
1. What i s er y thr ocy tosi s?
A pati ent w i th a hem atocr i t gr eater than 55% that i s not due to dehy dr ati on i s
consi der ed to hav e an er y thr ocy tosi s. The chr om i um 151â€“l abel ed r ed bl ood
cel l m easur em ent of the total r ed bl ood cel l m ass i s, how ev er , the gol d
standar d f or establ i shi ng the di agnosi s, but i f the pati ent has a hem atocr i t
gr eater than 60%, no f ur ther studi es ar e necessar y .
P. 310
2. What ar e the tw o m ajor ty pes of er y thr ocy tosi s?
When the el ev ated hem atocr i t i s due to i ncr eased er y thr opoi eti n secr eti on, thi s
consti tutes secondar y er y thr ocy tosi s. Pr i m ar y er y thr ocy tosi s i s caused by
i ncr eased r ed bl ood cel l pr oducti on that does not stem f r om i ncr eased
er y thr opoi eti n secr eti on.
3. What ar e som e causes of secondar y er y thr ocy tosi s due to appr opr i ate
Any di sor der that causes ti ssue hy pox i a sti m ul ates the r enal pr oducti on of
er y thr opoi eti n. These di sor der s i ncl ude chr oni c obstr ucti v e l ung di sease, l i v i ng
at hi gh al ti tudes, hem ogl obi n (Hb Chesapeak e and m ethem ogl obi n) that does
not r el ease ox y gen cor r ectl y , or car di ac di sease that causes â€œr i ghttol ef tâ€
shunti ng. In r el ati v e er y thr ocy tosi s, the r ed bl ood cel l m ass i s nor m al , and thi s
occur s i n the setti ngs of dehy dr ati on or decr eased pl asm a v ol um e.
4. What ar e som e causes of secondar y er y thr ocy tosi s due to i nappr opr i ate
Many di sease states can be associ ated w i th i ncr eased er y thr opoi eti n
pr oducti on. Di seased k i dney s m ay secr ete er y thr opoi eti n i nappr opr i atel y or
tum or s m ay secr ete hor m ones that f uncti on l i k e er y thr opoi eti n. Renal , adr enal ,
or hepati c tum or s, ov ar i an car ci nom a, or beni gn uter i ne m y om as al l secr ete
er y thr opoi eti nl i k e substances. Other causes of i ncr eased er y thr opoi eti n
secr eti on ar e r enal ar ter y stenosi s, hy dr onephr osi s, r enal cy sts, or r enal
tr anspl antati on.
5. What i s pol y cy them i a v er a?
Pol y cy them i a v er a i s an absol ute er y thr ocy tosi s secondar y to the cl onal
ex pansi on of r ed bl ood cel l s, m ak i ng i t a m y el opr ol i f er ati v e di sor der .
6. What ar e the sy m ptom s of pol y cy them i a v er a?
Sy m ptom s stem f r om v ascul ar congesti on or obstr ucti on due to i ncr eased bl ood
v i scosi ty . Pati ents com pl ai n of headaches, i tchi ng and bur ni ng f eet, or m al ai se.
The r eti nal v ei ns becom e engor ged and hepatospl enom egal y m ay be pr esent.
The i nci dence of car di ov ascul ar and cer ebr ov ascul ar di sease i s i ncr eased i n
these pati ents because of the el ev ated bl ood v i scosi ty .
7. How i s pol y cy them i a v er a di agnosed?
An i ncr eased r ed bl ood cel l m ass, an ox y gen satur ati on of 92% or m or e, and
spl enom egal y ar e the car di nal si gns of pol y cy them i a v er a. If spl enom egal y i s
not pr esent, pol y cy them i a v er a i s ev i dent i f the pati ent has a pl atel et count
that ex ceeds 400, 000/m m 3 , a w hi te bl ood cel l count gr eater than 12, 000/m m 3 ,
a cobal am i n l ev el of 900 pg/m L or gr eater , or an el ev ated neutr ophi l al k al i ne
phosphatase scor e.
8. What i s the l i k el y l ength of sur v i v al i n a pati ent w i th pol y cy them i a v er a?
Wi thout tr eatm ent, hal f the pati ents di e w i thi n 24 m onths, usual l y due to
v ascul ar di sease. Phl ebotom y to m ai ntai n a hem atocr i t of 45% can pr ol ong the
l i f e span to m or e than 6 y ear s, and m edi an sur v i v al i n pati ents w ho r ecei v e
ef f ecti v e chem other apy i s 12. 5 y ear s.
P. 311
9. What i s the r ar e hepati c com pl i cati on that can ar i se i n pati ents w i th
pol y cy them i a v er a?
BuddChi ar i sy ndr om e i s an occl usi on of the hepati c v ei ns som eti m es seen i n
pati ents w i th pol y cy them i a v er a and other di seases that i ncr ease bl ood
v i scosi ty . Thi s causes r i ght upper quadr ant pai n and el ev ati ons i n the l i v er
enzy m e l ev el s. It i s v er y di f f i cul t to tr eat, and i s best pr ev ented by tr eati ng
the er y thr ocy tosi s aggr essi v el y .
Case
A 55y ear ol d m an w ho i s a sm ok er and has hy per tensi on sees hi s i nter ni st because
of m al ai se and nasal stuf f i ness w i th f ul l sensati on i n hi s f r ontal si nuses. On f ur ther
questi oni ng, the pati ent al so descr i bes hav i ng i tchy , r ed f eet that w or sen i n the
show er . The pati ent has no shor tness of br eath w i th acti v i ty and does not snor e or
ex per i ence day ti m e dr ow si ness.
Phy si cal ex am i nati on r ev eal s a pl ethor i c pati ent w ho i s i n no acute di str ess. Hi s
l ungs ar e cl ear to auscul tati on. Hi s l i v er span i s 18 cm and hi s spl een ti p i s
pal pabl e.
The f ol l ow i ng l abor ator y v al ues ar e r epor ted: hem atocr i t, 65%; w hi te bl ood cel l
count, 8, 500/m m 3 ; pl atel ets, 210, 000/m m 3 ; and di f f er enti al : 50% segm ented
neutr ophi l s, 30% l y m phocy tes, 3% basophi l s, and 10% m onocy tes.
Ar ter i al bl ood gas deter m i nati ons per f or m ed on r oom ai r r ev eal a par ti al pr essur e
of ox y gen of 65 m m Hg, a par ti al pr essur e of car bon di ox i de of 38 m m Hg, and an
ox y gen satur ati on of 93%.
1. What i s the di agnosi s i n thi s pati ent?

2. Why i s i t i m por tant to k now w hether the pati ent snor es or ex per i ences day ti m e
dr ow si ness?
3. What i s the cause of thi s pati ent's nasal stuf f i ness?
4. What shoul d be the i ni ti al tr eatm ent i n thi s pati ent?
5. What i s thi s pati ent's pr ognosi s?
Case Discussion
1. What i s the di agnosi s i n thi s pati ent?
Thi s pati ent m ost l i k el y has pol y cy them i a v er a. The ox y gen satur ati on gr eater
than 90% and the pr esence of spl enom egal y suppor t the di agnosi s. The
pr esence of m ononucl ear and basophi l i c cel l s al so suppor ts the di agnosi s of a
m y el opr ol i f er ati v e di sor der , w hi ch w oul d be f ur ther suppor ted by a bone
m ar r ow bi opsy that show s tr i l i near hy per pl asi a.
2. Why i s i t i m por tant to k now w hether the pati ent snor es or ex per i ences day ti m e
dr ow si ness?
Snor i ng and day ti m e dr ow si ness ar e sy m ptom s of sl eep apnea, a cause of

secondar y er y thr ocy tosi s. Al though phl ebotom y can cur e the pati ent's
er y thr ocy tosi s,
P. 312
i t cannot tr eat the ni ghtti m e hy pox i a or sl eep apnea, and the pati ent coul d go
on to hav e r i ghtsi ded hear t f ai l ur e.
3. What i s the cause of thi s pati ent's nasal stuf f i ness?
Al though he m ay hav e a si nus i nf ecti on, the nasal stuf f i ness i s m ost l i k el y due
to i ncr eased bl ood v i scosi ty .
4. What shoul d be the i ni ti al tr eatm ent i n thi s pati ent?
Phl ebotom y shoul d be per f or m ed as soon as possi bl e to decr ease the
hem atocr i t to 45% to 50%. The i ncr eased bl ood v i scosi ty pl aces thi s pati ent
w ho has tw o other r i sk f actor s f or ather oscl er oti c di sease, nam el y sm ok i ng
and hy per tensi on, at r i sk f or a str ok e or car di ov ascul ar acci dent.
5. What i s thi s pati ent's pr ognosi s?
Ev en w i th car ef ul tr eatm ent of hi s er y thr ocy tosi s w i th phl ebotom y and
chem other apy , hi s l i f e ex pectancy w i l l pr obabl y be m or e l i m i ted because of hi s
sm ok i ng and hy per tensi on.
Suggested Readings
Conl ey CL. Pol y cy them i a v er a, di agnosi s and tr eatm ent. Hosp Pr act
1987;22:107.
El l i s JT, Peter son P, Gel l er SA, et al . Studi es of the bone m ar r ow i n
pol y cy them i a v er a and the ev ol uti on of m y el of i br osi s and second hem atol ogi c
m al i gnanci es. Sem i n Hem atol 1986;23:144.
Mur phy S. Di agnosti c cr i ter i a and pr ognosi s i n pol y cy them i a v er a and essenti al
thr om bocy topeni a. Sem i n Hem atol 1999;36:9.
Schw ar ts RS. Pol y cy them i a v er a: chance, death, and m utabi l i ty [Edi tor i al ]. N
Engl J Med 1998;338:613.
Lymphomas
1. How and w hen does Hodgk i n's di sease ty pi cal l y pr esent?
2. What i s the r el ati onshi p betw een the hi stol ogi c patter ns and the stage i n
Hodgk i n's di sease?
3. Of w hat shoul d the stagi ng ev al uati on i n pati ents w i th Hodgk i n's di sease
consi st, and how do the f i ndi ngs hav e an i m pact on ther apy ?
4. What ar e the cur e r ates and the l ongter m sequel ae of the tr eatm ent f or
5. What ar e the k now n causes or di seases associ ated w i th the dev el opm ent of
nonâ€“Hodgk i n's l y m phom a?
6. How does the Wor l d Heal th Or gani zati on's w or k i ng f or m ul ati on of nonâ
€“Hodgk i n's l y m phom a di f f er f r om the ol der cl assi f i cati ons?
7. How does the bi ol ogy of hi ghgr ade l y m phom a di f f er f r om that of l ow gr ade
l y m phom a, and how does thi s af f ect tr eatm ent and sur v i v al ?
8. What ty pe of l y m phom a ty pi cal l y i nv ol v es the sk i n, and how does thi s i nf l uence
stagi ng and tr eatm ent?
P. 313
9. What popul ati on of pati ents i s pr one to acqui r i ng secondar y CN S l y m phom a,
and can thi s be pr ev ented?
10. What com pl i cati on of ther apy can occur i n the setti ng of r api dl y gr ow i ng
tum or s, and how can thi s be pr ev ented?
Discussion
1. How and w hen does Hodgk i n's di sease ty pi cal l y pr esent?
Hodgk i n's di sease ty pi cal l y pr esents i n adol escence or y oung adul thood.
How ev er , a bi m odal age di str i buti on has been obser v ed, especi al l y i n
dev el oped countr i es. The f i r st peak i s i n adol escence or y oung adul thood,
w her eas the second peak occur s at 55 y ear s of age. Hodgk i n's di sease ty pi cal l y
pr esents as a w ax i ng and w ani ng adenopathy , m ost com m onl y i n the neck or
supr acl av i cul ar ar ea. Fi f ty per cent of pati ents pr esent w i th a m edi asti nal m ass
v i si bl e on chest r adi ogr aphy , and 40% pr esent w i th B sy m ptom s (f ev er , ni ght
sw eats, and 10% w ei ght l oss i n the pr ecedi ng 6 m onths).
2. What i s the r el ati onshi p betw een the hi stol ogi c patter ns and the stage i n
Ther e ar e f our di sti nct hi stol ogi c patter ns seen i n Hodgk i n's di sease, al l of
w hi ch possess the Ster nber gReed cel l . The f our hi stol ogi c patter ns and thei r
pr ev al ences ar e nodul ar scl er osi s (70%), l y m phocy te pr edom i nance (15%),
m i x ed cel l ul ar i ty (10%), and l y m phocy te depl eti on (5%).
Hodgk i n's di sease i s staged accor di ng to the Ann Ar bor cl assi f i cati on:
Stage I. Inv ol v em ent of a si ngl e l y m ph node r egi on (I) or a si ngl e
ex tr al y m phati c or gan or si te (I E ).
Stage II. Inv ol v em ent of tw o or m or e l y m ph node r egi ons on the sam e
si de of the di aphr agm (II), or l ocal i zed i nv ol v em ent of tw o or m or e
ex tr al y m phati c or gans or si tes (II E ).
Stage III. Inv ol v em ent of l y m ph node r egi ons on both si des of the
di aphr agm (III), or l ocal i zed i nv ol v em ent of an ex tr al y m phati c or gan or
si te (III E ) or spl een (III S ), or both (III SE ). III 1 r ef er s to i nv ol v em ent of
l y m ph nodes i n the upper abdom en; III 2 r ef er s to i nv ol v em ent of l ow er
abdom i nal nodes.
Stage IV. Di f f use or di ssem i nated i nv ol v em ent of one or m or e

ex tr al y m phati c or gans, w i th or w i thout associ ated l y m ph node
i nv ol v em ent. The or gan, or or gans, i nv ol v ed m ay be i denti f i ed by a
sy m bol .
Al so: A = asy m ptom ati c; B = f ev er , ni ght sw eats, and w ei ght l oss
ex ceedi ng 10% of the total body w ei ght.
Hodgk i n's di sease spr eads thr ough conti guous l y m ph nodes; how ev er , the
spl een i s com m onl y the onl y si te of i nv ol v em ent i n the abdom en, and i ts
i nv ol v em ent i s thought to be due to l y m phati c spr ead.
Hi stol ogi c pr ogr essi on i n Hodgk i n's di sease i nv ol v es the pr ogr essi v e l oss of
l y m phocy tes. For ex am pl e, l y m phocy te pr edom i nance can pr ogr ess to m i x ed
cel l ul ar i ty and ev entual l y l y m phocy te depl eti on. Those pati ents w ho pr esent
w i th nodul ar scl er osi s m ay al so ex per i ence som e changes i n hi stol ogi c ty pe,
al though m ost do not show obv i ous hi stol ogi c pr ogr essi on. The hi stol ogi c
P. 314
patter n al so cor r el ates w i th the stage of the di sease, and ther eby the
pr ognosi s. N odul ar scl er osi s and l y m phocy te pr edom i nance ar e m or e com m onl y
seen i n ear l y di sease (stages I and II). Ther ef or e, these hi stol ogi c patter ns ar e
associ ated w i th a better outcom e. Mi x ed cel l ul ar i ty and l y m phocy te depl eti on
ar e associ ated w i th a poor er pr ognosi s and ar e of ten seen i n pati ents w i th
adv anced di sease.
3. Of w hat shoul d the stagi ng ev al uati on i n pati ents w i th Hodgk i n's di sease
consi st, and how do the f i ndi ngs hav e an i m pact on ther apy ?
The stagi ng ev al uati on i n pati ents w i th Hodgk i n's di sease i ncl udes a com pl ete
hi stor y and phy si cal ex am i nati on. Labor ator y i nv esti gati ons shoul d i ncl ude a
com pl ete bl ood count and ev al uati on of the sm ear f or changes i ndi cati ng
anem i a, hem ol y si s, or abnor m al w hi te bl ood cel l s as w el l as a di f f er enti al ,
deter m i nati ons of the sedi m entati on r ate and al k al i ne phosphatase l ev el , and
ev al uati on of l i v er and r enal f uncti on. The r adi ol ogi c ev al uati on shoul d al w ay s
i ncl ude CT studi es of the chest, abdom en, and pel v i s or CT/PET scans.
A di agnosi s based on ti ssue f i ndi ngs i s a m ust. N eedl e aspi r ati on or cy tol ogi c
f i ndi ngs i s not adequate because the ti ssue obtai ned by these m ethods y i el ds
no i nf or m ati on about the nodal ar chi tectur e. It i s pr ef er abl e to obtai n a l y m ph
node or w edge of a l ar ge m ass, but ev en then i t m ay tak e m or e than one
l y m ph node bi opsy to docum ent the pr esence of the di sease i f onl y r eacti v e
hy per pl asi a i s seen. Bone m ar r ow bi opsy i s a r equi r ed par t of the stagi ng
w or k up, par ti cul ar l y i n sy m ptom ati c pati ents, but shoul d not be substi tuted f or
the ti ssue ex am i nati on because, agai n, the nodal ar chi tectur e cannot be
obser v ed. Gener al gui del i nes no l onger suggest per f or m i ng a stagi ng
l apar otom y unl ess i f the r esul ts w oul d af f ect the natur e of ther apy . Thi s m ay
happen i n ear l y stage di sease (i . e. , stages IB, IIB, and IIIA), w hen the f i ndi ngs
f r om l apar otom y coul d al ter a deci si on to use r adi ati on ther apy al one.
The choi ce of ther apy i n pati ents w i th Hodgk i n's di sease i s gov er ned by stage.
Pati ents w i th stage I and II di sease can be tr eated w i th r adi ati on ther apy
al one. If ther e i s bul k y di sease, com bi ned chem other apy and i r r adi ati on shoul d
be used. For pati ents w i th stage III and IV di sease, chem other apy shoul d be
used w i th r adi ati on del i v er ed to si tes of bul k y di sease. Ther e i s sti l l som e
contr ov er sy about w hat i s the best tr eatm ent f or stage IIB and IIIA di sease.
Most ther apeuti c opti ons hav e hi gh r em i ssi on r ates, and f r equentl y l ongter m
si de ef f ects di ctate the choi ce.
4. What ar e the cur e r ates and the l ongter m sequel ae of the tr eatm ent f or
Com bi nati on chem other apy and adv ances i n r adi ati on ther apy hav e achi ev ed
ov er al l cur e r ates of appr ox i m atel y 70% i n pati ents w i th Hodgk i n's di sease.
The cur e r ates seen f or ear l y stage di sease ar e gr eater , w i th a 90% to 95%
l ongter m sur v i v al r ate obser v ed f or pati ents w i th stage I and II di sease. The
gr eat num ber of sur v i v or s has al l ow ed l ongter m f ol l ow up and a study of the
ef f ects of com bi nati on chem other apy and r adi ati on ther apy .
Hodgk i n's di sease i s associ ated w i th i m m unol ogi c abnor m al i ti es i nv ol v i ng
changes i n both l y m phocy te f uncti on and hum or al i m m uni ty . These def ects
P. 315
ar e aggr av ated by tr eatm ent and thi s i ncr eases the r i sk of such i nf ecti ons as
di ssem i nated her pes zoster . Thi s i m m une dy sf uncti on can l ast f or y ear s af ter
tr eatm ent. Tr eatm ent w i th chem other apy i s associ ated w i th an i ncr eased r i sk
of secondar y l euk em i a, w hi ch i s f ur ther i ncr eased i n pati ents ol der than 40
y ear s, heav i l y tr eated pati ents (both chem other apy and r adi ati on ther apy ), and
those w ho under go pr ol onged ther apy w i th al k y l ati ng agents.
The sequel ae of the ther apy f or Hodgk i n's di sease ar e v ar i ous. It i s i m por tant
to be aw ar e of them , but i t i s al so i m por tant that ther apy not be sev er el y
m odi f i ed (i . e. , a l ow er dosage of ei ther chem other apy or r adi ati on ther apy ) to
m i ni m i ze r i sk , because attem pti ng to m i ni m i ze the r i sk i n thi s m anner m ay
com pr om i se cur e.
5. What ar e the k now n causes or di seases associ ated w i th the dev el opm ent of
nonâ€“Hodgk i n's l y m phom a?
The r i sk of l y m phom a i s i ncr eased i n pati ents w i th cer tai n connecti v e ti ssue
and i m m unol ogi c di sor der s. These i ncl ude hum an i m m unodef i ci ency v i r us (HIV)
i nf ecti on, Kl i nef el ter 's sy ndr om e, acqui r ed hy pogam m agl obul i nem i a, i atr ogeni c
i m m unosuppr essi on (especi al l y af ter or gan tr anspl antati on), atax i aâ
€“tel angi ectasi a sy ndr om e, SjÃ¶gr en's sy ndr om e, r heum atoi d ar thr i ti s and
sy stem i c l upus er y them atosus, Sw i ssty pe agam m agl obul i nem i a, com m on
v ar i abl e i m m unodef i ci ency di sease, acqui r ed i m m unodef i ci ency sy ndr om e, and
the Xl i nk ed l y m phopr ol i f er ati v e sy ndr om e.
A v i r al eti ol ogy of l y m phom a has been pr oposed, but no cl ear pr oof of thi s
v i r us ex i sts ex cept f or hum an Tcel l l euk em i a v i r us ty pe 1 (HTLV1) i nf ecti on.
Cer tai n ty pes of m or e com m on l y m phom as hav e been associ ated w i th a v i r al
eti ol ogy (e. g. , Bur k i tt's l y m phom a and Epstei nBar r v i r us and HIV or post
or gan tr anspl antati on l y m phom as). The sear ch to establ i sh a v i r al cause has
i m pl i cated oncogenes, l eadi ng to the i denti f i cati on of v ar i ous cy togeneti c
abnor m al i ti es i n l y m phom a. The com m on patter n i s f or a k now n oncogene to be
tr ansl ocated i nto an i m m unogl obul i n gene l ocus. The com m on tr ansl ocati ons
ar e l i sted i n Tabl e 79.
6. How does the Wor l d Heal th Or gani zati on's w or k i ng f or m ul ati on of nonâ
€“Hodgk i n's l y m phom a di f f er f r om the ol der cl assi f i cati ons?
The nonâ€“Hodgk i n's l y m phom as ar e cl assi f i ed accor di ng to hi stol ogi c ty pe.
The new er Wor l d Heal th Or gani zati on w or k i ng f or m ul ati on i s based on the
m or phol ogi c f eatur es of each ty pe of l y m phom a. Thi s cl assi f i cati on di v i des
P. 316
the l y m phom as i nto thr ee m ajor subgr oups: l ow gr ade, i nter m edi ate gr ade,
and hi gh gr ade. Ther ef or e, the l y m phom as ar e cl assi f i ed accor di ng to both
thei r m or phol ogi c f eatur es and thei r behav i or . N ew er cl assi f i cati ons ex am i ne
m ol ecul ar char acter i sti cs, as show n i n Tabl e 710.
Table 79 Common Translocations in Patients
with Lymphoma
Tra ns loc a tion His tologic Type of Lymphoma
t(8;14) chr om osom e Bur k i tt's and nonBur k i tt's
t(14;18) chr om osom e Fol l i cul ar
t(2;5) chr om osom e Anapl asti c l ar ge cel l
7. How does the bi ol ogy of hi ghgr ade l y m phom a di f f er f r om that of l ow gr ade
l y m phom a, and how does thi s af f ect tr eatm ent and sur v i v al ?
Hi ghgr ade nonâ€“Hodgk i n's l y m phom a i s a gr oup of di seases that behav e

aggr essi v el y , especi al l y com par ed w i th the behav i or that i s ty pi cal of l ow
gr ade
P. 317
nonâ€“Hodgk i n's l y m phom a or Hodgk i n's di sease. The m ean sur v i v al i n pati ents
w i th hi ghgr ade di sease w ho do not r espond to ther apy i s 2 y ear s, w her eas
pati ents w i th l ow gr ade di sease can l i v e f or up to 20 y ear s.
Table 710 WHO Classi.cation of the Nonâ
€“Hodgkin's Lymphomas
The indole nt lymphoma s

Bcel l neopl asm s
Sm al l l y m phocy ti c l y m phom a/Bcel l chr oni c l y m phocy ti c
l euk em i a
Ly m phopl asm acy ti c l y m phom a (Wal denstr om 's
m acr ogl obul i nem i a)
Pl asm a cel l l euk em i a
Hai r y cel l l euk em i a
Fol l i cul ar l y m phom a (gr ade 1 and 2)
Mar gi nal cel l l y m phom a a
Tcel l neopl asm s
Tcel l l ar ge gr anul ar l y m phocy te l euk em i a
My cosi s f ungoi des
Tcel l pr ol y m phocy ti c l euk em i a
N atur al k i l l er cel l neopl asm s
N atur al k i l l er cel l l ar ge gr anul ar l y m phocy te l euk em i a
The a ggre s s ive lymphoma s
Bcel l neopl asm s
Fol l i cul ar l y m phom a (gr ade 3)
Di f f use l ar ge Bcel l l y m phom a
Mantl e cel l l y m phom a a
Tcel l neopl asm
Per i pher al Tcel l l y m phom a
Anapl asti c l ar ge cel l l y m phom a, T/nul l cel l
The highly a ggre s s ive lymphoma s
Bcel l neopl asm s
Bur k i tt's l y m phom a
Pr ecur sor Bl y m phobl asti c l euk em i a/l y m phom a
Tcel l neopl asm s
Adul t Tcel l l y m phom a/l euk em i a
Pr ecur sor Tl y m phobl asti c l euk em i a/l y m phom a
a Mar gi nal or m antl e cel l l y m phom a can behav e cl i ni cal l y as ei ther
i ndol ent or an aggr essi v e di sor der .
WHO, Wor l d Heal th Or gani zati on.
Adapted f r om Har r i s N L, Jaf f e ES, Di ebol d J, et al . Wor l d Heal th

Or gani zati on cl assi f i cati on of neopl asti c di seases of the hem atopoi eti c
and l y m phoi d ti ssues: r epor t of the Cl i ni cal Adv i sor y Com m i ttee. Ai r l i e
House, Vi r gi ni a: 1997; J Cl i n Oncol 1999;17:3835.
Pati ents w i th hi ghgr ade l y m phom a can pr esent w i th l ocal i zed di sease (< 20%),
but m or e com m onl y ar e i n an adv anced stage. Ther e can be i nv ol v em ent of
ei ther ex tr anodal (35%) or pr i v i l eged si tes (the CN S or testes). Most di sease
i s of Bcel l or i gi n (85%), w i th the r em ai nder of Tcel l or i gi n.
Poor pr ognosti c f actor s i ncl ude poor per f or m ance status, bul k y di sease (> 10
cm ), hi gh LDH l ev el (> 500 IU /dL), bone m ar r ow i nv ol v em ent, and B sy m ptom s.
Hi ghgr ade nonâ€“Hodgk i n's l y m phom as ar e v er y sensi ti v e to chem other apy ,
and aggr essi v e tr eatm ent i s the onl y chance f or cur e. U p to 60% of pati ents
can be cur ed w i th the new er chem other apeuti c r egi m ens. Thi s i s i n shar p
contr ast to the ex per i ence w i th l ow gr ade l y m phom as, i n w hi ch cur e r ates of
l ess than 20% ar e seen and sur v i v al does not seem to be af f ected by the ty pe
of r esponse to chem other apy .
8. What ty pe of l y m phom a ty pi cal l y i nv ol v es the sk i n, and how does thi s i nf l uence
stagi ng and tr eatm ent?
Ly m phom atous i nv ol v em ent of the sk i n i s com m onl y seen i n the setti ng of T
cel l l y m phom a. It occur s i n appr ox i m atel y 10% of al l cases of nonâ€“Hodgk i n's
l y m phom a, and thi s gr oup of di seases i s cal l ed cutaneous Tcel l l y m phom a
(CTCL). The l ow gr ade f or m of CTCL i s m y cosi s f ungoi des or Sezar y sy ndr om e.
Sezar y sy ndr om e i s di agnosed i n the setti ng of m y cosi s f ungoi des w hen the
m al i gnant cel l s (Sezar y cel l s) ar e f ound i n the per i pher al bl ood.
The stagi ng cl assi f i cati on f or CTCL di f f er s f r om that f or other f or m s of nonâ
€“Hodgk i n's l y m phom a, and i s based on the TN M sy stem , as show n i n Tabl e 7
11.
The m ai nstay of m anagem ent of ear l y m y cosi s f ungoi des and Sezar y sy ndr om e
has been topi cal tr eatm ent, but ther e i s l i ttl e ev i dence that thi s pr ol ongs
sur v i v al .
9. What popul ati on of pati ents i s pr one to acqui r i ng secondar y CN S l y m phom a,
and can thi s be pr ev ented?
CN S i nv ol v em ent i s r ar el y seen i n pati ents w i th l ow gr ade l y m phom a. When

seen, a hi stol ogi c tr ansf or m ati on to hi ghgr ade l y m phom a shoul d be suspected.
Wi thi n thi s gr oup, CN S i nv ol v em ent i s m or e com m on w hen Wal dey er 's tonsi l l ar
r i ng, the bone m ar r ow , or the testes ar e af f ected. Am ong the hi ghgr ade
l y m phom as, ther e i s a gr oup of especi al l y aggr essi v e l y m phom as, and these
consi st of undi f f er enti ated l y m phom as (Bur k i tt's and nonâ€“Bur k i tt's ty pe),
l y m phobl asti c l y m phom a, and acute Tcel l l y m phom a. The i nci dence of CN S
i nv ol v em ent i s hi gh i n these pati ents and, ther ef or e the CN S shoul d be tr eated
pr ophy l acti cal l y w i th i ntr athecal chem other apy . Pati ents on i m m unosuppr essi on
af ter or gan tr anspl antati on [posttr anspl ant l y m phopr ol i f er ati v e di sease (PTLD)]
of ten pr esent w i th CN S l y m phom a.
P. 318
Table 711 National Cutaneous TCell Lymphoma
Workshop Staging Classification a
Tumor Sk in Node Lymph Me ta s ta s is Vis c e ra l

(T) (N) Node s (M) Orga ns
T1 Li m i ted N0 No M0 No
pl aques adenopathy , i nv ol v em ent
(< 10% body hi stol ogy
sur f ace ar ea) negati v e
T2 Gener al i zed N1 Adenopathy ; M1

pl aques hi stol ogy
negati v e
T3 Cutaneous N2 No
tum or s adenopathy ;

hi stol ogy
posi ti v e
T4 Gener al i zed N3 Adenopathy ;

er y thr oder m a hi stol ogy
posi ti v e
Stage I: Li m i ted (IA) or gener al i zed (IB) pl aques w i thout adenopathy or
hi stol ogi c i nv ol v em ent of l y m ph nodes or v i scer a (T1 N 0 M0 or T2 N 0 M0)
Stage II: Li m i ted or gener al i zed pl aques w i th adenopathy (IIA) or cutaneous
tum or s w i th or w i thout adenopathy (IIB); w i thout hi stol ogi c i nv ol v em ent of
l y m ph nodes or v i scer a (T1â€“2 N 1 M0 or T2 N 0â€“1 M0)
Stage III: Gener al i zed er y thr oder m a w i th or w i thout adenopathy ; w i thout
hi stol ogi c i nv ol v em ent of l y m ph nodes or v i scer a (T4 N 0â€“2 M0)
Stage IV: Hi stol ogi c i nv ol v em ent of l y m ph nodes (IVA) or v i scer a (IVB) w i th
any sk i n l esi on and w i th or w i thout adenopathy (T1â€“4 N 2â€“3 M0 f or IVA;
T1â€“4 N 0â€“3 M1 f or IVB)
a Bl ood i nv ol v em ent shoul d be r ecor ded as absent (B0) or pr esent (B1) but i s
not cur r entl y used to deter m i ne f i nal stage.
10. What com pl i cati on of ther apy can occur i n the setti ng of r api dl y gr ow i ng
tum or s, and how can thi s be pr ev ented?
The tum or l y si s sy ndr om e can occur i n the setti ng of tum or s that ar e
ex qui si tel y sensi ti v e to chem other apy and i s seen w hen ther e i s a l ar ge tum or
bur den. The sy ndr om e i s char acter i zed by hy per ur i caci dem i a,
hy per phosphatem i a, hy per k al em i a, and hy pocal cem i a, and can r esul t i n acute
r enal f ai l ur e and sudden death, i f not tr eated. For tunatel y , i f the si gns ar e
car ef ul l y w atched f or , the pati ent can be spar ed i ts ef f ects. The m anagem ent
of thi s sy ndr om e i ncl udes aggr essi v e hy dr ati on, the al k al i ni zati on of ur i ne, and
al l opur i nol ther apy bef or e and dur i ng chem other apy .
Case
A 42y ear ol d w om an i s r ef er r ed to y ou by her f am i l y phy si ci an f or the ev al uati on
of bi l ater al neck adenopathy . She has noti ced thi s sw el l i ng i nter m i ttentl y f or
appr ox i m atel y 6 m onths. She has occasi onal l y noti ced ax i l l ar y node sw el l i ng but
deni es any other adenopathy . She has noti ced that she ti r es m or e easi l y and seem s
to â€œpi ck up ev er y l i ttl e v i r us. â€
She adm i ts to ex per i enci ng occasi onal ear l y
sati ety , but deni es any i ncr ease i n abdom i nal gi r th or changes i n bow el habi ts. She
deni es any f ev er , chi l l s, ni ght sw eats, w ei ght l oss, or change i n appeti te.
Her f am i l y hi stor y i s r em ar k abl e f or a m other w i th br east cancer (the pati ent's l ast
m am m ogr am 1 y ear ago w as nor m al ). She does not sm ok e or dr i nk .
P. 319
Phy si cal ex am i nati on f i ndi ngs ar e r em ar k abl e f or bi l ater al neck and ax i l l ar y
adenopathy . She has no or al or phar y ngeal l esi ons and no br east m asses. Her
spl een i s m i l dl y enl ar ged but her l i v er si ze i s nor m al . She has no other phy si cal
abnor m al i ti es.
Labor ator y f i ndi ngs ar e r em ar k abl e f or a m i l d nor m ochr om i c, nor m ocy ti c anem i a
(hem ogl obi n, 13. 0 g/dL; hem atocr i t, 39%); the pl atel et count i s 250, 000/m m 3 and
the w hi te bl ood cel l count i s 5, 200/m m 3 w i th a nor m al di f f er enti al . A chem i str y
panel i s r em ar k abl e f or a sl i ghtl y el ev ated LDH l ev el , but the AST, ALT, bi l i r ubi n,
and al k al i ne phosphatase v al ues ar e nor m al . Her chest r adi ogr aphi c study i s
nor m al .
A stagi ng ev al uati on i s done and r ev eal s the f ol l ow i ng f i ndi ngs. Ti ssue anal y si s
r ev eal s m al i gnant l y m phom a consi sti ng of f ol l i cul ar sm al l cl eav ed (nodul ar poor l y
di f f er enti ated) cel l s that ar e CD20 posi ti v e. Bone m ar r ow bi opsy r ev eal s nor m al
cel l ul ar i ty w i th l y m phoi d f ol l i cl es (nor m al f or age), a sl i ght i ncr ease i n the num ber
of er y thr oi d pr ecur sor s, nor m al m egak ar y ocy tes, and a decr ease i n the i r on
content. Cy togeneti c ex am i nati on i denti f i es a bal anced tr ansl ocati on, t(14;18). CT
scan of the abdom en depi cts m oder ate spl enom egal y and m i l d r etr oper i toneal
adenopathy . Ser um i m m unoel ectr ophor esi s r ev eal s m i l d hy pogam m agl obul i nem i a
w i th a m onocl onal i m m unogl obul i n M (IgM) spi k e.
1. On the basi s of the phy si cal ex am i nati on and l abor ator y f i ndi ngs, w hat i s the
di f f er enti al di agnosi s i n thi s pati ent?
2. On the basi s of the f i ndi ngs f r om the stagi ng ev al uati on, w hat stage of nonâ
€“Hodgk i n's l y m phom a i s thi s pati ent i n, and w hat ar e her tr eatm ent opti ons
and pr ognosi s?
3. What ar e the i m pl i cati ons of her cy togeneti c abnor m al i ti es?
4. Is i t f ur ther necessar y to ev al uate or tr eat her hy pogam m agl obul i nem i a?
5. What i s the si gni f i cance of the m onocl onal IgM spi k e i n thi s pati ent?
The pati ent i s obser v ed to do f i ne at her 6m onth v i si ts, unti l 4 y ear s l ater ,
w hen pai nf ul and enl ar gi ng nodes dev el op.
6. What f or m of ther apy w oul d y ou of f er her w hen the pai nf ul and enl ar gi ng
nodes ar e detected, and w hat outcom e can she ex pect?
Wi th the onset of ther apy consi sti ng of or al al k y l ati ng agents, a sev er e anem i a
dev el ops i n thi s pati ent, r equi r i ng tr ansf usi on.
7. How w oul d y ou ev al uate the anem i a that dev el ops w i th the al k y l ati ng agent
ther apy ?
The r esul ts of i nv esti gati ons per f or m ed to deter m i ne the sour ce of her anem i a
ar e as f ol l ow s: Coom bs' di r ect and i ndi r ect test, posi ti v e; r eti cul ocy te count,
9%; bl ood sm ear , spher ocy tes and i ncr eased r eti cul ocy tes; and bone m ar r ow
bi opsy , i ncr eased cel l ul ar i ty w i th er y thr oi d hy per pl asi a pl us the pr esence of
sm al l l y m phocy tes, suggesti ng l y m phom atous i nv ol v em ent.
8. On the basi s of the f i ndi ngs y i el ded by the i nv esti gati ons f or her anem i a, w hat
ar e the tr eatm ent opti ons at thi s poi nt?
Thi s pati ent does w el l f or 6 m onths w i th m onthl y i ntr av enous chem other apy
and i m m unogl obul i n ther apy , as needed. Tw o y ear s af ter the star t of ther apy ,
i ncr eased spl enom egal y dev el ops that appear s r ef r actor y to the pr ev i ous
chem other apy .
9. Wi th the appear ance of i ncr eased spl enom egal y , w hat i s the di f f er enti al
di agnosi s, and how shoul d y ou conf i r m i t?
10. What ar e the tr eatm ent opti ons i n thi s pati ent w hose di sease i s now i n an
adv anced stage?
P. 320
Case Discussion
1. On the basi s of the phy si cal ex am i nati on and l abor ator y f i ndi ngs, w hat i s the
di f f er enti al di agnosi s i n thi s pati ent?
The neck adenopathy i n thi s pati ent can r epr esent a nor m al f i ndi ng; 50% of
pati ents can hav e l y m ph nodes that ar e l ess than 0. 5 cm i n di am eter . It can
al so si gni f y acute i nf ecti on stem m i ng f r om acute v i r al i nf ecti ons,
m ononucl eosi s, tox opl asm osi s, or pul m onar y i nf ecti ons, but i n thi s setti ng the
nodes ar e usual l y f i r m and tender and r ecede w i thi n 2 to 4 w eek s. Sol i d
tum or s ar e al so a consi der ati on i n the di f f er enti al di agnosi s, and i ncl ude head
and neck cancer , as w el l as thy m i c, l ung, and br east cancer ; l ung and br east
cancer s ar e m or e com m onl y associ ated w i th supr acl av i cul ar and ax i l l ar y
adenopathy . A f our th possi bi l i ty i s Hodgk i n's di sease or nonâ€“Hodgk i n's
l y m phom a. Pati ents w i th l y m phom a can hav e l y m ph nodes that â€œcom e and
go. â€
2. On the basi s of the f i ndi ngs f r om the stagi ng ev al uati on, w hat stage of nonâ
€“Hodgk i n's l y m phom a i s thi s pati ent i n, and w hat ar e her tr eatm ent opti ons
and pr ognosi s?
N onHodgk i n's l y m phom a i s usual l y staged accor di ng to the Ann Ar bor
cl assi f i cati on used f or Hodgk i n's di sease. Accor di ng to thi s sy stem 's cr i ter i a,
thi s pati ent has stage III di sease. In the setti ng of l ow gr ade l y m phom a, i t i s
i m por tant to i denti f y l ocal i zed v er sus di ssem i nated di sease. How ev er ,
pr ognosti c f actor s ar e of ten m ost i m por tant. Thi s pati ent has di sease abov e
and bel ow the di aphr agm as w el l as pr obabl e spl eni c i nv ol v em ent. She does
not cl ear l y hav e bone m ar r ow i nv ol v em ent, because l y m phoi d f ol l i cl es can be a
beni gn f i ndi ng.
In l i ght of these f i ndi ngs, her pr ognosi s i s f ai r l y good. The m edi an sur v i v al f or
tr eated f ol l i cul ar sm al l cl eav ed l y m phom a (f ol l i cul ar gr ade 1) can be up to 15
y ear s. The i ni ti al tr eatm ent f or adv anced l ow gr ade l y m phom a i s v er y
contr ov er si al . It r esponds to both si ngl e and m ul ti pl eagent chem other apy as
w el l as r adi ati on ther apy . How ev er , r egi m ens that i ncl ude anti CD20 anti body
do seem to i ncr ease sur v i v al . Attem pts to er adi cate di sease w i th hi ghdose
chem other apy (w i th or w i thout bone m ar r ow r escue) hav e not been show n to
pr ol ong ov er al l sur v i v al . It w oul d sti l l not be unr easonabl e to w ai t unti l thi s
pati ent becom es sy m ptom ati c bef or e star ti ng tr eatm ent.
3. What ar e the i m pl i cati ons of her cy togeneti c abnor m al i ti es?
The t(14;18) abnor m al i ty i s a com m on f i ndi ng i n the setti ng of f ol l i cul ar sm al l
cl eav ed l y m phom a. In thi s abnor m al i ty , the bc12 oncogene on chr om osom e 18
has been tr ansl ocated to the i m m unogl obul i n heav y chai n l ocus on chr om osom e
14. It i s now w i del y accepted that thi s abnor m al i ty i s f ound i n v i r tual l y al l
pati ents w i th thi s hi stol ogi c patter n. It i s al so f ound i n appr ox i m atel y 30% of
pati ents w i th di f f use l y m phom a, and, i n these cases, i t pr obabl y r epr esents a
hi stol ogi c tr ansf or m ati on f r om f ol l i cul ar sm al l cl eav ed l y m phom a, and can
ther ef or e be consi der ed a poor pr ognosti c i ndi cator . It i s not a pr ognosti c
f actor i n the setti ng of f ol l i cul ar sm al l cl eav ed l y m phom a. The pr esence of
CD20 sur f ace anti gen docum ents that thi s i s a Bcel l l y m phom a and pati ents
w i l l pr obabl y r espond to anti CD20 anti body .
4. Is i t necessar y to f ur ther ev al uate or tr eat her hy pogam m agl obul i nem i a?
Hy pogam m agl obul i nem i a i s occasi onal l y f ound i n associ ati on w i th l ow gr ade
l y m phom a and m or e of ten chr oni c l y m phocy ti c l euk em i a. It i s not of ten a
pr obl em ,
P. 321
as i t i s i n m ul ti pl e m y el om a, but thi s i m m unol ogi c def ect shoul d be consi der ed
w hen i nf ecti ons occur i n these pati ents or w hen neutr openi a i s pr eci pi tated by
tr eatm ent or bone m ar r ow i nv ol v em ent. Pati ents w i th l i f ethr eateni ng
i nf ecti ons m ay benef i t f r om gam m a gl obul i n ther apy .
5. What i s the si gni f i cance of the m onocl onal IgM spi k e i n thi s pati ent?
Al though the si ze of the spi k e i s not quanti f i ed, i t i s sti l l i m por tant i nf or m ati on
because of the possi bi l i ty of hy per v i scosi ty associ ated w i th IgM, unl i k e IgG f or
w hi ch hy per v i scosi ty i s f ar l ess l i k el y . Wal denstr om 's m acr ogl obul i nem i a i s
associ ated w i th l y m phom a, and i s usual l y seen i n pati ents w i th di f f use sm al l
l y m phocy ti c l y m phom a. A m onocl onal gam m opathy can af f ect up to 15% of the
pati ents w i th l ow gr ade l y m phom a and i s m ost com m onl y seen w hen the cel l s
hav e pl asm acy toi d f eatur es.
6. What f or m of ther apy w oul d y ou of f er her w hen the pai nf ul and enl ar gi ng
nodes ar e detected, and w hat outcom e can she ex pect?
The deci si on of w hen to tr eat l ow gr ade nonâ€“Hodgk i n's l y m phom a i s, as
al r eady m enti oned, a contr ov er si al i ssue. Most phy si ci ans r ecom m end w ai ti ng
unti l sy m ptom s appear , consi sti ng of r api dl y enl ar gi ng nodes, B sy m ptom s,
cy topeni as due to bone m ar r ow i nv ol v em ent, or an i ncr eased adenopathy that
thr eatens or gan f uncti on.
If the sy m ptom ati c di sease i s l ocal i zed, r adi ati on ther apy that f ocuses on the
si te i nv ol v ed i s a v i abl e opti on. For the m anagem ent of m or e gener al i zed
di sease, a si ngl e al k y l ati ng agent w i th or w i thout ster oi ds can be v er y
ef f ecti v e. Mor e aggr essi v e com bi nati on chem other apy can al so be consi der ed,
especi al l y w i th anti CD20 m onocl onal anti body ther apy .
In deter m i ni ng the l i k el y outcom e of tr eatm ent i n thi s pati ent, com pl ete
r em i ssi ons can be achi ev ed i n the setti ng of l ow gr ade l y m phom a, m ostl y f or
l ocal i zed (stage I and II) di sease. â€œSpontaneous r em i ssi onâ€ can al so occur
(appr ox i m atel y 5% to 10%). The cur e r ate f or adv anced l ow gr ade l y m phom a
i s v er y l ow . Ev en w i th the i nsti tuti on of aggr essi v e chem other apy (see
pr ecedi ng tex t), l ess than 10% of af f ected pati ents r em ai n di sease f r ee af ter 5
y ear s.
7. How w oul d y ou ev al uate the anem i a that dev el ops w i th the al k y l ati ng agent
ther apy ?
Dur i ng thi s pati ent's i ni ti al ev al uati on, she w as noted to hav e a m i l d anem i a
w i th a sl i ght i ncr ease i n er y thr oi d pr ecur sor s. Her LDH l ev el w as el ev ated, but
her l i v er enzy m e v al ues w er e nor m al . In thi s case, the r ai sed LDH l ev el coul d
r epr esent ei ther a hi gh tur nov er of tum or cel l s or the destr ucti on of r ed bl ood
cel l s (hem ol y si s), or both. The sl i ght el ev ati on i n the num ber of r ed bl ood cel l s
coul d al so be due to per i pher al destr ucti on. Thi s pati ent shoul d under go a
com pl ete assessm ent of her anem i a, i ncl udi ng ev al uati on f or hem ol y si s; i r on,
cobal am i n, and f ol ate def i ci ency ; and bone m ar r ow i nv ol v em ent by l y m phom a
(an unl i k el y cause i n thi s setti ng).
8. On the basi s of the f i ndi ngs y i el ded by the i nv esti gati ons f or her anem i a, w hat
ar e the tr eatm ent opti ons at thi s poi nt?
Thi s pati ent has hem ol y ti c anem i a. It i s m or e com m onl y seen w i th chr oni c
l y m phocy ti c l euk em i a (the l euk em i a phase of f ol l i cul ar sm al l cl eav ed
l y m phom a). Of ten pati ents hav e an under l y i ng com pensated hem ol y si s, as thi s
pati ent di d, w i th anem i a, i ncr eased er y thr oi ds, and an i ncr eased LDH l ev el .
Begi nni ng the tr eatm ent
P. 322
w i th chem other apy can unm ask the hem ol y si s because the bone m ar r ow
r esponse i s r etar ded by m ar r ow suppr essi v e agents.
The tr eatm ent f or hem ol y ti c anem i a i n thi s setti ng has tw o goal s (a) to
ter m i nate the hem ol y ti c pr ocess, and (b) to tr eat the under l y i ng di sease.
Tr eatm ent w i th ster oi ds m ay addr ess both pr obl em s. If the hem ol y si s i s not
stopped w i th hi ghdose ster oi ds, i m m unogl obul i n ther apy shoul d be star ted.
Once the hem ol y si s i s contr ol l ed, a m or e aggr essi v e chem other apeuti c r egi m en
m ay be i m pl em ented.
9. Wi th the appear ance of i ncr eased spl enom egal y , w hat i s the di f f er enti al
di agnosi s, and how shoul d y ou conf i r m i t?
The i ncr eased spl enom egal y that does not r espond to the pr ev i ousl y used
chem other apy m ay r epr esent a tr ansf or m ati on to a m or e aggr essi v e hi stol ogi c
ty pe of l y m phom a. Thi s occur s at a r ate of appr ox i m atel y 5% per y ear i n
pati ents w i th f ol l i cul ar sm al l cl eav ed l y m phom a; usual l y , the tr ansf or m ati on i s
to a di f f use l ar ge cel l l y m phom a. Hi stol ogi c tr ansf or m ati on r epr esents a
change i n the natur al hi stor y of the di sease and si gni f i es a m uch shor tened
sur v i v al .
Hi stol ogi c tr ansf or m ati on shoul d be docum ented by ti ssue ex am i nati on. Agai n,
a l y m ph node or m ass i s the best sour ce of ti ssue f or thi s pur pose.
10. What ar e the tr eatm ent opti ons i n thi s pati ent w hose di sease i s now i n an
adv anced stage?
When hi stol ogi c tr ansf or m ati on occur s, the pr ognosi s i s v er y poor and pati ents
r espond poor l y to ev en the m ost aggr essi v e chem other apeuti c r egi m ens
because of chem or esi stant di sease. In ol der pati ents w ho hav e concur r ent
di sease, i t m ay be r easonabl e to use onl y pal l i ati v e m easur es (pai n
m anagem ent) and per haps adm i ni ster l ocal r adi ati on ther apy , i f needed.
Suggested Readings
Bennett CL, Ar m i tage JL, Ar m i tage GO, et al . Costs of car e and outcom es f or
hi ghdose ther apy and autol ogous tr anspl antati on f or l y m phoi d m al i gnanci es:
r esul ts f r om the U ni v er si ty of N ebr ask a 1987 thr ough 1991. J Cl i n Oncol
1995;13:969.
Canel l os G. Is ther e an ef f ecti v e sal v age ther apy f or adv anced Hodgk i n's
di sease? Ann Oncol 1991;2:1.
DeVi ta VT Jr , Hubbar d SM, Longo DL. Tr eatm ent of Hodgk i n's di sease. J N atl
Cancer Inst 1990;10:19.
Hancock SL, Hoppe RT. Longter m com pl i cati ons of tr eatm ent and causes of
m or tal i ty af ter Hodgk i n's di sease. Sem i n Radi at Oncol 1996;6:225.
Koh HK, Foss FM. Cutaneous Tcel l l y m phom a. Hem atol Oncol Cl i n N or th Am
1995;9:943.
N ati onal Cancer Insti tute. Sum m ar y and descr i pti on of a w or k i ng f or m ul ati on f or
cl i ni cal usage: the N onHodgk i n's Ly m phom a Pathol ogi c Cl assi f i cati on Pr oject.
Cancer 1982;49:2112.
Wal dm ann TA, Dav i s MM, Bongi ov anni KF, et al . Rear r angem ents of genes f or
the anti gen r eceptor on T cel l s as m ar k er s of l i neage and cl onal i ty i n hum an
l y m phoi d neopl asm s. N Engl J Med 1985;313:776.
Young RC, Longo DL, Gl atstei n E, et al . The tr eatm ent of i ndol ent l y m phom as:
w atchf ul w ai ti ng v aggr essi v e com bi ned m odal i ty tr eatm ent. Sem i n Hem atol
1988;25:11.
P. 323
Lung Cancer
1. What ar e the appr ox i m ate i nci dence, death r ate, and r i sk f actor s f or l ung
cancer ?
2. What ar e the tw o pathol ogi c categor i es of l ung cancer , and thei r hi stol ogi c
f eatur es?
3. What ar e som e cl i ni cal f eatur es that m ay suggest a cor r el ati on w i th a cer tai n
pathol ogi c subty pe?
4. What i s essenti al l y the m ai nstay of cur ati v e ther apy i n nonâ€“sm al l cel l l ung
cancer (N SCLC)?
5. How does the stagi ng and tr eatm ent of sm al l cel l l ung cancer (SCLC) di f f er
f r om that of N SCLC?
6. What ar e the tw o m ajor deter m i nants of pr ognosi s f or both N SCLC and SCLC?
Discussion
1. What ar e the appr ox i m ate i nci dence, death r ate, and r i sk f actor s f or l ung
cancer ?
Each y ear , l ung cancer k i l l s m or e m en and w om en i n the U ni ted States than
any other cancer , and ther e ar e appr ox i m atel y 150, 000 new cases of l ung
cancer di agnosed each y ear . At the ti m e of di agnosi s, onl y 35% of pati ents
hav e l ocal di sease; ther ef or e, the di sease has spr ead to r egi onal nodes or
di stant si tes i n 65%. How ev er , ev en i n pati ents w i th nonm etastati c (l ocal )
di sease, com pl ete cur e i s the ex cepti on; ther ef or e, the y ear l y m or tal i ty r ate
appr oaches the annual i nci dence, and thi s w as esti m ated to be 172, 000 i n
2005.
Appr ox i m atel y 90% of al l pati ents di agnosed w i th l ung cancer hav e a hi stor y of
sm ok i ng, and the causal r el ati onshi p betw een tobacco use and l ung cancer
m ak es i t a m ajor publ i c heal th pr obl em and one of the m ost potenti al l y
pr ev entabl e di seases. Other i m por tant r i sk f actor s account f or l ess than 10%
of cases of l ung cancer di agnosed, and these i ncl ude ur ani um and r adon
ex posur e and passi v e sm ok i ng (another r eason f or sm ok i ng cessati on
pr ogr am s). The r i sk of acqui r i ng l ung cancer f al l s si gni f i cantl y i n the f i r st 5
y ear s af ter the cessati on of sm ok i ng, and, ev en af ter 20 y ear s, the r i sk i s
hi gher than i n peopl e w ho hav e nev er sm ok ed.
To i l l ustr ate the ser i ousness of the publ i c heal th pr obl em , the l ung cancer
i nci dence betw een 1940 and 2000 has r i sen by 60% i n w om en, f r om 7 to 45 per
100, 000, and thi s i s m ai nl y due to the i ncr eased use of tobacco i n the f em al e
popul ati on. In addi ti on, a hi gher thanex pected i nci dence of l ung cancer has
been seen i n w om en i n the l esser pack y ear categor i es, suggesti ng that w om en
ar e acqui r i ng l ung cancer at a y ounger age and af ter sm ok i ng f ew er y ear s than
m en.
Fur ther m or e, al though ov er al l tobacco use i s decr easi ng i n the U ni ted States,
sm ok i ng m ay be i ncr easi ng am ong cer tai n gr oups of m i nor i ti es and
adol escents, and r ecent tobacco com pany adv er ti si ng cam pai gns hav e been
P. 324
di r ected tow ar d these gr oups. The y ear s of potenti al l ost l i f e r esul ti ng f r om
l ung cancer m or tal i ty i n these gr oups i s pr obabl y tw i ce that seen f or the
r em ai ni ng popul ati on.
2. What ar e the tw o pathol ogi c categor i es of l ung cancer , and thei r hi stol ogi c
f eatur es?
For both tr eatm ent and pr ognosti c pur poses, m ost l ung cancer s ar e di v i ded i nto
tw o cl i ni cal l y usef ul categor i es: SCLC, w hi ch accounts f or 15% of al l l ung
cancer s, and N SCLC, w hi ch consi sts of squam ous cel l car ci nom as (40% of the
l ung cancer s), adenocar ci nom as (40% of the l ung cancer s), and l ar ge cel l
car ci nom as and other s (5% of the l ung cancer s).
3. What ar e som e cl i ni cal f eatur es that m ay suggest a cor r el ati on w i th a cer tai n
pathol ogi c subty pe?
Pati ents m ay pr esent w i th a v ar i ety of sy m ptom s, i ncl udi ng cough, hem opty si s,
shor tness of br eath, chest pai n, or unex pl ai ned w ei ght l oss (Tabl e 712).
Abnor m al i ti es r ev eal ed by the phy si cal ex am i nati on m ay suggest the di agnosi s
and i ncl ude si gns of l ung consol i dati on r esul ti ng f r om an obstr ucted br onchus,
supr acl av i cul ar adenopathy stem m i ng f r om the l ocal and r egi onal spr ead of the
cancer , or Hor ner sy ndr om e, w hi ch i s due to tum or i m pi ngem ent on the
sy m patheti c ner v e f i ber s that cour se near the apex of the l ung.
Labor ator y ex am i nati on m ay r ev eal the pr esence of hy ponatr em i a due to the
sy ndr om e of i nappr opr i ate anti di ur eti c hor m one secr eti on (SIADH); thi s i s a
par aneopl asti c sy ndr om e caused by i nappr opr i ate v asopr essi n secr eti on, and i s
seen m ost of ten i n the setti ng of SCLC. The hy ponatr em i a that pr esum abl y
r esul ts f r om SIADH can be dem onstr ated i n up to 60% of the pati ents w i th
SCLC, by adm i ni ster i ng a w ater l oad. Cushi ng's sy ndr om e m ay dev el op
secondar y to the ex cessi v e pr oducti on of adr enocor ti cotr opi c hor m one by the
tum or , and, agai n, i s m ost com m onl y seen i n SCLC. Both the absol ute and
i oni zed ser um cal ci um l ev el s m ay be hi gh, and thi s can be due to m ul ti pl e
r easons, i ncl udi ng m etastases to bone as w el l as the pr oducti on of a
par athy r oi d hor m oneâ€“l i k e substance f r om the cancer . Hy per cal cem i a i s m ost
of ten seen
P. 325
i n pati ents w i th squam ous (epi der m oi d) l ung cancer , but m ay be associ ated
w i th any hi stol ogi c subty pe. The l ocati on of the tum or by chest r adi ogr aphi c
studi es as w el l as speci f i c l abor ator y f i ndi ngs can suggest cer tai n hi stol ogi c
ty pes. Squam ous cel l car ci nom as and SCLCs tend to be f ound centr al l y on the
chest r adi ogr aphy . Squam ous cel l l ung cancer tends to cav i tate, and thi s can
be seen on chest r adi ogr aphs. Adenocar ci nom a tends to occur per i pher al l y i n
the l ung, and thi s i s the m ost com m on l ung cancer i n those w ho hav e nev er
sm ok ed.
Table 712 Signs and Symptoms of Lung Cancer
Signs a nd Symptoms No. of P a tie nts

(% )
Routi ne chest r adi ogr aphi c study 16

(asy m ptom ati c)
Hem opty si s 30
Cough 25
Dy spnea 11
Pneum oni ti s 8
Pai n 6
Wheezi ng 2
Dy sphagi a 1
Hoar seness 0. 5
Sy stem i c sy m ptom sâ€”w ei ght l oss 0. 5
Al though these cl i ni cal l y usef ul associ ati ons cannot establ i sh a di agnosi s, they
can hel p the oncol ogi st di r ect the natur e of the ev al uati on, both bef or e and
af ter the hi stol ogi c ty pe i s k now n.
4. What i s essenti al l y the m ai nstay of cur ati v e ther apy i n N SCLC?
Si gni f i cant cur e r ates f or N SCLC ar e achi ev ed onl y f or com pl ete sur gi cal
r esecti on of nonm etastati c di sease. The stagi ng pr ocess def i nes the ex tent of
di sease spr ead, and the stage cor r el ates w i th the r esectabi l i ty and hence w i th
the cur e r ates and sur v i v al . N o cur es ar e seen usi ng the cur r ent f or m s of
chem other apy , and cur e i s uncom m on w i th r adi ati on ther apy al one
(appr ox i m atel y 5% of stage III cases).
In al l cases i n w hi ch r esecti on i s per f or m ed w i th cur ati v e i ntent, the deci si on
to go ahead w i th r esecti on i s based on the ex pectati on that no gr oss r esi dual
di sease w i l l r em ai n at the concl usi on of the pr ocedur e. Thi s i nv ol v es m ul ti pl e
pr eoper ati v e deci si ons, i ncl udi ng (a) v er i f y i ng that the pati ent's l ung f uncti on
can tol er ate obl i gate r esecti on of som e nor m al l ung; (b) ensur i ng that ther e i s
no pul m onar y or ex tr apul m onar y di sease that w oul d pr ecl ude m ajor sur ger y
and gener al anesthesi a; and (c) accur atel y stagi ng the ex tent of di sease to
sel ect onl y those pati ents w i th a r easonabl e chance of com pl ete r esecti on.
Ev en w i th these consi der ati ons, how ev er , ov er al l onl y 20% of al l pati ents w i th
N SCLC sur v i v e 5 y ear s, and l ess than hal f of pati ents w ho under go successf ul
r esecti on r em ai n f r ee of di sease at 5 y ear s.
At pr esent, onl y stage I and II, and som e stage III, pati ents ar e consi der ed
good candi dates f or r esecti on w i th a r easonabl e chance of cur e. Thi s m eans
the tum or cannot be associ ated w i th m al i gnant ef f usi on, cannot hav e spr ead to
contr al ater al m edi asti nal l y m ph nodes, and cannot hav e m etastasi zed to any
di stant si te. The usual si tes of di stant m etastases i n pati ents w i th l ung cancer
i ncl ude the adr enal gl ands, bone, br ai n, l ung, l y m ph nodes, and pl eur a. Less
com m on si tes of m etastases ar e the sk i n and bone m ar r ow .
The standar d tr eatm ent f or stage IIIB pati ents (i . e. , those w i thout di stant
m etastases but w i th unr esectabl e and l ocal l y adv anced di sease) i s r adi ati on
ther apy to a total dose of 55 to 60 Gy al ong w i th chem other apy . Onl y 20% of
these pati ents ar e al i v e at 5 y ear s. Stage IV pati ents ar e those w i th di stant
m etastases and, by and l ar ge, tr eatm ent i n thi s setti ng i s f or pal l i ati on onl y
and consi sts m ostl y of chem other apy usi ng pl ati num based r egi m ens.
5. How does the stagi ng and tr eatm ent of SCLC di f f er f r om that of N SCLC?
Sm al l cel l l ung car ci nom a di f f er s m ar k edl y f r om the other pathol ogi c ty pes of
l ung cancer i n ter m s of i ts natur al hi stor y , cel l bi ol ogy , and r esponse to
ther apy , and i s di sti nct f r om N SCLC. SCLC has a r api d cl i ni cal cour se, and
P. 326
the m edi an sur v i v al i n untr eated pati ents i s onl y 2 m onths f or m etastati c and 6
m onths f or l ocal i zed di sease. On the basi s of autopsy data, 80% of pati ents
w i th SCLC hav e di stant m etastases at the ti m e of di agnosi s. Thi s i ncl udes the
40% w ho at di agnosi s hav e no ev i dence of di stant m etastases accor di ng to the
r esul ts of the usual stagi ng pr ocedur es.
For pr acti cal r easons, SCLC i s f ur ther def i ned as ei ther l i m i ted or ex tensi v e. In
l i m i ted di sease, the tum or i s conf i ned to the hem i thor ax of or i gi n and r egi onal
l y m ph nodes, and can be encom passed i n a tol er abl e r adi ati on ther apy f i el d. In
ex tensi v e di sease, tum or ex i sts bey ond these bounds, usual l y di stant
m etastases. Sur ger y (other than f or di agnosti c bi opsy ) has no r ol e i n the
m anagem ent of SCLC because ev en m ost of the pati ents w i th l i m i ted di sease
hav e subcl i ni cal di stant m etastases; com pl ete r esponse r ates to chem other apy
i n SCLC ar e as hi gh as 40% to 70%, w i th com pl ete pl us par ti al r esponse r ates
as hi gh as 80% to 85%, and sur v i v al i n the setti ng of untr eated di sease i s
di sm al . Instead, m ost pati ents shoul d r ecei v e com bi nati on chem other apy . Wi th
si x or m or e cour ses of chem other apy and r adi ati on, appr ox i m atel y 20% of
pati ents w i th l i m i ted di sease can ex pect to be al i v e at 5 y ear s, and these
r epr esent pr obabl e cur es. The cur r ent standar d of ther apy i ncl udes i r r adi ati on
of the i nv ol v ed ar eas as w el l as chem other apy to decr ease the chances of
r el apse, l ocal l y .
In pati ents w i th ex tensi v e di sease w ho under go chem other apy , the par ti al pl us
com pl ete r esponse r ates can r ange f r om 50% to 85% and the m edi an sur v i v al
can r ange f r om 7 to 11 m onths; how ev er , ther e ar e onl y anecdotal r epor ts of
cur e at 5 y ear s.
6. What ar e the tw o m ajor deter m i nants of pr ognosi s f or both N SCLC and SCLC?
For both SCLC and N SCLC, the pr ognosi s depends on (a) the tum or ex tent
(gr aded as l i m i ted or ex tensi v e i n SCLC and as stage I to IV i n N SCLC) and (b)
the per f or m ance status of the pati ent. Better r esponses to ther apy and
cer tai nl y m or e si gni f i cant cur e r ates ar e seen i n pati ents w i th l ow er stage l ung
cancer s. In addi ti on, the per f or m ance status [usual l y m easur ed by the Easter n
Cooper ati v e Oncol ogy Gr oup (ECOG) scal e] i s a m ajor pr edi ctor of r esponse to
ther apy and sur v i v al . Pati ents w ho ar e sy m ptom ati c or , m or e si gni f i cantl y ,
nonam bul ator y (as i ndi cated by thei r per f or m ance status) ar e l ess l i k el y to
r espond to ther apy and hav e shor ter sur v i v al s. The per f or m ance status scal es
m ost of ten used by cl i ni ci ans ar e gi v en i n Tabl e 713.
Case 1
A 56y ear ol d r eal estate br ok er w i th a 76 pack y ear hi stor y of tobacco use (he has
sm ok ed tw o pack s of ci gar ettes per day si nce 18 y ear s of age) has been f ol l ow ed
up r egul ar l y by hi s phy si ci an. He under goes y ear l y chest r adi ogr aphi c studi es, and
the m ost r ecent r adi ogr aphs obtai ned 8 m onths ear l i er w er e nor m al . He i s seen by
hi s phy si ci an because of 10 day s of hem opty si s, consi sti ng of bl oodti nged sputum
pr oducti on, i n the setti ng of a chr oni c cough. He deni es w ei ght l oss, chest pai n, and
bone pai n, and he ex per i ences no i ncr eased dy spnea on ex er ti on. On ex am i nati on,
hi s l ungs ar e f ound to be cl ear ; ther e i s nei ther hepatospl enom egal y nor cl ubbi ng
and the neur ol ogi c f i ndi ngs ar e gr ossl y nonf ocal . Labor ator y studi es show nor m al
l i v er f uncti on, a cal ci um l ev el of
P. 327
11. 1 m g/dL, and an al bum i n l ev el of 3. 9 g/dL. Hi s com pl ete bl ood count i s nor m al .
A chest r adi ogr aphi c study dem onstr ates a new , 2 Ã— 3 cm , r i ght hi l ar m ass.
Table 713 Karnofsky and Zubrod Performance
Status Scales
De finition Ka rnofs k y Sc a le Zubrod Sc a le

(% ) (Old (SW OG , ECOG
Comple x a re
Cla s s ific a tion) Va ria tions )
N or m al ; no com pl ai nts; no ev i dence 100 0

of di sease
Abl e to car r y on nor m al acti v i ty ; 90 1

m i nor si gns or sy m ptom s of di sease
N or m al acti v i ty w i th ef f or t; som e 80 1

si gns or sy m ptom s of di sease (no
speci al car e needed; f ul l y
am bul ator y )
Car es f or sel f but unabl e to car r y on 70 2

nor m al acti v i ty (unabl e to w or k ; i n
bed < 50%/d)
Requi r es occasi onal assi stance but i s 60 2

abl e to car e f or m ost needs (i n bed
> 50%/d but not bedr i dden)
Requi r es consi der abl e assi stance and 50 3

f r equent m edi cal car e
Di sabl ed; r equi r es speci al car e and 40 3

assi stance
Bedr i dden 30 4
Ver y si ck ; hospi tal i zati on necessar y 20 4
Mor i bund 10 4
Dead 0 5
SWOG, Southw est Oncol ogy Gr oup; ECOG, Easter n Cooper ati v e Oncol ogy
Gr oup.
1. What di agnosti c tests shoul d be per f or m ed i n thi s pati ent?
2. Was a y ear l y chest r adi ogr aphi c study a r easonabl e scr eeni ng pr ocedur e f or
thi s m an w ho sm ok es, or shoul d thi s hav e been done m or e f r equentl y ?
3. What cl i ni cal f i ndi ng suggests (al though does not establ i sh) the hi stol ogi c ty pe
of thi s pati ent's l ung cancer , and w hat ty pe i s i t?
4. What stage of l ung cancer i s thi s pati ent i n, and w hat f ur ther studi es shoul d be
per f or m ed?
5. If the pati ent has stage II N SCLC, w hat i s the appr opr i ate tr eatm ent?
6. What f ur ther m easur es can be tak en to r educe the pati ent's r i sk of death f r om
l ung cancer ?
Case Discussion
1. What di agnosti c tests shoul d be per f or m ed i n thi s pati ent?
Most l ung cancer s ar e di agnosed on the basi s of the f i ndi ngs y i el ded by
br onchoscopi c bi opsy of a l ung m ass. In som e si tuati ons, how ev er , ther e i s an
easi er
P. 328
sour ce of ti ssue. For ex am pl e, bi opsy of an abnor m al (pal pabl e)
supr acl av i cul ar l y m ph node, i f pr esent, w i l l l i k el y y i el d ti ssue adequate f or
hi stol ogi c study as w el l as f or stagi ng pur poses, and the i nf or m ati on gai ned i s
i m por tant i n pl anni ng tr eatm ent.
The cl i ni ci an m ust be w ar y of i ni ti al di agnoses of m al i gnancy based on the

f i ndi ngs r ev eal ed by the f i neneedl e aspi r ati on (FN A) techni que. Thi s m ethod
obtai ns ei ther onl y si ngl e cel l s or sm al l cl um ps of cel l s f or cy tol ogi c study
w i thi n the aspi r ate, and i t i s al m ost al w ay s di f f i cul t or i m possi bl e to deter m i ne
an ex act pathol ogi c di agnosi s based on the i nf or m ati on r ev eal ed. FN A bi opsy
shoul d usual l y be r eser v ed f or conf i r m ati on of m etastases or r ecur r ences af ter
an i ni ti al di agnosi s has al r eady been m ade. In m ost cases, br onchoscopi c
bi opsy obtai ns ti ssue adequate f or hi stol ogi c ex am i nati on.
Som eti m es, pati ents pr esent w i th sy m ptom s stem m i ng f r om m etastati c
di sease, and the sour ce of a pr i m ar y tum or i s not as cl ear as i t i s i n thi s
pati ent. In such an ev ent, cor r el ati on of the pathol ogi c char acter i sti cs i ncl udi ng
speci al stai ns w i th the l i k el y sour ces of the pr i m ar y cancer can suggest the
f ur ther r adi ol ogi c and di agnosti c tests to be per f or m ed to deter m i ne the or i gi n
of the tum or .
2. Was a y ear l y chest r adi ogr aphi c study a r easonabl e scr eeni ng pr ocedur e f or
thi s m an w ho sm ok es, or shoul d thi s hav e been done m or e f r equentl y ?
Because l ung cancer (both N SCLC and SCLC) cur e r ates ar e si gni f i cant onl y i n
the setti ng of ear l i er stage di sease (stage I and II N SCLC and l i m i tedstage
SCLC), i t seem s r easonabl e that ear l i er detecti on w oul d i ncr ease the
per centage of cur es. In sev er al r andom i zed, contr ol l ed tr i al s, m ass scr eeni ng
usi ng r oentgenogr aphi c and sputum cy tol ogy has been done i n 31, 360 hi ghr i sk
pati ents (m en 45 y ear s of age or ol der w ho sm ok ed at l east one pack of
ci gar ettes per day ). Al l these studi es hav e show n that i ntensi v e scr eeni ng can
detect ear l y l ung cancer , but 45% to 60% of pati ents so i denti f i ed actual l y
hav e stage II or III di sease, f or w hom the 5y ear sur v i v al r ate i s 35%.
Inv esti gator s at al l thr ee center s contend that the m or tal i ty r ates f or l ung
cancer do not di f f er si gni f i cantl y betw een the scr eeni ng gr oup and the contr ol
gr oup. Ther ef or e, at thi s ti m e ther e i s no justi f i cati on f or the l ar gescal e
appl i cati on of these scr eeni ng m ethods, ev en i n hi ghr i sk popul ati ons.
Year l y scr eeni ng chest r adi ogr aphi c studi es i n the sm ok i ng popul ati on i s not
r ecom m ended and no study f i ndi ngs suppor t m or e f r equent scr eeni ng chest
r oentgenogr aphy to decr ease the m or tal i ty .
3. What cl i ni cal f i ndi ng suggests (al though does not establ i sh) the hi stol ogi c ty pe
of thi s pati ent's l ung cancer , and w hat ty pe i s i t?
Thi s pati ent's chest r adi ogr aph r ev eal ed the l ung m ass to be centr al (hi l ar ) i n
l ocati on. The tw o com m on tum or ty pes ty pi cal l y f ound i n thi s l ocati on ar e
squam ous (epi der m oi d) cel l car ci nom a (a ty pe of N SCLC) and SCLC, al though
bi opsy f i ndi ngs ar e needed to establ i sh the di agnosi s. The hi gh cal ci um v al ue
i s m ost of ten seen w i th squam ous cel l car ci nom a.
4. What stage of l ung cancer i s thi s pati ent i n, and w hat f ur ther studi es shoul d be
per f or m ed?
Accor di ng to the cur r ent Am er i can Joi nt Com m i ttee on Cancer (TN M) stagi ng
sy stem , the stage of thi s pati ent's cancer i s T2 N X MX (tum or 3 cm i n gr eatest
di m ensi on, nodal status unk now n, and unk now n m etastases).
P. 329
In the setti ng of N SCLC, nor m al l i v er f uncti on test r esul ts (i ncl udi ng
am i notr ansf er ases, al k al i ne phosphatase, LDH, and Î³gl utam y l tr anspepti dase)
pr edi ct r easonabl y w el l that no l i v er m etastases w i l l be f ound on a
r adi onucl i de or CT scan. In thi s pati ent, a CT scan of the chest shoul d be
obtai ned to ev al uate the hi l ar and m edi asti nal nodes, and the ex am i nati on can
easi l y be ex tended thr ough the l i v er and adr enal s. If the CT f i ndi ngs and the
al k al i ne phosphatase l ev el ar e nor m al , and because the pati ent has no bone
pai n, these w oul d pr edi ct no bone m etastases, m ak i ng a bone scan
unnecessar y . If f i ndi ngs f r om a thor ough neur ol ogi c ex am i nati on per f or m ed by
a consul ti ng neur ol ogi st ar e nor m al , CT scanni ng of the head can be def er r ed.
In thi s setti ng, the pati ent w oul d cl i ni cal l y be i n stage II, gr aded T2 N 0 M0. A
PET scan w oul d better conf i r m thi s stagi ng i f sur ger y i s consi der ed (see
pr ecedi ng tex t).
5. If the pati ent has stage II N SCLC, w hat i s the appr opr i ate tr eatm ent?
For stage II N SCLC, sur gi cal ex ci si on (l obectom y or pneum onectom y ) w i th
i ntent of cur e i s the tr eatm ent of choi ce. If the ar ter i al bl ood gas v al ues,
pul m onar y f uncti on tests, el ectr ocar di ogr am , and past m edi cal hi stor y i ndi cate
that the pati ent has no ex cess r i sk f or m ajor sur ger y , a thor aci c sur geon i s
then consul ted. Because the pati ent m ay sti l l hav e spr ead of cancer to the
m edi asti nal or hi l ar nodes (and not seen on a CT or PET scan as bei ng
abnor m al ), w hi ch w oul d m ak e hi s cancer unr esectabl e, m edi asti noscopy m i ght
be per f or m ed especi al l y i f the pati ent i s not the best sur gi cal candi date.
If these f i ndi ngs ar e negati v e, a r i ght upper l obectom y thr ough a l ater al
thor acotom y can be per f or m ed w i th subsequent pathol ogi c study . If , f or
i nstance, a 2. 8 Ã— 3. 2cm tum or w i th tw o per i br onchi al nodes posi ti v e f or
squam ous cel l l ung cancer i s encounter ed at sur ger y , the pati ent i s i n
pathol ogi c stage II, desi gnated T2 N 1 M0, and hi s ov er al l chance of 5y ear
sur v i v al r anges f r om 35% to 45% (w i th postoper ati v e chem other apy ). If the
pati ent i s f ound to hav e a pathol ogi c stage I tum or , the 5y ear sur v i v al w oul d
appr oach 50% to 60%, m ostl y r epr esenti ng cur es.
6. What f ur ther m easur es can be tak en to r educe the pati ent's r i sk of death f r om
l ung cancer ?
Ev en pati ents sur gi cal l y cur ed of thei r l ung cancer hav e a si gni f i cant chance of
acqui r i ng subsequent l ung cancer s, as w el l as other tum or s. As w i th those i n
w hom tum or s hav e not y et dev el oped, cessati on of sm ok i ng can si gni f i cantl y
r educe subsequent r i sk , and thi s pati ent shoul d be str ongl y adv i sed to do so.
Case 2
A 68y ear ol d w om an pr esents to the em er gency r oom because of a new onset
gr and m al sei zur e. She i s l ethar gi c, but neur ol ogi c f i ndi ngs ar e other w i se nor m al . A
head CT scan r ev eal s a 2cm r i ght par i etal and a 0. 5cm l ef t occi pi tal enhanci ng
m ass, and a chest r adi ogr aphi c study r ev eal s a 4cm l ef t hi l ar m ass w i th di stal
atel ectasi s. She has sm ok ed one pack of ci gar ettes per day f or 40 y ear s, but qui t 1
m onth ago. Anti conv ul sants ar e adm i ni ster ed, the pati ent i s adm i tted to the
hospi tal , and br onchoscopy i s per f or m ed, w hi ch show s a m ass i n the r i ght m ai nstem
br onchus. Bi opsy i s done and pathol ogi c ex am i nati on r ev eal s a sm al l cel l cancer .
A bone scan show s an abnor m al i ty i n her l ef t f em ur , and her al k al i ne phosphatase
l ev el i s i ncr eased at 214 m U /m L. A CT scan of the abdom en i s nor m al .
P. 330

2. How shoul d thi s pati ent's cancer be tr eated?
3. If , 6 w eek s af ter di agnosi s, phy si cal ex am i nati on r ev eal s onl y al opeci a, and a
chest r adi ogr aph and bone scan ar e nor m al , w hat i s the l i k el i hood of cur e?
Case Discussion
The pati ent has ex tensi v e SCLC w i th m etastases to the br ai n.
2. How shoul d thi s pati ent's cancer be tr eated?
Most chem other apy tr av er ses the bl oodâ€“br ai n bar r i er poor l y . Ther ef or e, the
pati ent shoul d be star ted on w hol ebr ai n r adi ati on ther apy . Because SCLC i s a
r api dl y gr ow i ng tum or , and r adi ati on ther apy l asts 4 to 6 w eek s, com bi nati on
chem other apy shoul d al so be i ni ti ated.
3. If , 6 w eek s af ter di agnosi s, phy si cal ex am i nati on r ev eal s onl y al opeci a, and a
chest r adi ogr aph and bone scan ar e nor m al , w hat i s the l i k el i hood of cur e?
Sm al l cel l l ung cancer i s r esponsi v e to both r adi ati on ther apy and
chem other apy . Com pl ete r esponses ar e w i tnessed i n 15% to 30% of pati ents
w i th ex tensi v e di sease. How ev er , the 5y ear sur v i v al i s onl y 4% to 8% i n thi s
setti ng, and tum or usual l y r ecur s qui ck l y .
Suggested Readings
Bunn PA, Li chter AS, Mak uch RW, et al . Chem other apy al one or chem other apy
w i th chest r adi ati on ther apy i n l i m i ted stage sm al l cel l l ung cancer : a
pr ospecti v e r andom i zed tr i al . Ann Inter n Med 1987;106:655.
Car ney DN , de Lei j L. Lung cancer bi ol ogy . Sem i n Oncol 1988;15:199.
El der l y Lung Cancer Vi nor el bi ne Ital i an Study Gr oup. Ef f ects of v i nor el bi ne on
qual i ty of l i f e and sur v i v al of el der l y pati ents w i th adv anced nonsm al l cel l l ung
cancer . J N atl Cancer Inst 1999;91:66.
Far r ay D, Mi r k ov i c N , Al bai n KS. Mul ti m odal i ty ther apy f or stage III nonsm al l
cel l l ung cancer . J Cl i n Oncol 2005;23:3257.
Lababede O, Mezi ane MA, Ri ce TW. TN M stagi ng of l ung cancer : a qui ck
r ef er ence char t. Chest 1999;115:233.
Mountai n CF, Luck m an JM, Ham m er SP, et al . Lung cancer cl assi f i cati on: the
r el ati onshi p of di sease ex tent and cel l ty pe to sur v i v al i n a cl i ni cal tr i al s
popul ati on. J Sur g Oncol 1987;35:147.
Prostate Cancer
1. How com m on i s pr ostate cancer ?
2. How does pr ostate cancer ar i se and spr ead?
3. How i s pr ostate cancer gr aded and staged, and w hy i s thi s i m por tant?
P. 331
4. What i s the ty pi cal cl i ni cal pr esentati on of pr ostate cancer ?
5. Af ter a phy si cal ex am i nati on, how i s a suspi ci on of pr ostate cancer conf i r m ed?
6. Once pr ostate cancer i s di agnosed, how i s a stagi ng ev al uati on per f or m ed?
7. What tr eatm ent i s r ecom m ended f or stage Al pr ostate cancer ?
8. Whi ch categor y of pati ents i s consi der ed f or a r adi cal pr ostatectom y ?
9. Is any al ter nati v e ther apy av ai l abl e f or pati ents w i th stage A2 or B pr ostate
cancer ?
10. What ther apy m ay be adm i ni ster ed to pati ents w i th stage C or D di sease?
11. In ter m s of the r ecom m ended tr eatm ents, w hat sur v i v al can be ex pected i n
pati ents w i th stage A1, A2, B, or C pr ostate cancer ?
12. What com pl i cati ons attend the use of r adi cal pr ostatectom y and i r r adi ati on
w hi ch pati ents shoul d be aw ar e of i n adv ance?
13. What i s the tr eatm ent f or di ssem i nated pr ostate cancer ?
14. Is the pr ostatespeci f i c anti gen l ev el usef ul i n scr eeni ng asy m ptom ati c m en f or
pr ostate cancer ?
Discussion
1. How com m on i s pr ostate cancer ?
Appr ox i m atel y 90, 000 new cases of car ci nom a of the pr ostate ar e i denti f i ed
ev er y y ear . Of m en i n thei r ei ghti es and ol der than 90 y ear s, 50% and 90% of
the pr ostates, r especti v el y , ar e f ound to hav e car ci nom a at autopsy . It i s the
second m ost com m on m al i gnancy i n Am er i can m en and the m ost com m on
cancer ous cause of death i n m en ol der than 75 y ear s. The cl i ni cal i nci dence i s
hi gher i n bl ack s than i n w hi tes, and i t i s m uch l ow er f or Japanese m en l i v i ng i n
Japan. Ther ef or e, r aci al and env i r onm ental f actor s m ay be i nv ol v ed i n i ts
dev el opm ent.
2. How does pr ostate cancer ar i se and spr ead?
Pr ostate adenocar ci nom a ar i ses f r om the epi thel i um of the per i pher al aci nar
gl ands. It i s sl ow gr ow i ng, and hal f of al l cases of ear l y stage (A) pr ostate
cancer ar e f ound onl y at autopsy . Pr ostate cancer f i r st ex tends l ocal l y thr ough
i ts capsul e and then i nv ades the l y m phati cs and bl ood v essel s. Ly m ph node
i nv ol v em ent occur s sequenti al l y , w i th i ni ti al spr ead to the per i pr ostati c and
obtur ator nodes, and l ater the i l i ac and per i aor ti c nodes. Di stant hem atogenous
spr ead tends to occur l ate i n the di sease and f r equentl y i nv ol v es the ax i al and
pr ox i m al sk el eton, l i v er , and l ungs. How ev er , m or e than hal f of al l
sy m ptom ati c pati ents w i th pr ostate cancer pr esent w i th m etastases.
3. How i s pr ostate cancer gr aded and staged, and w hy i s thi s i m por tant?
Pr ostate cancer i s br oadl y staged i nto categor i es A, B, C, and D. Stage A i s

car ci nom a detected by pathol ogi c ex am i nati on of gl ands r em ov ed because of
cl i ni cal l y beni gn di sease. Stage A1 r epr esents w el l di f f er enti ated tum or
i nv ol v i ng l ess than 5% of the sur gi cal speci m en, and stage A2 consti tutes
tum or ei ther i nv ol v i ng m or e than 5% of the sur gi cal speci m en or a poor l y
di f f er enti ated tum or . Stage B i s cl i ni cal l y detectabl e di sease that i s
i ntr acapsul ar and i nv ol v es one l obe (B1) or m or e than one l obe (B2). In stage
A and B cancer , the pr ostatespeci f i c anti gen l ev el s ar e el ev ated 15% and 25%
of the i nstances,
P. 332
r especti v el y . Stage C i s cancer that has i nv aded thr ough the pr ostate capsul e
but i s conf i ned to the pel v i s. Stage D, or m etastati c di sease, i ncl udes tw o
categor i es: D1 (l ocal pel v i c nodal i nv ol v em ent) and D2 (di stant, nodal , bone,
or v i scer al di sease), and i s associ ated w i th el ev ated ser um tum or m ar k er s.
4. What i s the ty pi cal cl i ni cal pr esentati on of pr ostate cancer ?
Cl assi cal l y , the di sease i s detected i n el der l y m en w i th the occur r ence of back
pai n, w ei ght l oss, anem i a, ur i nar y f r equency , and noctur i a, and, l ess of ten,
dy sur i a, a sl ow ur i nar y str eam , ur i nar y r etenti on, and r ar el y hem atur i a.
Pr ostate cancer can be f ound dur i ng a r outi ne phy si cal ex am i nati on or
scr eeni ng, or w hen i nv esti gati ng f or a pathol ogi c f r actur e, bone pai n, pal pabl e
l y m phadenopathy , chr oni c r enal i nsuf f i ci ency , anem i a, cachex i a, or a num ber
of other seem i ngl y unr el ated si gns and sy m ptom s. Appr ox i m atel y 50% of the
i ndur ated pr ostati c l esi ons f el t on r ectal ex am i nati on tur n out to be
adenocar ci nom a on bi opsy . The m ost ef f ecti v e scr eeni ng test r em ai ns a car ef ul
r ectal ex am i nati on that shoul d be per f or m ed star ti ng f r om age 50.
5. Af ter a phy si cal ex am i nati on, how i s a suspi ci on of pr ostate cancer conf i r m ed?
Most of ten, the di agnosi s of pr ostate cancer i s conf i r m ed by needl e bi opsy
f i ndi ngs. The tr ansr ectal r oute has been m ade accur ate and saf e thr ough the
use of tr ansr ectal ul tr asonogr aphy and the bi opsy gun. Open bi opsy and
tr ansur ethr al bi opsy ar e l ess f r equentl y used ow i ng to the hi gher m or bi di ty
associ ated w i th thei r use.
6. Once pr ostate cancer i s di agnosed, how i s a stagi ng ev al uati on per f or m ed?
A thor ough phy si cal ex am i nati on i s per f or m ed to deter m i ne the si ze of the
pr i m ar y tum or and i f any ev i dence of m etastati c tum or i s pr esent. Ser um
pr ostatespeci f i c anti gen l ev el and l i v er f uncti on ar e assessed. A chest
r adi ogr aphi c study and r adi oi sotope bone scan ar e r outi nel y per f or m ed.
Dependi ng on the pati ent, pel v i c or other CT scans, ul tr asonogr aphy , bi pedal or
pel v i c l y m phadenectom y , and a sk el etal r adi ogr aphi c sur v ey m ay be r equi r ed.
Intr av enous py el ogr aphy i s per f or m ed to assess ur eter al status.
A com pl ete bl ood count as w el l as BU N and ser um cr eati ni ne m easur em ents
ar e r outi nel y done to detect anem i a or obstr ucti v e ur opathy . The pr ostate
speci f i c anti gen l ev el i s sensi ti v e (95%) and equal l y speci f i c (> 95%). A chest
r adi ogr aphi c study m ay r ev eal m etastases to the r i bs, l ungs, or hi l ar nodes.
The bone scan i s m or e sensi ti v e and has l ar gel y suppl anted the sk el etal
r adi ogr aphi c sur v ey , but r equi r es car ef ul i nter pr etati on. The abdom i nal CT
scan, together w i th posi ti v e FN A f i ndi ngs i n the pel v i c nodes, can of ten
el i m i nate the need f or a pel v i c l y m phadenectom y f or stagi ng pur poses. The
l atter i s not usef ul f or stage A1 l esi ons, w hi ch al m ost nev er m etastasi ze to
pel v i c nodes, or f or poor l y di f f er enti ated stage C pr ostate adenocar ci nom a w i th
el ev ated tum or m ar k er s, because m or e than 90% of these ar e m etastati c.
How ev er , pel v i c l y m phadenectom y i s f r equentl y usef ul i n stagi ng i nter m edi ate
di sease to deter m i ne the pr ognosi s and pl an the tr eatm ent.
7. What tr eatm ent i s r ecom m ended f or stage A1 pr ostate cancer ?
Onl y obser v ati on i s r ecom m ended by m ost ur ol ogi sts f or pati ents w i th stage A1
pr ostate cancer because of the v er y sl ow and i nf r equent (< 10%)
P. 333
pr ogr essi on of the tum or at thi s stage. The data f r om f ol l ow up studi es hav e
i ndi cated that the sur v i v al f or thi s gr oup i s si m i l ar to that of agem atched
contr ol subjects.
8. Whi ch categor y of pati ents i s consi der ed f or a r adi cal pr ostatectom y ?
A r adi cal pr ostatectom y i s ef f ecti v e i n pati ents w i th tum or conf i ned to the
pr ostateâ€” stages A2 and B car ci nom a. The r etr opubi c appr oach w i th a ner v e
spar i ng techni que to m i ni m i ze the r i sk of i m potence and/or i nconti nence i s
com m onl y used. Thi s i s usual l y pr eceded by bi l ater al pel v i c node di ssecti on
and f r ozensecti on ex am i nati on to conf i r m noni nv ol v em ent by the tum or .
9. Is any al ter nati v e ther apy av ai l abl e f or pati ents w i th stage A2 or B pr ostate
cancer ?
If a stagi ng l y m phadenectom y r ev eal s no pel v i c node m etastases or i f pati ents
ar e poor oper ati v e r i sk s, pr ostate cancer m ay be successf ul l y tr eated w i th
ex ter nal beam i r r adi ati on. In m ost center s, i nter nal r adi ati on com bi ned w i th
som e ex ter nal beam r adi ati on ther apy i s the tr eatm ent used. In gener al , the
l ongter m contr ol r ate and sur v i v al f or l ocal i zed pr ostate cancer ar e si m i l ar
r egar dl ess of w hether sur ger y or i r r adi ati on i s the ther apy sel ected.
10. What ther apy m ay be adm i ni ster ed to pati ents w i th stage C or D di sease?
Pati ents w i th stage C or D di sease of ten r ecei v e ex ter nal beam i r r adi ati on
del i v er ed to the pel v i c and per i aor ti c nodes, but thi s has not been obser v ed
consi stentl y and cl ear l y to enhance sur v i v al . In som e sy m ptom ati c pati ents
w ho hav e pel v i c pai n, l ow er ex tr em i ty edem a, hem atur i a, or ur ethr al
obstr ucti on, pal l i ati v e ex ter nal beam r adi ati on ther apy m ay be used. An
al ter nati v e i s to pr oceed di r ectl y to hor m onal abl ati on ther apy .
11. In ter m s of the r ecom m ended tr eatm ents, w hat sur v i v al can be ex pected i n
pati ents w i th stage A1, A2, B, or C pr ostate cancer ?
Onl y 1% of pati ents w i th stage A1 di sease di e of pr ostate cancer , and
m etastases dev el op i n onl y 5% w i thi n 5 to 10 y ear s w i thout tr eatm ent. The
natur al hi stor y of thi s gr oup i s deter m i ned i n the el der l y by coex i stent di sease.
Wi thout tr eatm ent, 35% of pati ents i n stage A2 hav e m etastases and 20% di e
w i thi n 5 to 10 y ear s of di agnosi s. The r esul ts of r adi cal pr ostatectom y cl osel y
appr ox i m ate the cl i ni cal pi ctur e seen i n untr eated pati ents w i th stage A1
di sease. The sam e appl i es to stage B1 and B2 di sease, and hence i t m ay be
concl uded that, w i th appr opr i ate tr eatm ent, sur v i v al i n pati ents w i th ear l y
stage pr ostate cancer i s si m i l ar to that of agem atched heal thy contr ol
subjects. Ther ef or e, m ost pati ents w i th stage A or B di sease, par ti cul ar l y those
ol der than 65 y ear s, di e of other causes.
12. What com pl i cati ons attend the use of r adi cal pr ostatectom y and i r r adi ati on,
w hi ch pati ents shoul d be aw ar e of i n adv ance?
Radi cal pr ostatectom y , ev en usi ng m oder n ner v espar i ng techni ques, can cause
i m potence i n 20% to 50% of pati ents and ur i nar y i nconti nence i n 5%. Radi ati on
ther apy i s associ ated w i th sy m ptom s of r adi ati on pr octi ti s and cy stour ethr i ti s.
N one of the i m m edi ate postoper ati v e com pl i cati ons occur s, but r adi ati on
ther apy has a si m i l ar i nci dence of the other si de ef f ects, al though thei r onset
m ay tak e l onger .
P. 334
13. What i s the tr eatm ent f or di ssem i nated pr ostate cancer ?
Hor m onal m ani pul ati on i s the standar d appr oach f or the tr eatm ent of
di ssem i nated pr ostate cancer . Chem other apy i s m i ni m al l y ef f ecti v e and i s
consi der ed onl y i f hor m onal tr eatm ent f ai l s (hor m one â€œr ef r actor y â€
cancer ).
The r esponse to tr eatm ent i n the setti ng of pr ostate cancer i s ty pi cal l y di f f i cul t
to assess. It i ncl udes phy si cal f i ndi ngs, per f or m ance status, bone pai n, w ei ght
change, and the hem ogl obi n l ev el . Bone scans and other i m agi ng techni ques
and, m ost i m por tant, pr ostatespeci f i c anti gen l ev el s al so pr edi ct r esponse.
Or chi ectom y l eads di r ectl y to l ow testoster one l ev el s. Lutei ni zi ng hor m one
r el easi ng hor m one agoni sts (l eupr ol i de and goser el i n) br i ng about suppr essed
testoster one l ev el s i n 2 to 3 w eek s and can be adm i ni ster ed conv eni entl y at
m onthl y i nter v al s or l onger as a subcutaneous depot pr epar ati on. Testoster one
r eceptor l ev el antagoni sm can be achi ev ed by the m or e r ecentl y i ntr oduced
nonster oi dal agent, f l utam i de.
Choosi ng am ong the com m onl y used i ni ti al hor m onal appr oaches (i . e. ,
l eupr ol i de or f l utam i de) of ten depends on i ndi v i dual pati ent pr ef er ence w i th
r espect to tox i ci ti es and cost.
The com bi nati on of a l utei ni zi ng hor m oner el easi ng hor m one agoni st and an
anti andr ogen m ay br i ng about an i ncr eased r esponse r ate i n pati ents w i th l ow
v ol um e stage D1 pr ostate cancer . How ev er , i n gener al , no one hor m onal
tr eatm ent has been concl usi v el y pr ov ed to be super i or i n ter m s of r esponse.
Appr ox i m atel y 10% of pati ents ex per i ence com pl ete or par ti al r esponses and,
i n another 20%, the di sease r em ai ns stabl e f or at l east 3 m onths. The
tr eatm ent of m etastati c pr ostate cancer doses pr ol ong sur v i v al but ther e ar e
no def i ni ti v e cur es. If i ni ti al hor m onal m ani pul ati on f ai l s, a second hor m onal
tr eatm ent achi ev es a r esponse i n onl y 10% to 20% of pati ents.
Chem other apy achi ev es r esponses (usual l y par ti al ) i n 40% of pati ents; i n
addi ti on, i t can of ten pr oduce tox i ci ty but does pr ol ong sur v i v al i n ter m s of
m onths. Pati ents w ho f ai l i ni ti al ther apy ar e usual l y of f er ed pal l i ati v e or
ex per i m ental chem other apy appr oaches. Som e ev i dence now ex i sts f or the
ef f i cacy of sur am i n, w hi ch bl ock s gr ow th f actor ef f ects i n pr ostate cancer .
14. Is the pr ostatespeci f i c anti gen l ev el usef ul i n scr eeni ng asy m ptom ati c m en f or
pr ostate cancer ?
An el ev ated pr ostatespeci f i c anti gen v al ue i s usef ul i n the detecti on of ear l y
pr ostate cancer i n asy m ptom ati c m en. How ev er , because ear l y pr ostate cancer
i s of ten not associ ated w i th cl i ni cal di sease, studi es ex am i ni ng the uti l i ty of
m ass pr ostatespeci f i c anti gen scr eeni ng ar e sti l l under w ay to deter m i ne i f
thi s scr eeni ng ul ti m atel y i m pr ov es sur v i v al . Most cl i ni ci ans agr ee that a pr oper
pr ostate ex am i nati on on r ectal ev al uati on f or m en ol der than 50 y ear s i s a
costef f ecti v e and potenti al l y hel pf ul scr eeni ng m ethod.
Case
A 65y ear ol d m an pr esents to the em er gency r oom because of a back ache that has
l asted f or sev er al day s, w hi ch becam e sev er e af ter a f al l . Si x y ear s bef or e, the
pati ent
P. 335
began to hav e ur i nar y f r equency and dr i bbl i ng on m i ctur i ti on, and w as noted to
hav e a har d, nontender pr ostate nodul e w i th obl i ter ati on of the l ater al sul cus and a
pal pabl e sem i nal v esi cl e on one si de, f or w hi ch he r ecei v ed ex ter nal beam
i r r adi ati on. He has been on l eupr ol i de i njecti ons si nce that ti m e. Hi s pr ostate
speci f i c anti gen l ev el w as sl i ghtl y el ev ated bef or e ther apy but r etur ned to nor m al
ther eaf ter , and w as nor m al 4 m onths ago.
Phy si cal ex am i nati on r ev eal s a di f f use tender ness ov er the l ow er thor aci c and
l um bar spi nes. Rectal ex am i nati on r ev eal s a har d, i r r egul ar pr ostate. The
r em ai nder of the phy si cal ex am i nati on f i ndi ngs ar e unr em ar k abl e. Labor ator y
w or k up show s the f ol l ow i ng: hem ogl obi n, 11. 5 g/dL; hem atocr i t, 32%; w hi te bl ood
cel l count, 9. 8 Ã— 10 9 /L; pl atel ets, 162 Ã— 10 9 /L; w hi te bl ood cel l di f f er enti al â€”
neutr ophi l s, 68%; l y m phocy tes, 26%; m onocy tes, 4%; band f or m s, 2%; er y thr ocy te
sedi m entati on r ate, 87 m m i n the f i r st hour ; and al k al i ne phosphatase, 320 U
(nor m al , up to 150 U ). Tw o nucl eated r ed bl ood cel l s ar e seen per 100 w hi te bl ood
cel l s.
A chest r adi ogr aphi c study show s i ncr eased bone densi ti es i n sev er al r i bs, and a
r adi ogr aph of the l um bar spi ne show s m ul ti pl e ar eas of bone scl er osi s but no
f r actur es. A bone scan show s m ul ti pl e ar eas of i ncr eased acti v i ty scatter ed ov er the
ax i al sk el eton.
1. What w as the stage of thi s pati ent's pr ostate cancer 3 y ear s ago?
2. Was the tr eatm ent gi v en at that ti m e appr opr i ate?
3. How w oul d y ou go about pr ov i ng a di agnosi s of pr ostate cancer now ?
4. What ar e the tr eatm ent opti ons and pr ognosi s i n thi s pati ent now ?
5. What ar e the com pl i cati ons of ex ter nal beam i r r adi ati on f or the tr eatm ent of
stage C pr ostate cancer ?
Case Discussion
1. What w as the stage of thi s pati ent's pr ostate cancer 3 y ear s ago?
The pati ent had stage C pr ostate cancer 6 y ear s ago based on pal pabl e
ex tensi on of the tum or acr oss the pr ostati c capsul e and a negati v e bone scan.
A pal pabl e sem i nal v esi cl e i s abnor m al .
2. Was the tr eatm ent gi v en at that ti m e appr opr i ate?
The tr eatm ent f or stage C pr ostate cancer i s ex ter nal beam i r r adi ati on, usual l y
w i th i nter nal r adi ati on or , i n sel ected i nstances, r adi cal pr ostatectom y .
Adjuv ant hor m onal tr eatm ent does pr ol ong ti m e to r ecur r ence and pr obabl y
i m pr ov es sur v i v al .
3. How w oul d y ou go about pr ov i ng a di agnosi s of pr ostate cancer now ?
The pr esence of i m m atur e w hi te and r ed bl ood cel l s i n the ci r cul ati on together
w i th the anem i a (a l euk oer y thr obl asti c pi ctur e) suggests the ex i stence of bone
m ar r ow i nf i l tr ati on. A bone m ar r ow bi opsy and stai ni ng f or aci d phosphatase
and pr ostatespeci f i c anti gen m i ght cl i nch the di agnosi s. An el ev ated ser um
pr ostatespeci f i c anti gen l ev el i n the pr esence of scl er oti c bone l esi ons
establ i shes the di agnosi s of m etastati c pr ostate cancer .
4. What ar e the tr eatm ent opti ons and pr ognosi s i n thi s pati ent now ?
The tr eatm ent opti on f or m etastati c pr ostate cancer w i th pr edom i nant bone
l esi ons i s to change to hor m onal ther apy . Radi ati on ther apy can be used f or
the m anagem ent of pai nf ul bone l esi ons not am enabl e to andr ogen depr i v ati on.
A
P. 336
change i n andr ogen depr i v ati on ther apy can be ef f ected by bl ock i ng andr ogen
r eceptor f uncti on. Thi s change gi v es a m edi an ti m e to f ur ther pr ogr essi on of
di sease of appr ox i m atel y 15 m onths and a m edi an sur v i v al of 30 m onths.
Bi l ater al or chi ectom y i s an opti on but m ay not be acceptabl e to som e pati ents
f or psy chol ogi cal r easons.
5. What ar e the com pl i cati ons of ex ter nal beam i r r adi ati on f or the tr eatm ent of
stage C pr ostate cancer ?
The com m on com pl i cati ons of ex ter nal beam i r r adi ati on ar e i m potence,
supr apubi c or per i neal edem a, pr octi ti s, per si stent tum or , and f i br osi s of the
pr ostate, m ak i ng i t har d and i ts substance cl i ni cal l y i ndi sti ngui shabl e f r om that
of m al i gnancy .
Suggested Readings
Al ber tsen PC, Fr y back DG, Stor er BE, et al . Longter m sur v i v al am ong m en w i th
conser v ati v el y tr eated l ocal i zed pr ostate cancer . JAMA 1995;274:626.
Car v al hal GF, Sm i th DS, Mager DE, et al . Di gi tal r ectal ex am i nati on f or
detecti ng pr ostate cancer at pr ostate speci f i c anti gen l ev el s of 4 ng/m L or l ess.
J U r ol 1999;161:835.
Cr aw f or d ED, Ei senber ger MA, McLeod DG, et al . A contr ol l ed tr i al of l eupr ol i de
w i th and w i thout f l utam i de i n pr ostati c car ci nom a. N Engl J Med 1989;321:419.
Geor ge N JR. N atur al hi stor y of l ocal i zed pr ostati c cancer m anaged by
conser v ati v e ther apy al one. Lancet 1988;1:494.
Ger ber GS, Chodak GW. Routi ne scr eeni ng f or cancer of the pr ostate. J N atl
Cancer Inst 1991;83:329.
Gl eason DF. Hi stol ogi c gr ade, cl i ni cal stage, and pati ent age i n pr ostate cancer .
N CI Monogr 1988;7:15.
Gw ede CK, Pow Sang J, Sei gne J, et al . Tr eatm ent deci si onm ak i ng str ategi es
and i nf l uences i n pati ents w i th l ocal i zed pr ostate car ci nom a. Cancer
2005;104:1381.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 8 P ulm o no lo g y
Chapter 8
Pulmonology
Ma rvin I. Sc hw a rz
Acute Respiratory Distress Syndrome
1. What i s the def i ni ti on of acute r espi r ator y di str ess sy ndr om e (ARDS)?
2. What ar e the pr i nci pl es of m anagem ent of the pati ent w i th ARDS?
Discussion
1. What i s the def i ni ti on of ARDS?
Many acute m edi cal condi ti ons such as congesti v e hear t f ai l ur e,
pneum oni a, or the acute noni nf ecti ous i nter sti ti al pneum oni as can
m i m i c the cl i ni cal
P. 338
pi ctur e of ARDS. A usef ul def i ni ti on i ncl udes the f ol l ow i ng: r el ati v el y
acute appear ance of di f f use pul m onar y i nf i l tr ates, pr of ound hy pox em i a
(usual l y r equi r i ng m echani cal v enti l ati on), pul m onar y com pl i ance l ess
than 20 m L/cm H 2 O (sti f f l ungs), and a pul m onar y capi l l ar y w edge
pr essur e l ess than 18 m m Hg (noncar di ogeni c edem a). Causes i ncl ude
bacter i al , v i r al , and pr otozoan pneum oni as, al l f or m s of shock ,
aspi r ati on, hi ghal ti tude and neur ogeni c pul m onar y edem a, tr ansf usi on
r el ated acute l ung i njur y (TRALI) w hi ch i s of ten postsur gi cal , tr aum a,
and bur ns. The under l y i ng hi stol ogi c appear ance i s di f f use al v eol ar
dam age. Thi s consi sts of tw o phases: the ear l y ex udati v e phase
dem onstr ati ng al v eol ar edem a and i ntr aal v eol ar f i br i n col l ecti v e k now n
as hy al i ne m em br anes and the f i br opr ol i f er ati v e phase consi sti ng of
f i br obl asti c pr ol i f er ati v e and col l agen deposi ti on.
2. What ar e the pr i nci pl es of m anagem ent i n the pati ent w i th ARDS?
Ther e ar e f ew speci f i c m edi cal ther api es f or ARDS other than the
tr eatm ent of the under l y i ng cause. Tr i al s of bi ol ogi c m odi f i er s hav e
been gener al l y di sappoi nti ng, ex cept i n sev er e sepsi s i n w hi ch hum an
r ecom bi nant acti v ated pr otei n C (acti v ated dr otr ecogi n Î± ) r educes
m or tal i ty r ates. Managem ent i s m ai nl y suppor ti v e and tr eati ng the
under l y i ng i ni ti ati ng cause i n the hope that the l ung can r etur n to
nor m al . The speci f i c goal s of ther apy ar e to m ai ntai n ti ssue
ox y genati on (m ax i m i ze ox y gen del i v er y ) w hi l e pr ev enti ng
com pl i cati ons r esul ti ng f r om m echani cal v enti l ati on, such as
bar otr aum a (pneum othor ax ), and l ung i njur y stem m i ng f r om hi gh
ai r w ay pr essur es or ox y gen tox i ci ty . A r ecent N ati onal Insti tutes of
Heal th (N IH)suppor ted study of m echani cal l y v enti l ated ARDS subjects
i ndi cated a l ow er m or tal i ty f or those v enti l ated w i th ti dal v ol um es of 6
m L/k g v er sus the standar d 12 m L/k g. Ther e i s ev i dence to suppor t that
hi gher r espi r ator y pr essur es aggr av ate the l ung i njur y .
Case
A 27y ear ol d w hi te m al e m otor cy cl i st i s tr anspor ted to the em er gency r oom
af ter he w as i nv ol v ed i n a hi ghspeed, headon col l i si on w i th an oncom i ng
autom obi l e. At the acci dent scene, he w as poor l y r esponsi v e; hi s i ni ti al
bl ood pr essur e w as 70/40 m m Hg and i njur i es i ncl uded a f l ai l chest on the
r i ght, sev er al pel v i c f r actur es, an open f r actur e of the f em ur , and a cl osed,
di spl aced f r actur e of the l ef t ti bi a. A centr al and tw o per i pher al catheter s
ar e i nser ted, and nor m al sal i ne i s adm i ni ster ed at m ax i m al r ates. Hi s bl ood
i s ty ped and cr ossm atched. He i s al so i ntubated i n the em er gency r oom , and
a chest tube i nser ted on the r i ght y i el ds a bl oody r etur n. Sucti on i s appl i ed
and no ai r l eak i s noted. Sev er al uni ts of bl ood ar e adm i ni ster ed, and
abdom i nal l av age f l ui d pr ov es bl oody . He i s r ushed to the oper ati ng r oom to
under go a l apar otom y , and a l i v er l acer ati on i s f ound and r epai r ed. Dur i ng
sur ger y he r ecei v es 8 uni ts of w hol e bl ood, 5 uni ts of pl atel ets, and 8 uni ts
of f r esh f r ozen pl asm a. Hi s or thopaedi c i njur i es ar e appr opr i atel y tr eated
and he i s tr ansf er r ed to the sur gi cal i ntensi v e car e uni t i n cr i ti cal but stabl e
condi ti on. Chest r adi ogr aphi c study conf i r m s that the endotr acheal and chest
tubes ar e i n good posi ti on and r ev eal s a r i ght l ow er l obe i nf i l tr ate thought
to be secondar y to a pul m onar y contusi on. The v enti l ator i s i ni ti al l y set at
an i nspi r ed ox y gen concentr ati on (FIO 2 ) of 40%, r espi r ator y
P. 339
r ate of 12 per m i nute, and ti dal v ol um e of 90 m L i n an assi stcontr ol m ode.
Ar ter i al bl ood gas m easur em ent r ev eal s a pH of 7. 46, a par ti al pr essur e of
car bon di ox i de (PCO 2 ) of 3 m m Hg, and a par ti al pr essur e of ox y gen (PO 2 )
of 59 m m Hg, w i th an ox y gen satur ati on of 92%. On the second hospi tal
day , 12 hour s af ter adm i ssi on, he becom es agi tated w hi l e on the v enti l ator ,
hi s r espi r ator y r ate r i ses to 25 per m i nute, hi s m i nute v enti l ati on i ncr eases
f r om 8. 5 to 18 L per m i nute, and ai r w ay pr essur e r i ses f r om 20 to 60 cm
H 2 O. A r epeat chest r adi ogr aph now show s di f f use ai r space patter n. Repeat
ar ter i al bl ood gas anal y si s r ev eal s a PO 2 of 39 m m Hg.
1. What i s the di f f er enti al di agnosi s of thi s pati ent's cl i ni cal

deter i or ati on?
2. What ar e the r i sk f actor s f or ARDS i n thi s pati ent?
3. How w oul d y ou m anage thi s pati ent's hy pox em i a?
4. What ar e the potenti al pr obl em s associ ated w i th posi ti v e end
ex pi r ator y pr essur e (PEEP)?
5. What i s the m or tal i ty r ate associ ated w i th ARDS?
Case Discussion
1. What i s the di f f er enti al di agnosi s of thi s pati ent's cl i ni cal deter i or ati on?
Sev er al possi bi l i ti es need to be consi der ed i n thi s setti ng. Fi r st, an
i nf ecti on (pneum oni a) m ust al w ay s be r ul ed out. It i s possi bl e that the
pati ent aspi r ated gastr i c contents at the acci dent scene w hi l e hi s l ev el
of consci ousness w as i m pai r ed, and thi s coul d hav e i njur ed the l ung
di r ectl y ow i ng to aci d aspi r ati on or set the stage f or an ov er w hel m i ng
pneum oni a. Al ter nati v el y , a nosocom i al (hospi tal acqui r ed) pneum oni a
coul d hav e been acqui r ed i n the sur gi cal i ntensi v e car e uni t, al though
the ear l y onset of hi s ARDS m ak es thi s unl i k el y . The m assi v e f l ui d
r esusci tati on coul d l ead to a f l ui dov er l oad congesti v e hear t f ai l ur e
sy ndr om e, ev en despi te a nor m al f uncti oni ng hear t bef or e the acci dent.
If a car di ac contusi on occur r ed, thi s w oul d m ak e hi m m or e suscepti bl e
to thi s com pl i cati on. Pul m onar y contusi ons ar e w or th consi der i ng, but
ar e usual l y m or e l ocal i zed and dev el op w i thi n sev er al hour s. Ai r w ay
hem or r hage, per haps stem m i ng f r om ei ther br onchi al f r actur e or a
tr aum ati c i ntubati on, can occur , but i s ty pi cal l y associ ated w i th bl oody
secr eti ons w hen sev er e. The ARDS coul d al so hav e r esul ted f r om
pr ol onged hy potensi on or r epl acem ent of bl ood pr oducts or TRALI.
Regar dl ess, thi s pati ent has ARDS and under these ci r cum stances,
pathol ogi c study w oul d show di f f use al v eol ar dam age consi sti ng of
hy al i ne m em br ane f or m ati on, al v eol ar w al l edem a, and i nf l am m ati on.
2. What ar e the r i sk f actor s that put thi s pati ent at r i sk f or ARDS?
Thi s pati ent's r i sk f actor s ar e: hy potensi onâ€”usual l y pr ol onged and

sev er e (sy stol i c bl ood pr essur e < 90 m m Hg); hy per tr ansf usi onâ€”m or e
than 10 uni ts of bl ood pr oducts i n a 24hour per i od; aspi r ati onâ€”any
pati ent w i th depr essed m ental status i s at gr eat r i sk f or gastr i c
aspi r ati on (the r esul ti ng chem i cal i njur y i s a com m on pr ecur sor f or
ARDS). Fat em bol i sy ndr om eâ€”thi s sy ndr om e consi sts of di f f use
pul m onar y i nf i l tr ates, m ental status changes, thr om bocy topeni a, and
conjuncti v al or ax i l l ar y petechi ae. It occur s m ost of ten i n the pr esence
of sev er e and m ul ti pl e l ong
P. 340
bone f r actur es, and i s thought to r esul t f r om f at em bol i m i gr ati ng f r om
the bone m ar r ow to the l ungs. How ev er , i t occur s usual l y 24 to 72
hour s af ter adm i ssi on, m ak i ng i t unl i k el y i n thi s pati ent.
Other r i sk f actor s i ncl ude sepsi s, pneum oni a, dr ugs, pancr eati ti s, l ung
contusi on, tox i c f um e i nhal ati on, and ox y gen tox i ci ty .
3. How w oul d y ou m anage thi s pati ent's hy pox em i a?
Acutel y , the FIO 2 shoul d be i ncr eased to 100%. How ev er , the pr ol onged
adm i ni str ati on of 100% ox y gen f or 3 or m or e day s i s l i k el y to l ead to
ox y gen tox i ci ty and f ur ther w or seni ng of ARDS. Accor di ngl y , the FIO 2
shoul d be decr eased to the l ow est l ev el that achi ev es an ox y gen
satur ati on of 90% to 92%. Ther e appear s to be a thr eshol d of 50% to
60%, bel ow w hi ch ox y gen tox i ci ty i s r ar e. The v enti l ator show s that
ti dal v ol um e shoul d be set at 6 m L/k g. If an FIO 2 abov e thi s r ange i s
necessar y , then a tr i al of PEEP i s i ndi cated. PEEP appear s to i m pr ov e
ox y genati on by r ecr ui ti ng col l apsed gasex change uni ts (atel ectasi s).
Data i ndi cate that pl aci ng the pati ent i n a pr one posi ti on al so i m pr ov es
ox y genati on, but not necessar i l y the outcom e.
4. What ar e the potenti al pr obl em s associ ated w i th PEEP?
PEEP m ay be l i f esav i ng by i m pr ov i ng ox y genati on and al l ow i ng the FIO 2
to be l ow er ed to â€œsaf eâ€ l ev el s; how ev er , i t i s associ ated w i th
sev er al potenti al pr obl em s. The f i r st i s hy potensi on. Hi gh l ev el s of
posi ti v e i ntr athor aci c pr essur e i m pede v enous r etur n to the hear t and
m ay be tr ansm i tted to the pul m onar y ar ter i es, causi ng pul m onar y
hy per tensi on. Both these f actor s ser v e to decr ease car di ac output,
w hi ch pr eci pi tates hy potensi on.
The r i sk of bar otr aum a i s gr eatl y i ncr eased w i th PEEP because of the
posi ti v e ai r w ay pr essur es and m ay r esul t i n pneum othor ax or
pneum om edi asti num . Pneum othor ax i n a v enti l ated pati ent i s of ten a
m edi cal em er gency because a tensi on pneum othor ax m ay ev ol v e. PEEP
l ev el s abov e 15 cm H 2 O ar e par ti cul ar l y r i sk y . The pr ophy l acti c
adm i ni str ati on of PEEP, bef or e the onset of ARDS, has been show n to
be of no v al ue.
5. What i s the m or tal i ty r ate associ ated w i th ARDS?
In 1967, the m or tal i ty r ate obser v ed f or ARDS w as 60%. Thi s has
decr eased to 30% to 40%, m ai nl y due to i m pr ov ed v enti l ator y
m anagem ent as opposed to the tr eatm ent of the ARDS i tsel f . In the
sur v i v or s, pul m onar y f uncti on can r etur n to nor m al , and thi s usual l y
occur s by 6 m onths. Per si stent abnor m al i ti es past thi s ti m e i ndi cate
pul m onar y f i br osi s and pul m onar y i m pai r m ent.
Suggested Readings
Cal f ee CS, Matthay MM. Recent adv ances i n m echani cal v enti l ati on. Am J
Med 2005;118:584â€“591.
Choc MK. Acute l ung i njur y /adul t r espi r ator y di str ess sy ndr om e: the
thi r d Pi ttsbur gh i nter nati onal l ung conf er ence. Pr oc Am Thor ac Soc
2005;2:181â€“245.
Vi nant JL, Abr aham E. The l ast 100 y ear s of sepsi s. Am J Respi r Cr i t
Car e Med 2006;173:256â€“263.
P. 341
Asthma
1. What i s asthm a, and how i s i t cl assi f i ed?
2. How i s asthm a di agnosed?
3. What condi ti ons ar e associ ated w i th or m ay com pl i cate asthm a?
Discussion
1. What i s asthm a, and how i s i t cl assi f i ed?
Asthm a i s not a si ngl e enti ty , but r ather a cl i ni cal sy ndr om e consi sti ng
of (a) an i ncr ease i n ai r w ay r esi stance to a v ar i ety of sti m ul i ; (b)
v ar i abl e ai r f l ow obstr ucti on, w hi ch i s usual l y r ev er si bl e, ei ther
spontaneousl y or w i th tr eatm ent; and (c) a chr oni c, m ul ti cel l ul ar
i nf l am m ator y r esponse w i thi n the ai r w ay s that pr oduces patchy
br onchi al epi thel i al denudati on, subm ucosal edem a, hy per secr eti on of
m ucus, and subbasem ent m em br ane col l agen deposi ti on. The asthm ati c
r esponse to sti m ul i m ay be i m m edi ate, occur r i ng w i thi n m i nutes and
ter m ed the ear l y asthm ati c r esponse, or del ay ed, ar i si ng sev er al hour s
af ter ex posur e and ter m ed the l ate asthm ati c r esponse. The ear l y
asthm ati c r esponse pr i m ar i l y r esul ts f r om br onchi al sm ooth m uscl e
constr i cti on and the l ate asthm ati c r esponse i s char acter i zed by
i nf l am m ator y cel l i nf i l tr ati on and acti v ati on. Both patter ns m ay be
tr i gger ed by ex posur e to the sam e sti m ul i , and m ay w or k i n concer t to
pr oduce sustai ned nar r ow i ng of the ai r w ay l um en.
Asthm a m ay be cl assi f i ed on the basi s of ei ther the pr esum pti v e
eti ol ogy or sy m ptom sev er i ty and the patter n of ai r f l ow obstr ucti on.
Hi stor i cal l y , attem pts hav e been m ade to cl assi f y asthm ati c subjects as
hav i ng ei ther i ntr i nsi c or ex tr i nsi c di sease. Intr i nsi c asthm ati cs hav e no
per sonal or f am i l y hi stor y of al l er gi es, thei r i m m unogl obul i n E (IgE)
l ev el s ar e nor m al , and they hav e no easi l y i denti f i abl e env i r onm ental
pr eci pi tants of thei r sy m ptom s. In contr ast, ex tr i nsi c asthm ati cs hav e
al l er gi c or atopi c hi stor i es, thei r IgE l ev el s ar e ty pi cal l y el ev ated, and
they hav e speci f i c anti geni c tr i gger s to thei r asthm a. Thi s tr adi ti onal
eti ol ogi c cl assi f i cati on i s now pr obabl y obsol ete because i ndi v i dual
asthm ati c subjects com m onl y ex hi bi t both IgE and nonâ€“IgEm edi ated
r esponses to br oncho pr ov ocati v e sti m ul i . Ther ef or e, a cl assi f i cati on
schem e that i s i nstead based on the sev er i ty of sy m ptom s and on l ung
f uncti on i s m or e cl i ni cal l y r el ev ant, and pr ov i des a f r am ew or k on w hi ch
to base a stepw i se tr eatm ent appr oach. One pr oposed cl assi f i cati on
schem e i s pr esented i n Tabl e 81.
Because the sev er i ty of an acute asthm a attack m ay be under esti m ated
by both pati ents and thei r f am i l i es, pati ents ar e encour aged to use
hom e ex pi r ator y f l ow r ate dev i ces, w hi ch can m or e objecti v el y
m easur e asthm a sev er i ty . Factor s that hav e been associ ated w i th an
i ncr eased r i sk of asthm a m or tal i ty i ncl ude f r equent em er gency r oom
v i si ts, hospi tal i zati on w i thi n the pr ev i ous y ear , pr i or l i f ethr eateni ng
epi sodes, a pr ev i ous need f or i ntubati on, a r ecent
P. 342
r educti on i n the cor ti coster oi d dosage or cessati on of use,
noncom pl i ance w i th m edi cal ther apy , the pr esence of ser i ous
depr essi on or psy chosoci al behav i or al pr obl em s, and a l ow er
soci oeconom i c status.
Table 81 Asthma Classification Scheme
As thma Clinic a l Fe a ture s P ulmona ry Func tion

Se ve rity
Mi l d Inter m i ttent, br i ef Ex pi r ator y f l ow

sy m ptom s (< 12 ti m es r ates > 80% of
per w eek ) pr edi cted
Rar e noctur nal Ex pi r ator y f l ow r ate

sy m ptom s (< 2 ti m es per v ar i abi l i ty < 20%
w eek )
Moder ate Ex acer bati ons (> 2 ti m es Ex pi r ator y f l ow

per w eek ) r ates 60%80% of
pr edi cted
N octur nal sy m ptom s (> 2 Ex pi r ator y f l ow r ate

ti m es per w eek ) v ar i abi l i ty 20%30%
Sev er e Al m ost dai l y Ex pi r ator y f l ow r ate

br onchodi l ator use < 60% of pr edi cted
Fr equent conti nuous Ex pi r ator y f l ow r ate

sy m ptom s v ar i abi l i ty > 30%
Fr equent noctur nal

aw ak eni ngs
Phy si cal acti v i ti es

l i m i ted by sy m ptom s
Hospi tal i zati on f or

asthm a w i thi n the
pr ev i ous y ear
2. How i s asthm a di agnosed?
Because pati ents w i th asthm a ar e a heter ogeneous gr oup, the di agnosi s
r equi r es assessm ent of a pati ent's pul m onar y f uncti on and attenti on to
sel ect detai l s r ev eal ed by the m edi cal hi stor y , phy si cal ex am i nati on,
and l abor ator y tests. Hi stor i cal f eatur es i m por tant i n establ i shi ng the
di agnosi s of asthm a i ncl ude the epi sodi c and v ar i abl e natur e of the
ai r f l ow obstr ucti on and the r ev er si bi l i ty of the obstr ucti on. The m ost
com m on sy m ptom sâ€”cough, w heezi ng, chest ti ghtness, shor tness of
br eath, and sputum pr oducti onâ€”ar e nonspeci f i c and by them sel v es
nondi agnosti c. The patter n of sy m ptom s m ay be suggesti v e, i n that
noctur nal (and ear l y m or ni ng) sy m ptom s ar e par ti cul ar l y char acter i sti c
of asthm a. Com m onl y r epor ted pr eci pi tants of br onchospasm i ncl ude
ex er ci se, col d ai r , env i r onm ental al l er gens, ex posur e to occupati onal
or chem i cal i r r i tants, and upper r espi r ator y tr act i nf ecti ons. The
di f f er enti al di agnosi s of adul t w heezi ng or cough m ay i ncl ude
m echani cal obstr ucti on of the ai r w ay (e. g. , f or ei gn body , tum or m ass,
or gr anul om atous nar r ow i ng), v ocal cor d dy sf uncti on, congesti v e hear t
f ai l ur e, pul m onar y em bol us, aspi r ati on i njur y , pul m onar y eosi nophi l i a
sy ndr om es, and other f or m s of chr oni c obstr ucti v e pul m onar y di sease
(COPD) (e. g. , cy sti c f i br osi s, chr oni c br onchi ti s, and em phy sem a).
The phy si cal ex am i nati on f i ndi ngs m ay be ei ther unr em ar k abl e or
suggest the pr esence of ai r tr appi ng and hy per i nf l ati on, w i th an
i ncr eased anter oposter i or thor aci c di am eter and a l ow di aphr agm .
Wheezi ng i s the m ost char acter i sti c br eath sound of asthm a but i s an
unr el i abl e i ndi cator of sev er i ty . Br onchospasm m ay pr oduce a
pr ol onged ex pi r ator y phase w i th r educed ti dal v ol um es and m i ni m al ai r
m ov em ent. In thi s setti ng, f ai nt w heezi ng par adox i cal l y i ntensi f i es as
ai r f l ow i m pr ov es. Rhonchi and other adv enti ti ous
P. 343
sounds m ay suggest the pr esence of secr eti ons i n the ai r w ay s. Si gns of
sev er e ai r f l ow obstr ucti on m ay i ncl ude an i ncr eased pul sus par adox us,
supr acl av i cul ar r etr acti ons w i th accessor y m uscl e use
(ster nocl ei dom astoi d and i nter costal s), and thor acoabdom i nal par adox
(the par adox i cal r etr acti on of abdom i nal m uscul atur e w i th i nspi r ati on).
Pul m onar y f uncti on testi ng shoul d be pur sued i n al l pati ents w i th
suspected asthm a. Spi r om etr i c f i ndi ngs of r educed ex pi r ator y f l ow
r ates w i th a nor m al i nspi r ator y f l ow â€“v ol um e cur v e, l ung v ol um es
suggesti ng i ncr eased thor aci c gas and r esi dual v ol um es, and i ncr eased
ai r w ay r esi stance ar e al l char acter i sti c si gns of asthm a and m ay be
al l ev i ated by br onchodi l ator tr eatm ent. Af ter an acute ex acer bati on of
asthm a, how ev er , pul m onar y f uncti on m ay r em ai n abnor m al l ong af ter
the sy m ptom s hav e r etur ned to thei r basel i ne status.
Addi ti onal studi es and si gns that m ay be usef ul i n the ev al uati on of
asthm a i ncl ude (a) br onchopr ov ocati on testi ng w i th m ethachol i ne,
hi stam i ne, or ex er ci se to docum ent i ncr eased ai r w ay r esponsi v eness to
sti m ul i ; (b) per i pher al eosi nophi l i a; (c) i ncr eased IgE l ev el s; (d)
Char cotLey den cr y stal s (cr y stal l i zed cati oni c pr otei ns), eosi nophi l s, or
Cur schm ann's spi r al s (br onchi ol ar casts of m ucus and cel l ul ar debr i s)
i n the sputum ; and (e) a chest r adi ogr aph show i ng hy per i nf l ati on or the
pr esence of bar otr aum a. N o si ngl e test or batter y of tests i s
appr opr i ate f or ev er y suspected case. Sel ected studi es m ay pr ov i de the
objecti v e ev i dence needed to conf i r m the di agnosi s of asthm a w hen the
hi stor y and phy si cal ex am i nati on f i ndi ngs ar e onl y suggesti v e.
3. What condi ti ons ar e associ ated w i th or m ay com pl i cate asthm a?
Sev er al condi ti ons m ay com pl i cate the asthm a sy ndr om e, and they
r equi r e speci al consi der ati on.
Al though a per son's cl i ni cal cour se i s not pr edi ctabl e, unstabl e asthm a
dev el ops dur i ng pre gna nc y i n appr ox i m atel y one thi r d of asthm ati c
w om en, one thi r d ex per i ence no change, and sy m ptom s ar e actual l y
l ess sev er e i n one thi r d. Poor l y contr ol l ed asthm a dur i ng pr egnancy
m ay contr i bute to pr enatal m or tal i ty , an i ncr eased l i k el i hood of
pr em atur i ty , and l ow bi r th w ei ght. Ther ef or e, usi ng m edi cati ons to
obtai n opti m al contr ol of asthm a i s appr opr i ate, ev en i f thei r saf ety i n
pr egnancy has not been unequi v ocal l y pr ov ed. An i nhal ed cor ti coster oi d
pr epar ati on, sel ecti v e Î² 2 agoni sts, appr opr i atel y m oni tor ed
theophy l l i ne use, and ev en sy stem i c cor ti coster oi ds can be used w hen
necessar y to pr ev ent f etal hy pox i a. Medi cati ons that shoul d be av oi ded
i ncl ude Î± adr ener gi c com pounds, br om pheni r am i ne, epi nephr i ne, and
som e decongestants (or al Î± agoni sts), anti bi oti cs (tetr acy cl i ne and
ci pr of l ox aci n), and l i v e v i r us v acci nes.
The l i k el i hood of asthm ar el ated pos tope ra tive c omplic a tions
depends on the sev er i ty of the pati ent's ai r w ay hy per r esponsi v eness,
the degr ee of ai r f l ow obstr ucti on, and the am ount of ex cess ai r w ay
secr eti ons at the ti m e of sur ger y . In addi ti on, endotr acheal i ntubati on
and the ty pe of pr ocedur e per f or m ed (thor aci c and upper abdom i nal )
m ay pose an addi ti onal r i sk . Pr eoper ati v e cor ti coster oi ds m ay be
i ndi cated i f ex pi r ator y f l ow r ates ar e r educed (< 80% of per sonal best)
or i f cor ti coster oi ds hav e been r equi r ed to contr ol asthm a i n the
pr ev i ous 6 m onths.
P. 344
Mai ntenance of nasal patency m ay i m pr ov e l ow er ai r w ay f uncti on and
asthm a contr ol . Al though the m echani sm s i nv ol v ed i n thi s r el ati onshi p
ar e not com pl etel y under stood, na s a l obs truc tion, such as that caused
by r hi ni ti s, si nusi ti s, and nasal pol y ps, m ay l ead to asthm a i nstabi l i ty
and w or seni ng of sy m ptom s. N asal Î² 2 agoni sts and cor ti coster oi ds ar e
som eti m es usef ul i n tr eati ng nasal obstr ucti on.
Appr ox i m atel y 2% of al l cases of asthm a ar e due to oc c upa tiona l

e x pos ure to speci f i c sensi ti zi ng substances. Pr otei ns, or gani c
com pounds, and som e i nor gani c chem i cal s (m etal sal ts) hav e been
i m pl i cated. Once the di agnosi s i s establ i shed, com pl ete av oi dance of
ex posur e i s m andator y because conti nued ex posur e to ev en m i nute
concentr ati ons m ay pr ov ok e sev er e and potenti al l y f atal br onchospasm .
Al so, once w el l establ i shed, occupati onal asthm a m ay not be
com pl etel y r ev er si bl e. The phar m acol ogi c ther apy used f or thi s ty pe of
asthm a i s si m i l ar to that used f or other f or m s of asthm a, but i s no
substi tute f or di l i gent av oi dance of ex posur e to the of f endi ng agents.
Che mic a l s e ns itivity m ay al so pr ov ok e asthm a attack s. Appr ox i m atel y

5% to 20% of adul ts w i th asthm a sustai n sev er e and potenti al l y f atal
ex acer bati ons of asthm a af ter tak i ng aspi r i n or other nonster oi dal
anti i nf l am m ator y dr ugs (tr i ad asthm a). Phy si cal ex am i nati on i n these
pati ents m ay r ev eal nasal pol y ps, and sy m ptom s of v asom otor r hi ni ti s
m ay pr ecede the dev el opm ent of aspi r i ni nduced br onchospasm . Less
com m onl y , sul f i tes, w hi ch m ay be used as a f ood pr eser v ati v e, and
tar tr azi ne, a y el l ow dy e that m ay be used as a f ood col or i ng, hav e
been l i nk ed to the occur r ence of acute br onchospasm .
Al though ga s troe s opha ge a l re flux i s m or e com m on i n peopl e w i th

asthm a, i ts r el ati onshi p to br onchospasm i s contr ov er si al . Most peopl e
w i th asthm a and sy m ptom ati c gastr oesophageal r ef l ux hav e hi atal
her ni as, and the associ ati on betw een the tw o condi ti ons m ay be best
dem onstr ated by si m ul taneousl y m oni tor i ng the esophageal pH and
pul m onar y f uncti on. Medi cal m anagem ent consi sti ng of pr oton pum p
i nhi bi tor s i s usual l y ef f ecti v e i n these pati ents.
Case
A 26y ear ol d w om an pr esents to the em er gency r oom at 3:00 a. m .
com pl ai ni ng of w or seni ng cough w i th y el l ow gr een sputum , shor tness of
br eath, and w heezi ng of 5 day s' dur ati on. Her sy m ptom s began af ter an
upper r espi r ator y tr act i nf ecti on that w as m ani f ested as a l ow gr ade f ev er ,
r hi nor r hea w i th postnasal dr i p, and nasal congesti on. She r epor ts poor sl eep
qual i ty f or the l ast 2 day s because of sev er e coughi ng and has used ov er
thecounter nasal spr ay s and cough suppr essants, but w i thout r el i ef . She i s
18 w eek s pr egnant, but has no si gni f i cant past m edi cal hi stor y . Her phy si cal
ex am i nati on r ev eal s that she i s di aphor eti c and unabl e to speak i n
sentences. Her v i tal si gns r ev eal a r espi r ator y r ate of 30 br eaths per
m i nute, a hear t r ate of 120 beats per m i nute, a tem per atur e of 37Â°C
(98. 6Â°F), and a pul sus par adox us of 22 m m Hg. Spi r om etr y i s attem pted
but pr ov es poor l y r epr oduci bl e, w i th a â€œbest ef f or tâ€ f or ced ex pi r ator y
v ol um e i n 1 m i nute (FEV 1 ) of 30% of pr edi cted. The r em ai nder of her
ex am i nati on f i ndi ngs ar e notew or thy f or the pr esence of supr acl av i cul ar
r etr acti ons w i th i nspi r ati on, di f f usel y di m i ni shed br eath sounds w i th
P. 345
scatter ed, hi ghpi tched i nspi r ator y and ex pi r ator y w heezes, and a pal pabl e
subcutaneous cr epi tati on ov er her anter i or thor ax . She i s qui te anx i ous, but
al er t and cooper ati v e.
1. What addi ti onal studi es m ay be i m por tant f or the pr oper m anagem ent
of thi s pati ent?
2. What ar e the i ni ti al m anagem ent consi der ati ons i n thi s pati ent?
3. What ar e the tr eatm ent consi der ati ons f or ongoi ng m anagem ent i n thi s
pati ent?
Case Discussion
1. What addi ti onal studi es m ay be i m por tant f or the pr oper m anagem ent
of thi s pati ent?
The pati ent's cl i ni cal pr esentati on suggests acute, sev er e

br onchospasm , and the i m m edi ate f ocus of the em er gency r oom ef f or t
shoul d be ther apeuti c r ather than di agnosti c. Al though thi s i s the i ni ti al
epi sode of asthm a f or thi s pati ent, num er ous f actor s suggest i t i s a
danger ousl y sev er e attack . Dy spnea at r est, an i nabi l i ty to speak , and
the use of accessor y m uscl es ar e i m por tant obser v ati ons. Objecti v e
m easur es of attack sev er i ty ar e an i ncr eased pul sus par adox us and
ex pi r ator y f l ow r ates l ess than 40% of pr edi cted. The i ntensi ty of
w heezi ng i s an unr el i abl e i ndi cator . The pr esence of subcutaneous
em phy sem a suggests an associ ated pneum othor ax or
pneum om edi asti num . On the basi s of thi s pr esentati on, chest
r adi ogr aphy and ar ter i al bl ood gas m easur em ent ar e i ndi cated,
al though tr eatm ent shoul d not be del ay ed to do these. The chest
r adi ogr aphi c f i ndi ngs m ay ex cl ude the di agnosi s of pneum oni a and
del i neate the sour ce of the subcutaneous em phy sem a. A
pneum om edi asti num can ty pi cal l y be w atched w i thout speci f i c ther apy ,
w her eas a pneum othor ax w oul d l i k el y r equi r e i nser ti on of a chest tube
w i th w ater seal sucti on to br i ng about r eex pansi on. The ar ter i al bl ood
gas studi es w oul d l i k el y show hy pox em i a w i th hy pocapni a. Hy pox em i a
w i th an el ev ated al v eol ar ar ter i al ox y gen gr adi ent i s the r esul t of
m i sm atched v enti l ati on and per f usi on. Acute br onchospasm r esul ts i n
hy per v enti l ati on, and the ar ter i al bl ood chem i str y data shoul d r ef l ect a
r espi r ator y al k al osi s w i th a r educed PaCO 2 . If the attack i s sev er e and
pr ol onged, the PaCO 2 m ay r i se as a r esul t of i ncr eased dead space
v enti l ati on (hi gh v enti l ati onâ€“per f usi on r ati o) and r espi r ator y m uscl e
f ati gue. A nor m al or el ev ated PaCO 2 i n the setti ng of sev er e ai r w ay
obstr ucti on suggests i m pendi ng r espi r ator y f ai l ur e and w ar r ants
i ntensi v e car e uni t obser v ati on, w i th consi der ati on gi v en to m echani cal
v enti l ati on.
2. What ar e the i ni ti al m anagem ent consi der ati ons i n thi s pati ent?
The i m m edi ate goal s of ther apy ar e to ensur e adequate ox y genati on
and gas ex change w hi l e r educi ng the br onchospasm and the w or k of
br eathi ng. In thi s case, the pati ent i s â€œbr eathi ng f or tw oâ€
and f etal
hy pox i a i s an i m por tant concer n. At a m i ni m um , adequate suppl em ental
ox y gen shoul d be gi v en i m m edi atel y to ensur e a PaO 2 ex ceedi ng 65
m m Hg and an ox y gen satur ati on gr eater than 90%. The deci si on to use
v enti l ator y suppor t consi sti ng of i ntubati on and m echani cal v enti l ati on
i s a di f f i cul t one, but m ay be l i f esav i ng i n pati ents w i th m ental status
deter i or ati on, w or seni ng r espi r ator y di str ess f r om ex hausti on, or
pr ogr essi v el y i ncr easi ng PaCO 2 l ev el s w i th r espi r ator y aci dosi s.
Fr equent dosi ng w i th an i nhal ed Î² 2 adr ener gi c agoni st del i v er ed by
nebul i zer or m eter eddose i nhal er i s the m ost ef f ecti v e br onchodi l ator
ther apy f or acute, sev er e
P. 346
asthm a (status asthm ati cus). Asthm ati c pati ents w ho ar e i ni ti al l y
unr esponsi v e to i ntensi v e i nhal ed ther apy m ay r espond to the
subcutaneous del i v er y of Î² 2 agoni sts, but or al adm i ni str ati on i s not
i ndi cated f or acute m anagem ent. Epi nephr i ne shoul d be av oi ded i n thi s
pati ent because i t i s a ter atogen.
In addi ti on to i nhal ed Î² 2 agoni sts and suppl em ental ox y gen, sy stem i c
cor ti coster oi ds shoul d be i nsti tuted ear l y i n the em er gency r oom
m anagem ent. Cor ti coster oi ds r educe ai r w ay obstr ucti on by i nter r upti ng
the i nf l am m ator y cascade at one or m or e cr i ti cal steps i n i ts genesi s,
and m ay al so hav e a sy ner gi sti c ef f ect on Î²adr ener gi c r eceptor
acti v i ty . In gener al , sy stem i c cor ti coster oi ds shoul d be consi der ed i f
si gni f i cant i m pr ov em ent i s not seen w i thi n the f i r st 30 to 60 m i nutes of
i ntensi v e br onchodi l ator tr eatm ent. Ear l y cor ti coster oi d use has been
show n to l ead to a r educti on i n both the r ate of hospi tal i zati on and the
r ate of r etur n to the em er gency r oom af ter di schar ge. Inhal ed
cor ti coster oi ds ar e not i ndi cated f or the m anagem ent of acute, sev er e
asthm a. Theophy l l i ne pr epar ati ons of f er l i ttl e addi ti onal benef i t w hen
added to i nhal ed Î² 2 agoni st tr eatm ent i n the em er gency r oom , but
they m ay augm ent r espi r ator y m uscl e f uncti on dur i ng hospi tal i zati on.
The use of i nhal ed Î² 2 agoni sts, sy stem i c cor ti coster oi ds, and ev en
theophy l l i ne pr epar ati ons (w i th ser um l ev el s k ept at < 12 Âµg/m L) m ay
be consi der ed appr opr i ate i n the setti ng of pr egnancy and unstabl e
asthm a. Cauti ous hy dr ati on i s al so appr opr i ate because i nsensi bl e
w ater l osses i ncr ease w i th hy per v enti l ati on. The use of anti bi oti cs i s
com m onl y r eser v ed f or objecti v el y docum ented i nf ecti ons. The sputum
pr oducti on, al though i t i s y el l ow gr een, does not m andate anti bi oti c
tr eatm ent unl ess ther e i s Gr am 's stai n ev i dence of a dom i nant
or gani sm .
3. What ar e the tr eatm ent consi der ati ons f or ongoi ng m anagem ent i n thi s
pati ent?
The opti m al m anagem ent of chr oni c asthm a r el i es on f our i nter r el ated
pr i nci pl es: objecti v e assessm ent of l ung f uncti on, phar m acol ogi c
ther apy , env i r onm ental contr ol , and pati ent educati on. The goal s of
ef f ecti v e m anagem ent ar e to m ai ntai n near nor m al pul m onar y f uncti on
and phy si cal acti v i ty l ev el s, m i ni m i ze sy m ptom s and pr ev ent
ex acer bati ons, and av oi d the adv er se ef f ects of asthm a m edi cati ons.
Spi r om etr y , based on the peak ex pi r ator y f l ow r ates or FEV 1 , pr ov i des
an objecti v e m easur e of asthm a contr ol and can be usef ul i n adjusti ng
m edi cati ons (par ti cul ar l y taper i ng sy stem i c cor ti coster oi ds) and
assessi ng the need f or i nter v enti on. Phar m acol ogi c ther apy i s ty pi cal l y
pr escr i bed i n a stepw i se m anner . In r ecogni ti on that asthm a i s a
chr oni c i nf l am m ator y di sease, tr ends i n ther apy hav e pl aced a gr eater
em phasi s on the use of i nhal ed cor ti coster oi ds or cr om ol y n as f i r stl i ne
m edi cati ons, w i th i nhal ed Î² 2 agoni sts used to br i ng about acute r el i ef
of br onchospasm , as needed. Theophy l l i ne pr epar ati ons and or al Î²
adr ener gi c agoni sts ar e of ten used as secondl i ne agents, and ar e
par ti cul ar l y usef ul f or contr ol l i ng the noctur nal w or seni ng of asthm a.
Shor t â€œbur stsâ€ of or al cor ti coster oi ds ar e best used i n the ear l y
tr eatm ent of acute, sev er e ex acer bati ons, and ev er y ef f or t shoul d be
m ade to av oi d chr oni c dependence on or al cor ti coster oi ds once the
acute attack i s contr ol l ed.
In sel ected cases, the i denti f i cati on and av oi dance of speci f i c tr i gger s
of br onchospasm m ay hav e si gni f i cant i m pact on asthm a contr ol .
Av oi dance of aer oal l er gens (dust m i tes, cat dander , pol l ens, and
m ol ds), chem i cal s (sul f i tes and tar tr azi ne),
P. 347
cer tai n m edi cati ons (aspi r i n, Î²bl ock er s, and acety l chol i nester ase
i nhi bi tor s), and str ong aer oi r r i tants (tobacco sm ok e, househol d spr ay s,
and w ood sm ok e) m ay be hel pf ul f or cer tai n pati ents. Al though
ex er ci se i s a com m on pr eci pi tati ng f actor , the use of i nhal ed Î² 2
agoni sts or cr om ol y n bef or e ex er ci se m ay m i ni m i ze the associ ated
br onchospasm . Last, pati ent educati on shoul d begi n at the ti m e of
di agnosi s and be encour aged thr oughout the conti nued car e. Lear ni ng to
i denti f y i m por tant si gns and sy m ptom s of asthm a, the cor r ect use of
the peak ex pi r ator y f l ow r ate m eter and m eter eddose i nhal er , and
addr essi ng i ssues r el ated to m edi cati on ef f ects and env i r onm ental
contr ol m ay m i ni m i ze pati ent m i sunder standi ngs r egar di ng the ongoi ng
m anagem ent of asthm a. In thi s pati ent, a w ar ni ng r egar di ng the
av oi dance of Î± adr ener gi c agoni sts unti l the com pl eti on of the
pr egnancy i s al so w ar r anted.
Suggested Readings
Busse WW, Lem ansk er F. Asthm a. N Engl J Med 2001;344:350â€“362.
Inter nati onal r epor t: i nter nati onal consensus r epor t on di agnosi s and
tr eatm ent of asthm a. Publ i cati on no. 923091. Washi ngton, DC: U . S.
Depar tm ent of Heal th and Hum an Ser v i ces, Publ i c Heal th Ser v i ce,
N ati onal Insti tutes of Heal th, June 1992.
McFadden ER. Acute sev er e asthm a. Am J Respi r Cr i t Car e Med

2003;168:740â€“759.
N ati onal Asthm a Educati on Pr ogr am . Ex ecuti v e sum m ar y : gui del i nes f or
the di agnosi s and m anagem ent of asthm a. Publ i cati on no. 913042 A.
Bethesda, MD: Of f i ce of Pr ev enti on, Educati on, and Contr ol , N ati onal
Hear t, Lung and Bl ood Insti tute, N ati onal Insti tutes of Heal th, Jul y 1991.
N ati onal Asthm a Educati on Pr ogr am . Ex ecuti v e sum m ar y : m anagem ent
of asthm a dur i ng pr egnancy . Publ i cati on no. 933279 A. Bethesda, MD:
Of f i ce of Pr ev enti on, Educati on, and Contr ol , N ati onal Hear t, Lung and
Bl ood Insti tute, N ati onal Insti tutes of Heal th, October 1992.
Chronic Obstructive Pulmonary Disease
1. What i s chr oni c obstr ucti v e pul m onar y di sease (COPD)?
2. What ar e the epi dem i ol ogi c tr ends i n COPD?
3. What i s the m ost com m onl y hel d theor y ex pl ai ni ng the dev el opm ent of
em phy sem a?
4. What ar e the com m on si gns and sy m ptom s of COPD?
5. What ar e the com m on l abor ator y and r adi ogr aphi c f i ndi ngs i n the
setti ng of COPD?
Discussion
1. What i s COPD?
The ter m COPD i s com m onl y appl i ed to tw o di sor der s: em phy sem a and
chr oni c br onchi ti s. Most pati ents w i th COPD hav e a com bi nati on of
these
P. 348
tw o condi ti ons. Som e author s al so i ncl ude chr oni c obstr ucti v e asthm a
and other di sor der s associ ated w i th chr oni c ai r f l ow l i m i tati on (e. g. ,
br onchi ol i ti s obl i ter ans and br onchi ectasi s) under the headi ng of COPD.
2. What ar e the epi dem i ol ogi c tr ends i n COPD?
Ther e has been an appr ox i m ate 60% i ncr ease i n the pr ev al ence of
COPD si nce the l ate 1970s. Al though em phy sem a i s a com m on
postm or tem f i ndi ng i n adul ts, i ts pr ev al ence i s str ongl y cor r el ated w i th
sm ok i ng. COPD i s m or e com m onl y di agnosed i n m en than w om en, but
as m or e adol escent gi r l s than boy s ar e begi nni ng to sm ok e, thi s tr end
m ay change. A heav y sm ok er ex hi bi ts an av er age decl i ne i n FEV 1 of 40
to 45 m L per y ear ; thi s decl i ne i s onl y 20 m L per y ear i n a nonsm ok i ng
adul t.
3. What i s the m ost com m onl y hel d theor y ex pl ai ni ng the dev el opm ent of
em phy sem a?
In par t, on the basi s of obser v ati ons gl eaned i n peopl e w i th Î± 1
anti tr y psi n def i ci ency , m ost author i ti es bel i ev e that the destr ucti on of
the al v eol ar w al l and the ai r space enl ar gem ent seen i n the setti ng of
em phy sem a ar e due to an i m bal ance betw een the pr oteases and
anti pr oteases i n the l ow er r espi r ator y tr ee (Î± 1 anti tr y psi n bei ng the
m ajor pr otei n i n thi s categor y ). Ci gar ette sm ok e i nacti v ates the nor m al
anti pr oteases i n peopl e w ho do not hav e Î± 1 anti tr y psi n def i ci ency .
4. What ar e the com m on si gns and sy m ptom s of COPD?
Al though the i ni ti al com pl ai nt i s usual l y dy spnea, som e pati ents seek
m edi cal car e because of chr oni c cough or sputum pr oducti on, w heezi ng,
r ecur r ent pul m onar y i nf ecti ons, or , i n r ar e ci r cum stances, w ei ght l oss
or l ow er ex tr em i ty sw el l i ng. Ear l y i n the di sease, phy si cal ex am i nati on
f i ndi ngs m ay be nor m al . Later , auscul tati on of the chest m ay r ev eal
w heezi ng, r honchi , or , i n pati ents w i th pr edom i nant em phy sem a,
decr eased br eath sounds. Per cussi on of the chest ty pi cal l y r ev eal s
hy per i nf l ati on and l ow di aphr agm s. In adv anced cases, the poi nt of
m ax i m al car di ac i m pul se m ay be f el t i n the subx i phoi d ar ea. Cy anosi s,
a r i ghtsi ded thi r d hear t sound (S 3 ), jugul ov enous di stenti on, and l ow er
ex tr em i ty edem a ar e l ate f i ndi ngs.
5. What ar e the com m on l abor ator y and r adi ogr aphi c f i ndi ngs i n the
setti ng of COPD?
Ther e ar e no speci f i c l abor ator y v al ues seen i n the setti ng of COPD.
The r outi ne bl ood count i s nor m al , al though COPD pati ents w i th chr oni c
hy pox i a m ay show an el ev ated hem atocr i t. The f i ndi ng of eosi nophi l i a
shoul d r ai se the possi bi l i ty of concom i tant asthm a. Ty pi cal l y i n COPD
the f l ow r ates ar e r educed, the l ung v ol um es ar e i ncr eased due to
hy per i nf l ati on as m easur ed by i ncr eased thor aci c gas v ol um e and
f uncti onal r esi dual capaci ty , and the di f f usi ng capaci ty i s decr eased i n
em phy sem a. Reducti ons i n both the FEV 1 and f or ced v i tal capaci ty
(FVC) ar e r outi nel y seen, al though the FEV 1 i s r educed out of
pr opor ti on to the FVC. Ear l y on, the chest r adi ogr aph i s usual l y nor m al .
As em phy sem a dev el ops, the l ungs show hy per i nf l ati on, f l atteni ng of
the di aphr agm s, and an i ncr eased r etr oster nal ai r space. Bul l ae can be
seen. The el ectr ocar di ogr am tends to be nor m al , ex cept i n adv anced
di sease, w hen i t m ay show l ow v ol tage i n the l i m b l eads, ear l y R
w av es i n V 1 and V 2 , and peak ed P w av es (P pul m onal e).
P. 349
Case
A 65y ear ol d m an i s seen because of a 5day hi stor y of pr ogr essi v e
shor tness of br eath and dy spnea on ex er ti on. He al so com pl ai ns of a cough
pr oducti v e of gr een sputum , as w el l as v ague r i ghtsi ded chest pai n. He has
f el t f ev er i sh at hom e, but deni es any shak i ng chi l l s, sor e thr oat, nausea,
v om i ti ng, di ar r hea, edem a, or ex posur e to any one w i th a si m i l ar i l l ness.
The pati ent has been sm ok i ng tw o pack s of ci gar ettes per day f or the l ast
30 y ear s. How ev er , he r ecentl y decr eased hi s habi t to one pack per day . He
w as seen by a phy si ci an appr ox i m atel y hal f a y ear ago and w as tol d that he
had em phy sem a. He has not been hospi tal i zed pr ev i ousl y . He i s a r eti r ed
bus dr i v er and l i v es at hom e w i th hi s w i f e. They hav e no pets. Al though he
has noted som e dy spnea on ex er ti on ov er the l ast 3 to 4 y ear s, he conti nues
to m ai ntai n an acti v e l i f esty l e and can sti l l m ow the l aw n w i thout m uch
di f f i cul ty . He can w al k 1 to 2 m i on a f l at sur f ace at a m odest pace. The
pati ent r ar el y dr i nk s al cohol . He deni es any other si gni f i cant past m edi cal
hi stor y , i ncl udi ng a hi stor y of chi l dhood asthm a or al l er gi c di seases,
si gni f i cant cough, sputum pr oducti on, or ex posur e to asbestos. Hi s
m edi cati ons i ncl ude sustai nedr el ease theophy l l i ne and ov er thecounter
v i tam i ns.
On phy si cal ex am i nati on, the pati ent i s f ound to be a som ew hat thi n but
w el l dev el oped and i n m oder ate r espi r ator y di str ess. Hi s bl ood pr essur e i s
150/98 m m Hg w i th a pul sus par adox us of 20 m m Hg, hi s pul se i s 110 beats
per m i nute, hi s tem per atur e i s 37. 9Â°C (100. 22Â°F) or al l y , and hi s
r espi r ator y r ate i s 24 br eaths per m i nute and l abor ed. Head, ey e, ear s,
nose, and thr oat f i ndi ngs ar e unr em ar k abl e. N o adenopathy i s f ound i n hi s
neck , and the neck v ei ns ar e f l at. Hi s chest i s hy per ex panded, and ther e i s
use of the accessor y m uscl es of r espi r ati on. Hy per r esonance to per cussi on
i s noted. Hi s br eath sounds ar e di stant w i th an occasi onal scatter ed w heeze.
Dur i ng the car di ac ev al uati on, the poi nt of m ax i m al i m pul se i s l ocated i n
the epi gastr i c ar ea. Ther e i s a r egul ar tachy car di a w i th a sy stol i c f our th
sound (S 4 ) hear d best at the r i ght l ow er ster nal bor der . N o m ur m ur s or r ubs
ar e noted. Hi s abdom en i s scaphoi d, bow el sounds ar e nor m al , and no
tender ness or or ganom egal y i s noted. Hi s ex tr em i ti es ar e f r ee of cl ubbi ng,
cy anosi s, and edem a. Pul se ox i m etr y show s a 91% satur ati on on r oom ai r .
1. What tests and studi es w oul d y ou or der i n thi s pati ent?
A chest r adi ogr aphi c study r ev eal s the pr esence of hy per ex panded l ung
f i el ds, a sm al l car di ac si l houette, ev i dence of bul l ous di sease i n both
l ungs, and an al v eol ar i nf i l tr ate i n the r i ght m i ddl e l obe w i th som e
degr ee of v ol um e l oss. N o ef f usi ons ar e seen.
Ar ter i al bl ood gas m easur em ent per f or m ed on r oom ai r r ev eal s a pH of
7. 50, a PaCO 2 of 23 m m Hg, a PaO 2 of 51 m m Hg, and an ox y gen
satur ati on of 92%. Respi r ator y al k al osi s i s pr esent w i th
hy per v enti l ati on. Resul ts of a com pl ete bl ood count ar e as f ol l ow s:
w hi te bl ood cel l s, 14, 300/m m 3 w i th 8% band f or m s and 8. 4%
pol y m or phonucl ear l euk ocy tes; and the hem atocr i t r eadi ng i s 44%. A
chem i str y panel r ev eal s the f ol l ow i ng f i ndi ngs: sodi um , 139 m Eq/L;
potassi um , 4. 1 m Eq/L; chl or i de, 108 m Eq/L; bi car bonate, 20 m Eq/L;
bl ood ur ea ni tr ogen, 21 m g/dL; and cr eati ni ne, 0. 9 m g/dL. Hi s
theophy l l i ne l ev el i s 3. 7 Âµg/m L. The el ectr ocar di ogr am r ev eal s si nus
tachy car di a w i th l ow v ol tage i n the l i m b l eads, and no acute changes.
2. What i s y our di agnosi s based on the i nf or m ati on y ou hav e, and how
w oul d y ou m anage thi s pati ent?
P. 350
3. What ther apy shoul d y ou i nsti tute w hi l e the pati ent i s i n the hospi tal ?
The pati ent i s star ted on i nhal ed Î² 2 agoni sts and i ntr av enous
am pi ci l l i n. Af ter 2 day s of tr eatm ent, hi s condi ti on f ai l s to i m pr ov e and
r espi r ator y f ati gue r equi r i ng em er gent endotr acheal i ntubati on and
v enti l ati on dev el ops. Hi s w i f e states that she does not w ant to pr ol ong
the pati ent's l i f e â€œby ar ti f i ci al m eansâ€ and i s w or r i ed that the
pati ent w i l l r equi r e i ndef i ni te m echani cal v enti l ati on. Another opti on
w oul d be the use of noni nv asi v e v enti l ati on w i th Bi PAP (i . e. , nasal
posi ti v e ai r w ay pr essur e dur i ng i nspi r ati on and ex pi r ati on).
4. How w oul d y ou r espond to hi s w i f e's concer n about the need f or
i ndef i ni te m echani cal v enti l ati on?
The pati ent's sputum cul tur e gr ow s Haem ophi l us i nf l uenzae that i s
r esi stant to am pi ci l l i n. Hi s anti bi oti cs ar e changed, and 4 day s l ater he
i s successf ul l y ex tubated. Af ter 14 day s i n the hospi tal , he i s r eady to
be di schar ged.
5. Af ter the pati ent i s di schar ged, how w oul d y ou pr ov i de f ol l ow up, and
w hat ar e y our tr eatm ent opti ons now ?
Case Discussion
1. What tests and studi es w oul d y ou or der i n thi s pati ent?
A c he s t ra diogra phic s tudy shoul d be obtai ned. Al though the v al ue of
a r outi ne chest r adi ogr aphi c study i n pati ents w i th an ex acer bati on of
COPD has been debated, thi s pati ent has a pr oducti v e cough, l ow gr ade
tem per atur e, and l ocal i zi ng chest pai n, al l of w hi ch i ndi cate the
ex i stence of an i ntr athor aci c abnor m al i ty , str essi ng the i m por tance of a
chest r adi ogr aph.
Despi te a pul se ox i m etr y r eadi ng of 91%, a rte ria l blood ga s
me a s ure me nts ar e i ndi cated f or i n thi s pati ent. Ther e ar e sev er al
f actor s that can cause a poor cor r el ati on betw een the pul se ox i m etr y
v al ue and the PaO 2 , as m easur ed by ar ter i al bl ood gas deter m i nati ons.
It i s poor i n pati ents w i th jaundi ce or dar k sk i n pi gm entati on, as w el l
as i n those w i th poor per i pher al ci r cul ati on. Fur ther m or e, under v ar i ous
phy si ol ogi c and pathol ogi c condi ti ons (e. g. , changes i n the pH or 2, 3
di phosphogl y cer i c aci d l ev el ), the ox y hem ogl obi n di ssoci ati on cur v e can
be shi f ted to the r i ght or l ef t. Ther ef or e, the ox i m eter can ei ther
under pr edi ct or ov er pr edi ct the actual PaO 2 . Fi nal l y , i n a pati ent w i th a
m oder atel y sev er e pul m onar y pr ocess, k now l edge of the PaCO 2 and pH
i s i m per ati v e.
A c omple te blood c ount and c he mis try pa ne l shoul d be obtai ned. The
com pl ete bl ood count can pr ov i de usef ul i nf or m ati on r egar di ng the
sev er i ty of the i nf ecti ous pr ocess (e. g. , l euk ocy tosi s). Fur ther m or e,
si gni f i cant pol y cy them i a m ay i ndi cate the ex i stence of l ongstandi ng
hy pox i a, w hi ch si gni f i es the chr oni ci ty and sev er i ty of the di sease. The
chem i str y pr of i l e can pr ov i de v al uabl e i nf or m ati on concer ni ng
el ectr ol y te i m bal ance (e. g. , hy ponatr em i a i n the sy ndr om e of
i nappr opr i ate anti di ur eti c hor m one secr eti on) or v ol um e depl eti on.
Know l edge of the ser um bi car bonate l ev el i s usef ul i n conjuncti on w i th
the ar ter i al bl ood gas f i ndi ngs to assess the chr oni ci ty of any
r espi r ator y aci dâ€“base di sor der s.
P. 351
In a pati ent of adv anced age w i th r i sk f actor s f or cor onar y ar ter y
di sease (tobacco abuse and hy per tensi on) and chest pai n, an
e le c troc a rdiogra phy i s i ndi cated. Fur ther m or e, m any ty pes of
ar r hy thm i as (e. g. , m ul ti f ocal atr i al tachy car di a) ar e seen
pr edom i nantl y i n the setti ng of decom pensated pul m onar y di sease.
The the ophylline le ve l m ust be deter m i ned. Because thi s dr ug has a
nar r ow ther apeuti c i ndex , cl ose m oni tor i ng of the ser um l ev el s i s
essenti al i n acutel y i l l pati ents.
2. What i s y our di agnosi s based on the i nf or m ati on y ou hav e, and how
w oul d y ou m anage thi s pati ent?
The pati ent has a r i ght m i ddl e l obe pneum oni a and, as a r esul t, an
ex acer bati on of hi s COPD. Gi v en the l ack of cough and sputum
pr oducti on i n hi s past hi stor y , as w el l as the bul l ae noted i n the chest
r adi ogr aphi c study , hi s cl i ni cal pi ctur e i s consi stent w i th em phy sem a,
as opposed to chr oni c br onchi ti s. Most pati ents hav e a com bi nati on of
both di sor der s. He shoul d be adm i tted to the hospi tal .
3. What ther apy shoul d y ou i nsti tute w hi l e the pati ent i s i n the hospi tal ?
Blood a nd s putum c ulture s shoul d be obtai ned. A Gr am 'sstai ned
sputum speci m en shoul d be ex am i ned both by the pr i m ar y phy si ci ans
and by the l abor ator y techni ci an.
Inha le d Î²a dre ne rgic a gonis ts (e. g. , 0. 5 m L of al buter ol i n 1. 5 m L

of sal i ne) ar e the m ai nstay of tr eatm ent f or a COPD ex acer bati on. The
i ni ti al dosi ng f r equency of thi s m edi cati on depends on the sev er i ty of
the di sease; i t can be adm i ni ster ed ev er y 1 to 3 hour s. As the pati ent's
condi ti on i m pr ov es, the dosi ng f r equency can be r educed to ev er y 4 to
6 hour s. Al though m eter eddose i nhal er s can be used w i th a si m i l ar
degr ee of success, thei r ef f i cacy depends on the abi l i ty of the pati ent
to coor di nate the ti m i ng of the i nhal ati on and the acti v ati on of the
i nhal er , m ak i ng them a l essthanopti m al tool i n an acutel y i l l pati ent.
The r ol e of the ophylline i n the m anagem ent of an acute ex acer bati on
of COPD r em ai ns contr ov er si al . Most author i ti es agr ee that theophy l l i ne
i s a w eak br onchodi l ator w i th a l ow ther apeuti c i ndex . In a r andom i zed,
contr ol l ed study , the addi ti on of am i nophy l l i ne to a w el l f or m ul ated
ther apeuti c r egi m en i n hospi tal i zed pati ents w i th COPD f ai l ed to show
any benef i t i n ter m s of i m pr ov em ent i n l ung f uncti on or on the dy spnea
scal e. If used, theophy l l i ne l ev el s shoul d be m oni tor ed cl osel y and the
pati ent obser v ed f or any si gns or sy m ptom s of tox i ci ty .
Inha le d a ntic holine rgic s m ay al so be usef ul . Ipr atr opi um br om i de i s
the agent of choi ce. It i s av ai l abl e i n a m eter eddose i nhal er
f or m ul ati on, and can be gi v en i nl i ne i nto v enti l ator tubi ng. Occasi onal
bl ur r ed v i si on or ur i nar y r etenti on has been noted i n pati ents usi ng i t.
For the tr eatm ent of a pati ent w i th stabl e COPD, ti otr opi um br om i de i s
super i or to Î²agoni sts. A com bi nati on of the tw o can m odestl y i m pr ov e
the br onchodi l ati on achi ev ed, as w el l as pr ol ong the ef f ecti v e dur ati on
of acti on of each agent. The star ti ng dose i s one i nhal ati on tw i ce dai l y .
The use of s ys te mic c ortic os te roids , l i k e that of theophy l l i ne, i s

contr ov er si al . A str onger case f or thei r use can be m ade i f the pati ent
has ex hi bi ted a pr ev i ousl y docum ented ster oi d r esponse, has
eosi nophi l i a, or has show n a si gni f i cant br onchodi l ator r esponse to the
i nhal ed agents. A r easonabl e star ti ng dose i s 40 to
P. 352
60 m g of i ntr av enous m ethy l pr edni sol one ev er y 6 hour s. Thi s r egi m en
i s changed to an or al f or m (e. g. , pr edni sone, 40 to 60 m g per day ) w i th
r api d taper i ng. Moni tor i ng of the si de ef f ects (e. g. , hy per gl y cem i a,
m ental status changes, and gastr i ti s) i s cr uci al . Inhal ed cor ti coster oi ds
hav e no r ol e i n the acute m anagem ent of thi s pati ent.
Anti bi oti cs ar e i ndi cated ev en w hen an i nf i l tr ate i s not f ound on the
chest r adi ogr aph. In a w el l desi gned, contr ol l ed cl i ni cal tr i al , pati ents
w i th COPD tr eated w i th br oadspectr um or al anti bi oti cs (the new er
cephal ospor i ns, m acr ol i des, and f l uor oqui nol ones) di d better than the
contr ol pati ents. In thi s si tuati on, the choi ce of anti bi oti c depends on
the Gr am 's stai n f i ndi ngs of the sputum . Bacter i a com m onl y r esponsi bl e
f or l ow er r espi r ator y tr act i nf ecti ons i n thi s pati ent popul ati on i ncl ude
Str eptococcus pneum oni ae, H. i nf l uenzae, and Br anham el l a catar r hal i s.
The l atter tw o usual l y pr oduce Î²l actam ase.
4. How w oul d y ou r espond to hi s w i f e's concer n about the need f or
i ndef i ni te m echani cal v enti l ati on?
The condi ti on of pati ents w i th COPD f r equentl y deter i or ates to the poi nt
w her e they r equi r e v enti l ator y suppor t. The pr ognosi s f or w eani ng the
pati ent f r om the v enti l ator , as w el l as the f utur e qual i ty of l i f e,
depends on the pati ent's pr em or bi d l ung f uncti on and f uncti onal state.
Al though the status of thi s pati ent's pul m onar y f uncti on i s unk now n,
gi v en hi s hi gh qual i ty of l i f e and f uncti onal status bef or e thi s epi sode,
the odds ar e ov er w hel m i ngl y i n hi s f av or that he can be successf ul l y
ex tubated. Ther ef or e, v er y aggr essi v e tr eatm ent i s i ndi cated.
5. Af ter the pati ent i s di schar ged, how w oul d y ou pr ov i de f ol l ow up, and
w hat ar e y our tr eatm ent opti ons now ?
Ev er y attem pt shoul d be m ade to encour age hi m to stop sm ok i ng. The
r ate of pul m onar y f uncti on l oss, i n sm ok er s w ho qui t sm ok i ng, r ev er ts
gr adual l y tow ar d the r ate seen i n the nor m al popul ati on. The r i sk of
l ung cancer and hear t di sease al so decl i nes si gni f i cantl y .
Am ong the ther apeuti c i nter v enti ons now av ai l abl e ar e w el l desi gned
sm ok i ng cessati on ther apy gr oups, such as the one of f er ed by the
Am er i can Lung Associ ati on, as w el l as the super v i sed use of ni coti ne
gum . It i s al so i m por tant that a f ol l ow up chest r adi ogr aphi c study be
obtai ned w i thi n 4 to 6 w eek s to dem onstr ate di sappear ance of the
i nf i l tr ate. An unr esol v ed i nf i l tr ate coul d be due to l ung cancer
(especi al l y w i th the v ol um e l oss seen ear l i er on hi s chest r adi ogr aph).
The i nci dence of l ung cancer i s m uch hi gher i n sm ok er s w i th COPD than
i n those w i thout. Thi s r i sk al so di m i ni shes si gni f i cantl y w i th the
cessati on of sm ok i ng. The pati ent shoul d al so r ecei v e annual i nf l uenza
v acci nes and, al though a contr ov er si al m easur e, a oneti m e pol y v al ent
pneum ococcal v acci ne. Hi s m edi cati ons shoul d i ncl ude an i nhal ed Î²
agoni st or i pr atr opi um br om i de (Atr ov ent), or both. The judi ci ous use
of sustai neddose or al theophy l l i nes and ster oi ds (i nhal ed i f possi bl e)
m ay be i ndi cated. Fi nal l y , a r epeat ar ter i al bl ood gas m easur em ent on
r oom ai r shoul d be per f or m ed w hen the pati ent's condi ti on i s cl i ni cal l y
stabl e. Suppl em ental ox y gen f or pati ents w i th a PaO 2 of 55 m m Hg or
l ess can i m pr ov e a pati ent's cogni ti v e abi l i ty , ex er ci se tol er ance, and
r i ght hear t f uncti on, as w el l as pr ev ent the dev el opm ent of pul m onar y
hy per tensi on. U l ti m atel y , i t can l engthen the pati ent's l i f e span.
P. 353
Suggested Readings
Chr oni c obstr ucti v e pul m onar y di sease: di sor der of the car di ov ascul ar
and r espi r ator y sy stem s. Pr oc Am Thor ac Soc 2005;2:1â€“94.
Snow V, Lasher S, Mottur Pi l son C. Ev i dence f or m anagem ent of acute

ex acer bati ons of chr oni c obstr ucti v e pul m onar y di sease. Ann Int Med
2001;134:595â€“599.
Idiopathic Pulmonary Fibrosis
1. What ar e the basi c pathol ogi c ev ents that l ead to i nter sti ti al l ung
di sease (ILD)?
2. What ar e the ty pi cal pul m onar y f uncti on test (PFT) abnor m al i ti es
obser v ed i n the setti ng of i di opathi c pul m onar y f i br osi s (IPF)?
3. What i s the outcom e i f IPF i s l ef t untr eated, and i s the di agnosi s one of
ex cl usi on?
4. What ar e the pr esenti ng sy m ptom s of IPF?
Discussion
1. What ar e the basi c pathol ogi c ev ents that l ead to ILD?
Regar dl ess of the under l y i ng cause of ILD, the m or phol ogi c patter n of
pr ogr essi on i s si m i l ar . A k now n or unk now n sti m ul us or i m m unol ogi c
ev ent causes al v eol ar epi thel i al /endothel i al i njur y r esul ti ng i n
m i gr ati on of i nf l am m ator y cel l s to the al v eol ar str uctur es. U nl i k e acute
i nsul ts, as seen i n bacter i al pneum oni a (w hi ch r esul ts i n a tr ansi ent
i nf l am m ator y i nf i l tr ate), the i njur y of ILD i s per si stent or r epeti ti v e.
The per si stence of the i njur y and i nf l am m ati on dam ages the
par enchy m al cel l s and causes di sr upti on of the al v eol ar capi l l ar y
m em br ane. Inf l am m ati on and abnor m al r epai r then l ead to
m esenchy m al cel l pr ol i f er ati on (f i br obl asts), w i th the attendant
pr oducti on of ex cess col l agen and connecti v e ti ssue el em ents
ex pandi ng the ex tr acel l ul ar m atr i x . U l ti m atel y , the nor m al ar chi tectur e
of the l ung i s r epl aced by f i br oti c bands and cy sti c spaces k now n as
honey com b l ung. IPF i s the pr ototy pi c ILD w hose under l y i ng pathol ogi c
pr ocess i s usual l y i nter sti ti al pneum oni a.
2. What ar e the ty pi cal PFT abnor m al i ti es obser v ed i n the setti ng of IPF?
The char acter i sti c PFT abnor m al i ti es i ncl ude a gr adual r educti on of l ung
v ol um es and ai r f l ow (FEV 1 and FVC), w i th pr eser v ati on of the FEV 1 /FVC
r ati o. The FEV 1 /FVC can be nor m al or i ncr eased due to the i ncr eased
el asti c r ecoi l of the sti f f l ung par enchy m a. Pati ents w i th som e ILD
(e. g. , chr oni c hy per sensi ti v i ty pneum oni ti s, Langer hans cel l
gr anul om atosi s of the l ung, and cy sti c f i br osi s) m ay i ni ti al l y ex hi bi t
nor m al or i ncr eased l ung v ol um es secondar y to sm al l ai r w ay
i nv ol v em ent w i th ai r f l ow obstr ucti on (a r educed FEV 1 /FVC r ati o) and ai r
tr appi ng. In addi ti on, the dev el opm ent of em phy sem a i n conjuncti on
w i th any ty pe of ILD m ay be i ni ti al l y associ ated w i th r el ati v el y m i l d
abnor m al i ti es on r outi ne PFTs. It i s, ther ef or e, i m por tant to r em em ber
P. 354
that the absence of ty pi cal PFT abnor m al i ti es does not ex cl ude IPF or
any other ILD. The gas ex change at r est i s i ni ti al l y nor m al i n m any
pati ents w i th IPF; how ev er , ex er ci sei nduced desatur ati on i s one of the
ear l i est si gns and the m ost sensi ti v e m eans to detect the di sease. The
di f f usi on capaci ty i s ty pi cal l y r educed but m ay be nor m al , especi al l y i n
the ear l y stages of the di sease.
3. What i s the outcom e i f IPF i s l ef t untr eated, and i s the di agnosi s one of
ex cl usi on?
IPF steadi l y pr ogr esses ev en w hen tr eated. Wi th ti m e, the chr oni c
i nf l am m ator y r esponse (al v eol i ti s) pr oduces f i br osi s, al ong w i th the
cl assi c phy si ol ogi c abnor m al i ti es al r eady descr i bed. Al though the
eti ol ogy i s unk now n, the cl i ni copathol ogi c m ani f estati ons ar e speci f i c,
and, ther ef or e, i t i s not a di agnosi s of ex cl usi on. U p to 50% of pati ents
di e betw een 2 and 3 y ear s af ter di agnosi s. At pr esent onl y l ung
tr anspl antati on i s a v i abl e tr eatm ent i n el i gi bl e subjects. Cur r entl y ,
nov el bi ol ogi c agents ar e bei ng tested.
4. What ar e the pr esenti ng sy m ptom s of IPF?
The i nsi di ous onset of br eathl essness and nonpr oducti v e cough i s
com m on to m ost cases. Fati gue, l ow gr ade f ev er i shness, ar thr al gi as,
and m y al gi as ar e al so r el ati v el y com m on, but nonspeci f i c, sy m ptom s.
The occur r ence of f r ank ar thr i ti s, m y osi ti s (m uscl e tender ness and
w eak ness), photosensi ti v i ty , Ray naud's phenom enon, v i sual pr obl em s,
and so on, suggests the ex i stence of other sy stem i c pr ocesses, such as
col l agen v ascul ar di sease, v ascul i ti s, or sar coi dosi s. Dr y i nspi r ator y
cr ack l es m ay be the onl y phy si cal f i ndi ng, al though di gi tal cl ubbi ng i s
seen i n 40% to 70% of cases. A chest r adi ogr aph usual l y r ev eal s
r eti cul ar (l i near ) or r eti cul onodul ar opaci ti es i n the l ow er l ung zones.
The hi ghr esol uti on CT scan i ndi cates per i pher al and basi l ar i nter sti ti al
i nf i l tr ates and honey com bi ng.
Case
A 58y ear ol d w om an i s r ef er r ed f or the ev al uati on of br eathl essness and
cough. She f i r st began noti ci ng dy spnea on ex er ti on appr ox i m atel y 3 to 4
y ear s ago w hen usi ng her f l oor sw eeper . How ev er , she noted no l i m i tati on
w hen per f or m i ng any of her other usual acti v i ti es. Her dy spnea w or sened
sl i ghtl y ov er the ensui ng y ear s w i thout any other sy m ptom s unti l 9 m onths
ago, w hen a nonpr oducti v e cough dev el oped. Thi s w as tr eated w i th
anti bi oti cs and i nhal ed br onchodi l ator s, w i thout i m pr ov em ent. Ov er the l ast
9 m onths, her br eathl essness has w or sened and she now has tr oubl e
cl i m bi ng one f l i ght of stai r s. She ti r es easi l y and occasi onal l y f eel s
f ev er i sh, but has not ex per i enced ar thr al gi as, m y al gi as, ni ght sw eats, or
other consti tuti onal sy m ptom s. She has ex per i enced no chest pai n or
hem opty si s and has no hi stor y of car di opul m onar y di sease. Her past m edi cal
hi stor y i s unr em ar k abl e. Medi cati ons i ncl ude i nhal ed br onchodi l ator s. She i s
m ar r i ed and has nev er sm ok ed. She has w or k ed as a r etai l sal es cl er k f or
17 y ear s w i thout ex posur es. She has had no pet bi r ds, l eak y pi pes, or m ol dy
condi ti ons i n her hom e.
Phy si cal ex am i nati on r ev eal s a r espi r ator y r ate of 20 unl abor ed br eaths per
m i nute w i th dr y i nspi r ator y r al es hear d ov er the l ow er thi r d of the poster i or
l ung f i el ds. She has no cl ubbi ng or edem a. Labor ator y ev al uati on r ev eal s a
nor m al hem ogr am and bi ochem i cal
P. 355
pr of i l e. Anti nucl ear anti bodi es show w eak posi ti v i ty at 1:80. Testi ng f or
r heum atoi d f actor i s negati v e.
A chest r adi ogr aph show s r eti cul ar opaci ti es that ar e m ost pr om i nent i n the
l ow er l ung zones as w el l as r educed l ung v ol um es and the hi ghr esol uti on
com puted tom ogr aphy scan (HRCT) show s per i pher al and basi l ar r eti cul ar
i nf i l tr ates as w el l as honey com b change i n a si m i l ar di str i buti on. PFTs
r ev eal a total l ung capaci ty of 70% of pr edi cted and a f uncti onal r esi dual
capaci ty that i s 66% of pr edi cted. The FEV 1 i s 50% of pr edi cted w i th an FVC
that i s 58% of pr edi cted. The FEV 1 /FVC r ati o i s 88%. Her di f f usi on capaci ty
i s 65% of pr edi cted. The PaO 2 on r oom ai r w hi l e r esti ng i s 60 m m Hg, w hi ch
dr ops to 38 m m Hg w i th ex er ci se.
1. How w oul d the di agnosi s of IPF best be conf i r m ed i n thi s pati ent?
2. If the thor acoscopi c l ung bi opsy speci m en r ev eal s the pr esence of the
usual i nter sti ti al pneum oni ti s, w hat ar e the tr eatm ent opti ons f or thi s
pati ent?
Case Discussion
1. How w oul d the di agnosi s of IPF best be conf i r m ed i n thi s pati ent?
Al though the cl i ni cal , r adi ol ogi c, and phy si ol ogi c pi ctur e i n thi s pati ent
i s m ost suggesti v e of IPF, other i nter sti ti al l ung pr ocesses, such as
chr oni c hy per sensi ti v i ty pneum oni ti s, nonspeci f i c i nter sti ti al pneum oni a
(N SIP), asbestosi s, stage III sar coi dosi s, and col l agen v ascul ar
di sease, m ay pr esent i n an i denti cal m anner . How ev er , the ty pi cal
HRCT and l ack of ev i dence f or one of the af or em enti oned ILDs,
establ i shes the di agnosi s. In cases w her e the r adi ol ogi c pr esentati on i s
not ty pi cal , sur gi cal l ung bi opsy by the v i deoassi sted thor acoscope
(VATS) i s i ndi cated f or the di agnosi s. The hi stol ogi c ex pr essi on of IPF
i s usual i nter sti ti al pneum oni a (U IP). Thi s i s char acter i zed by tem por al
heter ogenei ty i n w hi ch end stage honey com b i s adjacent to nor m al l ung
and ther e i s al v eol ar w al l f i br osi s of v ar y i ng degr ees. Another
i m por tant f eatur e i s the pr esence of f i br obl asti c f oci , w hi ch ar e
subepi thel i al col l ecti ons of m y of i br obl asts i n l oose connecti v e ti ssue
str om a.
2. If the thor acoscopi c l ung bi opsy speci m en r ev eal s the pr esence of the
usual i nter sti ti al pneum oni ti s, w hat ar e the tr eatm ent opti ons f or thi s
pati ent?
Cor ti coster oi ds and i m m unosuppr essi v e dr ugs (azathi opr i ne and
cy dophospham i de) hav e been r ecom m ended f or IPF. How ev er , at
pr esent ther e i s no ev i dence that thi s tr eatm ent i m pr ov es outcom e. For
el i gi bl e pati ents, tr anspl antati on i s an opti on. The addi ti on of N
acety l cy stei ne to pr edni soneâ€“azathi opr i ne r egi m en show s pr om i se f or
a f ew pati ents. N ew er bi ol ogi cs that potenti al l y i nhi bi t
f i br opr ol i f er ati on ar e i n tr i al s.
Suggested Readings
Ki ng TE. Idi opathi c pul m onar y f i br osi s. In: Schw ar z MI, Ki ng TE, eds.
Inter sti ti al l ung di sease, 4th ed. Tor onto: BC Deck er , 2003.
P. 356
Pleural Disease
1. What i s a pl eur al ef f usi on?
2. What ar e the phy si cal f i ndi ngs associ ated w i th a pl eur al ef f usi on?
3. What i s the si gni f i cance of di sti ngui shi ng betw een a tr ansudati v e and
an ex udati v e pl eur al ef f usi on?
4. What testi ng di sti ngui shes betw een pl eur al tr ansudates and ex udates?
5. What i s an em py em a?
6. How do y ou dev el op a tr eatm ent pl an i n the pati ent w i th a pl eur al
ef f usi on?
Discussion
1. What i s a pl eur al ef f usi on?
A pl eur al ef f usi on i s an abnor m al col l ecti on of f l ui d i n the potenti al
space betw een the v i scer al and par i etal pl eur a. N or m al l y , thi s space
contai ns onl y a f ew m i l l i l i ter s of f l ui d, w hi ch ser v es to l ubr i cate these
sur f aces.
2. What ar e the phy si cal f i ndi ngs associ ated w i th a pl eur al ef f usi on?
Pl eur al ef f usi ons can be detected on phy si cal ex am i nati on i f they ar e of
suf f i ci ent v ol um e to pr oduce a f l ui d l ev el i n the chest and com pr ess
under l y i ng l ung ti ssue. Dul l ness to per cussi on w i th decr eased or absent
br eath sounds i n a dependent anatom i c l ocati on i s ty pi cal of pl eur al
ef f usi on. Egophony i s an i m por tant f i ndi ng that di sti ngui shes an
ef f usi on stem m i ng f r om atel ectasi s secondar y to br onchi al obstr ucti on.
Lobar consol i dati on w i th a patent br onchus, as occur s i n pneum oni a,
m ay be di f f i cul t to di sti ngui sh f r om an ef f usi on, because these tw o
abnor m al i ti es of ten coex i st. Whi sper i ng pector i l oquy m ay be hear d i n
the pr esence of a consol i dati on but i s absent ov er a pl eur al ef f usi on. In
addi ti on, phy si cal f i ndi ngs that suggest a sy stem i c i l l ness, such as
congesti v e hear t f ai l ur e, ci r r hosi s, and l upus er y them atosus, pr ov i de
i m por tant cl ues to the potenti al cause and natur e of a pl eur al ef f usi on
di scov er ed on phy si cal ex am i nati on or a r adi ogr aphi c study .
3. What i s the si gni f i cance of di sti ngui shi ng betw een a tr ansudati v e and
an ex udati v e pl eur al ef f usi on?
Thi s di v i si on i s an i m por tant f i r st step i n the di agnosti c ev al uati on of a
pl eur al ef f usi on. In the contex t of a tr ansudati v e pl eur al ef f usi on, the
pl eur a i tsel f i s not di seased but f l ui d i s accum ul ati ng because of the
ef f ect of abnor m al Star l i ng f or ces stem m i ng f r om a sy stem i c i l l ness,
such as congesti v e hear t f ai l ur e, ci r r hosi s, or nephr oti c sy ndr om e. In
these condi ti ons, pl eur al f l ui d accum ul ates f or the sam e r easons that
per i pher al edem a and asci tes dev el op. In the setti ng of an ex udati v e
ef f usi on, the pl eur a i s pr i m ar i l y i nv ol v ed by the di sease. Ex am pl es
i ncl ude m al i gnanci es i n the pl eur a (usual l y m etastati c), i nf ecti ons,
col l agen v ascul ar di seases, and pul m onar y i nf ar cti ons. In these
condi ti ons, the pl eur al sur f ace i s i njur ed and f l ui d accum ul ates
i ndependent of Star l i ng f or ces.
P. 357
4. What testi ng di sti ngui shes betw een pl eur al tr ansudates and ex udates?
Ther e ar e a num ber of si m pl e l abor ator y tests that can hel p i n

di sti ngui shi ng tr ansudati v e and ex udati v e pl eur al ef f usi ons. Ex udates
hav e a hi gher pr otei n content and l actate dehy dr ogenase (LDH) l ev el
than tr ansudates because the m esothel i al cel l s ar e i njur ed by the
di sease pr ocess. A pl eur al f l ui d pr otei n l ev el gr eater than 50% of the
pati ent's cor r espondi ng pl asm a pr otei n l ev el , an LDH l ev el gr eater than
180 IU , or an LDH l ev el gr eater than 60% of the pati ent's
cor r espondi ng pl asm a l ev el di sti ngui shes pl eur al ex udates f r om
tr ansudates. If any of these ar e pr esent, i t i s m or e than 90% l i k el y
that the ef f usi on i s an ex udate. The f i ndi ng of a hi gh w hi te bl ood cel l
count i n the pl eur al f l ui d suggests the pr esence of an ex udate but i s a
l ess r el i abl e i ndi cator than the pr otei n and LDH v al ues. Once an
ex udate has been i denti f i ed, other studi es can be per f or m ed to hel p
el uci date i ts cause. These i ncl ude cy tol ogi c anal y si s, m i cr obi ol ogi c
stai ns and cul tur es, pH deter m i nati on, and ser ol ogi c testi ng f or
col l agen v ascul ar di sease.
5. What i s an em py em a?
Em py em a i s an i nf ecti on i n the pl eur al space. Thi s i nf ecti on m ay be

bacter i al , m y cobacter i al , or f ungal i n or i gi n. In addi ti on to m or e
com m on bacter i al speci es, Acti nom y ces and N ocar di a can al so cause
em py em a. Em py em as m ust be di sti ngui shed f r om par apneum oni c
ef f usi ons. In thi s case, a pneum oni a abutti ng the pl eur a can r esul t i n
an i nf l am m ator y ex udate. The di agnosti c hal l m ar k of em py em a i s
i denti f i cati on of the causati v e or gani sm ei ther by bacter i al stai ni ng or
cul tur e of the f l ui d. Of ten thi s i s not possi bl e due to pr i or anti bi oti c
ther apy . For ex am pl e, a cl i ni cal di agnosi s of em py em a i s m ade on the
basi s of ov er al l cl i ni cal pr esentati on. How ev er , a l ow pl eur al gl ucose
l ev el (< 50 m g/dL) or a pH (< 7. 30), or both, suggest the pr esence of
em py em a, but ar e al so seen i n m al i gnant ef f usi ons, esophageal
r uptur e, and r heum atoi d ar thr i ti s. Em py em as ar e di f f i cul t i nf ecti ons to
cur e w i th anti m i cr obi al ther apy al one, par ti cul ar l y w hen bacter i al i n
or i gi n. These em py em as ar e essenti al l y i ntr apl eur al abscesses and,
l i k e m ost abscesses, r equi r e dr ai nage to achi ev e r esol uti on.
6. How do y ou dev el op a tr eatm ent pl an i n the pati ent w i th a pl eur al
ef f usi on?
Tr eatm ent depends on the eti ol ogy of the ef f usi on. If i t i s a tr ansudate,
ef f ecti v e tr eatm ent of the congesti v e hear t f ai l ur e, nephr oti c
sy ndr om e, or ci r r hosi s, i f possi bl e, of ten r esul ts i n r esol uti on. If the
ef f usi on i s associ ated w i th an i nf ecti on, such as a par apneum oni c
ef f usi on or an em py em a, def i ni ti v e tr eatm ent of the i nf ecti on i s
i ndi cated. Mal i gnant ef f usi ons m ust be addr essed i n the contex t of the
under l y i ng m al i gnancy . Ther ef or e, the tr eatm ent of a pl eur al ef f usi on
depends on the i nf or m ati on gl eaned dur i ng an appr opr i ate cl i ni cal
ev al uati on of the pati ent as a w hol e.
Case
A 43y ear ol d m an w i th l ongstandi ng ser oposi ti v e r heum atoi d ar thr i ti s
pr esents to the em er gency r oom com pl ai ni ng of r i ght pl eur i ti c chest pai n.
He w as star ted on pr edni sone
P. 358
by hi s phy si ci an 1 w eek ear l i er f or an acute f l ar eup of sy nov i ti s i n hi s
w r i sts and hands. For sev er al day s bef or e the onset of the pl eur i ti c pai n,
the pati ent noted m al ai se, anor ex i a, and f ev er s. The ni ght bef or e
pr esentati on, he noted the onset of shar p, nonr adi ati ng pai n i n the r i ght
chest, w hi ch w or sened w i th coughi ng or deep br eathi ng. Hi s cough i s
nonpr oducti v e. He deni es ci gar ette or al cohol use.
On phy si cal ex am i nati on, he i s f ound to be i n m oder ate di str ess because of
hi s chest pai n. Hi s bl ood pr essur e i s 120/70 m m Hg, pul se i s 120 beats per
m i nute and r egul ar , the r espi r ator y r ate i s 20 br eaths per m i nute, and
tem per atur e i s 38Â°C (100. 4Â°F). Hi s phy si cal ex am i nati on i s r em ar k abl e
f or good denti ti on; a nor m al jugul ar v enous pr essur e; a r egul ar tachy car di a
w i thout m ur m ur s, gal l ops, or r ubs; and no per i pher al edem a. Lung
ex am i nati on r ev eal s dul l ness to per cussi on at the r i ght base w i th absent
br eath sounds i n that ar ea. Egophony i s pr esent at the r i ght base but
w hi sper i ng pector i l oquy i s absent. The l ef t l ung i s cl ear ex cept f or a sm al l
ar ea of decr eased br eath sounds at the base.
A com pl ete bl ood count r ev eal s a m i l d nor m ocy ti c anem i a w i th a hem ogl obi n
l ev el of 12. 5 g/dL. The w hi te bl ood cel l count i s 13, 000/m m 3 w i th an
i ncr ease i n the num ber of band f or m s. A chest r adi ogr aph show s a m oder ate
r i ght pl eur al ef f usi on, a sm al l l ef t pl eur al ef f usi on, and a nor m al car di ac
si l houette.
Thor acentesi s of the r i ght pl eur al ef f usi on y i el ds 250 m L of y el l ow , sl i ghtl y
cl oudy f l ui d. The w hi te bl ood cel l count i n the f l ui d i s 3, 500/m m 3 w i th 90%
neutr ophi l s. The r ed bl ood cel l count i s 1, 000/m m 3 . The pr otei n l ev el i s 4. 0
g/dL, the LDH l ev el i s 400 IU , the gl ucose content i s 10 m g/dL, and the pH
i s 7. 12.
1. What i s the m ost l i k el y cause of the r i ght pl eur i ti c chest pai n?

2. What f ur ther tests w oul d y ou do to v er i f y y our di agnosi s?
3. How w oul d y ou m anage thi s pati ent's acute pr obl em ?
4. What ar e the i ntr athor aci c m ani f estati ons of r heum atoi d ar thr i ti s?
Case Discussion
1. What i s the m ost l i k el y cause of the r i ght pl eur i ti c chest pai n?
The pr esentati on consi sti ng of f ev er , acute pl eur i ti c pai n, and an
ex udati v e pl eur al ef f usi on w i th a pr edom i nance of neutr ophi l s i s m ost
consi stent w i th a bacter i al i nf ecti on (em py em a) of the pl eur al space, or
em py em a. Em py em a i s usual l y the r esul t of a pneum oni a that ex tends
to and i nv ol v es the adjacent pl eur a. The pl eur al f l ui d m ay hav e a l ow
gl ucose l ev el and usual l y has a l ow pH (< 7. 30). The m ost com m on
causes i ncl ude anaer obi c bacter i a (of ten r esul ti ng f r om an aspi r ati on
pneum oni a), Staphy l ococcus aur eus, pneum ococcus, and tuber cul osi s.
In i m m unocom pr om i sed hosts, the di f f er enti al di agnosi s i ncl udes f ungi
and other oppor tuni sti c pathogens.
In thi s pati ent, the di agnosi s of pul m onar y em bol i sm w i th subsequent
pul m onar y i nf ar cti on cannot be ex cl uded. Thi s can pr esent w i th f ev er
and pl eur i ti c pai n as w el l . How ev er , the pl eur al f l ui d i s usual l y bl oody
as a r esul t of l ocal ti ssue i nf ar cti on. In addi ti on, hem opty si s m ay be an
associ ated f i ndi ng. Thi s pati ent's ef f usi on had a l ow r ed bl ood cel l
count and he had no r i sk f actor s f or pul m onar y em bol i , such as
pr ol onged bed r est or r ecent tr aum a.
P. 359
Rheum atoi d i nv ol v em ent of the pl eur a i s com m on. Most pati ents w i th
r heum atoi d ar thr i ti s hav e a pl eur al ef f usi on at som e ti m e dur i ng the
cour se of the di sease. The ty pi cal char acter i sti cs of the f l ui d ar e an
ex udati v e w i th a l ow gl ucose l ev el and a hi gh r heum atoi d f actor l ev el .
The pr esentati on i s subacute w hen the ef f usi on becom es l ar ge enough
to cause sy m ptom s or , i n m ost cases, i s noted on ex am i nati on or a
r adi ogr aphi c study i n an asy m ptom ati c pati ent.
Constr i cti v e per i car di ti s m ay be a r ar e consequence of r heum atoi d

i nv ol v em ent of the per i car di um . How ev er , i t i s usual l y m ani f ested by
r i ghtsi ded congesti on w i th an el ev ated jugul ar v enous pr essur e
(usual l y w i th a Kussm aul 's si gn), hepatom egal y , and per i pher al edem a.
2. What f ur ther tests w oul d y ou do to v er i f y y our di agnosi s?
Gr am 's stai ni ng and cul tur e of the pl eur al f l ui d i n a pati ent w i th
em py em a i s i m por tant to i denti f y a causati v e or gani sm and di r ect the
choi ce of anti bi oti c ther apy . The Gr am 's stai n f i ndi ngs ar e of ten
posi ti v e and can nar r ow the di f f er enti al di agnosi s and the anti bi oti c
choi ces. When tuber cul ous em py em a i s suspected, aci df ast stai ni ng of
a sam pl e of pl eur al f l ui d i s i ndi cated. Pl eur al ti ssue cul tur e i s opti m al .
Subsequent cul tur es and sensi ti v i ti es ar e usef ul i n adjusti ng dr ug
ther apy . In the ev ent of em py em a caused by anaer obi c bacter i a, the
Gr am 's stai n f i ndi ngs ar e m or e of ten than not negati v e, and cul tur es
m ay y i el d negati v e r esul ts unl ess the f l ui d i s car ef ul l y handl ed and
pr ocessed anaer obi cal l y . When anaer obi c em py em a i s suspected,
em pi r i c ther apy i s of ten necessar y i f an or gani sm cannot be i denti f i ed.
A CT angi ogr am i s i ndi cated i n cases of suspected pul m onar y em bol i
and w i l l show segm ental or subsegm ental f i l l i ng def ects i n pul m onar y
ar ter i es.
Deter m i nati on of the r heum atoi d f actor l ev el i n the pl eur al space can
be per f or m ed to ascer tai n w hether a pl eur al ef f usi on i n a pati ent w i th
r heum atoi d ar thr i ti s i s r el ated to the under l y i ng r heum atoi d pr ocess.
How ev er , the pr esence of a hi gh r heum atoi d f actor does not ex cl ude a
secondar y com pl i cati on of a r heum atoi d ef f usi on such as i nf ecti on.
An echocar di ogr am i s a usef ul w ay to assess the per i car di um w hen
per i car di al di sease, such as constr i cti v e per i car di ti s, i s suspected.
3. How w oul d y ou m anage thi s pati ent's acute pr obl em ?
The ther apy f or em py em a r equi r es appr opr i ate anti bodi es di r ected
tow ar d the k now n or pr esum ed causati v e or gani sm , or or gani sm s. In
pati ents w i th bacter i al em py em as, tr adi ti onal ther apy al so i nv ol v es
chest tube pl acem ent and, som eti m es, sur gi cal dr ai nage of the pl eur al
space because thi s essenti al l y r epr esents an abscess cav i ty and
anti bi oti c ther apy al one i s usual l y i nef f ecti v e. Dr ai nage i s not done i n
the ev ent of tuber cul ous em py em a, how ev er . The ther apy f or thi s i s
pr ol onged (6 to 12 m onths) tr eatm ent w i th anti tuber cul ous dr ugs. Som e
cl i ni ci ans hav e r ecom m ended that, i n the ev ent of pneum ococcal
em py em a, anti bi oti c ther apy al one i s of ten ef f ecti v e w hen the f l ui d i s
not l ocul ated and the pati ent i s cl i ni cal l y doi ng w el l . In thi s pati ent, the
l ow pH of the f l ui d and si gni f i cant pl eur i ti c pai n w oul d pr om pt
pl acem ent of a sm al l per cutaneous catheter i nto the r i ght pl eur al space
to dr ai n the em py em a com pl etel y . Per i car di ocentesi s i s the tr eatm ent
f or per i car di al tam ponade, but i s not i ndi cated f or constr i cti v e
per i car di ti s. Pr edni sone can be adm i ni ster ed to
P. 360
suppr ess a f l ar eup of r heum atoi d di sease i nv ol v i ng the joi nts, al though
i t does not appear to hav e any ef f ect on pl eur al or per i car di al
i nv ol v em ent.
4. What ar e the i ntr athor aci c m ani f estati ons of r heum atoi d ar thr i ti s?
Rheum atoi d ar thr i ti s i s a sy stem i c i l l ness. As al r eady noted, m ost

pati ents w i l l hav e pl eur al i nv ol v em ent. Per i car di al i nv ol v em ent i s l ess
com m on and, f or tunatel y , i s r ar el y cl i ni cal l y si gni f i cant. Pul m onar y
nodul es can al so f or m , par ti cul ar l y i n pati ents w i th r heum atoi d nodul es
on thei r ex tr em i ti es. These nodul es ar e si m i l ar hi stol ogi cal l y to the
per i pher al nodul es, they w ax and w ane w i th the i ntensi ty of the
sy stem i c di sease, and ar e r ar el y si gni f i cant cl i ni cal l y . In addi ti on to
these m ani f estati ons, r heum atoi d di sease can cause an ILDâ€”ei ther
usual i nter sti ti al pneum oni a, N SIP, or gani zi ng pneum oni a, or acute
i nter sti ti al pneum oni a. Rar el y , br onchi ol i ti s obl i ter ans m ay occur i n
r heum atoi d ar thr i ti s. Thi s i s char acter i zed by a pr ogr essi v e,
i r r ev er si bl e i l l ness si m i l ar to em phy sem a i n i ts r adi ogr aphi c
appear ance and phy si ol ogi c abnor m al i ti es, and i s usual l y f atal w i thi n 5
y ear s of pr esentati on.
Suggested Readings
Ham m H, Li ght RW. Par apneum oni c ef f usi on and em py em a. Eur Respi r J
1997;10:1150â€“1156.
Pulmonary Complications of Human
Immunodeficiency Virus Infection
1. What ar e the pul m onar y com pl i cati ons i n a pati ent w i th hum an
i m m unodef i ci ency v i r us (HIV) i nf ecti on?
2. What tests w oul d hel p y ou establ i sh a speci f i c di agnosi s?

Discussion
1. What ar e the pul m onar y com pl i cati ons i n a pati ent w i th HIV i nf ecti on?
HIV i s a l y m photr opi c r etr ov i r us that i nf ects T4 (hel per ) l y m phocy tes,
B cel l s, and m onocy tes, l eadi ng to a def ect i n cel l m edi ated i m m uni ty ,
w hi ch then pr edi sposes to the dev el opm ent of a v ar i ety of neopl asm s
and oppor tuni sti c i nf ecti ons. The l ung i s one of the pr i m ar y tar get
or gans i n HIV di sease, and pul m onar y com pl i cati ons ar e the l eadi ng
cause of hospi tal i zati on and death i n HIVi nf ected pati ents. The
spectr um of pul m onar y di sor der s associ ated w i th HIV i nf ecti on i ncl udes
both i nf ecti ous and noni nf ecti ous di seases. The i nf ecti ous causes of
pul m onar y di sease i ncl ude both oppor tuni sti c and nonoppor tuni sti c
agents. The m ost com m on oppor tuni sti c or gani sm s ar e Pneum ocy sti s
ji r ov eci , cy tom egal ov i r us, and My cobacter i um av i um i ntr acel l ul ar e
(MAI). Al though oppor tuni sti c i nf ecti ons ar e com m on i n HIVi nf ected
pati ents, these pati ents ar e al so m or e suscepti bl e to nonoppor tuni sti c
i nf ecti ons,
P. 361
i ncl udi ng py ogeni c or gani sm s (S. pneum oni ae and H. i nf l uenzae),
My cobacter i um tuber cul osi s, and f ungal i nf ecti ons. The speci f i c
i nf ecti on the pati ent acqui r es depends on the degr ee of i m m une
def i ci ency and hi s or her ex posur e to speci f i c or gani sm s. The
noni nf ecti ous pul m onar y di sor der s i ncl ude Kaposi 's sar com a, nonâ
€“Hodgk i n's l y m phom a, l y m phocy ti c i nter sti ti al pneum oni ti s,
nonspeci f i c i nter sti ti al pneum oni a, al v eol ar pr otei nosi s, br onchi ol i ti s
obl i ter ans or gani zi ng pneum oni a, pr i m ar y pul m onar y hy per tensi on, and
em phy sem a.
2. What tests w oul d hel p y ou establ i sh a speci f i c di agnosi s?
Chest i m agi ng, ar ter i al bl ood gas deter m i nati ons, a com pl ete bl ood
count, ser um LDH m easur em ent, and sputum studi es shoul d al l be
obtai ned i n an HIVi nf ected pati ent pr esenti ng w i th f ev er and
i ncr easi ng shor tness of br eath. Al though the chest r adi ogr aph or CT
scan can be hel pf ul , the r adi ogr aphi c m ani f estati ons of pul m onar y
di sease ov er l ap si gni f i cantl y i n thi s gr oup of pati ents. Most pati ents
w i th Pneum ocy sti s pneum oni a (PCP) ar e hy pox i c and hy pocapni c, and
ex hi bi t a w i dened al v eol ar ar ter i al gr adi ent, of ten bef or e any
abnor m al i ty i s detected on a chest r adi ogr aph. The com pl ete bl ood
count i n HIVi nf ected pati ents ty pi cal l y dem onstr ates an absol ute
l y m phopeni a, w hi ch pr i m ar i l y stem s f r om a decr ease i n the num ber of
T4 cel l s. The LDH l ev el i s el ev ated i n 95% of the pati ents and has been
show n to i ncr ease w i th w or seni ng sy m ptom s and decl i ne i n r esponse to
ther apy . Sputum i n pati ents w i th py ogeni c bacter i al i nf ecti ons i s of ten
pur ul ent, and the Gr am 's stai n and cul tur e f i ndi ngs shoul d di ctate the
anti bi oti c choi ce. Pati ents w i th PCP of ten hav e a nonpr oducti v e cough,
m ak i ng i t necessar y to obtai n a sputum speci m en that i s i nduced by the
i nhal ati on of hy per toni c sal i ne. Sputum and bl ood cul tur es ar e al so
i ndi cated f or MAI i nf ecti on and tuber cul osi s. Thi s has a y i el d of 25% to
85%, dependi ng on the ex per i ence of the per son per f or m i ng the test.
Methenam i ne si l v er stai ni ng i s used to i denti f y the cy sts. If sputum
studi es ar e unr ev eal i ng, stai ni ng of br onchoal v eol ar cel l s (BAL) has a
hi gher posi ti v i ty r ate.
Case
A 37y ear ol d hom osex ual m an, k now n to be HIV posi ti v e, i s seen f or
ev al uati on of pr ogr essi v e dy spnea and f ev er . He w as w el l unti l 7 to 8
m onths ago, w hen he noted the onset of w ei ght l oss, di f f use adenopathy ,
and ni ght sw eats. Ov er the l ast m onth, he has noted pr ogr essi v e dy spnea, a
dr y , nonpr oducti v e cough, and dai l y f ev er spi k es. He has sm ok ed 20
ci gar ettes a day f r om the age of 18 y ear s, deni es al cohol or dr ug abuse,
and has l i v ed i n the Ohi o Ri v er Val l ey as w el l as the Southw est. Phy si cal
ex am i nati on r ev eal s a bl ood pr essur e of 110/65 m m Hg, pul se of 100 beats
per m i nute, r espi r ator y r ate of 32 br eaths per m i nute, and tem per atur e of
39Â°C (102. 2Â°F). Thr oat ex am i nati on f i ndi ngs ar e r em ar k abl e f or a w hi te
ex udate on the poster i or phar y ngeal w al l . The l y m ph nodes ar e di f f usel y
enl ar ged and nontender . Dur i ng chest ex am i nati on, bi l ater al cr ack l es ar e
noted. The r em ai nder of the ex am i nati on f i ndi ngs ar e unr em ar k abl e. A chest
r adi ogr aph r ev eal s the pr esence of di f f use bi l ater al i nter sti ti al i nf i l tr ates.
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, and do the chest
r adi ogr aph f i ndi ngs i nf l uence thi s?
P. 362
2. If the i ni ti al test r esul ts do not conf i r m y our di agnosi s, w hat test w oul d
y ou do nex t?
3. What ther apy w oul d y ou i ni ti ate, and i s ther e a r ol e f or pr ophy l acti c
ther apy ?
Case Discussion
1. What i s the di f f er enti al di agnosi s i n thi s pati ent, and do the chest
r adi ogr aph f i ndi ngs i nf l uence thi s?
Al though m al i gnancy and a chr oni c i nf ecti ous pr ocess such as

tuber cul osi s coul d account f or these chr oni c and subacute sy m ptom s,
thi s pati ent's cl i ni cal pi ctur e i s m ost consi stent w i th a com pl i cati on of
HIV i nf ecti on. Besi des the spectr um of pul m onar y di sor der s associ ated
w i th HIV i nf ecti ons, pr i m ar y car di ac di sor der s shoul d al so be
consi der ed w hen dy spnea and bi l ater al r al es ar e encounter ed. The
f ev er and chi l l s i n thi s pati ent i ndi cate an i nf ecti ous cause. The
di f f er enti al di agnosi s i n thi s pati ent w oul d i ncl ude pneum ocy sti s,
tuber cul osi s, and i nf ecti on w i th nonoppor tuni sti c pul m onar y pathogens,
such as S. pneum oni ae, H. i nf l uenzae, and S. aur eus.
As al r eady m enti oned, the chest r adi ogr aph can be hel pf ul i n m ak i ng
the di agnosi s, al though ther e i s si gni f i cant ov er l ap i n the r adi ogr aphi c
m ani f estati ons of the v ar i ous pul m onar y di seases. In PCP, the m ost
com m on f i ndi ng i s a di f f use i ncr ease i n the i nter sti ti al and al v eol ar
m ar k i ngs, al though nodul ar i nf i l tr ates, cav i ti es, pneum atocel es and
pneum othor aces, and pl eur al ef f usi ons hav e al l been obser v ed i n thi s
setti ng. In addi ti on, 20% of pati ents w i th PCP can hav e a nor m al
r adi ogr aph. Kaposi 's sar com a of ten pr esents w i th nodul ar i nf i l tr ates,
w i th or w i thout a pl eur al ef f usi on. The ef f usi on i s ei ther
ser osangui neous or hem or r hagi c and i s due to pl eur al i nv ol v em ent by
the sar com a. The pr esence of i ntr athor aci c adenopathy suggests
tuber cul osi s, nonâ€“Hodgk i n's l y m phom a, Kaposi 's sar com a, or MAI
i nf ecti on.
2. If the i ni ti al test r esul ts do not conf i r m y our di agnosi s, w hat test w oul d
y ou do nex t?
If the sputum speci m en f i ndi ngs ar e nondi agnosti c, the nex t di agnosti c
pr ocedur e w oul d be f i ber opti c br onchoscopy w i th br onchoal v eol ar
l av age and, i n som e cases, a tr ansbr onchi al bi opsy . Thi s al l ow s the
al v eol ar ti ssue to be di r ectl y sam pl ed. Br onchoal v eol ar l av age i s
per f or m ed by pl aci ng the br onchoscope i n the di stal ai r w ay , i nsti l l i ng
100 to 200 m L of sal i ne i nto the ai r w ay , and then i m m edi atel y
r em ov i ng the sol uti on. The l av age techni que has a y i el d of 75% to 95%
i n the setti ng of PCP, and tr ansbr onchi al bi opsy has a y i el d of 85% to
95%. Kaposi 's sar com a, how ev er , i s di f f i cul t to di agnose usi ng
br onchoscopy . If br onchoscopi c f i ndi ngs ar e nondi agnosti c, an open
l ung bi opsy shoul d be done. Thi s i nv ol v es an open thor acotom y and i s
r ar el y needed.
3. What ther apy w oul d y ou i ni ti ate, and i s ther e a r ol e f or pr ophy l acti c
ther apy ?
Tr eatm ent w i th tr i m ethopr i m â€“sul f am ethox azol e shoul d be star ted i n
conjuncti on w i th i ntr av enous cor ti coster oi ds. The r ol e of pr ophy l acti c
ther apy i s under i nv esti gati on. It al so appear s that pr ophy l acti c or al
ther apy w i th tr i m ethopr i m â€“sul f am ethox azol e i s hi ghl y ef f i caci ous i n
pr ev enti ng r ecur r ence of PCP. How ev er , m any pati ents ar e unabl e to
endur e pr ol onged ther apy because of adv er se si de ef f ects. Aer osol i zed
pentam i di ne i s al so used f or PCP pr ophy l acti c tr eatm ent, and has been
show n to be ef f ecti v e.
P. 363
Suggested Readings
Hopew el l PC, Luce JM. Pul m onar y m ani f estati ons of the acqui r ed
i m m unodef i ci ency sy ndr om e. Cl i n Im m unol Al l er gy 1986;6:489.
Mur r ay JF, Mi l l s J. Pul m onar y i nf ecti ous com pl i cati ons of hum an
i m m unodef i ci ency v i r us i nf ecti on: par t I. Am Rev Respi r Di s
1990;141:1356.
Mur r ay JF, Mi l l s J. Pul m onar y i nf ecti ous com pl i cati ons of hum an
i m m unodef i ci ency v i r us i nf ecti on: par t II. Am Rev Respi r Di s
1990;141:1582.
Solitary Pulmonary Nodule
1. What i s a sol i tar y pul m onar y nodul e (SPN )?
2. What per centage of SPN s i s beni gn?
3. What cl i ni cal and r adi ol ogi c f i ndi ngs ar e associ ated w i th a hi gher
i nci dence of m al i gnancy i n an SPN ?
4. What i s the m ost com m on cause of an SPN ?
Discussion
1. What i s an SPN ?
Sol i tar y pul m onar y nodul es ar e si ngl e opaci ti es l ocated enti r el y w i thi n
the l ung par enchy m a and usual l y l ess than 4 cm i n di am eter . They ar e
not associ ated w i th atel ectasi s or hi l ar adenopathy on pl ai n chest
r oentgenogr am s.
2. What per centage of SPN s i s beni gn?
Sev enty f i v e to 85% of SPN s ar e beni gn, and 15% to 25% ar e
m al i gnant (ei ther pr i m ar y or m etastati c di sease). The phy si ci an's r ol e
i s to ex pedi te the w or k up and r esecti on of potenti al l y cur abl e
m al i gnant SPN s, w hi l e av oi di ng costl y ev al uati ons and pai nf ul
thor acotom i es f or SPN s that ar e beni gn or al r eady unr esectabl e (i . e. ,
m etastati c).
3. What cl i ni cal and r adi ol ogi c f i ndi ngs ar e associ ated w i th a hi gher
i nci dence of m al i gnancy i n an SPN ?
Ther e ar e sev er al f eatur es that suggest m al i gnancy :
Age . Most SPN s i n adul ts y ounger than 35 y ear s ar e beni gn. The
r i sk of m al i gnant di sease i ncr eases w i th i ncr easi ng age.
Nodule s ize . Mor e than 80% of the SPN s l ar ger than 3 cm i n

di am eter ar e m al i gnant; 20% or f ew er of the SPN s l ess than 2 cm
i n di am eter ar e m al i gnant. Spi cul ati on on CT scan of the chest i s
m or e l i k el y m al i gnant.
P re s e nc e a nd pa tte rn of c a lc ific a tion. Cal ci f i cati on, par ti cul ar l y
that w i th a centr al , l am i nated, or di f f use patter n, i s suggesti v e of
beni gn di sease. Mal i gnant di sease onl y r ar el y show s ev i dence of
cal ci f i cati on, and m or e f r equentl y ex hi bi ts an eccentr i c patter n.
His tory of prior ma ligna nc y. As m any as 30% of m al i gnant SPN s

ar e m etastases f r om ex tr athor aci c m al i gnanci es.
Smok ing his tory. Al though the ef f ect of sm ok i ng on m al i gnancy

i n the setti ng of SPN s has not been speci f i cal l y deter m i ned, ther e
i s a
P. 364
w el l k now n associ ati on betw een sm ok i ng and the dev el opm ent of
pr i m ar y br onchogeni c car ci nom a. Thi s r i sk i s si m i l ar to that of the
gener al nonsm ok i ng popul ati on betw een 10 and 15 y ear s af ter
sm ok i ng cessati on.
4. What i s the m ost com m on cause of an SPN ?
Mor e than hal f of al l SPN s ar e f ound to be gr anul om as on pathol ogi c
ex am i nati on. Ham ar tom as r epr esent the nex t m ost com m on beni gn
cause, but consti tute l ess than 10% of al l SPN s.
Case
A 40y ear ol d w om an i s seen f or a pr eoper ati v e ev al uati on bef or e
under goi ng l apar oscopi c chol ecy stectom y . Her m edi cal hi stor y i s r em ar k abl e
f or m i l d untr eated hy per tensi on. She has under gone no pr ev i ous sur gi cal
pr ocedur es. She had a 5pack y ear hi stor y of sm ok i ng, but qui t 8 y ear s ago.
She w as bor n and r ai sed i n Ci nci nnati . She w or k s as a par al egal i n a
dow ntow n l aw f i r m . She tak es no m edi cati ons other than an occasi onal
aspi r i n f or headache.
A thor ough r ev i ew r ev eal s sy m ptom s r ef er abl e to her chol el i thi asi s.
Speci f i cal l y , she deni es any sy stem i c or chest com pl ai nts, i ncl udi ng f ev er ,
m al ai se, w ei ght change, m y al gi as or ar thr al gi as, chest pai n, shor tness of
br eath or dy spnea on ex er ti on, cough, and hem opty si s.
Phy si cal ex am i nati on r ev eal s a m i l dl y obese w om an i n no di str ess. Vi tal
si gns ar e nor m al ex cept f or a bl ood pr essur e of 170/90 m m Hg. Head and
neck f i ndi ngs ar e nor m al , and her l ungs ar e cl ear . Hear t f i ndi ngs ar e al so
nor m al . Abdom i nal ex am i nati on r ev eal s r i ght upper quadr ant tender ness i n
r esponse to deep pal pati on w i thout r ebound or guar di ng. Ther e ar e no
m asses or hepatospl enom egal y . Stool i s guai ac negati v e. Her ex tr em i ti es
ar e nor m al , as ar e the f i ndi ngs f r om a thor ough neur ol ogi c ex am i nati on.
Ther e i s no adenopathy .
Labor ator y ex am i nati on f i ndi ngs, i ncl udi ng a com pl ete bl ood count, r outi ne
chem i str i es, ar ter i al bl ood gases m easur em ent, and ur i nal y si s, ar e w i thi n
nor m al l i m i ts. An el ectr ocar di ogr am i s nor m al . A chest r adi ogr aphi c study
r ev eal s a 1. 8cm , r ound opaci ty i n the l ef t l ow er l obe, but i s other w i se
nor m al .
1. What i s the m ost i m por tant nex t di agnosti c step at thi s ti m e?
2. What ar e the m ajor possi bl e di agnoses of thi s pati ent's nodul e?
3. What noni nv asi v e di agnosti c test m ay hel p i n di sti ngui shi ng betw een
the possi bl e di agnoses i n thi s pati ent?
4. If the test r esul ts up to thi s poi nt hav e been nondi agnosti c or
i ndeter m i nate, w hat opti ons shoul d be pr esented to the pati ent at thi s
ti m e?
Case Discussion
1. What i s the m ost i m por tant nex t di agnosti c step at thi s ti m e?
If possi bl e, an ol d chest r adi ogr aphi c study shoul d be obtai ned. If the
nodul e w as pr esent and i s unchanged i n si ze on a study f r om at l east 2
y ear s bef or e, i t i s v er y l i k el y that thi s r epr esents a beni gn l esi on, and
no f ur ther w or k up i s necessar y . Mal i gnant l esi ons usual l y hav e a
doubl i ng ti m e of w eek s to m onths. In other w or ds, a l esi on that gr ow s
ei ther v er y r api dl y (day s) or v er y sl ow l y (y ear s) i s l i k el y to be beni gn.
P. 365
In the ev ent of v er y r api d gr ow th, the pati ent usual l y has other
pul m onar y sy m ptom s consi stent w i th a beni gn di agnosi s, such as
i nf ecti on or pul m onar y i nf ar cti on.
2. What ar e the m ajor possi bl e di agnoses of thi s pati ent's nodul e?
The di f f er enti al di agnosi s f or thi s pati ent i ncl udes gr anul om atous
di sease, br onchogeni c car ci nom a, ham ar tom a, pul m onar y m etastasi s
f r om an unk now n pr i m ar y tum or , and â€œr oundâ€ pneum oni a.
Inf ecti ous gr anul om atous di seases r esul ti ng i n SPN s i ncl ude
hi stopl asm osi s, cocci di oi dom y cosi s, and tuber cul osi s. Gr anul om as can
al so appear as SPN s i n the setti ngs of sar coi dosi s, r heum atoi d
ar thr i ti s, and v ascul i ti des such as Wegener 's gr anul om atosi s. Pr i m ar y
br onchogeni c car ci nom a i s the m ost f r equent sour ce of r esected
m al i gnant SPN s. Metastati c di sease, of ten or i gi nati ng f r om pr i m ar y
adenocar ci nom as of the br east, pr ostate, or col on, f r equentl y pr esent
as SPN s. â€œRoundâ€ pneum oni a i s an uncom m on pr esentati on of an
acute pul m onar y i nf ecti on i n w hi ch the al v eol ar spacef i l l i ng di sease
assum es a m or e r ounded, nodul ar appear ance. In the absence of other
si gns or sy m ptom s, thi s can be conf used w i th an SPN . Less com m on
causes of SPN s i ncl ude ar ter i ov enous m al f or m ati ons, br onchogeni c
cy sts, pul m onar y i nf ar cti on, and par asi ti c di sease.
3. What noni nv asi v e di agnosti c test m ay hel p di sti ngui sh betw een the
possi bl e di agnoses i n thi s pati ent?
HRCT i s i ndi cated f or thi s pati ent. SPN s ar e of ten f ound to be m ul ti pl e
on CT, suggesti ng the pr esence of ei ther gr anul om atous di sease or
pul m onar y m etastases. Less than 1% of pr i m ar y l ung cancer s pr esent
as m ul ti pl e and sy nchr onous l esi ons. CT i s al so v er y sensi ti v e i n
def i ni ng the densi ty and conf i gur ati on of an SPN . The f i ndi ng of a f at
densi ty i n the nodul e str ongl y suggests the di agnosi s of ham ar tom a.
Centr al , l am i nated, or di f f use patter ns of cal ci f i cati on al so suggest a
beni gn di agnosi s (par ti cul ar l y gr anul om atous di sease or ham ar tom a),
w her eas eccentr i c cal ci f i cati on can be f ound i n ei ther beni gn or
m al i gnant di sease. Less hel pf ul i s the conf i gur ati on of the SPN . Poor l y
m ar gi nated or spi cul ated nodul es ar e of ten m al i gnant, but w el l
m ar gi nated spher i cal nodul es can be ei ther beni gn or m al i gnant.
Ipsi l ater al m edi asti nal or hi l ar adenopathy (def i ned by m ost
r adi ol ogi sts as l y m ph nodes > 1 cm i n tr ansv er se di am eter ) can be
associ ated w i th ei ther beni gn or m al i gnant l esi ons. How ev er ,
adenopathy i nv ol v i ng the hem i thor ax contr al ater al to the SPN i s hi ghl y
suggesti v e of nonr esectabl e m al i gnant di sease.
4. If the test r esul ts up to thi s poi nt hav e been nondi agnosti c or
i ndeter m i nate, w hat opti ons shoul d be pr esented to the pati ent at thi s
ti m e?
Ther e ar e thr ee opti ons at thi s poi nt.
Obs e rva tion i s appr opr i ate i n m any pati ents, par ti cul ar l y those w i th a
v er y l ow l i k el i hood of m al i gnancy or those f or w hom an i nv asi v e
di agnosti c pr ocedur e w oul d car r y an unacceptabl y hi gh r i sk of
m or bi di ty and m or tal i ty . The cour se of the SPN can be m oni tor ed w i th
ser i al i m agi ng ev er y 3 m onths f or the f i r st y ear , and ev er y 6 m onths
f or the second y ear .
Biops y can be per f or m ed usi ng ei ther CT or f l uor oscopy gui ded
tr ansthor aci c f i neneedl e aspi r ati on (FN A) or f i ber opti c br onchoscopy
w i th tr ansbr onchi al bi opsy . The l atter pr ocedur e i s associ ated w i th a
l ow er di agnosti c y i el d, par ti cul ar l y f or sm al l (< 2 cm ) per i pher al SPN s.
In any ev ent, i f the di agnosi s i s not establ i shed, m or e
P. 366
aggr essi v e attem pts to obtai n def i ni ti v e ti ssue m ust be pur sued.
N ondi agnosti c ti ssue f i ndi ngs shoul d not be constr ued as ev i dence of a
beni gn l esi on.
Surgic a l lung biops y i s a thi r d opti on. Thi s has the adv antage of bei ng
both a di agnosti c and a ther apeuti c pr ocedur e. It i s al so associ ated
w i th hi gher m or bi di ty . Many sur geons per f or m m edi asti noscopi c l y m ph
node bi opsy bef or e open thor acotom y , especi al l y i n cases of CTpr ov en
m edi asti nal adenopathy , to av oi d the m or e ex tensi v e pr ocedur e i f
possi bl e.
Suggested Readings
Li l l i ngton GA, Cask ey CI. Ev al uati on and m anagem ent of sol i tar y and
m ul ti pl e pul m onar y nodul es. Cl i n Chest Med 1993;14:111.
Mi dthun DE, Sw ensen SJ, Jett JR. Cl i ni cal str ategi es f or sol i tar y
pul m onar y nodul e. Annu Rev Med 1992;43:195.
Mi dthun DE, Sw ensen SJ, Jett JR. Appr oach to the sol i tar y pul m onar y
nodul e. May o Cl i n Pr oc 1993;68:378.
Webb WR. Radi ol ogi c ev al uati on of the sol i tar y pul m onar y nodul e. AJR
Am J Roentgenol 1990;154:701.
Acute Pulmonary Embolism
1. What i s a pul m onar y em bol i sm ?
2. What ar e the com m on sour ces of pul m onar y em bol i ?
3. What ar e the r i sk f actor s f or pul m onar y em bol i ?
4. Ar e al l acute pul m onar y em bol i si m i l ar ?
Discussion
1. What i s a pul m onar y em bol i sm ?
A pul m onar y em bol i sm r esul ts f r om the m i gr ati on of v enous thr om bi
f r om the sy stem i c v ei ns to pul m onar y ar ter i al sy stem , r esul ti ng i n
v ar y i ng degr ees of obstr ucti on of pul m onar y ar ter i al bl ood f l ow . The
i nci dence of pul m onar y em bol i i n the U ni ted States ex ceeds 500, 000
per y ear , w i th a m or tal i ty appr oachi ng 10%. If not di agnosed or i f
i m pr oper l y tr eated, the m or tal i ty r ate can r each 30%.
2. What ar e the com m on sour ces of pul m onar y em bol i ?
U p to 90% of pul m onar y em bol i or i gi nate f r om the deep v enous sy stem
of the l egs. The upper ex tr em i ti es can al so be a sour ce of v enous
thr om bi . U sual l y r el ated to tr aum a, congeni tal f i br om uscul ar bands, or
the use of centr al v enous catheter s, 12% of al l upper ex tr em i ty
thr om bi r esul t i n pul m onar y em bol i . In addi ti on, bl ood cl ot f or m ati on i n
the pel v i c v ei ns m ay cause ei ther septi c or bl and pul m onar y em bol i ,
especi al l y i n the setti ng of com pl i cated obstetr i c pr ocedur es or
gy necol ogi c sur ger y .
Other causes of pul m onar y ar ter i al obstr ucti v e em bol i i ncl ude ai r
i ntr oduced dur i ng i ntr av enous i njecti ons, hem odi al y si s, or the
pl acem ent
P. 367
of centr al v enous catheter s; am ni oti c f l ui d secondar y to v i gor ous
uter i ne contr acti ons; f at as a r esul t of m ul ti pl e l ong bone f r actur es;
par asi tes; tum or cel l s; or i njected f or ei gn m ater i al (tal c, m er cur y ).
Table 82 Risk Factors for Venous
Thrombosis
Sta s is Hype rc oa gula bility Endothe lia l

Injury
Congesti v e Def i ci ency of Ex tensi v e pel v i c

hear t f ai l ur e anti thr om bi n III sur ger y
Obesi ty Def i ci ency of pr otei ns Pr i or i njur y

C and S
Pr ol onged bed Mal i gnanci es Tr aum a

r est
Pr ol onged Or al contr acepti v es

tr av el
Pr esence of a l upus

anti coagul ant
Factor V Lei den

def i ci ency
3. What ar e the r i sk f actor s f or pul m onar y em bol i ?
Thr ee basi c r i sk f actor s, k now n col l ecti v el y as Vi r chow 's tr i ad, ar e
associ ated w i th thr om bus f or m ati on and subsequent pul m onar y em bol i :
stasi s, hy per coagul abi l i ty , and endothel i al i njur y . Most cl i ni cal r i sk
f actor s ar e der i v ed f r om one of these pathogeni c m echani sm s, and
these ar e l i sted i n Tabl e 82.
4. Ar e al l acute pul m onar y em bol i si m i l ar ?
Pul m onar y em bol i pr oduce sev er al cl i ni cal sy ndr om es. The r ar est,
a c ute ma s s ive oc c lus ion, i s def i ned as an em bol us that occl udes
enough of the pul m onar y ci r cul ati on to pr oduce ci r cul ator y col l apse. In
pati ents w ho do not sur v i v e thi s ev ent, autopsy r ev eal s occl usi on,
usual l y at the bi f ur cati on of the m ai n pul m onar y ar ter y , and the
f or m ati on of saddl e em bol i . P ulmona ry infa rc tion r ef er s to an
em bol i sm that obstr ucts enough bl ood f l ow to a por ti on of the l ung,
causi ng l oss of v i abi l i ty of the l ung ti ssue. Thi s occur s i n 10% of cases
of acute pul m onar y em bol i sm . The thi r d and m ost com m on cl i ni cal
occur r ence i s pulmona ry e mbolis m w ithout infa rc tion. These ar e the
m ost di f f i cul t to di agnose because they m i m i c other pul m onar y and
car di ac condi ti ons. Because m ost em bol i ar e m ul ti pl e, both i nf ar cted
and noni nf ar cted ar eas i n the l ung can coex i st.
Case
A 27y ear ol d w om an pr esents to the em er gency r oom af ter 24 hour s of
r i ghtsi ded chest pai n, w hi ch i s w or se w i th i nspi r ati on. She i s shor t of
br eath and anx i ous. The pati ent deni es sputum pr oducti on, hem opty si s,
cough or w heezi ng but states that she f el t w ar m at hom e but di d not tak e
her tem per atur e. She deni es any r ecent i njur y or sw el l i ng of her l egs, and
i s a v er y acti v e per son. The pati ent has no pr i or hi stor y of l ung or hear t
di sease.
She tak es or al contr acepti v es, and has no k now n dr ug al l er gi es. She has
under gone no sur gi cal pr ocedur es.
P. 368
She sm ok es one pack of ci gar ettes per day , and does not consum e al cohol .
She deni es i ntr av enous dr ug use and has no r i sk f actor s f or HIV di sease.
She w or k s as an accountant. Her f am i l y hi stor y i s negati v e f or asthm a and
hear t di sease.
Phy si cal ex am i nati on r ev eal s a m i l dl y obese w om an i n m oder ate r espi r ator y
di str ess. Her tem per atur e i s 38. 0Â°C (100. 4Â°F), her pul se i s 115 beats per
m i nute, her bl ood pr essur e i s 140/80 m m Hg, and her r espi r ator y r ate i s 26
br eaths per m i nute. N o jugul ar v enous di stenti on i s obser v ed. Her chest i s
cl ear .
Car di ac ex am i nati on r ev eal s r egul ar r ate and r hy thm , w i th nor m al i ntensi ty
of the f i r st and second hear t sounds. Ther e ar e no thi r d or f our th sounds,
m ur m ur s, or r ubs. Abdom i nal ex am i nati on r ev eal s posi ti v e bow el sounds
and no hepatospl enom egal y . Her ex tr em i ti es show no cy anosi s, cl ubbi ng, or
edem a.
Her l abor ator y v al ues ar e as f ol l ow s: hem ogl obi n, 14. 5 g/dL; hem atocr i t,
42%; w hi te bl ood cel l s, 6, 000/m m 3 w i th 74% segm ented neutr ophi l s and
26% l y m phocy tes. Peak ex pi r ator y f l ow i s 450 L per m i nute, w hi ch i s
nor m al .
A chest r adi ogr aphi c study r ev eal s a nor m al car di ac si l houette and cl ear
l ung f i el ds, ex cept f or a sm al l per i pher al i nf i l tr ate i n the l ow er l ef t l obe. An
el ectr ocar di ogr am show s si nus tachy car di a w i thout i schem i c changes.
Ar ter i al bl ood gas m easur em ent per f or m ed on r oom ai r r ev eal s a pH of
7. 49, a PCO 2 of 32 m m Hg, a PO 2 of 60 m m Hg, and an al v eol ar ar ter i al
ox y gen gr adi ent of 40 m m Hg.
1. What i s the di f f er enti al di agnosi s?
2. What addi ti onal tests shoul d be done to hel p nar r ow the di f f er enti al
di agnosi s?
3. How do y ou i nter pr et the addi ti onal test r esul ts?
4. What i s the nex t step i n di agnosi ng an acute pul m onar y em bol i sm ?
5. What i s the acute m anagem ent of pul m onar y em bol i sm ?
6. How l ong shoul d anti coagul ati on ther apy be conti nued?
7. What r ol e w oul d thr om bol y ti c ther apy hav e i n thi s pati ent?
8. When shoul d a v ena cav al f i l ter be pl aced?
Case Discussion
1. What i s the di f f er enti al di agnosi s?
The di f f er enti al di agnosi s i n thi s y oung w om an w i th acute onset of

shor tness of br eath and chest pai n i s l engthy . N ot al l br eathi ng
di sor der s ar e due to pul m onar y di sease because i schem i c car di ac
di sease can pr esent w i th dy spnea w hen associ ated w i th l ef t v entr i cul ar
f ai l ur e. How ev er , the natur e and l ocati on of the pai n, the l ack of
substanti al car di ac r i sk f actor s, and the pati ent's age m ak e car di ac
i schem i a unl i k el y .
Sev er al pul m onar y di sor der s can hav e a si m i l ar pr esentati on. Pati ents
w i th acute bacter i al pneum oni a com pl ai n of shor tness of br eath, l ow
gr ade f ev er , and chest pai n. How ev er , pneum oni a al so usual l y causes
sputum pr oducti on and an el ev ated w hi te bl ood cel l count, w hi ch w er e
not pr esent i n thi s pati ent. Asthm a can al so pr esent i nsi di ousl y w i th
acute shor tness of br eath. How ev er , the l ack of a hi stor y of asthm a,
ex posur e to k now n tr i gger s of asthm a, and a nor m al peak ex pi r ator y
f l ow m ak e thi s di agnosi s unl i k el y . A spontaneous pneum othor ax can
cause sy m ptom s, y et i t w oul d be unusual f or thi s to be accom pani ed by
a l ow gr ade f ev er .
P. 369
The m ost com m on sy m ptom s of pul m onar y em bol i i ncl ude shor tness of
br eath, pl eur i ti c pai n, cough, and hem opty si s. Pul m onar y em bol i shoul d
al w ay s be consi der ed i n a pati ent w i th acute shor tness of br eath and a
k now n r i sk f actor f or thr om bosi s (or al contr acepti v es). Pl eur i ti c chest
pai n, as seen i n thi s pati ent, and hem opty si s occur onl y i f the
em bol i sm causes a pul m onar y i nf ar cti on. Fev er s as hi gh as 39Â°C
(102. 2Â°F) hav e al so been r epor ted i n the setti ng of i nf ar cti on or a
concur r ent i nf ecti on. On phy si cal ex am i nati on, the m ost com m on si gn
i s i sol ated si nus tachy car di a; how ev er , i n those pati ents w i th m assi v e
em bol i sm , ev i dence of acute r i ght v entr i cul ar f ai l ur e m ay be f ound.
When consi der i ng pul m onar y em bol i sm , ther e ar e no uni v er sal cl i ni cal
f i ndi ngs and the absence of speci f i c f i ndi ngs does not ex cl ude the
di agnosi s.
2. What addi ti onal tests shoul d be done to hel p nar r ow the di f f er enti al
di agnosi s?
To hel p di f f er enti ate betw een the v ar i ous di agnoses, a chest
r adi ogr aphi c study , el ectr ocar di ogr am , ar ter i al bl ood gas anal y si s, and
Gr am 's stai ni ng of a sputum sam pl e shoul d be done.
3. How do y ou i nter pr et the addi ti onal test r esul ts?
In the setti ng of an acute pul m onar y em bol i sm , the ar ter i al bl ood gas
m easur em ent cl assi cal l y r ev eal s a l ow PCO 2 , l ow PO 2 , and a w i dened
al v eol ar ar ter i al ox y gen gr adi ent. How ev er , m any other di sor der s
cause si m i l ar abnor m al ar ter i al bl ood gas r esul ts and 10% to 15% of
pati ents w i th pr ov en pul m onar y em bol i m ai ntai n a nor m al al v eol ar
ar ter i al ox y gen gr adi ent.
The chest r adi ogr aph f i ndi ngs of pul m onar y em bol i ar e nonspeci f i c.
Ty pi cal l y , i nf i l tr ates, atel ectasi s, ef f usi ons, or any com bi nati on of
these ar e encounter ed. It i s not usual f or the chest r adi ogr aph to be
nor m al . A per i pher al w edgeshaped i nf i l tr ate, som eti m es r ef er r ed to as
a Ham pton's hum p, occur s w hen the em bol i sm i s associ ated w i th
i nf ar cti on, and occasi onal l y decr eased pul m onar y v ascul ar m ar k i ngs
ar e noted (Wester m ar k 's si gn), i ndi cati v e of decr eased bl ood f l ow to a
secti on of the l ung.
The el ectr ocar di ogr am i s hel pf ul i n r ul i ng out i schem i c hear t di sease.
In pati ents w i th pul m onar y em bol i , the el ectr ocar di ogr am usual l y
dem onstr ates si nus tachy car di a or i s nor m al . Onl y i n the pr esence of
m assi v e em bol i zati on i s a r i ght ax i s dev i ati on and an S 1 , Q 3 , T 3
patter n seen.
These test r esul ts hel p nar r ow the di f f er enti al di agnosi s. The chest
r adi ogr aph f i ndi ngs r ul e out a pneum othor ax , and a tr ue bacter i al
pneum oni a i s l ess l i k el y i n l i ght of the nor m al sputum f i ndi ngs. The
l ack of i schem i a on the el ectr ocar di ogr am m ak es a pr i m ar y car di ac
abnor m al i ty unl i k el y . Wi th the pr esentati on of shor tness of br eath, a
w i dened al v eol ar ar ter i al ox y gen gr adi ent, and chest r adi ogr aph
f i ndi ngs consi stent w i th an i nf ar cti on, a pul m onar y em bol i sm i s now the
m ost l i k el y di agnosi s.
4. What i s the nex t step i n di agnosi ng an acute pul m onar y em bol i sm ?
CT angi ogr aphy i s i ndi cated and i f posi ti v e show s f i l l i ng def ects i n
l ar ge and m edi um si zed pul m onar y ar ter i es. Venti l ati on/per f usi on
scans ar e now r eser v ed f or pati ents w ho cannot tol er ate a dy e l oad due
to r enal i nsuf f i ci ency or hav e a k now n i odi ne al l er gy . Measur em ent of
the ser um Ddi m er , a f i br i n degr adati on pr oduct that dem onstr ates a
l ev el bel ow 500 Âµg/L, ex cl udes the di agnosi s of pul m onar y em bol i sm .
Pul m onar y angi ogr aphy i s r ar el y i ndi cated.
P. 370
If the CT angi ogr am i s i nconcl usi v e and the suspi ci on sti l l hi gh Doppl er
v enous studi es of the l ow er ex tr em i ti es, i f posi ti v e, m ay substanti ate
the need f or anti coagul ati on.
5. What i s the acute m anagem ent of pul m onar y em bol i sm ?
The goal of ther apy i s to pr ev ent f ur ther em bol i c epi sodes, and hepar i n
i s the i ni ti al dr ug of choi ce f or accom pl i shi ng thi s. Fi r st, a l ar ge
i ntr av enous l oadi ng bol us shoul d be gi v en, f ol l ow ed by conti nuousdr i p
i nf usi on, m ai ntai ned f or at l east 5 and of ten 7 to 10 day s.
Anti coagul ati on shoul d not be w i thhel d pendi ng the r esul ts of f ur ther
studi es unl ess the pati ent's r i sk of bl eedi ng com pl i cati ons i s gr eater
than the cl i ni cal suspi ci on of pul m onar y em bol i . The par ti al
thr om bopl asti n ti m e shoul d be m oni tor ed and the hepar i n dosage
adjusted to k eep the ti m e betw een 1. 5 to 2. 0 ti m es the contr ol .
War f ar i n i s star ted 24 to 48 hour s af ter hepar i n ther apy has been
i ni ti ated. Dur i ng the f i r st 3 day s of w ar f ar i n ther apy , the pr othr om bi n
ti m e or IN R i s i ncr eased bef or e the onset of tr ue anti coagul ati on.
Ther ef or e, bef or e di sconti nui ng the hepar i n, the pr othr om bi n ti m e or
IN R shoul d be ther apeuti c (1. 5 to 2 ti m es nor m al ) f or appr ox i m atel y 2
to 3 day s. Low m ol ecul ar w ei ght hepar i ns ar e i ndi cated f or pr ophy l ax i s
i n postoper ati v e pati ents and pr obabl y hav e a r ol e i n the m anagem ent
of acute pul m onar y em bol i sm and deep v enous thr om bosi s because
they do not r equi r e m oni tor i ng of the anti coagul ati on ef f ects.
6. How l ong shoul d anti coagul ati on ther apy be conti nued?
Longter m anti coagul ati on i s usual l y achi ev ed w i th w ar f ar i n, al though
l ow m ol ecul ar w ei ght hepar i ns can al so be used. Pati ents w i th
r ev er si bl e r i sk f actor s that ar e subsequentl y el i m i nated shoul d under go
anti coagul ati on f or a total of 3 m onths. If thi s i s an i ni ti al epi sode of
em bol i sm and the pati ent has no cl ear r i sk f actor s, tr eatm ent shoul d
pr obabl y be m ai ntai ned f or 3 to 6 m onths. Fi nal l y , those pati ents w i th
r ecur r ent em bol i and nonr ev er si bl e r i sk f actor s (e. g. , adenocar ci nom a,
anti phosphol i pi d sy ndr om e, or f actor V Lei den def i ci ency ) shoul d be
tr eated f or l i f e. When i t i s uncer tai n how l ong to m ai ntai n ther apy ,
i m pedance pl ethy sm ogr aphy can hel p i n i denti f y i ng r ecur r ent deep v ei n
thr om bosi s.
7. What r ol e w oul d thr om bol y ti c ther apy hav e i n thi s pati ent?
The r ol e of thr om bol y ti c agents (str eptok i nase, ur ok i nase, and ti ssue
pl asm i nogen acti v ator ) i s y et to be el uci dated i n the m anagem ent of
acute pul m onar y em bol i sm . Ther e appear to be no si gni f i cant
di f f er ences betw een the thr ee agents i n the tr eatm ent of pul m onar y
em bol i , ex cept f or thei r r especti v e costs. Thr om bol y ti c agents do
accel er ate the r esol uti on of the pul m onar y ar ter y cl ot, but they hav e
not been cl ear l y show n to i m pr ov e sur v i v al as com par ed w i th the
r esul ts obser v ed f or conv enti onal hepar i n ther apy . The onl y adopted
use of these agents i s f or pati ents w i th m assi v e em bol i sm and sy stem i c
hy potensi on. When used, thr om bol y ti c ther apy m ust be f ol l ow ed by a
standar d cour se of hepar i n.
8. When shoul d a v ena cav al f i l ter be pl aced?
The pur pose of v ena cav al f i l ter s i s both to tr ap em bol i and m ai ntai n
the patency of the i nf er i or v ena cav a. These f i l ter s ar e l ar gel y v i ew ed
as an al ter nati v e ther apy f or thr om boem bol i sm w hen anti coagul ati on i s
unacceptabl e. The thr ee m ost com m on i ndi cati ons f or f i l ter pl acem ent
ar e (a) a contr ai ndi cati on to anti coagul ati on,
P. 371
(b) f ai l ur e of pr oper anti coagul ati on to pr ev ent the f or m ati on of f ur ther
em bol i , and (c) a com pl i cati on of anti coagul ati on ther apy .
Suggested Readings
Fi shm an AP, Kel l ey MA. Pul m onar y thr om boem bol i sm (i ncl udi ng
pr ophy l ax i s, tr eatm ent, si ck l e cel l di sease, and m ul ti pl e pul m onar y
thr om bi ). In: Fi shm an AP, ed. Pul m onar y di seases and di sor der s, 2nd ed.
N ew Yor k : McGr aw Hi l l , 1987.
Hur ew i tz AN , Ber gof sk y EH. Pul m onar y em bol i sm . In: Cher ni ack RM, ed.
Cur r ent ther apy of r espi r ator y di sease. Tor onto: BC Deck er , 1989:259.
Per r i er A, Desm ar i s S, Goehr i ng C, et al . Ddi m er testi ng f or suspected

pul m onar y em bol i sm i n outpati ents. Am J Respi r Cr i t Car e Med
1997;136:492.
PIOPED Inv esti gator s. Val ue of the v enti l ati on/per f usi on scan i n acute
pul m onar y em bol i sm : r esul ts of the pr ospecti v e i nv esti gati on of
pul m onar y em bol i sm di agnosi s (PIOPED). JAMA 1990;263:2753.
Sarcoidosis
1. What ar e the sy m ptom s and si gns of sar coi dosi s?
2. What tests ar e used to establ i sh the di agnosi s?
3. What ar e the ther apeuti c opti ons?
Discussion
1. What ar e the sy m ptom s and si gns of sar coi dosi s?
Sar coi dosi s i s a sy stem i c di sor der char acter i zed hi stol ogi cal l y by the
pr esence of noncaseati ng gr anul om as. The gr anul om as can be f ound i n
any ti ssue, such as the l ung, sk i n, m y ocar di um , centr al ner v ous
sy stem , and k i dney s. The sy m ptom s and si gns m ost com m onl y seen
stem f r om the i nv ol v em ent of the r eti cul oendothel i al sy stem and the
l ung. Pati ents m ay pr esent w i th one or m or e of the f ol l ow i ng: f ati gue;
a pi gm ented papul onodul ar sk i n r ash; spl enom egal y ; ar thr i ti s; and
chest r adi ogr aphi c f i ndi ngs i ndi cati ng bi l ater al hi l ar adenopathy or
patchy nodul ar pul m onar y i nf i l tr ates, or both. Labor ator y abnor m al i ti es
i ncl ude anem i a, l euk openi a, hy per cal cem i a, el ev ati on of the l i v er
enzy m e l ev el s i n a chol estati c patter n, and a pol y cl onal gam m opathy .
2. What tests ar e used to establ i sh the di agnosi s?
The m ost def i ni ti v e test to establ i sh the di agnosi s of sar coi dosi s i s
ti ssue bi opsy . Si tes f or bi opsy i ncl ude the sk i n (i f a r ash ex i sts) or
l ung. The sensi ti v i ty of br onchoscopy w i th tr ansbr onchi al bi opsy
ex ceeds 90% i n obtai ni ng noncaseati ng gr anul om as i n pati ents w i th
sar coi dosi s w ho pr esent w i th hi l ar adenopathy and pul m onar y
i nf i l tr ates. How ev er , noncaseati ng gr anul om as ar e onl y suggesti v e, but
not pathognom oni c, ev i dence f or the di sease. Other di seases that
pr oduce gr anul om as, such as m y cobacter i al and f ungal di seases, m ust
al so be consi der ed. These enti ti es can be r ul ed out by br onchoscopy
w i th bi opsy and br onchoal v eol ar l av age.
P. 372
The ser um l ev el of the angi otensi nconv er ti ng enzy m e (ACE) i s
el ev ated i n som e pati ents w i th sar coi dosi s, but thi s i s nei ther a
sensi ti v e nor speci f i c enough f i ndi ng f or i t to ser v e as a di agnosti c
test. Thi s l ev el i s el ev ated i n appr ox i m atel y 66% of pati ents w i th
sar coi dosi s, but al so occur s i n a v ar i ety of di sor der s such as
tuber cul osi s, cocci di oi dom y cosi s, hy per thy r oi di sm , and di abetes
m el l i tus. How ev er , the ACE l ev el has been show n to decr ease w i th
ther apy , and thi s m ay , ther ef or e, be a usef ul objecti v e m easur e f or
m oni tor i ng the ef f ecti v eness of tr eatm ent.
3. What ar e the ther apeuti c opti ons?
Sar coi dosi s i s a v er y heter ogeneous di sease, w i th appr ox i m atel y one
thi r d of pati ents i m pr ov i ng w i thout tr eatm ent, one thi r d pr ogr essi ng
cl i ni cal l y , and one thi r d r em ai ni ng i n r el ati v el y stabl e condi ti on.
U nf or tunatel y , ther e i s no r el i abl e w ay to pr edi ct i n w hi ch gr oup
pati ents w i l l f al l . Factor s that suggest an unf av or abl e pr ognosi s i ncl ude
ex tensi v e pul m onar y par enchy m al i nv ol v em ent, r estr i cti v e phy si ol ogy
on pul m onar y f uncti on testi ng, an el ev ated ACE l ev el , i nv ol v em ent of at
l east thr ee or gan sy stem s, and bl ack r ace. Or gan i nv ol v em ent that
m andates the i nsti tuti on of ther apy i ncl udes ey e, centr al ner v ous
sy stem , or car di ac i nv ol v em ent, as w el l as hy per cal cem i a.
Tr eatm ent consi sts of cor ti coster oi ds, usual l y pr edni sone or i ts equi v al ent
i ni ti ated at a dosage of 30 to 40 m g per day . Ther e i s no ev i dence that any
one ster oi d pr epar ati on i s super i or to another . Inhal ed cor ti coster oi ds hav e
not been f ound to be benef i ci al i n the tr eatm ent of sar coi dosi s. Betw een
80% and 90% of pati ents r espond to ster oi d ther apy . When ef f ecti v e, a
cl i ni cal and r adi ogr aphi c r esponse i s usual l y w i tnessed w i thi n 2 to 4 w eek s.
Thi s dosage i s usual l y conti nued f or 1 to 2 m onths, then gr adual l y taper ed
ov er the cour se of the nex t 1 to 6 m onths. Many pati ents can then
di sconti nue tak i ng ster oi ds, but other s r equi r e ongoi ng ster oi d ther apy at a
dosage of 10 to 15 m g dai l y or ev er y other day . The r esponse to ther apy i s
conf i r m ed by sy m ptom ati c and r adi ogr aphi c i m pr ov em ent, suppor ted by a
decr easi ng ACE l ev el and stabl e or i m pr ov i ng pul m onar y f uncti on. Al though
ther e i s sy m ptom ati c and r adi ogr aphi c i m pr ov em ent w i th cor ti coster oi ds,
ther e i s l i ttl e ev i dence that they i nf l uence the natur al cour se of the di sease.
Case
A 34y ear ol d bl ack w om an i s r ef er r ed to the pul m onar y cl i ni c f or
ev al uati on of a 2m onth hi stor y of dr y cough, a r ash on her f or ehead and
ar m s, a 5pound (2. 25k g) w ei ght l oss, and an abnor m al chest r adi ogr aphi c
study . She has an 8pack y ear sm ok i ng hi stor y and a hi stor y of pr i or
i ntr av enous cocai ne use, and 6 m onths ago tr av el ed to Bak er sf i el d,
Cal i f or ni a, f or a v acati on.
Phy si cal ex am i nati on r ev eal s a thi n w om an i n no di str ess. Her tem per atur e
i s 99Â°F (37. 2Â°C), pul se i s 80 beats per m i nute, bl ood pr essur e i s 110/70
m m Hg, and r espi r ator y r ate i s 20 br eaths per m i nute. A pi gm ented,
papul onodul ar r ash i s pr esent on her f or ehead and upper ar m s. Funduscopi c
f i ndi ngs ar e nor m al . Bi basi l ar cr ack l es ar e hear d on chest ex am i nati on.
Abdom i nal ex am i nati on r ev eal s an 8cm l i v er and pal pabl e spl een ti p. Ther e
i s no cy anosi s, cl ubbi ng, or edem a on ex am i nati on of her ex tr em i ti es.
P. 373
The chest r adi ogr aphi c study r ev eal s bi l ater al hi l ar adenopathy and di f f use
al v eol ar and nodul ar i nf i l tr ates. Labor ator y f i ndi ngs ar e as f ol l ow s: w hi te
bl ood cel l count, 4, 000/m m 3 w i th 70% pol y m or phonucl ear l euk ocy tes, 10%
m onocy tes, 2% eosi nophi l s, and 17% l y m phocy tes; hem ogl obi n, 11 g/dL;
hem atocr i t, 33%; pl atel et count, 300, 000/ÂµL; nor m al ser um el ectr ol y te
l ev el s; cal ci um , 10 m g/dL; al bum i n, 3. 8 g/dL; and total pr otei n, 8. 0 g/dL.
1. What i s the di f f er enti al di agnosi s i n thi s pati ent?

2. What tests shoul d be done to establ i sh the di agnosi s i n thi s pati ent?
Pul m onar y f uncti on testi ng r ev eal s the f ol l ow i ng l ung v ol um es: total
l ung capaci ty , 3. 32 L (72% of pr edi cted); thor aci c gas v ol um e, 1. 63 L
(64% of pr edi cted); and r esi dual v ol um e, 0. 72 L (59% of pr edi cted).
Spi r om etr y show s an FVC of 2. 72 L (70% of pr edi cted) and FEV 1 of
2. 12 L (75% of pr edi cted). The di f f usi ng capaci ty f or car bon m onox i de
(DLCO) i s 15. 6 (46% of pr edi cted) and the DLCO/al v eol ar v enti l ati on
(VA) i s 4. 97 (85% of pr edi cted). Ar ter i al bl ood gas m easur em ents on
r oom ai r r ev eal a pH of 7. 41, PaCO 2 of 32 m m Hg, PaO 2 of 68 m m Hg,
and ox y gen satur ati on of 94%.
3. How w oul d y ou i nter pr et the r esul ts of the PFTs?
Case Discussion
1. What i s the di f f er enti al di agnosi s i n thi s pati ent?
As i s tr ue of m any pul m onar y di sor der s, the r adi ogr aphi c patter n
com bi ned w i th the pati ent's cl i ni cal hi stor y and phy si cal ex am i nati on
f i ndi ngs nar r ow s the di f f er enti al di agnosi s. In a pati ent w ho pr esents
w i th thi s cl i ni cal scenar i o and nor m al cel l ul ar i m m uni ty , the di f f er enti al
di agnosi s i s br oad and i ncl udes v ar i ous i ndol ent i nf ecti ous pr ocesses
such as tuber cul osi s; f ungal i nf ecti ons such as hi stopl asm osi s,
cocci di oi dom y cosi s, and Cr y ptococcus neof or m ans i nf ecti on; i di opathi c
i m m unol ogi c di sor der s such as sar coi dosi s; and, l ess com m onl y ,
m etastati c neopl asti c di sease, Hodgk i n's di sease, nonâ€“Hodgk i n's
l y m phom a, and occupati onal l ung di seases such as ber y l l i osi s and
si l i cosi s. How ev er , i n a pati ent i nf ected w i th HIV, the di f f er enti al
di agnosi s i ncl udes a hi gher pr obabi l i ty of m y cobacter i al i nf ecti on,
f ungal i nf ecti on, and Kaposi 's sar com a.
2. What tests shoul d be done to establ i sh the di agnosi s i n thi s pati ent?
A ser um HIV test shoul d be done i n thi s pati ent because of her hi stor y
of i ntr av enous dr ug abuse. For m ost peopl e w i th possi bl e sar coi dosi s,
how ev er , thi s test i s not necessar y .
A sputum sam pl e shoul d be obtai ned f or aci df ast stai ni ng and
m y cobacter i al cul tur e. In pati ents w i th ex tensi v e pul m onar y i nf i l tr ates
due to M. tuber cul osi s i nf ecti on, thr ee separ ate m or ni ng sputum
sam pl es ar e hi ghl y sensi ti v e f or detecti ng the pathogen. In m ost
heal thy hosts w i th acti v e pul m onar y tuber cul osi s, the PPD (pur i f i ed
pr otei n der i v ati v e) sk i n test r esul t i s posi ti v e. Pati ents w i th sar coi dosi s
ar e f r equentl y aner gi c i n r esponse to a v ar i ety of sk i n tests, i ncl udi ng
the PPD test.
Sputum speci m ens f or f ungal stai ni ng and cul tur e shoul d al so be
obtai ned. The f ungi that m i m i c sar coi dosi s ar e r estr i cted to cer tai n
endem i c ar eas. For i nstance,
P. 374
hi stopl asm osi s i s f ound i n the m i dw ester n and southeaster n U ni ted
States. Cocci di oi dom y cosi s i s endem i c to the deser t southw est and ar i d
r egi ons of Cal i f or ni a, such as the Mojav e Deser t and the San Joaqui n
Val l ey . Gi v en the pati ent's r ecent tr i p to Bak er sf i el d, Cal i f or ni a, i t i s
necessar y to ex cl ude possi bl e i nf ecti on w i th cocci di oi dom y cosi s. A
thor ough tr av el and occupati onal hi stor y shoul d al w ay s be tak en to
ex cl ude any aty pi cal f ungal ex posur e.
Ti ssue shoul d al so be obtai ned f or the pur pose of ex cl udi ng i nf ecti on
and neopl asm , and to suppor t the di agnosi s of sar coi dosi s. As al r eady
di scussed, sk i n bi opsy or br onchoscopy w i th tr ansbr onchi al bi opsy
w oul d be hel pf ul i f the r esul ts r ev eal ed noncaseati ng gr anul om as. Aci d
f ast and si l v er stai ni ng can be per f or m ed on the bi opsy speci m ens to
ex cl ude m y cobacter i al and f ungal i nf ecti ons. For thi s pati ent, m ost
cl i ni ci ans w oul d r ecom m end f i ber opti c br onchoscopy w i th
br onchoal v eol ar l av age and tr ansbr onchi al bi opsy . In the setti ng of
sar coi dosi s, the br onchoal v eol ar l av age f l ui d char acter i sti cal l y show s
an i ncr eased per centage of l y m phocy tes w i th a pr edom i nant CD4
phenoty pe. In addi ti on, stai ns and cul tur es f or m y cobacter i al and
f ungal di seases can be per f or m ed on the br onchoal v eol ar l av age f l ui d.
3. How w oul d y ou i nter pr et the r esul ts of the PFTs?
The PFTs show r estr i cted l ung v ol um es. Spi r om etr y show s a m i l d
degr ee of obstr ucti on, par ti cul ar l y gi v en the under l y i ng r estr i cti v e
phy si ol ogy . The DLCO i s r educed.
PFTs, i ncl udi ng l ung v ol um es, DLCO, spi r om etr y , and ar ter i al bl ood gas
m easur em ent, shoul d be per f or m ed f or ev er y pati ent w i th sar coi dosi s
and pul m onar y par enchy m al i nv ol v em ent. The m ost f r equent
abnor m al i ti es encounter ed ar e a r educti on i n l ung v ol um es (r estr i cti v e
phy si ol ogy ), of ten accom pani ed by a r educti on i n DLCO. It i s al so not
uncom m on to f i nd r educed ex pi r ator y f l ow r ates, i ndi cati ng ai r w ay
i nv ol v em ent w i th sar coi dosi s. The ar ter i al ox y gen satur ati on usual l y
r em ai ns r el ati v el y nor m al at r est, unl ess adv anced di sease i s pr esent.
Wi th ex er ci se, the PaO 2 f r equentl y f al l s.
Suggested Readings
Gi l m an MJ, Wang KP. Tr ansbr onchi al l ung bi opsy i n sar coi dosi s. Am Rev
Respi r Di s 1980;122:721.
Hi l l er dal G, N ou E, Oster m an K, et al . Sar coi dosi s: epi dem i ol ogy and
pr ognosi s: a 15y ear Eur opean study . Am Rev Respi r Di s 1984;130:29.
Rust M, Ber gm ann L, Kuhn T. Pr ognosti c v al ue of chest r adi ogr aph,
ser um angi otensi nconv er ti ng enzy m e and T hel per cel l count i n bl ood
and i n br onchoal v eol ar l av age of pati ents w i th pul m onar y sar coi dosi s.
Respi r ati on 1985;48:231.
Tuberculosis
1. What i s the contem por ar y epi dem i ol ogy of tuber cul osi s?
2. What sy m ptom s and r adi ogr aphi c f eatur es ar e associ ated w i th
tuber cul osi s?
3. Who shoul d r ecei v e tr eatm ent (pr ophy l ax i s) f or tuber cul osi s i nf ecti on?
P. 375
Discussion
1. What i s the contem por ar y epi dem i ol ogy of tuber cul osi s?
Despi te num er ous m edi cal adv ances i n the past centur y , tuber cul osi s i s
sti l l the cause of at l east 1 m i l l i on deaths w or l dw i de each y ear , and i ts
i nci dence, w hi ch w as i ncr easi ng i n the 1980s and ear l y 1990s pr i m ar i l y
because of AIDS, i s agai n decr easi ng. El der l y pati ents now consti tute
near l y hal f of the new l y di agnosed cases of tuber cul osi s i n the U ni ted
States because these peopl e w er e ex posed to the tuber cul osi s epi dem i c
i n the f i r st quar ter of the 20th centur y and hav e been har bor i ng l atent
i nf ecti on f or m any decades. The case f atal i ty r ate i n the el der l y i s al so
di spr opor ti onatel y hi gh, and they f ace a hi gher r i sk of com pl i cati ons
w i th tr eatm ent. Other s at r i sk f or tuber cul osi s i ncl ude m edi cal l y
under ser v ed, l ow i ncom e, ethni c m i nor i ty popul ati ons, especi al l y
Af r i can Am er i cans, N ati v e Am er i cans, and Hi spani cs; i nsti tuti onal i zed
peopl e; pati ents w i th chr oni c r enal f ai l ur e, si l i cosi s, di abetes m el l i tus,
or l y m phor eti cul ar m al i gnanci es; al cohol i cs or those w i th other
substance abuse habi ts; those w i th m al nutr i ti on; those w ho hav e
under gone gastr ectom y ; and those under goi ng i m m unosuppr essi v e or
l ongter m cor ti coster oi d ther apy .
2. What sy m ptom s and r adi ogr aphi c f eatur es ar e associ ated w i th
tuber cul osi s?
Di v er si ty char acter i zes the cl i ni cal m ani f estati ons of tuber cul osi s.
Al though m any pati ents hav e consti tuti onal sy m ptom s consi sti ng of
w ei ght l oss, f ati gue, f ev er , and ni ght sw eats, as w el l as pul m onar y
sy m ptom s such as cough, i nter m i ttent hem opty si s, chest pai n, and
dy spnea, none of these i s uni f or m l y pr esent. In addi ti on, the el der l y
and pati ents w i th AIDS of ten hav e ex tr apul m onar y di sease and the
sy m ptom s and si gns ar e aty pi cal .
The cl assi c chest r adi ogr aph i n an adul t w i th pul m onar y tuber cul osi s
dem onstr ates f i br onodul ar i nf i l tr ati on of the poster i or or api cal
segm ents of the upper l obe. Ther e m ay al so be cav i tati on. Tuber cul osi s
can, how ev er , pr oduce al m ost any f or m of pul m onar y r adi ogr aphi c
abnor m al i ty . Mor eov er , nor m al r adi ogr aphi c f i ndi ngs do not ex cl ude a
di agnosi s of di ssem i nated tuber cul osi s i n an el der l y or
i m m unocom pr om i sed pati ent. Hi l ar adenopathy on a chest r adi ogr aph i n
a pati ent ser oposi ti v e f or HIV i s consi der ed tuber cul osi s unti l pr ov ed
other w i se.
3. Who shoul d r ecei v e tr eatm ent (pr ophy l ax i s) f or tuber cul osi s i nf ecti on?
The tuber cul i n sk i n test i s the tr adi ti onal m ethod of dem onstr ati ng
i nf ecti on w i th M. tuber cul osi s, and i s based on the pr i nci pl e that
i nf ecti on el i ci ts del ay edty pe hy per sensi ti v i ty to cer tai n anti gens i n
cul tur e ex tr acts cal l ed tuber cul i ns. The tuber cul i n m ost com m onl y used
i s PPD; i t i s i njected i ntr acutaneousl y on the v ol ar aspect of the
f or ear m i n a dose of 5 tuber cul i n uni ts. Indur ati on of the si te at 48 to
72 hour s i ndi cates del ay ed hy per sensi ti v i ty to i nf ecti on w i th M.
tuber cul osi s, but does not necessar i l y si gni f y the pr esence of acti v e
di sease, onl y i nf ecti on.
Pr ev enti v e ther apy w i th i soni azi d (IN H) gi v en f or 6 to 12 m onths cl ear l y
decr eases the r i sk of f utur e tuber cul osi sâ€”i n other w or ds, the pr ogr essi on
f r om an i nf ected state to an acti v el y di seased state m ani f esti ng the cl i ni cal ,
r adi ogr aphi c, and
P. 376
m i cr obi ol ogi c pr of i l e. The goal of IN H m onother apy i s ther ef or e to tr eat
subcl i ni cal i nf ecti on br ought to l i ght by the posi ti v e r esul t of tuber cul i n sk i n
test. By str i ct def i ni ti on, i t i s not tr ue pr ophy l ax i s, but i t i s of ten r ef er r ed to
as such. The dosage of IN H i n adul ts i s 5 m g/k g, up to a total of 300 m g
or al l y per day . Peopl e w ho hav e contact w i th a pati ent hav i ng new l y
di agnosed pul m onar y tuber cul osi s, and w hose tuber cul i n sk i n test r esul t i s
posi ti v e, shoul d under go IN H pr ev enti v e ther apy . If a chest r adi ogr aph
show s i nacti v e par enchy m al tuber cul osi s (upper l obe scar r i ng), the sk i n test
r esul t i s posi ti v e, and acti v e di sease has been ex cl uded by negati v e sputum
f i ndi ngs, such pati ents shoul d r ecei v e IN H ther apy . Peopl e y ounger than 35
y ear s w i th a posi ti v e r esul t on sk i n test and a nor m al chest r adi ogr aph
shoul d al so be tr eated. Pati ents w hose sk i n test r esul t i s posi ti v e and i n
w hom the f ol l ow i ng cl i ni cal si tuati ons appl y shoul d r ecei v e 6 to 12 m onths
of pr ev enti v e ther apy : HIV posi ti v i ty ; si l i cosi s; di abetes m el l i tus, especi al l y
poor l y contr ol l ed i nsul i ndependent di abetes; ster oi d ther apy , especi al l y
m or e than 15 m g of pr edni sone per day ; chr oni c r enal f ai l ur e;
l y m phor eti cul ar m al i gnanci es: l euk em i a, l y m phom a, and Hodgk i n's di sease;
i m m unosuppr essi v e ther apy ; gastr ectom y ; jejunoi l eal by pass; and w ei ght
l oss of 10% or m or e of the i deal body w ei ght.
Case
A 68y ear ol d Af r i canAm er i can m an w i th a l ong hi stor y of tobacco and
ethanol abuse i s br ought i n by hi s f am i l y f or ev al uati on of w ei ght l oss, l ow
gr ade f ev er s, and f ai l ur e to thr i v e. The pati ent r epor ts a 2 to 3m onth
hi stor y of pr ogr essi v e 20pound (9k g) w ei ght l oss, as w el l as f ev er s,
nonpr oducti v e cough, and gener al i zed w eak ness. Hi s cough becam e
pr oducti v e of w hi te sputum 2 day s ear l i er . The pati ent deni es chest pai n,
hem opty si s, i l l contacts, r ecent tr av el , or HIV r i sk f actor s. He has sm ok ed
one pack of ci gar ettes per day f or 40 y ear s. He dr i nk s appr ox i m atel y one
pi nt (hal f a l i ter ) of al cohol a day and has done so f or m any y ear s. Car ef ul
r ev i ew of hi s ol d r ecor ds r ev eal s that a PPD test w as posi ti v e appr ox i m atel y
12 y ear s ago.
Phy si cal ex am i nati on di scl oses a cachecti c, i l l appear i ng, el der l y m an i n
m oder ate r espi r ator y di str ess. Hi s or al tem per atur e i s 38. 5Â°C (101. 3Â°F),
w i th a r espi r ator y r ate of 30 br eaths per m i nute, hear t r ate of 126 beats
per m i nute, and bl ood pr essur e of 100/60 m m Hg. Phy si cal ex am i nati on
f i ndi ngs ar e r em ar k abl e f or poor denti ti on, and r al es and r honchi thr oughout
the r i ght chest, but other w i se negati v e. Ini ti al l abor ator y ev al uati on r ev eal s
a w hi te bl ood cel l count of 16, 000/m m 3 w i th a l ef tw ar d shi f t and a
hem atocr i t of 35%. Hi s ox y gen satur ati on i s 80% on r oom ai r . A chest
r adi ogr aph show s a l ar ge i nter sti ti al and al v eol ar i nf i l tr ate w i th ai r
br onchogr am s i n the r i ght upper l obe; no cav i tati on, pl eur al ef f usi on, or
v ol um e l oss i s noted. Ar ter i al bl ood gas m easur em ents on the ni ght of
adm i ssi on show w or seni ng hy pox em i a and hy per capni a.
The pati ent i s pl aced i n r espi r ator y i sol ati on and i s el ecti v el y i ntubated on
the ni ght of adm i ssi on. Ex am i nati on of hi s sputum , done the nex t m or ni ng,
r ev eal s a pathogen.
1. What i s the di f f er enti al di agnosi s of thi s pati ent's r espi r ator y f ai l ur e?

2. What i s the di agnosti c str ategy at thi s poi nt i n hi s i l l ness?
3. What i s the cor r ect ther apeuti c pl an?
P. 377
Case Discussion
1. What i s the di f f er enti al di agnosi s of thi s pati ent's r espi r ator y f ai l ur e?
Thi s pati ent's hi stor y i s consi stent w i th an i nf ecti ous pr ocess, per haps
super i m posed on an under l y i ng m al i gnancy . Bacter i al pathogens such
as S. pneum oni ae, Legi onel l a pneum ophi l a, and H. i nf l uenzae ar e
possi bl e causes. Because of hi s hi stor y of ethanol abuse and poor
denti ti on, aspi r ati on pneum oni a (w i th anaer obi c pathogens) i s al so a
possi bi l i ty , but the l ocati on of the i nf i l tr ates i n the upper l obe m ak es
thi s l ess l i k el y as aspi r ati on pneum oni a tends to f av or dependent
por ti ons of the l ung, such as the super i or segm ents of both l ow er
l obes. Bacter i al pneum oni a di stal to an obstr ucti ng endothel i al l esi on i s
cl ear l y a possi bi l i ty gi v en hi s l ongstandi ng tobacco use and age;
how ev er , the absence of v ol um e l oss and pr esence of ai r br onchogr am s
on hi s r adi ogr aph som ew hat m i l i tate agai nst thi s di agnosi s. Vi r al
i nf ecti on i s l ess l i k el y , gi v en hi s hi stor y and the l obar i nf i l tr ate. Fungal
i nf ecti on, par ti cul ar l y w i th Hi stopl asm a capsul atum , i s a possi bi l i ty , but
l ess l i k el y gi v en hi s negati v e geogr aphi c hi stor y and the absence of
adenopathy on the r adi ogr aph. He has no HIV r i sk f actor s.
An i m por tant cl ue to the di agnosi s i s the posi ti v e r esul t of PPD sk i n
test. Because m ost acti v e cases of pul m onar y tuber cul osi s i n adul ts
consti tute ei ther postpr i m ar y di sease or the r eacti v ati on of a
pr otr acted, ev en l i f el ong, i nf ecti on w i th the tuber cl e baci l l us, thi s pl us
hi s posi ti v e PPD test r esul t poi nt to the di agnosi s. The i m por tant poi nt
her e i s that the cl i ni ci an shoul d suspect r eacti v ati on of tuber cul osi s
ev en w i thout a hi stor y of a posi ti v e PPD test r esul t. Thi s pati ent has
sev er al cur r entl y r ecogni zed epi dem i ol ogi c r i sk f actor s f or
tuber cul osi s: he i s el der l y , Af r i can Am er i can, and a substance abuser
(ethanol ), and he has poor nutr i ti onal status. He has an upper l obe
i nf i l tr ate. The absence of an upper l ob i nf i l tr ate, how ev er , does not
r ul e out tuber cul osi s, because the cl assi c f i br onodul ar i nf i l tr ati on of the
poster i or or api cal segm ents of the upper l obe (r i ght gr eater than l ef t)
m ay not be pr esent i n the el der l y or , especi al l y , i n HIVi nf ected
pati ents. Tuber cul osi s pr obabl y needs to be consi der ed i n the
di f f er enti al di agnosi s of pneum oni a i n ev er y pati ent ol der than 60
y ear s. Thi s pati ent's r espi r ator y f ai l ur e w i th hy pox em i a and r espi r ator y
m uscl e f ati gue (hy per capni a) coul d be due to any one of the pr ocesses
di scussed, but tuber cul osi s i s the m ost l i k el y di agnosi s.
2. What i s the di agnosti c str ategy at thi s poi nt i n hi s i l l ness?
A car ef ul sear ch f or the pathogen, or pathogens, shoul d be under tak en.
Bl ood cul tur es, Gr am 's stai ni ng and cul tur e of sputum sam pl es, pl us
sputum stai ns f or aci df ast or gani sm s (m y cobacter i a) and the
possi bi l i ty of Legi onel l a i ndi cate that a f l uor escent anti body test shoul d
be per f or m ed. The v al ue of sputum ex am i nati on cannot be
ov er em phasi zed. Gr am 's stai ni ng, especi al l y of a tr acheal aspi r ate or
sputum pr oduced by a str ong deep cough, can hel p i n the di agnosi s of
v i r tual l y any bacter i al i nf ecti ous agent i n the di f f er enti al di agnosi s.
(Legi onel l a i s di f f i cul t to see, but a l ar ge num ber of neutr ophi l s w i thout
or gani sm s suggest thi s di agnosi s. ) In addi ti on to the stai ns f or aci d
f ast baci l l i (AFB), tuber cul osi s can be di agnosed w i th a f l uor ochr om e
techni que cal l ed aur am i ne O. Thi s pati ent's sputum w as posi ti v e f or
AFB. Appr ox i m atel y 10 4 or gani sm s/m L of sputum ar e r equi r ed f or an
AFB sm ear to be
P. 378
posi ti v e, and onl y 50% to 80% of pati ents w i th pul m onar y tuber cul osi s
hav e posi ti v e sputum sm ear f i ndi ngs. A r api d r adi om etr i c techni que
k now n as BACTEC al l ow s the r ecov er y and i denti f i cati on of tuber cul osi s
i n 10 day s, w hi ch i s an adv antage ov er conv enti onal cul tur e m ethods
that can tak e 3 to 6 w eek s to gr ow m y cobacter i a.
A PPD test w i th tw o contr ol s shoul d be pl aced and an i ndur ati on of 10
m m or m or e i s consi der ed a posi ti v e r esul t. How ev er , i n the setti ng of
HIV i nf ecti onâ€”HIV r i sk f actor s, r ecent cl ose contact w i th i nf ecti ous
peopl e, or chest r adi ogr aphi c f i ndi ngs consi stent w i th ol d heal ed
tuber cul osi s (upper l obe scar r i ng)â€”an i ndur ati on of 5 m m or m or e i s
consi der ed a posi ti v e r eacti on. How ev er , as al r eady m enti oned, a
negati v e r esul t does not ex cl ude tuber cul osi s because up to 25% to
30% of new l y di agnosed pati ents w i th tuber cul osi s hav e a negati v e (â
‰¤9 m m ) sk i n test r esul t. A booster ef f ect i s m or e pow er f ul (â‰￥6
m m i ncr ease) i n the cutaneous r eacti on, and i s achi ev ed by per f or m i ng
a second PPD test 7 to 10 day s af ter the f i r st. A second PPD shoul d
ther ef or e be consi der ed i n thi s pati ent, but especi al l y i n an el der l y
pati ent w i th a negati v e PPD, i n w hom the cl i ni cal suspi ci on f or
tuber cul osi s i s hi gh. How ev er , the si ne qua non test f or tuber cul osi s
r em ai ns the sputum sm ear and cul tur e.
Addi ti onal di agnosti c tests that shoul d be par t of the ev al uati on of thi s
pati ent i ncl ude an HIV test and com par i son of pr ev i ous and cur r ent
chest r adi ogr aphs, i f possi bl e. The l atter w oul d consti tute an i m por tant
par t of the ev al uati on i n thi s pati ent. Fi ber opti c br onchoscopy coul d
al so hel p i n deter m i ni ng i f ther e i s an endobr onchi al l esi on, or ex tr i nsi c
com pr essi on f r om a m ass, as w el l as enabl e sam pl i ng of secr eti ons and
bi opsi es f or m i cr obi ol ogi c ev al uati on.
3. What i s the cor r ect ther apeuti c pl an?
Af ter appr opr i ate cul tur e r esul ts ar e obtai ned, tr eatm ent needs to be
di r ected tow ar d the m ost l i k el y pathogens i n thi s m an's i l l ness. On the
basi s of the di f f er enti al di agnosi s, y ou w oul d need to pr ov i de anti bi oti c
cov er age f or S. pneum oni ae, H. i nf l uenzae, possi bl y anaer obes, as w el l
as Legi onel l a speci es. The sev er i ty of thi s pati ent's i l l ness m andates
aggr essi v e, but w el l consi der ed, ther apy . Hi s i ni ti al r egi m en shoul d
i ncl ude cov er age f or com m uni ty acqui r ed pneum oni a and Legi onel l a.
Anti tuber cul ous ther apy shoul d be i ni ti ated onl y af ter hi s AFB sm ear s
pr ov e posi ti v e. It w as al so v er y i m por tant that on adm i ssi on the
pati ent w as pl aced i n r espi r ator y i sol ati on to pr ev ent the spr ead of
tuber cul osi s, w hi ch i s tr ansm i tted al m ost ex cl usi v el y by m eans of
aer osol i zed r espi r ator y secr eti ons, not onl y to other pati ents but to
heal th car e w or k er s as w el l . Hi s sputum sm ear posi ti v i ty f or M.
tuber cul osi s consti tutes a state of i nf ecti ousness. Peopl e r ecei v i ng
ther apy pr om ptl y becom e noni nf ecti ous as thei r cough subsi des and the
concentr ati on of or gani sm s i n thei r sputum decr eases. Most author i ti es
bel i ev e that tr eatm ent r ev er ses i nf ecti ousness w i thi n appr ox i m atel y 2
w eek s of the star t of ther apy ; unti l then, i sol ati on m easur es shoul d be
m ai ntai ned.
Hi s anti tuber cul ous chem other apy shoul d consi st of a f our dr ug
r egi m en, com pr i si ng IN H, r i f am pi n, py r azi nam i de, and str eptom y ci n,
and be m ai ntai ned f or 6 m onths. Many studi es hav e conv i nci ngl y
dem onstr ated the cur ati v e ef f i cacy of m ul ti dr ug r egi m ens gi v en f or 6 to
9 m onths. A standar d tr eatm ent i s ef f ecti v e w hen gi v en f or 6 m onths i n
a super v i sed setti ng. Com pl i ance w i th anti tuber cul ous ther apy i s
absol utel y cr i ti cal f or cur e. N oncom pl i ance i s al so one of the m ajor
r easons f or the em er gence of dr ug r esi stance. Mul ti dr ug ther apy i s
al w ay s used i n the tr eatm ent of
P. 379
tuber cul osi s because of the potenti al f or pr i m ar y or spontaneous
r esi stance, w hi ch occur s i n 1 Ã— 10 6 or gani sm s. Ex tr apul m onar y
tuber cul osi s i s tr eated l i k e pul m onar y tuber cul osi s, and tuber cul osi s
contr acted i n the setti ng of AIDS i s al so tr eated w i th standar d
r egi m ens, and i s sti l l cur abl e.
Suggested Readings
Am er i can Thor aci c Soci ety /Center s f or Di sease Contr ol and
Pr ev enti on/Inf ecti ous Di sease Soci ety of Am er i ca: Contr ol l i ng
tuber cul osi s i n the U ni ted States. Am J Respi r Cr i t Car e Med
2005;172:1169â€“1227; Tr eatm ent of tuber cul osi s. Am J Respi r Cr i t Car e
m ed 2003;167:603â€“662.
Bass JB, Far er LS, Hopew el l PC, et al . Am er i can Thor aci c Soci ety ,
Medi cal Secti on of the Am er i can Lung Associ ati on. Tr eatm ent of
tuber cul osi s and tuber cul ous i nf ecti on i n adul ts and chi l dr en. Am Rev
Respi r Di s 1986;134:355.
Bass JB, Far er LS, Hopew el l PC, et al . Am er i can Thor aci c Soci ety ,
Medi cal Secti on of the Am er i can Lung Associ ati on. Di agnosti c standar ds
and cl assi f i cati on of tuber cul osi s. Am Rev Respi r Di s 1990;142:725.
Cohn DL, Catl i n BJ, Peter son KL, et al . A 62dose, 6m onth ther apy f or
pul m onar y and ex tr apul m onar y tuber cul osi s: a tw i cew eek l y , di r ectl y
obser v ed, and costef f ecti v e r egi m en. Ann Inter n Med 1990;112:407.
Hef f ner JE, Str ange C, Sahn SA. The i m pact of r espi r ator y f ai l ur e on the
di agnosi s of tuber cul osi s. Ar ch Inter n Med 1988;148:1103.
Isem an M. Tuber cul osi s. In: Sy nopsi s of cl i ni cal pul m onar y di sease, 4th
ed. St. Loui s: Mosby â€“Year Book , 1989.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 9 Ne p hr o lo g y
Chapter 9
Nephrology
Toma s Be rl
Is a a c Te ite lba um
Acute Renal Failure
1. U nder w hat ci r cum stances i s ser um cr eati ni ne a r easonabl e m ar k er f or
gl om er ul ar f i l tr ati on r ate (GFR)? How i s the cr eati ni ne cl ear ance
esti m ated f r om the ser um cr eati ni ne?
2. What cl i ni cal f i ndi ngs m ost com m onl y suggest the pr esence of acute r enal
f ai l ur e?
3. What pr ocesses need to be consi der ed w hen attem pti ng to ascer tai n the
cause of acute r enal f ai l ur e?
4. What ar e the m ost com m on causes of acute r enal f ai l ur e i n hospi tal i zed
pati ents and i n outpati ents?
P. 381
5. What ar e the ur i nar y f i ndi ngs that assi st i n di f f er enti ati ng pr er enal
azotem i a f r om i ntr ar enal acute r enal f ai l ur e?
6. What ar e the com pl i cati ons of acute r enal f ai l ur e?
Discussion
1. U nder w hat ci r cum stances i s ser um cr eati ni ne a r easonabl e m ar k er f or
GFR? How i s the cr eati ni ne cl ear ance esti m ated f r om the ser um
cr eati ni ne?
The ser um cr eati ni ne i s a r easonabl e m ar k er f or cr eati ni ne cl ear ance and
GFR onl y i n the steady state, that i s, w hen the ser um cr eati ni ne i s nei ther
i ncr easi ng nor decr easi ng. In the steady state, the cr eati ni ne cl ear ance
(C Cr ) m ay be esti m ated f r om the ser um cr eati ni ne (S Cr ) by the Cock r of t
Gaul t equati on:
Another equati on der i v ed as a r esul t of the Modi f i cati on of Di et i n Renal
Di sease (MDRD) study has r ecentl y been v al i dated as a m or e r el i abl e
pr edi ctor of GFR i n som e ci r cum stances, such as chr oni c k i dney di seases:
A GFR cal cul ator uti l i zi ng thi s equati on m ay be f ound at the w ebsi te,
http://w w w . nephr on. com /cgi bi n/MDRD. cgi , and i s al so av ai l abl e on m any
â€œhandhel dâ€ dev i ces.
2. What cl i ni cal f i ndi ngs m ost com m onl y suggest the pr esence of acute r enal
f ai l ur e?
A r i se i n the bl ood ur ea ni tr ogen (BU N ) and ser um cr eati ni ne l ev el s and
dev el opm ent of ol i gur i a (< 400 m L per day ) ar e the com m on cl i ni cal
f i ndi ngs that suggest the pr esence of acute r enal f ai l ur e. How ev er , the
absence of ol i gur i a does not ex cl ude acute r enal f ai l ur e because the
pr ocess m ay al so be nonol i gur i c. In f act, 20% to 30% of pati ents w i th
acute r enal f ai l ur e ar e nonol i gur i c (> 400 m L per day ).
3. What pr ocesses need to be consi der ed w hen attem pti ng to ascer tai n the
cause of acute r enal f ai l ur e?
In pati ents w i th acute r enal f ai l ur e, pr er enal , postr enal , and i ntr ar enal
pr ocesses need to be consi der ed. The r especti v e causes of pr er enal and
postr enal azotem i a as w el l as i ntr i nsi c r enal di sease ar e l i sted i n Tabl es
91, 92, 93.
4. What ar e the m ost com m on causes of acute r enal f ai l ur e i n hospi tal i zed
pati ents and i n outpati ents?
In hospi tal i zed pati ents, the m ost com m on cause of acute r enal f ai l ur e
(45%) i s acute tubul ar necr osi s, f ol l ow ed by pr er enal azotem i a and
obstr ucti on. Gl om er ul onephr i ti s, v ascul i ti s, i nter sti ti al nephr i ti s, and
ather oem bol i c
P. 382
di sease com pr i se m ost of the r em ai ni ng causes. In contr ast, acute r enal
f ai l ur e i n outpati ents i s m ost com m onl y due to pr er enal azotem i a (70%),
f ol l ow ed by obstr ucti on. Dr ug nephr otox i ci ty [e. g. , am i nogl y cosi des,
angi otensi nconv er ti ng enzy m e (ACE) i nhi bi tor s, angi otensi n r eceptor
bl ock er s (ARBs), and nonster oi dal anti i nf l am m ator y dr ugs (N SAIDs)]
accounts f or m ost of the r em ai ni ng cases.
Table 91 Causes of Prerenal Azotemia
Reduced ex tr acel l ul ar and i ntr av ascul ar v ol um e

Gastr oi ntesti nal l osses (v om i ti ng, di ar r hea,
nasogastr i c sucti on)
Dehy dr ati on
Bur ns
Hem or r hage
Reduced i ntr av ascul ar v ol um e but i ncr eased ex tr acel l ul ar
v ol um e
Ci r r hosi s
N ephr oti c sy ndr om e
Congesti v e hear t f ai l ur eâ€”car di ogeni c shock
Thi r dspace f l ui d accum ul ati on (postoper ati v e f r om
abdom i nal sur ger y , sev er e pancr eati ti s, per i toni ti s)
Hem ody nam i cal l y m edi ated acute r enal f ai l ur e
Anesthesi a
N onster oi dal anti i nf l am m ator y agents (due to r enal
pr ostagl andi n i nhi bi ti on)
Inhi bi tor s of the r eni nangi otensi n sy stem (due to a
decr ease i n ef f er ent ar ter i ol ar tone)
Hepator enal sy ndr om e
Vasoconstr i ctor agents
Cal ci neur i n i nhi bi tor s
Contr ast agents
5. What ar e the ur i nar y f i ndi ngs that assi st i n di f f er enti ati ng pr er enal
azotem i a f r om i ntr ar enal acute r enal f ai l ur e?
The ur i nar y f i ndi ngs that can be used to hel p di f f er enti ate betw een
pr er enal azotem i a and i ntr ar enal acute r enal f ai l ur e ar e l i sted i n Tabl e 9
4.
6. What ar e the com pl i cati ons of acute r enal f ai l ur e?
The v ar i ous com pl i cati ons of acute r enal f ai l ur e ar e l i sted by categor y i n

Tabl e 95.
Case
A 65y ear ol d di abeti c w om an pr esents to the em er gency r oom w i th r i ght
upper quadr ant pai n that r adi ates ar ound to the back , together w i th nausea,
v om i ti ng, anor ex i a, l i ghtheadedness, and a di m i ni shed ur i ne output dur i ng the
l ast 24 hour s. She has no pr ev i ous hi stor y of r enal dy sf uncti on. Her
tem per atur e i s 37. 5Â°C (99. 5Â°F); supi ne, her bl ood pr essur e i s 110/70 m m
Hg and pul se i s 80 beats per m i nute; upr i ght, her bl ood pr essur e i s 85/60 m m
Hg and pul se i s 110 beats per m i nute. The phy si cal ex am i nati on f i ndi ngs ar e
other w i se r em ar k abl e f or the pr esence of decr eased sk i n tur gor , dr y m ucosal
P. 383
m em br anes, f l at neck v ei ns, and absence of ax i l l ar y sw eat. Her l ungs ar e
cl ear and the car di ac f i ndi ngs ar e nor m al . Ther e i s ex qui si te r i ght upper
quadr ant abdom i nal tender ness that w or sens w i th i nspi r ati on, her stool i s
guai ac negati v e, and no edem a i s noted. N eur ol ogi c ex am i nati on r ev eal s
nonf ocal f i ndi ngs.
Table 92 Causes of Postrenal Azotemia
U r ethr al obstr ucti on

Val v es
Str i ctur es
Bl adder neck obstr ucti on
Pr ostati c hy per tr ophy
Bl adder car ci nom a
Bl adder i nf ecti on
Functi onal
Autonom i c neur opathy
aAdr ener gi c bl ock er s
Obstr ucti on of ur eter s, bi l ater al
U ni l ater al obstr ucti on i n sol i tar y k i dney
Intr aur eter al
Sul f onam i de, ur i c aci d, acy cl ov i r , anti r etr ov i r al agent
cr y stal s
Bl ood cl ots
Stones
N ecr oti zi ng papi l l i ti s
Ex tr aur eter al
Tum or of cer v i x , pr ostate, bl adder
Endom etr i osi s
Per i ur eter al f i br osi s
Acci dental ur eter al l i gati on
Pel v i c abscess or hem atom a
The f ol l ow i ng l abor ator y data ar e obtai ned: hem atocr i t, 50. 2%; w hi te bl ood
cel l count, 19, 500/m m 3 w i th 82% pol y m or phonucl ear l euk ocy tes, 16% band
f or m s, and 2% l y m phocy tes; pl atel ets, 312, 000/m m 3 ; sodi um , 146 m Eq/L;
potassi um , 4. 1 m Eq/L; chl or i de, 111 m Eq/L; car bon di ox i de, 22 m Eq/L;
gl ucose, 195 m g/dL; BU N , 35 m g/dL; cr eati ni ne, 1. 6 m g/dL; total bi l i r ubi n, 1. 8
m g/dL; al k al i ne phosphatase, 289 IU ; and aspar tate am i notr ansf er ase (AST),
35 U /L.
U r i nal y si s r ev eal s a pH of 5, a speci f i c gr av i ty of 1. 028; 1+ gl ucose, tr ace
k etones, occasi onal nonpi gm ented gr anul ar casts, and no cel l ul ar casts or
bacter i a. The ur i ne sodi um l ev el i s 10 m Eq/L and the ur i ne cr eati ni ne l ev el i s
80 m g/dL.
Abdom i nal ul tr asonogr aphy r ev eal s the ex i stence of gal l stones and di l atati on
of the bi l i ar y tr ee. The k i dney s m easur e 11 cm but ex hi bi t no hy dr onephr osi s
or i ncr eased echogeni ci ty .
Whi l e i n the em er gency r oom , the pati ent's f ev er spi k es to 39Â°C (102. 2Â°F),
w hi ch i s accom pani ed by 3 m i nutes of r i gor s and a decr ease i n bl ood pr essur e
to
P. 384
P. 385
80/50 m m Hg. She i s adm i tted to the hospi tal w i th a di agnosi s of acute
chol ecy sti ti s f or the pur pose of obser v ati on and ev entual chol ecy stectom y .
She i s gi v en gentam i ci n [2 m g/k g i ntr av enousl y (IV)] and am pi ci l l i n (2 g IV
ev er y 6 hour s). Her ur i ne output ov er 12 hour s i s 100 m L. The nex t m or ni ng,
the f ol l ow i ng l abor ator y v al ues ar e r epor ted: sodi um , 140 m Eq/L; potassi um ,
5 m Eq/L; chl or i de, 100 m Eq/L; car bon di ox i de, 15 m Eq/L; gl ucose, 130 m g/dL;
BU N , 40 m g/dL; and cr eati ni ne, 2. 5 m g/dL. U r i nal y si s now r ev eal s a pH of 5
and a speci f i c gr av i ty of 1. 010 w i th occasi onal r enal tubul ar epi thel i al cel l s
and a r ar e, m uddy br ow n gr anul ar cast. The ur i ne sodi um l ev el i s 80 m Eq/L
and the ur i ne cr eati ni ne l ev el i s 40 m g/dL. Bl ood cul tur es ar e posi ti v e f or a
gr am negati v e baci l l us.
Table 93 Causes of Intrarenal Acute Renal
Failure
Gl om er ul ar di seases
Rapi dl y pr ogr essi v e gl om er ul onephr i ti s
Posti nf ecti ous gl om er ul onephr i ti s
Focal gl om er ul oscl er osi s associ ated w i th acqui r ed
i m m unodef i ci ency sy ndr om e
Tubul oi nter sti ti al nephr i ti s
Hy per sensi ti v i ty r eacti ons: peni ci l l i ns, sul f onam i des,
f l uor oqui nol ones, and m any other dr ugs
Associ ated w i th sy stem i c i nf ecti ons (Legi onel l a,
Tox opl asm a)
Acute tubul ar necr osi s
Ischem i a, hy potensi on, septi cem i a
Di r ect dr ug tox i ci ty : am i nogl y cosi des, ci spl ati n,
am photer i ci n, contr ast agents
My ogl obi n or hem ogl obi n
Acute tubul ar necr osi s i n pr egnancy
Vascul ar di seases
Renal ar ter y occl usi on
Acute v ascul i ti s
Mal i gnant hy per tensi on
Ather oem bol i c di sease, m ul ti pl e chol ester ol em bol i
sy ndr om e
Thr om boti c m i cr oangi opathy
Other s
Acute ur i c aci d nephr opathy
Hy per cal cem i c nephr opathy
Table 94 Urine Findings in Prerenal Azotemia
and Acute Renal Failure
La bora tory Te s t P re re na l Azote mia Intra re na l Ac ute

Re na l Fa ilure
U r i nar y osm ol al i ty > 500 < 400

(m Osm /k g)
U r i nar y sodi um < 20 > 40

(m Eq/L)
U r i nepl asm a > 40 < 20

cr eati ni ne r ati o
Renal f ai l ur e <1 >2

i ndex :
U N a/U Cr /PCr
Fr acti onal <1 >2

ex cr eti on of
sodi um :
U N a/PN a
Ã· U Cr /PCr Ã— 100
U r i nar y sedi m ent N or m al or occasi onal Br ow n gr anul ar casts,

gr anul ar casts cel l ul ar debr i s
U N a, ur i nar y sodi um l ev el ; U Cr , ur i nar y cr eati ni ne l ev el ; PCr , ser um

cr eati ni ne l ev el ; PN a, ser um sodi um l ev el .
Fr om Edel stei n CH, Schr i er RW. Acute r enal f ai l ur e: pathogenesi s,

di agnosi s, and m anagem ent. In:
Schr i er RW, ed. Renal and el ectr ol y te di sor der s, 6th ed. Phi l adel phi a:
Li ppi ncott Wi l l i am s & Wi l k i ns
2003. Repr i nted w i th per m i ssi on.

Table 95 Complications of Acute Renal Failure
Metabol i c
Hy ponatr em i a, hy per k al em i a, hy pocal cem i a,
hy per phosphatem i a, hy per m agnesem i a, hy per ur i cem i a
Car di ov ascul ar
Pul m onar y edem a, ar r hy thm i as, hy per tensi on, per i car di ti s
N eur ol ogi c
Aster i x i s, neur om uscul ar i r r i tabi l i ty , som nol ence, com a,
sei zur es
Hem atol ogi c
Anem i a, coagul opathi es, hem or r hagi c di athesi s
Gastr oi ntesti nal
N ausea, v om i ti ng, bl eedi ng
Inf ecti ous
Pneum oni a, ur i nar y tr act i nf ecti on, w ound i nf ecti on,
septi cem i a
Fr om Edel stei n CH, Schr i er RW. Acute r enal f ai l ur e: pathogenesi s,

di agnosi s, and m anagem ent. In: Schr i er RW, ed. Renal and el ectr ol y te
di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns 2003.
Repr i nted w i th per m i ssi on.
Dur i ng the nex t 3 day s, the pati ent r em ai ns ol i gur i c and m i l d congesti v e hear t
f ai l ur e dev el ops. The BU N and cr eati ni ne l ev el s r i se steadi l y to 100 and 5. 5
m g/dL, r especti v el y .
1. At the ti m e of ar r i v al i n the em er gency r oom , w hat i s the m ost l i k el y

ex pl anati on f or thi s pati ent's acute r enal dy sf uncti on, and w hy ?
2. At the ti m e of the pati ent's ar r i v al i n the em er gency r oom , w hat
tr eatm ent w oul d y ou pr escr i be, and w hy ?
3. What i s the cause of the conti nui ng r i se i n the ser um cr eati ni ne l ev el
af ter the pati ent i s adm i tted to the hospi tal , and w hy ?
4. What i s the r ol e f or di ur eti cs i n thi s pati ent, and w hat i s the pr oper
dosage?
5. What i s the appr opr i ate appr oach to f l ui d m anagem ent w hen the pati ent
becom es ol i gur i c?
6. What ar e the i ndi cati ons f or acute di al y si s i n acute r enal f ai l ur e, and
w hat al ter nati v e ex tr acor por eal pr ocedur es coul d be consi der ed?
P. 386
Case Discussion
1. At the ti m e of ar r i v al i n the em er gency r oom , w hat i s the m ost l i k el y
ex pl anati on f or thi s pati ent's acute r enal dy sf uncti on, and w hy ?
Ther e i s no ev i dence f or a postr enal cause of the acute r enal f ai l ur e i n

thi s pati ent, gi v en the r enal ul tr asound study show i ng no obstr ucti on. Thi s
l eav es pr er enal and i ntr ar enal causes as the sour ce of the acute r enal
f ai l ur e. The hi stor y and phy si cal ex am i nati on f i ndi ngs suggest pr er enal
azotem i a stem m i ng f r om v ol um e depl eti on. The l abor ator y data that
cor r obor ate thi s di agnosi s i ncl ude a BU N â€“cr eati ni ne r ati o that ex ceeds
20 and a f r acti onal ex tr acti on of sodi um (FEN a) of 0. 13%. The FEN a i s
cal cul ated as f ol l ow s: U N a /P N a Ã· U Cr /P Cr Ã— 100% = 10/146 Ã· 80/1. 6 Ã
— 100% = 0. 13%, w her e U N a and P N a ar e the ur i ne and ser um sodi um
l ev el s, r especti v el y , and U Cr and P Cr ar e the ur i ne and ser um l ev el s of
cr eati ni ne, r especti v el y . In the setti ng of ol i gur i a (< 400 m L of ur i ne per
day ), an FEN a of l ess than 1% i m pl i es pr er enal azotem i a, w her eas an
FEN a of gr eater than 2% i m pl i es an i ntr ar enal pr ocess. In pati ents w ho
ar e v ol um e contr acted due to di ur eti c use, the FEN a i s of ten el ev ated. In
such pati ents the f r acti onal ex cr eti on of ur ea (FEur ea) m ay be m or e
usef ul , cal cul ated as U u rea /P u rea Ã· U Cr /P Cr Ã— 100. A v al ue of l ess than
35% suggests pr er enal azotem i a.
2. At the ti m e of the pati ent's ar r i v al i n the em er gency r oom , w hat

tr eatm ent w oul d y ou pr escr i be, and w hy ?
In thi s cl i ni cal setti ng, r epl eti on of the ex tr acel l ul ar f l ui d v ol um e i s the
m ost cr i ti cal el em ent of ther apy . Thi s can be accom pl i shed by the
adm i ni str ati on of ei ther nor m al sal i ne or l actated Ri nger 's sol uti on; 250
to 500 m L can be gi v en r api dl y ov er 1 to 2 hour s. These sol uti ons, w hi ch
ar e dev oi d of col l oi d, di str i bute i n both i ntr av ascul ar and ex tr av ascul ar
spaces. Fl ui d i nf usi on shoul d be conti nued unti l the bl ood pr essur e
changes ar e no l onger ev i dent and a euv ol em i c state has been r estor ed.
Thi s w i l l al so be accom pani ed by the r eappear ance of sodi um i n the
ur i ne. In the setti ng of pr er enal azotem i a, thi s m aneuv er shoul d pr om ptl y
r etur n r enal f uncti on to basel i ne.
3. What i s the cause of the conti nui ng r i se i n the ser um cr eati ni ne l ev el
af ter the pati ent i s adm i tted to the hospi tal , and w hy ?
Af ter she i s adm i tted to the hospi tal , the pati ent's cl i ni cal pi ctur e
becom es m or e consi stent w i th an i ntr ar enal cause of acute r enal f ai l ur e,
such as acute tubul ar necr osi s. Thi s i s suppor ted by the pr esence of
tubul ar epi thel i al cel l s and br ow n gr anul ar casts i n the ur i ne. In addi ti on,
both the decr em ent i n the U Cr /P Cr to 16 and the i ncr ease i n the FEN a to
3. 57% str ongl y suppor t thi s di agnosi s. As to the cause of the i ntr ar enal
i njur y i tsel f , gr am negati v e sepsi s appear s to be the m ost l i k el y cul pr i t.
Am i nogl y cosi des can al so cause acute r enal f ai l ur e; how ev er , thi s pati ent
r ecei v ed onl y one dose of the anti bi oti c and, m or e com m onl y , the
associ ated r enal f ai l ur e i s nonol i gur i c. Am pi ci l l i n can cause acute
i nter sti ti al nephr i ti s, w hi ch has been r epor ted f or a num ber of anti bi oti cs.
The ur i nal y si s w oul d be ex pected to show w hi te bl ood cel l s, r ed bl ood
cel l s, w hi te bl ood cel l casts, and eosi nophi l s.
4. What i s the r ol e f or di ur eti cs i n thi s pati ent, and w hat i s the pr oper
dosage?
Di ur eti cs hav e been used i n an attem pt to conv er t ol i gur i c pati ents w i th
acute r enal f ai l ur e to a nonol i gur i c state, w hi ch i s associ ated w i th a
better outcom e and si m pl er f l ui d m anagem ent. Whether thi s â
€œconv er si onâ€ tr ul y al ter s the pr ognosi s has
P. 387
not been settl ed. Di ur eti cs can pl ay a m ajor r ol e i n the tr eatm ent of f l ui d
ov er l oad that accom pani es the pati ent's di m i ni shed ur i ne output. Because
l oop di ur eti cs need to r each the l um i nal m em br ane i n thi s setti ng, v er y
hi gh doses ar e r equi r ed (240 to 300 m g IV of f ur osem i de or 8 to 12 m g IV
of bum etani de). Doses hi gher than these hav e been used, but ar e not
associ ated w i th an i m pr ov ed outcom e and can cause per m anent
ototox i ci ty .
5. What i s the appr opr i ate appr oach to f l ui d m anagem ent w hen the pati ent
becom es ol i gur i c?
When a pati ent i s ol i gur i c (ur i ne v ol um e â‰¤400 m L), f l ui d r estr i cti on i s
needed and i ntak e shoul d not ex ceed 1 L because dai l y i nsensi bl e l osses
ar e esti m ated to be betw een 500 and 700 m L. Li k ew i se, sodi um and
potassi um r estr i cti on i s necessar y . Ther ef or e, the adm i ni str ati on of 1 L of
0. 5 N N aCl (i . e. , appr ox i m atel y 75 m Eq of sodi um ) w i thout potassi um
suppl em entati on i s l i k el y to pr ev ent ex pansi on of the ex tr acel l ul ar f l ui d
v ol um e, hy ponatr em i a, and hy per k al em i a. If the epi sode of acute r enal
f ai l ur e i s m or e pr ol onged, nutr i ti onal suppor t i s al so i m por tant.
6. What ar e the i ndi cati ons f or acute di al y si s i n acute r enal f ai l ur e, and

w hat al ter nati v e ex tr acor por eal pr ocedur es coul d be consi der ed?
Di al y si s i s under tak en w henev er any of the com pl i cati ons of acute r enal
f ai l ur e ensue. These ar e l i sted i n Tabl e 95. Most com m onl y , di al y si s i s
i nsti tuted f or the m anagem ent of f l ui d ov er l oad that i s r ef r actor y to
di ur eti c ther apy , hy per k al em i a that i s r esi stant to ther apy , or m etabol i c
aci dosi s that cannot be adequatel y tr eated w i th bi car bonate. In ol i gur i c,
catabol i c pati ents, di al y si s has al so been used to pr ev ent r ather than
tr eat ur em i c sy m ptom s, the socal l ed â€œpr ophy l acti c di al y si s. â€
Conti nuous v enov enous hem of i l tr ati on (CVVH) and conti nuous v enov enous
hem odi al y si s (HD) ar e al ter nati v es to i nter m i ttent HD, and ar e bei ng used
i ncr easi ngl y .
Suggested Readings
Edel stei n CL, Schr i er RW. Acute r enal f ai l ur e: pathogenesi s, di agnosi s, and
m anagem ent. In: Schr i er RW, ed. Renal and el ectr ol y te di sor der s, 6th ed.
Ki er an N , Br ady HR. Cl i ni cal ev al uati on, m anagem ent, and outcom e of
acute r enal f ai l ur e. In: Johnson R, Feehal l y J, eds. Com pr ehensi v e cl i ni cal
nephr ol ogy , 2nd ed. Mosby , 2003.
Metabolic Acidosis
1. What i s the def i ni ti on of m etabol i c aci dosi s?
2. What com pensator y m echani sm i s tr i gger ed by m etabol i c aci dosi s?
3. How i s the ani on gap cal cul ated, and how i s i t hel pf ul i n ev al uati ng
m etabol i c aci dosi s?
4. What ar e the causes of a m etabol i c aci dosi s w i th an i ncr eased ani on gap,
and w hat i s the ani on r esponsi bl e f or the i ncr eased ani on gap?
5. How i s the osm ol ar gap cal cul ated, and how i s thi s v al ue usef ul i n
ev al uati ng pati ents w i th a m etabol i c aci dosi s?
P. 388
6. What ar e the causes of a m etabol i c aci dosi s w i th a nor m al ani on gap?
7. What i s ur i nar y ani on gap (U AG) and i n w hat ci r cum stances i s i t usef ul ?
8. What i s the di f f er ence betw een pr ox i m al and di stal r enal tubul ar aci dosi s
(RTA), and how ar e these tw o f or m s of RTA di f f er enti ated?
Discussion
1. What i s the def i ni ti on of m etabol i c aci dosi s?
Metabol i c aci dosi s i s a di sor der that r esul ts f r om ei ther the addi ti on of
hy dr ogen i on or the l oss of bi car bonate, w hi ch, i f unopposed, r esul ts i n
aci dem i a. How ev er , m etabol i c aci dosi s i s not def i ned ei ther as a
decr em ent i n the ser um bi car bonate l ev el or as any gi v en sy stem i c
ar ter i al pH because, i n the setti ng of m i x ed aci dâ€“base di sor der s. The
ser um bi car bonate l ev el or pH, or both, m ay be nor m al or ev en el ev ated
despi te the pr esence of m etabol i c aci dosi s.
2. What com pensator y m echani sm i s tr i gger ed by m etabol i c aci dosi s?
When m etabol i c aci dosi s dev el ops, the decr ease i n pH acti v ates car oti d
chem or eceptor s and centr al ner v ous sy stem r eceptor s to sti m ul ate
v enti l ati on. The i ncr ease i n the m i nute v enti l ati on l ow er s the par ti al
pr essur e of car bon di ox i de (Pco 2 ), ther eby r etur ni ng the pH tow ar d
nor m al .
3. How i s ani on gap cal cul ated, and how i s i t hel pf ul i n ev al uati ng m etabol i c
aci dosi s?
Metabol i c aci dosi s i s br oadl y cl assi f i ed on the basi s of the pr esence or
absence of an i ncr eased ani on gap. The ani on gap (i n m i l l i m ol es per l i ter )
i s cal cul ated usi ng the f ol l ow i ng f or m ul a: pl asm a sodi um (pl asm a
chl or i de + pl asm a bi car bonate). In m ost l abor ator i es, a nor m al ani on gap
i s consi der ed to be 12 Â± 2 m m ol /L. A nor m al ani on gap m etabol i c
aci dosi s r esul ts f r om ei ther the addi ti on of hy dr ochl or i c aci d or the l oss
of bi car bonate w i th the concom i tant r etenti on of chl or i de. Because
chl or i de i s r etai ned and i s i ncl uded i n the cal cul ati on, the ani on gap
m etabol i c aci dosi s i s m ai ntai ned i n the nor m al r ange. An i ncr eased ani on
gap r esul ts f r om the addi ti on of an ex ogenous or endogenous aci d. The
ani ons pr oduced by these aci ds ar e not m easur ed and chl or i de i s not
r etai ned. The ani on gap i ncr eases because bi car bonate i s consum ed to
buf f er the or gani c aci d. For ex am pl e, or gani c ani on + H + + N aHCO 3 â†’
H 2 O + CO 2 + N a or gani c ani on + or gani c aci d. Because the or gani c ani on
i s not m easur ed or i ncl uded i n the cal cul ati on, the ani on gap i ncr eases.
4. What ar e the causes of a m etabol i c aci dosi s w i th an i ncr eased ani on gap,
and w hat i s the ani on r esponsi bl e f or the i ncr eased ani on gap?
The v ar i ous causes of m etabol i c aci dosi s w i th an i ncr eased ani on gap ar e
l i sted i n Tabl e 96.
5. How i s the osm ol ar gap cal cul ated, and how i s thi s v al ue usef ul i n
ev al uati ng pati ents w i th a m etabol i c aci dosi s?
The pl asm a osm ol al i ty i s cal cul ated usi ng the f ol l ow i ng f or m ul a:
Cal cul ated osm ol al i ty = 2[N a] + [gl ucose]/18 + [BU N ]/2. 8 +
[ethanol ]/4. 6. The osm ol ar gap i s equal to the m easur ed osm ol al i ty m i nus
the cal cul ated osm ol al i ty . A nor m al osm ol ar gap i s l ess than 10
m Osm /k g. When the osm ol ar
P. 389
gap i s el ev ated i n an aci dem i c pati ent, ethy l ene gl y col or m ethanol
i ntox i cati on m ust be str ongl y suspected.
Table 96 Causes of Metabolic Acidosis with
an Increased Anion Gap
Ca us e Anion
Incr eased aci d pr oducti on
Di abeti c k etoaci dosi s BHB, AcAc
Lacti c aci dosi s Lactate, py r uv ate

Star v ati on â€”
Al cohol i c k etoaci dosi s BHB > AcAc
N onk etoti c hy per osm ol ar com a â€”
Inbor n er r or s of m etabol i sm â€”
Ingesti on of aci dgener ati ng tox i c

substances
Sal i cy l ate ov er dose (> 30 m g/dL) Var i ety
Methanol i ngesti on For m ate, l actate
Ethy l ene gl y col i ngesti on Lactate, gl y col ate,

ox al ate
Sol v ent i nhal ati on â€”
Fai l ur e of aci d ex cr eti on
Acute r enal f ai l ur e Var i ety , SO4, PO4
Chr oni c r enal f ai l ur e â€”
BHB, betahy dr ox y buty r ate; AcAc, acetoacetate.
6. What ar e the causes of a m etabol i c aci dosi s w i th a nor m al ani on gap?
The causes of m etabol i c aci dosi s w i th a nor m al ani on gap ar e l i sted i n
Tabl e 97.
7. What i s U AG and i n w hat ci r cum stances i s i t usef ul ?
On occasi on, the U AG m ay hel p di sti ngui sh gastr oi ntesti nal l oss f r om
r enal l oss of HCO 3 as the cause of hy per chl or em i c m etabol i c aci dosi s:
The U AG i s an esti m ate of the ur i nar y am m oni um that i s el ev ated i n
gastr oi ntesti nal HCO 3 l oss but l ow i n di stal RTA. U AG i s a negati v e v al ue
i f ur i ne am m oni um i s hi gh (as i n di ar r hea; av er age, 20 m Eq/L), w her eas
i t i s posi ti v e i f ur i ne am m oni um i s l ow (as i n di stal RTA; av er age, + 23
m Eq/L).
8. What i s the di f f er ence betw een pr ox i m al and di stal RTA, and how ar e
these tw o f or m s of RTA di f f er enti ated?
RTA i s one of the com m on causes of m etabol i c aci dosi s w i th a nor m al
ani on gap. Pr ox i m al RTA r esul ts f r om a f ai l ur e to r esor b the nor m al
am ount of bi car bonate i n the pr ox i m al tubul e, w her eas di stal RTA r esul ts
f r om a def ect i n hy dr ogen i on secr eti on i n the di stal tubul e. These tw o
f or m s of RTA can be di f f er enti ated by deter m i ni ng the ur i ne pH dur i ng
sy stem i c aci dosi s. In pr ox i m al RTA, w hen the ser um bi car bonate, and
ther ef or e the f i l ter ed
P. 390
bi car bonate l ev el , i s l ow er ed to one that al l ow s f or pr ox i m al r eabsor pti on
of al l the f i l ter ed bi car bonate, the ur i ne can be m ax i m al l y aci di f i ed (pH
< 5. 4) as ther e i s no i ncr eased di stal del i v er y of unr eabsor bed
bi car bonate. In contr ast, i n di stal RTA, the ur i ne cannot be m ax i m al l y
aci di f i ed (pH > 5. 4) i ndependent of the ser um bi car bonate concentr ati on.
Table 97 The Causes of a Metabolic Acidosis
with a Normal Anion Gap
Gastr oi ntesti nal l oss of HCO3

Di ar r hea
Sm al l bow el or pancr eati c dr ai nage or f i stul a
U r eter osi gm oi dostom y , l ong or obstr ucted i l eal l oop condui t
Ani on ex change r esi ns
Ingesti on of CaCl 2 or MgCl 2
Renal l oss of HCO3
Car boni c anhy dr ase i nhi bi tor s
Renal tubul ar aci dosi s
Hy per par athy r oi di sm
Hy poal doster oni sm
Mi scel l aneous
Recov er y f r om k etoaci dosi s
Di l uti onal aci dosi s
Inf usi on of HCl or i ts congener s
Par enter al al i m entati on aci dosi s a
a Som e f or m ul as contai n ex cess or gani c cati ons (bal anced by Cl ),
w hi ch y i el d H+ on m etabol i sm .
Case
A 29y ear ol d m an has been hospi tal i zed i n the psy chi atr y ser v i ce f or 2
m onths because of depr essi on. The pati ent l eav es the hospi tal on a pass and,
on r etur ni ng, com pl ai ns of abdom i nal pai n and v om i ti ng. Ov er the nex t sev er al
hour s, he becom es m or e agi tated and i s then f ound i n an unar ousabl e state
and postur i ng.
Phy si cal ex am i nati on r ev eal s a tem per atur e of 102Â°F (38. 8Â°C), pul se of 102
beats per m i nute, r espi r ator y r ate of 35 br eaths per m i nute, and bl ood
pr essur e of 160/100 m m Hg. The pati ent i s unr esponsi v e to pai n. Funduscopi c
f i ndi ngs ar e w i thi n nor m al l i m i ts. N o odor s ar e noted on hi s br eath.
Labor ator y f i ndi ngs r ev eal the f ol l ow i ng: sodi um , 142 m Eq/L; potassi um , 4. 7
m Eq/L; chl or i de, 111 m Eq/L; bi car bonate, 10 m m ol /L; ser um cal ci um , 9. 4
m g/dL; BU N , 12 m g/dL; and cr eati ni ne, 1. 3 m g/dL. Ar ter i al bl ood gas
m easur em ents per f or m ed on r oom ai r show a pH of 7. 2, PCO 2 of 17 m m Hg,
and par ti al pr essur e of ox y gen (PO 2 ) of 100 m m Hg.
1. What i s thi s pati ent's aci dâ€“base di stur bance, and w hat ar e the possi bl e
causes?
2. Why i s the pati ent tachy pnei c, and i s the com pensati on appr opr i ate?
3. What other tests or l abor ator y f i ndi ngs w oul d be usef ul i n m ak i ng the
speci f i c di agnosi s?
P. 391
4. In thi s pati ent, the ser um gl ucose l ev el pr ov es to be nor m al and no
ser um k etones ar e detected. The pl asm a osm ol al i ty i s 347 m Osm /k g and
the osm ol ar gap i s cal cul ated to be 51 m Osm /k g. Wi th the new
i nf or m ati on y i el ded by these addi ti onal tests, w hat possi bl e di agnoses
sti l l r em ai n?
5. How w oul d y ou pr oceed to deter m i ne w hi ch substance i s r esponsi bl e f or
thi s pati ent's pr esentati on?
6. How w oul d y ou tr eat thi s pati ent?
Case Discussion
1. What i s thi s pati ent's aci dâ€“base di stur bance, and w hat ar e the possi bl e
causes?
The pati ent has an aci dem i a because the pH i s 7. 2. Thi s coul d r esul t f r om
ei ther a m etabol i c or a r espi r ator y aci dosi s. The com bi nati on of a l ow
PCO 2 and a l ow ser um bi car bonate concentr ati on conf i r m s the pr esence of
a m etabol i c aci dosi s. In addi ti on, the ani on gap i s el ev ated. The m ost
l i k el y causes of a m etabol i c aci dosi s w i th an i ncr eased ani on gap, as
outl i ned i n Tabl e 96, i ncl ude di abeti c k etoaci dosi s, l acti c aci dosi s,
star v ati on, al cohol i c k etoaci dosi s, sal i cy l ate ov er dose, m ethanol or
ethy l ene gl y col i ngesti on, and r enal f ai l ur e.
2. Why i s the pati ent tachy pnei c, and i s the com pensati on appr opr i ate?
The pati ent i s tachy pnei c as a com pensator y r esponse to the m etabol i c
aci dosi s. If the pati ent w er e not tachy pnei c, the pH w oul d be ev en l ow er
and thi s w oul d suggest an addi ti onal r espi r ator y di sor der . Thi s pati ent i s
ex hi bi ti ng an appr opr i ate r espi r ator y com pensator y r esponse. The ser um
bi car bonate l ev el i s decr eased by 14 m m ol /L f r om nor m al . Ther ef or e, the
PCO 2 shoul d be decr eased by 14 to 21 m m Hg (Tabl e 98). The pati ent
has a PCO 2 that i s decr eased by 21 m m Hg f r om nor m al , and thi s
com pensati on i s appr opr i ate f or the degr ee of m etabol i c aci dosi s
i nv ol v ed. Tabl e 98 sum m ar i zes the gener al ex pected com pensator y
r esponses to aci dâ€“base di sor der s.
3. What other tests or l abor ator y f i ndi ngs w oul d be usef ul i n m ak i ng the
speci f i c di agnosi s?
The pati ent cl ear l y has a m etabol i c aci dosi s w i th an i ncr eased ani on gap,
but i t i s necessar y to i denti f y the speci f i c cause w i th f ur ther testi ng.
Ini ti al tests that m i ght el uci date the cause of the pr ocess i ncl ude (a) the
ser um gl ucose l ev el to deter m i ne w hether hy per gl y cem i a i s pr esent; (b)
ser um k etone l ev el s to ascer tai n i f acetoacetate i s pr esent; (c) ser um
sal i cy l ate and l actate l ev el s to deter m i ne w hether sal i cy l ate i ntox i cati on
or l acti c aci dosi s i s pr esent; and (d) ser um osm ol al i ty to deter m i ne i f the
osm ol ar gap i s el ev ated.
4. In thi s pati ent, the ser um gl ucose l ev el pr ov es to be nor m al and no
ser um k etones ar e detected. The pl asm a osm ol al i ty i s 347 m Osm /k g and
the osm ol ar gap i s cal cul ated to be 51 m Osm /k g. Wi th the new
i nf or m ati on y i el ded by these addi ti onal tests, w hat possi bl e di agnoses
sti l l r em ai n?
Wi th thi s addi ti onal i nf or m ati on, y ou k now that the pati ent has m etabol i c
aci dosi s w i th an i ncr eased ani on and osm ol ar gap. Thi s l i m i ts the possi bl e
di agnoses to ei ther m ethanol or ethy l ene gl y col i ngesti on.
P. 392
5. How w oul d y ou pr oceed to deter m i ne w hi ch substance i s r esponsi bl e f or
thi s pati ent's pr esentati on?
Table 98 Rules of Thumb for Bedside
Interpretation of AcidBase Disorders
Metabol i c aci dosi s

Paco 2 shoul d f al l by 1. 01. 5 Ã— the f al l i n pl asm a
[HCO3]
Metabol i c al k al osi s
Paco 2 shoul d r i se by 0. 251. 0 Ã— the r i se i n pl asm a
[HCO3]
Acute r espi r ator y aci dosi s
Pl asm a [HCO3 ] shoul d r i se by appr ox i m atel y 1
m m ol /L f or each 10m m Hg i ncr em ent i n Paco 2 (Â± 3
m m ol /L)
Chr oni c r espi r ator y aci dosi s
Pl asm a [HCO3 ] shoul d r i se by appr ox i m atel y 4
m m ol /L f or each 10m m Hg i ncr em ent i n Paco 2 (Â± 4
m m ol /L)
Acute r espi r ator y al k al osi s
Pl asm a [HCO3 ] shoul d f al l by appr ox i m atel y 1 3
m m ol /L f or each 10m m Hg decr em ent i n Paco2, but
usual l y not to< 18 m m ol /L
Chr oni c r espi r ator y al k al osi s
Pl asm a [HCO3 ] shoul d f al l by appr ox i m atel y 2
5m m ol /L per 10m m Hg decr em ent i n Paco2, but
usual l y not to< 14 m m ol /L
Paco2, ar ter i al car bon di ox i de tensi on; [HCO3 ], bi car bonate i on
concentr ati on.
Fr om Shapi r o JI, Kaehny WD. Pathogenesi s and m anagem ent of

m etabol i c aci dosi s and al k al osi s. In: Schr i er RW, ed. Renal and
el ectr ol y te di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2003. Repr i nted w i th per m i ssi on.
To deter m i ne w hi ch substance i s r esponsi bl e f or thi s pati ent's

pr esentati on, both m ethanol and ethy l ene gl y col l ev el s shoul d be assay ed
i n the bl ood. In addi ti on, the ur i ne shoul d be ex am i ned f or the pr esence
of cal ci um ox al ate cr y stal s, w hi ch ar e f r equentl y pr esent i n the setti ng of
ethy l ene gl y col i ngesti on because of the m etabol i c conv er si on of the
ethy l ene gl y col to ox al ate. In the setti ng of m ethanol i ntox i cati on, v i sual
di stur bances coul d ensue.
The tr eatm ent of m etabol i c aci dosi s i nv ol v es tr eati ng the under l y i ng
di sor der . In acute m etabol i c aci dosi s, the r api d cor r ecti on of pH thr ough
the adm i ni str ati on of bi car bonate appear s to pr oduce der angem ents i n
car di ov ascul ar f uncti on, pr obabl y caused by a par adox i cal i ntr acel l ul ar
aci dosi s. The use of bi car bonate i n thi s setti ng i s ther ef or e contr ov er si al .
Mor e speci f i cal l y , tw o goal s becom e i m por tant i n a pati ent w ho has
i ngested ethy l ene gl y col . The f i r st i s to i nhi bi t the m etabol i sm of
ethy l ene gl y col . Al though ethy l ene gl y col by i tsel f i s not a tox i c
substance, the m etabol i tes pr oduced by the l i v er ar e qui te tox i c and can
pr eci pi tate acute r enal f ai l ur e and ev en cause death. Al cohol
dehy dr ogenase (ADH) i s the enzy m e r esponsi bl e f or the m etabol i sm of
ethy l ene gl y col , and i t can be com peti ti v el y i nhi bi ted by ethanol .
Fom epi zol e, a di r ect i nhi bi tor of ADH has al so been em pl oy ed. Ethy l ene
gl y col i ngesti on i s sti l l m ost com m onl y tr eated by the i nf usi on of ethanol .
The second goal
P. 393
i s to r em ov e the ethy l ene gl y col f r om the body . Ethy l ene gl y col i s
ex cr eted v er y sl ow l y by the k i dney s and, i f the bl ood l ev el i s v er y hi gh,
HD m ay becom e necessar y to i m pr ov e r em ov al of thi s substance f r om the
bl ood. A si m i l ar appr oach i s used f or m ethanol i ngesti on.
Suggested Readings
Pal m er BF, Al per n RJ. N or m al aci dbase bal ance and m etabol i c aci dosi s.
In: Johnson R, Feehal l y J, eds. Com pr ehensi v e cl i ni cal nephr ol ogy , 2nd ed.
Mosby , 2003.
Shapi r o JI, Kaehny WD. Pathogenesi s and m anagem ent of m etabol i c

aci dosi s and al k al osi s. In: Schr i er RW, ed. Renal and el ectr ol y te di sor der s,
6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003: 115.
Metabolic Alkalosis
1. What i s the def i ni ti on of m etabol i c al k al osi s?
2. What ar e the pr ocesses i nv ol v ed i n the gener ati on of m etabol i c al k al osi s?
3. What ar e the pr ocesses i nv ol v ed i n the m ai ntenance of m etabol i c

al k al osi s?
4. What ar e the tw o m ajor categor i es of m etabol i c al k al osi s, and w hat

l abor ator y test i s used to di f f er enti ate betw een the tw o?
5. What ar e the causes of N aCl r esponsi v e m etabol i c al k al osi s?
6. What ar e the causes of N aCl r esi stant m etabol i c al k al osi s?
7. What ar e the causes of m etabol i c al k al osi s that ar e uncl assi f i ed?
8. What i s the com pensator y m echani sm that i s sti m ul ated by m etabol i c

al k al osi s?
Discussion
1. What i s the def i ni ti on of m etabol i c al k al osi s?
Metabol i c al k al osi s i s a di sor der that r esul ts f r om ei ther the l oss of
hy dr ogen i ons or the addi ti on of bi car bonate, w hi ch, i f unopposed, r esul ts
i n al k al em i a. Metabol i c al k al osi s i s not def i ned ei ther as an i ncr em ent i n
the ser um bi car bonate concentr ati on or as a gi v en sy stem i c ar ter i al pH
because, i n the setti ng of m i x ed aci dâ€“base di sor der s. The ser um
bi car bonate l ev el or the pH, or both, coul d be ei ther nor m al or ev en
decr eased i n the pr esence of m etabol i c al k al osi s.
2. What ar e the pr ocesses i nv ol v ed i n the gener ati on of m etabol i c al k al osi s?
Pathophy si ol ogi cal l y , the dev el opm ent of m etabol i c al k al osi s i nv ol v es tw o
phases (see Fi g. 91). The f i r st i nv ol v es the gener ati on of m etabol i c
al k al osi s. As f ol l ow s f r om the def i ni ti on just gi v en, m etabol i c al k al osi s
can be gener ated as a r esul t of ei ther a net l oss of hy dr ogen i ons f r om
the ex tr acel l ul ar f l ui d, m ost com m onl y f r om ei ther the upper
gastr oi ntesti nal tr act or m or e r ar el y thr ough the k i dney s, or f r om the net
addi ti on of bi car bonate or substances that gener ate bi car bonate (e. g. ,
l actate, ci tr ate, and acetate). In addi ti on, the
P. 394
l oss of f l ui d hav i ng hi gh concentr ati ons of chl or i de and l ow concentr ati ons
of bi car bonate, as occur s w i th di ur eti c use and cer tai n gastr oi ntesti nal
tr act di seases such as v i l l ous adenom a, gener ates a m etabol i c al k al osi s.
Figure 91 The f actor s r esponsi bl e f or the gener ati on and m ai ntenance of
m etabol i c al k al osi s. ECF, ex tr acel l ul ar f l ui d; AII, angi otensi n II; Paco 2 ,
par ti al pr essur e of car bon di ox i de. (Fr om Shapi r o JI, Kaehny WD.
Pathogenesi s and m anagem ent of m etabol i c aci dosi s and al k al osi s. In:
Schr i er RW, ed. Renal and el ectr ol y te di sor der s, 6th ed. Phi l adel phi a:
Li ppi ncott Wi l l i am s & Wi l k i ns, 2003. Repr i nted w i th per m i ssi on. )
3. What ar e the pr ocesses i nv ol v ed i n the m ai ntenance of m etabol i c

al k al osi s?
The k i dney pr ov i des the cor r ecti v e r esponse to m etabol i c al k al osi s by
ex cr eti ng ex cess bi car bonate. When the ser um bi car bonate l ev el ex ceeds
28 m Eq/L, the ani on appear s i n the ur i ne, ther eby pr ev enti ng a f ur ther
i ncr ease i n i ts concentr ati on. The m ai ntenance of al k al osi s ther ef or e
r equi r es an al ter ati on i n r enal bi car bonate r eabsor pti on. Sev er al f actor s
constr ai n the k i dney 's abi l i ty to ex cr ete bi car bonate and ar e i m por tant i n
the m ai ntenance phase of m etabol i c al k al osi s. Pr obabl y , the m ost
i m por tant f actor i n thi s r egar d i s ex tr acel l ul ar f l ui d v ol um e depl eti on,
w hi ch ser v es to sti m ul ate i ncr eased sodi um r esor pti on and bi car bonate
r ecl am ati on i n the pr ox i m al tubul e. A decr em ent i n GFR w i th a decr ease
i n bi car bonate f i l tr ati on contr i butes to the m ai ntenance of the m etabol i c
al k al osi s. Another i m por tant f actor i n the m ai ntenance of m etabol i c
al k al osi s i s the chl or i de concentr ati on. When the pl asm a bi car bonate
concentr ati on r i ses, the chl or i de concentr ati on m ust f al l . Because chl or i de
i s the onl y ani on other than bi car bonate that can accom pany sodi um
r esor pti on, bi car bonate r esor pti on i s enhanced i n i ts absence. Ther ef or e,
chl or i de m ust ex i st i n suf f i ci ent quanti ty to al l ow f or bi car bonate
ex cr eti on. The hor m one al doster one sti m ul ates the ex change of sodi um
r eabsor pti on f or hy dr ogen or potassi um i on secr eti on i n the di stal tubul e.
Wi th
P. 395
the secr eti on of hy dr ogen i ons, bi car bonate gener ati on occur s i n the
pl asm a. Potassi um i on depl eti on di r ectl y enhances bi car bonate
r eabsor pti on. An el ev ati on i n the Pco 2 al so sti m ul ates bi car bonate
r eabsor pti on, and i s i m por tant i n the com pensator y m echani sm that k eeps
r espi r ator y aci dosi s i n check .
Table 99 Causes of NaClResponsive
Metabolic Alkalosis
Gastr oi ntesti nal di sor der s

Vom i ti ng
Gastr i c dr ai nage
Vi l l ous adenom a of the col on
Chl or i de di ar r hea
Di ur eti c ther apy
Cor r ecti on of chr oni c hy per capni a
Cy sti c f i br osi s
4. What ar e the tw o m ajor categor i es of m etabol i c al k al osi s, and w hat
l abor ator y test i s used to di f f er enti ate betw een the tw o?
Metabol i c al k al osi s can be di v i ded i nto tw o gr oups: N aCl r esponsi v e and
N aCl r esi stant. The f or m er i s f ound i n al k al em i c pati ents w ho ar e v ol um e
depl eted, and the l atter i n those w i th v ol um e ex pansi on. The m ost usef ul
l abor ator y test f or di f f er enti ati ng betw een the tw o gr oups i s a spot ur i ne
chl or i de deter m i nati on done bef or e the i ni ti ati on of ther apy . In N aCl
r esponsi v e states, the ur i ne chl or i de concentr ati on i s usual l y l ess than 20
m Eq/L, and f r equentl y ev en l ess than 10 m Eq/L; i n N aCl r esi stant states,
the ur i ne chl or i de l ev el ex ceeds 20 m Eq/L. How ev er , al though m etabol i c
al k al osi s i s r outi nel y di v i ded i nto these tw o categor i es, ther e ar e sev er al
di sor der s that ar e uncl assi f i ed.
5. What ar e the causes of N aCl r esponsi v e m etabol i c al k al osi s?
The causes of N aCl r esponsi v e m etabol i c al k al osi s ar e l i sted i n Tabl e 99.
6. What ar e the causes of N aCl r esi stant m etabol i c al k al osi s?
The causes of N aCl r esi stant m etabol i c al k al osi s ar e l i sted i n Tabl e 910.
7. What ar e the causes of m etabol i c al k al osi s that ar e uncl assi f i ed?
The uncl assi f i ed causes of m etabol i c al k al osi s ar e l i sted i n Tabl e 911.
8. What i s the com pensator y m echani sm that i s sti m ul ated by m etabol i c

al k al osi s?
When m etabol i c al k al osi s dev el ops, the al k al em i a i s sensed by

chem or eceptor s i n the r espi r ator y sy stem . Thi s l eads to hy pov enti l ati on
and an i ncr ease
P. 396
i n Pco 2 . As a gener al r ul e, the Î” Pco 2 (m m Hg) = 0. 25 1. 0 M Ã—
[HCO 3 ] m Eq/L, w her e Î” Pco 2 i s the change i n the Pco 2 . How ev er , thi s
hy pov enti l ator y r esponse i s not as ef f i ci ent as the hy per v enti l ator y
r esponses that accom pany a m etabol i c aci dosi s.
Table 910 Causes of NaClResistant Metabolic
Alkalosis
Ex cess m i ner al ocor ti coi d

Hy per al doster oni sm
Cushi ng's
Bar tter sy ndr om e
Ex cessi v e l i cor i ce i ntak e
Pr of ound potassi um depl eti on (8001, 000 m Eq def i ci t)
Table 911 Unclassified Causes of Metabolic
Alkalosis
Al k al i adm i ni str ati on

Recov er y f r om or gani c aci dosi s
Antaci ds and ex change r esi ns adm i ni ster ed i n r enal f ai l ur e
Mi l k al k al i sy ndr om e
Massi v e bl ood or pl asm anate (hum an pl asm a pr otei n f acti on)
tr ansf usi ons
N onpar athy r oi d hy per cal cem i a
Gl ucose i ngesti on af ter star v ati on
Lar ge doses of car beni ci l l i n or peni ci l l i n
Case
A 25y ear ol d m an w i th no pr ev i ous m edi cal hi stor y pr esents to the
em er gency r oom because of abdom i nal pai n and sev er e v om i ti ng of 2 day s'
dur ati on, dur i ng w hi ch ti m e he has been unabl e to eat or dr i nk . He i s tak i ng
no m edi cati ons.
Phy si cal ex am i nati on r ev eal s the f ol l ow i ng: tem per atur e, 37. 6Â°C (99. 68Â°F);
pul se, 120 beats per m i nute; r espi r ator y r ate, 18 br eaths per m i nute; and
bl ood pr essur e, 120/80 m m Hg. Or thostati c changes i n the pul se and bl ood
pr essur e ar e f ound, and ther e i s m i l d, di f f use abdom i nal tender ness.
The f ol l ow i ng l abor ator y f i ndi ngs ar e r epor ted: sodi um , 140 m Eq/L; potassi um ,
3. 4 m Eq/L; chl or i de, 90 m Eq/L; bi car bonate, 35 m m ol /L; and cr eati ni ne, 1. 5
m g/dL. Ar ter i al bl ood gas m easur em ents on r oom ai r r ev eal a pH of 7. 55,
PCO 2 of 44 m m Hg, and PO 2 of 77 m m Hg.
1. What aci dâ€“base di stur bances ar e pr esent i n thi s pati ent?

2. What ar e the possi bl e causes of thi s pati ent's m etabol i c al k al osi s, and
w hat l abor ator y test m i ght be usef ul to el uci date the natur e of the cause?
3. What f actor s ar e r esponsi bl e f or the gener ati on and m ai ntenance of the
m etabol i c al k al osi s i n thi s pati ent?
4. If the pati ent's v om i ti ng w er e to stop spontaneousl y , w oul d the aci dâ
€“base di stur bance al so r esol v e?
Case Discussion
1. What aci dâ€“base di stur bances ar e pr esent i n thi s pati ent?
The pati ent i s al k al em i c (pH, 7. 55). Ther ef or e, ei ther a m etabol i c

al k al osi s or a r espi r ator y al k al osi s, or both, ex i st. The ser um bi car bonate
l ev el i s el ev ated to 35 m Eq/L, and thi s i ndi cates a m etabol i c al k al osi s. In
the setti ng of a r espi r ator y
P. 397
al k al osi s, the PCO 2 w oul d be decr eased, w hi ch i s not the case i n thi s
pati ent. In the setti ng of m etabol i c al k al osi s, the ex pected r espi r ator y
com pensati on (hy pov enti l ati on) w oul d i ncr ease the PCO 2 . Because the
PCO 2 of 44 m m Hg i s an i ncr eased v al ue, thi s f ur ther suppor ts the
pr esence of a si m pl e m etabol i c al k al osi s w i th appr opr i ate r espi r ator y
com pensati on.
2. What ar e the possi bl e causes of thi s pati ent's m etabol i c al k al osi s, and
w hat l abor ator y test m i ght be usef ul to el uci date the natur e of the cause?
As al r eady di scussed, m etabol i c al k al osi s can be di v i ded i nto tw o br oad
categor i es: N aCl r esponsi v e and N aCl r esi stant states. The hal l m ar k of
N aCl r esponsi v e m etabol i c al k al osi s i s i ntr av ascul ar v ol um e depl eti on. In
thi s pati ent, the hi stor y of sev er e v om i ti ng pl us the v i tal si gns that
ex hi bi t or thostati c changes ar e v er y suggesti v e of an N aCl r esponsi v e
m etabol i c al k al osi s w i th i ntr av ascul ar v ol um e depl eti on. The other causes
of an N aCl r esponsi v e m etabol i c al k al osi s ar e nasogastr i c dr ai nage,
v i l l ous adenom a of the col on, chl or i de di ar r hea, and di ur eti c ther apy .
Measur em ent of a spot ur i ne chl or i de concentr ati on w oul d hel p conf i r m
the di agnosi s. In thi s pati ent, i t w oul d l i k el y be l ow (< 20 m Eq/L).
3. What f actor s ar e r esponsi bl e f or the gener ati on and m ai ntenance of the
m etabol i c al k al osi s i n thi s pati ent?
In the m etabol i c al k al osi s associ ated w i th v om i ti ng, the l oss of hy dr ogen
i ons i n the v om i tus i s r esponsi bl e f or gener ati ng the al k al osi s.
Mai ntenance of the m etabol i c al k al osi s i s per petuated by sev er al f actor s.
The N aCl l ost w i th v om i ti ng l eads to a state of i ntr av ascul ar v ol um e
depl eti on, w hi ch, i n tur n, sti m ul ates pr ox i m al tubul e r esor pti on of both
N aCl and N aHCO 3 . It al so sti m ul ates the r eni nangi otensi nal doster one
sy stem . The r esul tant i ncr eased al doster one secr eti on sti m ul ates N a + /H +
and N a + /K + ex change i n the di stal tubul e. The f or m er i ncr eases
bi car bonate r esor pti on, w her eas the l atter l eads to potassi um i on
depl eti on, w hi ch al so accel er ates pr ox i m al bi car bonate r esor pti on. The
i ncr eased PCO 2 associ ated w i th the com pensati on f or m etabol i c al k al osi s
al so i ncr eases bi car bonate r esor pti on. These ev ents ar e depi cted i n Fi g.
91.
4. If the pati ent's v om i ti ng w er e to stop spontaneousl y , w oul d the aci dâ
€“base di stur bance al so r esol v e?
Cessati on of v om i ti ng w oul d not necessar i l y r estor e the aci dâ€“base
bal ance. The pati ent's v om i ti ng i s onl y the pr eci pi tati ng cause of hi s
m etabol i c al k al osi s. At thi s poi nt, i f hi s v om i ti ng w er e to stop, sev er al
f actor s w oul d sti l l pr ev ai l (as di scussed ear l i er ) and m ai ntai n the
m etabol i c al k al osi s. Onl y w hen both the gener ati ng and m ai ntai ni ng
f actor s ar e el i m i nated can the aci dâ€“base di stur bance r esol v e.
In al l cases, the tr eatm ent of m etabol i c al k al osi s i nv ol v es m anagem ent of
the under l y i ng pr ocess. How ev er , the pr ocess that has been the sour ce of
the m etabol i c al k al osi s m ay hav e r esol v ed, and other f actor s m ay be
m ai ntai ni ng the m etabol i c al k al osi s. Ther ef or e, tr eati ng those f actor s that
ar e m ai ntai ni ng the m etabol i c al k al osi s m ay be m ost i m por tant. Thi s
pati ent shoul d r ecei v e dual ther apy . Fi r st, the v om i ti ng (w hi ch i s the
sour ce of the m etabol i c al k al osi s) shoul d be tr eated usi ng an anti em eti c
agent. Second, the i ntr av ascul ar v ol um e and potassi um depl eti on m ust be
cor r ected. Thi s i s accom pl i shed by the adm i ni str ati on of nor m al sal i ne
P. 398
pl us suppl em ental potassi um . The nor m al sal i ne i s adm i ni ster ed unti l the
or thostati c changes i n the pul se and bl ood pr essur e r esol v e.
Suggested Readings
Gennar i FJ. Metabol i c al k al osi s. In: Johnson R, Feehal l y J, eds.
Com pr ehensi v e cl i ni cal nephr ol ogy , 2nd ed. Mosby , 2003.
Sel di n D, Rector F. The gener ati on and m ai ntenance of m etabol i c al k al osi s.
Ki dney Int 1972;1:306.
Shapi r o JI, Kaehny WD. Pathogenesi s and m anagem ent of m etabol i c

aci dosi s and al k al osi s. In: Schr i er RW, ed. Renal and el ectr ol y te di sor der s,
6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:115.
Secondary Hypertension
1. What ar e the m ajor causes of hy per tensi on, and w hat i s the natur e of the
pathophy si ol ogi c m echani sm , or m echani sm s, r esponsi bl e f or causi ng the
el ev ati on i n bl ood pr essur e?
2. What shoul d the i ni ti al ev al uati on of a pati ent w ho pr esents w i th an
el ev ati on i n bl ood pr essur e consi st of , and, based on the ev al uati on
f i ndi ngs, w hat speci f i c cl i ni cal f eatur es w oul d poi nt tow ar d a par ti cul ar
secondar y cause of hy per tensi on?
3. If a secondar y cause of hy per tensi on i s suspected, w hat w oul d the f ur ther
di agnosti c ev al uati on com pr i se, and w hat w oul d be the l i k el y f i ndi ngs f or
each cause?
4. What ar e the r especti v e tr eatm ent opti ons f or r enal ar ter y stenosi s,
pheochr om ocy tom a, Cushi ng's sy ndr om e, and pr i m ar y
hy per al doster oni sm ?
Discussion
1. What ar e the m ajor causes of hy per tensi on, and w hat i s the natur e of the
pathophy si ol ogi c m echani sm , or m echani sm s, r esponsi bl e f or causi ng the
el ev ati on i n bl ood pr essur e?
Es s e ntia l hype rte ns ion i s the m ost com m on cause of hy per tensi on and
accounts f or appr ox i m atel y 90% of al l cases. It i s usual l y asy m ptom ati c.
The usual age of onset i s betw een 30 and 50 y ear s and pati ents usual l y
hav e a geneti c pr edi sposi ti on f or acqui r i ng i t. Other f or m s of
hy per tensi on m ust be r ul ed out by an i ni ti al scr eeni ng ev al uati on bef or e
thi s di agnosi s i s conf i dentl y assi gned. The r egul ati on of ar ter i al pr essur e
i nv ol v es a com pl ex , and as y et not f ul l y under stood, i nter acti on am ong
neur ohum or al m echani sm s, sodi um ex cr eti on, and bar or eceptor r ef l ex es.
Ther e i s ev i dence to suggest that the m echani sm r esponsi bl e f or the
el ev ati on of bl ood pr essur e i n essenti al hy per tensi on m ay i nv ol v e
i nher i ted abnor m al i ti es i n sodi um ex cr eti on. Thi s l i m i tati on i n the
P. 399
abi l i ty to ex cr ete sodi um m ay am pl i f y the m echani sm s that cause a r i se
i n ar ter i al pr essur e, ther eby pr oduci ng an abnor m al r esponse. These
m echani sm s i ncl ude (a) an i ncr em ent i n the ex tr acel l ul ar f l ui d v ol um e
and car di ac output, w i th secondar y autor egul ati on causi ng an i ncr em ent
i n per i pher al v ascul ar r esi stance; (b) an i ncr ease i n the v ascul ar
r esponse to v asoconstr i cti on and (c) an i ncr ease i n a putati v e ci r cul ati ng
N a + /K + adenosi ne tr i phosphatase i nhi bi tor , w hi ch el ev ates the
i ntr acel l ul ar sodi um and cal ci um l ev el s, ther eby al so augm enti ng
per i pher al v ascul ar r esi stance.
Table 912 Identifiable Causes of
Hypertension
Metabol i c sy ndr om e (obesi ty , i nsul i n r esi stance, i m pai r ed

gl ucose tol er ance, dy sl i pi dem i a, hy per tensi on)
Obstr ucti v e sl eep apnea
Dr ugi nduced hy per tensi on
Decongestants
Adr ener gi c agents
N SAIDs
Chr oni c k i dney di sease
Pr i m ar y hy per al doster oni sm
Renov ascul ar di sease
Chr oni c ster oi d use or Cushi ng's
Coar ctati on of the aor ta
Thy r oi d or par athy r oi d di sease
N SAIDs, nonster oi dal anti i nf l am m ator y dr ugs.
Modi f i ed f r om N ol an CR. The pati ent w i th hy per tensi on. In:
Schr i er RW, ed. Manual of nephr ol ogy , 6th ed. Phi l adel phi a:
Li ppi ncott Wi l l i am s & Wi l k i ns, 2005. Repr i nted w i th per m i ssi on.
The m ajor secondar y causes of hy per tensi on ar e l i sted i n Tabl e 912.
The ex act pr ev al ence of re na l a rte ry s te nos is i s not k now n, but i t
pr obabl y accounts f or appr ox i m atel y 5% of the gener al hy per tensi v e
popul ati on. It i s an i m por tant di agnosi s to m ak e because i t i s the m ost
com m on tr eatabl e f or m of secondar y hy per tensi on at any age, and i t i s
one of the f ew potenti al l y r ev er si bl e causes of chr oni c r enal f ai l ur e. The
di agnosi s m ust be consi der ed i n any pati ent w i th sev er e hy per tensi on
r ef r actor y to ther apy or i n any pati ent w ho ex per i ences the onset of
hy per tensi on ei ther w hen v er y y oung or v er y ol d. Ather oscl er oti c pl aques
on the r enal ar ter i es ar e the cause i n m ost cases, par ti cul ar l y i n pati ents
ol der than 50 y ear s. Fi br om uscul ar dy spl asi a, an enti ty seen i n y ounger
pati ents, par ti cul ar l y w om en, i s the second m ost com m on cause of
r enov ascul ar hy per tensi on. Ther e i s ev i dence to suggest that both r eni n
and v ol um edependent m echani sm s pl ay a r ol e i n the pathophy si ol ogy of
r enov ascul ar hy per tensi on i n hum ans. The f ol l ow i ng ev i dence suppor ts
the i nter pl ay of both m echani sm s: (a) the pl asm a r eni n acti v i ty i s usual l y
nor m al or hi gh i n pati ents w i th r enal ar ter y stenosi s, but nev er l ow ; (b)
ther e i s
P. 400
uni l ater al hy per secr eti on of r eni n f r om the af f ected k i dney w i th
contr al ater al suppr essi on; (c) i n pati ents w i th uni l ater al r enal ar ter y
stenosi s, r em ov al of the constr i cti on or tr eatm ent w i th an i nhi bi tor of the
r eni nâ€“angi otensi n sy stem usual l y r estor es the bl ood pr essur e to nor m al
or near nor m al v al ues; and (d) the ef f ect of angi otensi n bl ock ade and
sal t r estr i cti on on bl ood pr essur e i n pati ents w i th bi l ater al r enal ar ter y
stenosi s i s f r equentl y addi ti v e.
P rima ry hype ra ldos te ronis m i s an uncom m on cause of secondar y

hy per tensi on, w i th a pr ev al ence of appr ox i m atel y 1% i n the hy per tensi v e
popul ati on. Thi s di sease can occur at any age. The cl assi c f or m (Conn's
sy ndr om e) r esul ts f r om a uni l ater al adr enocor ti cal adenom a, and
accounts f or appr ox i m atel y hal f the cases of hy per al doster oni sm . The
other hal f of the pati ents hav e bi l ater al adr enal hy per pl asi a. A sm al l
per centage has ov er pr oducti on that can be suppr essed w i th
gl ucocor ti coi ds. As i n other f or m s of hy per tensi on, the ex act pathogenesi s
i s uncl ear . The f i ndi ngs f r om ear l y studi es suggested that the ex pected
sal t and w ater r etenti on secondar y to the al doster one ex cess r ai ses the
i ntr av ascul ar v ol um e and subsequentl y car di ac output, ther eby r ai si ng the
bl ood pr essur e. How ev er , hy per v ol em i a i s not a uni v er sal f i ndi ng i n
pati ents w i th pr i m ar y hy per al doster oni sm . The r esul ts of studi es i n
ani m al s hav e suggested that the m or e i m por tant m echani sm i s an
i ncr ease i n sodi um stor es and total per i pher al v ascul ar r esi stance. The
m echani sm r esponsi bl e f or thi s i s uncer tai n, but som e study f i ndi ngs
suggest that ex cess m i ner al ocor ti coi ds i nduce m em br ane changes i n
v ascul ar sm ooth m uscl e, l eadi ng to abnor m al cati on tur nov er (possi bl y
sodi um and cal ci um ), w hi ch, i n tur n, augm ents v asoconstr i cti on and
i ncr eases per i pher al v ascul ar r esi stance.
P he oc hromoc ytoma i s al so a r ar e cause of hy per tensi on. It i s esti m ated
to af f ect 0. 1% of pati ents w i th hy per tensi on. Pheochr om ocy tom a can
occur at any age, but i t ar i ses m ost f r equentl y i n the f our th and f i f th
decades. In adul ts, m ost pheochr om ocy tom as af f ect w om en.
Pheochr om ocy tom as ar e tum or s of neur oectoder m al or i gi n. If they go
undi agnosed, they car r y a hi gh r i sk of causi ng m or bi di ty and m or tal i ty
secondar y to hy per tensi v e cr i si s, shock , ar r hy thm i as, car di ac ar r est, and
str ok e. The hy per tensi on of pheochr om ocy tom a i s a f uncti on of the
nor epi nephr i ne r el eased i nto the sy napti c cl ef t. Ci r cul ati ng l ev el s of
nor epi nephr i ne hav e l i ttl e di r ect i nv ol v em ent i n the cause or m ai ntenance
of the hy per tensi on.
Hy per tensi on com pl i cates both a c ute a nd c hronic re na l pa re nc hyma l
dis e a s e s , and af f ects appr ox i m atel y 80% to 90% of pati ents on di al y si s.
Ther e ar e sev er al m echani sm s that m ay be i nv ol v ed i n pr oduci ng the
hy per tensi on i n thi s setti ng, and these i ncl ude (a) a m ar k edl y i m pai r ed
abi l i ty of the di seased k i dney to ex cr ete sal t and w ater ; (b) the
pr oducti on of an uni denti f i ed v asopr essor substance by the k i dney ; (c)
absent pr oducti on of a necessar y hum or al v asodi l ator substance by the
k i dney ; (d) f ai l ur e of the k i dney s to i nacti v ate ci r cul ati ng v asopr essor
substances; and (e) acti v ati on of the r eni nâ€“angi otensi n sy stem .
The bl ood pr essur e i n the upper ex tr em i ti es i s el ev ated i n 80% of

chi l dr en and adul ts w i th c oa rc ta tion of the a orta . The m echani sm
r esponsi bl e f or thi s
P. 401
hy per tensi on i s an i nappr opr i ate acti v ati on of the r eni nâ€“angi otensi n
sy stem i n the pr esence of an ex panded body f l ui d v ol um e.
Hy per tensi on af f ects 80% of pati ents w i th i di opathi c Cus hing's
s yndrome . Other cl i ni cal f eatur es of the di sor der i ncl ude gl ucose
i ntol er ance, m enstr ual di sor der s, ster i l i ty , l oss of l i bi do, acne, str i ae,
osteopor osi s, m uscl e w eak ness and w asti ng, edem a, pol y ur i a, and r enal
stones. How ev er , the m echani sm w her eby adr enocor ti cotr opi c hor m one
and cor ti sol r ai se bl ood pr essur e i n hum ans has not been el uci dated,
al though ther e i s ev i dence to suggest that gl ucocor ti coi ds possess a â
€œhy per tensi nogeni câ€ acti on that i s separ ate f r om thei r gl ucocor ti coi d
acti v i ty .
In the setti ng of re ninproduc ing tumors , hy per tensi on r esul ts f r om the
ex cess secr eti on of r eni n by ei ther a jux tagl om er ul ar cel l tum or or
nephr obl astom a. Thi s causes the per i pher al r eni n l ev el s to be el ev ated,
w hi ch m edi ates the hy per tensi on.
2. What shoul d the i ni ti al ev al uati on of a pati ent w ho pr esents w i th an
el ev ati on i n bl ood pr essur e consi st of , and, based on the ev al uati on
f i ndi ngs, w hat speci f i c cl i ni cal f eatur es w oul d poi nt tow ar d a par ti cul ar
secondar y cause of hy per tensi on?
The i ni ti al ev al uati on of pati ents w i th hy per tensi on shoul d i ncl ude hi stor y
tak i ng, phy si cal ex am i nati on, and l abor ator y tests di r ected tow ar d
uncov er i ng a cor r ectabl e f or m of secondar y hy per tensi on.
In ter m s of the his tory, a str ong f am i l y hi stor y , as w el l as past
obser v ati ons of i nter m i ttent bl ood pr essur e el ev ati ons, suggest essenti al
hy per tensi on. Secondar y hy per tensi on of ten dev el ops ei ther bef or e 30 or
af ter 55 y ear s of age. Other per ti nent gener al questi ons shoul d el i ci t
i nf or m ati on about ster oi d use, use of dr ugs, i ncl udi ng or al contr acepti v es,
and w hether ther e hav e been r ecur r ent ur i nar y tr act i nf ecti ons or a
hi stor y of pr otei nur i a, noctur i a, tr aum a, or w ei ght gai n or l oss.
P hys ic a l e x a mina tion shoul d di v ul ge f ur ther di agnosti c cl ues as to the
possi bl e cause of the hy per tensi on. The ex am i nati on shoul d f ocus on the
pati ent's gener al appear ance, m uscul ar dev el opm ent, bl ood pr essur e and
pul ses i n both upper ex tr em i ti es and a l ow er ex tr em i ty , the supi ne and
standi ng bl ood pr essur e, f unduscopy , pal pati on and auscul tati on of the
car oti d ar ter i es, car di ac and pul m onar y ex am i nati on, auscul tati on of the
abdom en f or br ui ts and pal pati on f or an abdom i nal aneur y sm and
enl ar ged k i dney s, and ex am i nati on of the l ow er ex tr em i ti es f or edem a.
La bora tory e va lua tion at the i ni ti al w or k up shoul d i ncl ude ur i nal y si s f or
the pr esence of pr otei n, bl ood, and gl ucose, together w i th a m i cr oscopi c
ex am i nati on; the ser um cr eati ni ne and BU N l ev el s; hem atocr i t; the ser um
potassi um l ev el ; the w hi te bl ood cel l count; the ser um gl ucose,
chol ester ol , tr i gl y cer i de, cal ci um , phosphate, and ur i c aci d l ev el s;
el ectr ocar di ogr aphy ; and a chest r adi ogr aphi c study .
The cl i ni cal f eatur es that suggest r enal v ascul ar hy per tensi on ar e l i sted
i n Tabl e 913. The cl i ni cal f eatur es suggesti ng other secondar y causes of
hy per tensi on ar e l i sted i n Tabl e 914.
P. 402
Table 913 Clinical Features Suggestive of
Renal Vascular Hypertension
Epi dem i ol ogi c f eatur es

Hy per tensi on i n the absence of f am i l y hi stor y
Age < 25 y or > 55 y
Ci gar ette sm ok i ng
Whi te r ace
Featur es of the hy per tensi on
Abr upt onset of m oder ate to sev er e hy per tensi on
Sudden onset of hy per tensi on af ter abdom i nal tr aum a
Recent accel er ati on of sev er i ty of hy per tensi on
Headaches
Resi stance or f ai l ur e of bl ood pr essur e contr ol w i th
usual ther apy
Dev el opm ent of sev er e or m al i gnant hy per tensi on
Reti nopathy out of pr opor ti on to sev er i ty of bl ood
pr essur e
Ex cel l ent anti hy per tensi v e r esponse to angi otensi n
conv er ti ng enzy m e i nhi bi tor
Deter i or ati on i n r enal f uncti on i n r esponse to
angi otensi nconv er ti ng enzy m e i nhi bi tor
Bl ood pr essur e unaf f ected or i ncr eased w i th di ur eti c
ther apy
Associ ated f eatur es
U npr ov ok ed hy pok al em i a
Hy pok al em i a i n r esponse to a thi azi de di ur eti c
Abdom i nal or f l ank sy stol i cdi astol i c br ui ts
Car oti d br ui ts or other ev i dence of l ar gev essel
di sease
El ev ated per i pher al pl asm a r eni n acti v i ty i n absence of
al ter nati v e ex pl anati on
Modi f i ed f r om Pl oth DW. Renov ascul ar hy per tensi on. In:
Jacobson HR, Str i k er GE, Kl ahr S, eds. The pr i nci pl es and
pr acti ce of nephr ol ogy . Phi l adel phi a: BC Deck er , 1991:379.
3. If a secondar y cause of hy per tensi on i s suspected, w hat w oul d the f ur ther
di agnosti c ev al uati on com pr i se, and w hat w oul d be the l i k el y f i ndi ngs f or
each cause?
A num ber of tests hav e ev ol v ed to assess the l i k el i hood of re na l

va s c ula r hype rte ns ion. Magneti c r esonance angi ogr aphy (MRA) or
Doppl er ul tr asonogr aphy of the r enal ar ter i es hav e been used f or the
ev al uati on of r enal ar ter y stenosi s. How ev er , these tests hav e v ar i abl e
degr ees of sensi ti v i ty and speci f i ci ty , l ar gel y due to v ar y i ng degr ees of
ex per ti se w i th these techni ques at di f f er ent center s. Ther ef or e,
conv enti onal r enal ar ter i ogr aphy r em ai ns the gol d standar d. It m ust be
r ecogni zed, how ev er , that the f i ndi ng of r enal ar ter y stenosi s pr ov i des no
i nf or m ati on concer ni ng the pathophy si ol ogy of the v ascul ar l esi on. A
postcaptopr i l (25 m g) el ev ati on i n pl asm a r eni n acti v i ty or a decr ease i n
r enal per f usi on postcaptopr i l as assessed by sci nti l l ati on techni ques or
r enal v ei n r eni ns can pr ov i de pathophy si ol ogi c i nf or m ati on.
If ther e ar e cl i ni cal f eatur es hi ghl y suggesti v e of a phe oc hromoc ytoma ,

the ev al uati on shoul d begi n w i th an assay of the total pl asm a
catechol am i ne l ev el , as m easur ed thr ough an i ndw el l i ng 21gauge
butter f l y needl e i n a pati ent w ho has been r esti ng supi ne f or 30 m i nutes.
Val ues m or e than 2, 000 pg/m L w ar r ant per f or m ance of abdom i nal
com puted tom ogr aphy (CT).
P. 403
P. 404
Val ues betw een 1, 000 and 2, 000 pg/m L r equi r e per f or m ance of the
cl oni di ne suppr essi on test to deter m i ne w hether a pheochr om ocy tom a i s
pr esent. Cl oni di ne does not suppr ess the r el ease of catechol am i nes i n
pati ents w i th a pheochr om ocy tom a, as i t does i n pati ents w i th essenti al
hy per tensi on. If the pl asm a catechol am i ne v al ues ar e bel ow 1, 000 pg/m L,
and the pati ent i s hy per tensi v e, the cl oni di ne suppr essi on test shoul d be
per f or m ed, but, i f the pati ent i s nor m otensi v e, the gl ucagon sti m ul ati on
test m ay be hel pf ul . For the gl ucagon test to be posi ti v e, the pl asm a
catechol am i ne l ev el m ust i ncr ease by thr eef ol d, or to gr eater than 2, 000
pg/m L, 1 to 3 m i nutes af ter adm i ni str ati on of the dr ug. If any of these
test r esul ts ar e posi ti v e, abdom i nal CT shoul d be per f or m ed. In pati ents
w hose cl i ni cal pr esentati on suggests a pheochr om ocy tom a but w ho hav e
onl y a sl i ght or m oder ate r i se i n the catechol am i ne l ev el (< 1, 000 pg/m L),
r epeat testi ng, i ncl udi ng m easur em ent of the ur i nar y catechol am i ne
l ev el s, shoul d be per f or m ed.
Table 914 Clinical Features of Other
Secondary Causes of Hypertension
Pr i m ar y hy per al doster oni sm

Hi stor y
Pr ox i m al m uscl e w eak ness, pol y ur i a, noctur i a,
pol y di psi a, par esthesi a, tetany , m uscl e par al y si s,
f r ontal headaches
Labor ator y f eatur es
The di agnosti c hal l m ar k of thi s di sease i s
hy pok al em i c m etabol i c al k al osi s
Hy per gl y cem i a m ay al so be pr esent
Sy m ptom s
Pati ents m ay pr esent i n a w i de v ar i ety of cl i ni cal
setti ngs, i ncl udi ng tr ansi ent i schem i c attack s,
str ok e, headache (usual l y poundi ng and sev er e),
pal pi tati ons w i th or w i thout tachy car di a, and
ex cessi v e sw eati ng; l ess com m on sy m ptom s
i ncl ude tr em or , pal l or , nausea, w eak ness,
f ati gue, w ei ght l oss, and chest or abdom i nal pai n
Phy si cal ex am i nati on
Postur al hy potensi on occur s i n 50%75% of
pati ents; par ox y sm al epi sodes of hy per tensi on
occur i n appr ox i m atel y one thi r d of pati ents;
sw eati ng and m uscul ar w eak ness m ay be ev i dent
Hy per gl y cem i a or hy per cal cem i a m ay be pr esent
Coar ctati on of the aor ta
Sy m ptom s
Epi stax i s, thr obbi ng headache, l eg f ati gue, col d
ex tr em i ti es, and occasi onal cl audi cati on
Di spar i ty i n the pul sati ons and bl ood pr essur e
betw een the ar m s and l egsâ€”the pul sati ons i n
the upper ex tr em i ti es ar e poundi ng; those i n the
l ow er ex tr em i ti es ar e w eak , del ay ed, or absent;
the bl ood pr essur e i n the ar m s ex ceeds that i n
the l egs; ther e i s col l ater al ar ter i al ci r cul ati on;
m ur m ur s ar e usual l y pr esent but v ar y i n l ocati on
Chest r adi ogr aph m ay show pr om i nence of the
l ef t v entr i cl e, notchi ng of the i nf er i or bor der of
the r i bs f r om col l ater al v essel s, and poststenoti c
di l atati on of the aor ta
Cushi ng's sy ndr om e
Sy m ptom s
Menstr ual di sor der s, l oss of l i bi do, hi r suti sm ,
acne, str i ae, m uscl e w eak ness, easy br ui si ng,
edem a, pol y ur i a
Hi r suti sm , acne, str i ae, m uscl e w eak ness and
w asti ng, pur pur a, br ui si ng, edem a, and poor
w ound heal i ng
Hy per gl y cem i a, i m pai r ed gl ucose tol er ance,
neutr ophi l i a, l y m phopeni a, and hy pok al em i a
Renal par enchy m al di sease
Sy m ptom s
U r em i a and anem i a; associ ated w i th r enal f ai l ur e
If any f i ndi ngs, those associ ated w i th r enal
f ai l ur e
Sev er al l abor ator y abnor m al i ti es m ay be
pr esentâ€”these i ncl ude el ev ati on of the BU N and
cr eati ni ne l ev el s, anem i a, hy pocal cem i a,
hy per phosphatem i a, hy per k al em i a, m etabol i c
aci dosi s, pr otei nur i a, and hem atur i a
BU N , bl ood ur ea ni tr ogen.
Echocar di ogr aphy can v i sual i ze the ar ea of a ortic c oa rc ta tion, but thi s i s
best conf i r m ed by car di ac catheter i zati on.
Hi stor i cal l y , Cus hing's s yndrome has been di agnosed on the basi s of the
f ol l ow i ng f i ndi ngs: el ev ated l ev el s of ur i nar y 17hy dr ox y cor ti coster oi ds
and ur i nar y f r ee cor ti sol , l oss of di ur nal r hy thm i n the pl asm a cor ti sol
concentr ati ons, and f ai l ur e of pl asm a cor ti sol l ev el s to suppr ess ov er ni ght
af ter a si ngl e 1m g dose of dex am ethasone. Because the ov er ni ght
dex am ethasone suppr essi on test m ay not el i ci t suppr essi on i n obese and
acr om egal i c pati ents, the l ow dose dex am ethasone suppr essi on test (0. 5
m g ev er y 6 hour s f or 2 day s) shoul d be done to di sti ngui sh pati ents w i th
Cushi ng's sy ndr om e f r om heal thy subjects. The hi ghdose dex am ethasone
suppr essi on test (2 m g ev er y 6 hour s f or 2 day s) can di sti ngui sh
Cushi ng's di sease f r om an adr enal tum or , w hi ch does not suppr ess.
If the cause of re na l pa re nc hyma l dis e a s e cannot be i denti f i ed w i th

cer tai nty on the basi s of the hi stor y , phy si cal ex am i nati on, and
l abor ator y f i ndi ngs, r enal bi opsy m ay be i ndi cated. The bi opsy r esul ts
m ay shed l i ght on w hether the pr ocess i s r ev er si bl e, and ther eby poi nt
tow ar d tr eatm ent opti ons, i f any .
P. 405
In the setti ng of re ninproduc ing tumors , deter m i nati on of the pl asm a
r eni n acti v i ty by r enal v ei n sam pl i ng usual l y show s a uni l ater al i ncr ease
i n the absence of a r enal ar ter y l esi on.
4. What ar e the r especti v e tr eatm ent opti ons f or r enal ar ter y stenosi s,
pheochr om ocy tom a, Cushi ng's sy ndr om e, and pr i m ar y
hy per al doster oni sm ?
The tr eatm ent opti ons f or re na l a rte ry s te nos is ar e ei ther sur gi cal or
m edi cal , and the choi ce depends on the pati ent i nv ol v ed. The sur gi cal
opti ons i ncl ude r ev ascul ar i zati on of the af f ected k i dney usi ng saphenous
v ei n, autogenous ar ter y , or sy ntheti c (Dacr on or pol y tetr af l uor oethy l ene)
gr af ts. A r enal ar ter y endar ter ectom y m ay be per f or m ed i n pati ents w i th
osti al ather om atous l esi ons. The m ost popul ar m ethod of tr eatm ent, at
l east i ni ti al l y , i s per cutaneous tr ansl um i nal bal l oon angi opl asty w i th
pl acem ent of stents. If these pr ocedur es ar e ei ther unsuccessf ul or
cannot be under tak en, m edi cal m anagem ent m ust be i nsti tuted.
Cur e of a phe oc hromoc ytoma consi sts of sur gi cal r em ov al of the tum or ,
and pr oper pr eoper ati v e pr epar ati on hel ps r educe the attendant m or bi di ty
and m or tal i ty . In the pr esence of hy per tensi on, adm i ni str ati on of an
adr ener gi cbl ock i ng agent such as phenox y benzam i ne (10 to 20 m g tw i ce
per day , i ncr easi ng to 100 m g per day i f tol er ated) i s r ecom m ended.
Pr azosi n i s not as ef f ecti v e. How ev er , i f the l ocati on of the tum or i s i n
doubt or i f m ul ti pl e tum or s ar e suspected, i t i s best not to adm i ni ster Î±
adr ener gi c bl ock i ng agents bef or e sur ger y . The i ntr av ascul ar v ol um e
shoul d be ex panded both bef or e and af ter sur ger y . In pati ents w i th
i noper abl e m al i gnant pheochr om ocy tom as, dr ug ther apy i s needed. Î±
and Î²Bl ock er s m ay be used to contr ol ar r hy thm i as, or m ethy l ty r osi ne
m ay be pr escr i bed to i nhi bi t catechol am i ne sy nthesi s.
The best sur gi cal appr oach i n a pati ent w i th Cushi ng's di sease i s sel ected
ex ci si on of the pituita ry a de noma thr ough a tr anssphenoi dal appr oach.
Sur gi cal r em ov al i s som eti m es f ol l ow ed by pi tui tar y i r r adi ati on to pr ev ent
r ecur r ence. A v ar i ety of dr ugs hav e al so been used to tr eat pati ents w i th
Cushi ng's di sease. Adr enal tum or s ar e best tr eated sur gi cal l y .
Hy per al doster oni sm can be tr eated by ei ther m edi cal or sur gi cal m eans.
Mi l d al doster one ex cess due to an adenom a, and al l cases of bi l ater al
hy per pl asi a, shoul d be m anaged w i th al doster one antagoni sts such as
spi r onol actone because thi s di sor der i s not am enabl e to sur gi cal
tr eatm ent. Al doster onepr oduci ng adenom as can be r em ov ed to ef f ect
cur e once they hav e been appr opr i atel y l ocal i zed by r adi ol ogi c (CT)
techni ques.
Case
A 38y ear ol d adopted w hi te m an i s seen by hi s f am i l y phy si ci an f or the
m anagem ent of hy per tensi on of 2 y ear s' dur ati on. Cur r ent m edi cati ons i ncl ude
am i l or i de (5 m g) and hy dr ochl or othi azi de (50 m g), w i th good bl ood pr essur e
contr ol unti l now . Rev i ew of sy stem s r ev eal s i ncr easi ng f ati gue, headaches,
and m uscl e cr am ps. Phy si cal ex am i nati on r ev eal s a bl ood pr essur e of 140/100
m m Hg i n the l ef t ar m and 136/100 m m Hg i n the r i ght ar m . N o di spar i ty i n
the bl ood pr essur e betw een the ar m s and the l egs i s f ound. The r em ai nder of
the ex am i nati on f i ndi ngs ar e other w i se unr em ar k abl e.
P. 406
The f ol l ow i ng l abor ator y data ar e r epor ted: sodi um , 145 m Eq/L; potassi um ,
2. 7 m Eq/L; chl or i de, 109 m Eq/L; bi car bonate, 29 m Eq/L; BU N , 10 m Eq/L;
cr eati ni ne, 1. 2 m g/dL; cal ci um , 9. 1 m g/dL; chol ester ol , 213 m g/dL;
tr i gl y cer i des, 163 m g/dL; ur i c aci d, 6. 1 m g/dL; phosphate, 2. 1 m g/dL; and
gl ucose, 99 m g/dL. Resul ts of ur i nal y si s, i ncl udi ng m i cr oscopi c ex am i nati on,
ar e nor m al .
The di ur eti cs ar e stopped and the pati ent i s pl aced on potassi um suppl em ents.
Repeat l abor ator y w or k r ev eal s that hi s sodi um l ev el i s 147 m Eq/L, potassi um
l ev el i s 3 m Eq/L, and bl ood pr essur e i s 146/104 m m Hg.
1. What i s the di f f er enti al di agnosi s of thi s pati ent's hy per tensi on?
2. What sy m ptom s ar e r el ated to the pati ent's hy pok al em i a?
3. What di agnosti c steps w oul d hel p conf i r m the di agnosi s i n thi s pati ent?
4. What ar e the tr eatm ent opti ons i n thi s pati ent?
Case Discussion
1. What i s the di f f er enti al di agnosi s of thi s pati ent's hy per tensi on?
The di f f er enti al di agnosi s i ncl udes essenti al hy per tensi on, pr i m ar y

hy per al doster oni sm , pheochr om ocy tom a, Cushi ng's sy ndr om e, a r eni n
pr oduci ng tum or , and r enal ar ter y stenosi s. Renal par enchy m al di sease
and coar ctati on of the aor ta can be l ar gel y ex cl uded as a cause of thi s
pati ent's hy per tensi on because the ser um cr eati ni ne l ev el and ur i nal y si s
f i ndi ngs ar e nor m al , as ar e the phy si cal ex am i nati on f i ndi ngs. The
str i k i ng f eatur e of thi s pati ent's hy per tensi on i s the hy pok al em i a despi te
tr eatm ent w i th a potassi um spar i ng di ur eti c pl us potassi um
suppl em entati on. Hy pok al em i a m ay be a f eatur e of pr i m ar y
hy per al doster oni sm , Cushi ng's sy ndr om e, r enal ar ter y stenosi s, and
r eni npr oduci ng tum or s. Pheochr om ocy tom a i s consi der ed a possi bi l i ty
because of the pati ent's com pl ai nts of headache and f ati gue, al though the
cl i ni cal suspi ci on f or thi s i s l ow . Al though hy pok al em i a occur s i n
Cushi ng's sy ndr om e, the other cl i ni cal f eatur es of the di sor der appear to
be l ack i ng. Renal ar ter y stenosi s i s al so unl i k el y unl ess the pati ent has
f i br om uscul ar dy spl asi a. Because the pati ent's f am i l y hi stor y i s unk now n,
hi s geneti c pr opensi ty f or ather oscl er osi s i s not k now n, but he does not
appear to hav e other ev i dence of ar ter i oscl er oti c di sease (e. g. , br ui ts,
angi na, and cl audi cati on). Ther ef or e, the m ost l i k el y causes i ncl ude
pr i m ar y al doster oni sm and a r eni npr oduci ng tum or . Essenti al
hy per tensi on can be di agnosed onl y af ter the m ost l i k el y secondar y
causes hav e been ex cl uded.
2. What sy m ptom s ar e r el ated to the pati ent's hy pok al em i a?
Hy pok al em i a coul d ex pl ai n thi s pati ent's headaches, m uscl e cr am ps, and

f ati gue. Addi ti onal sy m ptom s m ay i ncl ude m uscl e w eak ness, pol y ur i a, and
par esthesi as.
3. What di agnosti c steps w oul d hel p conf i r m the di agnosi s i n thi s pati ent?
Pati ents w i th a hi stor y of spontaneous hy pok al em i a, m ar k ed sensi ti v i ty to

potassi um w asti ng di ur eti cs, and r ef r actor y hy per tensi on shoul d be
ev al uated f or pr i m ar y hy per al doster oni sm . The i ni ti al scr eeni ng test i s to
deter m i ne the status of al doster one ex cr eti on dur i ng pr ol onged sal t
l oadi ng. To per f or m thi s, 10 to 12 g of N aCl i s added to the pati ent's
dai l y i ntak e. Af ter 5 to 7 day s of i ncr eased sal t i ntak e, the ser um
potassi um concentr ati ons and a 24hour ur i ne ex cr eti on of
P. 407
sodi um , potassi um , and al doster one ar e m easur ed. The ser um and ur i ne
potassi um v al ues i ndi cate w hether ther e i s i nappr opr i ate k al i ur esi s (a
ser um potassi um l ev el of < 3 m Eq/L w i th a ur i ne potassi um l ev el > 30
m Eq/24 hour s). The 24hour ur i ne sodi um l ev el v er i f i es com pl i ance w i th
the pr escr i bed sal t i ntak e (â‰￥250 m Eq per day ). If , under these
condi ti ons, the pati ent's r ate of al doster one ex cr eti on f ai l s to show
suppr essi on bel ow 14 Âµg per 24 hour s, thi s m ak es hi m a pr i m e
candi date f or addi ti onal studi es. The pr esence of hy pok al em i a and
suppr essed pl asm a r eni n acti v i ty f ur ther suppor ts the di agnosi s of
pr i m ar y hy per al doster oni sm . Thi s can be f ur ther conf i r m ed by hi gh
al doster one/r eni n r ati o of gr eater than 100. If a r eni npr oduci ng tum or
w er e the cause of thi s pati ent's hy per tensi on, the pl asm a r eni n acti v i ty
w oul d be el ev ated. If pr i m ar y hy per al doster oni sm i s suspected, adr enal
CT scanni ng shoul d be per f or m ed. The f i ndi ng of an adr enal m ass w oul d
establ i sh the di agnosi s. Adr enal sci nti gr aphy shoul d be done i f the CT
f i ndi ngs ar e i nconcl usi v e. If the r esul ts of sci nti gr aphy ar e al so
am bi guous, then adr enal v ei n sam pl i ng shoul d be per f or m ed to m easur e
the al doster one l ev el s. Adr enal v ei n sam pl i ng i s sti l l the m ost accur ate
test to l ocal i ze al doster onepr oduci ng tum or s.
4. What ar e the tr eatm ent opti ons i n thi s pati ent?
The hy per tensi on associ ated w i th pr i m ar y hy per al doster oni sm can be
m anaged adequatel y i n m ost cases by m eans of sal t and w ater depl eti on.
The com bi nati on of spi r onol actone w i th hy dr ochl or othi azi de or f ur osem i de
has been used successf ul l y . How ev er , i f the adr enal adenom a i s conf i ned
to one gl and and ther e ar e no contr ai ndi cati ons, the tum or shoul d be
r em ov ed. Onl y appr ox i m atel y hal f of pati ents ar e nor m otensi v e 5 y ear s
af ter sur ger y , but nor m al potassi um hom eostasi s i s r estor ed
per m anentl y . If pr i m ar y hy per al doster oni sm stem s f r om bi l ater al
hy per pl asi a of the adr enal gl and, thi s i s best m anaged m edi cal l y because
sur gi cal r em ov al of too m uch of the adr enal gl and can r esul t i n adr enal
Suggested Readings
N ol an CR. The pati ent w i th hy per tensi on. In: Schr i er RW, ed. Manual of
nephr ol ogy , 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2005:242.
Tex tor SC. Renov ascul ar hy per tensi on. In: Johnson R, Feehal l y J, eds.
Com pr ehensi v e cl i ni cal nephr ol ogy , 2nd ed. Mosby , 2003.
Nephrolithiasis
1. What ar e the f our m ajor ty pes of k i dney stones, and w hi ch ar e
r adi opaque?
2. What i s the shar ed pathogenesi s f or the f or m ati on of al l ty pes of k i dney
stones?
3. What ar e the f undam ental causes of ov er satur ati on of the ur i ne?
4. What ar e the acute and chr oni c sequel ae of k i dney stones?
5. In the setti ng of ur i c aci d k i dney stones, i s the ov er satur ati on of ur i ne
w i th ur i c aci d condi ti oned pr i m ar i l y by the ur i ne pH or by the am ount of
ur i c aci d ex cr eted?
P. 408
6. What ar e the thr ee ty pes of k i dney stones that m ay pr esent i n the f or m
of staghor n cal cul i , and w hat ar e the r especti v e m echani sm s r esponsi bl e
f or thei r f or m ati on?
7. What ar e the pr i nci pal causes of cal ci um stones?
8. What ar e the r outi ne outpati ent studi es that shoul d be per f or m ed i n
pati ents w i th r ecur r ent stones?
9. What i s the i ndi cati on f or m easur i ng the ex cr eti on of ur i c aci d i n the
setti ng of hy per cal ci ur i a?
10. What ar e the potenti al causes of hy per cal ci ur i a and how shoul d i t be
tr eated?
Discussion
1. What ar e the f our m ajor ty pes of k i dney stones, and w hi ch ar e
r adi opaque?
The pr i nci pal ty pes of k i dney stones ar e com posed of cal ci um sal ts, ur i c
aci d, cy sti ne, and str uv i te. Al l ex cept ur i c aci d stones ar e r adi opaque.
Cal ci um contai ni ng stones account f or 80% of al l stones, 15% ar e
com posed of str uv i te, 5% ar e m ade up of ur i c aci d, and cy sti ne stones
ar e v er y r ar e.
2. What i s the shar ed pathogenesi s f or the f or m ati on of al l ty pes of k i dney
stones?
Al l k i dney stones r esul t f r om an ex cessi v e super satur ati on of the ur i ne.
The i on concentr ati on pr oduct at w hi ch sal ts i n sol uti on ar e i n equi l i br i um
w i th thei r sol i d phase i s cal l ed the equi l i br i um sol ubi l i ty pr oduct. In the
absence of a sol i d phase, sal ts m ay ex i st i n a super satur ated state,
abov e the equi l i br i um sol ubi l i ty pr oduct. In thi s setti ng, cr y stal s
com posed of other com pounds m ay act as heter ogeneous seed nucl ei that
f oster the f or m ati on of stones. If the i on pr oduct i s suf f i ci entl y hi gh, then
new cr y stal s f or m . Because an i ncr ease i n ur i ne v ol um e l eads to a
decr ease i n the concentr ati on of al l sol utes i n the ur i ne, an i ncr eased
f l ui d i ntak e of 2. 5 to 3 L per day i s par t of the tr eatm ent f or al l k i dney
stones.
3. What ar e the f undam ental causes of ov er satur ati on of the ur i ne?
Ther e ar e thr ee m ajor r easons f or the ov er satur ati on of ur i ne: (a)
hy per ex cr eti on of a substance that i s r el ati v el y i nsol ubl e i n ur i ne, (b) l ow
ur i ne v ol um e, and (c) an abnor m al ur i ne pH. Ci tr ate i s a natur al l y
occur r i ng i nhi bi tor of stone f or m ati on. Ther ef or e, l ow ur i nar y ci tr ate
ex cr eti on has al so been i m pl i cated as an i ndependent cause of cal ci um
stone f or m ati on.
4. What ar e the acute and chr oni c sequel ae of k i dney stones?
The acute consequences of k i dney stones ar e ur i nar y tr act obstr ucti on,
i nf ecti on, hem atur i a, pai n, and, uncom m onl y , acute r enal f ai l ur e. Chr oni c
consequences of nephr ol i thi asi s ar e i nf ecti on, RTA, and chr oni c r enal
5. In the setti ng of ur i c aci d k i dney stones, i s the ov er satur ati on of ur i ne
w i th ur i c aci d condi ti oned pr i m ar i l y by the ur i ne pH or by the am ount of
ur i c aci d ex cr eted?
Because m onosodi um ur ate i s m or e sol ubl e than ur i c aci d, ur ate stones

ar e r ar e. Ther e i s a si gni f i cant r i sk f or such stones onl y w hen the ur i nar y
f or m i s m ai nl y ur i c aci d. U r i c aci d i s a w eak aci d that has one pr oton that
i s di ssoci abl e under phy si ol ogi c condi ti ons w i th a pK (the negati v e
l ogar i thm of the i oni zati on constant of an aci d) of 5. 3. Ther ef or e, ur ate
m ay ex i st i n ur i ne as
P. 409
ei ther m onosodi um ur ate or as ur i c aci d. The concentr ati on r ati os of
these tw o f or m s i s a f uncti on of the am bi ent pH. A change i n the ur i nar y
pH f r om 5 to 6. 5 al ter s the undi ssoci ated aci d concentr ati on ei ghtf ol d,
w her eas the ur i nar y ex cr eti on of ur i c aci d can i ncr ease onl y up to
thr eef ol d. Ther ef or e, changes i n the ur i ne pH pl ay a gr eater r ol e i n ur i c
aci d stone f or m ati on than do changes i n the am ount of ur i c aci d ex cr eted.
6. What ar e the thr ee ty pes of k i dney stones that m ay pr esent i n the f or m
of staghor n cal cul i , and w hat ar e the r especti v e m echani sm s r esponsi bl e
f or thei r f or m ati on?
U r i c aci d, cy sti ne, and str uv i te k i dney stones m ay f or m i n the r enal
col l ecti ng sy stem and assum e a staghor n conf i gur ati on.
Str uv i te k i dney stones, w hi ch ar e the m ost com m on staghor n cal cul i , ar e
a consequence of i nf ecti on of the ur i nar y tr act w i th bacter i a, usual l y
Pr oteus speci es, w hi ch contai n ur ease. Thi s causes ur ea to be br ok en
dow n to 2N H 3 + H 2 O + CO 2 . Am m oni a r eacts w i th a pr oton, f or m i ng
am m oni um . Thi s r eacti on r ai ses the ur i ne pH, r esul ti ng i n an i ncr eased
concentr ati on of phosphate i ons. These condi ti ons spaw n the f or m ati on of
str uv i te (MgN H 4 PO 4 Â· 6H 2 O), and m ay al so l ead to the f or m ati on of
car bonate apati te (Ca 1 0 [PO 4 ] 6 Â· CO 3 ) cr y stal s; ther ef or e, str uv i te stones
m ay contai n v ar i abl e pr opor ti ons of car bonate apati te and str uv i te.
Cy sti ne stones ar e a m ani f estati on of cy sti nur i a, a r ar e her edi tar y
di sor der that i s char acter i zed by def ects i n di basi c am i no aci d tr anspor t.
N or m al l y , am i no aci ds ar e al m ost com pl etel y r eabsor bed by the pr ox i m al
tubul e. The ur i nar y ex cr eti on of cy sti ne i s abnor m al l y hi gh i n peopl e w i th
cy sti ne stones, how ev er , and thi s pr edi sposes them to the f or m ati on of
cy sti ne stones. The ur i ne pH has l i ttl e ef f ect on the sol ubi l i ty of cy sti ne.
The m echani sm r esponsi bl e f or the f or m ati on of ur i c aci d stones i s
di scussed i n the pr ecedi ng questi on.
7. What ar e the pr i nci pal causes of cal ci um stones?
Ther e ar e num er ous speci f i c causes of cal ci um k i dney stones, but the
m ajor causes can be gr ouped i nto the f ol l ow i ng categor i es: l ow ur i nar y
v ol um e, hy per cal ci ur i a, hy per ox al ur i a, hy per ur i cosur i a, and al k al i ne
ur i ne. Hy poci tr atur i a m ay al so be an i ndependent cause of cal ci um stone
f or m ati on, al though a l ow ur i nar y ex cr eti on of ci tr ate m ay actual l y be a
consequence of an al k al i ne ur i ne.
8. What ar e the r outi ne outpati ent studi es that shoul d be per f or m ed i n
pati ents w i th r ecur r ent stones?
The ur i ne pH and v ol um e shoul d be assessed, and the 24hour ur i nar y
ex cr eti on of sodi um , cal ci um , ur i c aci d, ci tr ate, ox al ate, phosphate, and
cr eati ni ne shoul d be deter m i ned.
9. What i s the i ndi cati on f or m easur i ng the ex cr eti on of ur i c aci d i n the
setti ng of hy per cal ci ur i a?
In the setti ng of hy per cal ci ur i a, ur i c aci d cr y stal s m ay act as seed
cr y stal s that i ni ti ate the pr eci pi tati on of cal ci um ox al ate f r om the ur i ne.
If pati ents ar e f ound to be hy per ur i cosur i c, al l opur i nol tr eatm ent m i ght
be w ar r anted.
10. What ar e the potenti al causes of hy per cal ci ur i a and how shoul d i t be
tr eated?
Most com m onl y , hy per cal ci ur i a i s i di opathi c i n or i gi n. Bef or e m ak i ng such

a di agnosi s, how ev er , other causes of hy per cal ci ur i a (i . e. , sar coi dosi s,
P. 410
i m m obi l i zati on, v i tam i n D ex cess, hy per thy r oi di sm , Paget's di sease, and
m al i gnant tum or s w i th m etastasi s) need to be ex cl uded (Tabl e 915). The
pr i m ar y appr oach to tr eatm ent i nv ol v es the attenti on to the under l y i ng
di sor der w hen i denti f i ed. For pati ents w i th i di opathi c hy per cal ci ur i a,
tr eatm ent i s di r ected at l ow er i ng ur i nar y cal ci um ex cr eti on. Thi s i s best
achi ev ed w i th thi azi de di ur eti cs, acti ng on the di stal tubul e. Thi s
appr oach needs to be coupl ed w i th a decr ease i n sodi um i ntak e, w hi ch
w i l l enhance pr ox i m al cal ci um r eabsor pti on.
Table 915 Causes of Hypercalciuria
Ca us e Se rum Othe r Se rum U s ua l Stone

Ca lc ium Va lue s Type
Le ve l
Idi opathi c N or m al N or m al Cal ci um
hy per cal ci ur i a a ox al ate or
cal ci um
phosphate
Pr i m ar y Hi gh Hy pophosphatem i a, Cal ci um
hy per par athy r oi di sm occasi onal l y ox al ate or
hy per chl or em i c cal ci um
aci dosi s phosphate
Renal tubul ar N or m al Hy per chl or em i c

aci dosi s aci dosi s Cal ci um
phosphate
a Sar coi dosi s, Cushi ng's m m obi l i zati on, v i tam i n D ex cess,
hy per thy r oi di sm , sy ndr om e, al k al i Paget's nd m al i gnant tum or s (w hi ch

cause hy per cal ci ur i a, di sease, r api dl y pr ogr essi v e bone al though not
stones) m ust be ex cl uded on cl i ni cal gr ounds.
Case
A 48y ear ol d m an pr esents to a l ocal em er gency r oom because of r i ght f l ank
pai n r adi ati ng to hi s r i ght testi cl e that has l asted f or 2 hour s. The pai n w as
i ni ti al l y m i l d and then becam e pr ogr essi v el y sev er e ov er an hour . He has no
nausea or v om i ti ng, f ev er or chi l l s, dy sur i a, hesi tancy , or decr eased ur i nar y
str eam . He has no hi stor y of pr ev i ous k i dney stones or ur i nar y tr act
i nf ecti ons. Hi s past m edi cal hi stor y i s r em ar k abl e onl y f or a hi stor y of Cr ohn's
di sease, w hi ch r equi r ed r esecti on of a por ti on of hi s i l eum . He tak es no
m edi cati ons.
On ex am i nati on, he i s f ound to be i n obv i ous di scom f or t. Hi s abdom en i s sof t
and nontender w i th no m asses. Ther e i s m i l d costov er tebr al angl e tender ness.
Hi s testi cl es ar e nor m al . The r em ai nder of hi s ex am i nati on f i ndi ngs ar e
unr em ar k abl e. The ur i ne pH i s 6, and ur i nal y si s show s 1+ pr otei n and 2+
hem e. The sedi m ent contai ns 10 to 15 r ed bl ood cel l s, 0 to 5 w hi te bl ood cel l s
per hi ghpow er f i el d, and a m oder ate am ount of am or phous cr y stal s. Ther e
ar e no casts. Hi s com pl ete bl ood count and el ectr ol y te l ev el s ar e nor m al . A
chest r adi ogr aphi c study and k i dney , ur eter , and bl adder (KU B) f i l m ar e
i nter pr eted as nor m al .
The f ol l ow i ng l abor ator y data ar e r epor ted: cal ci um , 10 m g/dL; phosphor us,
3. 7 m g/dL; al bum i n, 4. 1 g/dL; cr eati ni ne, 1 m g/dL; and BU N , 12 m g/dL. Hi s
bl ood pr essur e i s 140/85 m m Hg, pul se i s 95 beats per m i nute, r espi r ator y
r ate i s 20 br eaths per m i nute, and tem per atur e i s 37. 2Â°C (98. 96Â°F).
1. What ar e som e of the possi bl e r enal causes of thi s pati ent's sy m ptom s?
2. What i s the si gni f i cance of the cr y stal l ur i a?
P. 411
3. Does the absence of a col i cl i k e pai n suggest that thi s pati ent's pai n i s
not due to a k i dney stone?
4. What w oul d be the appr opr i ate test f or conf i r m i ng the di agnosi s of a
k i dney stone i n thi s pati ent?
5. Once the di agnosi s of a k i dney stone i s establ i shed, w hat i s the
appr opr i ate m anagem ent that shoul d be i m pl em ented i n the em er gency
r oom ?
N oncontr ast hel i cal CT scan r ev eal s a r adi opaque stone at the l ef t
ur eter opel v i c juncti on. Subsequentl y , the pati ent passes the stone i n hi s
ur i ne w hi l e i n the em er gency r oom . Labor ator y anal y si s r ev eal s that the
stone i s com posed pr i m ar i l y of cal ci um ox al ate. Subsequentl y , a 24hour
ur i ne col l ecti on r ev eal ed an i ncr ease i n ur i nar y ox al ate ex cr eti on (> 50
m g per 24 hour s).
6. What ar e the possi bl e causes and the tr eatm ents of hy per ox al ur i a as
seen i n thi s pati ent?
Case Discussion
1. What ar e som e of the possi bl e r enal causes of thi s pati ent's sy m ptom s?
Ki dney stones, r enal i nf ar cti on, and papi l l ar y necr osi s m ay al l pr esent
w i th the acute onset of f l ank pai n together w i th hem atur i a. How ev er ,
r enal i nf ar cti on usual l y occur s i n a pati ent w ho has ei ther a l ocal or
sy stem i c cause f or thr om bosi s (e. g. , tr aum a, aneur y sm , or v ascul i ti s
i nv ol v i ng the r enal ar ter y ) or thr om boem bol i sm (e. g. , endocar di ti s, m ur al
thr om bi , or f at em bol i ). Papi l l ar y necr osi s ty pi cal l y occur s i n pati ents
w i th ei ther adv anced di abeti c nephr opathy or si ck l e cel l di sease. In
contr ast, k i dney stones of ten ar i se i n peopl e w ho hav e no k now n
contr i butor y m edi cal i l l ness.
2. What i s the si gni f i cance of the cr y stal l ur i a?
Ex cept f or the f i ndi ng of cy sti ne cr y stal s, w hi ch i ndi cates cy sti nur i a,
cr y stal l ur i a i s of no di agnosti c v al ue w hen ev al uati ng a pati ent f or
nephr ol i thi asi s, as cr y stal s can appear i n nor m al ur i ne.
3. Does the absence of a col i cl i k e pai n suggest that thi s pati ent's pai n i s
not due to a k i dney stone?
N o. Ty pi cal l y , the pai n associ ated w i th k i dney stones i s a steady pai n that
gr adual l y w or sens; i t does not f l uctuate, as the ter m r enal col i c suggests.
4. What w oul d be the appr opr i ate test f or conf i r m i ng the di agnosi s of a
k i dney stone i n thi s pati ent?
Al though i n som e cases nephr ol i thi asi s can be di agnosed on the basi s of
the KU B r adi ogr aphi c f i ndi ngs, i t i s usual l y necessar y to per f or m
ex cr etor y ur ogr aphy , as i n thi s pati ent, to establ i sh the di agnosi s. It
al l ow s the l ocati on, si ze, shape, and r adi ol ucency of k i dney stones to be
deter m i ned. Al though r etr ogr ade py el ogr aphy can y i el d the sam e
i nf or m ati on, i t i s a m or e ex pensi v e and i nv asi v e pr ocedur e.
U l tr asonogr aphy i s not as sensi ti v e as ex cr etor y ur ogr aphy f or detecti ng
k i dney stones. Mor e r ecentl y , noncontr ast hel i cal CT has becom e the
pr ocedur e of choi ce i n m ost center s.
5. Once the di agnosi s of a k i dney stone i s establ i shed, w hat i s the

appr opr i ate m anagem ent that shoul d be i m pl em ented i n the em er gency
r oom ?
The pati ent shoul d be k ept w el l hy dr ated, usual l y w i th i ntr av enous f l ui ds,
to m ai ntai n a br i sk ur i ne f l ow , w hi ch m ay pr om ote passage of the stone,
and to
P. 412
di m i ni sh the r i sk of nephr otox i ci ty f r om the r adi ocontr ast agent. Al l of
the pati ent's ur i ne shoul d be str ai ned to deter m i ne i f the pati ent has
passed any stones. If any stones ar e obtai ned, they shoul d be sent f or
anal y si s. Pati ents al m ost al w ay s r equi r e nar coti c anal gesi cs f or
m anagem ent of the pai n. Pati ents shoul d be adm i tted to the hospi tal i f
i nadequate pai n r el i ef i s obtai ned w i th or al anal gesi cs, or i n the ev ent of
ur i nar y tr act i nf ecti on or acute r enal f ai l ur e.
6. What ar e the possi bl e causes and the tr eatm ents of hy per ox al ur i a as seen
i n thi s pati ent?
Hy per ox al ur i a can r esul t i n suf f i ci ent super satur ati on of the ur i ne w i th
cal ci um ox al ate to cause the pr eci pi tati on of k i dney stones. Mor e than
80% of ur i nar y ox al ate i s der i v ed f r om endogenous pr oducti on, pr i m ar i l y
as a br eak dow n pr oduct of gl y ox y l ate. The r em ai nder of ur i nar y ox al ate
i s obtai ned f r om di etar y sour ces. Ther ef or e, hy per ox al ur i a can be caused
by pr i m ar y ov er pr oducti on, i ntesti nal di sease, and di et. Ov er pr oducti on of
ox al ate (pr i m ar y hy per ox al ur i a) i s her edi tar y and sev er e, but r ar e. Injur y
of the bow el w al l i nf l i cted by f atty aci ds or bi l e sal ts can r esul t i n an
i ncr eased per m eabi l i ty to ox al ate. The m ost usual cl i ni cal setti ng, as i n
thi s pati ent, i s Cr ohn's di sease, i l eal r esecti on, or jejunoi l eal by pass. A
hi gh di etar y i ntak e of ox al ate m ay be due to the i ngesti on of f oods such
as chocol ate, nuts, r hubar b, tea, and som e f r ui t jui ces, as w el l as the
i ntak e of v i tam i n C i n ex cess of 1, 000 m g per day . Tr eatm ent usual l y
i nv ol v es the com bi nati on of a l ow ox al ate and l ow f at di et together w i th
adm i ni str ati on of or al cal ci um or chol esty r am i ne to â€œbi ndâ€ ox al ate i n
the i ntesti ne. Contr ar y to pr ev i ousl y hel d noti ons, r estr i cti on of cal ci um
i ntak e coul d be del eter i ous.
Suggested Readings
Coe FL. The pati ent w i th r enal stones. In: Schr i er RW, ed. Manual of
nephr ol ogy , 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2005:90.
Monk RD, Bushi nsk y DA. N ephr ol i thi asi s and nephr ocal ci nosi s. In: Johnson
R, Feehal l y J, eds. Com pr ehensi v e cl i ni cal nephr ol ogy , 2nd ed. Mosby ,
2003.
Nephrotic Syndrome
1. What i s the def i ni ti on of nephr oti c sy ndr om e?
2. What ar e the causes of nephr oti c sy ndr om e?
3. What ar e the possi bl e com pl i cati ons of nephr oti c sy ndr om e?
4. What ar e the tr eatm ent opti ons f or nephr oti c sy ndr om e?
Discussion
1. What i s the def i ni ti on of nephr oti c sy ndr om e?
N ephr oti c sy ndr om e i s a cl i ni cal enti ty char acter i zed by (a) pr otei nur i a i n
ex cess of 3. 5 g/1. 73 m 2 of body sur f ace ar ea (or 50 m g/k g of body
w ei ght) per day ; (b) hy poal bum i nem i a (< 3 g/dL), w hi ch i s a consequence
of the r enal l osses
P. 413
coupl ed w i th i nadequate hepati c com pensator y sy nthesi s; (c) edem a,
w hi ch i s a consequence of both the hy poal bum i nem i a and the sodi um
r etenti on; (d) hy per l i pi dem i a, w hi ch i s pr obabl y due to the i ncr eased
hepati c sy nthesi s of v er y â€“l ow densi ty l i popr otei ns w hi ch ar e conv er ted
to chol ester ol car r y i ng l ow densi ty l i popr otei ns; and (e) pr esence of
l i pi dur i a. Im pai r ed r em ov al pl ay s an i m por tant but pr obabl y secondar y
r ol e i n thi s setti ng.
2. What ar e the causes of nephr oti c sy ndr om e?
The causes of nephr oti c sy ndr om e can be easi l y di v i ded i nto tw o br oad
categor i es. The pr i m ar y , or i di opathi c, f or m s of nephr oti c sy ndr om e ar e
those f or w hi ch a speci f i c cause cannot be i denti f i ed despi te a r easonabl y
thor ough ev al uati on. The f i v e m ajor hi stol ogi c subty pes of pr i m ar y
nephr oti c sy ndr om e i ncl ude m i ni m al change di sease (al so cal l ed l i poi d
nephr osi s or ni l di sease), m em br anous gl om er ul onephr i ti s,
m em br anopr ol i f er ati v e gl om er ul onephr i ti s (al so cal l ed m esangi ocapi l l ar y
gl om er ul onephr i ti s), f ocal segm ental gl om er ul ar scl er osi s (FSGS), and
pr ol i f er ati v e gl om er ul onephr i ti s. The cl i ni cal and hi stol ogi c
char acter i sti cs of pr i m ar y nephr oti c sy ndr om e ar e l i sted i n Tabl e 916.
Table 916 The Clinical and Histologic Features
of the Primary (Idiopathic) Nephrotic
Syndrome
G lome rula r Dis e a s e Dis tinguis hing Cha ra c te ris tic
Clinic a l a nd Morphologic
La bora tory Findings Fe a ture s
Mi ni m al change Most com m on cause LM: nor m al

di sease i n chi l dr en (75%); IF: negati v e
20% of adul ts; EM: podocy te
ster oi d or ef f acem ent; no
cy cl ophospham i de i m m une
sensi ti v e (80%); deposi ts
nonpr ogr essi v e;
nor m al r enal
f uncti on; scant
hem atur i a
Focal segm ental Most com m on cause LM: ear l y â

gl om er ul oscl er osi s i n adul ts €”segm ental
(40%50%); scl er osi s i n
m i cr oscopi c som e gl om er ul i
hem atur i a; w i th tubul ar
pr ogr essi v e r enal atr ophy ; l ateâ
f ai l ur e (75%) €”scl er osi s of
m ost gl om er ul i
Mem br anous Peak i nci dence, LM: ear l y â

nephr opathy f our th and si x th €”nor m al ; l ateâ
decades; m al e €”GBM
f em al e, 23:1; ear l y thi ck eni ng
hy per tensi on (30%); IF: gr anul ar IgG
spontaneous and C3
r em i ssi on (20%); EM:
pr ogr essi v e r enal subepi thel i al
f ai l ur e (30%40%) deposi ts and
GBM ex pansi on
Mem br anopr ol i f er ati v e Peak i nci dence, LM:

gl om er ul onephr i ti s second thr ough thi r d hy per cel l ul ar
decades; m i x ed gl om er ul i w i th
nephr oti cnephr i ti c dupl i cated GBM
f eatur es; sl ow l y EM: ty pe Iâ
pr ogr essi v e i n m ost, €”subendothel i al
r api d i n som e; i m m une
hy pocom pl em entem i a deposi ts; ty pe
IIâ€”dense
deposi t GBM
Pr ol i f er ati v e See Tabl e 919
LM, l i ght m i cr oscopy ; IF, i m m unof l uor escence; IgG, i m m u

nogl obul i n G; EM, el ectr on m i cr oscopy ; GBM, gl om er ul ar basem ent
m em br ane.
P. 414
The secondar y f or m s of the nephr oti c sy ndr om e ar e those associ ated w i th
speci f i c eti ol ogi c ev ents or i n w hi ch gl om er ul ar di sease ar i ses as a
com pl i cati on of another di sease or sy stem i c pr ocess. These m ay be
br oadl y categor i zed i nto those stem m i ng f r om i nf ecti ons, neopl asi a,
m edi cati ons, al l er gens, m ul ti sy stem di seases, and her edof am i l i al
di seases, and al so i ncl ude v ar i ous m i scel l aneous causes (Tabl e 917).
Secondar y nephr oti c sy ndr om e m ay be associ ated w i th any of the m ajor
hi stol ogi c subty pes f ound i n i di opathi c nephr oti c sy ndr om e. The i di opathi c
nephr oti c sy ndr om e i s m or e com m on than the secondar y f or m .
3. What ar e the possi bl e com pl i cati ons of nephr oti c sy ndr om e?
The com pl i cati ons of nephr oti c sy ndr om e i ncl ude accel er ated
ather oscl er osi s, i ncr eased suscepti bi l i ty to i nf ecti ons, osteom al aci a, and
an i ncr eased i nci dence of thr om boem bol i c ev ents.
4. What ar e the tr eatm ent opti ons f or nephr oti c sy ndr om e?
The tr eatm ent of nephr oti c sy ndr om e depends on i ts cause. Cer tai nl y , i n
the case of the secondar y nephr oti c sy ndr om e, i f the pr i m ar y di sor der i s
tr eated ef f ecti v el y , the nephr oti c sy ndr om e tends to r esol v e as w el l . In
the case of the pr i m ar y nephr oti c sy ndr om e, cer tai n hi stol ogi c subty pes
(i . e. , m i ni m al change di sease and possi bl y m em br anous nephr opathy )
r espond to tr eatm ent w i th ster oi ds, w i th or w i thout cy totox i c agents.
Di scussi on of the potenti al r ol e f or other agents such as cy cl ospor i ne or
m y cophenol ate i s bey ond the scope of thi s book . Other l esi ons m ay be
r ef r actor y to any ty pe of ther apy . Dr ugs such as the ACE i nhi bi tor s or
ARBs m ay be usef ul i n r educi ng the pr otei nur i a by af f ecti ng i ntr ar enal
hem ody nam i cs, but they cannot i n any w ay al ter the pr i m ar y gl om er ul ar
abnor m al i ty i nv ol v ed.
Case
A 40y ear ol d w om an i s r ef er r ed f or ev al uati on of pr otei nur i a. Apar t f r om
occasi onal ar thr al gi as, she has f el t w el l but i s concer ned about pr ogr essi v e
w ei ght gai n and m ar k ed sw el l i ng of her l ow er ex tr em i ti es. She has no
per sonal or f am i l y hi stor y of r enal di sease, no k now n chr oni c sy stem i c i l l ness,
nor i s she tak i ng any m edi cati ons. Phy si cal ex am i nati on f i ndi ngs, i ncl udi ng
bl ood pr essur e, ar e nor m al , ex cept f or the pr esence of edem a that i s m ost
notabl e i n dependent ar eas. Labor ator y ev al uati on r ev eal s a nor m al
hem atocr i t, as w el l as ser um gl ucose, BU N , and cr eati ni ne l ev el s, but she has
pr of ound hy poal bum i nem i a (1. 9 g/dL) and hy per chol ester ol em i a (490 m g/dL).
U r i nal y si s show s 4+ pr otei nur i a, ov al f at bodi es, and f r ee f at dr opl ets, but no
cel l ul ar el em ents or casts. Her 24hour ur i nar y ex cr eti on of pr otei n i s f ound to
be 8. 6 g.
1. What i s the m ost com m on cause of the secondar y nephr oti c sy ndr om e i n
adul ts i n the U ni ted States? In pati ents w i th thi s di sor der , w hi ch ear l y
f i ndi ng ser v es as a har bi nger f or the subsequent dev el opm ent of
nephr oti c sy ndr om e and r enal i nsuf f i ci ency ?
2. What f eatur es of the hi stor y and phy si cal ex am i nati on ar e i m por tant i n
deter m i ni ng i f thi s pati ent has a pr i m ar y (i di opathi c) or secondar y f or m
of the nephr oti c sy ndr om e?
3. What addi ti onal l abor ator y tests w oul d y ou or der ei ther to establ i sh or
r ef ute a secondar y cause of the nephr oti c sy ndr om e?
4. How shoul d thi s pati ent's ev al uati on pr oceed?
P. 415
Table 917 Disorders Associated with Secondary
Nephrotic Syndrome
Inf ecti ous di seases

Bacter i al : poststr eptococcal gl om er ul onephr i ti s, i nf ecti v e
endocar di ti s, nephr i ti s, â€œshuntâ€ sy phi l i s, l epr osy
Vi r al : hepati ti s B and C, cy tom egal ov i r us, Epstei nBar r
v i r us, her pes zoster , hum an i m m unodef i ci ency v i r us
i nf ecti ons
Pr otozoal : m al ar i a, tox opl asm osi s
Hel m i nthi c: schi stosom i asi s, tr y panosom i asi s, f i l ar i asi s
N eopl asti c di seases
Sol i d tum or s (car ci nom a and sar com a): col on, l ung, br east,
stom ach, k i dney
Hem atol ogi c m al i gnanci es (l euk em i as and l y m phom as)
Medi cati ons
N onster oi dal anti i nf l am m ator y agents
Or gani c, i nor gani c, el em ental m er cur y
Or gani c gol d
Peni ci l l am i ne
â€œStr eetâ€ her oi n
Pr obeneci d
Bi sm uth
Captopr i l
Mul ti sy stem di seases
Sy stem i c l upus er y them atosus
Mi x ed connecti v e ti ssue di sease
Der m atom y osi ti s
Der m ati ti s her peti f or m i s
Sar coi dosi s
HenochSchÃ¶nl ei n pur pur a
Goodpastur e's sy ndr om e
Rheum atoi d ar thr i ti s
Am y l oi dosi s
Pol y ar ter i ti s
Al l er gi c r eacti ons
Bee sti ng
Pol l ens
Poi son i v y and poi son oak
Ser um si ck ness (anti tox i ns)
Metabol i c di seases
Di abetes m el l i tus
My x edem a
Hy per thy r oi di sm
Her edof am i l i al di seases
Al por t's sy ndr om e
Fabr y 's di sease
N ai l patel l a sy ndr om e
Si ck l e cel l di sease
a1Anti tr y psi n def i ci ency
Congeni tal nephr oti c sy ndr om e (Fi nni sh ty pe)
Her edi tar y am y l oi dosi s (f am i l i al Medi ter r anean f ev er )
Mi scel l aneous
Chr oni c r enal al l ogr af t r ejecti on
Pr egnancy associ ated (pr eecl am psi a, r ecur r ent or tr ansi ent)
Vesi cour eter i c r ef l ex
P. 416
Case Discussion
1. What i s the m ost com m on cause of the secondar y nephr oti c sy ndr om e i n
adul ts i n the U ni ted States? In pati ents w i th thi s di sor der , w hi ch ear l y
f i ndi ng ser v es as a har bi nger f or the subsequent dev el opm ent of
nephr oti c sy ndr om e and r enal i nsuf f i ci ency ?
Di abetes m el l i tus i s the m ost com m on cause of secondar y nephr oti c
sy ndr om e i n adul ts i n the U ni ted States. In pati ents w i th ei ther ty pe 1 or
ty pe 2 di abetes, the onset of m i cr oal bum i nur i a (al bum i n ex cr eti on of 20
to 200 Âµg per m i nute or 30 to 300 m g/g Cr per day ) pr edi cts the
subsequent dev el opm ent of nephr oti c sy ndr om e and r enal i nsuf f i ci ency .
These pati ents shoul d begi n tr eatm ent w i th an ACE i nhi bi tor or ARBs.
2. What f eatur es of the hi stor y and phy si cal ex am i nati on ar e i m por tant i n
deter m i ni ng i f thi s pati ent has a pr i m ar y (i di opathi c) or secondar y f or m
of the nephr oti c sy ndr om e?
Di f f er enti ati ng betw een the pr i m ar y and secondar y f or m s of the nephr oti c
sy ndr om e depends on a car ef ul r ev i ew of the pati ent's hi stor y and
phy si cal ex am i nati on f i ndi ngs and the per f or m ance of sel ected l abor ator y
tests that can i denti f y under l y i ng di sease states. It i s i m per ati v e to
deter m i ne i f ther e i s a f am i l y or per sonal hi stor y of di abetes m el l i tus or
connecti v e ti ssue di sease, her edi tar y condi ti ons such as si ck l e cel l
di sease or Al por t's sy ndr om e, al l er gen ex posur e, and so f or th. A
com pl ete m edi cati on l i st m ust be obtai ned, i ncl udi ng the use of
nonpr escr i pti on m edi ci nes such as N SAIDs. A hi stor y of i l l i ci t dr ug use i s
equal l y i m por tant because her oi n nephr opathy i s not r ar e i n dr ug
abuser s. In addi ti on, a tr av el hi stor y i s a cr uci al par t of the hi stor y
tak i ng because, f or ex am pl e, m al ar i a i s a w el l k now n cause of the
nephr oti c sy ndr om e and shoul d be consi der ed i n those pati ents w ho hav e
tr av el ed to endem i c ar eas. Ri sk f actor s f or hepati ti s and hum an
i m m unodef i ci ency v i r us (HIV) i nf ecti on m ust al so be sought because hi gh
r i sk popul ati ons shoul d be scr eened f or these di sor der s. In thi s par ti cul ar
pati ent (a y oung w om an), the hi stor y of occasi onal ar thr al gi as br i ngs up
the possi bi l i ty of a m ul ti sy stem di sease as the sour ce of the nephr oti c
sy ndr om e.
3. What addi ti onal l abor ator y tests w oul d y ou or der ei ther to establ i sh or
r ef ute a secondar y cause of the nephr oti c sy ndr om e?
Labor ator y tests that ar e usef ul i n establ i shi ng a secondar y cause of the
nephr oti c sy ndr om e i ncl ude the ser um gl ucose l ev el , an anti nucl ear
anti body (AN A)
P. 417
deter m i nati on, com pl em ent l ev el s, hepati ti s scr eeni ng, v ener eal di sease
r esear ch l abor ator y test, HIV test, si ck l e cel l pr epar ati on, an
anti str eptol y si n ti ter , thr oat cul tur e, and ser um and ur i nar y pr otei n
el ectr ophor esi s. The f i ndi ngs y i el ded by the hi stor y and phy si cal
ex am i nati on di ctate w hi ch of these tests shoul d be per f or m ed i n a
par ti cul ar pati ent. In thi s pati ent, the AN A test i s posi ti v e and the
com pl em ent l ev el s ar e l ow , i ndi cati ng that she m ay hav e sy stem i c l upus
er y them atosus (SLE) as the cause of her nephr oti c sy ndr om e.
4. How shoul d thi s pati ent's ev al uati on pr oceed?
In the setti ng of SLE, a k i dney bi opsy shoul d be per f or m ed i n an ef f or t to
establ i sh the natur e of the under l y i ng di sor der r esponsi bl e f or the
nephr oti c sy ndr om e. Thi s pati ent m ost l i k el y has ei ther di f f use
pr ol i f er ati v e gl om er ul onephr i ti s or m em br anous nephr opathy w i th SLE.
The ther apy f or the f or m er cal l s f or tr eatm ent w i th ster oi ds and cy totox i c
agents, al though the l atter does not.
Suggested Readings
Ber nar d DB. Ex tr ar enal com pl i cati ons of the nephr oti c sy ndr om e. Ki dney
Int 1988;33:1184.
Kay sen GA. Pr otei nur i a and the nephr oti c sy ndr om e. In: Schr i er RW, ed.
Renal and el ectr ol y te di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2003:580.
Glomerulonephritis
1. What i s the def i ni ti on of hem atur i a?
2. What ar e the m ajor causes of hem atur i a?
3. What can hel p poi nt tow ar d a gl om er ul ar or i gi n as the sour ce of the
hem atur i a?
4. What i s the def i ni ti on of the nephr i ti c sy ndr om e?
5. What ar e the pr i m ar y di seases of the k i dney associ ated w i th gl om er ul ar

hem atur i a (nephr i ti c sy ndr om e)?
6. What sy stem i c di seases ar e associ ated w i th gl om er ul ar hem atur i a?
7. How i s r api dl y pr ogr essi v e gl om er ul onephr i ti s (RPGN ) def i ned?
8. What cl i ni cal di sor der s cause RPGN ?
Discussion
1. What i s the def i ni ti on of hem atur i a?
Hem atur i a r ef er s to the pr esence of an abnor m al l y hi gh num ber of r ed
bl ood cel l s (> 5 per hi ghpow er f i el d) i n the ur i ne. Thi s i s m ost com m onl y
detected by a di psti ck (Hem asti x ) m ethod, w hi ch i denti f i es the pr esence
of hem ogl obi n. The hem atur i a i s consi der ed m acr oscopi c w hen the ur i ne
i s obv i ousl y r ed due to the pr esence of bl ood, and i t i s deem ed
m i cr oscopi c w hen the ur i ne gr ossl y appear s nor m al . A num ber of f oods
(such as beets) and som e dr ugs (such as phenazopy r i di ne hy dr ochl or i de)
as w el l as por phy r i a can tur n the ur i ne r ed. In these ci r cum stances, the
di psti ck r esul t i s negati v e.
P. 418
2. What ar e the m ajor causes of hem atur i a?
The causes of hem atur i a ar e best appr oached i n ter m s of thei r bei ng
ei ther ex tr ar enal or r enal i n or i gi n. Ex tr ar enal bl eedi ng can occur i n the
ur eter s due to cal cul i or car ci nom a; i n the bl adder due to hem or r hagi c
cy sti ti s stem m i ng f r om i nf ecti on (i ncl udi ng Schi stosom a haem atobi um i n
endem i c ar eas), as w el l as f r om cy cl ophospham i de use, car ci nom a,
catheter i zati on, or cal cul i ; i n the pr ostate due to hy per tr ophy , car ci nom a,
or pr ostati ti s; and i n the ur ethr a due to ur ethr i ti s or tr aum a. Renal
causes of hem atur i a can be cl assi f i ed as ei ther gl om er ul ar or
nongl om er ul ar and ar e l i sted i n Tabl e 918.
3. What can hel p poi nt tow ar d a gl om er ul ar or i gi n as the sour ce of the
hem atur i a?
The f ol l ow i ng f i ndi ngs poi nt tow ar d a gl om er ul ar cause as the sour ce of
hem atur i a: (a) the pr esence of dy sm or phi c r ed bl ood cel l s on phase
contr ast m i cr oscopy ; (b) the pr esence of r ed bl ood cel l casts, w hi ch i s
v i r tual l y a di agnosti c f i ndi ng; and (c) pr otei nur i a ex ceedi ng 500 m g per
day .
4. What i s the def i ni ti on of the nephr i ti c sy ndr om e?
The nephr i ti c sy ndr om e i s def i ned by a constel l ati on of ur i nar y f i ndi ngs
that i ncl ude the pr esence of hem atur i a, pr otei nur i a, and r ed bl ood cel l
casts. These f i ndi ngs i ndi cate the pr esence of a gl om er ul ar l esi on and ar e
f r equentl y accom pani ed by azotem i a, hy per tensi on, and edem a.
5. What ar e the pr i m ar y di seases of the k i dney associ ated w i th gl om er ul ar

hem atur i a (nephr i ti c sy ndr om e)?
The pr i m ar y di seases associ ated w i th gl om er ul ar hem atur i a ar e

i m m unogl obul i n A (IgA) nephr opathy , poststr eptococcal
gl om er ul onephr i ti s, m em br anopr ol i f er ati v e gl om er ul onephr i ti s, and
i di opathi c RPGN .
6. What sy stem i c di seases ar e associ ated w i th gl om er ul ar hem atur i a?
SLE, HenochSchÃ¶nl ei n pur pur a, Goodpastur e's sy ndr om e, v ascul i ti s

(i ncl udi ng pol y ar ter i ti s nodosa and Wegener 's gr anul om atosi s), and
essenti al m i x ed cr y ogl obul i nem i a ar e al l associ ated w i th gl om er ul ar
hem atur i a.
7. How i s RPGN def i ned?
RPGN i s pr i m ar i l y def i ned i n cl i ni cal ter m s as a gl om er ul ar di sease

char acter i zed by pr ogr essi on to endstage r enal di sease w i thi n w eek s to
m onths. The pathol ogi c cor r el ate i s ex tensi v e cr escent f or m ati on i n the
gl om er ul i , as seen i n k i dney bi opsy speci m ens.
8. What cl i ni cal di sor der s cause RPGN ?
A num ber of di sor der s cause RPGN . These ar e best def i ned i n
i m m unopathol ogi c ter m s, dependi ng on the absence or pr esence (and
patter n) of i m m une deposi ts (Tabl e 919).
Case
A 21y ear ol d col l ege student i s r ef er r ed to the r enal cl i ni c f or f ur ther
ev al uati on of m i cr oscopi c hem atur i a, w hi ch w as di scov er ed dur i ng a
pr eem pl oy m ent phy si cal ex am i nati on. Ther e i s no hi stor y of r ecent i nf ecti ons,
tr aum a, or i ntr av enous dr ug abuse. She deni es any hi stor y of r ashes,
ar thr al gi a, m y al gi as, f ev er s, or epi sodes of gr oss hem atur i a.
Phy si cal ex am i nati on r ev eal s a w el l dev el oped, w el l nour i shed w om an w ho i s
i n no acute di str ess. Her bl ood pr essur e i s 125/85 m m Hg; pul se, 72 beats per
m i nute; and
P. 419
P. 420
r espi r ator y r ate, 16 br eaths per m i nute. N o r ashes, l y m phadenopathy , or joi nt
tender ness i s noted. The r em ai nder of the phy si cal ex am i nati on f i ndi ngs ar e
w i thi n nor m al l i m i ts.
Table 918 Glomerular and Nonglomerular Renal
Parenchymal Causes of Hematuria
Gl om er ul ar
Pr ol i f er ati v e gl om er ul onephr i ti s
Pr i m ar y
Secondar y
Fam i l i al di seases of the gl om er ul us
Al por t's sy ndr om e
Recur r ent beni gn hem atur i a (thi n basem ent m em br ane
di sease)
N ongl om er ul ar
N eopl asm s
Renal cel l car ci nom a
Wi l m s' tum or
Beni gn cy sts
Vascul ar
Renal i nf ar ct
Renal v ei n thr om bosi s
Ar ter i ov enous m al f or m ati on
Capi l l ar y necr osi s
Loi n pai nhem atur i a sy ndr om e
Metabol i c
Hy per cal ci ur i a
Hy per ur i cosur i a
Fam i l i al
Pol y cy sti c k i dney di sease
Medul l ar y sponge k i dney
Papi l l ar y necr osi s
Anal gesi c abuse
Si ck l e cel l di sease and tr ai t
Renal tuber cul osi s
Di abetes
Obstr ucti v e ur opathy
Dr ugs
Anti coagul ants (hepar i n, coum ar i n)
Dr ugi nduced acute i nter sti ti al nephr i ti s
Tr aum a
Adapted f r om Li eber thal W. Hem atur i a and the acute nephr i ti c
sy ndr om e. In: Jacobson HR, Str i k er GE, Kl ahr S, eds. The pr i nci pl es
and pr acti ce of nephr ol ogy . Phi l adel phi a: BC Deck er , 1991.
Table 919 Immunopathogenetic Classification of
Rapidly Progressive Glomerulonephritis
Anti GBM anti body (l i near i m m une deposi ts)

Wi th l ung hem or r hage (Goodpastur e's
Wi thout l ung hem or r hage (i di opathi c)
Im m une com pl ex (gr anul ar i m m une deposi ts)
Pr edom i nantl y IgA
IgA nephr opathy
HenochSchonl ei n pur pur a
Pr edom i nantl y IgG (other s m ay be pr esent)
Posti nf ecti ous
Vi scer al abscess
Bacter i al endocar di ti s
Lupus nephr i ti s
Cr y ogl obul i nem i a
Mem br anopr ol i f er ati v e gl om er ul onephr i ti s
Pauci i m m une (no i m m une deposi ts)
Vascul i ti s
Mi cr oscopi c pol y ar ter i ti s
Wegener 's
Hy per sensi ti v i ty v ascul i ti des (e. g. , Chur gStr auss
sy ndr om e)
Idi opathi c
GBM, gl om er ul ar basem ent m em br ane; IgA, i m m unogl obul i n A; IgG,

i m m unogl obul i n G.
The f ol l ow i ng l abor ator y data ar e r epor ted: ser um sodi um , 135 m Eq/L;
potassi um , 4. 5 m Eq/L; chl or i de, 105 m Eq/L; car bon di ox i de, 25 m Eq/L;
gl ucose, 98 m g/dL; BU N , 12 m g/dL; and cr eati ni ne, 0. 8 m g/dL. U r i nal y si s
show s a speci f i c gr av i ty of 1. 015, pH of 5. 0, 1+ hem e, and 1+ pr otei n on
di psti ck ex am i nati on. Mi cr oscopi c ex am i nati on of the ur i ne r ev eal s 5 to 10 r ed
bl ood cel l s per hi ghpow er f i el d, and possi bl y one r ed bl ood cel l cast i s noted
on cl ose scr uti ny of the enti r e sl i de. The 24hour ur i ne ex cr eti on i s of 1. 5 L
total v ol um e, w i th 1, 200 m g of cr eati ni ne and 1, 200 m g of pr otei n.
On f ur ther l abor ator y ex am i nati on, no secondar y sy stem i c cause f or the
nephr i ti c sy ndr om e i s i denti f i ed. Speci f i cal l y , AN A and anti neutr ophi l
cy topl asm i c anti body tests ar e negati v e, as ar e tests f or hepati ti s B and C.
Li k ew i se, both the C3 and C4 com pl em ent l ev el s ar e nor m al . Consequentl y , a
per cutaneous r enal bi opsy i s per f or m ed. The hi stol ogi c, i m m unof l uor escence,
and el ectr on m i cr oscopy f i ndi ngs ar e al l consi stent w i th IgA nephr opathy .
1. What ar e the cl i ni cal enti ti es that hav e been associ ated w i th pr om i nent
m esangi al IgA deposi ts?
2. What cl i ni cal f i ndi ngs i ndi cate a poor pr ognosi s i n IgA nephr opathy ?
3. What i s the cl i ni cal cour se of IgA nephr opathy ?
P. 421
4. What w oul d y ou adv i se thi s pati ent i f she w er e to contem pl ate
pr egnancy ?
5. What tr eatm ent opti ons ar e av ai l abl e f or thi s pati ent?
Case Discussion
1. What ar e the cl i ni cal enti ti es that hav e been associ ated w i th pr om i nent
m esangi al IgA deposi ts?
HenochSchÃ¶nl ei n pur pur a, chr oni c l i v er di sease, der m ati ti s

her peti f or m i s, ax i al ar thr opathi es, and Ber ger 's di sease hav e al l been
f ound i n the setti ng of m esangi al IgA deposi ts.
2. What cl i ni cal f i ndi ngs i ndi cate a poor pr ognosi s i n IgA nephr opathy ?
The cl i ni cal f i ndi ngs that por tend a poor pr ognosi s i n IgA nephr opathy ar e
per si stent pr otei nur i a of gr eater than 1 g per day , el ev ated bl ood
pr essur e, m al e gender , an el ev ated ser um cr eati ni ne l ev el , and the
absence of m acr oscopi c hem atur i a.
3. What i s the cl i ni cal cour se of IgA nephr opathy ?
Pati ents w i th IgA nephr opathy m ay ex per i ence i nter m i ttent epi sodes of
gr oss hem atur i a, and 5% to 10% of the pati ents m ay hav e ear l y nephr oti c
sy ndr om e. Endstage r enal di sease dev el ops i n appr ox i m atel y 10% of
af f ected pati ents by 10 y ear s, and by 20 y ear s i n 20% of af f ected
pati ents. In addi ti on, another 20% to 30% m ay ex per i ence som e decl i ne
i n r enal f uncti on w i thi n 20 y ear s.
4. What w oul d y ou adv i se thi s pati ent i f she w er e to contem pl ate pr egnancy ?
Despi te ear l y r epor ts to the contr ar y , l ar ge r etr ospecti v e sur v ey s r ev eal
no ev i dence i ndi cati ng that IgA nephr opathy unf av or abl y al ter s the cour se
of pr egnancy . In addi ti on, the chances f or a successf ul pr egnancy ar e
ex cel l ent i f the pati ent r em ai ns f r ee of hy per tensi on or r enal
5. What tr eatm ent opti ons ar e av ai l abl e f or thi s pati ent?

Ther e i s no pr ov en tr eatm ent f or IgA nephr opathy . The r esul ts of som e
tr i al s of ster oi ds hav e suggested that they ar e som ew hat ef f ecti v e i n
pati ents w i th per si stent pr otei nur i a, w hen r enal f uncti on i s sti l l w el l
pr eser v ed (S Cr < 1. 4 m g/dL).
Suggested Readings
Adl er SG, Fai r l ey K. The pati ent w i th hem atur i a, pr otei nur i a, or both, and
abnor m al f i ndi ngs on ur i nar y m i cr oscopy . In: Schr i er RW, ed. Manual of
nephr ol ogy , 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2005: 116.
Gl assock RJ. The gl om er ul opathi es. In: Schr i er RW, ed. Renal and
el ectr ol y te di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns,
2003:623.
Hyperkalemia
1. What ar e the causes of spur i ous hy per k al em i a?
2. What ar e the pr i m ar y m echani sm s that under l i e hy per k al em i a, and w hat

ar e the causes of each?
P. 422
3. At w hat l ev el of r enal i nsuf f i ci ency does hy per k al em i a occur ?
4. What ar e the cl i ni cal consequences of hy per k al em i a?
5. What ther apeuti c opti ons ar e av ai l abl e f or hy per k al em i c pati ents, and
how r api dl y do they r ev er se the pr ocess?
Discussion
1. What ar e the causes of spur i ous hy per k al em i a?
The causes of spur i ous hy per k al em i a (pseudohy per k al em i a) com pr i se

hem ol y si s of the bl ood sam pl e, a m ar k ed l euk ocy tosi s (w hi te bl ood cel l
count > 50, 000/m m 3 ), thr om bocy tosi s (pl atel et count > 800, 000/m m 3 ), and
an ex cessi v el y ti ght tour ni quet.
2. What ar e the pr i m ar y m echani sm s that under l i e hy per k al em i a, and w hat

ar e the causes of each?
The pr i m ar y m echani sm s that br i ng about hy per k al em i a ar e an i ncr eased

potassi um i nput f r om ei ther endogenous (e. g. , hem atom as or
r habdom y ol y si s) or ex ogenous sour ces, a tr anscel l ul ar r edi str i buti on of
potassi um , and decr eased ur i nar y ex cr eti on of potassi um as occur s i n
r enal i nsuf f i ci ency . The causes of these potassi um r el ated abnor m al i ti es
ar e l i sted i n Tabl e 920.
3. At w hat l ev el of r enal i nsuf f i ci ency does hy per k al em i a occur ?
In the absence of other f actor s, hy per k al em i a super v enes i n pati ents w i th
r enal di sease w hen the GFR i s l ess than 10 m L per m i nute. The adapti v e
r esponse to decr eased r enal m ass i nv ol v es the i ncr eased ex cr eti on of
potassi um per nephr on; thi s m ai ntai ns nor m ok al em i a despi te an
unchanged potassi um i ntak e (usual l y 60 to 80 m Eq per day ). How ev er , i n
the pr esence of the pr ocesses l i sted i n the answ er to the pr ev i ous
questi on, hy per k al em i a ar i ses w hen the GFR i s hi gher (as hi gh as 40 m L
per m i nute).
4. What ar e the cl i ni cal consequences of hy per k al em i a?
The m ost i m m edi ate and i m por tant i m pact of hy per k al em i a i s on the cel l s
possessi ng ex ci tabl e m em br anes (ner v e and m uscl e) because i t
depol ar i zes such cel l s. The m ost si gni f i cant ef f ect of hy per k al em i a i s on
the hear t. The ty pi cal sequence of el ectr ocar di ogr aphi c changes seen w i th
i ncr easi ng degr ees of hy per k al em i a i ncl ude tal l , peak ed T w av es; Pw av e
abnor m al i ti es (i ncl udi ng l oss of the P w av e); pr ol ongati on of the QRS
com pl ex ; si nus ar r est; atr i ov entr i cul ar di ssoci ati on; v entr i cul ar
f i br i l l ati on; and car di ac ar r est.
5. What ther apeuti c opti ons ar e av ai l abl e f or hy per k al em i c pati ents, and
how r api dl y do they r ev er se the pr ocess?
The v ar i ous ther apeuti c opti ons f or hy per k al em i a ar e l i sted i n Fi g. 92. As

show n, cal ci um gl uconate has the m ost r api d onset and shoul d ther ef or e
be the f i r stl i ne tr eatm ent to pr otect agai nst the neur om uscul ar ef f ects of
hy per k al em i a. N ote al so that the use of cal ci um gl uconate, i nsul i n w i th
gl ucose, or sodi um bi car bonate does not decr ease total body potassi um
content; unl ess a decr ease i n total body potassi um i s achi ev ed (e. g. , w i th
k al i ur esi s, k ay ex al ate, or di al y si s), hy per k al em i a w i l l r ecur w hen the
ther apeuti c ef f ect of these agents di ssi pates.
P. 423
Table 920 The Causes of Hyperkalemia
Causes of i ncr eased potassi um i nput

Ex ogenous potassi um l oads
Rapi d i ntr av enous potassi um adm i ni str ati on
Hi gh potassi um i ntak e w i th sev er e sodi um r estr i cti on
Endogenous potassi um l oads
Rhabdom y ol y si s
Hem ol y si s
Tum or l y si s sy ndr om e
Hem atom as
Incr eased catabol i sm
Bur ns
Causes of tr anscel l ul ar shi f t
Insul i n def i ci ency
Metabol i c aci dosi s due to m i ner al aci d r etenti on
Hy per toni ci ty (gl ucose or m anni tol )
Ex er ci se
Hy per k al em i c per i odi c par al y si s
Di gi tal i s i ntox i cati on
Î²Adr ener gi c antagoni sts
Causes of i m pai r ed r enal ex cr eti on
Di f f use adr enal i nsuf f i ci ency (Addi son's
Sel ecti v e m i ner al ocor ti coi d (al doster one) def i ci ency
Pr i m ar y r enal tubul ar secr etor y def ect
Obstr ucti v e ur opathy
Si ck l e cel l di sease
Sy stem i c l upus er y them atosus
Renal tr anspl antati on
Tubul oi nter sti ti al nephr opathy
Dr ug i nduced
Spi r onol actone
Tr i am ter ene
Am i l or i de
Inhi bi tor s of the r eni nangi otensi n sy stem
Pentam i di ne
N onster oi dal anti i nf l am m ator y dr ugs
Tr i m ethopr i m
Hepar i n
P. 424
Figure 92 Tr eatm ent of hy per k al em i a. GFR, gl om er ul ar f i l tr ati on r ate; K,
potassi um . (Fr om Kel l eher CL, Li nas S. The pati ent w i th hy pok al em i a or
hy per k al em i a. In: Schr i er RW, ed. Manual of N ephr ol ogy , 6th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2005. Repr i nted w i th
per m i ssi on. )
Case
A 30y ear ol d w hi te m an has both di abetes m el l i tus and hy per tensi on. The
di abetes w as di agnosed at 8 y ear s of age w hen k etoaci dosi s dev el oped. He
has si nce had pr ol i f er ati v e r eti nopathy , nephr opathy , and per i pher al and
autonom i c neur opathy . The nephr opathy w as r ecogni zed w hen the nephr oti c
sy ndr om e dev el oped 3 y ear s ago, and ther e has al so been a gr adual i ncr ease
i n hi s ser um cr eati ni ne l ev el ov er the l ast 18 m onths. Hy per tensi on w as f i r st
detected a y ear ago. Al though hi s ser um gl ucose l ev el s hav e i n gener al been
w el l contr ol l ed w i th the tw i cedai l y adm i ni str ati on of i nsul i n, bl ood pr essur e
contr ol has been subopti m al despi te tr eatm ent w i th l osar tan and
hy dr ochl or othi azi de.
The f ol l ow i ng phy si cal ex am i nati on f i ndi ngs ar e noted: supi ne hear t r ate of 76
beats per m i nute and bl ood pr essur e of 160/110 m m Hg; standi ng hear t r ate
of 80 beats per m i nute and bl ood pr essur e of 130/90 m m Hg. Funduscopy
r ev eal s the pr esence of hem or r hages, ex udates, and neov ascul ar i zati on. Hi s
l ung f i el ds ar e cl ear , no car di ac m ur m ur i s pr esent, and ther e i s tr ace l ow er
ex tr em i ty edem a, decr eased sensati on to pi npr i ck and v i br ati on i n the di stal
l ow er ex tr em i ti es, and absent deep tendon r ef l ex es i n the l ow er ex tr em i ti es.
The f ol l ow i ng l abor ator y v al ues ar e r epor ted: sodi um , 138 m Eq/L; potassi um ,
7. 2 m Eq/L; chl or i de, 110 m Eq/L; car bon di ox i de, 20 m Eq/L; gl ucose, 129
m g/dL;
P. 425
cr eati ni ne, 2. 4 m g/dL; BU N , 30 m g/dL; and hem ogl obi n A Ic , 8. 8%.
El ectr ocar di ogr aphy dem onstr ates r egul ar si nus r hy thm at 76 beats per m i nute
w i th a nor m al ax i s. The P w av es ar e f l attened, the QRS com pl ex i s 0. 12
seconds i n dur ati on, and ther e ar e peak ed T w av es i n the pr ecor di al l eads.
U r i nal y si s r ev eal s a speci f i c gr av i ty of 1. 015, pH of 5. 0, 3+ pr otei n, and
hy al i ne casts. A 24hour ur i ne sam pl e show s a cr eati ni ne cl ear ance (C Cr ) of 35
m L per m i nute and 4. 6 g of pr otei n.
1. What do the el ectr ocar di ogr aphi c f i ndi ngs si gni f y ? How shoul d the pati ent
be tr eated?
2. What ar e the m ost l i k el y f actor s contr i buti ng to thi s pati ent's
hy per k al em i a?
3. What ar e the dr ugs that can cause hy poal doster oni sm ?
4. What i s the appr opr i ate subsequent ther apy f or thi s pati ent?
Case Discussion
1. What do the el ectr ocar di ogr aphi c f i ndi ngs si gni f y ? How shoul d the pati ent
be tr eated?
The el ectr ocar di ogr aphi c f i ndi ngs ar e char acter i sti c of hy per k al em i a. The
pati ent shoul d be tr eated i m m edi atel y w i th cal ci um gl uconate f ol l ow ed by
m easur es to l ow er the ser um potassi um , as outl i ned i n Fi g. 92.
2. What ar e the m ost l i k el y f actor s contr i buti ng to thi s pati ent's
hy per k al em i a?
The m ajor contr i butor y f actor s r esponsi bl e f or the hy per k al em i a i n thi s

pati ent i ncl ude a decr em ent i n the GFR, the use of l osar tan, and
hy por eni nem i c hy poal doster oni sm . Di etar y potassi um ex cess m ay be
oper ant as w el l .
The pati ent al so has a m etabol i c aci dosi s that i s pr obabl y contr i buti ng to
the hy per k al em i a. The dev el opm ent of hy per k al em i a w hen the r enal
i nsuf f i ci ency i s onl y m oder ate i s l i k el y because other f actor s ar e i nv ol v ed
i n the pr ocess. The sy ndr om e of hy por eni nem i c hy poal doster oni sm i s
com m on i n pati ents w i th di abetes, and the pr esence of hy per chl or em i c
aci dosi s f ur ther suppor ts thi s possi bi l i ty .
3. What ar e the dr ugs that can cause hy poal doster oni sm ?

Inhi bi tor s of the r eni nâ€“angi otensi n sy stem , hepar i n, N SAIDs, and
spi r onol actone can al l pr eci pi tate hy poal doster oni sm . Î²Adr ener gi c
bl ock er s m ay contr i bute to hy poal doster oni sm by i m pai r i ng r eni n
secr eti on. Spi r onol actone i s a com peti ti v e i nhi bi tor of al doster one's
cy tosol i c r eceptor , w her eas am i l or i de i nhi bi ts potassi um secr eti on
thr ough the oper ati on of an al doster onei ndependent m echani sm . Cal ci um
channel bl ock er s hav e not been r epor ted to i nhi bi t al doster one sy nthesi s,
but spi r onol actone i s k now n to i nhi bi t al doster one acti on. Tr i m ethopr i m
has been r epor ted to hav e an am i l or i del i k e ef f ect i n pati ents w i th the
acqui r ed i m m unodef i ci ency sy ndr om e; pentam i di ne has si m i l ar ef f ects i n
these pati ents. Cal ci neur i n i nhi bi tor s al so cause hy per k al em i a, pr obabl y
by an al doster onem edi ated m echani sm .
4. What i s the appr opr i ate subsequent ther apy f or thi s pati ent?
Thi s pati ent shoul d r estr i ct hi s di etar y potassi um i ntak e and tak e l oop
di ur eti cs to m anage the hy por eni nem i c hy poal doster oni sm .
Hi s l osar tan (an ARB) dose needs to be decr eased. Mi ner al ocor ti coi d
r epl acem ent can w or sen the hy per tensi on and sodi um r etenti on, and
shoul d ther ef or e
P. 426
be av oi ded. Sodi um r estr i cti on shoul d al so be av oi ded because i t
attenuates the k al i ur eti c ef f ect of the di ur eti c; sodi um del i v er y i s
i m por tant to potassi um ex cr eti on.
Suggested Readings
Kel l eher CL, Li nas S. The pati ent w i th hy pok al em i a or hy per k al em i a. In:
Schr i er RW, ed. Manual of nephr ol ogy , 6th ed. Phi l adel phi a: Li ppi ncott
Peter son LN , Lev i M. Di sor der s of potassi um m etabol i sm . In: Schr i er RW,
ed. Renal and el ectr ol y te di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott
Hyponatremia
1. What does the ser um sodi um concentr ati on r ef l ect, and w hat f actor s can
al ter the w ay i n w hi ch i t i s i nter pr eted? In w hat setti ng i s
pseudohy ponatr em i a obser v ed?
2. What i s the under l y i ng pathogenesi s of hy ponatr em i a?
3. What i s the di agnosti c appr oach to hy ponatr em i a, and w hat ar e i ts m ajor
causes?
4. What ar e som e of the dr ugs that pr oduce hy ponatr em i a?

5. What ar e the m ost com m on di sor der s associ ated w i th the sy ndr om e of
i nappr opr i ate anti di ur eti c hor m one secr eti on (SIADH)?
Discussion
1. What does the ser um sodi um concentr ati on r ef l ect, and w hat f actor s can
al ter the w ay i n w hi ch i t i s i nter pr eted? In w hat setti ng i s
pseudohy ponatr em i a obser v ed?
Hy ponatr em i a r epr esents a decr ease i n the concentr ati on of sodi um
r el ati v e to that of w ater i n the ser um . Total body sodi um content m ay be
decr eased, unchanged, or ev en i ncr eased. The ser um sodi um
concentr ati on i s a m easur e of the toni ci ty of body f l ui ds, and i t i s the
m ajor contr i butor to the ser um osm ol al i ty , as show n by the equati on:
P osm = 2 Ã— P N a + (gl ucose/18) + (ur ea/2. 8), w her e P osm i s the ser um
osm ol al i ty and P N a i s the ser um sodi um concentr ati on.
Hy per gl y cem i a can cause a decr em ent i n the ser um sodi um l ev el by

shi f ti ng i ntr acel l ul ar w ater out of cel l s. Because gl ucose i s not f r eel y
m ov abl e acr oss cel l m em br anes, w hen the ex tr acel l ul ar gl ucose
concentr ati on i s el ev ated i n i nsul i ndef i ci ent or r esi stant pati ents, w ater
m ov es out of the cel l s to equal i ze osm ol al i ty on both si des of the
m em br ane. The m ov em ent of w ater di l utes the ser um sodi um
concentr ati on, but the ser um osm ol al i ty i s m ai ntai ned. Cl i ni cal l y ,
hy per gl y cem i ai nduced hy ponatr em i a i s f r equentl y encounter ed i n the
setti ngs of di abeti c k etoaci dosi s and nonk etoti c hy per osm ol ar com a. To
deter m i ne w hether a pati ent has a sodi um or w ater def i ci t, the ser um
sodi um l ev el shoul d
P. 427
be esti m ated as i f the pati ent w er e nor m ogl y cem i c. The cor r ecti on f actor
i s as f ol l ow s: f or each 100m g/dL i ncr ease i n the ser um gl ucose l ev el ,
the ser um sodi um concentr ati on decr eases by 1. 6 m Eq/L. For ex am pl e, i f
the sodi um concentr ati on i s 109 m Eq/L and the ser um gl ucose content i s
1, 600 m g/dL, the cor r ected sodi um concentr ati on (N a c ) w oul d be
cal cul ated as f ol l ow s:
Ther ef or e, the ser um sodi um concentr ati on al w ay s needs to be

i nter pr eted i n l i ght of the gl ucose concentr ati on. Ev ents i denti cal to these
occur w i th ex ogenous m anni tol adm i ni str ati on.
In pseudohy ponatr em i a, the ser um sodi um concentr ati on i s l ow but the
ser um osm ol al i ty i s nor m al . It occur s i n setti ngs of sev er e hy per l i pi dem i a
and hy per pr otei nem i a, and i s r ar e. The m echani sm r esponsi bl e f or the
l ow ser um sodi um concentr ati on caused by hy per l i pi dem i a and
hy per pr otei nem i a di f f er s f r om that of hy per gl y cem i a. At ex tr em el y
el ev ated concentr ati ons, both l i pi d and pr otei n cause the sodi um
di str i buti on space (i . e. , pl asm a w ater space) to be decr eased. Al though
the sodi um concentr ati on i n pl asm a w ater i s nor m al , i t i s decr eased i n
the total pl asm a because of ex cess l i pi d or pr otei n.
2. What i s the under l y i ng pathogenesi s of hy ponatr em i a?
Hy ponatr em i a ar i ses w hen ur i nar y di l uti on i s abnor m al . The abi l i ty to

ex cr ete a l ar ge v ol um e of sol utef r ee w ater depends on thr ee f actor s: (a)
nor m al f l ui d del i v er y to the di stal nephr on (i . e. , nor m al GFR and nor m al
pr ox i m al tubul e r eabsor pti on); (b) nor m al f uncti oni ng of the thi ck
ascendi ng l i m b of Henl e and the cor ti cal di l uti ng segm ents, w hi ch ar e
si tes of ur i nar y di l uti on; and (c) the absence of v asopr essi n i n the
ci r cul ati on, ther eby al l ow i ng the col l ecti ng duct to r em ai n w ater
i m per m eabl e. In the pr esence of v asopr essi n, the tubul ar f l ui d
equi l i br ates osm oti cal l y w i th the i sotoni c or hy per toni c ur i ne, ther eby
pr ev enti ng the ex cr eti on of m ax i m al l y di l ute ur i ne.
3. What i s the di agnosti c appr oach to hy ponatr em i a, and w hat ar e i ts m ajor
causes?
Once hy ponatr em i a i s conf i r m ed, the nex t step i s to deter m i ne w hether i t
i s associ ated w i th a l ow , nor m al , or hi gh total body sodi um
concentr ati on. U sual l y , a phy si cal ex am i nati on can di sti ngui sh am ong
these possi bi l i ti es. Or thostati c hy potensi on and f l at neck v ei ns ar e seen
i n pati ents w i th a l ow total body sodi um content. Edem a and asci tes ar e
com m on f i ndi ngs i n pati ents w i th a hi gh total body sodi um content.
Pati ents w i th nor m al total body sodi um ex hi bi t nei ther or thostati c
changes nor edem a. The m ajor causes of each categor y of sodi um
concentr ati on ar e sum m ar i zed i n Tabl e 921.
4. What ar e som e of the dr ugs that pr oduce hy ponatr em i a?
Dr ugs can i m pai r w ater ex cr eti on ei ther by enhanci ng the r enal acti on of
v asopr essi n or by causi ng r el ease of the hor m one. Som e of the m or e
com m on agents ar e l i sted i n Tabl e 922.
P. 428
5. What ar e the m ost com m on di sor der s associ ated w i th SIADH?
In hospi tal i zed pati ents, SIADH i s the m ost com m on cause of
hy ponatr em i a. Thi s i s br oadl y due to a m al i gnancy , pul m onar y di sor der ,
or centr al ner v ous sy stem di sor der , as show n i n Tabl e 923.
Table 921 Causes of Hyponatremia
Hypovole mia (De c re a s e d Euvole mia (Ne a r Hype rvole mia

Tota lBody Sodium) Norma l Tota lBody (Inc re a s e d Tota l
Sodium) Body Sodium)
Ex tr ar enal sodi um Di ur eti cs Ex tr ar enal
l osses Hy pothy r oi di sm di sor der s
Vom i ti ng Gl ucocor ti coi d Congesti v e
(steady state) def i ci ency hear t
Di ar r hea Dr ugs f ai l ur e
Fl ui d Pai n or Hepati c
sequestr ati on em oti onal ci r r hosi s
in str ess Renal di sor der s
Per i toni ti s Respi r ator y N ephr oti c
Pancr eati ti s f ai l ur e sy ndr om e
Rhabdom y ol y si s Posi ti v e Acute
Bur ns pr essur e r enal
Renal sodi um l osses br eathi ng f ai l ur e
Di ur eti cs Sy ndr om e of Chr oni c
Osm oti c di ur esi s i nappr opr i ate r enal
(gl ucose, ur ea, anti di ur eti c f ai l ur e
m anni tol ) hor m one
Mi ner al ocor ti coi d secr eti on
def i ci ency
Sal tl osi ng nephr i ti s
Case
A 68y ear ol d m an i s hospi tal i zed because of a per si stent cough and 20l b (9
k g) w ei ght l oss dur i ng the l ast 3 m onths. He has a 40pack y ear sm ok i ng
hi stor y . On phy si cal ex am i nati on, he i s f ound to be sl i ghtl y conf used and sl ow
to r espond. Ther e ar e no or thostati c changes i n hi s bl ood pr essur e or pul se.
Chest ex am i nati on r ev eal s f i ndi ngs com pati bl e w i th a l ef t pl eur al ef f usi on.
Abdom i nal ex am i nati on r ev eal s no m asses or or ganom egal y . Ther e i s no
edem a. He w ei ghs 60 k g.
The f ol l ow i ng l abor ator y v al ues ar e r epor ted: sodi um , 109 m Eq/L; potassi um ,
3. 4 m Eq/L; chl or i de, 78 m Eq/L; bi car bonate, 24 m Eq/L; BU N , 4 m g/dL;
gl ucose, 85 m g/dL; ur i c aci d, 3. 5 m g/dL; ser um osm ol al i ty , 230 m Osm ; and
ur i ne osm ol al i ty , 300 m Osm . A chest r adi ogr aphi c study show s a l ef t pl eur al
ef f usi on. Pur i f i ed pr otei n der i v ati v e (PPD) testi ng i s posi ti v e.
The pati ent's ser um sodi um concentr ati on i ncr eases to 133 m Eq/L w i thi n 24
hour s. At that ti m e, the pati ent i s noted to be al er t and hi s behav i or
appr opr i ate. How ev er , by the nex t day , he has becom e uncom m uni cati v e and
agi tated.
1. What ar e the m ost l i k el y causes of hy ponatr em i a i n thi s pati ent, and

w hy ?
2. How do the ser um potassi um , BU N , and ur i c aci d l ev el s hel p i n the
assessm ent of thi s pati ent?
P. 429
3. What ar e the pr i m ar y consi der ati ons i n tr eati ng pati ents w i th
hy ponatr em i a, and how shoul d thi s pati ent's condi ti on be m anaged?
Table 922 Drugs Associated with
Hyponatremia
Anti di ur eti c hor m one anal ogs

Deam i nodar gi ni ne v asopr essi n
Ox y toci n
Dr ugs that enhance anti di ur eti c hor m one r el ease
Chl or pr opam i de
Cl of i br ate
Car bam azepi neox car bazepi ne
Vi ncr i sti ne
N i coti ne
N ar coti cs (Âµopi oi d r eceptor s)
Anti psy choti cs or anti depr essants a
Dr ugs that potenti ate r enal acti on of anti di ur eti c hor m one
Chl or pr opam i de
Cy cl ophospham i de
N onster oi dal anti i nf l am m ator y dr ugs
Acetam i nophen
Dr ugs that cause hy ponatr em i a by unk now n m echani sm s
Hal oper i dol
Fl uphenazi ne
Am i tr i pty l i ne
Ser otoni n uptak e i nhi bi tor s
â€œEcstacy â€ (am phetam i ne r el ated)
a Anti di ur eti c hor m one r el ease m ay be secondar y to under l y i ng
psy chosi s.
Fr om Ber l T, Schr i er RW. Di sor der s of w ater m etabol i sm . In:

Schr i er RW, ed. Renal and el ectr ol y te di sor der s, 6th ed.
Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:45. Repr i nted
w i th per m i ssi on.
4. What coul d account f or thi s pati ent's neur ol ogi c deter i or ati on af ter hi s
i ni ti al i m pr ov em ent?
Case Discussion
1. What ar e the m ost l i k el y causes of hy ponatr em i a i n thi s pati ent, and
w hy ?
Thi s pati ent appear s to hav e hy ponatr em i a associ ated w i th a nor m al
total body sodi um concentr ati on because ther e ar e nei ther or thostati c
changes nor edem a. He ther ef or e has euv ol em i c hy ponatr em i a. Pi tui tar y
i nsuf f i ci ency appear s cl i ni cal l y unl i k el y and no w ater r etai ni ng
m edi cati ons ar e pr esent, ther eby m ak i ng SIADH the m ost l i k el y cause of
the hy ponatr em i a. The tw o l eadi ng di agnoses ar e l ung cancer or
pul m onar y tuber cul osi s. In SIADH, a pati ent i s sl i ghtl y v ol um e ex panded.
Ther ef or e, as i n thi s pati ent, the BU N and ur i c aci d l ev el s tend to be l ow .
Fr om the cl i ni cal
P. 430
poi nt of v i ew , SIADH i s the m ost l i k el y di agnosi s i n thi s pati ent, but
hy pothy r oi di sm shoul d al so be consi der ed.
Table 923 The Most Common Disorders
Associated with the Syndrome of
Inappropriate Secretion of Antidiuretic
Hormone
Mal i gnancy
Lung
Duodenum
Pancr eas
Ly m phom a
Pul m onar y di sor der s
Pneum oni a
Abscess
Asper gi l l osi s
Respi r ator y f ai l ur e
Posi ti v epr essur e br eathi ng
Centr al ner v ous sy stem di sor der s
N eopl asm
Encephal i ti s
Meni ngi ti s
Br ai n abscess
Head tr aum a
Gui l l ai nBar r Ã© sy ndr om e
Subdur al or subar achnoi d hem or r hage
Acute i nter m i ttent por phy r i a
Acute psy chosi s
Str ok e
Other
AIDS
Pr ol onged ex er ci se
Idi opathi c (el der l y )
AIDS, acqui r ed i m m unodef i ci ency sy ndr om e.
Modi f i ed f r om Ber l T, Schr i er RW. Di sor der s of w ater

m etabol i sm . In: Schr i er RW, ed. Renal and el ectr ol y te di sor der s,
6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s & Wi l k i ns, 2003:47.
2. How do the ser um potassi um , BU N , and ur i c aci d l ev el s hel p i n the

assessm ent of thi s pati ent?
The ser um potassi um concentr ati on of 3. 4 m Eq/L and the BU N v al ue of 5
m g/dL v i r tual l y r ul e out adr enal i nsuf f i ci ency because thi s i s
char acter i zed by a hy per k al em i c aci dosi s and an el ev ati on i n the BU N and
ser um cr eati ni ne l ev el s as a consequence of v ol um e contr acti on. Al though
the l ow ser um potassi um concentr ati on br i ngs i nto questi on the use of
di ur eti cs, the l ow ur i c aci d l ev el m ak es thi s unl i k el y . A l ow ur i c aci d
l ev el i s com m onl y obser v ed i n the setti ng of SIADH.
P. 431
3. What ar e the pr i m ar y consi der ati ons i n tr eati ng pati ents w i th
hy ponatr em i a, and how shoul d thi s pati ent's condi ti on be m anaged?
The opti m al tr eatm ent f or sev er e hy ponatr em i a i s sti l l contr ov er si al

because al though pr of ound hy ponatr em i a i s associ ated w i th hi gh m or tal i ty
and m or bi di ty , i ts r api d cor r ecti on m ay cause the f or m ati on of neur ol ogi c
l esi ons, w hi ch ar e usual l y i r r ev er si bl e. The pr i m ar y consi der ati ons i n the
ther apy ar e the acuteness or chr oni ci ty of the pr ocess and the pr esence
or absence of neur ol ogi c sy m ptom s attr i butabl e to hy ponatr em i a. The
f ol l ow i ng ar e gener al tr eatm ent gui del i nes.
In the setti ng of a c ute s ymptoma tic hypona tre mia w i th a change i n
m ental status or sei zur es, the r i sk f or com pl i cati ons stem m i ng f r om
cer ebr al edem a ex ceeds the r i sk of com pl i cati ons due to r api d tr eatm ent.
The pati ent shoul d r ecei v e f ur osem i de and hy per toni c sal i ne unti l
conv ul si ons subsi de.
As ymptoma tic hypona tre mia i s al m ost al w ay s chr oni c, and r api d
cor r ecti on i s l i k el y to do m or e har m than good. The tr eatm ent i n these
pati ents shoul d consi st of w ater r estr i cti on r egar dl ess of thei r ser um
sodi um status.
In the setti ng of s ymptoma tic hypona tre mia of chr oni c or unk now n
dur ati on, the ser um sodi um l ev el shoul d be r ai sed pr om ptl y by
appr ox i m atel y 10 m Eq/L thr ough the adm i ni str ati on of hy per toni c sal i ne,
and then w ater r estr i cti on. A cor r ecti on r ate of 1 to 2 m Eq/L per hour at
any gi v en ti m e or an i ncr ease i n the ser um sodi um l ev el by m or e than 12
m Eq per day shoul d not be ex ceeded.
In the pr esent case, because the pati ent i s sy m ptom ati c, i t i s pr udent to
cor r ect the ser um sodi um l ev el to appr ox i m atel y 120 m Eq/L i n 8 to 12
hour s. The sol utef r ee w ater l oss needed to accom pl i sh thi s m ay be
esti m ated by m ul ti pl y i ng total body w ater Ã— (1 actual ser um
sodi um /desi r ed ser um sodi um ). Ther ef or e, to cor r ect the ser um sodi um i n
thi s 60k g m an f r om 109 to 120 m Eq/L, he m ust hav e a negati v e w ater
bal ance of 60 Ã— 0. 6 Ã— (1 109/120) = 3. 3 L. Thi s m ay be
accom pl i shed by i nf usi ng nor m al sal i ne at a r ate of 250 m L per hour
w hi l e r epl aci ng ur i nar y sodi um l osses w i th 3% sal i ne so as to achi ev e a
net sol utef r ee w ater l oss. A si ngl e i njecti on of f ur osem i de (20 m g IV)
m ay be adm i ni ster ed to pr om ote di ur esi s; ur i nar y potassi um l osses
shoul d be r epl aced. The ser um sodi um concentr ati on m ay be r ai sed by
1. 0 to 1. 5 m Eq/L per hour . Once the ser um sodi um l ev el has i ncr eased by
appr ox i m atel y 10 m Eq/L, thi s r egi m en shoul d be di sconti nued.
As f or the l ongter m m anagem ent of thi s pati ent, w ater r estr i cti on to
1, 000 m L per day i s the tr eatm ent of choi ce. How ev er , because
com pl i ance m ay be di f f i cul t to achi ev e, dem ecl ocy cl i ne can be gi v en. Thi s
dr ug i nter f er es w i th the anti di ur eti c hor m one ef f ect on the k i dney and
r esul ts i n m or e di l ute ur i ne. If the pati ent's pr i m ar y di sease, l ung cancer ,
or tuber cul osi s r esponds to tr eatm ent, thi s w oul d l i k el y pr om ote
r esol uti on of the SIADH. N ov el v asopr essi n antagoni sts that hav e
aquar eti c pr oper ti es ar e l i k el y to be pr ef er abl e to dem ecl ocy cl i ne.
4. What coul d account f or thi s pati ent's neur ol ogi c deter i or ati on af ter hi s
i ni ti al i m pr ov em ent?
Thi s pati ent's ser um sodi um l ev el i ncr eased by 24 m Eq/L i n the f i r st 24
hour s. Thi s, ther ef or e, puts hi m at r i sk f or dev el opm ent of osm oti c
dem y el i nati on (OD) that i s char acter i zed by a f l acci d quadr i par esi s,
i m pai r ed speech and sw al l ow i ng,
P. 432
f aci al w eak ness, and poor r esponse to pai nf ul sti m ul i . Pathol ogi cal l y , l oss
of m y el i n ar ound ner v e sheaths can be seen i n ponti ne as w el l as
ex tr aponti ne ar eas. The pathogenesi s of thi s l esi on r em ai ns unk now n.
Ther e ar e sev er al r i sk f actor s f or the dev el opm ent of OD, i ncl udi ng
al cohol i sm , m al nutr i ti on, and bur ns, and i t i s al so seen i n w om en tak i ng
thi azi de di ur eti cs. The r esul ts of hum an and ani m al studi es suggest that
r api d cor r ecti on of sev er e chr oni c hy ponatr em i a m ay be associ ated w i th
OD, w her eas the hy ponatr em i a i tsel f i s unr el ated.
The f i ndi ngs f r om studi es of osm oti cal l y i nacti v e sol utes (such as am i no
aci ds, m y oi nosi tol , sor bi tol , and m ethy l am i ne) m ay hav e i m pl i cati ons f or
the pathogenesi s of OD. The i ntr acel l ul ar l ev el s of these sol utes decr ease
sl ow l y dur i ng the adaptati on to changes i n ex tr acel l ul ar osm ol al i ty so that
the cel l v ol um e i s m ai ntai ned. Ther ef or e, i n the setti ng of chr oni c
hy ponatr em i a, the r api d i ncr ease i n ex tr acel l ul ar osm ol al i ty m ay shr i nk
br ai n cel l s, w hi ch hav e di m i ni shed osm oti cal l y acti v e sol utes as a
consequence of adaptati on to the chr oni c hy ponatr em i a.
Suggested Readings
Ber l T, Schr i er RW. Di sor der s of w ater m etabol i sm . In: Schr i er RW, ed.
Renal and el ectr ol y te di sor der s, 6th ed. Phi l adel phi a: Li ppi ncott Wi l l i am s &
Wi l k i ns, 2003:1.
Par i k h C, Kum ar S, Ber l T. Di sor der s of w ater bal ance. In: Johnson R,
Feehal l y J, eds. Com pr ehensi v e cl i ni cal nephr ol ogy , 2nd ed. Mosby , 2003.
3rd Edition
> T a b le o f C o nte nts > C ha p te r 10 R he um a to lo g y
Chapter 10
Rheumatology
Robe rt W . Ja ns on
Ankylosing Spondylitis
1. What ar e thr ee possi bl e causes of l ow back pai n (LBP) i n y oung m en?
2. What f eatur es i n the hi stor y and phy si cal ex am i nati on ar e hel pf ul i n
di f f er enti ati ng i nf l am m ator y LBP i n ank y l osi ng spondy l i ti s (AS) f r om
m echani cal LBP?
3. What f i v e di seases ar e cl assi f i ed as ser onegati v e

spondy l oar thr opathi es?
4. What i s the def i ni ti on of sci ati ca and w hat ar e thr ee possi bl e causes of
i t?
P. 434
Discussion
1. What ar e thr ee possi bl e causes of LBP i n y oung m en?
Thr ee possi bl e causes of back pai n i n y oung m en i ncl ude l um bosacr al
m uscl e spasm , a r uptur ed i nter v er tebr al di sc, and AS or another
ser onegati v e spondy l oar thr opathy . For m s of com m on autoi m m une and
chr oni c i nf l am m ator y di seases, such as r heum atoi d ar thr i ti s (RA) or
sy stem i c l upus er y them atosus (SLE), r ar el y i nv ol v e the joi nts of the
l ow back . Ther ef or e, LBP i s not one of the i ni ti al sy m ptom s of these
di sor der s.
2. What f eatur es i n the hi stor y and phy si cal ex am i nati on ar e hel pf ul i n
di f f er enti ati ng i nf l am m ator y LBP i n AS f r om m echani cal LBP?
Infla mma tory LBP Me c ha nic a l LBP
Age at onset < 40 y Any age

Ty pe of onset Insi di ous Acute
Sy m ptom dur ati on > 3 m o < 4 w k
Mor ni ng sti f f ness > 60 m i n < 30 m i n
N octur nal pai n Fr equent Absent
Ef f ect of ex er ci se Im pr ov em ent Ex acer bati on
Sacr oi l i ac joi nt tender ness Fr equent Absent
Back m obi l i ty Loss i n al l pl anes Abnor m al f l ex i on
Chest ex pansi on Of ten decr eased N or m al
N eur ol ogi c def i ci ts U nusual Possi bl e
LBP, l ow back pai n.
3. What f i v e di seases ar e cl assi f i ed as ser onegati v e

spondy l oar thr opathi es?
The spondy l oar thr opathi es consi st of AS, r eacti v e ar thr i ti s (f or m er l y
k now n as Rei ter 's sy ndr om e), psor i ati c ar thr i ti s, ar thr i ti s secondar y to
i nf l am m ator y bow el di sease, and undi f f er enti ated spondy l oar thr opathy .
4. What i s the def i ni ti on of sci ati ca, and w hat ar e thr ee possi bl e causes of
i t?
Sci ati ca i s def i ned as back pai n that r adi ates l ater al l y dow n one l eg
bel ow the k nee. The pai n i s usual l y shar p or bur ni ng. Sci ati ca usual l y
occur s as a consequence of l um bar spondy l osi s (degener ati v e di sc or
f acet joi nt di sease) and can be associ ated w i th a r uptur ed
i nter v er tebr al di sc or an i di opathi c sci ati c ner v e i r r i tati on. Inf ecti ous,
neopl asti c, and i nf i l tr ati v e di sor der s shoul d al w ay s be consi der ed.
Case
A 34y ear ol d w hi te m an com pl ai ns of neck pai n. At the age of 22, the
pati ent f i r st noted l ow back , buttock , and spi ne pai n. He had been i nv ol v ed
i n a m otor v ehi cl e acci dent to w hi ch he attr i buted som e of hi s back pai n. At
that ti m e, he saw a num ber of phy si ci ans w ho di agnosed m echani cal LBP
and r ecom m ended bed r est. How ev er , he f ound thi s onl y seem ed to m ak e
hi s back and buttock pai n w or se. Ty pi cal l y , he w as v er y sti f f i n the
P. 435
m or ni ng f or m or e than 2 hour s but i n the af ter noon he f el t better w i th
m ov em ent and ex er ci se. He al so noted i ncr easi ng f ati gue and som e m i l d
w ei ght l oss. Ten y ear s ago, hi s r i ght hi p star ted hur ti ng. Ei ght y ear s ago,
pai n suddenl y dev el oped i n hi s r i ght ey e. He saw an ophthal m ol ogi st w ho
di agnosed acute i r i ti s and pl aced hi m on ster oi d ey e dr ops. Tw o y ear s ago,
hi s k nees star ted to sw el l i nter m i ttentl y . Hi s l um bar and thor aci c spi ne
r egi ons becam e f used and to stand up and l ook str ai ght ahead he had to
bend hi s k nees. He f i nal l y had to qui t hi s job as a tr uck dr i v er because i t
r equi r ed pr ol onged si tti ng that m ade hi s back pai n and sti f f ness w or se.
Muscul osk el etal ex am i nati on r ev eal s no obv i ous sw el l i ng i n any joi nt. N o
m ov em ent i n the l um bar or thor aci c spi ne i s noted w hi l e the pati ent i s
bendi ng ov er . Hi s r i ght hi p i s f ound to be pai nf ul on f l ex i on w i th i nter nal
r otati on.
Radi ogr aphi c studi es of the l um bosacr al spi ne ar e obtai ned and i nter pr eted
to show al m ost com pl ete obl i ter ati on of both sacr oi l i ac joi nt spaces. The
poster i or el em ents i n the di stal l um bar ar ea ar e al so f ound to be
obl i ter ated, together w i th br i dgi ng or â€œbam booi ngâ€ of the spi ne. A chest
r adi ogr aphi c study show s squar i ng of the thor aci c v er tebr ae w i th si gni f i cant
sy ndesm ophy te f or m ati on.
1. Wher e i s the pr i m ar y si te of di sease i n AS?

2. What or gans can be i nv ol v ed i n AS, and w hat ar e the cl i ni cal
m ani f estati ons?
3. What ar e thr ee char acter i sti c cl i ni cal f i ndi ngs i n pati ents w i th AS that
hel p di sti ngui sh i t f r om RA?
4. What i s the char acter i sti c f am i l y hi stor y , gender i nci dence, and hum an
l y m phocy te anti gen (HLA) patter n f ound i n the contex t of AS?
5. What ty pes of tr eatm ent ar e hel pf ul i n AS?
Case Discussion
1. Wher e i s the pr i m ar y si te of di sease i n AS?
In AS, i nf l am m ati on occur s at the i nser ti on of a l i gam ent, tendon, or
ar ti cul ar capsul e i nto bone, a str uctur e k now n as the enthesi s. The
cause of thi s l ocal i zed i nf l am m ati on r em ai ns unk now n. Si tes of
enthesopathy i n AS i ncl ude the sacr oi l i ac joi nts; l i gam entous str uctur es
of the i nter v er tebr al di scs, m anubr i oster nal joi nts, and sy m phy si s
pubi s; l i gam entous attachm ents i n the spi nous pr ocesses, the i l i ac
cr ests (w hi sk er i ng), tr ochanter s, patel l ae, cl av i cl es, and cal canei
(Achi l l es enthesi ti s or pl antar f asci i ti s); and capsul es and i ntr acapsul ar
l i gam ents of l ar ge sy nov i al joi nts. Inf l am m ati on can al so be seen i n the
sy nov i um , the ti ssue l i ni ng the joi nts.
2. What or gans can be i nv ol v ed i n AS, and w hat ar e the cl i ni cal
m ani f estati ons?
Ocul ar i nv ol v em ent pr esents as anter i or uv ei ti s (25% to 40% of

pati ents); secondar y gl aucom a and catar acts can al so occur . Car di ac
i nv ol v em ent i ncl udes aor ti c i nsuf f i ci ency , aor ti ti s, conducti on
abnor m al i ti es, di astol i c dy sf uncti on, and per i car di ti s. Pul m onar y
i nv ol v em ent i ncl udes upper l obe f i br osi s and r estr i cti v e changes. Renal
i nv ol v em ent i ncl udes IgA nephr opathy , secondar y am y l oi dosi s, and
chr oni c pr ostati ti s. Per i pher al joi nt i nv ol v em ent (par ti cul ar l y hi ps and
shoul der s) can occur i n appr ox i m atel y 30% of pati ents. Si gni f i cant
spi nal osteopor osi s can occur . N eur ol ogi c i nv ol v em ent i ncl udes
atl antoax i al subl ux ati ons and cauda equi na sy ndr om e.
P. 436
3. What ar e thr ee char acter i sti c cl i ni cal f i ndi ngs i n pati ents w i th AS that
hel p di sti ngui sh i t f r om RA?
The thr ee cl i ni cal m ani f estati ons char acter i sti c of AS ar e i nf l am m ator y
ar thr i ti s of the spi ne, Achi l l es tendi ni ti s, and pl antar f asci i ti s. These
thr ee f i ndi ngs ar e ex tr em el y r ar e i n pati ents w i th RA.
4. What i s the char acter i sti c f am i l y hi stor y , gender i nci dence, and HLA
patter n f ound i n the contex t of AS?
Ty pi cal l y , ther e i s a f am i l y hi stor y of AS, par ti cul ar l y i n m al e f am i l y

m em ber s. In f act, i t occur s m or e com m onl y i n m en than w om en (3:1).
Thi s di sease i s v er y hi ghl y associ ated w i th the pr esence of HLAB27.
Tw o per cent of HLAB27â€“posi ti v e per sons dev el op AS. Am ong those
HLAB27â€“posi ti v e per sons w i th an af f ected f i r stdegr ee r el ati v e, the
r ate r i ses to 15% to 20%.
5. What ty pes of tr eatm ent ar e hel pf ul i n AS?
The tr eatm ent of AS i ncl udes nonster oi dal anti i nf l am m ator y dr ugs
(N SAIDs), ex tensi on ex er ci ses f or the back , and phy si cal ther apy . It i s
r ecom m ended that al l thr ee f or m s of ther apy be used i n af f ected
pati ents. It i s thought that ex tensi on ex er ci ses f or the back m ay hel p
pati ents m ai ntai n a m or e nor m al upr i ght postur e as the back f uses ov er
ti m e. Sul f asal azi ne or l ow dose w eek l y m ethotr ex ate (MTX) ther apy
m ay be benef i ci al i n pati ents hav i ng pr ogr essi v e di sease w i th
per i pher al ar thr i ti s but does not al ter the sacr oi l i i ti s. Or al
cor ti coster oi ds ar e of no v al ue. Local cor ti coster oi d i njecti ons m ay be
usef ul i n the tr eatm ent of enthesopathi es and r ecal ci tr ant per i pher al
sy nov i ti s. The tum or necr osi s f actor Î± (TN FÎ± ) bl ock i ng dr ugs ar e
v er y ef f ecti v e i n AS, act on both spi nal and per i pher al joi nts, and m ay
possi bl y del ay or pr ev ent spi nal ank y l osi s (tr eatm ent r esul ts i n
i m pr ov em ent i n m agneti c r esonance i m agi ng (MRI) appear ance of
enthesi ti s and sacr oi l i i ti s). The use of anti TN F agents shoul d be
consi der ed i n pati ents w i th acti v e AS w ho hav e f ai l ed to r espond to tw o
or m or e N SAIDs f or ax i al di sease and one or m or e di seasem odi f y i ng
anti r heum ati c dr ug (DMARD) f or per i pher al ar thr i ti s.
Suggested Readings
Hasl ock I. Ank y l osi ng spondy l i ti s: m anagem ent. In: Hochber g MC,
Si l m an AJ, Sm ol en JS, et al . eds. Rheum atol ogy , 3r d ed. Edi nbur gh:
Mosby , 2003:1211â€“1224.
Janson RW. Ank y l osi ng spondy l i ti s. In: West SG, ed. Rheum atol ogy
secr ets, 2nd ed. Phi l adel phi a: Hanl ey & Bel f us, 2002:255â€“261.
Khan MA. Cl i ni cal f eatur es of ank y l osi ng spondy l i ti s. In: Hochber g MC,
Mosby , 2003:1161â€“1182.
Van der Li nden S, Van der Hei jde D, Br aun J. Ank y l osi ng spondy l i ti s. In:
Har r i s ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of
r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er Saunder s, 2005:1125â
€“1141.
CrystalInduced Arthritis
1. What ar e thr ee di f f er ent f or m s of cr y stal i nduced ar thr i ti s, and w hat
ar e the cr y stal s i nv ol v ed?
P. 437
2. What ar e f our di f f er ent di seases that char acter i sti cal l y pr esent w i th
ar thr i ti s of a si ngl e joi nt?
3. What thr ee joi nts ar e m ost com m onl y i nv ol v ed i n acute attack s of gout?
4. What ar e som e hi stor i cal f eatur es of ten f ound i n pati ents w i th gout?
5. What ar e thr ee l abor ator y test f i ndi ngs that m ay be abnor m al i n the
setti ng of gout?
Discussion
1. What ar e thr ee di f f er ent f or m s of cr y stal i nduced ar thr i ti s, and w hat
ar e the cr y stal s i nv ol v ed?
Gout i s a cr y stal i nduced ar thr i ti s due to the deposi ti on of m onosodi um
ur ate (MSU ) cr y stal s. Pseudogout r esul ts f r om the f or m ati on and
r el ease of cal ci um py r ophosphate di hy dr ate (CPPD) cr y stal s. The
deposi ti on of hy dr ox y apati te cr y stal s can i nduce acute i nf l am m ator y
ar thr i ti des such as cal ci f i c per i ar thr i ti s/tendi ni ti s and the Mi l w auk ee
shoul der sy ndr om e, a destr ucti v e ar thr opathy of the shoul der
associ ated w i th r otator cuf f def ects.
2. What ar e f our di f f er ent di seases that char acter i sti cal l y pr esent w i th
ar thr i ti s of a si ngl e joi nt?
Ar thr i ti s of a si ngl e joi nt (m onoar ti cul ar ar thr i ti s) m ay be the i ni ti al
sy m ptom of septi c ar thr i ti s, cr y stal deposi ti on di seases, tr aum ati c
ar thr i ti s, and other causes such as osteoar thr i ti s (OA), coagul opathy ,
av ascul ar necr osi s, and pi gm ented v i l l onodul ar sy nov i ti s. Other
hi stor i cal and cl i ni cal f eatur es m ay be used to di sti ngui sh am ong these
thr ee di agnoses. A def i ni ti v e di agnosi s i s m ade on the basi s of the
f i ndi ngs y i el ded by sy nov i al f l ui d ex am i nati on i ncl udi ng cel l count w i th
di f f er enti al , Gr am 's stai n and cul tur e, and pol ar i zed l i ght m i cr oscopy
f or cr y stal anal y si s.
3. What thr ee joi nts ar e m ost com m onl y i nv ol v ed i n acute attack s of gout?
Acute gout m ost com m onl y ar i ses i n the f i r st m etatar sophal angeal
(MTP) joi nt; thi s i s k now n as podagr a. The nex t m ost com m onl y
i nv ol v ed si tes ar e the i nstep and ank l e. Knees, w r i sts, f i nger s, and
el bow s can al so be i nv ol v ed. Gout has a pr edi l ecti on f or cool ,
per i pher al joi nts w her e the sol ubi l i ty of MSU cr y stal s m ay be
di m i ni shed as a r esul t of the cool er tem per atur e.
4. What ar e som e hi stor i cal f eatur es of ten f ound i n pati ents w i th gout?
Pati ents w i th gout m ay hav e a posi ti v e f am i l y hi stor y f or the di sease,

par ti cul ar l y i n m al e m em ber s. Gout i s al so m or e com m on i n peopl e
w ho hav e a hi stor y of obesi ty , m etabol i c sy ndr om e, or al cohol i sm .
Acute attack s of gout m ay occur dur i ng or af ter an epi sode of
ex cessi v e al cohol i ngesti on, ex cess di etar y pur i ne i ntak e, tr aum a,
acute m edi cal i l l ness, or sur ger y . The attack s com m onl y begi n abr uptl y
dur i ng the ni ght or ear l y m or ni ng hour s.
5. What ar e the thr ee l abor ator y test f i ndi ngs that m ay be abnor m al i n
the setti ng of gout?
Pati ents w i th acute attack s of gout of ten hav e a m i l d l euk ocy tosi s and
an el ev ated er y thr ocy te sedi m entati on r ate (ESR). To dev el op gout,
these pati ents hav e to be chr oni cal l y hy per ur i cem i c, def i ned as a
ser um ur i c aci d l ev el gr eater
P. 438
than 7. 0 m g/dL i n m en and 6. 0 m g/dL i n w om en. At the ti m e of an
acute attack , up to 30% of pati ents m ay hav e a nor m al ser um ur i c aci d
l ev el .
Case
A 52y ear ol d m an com es to the em er gency r oom com pl ai ni ng of pai n i n hi s
bi g toe. He w as w el l unti l 5:00 thi s m or ni ng, w hen he w as aw ak ened by an
achi ng pai n i n hi s r i ght gr eat toe. Wi thi n a f ew hour s, the joi nt w as dusk y
r ed and hot, and w as ex qui si tel y tender to the poi nt that ev en the w ei ght of
the beddi ng hur t hi s toe. By 8:00 a. m . , the pati ent coul d bear onl y par ti al
w ei ght on the f oot. The pati ent r epor ts a f ew sel f l i m i ted, tr i v i al epi sodes of
tw i nges of pai n i n thi s toe ov er the past y ear . The pati ent descr i bes f eel i ng
f ev er i sh w i thout r i gor s or chi l l s. Ther e i s no hi stor y of tr aum a to the f oot,
nor i s ther e a f am i l y hi stor y of ar thr i ti s or si m i l ar attack s. He i s tak i ng
hy dr ochl or othi azi de f or contr ol of hy per tensi on.
On phy si cal ex am i nati on, the pati ent i s f ound to be a stock y , ov er w ei ght,
and r edf aced m an. Hi s bl ood pr essur e i s 170/100 m m Hg, hi s pul se i s 90
beats per m i nute and r egul ar , and hi s tem per atur e i s 38Â°C (100. 4Â°F).
Sk i n ex am i nati on di scl oses no l esi ons or nodul es. On ex am i nati on of hi s
joi nts, al l show a nor m al r ange of m oti on w i thout sy nov i ti s or def or m i ty ,
ex cept f or the r i ght f i r st MTP joi nt, w hi ch show s sy nov i ti s, 2+ /4; w ar m th,
4+ /4; tender ness, 4+ /4; and er y them a at the base of the toe ex tendi ng onto
the dor sal aspect of the f or ef oot w i th sl i ght edem a.
The f ol l ow i ng l abor ator y v al ues ar e r epor ted: w hi te bl ood cel l (WBC) count
12, 500 cel l s/m m 3 w i th 92% pol y m or phonucl ear l euk ocy tes and 2% band
f or m s; ur i c aci d 9. 0 m g/dL; cr eati ni ne 1. 0 m g/dL. U r i nal y si s r ev eal s no r ed
bl ood cel l s or pr otei n. A r adi ogr aphi c study of the r i ght f oot di scl oses sof t
ti ssue sw el l i ng ar ound the r i ght f i r st MTP joi nt, but no er osi ons.
1. How i s the di agnosi s of gout establ i shed?

2. Why ar e hum ans pr edi sposed to dev el opi ng gout?
3. What ar e the f our r ev er si bl e secondar y causes of hy per ur i cem i a?
4. What ar e the f our cl i ni cal stages of gout?
5. What ar e the appr opr i ate ther api es f or an acute attack of gout and
chr oni c sy m ptom ati c hy per ur i cem i a?
Case Discussion
1. How i s the di agnosi s of gout establ i shed?
The di agnosi s of gout r equi r es aspi r ati on of sy nov i al f l ui d or a tophus
f or cr y stal anal y si s by pol ar i zed m i cr oscopy . MSU cr y stal s ar e needl e
shaped and negati v el y bi r ef r i ngent. In contr ast, CPPD cr y stal s
(pseudogout) ar e r hom boi dshaped and posi ti v el y bi r ef r i ngent. In gout,
sy nov i al f l ui d i s i nf l am m ator y (ty pi cal l y 20, 000 to 100, 000
l euk ocy tes/m m 3 ). The sy nov i al f l ui d shoul d be sent f or Gr am 's stai n
and cul tur e as i n r ar e cases, septi c joi nt f l ui ds can contai n MSU
cr y stal s. El ev ated ser um ur i c aci d l ev el s ar e not di agnosti c of gout as
m any i ndi v i dual s hav e asy m ptom ati c hy per ur i cem i a and nev er dev el op
gout.
P. 439
2. Why ar e hum ans pr edi sposed to dev el opi ng gout?
U r i c aci d i s the end pr oduct of the degr adati on of pur i nes. Hum ans l ack
the enzy m e ur i case, w hi ch ox i di zes ur i c aci d to the hi ghl y sol ubl e
com pound al l antoi n. The l ack of thi s enzy m e subjects hum ans to the
potenti al r i sk of dev el opi ng hy per ur i cem i a and gout. Al though hum ans
possess the ur i case gene, i t i s i nacti v e. U r i c aci d m ay hav e anti ox i dant
and f r ee r adi cal scav enger pr oper ti es.
3. What ar e the f our r ev er si bl e secondar y causes of hy per ur i cem i a?
The r ev er si bl e secondar y causes of hy per ur i cem i a i ncl ude al cohol

consum pti on, di ets contai ni ng pur i ner i ch f oods (m eats and or gan
m eats; seaf ood, par ti cul ar l y shel l f i sh), m edi cati ons that decr ease the
r enal ex cr eti on of ur i c aci d (cy cl ospor i ne, ni coti ni c aci d, di ur eti cs,
etham butol , l ow dose aspi r i n, py r azi nam i de), and obesi ty (w ei ght l oss
can i m pr ov e hy per ur i cem i a). The cur r ent di etar y r ecom m endati ons ar e
consum pti on of m eat, seaf ood, and al cohol hav e to be i n m oder ati on;
pur i ner i ch v egetabl es ar e acceptabl e; and l ow f at dai r y pr oducts and
w i ne m ay be pr otecti v e f r om gout.
4. What ar e the f our cl i ni cal stages of gout?
The f our stages of gout ar e asy m ptom ati c hy per ur i cem i a, acute gouty
ar thr i ti s, i nter cr i ti cal gout (the asy m ptom ati c i nter v al betw een
attack s), and chr oni c tophaceous gout. Many pati ents w i th
asy m ptom ati c hy per ur i cem i a do not pr ogr ess to gouty ar thr i ti s. Ther e
m ay not be shar p dem ar cati ons betw een the l ast thr ee stages of gout
because som e pati ents hav e both chr oni c tophaceous gout as w el l as
i nter m i ttent acute attack s.
5. What ar e the appr opr i ate ther api es f or an acute attack of gout and
chr oni c sy m ptom ati c hy per ur i cem i a?
The pr ef er r ed tr eatm ent f or an acute attack of gout i s an or al N SAID, i f
not contr ai ndi cated. Thi s shoul d be gi v en i n hi gh doses f or a f ew day s
f ol l ow ed by a taper i ng, w i th di sconti nuati on by 7 to 10 day s. Or al
col chi ci ne can onl y be used i n y ounger pati ents w i th nor m al r enal and
hepati c f uncti on. Its use i s l i m i ted by the hi gh i nci dence of acute
gastr oi ntesti nal si de ef f ects. Intr av enous col chi ci ne shoul d be av oi ded
because of the potenti al f or ex cess dosi ng i n hi ghr i sk pati ents, l i k el y
r esul ti ng i n death. Both or al l y and i ntr aar ti cul ar l y adm i ni ster ed
cor ti coster oi ds ar e ef f ecti v e i n the m anagem ent of acute attack s of
gout i n pati ents w ho ar e i ntol er ant of or hav e contr ai ndi cati ons to the
af or em enti oned m edi cati ons. Pati ents w i th chr oni c sy m ptom ati c
hy per ur i cem i a r equi r e l i f el ong ther apy w i th a ur atel ow er i ng
m edi cati on. Pr obeneci d, a ur i cosur i c, can be used i f they ar e r enal
under ex cr etor s of ur i c aci d (< 700 m g per 24 hour s), hav e a cr eati ni ne
cl ear ance gr eater than 50 m L per m i nute, and ar e not tak i ng m or e than
81 m g of aspi r i n per day . Al l opur i nol , a x anthi ne ox i dase i nhi bi tor , i s
i ndi cated i f they ar e ov er pr oducer s (> 700 m g per 24 hour s), hav e ur i c
aci d or cal ci um stones, or tophaceous di sease. Al l opur i nol i s m or e
com m onl y used as i t w or k s f or both under ex cr etor s and ov er pr oducer s
of ur i c aci d, and i s tak en onl y once dai l y w hi ch i ncr eases com pl i ance.
N ew ther api es under i nv esti gati on i ncl ude i ntr av enous pol y ethy l ene
gl y col (PEG)ur i case and f ebux ostat (a nonpur i ne, sel ecti v e i nhi bi tor of
x anthi ne ox i dase).
P. 440
Suggested Readings
Gi bson T. Cl i ni cal f eatur es of gout. In: Hochber g MC, Si l m an AJ, Sm ol en
JS, et al . eds. Rheum atol ogy , 3r d ed. Edi nbur gh: Mosby , 2003:1919â
€“1928.
Janson RW. Gout. In: West SG, ed. Rheum atol ogy secr ets, 2nd ed.
Phi l adel phi a: Hanl ey & Bel f us, 2002:325â€“333.
Ter k el taub R. Di seases associ ated w i th the ar ti cul ar deposi ti on of
cal ci um py r ophosphate dehy dr ate and basi c cal ci um phosphate cr y stal s.
In: Har r i s ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of
r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er Saunder s, 2005:1430â
€“1448.
Wor tm ann RL, Kel l ey WN . Gout and hy per ur i cem i a. In: Har r i s ED Jr ,
Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of r heum atol ogy , 7th
ed. Phi l adel phi a: El sev i er Saunder s, 2005:1402â€“1429.
Fibromyalgia
1. What i s the def i ni ti on of nonar ti cul ar r heum ati sm and w hat ar e the f our
f or m s of the di sor der ?
2. N am e f our com m on ty pes of tendi ni ti s and bur si ti s, and the m ajor
str uctur e i nv ol v ed i n each ty pe?
3. What ar e the cr i ter i a f or di agnosi s of f i br om y al gi a sy ndr om e (FMS)?
4. What ar e f i v e m edi cal i l l nesses that m ay ex hi bi t sy m ptom s si m i l ar to

those of FMS?
Discussion
1. What i s the def i ni ti on of nonar ti cul ar r heum ati sm , and w hat ar e the
f our f or m s of the di sor der ?
N onar ti cul ar r heum ati sm r ef er s to aches and pai ns that ar i se f r om
str uctur es outsi de of joi nts, so i t i s not actual l y a tr ue f or m of
ar thr i ti s. Four f or m s of nonar ti cul ar r heum ati sm ar e tendi ni ti s, bur si ti s,
FMS, and the m y of asci al pai n sy ndr om e. Tendi ni ti s i nv ol v es
i nf l am m ati on and pai n i n speci f i c tendons and i s usual l y due to str ess
or ov er use. Bur sae ar e sy nov i um l i ned sacs that ei ther ov er l i e or ar e
adjacent to joi nts and m ay al so becom e i nf l am ed secondar y to ov er use.
FMS i s a di f f use chr oni c pai n di sor der that i s di scussed i n l ater
questi ons. The m y of asci al pai n sy ndr om e, som eti m es ter m ed r epeti ti v e
str ai n sy ndr om e, consi sts of l ocal i zed (one anatom i c r egi on) tender and
pai nf ul m uscl es i n the absence of any ev i dence of an i nf l am m ator y
m uscl e di sease or FMS.
2. N am e f our com m on ty pes of tendi ni ti s and bur si ti s, and the m ajor
str uctur e i nv ol v ed i n each ty pe?
â€œTenni s el bow â€ i s pai n ov er the l ater al epi condy l e of the el bow due
to i nf l am m ati on of the tendons of the w r i st ex tensor m uscl es that
i nser t at thi s l ocati on. â€œGol f er 's el bow â€ i s pai n ov er the m edi al
epi condy l e due to i nf l am m ati on of the w r i st f l ex or tendons that i nser t
at thi s l ocati on. The
P. 441
â€œshoul der i m pi ngem ent sy ndr om eâ€ r esul ts f r om i m pi ngem ent of the
tendons of the r otator cuf f w i th shoul der abducti on or f l ex i on and can
be associ ated w i th supr aspi natus tendi ni ti s, subacr om i al bur si ti s, or
r otator cuf f tear s. â€œHousem ai d's k neeâ€ i s pr epatel l ar bur si ti s
br ought about by r epeti ti v e tr aum a or ov er use such as k neel i ng.
Another com m on ar ea f or bur si ti s i s ov er the gr eater tr ochanter of the
l ater al hi p.
3. What ar e the cr i ter i a f or di agnosi s of FMS?
The di agnosti c cr i ter i a f or FMS i ncl ude at l east 3 m onths of w i despr ead
pai n that i s bi l ater al , abov e and bel ow the w ai st, and i ncl udes ax i al
sk el etal pai n, and pai n to pal pati on at a m i ni m um of 11 of 18
pr edef i ned tender poi nts (di scussed i n subsequent tex t). The di agnosi s
of other di seases does not ex cl ude the di agnosi s of FMS.
4. What ar e f i v e m edi cal i l l nesses that m ay ex hi bi t sy m ptom s si m i l ar to

those of FMS?
Il l nesses that m ay ex hi bi t sy m ptom s si m i l ar to those of FMS i ncl ude

cel i ac spr ue, hepati ti s C, hy per par athy r oi di sm , hy pothy r oi di sm , and
pol y m y al gi a r heum ati ca (PMR). How ev er , each of these i l l nesses i s
associ ated w i th char acter i sti c hi stor i cal , cl i ni cal , and l abor ator y
abnor m al i ti es that di sti ngui sh i t f r om FMS. In addi ti on, i t i s of ten
di f f i cul t to di f f er enti ate the sy m ptom s of FMS f r om those of chr oni c
f ati gue sy ndr om e. The di f f er enti al di agnosi s f or FMS al so i ncl udes RA,
SLE, i nf l am m ator y m y opathi es, obstr ucti v e sl eep apnea, par aneopl asti c
di sor der s, and ser onegati v e spondy l oar thr opathi es.
Case
A 38y ear ol d w om an i s r ef er r ed f or ev al uati on because of di f f use pai n and
f ati gue. She com pl ai ns of 6 m onths of f ati gue, gener al i zed pai n, di f f i cul ty
sl eepi ng, m or ni ng sti f f ness, and i nter m i ttent sw el l i ng of her f i nger s. The
sti f f ness i s w or se i n the m or ni ng, but she cannot put a def i ni te ti m e l i m i t on
i t. She has a hi stor y of m i gr ai ne headaches and i r r i tabl e bow el sy ndr om e.
She w as f i r st seen by her f am i l y phy si ci an com pl ai ni ng of â€œpai n al l
ov er . â€
She w as i ni ti al l y tr eated w i th i ndom ethaci n w i thout r el i ef .
Subsequentl y , she has tr i ed sev er al di f f er ent N SAIDs w i thout r el i ef of her
sy m ptom s.
She i s a di v or ced m other of thr ee chi l dr en, w ho w or k s f ul l ti m e as a
l i censed pr acti cal nur se. She has no hi stor y of a r ash, or al ul cer s, sei zur es,
bl ood di sor der , or k now n k i dney di sease.
Phy si cal ex am i nati on r ev eal s nor m al v i tal si gns, as w el l as nor m al head,
ear , ey es, nose, thr oat, neck , sk i n, chest, and abdom i nal f i ndi ngs. Her
f i nger s and joi nts ar e nor m al w i thout any sw el l i ng or sy nov i ti s. Her
m uscul ar and neur ol ogi c ex am i nati ons ar e nonf ocal . Sev er al tender poi nts
ar e i denti f i ed.
1. What ar e tw o char acter i sti cs of the sl eep di sor der that com m onl y
accom pani es FMS?
2. What ar e the char acter i sti c phy si cal f i ndi ngs i n FMS?
3. Ar e ther e any l abor ator y test abnor m al i ti es char acter i sti c of FMS?
4. What i s the ther apy f or FMS?
5. Whi ch psy chol ogi cal di sor der s ar e of ten associ ated w i th FMS?
P. 442
Case Discussion
1. What ar e tw o char acter i sti cs of the sl eep di sor der that com m onl y
accom pani es FMS?
The sl eep di sor der seen i n the contex t of FMS i s char acter i zed by ear l y
m or ni ng aw ak eni ng and unr ef r eshi ng or nonr estor ati v e sl eep.
Di sr upti on of del taw av e sl eep (nonREM stage IV sl eep) occur s due to
al phaw av e i ntr usi on, and i s ter m ed the al phadel ta sl eep patter n of
FMS. Obstr ucti v e sl eep apnea and r estl ess l eg sy ndr om e shoul d al so be
consi der ed i n pati ents pr esenti ng w i th FMS.
2. What ar e the char acter i sti c phy si cal f i ndi ngs i n f i br om y al gi a?
Pati ents w i th FMS hav e a nor m al phy si cal ex am i nati on ex cept f or
tender poi nts i n pr eci se l ocati ons. These tender poi nts ar e ty pi cal l y
l ocated at the occi put, at the m i dpor ti on of the tr apezi us, the or i gi n of
the supr aspi natus, l ow anter i or cer v i cal r egi on, second costochondr al
juncti on, l ater al epi condy l e, outer upper quadr ant of the buttock s,
gr eater tr ochanter r egi on, and m edi al k nee ar ea. These ar eas ar e
usual l y tender bi l ater al l y i n pati ents w i th FMS. Contr ol poi nts such as
the m i df or ear m and anter i or m i dthi gh ar e not nor m al l y pai nf ul i n
pati ents w i th FMS.
3. Ar e ther e any l abor ator y test abnor m al i ti es char acter i sti c of FMS?
Al l l abor ator y test r esul ts i n the setti ng of FMS ar e usual l y com pl etel y
nor m al . To i ni ti al l y ex cl ude di sor der s that m ay m i m i c FMS, a com pl ete
bl ood count, ESR, cr eati ni ne, l i v er f uncti on tests, thy r oi dsti m ul ati ng
hor m one, cr eati ne phosphok i nase (CPK), cal ci um , phosphor us, and
ur i nal y si s shoul d be per f or m ed. Anti nucl ear anti body (AN A) testi ng
shoul d not be per f or m ed unl ess ther e i s pr etest pr obabi l i ty of a
connecti v e ti ssue di sease (CTD) si nce a substanti al num ber of
i ndi v i dual s w i th FMS (12% to 30%) can hav e a l ow ti ter , nonspeci f i c
posi ti v e AN A.
4. What i s the ther apy f or FMS?
The appr opr i ate ther apy f or FMS i ncl udes pati ent educati on, anal gesi cs
such as acetam i nophen or tr am adol , l ow dose tr i cy cl i c anti depr essants
or cy cl obenzapr i ne at bedti m e to i m pr ov e the sl eep cy cl e, and l ow
i m pact aer obi c ex er ci ses. Anti i nf l am m ator y m edi cati ons ar e not
gener al l y hel pf ul . Sel ecti v e ser otoni n r euptak e i nhi bi tor s (SSRIs) and
pr egabal i n m ay hav e som e ef f i cacy i n FMS. Thi s i s a v er y f r ustr ati ng
di sor der f or both the pati ent and phy si ci an. Many pati ents m ay be
hel ped by thi s appr oach to ther apy , the m ost i m por tant el em ent of
w hi ch i s an ex er ci se pr ogr am .
5. Whi ch psy chol ogi cal di sor der s ar e of ten associ ated w i th FMS?
Functi onal psy chi atr i c di sor der s, such as the som atof or m di sor der s, and
or gani c psy chi atr i c di sor der s, such as m ajor depr essi on and anx i ety
di sor der s, hav e been associ ated w i th FMS i n appr ox i m atel y 30% of
pati ents. The anx i ety and m i l d depr essi on that of ten pr esent i n FMS
m ay be secondar y to chr oni c pai n and concer ns r egar di ng per sonal
i ndependence and debi l i ty .
Suggested Readings
Bur k ham J, Har r i s ED Jr . Fi br om y al gi a: a chr oni c pai n sy ndr om e. In:
r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er , Saunder s, 2005:522â€“536.
P. 443
Gol denber g DL. Fi br om y al gi a and r el ated sy ndr om es. In: Hochber g MC,
Mosby , 2003:701â€“712.
Mal y ak M. Fi br om y al gi a. In: West SG, ed. Rheum atol ogy secr ets, 2nd ed.
Phi l adel phi a: Hanl ey & Bel f us, 2002:428â€“440.
Osteoarthritis
1. What i s the joi nt str uctur e that i s pr i m ar i l y i nv ol v ed i n OA?
2. Why i s pai n at the base of the thum b and the gr adual onset of pai n i n a
k nee w i th m i ni m al sw el l i ng m or e char acter i sti c of OA than of RA?
3. What ar e the r i sk f actor s f or dev el opi ng OA?
4. What ar e som e of the char acter i sti c f i ndi ngs encounter ed dur i ng
phy si cal ex am i nati on i n pati ents w i th OA?
Discussion
1. What i s the joi nt str uctur e that i s pr i m ar i l y i nv ol v ed i n OA?
OA i s the m ost com m on joi nt di sor der i n the w or l d. It i s a di sor der of
ar ti cul ar car ti l age w i th secondar y changes i n the adjacent bone.
2. Why i s pai n at the base of the thum b and the gr adual onset of pai n i n a
k nee w i th m i ni m al sw el l i ng m or e char acter i sti c of OA than of RA?
Pai n at the base of the thum b r epr esents ar thr i ti s of the f i r st
car pom etacar pal (CMC) joi nt. Thi s joi nt i s com m onl y i nv ol v ed i n the
setti ng of OA because of f r equent m echani cal dam age i ncur r ed dur i ng
nor m al use of the hand. Ear l y OA m ay be char acter i zed by joi nt pai n
w i th use, w i thout si gns of i nf l am m ati on; m or ni ng sti f f ness i s ty pi cal l y
f or l ess than 30 m i nutes. OA i s noni nf l am m ator y and can i nv ol v e the
di stal i nter phal angeal s (DIPs) w i th associ ated Heber den's nodes;
pr ox i m al i nter phal angeal s (PIPs) w i th associ ated Bouchar d's nodes; the
f i r st CMC of the hand; the f i r st MTP joi nts; the spi ne; hi ps; and k nees.
RA i s an i nf l am m ator y ar thr i ti s and i nv ol v es bi l ater al
m etacar pophal angeal s (MCPs) and PIPs i n a sy m m etr i c m anner and can
al so i nv ol v e the MTPs and other sy nov i um l i ned joi nts; m or ni ng
sti f f ness i s ty pi cal l y f or m or e than 60 m i nutes.
3. What ar e the r i sk f actor s f or dev el opi ng OA?
The r i sk f actor s f or dev el opi ng OA ar e age, obesi ty , abnor m al joi nt
m echani cs, pr ev i ous joi nt tr aum a or i nf l am m ator y joi nt di sease,
her edi ty (especi al l y OA of the DIP joi nts), and cer tai n occupati ons that
r equi r e r epeti ti v e use of joi nt gr oups, bendi ng, or car r y i ng heav y
l oads. Metabol i c di sor der s associ ated w i th OA i ncl ude cr y stal deposi ti on
di seases, Paget's di sease, ochr onosi s, acr om egal y , hem ochr om atosi s,
and Wi l son's di sease.
4. What ar e som e of the char acter i sti c f i ndi ngs encounter ed dur i ng
phy si cal ex am i nati on i n pati ents w i th OA?
Ty pi cal f i ndi ngs encounter ed dur i ng phy si cal ex am i nati on i n pati ents
w i th OA i ncl ude bony ov er gr ow th (osteophy tes), joi nt l i ne tender ness,
cr epi tus on
P. 444
passi v e m oti on, and l i m i tati on of m oti on w i th pai n on ex tr em es of
m oti on. The end r esul t m ay be joi nt def or m i ty .
Case
A 56y ear ol d m al e constr ucti on w or k er com pl ai ns of chr oni c pai n i n hi s
k nees and i nter m i ttent pai n at the base of hi s thum b. When gr i ppi ng
som ethi ng f or cef ul l y , the pai n at the base of the thum b (f i r st CMC) i s
som eti m es so shar p that he i s f or ced m om entar i l y to stop w hat he i s doi ng.
Hi s k nees ache di f f usel y af ter ex cessi v e use. These com pl ai nts k eep hi m
f r om w or k i ng as of ten as he w oul d l i k e. He r epor ts no si gni f i cant m or ni ng
sti f f ness. Hi s f am i l y hi stor y i s unr em ar k abl e. Past m edi cal hi stor y i s
si gni f i cant f or m i l d essenti al hy per tensi on f or w hi ch he has been tak i ng
hy dr ochl or othi azi de f or 8 y ear s.
Phy si cal ex am i nati on r ev eal s sl i ght quadr i ceps atr ophy on the r i ght w i th
sl i ght genu v ar um and a pes anser i nus bur si ti s, f l attened ar ches, and
m oder ate obesi ty . Ther e i s m i l d cr epi tus i n both k nees w i thout l i gam entous
i nstabi l i ty or ef f usi ons. Ther e i s m oder ate tender ness of the f i r st CMC joi nts
bi l ater al l y . Ther e ar e no Heber den's or Bouchar d's nodes.
1. What ar e som e of the char acter i sti c changes that af f ect the ar ti cul ar
car ti l age i n pati ents w i th OA?
2. What ar e f our char acter i sti c r adi ogr aphi c f i ndi ngs encounter ed i n
pati ents w i th OA?
3. Di scuss the nonphar m acol ogi c m anagem ent of OA?
4. Di scuss the phar m acol ogi c opti ons f or the tr eatm ent of OA?
Case Discussion
1. What ar e som e of the char acter i sti c changes that af f ect the ar ti cul ar
car ti l age i n pati ents w i th OA?
Abnor m al joi nt m echani cal f actor s r esul t i n pi ts, cl ef ts, and ul cer ati ons
i n the gr oss ar ti cul ar car ti l age sur f ace i n OA. Mi cr oscopi cal l y ,
osteoar thr i ti c car ti l age r ev eal s i ni ti al chondr ocy te pr ol i f er ati on
f ol l ow ed by ev entual chondr ocy te death; decr eased pr oteogl y can and
col l agen concentr ati ons w i th r esul tant i ncr eased w ater content of the
car ti l age; i ncr eased am ounts of m atr i x m etal l opr otei nases (MMPs) and
i nf l am m ator y m edi ator s; and decr eased am ounts of ti ssue i nhi bi tor s of
m etal l opr otei nases (TIMPs). Thi s r esul ts i n car ti l age l oss w i th
secondar y thi ck eni ng of the subchondr al bone and f or m ati on of
osteophy tes.
2. What ar e f our char acter i sti c r adi ogr aphi c f i ndi ngs encounter ed i n
pati ents w i th OA?
Radi ogr aphi c f i ndi ngs ty pi cal l y encounter ed i n pati ents w i th OA i ncl ude
l oss of joi nt space, cy sts i n subchondr al bone, subchondr al scl er osi s or
ebur nati on, and osteophy tes (bony spur s) at the joi nt m ar gi ns.
3. Di scuss the nonphar m acol ogi c m anagem ent of OA?
N onphar m acol ogi c m odal i ti es hel pf ul i n the m anagem ent of OA consi st
of pati ent educati on, heat or col d appl i cati on, w ei ght r educti on,
phy si cal ther apy that f ocuses on m uscl estr engtheni ng ex er ci ses,
or thoti cs and br aci ng, and or thopaedi c sur gi cal opti ons i n sel ect
pati ents.
P. 445
4. Di scuss the phar m acol ogi c opti ons f or the tr eatm ent of OA?
Acetam i nophen, an anal gesi c, shoul d be the f i r stl i ne ther apy f or OA. If
thi s i s unsuccessf ul , N SAIDs can be used. N ar coti c anal gesi cs shoul d be
consi der ed i n pati ents w i th r ef r actor y pai n. Topi cal appl i cati on of
capsai ci n cr eam or i ntr aar ti cul ar i njecti on of hy al ur onate or
cor ti coster oi ds m ay be benef i ci al i n som e pati ents. The nutr aceuti cal s,
gl ucosam i ne and chondr oi ti n sul f ate, m ay hav e som e benef i t i n tr eati ng
OA sy m ptom s. Longter m chondr opr otecti v e ef f ects of these agents
hav e not been establ i shed.
Suggested Readings
Al tm an RD, Lozada CJ. Osteoar thr i ti s and r el ated di sor der s: cl i ni cal
f eatur es. In: Hochber g MC, Si l m an AJ, Sm ol en JS, et al . eds.
Rheum atol ogy , 3r d ed. Edi nbur gh: Mosby , 2003:1793â€“1800.
Dougados M. Cl i ni cal f eatur es of osteoar thr i ti s. In: Har r i s ED Jr , Budd
RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of r heum atol ogy , 7th ed.
Phi l adel phi a: El sev i er , Saunder s, 2005:1514â€“1527.
Lozada CJ. Managem ent of osteoar thr i ti s. In: Har r i s ED Jr , Budd RC,
Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of r heum atol ogy , 7th ed.
Vogel gesang S. Osteoar thr i ti s. In: West SG, ed. Rheum atol ogy secr ets,
2nd ed. Phi l adel phi a: Hanl ey & Bel f us, 2002:365â€“374.
Polymyositis and Dermatomyositis
1. What thr ee gener al categor i es of joi nt or m uscl e di sease need to be
consi der ed i n a pati ent pr esenti ng w i th di f f use aches and m uscl e
w eak ness?
2. What ar e the f i v e subgr oups of i nf l am m ator y m uscl e di sease?
3. What hi stor i cal i nf or m ati on w oul d suggest the pr esence of

i nf l am m ator y m uscl e di sease?
4. What tw o l abor ator y test r esul ts m i ght be abnor m al i n pati ents w i th
5. What f our di agnosti c tests or pr ocedur es shoul d be per f or m ed i n any
pati ent w i th suspected i nf l am m ator y m uscl e di sease?
Discussion
1. What thr ee gener al categor i es of joi nt or m uscl e di sease need to be
consi der ed i n a pati ent pr esenti ng w i th di f f use aches and m uscl e
w eak ness?
A pati ent w i th di f f use aches and m uscl e w eak ness m ay hav e a f or m of
i nf l am m ator y ar thr i ti s, par ti cul ar l y RA; an endocr i nopathy , par ti cul ar l y
thy r oi d or par athy r oi d di sease; or a f or m of i nf l am m ator y m uscl e
di sease. The di f f er enti al di agnosi s al so i ncl udes neur opathi c di seases,
m edi cati ons, i nf ecti ons, m etabol i c m y opathi es, and neopl asi a.
P. 446
2. What ar e the f i v e subgr oups of i nf l am m ator y m uscl e di sease?
Inf l am m ator y m uscl e di sease can be di v i ded i nto the f ol l ow i ng

di sor der s: pr i m ar y i di opathi c pol y m y osi ti s, pr i m ar y i di opathi c
der m atom y osi ti s, chi l dhood der m atom y osi ti s associ ated w i th v ascul i ti s,
pol y m y osi ti s and der m atom y osi ti s associ ated w i th col l agen v ascul ar
di sease such as SLE or scl er oder m a, and pol y m y osi ti s and
der m atom y osi ti s associ ated w i th m al i gnancy .
3. What hi stor i cal i nf or m ati on w oul d suggest the pr esence of

Inf l am m ator y m uscl e di sease has an i nsi di ous onset ov er 3 to 6 m onths
usual l y w i th no i denti f i abl e pr eci pi tati ng ev ent. The w eak ness i ni ti al l y
af f ects the m uscl es of the shoul der and pel v i c gi r dl e. The pati ents m ay
ex per i ence di f f i cul ty i n cl i m bi ng stai r s, getti ng out of chai r s, or
com bi ng thei r hai r . Weak ness of neck f l ex or s occur s i n appr ox i m atel y
50% of pati ents. Phar y ngeal m uscl e i nv ol v em ent m ay cause dy sphoni a,
dy sphagi a, or aspi r ati on. Ocul ar , f aci al , and bul bar m uscl e w eak ness i s
ex tr em el y r ar e.
4. What tw o l abor ator y test r esul ts m i ght be abnor m al i n pati ents w i th
Tw o abnor m al l abor ator y test f i ndi ngs i n pati ents w i th pol y m y osi ti s or
der m atom y osi ti s ar e el ev ati ons i n the ESR and the ser um CPK l ev el .
Appr ox i m atel y 50% of pati ents hav e a posi ti v e AN A. My osi ti sspeci f i c
anti bodi es, such as anti â€“Jo1, can occur i n a subset of pati ents and
can pr edi ct cl i ni cal m ani f estati ons (m y osi ti s, i nter sti ti al l ung di sease,
noner osi v e ar thr i ti s, Ray naud's phenom enon, and m echani c's hands)
and pr ognosi s.
5. What f our di agnosti c tests or pr ocedur es shoul d be per f or m ed i n any
pati ent w i th suspected i nf l am m ator y m uscl e di sease?
The di agnosti c ev al uati on of pati ents w i th suspected i nf l am m ator y

m uscl e di sease shoul d i ncl ude ser ol ogi c testi ng f or AN A subty pes to
r ul e out a m y osi ti s ov er l ap sy ndr om e, el ectr ocar di ogr aphy to scr een
f or car di ac i nv ol v em ent, el ectr om y ogr aphy (EMG) to conf i r m a
m y opathi c pr ocess, and m uscl e bi opsy to conf i r m the suspected
di agnosi s.
Case
A 47y ear ol d w om an i s seen by her pr i m ar y car e phy si ci an w i th a chi ef
com pl ai nt of a 3m onth hi stor y of m uscl e w eak ness al ong w i th v ague
com pl ai nts of decr eased ener gy and di f f use aches and pai ns. Routi ne
phy si cal ex am i nati on f i ndi ngs ar e unr em ar k abl e. The r esul ts of a basel i ne
bi ochem i cal scr een i ncl udi ng thy r oi d f uncti on studi es ar e w i thi n nor m al
l i m i ts. El ectr ocar di ogr aphy , a chest r adi ogr aphi c study , and pul m onar y
f uncti on test r esul ts ar e al so unr ev eal i ng. She i s gi v en an em pi r i c tr i al of
napr ox en.
Tw o m onths l ater , she begi ns to ex per i ence actual m uscl e tender ness and
di f f i cul ty cl i m bi ng the tw o f l i ghts of stai r s to her apar tm ent. On questi oni ng,
she al so com pl ai ns of pai n, di f f i cul ty i n chew i ng m eats, and an 8l b (3. 6k g)
w ei ght l oss. She deni es f ev er s, chest pai n, shor tness of br eath, a change i n
bow el habi ts, or sk i n r ashes.
Phy si cal ex am i nati on r ev eal s gr ade 4/5 str ength i n the pr ox i m al m uscl e
gr oups of both the upper and l ow er ex tr em i ti es w i thout atr ophy . Ther e i s
al so gr ade 4/5 w eak ness
P. 447
of the neck f l ex or s. Her di stal str ength i s nor m al . Her r ef l ex es ar e
sy m m etr i c. Her sk i n i s cl ear . Br east and pel v i c ex am i nati on f i ndi ngs ar e
unr em ar k abl e.
The f ol l ow i ng l abor ator y r esul ts ar e r epor ted: hem atocr i t 34%; ESR 63 m m
per hour ; AN A 1:256 f i ne speck l ed patter n; r heum atoi d f actor (RF) negati v e;
CPK 1, 850 U /L (nor m al < 150 U /L).
She i s schedul ed to under go r i ghtsi ded EMG and m uscl e bi opsy of the l ef t
tr i ceps.
1. What other or gans besi de m uscl e m ay be i nv ol v ed i n pati ents w i th
pol y m y osi ti s or der m atom y osi ti s?
2. What f our di f f er ent sk i n l esi ons ar e seen i n pati ents w i th
der m atom y osi ti s?
3. What di agnosti c ev al uati on i s i ndi cated to sear ch f or a possi bl e
m al i gnancy i n pati ents w i th pol y m y osi ti s or der m atom y osi ti s, and w hat
m ay happen to the m uscl e di sease w hen the m al i gnancy i s tr eated?
4. What i s the appr oach to tr eatm ent of pol y m y osi ti s/der m atom y osi ti s?
Case Discussion
1. What other or gans besi de m uscl e m ay be i nv ol v ed i n pati ents w i th
pol y m y osi ti s or der m atom y osi ti s?
The l ungs, hear t, and joi nts m ay al so be i nv ol v ed i n pati ents w i th
pol y m y osi ti s or der m atom y osi ti s. Pul m onar y i nv ol v em ent i ncl udes
i nter sti ti al l ung di sease, aspi r ati on pneum oni a, r espi r ator y m uscl e
w eak ness, and pul m onar y hy per tensi on. Car di ac m ani f estati ons ar e
dy sr hy thm i as, conducti on bl ock s, and m y ocar di ti s. Pati ents m ay
ex per i ence pol y ar thr al gi a or an i nf l am m ator y ar thr i ti s. Char acter i sti c
sk i n f i ndi ngs (di scussed i n subsequent tex t) ar e r equi r ed f or a
di agnosi s of der m atom y osi ti s.
2. What f our di f f er ent sk i n l esi ons ar e seen i n pati ents w i th

der m atom y osi ti s?
The sk i n l esi ons seen i n pati ents w i th der m atom y osi ti s i ncl ude an
er y them atous r ash ov er the anter i or chest and neck (Vsi gn r ash), an
er y them atous r ash ov er the shoul der s and pr ox i m al ar m s (shaw l si gn
r ash), er y them atous r ai sed l esi ons ov er the k nuck l es (Gottr on's
papul es), and a per i or bi tal l i l ac col or ed r ash (hel i otr ope r ash).
Gottr on's papul es and the hel i otr ope r ash ar e consi der ed
pathognom oni c cutaneous f eatur es of der m atom y osi ti s. Mechani c's
hands (cr ack i ng and/or f i ssur i ng of the sk i n of the f i nger pads) can be
seen i n the anti sy nthetase sy ndr om e of ten associ ated w i th anti â€“Jo1
anti bodi es.
3. What di agnosti c ev al uati on i s i ndi cated to sear ch f or a possi bl e
m al i gnancy i n pati ents w i th pol y m y osi ti s or der m atom y osi ti s, and w hat
m ay happen to the m uscl e di sease w hen the m al i gnancy i s tr eated?
Mal i gnanci es m ay dev el op i n pati ents w i th pol y m y osi ti s or
der m atom y osi ti s, ei ther bef or e or af ter (3 to 5 y ear s) the onset of
i nf l am m ator y m uscl e di sease. The di agnosti c ev al uati on f or a possi bl e
m al i gnancy i n thi s setti ng shoul d be age appr opr i ate and usual l y
i ncl udes a good hi stor y and phy si cal ex am i nati on (i ncl udi ng br east,
pel v i s, and pr ostate), a chest r adi ogr aphi c study , m am m ogr aphy , stool
guai ac testi ng, and r outi ne l abor ator y tests. The m al i gnanci es f ound i n
these pati ents i ncl ude am ong other s car ci nom as of the l ung,
gastr oi ntesti nal tr act, br east, ov ar i es,
P. 448
and pancr eas, and Hodgk i n's l y m phom a. If the m al i gnancy i s tr eated,
the m uscl e di sease m ay i m pr ov e.
4. What i s the appr oach to tr eatm ent of pol y m y osi ti s/der m atom y osi ti s?
The tr eatm ent of pol y m y osi ti s and der m atom y osi ti s shoul d f i r st consi st
of sy stem i c cor ti coster oi ds gi v en i n hi gh doses. If pati ents show a poor
r esponse to ster oi ds or i f the dosage cannot be decr eased,
i m m unosuppr essi v e dr ug tr eatm ent w i th such agents as azathi opr i ne or
MTX m ay be i nsti tuted. Hy dr ox y chl or oqui ne can be used to tr eat the
cutaneous m ani f estati ons of der m atom y osi ti s. Ref r actor y cases of
i nf l am m ator y m y opathi es m ay r espond to i ntr av enous i m m une gl obul i n.
Pr ogr essi v e phy si cal ther apy i s r ecom m ended to m ai ntai n r ange of
m oti on, pr ev ent contr actur es, and, as m uscl e i nf l am m ati on subsi des, to
r egai n m uscl e str ength.
Suggested Readings
Oddi s CV, Medsger TA Jr . Inf l am m ator y m uscl e di sease: cl i ni cal
Spencer RT. Inf l am m ator y m uscl e di sease. In: West SG, ed.
Rheum atol ogy secr ets, 2nd ed. Phi l adel phi a: Hanl ey & Bel f us, 2002:167â
€“173.
Wor tm ann RL. Inf l am m ator y di sease of m uscl e and other m y opathi es. In:
r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er , Saunder s, 2005:1309â
€“1335.
Reactive Arthritis
1. What i s r eacti v e ar thr i ti s?
2. In w hat tw o di seases i s ar thr i ti s associ ated w i th di ar r hea?
3. What tw o possi bl e di agnoses ar e suggested w hen acute ar thr i ti s occur s

i n a pati ent w i th ur ethr al di schar ge?
4. What ar e the hi stor y and phy si cal ex am i nati on f i ndi ngs ty pi cal l y
obser v ed i n pati ents w i th r eacti v e ar thr i ti s?
Discussion
1. What i s r eacti v e ar thr i ti s?
Reacti v e ar thr i ti s i s a ster i l e i nf l am m ator y sy nov i ti s f ol l ow i ng a di stant

i nf ecti on by an or gani sm that i nf ects m ucosal sur f aces, par ti cul ar l y
ur ogeni tal or enter i c i nf ecti ons. Reacti v e ar thr i ti s has r epl aced the
ter m Rei ter 's sy ndr om e as m ost pati ents do not hav e the Rei ter 's
sy ndr om e's cl assi c tr i ad of ar thr i ti s, conjuncti v i ti s, and ur ethr i ti s.
2. In w hat tw o di seases i s ar thr i ti s associ ated w i th di ar r hea?
Ar thr i ti s associ ated w i th di ar r hea m ay be seen i n the setti ng of ei ther
r eacti v e ar thr i ti s or i nf l am m ator y bow el di sease. In r eacti v e ar thr i ti s,
the
P. 449
di ar r hea m ay pr ecede the ar thr i ti s by a f ew w eek s. In i nf l am m ator y
bow el di sease, the per i pher al ar thr i ti s and di ar r hea of ten ar i se at the
sam e ti m e and the cl i ni cal acti v i ty of the ar thr i ti s m ay cor r el ate w i th
the acti v i ty of the i nf l am m ator y bow el di sease.
3. What tw o possi bl e di agnoses ar e suggested w hen acute ar thr i ti s occur s

i n a pati ent w i th ur ethr al di schar ge?
Acute ar thr i ti s occur r i ng i n a pati ent w i th a ur ethr al di schar ge suggests
a di agnosi s of ei ther di ssem i nated gonococcal i nf ecti on or r eacti v e
ar thr i ti s. These di agnoses can be di f f er enti ated on the basi s of
char acter i sti c cl i ni cal f eatur es as w el l as by a posi ti v e ur ethr al or
cer v i cal cul tur e f or N ei sser i a gonor r hoeae. The ur ethr i ti s associ ated
w i th r eacti v e ar thr i ti s can pr esent as an asepti c py ur i a or be secondar y
to an i nf ecti on w i th Chl am y di a or U r eapl asm a.
4. What ar e the hi stor y and phy si cal ex am i nati on f i ndi ngs ty pi cal l y
obser v ed i n pati ents w i th r eacti v e ar thr i ti s?
Reacti v e ar thr i ti s i s di agnosed on the basi s of hi stor y and phy si cal
ex am i nati on f i ndi ngs and not on the basi s of any l abor ator y r esul t.
These cl i ni cal f i ndi ngs i ncl ude the dev el opm ent of an acute ar thr i ti s i n
one or a f ew joi nts, of ten of the l ow er ex tr em i ti es, af ter an epi sode of
ei ther di ar r hea, or pai nl ess ur ethr i ti s or cer v i ci ti s. The di agnosi s m ay
be f ur ther str engthened by the pr esence of or al ul cer s, conjuncti v i ti s,
or anter i or uv ei ti s, as w el l as char acter i sti c sk i n f i ndi ngs of ci r ci nate
bal ani ti s or k er atoder m a bl ennor r hagi cum . Enthesopathi es (dacty l i ti s,
pl antar f asci i ti s, and Achi l l es tendi ni ti s) and tenosy nov i ti s can al so be
com m on cl i ni cal f eatur es of r eacti v e ar thr i ti s.
Case
A 32y ear ol d m an i s seen because of i ncr easi ng r i ght k nee pai n and
sw el l i ng ov er the l ast 3 day s. On f ur ther questi oni ng, i t i s di scov er ed that 2
w eek s ago, the pati ent had an epi sode of m i l d dy sur i a associ ated w i th a
m ucous di schar ge. Thi s i l l ness r esol v ed spontaneousl y af ter 4 day s. Si x
day s ago, pai nl ess, shal l ow ul cer ati ons of the gl ans peni s dev el oped. Dur i ng
thi s per i od, he al so noted the onset of bi l ater al r edness and pr ur i tus of the
ey es al ong w i th a cl ear di schar ge. Thr ee day s ago, acute sw el l i ng of the
r i ght k nee associ ated w i th pai n ar ose spontaneousl y and has steadi l y
w or sened.
Phy si cal ex am i nati on r ev eal s m i l d i njecti on of the conjuncti v al v essel s
bi l ater al l y . Hi s v i sual acui ty and r eti na ar e nor m al . Sl i tl am p ex am i nati on
by ophthal m ol ogy dem onstr ates no ev i dence of anter i or uv ei ti s. Ex am i nati on
of the sk i n r ev eal s di scr ete hy per k er atoti c nodul es ov er the sol es of hi s f eet
bi l ater al l y and ther e ar e thr ee shal l ow ul cer s on the gl ans peni s. Hi s r i ght
k nee i s w ar m and tender , and ther e i s a si gni f i cant am ount of pal pabl e
sy nov i al f l ui d. The r em ai nder of the ex am i nati on f i ndi ngs ar e unr em ar k abl e.
1. What other f or m s of r heum ati c di sease need to be consi der ed w hen
r eacti v e ar thr i ti s i s suspected, and w hat di agnosti c tests or pr ocedur es
shoul d be per f or m ed to ex cl ude them ?
2. What ar e som e of the cl i ni cal or l abor ator y char acter i sti cs of r eacti v e
ar thr i ti s that hel p di f f er enti ate i t f r om RA?
3. What ar e the thr ee ty pes of sk i n l esi ons seen i n pati ents w i th r eacti v e
ar thr i ti s?
P. 450
4. The back di sease i n pati ents w i th r eacti v e ar thr i ti s i s char acter i zed by
w hat r adi ogr aphi c f i ndi ngs?
5. What i s the ther apy f or r eacti v e ar thr i ti s?
Case Discussion
1. What other f or m s of r heum ati c di sease need to be consi der ed w hen
r eacti v e ar thr i ti s i s suspected, and w hat di agnosti c tests or pr ocedur es
shoul d be per f or m ed to ex cl ude them ?
In a pati ent suspected of hav i ng r eacti v e ar thr i ti s, septi c ar thr i ti s
needs to be ex cl uded. The f i ndi ngs y i el ded by joi nt aspi r ati on, w hi ch
i ncl udes ex am i nati on of the f l ui d f or cel l count w i th di f f er enti al ,
together w i th Gr am 's stai ni ng and cul tur e, can cl i nch the di agnosi s of a
nongonococcal bacter i al septi c joi nt. Gonococcal ar thr i ti s i s another
possi bl e di agnosi s. Besi de ex am i nati on and cul tur e of sy nov i al f l ui d,
the ev al uati on shoul d i ncl ude ur ethr al or cer v i cal , bl ood, phar y ngeal ,
and per i r ectal cul tur es. Cr y stal i nduced ar thr i ti s i s di agnosed by the
f i ndi ng of cr y stal s i n the sy nov i al f l ui d by pol ar i zed m i cr oscopy . Both
SLE and RA need to be consi der ed. Ser ol ogi c testi ng f or AN A, RF, and
anti cy cl i c ci tr ul l i nated pepti de (anti CCP) anti bodi es i s per f or m ed to ai d
i n the di agnosi s of these condi ti ons. A r outi ne com pl ete bl ood count
and a f ul l chem i str y pr of i l e, i ncl udi ng l i v er f uncti on tests, shoul d al so
be per f or m ed to sear ch f or a sy stem i c di sease that m ay pr esent w i th
joi nt f i ndi ngs si m i l ar to those seen i n the setti ng of r eacti v e ar thr i ti s.
Reacti v e ar thr i ti s can be associ ated w i th hum an i m m unodef i ci ency
v i r us (HIV) i nf ecti on. The m ost usef ul l abor ator y tests i n r eacti v e
ar thr i ti s ar e sw abs or cul tur es that conf i r m the pr esence of
ar thr i togeni c or gani sm s such as Chl am y di a, U r eapl asm a, Sal m onel l a,
Shi gel l a, Yer si ni a, Cam py l obacter , and Cl ostr i di um di f f i ci l e i n the
ur ogeni tal or gastr oi ntesti nal tr acts.
2. What ar e som e of the cl i ni cal or l abor ator y char acter i sti cs of r eacti v e
ar thr i ti s that hel p di f f er enti ate i t f r om RA?
In contr ast to RA, an asy m m etr i c ar thr i ti s that pr edom i nates i n the
l ow er ex tr em i ti es i s char acter i sti c of r eacti v e ar thr i ti s. In addi ti on,
sacr oi l i i ti s (of ten uni l ater al or asy m m etr i c) af f ects 20% to 30% of
pati ents, the sy ndr om e i s associ ated w i th HLAB27 (80% of pati ents),
and pati ents f r equentl y hav e an enthesopathy . Si nce r eacti v e ar thr i ti s
i s one of the ser ol ogi cal l y negati v e spondy l oar thr opathi es, the AN A, RF,
and anti CCP anti bodi es ar e negati v e.
3. What ar e the thr ee ty pes of sk i n l esi ons seen i n pati ents w i th r eacti v e
ar thr i ti s?
The sk i n l esi ons of r eacti v e ar thr i ti s i ncl ude pai nl ess m outh ul cer s,
k er atoder m a bl ennor r hagi cum (psor i af or m l esi ons on the sol es of the
f eet; m ay al so i nv ol v e the scr otum , peni s, pal m s, tr unk , and scal p),
and ci r ci nate bal ani ti s (ser pi gi nous ul cer ati on of the gl ans peni s). The
l atter tw o condi ti ons ar e pr edom i nantl y associ ated w i th ur ogeni tal
r eacti v e ar thr i ti s.
4. The back di sease i n pati ents w i th r eacti v e ar thr i ti s i s char acter i zed by
w hat r adi ogr aphi c f i ndi ngs?
The l um bosacr al spi ne f i l m of a pati ent w i th r eacti v e ar thr i ti s m ay

show asy m m etr i c and bul k y sy ndesm ophy tes. Thi s i s i n contr ast w i th
AS, i n w hi ch the
P. 451
sy ndesm ophy tes ar e usual l y sy m m etr i c and f l ow i ng. In r eacti v e
ar thr i ti s, sacr oi l i i ti s, i f pr esent, i s of ten uni l ater al and asy m m etr i c.
5. What i s the ther apy f or r eacti v e ar thr i ti s?
Pati ents w i th r eacti v e ar thr i ti s ar e i ni ti al l y tr eated w i th N SAIDs

(ty pi cal l y i ndom ethaci n) together w i th appr opr i ate anti bi oti cs dur i ng
the acute phase, par ti cul ar l y i f ur ethr i ti s or cer v i ci ti s i s pr esent. If the
di sease pr ogr esses despi te N SAID tr eatm ent, sul f asal azi ne or MTX m ay
be of v al ue f or m anagi ng the i nf l am m ator y ar thr i ti s. Intr aar ti cul ar
cor ti coster oi ds m ay be hel pf ul but sy stem i c cor ti coster oi ds ar e usual l y
i nef f ecti v e. The TN FÎ± bl ock i ng dr ugs ar e v er y ef f ecti v e i n r ef r actor y
cases of r eacti v e ar thr i ti s. Topi cal cor ti coster oi ds and k er atol y ti c
agents ar e usef ul f or k er atoder m a bl ennor r hagi cum . Phy si cal ther apy
consi sti ng of heat, ul tr asound, and r angeof m oti on ex er ci ses m ay be
hel pf ul i n pati ents w i th r eacti v e ar thr i ti s.
Suggested Readings
Meehan RT. Rei ter 's sy ndr om e and r eacti v e ar thr i ti des. In: West SG, ed.
€“275.
Tak Yan Yu D, Fan PT. Rei ter 's sy ndr om e, undi f f er enti ated
spondy l oar thr opathy , and r eacti v e ar thr i ti s. In: Har r i s ED Jr , Budd RC,
Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of r heum atol ogy , 7th ed.
Toi v anen A. Reacti v e ar thr i ti s: cl i ni cal f eatur es and tr eatm ent. In:
Hochber g MC, Si l m an AJ, Sm ol en JS, et al . eds. Rheum atol ogy , 3r d ed.
Edi nbur gh: Mosby , 2003:1233â€“1240.
Rheumatoid Arthritis
1. What f our char acter i sti cs of RA hel p di sti ngui sh i t f r om OA?
2. What consti tuti onal sy m ptom s m ay be seen i n RA?
3. What ar e thr ee char acter i sti c phy si cal f i ndi ngs i n RA?
4. What f i v e di seases m ay m i m i c RA?
5. Whi ch ser ol ogi c tests m ay be usef ul i n the di agnosi s of RA?
Discussion
1. What f our char acter i sti cs of RA hel p di sti ngui sh i t f r om OA?
U nl i k e pati ents w i th OA (noni nf l am m ator y ), those w i th RA

(i nf l am m ator y ) ex per i ence m or ni ng sti f f ness l asti ng m or e than 30
m i nutes pl us gel phenom enon (w or se sti f f ness af ter r est); sy m m etr i c
joi nt di sease; char acter i sti c bi l ater al sy nov i ti s of the hands and f eet
(PIPs, MCPs, and MTPs); and an i nter m i ttent or w ax i ng and w ani ng
cour se.
2. What consti tuti onal sy m ptom s m ay be seen i n RA?
Most pati ents ex per i ence gener al i zed m al ai se or f ati gue. Occasi onal l y
w ei ght l oss, l ow gr ade f ev er , sl eep di stur bance, or m i l d
l y m phadenopathy m ay be pr esent. These sy m ptom s m ay be the end
r esul t of ci r cul ati ng
P. 452
i nf l am m ator y cy tok i nes pr oduced i n the i nf l am ed sy nov i al ti ssue of the
af f ected joi nts.
3. What ar e thr ee char acter i sti c phy si cal f i ndi ngs i n RA?
Phy si cal f i ndi ngs encounter ed i n the setti ng of RA m ay i ncl ude sw el l i ng
and w ar m th of one or m or e joi nts ty pi cal l y i n a sy m m etr i c di str i buti on,
tender ness on pal pati on of the sw ol l en joi nts, and the pr esence of
nontender subcutaneous nodul es (r heum atoi d nodul es) ov er the
ex tensor sur f ace of the f or ear m , Achi l l es tendon, and di gi ts of the
hands.
4. What f i v e di seases m ay m i m i c RA?
RA m ay be m i m i ck ed by SLE and other CTDs such as m i x ed connecti v e
ti ssue di sease (MCTD), scl er oder m a, and PMR; pol y ar ti cul ar gout or
pseudogout; the ar thr i ti s of subacute bacter i al endocar di ti s; the
ar thr i ti s secondar y to m al i gnancy ; and the ser onegati v e
spondy l oar thr opathi es. The di agnosi s of RA i s based on the hi stor y ,
phy si cal ex am i nati on, and l abor ator y f i ndi ngs.
5. Whi ch ser ol ogi c tests m ay be usef ul i n the di agnosi s of RA?
RFs ar e autoanti bodi es di r ected agai nst the Fc por ti on of IgG. In RA, RF
has a sensi ti v i ty of appr ox i m atel y 80% and speci f i ci ty of 80%.
Ther ef or e, RF i s detected i n appr ox i m atel y 80% of pati ents w i th RA but
i t i s nonspeci f i c and can be detected i n m any other di sor der s such as
other CTDs and chr oni c v i r al or bacter i al i nf ecti ons. Anti CCP
anti bodi es ar e di r ected agai nst ci tr ul l i nem odi f i ed ar gi ni ne r esi dues i n
a pr otei n. In RA, anti CCP anti bodi es hav e a sensi ti v i ty of 60% to 75%
and a hi gh speci f i ci ty of 90% to 96%. Ther ef or e, anti CCP anti bodi es
ar e usual l y detected onl y i n RA. Pati ents w i th RA w ho hav e a posi ti v e
RF and/or anti CCP anti bodi es ar e at a hi gher r i sk of dev el opi ng
er osi v e joi nt destr ucti on and debi l i ty . An el ev ated ESR or Cr eacti v e
pr otei n (CRP) l ev el suggests the pr esence of an acute i nf l am m ator y
di sease. A com pl ete bl ood count m ay show an anem i a of chr oni c
(i nf l am m ator y ) di sease. AN As ar e f ound i n 30% of pati ents w i th RA,
usual l y i n a l ow ti ter w i th a negati v e AN A pr of i l e, and ar e of l i ttl e
di agnosti c v al ue.
Case
A 38y ear ol d w om an i s seen because of pai n and sw el l i ng i n the joi nts of
her hands, as w el l as i n her w r i sts, el bow s, and k nees. Her sy m ptom s hav e
been i nter m i ttent ov er the l ast 8 m onths but hav e w or sened r ecentl y and
becom e m or e pr ol onged. The pai n and sw el l i ng hav e been accom pani ed by
hand sti f f ness i n the m or ni ng, f r equentl y l asti ng f or 2 hour s or m or e, and
she has noted r etur n of the sti f f ness l ater i n the day af ter per i ods of
i nacti v i ty . She al so com pl ai ns of pr ogr essi v el y w or seni ng f ati gue and l ack
of ener gy . She deni es r ash, photosensi ti v i ty , al opeci a, or al ul cer s, or
sy m ptom s of Ray naud's phenom enon. She ex per i ences l ef t w r i st pai n that
r adi ates to her el bow and i nto her f i nger s, w hi ch i s w or se i n the m or ni ng
and occasi onal l y aw ak ens her at ni ght.
On phy si cal ex am i nati on, sw el l i ng, w ar m th, and tender ness ar e noted i n
sev er al MCP and PIP joi nts bi l ater al l y . Her w r i sts ar e sl i ghtl y sw ol l en and
tender to pal pati on especi al l y i n the r egi on of the ul nar sty l oi d pr ocesses.
Her el bow s ex hi bi t sl i ght tender ness to pal pati on and m i l d f l ex i on
contr actur es bi l ater al l y . Sm al l ef f usi ons ar e pr esent i n both k nees.
Tender ness i s el i ci ted ov er sev er al MTP joi nts i n both f eet. Ti nel 's si gn
(tappi ng
P. 453
ov er the v ol ar car pal l i gam ent w i th the w r i st i n ex tensi on) i s el i ci ted ov er
the l ef t w r i st and Phal en's test (posi ti oni ng the w r i st at f ul l v ol ar f l ex i on f or
60 seconds) r epr oduces the pati ent's l ef t w r i st and f or ear m pai n.
Ex am i nati on of the sk i n r ev eal s the pr esence of sev er al subcutaneous
nodul es ov er the pr ox i m al ex tensor aspects of both f or ear m s.
1. What i s the pr i m ar y pathophy si ol ogi c pr ocess i n RA?

2. What ar e f our char acter i sti c r adi ogr aphi c f i ndi ngs i n RA, and w hat ar e
the m echani sm s r esponsi bl e f or thei r dev el opm ent?
3. What ar e the f our m ost com m on ex tr aar ti cul ar m ani f estati ons of RA?
4. The natur al hi stor y of the joi nt di sease i n pati ents w i th RA assum es
w hat thr ee patter ns?
5. What i s the tr eatm ent f or RA?
Case Discussion
1. What i s the pr i m ar y pathophy si ol ogi c pr ocess i n RA?
The joi nt di sease i n RA begi ns as i nf l am m ati on i n the sy nov i um and
i nv ol v es the i nf i l tr ati on of m acr ophages, T cel l s, and B cel l s. The
sy nov i al ti ssue pr ol i f er ates and can gr ow ov er the car ti l age and bone.
Thi s i nf l am m ator y pr ol i f er ati v e sy nov i ti s i s k now n as pannus. The
pr oducts of m acr ophages, i nter l euk i n 1 (IL1) and TN FÎ± , and
f i br obl asts ar e abundant i n the r heum atoi d sy nov i um . The ov er al l
pr ocess can r esul t i n car ti l age l oss and er osi v e joi nt destr ucti on.
2. What ar e f our char acter i sti c r adi ogr aphi c f i ndi ngs i n RA, and w hat ar e
the m echani sm s r esponsi bl e f or thei r dev el opm ent?
The sof t ti ssue sw el l i ng seen on r adi ogr aphi c studi es i n pati ents w i th
RA i s due to the i nf l am ed, pr ol i f er ati v e sy nov i ti s. Joi nt space nar r ow i ng
r esul ts f r om the l oss of ar ti cul ar car ti l age; the r esul t of destr ucti v e
enzy m es pr oduced by sy nov i al f i br obl asts, and chondr ocy tes.
Jux taar ti cul ar osteopeni a i s due to the l oss of cal ci um i n bones
sur r oundi ng the i nf l am m ator y ar thr i ti s and r esul ts f r om the ef f ects of
pr ostagl andi ns, IL1, and TN FÎ± , w hi ch ar e r el eased by the i nf l am ed
sy nov i um . Mar gi nal er osi ons ar e pr oduced by the pr ol i f er ati v e sy nov i ti s
as i t ex tends i nto the subchondr al bone at the joi nt m ar gi ns.
3. What ar e the f our m ost com m on ex tr aar ti cul ar m ani f estati ons of RA?
The f our m ost com m on ex tr aar ti cul ar m ani f estati ons of RA ar e
subcutaneous nodul es (r heum atoi d nodul es), car pal tunnel sy ndr om e,
i nter sti ti al l ung di sease, and Fel ty 's sy ndr om e (spl enom egal y and
neutr openi a i n the setti ng of RA). Other ex tr aar ti cul ar f eatur es i ncl ude
ocul ar i nv ol v em ent (k er atoconjuncti v i ti s si cca, epi scl er i ti s, and
scl er i ti s), addi ti onal pul m onar y i nv ol v em ent (pl eur al di sease, nodul es,
br onchi ol i ti s, and pul m onar y hy per tensi on), car di ac i nv ol v em ent
(per i car di ti s and r ar e m y ocar di ti s), and r heum atoi d v ascul i ti s.
4. The natur al hi stor y of the joi nt di sease i n pati ents w i th RA assum es
w hat thr ee patter ns?
The natur al hi stor y of RA m ay consi st of a m onocy cl i c patter n (20% of

pati ents), al though i n r etr ospect som e of these cases m ay hav e been a
v i r al i nduced, sel f l i m i ted pol y ar thr i ti s; a pol y cy cl i c patter n (70% of
pati ents) w i th r epeated epi sodes of
P. 454
acti v e di sease i nter sper sed w i th per i ods of i nacti v i ty ; or a pr ogr essi v e
patter n (10% of pati ents) w i th i ncr easi ng joi nt i nv ol v em ent and no
di seasef r ee i nter v al s.
5. What i s the tr eatm ent f or RA?
Ear l y detecti on and suppr essi on of i nf l am m ator y sy nov i ti s w i l l l i k el y

pr ev ent the pr ogr essi on of car ti l age and bony destr ucti on al ong w i th
f uncti onal i m pai r m ent. N SAIDs and l ow dose cor ti coster oi ds can
pr ov i de r api d r el i ef of pai n and sti f f ness. Ear l y i n the di sease (w i thi n 3
m onths), tr eatm ent w i th DMARDs shoul d be i ni ti ated i n m ost pati ents.
These agents i ncl ude hy dr ox y chl or oqui ne, sul f asal azi ne, MTX, and
l ef l unom i de. The choi ce of DMARD i s a cl i ni cal deci si on based on
sev er i ty of di sease and pr ognosi s. MTX i s the m ost com m onl y
pr escr i bed DMARD. An appr oach to tr eatm ent of RA w oul d be to i ni ti ate
MTX w i th r api d dose escal ati on or MTX i n com bi nati on w i th other
DMARDs such as hy dr ox y chl or oqui ne and/or sul f asal azi ne. If the
di sease i s r ef r actor y to thi s tr eatm ent, an anti TN F bi ol ogi c agent
shoul d be consi der ed w i th conti nuati on of MTX. The av ai l abl e anti TN F
agents ar e etaner cept, i nf l i x i m ab, and adal i m um ab. Another opti on i s
anak i nr a, an IL1 r eceptor antagoni st. N ew ther api es f or r ef r actor y RA
i ncl ude abatacept, cy totox i c Tl y m phocy teâ€“associ ated anti gen 4Ig,
and the Bcel l depl eti ng m onocl onal anti body , r i tux i m ab. When joi nts
becom e sev er el y dam aged because of chr oni c RA, r econstr ucti v e
or thopaedi c sur gi cal pr ocedur es m ay be per f or m ed to hel p r estor e
f uncti on.
Suggested Readings
El l i ott JR, O'Del l J. Rheum atoi d ar thr i ti s. In: West SG, ed. Rheum atol ogy
Genov ese MC, Har r i s ED Jr . Tr eatm ent of r heum atoi d ar thr i ti s. In: Har r i s
ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of
€“1100.
Gor don DA, Hasti ngs DE. Cl i ni cal f eatur es of r heum atoi d ar thr i ti s. In:
Har r i s ED Jr . Cl i ni cal f eatur es of r heum atoi d ar thr i ti s. In: Har r i s ED Jr ,
Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of r heum atol ogy , 7th
ed. Phi l adel phi a: El sev i er , Saunder s, 2005:1043â€“1078.
Scleroderma
1. What thr ee di f f er ent r heum ati c di seases ar e suggested by a
pr edom i nance of sk i n f i ndi ngs?
2. Ray naud's phenom enon m ay occur i n associ ati on w i th w hat f our
r heum ati c di seases?
3. Dy sphagi a or hear tbur n m ay pr edom i nate i n w hat tw o r heum ati c

di seases?
4. What f eatur es char acter i ze CREST sy ndr om e?
5. What i s the di f f er ence betw een l i m i ted and di f f use scl er oder m a
(sy stem i c scl er osi s)?
P. 455
Discussion
1. What thr ee di f f er ent r heum ati c di seases ar e suggested by a
pr edom i nance of sk i n f i ndi ngs?
A pr edom i nance of sk i n f i ndi ngs i n a pati ent w i th a suspected

r heum ati c di sease suggests a di agnosi s of SLE, der m atom y osi ti s, or
scl er oder m a. The sk i n f i ndi ngs i n each of these di seases, how ev er , ar e
di sti nct, w hi ch al l ow s thei r di f f er enti ati on.
2. Ray naud's phenom enon m ay occur i n associ ati on w i th w hat f our
r heum ati c di seases?
Ray naud's phenom enon (a col di nduced bl anchi ng or cy anosi s of the
f i nger s or toes) m ay be seen i n the setti ngs of scl er oder m a (90%),
MCTD (70%), SLE (20%), or pol y m y osi ti s/der m atom y osi ti s (20%).
When the phenom enon occur s al one, w i thout an associ ated CTD, i t i s
cal l ed Ray naud's di sease.
3. Dy sphagi a or hear tbur n m ay pr edom i nate i n w hat tw o r heum ati c

di seases?
Dy sphagi a (di scom f or t w hen sw al l ow i ng f ood) and hear tbur n ar e

esophageal abnor m al i ti es that m ay occur i n the setti ng of ei ther
scl er oder m a or pol y m y osi ti s and der m atom y osi ti s. In scl er oder m a, the
l ow er por ti on of the esophagus i s i nv ol v ed. In der m atom y osi ti s and
pol y m y osi ti s, the m uscl es i n the phar y nx and upper thi r d of the
esophagus m ay be i nv ol v ed.
4. What f eatur es char acter i ze CREST sy ndr om e?
CREST sy ndr om e i s a cl i ni cal v ar i ant of l i m i ted scl er oder m a that i s

char acter i zed by cal ci nosi s, Ray naud's phenom enon, esophageal
dy sm oti l i ty , scl er odacty l y , and tel angi ectases. Pati ents w i th the
sy ndr om e m ay ex per i ence a m or e beni gn cour se than those w i th m or e
w i despr ead scl er oder m a that i nv ol v es other i nter nal or gans. Ther e i s
an i ncr eased r i sk f or the dev el opm ent of pul m onar y hy per tensi on w i th
l i m i ted scl er oder m a.
5. What i s the di f f er ence betw een l i m i ted and di f f use scl er oder m a
(sy stem i c scl er osi s)?
In l i m i ted sy stem i c scl er osi s, f i br oti c sk i n di sease i s l i m i ted to the
hands and f or ear m s, f eet, neck , and f ace. Pul m onar y hy per tensi on can
occur . Pati ents w i th l i m i ted sy stem i c scl er osi s hav e a hi gh i nci dence of
anti centr om er e anti bodi es. In di f f use sy stem i c scl er osi s, f i br oti c sk i n
i nv ol v es the f i nger s, hands, ar m s, l egs, and ty pi cal l y the tr unk and
f ace. Pul m onar y (i nter sti ti al l ung di sease), r enal , gastr oi ntesti nal , and
car di ac i nv ol v em ent can occur . Pati ents w i th di f f use sy stem i c scl er osi s
ar e m or e l i k el y to hav e anti bodi es to topoi som er ase 1 (anti â€“Scl 70).
Case
A 45y ear ol d w om an seek s m edi cal attenti on because of pr ogr essi v e
sy m m etr i c sk i n ti ghteni ng that has i nv ol v ed the di gi ts, hands, and f or ear m s
dur i ng the l ast 6 m onths. These sk i n changes ar e pai nl ess and ar e
associ ated w i th m i l d pr ur i tus. Dur i ng the l ast 12 m onths, she has al so noted
the onset of col d sensi ti v i ty of the hands, especi al l y w hen handl i ng objects
i n the r ef r i ger ator , w i th m ul ti pl e f i nger s becom i ng col d, pal e, and num b.
She al so r epor ts gener al i zed f ati gue, dy spnea on ex er ti on, and a decr ease
i n ex er ci se tol er ance. She deni es chest pai n, pal pi tati ons, or par ox y sm al
noctur nal dy spnea, but has
P. 456
noti ced sy m m etr i c sw el l i ng i n both l ow er ex tr em i ti es. She has noted a 10l b
(4. 5k g) w ei ght l oss i n the l ast 6 m onths, w hi ch she has attr i buted to
decr eased f ood i ntak e because of her hear tbur n and dy sphagi a.
On phy si cal ex am i nati on, the w om an appear s y ounger than her stated age
as she l ack s the nor m al f or ehead w r i nk l i ng and has a â€œpur sedl i psâ€
appear ance. A f ew scatter ed f aci al tel angi ectases ar e noted. Her sk i n i s
v er y ti ght and cannot be easi l y l i f ted f r om ov er the dor sum of the hands,
f i nger s, and l ow er f or ear m s. Ther e ar e v er y sm al l punctate heal ed
ul cer ati ons on sev er al f i nger ti ps. N ai l f i ndi ngs ar e unr em ar k abl e. Her
m uscl e str ength i s nor m al and ther e i s no ev i dence of sy nov i ti s. Chest
ex am i nati on r ev eal s cl ear l ung f i el ds. On car di ac ex am i nati on, no gal l ops,
m ur m ur s, or r ubs ar e hear d but the pul m oni c second sound (P 2 ) i s l oud. Her
jugul ar v enous pr essur e i s sl i ghtl y el ev ated, and ther e i s 1 + pi tti ng edem a
ov er both l ow er ex tr em i ti es.
1. What i s the pr i m ar y pathophy si ol ogi c pr ocess i n sy stem i c scl er osi s?

2. What f our r adi ogr aphi c f i ndi ngs m ay be seen i n pati ents w i th sy stem i c
scl er osi s?
3. What ar e som e of the com pl i cati ons associ ated w i th esophageal and
sm al l i ntesti nal i nv ol v em ent i n sy stem i c scl er osi s?
4. What car di ac and r enal pr obl em s m ay ar i se i n pati ents w i th sy stem i c
scl er osi s?
5. What i s the ther apy f or pati ents w i th sy stem i c scl er osi s?
Case Discussion
1. What i s the pr i m ar y pathophy si ol ogi c pr ocess i n sy stem i c scl er osi s?
Sy stem i c scl er osi s i s a sy stem i c f i br oti c di sor der . In the sk i n, ther e i s
ear l y CD4 + Tcel l i nf i l tr ati on and m assi v e nor m al ty pe I col l agen
deposi ti on by der m al f i br obl asts l i k el y i nduced by tr ansf or m i ng gr ow th
f actor Î² (TGFÎ²). Ar ter i al endothel i al cel l dam age w i th m y oi nti m al cel l
pr ol i f er ati on (oni on sk i nni ng) occur s, r esul ti ng i n nar r ow i ng of the
v ascul ar l um en. Ischem i c dam age and f i br osi s can occur i n v i scer al
or gans as a r esul t of thi s v ascul opathy .
2. What f our r adi ogr aphi c f i ndi ngs m ay be seen i n pati ents w i th sy stem i c
scl er osi s?
Radi ogr aphi c abnor m al i ti es that m ay be f ound i n pati ents w i th
scl er oder m a i ncl ude w i dem outh di v er ti cul a of the tr ansv er se and
descendi ng col on on bar i um enem a, pul m onar y i nter sti ti al f i br osi s, l oss
of di stal di gi tal tuf ts, and subcutaneous cal ci nosi s par ti cul ar l y i n the
hands.
3. What ar e som e of the com pl i cati ons associ ated w i th esophageal and
sm al l i ntesti nal i nv ol v em ent i n sy stem i c scl er osi s?
The l ow er esophageal i nv ol v em ent that can occur i n pati ents w i th

sy stem i c scl er osi s m ay l ead to sev er e esophageal r ef l ux , dy sphagi a,
and ul ti m atel y esophageal str i ctur es m ay dev el op. Inv ol v em ent of the
sm al l i ntesti ne m ay l ead to l oss of m oti l i ty w i th m al absor pti on
secondar y to bacter i al ov er gr ow th. Other com pl i cati ons of
gastr oi ntesti nal i nv ol v em ent w i th sy stem i c scl er osi s i ncl ude
w ater m el on stom ach (gastr i c antr al v ascul ar ectasi a) and pneum atosi s
cy stoi des i ntesti nal i s.
P. 457
4. What car di ac and r enal pr obl em s m ay ar i se i n pati ents w i th sy stem i c
scl er osi s?
The hear ts of pati ents w i th sy stem i c scl er osi s m ay be af f ected by
patchy f i br osi s, w hi ch can cause conducti on di stur bances and
ar r hy thm i as. Per i car di ti s and congesti v e hear t f ai l ur e can al so occur .
In the ev ent of r enal i nv ol v em ent, pati ents can hav e hy per tensi on w i th
m i l d pr otei nur i a that som eti m es l eads to scl er oder m a r enal cr i si s
(accel er ated hy per tensi on and r api d l oss of k i dney f uncti on pr ogr essi ng
to r enal f ai l ur e). Most pati ents w ho dev el op scl er oder m a r enal cr i si s
hav e di f f use cutaneous i nv ol v em ent. Mi cr oangi opathi c hem ol y ti c
anem i a and thr om bocy topeni a can be pr esent i n the setti ng of r enal
cr i si s.
5. What i s the ther apy f or pati ents w i th sy stem i c scl er osi s?
Ther e ar e cur r entl y no k now n m edi cati ons that can al ter the natur al
cour se of scl er oder m a. Aggr essi v e sk i n car e i s hel pf ul i n pr ev enti ng
br eak dow n and l ocal i nf ecti on. Ray naud's phenom enon i s tr eated w i th
pr otecti on f r om the col d and cal ci um channel bl ock er s.
Gastr oesophageal r ef l ux r equi r es aggr essi v e ther apy w i th a pr oton
pum p i nhi bi tor . Br oadspectr um anti bi oti cs m ay be used i f di ar r hea
ar i ses as a r esul t of sm al l i ntesti nal i nv ol v em ent. An angi otensi n
conv er ti ng enzy m e i nhi bi tor shoul d be used i n hy per tensi v e pati ents
w i th sy stem i c scl er osi s i n an ef f or t to pr ev ent f ur ther r enal dam age
and possi bl e r enal cr i si s by r ev er si ng the under l y i ng hy per r eni nem i a.
Pati ents w i th ear l y pr ogr essi v e i nter sti ti al l ung di sease m ay benef i t
f r om tr eatm ent w i th cy cl ophospham i de. Si gni f i cant pul m onar y ar ter i al
hy per tensi on, the l eadi ng cause of death i n pati ents w i th l i m i ted
scl er oder m a, of ten r equi r es aggr essi v e ther apy w i th ox y gen,
anti coagul ati on, and agents such as bosentan, si l denaf i l , or
pr ostanoi ds.
Suggested Readings
Col l i er DH. Sy stem i c Scl er osi s. In: West SG, ed. Rheum atol ogy secr ets,
2nd ed. Phi l adel phi a: Hanl ey & Bel f us, 2002:151â€“161.
Sei bol d JR. Scl er oder m a. In: Har r i s ED Jr , Budd RC, Fi r estei n GS, et al .
eds. Kel l ey 's tex tbook of r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er ,
Saunder s, 2005:1279â€“1308.
Wi gl ey FM, Hum m er s LK. Cl i ni cal f eatur es of sy stem i c scl er osi s. In:
Synovial Fluid Analysis and Septic Arthritis
1. When shoul d ar thr ocentesi s be per f or m ed?
2. What di agnosti c tests shoul d be per f or m ed on al l sy nov i al f l ui d

aspi r ates r egar dl ess of the suspected di agnosi s?
3. What ar e the char acter i sti cs of nor m al , noni nf l am m ator y ,

i nf l am m ator y , and septi c sy nov i al ef f usi ons?
4. What ar e the causes of bl oody or hem or r hagi c sy nov i al f l ui d?
P. 458
Discussion
1. When shoul d ar thr ocentesi s be per f or m ed?
The m ost i m por tant r eason to per f or m an ar thr ocentesi s i s to ex cl ude a
joi nt i nf ecti on. Sy nov i al f l ui d anal y si s i s of ten hel pf ul di agnosti cal l y i n
a pati ent w i th joi nt pai n and sw el l i ng of uncl ear eti ol ogy . Sy nov i al f l ui d
anal y si s w i l l deter m i ne i f the f l ui d i s nor m al , noni nf l am m ator y ,
i nf l am m ator y i ncl udi ng cr y stal di sease, or septi c.
2. What di agnosti c tests shoul d be per f or m ed on al l sy nov i al f l ui d

aspi r ates r egar dl ess of the suspected di agnosi s?
Sy nov i al f l ui d shoul d be r outi nel y sent f or cel l count w i th di f f er enti al ,
cr y stal anal y si s, and Gr am 's stai n and cul tur e. Chem i str y
deter m i nati ons ar e unl i k el y to y i el d addi ti onal usef ul i nf or m ati on and
shoul d not be or der ed r outi nel y .
3. What ar e the char acter i sti cs of nor m al , noni nf l am m ator y ,

i nf l am m ator y , and septi c sy nov i al ef f usi ons?
Spe c ia l
Type of Fluid Le uk oc yte s /ÂµL
Fe a ture s
N or m al Cl ear , < 200 (< 25% PMN s)

col or l ess,
v i scous
N oni nf l am m ator y Cl ear , y el l ow , 2002, 000 (< 25% PMN s)

(ty pe I f l ui d) v i scous
Inf l am m ator y Cl oudy , y el l ow , > 2, 000 (> 50% PMN s)
(ty pe II f l ui d) l ow v i scosi ty ,
cul tur e
negati v e
Septi c (ty pe III Pur ul ent, > 50, 000 (> 95% PMN s) but not
f l ui d) cul tur e posi ti v e al l f l ui ds > 50, 000 ar e septi c,
they m ay be i nf l am m ator y
PMN s, pol y m or phonucl ear l euk ocy tes.
4. What ar e the causes of bl oody or hem or r hagi c sy nov i al f l ui d?
The causes of hem or r hagi c sy nov i al f l ui d ar e tr aum a w i th or w i thout

f r actur e; bl eedi ng di sor der s i ncl udi ng anti coagul ati on, hem ophi l i a, v on
Wi l l ebr and's di sease, scur v y , and thr om bocy topeni a; cr y stal l i ne
ar thr opathy , par ti cul ar l y acute pseudogout and hy dr ox y apati te
deposi ti on di sease; Char cot's ar thr opathy ; tum or s i ncl udi ng pi gm ented
v i l l onodul ar sy nov i ti s; hem angi om a; and si ck l e cel l ar thr opathy .
Case
A 52y ear ol d w om an i s seen i n the em er gency r oom because of an acutel y
pai nf ul and sw ol l en r i ght k nee. The pati ent has a 10y ear hi stor y of RA that
has not r esponded w el l to m ul ti pl e m edi cati ons. For the l ast 6 m onths, she
has been tak i ng i bupr of en, azathi opr i ne 100 m g dai l y , and pr edni sone 10 m g
dai l y . Despi te thi s r egi m en, she conti nues to
P. 459
ex per i ence 2 hour s of m or ni ng sti f f ness w i th sw el l i ng, er y them a, and pai n
i n m ul ti pl e sm al l joi nts of her hands, w r i sts, k nees, and ank l es. She i s now
unabl e to bear w ei ght on the r i ght l eg. A l ow gr ade f ev er al so dev el oped.
On phy si cal ex am i nati on, the pati ent's tem per atur e i s f ound to be 38. 5Â°C
(101. 3Â°F) and her bl ood pr essur e i s 150/100 m m Hg. She appear s both
acutel y and chr oni cal l y i l l w i th m i l d sw el l i ng of m ul ti pl e MCP and PIP joi nts
as w el l as both w r i sts and ank l es. Her r i ght k nee i s hel d i n 10 degr ees of
f l ex i on and i t cannot be m ov ed because of sev er e pai n. The k nee ex hi bi ts a
l ar ge ef f usi on and i s di f f usel y tender w i th er y them a ar ound the enti r e joi nt.
Joi nt aspi r ati on i s per f or m ed and 20 m L of opaque, y el l ow f l ui d i s r em ov ed
that has l ow v i scosi ty . The WBC count i n the sy nov i al f l ui d aspi r ate i s
75, 000/ÂµL w i th 98% pol y m or phonucl ear l euk ocy tes. Sy nov i al f l ui d cr y stal
anal y si s i s negati v e. Ther e ar e gr am posi ti v e cocci on Gr am 's stai n of the
sy nov i al f l ui d. The f l ui d i s cul tur ed f or or gani sm s.
1. How do bacter i a r each the sy nov i um to cause a septi c ar thr i ti s?
2. What ar e the r i sk f actor s f or dev el opi ng a septi c ar thr i ti s?
3. How do nongonococcal bacter i al septi c ar thr i ti s and di ssem i nated
gonococcal ar thr i ti s di f f er ?
4. What i s â€œpseudosepti câ€
ar thr i ti s?
Case Discussion
1. How do bacter i a r each the sy nov i um to cause a septi c ar thr i ti s?
Inf ecti ous or gani sm s r each the sy nov i al m em br ane thr ough
hem atogenous spr ead due to a r em ote i nf ecti on (m ost com m on),
di ssem i nati on f r om an adjacent sof t ti ssue i nf ecti on or osteom y el i ti s,
di agnosti c or ther apeuti c m easur es, or penetr ati ng punctur e f r om
tr aum a. The m ost com m on or gani sm causi ng septi c ar thr i ti s i n y oung
sex ual l y acti v e adul ts i s N . gonor r hoeae and i n pati ents ol der than 50
y ear s i s Staphy l ococcus aur eus f ol l ow ed by gr am negati v e or gani sm s.
2. What ar e the r i sk f actor s f or dev el opi ng a septi c ar thr i ti s?
The r i sk f actor s f or dev el opi ng a septi c ar thr i ti s i ncl ude abnor m al
joi nts due to ar thr i ti s; pr ostheti c joi nts; i m pai r ed host def ense
m echani sm s i ncl udi ng ex tr em es of age, i m m unosuppr essi v e dr ugs,
al cohol i sm , neopl asti c di seases, and chr oni c di seases such as di abetes,
chr oni c k i dney di sease, ci r r hosi s, hem ogl obi nopathi es, and HIV; and
host phagocy ti c def ects such as i m pai r ed chem otax i s and com pl em ent
def i ci enci es. Intr av enous dr ug abuse i s al so a pr edi sposi ng r i sk f or
dev el opi ng a septi c ar thr i ti s of ten w i th aty pi cal joi nt i nv ol v em ent. In
addi ti on to joi nts of the l ow er ex tr em i ti es, i ntr av enous dr ug abuser s
can dev el op septi c ar thr i ti s of the ax i al sk el eton, v er tebr al di sc spaces,
sacr oi l i ac joi nts, acr om i ocl av i cul ar joi nts, and ster nocl av i cul ar joi nts.
3. How do nongonococcal bacter i al septi c ar thr i ti s and di ssem i nated

gonococcal ar thr i ti s di f f er ?
P. 460
Nongonoc oc c a l
G onoc oc c a l Arthritis
Ba c te ria l Arthritis
Host Ex tr em es of age, Young, heal thy adul ts

i m m unosuppr essed
Joi nt patter n Monoar ti cul ar Mi gr ator y pol y ar thr al gi as,

ar thr i ti s
Der m ati ti s Rar e Com m on
Tenosy nov i ti s Rar e Com m on
Posi ti v e joi nt > 95% < 25%

cul tur es
Posi ti v e 50% < 10%
bl ood
cul tur es
Tr eatm ent Ar thr oscopi c or Cef tr i ax one dai l y unti l cl i ni cal

open joi nt l av age i m pr ov em ent f ol l ow ed by 7d
and pr ol onged tr eatm ent w i th or al cef i x i m e
i ntr av enous or a f l uor oqui nol one
anti bi oti cs
Mechani sm Bacter em i c seedi ng Im m une com pl ex or

of the joi nt hy per sensi ti v i ty r eacti on
4. What i s â€œpseudosepti câ€

ar thr i ti s?
Pseudosepti c ar thr i ti s ty pi cal l y occur s i n the setti ng of poor l y

contr ol l ed RA. The pati ent pr esents w i th acute onset of one or m or e
sw ol l en joi nts w i th sy nov i al f l ui d WBC count gr eater than 100, 000 cel l s/
ÂµL and a negati v e Gr am 's stai n and cul tur e of the f l ui d. Af ter joi nt
i nf ecti on has been ex cl uded, the pati ent r esponds to i ncr eased doses of
cor ti coster oi ds r ather than anti bi oti cs. Pseudosepti c ar thr i ti s can al so
occur i n acute cr y stal i nduced ar thr i ti s, par ti cul ar l y acute pseudogout,
and i n ser onegati v e spondy l oar thr opathi es, especi al l y r eacti v e
ar thr i ti s.
Suggested Readings
Ger l ag M, Tak PP. Sy nov i al f l ui d anal y si s, sy nov i al bi opsy , and sy nov i al
pathol ogy . In: Har r i s ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's
tex tbook of r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er , Saunder s,
2005:675â€“690.
Gi l l i l and WR. Bacter i al septi c ar thr i ti s. In: West SG, ed. Rheum atol ogy
Li dgr en l . Septi c ar thr i ti s and osteom y el i ti s. In: Hochber g MC, Si l m an

AJ, Sm ol en JS, et al . eds. Rheum atol ogy , 3r d ed. Edi nbur gh: Mosby ,
2003:1055â€“1065.
Mahow al d ML. Gonococcal ar thr i ti s. In: Hochber g MC, Si l m an AJ, Sm ol en

JS, et al . eds. Rheum atol ogy , 3r d ed. Edi nbur gh: Mosby , 2003:1067â
€“1075.
Spencer RT. Ar thr ocentesi s and sy nov i al f l ui d anal y si s. In: West SG, ed.
€“67.
P. 461
Systemic Lupus Erythematosus
1. What cl i ni cal f eatur es suggest a di agnosi s of SLE?
2. What abnor m al l abor ator y r esul ts suggest a di agnosi s of SLE?
3. Besi des SLE, AN As ar e com m onl y f ound i n w hat other di seases?
Discussion
1. What cl i ni cal f eatur es suggest a di agnosi s of SLE?
For the pur poses of cl i ni cal studi es, any per son hav i ng 4 or m or e of the
f ol l ow i ng 11 cr i ter i a i s consi der ed to hav e SLE: m al ar r ash, di scoi d
r ash, photosensi ti v i ty , or al ul cer s, ar thr i ti s, ser osi ti s (pl eur i ti s or
per i car di ti s), r enal di sor der (per si stent pr otei nur i a > 0. 5 g per day or
cel l ul ar casts), neur ol ogi c di sor der (sei zur es or psy chosi s),
hem atol ogi c di sor der (hem ol y ti c anem i a, l euk openi a, l y m phopeni a, or
thr om bocy topeni a), i m m unol ogi c di sor der (anti DN A anti bodi es, anti
Sm i th [Sm ] anti bodi es, or posi ti v e f i ndi ngs of anti phosphol i pi d
anti bodi es), and AN A.
2. What abnor m al l abor ator y r esul ts suggest a di agnosi s of SLE?
Al m ost al l pati ents w i th SLE dem onstr ate el ev ated ser um l ev el s of AN A.
How ev er , thi s test i s not speci f i c f or SLE. Other l abor ator y
abnor m al i ti es i n SLE can i ncl ude anti â€“doubl estr anded DN A
anti bodi es, anti Sm anti bodi es, f al seposi ti v e test f or sy phi l i s, l ow
ser um com pl em ent l ev el s, pr ol onged par ti al thr om bopl asti n ti m e,
anti phosphol i pi d anti bodi es, cy topeni as, and acti v e ur i ne sedi m ent.
3. Besi des SLE, AN As ar e com m onl y f ound i n w hat other di seases?
In SLE, AN As hav e a sensi ti v i ty of 93% to 100% but a l ow er speci f i ci ty
of appr ox i m atel y 50% si nce AN As can occur i n m any other di seases.
Condi ti ons associ ated w i th a posi ti v e AN A i ncl ude other autoi m m une
di seases (scl er oder m a: 60% to 85%, MCTD: 90% to 100%,
i nf l am m ator y m y opathi es: 50%, RA: 30% to 50%, SjÃ¶gr en's
sy ndr om e: 40% to 70%, and dr ugi nduced l upus: 100%), or ganspeci f i c
autoi m m une di seases (such as Hashi m oto's thy r oi di ti s: 46%, Gr av es'
di sease: 50%, autoi m m une hepati ti s: 63% to 91%, pr i m ar y bi l i ar y
ci r r hosi s: 10% to 40%, i di opathi c thr om bocy topeni c pur pur a: 10% to
40%, and m ul ti pl e scl er osi s: 25%), chr oni c i nf ecti ons (such as
m ononucl eosi s, hepati ti s C, HIV i nf ecti on, par v ov i r us B19 i nf ecti on,
bacter i al endocar di ti s, and tuber cul osi s), l y m phopr ol i f er ati v e di seases,
FMS: 12% to 30%, and heal thy w om en and el der l y pati ents: 5% to
30%. In SLE, the posi ti v e and negati v e pr edi cti v e v al ues of an AN A ar e
11% to 30%, and 95%, r especti v el y . Ther ef or e, an AN A shoul d be
tested onl y w hen the pati ent has a hi gh cl i ni cal pr etest pr obabi l i ty of
hav i ng a CTD.
Case
A 28y ear ol d w om an pr esents w i th a 2m onth hi stor y of pai nf ul joi nts and
f ati gue. She states that the joi nt pai n af f ects her hands, w r i sts, f eet,
ank l es, and k nees and i s
P. 462
associ ated w i th som e joi nt sw el l i ng and 2 to 3 hour s of m or ni ng sti f f ness.
Ov er the l ast 3 to 4 m onths, the pati ent has noted gr adual l y i ncr easi ng
f ati gue and has had thr ee or f our epi sodes of r ash ov er her f ace and neck .
Dur i ng the l ast sum m er , she states that she had a si m i l ar r ash that w as
pr eci pi tated by ex posur e to the sun. She has al so noted that pr ol onged sun
ex posur e r esul ts i n i ncr easi ng f ati gue and a f l ul i k e sy ndr om e. Tw o w eek s
ago, she noted her ank l es tend to sw el l at the end of the day . Past m edi cal
hi stor y r ev eal s that 8 m onths ago she had an epi sode of pl eur i ti c chest pai n
that l asted 8 to 10 day s and w as tr eated by her f am i l y doctor w i th
i ndom ethaci n f ol l ow ed by gr adual r esol uti on.
Phy si cal ex am i nati on r ev eal s a ti r edl ook i ng w om an w ho i s i n no acute
di str ess. Her tem per atur e i s 38. 2Â°C (100. 8Â°F), bl ood pr essur e i s 140/100
m m Hg, and pul se i s 96 beats per m i nute and r egul ar . On ex am i nati on of
the sk i n, an er y them atous r ash i s noted ov er her nose and cheek s that
spar es the nasol abi al f ol ds. Sev er al shal l ow pai nl ess ul cer s ar e f ound i n her
m outh. Joi nt ex am i nati on r ev eal s m i ni m al sw el l i ng of the w r i sts and MCP
joi nts. Pul m onar y and car di ac f i ndi ngs ar e nor m al ex cept f or 2+ pi tti ng
edem a i n the pr eti bi al ar ea, bi l ater al l y .
1. What ar e the tw o m ost com m on m echani sm s of ti ssue dam age i n

pati ents w i th SLE?
2. Besi des the sk i n and joi nts, w hat other or gans ar e com m onl y af f ected
i n pati ents w i th SLE?
3. What ser ol ogi c tests and di agnosti c pr ocedur es m ay be hel pf ul i n the
m anagem ent of l upus nephr i ti s?
4. What ar e the f our possi bl e causes of per i pher al edem a i n pati ents w i th
SLE?
5. What i s the ther apy f or SLE?
Case Discussion
1. What ar e the tw o m ost com m on m echani sm s of ti ssue dam age i n
pati ents w i th SLE?
Ti ssue dam age i n pati ents w i th SLE m ay be caused by anti bodi es to cel l
sur f ace com ponents or by the pr esence of sol ubl e i m m une com pl ex es i n
the ci r cul ati on. Anti bodi es to pl atel ets, WBCs, or r ed bl ood cel l s m ay
i nduce thr om bocy topeni a, l euk openi a, or anem i a, r especti v el y .
Anti phosphol i pi d anti bodi es m ay i nduce v enous or ar ter i al thr om boses,
r ecur r ent f etal l oss, or thr om bocy topeni a. Sol ubl e i m m une com pl ex es
i n the ci r cul ati on m ay deposi t i n bl ood v essel s or al ong basem ent
m em br anes i n the sk i n or k i dney s, r esul ti ng i n v ascul i ti s, der m ati ti s,
or gl om er ul onephr i ti s.
2. Besi des the sk i n and joi nts, w hat other or gans ar e com m onl y af f ected
i n pati ents w i th SLE?
Other or gans that m ay be af f ected i n the setti ng of SLE i ncl ude the
centr al and per i pher al ner v ous sy stem s, l ungs (pl eur i ti s, capi l l ar i ti s,
pneum oni ti s, pul m onar y hy per tensi on, and â€œshr i nk i ng l ung
sy ndr om eâ€ ) , hear t (per i car di ti s, m y ocar di ti s, and v al v ul ar di sease),
k i dney s (m esangi al nephr i ti s, di f f use pr ol i f er ati v e gl om er ul onephr i ti s,
and m em br anous nephr opathy ), and gastr oi ntesti nal sy stem
(pancr eati ti s and m esenter i c v ascul i ti s), as w el l as the f or m ed
el em ents of the bl ood and ser ous m em br anes.
P. 463
3. What ser ol ogi c tests and di agnosti c pr ocedur es m ay be hel pf ul i n the
m anagem ent of l upus nephr i ti s?
Low ser um com pl em ent l ev el s and/or hi gh ti ter s of anti bodi es to
doubl estr anded DN A m ay pr ecede f l ar es of r enal di sease. A k i dney
bi opsy m ay ai d i n the m anagem ent of pati ents w i th l upus nephr i ti s
par ti cul ar l y w hen the sev er i ty of the di sease appear s to be changi ng,
the di sease i s r ef r actor y to hi ghdose pr edni sone ther apy , and
cy totox i c ther apy w i th i ntr av enous bol us cy cl ophospham i de ther apy i s
bei ng consi der ed.
4. What ar e the f our possi bl e causes of per i pher al edem a i n pati ents w i th
SLE?
Per i pher al edem a i n a pati ent w i th SLE m ay be due to r enal di sease
w i th si gni f i cant pr otei nur i a, congesti v e hear t f ai l ur e secondar y to
car di ac i nv ol v em ent, pr otei nl osi ng enter opathy due to m esenter i c
v ascul i ti s, or per i pher al v enous thr om bosi s stem m i ng f r om the
f or m ati on of anti car di ol i pi n anti bodi es.
5. What i s the ther apy f or SLE?
Pati ents w i th SLE ar e m anaged accor di ng to the ex tent and sev er i ty of
thei r or gan i nv ol v em ent. Pati ents w i th m i l d di sease consi sti ng of
ar thr i ti s, sk i n, and nonâ€“l i f ethr eateni ng bl ood or other or gan
i nv ol v em ent m ay be tr eated w i th N SAIDs, anti m al ar i al s such as
hy dr ox y chl or oqui ne, and l ow dose cor ti coster oi ds i f necessar y . Pati ents
w i th m or e sev er e or gan i nv ol v em ent, par ti cul ar l y of the centr al
ner v ous sy stem and k i dney s, m ay be tr eated w i th hi gh doses of
cor ti coster oi ds and or al azathi opr i ne or i ntr av enous cy cl ophospham i de.
Recent ev i dence suggests that m y cophenol ate m of eti l m ay be usef ul i n
som e pati ents w i th l upus nephr i ti s. Other ther api es m ay be used f or
the am el i or ati on of speci f i c or gan i nv ol v em ent.
Suggested Readings
Edw or thy SM. Cl i ni cal m ani f estati ons of sy stem i c l upus er y them atosus.
In: Har r i s ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's tex tbook of
€“1224.
Gl adm an DD, U r ow i tz MB. Sy stem i c l upus er y them atosus: cl i ni cal
Hahn BH. Managem ent of sy stem i c l upus er y them atosus. In: Hochber g
MC, Si l m an AJ, Sm ol en JS, et al . eds. Rheum atol ogy , 3r d ed. Edi nbur gh:
Mosby , 2003:1225â€“1247.
Kotzi n BL. Sy stem i c l upus er y them atosus. In: West SG, ed.
€“147.
Vasculitis
1. Vascul i ti s shoul d be suspected i n pati ents pr esenti ng w i th any
com bi nati on of w hat cl i ni cal m ani f estati ons?
2. N am e the pr i m ar y v ascul i ti c di sor der s based on the dom i nant v essel
si ze and anti neutr ophi l cy topl asm i c anti bodi es (AN CA).
3. What ser ol ogi c tests or di agnosti c pr ocedur es shoul d be per f or m ed i n
pati ents w i th suspected v ascul i ti s?
P. 464
4. What m or e ex tensi v e pr ocedur es m ay be of v al ue i n hel pi ng to
establ i sh the di agnosi s of a speci f i c f or m of v ascul i ti s?
Discussion
1. Vascul i ti s shoul d be suspected i n pati ents pr esenti ng w i th any
com bi nati on of w hat cl i ni cal m ani f estati ons?
Vascul i ti s com pr i ses a heter ogeneous gr oup of di seases char acter i zed
by i nf l am m ator y changes i n the bl ood v essel s w i th subsequent
i m pai r m ent of f l ow and ti ssue/or gan i schem i a. Pati ents pr esent w i th a
m ul ti sy stem i nf l am m ator y di sease of ten w i th f ev er of unk now n or i gi n
and/or unex pl ai ned consti tuti onal sy m ptom s; suspi ci ous sk i n l esi ons
such as ul cer s, l i v edo r eti cul ar i s, and pal pabl e pur pur a; i schem i c
neur opathi es; and r api dl y pr ogr essi v e or gan dy sf uncti on such as
str ok es, pul m onar y â€“r enal sy ndr om es, and other or gan i schem i a.
2. N am e the pr i m ar y v ascul i ti c di sor der s based on the dom i nant v essel
si ze and AN CA.
Vascul i ti des af f ecti ng l ar ge ar ter i es:
Tak ay asu's ar ter i ti s: aor ti c ar ch and i ts br anches, can i nv ol v e any
par t of the aor ta; m or e cl audi cati on of upper than l ow er
ex tr em i ti es, centr al ner v ous sy stem ev ents; gr anul om atous
panar ter i ti s.
Gi ant cel l (tem por al ) ar ter i ti s (GCA): tem por al ar ter i es, v essel s
or i gi nati ng f r om the aor ti c ar ch, other ar ter i es l ess com m on;
tem por al headache, jaw cl audi cati on, scal p tender ness, v i sual
l oss; ar ter i ti s w i th gi ant cel l s and di sr upti on of the i nter nal el asti c
l am i na.
Vascul i ti des af f ecti ng pr edom i nantl y m edi um si zed ar ter i es:
Pol y ar ter i ti s nodosa (PAN ): sm al l and m edi um si zed ar ter i es;
m ay af f ect any or gan, but sk i n, joi nts, per i pher al ner v es, gut, and
k i dney ar e m ost com m onl y i nv ol v ed; f ocal but panm ur al
necr oti zi ng ar ter i ti s w i th a pr edi l ecti on f or i nv ol v em ent at the
v essel bi f ur cati on.
Kaw asak i di sease: sm al l and m edi um si zed ar ter i es; acute
f ebr i l e i l l ness pr i m ar i l y af f ecti ng i nf ants and y oung chi l dr en;
f ev er , pr om i nent m ucocutaneous changes, cer v i cal
l y m phadenopathy , pol y m or phous r ash, er y them a and edem a of
hands and f eet, desquam ati on, m y ocar di ti s, cor onar y v ascul i ti s;
pr obabl e i nf ecti ous v ector r esul ti ng i n cy tok i nem edi ated
endothel i al dam age.
Vascul i ti des af f ecti ng pr edom i nantl y sm al l v essel s (AN CAposi ti v e):
Wegener 's gr anul om atosi s: sm al l and m edi um si zed ar ter i es;
upper r espi r ator y tr act (si nuses), l ungs, and k i dney s, m ay af f ect
other or gans; pauci i m m une, necr oti zi ng, gr anul om atous ar ter i ti s
usual l y associ ated w i th ser um cy topl asm i câ€“anti neutr ophi l
cy topl asm i c anti bodi es (cAN CA) usual l y di r ected agai nst
pr otei nase 3 i n the pr i m ar y gr anul es of neutr ophi l s.
Mi cr oscopi c pol y angi i ti s (MPA): ar ter i ol es, capi l l ar i es, and

v enul es; pul m onar y hem or r hage, gl om er ul onephr i ti s, pal pabl e
pur pur a, per i pher al neur opathy , joi nt and abdom i nal pai n;
pauci i m m une, necr oti zi ng v ascul i ti s, ser um per i nucl ear â
€“anti neutr ophi l cy topl asm i c anti bodi es
P. 465
(pAN CA) usual l y di r ected agai nst m y el oper ox i dase i n the pr i m ar y
gr anul es of neutr ophi l s.
Chur gStr auss sy ndr om e: sm al l ar ter i es and v enul es; asthm a,
eosi nophi l i a, m ul ti or gan i nv ol v em ent [l ungs, sk i n, per i pher al
ner v es, gut, hear t, and k i dney s (r ar e)]; necr oti zi ng ex tr av ascul ar
gr anul om as and v ascul i ti s of sm al l ar ter i es and v enul es,
eosi nophi l s pr esent i n ear l y stage.
Vascul i ti des af f ecti ng pr edom i nantl y sm al l v essel s (AN CAnegati v e):
HenochSchÃ¶nl ei n pur pur a (HSP): ar ter i ol es and v enul es;

pal pabl e pur pur i c sk i n l esi ons on l ow er ex tr em i ti es, ar thr i ti s,
abdom i nal pai n, hem atur i a; l euk ocy tocl asti c (neutr ophi l i c
per i v ascul ar /tr ansm ur al i nf i l tr ate) or necr oti zi ng v ascul i ti s of ten
w i th IgA deposi ti on.
Cutaneous l euk ocy tocl asti c angi i ti s: ar ter i ol es and v enul es;
pal pabl e pur pur i c sk i n l esi ons, ar thr al gi as, sy stem i c sy m ptom s
m ay be pr esent, usual l y secondar y to i m m une com pl ex es [dr ugs,
bugs (i nf ecti ons), CTD or m al i gnancy ]; l euk ocy tocl asti c v ascul i ti s.
Cr y ogl obul i nem i c v ascul i ti s: cr y ogl obul i ns ar e i m m unogl obul i ns
that ar e r ev er si bl y pr eci pi tated by r educed tem per atur es;
cr y ogl obul i ns ar e deposi ted i n sm al l v essel s i ncl udi ng
gl om er ul ocapi l l ar i es; pur pur a, ar thr al gi as, per i pher al neur opathy ,
Ray naud's phenom enon, pul m onar y hem or r hage,
gl om er ul onephr i ti s ar e possi bl e; of ten RF and hepati ti s C anti body
posi ti v e.
3. What ser ol ogi c tests or di agnosti c pr ocedur es shoul d be per f or m ed i n
pati ents w i th suspected v ascul i ti s?
The di agnosti c ev al uati on of a pati ent w i th suspected v ascul i ti s shoul d
be based on the cl i ni cal si tuati on but of ten i ncl udes a chest
r adi ogr aphi c study , ESR, CRP, a com pl ete bl ood count w i th di f f er enti al ,
l i v er f uncti on tests, CPK, cr eati ni ne and ur i nal y si s, tests f or the
pr esence of AN As, AN CAs and RF, cr y ogl obul i ns, and bi opsy of a sk i n
l esi on or an i nv ol v ed or gan. In som e ty pes of v ascul i ti s, com pl em ent
l ev el s m ay be l ow secondar y to consum pti on. An ESR gr eater than 100
m m per hour and a CRP gr eater than 10 m g/dL i n the absence of a
w i despr ead m al i gnancy or bacter i al i nf ecti on shoul d suggest a
v ascul i ti c pr ocess.
4. What m or e ex tensi v e pr ocedur es m ay be of v al ue i n hel pi ng to

establ i sh the di agnosi s of a speci f i c f or m of v ascul i ti s?
Mor e ex tensi v e di agnosti c pr ocedur es f or establ i shi ng the di agnosi s of
a speci f i c f or m of v ascul i ti s i ncl ude ar ter i ogr aphy of the m esenter i c
v essel s i f a ti ssue bi opsy i s i naccessi bl e, and an el ectr om y ogr aphy w i th
ev al uati on of ner v e conducti on v el oci ti es to ev al uate a per i pher al
neur opathy or a m ononeur i ti s m ul ti pl ex . A com puted tom ogr aphy (CT)
scan of the si nuses and chest i s i ndi cated i f a di agnosi s of Wegener 's
gr anul om atosi s i s bei ng consi der ed.
Case
A 45y ear ol d w hi te m an seek s m edi cal car e because of hem opty si s of 1
w eek dur ati on. He has not f el t w el l f or appr ox i m atel y 4 m onths and has l ost
10 l b (4. 5 k g) dur i ng thi s ti m e. He has been r ecei v i ng v ar i ous anti bi oti cs f or
the tr eatm ent of chest r adi ogr aphi c
P. 466
abnor m al i ti es thought to r epr esent pneum oni a. Al though these changes hav e
v ar i ed i n pr esentati on, they hav e not di sappear ed. A f ew w eek s ear l i er , he
noted som e bl oody nasal di schar ge. He star ted coughi ng up bl ood 1 w eek
ago but attr i buted i t to hi s bl oody nose. The pati ent al so com pl ai ns that hi s
l ef t k nee has been hur ti ng and that r ed spots hav e appear ed on hi s ar m s
and l egs. He deni es f ev er , pur ul ent sputum , al l er gi es or asthm a, k now n
tuber cul osi s, or chest pai n.
On phy si cal ex am i nati on, ther e i s a cur i ous depr essi on i n hi s upper nose
(saddl enose def or m i ty ), bl oody di schar ge i n hi s nasal cav i ty , a pai nl ess
ul cer on hi s sof t pal ate, and a sl i ghtl y w ar m and sw ol l en l ef t k nee. Chest
f i ndi ngs ar e nor m al . Ther e ar e m any sm al l , pur pur i c, r ai sed l esi ons on the
sk i n of hi s l ow er ex tr em i ti es that ar e pai nl ess.
1. What ar e f our possi bl e di agnoses i n thi s pati ent?

2. What di agnosti c studi es or pr ocedur es m i ght be of v al ue i n thi s
pati ent?
3. Whi ch di sor der s ar e associ ated w i th pAN CA?
4. What consti tutes appr opr i ate ther apy f or thi s pati ent w i th Wegener 's
gr anul om atosi s?
Case Discussion
1. What ar e f our possi bl e di agnoses i n thi s pati ent?
Four possi bl e di agnoses i n thi s pati ent ar e Wegener 's gr anul om atosi s,
Chur gStr auss sy ndr om e (al l er gi c gr anul om atosi s), i ntr anasal dr ug
abuse, or a l ung tum or . Chur gStr auss sy ndr om e occur s pr i m ar i l y i n
pati ents w i th a hi stor y of al l er gi es or asthm a and i s of ten associ ated
w i th per i pher al eosi nophi l i a. AN CA r eacti ng w i th hum an neutr ophi l
el astase can occur i n cocai nei nduced m i dl i ne destr ucti v e l esi ons. The
saddl enose def or m i ty and pal pabl e pur pur a w oul d be uncom m on
m ani f estati ons of a pr i m ar y l ung car ci nom a.
2. What di agnosti c studi es or pr ocedur es m i ght be of v al ue i n thi s pati ent?
N asophar y ngeal ex am i nati on w i th bi opsy , CT scan of the si nuses and
chest, cr eati ni ne and ur i nal y si s, and br onchoscopy w i th bi opsy or open
l ung bi opsy w oul d al l be hel pf ul i n the ev al uati on of thi s pati ent's
di sor der . An AN CA shoul d be or der ed because m ost pati ents w i th
sy stem i c Wegener 's gr anul om atosi s ar e cAN CA posi ti v e and hav e
anti pr otei nase 3 anti bodi es. In appr ox i m atel y 60% of pati ents, cAN CA
ti ter s cor r el ate w i th Wegener 's di sease acti v i ty .
3. Whi ch di sor der s ar e associ ated w i th pAN CA?
A pAN CA m ay be pr esent due to a v ar i ety of di f f er ent anti bodi es
di r ected agai nst m y el oper ox i dase, el astase, cathepsi n, and l actof er r i n,
and can occur i n m any di f f er ent di seases. Di seases associ ated w i th p
AN CA di r ected agai nst m y el oper ox i dase i ncl ude Wegener 's
gr anul om atosi s (10%), Chur gStr auss sy ndr om e (50%), MPA (50% to
80%), and i di opathi c cr escenti c gl om er ul onephr i ti s (65%). N onspeci f i c
pAN CAs di r ected agai nst other v ar i ous pr otei ns can occur i n CTDs,
Cr ohn's di sease, ul cer ati v e col i ti s, scl er osi ng chol angi ti s, cy sti c
f i br osi s, chr oni c i nf ecti ons, and r ar e dr ugi nduced v ascul i ti c sy ndr om es
associ ated w i th pr opy l thi our aci l , hy dr al azi ne, and m i nocy cl i ne.
P. 467
4. What consti tutes appr opr i ate ther apy f or thi s pati ent w i th Wegener 's
gr anul om atosi s?
Standar d ther apy f or Wegener 's gr anul om atosi s i ncl udes both hi gh
doses of cor ti coster oi ds and or al cy cl ophospham i de. Or al
tr i m ethopr i m /sul f am ethox azol e pr ophy l ax i s agai nst Pneum ocy sti s
car i ni i shoul d be consi der ed w hi l e on the abov e ther apy .
Suggested Readings
Cohen MD. Appr oach to the pati ent w i th suspected v ascul i ti s. In: West
SG, ed. Rheum atol ogy secr ets, 2nd ed. Phi l adel phi a: Hanl ey & Bel f us,
2002:201â€“207.
Hel l m ann DB, Hunder GG. Gi ant cel l ar ter i ti s and pol y m y al gi a
r heum ati ca. In: Har r i s ED Jr , Budd RC, Fi r estei n GS, et al . eds. Kel l ey 's
tex tbook of r heum atol ogy , 7th ed. Phi l adel phi a: El sev i er , Saunder s,
2005:1343â€“1356.
Stone JH. The cl assi f i cati on and epi dem i ol ogy of sy stem i c v ascul i ti s. In:
€“1342.
Watts RA, Scott DGI. Ov er v i ew of the i nf l am m ator y v ascul ar di seases.

In: Hochber g MC, Si l m an AJ, Sm ol en JS, et al . eds. Rheum atol ogy , 3r d
ed. Edi nbur gh: Mosby , 2003:1583â€“1591.

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Editors :

Sc hrie r, Robe rt W .

> Fr o nt o f B o o k > Ed ito r s

Kimbe rly Sc honbe rge r

Ca ndic e Ca rta ­Mye rs

La s e rw ords P riva te Limite d, Che nna i, India

RR Donne lle y Cra w fords ville

W illia m R. Brow n MD

He nry N. Cla ma n MD

Ste phe n C. Dre s k in MD

Ste phe n C. Dre s k in MD

Robe rt W . Ja ns on MD

Robe rt W . Ja ns on MD

JoAnn Linde nfe ld MD

Ja ne E. B. Re us c h MD

La ure nc e Robbins MD

La ure nc e Robbins MD

Ire ne E. Sc ha ue r MD

Robe rt T. Sc hoole y MD

Ma rvin I. Sc hw a rz MD

P a ul A. Se ligma n MD

Is a a c Te ite lba um MD

Is a a c Te ite lba um MD

> Fr o nt o f B o o k > P r e f a c e

> T a b le o f C o nte nts > C ha p te r 1 ­ A lle r g y a nd C linic a l I m m uno lo g y

Ste phe n C. Dre s k in

2. What i s the under l y i ng pathophy si ol ogi c pr ocess?

2. What i s the under l y i ng pathophy si ol ogi c pr ocess?

1. What m i ght be the cause or causes of her r eacti on?

Ex er ci se can cause a l i m i ted ar r ay of sy stem i c r eacti ons, par ti cul ar l y a

2. How shoul d she be tr eated?

Ther e i s a gener al l y accepted pr otocol f or tr eati ng anaphy l acti c

3. What f ol l ow ­up shoul d be r ecom m ended?

Li eber m an P. Bi phasi c anaphy l acti c r eacti ons. Ann Al l er gy Asthm a

Li eber m an P. Anaphy l ax i s. Med Cl i n N or th Am 2006;90:77.

Si cher er SH, Sam pson HA. Food al l er gy . J Al l er gy Cl i n Im m unol

Si m ons FE. Anaphy l ax i s, k i l l er al l er gy : l ong­ter m m anagem ent i n the

Wi ener ES, Bajaj L. Di agnosi s and em er gent m anagem ent of anaphy l ax i s

3. How i s her edi tar y angi oedem a (HAE) di agnosed?

2. What pathophy si ol ogi c pr ocesses under l i e angi oedem a?

3. How i s HAE di agnosed?

1. What i s the m ost l i k el y di agnosi s i n thi s w om an?

3. How shoul d an acute attack of HAE be tr eated?

4. What pr ophy l acti c m easur es ar e av ai l abl e f or HAE?

2. What i s the pathogenesi s of chr oni c ur ti car i a?

2. What i s the pathogenesi s of chr oni c ur ti car i a?

The pathogenesi s of chr oni c ur ti car i a i ncl udes a spectr um of ev ents.

If the pr esence of an el ev ated ESR suggests the possi bi l i ty of

3. What ther apeuti c appr oach i s desi r abl e?

4. What i s the pr ognosi s i n thi s pati ent i f no speci f i c al l er gen i s

1. If y ou w er e consi der i ng a di agnosi s of a m onocl onal gam m opathy

2. What f ur ther i m m unol ogi c tests shoul d be or der ed?

3. What f ur ther tests ar e i m por tant i n thi s case?

5. What i s the cur r ent tr eatm ent f or such a pati ent?

Ky l e RA, Rajk um ar SV. Mul ti pl e m y el om a. N Engl J Med 2004;351

2. What ar e the i m m unol ogi c m echani sm s r esponsi bl e f or the cl i ni cal

2. What ar e the i m m unol ogi c m echani sm s r esponsi bl e f or the cl i ni cal

Sk i n testi ng f or peni ci l l i n can be an ex tr em el y usef ul pr ocedur e f or

3. What i s the pr ev al ence of al l er gi c cr oss­sensi ti v i ty betw een peni ci l l i n

5. If the sk i n test r esul t to peni ci l l i n i s posi ti v e, coul d y ou av oi d a

Yes. How ev er , thi s i s a potenti al l y danger ous and al w ay s ti m e­

Pi chi cher o ME. A r ev i ew of ev i dence suppor ti ng the Am er i can Academ y

Copy r i ght Â©2007 Li ppi ncott Wi l l i am s & Wi l k i ns

> T a b le o f C o nte nts > C ha p te r 2 ­ C a r d io lo g y

Ca ndic e Ca rta Mye rs

> T a b le o f C o nte nts > C ha p te r 1 A lle r g y a nd C linic a l I m m uno lo g y

3. What f ol l ow up shoul d be r ecom m ended?

Si m ons FE. Anaphy l ax i s, k i l l er al l er gy : l ongter m m anagem ent i n the

3. What i s the pr ev al ence of al l er gi c cr osssensi ti v i ty betw een peni ci l l i n

Yes. How ev er , thi s i s a potenti al l y danger ous and al w ay s ti m e

> T a b le o f C o nte nts > C ha p te r 2 C a r d io lo g y

6. What l ongter m car e i s i ndi cated f or thi s pati ent?

Dr ugi nduced hy per tensi on (cocai ne)

Pr ehy per tensi on 120 or 80 89 Yes No Dr ug(s) f or the

Stage 1 140 or 9099 Yes Thi azi dety pe Dr ug(s) f or the

Stage 2 â‰ or â‰ Yes Tw odr ug Dr ug(s) f or the

Sodi um IV Seconds 35 m i n 0. 2510 Âµ g/k g/m i n

N i car di pi ne IV 510 m i n 14 hr 210 m g/hr

Fenol dopam IV < 5 m i n 30 m i n 0. 10 . 3 Âµ g/k g/m i n

N i tr ogl y cer i n IV 12 m i n 35 m i n 5100 Âµ g/m i n

Di azox i de IV bol us 15 m i n 612 hr 50 m g IV ev er y 510 m i n ov er 30 s,

Hy dr al azi ne IV 1020 38 hr 1020 m g IV

IM (al so 30 m i n 38 hr 1050 m g IM

Labetal ol IV 5 m i n 36 hr 0. 52 m g/m i n IV i nf usi on or 2080

Tr i m ethaphan IV 15 m i n 10 m i n 0. 55 m g/m i n

Phentol am i ne IV bol us 12 m i n 310 Load 515 m g IV ev er y 5 m i n